4’-HALOGEN CONTAINING NUCLEOTIDE AND NUCLEOSIDE THERAPEUTIC COMPOSITIONS AND USES RELATED THERETO CROSS REFERECE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application 63/149,403 filed February 15, 2021, which is incorporated by reference herein in its entirety. STATEMENT ACKNOWLEDGING OF GOVERNMENT SUPPORT This invention was made with government support under contract No. MCDC2005-005 by Advanced Technology International (“MCDC CMF”). The government has certain rights in the invention. FIELD This disclosure relates to halogen containing 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, togaviridae, bunyaviridae, arenaviridae, coronaviridae, flaviviridae, picornaviridae, orthomyxoviridae, pneumoviridae, Eastern, Western, and Venezuelan Equine Encephalitis (EEE, WEE and VEE, respectively), Chikungunya fever (CHIK), Ebola, Influenza, RSV, Junin virus, Lassa fever virus, Rift Valley fever virus, SARS- CoV-2, and Zika virus infections. BACKGROUND RNA viruses are the most common cause of human illness, and at any given time are responsible for 80% of the viral disease burden worldwide. They are also the major contributors to the pool of emerging and re-emerging infectious diseases in humans. Riboviruses of the genus Alphavirus (family Togaviridae) and of the genus Mammarenavirus (family Arenaviridae) cause mild to severe disease and death in humans. Eastern Equine Encephalitis (EEE), Western Equine Encephalitis (WEE), and Venezuelan Equine Encephalitis (VEE) viruses are enveloped, plus- strand alphaviruses that under natural conditions are transmitted to humans through mosquito bites. Although the frequency of severe disease in the United States associated with natural outbreaks is generally low, all three viruses are classified as CDC and NIAID Category B pathogens, and the viruses are of significant public health concern since they are potential agents of bioterrorism that can be delivered by the aerosol route. Venezuelan Equine Encephalitis virus (VEEV) in particular has been deemed a significant biothreat, owing to its ability to rapidly produce CNS infections after aerosol exposure with high levels of morbidity and mortality. Arenaviruses, like Lassa fever virus (LASV) and Junin virus (JUNV), are enveloped, negative- strand viruses that cause hemorrhagic disease with significant morbidity in humans. The NIAID and the CDC have classified arenaviruses as Category A priority pathogens for posing a significant threat to public health and biodefense. 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. The genus Mammarenavirus (family Arenaviridae) contains more than 30 species, which are pleomorphic and covered with surface glycoproteins, classified into two groups based on antigenic properties. The Old World (OW, Eastern Hemisphere) group, also referred to as the Lassa-lymphocytic chorimeningitis (LCM) serocomplex, contains LCM and viruses indigenous to Africa. The New World (NW, Western Hemisphere) group also called the Tacaribe serocomplex is divided into clades A, B, and C. Arenaviruses are zoonotic pathogens with each virus maintained in a specific rodent host species. Mucosal exposure to aerosolized infectious rodent excreta and direct contact of skin with infectious materials from rodents are the primary routes humans are infected with arenaviruses. Arenaviruses, such as Lassa fever virus (LASV) and Junin virus (JUNV), cause hemorrhagic disease that can lead to significant morbidity and death in humans. The NIAID and the CDC have classified arenaviruses as Category A priority pathogens for posing a significant threat to public health and fears that they could be weaponized. Furthermore, LASV remains the only imported arenavirus to the United States documented and has been identified by the WHO as highly likely to cause a future epidemic. Currently, there is no FDA approved vaccine for the prevention of arenavirus infections and treatment is limited to supportive care and use of the non-specific antiviral drug, ribavirin. 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 2 pathogen. SARS-CoV-2 causes disease refered 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. 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. 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 halogen, e.g., 4’-halogen, containing 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 Formula A, Formula A wherein R ¹ , R ^2’ , R ² , R ^3’ , R ³ , R ⁴ , X, U, and Q are as defined elsewhere herein. or a pharmaceutically acceptable salt, derivative, or prodrug thereof, as defined herein. 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 or pharmaceutical composition 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 or pharmaceutical composition disclosed herein to a subject in need thereof. In certain embodiments, the viral infection is togaviridae, bunyaviridae, arenaviridae, coronaviridae, including SARS-CoV-2, 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), SARS-CoV-2, Rift Valley fever, Lassa fever, Junin, Ebola, Influenza, RSV, Oropouche, Heartland virus, EV71, 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 FIGURE Figure 1 shows chemical stability of EIDD-2749, EIDD-3031, EIDD-3032, and EIDD- 3033 in water. Figure 2 shows survival in a mouse Oropouche infection model with EIDD-2749 treatment initiated 2 hours prior to viral challenge. Figure 3 shows Day 4 viral titers in plasma and organs from mice infected with Oropouche virus and with EIDD-2749 treatment initiated 2 hours prior to viral challenge. Figure 4 shows survival in a mouse Oropouche infection model with EIDD-2749 treatment initiated at various times post viral challenge. Figure 5 shows Day 4 viral titers in plasma and organs from mice infected with Oropouche virus and with EIDD-2749 treatment initiated at various times post viral challenge. Figure 6 shows survival in a guinea pig JUNV infection model with EIDD-2749 treatment initiated 1 hour prior to viral challenge. Figure 7 shows Day 12 viremia from guinea pigs infected with JUNV and with EIDD- 2749 treatment initiated 1 hour prior to viral challenge. Figure 8 shows survival in a guinea pig JUNV infection model with EIDD-2749 treatment initiated at various times post viral challenge. Figure 9 shows Day 12 viremia from guinea pigs infected with JUNV and with EIDD- 2749 treatment initiated at various times post viral challenge. Figure 10 shows survival in a guinea pig JUNV infection model with lower QD and QOD EIDD-2749 treatments initiated 7 days post viral challenge. Figure 11 shows survival in a mouse Ebolavirus infection model with EIDD-2749 treatment initiated 1 hour post viral challenge. Figure 12 shows survival in a mouse Ebolavirus infection model with EIDD-2749 treatment initiated 6, 12, and 24 hours post viral challenge. Figure 13 shows survival in a mouse Rift Valley fever virus infection model with EIDD- 2749 treatment initiated 1 hour prior to virus challenge. Figure 14 shows Day 4 viral titers in serum and organs from mice infected with Rift Valley fever virus and with EIDD-2749 treatment initiated 1 hour prior to virus challenge. Figure 15 shows survival in a mouse Rift Valley fever virus infection model with EIDD- 2749 treatment initiated at various times post virus challenge. Figure 16 shows Day 3 viral titers in serum and organs from mice infected with Rift Valley fever virus and with EIDD-2749 treatment initiated at various times post virus challenge. Figure 17 shows survival in a mouse Heartland virus infection model with EIDD-2749 treatment initiated 2 hours prior to virus challenge. Figure 18 shows Day 5 viral titers in serum and organs from mice infected with Heartland virus and with EIDD-2749 treatment initiated 2 hours prior to virus challenge. Figure 19 shows survival in a mouse Heartland virus infection model with EIDD-2749 treatment initiated at various times post virus challenge. Figure 20 shows Day 5 viral titers in serum and organs from mice infected with Heartland virus and with EIDD-2749 treatment initiated at various times post virus challenge. Figure 21 shows survival in a mouse VEEV infection model with EIDD-2749 treatment initiated 6 hours prior to virus challenge. Figure 22 shows survival in a mouse VEEV infection model with EIDD-2749 treatment initiated at various times post virus challenge. Figure 23 shows survival in a mouse EV71 infection model with EIDD-2749 treatment initiated at various times post virus challenge. 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 phosphoroamidate. 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 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 pharmaceutical composition 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 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, SARS-CoV-2, human 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, poliovirus, enterovirus, enterovirus-68, enterovirus-71, 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), Ross River virus, Mayaro virus, California encephalitis virus, Rift Valley fever virus (RVFV), Oropouche virus, heartland virus, La Crosse virus, Marpol virus, Oropouche virus, Severe fever thrombocytopenia syndrome virus, Pichinde virus, hantavirus, Tacaribe virus, Junin, Lassa fever virus, 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). 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. 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 phosphoroamidate. 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 10 carbon atoms. A “higher alkyl” refers to saturated hydrocarbon having 11 or more carbon atoms. A “C ₆ -C ₁₆ ” 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. Unless otherwise specified, C ₁ - C24 (e.g., C1-C22, C1-C20, C1-C18, C1-C16, C1-C14, C1-C12, C1-C10, C1-C8, C1-C6, or C1-C4) are intended. 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, C ₂ -C ₂₀ , C ₂ -C ₁₈ , C ₂ -C ₁₆ , C ₂ -C ₁₄ , C ₂ -C ₁₂ , C ₂ -C ₁₀ , C ₂ -C ₈ , C ₂ -C ₆ , or C ₂ -C ₄ ) 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 (Z ¹ Z ² )C=C(Z ³ Z ⁴ ) 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, C ₂ -C ₁₄ , C ₂ -C ₁₂ , C ₂ -C ₁₀ , C ₂ -C ₈ , C ₂ -C ₆ , or C ₂ -C ₄ ) 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 (e.g., with from 3 to 15 carbon atoms) 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 from 4 to 10 carbon atoms and from 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, and 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) ₂ aryl). "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) ₂ Ra, -OS(=O) ₂ Ra and -S(=O) ₂ ORa. 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. 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. They may, for instance, be bioavailable 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. Examples of prodrugs that can be used to improve bioavailability 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, sulfenyl thiocarbonates, optionally substituted sulfenyl thiocarbonates, 2-hydroxypropanoate ester, optionally substitute 2- hydroxypropanoate ester, S-thiocarbonate, optionally substituted S-thiocarbonate, dithiocarbonates, optionally substituted dithiocarbonates, thiocarbamates, optionally substituted thiocarbamates, oxymethoxycarbonyl, optionally substituted oxymethoxycarbonyl, oxymethoxycarbonate, optionally substituted oxymethoxycarbonate, oxymethoxythiocarbonyl, optionally substituted oxymethoxythiocarbonyl, oxymethylcarbonyl, optionally substituted oxymethylcarbonyl, oxymethylthiocarbonyl, optionally substituted oxymethylthiocarbonyl, oxymethoxythiocarbonate, optionally substituted oxymethoxythiocarbonate, L-amino acid esters, D-amino acid esters, oxymethoxy amino ester, 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, sulfinyl, sulfonyl, sulfite, sulfate, sulfonamide, 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, (acyloxybenzyl)ether, (acyloxybenzyl)ester, PEG ester, PEG carbonate, bis-(acyloxybenzyl)esters, optionally substituted bis-(acyloxybenzyl)esters, (acyloxybenzyl)esters, optionally substituted (acyloxybenzyl)esters, and bis-acetoxy benzyl. 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. As used herein, the term “derivative” refers to a structurally similar compound that retains sufficient functional attributes of the identified analogue. The derivative may be structurally similar because it is lacking one or more atoms, substituted 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. Those skilled in the art will recognize that certain compounds, and in particular compounds containing certain heteroatoms and double or triple bonds, can be tautomers, structural isomers that readily interconvert. Thus, tautomeric compounds can be drawn in a number of different ways that are equivalent. Non-limiting examples of such tautomers include those exemplified below. Compounds In certain embodiments, the disclosure relates to nucleosides conjugated to a phosphorus moiety or pharmaceutically acceptable salts thereof. In certain embodiments, the disclosure relates to a compound of Formula I, or a pharmaceutical or physiological salt thereof, wherein X is CH ₂ , CHMe, CMe ₂ , CHF, CF ₂ , or CD ₂ ; U is O, S, NH, NR’’’, CH ₂ , CHF, CF ₂ , CCH ₂ , or CCF ₂ ; Q is a natural or unnatural nucleobase; R ¹ is selected from prodrug, H,

or together with the oxygen to which it is bound, R ¹ , form 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, sulfenyl thiocarbonates, optionally substituted sulfenyl thiocarbonates, 2-hydroxypropanoate ester, optionally substitute 2-hydroxypropanoate ester, S-thiocarbonate, optionally substituted S-thiocarbonate, dithiocarbonates, optionally substituted dithiocarbonates, thiocarbamates, optionally substituted thiocarbamates, oxymethoxycarbonyl, optionally substituted oxymethoxycarbonyl, oxymethoxycarbonate, optionally substituted oxymethoxycarbonate, oxymethoxythiocarbonyl, optionally substituted oxymethoxythiocarbonyl, oxymethylcarbonyl, optionally substituted oxymethylcarbonyl, oxymethylthiocarbonyl, optionally substituted oxymethylthiocarbonyl, oxymethoxythiocarbonate, optionally substituted oxymethoxythiocarbonate, L-amino acid esters, D-amino acid esters, oxymethoxy amino ester, 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, sulfinyl, sulfonyl, sulfite, sulfate, sulfonamide, 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, (acyloxybenzyl)ether, (acyloxybenzyl)ester, PEG ester, PEG carbonate, bis-(acyloxybenzyl)esters, optionally substituted bis-(acyloxybenzyl)esters, (acyloxybenzyl)esters, optionally substituted (acyloxybenzyl)esters, and bis-acetoxy benzyl, wherein R ¹ is optionally substituted with one or more, the same or different, R ¹⁰ ; the moiety R ¹ -O is selected from monophosphate, diphosphate, triphosphate, amide, lactam, peptide, or carboxylic acid ester, wherein R ¹ is optionally substituted with one or more, the same or different, R ^10; Y is O or S; Y ¹ is OH, OY ³ , or BH ₃ -M ⁺ ; Y ² is OH or BH3-M ⁺ ; Y ³ is aryl, heteroaryl, or heterocyclyl, wherein Y ³ is optionally substituted with one or more, the same or different, R ¹⁰ ; M is Li, Na, K, NH _4, Et ₃ NH, or Bu ₄ N; R is F or Cl; R ² , R ^2’ , R ³ , R ^3’ are each independently selected from hydrogen, deuterium, alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, azido, formyl, acyl, alkanoyl, esteryl, carbonyl, cyano, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R ² , R ^2’ , R ³ , R ^3’ are optionally substituted with one or more, the same or different, R ¹⁰ ; R ² and R ^2’ can form a ring with the carbon they are attached to, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ³ and R ^3’ can form a ring with the carbon they are attached to, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁴ is selected from alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, azido, formyl, acyl, alkanoyl, esteryl, carbonyl, cyano, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R ⁴ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁵ is selected from hydrogen, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, allenyl, or lipid, wherein R ⁵ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁶ , R ^6’ , R ^6’’ , and R ^6’’’ are each independently selected from hydrogen, deuterium, hydroxyl, amino, azido, thiol, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, halogen, nitro, alkyl, alkenyl, alkynyl, allenyl, 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 R ⁶ , R ^6’ , R ^6’’ , and R ^6’’’ can each be optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁷ and R ^7’ are each independently selected from hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, wherein R ⁷ and R ^7’ are optionally substituted with one or more, the same or different, R ¹⁰ ; R’’’ is selected from alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, formyl, acyl, alkanoyl, esteryl, carbonyl, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R’’’ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁸ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, wherein R ⁸ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁹ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, wherein R ⁹ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁷ , R ^7’ , R ⁸ , and R ⁹ can 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, R ¹⁰ ; R ⁷ and R ^7’ can form a ring with the α-carbon which they are attached, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁸ and R ⁹ can form a ring with the α-carbon which they are attached, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ¹⁰ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, 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 R ¹⁰ is optionally substituted with one or more, the same or different, R ¹¹ ; R ¹¹ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, 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; and Lipid is a C ₁₁ -C ₂₂ higher alkyl, C ₁₁ -C ₂₂ higher alkoxy, polyethylene glycol, or aryl substituted with an alkyl group, or a lipid as described herein. In certain embodiments, the lipid is a C ₁₁ -C ₂₂ fatty alcohol, C ₁₁ -C ₂₂ fatty amine, or C ₁₁ - C22 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, R ¹² of the sphingolipid is hydrogen, alkyl, C(=O)R ¹⁶ , C(=O)OR ¹⁶ , or C(=O)NHR ¹⁶ ; R ¹³ of the sphingolipid is hydrogen, fluoro, OR ¹⁶ , OC(=O)R ¹⁶ , OC(=O)OR ¹⁶ , or OC(=O)NHR ¹⁶ ; R ¹⁴ of 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; R ¹⁵ of the sphingolipid is OR ¹⁶ , OC(=O)R ¹⁶ , OC(=O)OR ¹⁶ , or OC(=O)NHR ¹⁶ ; R ¹⁶ of 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) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, or lipid; wherein R ¹⁶ is optionally substituted with one or more, the same or different R ¹⁷ ; and R ¹⁷ of 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, R ¹² of 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, R ¹² of the sphingolipid is hydrogen, hydroxy, fluoro, OR ¹⁶ , OC(=O)R ¹⁶ , OC(=O)OR ¹⁶ , or OC(=O)NHR ¹⁶ ; R ¹³ of the sphingolipid is hydrogen, hydroxy, fluoro, OR ¹⁶ , OC(=O)R ¹⁶ , OC(=O)OR ¹⁶ , or OC(=O)NHR ¹⁶ ; R ¹⁴ of 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; R ¹⁶ of 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 R ¹⁶ is optionally substituted with one or more, the same or different R ¹⁷ ; and R ¹⁷ of 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) ₂ amino, 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, R ¹⁶ of 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-ami nocyclopropyl)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, R ¹ is hydrogen, , , and . In exemplified embodiments of Formula I, X is CH ₂ . In exemplified embodiments of Formula I, U is O. In exemplified embodiments of Formula I, Q is uracil, cytosine, adenine, and guanine. In exemplified embodiments of Formula I, R ² , R ^2’ , R ³ , R ^3’ are hydrogen, hydroxyl, amino, fluoro, chloro, cyano, methyl, fluoromethyl, methoxy, vinyl, ethynyl, and chloroethynyl. In exemplified embodiments of Formula I, R ⁵ is 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, R ⁶ is 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, R ⁷ is 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, R ⁸ is 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, R ⁹ is 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 certain embodiments, the disclosure relates to a compound of Formula II, Formula II or a pharmaceutical or physiological salt thereof, wherein X is CH ₂ , CHMe, CMe ₂ , CHF, CF ₂ , or CD ₂ ; U is O, S, NH, NR’’’, CH2, CHF, CF2, CCH2, or CCF2; X ₁ is selected from O or S; X2 is selected from O or S; W is selected from N or CR’; Z is selected from N or CR’’; R ^’ and R’’ are each independently selected from hydrogen, deuterium, alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, azido, formyl, acyl, alkanoyl, esteryl, carbonyl, cyano, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R ^’ and R’’ are optionally substituted with one or more, the same or different, R ¹⁰ ; R ¹ is selected from prodrug, H,

or together with the oxygen to which it is bound, R ¹ , forms 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, sulfenyl thiocarbonates, optionally substituted sulfenyl thiocarbonates, 2-hydroxypropanoate ester, optionally substitute 2- hydroxypropanoate ester, S-thiocarbonate, optionally substituted S-thiocarbonate, dithiocarbonates, optionally substituted dithiocarbonates, thiocarbamates, optionally substituted thiocarbamates, oxymethoxycarbonyl, optionally substituted oxymethoxycarbonyl, oxymethoxycarbonate, optionally substituted oxymethoxycarbonate, oxymethoxythiocarbonyl, optionally substituted oxymethoxythiocarbonyl, oxymethylcarbonyl, optionally substituted oxymethylcarbonyl, oxymethylthiocarbonyl, optionally substituted oxymethylthiocarbonyl, oxymethoxythiocarbonate, optionally substituted oxymethoxythiocarbonate, L-amino acid esters, D-amino acid esters, oxymethoxy amino ester, 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, sulfinyl, sulfonyl, sulfite, sulfate, sulfonamide, 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, (acyloxybenzyl)ether, (acyloxybenzyl)ester, PEG ester, PEG carbonate, bis-(acyloxybenzyl)esters, optionally substituted bis-(acyloxybenzyl)esters, (acyloxybenzyl)esters, optionally substituted (acyloxybenzyl)esters, and bis-acetoxy benzyl, wherein R ¹ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ¹ -O is selected from monophosphate, diphosphate, triphosphate, amide, lactam, peptide, or carboxylic acid ester, wherein R ¹ is optionally substituted with one or more, the same or different, R ^10; Y is O or S; Y ¹ is OH, OY ³ , or BH ₃ -M ⁺ ; Y ² is OH or BH3-M ⁺ ; Y ³ is aryl, heteroaryl, or heterocyclyl, wherein Y ³ is optionally substituted with one or more, the same or different, R ¹⁰ ; M is Li, Na, K, NH _4, Et ₃ NH, Bu ₄ N; R is F or Cl; R ² , R ^2’ , R ³ , R ^3’ are each independently selected from hydrogen, deuterium, alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, azido, formyl, acyl, alkanoyl, esteryl, carbonyl, cyano, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R ² , R ^2’ , R ³ , R ^3’ are optionally substituted with one or more, the same or different, R ¹⁰ ; R ² and R ^2’ can form a ring with the carbon they are attached to, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ³ and R ^3’ can form a ring with the carbon they are attached to, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁴ is selected from alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, azido, formyl, acyl, alkanoyl, esteryl, carbonyl, cyano, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R ⁴ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁵ is selected from hydrogen, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, allenyl, or lipid, wherein R ⁵ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁶ , R ^6’ , R ^6’’ , and R ^6’’’ are each independently selected from hydrogen, deuterium, hydroxyl, amino, azido, thiol, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, halogen, nitro, alkyl, alkenyl, alkynyl, allenyl, 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 R ⁶ , R ^6’ , R ^6’’ , and R ^6’’’ can each be optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁷ and R ^7’ are each independently selected from hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, wherein R ⁷ and R ^7’ are optionally substituted with one or more, the same or different, R ¹⁰ ; R’’’ is selected from alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, formyl, acyl, alkanoyl, esteryl, carbonyl, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R’’’ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁸ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, 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 R ⁸ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁹ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, 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 R ⁹ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁷ , R ^7’ , R ⁸ , and R ⁹ can 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, R ¹⁰ ; R ⁷ and R ^7’ can form a ring with the α-carbon which they are attached, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁸ and R ⁹ can form a ring with the α-carbon which they are attached, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ¹⁰ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, wherein R ¹⁰ is optionally substituted with one or more, the same or different, R ¹¹ ; R ¹¹ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, 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; and Lipid is a C ₁₁ -C ₂₂ higher alkyl, C ₁₁ -C ₂₂ higher alkoxy, polyethylene glycol, or aryl substituted with an alkyl group, or a lipid as described herein. In certain embodiments, the disclosure relates to a compound of Formula III, Formula III or a pharmaceutical or physiological salt thereof, wherein X ₁ is selected from O or S; X2 is selected from O or S; W is selected from N or CR’ Z is selected from N or CR’’; R ^’ and R’’ are each independently selected from hydrogen, deuterium, alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, azido, formyl, acyl, alkanoyl, esteryl, carbonyl, cyano, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R ^’ and R’’ are optionally substituted with one or more, the same or different, R ¹⁰ ; R ¹ is selected from prodrug, H,

or together with the oxygen to whi ¹ ch it is bound, R , forms 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, sulfenyl thiocarbonates, optionally substituted sulfenyl thiocarbonates, 2-hydroxypropanoate ester, optionally substitute 2-hydroxypropanoate ester, S-thiocarbonate, optionally substituted S-thiocarbonate, dithiocarbonates, optionally substituted dithiocarbonates, thiocarbamates, optionally substituted thiocarbamates, oxymethoxycarbonyl, optionally substituted oxymethoxycarbonyl, oxymethoxycarbonate, optionally substituted oxymethoxycarbonate, oxymethoxythiocarbonyl, optionally substituted oxymethoxythiocarbonyl, oxymethylcarbonyl, optionally substituted oxymethylcarbonyl, oxymethylthiocarbonyl, optionally substituted oxymethylthiocarbonyl, oxymethoxythiocarbonate, optionally substituted oxymethoxythiocarbonate, L-amino acid esters, D-amino acid esters, oxymethoxy amino ester, 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, sulfinyl, sulfonyl, sulfite, sulfate, sulfonamide, 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, (acyloxybenzyl)ether, (acyloxybenzyl)ester, PEG ester, PEG carbonate, bis-(acyloxybenzyl)esters, optionally substituted bis-(acyloxybenzyl)esters, (acyloxybenzyl)esters, optionally substituted (acyloxybenzyl)esters, and bis-acetoxy benzyl, wherein R ¹ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ¹ -O is selected from monophosphate, diphosphate, triphosphate, amide, lactam, peptide, or carboxylic acid ester, wherein R ¹ is optionally substituted with one or more, the same or different, R ^10; Y is O or S; Y ¹ is OH, OY ³ , or BH ₃ -M ⁺ ; Y ² is OH or BH3-M ⁺ ; M is Li, Na, K, NH _4, Et ₃ NH, or Bu ₄ N; Y ³ is aryl, heteroaryl, or heterocyclyl, wherein Y ³ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ² , R ^2’ , R ³ , R ^3’ are each independently selected from hydrogen, deuterium, alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, azido, formyl, acyl, alkanoyl, esteryl, carbonyl, cyano, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R ² , R ^2’ , R ³ , R ^3’ are optionally substituted with one or more, the same or different, R ¹⁰ ; R ² and R ^2’ can form a ring with the carbon they are attached to, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ³ and R ^3’ can form a ring with the carbon they are attached to, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁴ is selected from alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, azido, formyl, acyl, alkanoyl, esteryl, carbonyl, cyano, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R ⁴ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁵ is selected from hydrogen, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, allenyl, or lipid, wherein R ⁵ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁶ , R ^6’ , R ^6’’ , and R ^6’’’ are each independently selected from hydrogen, deuterium, hydroxyl, amino, azido, thiol, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, halogen, nitro, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, sulfinyl, sulfamoyl, sulfonyl allenyl, cyano, or lipid, wherein R ⁶ , R ^6’ , R ^6’’ , and R ^6’’’ can each be optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁷ and R ^7’ are each independently selected from hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, 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 R ⁷ and R ^7’ are optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁸ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, wherein R ⁸ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁹ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, 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 R ⁹ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁷ , R ^7’ , R ⁸ , and R ⁹ can 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, R ¹⁰ ; R ⁷ and R ^7’ can form a ring with the α-carbon which they are attached, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁸ and R ⁹ can form a ring with the α-carbon which they are attached, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ¹⁰ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, 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 R ¹⁰ is optionally substituted with one or more, the same or different, R ¹¹ ; R ¹¹ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; and Lipid is a C ₁₁ -C ₂₂ higher alkyl, C ₁₁ -C ₂₂ higher alkoxy, polyethylene glycol, or aryl substituted with an alkyl group, or a lipid as described herein. In certain embodiments, the disclosure relates to a compound of Formula IV, Formula IV or a pharmaceutical or physiological salt thereof, wherein X ₁ is selected from O or S; X2 is selected from O or S; W is selected from N or CR’ Z is selected from N or CR’’; R ^’ and R’’ are each independently selected from hydrogen, deuterium, alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, azido, formyl, acyl, alkanoyl, esteryl, carbonyl, cyano, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R ^’ and R’’ are optionally substituted with one or more, the same or different, R ¹⁰ ; R ¹ is selected from prodrug, H,

, or together with the oxygen to which it is b ¹ ound, R , forms 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, sulfenyl thiocarbonates, optionally substituted sulfenyl thiocarbonates, 2-hydroxypropanoate ester, optionally substitute 2-hydroxypropanoate ester, S-thiocarbonate, optionally substituted S-thiocarbonate, dithiocarbonates, optionally substituted dithiocarbonates, thiocarbamates, optionally substituted thiocarbamates, oxymethoxycarbonyl, optionally substituted oxymethoxycarbonyl, oxymethoxycarbonate, optionally substituted oxymethoxycarbonate, oxymethoxythiocarbonyl, optionally substituted oxymethoxythiocarbonyl, oxymethylcarbonyl, optionally substituted oxymethylcarbonyl, oxymethylthiocarbonyl, optionally substituted oxymethylthiocarbonyl, oxymethoxythiocarbonate, optionally substituted oxymethoxythiocarbonate, L-amino acid esters, D-amino acid esters, oxymethoxy amino ester, 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, sulfinyl, sulfonyl, sulfite, sulfate, sulfonamide, 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, (acyloxybenzyl)ether, (acyloxybenzyl)ester, PEG ester, PEG carbonate, bis-(acyloxybenzyl)esters, optionally substituted bis-(acyloxybenzyl)esters, (acyloxybenzyl)esters, optionally substituted (acyloxybenzyl)esters, and bis-acetoxy benzyl, wherein R ¹ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ¹ -O is selected from monophosphate, diphosphate, triphosphate, amide, lactam, peptide, or carboxylic acid ester, wherein R ¹ is optionally substituted with one or more, the same or different, R ^10; Y is O or S; Y ¹ is OH, OY ³ , or BH ₃ -M ⁺ ; Y ² is OH or BH3-M ⁺ ; Y ³ is aryl, heteroaryl, or heterocyclyl, wherein Y ³ is optionally substituted with one or more, the same or different, R ¹⁰ ; M is Li, Na, K, NH _4, Et ₃ NH, or Bu ₄ N; R ⁴ is selected from alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, azido, formyl, acyl, alkanoyl, esteryl, carbonyl, cyano, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R ⁴ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁵ is selected from hydrogen, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, allenyl, or lipid, wherein R ⁵ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁶ , R ^6’ , R ^6’’ , and R ^6’’’ are each independently selected from hydrogen, deuterium, hydroxyl, amino, azido, thiol, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, halogen, nitro, alkyl, alkenyl, alkynyl, allenyl, 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 R ⁶ , R ^6’ , R ^6’’ , and R ^6’’’ can each be optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁷ and R ^7’ are each independently selected from hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, 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 R ⁷ and R ^7’ are optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁸ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, 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 R ⁸ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁹ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, 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 R ⁹ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁷ , R ^7’ , R ⁸ , and R ⁹ can 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, R ¹⁰ ; R ⁷ and R ^7’ can form a ring with the α-carbon which they are attached, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁸ and R ⁹ can form a ring with the α-carbon which they are attached, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ¹⁰ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, 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 R ¹⁰ is optionally substituted with one or more, the same or different, R ¹¹ ; R ¹¹ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, 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; and Lipid is a C ₁₁ -C ₂₂ higher alkyl, C ₁₁ -C ₂₂ higher alkoxy, polyethylene glycol, or aryl substituted with an alkyl group, or a lipid as described herein. In certain embodiments, the disclosure relates to a compound of Formula V,

Formula V or a pharmaceutical or physiological salt thereof, wherein X ₁ is selected from O or S; X2 is selected from O or S; W is selected from N or CR’; R ^’ is selected from prodrug,hydrogen, deuterium, alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, azido, formyl, acyl, alkanoyl, esteryl, carbonyl, cyano, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R ^’ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ¹ is selected from prodrug, H,

, or together with the oxygen to w ¹ hich it is bound, R , forms 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, sulfenyl thiocarbonates, optionally substituted sulfenyl thiocarbonates, 2-hydroxypropanoate ester, optionally substitute 2-hydroxypropanoate ester, S-thiocarbonate, optionally substituted S-thiocarbonate, dithiocarbonates, optionally substituted dithiocarbonates, thiocarbamates, optionally substituted thiocarbamates, oxymethoxycarbonyl, optionally substituted oxymethoxycarbonyl, oxymethoxycarbonate, optionally substituted oxymethoxycarbonate, oxymethoxythiocarbonyl, optionally substituted oxymethoxythiocarbonyl, oxymethylcarbonyl, optionally substituted oxymethylcarbonyl, oxymethylthiocarbonyl, optionally substituted oxymethylthiocarbonyl, oxymethoxythiocarbonate, optionally substituted oxymethoxythiocarbonate, L-amino acid esters, D-amino acid esters, oxymethoxy amino ester, 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, sulfinyl, sulfonyl, sulfite, sulfate, sulfonamide, 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, (acyloxybenzyl)ether, (acyloxybenzyl)ester, PEG ester, PEG carbonate, bis-(acyloxybenzyl)esters, optionally substituted bis-(acyloxybenzyl)esters, (acyloxybenzyl)esters, optionally substituted (acyloxybenzyl)esters, and bis-acetoxy benzyl, wherein R ¹ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ¹ -O is selected from monophosphate, diphosphate, triphosphate, amide, lactam, peptide, or carboxylic acid ester, wherein R ¹ is optionally substituted with one or more, the same or different, R ^10; Y is O or S; Y ¹ is OH, OY ³ , or BH3-M ⁺ ; Y ² is OH or BH3-M ⁺ ; Y ³ is aryl, heteroaryl, or heterocyclyl, wherein Y ³ is optionally substituted with one or more, the same or different, R ¹⁰ ; M is Li, Na, K, NH _4, Et ₃ NH, or Bu ₄ N; R ⁴ is selected from alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, azido, formyl, acyl, alkanoyl, esteryl, carbonyl, cyano, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R ⁴ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁵ is selected from hydrogen, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, allenyl, or lipid, wherein R ⁵ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁶ , R ^6’ , R ^6’’ , and R ^6’’’ are each independently selected from hydrogen, deuterium, hydroxyl, amino, azido, thiol, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, halogen, nitro, alkyl, alkenyl, alkynyl, allenyl, 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 R ⁶ , R ^6’ , R ^6’’ , and R ^6’’’ can each be optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁷ and R ^7’ are each independently selected from hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, 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 R ⁷ and R ^7’ are optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁸ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, 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 R ⁸ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁹ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, wherein R ⁹ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁷ , R ^7’ , R ⁸ , and R ⁹ can 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, R ¹⁰ ; R ⁷ and R ^7’ can form a ring with the α-carbon which they are attached, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁸ and R ⁹ can form a ring with the α-carbon which they are attached, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ¹⁰ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, 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 R ¹⁰ is optionally substituted with one or more, the same or different, R ¹¹ ; R ¹¹ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, 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; and Lipid is a C11-C22 higher alkyl, C11-C22 higher alkoxy, polyethylene glycol, or aryl substituted with an alkyl group, or a lipid as described herein. In certain embodiments, the disclosure relates to a compound of Formula VI, Formula VI or a pharmaceutical or physiological salt thereof, wherein X is CH2, CHMe, CMe2, CHF, CF2, or CD2; U is O, S, NH, NR’’’, CH ₂ , CHF, CF ₂ , CCH ₂ , or CCF ₂ ; X1 is OH, SH, NH2, OR’’’’, SR’’’’, NHR’’’’, NHOH, NHOR’’’’, NHNH2; X ₂ is selected from O or S; W is selected from N or CR’ Z is selected from N or CR’’; R ^’ and R’’ are each independently selected from hydrogen, deuterium, alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, azido, formyl, acyl, alkanoyl, esteryl, carbonyl, cyano, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R ^’ and R’’ are optionally substituted with one or more, the same or different, R ¹⁰ ; R ¹ is selected from prodrug, H,

or together with the oxygen to which it is bound, R ¹ , forms 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, sulfenyl thiocarbonates, optionally substituted sulfenyl thiocarbonates, 2-hydroxypropanoate ester, optionally substitute 2-hydroxypropanoate ester, S-thiocarbonate, optionally substituted S-thiocarbonate, dithiocarbonates, optionally substituted dithiocarbonates, thiocarbamates, optionally substituted thiocarbamates, oxymethoxycarbonyl, optionally substituted oxymethoxycarbonyl, oxymethoxycarbonate, optionally substituted oxymethoxycarbonate, oxymethoxythiocarbonyl, optionally substituted oxymethoxythiocarbonyl, oxymethylcarbonyl, optionally substituted oxymethylcarbonyl, oxymethylthiocarbonyl, optionally substituted oxymethylthiocarbonyl, oxymethoxythiocarbonate, optionally substituted oxymethoxythiocarbonate, L-amino acid esters, D-amino acid esters, oxymethoxy amino ester, 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, sulfinyl, sulfonyl, sulfite, sulfate, sulfonamide, 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, (acyloxybenzyl)ether, (acyloxybenzyl)ester, PEG ester, PEG carbonate, bis-(acyloxybenzyl)esters, optionally substituted bis-(acyloxybenzyl)esters, (acyloxybenzyl)esters, optionally substituted (acyloxybenzyl)esters, and bis-acetoxy benzyl, wherein R ¹ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ¹ -O is selected from monophosphate, diphosphate, triphosphate, amide, lactam, peptide, or carboxylic acid ester, wherein R ¹ is optionally substituted with one or more, the same or different, R ^10; Y is O or S; Y ¹ is OH, OY ³ , or BH ₃ -M ⁺ ; Y ² is OH or BH3-M ⁺ ; Y ³ is aryl, heteroaryl, or heterocyclyl, wherein Y ³ is optionally substituted with one or more, the same or different, R ¹⁰ ; M is Li, Na, K, NH _4, Et ₃ NH, Bu ₄ N; R is F or Cl; R ² , R ^2’ , R ³ , R ^3’ are each independently selected from hydrogen, deuterium, alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, azido, formyl, acyl, alkanoyl, esteryl, carbonyl, cyano, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R ² , R ^2’ , R ³ , R ^3’ are optionally substituted with one or more, the same or different, R ¹⁰ ; R ² and R ^2’ can form a ring with the carbon they are attached to, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ³ and R ^3’ can form a ring with the carbon they are attached to, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁴ is selected from alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, azido, formyl, acyl, alkanoyl, esteryl, carbonyl, cyano, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R ⁴ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁵ is selected from hydrogen, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, allenyl, or lipid, wherein R ⁵ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁶ , R ^6’ , R ^6’’ , and R ^6’’’ are each independently selected from hydrogen, deuterium, hydroxyl, amino, azido, thiol, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, halogen, nitro, alkyl, alkenyl, alkynyl, allenyl, 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 R ⁶ , R ^6’ , R ^6’’ , and R ^6’’’ can each be optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁷ and R ^7’ are each independently selected from hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, wherein R ⁷ and R ^7’ are optionally substituted with one or more, the same or different, R ¹⁰ ; R’’’ is selected from alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, formyl, acyl, alkanoyl, esteryl, carbonyl, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R ^’’’ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁸ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, 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 R ⁸ is optionally substituted with one or more, the same or different, R ¹⁰ ; R’’’’ is selected from alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, formyl, acyl, alkanoyl, esteryl, carbonyl, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R ^’’’’ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁹ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, wherein R ⁹ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁷ , R ^7’ , R ⁸ , and R ⁹ can 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, R ¹⁰ ; R ⁷ and R ^7’ can form a ring with the α-carbon which they are attached, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁸ and R ⁹ can form a ring with the α-carbon which they are attached, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ¹⁰ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, wherein R ¹⁰ is optionally substituted with one or more, the same or different, R ¹¹ ; R ¹¹ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; and Lipid is a C ₁₁ -C ₂₂ higher alkyl, C ₁₁ -C ₂₂ higher alkoxy, polyethylene glycol, or aryl substituted with an alkyl group, or a lipid as described herein. In certain embodiments, the disclosure relates to a compound of Formula VII, Formula VII or a pharmaceutical or physiological salt thereof, wherein X1 is OH, SH, NH2, OR’’’’, SR’’’’, NHR’’’’, NHOH, NHOR’’’’, NHNH2; X ₂ is selected from O or S; W is selected from N or CR’; Z is selected from N or CR’’; R ^’ and R’’ are each independently selected from hydrogen, deuterium, alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, azido, formyl, acyl, alkanoyl, esteryl, carbonyl, cyano, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R ^’ and R’’ are optionally substituted with one or more, the same or different, R ¹⁰ ; R ¹ is selected from prodrug, H,

or together with the oxygen to which it ¹ is bound, R , forms 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, sulfenyl thiocarbonates, optionally substituted sulfenyl thiocarbonates, 2-hydroxypropanoate ester, optionally substitute 2-hydroxypropanoate ester, S-thiocarbonate, optionally substituted S-thiocarbonate, dithiocarbonates, optionally substituted dithiocarbonates, thiocarbamates, optionally substituted thiocarbamates, oxymethoxycarbonyl, optionally substituted oxymethoxycarbonyl, oxymethoxycarbonate, optionally substituted oxymethoxycarbonate, oxymethoxythiocarbonyl, optionally substituted oxymethoxythiocarbonyl, oxymethylcarbonyl, optionally substituted oxymethylcarbonyl, oxymethylthiocarbonyl, optionally substituted oxymethylthiocarbonyl, oxymethoxythiocarbonate, optionally substituted oxymethoxythiocarbonate, L-amino acid esters, D-amino acid esters, oxymethoxy amino ester, 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, sulfinyl, sulfonyl, sulfite, sulfate, sulfonamide, 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, (acyloxybenzyl)ether, (acyloxybenzyl)ester, PEG ester, PEG carbonate, bis-(acyloxybenzyl)esters, optionally substituted bis-(acyloxybenzyl)esters, (acyloxybenzyl)esters, optionally substituted (acyloxybenzyl)esters, and bis-acetoxy benzyl, wherein R ¹ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ¹ -O is selected from monophosphate, diphosphate, triphosphate, amide, lactam, peptide, or carboxylic acid ester, wherein R ¹ is optionally substituted with one or more, the same or different, R ^10; Y is O or S; Y ¹ is OH, OY ³ , or BH ₃ -M ⁺ ; Y ² is OH or BH3-M ⁺ ; Y ³ is aryl, heteroaryl, or heterocyclyl, wherein Y ³ is optionally substituted with one or more, the same or different, R ¹⁰ ; M is Li, Na, K, NH _4, Et ₃ NH, Bu ₄ N; R is F or Cl; R ² , R ^2’ , R ³ , R ^3’ are each independently selected from hydrogen, deuterium, alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, azido, formyl, acyl, alkanoyl, esteryl, carbonyl, cyano, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R ² , R ^2’ , R ³ , R ^3’ are optionally substituted with one or more, the same or different, R ¹⁰ ; R ² and R ^2’ can form a ring with the carbon they are attached to, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ³ and R ^3’ can form a ring with the carbon they are attached to, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁴ is selected from alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, azido, formyl, acyl, alkanoyl, esteryl, carbonyl, cyano, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R ⁴ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁵ is selected from hydrogen, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, allenyl, or lipid, wherein R ⁵ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁶ , R ^6’ , R ^6’’ , and R ^6’’’ are each independently selected from hydrogen, deuterium, hydroxyl, amino, azido, thiol, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, halogen, nitro, alkyl, alkenyl, alkynyl, allenyl, 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 R ⁶ , R ^6’ , R ^6’’ , and R ^6’’’ can each be optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁷ and R ^7’ are each independently selected from hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, wherein R ⁷ and R ^7’ are optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁸ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, 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 R ⁸ is optionally substituted with one or more, the same or different, R ¹⁰ ; R’’’’ is selected from alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, formyl, acyl, alkanoyl, esteryl, carbonyl, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R ^’’’’ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁹ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, 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 R ⁹ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁷ , R ^7’ , R ⁸ , and R ⁹ can 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, R ¹⁰ ; R ⁷ and R ^7’ can form a ring with the α-carbon which they are attached, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁸ and R ⁹ can form a ring with the α-carbon which they are attached, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ¹⁰ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, wherein R ¹⁰ is optionally substituted with one or more, the same or different, R ¹¹ ; R ¹¹ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, 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; and Lipid is a C ₁₁ -C ₂₂ higher alkyl, C ₁₁ -C ₂₂ higher alkoxy, polyethylene glycol, or aryl substituted with an alkyl group, or a lipid as described herein. In certain embodiments, the disclosure relates to a compound of Formula VIII, Formula VIII or a pharmaceutical or physiological salt thereof, wherein X ₁ is OH, SH, NH ₂ , OR’’’’, SR’’’’, NHR’’’’, NHOH, NHOR’’’’, NHNH ₂ ; X2 is selected from O or S; W is selected from N or CR’; Z is selected from N or CR’’; R ^’ and R’’ are each independently selected from hydrogen, deuterium, alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, azido, formyl, acyl, alkanoyl, esteryl, carbonyl, cyano, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R ^’ and R’’ are optionally substituted with one or more, the same or different, R ¹⁰ ; R ¹ is selected from prodrug, H, ,

or together with the oxygen to which it is bound, R ¹ , forms 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, sulfenyl thiocarbonates, optionally substituted sulfenyl thiocarbonates, 2- hydroxypropanoate ester, optionally substitute 2-hydroxypropanoate ester, S-thiocarbonate, optionally substituted S-thiocarbonate, dithiocarbonates, optionally substituted dithiocarbonates, thiocarbamates, optionally substituted thiocarbamates, oxymethoxycarbonyl, optionally substituted oxymethoxycarbonyl, oxymethoxycarbonate, optionally substituted oxymethoxycarbonate, oxymethoxythiocarbonyl, optionally substituted oxymethoxythiocarbonyl, oxymethylcarbonyl, optionally substituted oxymethylcarbonyl, oxymethylthiocarbonyl, optionally substituted oxymethylthiocarbonyl, oxymethoxythiocarbonate, optionally substituted oxymethoxythiocarbonate, L-amino acid esters, D-amino acid esters, oxymethoxy amino ester, 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, sulfinyl, sulfonyl, sulfite, sulfate, sulfonamide, 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, (acyloxybenzyl)ether, (acyloxybenzyl)ester, PEG ester, PEG carbonate, bis-(acyloxybenzyl)esters, optionally substituted bis-(acyloxybenzyl)esters, (acyloxybenzyl)esters, optionally substituted (acyloxybenzyl)esters, and bis-acetoxy benzyl, wherein R ¹ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ¹ -O is selected from monophosphate, diphosphate, triphosphate, amide, lactam, peptide, or carboxylic acid ester, wherein R ¹ is optionally substituted with one or more, the same or different, R ^10; Y is O or S; Y ¹ is OH, OY ³ , or BH3-M ⁺ ; Y ² is OH or BH ₃ -M ⁺ ; Y ³ is aryl, heteroaryl, or heterocyclyl, wherein Y ³ is optionally substituted with one or more, the same or different, R ¹⁰ ; M is Li, Na, K, NH4, Et3NH, or Bu4N; R is F or Cl; R ⁴ is selected from alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, azido, formyl, acyl, alkanoyl, esteryl, carbonyl, cyano, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R ⁴ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁵ is selected from hydrogen, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, allenyl, or lipid, wherein R ⁵ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁶ , R ^6’ , R ^6’’ , and R ^6’’’ are each independently selected from hydrogen, deuterium, hydroxyl, amino, azido, thiol, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, halogen, nitro, alkyl, alkenyl, alkynyl, allenyl, 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 R ⁶ , R ^6’ , R ^6’’ , and R ^6’’’ can each be optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁷ and R ^7’ are each independently selected from hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, wherein R ⁷ and R ^7’ are optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁸ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, wherein R ⁸ is optionally substituted with one or more, the same or different, R ¹⁰ ; R’’’’ is selected from alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, formyl, acyl, alkanoyl, esteryl, carbonyl, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R ^’’’’ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁹ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, wherein R ⁹ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁷ , R ^7’ , R ⁸ , and R ⁹ can 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, R ¹⁰ ; R ⁷ and R ^7’ can form a ring with the α-carbon which they are attached, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁸ and R ⁹ can form a ring with the α-carbon which they are attached, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ¹⁰ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, 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 R ¹⁰ is optionally substituted with one or more, the same or different, R ¹¹ ; R ¹¹ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, 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; and Lipid is a C ₁₁ -C ₂₂ higher alkyl, C ₁₁ -C ₂₂ higher alkoxy, polyethylene glycol, or aryl substituted with an alkyl group, or a lipid as described herein. In certain embodiments, the disclosure relates to a compound of Formula IX, Formula IX or a pharmaceutical or physiological salt thereof, wherein X ₁ is OH, SH, NH ₂ , OR’’’’, SR’’’’, NHR’’’’, NHOH, NHOR’’’’, NHNH ₂ ; X2 is selected from O or S; W is selected from N or CR’ R ^’ is selected from hydrogen, deuterium, alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, azido, formyl, acyl, alkanoyl, esteryl, carbonyl, cyano, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R ^’ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ¹ is selected from prodrug, H,

or together with the oxygen to which it is bound, R ¹ , forms 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, sulfenyl thiocarbonates, optionally substituted sulfenyl thiocarbonates, 2- hydroxypropanoate ester, optionally substitute 2-hydroxypropanoate ester, S-thiocarbonate, optionally substituted S-thiocarbonate, dithiocarbonates, optionally substituted dithiocarbonates, thiocarbamates, optionally substituted thiocarbamates, oxymethoxycarbonyl, optionally substituted oxymethoxycarbonyl, oxymethoxycarbonate, optionally substituted oxymethoxycarbonate, oxymethoxythiocarbonyl, optionally substituted oxymethoxythiocarbonyl, oxymethylcarbonyl, optionally substituted oxymethylcarbonyl, oxymethylthiocarbonyl, optionally substituted oxymethylthiocarbonyl, oxymethoxythiocarbonate, optionally substituted oxymethoxythiocarbonate, L-amino acid esters, D-amino acid esters, oxymethoxy amino ester, 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, sulfinyl, sulfonyl, sulfite, sulfate, sulfonamide, 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, (acyloxybenzyl)ether, (acyloxybenzyl)ester, PEG ester, PEG carbonate, bis-(acyloxybenzyl)esters, optionally substituted bis-(acyloxybenzyl)esters, (acyloxybenzyl)esters, optionally substituted (acyloxybenzyl)esters, and bis-acetoxy benzyl, wherein R ¹ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ¹ -O is selected from monophosphate, diphosphate, triphosphate, amide, lactam, peptide, or carboxylic acid ester, wherein R ¹ is optionally substituted with one or more, the same or different, R ¹⁰ ; Y is O or S; Y ¹ is OH, OY ³ , or BH3-M ⁺ ; Y ² is OH or BH3-M ⁺ ; Y ³ is aryl, heteroaryl, or heterocyclyl, wherein Y ³ is optionally substituted with one or more, the same or different, R ¹⁰ ; M is Li, Na, K, NH4, Et3NH, or Bu4N; R is F or Cl; R ⁴ is selected from alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, azido, formyl, acyl, alkanoyl, esteryl, carbonyl, cyano, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R ⁴ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁵ is selected from hydrogen, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, allenyl, or lipid, wherein R ⁵ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁶ , R ^6’ , R ^6’’ , and R ^6’’’ are each independently selected from hydrogen, deuterium, hydroxyl, amino, azido, thiol, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, halogen, nitro, alkyl, alkenyl, alkynyl, allenyl, 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 R ⁶ , R ^6’ , R ^6’’ , and R ^6’’’ can each be optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁷ and R ^7’ are each independently selected from hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, wherein R ⁷ and R ^7’ are optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁸ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, wherein R ⁸ is optionally substituted with one or more, the same or different, R ¹⁰ ; R’’’’ is selected from alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, formyl, acyl, alkanoyl, esteryl, carbonyl, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R’’’’ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁹ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, wherein R ⁹ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁷ , R ^7’ , R ⁸ , and R ⁹ can 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, R ¹⁰ ; R ⁷ and R ^7’ can form a ring with the α-carbon which they are attached, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁸ and R ⁹ can form a ring with the α-carbon which they are attached, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ¹⁰ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, 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 R ¹⁰ is optionally substituted with one or more, the same or different, R ¹¹ ; R ¹¹ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; and Lipid is a C ₁₁ -C ₂₂ higher alkyl, C ₁₁ -C ₂₂ higher alkoxy, polyethylene glycol, or aryl substituted with an alkyl group, or a lipid as described herein. In certain embodiments, the disclosure relates to a compound of Formula X, or a pharmaceutical or physiological salt thereof, wherein X is CH2, CHMe, CMe2, CHF, CF2, or CD2; U is O, S, NH, NR’’’, CH ₂ , CHF, CF ₂ , CCH ₂ , or CCF ₂ ; X1 is selected from O or S; X ₂ is selected from hydrogen, deuterium, alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, azido, formyl, acyl, alkanoyl, esteryl, carbonyl, cyano, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein X2 is optionally substituted with one or more, the same or different, R ¹⁰ ; Z is selected from N or R’; R ^’ is selected from hydrogen, deuterium, alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, azido, formyl, acyl, alkanoyl, esteryl, carbonyl, cyano, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R ^’ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ¹ is selected from prodrug, H,

or together with the oxygen to which it is bound, R ¹ , forms 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, sulfenyl thiocarbonates, optionally substituted sulfenyl thiocarbonates, 2- hydroxypropanoate ester, optionally substitute 2-hydroxypropanoate ester, S-thiocarbonate, optionally substituted S-thiocarbonate, dithiocarbonates, optionally substituted dithiocarbonates, thiocarbamates, optionally substituted thiocarbamates, oxymethoxycarbonyl, optionally substituted oxymethoxycarbonyl, oxymethoxycarbonate, optionally substituted oxymethoxycarbonate, oxymethoxythiocarbonyl, optionally substituted oxymethoxythiocarbonyl, oxymethylcarbonyl, optionally substituted oxymethylcarbonyl, oxymethylthiocarbonyl, optionally substituted oxymethylthiocarbonyl, oxymethoxythiocarbonate, optionally substituted oxymethoxythiocarbonate, L-amino acid esters, D-amino acid esters, oxymethoxy amino ester, 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, sulfinyl, sulfonyl, sulfite, sulfate, sulfonamide, 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, (acyloxybenzyl)ether, (acyloxybenzyl)ester, PEG ester, PEG carbonate, bis-(acyloxybenzyl)esters, optionally substituted bis-(acyloxybenzyl)esters, (acyloxybenzyl)esters, optionally substituted (acyloxybenzyl)esters, and bis-acetoxy benzyl, wherein R ¹ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ¹ -O is selected from monophosphate, diphosphate, triphosphate, amide, lactam, peptide, or carboxylic acid ester, wherein R ¹ is optionally substituted with one or more, the same or different, R ^10; Y is O or S; Y ¹ is OH, OY ³ , or BH3-M ⁺ ; Y ² is OH or BH ₃ -M ⁺ ; Y ³ is aryl, heteroaryl, or heterocyclyl, wherein Y ³ is optionally substituted with one or more, the same or different, R ¹⁰ ; M is Li, Na, K, NH _4, Et ₃ NH, Bu ₄ N; R is F or Cl; R ² , R ^2’ , R ³ , R ^3’ are each independently selected from hydrogen, deuterium, alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, azido, formyl, acyl, alkanoyl, esteryl, carbonyl, cyano, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R ² , R ^2’ , R ³ , R ^3’ are optionally substituted with one or more, the same or different, R ¹⁰ ; R ² and R ^2’ can form a ring with the carbon they are attached to, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ³ and R ^3’ can form a ring with the carbon they are attached to, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁴ is selected from alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, azido, formyl, acyl, alkanoyl, esteryl, carbonyl, cyano, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R ⁴ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁵ is selected from hydrogen, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, allenyl, or lipid, wherein R ⁵ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁶ , R ^6’ , R ^6’’ , and R ^6’’’ are each independently selected from hydrogen, deuterium, hydroxyl, amino, azido, thiol, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, halogen, nitro, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, sulfinyl, sulfamoyl, sulfonyl allenyl, cyano, or lipid, wherein R ⁶ , R ^6’ , R ^6’’ , and R ^6’’’ can each be optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁷ and R ^7’ are each independently selected from hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, wherein R ⁷ and R ^7’ are optionally substituted with one or more, the same or different, R ¹⁰ ; R’’’ is selected from alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, formyl, acyl, alkanoyl, esteryl, carbonyl, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R’’’ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁸ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, wherein R ⁸ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁹ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, 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 R ⁹ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁷ , R ^7’ , R ⁸ , and R ⁹ can 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, R ¹⁰ ; R ⁷ and R ^7’ can form a ring with the α-carbon which they are attached, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁸ and R ⁹ can form a ring with the α-carbon which they are attached, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ¹⁰ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, wherein R ¹⁰ is optionally substituted with one or more, the same or different, R ¹¹ ; R ¹¹ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; and Lipid is a C ₁₁ -C ₂₂ higher alkyl, C ₁₁ -C ₂₂ higher alkoxy, polyethylene glycol, or aryl substituted with an alkyl group, or a lipid as described herein. In certain embodiments, the disclosure relates to a compound of Formula XI, or a pharmaceutical or physiological salt thereof, wherein X1 is selected from O or S; X ₂ is selected from hydrogen, deuterium, alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, azido, formyl, acyl, alkanoyl, esteryl, carbonyl, cyano, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein X2 is optionally substituted with one or more, the same or different, R ¹⁰ ; Z is selected from N or R’; R ^’ is selected from hydrogen, deuterium, alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, azido, formyl, acyl, alkanoyl, esteryl, carbonyl, cyano, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R ^’ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ¹ is selected from prodrug, H,

or together with the oxygen to which it is bound, R ¹ , forms 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, sulfenyl thiocarbonates, optionally substituted sulfenyl thiocarbonates, 2- hydroxypropanoate ester, optionally substitute 2-hydroxypropanoate ester, S-thiocarbonate, optionally substituted S-thiocarbonate, dithiocarbonates, optionally substituted dithiocarbonates, thiocarbamates, optionally substituted thiocarbamates, oxymethoxycarbonyl, optionally substituted oxymethoxycarbonyl, oxymethoxycarbonate, optionally substituted oxymethoxycarbonate, oxymethoxythiocarbonyl, optionally substituted oxymethoxythiocarbonyl, oxymethylcarbonyl, optionally substituted oxymethylcarbonyl, oxymethylthiocarbonyl, optionally substituted oxymethylthiocarbonyl, oxymethoxythiocarbonate, optionally substituted oxymethoxythiocarbonate, L-amino acid esters, D-amino acid esters, oxymethoxy amino ester, 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, sulfinyl, sulfonyl, sulfite, sulfate, sulfonamide, 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, (acyloxybenzyl)ether, (acyloxybenzyl)ester, PEG ester, PEG carbonate, bis-(acyloxybenzyl)esters, optionally substituted bis-(acyloxybenzyl)esters, (acyloxybenzyl)esters, optionally substituted (acyloxybenzyl)esters, and bis-acetoxy benzyl, wherein R ¹ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ¹ -O is selected from monophosphate, diphosphate, triphosphate, amide, lactam, peptide, or carboxylic acid ester, wherein R ¹ is optionally substituted with one or more, the same or different, R ^10; Y is O or S; Y ¹ is OH, OY ³ , or BH3-M ⁺ ; Y ² is OH or BH ₃ -M ⁺ ; Y ³ is aryl, heteroaryl, or heterocyclyl, wherein Y ³ is optionally substituted with one or more, the same or different, R ¹⁰ ; M is Li, Na, K, NH4, Et3NH, Bu4N; R is F or Cl; R ² , R ^2’ , R ³ , R ^3’ are each independently selected from hydrogen, deuterium, alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, azido, formyl, acyl, alkanoyl, esteryl, carbonyl, cyano, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R ² , R ^2’ , R ³ , R ^3’ are optionally substituted with one or more, the same or different, R ¹⁰ ; R ² and R ^2’ can form a ring with the carbon they are attached to, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ³ and R ^3’ can form a ring with the carbon they are attached to, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁴ is selected from alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, azido, formyl, acyl, alkanoyl, esteryl, carbonyl, cyano, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R ⁴ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁵ is selected from hydrogen, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, allenyl, or lipid, wherein R ⁵ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁶ , R ^6’ , R ^6’’ , and R ^6’’’ are each independently selected from hydrogen, deuterium, hydroxyl, amino, azido, thiol, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, halogen, nitro, alkyl, alkenyl, alkynyl, allenyl, 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 R ⁶ , R ^6’ , R ^6’’ , and R ^6’’’ can each be optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁷ and R ^7’ are each independently selected from hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, wherein R ⁷ and R ^7’ and optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁸ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, wherein R ⁸ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁹ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, wherein R ⁹ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁷ , R ^7’ , R ⁸ , and R ⁹ can 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, R ¹⁰ ; R ⁷ and R ^7’ can form a ring with the α-carbon which they are attached, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁸ and R ⁹ can form a ring with the α-carbon which they are attached, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ¹⁰ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, 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 R ¹⁰ is optionally substituted with one or more, the same or different, R ¹¹ ; R ¹¹ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; and Lipid is a C11-C22 higher alkyl, C11-C22 higher alkoxy, polyethylene glycol, or aryl substituted with an alkyl group, or a lipid as described herein. In certain embodiments, the disclosure relates to a compound of Formula XII, Formula XII or a pharmaceutical or physiological salt thereof, wherein X1 is selected from O or S; X2 is selected from hydrogen, deuterium, alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, azido, formyl, acyl, alkanoyl, esteryl, carbonyl, cyano, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein X ₂ is optionally substituted with one or more, the same or different, R ¹⁰ ; Z is selected from N or R’; R ^’ is selected from hydrogen, deuterium, alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, azido, formyl, acyl, alkanoyl, esteryl, carbonyl, cyano, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R ^’ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ¹ is selected from prodrug, H,

or together with the oxygen to which it is bound, R ¹ , forms 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, sulfenyl thiocarbonates, optionally substituted sulfenyl thiocarbonates, 2- hydroxypropanoate ester, optionally substitute 2-hydroxypropanoate ester, S-thiocarbonate, optionally substituted S-thiocarbonate, dithiocarbonates, optionally substituted dithiocarbonates, thiocarbamates, optionally substituted thiocarbamates, oxymethoxycarbonyl, optionally substituted oxymethoxycarbonyl, oxymethoxycarbonate, optionally substituted oxymethoxycarbonate, oxymethoxythiocarbonyl, optionally substituted oxymethoxythiocarbonyl, oxymethylcarbonyl, optionally substituted oxymethylcarbonyl, oxymethylthiocarbonyl, optionally substituted oxymethylthiocarbonyl, oxymethoxythiocarbonate, optionally substituted oxymethoxythiocarbonate, L-amino acid esters, D-amino acid esters, oxymethoxy amino ester, 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, sulfinyl, sulfonyl, sulfite, sulfate, sulfonamide, 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, (acyloxybenzyl)ether, (acyloxybenzyl)ester, PEG ester, PEG carbonate, bis-(acyloxybenzyl)esters, optionally substituted bis-(acyloxybenzyl)esters, (acyloxybenzyl)esters, optionally substituted (acyloxybenzyl)esters, and bis-acetoxy benzyl, wherein R ¹ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ¹ -O is selected from monophosphate, diphosphate, triphosphate, amide, lactam, peptide, or carboxylic acid ester, wherein R ¹ is optionally substituted with one or more, the same or different, R ^10; Y is O or S; Y ¹ is OH, OY ³ , or BH3-M ⁺ ; Y ² is OH or BH ₃ -M ⁺ ; Y ³ is aryl, heteroaryl, or heterocyclyl, wherein Y ³ is optionally substituted with one or more, the same or different, R ¹⁰ ; M is Li, Na, K, NH4, Et3NH, or Bu4N; R is F or Cl; R ⁴ is selected from alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, azido, formyl, acyl, alkanoyl, esteryl, carbonyl, cyano, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R ⁴ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁵ is selected from hydrogen, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, allenyl, or lipid, wherein R ⁵ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁶ , R ^6’ , R ^6’’ , and R ^6’’’ are each independently selected from hydrogen, deuterium, hydroxyl, amino, azido, thiol, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, halogen, nitro, alkyl, alkenyl, alkynyl, allenyl, 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 R ⁶ , R ^6’ , R ^6’’ , and R ^6’’’ can each be optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁷ and R ^7’ are each independently selected from hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, wherein R ⁷ and R ^7’ are optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁸ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, wherein R ⁸ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁹ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, 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 R ⁹ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁷ , R ^7’ , R ⁸ , and R ⁹ can 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, R ¹⁰ ; R ⁷ and R ^7’ can form a ring with the α-carbon which they are attached, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁸ and R ⁹ can form a ring with the α-carbon which they are attached, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ¹⁰ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, wherein R ¹⁰ is optionally substituted with one or more, the same or different, R ¹¹ ; R ¹¹ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; and Lipid is a C ₁₁ -C ₂₂ higher alkyl, C ₁₁ -C ₂₂ higher alkoxy, polyethylene glycol, or aryl substituted with an alkyl group, or a lipid as described herein. In certain embodiments, the disclosure relates to a compound of Formula XIII,

Formula XIII or a pharmaceutical or physiological salt thereof, wherein Z is selected from N or R’; R ^’ is selected from hydrogen, deuterium, alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, azido, formyl, acyl, alkanoyl, esteryl, carbonyl, cyano, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R ^’ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ¹ is selected from prodrug, H, or together with the oxygen to which it is bound, R ¹ , forms 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, sulfenyl thiocarbonates, optionally substituted sulfenyl thiocarbonates, 2- hydroxypropanoate ester, optionally substitute 2-hydroxypropanoate ester, S-thiocarbonate, optionally substituted S-thiocarbonate, dithiocarbonates, optionally substituted dithiocarbonates, thiocarbamates, optionally substituted thiocarbamates, oxymethoxycarbonyl, optionally substituted oxymethoxycarbonyl, oxymethoxycarbonate, optionally substituted oxymethoxycarbonate, oxymethoxythiocarbonyl, optionally substituted oxymethoxythiocarbonyl, oxymethylcarbonyl, optionally substituted oxymethylcarbonyl, oxymethylthiocarbonyl, optionally substituted oxymethylthiocarbonyl, oxymethoxythiocarbonate, optionally substituted oxymethoxythiocarbonate, L-amino acid esters, D-amino acid esters, oxymethoxy amino ester, 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, sulfinyl, sulfonyl, sulfite, sulfate, sulfonamide, 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, (acyloxybenzyl)ether, (acyloxybenzyl)ester, PEG ester, PEG carbonate, bis-(acyloxybenzyl)esters, optionally substituted bis-(acyloxybenzyl)esters, (acyloxybenzyl)esters, optionally substituted (acyloxybenzyl)esters, and bis-acetoxy benzyl, wherein R ¹ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ¹ -O is selected from monophosphate, diphosphate, triphosphate, amide, lactam, peptide, or carboxylic acid ester, wherein R ¹ is optionally substituted with one or more, the same or different, R ^10; Y is O or S; Y ¹ is OH, OY ³ , or BH ₃ -M ⁺ ; Y ² is OH or BH3-M ⁺ ; Y ³ is aryl, heteroaryl, or heterocyclyl, wherein Y ³ is optionally substituted with one or more, the same or different, R ¹⁰ ; M is Li, Na, K, NH4, Et3NH, Bu4N; R is F or Cl; R ⁴ is selected from alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, azido, formyl, acyl, alkanoyl, esteryl, carbonyl, cyano, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R ⁴ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁵ is selected from hydrogen, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, allenyl, or lipid, wherein R ⁵ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁶ , R ^6’ , R ^6’’ , and R ^6’’’ are each independently selected from hydrogen, deuterium, hydroxyl, amino, azido, thiol, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, halogen, nitro, alkyl, alkenyl, alkynyl, allenyl, 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 R ⁶ , R ^6’ , R ^6’’ , and R ^6’’’ can each be optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁷ and R ^7’ are each independently selected from hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, 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 R ⁷ and R ^7’ are optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁸ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, 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 R ⁸ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁹ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, wherein R ⁹ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁷ , R ^7’ , R ⁸ , and R ⁹ can 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, R ¹⁰ ; R ⁷ and R ^7’ can form a ring with the α-carbon which they are attached, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁸ and R ⁹ can form a ring with the α-carbon which they are attached, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ¹⁰ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, 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 R ¹⁰ is optionally substituted with one or more, the same or different, R ¹¹ ; R ¹¹ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, 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; and Lipid is a C11-C22 higher alkyl, C11-C22 higher alkoxy, polyethylene glycol, or aryl substituted with an alkyl group, or a lipid as described herein. In certain embodiments, the disclosure relates to a compound of Formula XIV, Formula XIV or a pharmaceutical or physiological salt thereof, wherein X is CH ₂ , CHMe, CMe ₂ , CHF, CF ₂ , or CD ₂ ; U is O, S, NH, NR’’’, CH2, CHF, CF2, CCH2, or CCF2; X ₁ is OH, SH, NH ₂ , OR ₈ , SR ₈ , NHR ₈ , NHOH, NHOR ₈ , NHNH ₂ ; X2 is selected from hydrogen, deuterium, alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, azido, formyl, acyl, alkanoyl, esteryl, carbonyl, cyano, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein X ₂ is optionally substituted with one or more, the same or different, R ¹⁰ ; Z is selected from N or R’; R ^’ is selected from hydrogen, deuterium, alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, azido, formyl, acyl, alkanoyl, esteryl, carbonyl, cyano, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R ^’ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ¹ is selected from prodrug, H,

or together with the oxygen to which it is bound, R ¹ , forms 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, sulfenyl thiocarbonates, optionally substituted sulfenyl thiocarbonates, 2- hydroxypropanoate ester, optionally substitute 2-hydroxypropanoate ester, S-thiocarbonate, optionally substituted S-thiocarbonate, dithiocarbonates, optionally substituted dithiocarbonates, thiocarbamates, optionally substituted thiocarbamates, oxymethoxycarbonyl, optionally substituted oxymethoxycarbonyl, oxymethoxycarbonate, optionally substituted oxymethoxycarbonate, oxymethoxythiocarbonyl, optionally substituted oxymethoxythiocarbonyl, oxymethylcarbonyl, optionally substituted oxymethylcarbonyl, oxymethylthiocarbonyl, optionally substituted oxymethylthiocarbonyl, oxymethoxythiocarbonate, optionally substituted oxymethoxythiocarbonate, L-amino acid esters, D-amino acid esters, oxymethoxy amino ester, 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, sulfinyl, sulfonyl, sulfite, sulfate, sulfonamide, 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, (acyloxybenzyl)ether, (acyloxybenzyl)ester, PEG ester, PEG carbonate, bis-(acyloxybenzyl)esters, optionally substituted bis-(acyloxybenzyl)esters, (acyloxybenzyl)esters, optionally substituted (acyloxybenzyl)esters, and bis-acetoxy benzyl, wherein R ¹ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ¹ -O is selected from monophosphate, diphosphate, triphosphate, amide, lactam, peptide, or carboxylic acid ester, wherein R ¹ is optionally substituted with one or more, the same or different, R ^10; Y is O or S; Y ¹ is OH, OY ³ , or BH3-M ⁺ ; Y ² is OH or BH ₃ -M ⁺ ; Y ³ is aryl, heteroaryl, or heterocyclyl, wherein Y ³ is optionally substituted with one or more, the same or different, R ¹⁰ ; M is Li, Na, K, NH4, Et3NH, Bu4N; R is F or Cl; R ² , R ^2’ , R ³ , R ^3’ are each independently selected from hydrogen, deuterium, alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, azido, formyl, acyl, alkanoyl, esteryl, carbonyl, cyano, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R ² , R ^2’ , R ³ , R ^3’ are optionally substituted with one or more, the same or different, R ¹⁰ ; R ² and R ^2’ can form a ring with the carbon they are attached to, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ³ and R ^3’ can form a ring with the carbon they are attached to, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁴ is selected from alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, azido, formyl, acyl, alkanoyl, esteryl, carbonyl, cyano, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R ⁴ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁵ is selected from hydrogen, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, allenyl, or lipid, wherein R ⁵ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁶ , R ^6’ , R ^6’’ , and R ^6’’’ are each independently selected from hydrogen, deuterium, hydroxyl, amino, azido, thiol, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, halogen, nitro, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, sulfinyl, sulfamoyl, sulfonyl allenyl, cyano, or lipid, wherein R ⁶ , R ^6’ , R ^6’’ , and R ^6’’’ can each be optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁷ and R ^7’ are each independently selected from hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, 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 R ⁷ and R ^7’ are optionally substituted with one or more, the same or different, R ¹⁰ ; R’’’ is selected from alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, formyl, acyl, alkanoyl, esteryl, carbonyl, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R’’’ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁸ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, wherein R ⁸ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁹ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, wherein R ⁹ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁷ , R ^7’ , R ⁸ , and R ⁹ can 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, R ¹⁰ ; R ⁷ and R ^7’ can form a ring with the α-carbon which they are attached, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁸ and R ⁹ can form a ring with the α-carbon which they are attached, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ¹⁰ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, 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 R ¹⁰ is optionally substituted with one or more, the same or different, R ¹¹ ; R ¹¹ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; and Lipid is a C11-C22 higher alkyl, C11-C22 higher alkoxy, polyethylene glycol, or aryl substituted with an alkyl group, or a lipid as described herein. In certain embodiments, the disclosure relates to a compound of Formula XV, Formula XV or a pharmaceutical or physiological salt thereof, wherein X1 is OH, SH, NH2, OR’’’’, SR’’’’, NHR’’’’, NHOH, NHOR’’’’, NHNH2; X ₂ is selected from hydrogen, deuterium, alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, azido, formyl, acyl, alkanoyl, esteryl, carbonyl, cyano, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein X ₂ is optionally substituted with one or more, the same or different, R ¹⁰ ; Z is selected from N or R’; R ^’ is selected from hydrogen, deuterium, alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, azido, formyl, acyl, alkanoyl, esteryl, carbonyl, cyano, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R ^’ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ¹ is selected from prodrug, H,

or together with the oxygen to which it is bound, R ¹ , forms 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, sulfenyl thiocarbonates, optionally substituted sulfenyl thiocarbonates, 2- hydroxypropanoate ester, optionally substitute 2-hydroxypropanoate ester, S-thiocarbonate, optionally substituted S-thiocarbonate, dithiocarbonates, optionally substituted dithiocarbonates, thiocarbamates, optionally substituted thiocarbamates, oxymethoxycarbonyl, optionally substituted oxymethoxycarbonyl, oxymethoxycarbonate, optionally substituted oxymethoxycarbonate, oxymethoxythiocarbonyl, optionally substituted oxymethoxythiocarbonyl, oxymethylcarbonyl, optionally substituted oxymethylcarbonyl, oxymethylthiocarbonyl, optionally substituted oxymethylthiocarbonyl, oxymethoxythiocarbonate, optionally substituted oxymethoxythiocarbonate, L-amino acid esters, D-amino acid esters, oxymethoxy amino ester, 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, sulfinyl, sulfonyl, sulfite, sulfate, sulfonamide, 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, (acyloxybenzyl)ether, (acyloxybenzyl)ester, PEG ester, PEG carbonate, bis-(acyloxybenzyl)esters, optionally substituted bis-(acyloxybenzyl)esters, (acyloxybenzyl)esters, optionally substituted (acyloxybenzyl)esters, and bis-acetoxy benzyl, wherein R ¹ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ¹ -O is selected from monophosphate, diphosphate, triphosphate, amide, lactam, peptide, or carboxylic acid ester, wherein R ¹ is optionally substituted with one or more, the same or different, R ^10; Y is O or S; Y ¹ is OH, OY ³ , or BH3-M ⁺ ; Y ² is OH or BH ₃ -M ⁺ ; Y ³ is aryl, heteroaryl, or heterocyclyl, wherein Y ³ is optionally substituted with one or more, the same or different, R ¹⁰ ; M is Li, Na, K, NH4, Et3NH, or Bu4N; R is F or Cl; R ² , R ^2’ , R ³ , R ^3’ are each independently selected from hydrogen, deuterium, alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, azido, formyl, acyl, alkanoyl, esteryl, carbonyl, cyano, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R ² , R ^2’ , R ³ , R ^3’ are optionally substituted with one or more, the same or different, R ¹⁰ ; R ² and R ^2’ can form a ring with the carbon they are attached to, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ³ and R ^3’ can form a ring with the carbon they are attached to, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁴ is selected from alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, azido, formyl, acyl, alkanoyl, esteryl, carbonyl, cyano, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R ⁴ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁵ is selected from hydrogen, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, allenyl, or lipid, wherein R ⁵ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁶ , R ^6’ , R ^6’’ , and R ^6’’’ are each independently selected from hydrogen, deuterium, hydroxyl, amino, azido, thiol, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, halogen, nitro, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, sulfinyl, sulfamoyl, sulfonyl allenyl, cyano, or lipid, wherein R ⁶ , R ^6’ , R ^6’’ , and R ^6’’’ can each be optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁷ and R ^7’ are each independently selected from hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, 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 R ⁷ and R ^7’ are optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁸ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, wherein R ⁸ is optionally substituted with one or more, the same or different, R ¹⁰ ; R’’’’ is selected from alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, formyl, acyl, alkanoyl, esteryl, carbonyl, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R ^’’’’ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁹ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, wherein R ⁹ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁷ , R ^7’ , R ⁸ , and R ⁹ can 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, R ¹⁰ ; R ⁷ and R ^7’ can form a ring with the α-carbon which they are attached, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁸ and R ⁹ can form a ring with the α-carbon which they are attached, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ¹⁰ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, 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 R ¹⁰ is optionally substituted with one or more, the same or different, R ¹¹ ; R ¹¹ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; and Lipid is a C11-C22 higher alkyl, C11-C22 higher alkoxy, polyethylene glycol, or aryl substituted with an alkyl group, or a lipid as described herein. In certain embodiments, the disclosure relates to a compound of Formula XVI, Formula XVI or a pharmaceutical or physiological salt thereof, wherein X1 is OH, SH, NH2, OR’’’’, SR’’’’, NHR’’’’, NHOH, NHOR’’’’, NHNH2; X ₂ is selected from hydrogen, deuterium, alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, azido, formyl, acyl, alkanoyl, esteryl, carbonyl, cyano, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein X ₂ is optionally substituted with one or more, the same or different, R ¹⁰ ; Z is selected from N or R’; R ^’ is selected from hydrogen, deuterium, alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, azido, formyl, acyl, alkanoyl, esteryl, carbonyl, cyano, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R ^’ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ¹ is selected from prodrug, H,

or together with the oxygen to which it is bound, R ¹ , forms 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, sulfenyl thiocarbonates, optionally substituted sulfenyl thiocarbonates, 2- hydroxypropanoate ester, optionally substitute 2-hydroxypropanoate ester, S-thiocarbonate, optionally substituted S-thiocarbonate, dithiocarbonates, optionally substituted dithiocarbonates, thiocarbamates, optionally substituted thiocarbamates, oxymethoxycarbonyl, optionally substituted oxymethoxycarbonyl, oxymethoxycarbonate, optionally substituted oxymethoxycarbonate, oxymethoxythiocarbonyl, optionally substituted oxymethoxythiocarbonyl, oxymethylcarbonyl, optionally substituted oxymethylcarbonyl, oxymethylthiocarbonyl, optionally substituted oxymethylthiocarbonyl, oxymethoxythiocarbonate, optionally substituted oxymethoxythiocarbonate, L-amino acid esters, D-amino acid esters, oxymethoxy amino ester, 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, sulfinyl, sulfonyl, sulfite, sulfate, sulfonamide, 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, (acyloxybenzyl)ether, (acyloxybenzyl)ester, PEG ester, PEG carbonate, bis-(acyloxybenzyl)esters, optionally substituted bis-(acyloxybenzyl)esters, (acyloxybenzyl)esters, optionally substituted (acyloxybenzyl)esters, and bis-acetoxy benzyl, wherein R ¹ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ¹ -O is selected from monophosphate, diphosphate, triphosphate, amide, lactam, peptide, or carboxylic acid ester, wherein R ¹ is optionally substituted with one or more, the same or different, R ^10; Y is O or S; Y ¹ is OH, OY ³ , or BH3-M ⁺ ; Y ² is OH or BH ₃ -M ⁺ ; Y ³ is aryl, heteroaryl, or heterocyclyl, wherein Y ³ is optionally substituted with one or more, the same or different, R ¹⁰ ; M is Li, Na, K, NH4, Et3NH, or Bu4N; R is F or Cl; R ⁴ is selected from alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, azido, formyl, acyl, alkanoyl, esteryl, carbonyl, cyano, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R ⁴ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁵ is selected from hydrogen, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, allenyl, or lipid, wherein R ⁵ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁶ , R ^6’ , R ^6’’ , and R ^6’’’ are each independently selected from hydrogen, deuterium, hydroxyl, amino, azido, thiol, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, halogen, nitro, alkyl, alkenyl, alkynyl, allenyl, 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 R ⁶ , R ^6’ , R ^6’’ , and R ^6’’’ can each be optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁷ and R ^7’ are each independently selected from hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, wherein R ⁷ and R ^7’ are optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁸ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, wherein R ⁸ is optionally substituted with one or more, the same or different, R ¹⁰ ; R’’’’ is selected from alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, formyl, acyl, alkanoyl, esteryl, carbonyl, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R ₈ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁹ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, wherein R ⁹ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁷ , R ^7’ , R ⁸ , and R ⁹ can 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, R ¹⁰ ; R ⁷ and R ^7’ can form a ring with the α-carbon which they are attached, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁸ and R ⁹ can form a ring with the α-carbon which they are attached, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ¹⁰ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, 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 R ¹⁰ is optionally substituted with one or more, the same or different, R ¹¹ ; R ¹¹ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, 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; and Lipid is a C ₁₁ -C ₂₂ higher alkyl, C ₁₁ -C ₂₂ higher alkoxy, polyethylene glycol, or aryl substituted with an alkyl group, or a lipid as described herein. In certain embodiments, the disclosure relates to a compound of Formula XVII, Formula XVII or a pharmaceutical or physiological salt thereof, wherein X2 is selected from hydrogen, alkyl, alkenyl, alkynyl, amino, cyano, halogen, or aryl, wherein X ₂ is optionally substituted with one or more, the same or different, R ¹⁰ ; Z is selected from N or R’; R ^’ is selected from hydrogen, alkyl, alkenyl, alkynyl, formyl, acyl, alkanoyl, cyano, halogen, or aryl, wherein R ^’ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ¹ is selected from prodrug, H,

or together with the oxygen to which it is bound, R ¹ , forms 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, sulfenyl thiocarbonates, optionally substituted sulfenyl thiocarbonates, 2- hydroxypropanoate ester, optionally substitute 2-hydroxypropanoate ester, S-thiocarbonate, optionally substituted S-thiocarbonate, dithiocarbonates, optionally substituted dithiocarbonates, thiocarbamates, optionally substituted thiocarbamates, oxymethoxycarbonyl, optionally substituted oxymethoxycarbonyl, oxymethoxycarbonate, optionally substituted oxymethoxycarbonate, oxymethoxythiocarbonyl, optionally substituted oxymethoxythiocarbonyl, oxymethylcarbonyl, optionally substituted oxymethylcarbonyl, oxymethylthiocarbonyl, optionally substituted oxymethylthiocarbonyl, oxymethoxythiocarbonate, optionally substituted oxymethoxythiocarbonate, L-amino acid esters, D-amino acid esters, oxymethoxy amino ester, 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, sulfinyl, sulfonyl, sulfite, sulfate, sulfonamide, 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, (acyloxybenzyl)ether, (acyloxybenzyl)ester, PEG ester, PEG carbonate, bis-(acyloxybenzyl)esters, optionally substituted bis-(acyloxybenzyl)esters, (acyloxybenzyl)esters, optionally substituted (acyloxybenzyl)esters, and bis-acetoxy benzyl, wherein R ¹ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ¹ -O is selected from monophosphate, diphosphate, triphosphate, amide, lactam, peptide, or carboxylic acid ester, wherein R ¹ is optionally substituted with one or more, the same or different, R ^10; Y is O or S; Y ¹ is OH, OY ³ , or BH3-M ⁺ ; Y ² is OH or BH3-M ⁺ ; Y ³ is aryl, heteroaryl, or heterocyclyl, wherein Y ³ is optionally substituted with one or more, the same or different, R ¹⁰ ; M is Li, Na, K, NH4, Et3NH,or Bu4N; R is F or Cl; R ⁴ is selected from alkyl, alkenyl, alkynyl, allenyl, alkoxy, hydroxy, thiol, amino, azido, formyl, acyl, alkanoyl, esteryl, carbonyl, cyano, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, heterocarbocyclyl, sulfinyl, sulfamoyl, or sulfonyl, wherein R ⁴ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁵ is selected from hydrogen, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, allenyl, or lipid, wherein R ⁵ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁶ , R ^6’ , R ^6’’ , and R ^6’’’ are each independently selected from hydrogen, deuterium, hydroxyl, amino, azido, thiol, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, halogen, nitro, alkyl, alkenyl, alkynyl, allenyl, 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 R ⁶ , R ^6’ , R ^6’’ , and R ^6’’’ can each be optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁷ and R ^7’ are each independently selected from hydrogen, deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, wherein R ⁷ and R ^7’ are optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁸ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, wherein R ⁸ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁹ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, 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 R ⁹ is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁷ , R ^7’ , R ⁸ , and R ⁹ can 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, R ¹⁰ ; R ⁷ and R ^7’ can form a ring with the α-carbon which they are attached, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ⁸ and R ⁹ can form a ring with the α-carbon which they are attached, wherein the ring is optionally substituted with one or more, the same or different, R ¹⁰ ; R ¹⁰ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl, wherein R ¹⁰ is optionally substituted with one or more, the same or different, R ¹¹ ; R ¹¹ is selected from deuterium, hydroxy, azido, thiol, amino, cyano, halogen, acyl, alkanoyl, esteryl, formyl, acyloxybenzyl, alkyl, alkenyl, alkynyl, allenyl, carbocyclyl, heterocarbocyclyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, carbocycloxy, heterocarbocycloxy, aryloxy, heteroaryloxy, heterocycloxy, cycloalkoxy, cycloalkenoxy, alkylamino, (alkyl) ₂ amino, carbocyclamino, heterocarbocyclamino, arylamino, heteroarylamino, heterocyclamino, cycloalkamino, cycloalkenamino, alkylthio, carbocyclylthio, heterocarbocyclylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, allenyl, sulfinyl, sulfamoyl, sulfonyl, lipid, nitro, or carbonyl; and Lipid is a C ₁₁ -C ₂₂ higher alkyl, C ₁₁ -C ₂₂ higher alkoxy, polyethylene glycol, or aryl substituted with an alkyl group, or a lipid as described herein. In some embodiments, the compound is selected from: In some embodiments, the compound is selected from:

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In some embodiments, the compound is selected from: In some embodiments, the compound is selected from: Infectious Diseases The compounds provided herein can be used to treat viral infectious diseases. 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 HRV ^1A (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, SARS-CoV-2, 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. 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, La Crosse, Oropouche, 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 alpharetroviruses (for example, Rous sarcoma virus and avian leukemia virus), betaretroviruses (for example, mouse mammary tumor virus, Mason-Pfizer monkey virus and Jaagsiekte sheep retrovirus), gammaretroviruses (for example, murine leukemia virus and feline leukemia virus, deltraretroviruses (for example, human T cell leukemia viruses (HTLV-1, HTLV-2), bovine leukemia virus, STLV-1 and STLV- 2), epsilonretriviruses (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). 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 disclosure relates to methods of treating or preventing a viral infection comprising administering an effective amount of a compound or pharmaceutical composition 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 or pharmaceutical composition 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, SAR-CoV-2, 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, Mayaro virus, Barmah Forest virus, yellow fever virus, West Nile 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, SARS-CoV-2, 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, Powassan virus, tick-borne encephalitis virus, Rift Valley fever virus (RVFV), Heartland virus, La Crosse virus, Oropouche virus, hantavirus, Dengue virus serotypes 1, 2, 3 and 4, Zika virus, West Nile virus, Tacaribe virus, Junin, Lassa fever virus, Coxsackie virus, poliovirus, enterovirus, enterovirus-68, enterovirus-71, 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. 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 disclosure relates to methods of treating or preventing a viral infection comprising administering an effective amount of a compound or pharmaceutical composition disclosed herein to a subject in need thereof. Also disclosed are methods of treating or preventing a viral infection comprising administing an effective amount of a compound or pharmaceutical composition made by the methods disclosed herein. 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 or pharmaceutical composition disclosed herein to a subject in need thereof. In certain embodiments, the viral infection is, or is caused by, an alphavirus, arenavirus, flavivirus, coronaviruses (including SARS-CoV-2 and varients 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), 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 embodiments, the disclosure relates to methods of treating or preventing a viral infection in the central nervous system (CNS) comprising administering an effective amount of a compound or pharmaceutical composition disclosed herein to a subject in need thereof. In certain embodiments, the disclosure relates to methods of treating or preventing a viral infection in the lungs comprising administering an effective amount of a compound or pharmaceutical composition disclosed herein to a subject in need thereof. In certain embodiments, the disclosure relates to methods of treating or preventing a viral infection in the central nervous system (CNS) comprising delivering an effective amount of a compound or pharmaceutical composition disclosed herein to a subject in need thereof. In certain embodiments, the disclosure relates to methods of treating or preventing a viral infection in the lungs comprising delivering an effective amount of a compound or pharmaceutical composition disclosed herein to a subject in need thereof. In certain embodiments, the disclosure relates to methods of treating or preventing a viral infection in the central nervous system (CNS) comprising delivering an effective amount of a compound or pharmaceutical composition disclosed herein to the CNS of a subject in need thereof. In certain embodiments, the disclosure relates to methods of treating or preventing a viral infection in the lungs comprising delivering an effective amount of a compound or pharmaceutical composition disclosed herein to the lungs of a subject in need thereof. 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 some embodiments, the disclosure relates to treating or preventing an infection by viruses, bacteria, fungi, protozoa, and parasites. 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 occurs 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, AT-511, AT-527, atazanavir, atripla, balapiravir, baloxavir marboxil, BCX4430/Galidesivir, boceprevir, cidofovir, combivir, daclatasvir, darunavir, dasabuvir, delavirdine, didanosine, docosanol, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, fomivirsen, fosamprenavir, foscarnet, fosfonet, ganciclovir, GS-441524, GS-5734/Remdesivir, ibacitabine, imunovir, idoxuridine, imiquimod, indinavir, inosine, interferon type III, interferon type II, interferon type I, lamivudine, ledipasvir, lopinavir, loviride, maraviroc, molnupiravir, moroxydine, methisazone, nelfinavir, nevirapine, nexavir, NITD008, ombitasvir, oseltamivir, paritaprevir, PAXLOVID ^TM , 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: 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 exemplified embodiments, pharmaceutical compositions disclosed herein can be combined with , , , and In exemplified embodiments, pharmaceutical compositions disclosed herein or a pharmaceutical or physiological salt thereof can be found in combination with or a pharmaceutical or physiological salt thereof in host plasma or whole blood. In exemplified embodiments, pharmaceutical compositions disclosed hereinor a pharmaceutical or physiological salt thereof can be found in combination with or a pharmaceutical or physiological salt thereof in host plasma or whole blood. In exemplified embodiments, pharmaceutical compositions disclosed hereinor a pharmaceutical or physiological salt thereof can be found in combination with or a pharmaceutical or physiological salt thereof in host plasma or whole blood. In exemplified embodiments, pharmaceutical compositions disclosed hereinor a pharmaceutical or physiological salt thereof can be found in combination with or a 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 with PAXLOVID ^TM ;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. The additional active agent(s) may be one or more agents selected from the group consisting of antiviral compounds, antigens, adjuvants, anti-cancer agents, CTLA-4 agonists, LAG-3 agonists, PD-1 pathway antagonists, lipids, liposomes, peptides, cytotoxic agents, chemotherapeutic agents, immunomodulatory cell lines, checkpoint inhibitors, vascular endothelial growth factor (VEGF) receptor inhibitors, topoisomerase II inhibitors, smoothen inhibitors, alkylating agents, antibiotics, anti-metabolites, retinoids, steroids, and immunomodulatory agents, including but not limited to antiviral vaccines. It will be understood the descriptions of the above additional active agents, and of those listed below, may be overlapping. It will also be understood that the treatment combinations are subject to optimization, and it is understood that the best combination to use of the antiviral nucleoside, and one or more additional active agents will be determined based on the individual patient needs. Antiviral compounds that may be used in combination with the therapies disclosed herein include direct acting antivirals and antiviral compounds that target intracellular environments. In particular, antiviral compounds that may be used in combination with the therapies disclosed herein include antivirals that target SARS-Co V -2 virus ( and COVID-19 caused by SARS-Co V-2 infection), influenza, hepatitis B virus (HBV) inhibitors, hepatitis C virus (HCV) protease inhibitors, HCV polymerase inhibitors, HCV NS4A inhibitors, HCV NS5A inhibitors, HCV NS5b inhibitors, and human immunodeficiency virus (HIV) inhibitors. Such antiviral compounds include but are not limited to 2-DG, 2x-121, AB00l, AT-527, avifavir, AVM-0703, C21, CAL-02, CYTO-201 (naltrexone hydrochloride), Conronavir (TL-FVP-t), DW-2008S, DWJ-1248, elsufavirine, emtricitabine, eFT226, HP-163, IML-206, IMU-838, LAU-7b, MAN- 19, MMS-019, OBP-2001, omega 3 viruxide, OPN-019, OYA-1, PP-001, PRTX-007, RBI-5000, RBT-9, RECCE529, RS-5614, SKll, SLV-213, T-COVID, TL-895, TYME-19, UCI-1, XC-221, fenretinide, molnupiravir, nafamostat, nafamostat mesylate, nanomedivir (atazanavir/dexamethasone), nanofenretinide (ST-001), necuparanib (M-402), nelfinavir, nitazoxanide, paxlovid, piclidenoson, pixatimod, polyinosinic-plycytidylic acid, proxalutamide, hydrochloroquine, hydroxychloroquine, chloroquine, oseltamivir, oseltamivir phosphate, zanamivir, peramivir, baloxavir marboxil, remdesivir, favilavir, avifavir, favilavir/avifavir, vaniprevir, grazoprevir, elbasvir, narlaprevir, nitazoxanide, atazanavir, ritonavir, daclatasvir, farunavir, darunavir/cobicistat, saquinavir, indinavir, carfilzomib, ivaltinostat (CG200745), isotretinoin/tamoxifen, isotretinoin, tamoxifen, levamisole, prexasertib, ebselen, merimepodib, 1-deoxy-D-glucose prodrugs, formoterol, budesonide, rigosertib, erlotinib, silmitasertib, favipiravir, galidesivir, ledipasvir, lopinavir, lopinavir/ritonavir, levovir, tenofovir, and sofosbuvir, and combinations thereof. Additional therapies that may be used in combination with the therapies disclosed herein include but are 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 particular, the additional therapies that may be used in combination with the therapies disclosed herein include 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, abiraterone acetate, ABX464, abibertinib, acalabrutinib, ACE2-Fc, ACE-MAB (STI-4920, CMAB020), acetylsalicylic acid, acetaminophen, ACT-20, Actemra, Actemra/RoActemra, 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, Amnioboost, Ampion, altretamine, amiodarone, 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, 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, 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, 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, EB-05, EB-201, ebastine, eculizumab, EDP-1815, efineptakin alfa, emapalumab, emtricitabine, ensifentrine, ENU-200, enoxaparin, enzalutarnide, epaspire, etanercept, etoposide, eravacycline, famotidine, finasteride, fingolimod, flebogamma (IGIV31), fluvoxarnine, foalumab (NI-0401, TZLS-401), fostamatinib, flutarnide, FSD-201, FW1022, FT516, 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, 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, sarilumab, K-NK-1D101, KTH- 222, 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, 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, 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, octagam, olokizumab, omeprazole, onapristone, opaganib, OP-101, OT-101 (trabedersen), otilimab, ozanimod, paclitaxel, pacritinib, panaphix, pamrevlumab, paracetamol, PAXLOVID ^TM , 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, 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, SARS-CoV-2 antibodies, SARS-Co V-2 monoclonal antibodies, SARS-Co V-2 poly clonal antibodies, SARS-Co V-2 neutralizing antibodies, 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, 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, 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, XAV-19, Xpro-1595, XRx-101, zanubrutinib, zilucoplan, and zinc, and combinations thereof. In certain embodiments, pharmaceutical compositions disclosed herein can be administered once a day in an effective amount to a patient in need thereof for 1 to 50 days after clinical signs of disease are observed. In certain embodiments, pharmaceutical compositions disclosed herein can be administered once a day in an effective amount to a patient in need thereof for 1 to 25 days after clinical signs of disease are observed. In certain embodiments, pharmaceutical compositions disclosed herein can be administered once a day in an effective amount to a patient in need thereof for 1 to 14 days after clinical signs of disease are observed. In certain embodiments, pharmaceutical compositions disclosed herein can be administered once a day in an effective amount to a patient in need thereof for 1 to 7 days after clinical signs of disease are observed. In certain embodiments, pharmaceutical compositions disclosed herein can be administered once a day in an effective amount to a patient in need thereof for 1 to 5 days after clinical signs of disease are observed. In certain embodiments, pharmaceutical compositions disclosed herein can be administered twice a day in an effective amount to a patient in need thereof for 1 to 50 days after clinical signs of disease are observed. In certain embodiments, pharmaceutical compositions disclosed herein can be administered twice a day in an effective amount to a patient in need thereof for 1 to 25 days after clinical signs of disease are observed. In certain embodiments, pharmaceutical compositions disclosed herein can be administered twice a day in an effective amount to a patient in need thereof for 1 to 14 days after clinical signs of disease are observed. In certain embodiments, pharmaceutical compositions disclosed herein can be administered twice a day in an effective amount to a patient in need thereof for 1 to 7 days after clinical signs of disease are observed. In certain embodiments, pharmaceutical compositions disclosed herein can be administered twice a day in an effective amount to a patient in need thereof for 1 to 5 days after clinical signs of disease are observed. In certain embodiments, pharmaceutical compositions disclosed herein can be administered once every other day in an effective amount to a patient in need thereof for 1 to 50 days after clinical signs of disease are observed. In certain embodiments, pharmaceutical compositions disclosed herein can be administered once every other day in an effective amount to a patient in need thereof for 1 to 25 days after clinical signs of disease are observed. In certain embodiments, pharmaceutical compositions disclosed herein can be administered once every other day in an effective amount to a patient in need thereof for 1 to 14 days after clinical signs of disease are observed. In certain embodiments, pharmaceutical compositions disclosed herein can be administered once every other day in an effective amount to a patient in need thereof for 1 to 7 days after clinical signs of disease are observed. In certain embodiments, pharmaceutical compositions disclosed herein can be administered once every other day in an effective amount to a patient in need thereof for 1 to 5 days after clinical signs of disease are observed. In certain embodiments, pharmaceutical compositions disclosed herein can be administered in an effective amount to a patient in need thereof greater than or equal to 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20 days after clinical signs of disease are observed. In certain embodiments, pharmaceutical compositions disclosed herein can be administered in an effective amount to a patient in need thereof resulting in 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100% protection of a population. Such protection of the population can be obtained when administered in an effective amount to a patient in need thereof greater than or equal to 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 days after clinical signs of disease are observed. 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-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-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. 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 ^TM ]); and the agent anegrilide [Agrylin ^TM ]; 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-ami ne (erlotinib), and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinoprop oxy)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 ocvβ3 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. 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 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, ocular, 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 Carbopol ^TM ); 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 occurring β-D nucleosides), cis (with both groups "down", which is a nonnaturally occurring 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 occurring configuration. Likewise, most amino acids are chiral (designated as L or D, wherein the L enantiomer is the naturally occurring 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 occurs as a result of the non-racemic chiral nature of the membrane that allows only one enantiomer of the racemate to pass through. Chiral chromatography, including 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, carfilzomib, 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, polygonum cuspidatum, 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, 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, AT-511, AT-527, atazanavir, atripla, balapiravir, baloxivir marboxil, BCX4430/Galidesivir, boceprevir, cidofovir, combivir, daclatasvir, darunavir, dasabuvir, delavirdine, didanosine, docosanol, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, fomivirsen, fosamprenavir, foscarnet, fosfonet, ganciclovir, GS-441524, GS-5734/Remdesivir, 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, tipranavir, trifluridine, trizivir, tromantadine, truvada, valaciclovir, valganciclovir, vicriviroc, vidarabine, viramidine zalcitabine, zanamivir, or zidovudine and combinations thereof. In certain embodiments, the exemplary compounds and pharmaceutical compositions can be administered in combination with another agent(s) such as chloroquine, chloroquine phosphate, hydroxychloroquine, hydroxychloroquine sulfate, Ampligen, APN01, Ganovo, IFX- 1, BXT-25, CYNK-001, Tocilizumab, Leronlimab, Ii-key, COVID-19 S-Trimer, Camrelizumab, thymosin, Brilacidin, INO-4800, Prezcobix, cobicistat, mRNA-1273, Arbidol, umifenovir, REGN3048, REGN3051, TNX-1800, fingolimod, methylprednisolone, nitazoxanide, benzopurpin B, C-467929, C-473872, NSC-306711, N-65828, C-21, CGP-42112A, L-163491, xanthoangelol, or bevacizumab and combinations thereof. In certain embodiments, the exemplary compounds and pharmaceutical compositions disclosed herein can be administered in combination with any of the compounds disclosed in: WO2003090690A2, WO2003090690A3, WO2003090691A2, WO2003090691A3, WO2004005286A2, WO2004005286A3, WO2004006843A2, WO2004006843A3, WO2004031224A2, WO2004031224A3, WO2004035576A2, WO2004035576A3, WO2004035577A2, WO2004035577A3, WO2004050613A2, WO2004050613A3, WO2004064845A1, WO2004064846A1, WO2004096286A2, WO2004096286A3, WO2004096287A2, WO2004096287A3, WO2004096818A2, WO2004096818A3, WO2004100960A2, WO2005002626A2, WO2005002626A3, WO2005012324A2, WO2005012324A3, WO2005028478A1, WO2005039552A2, WO2005039552A3, WO2005042772A1, WO2005042773A1, WO2005047898A2, WO2005047898A3, WO2005063744A2, WO2005063744A3, WO2005063751A1, WO2005064008A1, WO2005064008A9, WO2005066189A1, WO2005070901A2, WO2005070901A3, WO2005072748A1, WO2005117904A2, WO2005117904A3, WO2006015261A2, WO2006015261A3, WO2006017044A2, WO2006017044A3, 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CN1911963, CN1903878, WO2006095180, WO2006086561, CN1664100, CN1660912, WO2006051091, WO2006051091, CN1673231, US20060240551, WO2005054469, WO2005060520, US20050106563, US20050069869, WO2005012360, CN1566155, WO2005007671, WO2005058815, WO2017095875, WO200505824, WO2011072487, WO2016180335, WO2004096852, WO2005097165, US20090053173, CN101942026, CN101173275, CN1648249, US20050004063, JP2007043942, WO2005023083, US20060039926, WO2005081716, WO2015081155, WO2010063685, US20070003577, US20060002947, WO2015042373, WO2017070626, WO2018048937A1, WO2019200005A1, WO2020117966A1 , or WO2019173310, each of which is incorporated by reference herein for their teachings of exemplary compounds and pharmaceutical compositions that can be administered in combination with any of the compounds disclosed herein. Specific examples of agents include abacavir, acyclovir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, AT-511, AT-527, atazanavir, atripla, balapiravir, baloxivir marboxil, BCX4430/Galidesivir, boceprevir, cidofovir, combivir, daclatasvir, darunavir, dasabuvir, delavirdine, didanosine, docosanol, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, favipiravir, fomivirsen, fosamprenavir, foscarnet, fosfonet, ganciclovir, GS-41524, GS-5734/Remdesivir, ibacitabine, imunovir, idoxuridine, imiquimod, indinavir, inosine, interferon type III, interferon type II, interferon type I, lamivudine, ledipasvir, lopinavir, loviride, maraviroc, CD24Fc, 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, zidovudine, or chloroquine, chloroquine phosphate, hydroxychloroquine, hydroxychloroquine sulfate, Ampligen, APN01, Ganovo, IFX-1, BXT-25, CYNK-001, Tocilizumab, Leronlimab, Ii- key, COVID-19 S-Trimer, Camrelizumab, thymosin, Brilacidin, INO-4800, Prezcobix, cobicistat, mRNA-1273, Arbidol, umifenovir, REGN3048, REGN3051, TNX-1800, fingolimod, methylprednisolone, nitazoxanide, benzopurpin B, C-467929, C-473872, NSC-306711, N- 65828, C-21, CGP-42112A, L-163491, xanthoangelol, bevacizumab, polyclonal antibodies derived from patients and monoclonal antibodies (including those antibodies from patients of COVID-19 or monoclonal or polyclonal antibodies which bind SARS-CoV-2), and combinations thereof. In addition, the compounds of this invention can be combined with compounds that are favorable to preventing lung damage associated with COVID-19, including for example anti-IL- 6 and TNF inhibitors, specifically including for example , tocilizumab (Actemra), siltuximab (Sylvant), Tocilizumab, Sarilumab, olokizumab (CDP6038), elsilimomab, BMS-945429 (ALD518), sirukumab (CNTO 136), levilimab (BCD-089), and CPSI-2364 and ALX-0061, ARGX-109, FE301, FM10, infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), and golimumab (Simponi), etanercept (Enbrel), Thalidomide (Immunoprin) and its derivatives lenalidomide (Revlimid) and pomalidomide (Pomalyst, Imnovid), xanthine derivatives (e.g. pentoxifylline) and bupropion and 5-HT, agonist hallucinogens including (R)- DOI, TCB-2, LSD and LA-SS-Az. In embodiments, the disclosed compounds and pharmaceutical compositions can be administered in combination with In embodiments, the disclosed compounds and pharmaceutical compositions can be administered in combination with one or more AT-527, CD24Fc, EXAMPLES Example 1. Conjugate Preparation Mono and diphosphate prodrugs have been prepared by several groups. See Jessen et al., Bioreversible Protection of Nucleoside Diphosphates, Angewandte Chemie-International Edition English 2008, 47 (45), 8719-8722, hereby incorporated by reference. In order to prevent rupture of the P-O-P anhydride bond, one utilizes a pendant group that fragments rapidly (e.g. bis-(4- acyloxybenzyl)-nucleoside diphosphates (BAB-NDP) that is deacylated by an endogenous esterase) to generate a negative charge on the second phosphate. See also Routledge et al., Synthesis, Bioactivation and Anti-HIV Activity of 4-Acyloxybenzyl-bis(nucleosid-5'-yl) Phosphates, Nucleosides & Nucleotides 1995, 14 (7), 1545-1558 and Meier et al., Comparative study of bis(benzyl)phosphate triesters of 2',3'-dideoxy-2',3'-didehydrothymidine (d4T) and cycloSal-d4TMP -hydrolysis, mechanistic insights and anti-HIV activity, Antiviral Chemistry and Chemotherapy 2002, 13,101-114, both hereby incorporated by reference. Once this occurs, the P-O-P anhydride bond is less susceptible to cleavage and the remaining protecting group can then do its final unraveling to produce the nucleoside diphosphate. Standard coupling conditions are used to prepare sphingolipid- nucleoside monophosphate prodrugs. The corresponding diphosphate prodrugs may be prepared according to the protocols as provided in Smith et al., Substituted Nucleotide Analogs. U.S. Patent Application 2012/0071434; Skowronska et al., Reaction of Oxophosphorane-Sulfenyl and Oxophosphorane-Selenenyl Chlorides with Dialkyl Trimethylsilyl Phosphites - Novel Synthesis of Compounds Containing a Sulfur or Selenium Bridge Between 2 Phosphoryl Centers, Journal of the Chemical Society-Perkin Transactions 11988, 8, 2197-2201; Dembinski et al., An Expedient Synthesis of Symmetrical Tetra-Alkyl Mono-thiopyrophosphates, Tetrahedron Letters 1994, 35 (34), 6331-6334; Skowronska et al., Novel Synthesis of Symmetrical Tetra-Alkyl Monothiophosphates, Tetrahedron Letters 1987, 28 (36), 4209-4210; and Chojnowski et al., Methods of Synthesis of O,O-Bis TrimethylSilyl Phosphorothiolates. Synthesis-Stuttgart 1977, 10, 683-686, all hereby incorporated by reference in their entirety. Example 2. General Procedure for Base Coupling The persilylated nucleobase was prepared in a round bottom flask charged with dry nucleobase (15.5 mmol), chlorotrimethylsilane (12.21 mmol), and bis(trimethylsilyl)amine (222 mmol) under nitrogen. The mixture was refluxed with stirring overnight (16 h) until all solids dissolved. The mixture was cooled to room temperature and volatiles were removed by rotary evaporation followed by high vacuum to give persilylated nucleobase. This compound was used immediately in the next step. The freshly prepared persilylated nucleobase (15.50 mmol) was dissolved in 1,2- dichloroethane (50 mL) or chlorobenzene (50 mL) under nitrogen with stirring at room temperature. A solution of D-ribofuranose 1,2,3,5-tetraacetate (7.75 mmol) in 1,2- dichloroethane (50 mL) or chlorobenzene (50 mL) was added all at once to the stirred mixture. To this mixture was added SnCl4 (11.63 mmol) dropwise via syringe, and the mixture was stirred at room temperature 6 h until all starting material was consumed. The mixture was cooled to 0°C and a sat. aq. NaHCO3 solution (125 mL) was added. The mixture was warmed to room temperature and stirred 30 min. The mixture was extracted with EtOAc (2 x 200 mL) and the combined organic layers were washed with brine (1 x 100 mL), dried over Na2SO4, filtered, and concentrated by rotary evaporation to give 5.5 g crude product. The crude material was taken up in dichloromethane, immobilized on Celite, and subjected to flash chromatography to provide the desired acetate protected product. The ribonucleoside was deprotected using the general deprotection conditions. Example 3. General Cytosine Analog Coupling In a flask charged with N ⁴ -benzoyl protected cytosine analog (0.793 mmol) was added bis(trimethylsilyl)amine (8.45 mmol) and ammonium sulfate (0.02 mmol) under N2. This was heated at reflux for 2 h, after cooling to rt, solvent was removed in vacuo and further dried under high vacuum for 1 h. The residue was dissolved in dry chlorobenzene (10 ml) and D- or L- ribofuranose 1,2,3,5-tetraacetate (0.53 mmol) was added. Then SnCl ₄ (0.27 ml, 2.3 mmol) was added dropwise. After stirring at rt for 1 h, this was heated to 60 ^o C overnight. After cooling to 0 ^o C, solid sodium bicarbonate (0.85 g) was added, followed by EtOAc (5 mL). This was allowed to stir for 15 min and then water (0.5 mL) was added slowly. The insoluble material was filtered off and washed wtih more EtOAc (2.5 mL). The filtrate was washed with water once, bine once, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude material was purified by SiO ₂ column chromatography. Example 4. General Deamination Conditions A solution of benzoyl protected cytidine ribonucleoside (1.02 mmol) in 80% aqueous AcOH (30 mL) was heated under reflux for 16 h. The solvent was then removed in vacuo and dried under high vacuum. The white solid was triturated with ether, filtered off and washed with more ether to obtain the desired product. Example 5. General Uracil Analog Coupling The persilylated uracil was prepared in a round bottom flask charged with uracil (15.5 mmol), chlorotrimethylsilane (12.21 mmol), and bis(trimethylsilyl)amine (222 mmol) under nitrogen. The mixture was refluxed with stirring overnight (16 h) until all solids dissolved until a clear colorless solution formed. The mixture was cooled to room temperature and volatiles were removed by rotary evaporation followed by high vacuum to give persilylated uracil. This compound was used immediately in the next step. The freshly prepared persilylated uracil (15.50 mmol) was dissolved in 1,2- dichloroethane (50 mL) under nitrogen with stirring at room temperature. A solution of D- or L- ribofuranose 1,2,3,5-tetraacetate (7.75 mmol) in 1,2-dichloroethane (50 mL) was added all at once to the stirred mixture. To this mixture was added SnCl ₄ (11.63 mmol) dropwise via syringe, and the mixture was stirred at room temperature 6 h until all starting material was consumed. The mixture was cooled to 0°C and a sat. aq. NaHCO ₃ solution (125 mL) was added. The mixture was warmed to room temperature and stirred 30 min. The mixture was extracted with EtOAc (2 x 200 mL) and the combined organic layers were washed with brine (1 x 100 mL), dried over Na2SO4, filtered, and concentrated by rotary evaporation to give 5.5 g crude product. The crude material was taken up in dichloromethane, immobilized on Celite, and subjected to flash chromatography on the Combiflash (120 g column, 5 to 50% EtOAc in hexanes gradient) to provide the product. Example 6. General Acetate or Benzoyl Deprotection Conditions Benzoyl protected ribonucleoside analog (0.25 mmol) was stirred with 7 N ammonia in MeOH at rt for 15.5 h. The solvent was then removed and the crude material was purified by SiO2 column chromatography to obtain the desired ribonucleoside. Example 7. Synthesis of 1’-Deuterated Nucleoside Analogs The lactone (0.0325 mol) was added to a dry flask under an argon atmosphere and was then dissolved in dry THF (250 mL). The solution as then cooled to -78˚C and a DIBAL-D solution in toluene (0.065 mol) was dropwise. The reaction was allowed to stir at -78˚C for 3-4 hours. The reaction was then quenched with the slow addition of water (3 mL). The reaction was then allowed to stir while warming to room temperature. The mixture was then diluted with two volumes of diethyl ether and was then poured into an equal volume of saturated sodium potassium tartrate solution. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified on silica eluting with hexanes/ethyl acetate. The resulting lactol was then converted to an acetate or benzolyate and subjected to base coupling conditions to introduce the desired nucleobase.

Example 8. A 1 L rbf was charged with uridine (36.6 g, 150 mmol) and acetone (Volume: 700 ml) with stirring under nitrogen at rt. The slurry was treated with concentrated sulfuric acid (0.800 ml, 15.00 mmol) and the mixture was stirred at rt overnight. After stirring 16 h, triethylamine (41.8 ml, 300 mmol) was added all at once, the mixture was stirred 30 min, and then concentrated by rotary evaporation to give a sticky white solid. The solid was dissolved in boiling iPrOH (~1.4 L) and allowed to cool overnight at rt. After cooling overnight, small crystals had formed. The flask was placed in the freezer for 3 h and more crystals formed. The mixture was vacuum filtered, and the solids were washed with ice-cold iPrOH (2 x 200 mL) and ice-cold ether (2 x 200 mL). The solid was recovered to give compound 1 (21.75 g, 77 mmol, 51.0 % yield) as a white powdery solid. A round bottom flask was charged with compound 1 (21.75 g, 77 mmol) and DCM (219 ml) and the mixture was stirred under nitrogen. Solid 4-DMAP (23.37 g, 191 mmol) was added all at once, and the mixture was stirred at rt until all solids dissolved. The mixture was cooled to 0°C, and tosyl chloride (17.50 g, 92 mmol) was added portionwise as a solid over 5 min. The mixture was stirred at rt for 1 h until all starting material was consumed. The mixture was transferred to a separatory funnel, and the organic layer was washed with 1 N HCl (2 x 200 mL), sat. aq. NaHCO3 (1 x 200 mL), and brine (1 x 200 mL), then dried over Na2SO4, filtered and concentrated by rotary evaporation to give compound 2 (34.52 g, 74.8 mmol, 98 % yield) as a white solid. To a stirred solution of compound 2 (3.95 g, 9.01 mmol) in THF (30 mL) at 0°C under nitrogen. Solid potassium tert-butoxide (3.03 g, 27.0 mmol) was added all at once, the reaction mixture turned into a yellow slurry. The mixture was stirred at 0°C for 2 h. Silica gel (6 g) and Celite (14 g) were added along with more THF, and the mixture was concentrated by rotary evaporation. Flash chromatography on the Isco (80 g column, 1 to 5% MeOH in DCM) gave compound 3 (2.17 g, 8.15 mmol, 90 % yield) as a white powdery solid. A round bottom flask was charged with a stir bar, compound 3 (2.17 g, 8.15 mmol), silver(I) fluoride (5.17 g, 40.8 mmol), and DCM (Volume: 152 ml, Ratio: 14) at 0°C. To this vigorously stirred mixture was added a solution of iodine (4.14 g, 16.30 mmol) in THF (Volume: 10.87 ml, Ratio: 1.000) dropwise via syringe over 40 min. After addition was complete, the mixture was stirred another 15 min at 0°C, then a 1:1 mixture of sat. aq. NaHCO3:sat. aq. Na ₂ S2O ₃ was added (75 mL) and the whole mixture was filtered through a Celite pad, washing with DCM (2 x 50 mL). The filtrates were transferred to a separation funnel, and the organic layer was dried over Na ₂ SO ₄ , filtered, and concentrated by rotary evaporation to give 4 g. Flash chromatography on the Isco (120 g column, 5 to 25% EtOAc in DCM) gave compound 4 (2.06 g, 5.00 mmol, 61.3 % yield) as a pale yellow flaky solid. A round bottom flask was charged with compound 4 (10.76 g, 26.1 mmol), tetrabutylammonium sulfate (8.86 g, 26.1 mmol), potassium hydrogen phosphate dibasic trihydrate (8.94 g, 39.2 mmol), DCM (Volume: 1088 ml, Ratio: 5) and water (Volume: 218 ml, Ratio: 1.000) and the biphasic mixture was stirred vigorously at rt. To this mixture was added solid mCPBA, 77% w/w (29.3 g, 131 mmol) all at once and the mixture was stirred at rt overnight. After stirring 20 h at rt, all SM had been consumed by TLC analysis. The mixture was quenched by slow addition of sat. aq. Na ₂ S ₂ O ₃ (375 mL) followed by sat. aq. Na ₂ CO ₃ (375 mL). The organic layer was removed, and the aqueous layer was extracted with DCM (1 x 450 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated by rotary evaporation to give 22 g crude. The crude was taken up in DCM, and flash chromatography on the Isco (330 g column, 5 to 25% EtOAc in DCM) gave 10 g of semipure product. The compound was taken up in DCM, and flash chromatography on the Isco (330 g column, 5 to 70% EtOAc in hexanes) gave compound 5 (6.91 g, 15.68 mmol, 60.0 % yield) as an off-white flaky solid. A round bottom flask was charged with compound 5 (3.53 g, 8.0 mmol) and ammonia in MeOH (34.3 ml, 240 mmol) at 0°C. The mixture was stirred for 5 h, at which point all starting material was consumed. The mixture was concentrated by rotary evaporation to give ~4 g crude as a yellow oil. The crude was taken up in DCM, and flash chromatography on the Isco (120 g column, 1 to 5% MeOH in DCM) gave compound 6 (2.20 g, 7.28 mmol, 91 % yield) as a white powdery solid. A 1L 3-neck RBF equipped with temperature probe, overhead stirrer and additiion funnel (argon inlet) was charged with phosphorus oxychloride (15.50 ml, 166 mmol) in THF (300 ml), evacuated and purged with argon 3x, then cooled to <-70°C using dry ice/acetone. A solution of 2-(hydroxymethyl)phenol (18.77 g, 151 mmol) and triethylamine (44.3 ml, 317 mmol) in 200mL of THF was slowly added via addition funnel over 30minutes. The resulting light tan mixture was slowly warmed to RT and stirred for 3hrs. Cooled to 0°C using an ice bath and added triethylamine (25.3 ml, 181 mmol), then slowly added a THF (100mL) solution of 2,3,4,5,6- pentafluorophenol (25.05 g, 136 mmol) to the rapidly stirred mixture. Warmed to RT and monitored by TLC (25% EtOAc/hexanes). SM consumed in <2hrs, only product (Rf = 0.5) present. The oil was purified by SGC (glass column, 10-25% EtOAc/hexanes), fractions containing product were pooled and concentrated under reduced pressure to yield compound 7 (41.2 g, 117 mmol, 77 % yield) as a white solid. To a stirred solution of compound 6 (1.95 g, 6.45 mmol) in THF (Volume: 96 ml, Ratio: 5) at 0°C under nitrogen, was added a solution of tert-butylmagnesium chloride, 1.0 M in THF (14.19 ml, 14.19 mmol) dropwise via syringe. A white precipitate formed; the mixture was warmed to rt and stirred for 30 min, then recooled to 0°C. A solution of compound 7 (5.68 g, 16.13 mmol) in THF (Volume: 19.20 ml, Ratio: 1.000) was added dropwise via syringe, and the mixture was warmed to rt and stirred overnight. After 18 h stirring, a little SM remained and one slightly less polar product had formed. The mixture was quenched by addition of solid NH ₄ Cl (2 g) and the mixture was immobilized on Celite. Flash chromatography on the Isco (220 g column, 1 to 5% MeOH in DCM) gave 1.94 g of a white solid that consisted of desired product and pentafluorophenol. The solid was taken up in DCM and washed with sat. aq. NaHCO3 (3 x 100 mL). The organic layer was dried over Na ₂ SO ₄ , filtered, and concentrated by rotary evaporation to give compound 8 (1.70 g, 3.61 mmol, 56.0 % yield) as a white powdery solid. A round bottom flask was charged with compound 8 (.250 g, 0.532 mmol) and formic acid, 80% aq. (Volume: 10 mL). The mixture was stirred at rt under nitrogen overnight. After stirring 20 h, all volatiles were removed by rotary evaporation. The residue was taken up in MeOH and immobilized on Celite. Flash chromatography on the Isco (24 g column, 1 to 15% MeOH in DCM) gave a white powdery solid, 175 mg, 90-95% pure by NMR. The white powder was taken up in a 5:1 water:MeCN mixture, and reverse phase flash chromatography on the Isco (100 g C18 column, 100% water to 100% MeCN) gave good separation of the impurity. The fractions containining desired product were concentrated, taken up in 5:1 water:MeCN, frozen in a dry ice bath, and lyophilized to provide compound 9, EIDD-02838. Example 9. Uridine (1 mmol) was suspended in dioxane (4 mL) followed by the addition of pyridine (2 mmol), PPh ₃ (1.5 mmol), and iodine (1.5 mmol) under an argon atmosphere. The mixture was stirrd at room temperature overnight. The reaction mixture was quenched with methanol and saturated aqueous Na ₂ S ₂ O ₃ and was then evaporated to dryness to provide crude compound 10, which was used directly in the next step. Crude compound 10 was dissolved in dry DMF under an argon atmosphere followed by the addition of imidazole (5 equivalents) and TBSCl (4 equivalents) at 0°C. The mixture was allowed to warm to room temperature and stir overnight. The reaction mixture was partitioned between AcOEt/H ₂ O (3:1). The organic layer was dried over MgSO ₄ , filtered, and concentrated under reduced pressure. The resulting residue was purified on a silica gel column eluting with hexanes and etheyl acetate to provide compound 11. Compound 11 was dissolved in dry MeCN and treated with DBN (2.25 equivalents) at 0°C under an argon atmosphere. The reaction was allowed to stir overnight. The reaction mixture was neutralized with AcOH and then was evaporated to dryness. The residue was partitioned between DCM and saturated aqueous NaHCO ₃ . The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified on a silica gel column eluting with hexanes and etheyl acetate to provide compound 12. To a solution of compound 12 in dry DCM (20 mL/mmol 12) was added DMDO (0.1M in acetone, 1.2 equivalents) at -30°C under an argon atmosphere. The reaction was allowed to stir for 1 hour and was then evaporated to dryness to afford compound 13, which was used immediately in the next step. To a solution of compound 13 in dry DCM (20 mL/mmol 13) was added SnCl4 (3 equivalents) at -30°C under an argon atmosphere. The misture was allowed to stir for 1 hour and was then quenched with saturated aqueous NaHCO3. The mixture was filtered through a celite pad, and the filtrate was partitioned between DCM and saturated aqueous NaHCO3. The organic layer was dried over MgSO ₄ , filtered, and concentrated under reduced pressure. The resulting residue was purified on a silica gel column eluting with hexanes and etheyl acetate to provide compounds 14 and 15 in a 2:1 ratio. Compound 15 was treated with TBAF (2.5 equivalents) in THF. After starting material was consumed, the reaction mixture was concentrated under reduced pressure and purified by reverse phase to obtain compound 16. Compound 15 was treated under the same conditions as compound 6 followed by treatment with TBAF to obtain compound 17. Example 10. A round bottom flask was charged with compound 5 (.250 g, 0.567 mmol) and formic acid, 80% aq. (Volume: 10 mL). The mixture was stirred at room temperature under nitrogen overnight. After stirring 20 h, all volatiles were removed by rotary evaporation. The residue was taken up in MeOH and immobilized on Celite. Flash chromatography on the Isco (24 g column, 1 to 15% MeOH in DCM) gave a white powdery solid 90-95% pure by NMR. The white powder was taken up in a 5:1 water:MeCN mixture, and reverse phase flash chromatography on the Isco (100 g C18 column, 100% water to 100% MeCN) gave good separation of the impurity. The fractions containining desired product were concentrated, taken up in 5:1 water:MeCN, frozen in a dry ice bath, and lyophilized to provide compound 18. A round bottom flask was charged with compound 18 (3.53 g, 8.8 mmol) and ammonia in MeOH (34.3 ml, 240 mmol) at 0°C. The mixture was allowed to stir for 5 hours, at which point all starting material was consumed. The mixture was concentrated by rotary evaporation to give ~4 g crude as a yellow oil. The crude was taken up in DCM, and flash chromatography on the Isco (120 g column, 1 to 5% MeOH in DCM) gave compound 19, EIDD-02749, (2.20 g, 7.28 mmol, 91 % yield) as a white powdery solid. Example 11. Nucleoside was suspended in methylene chloride (40 mL, partially soluble). After stirring at rt for 30 min the mixture was treated sequentially with PDC, acetic anhydride and then tert-butanol. The mixture was allowed to stir at room temperature. TLC (5% methanol in DCM) and LCMS indicated only a small amount of remaining starting material at 4 hours. The mixture was filtered through a pad of silica gel that was loaded into a 150 mL fritted funnel. The silica was eluted with ethyl acetate. The collected filtrate was concentrated by under reduced pressure. The crude dark oil was purified by chromatography over silica gel (25 mm x 175 mm) with 2:1 hexanes:ethyl acetate to ethyl acetate gradient. The pure fractions were collected and concentrated under reduced pressure to give of a white gum. The material was placed under high vacuum for 2 days. The material was used in the next step without further purification. The 5’-protected nucleoside was dissolved in 200 proof ethanol and was then treated with solid sodium borodeuteride. The mixture became homogeneous and was then heated to 80°C. After 12h, a white/pale yellow precipitate formed. The mixture was allowed to cool to rt. TLC (5% methanol in methylene chloride) indicates complete conversion of starting material. The mixture was cooled to 0°C with an ice-bath and then slowly quenched with acetic acid (approximately 1 mL). The clear solution was warmed to rt and then partitioned between ethyl acetate (30 mL) and brine (3 mL). The organic phase was concentrated and then purified by chromatography over silica gel (19 mm x 180 mm) using a mobile phase of 5% methanol in methylene chloride to provide the product. Example 12. 124 Prepared according to Boumendjel, Ahcene and Miller, Stephen Journal of Lipid Research 1994, 35, 2305. A mixture of sphingosine (450 mg, 1.50 mmol) and di-tert-butyl dicarbonate (0.656 g, 3.01 mmol) in methylene chloride (100 mL) at 4 ^o C was treated dropwise with diisopropylethylamine (0.53 mL, 3.01 mmol). After gradual warming to rt, the mixture was stirred for an additional 12 h and then diluted with methylene chloride (100 mL) followed by a wash with water (30 mL) and brine (30 mL). The organic phase was dried over sodium sulfate, filtered and concentrated to dryness. The crude residue was purified by flash column chromatography over silica gel (19 mm x 175 mm) using 50% ethyl acetate in hexanes to give N-tert-butyloxycarbonyl-sphingosine (540 mg, 90%) as a white solid. 1H NMR (300 MHz, Chloroform-d) δ 5.77 (dt, J = 15.4, 8.4 Hz, 1H), 5.52 (dd, J= 15.4, 8.4 Hz, 1H), 3.93 (dd, J = 11.4, 3.7 Hz, 1H), 3.70 (dd, J = 11.4, 3.7 Hz, 1H), 3.59 (s, 3H), 2.05 (q, J = 7.0 Hz, 2H), 1.52 (s, 9H), 1.25 (s, 22 H), 0.87 (t, J = 6.5 Hz, 3H). Example 13. 125 N-tert-Butyloxycarbonyl-sphingosine 124(540 mg, 1.35 mmol) was rendered anhydrous by co-evaporation with anhydrous pyridine (2 x 12 mL). The residue was then dissolved in anhydrous pyridine and treated with carbon tetrabromide (622 mg, 1.88 mmol). The mixture was cooled to 0 ^o C and treated dropwise with a solution of trimethylphosphite (0.25 mL, 2.10 mmol) in anhydrous pyridine (3 mL) over a 30 min period. After an additional 12 h at rt, both LCMS and tlc (5% methanol in methylene chloride) analysis indicated complete conversion. The mixture was quenched with water (2 mL) and then concentrated to dryness. The resulting dark oil was dissolved in ethyl acetate (150 mL) and washed with 3% HCL solution ( 2 x 20 mL) followed by saturated sodium bicarbonate solution (30 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude residue was purified by flash column chromatography over silica gel (19 mm x 175 mm) using 2% methanol in methylene chloride to give N-tert-butyloxycarbonyl-sphingosine-1-O-dimethylphosphate 125 (350 mg, 51%) as a gum. 1H NMR (400 MHz, Chloroform-d) δ 5.82 (dt, J = 15.4, 7.1 Hz, 1H), 5.48 (dd, J = 15.4, 7.1 Hz, 1H), 4.99 (d, J = 8.9 Hz, 1H), 4.32 (ddd, J = 10.7, 8.0, 4.6 Hz, 1H), 4.11 (ddt, J = 10.7, 7.4, 3.1 Hz, 2H), 3.77 (dd, J = 11.1, 2.1 Hz, 6H), 2.01 (q, J = 7.1 Hz, 2H), 1.41 (s, 9H), 1.34 (m, 2H), 1.23 (m, 20H), 0.86 (t, J = 6.4 Hz, 3H). 3 ¹ P NMR (162 MHz, Chloroform-d) δ 2.00. MS C17H25NO4 [M+Na+]; calculated: 330.2, found: 330.2. Example 14. A solution ofN-tert-butyloxycarbonyl-sphingosine-1-O-dimethylphosphate 125 (350 mg, 0.689 mmol) in anhydrous methylene chloride (8 mL) was treated dropwise with trimethylsilyl bromide (0.45 mL, 3.45 mmol) at 0 ^o C. After warming to room temperature, the mixture was allowed to stir at rt for 6h and then concentrated to dryness. The resulting residue was co- evaporated with methylene chloride to remove excess trimethylsilyl bromide and then treated with 66% aqueous THF (6 mL). The resulting precipitate was collected by filtration to give sphingosine-1-phosphate 126 (218 mg, 83%) as a white solid. 1H NMR (400 MHz, Methanol-d4+ CD3CO2D) δ 5.84 (dt, J = 15.5, 6.7 Hz, 1H), 5.46 (dd, J = 15.5, 6.7 Hz, 1H), 4.33 (t, J = 6.0 Hz, 1H), 4.13 (ddd, J = 11.8, 7.7, 3.6 Hz, 1H), 4.03 (dt, J = 11.8, 8.4 Hz, 1H), 3.47 (ddd, J = 8.3, 4.8, 3.2 Hz, 1H), 2.10 – 1.99 (m, 2H), 1.37 (m, 2H), 1.24 (m, 20H), 0.83 (t, J = 6.4 Hz, 3H). 3 ¹ P NMR (162 MHz, Chloroform-d) δ 0.69. MS C18H38NO5P [M-H ⁺ ]; calculated: 378.2, found: 378.2. Example 15. To a slurry of phytosphingosine (4 g, 12.6 mmol) and anhydrous powdered potassium carbonate (5.22 g, 37.8 mmol) in methylene chloride (85 mL) was added trifluoroacetic anhydride (1.96 mL, 13.9 mmol). The mixture was stirred at rt for 18 h and then diluted with methylene chloride (500 mL). The mixture was washed with water (100 mL). Methanol (60 mL) was added to break the emulsion. The organic phase was then dried over sodium sulfate, filtered and concentrated to give 131 (4.9 g, 94 %) as a white solid 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.90 (s, 1H), 4.90 – 4.68 (m, 1H), 4.56 (d, J = 6.1 Hz, 1H), 4.43 (s, 1H), 3.97 (d, J = 7.6 Hz, 1H), 3.65 (d, J = 10.8 Hz, 1H), 3.46 (t, J = 10.2 Hz, 1H), 3.32 – 3.16 (m, 1H), 1.42 (tt, J = 15.7, 7.5 Hz, 2H), 1.20 (s, 24H), 0.83 t, J = 6.8 Hz, 3H). Example 16. N-Trifluoroacetyl-phytosphingosine (131, 1.88 g, 4.5 mmol) in anhydrous pyridine (23 mL) was treated with DMAP (56 mg, 0.45 mmol) and then dropwise with tert-butyldiphenylsilyl chloride (1.38 g, 5.0 mmol). After 18 h concentrated to dryness. The resulting residue was dissolved in ethyl acetate (200 mL) and washed with saturated ammonium chloride (2x 50 mL) and then brine (50 mL). The aqueous phases was back-extracted with ethyl acetate (50 mL). Combined organic phases were dried over sodium sulfate and concentrated to give crude 1-O- tert-Butyldiphenylsilyl-2-N-trifluoroacetyl-phytosphingosine 132 (3g, 100%) as a gum. The material was used in the next step without further purification. 1H NMR (400 MHz, Chloroform-d) δ 7.62 (m, 2H), 7.60 – 7.56 (m, 2H), 7.47 – 7.31 (m, 6H), 7.07 (d, J = 8.4 Hz, 1H), 4.23 (dd, J = 8.5, 4.1 Hz, 1H, 4.04 (dt, J = 11.0, 2.5 Hz, 1H), 3.82 (ddd, J = 11.0, 4.3, 1.8 Hz, 1H), 3.64 (dq, J = 10.6, 6.0, 4.3 Hz, 2H), 1.45 (m, 2H), 1.39 – 1.15 (m, 24H), 1.05 (m, 9H), 0.94 – 0.80 (t, J = 6.9 Hz 3H). Example 17. A solution of 1-O-tert-Butyldiphenylsilyl-2-N-trifluoroacetyl-phytosphingo sine 132 (3g,4.5 mmol) in 1/1 (v/v) 2,2-dimethoxypropane/THF was treated with catalytic amount of p- toluenesulfonic acid (87 mg, 0.45 mmol) and allowed to stir for 16h at rt. The mixture was quenched with saturated sodium bicarbonate (30 mL) and then excess THF/2,2- dimethoxypropane was removed under vacuum. The mixture was extracted with ethyl acetate (200 mL). After washing with brine, the organic layer was dried over sodium sulfate, filtered and concentrated. The crude oil was purified by column chromatography (25 mm x 175mm) over silica gel with a hexanes/ethyl acetate mobile phase to give 133(2.45 g, 78%). 1H NMR (400 MHz, Chloroform-d) δ 7.68 – 7.63 (m, 2H), 7.63 – 7.57 (m, 2H), 7.39 (m, 6H), 6.54 (d, J = 9.4 Hz, 1H), 4.23 (dd, J = 8.2, 5.6 Hz, 1H), 4.12 (ddd, J = 13.3, 6.9, 3.8 Hz, 2H), 3.96 (dd, J = 10.5, 3.9 Hz, 1H), 3.69 (dd, J = 10.5, 2.9 Hz, 1H), 1.52 – 1.36 (m, 2H), 1.33 (s, 3H), 1.31 (s, 3H), 1.24 (m, 24H), 1.03 (s, 9H), 0.86 (t, J = 53.7, 6.9 Hz, 3H). Example 18. A solution of 1-O-tert-Butyldiphenylsilyl-3,4-O-isopropylidene-2-N-trifluo roacetyl- phytosphingosine 133 (2.45 g, 3.54 mmol)in THF (18 mL) was treated with tetrabutylammonium fluoride (4.25 mL of a 1.0 M solution in THF, 4.25 mmol) and stirred at rt for 12h. The mixture was diluted with ethyl acetate (100 mL) and saturated ammonium chloride (2 x 50 mL) and then brine (50 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated to give a white solid that was further purified by column chromatography (25 mm x 175 mm) over silica gel with a 9:1 hexanes: ethyl acetate mobile phase to afford 134(1.5g, 93%) as a white solid. 1H NMR (300 MHz, Chloroform-d) δ 6.92 (d, J = 8.7 Hz, 1H), 4.31 – 4.16 (m, 2H), 4.11 (dq, J = 11.7, 3.7 Hz, 1H), 4.00 (dd, J = 11.5, 2.6 Hz, 1H), 3.70 (dd, J = 11.5, 3.6 Hz, 1H), 1.48 (s, 3H), 1.35 (s, 3H), 1.25 (m, 26H), 0.88 (t, J = 6.9 Hz 3H). Example 19. A solution of 3,4-O-Isopropylidene-2-N-Trifluoroacetyl-phytosphingosine 134(630 mg, 1.39 mmol) was rendered anhydrous by co-evaporation with anhydrous pyridine (2 x 12 mL). The residue was then dissolved in anhydrous pyridine (12 mL) and treated with carbon tetrabromide (533 mg, 1.67 mmol). The mixture was cooled to 0 ^o C and treated dropwise with a solution of trimethylphosphite (0.23 mL, 1.95 mmol) in anhydrous pyridine (3 mL) over a 30 min period. After an additional 12 h at rt, both LCMS and tlc (5% methanol in methylene chloride) analysis indicated complete conversion. The mixture was quenched with water (2 mL) and then concentrated to dryness. The resulting dark oil was dissolved in ethyl acetate (100 mL) and washed with 3% HCL solution ( 2 x 20 mL) followed by saturated sodium bicarbonate solution (30 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude residue was purified by flash column chromatography over silica gel (19 mm x 175 mm) using 2% methanol in methylene chloride to give 135 (650 mg, 83%). 1H NMR (300 MHz, Chloroform-d) δ 7.42 (d, J = 8.8 Hz, 1H), 4.36 (td, J = 10.9, 5.0 Hz, 1H), 4.25 (m, 1H), 4.19 (m, J = 6.5, 2.0 Hz, 3H), 3.77 (dd, J = 11.2, 7.5 Hz, 6H), 1.44 (s, 3H), 1.33 (s, 3H), 1.25 (m, 26H), 0.87 (t, J = 6.6 Hz, 3H). ³¹ P NMR (121 MHz, Chloroform-d) δ 1.69. MS C ₂₅ H ₄₇ F ₃ NO ₇ P [M-H ⁺ ]; calculated: 560.3, found: 560.2. Example 20.3,4-O-Isopropylidene-2-N-trifluoroacetyl-phytosphingosine -1-phosphate (136) A solution of 3,4-O-Isopropylidene-2-N-trifluoroacetyl-phytosphingosine-1- O- dimethylphosphate 135 (650 mg, 1.16 mmol) in anhydrous methylene chloride (12 mL) was treated dropwise with trimethylsilyl bromide (0.81 mL, 6.23 mmol) at 0 ^o C. After 12h at rt, the mixture was concentrated to dryness and the resulting residue co-evaporated with methylene chloride (3 x 50 mL) to remove excess trimethylsilyl bromide. The residue then was dissolved in cold (4 ^o C) solution of 1% NH ₄ OH while maintaining pH 7-8. After 10 min at rt, the mixture was concentrated to dryness, and the resulting solid triturated with methanol/acetonitrile. The solid was collected by filtration, washed with acetonitrile, and dried under high vacuum to give 136 (500 mg, 75%) as a white solid. 1H NMR (300 MHz, Methanol-d ₄ ) δ 4.31 (dd, J = 8.7, 5.4 Hz, 1H), 4.09 (m, 4H), 1.42 (s, 3H), 1.36 (s, 3H), 1.31 (m, 26H), 0.89 (t, J = 6.4 Hz, 3H). 3 ¹ P NMR (121 MHz, Methanol-d ₄ ) δ 1.28. 1 ⁹ F NMR (282 MHz, Methanol-d4) δ -77.13. HRMS C23H42F3NO7P [M-H ⁺ ]; calculated: 532.26565, found: 532.26630. Example 21. A mixture of N-trifluoroacetyl-phytosphingosine-1-phosphate 136(200mg, 0.373 mmol) and 2’,3’-dideoxy-2’-fluoro-7-deazaguanine (100 mg, 0.373 mmol) was rendered anhydrous by co-evaporation with anhydrous pyridine (3 x 10 mL). The resulting residue then was dissolved in anhydrous pyridine (4 mL) and treated with diisopropylcarbodiimide (127 mg, 1.01 mmol) and HOBt (60 mg, 0.447 mmol). After 24 h at 75 ^o C, the reaction mixture was cooled to rt and concentrated to dryness. The crude material was purified by flash column chromatography (19 mm x 170 mm) over silica gel using a solvent gradient from 5 to 7.5% methanol in chloroform with 1% (v/v) NH ₄ OH to give 137(80 mg, 27%) as a white solid. 1H NMR (300 MHz, Methanol-d ₄ ) δ 6.88 (d, J = 3.8 Hz, 1H), 6.46 (d, J = 3.8 Hz, 1H), 6.24 (d, J = 19.9 Hz, 1H), 5.34 (dd, J = 52.4, 4.6 Hz, 1H), 4.53 (s, 1H), 4.34 – 3.97 (m, 6H), 2.63 – 2.17 (m, 2H), 1.40 (s, 3H), 1.30 (s, 3H), 1.27 (m, 26H), 0.89 (t, J = 6.6 Hz, 3H). 3 ¹ P NMR (121 MHz, Methanol-d4) δ 12.50. 1 ⁹ F NMR (282 MHz, Methanol-d4) δ -77.10 , -179.69 – -180.25 (m). MS C34H522F4N5O9P [M-H ⁺ ]; calculated: 781.3, found: 782.2. Example 22. Experimental procedure for synthesis of prodrugs A solution of isopropyl 2-((chloro(phenoxy)phosphoryl)amino)propanoate (0.397 g, 1.300 mmol) in anhydrous THF (5 ml) was added to a -78 °C stirred solution of 2’-deoxy-2’- fluoronucleoside (0.812 mmol) and 1-methyl-1H-imidazole (0.367 ml, 4.63 mmol) in pyridine (10.00 ml). After 15 min the reaction was allowed to warm to room temperature and was stirred for an additional 3 hours. Next, the solvent was removed under reduced pressure. The crude product was dissolved in 120 ml of DCM and was washed with 20 ml 1 N HCl solution followed by 10 ml water. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residues were separated over silica column (neutralized by TEA) using 5% MeOH in DCM as a mobile phase to yield the respective products as diastereomers. Example 23. N-tert-Butyloxycarbonyl-phytosphingosine (174) A suspension of phytosphingosine (10.6 g, 33.5 mmol) and triethylamine (5.6 ml, 40.2 mmol) in THF (250 mL) was treated dropwise with di-tert-butyl dicarbonate (8.6 mL, 36.9 mmol). After 12h at rt, the mixture was concentrated to dryness and the resulting white solid was recrystallized from ethyl acetate (80 mL) and then dried under high vacuum at 35 ^o C for 12h to give 174(10.5 g, 75%). 1H NMR (400 MHz, Chloroform-d) δ 5.31 (d, J = 8.5 Hz, 1H), 3.89 (d, J = 11.1 Hz, 1H), 3.83 (s, 2H), 3.74 (dd, J = 11.1, 5.2 Hz, 1H), 3.65 (d, J = 8.3 Hz, 1H), 3.61 (d, J = 3.9 Hz, 1H), 1.43 (s, 9H), 1.23 (s, 27H), 0.86 (t, J = 6.4 Hz, 3H). Example 24.2-O-tert-Butyldiphenylsilyl-1-N-tert-butyloxycarbonyl-phy tosphingosine (175) A solution of N-tert-Butyloxycarbonyl-phytosphingosine 174 (9.5 g, 22.65 mmol) and triethylamine (3.8 mL, 27.2 mmol) in anhydrous methylene chloride/DMF (120 mL/10 mL) was treated dropwise with tert-butylchlorodiphenylsilane (7 mL, 27.25 mmol). After 18h at rt, the mixture was diluted with methylene chloride (200 mL) and washed with 0.2N HCl (100 mL) and then brine (100 mL). The organic phase was dried over sodium sulfate, filtered and then concentrated to give 175 (14.9 g) as an oil which was used in the next reaction without further purification. ¹ H NMR (400 MHz, Chloroform-d) δ 5.31 (d, J = 8.5 Hz, 1H), 3.89 (d, J = 11.1 Hz, 1H), 3.83 (m, 1H), 3.74 (dd, J = 11.1, 5.2 Hz, 1H), 3.65 (d, J = 8.3 Hz, 1H), 3.61 (d, J = 3.9 Hz, 1H), 1.43 (s, 9H), 1.23 (s, 27H), 0.86 (t, J = 6.4 Hz, 3H). Example 25.2-O-tert-Butyldiphenylsilyl-1-N-tert-butyloxycarbonyl-3,4 -O-isopropylidene- phytosphingosine (176) A solution of 2-O-tert-Butyldiphenylsilyl-1-N-tert-butyloxycarbonyl-phytos phingosine (175, 14.9 g, 22.65 mmol) in 1/1 (v/v) THF/2,2-dimethoxypropane was treated with catalytic para-toluenesulfonic acid (860 mg, 4.53 mmol). After 24h, the mixture was quenched with saturated sodium bicarbonate solution (50 mL). The mixture was concentrated and then dissolved in ethyl acetate (200 mL) and washed with brine (2 x 50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated to give 176 (15.7 g) as a gum which was used in the next step without further purification. 1H NMR (400 MHz, Chloroform-d) δ 7.66 (m, 4H), 7.51 – 7.27 (m, 6H), 4.78 (d, J = 10.0 Hz, 1H), 4.18 (dd, J = 9.3, 5.5 Hz, 1H), 3.89 (dd, J = 9.9, 3.3 Hz, 1H), 3.80 (d, J = 9.9 Hz, 1H), 3.72 (d, J = 9.9 Hz, 1H), 1.45 (s, 9H), 1.42 (s, 3H), 1.35 (s, 3H), 1.25 (s, 27H), 1.05 (s, 9H), 0.87 (t, J = 6.5 Hz, 3H). Example 26.1-N-tert-butyloxycarbonyl-3,4-O-isopropylidene-phytosphin gosine (177). A solution of 2-O-tert-Butyldiphenylsilyl-1-N-tert-butyloxycarbonyl-3,4-O- isopropylidene-phytosphingosine 176 (15.7 g,22.6 mmol) in THF at 0 ^o C was treated dropwise with a solution of tetrabutylammonium fluoride (1.0 M in THF, 24.9 mL, 24.9 mmol) over a 20 min period. After 16h at rt, tlc (3:1 hexanes:ethyl acetate) indicated complete conversion. The mixture was concentrated to dryness and the resulting residue was dissolved in ethyl acetate (300 mL) and washed with water (3 x 100 mL). The organic phase was dried over sodium sulfate, filtered and concentrated. The resulting oil purified by flash column chromatography (35 mm x 180 mm) using a solvent gradient from 25 to 50% ethyl acetate in hexanes to give 177 (7.3 g, 71% over 3 steps) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 4.93 (d, J = 9.1, 1H), 4.16 (q, J = 7.1, 6.4 Hz, 1H), 4.07 (t, J = 6.5 Hz, 1H), 3.83 (dd, J = 11.1, 2.4 Hz, 1H), 3.76 (m, 1H), 3.67 (dd, J = 11.2, 3.6 Hz, 1H), 1.43 (s, 3H), 1.42 (s, 9H), 1.32 (s, 3H), 1.23 (s, 27H), 0.86 (t, J = 6.9 Hz, 3H). Example 27. General Procedure for the Preparation of 5’-Phosphoramidate Prodrugs Synthesis of chlorophosphoramidate: Thionyl chloride (80 g, 49.2 mL, 673 mmol) was added dropwise over a 30 min period to a suspension of L-alanine (50g, 561 mmol) in isopropanol (500 mL). The mixture was heated to a gentle reflux for 5h and then concentrated by rotary evaporator (bath set at 60 ^o C). The resulting thick gum solidified upon trituration with ether (150 ml). The white powder was triturated a second time with ether (150 mL), collected by filtration while under a stream of argon, and then dried under high vacuum for 18h to give (S)-isopropyl 2-aminopropanoate hydrochloride (88 g, 94%). 1H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 3H), 5.10 – 4.80 (m, 1H), 3.95 (q, J = 7.2 Hz, 1H), 1.38 (d, J = 7.2 Hz, 3H), 1.22 (d, J = 4.6 Hz, 3H), 1.20 (d, J = 4.6 Hz, 3H). Example 28. A solution of phenyl dichlorophosphate (30.9 g, 146 mmol) in dichloromethane (450 mL) was cooled to 0 ^o C then treated with (S)-isopropyl 2-aminopropanoate hydrochloride (24.5 g, 146 mmol). The mixture was further cooled to -78 ^o C and then treated dropwise with triethylamine (29.6 g, 40.8 mL, 293 mmol) over a 30 min period. The mixture continued to stir at -78 ^o C for an additional 2 h and then allowed to gradually warm to rt. After 18h the mixture was concentrated to dryness and the resulting gum dissolved in anhydrous ether (150 mL). The slurry was filtered while under a stream of argon, and the collected solid washed with small portions of anhydrous ether (3 x 30 mL). Combined filtrates were concentrated to dryness by rotary evaporator to give a 1:1 diastereomeric mixture of phosphochloridate (41.5 g, 93%) as pale yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.43 – 7.14 (m, 5H), 5.06 (m, 1H), 4.55 (dd, J = 14.9, 7.0 Hz, 1H), 4.21 – 4.01 (m, 1H), 1.48 (d, J = 7.0 Hz, 2H), 1.27 (d, J = 6.2 Hz, 3H), 1.26 (d, J = 5.8 Hz, 3H). 3 ¹ P NMR (121 MHz, Chloroform-d) δ 8.18 and 7.87. Example 29. Synthesis of 2-chloro-4-nitrophenyl phosphoramidate A solution of phenyl dichlorophosphate (60 g, 42.5 mL, 284 mmol) in dichloromethane (300 mL) was cooled to 0 ^o C and then treated with (S)-isopropyl 2-aminopropanoate hydrochloride (47.7 g, 284 mmol). The mixture was further cooled to -78 ^o C and treated dropwise with a solution of triethylamine (57.6 g, 79 mL, 569 mmol) in methylene chloride (300 mL) over a 1 h period. The reaction mixture was warmed to 0 ^o C for 30 min and then treated with a preformed mixture of 2-chloro-4-nitrophenol (46.9 g, 270 mmol) and triethylamine (28.8 g, 39.6 mL, 284 mmol) in dichloromethane (120 mL) over a 20 min period. After 2 h at 0 ^o C, the mixture was filtered through a fritted funnel, and the collected filtrate concentrated to dryness. The crude gum was dissolved MTBE (500 mL) and washed with 0.2 M K2CO3 (2 x 100 mL) followed by 10% brine (3 x 75 mL). The organic phase was dried over sodium sulfate, filtered and concentrated to dryness by rotary evaporator to give a diastereomeric mixture (100 g, 93%) as a pale yellow oil. 1H NMR (400 MHz, Chloroform-d) δ 8.33 (dd, J = 2.7, 1.1 Hz, 1H, diastereomer 1), 8.31 (dd, J = 2.7, 1.1 Hz, 1H, diastereomer 2), 8.12 (dd, J = 9.1, 2.7 Hz, 1H), 7.72 (dt, J = 9.1, 1.1 Hz, 1H), 7.40 – 7.31 (m, 2H), 7.28 – 7.19 (m, 6H), 5.01 (pd, J = 6.3, 5.2 Hz, 1H), 4.22 – 4.08 (m, 1H), 3.96 (td, J = 10.7, 9.1, 3.6 Hz, 1H), 1.43 (dd, J = 7.0, 0.6 Hz, 3H), 1.40 (dd, J = 7.2, 0.6 Hz, 3H, diastereomer 2), 1.25 – 1.20 (m, 9H). Example 30. Separation of compound 253 diastereomers The diastereomeric mixture 253 (28 g, 63.2 mmol) was dissolved in 2:3 ethyl acetate:hexanes (100 mL) and cooled to -20 ^o C. After 16 h, the resulting white solid was collected by filtration and dried under high vacuum to give a 16:1 Sp:Rp-diastereomeric mixture (5.5 g, 19.6%). The mother liquor was concentrated and the resulting residue dissolved in 2:3 ethyl acetate:hexanes (50 mL). After 16h at -10 ^o C, the resulting white solid was collected and dried under high vacuum to give a 1:6 Sp:Rp-diastereomeric mixture (4g, 14%). The 16:1 Sp:Rp- diastereomeric mixture (5.5 g, 12.4 mmol) was suspended in hot hexanes (50 mL) and treated slowly with ethyl acetate (approximately 10 mL) until complete dissolution. After cooling to 0 ^o C, the resulting white solid was collected by filtration, washed with hexanes, and dried under high vacuum to give the Sp –diastereomer of 254 (4.2 g, 76%) as a single isomer. 1H NMR (S _p -diastereomer, 400 MHz, Chloroform-d) δ 8.33 (dd, J = 2.7, 1.1 Hz, 1H), 8.12 (dd, J = 9.1, 2.7 Hz, 1H), 7.71 (dd, J = 9.1, 1.2 Hz, 1H), 7.41 – 7.30 (m, 2H), 7.29 – 7.11 (m, 3H), 5.00 (m, 1H), 4.25 – 4.07 (m, 1H), 3.97 (dd, J = 12.7, 9.4 Hz, 1H), 1.43 (d, J = 7.0 Hz, 3H), 1.23 (d, J = 2.2 Hz,3H), 1.21 (d, J = 2.2 Hz, 3H). The 1:6 S _p :R _p -diastereomeric mixture (4 g, 12.4 mmol) was suspended in hot hexanes (50 mL) and treated slowly with ethyl acetate (approximately 5 mL) until complete dissolution. After cooling to 0 ^o C, the resulting white solid was collected by filtration, washed with hexanes, and dried under high vacuum to give the R _p –diastereomer of 255 (3.2g, 80%) as a single isomer. Absolute stereochemistry was confirmed by X-ray analysis. ¹ H NMR (R _p -diastereomer , 400 MHz, Chloroform-d) δ 8.31 (dd, J = 2.7, 1.1 Hz, 1H), 8.11 (dd, J = 9.1, 2.7 Hz, 1H), 7.72 (dd, J = 9.1, 1.2 Hz, 1H), 7.42 – 7.30 (m, 2H), 7.31 – 7.14 (m, 3H), 5.01 (p, J = 6.3 Hz, 1H), 4.15 (tq, J = 9.0, 7.0 Hz, 1H), 4.08 – 3.94 (m, 1H), 1.40 (d, J = 7.0 Hz, 3H), 1.24 (d, J = 3.5 Hz, 3H), 1.22 (d, J = 3.5 Hz, 3H). Example 31. General procedure for phosphoramidate prodrug formation The desired nucleoside (1 equivalent) to be converted into its 5’-phosphoramidate prodrug was dried in a vaccum oven at 50˚C overnight. The dry nucleoside is placed in a dry flask under an inert atmosphere and suspended in either dry THF or dry DCM to achieve a 0.05M solution. The flask was then cooled to 0˚C, and the chlorophosphoramidate reagent (5 equivalents) was added to the suspended nucleoside. Next, 1-methylimidazole (8 equivalents) was added to the reaction mixture dropwise. The reaction was allowed to stir at room temperature for 12-72 hours. After the reaction was complete as judged by TLC, the reaction mixture was diluted with ethyl acetate. The diluted reaction mixture was then washed with saturated aqueous ammonium chloride solution. The aqueous layer was re-extracted with ethyl acetate. The combined organic layers were then washed with brine, dried over MgSO4, filtered, and concentrated. The concentrated crude product was then purified on silica eluting with a gradient of DCM to 5% MeOH in DCM. Example 32. General Procedure for Preparation of 5’-Triphosphates Nucleoside analogue was dried under high vacuum at 50 ^o C for 18h and then dissolved in anhydrous trimethylphosphate (0.3 M). After addition of proton-sponge® (1.5 molar equiv), the mixture was cooled to 0 ^o C and treated dropwise with phosphoryl chloride (1.3 molar equiv) via microsyringe over a 15 min period. The mixture continued stirring at 0 ^o C for 4 to 6 h while being monitored by tlc (7:2:1 isopropanol: conc. NH4OH: water). Once greater than 85% conversion to the monophosphate, the reaction mixture was treated with a mixture of bis(tri-n- butylammonium pyrophosphate) (3 molar equiv) and tributylamine (6 molar equiv) in anhydrous DMF (1 mL). After 20 min at 0 ^o C with monitoring by tlc (11:7:2 NH4OH: isopropanol: water), the mixture was treated with 20 mL of a 100 mM solution of triethylammonium bicarbonate (TEAB), stirred for 1h at rt and then extracted with ether (3 x 15 mL). The aqueous phase was then purified by anion-exchange chromatography over DEAE Sephadex® A-25 resin (11 x 200 mm) using a buffer gradient from 50 mM (400 mL) to 600 mM (400 mL) TEAB. Fractions of 10 mL were analyzed by tlc (11:7:2 NH ₄ OH: isopropanol: water). Triphosphate (eluted @ 500 mM TEAB) containing fractions were combined and concentrated by rotary evaporator (bath < 25 ^o C). The resulting solid was reconstituted in DI water (10 mL) and concentrated by lyophilization. Example 33. Synthesis of (R)-2,2,2-trifluoro-N-(1-hydroxyoctadecan-2-yl)acetamide Phytosphingosine (15.75 mmol) was dissolved in EtOH (0.5M) and ethyl trifluoroacetate (15.75 mmol) was added dropwise. NEt ₃ (24.41mmol) was added next the reaction mixture stirred overnight. The solvent was removed in vacuo and the residue was taken up in EtOAc and brine, washed, dried and concentrated. The crude material that was a white powder was good enough to use in the next step without further purification. Characterization matched literature: Synthesis, 2011, 867. Example 34. The primary alcohol (15.75 mmol), DMAP (1.575 mmol) and NEt ₃ (39.4 mmol) were dissolved in CH2Cl2 and DMF (0.18M) mixture and cooled to 0˚C. TBDPSCl (19.69 mmol) was added dropwise then the solution was allowed to warm to room temperature and stirred overnight. NH ₄ Cl solution was added to quench. The reaction mixture was extracted with EtOAc and the combined organic layers were washed with water (x2) to remove DMF. It was then dried and concentrated. A column was run to purify the mixture.10-20% EtOAc/Hex. Characterization matched literature: Synthesis, 2011, 867. Example 35. The diol (12.58 mmol), triphenylphosphine (50.3 mmol) and imidazole (50.03 mmol) were dissolved in toluene and reheated to reflux. The iodine (37.7 mmol) was then added slowly and the reaction mixture continued to be stirred at reflux. After three hours it was cooled to room temperature and 1 equivalent of iodine (12.58 mmol) was added followed by 8 equivalents of 1.5M NaOH (100.64 mmol). The reaction mixture was stirred until all the solids dissolved. The aqueous layer was removed in a separatory funnel and the organic layer was washed with Na ₂ S ₂ O ₃ solution then NaHCO ₃ solution then brine. It was dried and concentrated. A column was run to purify the mixture 0-20% EtOAc/Hex and a mixture of cis and trans was obtained but carried on to the next step. δ ¹ H NMR (400 MHz, Chloroform-d) δ 7.64 (ddt, J = 7.8, 3.8, 1.7 Hz, 4H), 7.51 – 7.35 (m, 6H), 6.68 (dd, J = 16.0, 8.2 Hz, 1H), 5.6 – 5.40 (m, 2H), 4.57 – 4.46 (m, 1H), 3.84 – 3.62 (m, 2H), 2.04 (q, J = 7.0 Hz, 1H), 1.28-1.21 (m, 24H), 1.15 – 0.98 (m, 9H), 0.90 (t, J = 6.8 Hz, 3H). HRMS: 617.38759. Example 36. The alkene (2.91 mmol) was dissolved in MeOH (0.1M) and Pd(OH) ₂ /C (0.146 mmol) was added. A Parr Hydrogenator was used at 40 psi. The palladium catalyst was carefully filtered off through celite and rinsed with EtOAc. The crude material was used in the next step and provided quantitative yield. Example 37. The silyl ether was dissolved in THF and cooled to 0⁰C then TBAF was added dropwise. After stirring for 1 hour it was warmed to room temperature. After two hours NH4Cl solution was added and it was extracted with EtOAc, washed with brine and dried and concentrated. A column was run 10-50% EtOAc/Hex. 1H NMR (400 MHz, Chloroform-d) δ 7.60 (tt, J = 7.0, 1.5 Hz, 2H), 7.48 – 7.33 (m, 4H), 3.733.61 (m, 1H), 1.24 (d, J = 3.5 Hz, 18H), 1.05 (s, 6H), 0.86 (t, J = 6.8 Hz, 3H). HRMS : 381.28546. Example 38. To 33.4 g sodium ethoxide solution (21% wt) in ethanol, diethyl malonate(15g) and then 1-bromohexadecane (31.5g) were added dropwise. After reflux for 8 hrs, ethanol was evaporated in vacuo. The remaining suspension was mixed with ice-water( 200 ml) and extracted with diethyl ether (3 X 200ml). The combined organic layers were dried over MgSO4, filtered and the filtrate was evaporated in vacuo to yield a viscous oil residue. This residue was purified by column chromatography(silica: 500 g) using hexane/diethyl ether( 12:1) as mobile phase to yield the main compound. Example 39. In a 250 mL round-bottomed flask was aluminum lithium hydride (2.503 g, 66.0 mmol) in Diethyl ether (90 ml) to give a suspension. To this suspension was added diethyl 2- hexadecylmalonate (18.12 g, 47.1 mmol) dropwise and the reaction was refluxed for 6 h. The reaction was followed up by TLC using PMA and H2SO4 as drying agents. The excess lithium aluminium hydride was destroyed by 200ml of ice-water.150 ml of 10 % H2SO4 was added to dissolve aluminium hydrate. The reaction mixture was extracted by diethyl ether (100 ml X 3). The organic layer including undissolved product was filtered. The collect solids were washed with ethyl acetate. The filtrate was dried over MgSO4, filtered and concentrated under reduced pressure. The product was purified on silica (100g) column eluting with Hexane:EtOAc (3:1) to (1:1). Example 40. To a solution of 2-hexadecylpropane-1,3-diol (7.04 g, 23.43 mmol) in 100 ml of DCM was added dropwise phosphorous trichloride (3.59 g, 23.43 mmol) dissolved in 20 ml of DCM followed by triethylamine (6.53 ml, 46.9 mmol). The reaction was refluxed for one hour. TLC analysis showed that the starting material was consumed and two new spots formed. The mixture was concentrated to dryness, dissolved in dry diethyl ether and filtered. The filtrate was concentrated to yield the crude product (8.85 g) that was used in the next step without further purification. Example 41. Synthesis of 5’-Deuterated Nucleoside Analogs The nucleoside was suspended in methylene chloride (40 mL, partially soluble). After stirring at rt for 30 min the mixture was treated sequentially with PDC, acetic anhydride and then tert-butanol. The mixture continued to stir at room temperature. TLC (5% methanol in DCM) and LCMS indicated only a small amount of remaining starting material at 4 hours. The mixture was filtered through a pad of silica gel that was loaded into a 150 mL fritted funnel. The silica was eluted with ethyl acetate. The collected filtrate was concentrated by under reduced pressure. The crude dark oil was purified by chromatography over silica gel (25 mm x 175 mm) with 2:1 hexanes:ethyl acetate to ethyl acetate gradient. The pure fractions were collected and concentrated to give of a white gum. The material was placed under high vacuum for 2 days and was used in the next step without further purification. The 5’-protected nucleoside was dissolved in 200 proof ethanol and was then treated with solid sodium borodeuteride. The mixture became homogeneous and was then heated to 80°C. After 12h, a white/pale yellow precipitate formed. The mixture was allowed to cool to rt. TLC (5% methanol in methylene chloride) indicates complete conversion of starting material. The mixture was cooled to 0°C with an ice-bath and then slowly quenched with acetic acid (approximately 1 mL). The clear solution was warmed to rt and then partitioned between ethyl acetate (30 mL) and brine (3 mL). The organic phase was concentrated and then purified by chromatography over silica gel (19 mm x 180 mm) using a mobile phase of 5% methanol in methylene chloride. Example 42. Synthesis of EIDD-02749-5’-Monophosphate (EIDD-02986) A heavy wall 350 mL round-bottomed pressure vessel was charged with 5’-(3- chlorobenzoyloxy)-4’-fluoro-2’,3’-O-isopropylideneurid ine (4.1 g, 9.3 mmol) and 7N ammonia in methanol (66 mL, 462 mmol). The mixture was stirred for 6h at room temperature after which time tlc indicated complete consumption of starting material. The mixture was concentrated in vacuo, and the resulting residue purified by column chromatography over silica gel (40 g) eluting with a methylene chloride/methanol gradient to give 4’-fluoro-2’,3’-O- isopropylideneuridine (2.5 g, 89%) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 9.24 (s, 1H), 7.23 (d, J = 8.0 Hz, 1H), 5.77 (d, J = 8.0 Hz, 1H), 5.72 (s, 1H), 5.24 (dd, J = 12.6, 6.5 Hz, 1H), 5.07 (dd, J = 6.4, 1.3 Hz, 1H), 2.50 (s, 1H), 1.59 (s, 3H), 1.38 (s, 3H). 1 ⁹ F NMR (376 MHz, Chloroform-d) δ -115.53 (dd, J = 12.4, 8.8 Hz). A solution of tristriazolide in acetonitrile was freshly prepared by treating a mixture of 1,2,4-triazole (468.91 mg, 6.79 mmol) and triethylamine (0.95 mL, 6.79 mmol) in acetonitrile (7.5 mL) dropwise with phosphorus oxychloride (0.21mL, 2.27mmol) over a 5 min period at - 15°C. After stirring for an additional 20 min at -15°C, the triethylammonium precipitate was removed by centrifuge, and the solution of tristriazolide was added to an acetonitrile solution (7.5 mL) of 4’-fluoro-2’,3’-O-isopropylideneuridine (225 mg, 0.74 mmol) at -15°C. After stirring for 15 min at -15°C, the mixture was allowed to warm to rt, and continued for another 1.5 hr. The mixture was quenched with 50 mM TEAB (30 mL), stirred for 1h at rt, and concentrated to dryness in vacuo. The resulting residue was co-evaporated with water (2 x 20 mL) and purified by ion-exchange chromatography over DEAE-Sephadex A-25 (HCO ₃ - form) eluting with a gradient from 0 to 0.2 M (700 mL) aqueous ammonium bicarbonate in 10% ethanol. Fractions were analyzed by tlc (7:2:1 iPa:NH ₄ OH:water), and target fractions combined and concentrated. The product was further purified by reversed-phase chromatography with a CombiFlash equipped with a C-18 column (50g) eluting with 0.01M aqueous ammonium bicarbonate. Product containing fractions were pooled, frozen, and concentrated by lyophilization to give 4’-fluoro-2’,3’-O-isopropylideneuridine 5’-O-phosphate (131 mg, 46%) as a white solid. 1H NMR (400 MHz, D ₂ O) δ 7.64 (d, J = 8.0 Hz, 1H), 6.08 (s, 1H), 5.81 (d, J = 7.8 Hz, 1H), 5.21 (dd, J = 12.4, 6.6 Hz, 1H), 5.14 (d, J = 6.5 Hz, 1H), 4.02 – 3.73 (m, 2H), 1.54 (s, 3H), 1.36 (s, 3H). 3 ¹ P NMR (162 MHz, D2O) δ 3.46. 1 ⁹ F NMR (376 MHz, D2O) δ -113.90 (q, J = 12.4, 11.9 Hz). 4’-Fluorouridine-5’-monophosphate (EIDD-02986) A 50 mL round-bottomed flask was charge with 4’-fluoro-2’,3’-O-isopropylideneuridine- 5’-O-phosphate (171 mg, 0.43 mmol), water (0.5 mL) and acetic acid (1.5 mL). The solution was cooled to 10°C and treated with cold aqueous 90% trifluoroacetic acid (3.3 mL, 43.15 mmol). After 5 min, the mixture was allowed to warm to room temperature and stirred an additional 2h. The mixture was concentrated in vacuo and the resulting gum co-evaporated with water (5 x 10 mL) followed by methanol (3 x 10 ml). The crude product as a solution in methanol (10 mL) was filtered, concentrated to approximately 4mL in volume and treated with a cold solution of 1M sodium perchlorate in acetone (20 mL). After 20 min at 0°C, the white precipitate was collected by centrifuge. The white solid was washed with acetone (5 x 14 mL), dissolved in water (4 mL) and concentrated by lyophilization to give 4’-fluorouridine-5’- monophosphate (EIDD-02986) (78 mg, 45%) as the disodium form. 1H NMR (400 MHz, D2O) δ 7.75 (d, J = 8.1 Hz, 1H), 6.09 (s, 1H), 5.92 – 5.82 (m, 1H), 4.58 – 4.49 (m, 1H), 4.42 (dd, J = 6.4, 1.9 Hz, 1H), 4.11 (t, J = 5.2 Hz, 3H). 3 ¹ P NMR (162 MHz, D2O) δ -0.27. 1 ⁹ F NMR (376 MHz, D ₂ O) δ -121.26 (dt, J = 19.1, 5.1 Hz). LCMS Calculated for C ₉ H ₁₁ FN ₂ O ₉ P [M-H ⁺ ]: 341.0; found: 340.9. Example 43. Synthesis of EIDD-02749-5’-triphosphate (EIDD-02991) A 2 L three-necked round-bottomed flask flushed with argon and fitted with a mechanical stirrer, thermometer was charged with 5’-deoxy-5’-iodouridine (80 g, 225.92 mmol) and dry methanol (500 mL). Under argon atm, the white suspension was treated with a solution of 25% (4.37 M) sodium methoxide in methanol (103.4 mL, 451.85 mmol). The resulting homogeneous solution was stirred at 60°C for 3 h. Methanol was removed in vacuo, and the resulting residue dissolved in anhydrous acetonitrile (300 mL). After addition of acetic anhydride (70.2 mL, 743 mmol), the mixture was heated to 60°C for 5 h. Once cooled to room temperature, the mixture was concentrated in vacuo, and the resulting residue dissolved in ethyl acetate (500 mL) and treated with saturated sodium bicarbonate (100 mL). The organic layer was separated, washed with brine (100 mL), dried and concentrated to dryness to give 2’,3’-di-O- acetyl-4’,5’-didehydro-5’-deoxyuridine (70 g, 99% yield). 1H NMR (400 MHz, DMSO-d ₆ ) δ 11.53 (d, J = 1.9 Hz, 1H), 7.75 (d, J = 8.1 Hz, 1H), 6.07 (d, J = 4.3 Hz, 1H), 5.92 (d, J = 6.5 Hz, 1H), 5.69 (dd, J = 8.0, 1.8 Hz, 1H), 5.63 (dd, J = 6.4, 4.3 Hz, 1H), 4.52 (t, J = 1.9 Hz, 1H), 4.28 (d, J = 2.4 Hz, 1H), 2.08 (s, 3H), 2.04 (s, 3H). In a 1 L round-bottomed flask, a solution of 2’,3’-di-O-acetyl-4’,5’-didehydro-5’- deoxyuridine (70 g, 225.6 mmol) in methanol (350 mL) was treated with 30% ammonium hydroxide (85.3 mL, 2190.7 mmol). After 18 h at room temperature, the mixture was concentrated in vacuo and the resulting residue dissolved in a 65:35:5 mixture of acetonitrile:isopropanol:methanol. After 30 min, the white precipitate was collected by vacuum filtration and washed with acetonitrile and hexanes. A second crop was isolated by concentrating the filtrate and stirring the resulting solid with acetonitrile. Combined crops were dried under high vacuum for 18 h to give 4’,5’-didehydro-5’-deoxyuridine (35 g.68% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.44 (s, 1H), 7.59 (d, J = 8.1 Hz, 1H), 5.96 (d, J = 5.4 Hz, 1H), 5.64 (d, J = 8.1 Hz, 1H), 5.60 (d, J = 5.8 Hz, 1H), 5.46 (d, J = 5.7 Hz, 1H), 4.38 (t, J = 5.5 Hz, 1H), 4.33 (s, 1H), 4.24 (q, J = 5.5 Hz, 1H), 4.17 (d, J = 1.8 Hz, 1H). A 2 L three-necked round-bottomed flask was charged with 4’,5’-didehydro-5’- deoxyuridine (35 g, 154.7 mmol) and anhydrous acetonitrile (400 mL). The suspension was cooled to 0°C under argon atm and treated with triethylamine trihydrofluoride (12.6 mL, 77.4 mmol) followed by the addition of N-iodosuccinimide (45.3 g, 201.2 mmol). After 1 h at 0°C, tlc (10% methanol in methylene chloride) indicated complete conversion. While still cold, the mixture was vacuum filtered. The isolated solid was washed sequentially with acetonitrile, dichloromethane, hexanes, and then dried under high vacuum for 18 h to give 5’-deoxy-4’- fluoro-5’-iodouridine (35 g, 61%). 1H NMR (400 MHz, Methanol-d4) δ 7.77 (d, J = 8.1 Hz, 1H), 6.05 (s, 1H), 5.69 (d, J = 8.1 Hz, 1H), 4.43 (dd, J = 18.2, 6.5 Hz, 1H), 4.25 (d, J = 6.6 Hz, 1H), 3.85 – 3.63 (m, 2H). 1 ⁹ F NMR (376 MHz, Methanol-d ₄ ) δ -112.49 (ddd, J = 20.9, 18.1, 6.1 Hz). A 150 mL round-bottomed flask was charged with 5’-deoxy-5’-iodo-4’-fluorouridine (2.6 g, 6.99 mmol) and methylene chloride (35 mL). After stirring for 20 min at room temperature, the suspension was cooled to 0°C and treated with benzyl chloroformate (4.49 mL, 31.44 mmol) followed by dropwise addition of 1-methylimidazole (3.34 mL, 41.93 mmol) over a 10 min period. The mixture was stirred an additional 10 min at 0°C and then allowed to slowly warm to room temperature. After 18h, the turbid mixture was diluted with methylene chloride (120 mL) and washed with 0.5M HCl solution (75 mL), water (50 mL), and brine (50 mL). The organic layer was separated, dried and concentrated in vacuo. The resulting residue was purified by column chromatography over silica gel (80g) eluting with a methylene chloride/methanol gradient. Pure fractions were combined and concentrated in vacuo to give 2’,3’-di-O- benzyloxycarbonyl-5’-deoxy-4’-fluoro-5’-iodouridine (4.2 g, 94% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 9.02 (s, 1H), 7.44 – 7.28 (m, 10H), 7.14 (d, J = 8.0 Hz, 1H), 5.86 – 5.72 (m, 2H), 5.69 – 5.57 (m, 2H), 5.19 (d, J = 4.3 Hz, 2H), 5.09 (d, J = 3.1 Hz, 2H), 3.71 – 3.35 (m, 2H). 1 ⁹ F NMR (376 MHz, CDCl ₃ ) δ -107.06 (td, J = 18.6, 7.3 Hz). In a 100 mL round-bottomed flask a 55% tetrabutylammonium hydroxide solution in water (8.04mL, 9.37mmol) was adjusted to pH 3.5 by dropwise addition of trifluoroacetic acid (0.72mL, 9.37mmol) while maintaining a temperature below 25°C. The mixture was then treated with a methylene chloride (15 mL) solution of 2’,3’-di-O-benzyloxycarbonyl-5’-deoxy- 4’-fluoro-5’-iodouridine (2g, 3.12 mmol) followed by addition of 3-chloroperbenzoic acid (3.6g, 15.62 mmol) in portions over a 30 min period. After one hour the pH drifted to pH 1.4. The mixture was adjusted back to pH 3.5 with 1N sodium hydroxide and allowed to stir for 16 h after which time tlc (10% methanol in methylene chloride) and LCMS indicated complete conversion. The reaction mixture was quenched by addition of sodium thiosulfate (3.21g, 20.31 mmol) slowly in portions while maintaining a temperature below 25°C. After stirring for 30 min, the methylene chloride layer was separated, and the aqueous layer extracted with additional methylene chloride (2 x 30 mL). Combined organic layers were dried over sodium sulfate, concentrated, and purified by column chromatography over silica gel (80 g) eluting with 60% ethyl acetate in hexanes followed by a second column of silica gel (80 g) eluting with a methylene chloride/methanol gradient to give 2’,3’-di-O-benzyloxycarbonyl-4’-fluorouridine (1.05 g , 63% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 9.30 (s, 1H), 7.39 – 7.29 (m, 10H), 7.21 (d, J = 8.1 Hz, 1H), 5.83 (dd, J = 17.8, 7.0 Hz, 1H), 5.77 – 5.71 (m, 2H), 5.61 (dd, J = 7.0, 2.4 Hz, 1H), 5.17 (d, J = 4.8 Hz, 2H), 5.09 (s, 2H), 3.86 (q, J = 5.8, 4.9 Hz, 2H), 3.06 (s, 1H). 1 ⁹ F NMR (376 MHz, CDCl3) δ -121.03 (dt, J = 17.7, 4.6 Hz). 4’-Fluorouridine 5’-O-triphosphate (EIDD-02991) A 10 mL round-bottomed flask charged with 2’,3’-di-O-benzyloxycarbonyl-4’- fluorouridine (348 mg, 0.66 mmol) and anhydrous trimethyl phosphate (3.5 mL). After stirring for 20 min at room temperature, the solution was cooled to 0°C and treated with 1-methyl- imidazole (115 µL, 1.44 mmol) followed by dropwise addition of phosphorus oxychloride (122 µL, 1.31 mmol) over a 40 min period. The mixture continued to stir at 0°C for 3.5h after which time tlc (10% methanol in DCM and then 7:2:1 iPa:NH ₄ OH:water) indicated complete phosphorylation. The mixture was treated with tributylamine (0.94mL, 3.94mmol), tris(tetrabutylammonium)pyrophosphate (887 mg, 0.98 mmol), and anhydrous DMF (1.5 mL). After 1h at room temperature, the reaction mixture was quenched with 100 mM TEAB (20 mL), stirred for 1h, degassed by pump-fill with argon (3x) and treated with 10% palladium on carbon (100 mg). After cooling with an ice-bath, the mixture was pump-filled with hydrogen (2x) followed by vigorous stirring under atm pressure of hydrogen for 30 min. The mixture was pump-filled with argon and then vacuum filtered through a pad of Celite. The palladium was washed with water (2 x 20 mL). Combined filtrates were washed with ether (4 x 60 mL) and then concentrated in vacuo at 25°C. The residue was co-evaporated with water (2 x 25 mL) and purified by column chromatography over DEAE-Sephadex GE A-25 (10 mm x 130 mm) eluting with a gradient from 100 mM to 500 mM TEAB (900 mL). Pure fractions as determined by tlc (8:1:1 NH4OH:iPrOH:water) were combined and concentrated in vacuo with the bath temperature set at 25°C. The resulting solid was dissolved in methanol (1 mL) and treated with saturated solution of sodium perchlorate in acetone (10 mL). The resulting white precipitate was collected by centrifuge and washed with acetone (5 x 5 mL).The solid was dissolved in water (1 mL), frozen and lyophilized to yield 4’-fluorouridine 5’-O-triphosphate (3.14 mg, 0.81% yield) as the tetrasodium form.. 1H NMR (400 MHz, D2O) δ 7.77 (d, J = 8.0 Hz, 1H), 6.15 (d, J = 1.9 Hz, 1H), 5.91 (d, J = 8.1 Hz, 1H), 4.72 – 4.57 (m, 1H), 4.41 (d, J = 6.3 Hz, 1H), 4.30 (ddd, J = 10.2, 6.3, 3.0 Hz, 1H), 4.17 (dt, J = 10.8, 5.0 Hz, 1H). 3 ¹ P NMR (162 MHz, D2O) δ -7.81(d), -11.84 (d, J = 19.2 Hz), -22.23 (t). 1 ⁹ F NMR (376 MHz, D2O) δ -121.09 (unresolved dt, J = 19.2 Hz). LCMS Calculated for C ₉ H ₁₃ FN ₂ O ₁₅ P ₃ [M-H ⁺ ]: 500.9; found: 500.8. Example 44. Synthesis of 4′-fluoro-4-thiouridine Preparation of 2′,3′,5′-tri-O-(t-butyldimethylsilyl)-4′-fluoro-urid ine To a solution of 4′-fluoro-uridine (500 mg, 1.9 mmol) in DMF (20ml) taken in 100 ml RBF, TBDMSCl (1.2 gm, 7.6 mmol) and imidazole (650 mg, 9.5 mmol) were added under inert atmosphere at 0 °C and continued stirring at room temperature. After completion, the reaction mixture was concentrated under reduced pressure and the crude product was dissolved in dichloromethane and washed with saturated aq. NaHCO3 followed by brine. The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by chromatography. Product was obtained as colorless foam (yield 58%). Preparation of 2′,3′,5′-tri-O-(t-butyldimethylsilyl)-4′-fluoro-4-th iouridine To a solution of 2′,3′,5′-tri-O-(t-butyldimethylsilyl)-4′-fluoro-urid ine (600 mg, 1 mmol) in anhydrous THF (20 ml), Lawesson’s reagent (freshly purchased) (590 mg, 1.5 mmol) and potassium carbonate (29 mg, 0.2 mmol) were added and the reaction mixture was refluxed for 5 hr. After completion the reaction mixture was concentrated under reduced pressure and the crude product was purified by column chromatography. Product was obtained as colorless foam (yield 52%). Preparation of 4′-fluoro-4-thiouridine To a solution of 2′,3′,5′-tri-O-(t-butyldimethylsilyl)-4′-fluoro-4-th iouridine (250 mg, 0.41 mmol) in anhydrous tetrahydrofuran (5 ml), 1M solution of tetrabutylammonium fluoride (2 ml) was added and stirred at room temperature for 5 hr. After completion, the reaction mixture was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography. 1H NMR 400 MHz, CD3OD, δ 7.77 (1H, d, J = 8 Hz), 6.06 (1H, d, J = 4 Hz), 5.69 (1H, d, J = 8 Hz), 4.42 (1H, dd, J = 6.4 Hz, 20 Hz), 4.25 (1H, dd, 6.4 Hz, 2.4 Hz), 3.73 (2H, m); 19F NMR 376 MHz δ -123.57, (1F, dt, J = 18.8 Hz, 3.7 Hz) Example 45. Preparation of 2’,3’-di-O-acetyl-5’-m-chlorobenzoate-4’-fluorouridi ne Preparation of 5’-deoxy-5’-iodo-uridine Uridine (2 mmol), or a uridine analog, was suspended in THF. Triphenylphosphine (786 mg, 3 mmol), imidazole (200 mg, 3 mmol) and iodine (600 mg, 2.3 mmol) were added and stirred at room temperature for 8 hr. After completion of the reaction determined by TLC, the reaction mixture was concentrated under reduced pressure and the residue was stirred with isopropanol. The colorless solid formed was filtered and dried (yield 45%). Preparation of compound 2’,3’-di-O-acetyl-5’-deoxy-4’,5’-didehydrouridine To a solution of 5’-deoxy-5’-iodo-uridine (530 mg, 1.5 mmol), or an analog version, in methanol, sodium methoxide 25% by weight in methanol (325 µL) was added and stirred at 65 °C under inert atmosphere. After completion, the reaction mixture was concentrated under reduced pressure. The crude product was taken in MeCN (10ml) and treated with acetic anhydride (425 µL, 4.5 mmol) and DMAP (20 mg, 0.15 mmol) and stirred at room temperature for 12 hr. After completion, the reaction mixture was quenched with saturated aq. NaHCO3, diluted with DCM, washed with saturated aq. NaHCO3 and brine. The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by chromatography yielding product as a colorless solid. Preparation of compound 2’,3’-di-O-acetyl-5’-deoxy-5’-iodo-4’-fluorouridin e To a solution of compound 2’,3’-di-O-acetyl-5’-deoxy-4’,5’-didehydrouridine (460 mg, 2mmol), or an analog version, in anhydrous acetonitrile (5ml) in 50 ml RBF, triethylamine trihydrofluoride (162 µL, 1 mmol) and N-iodosuccinimide (2.6 mmol) were added at 0 °C. After 60 min, the reaction mixture was slowly warmed to room temperature. After completion, the reaction mixture was concentrated under reduced pressure and purified by column chromatography. Preparation of compound 2’,3’-di-O-acetyl-5’-m-chlorobenzoate-4’-fluorouridi ne To a solution of 2’,3’-di-O-acetyl-5’-deoxy-5’-fluoro-4’-iodouridin e (460 mg, 1 mmol), or an anlog version, in 5:1 (DCM:H ₂ O) (50 ml) in a 100 ml RBF, tetrabutylammonium hydrogen sulfate (370 mg, 1.1 mmol) and potassium phosphate dibasic (260 mg, 1.5 mmol) were added, and the reaction mixture was cooled to 0 °C. meta-chloroperbenzoic acid (860mg, 4 mmol) was added slowly in portions and reaction mixture was allowed to warm to room temperature and vigorous stirring was continued for another 12 hr. After completion, the reaction mixture was quenched with aq. Na2SO3 and diluted with DCM (30 ml). The organic layer was separated and washed with saturated aq. NaHCO ₃ and brine. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography. Example 46. General preparation of 2’,3’,5’-tri-O-acetyl protection of 4’-halouridine or analogs thereof 4’-Halouridine or an analog thereof (1.5 mmol) was dissolved in MeCN (10ml) and treated with acetic anhydride (4.5 mmol) and DMAP (0.15 mmol) and stirred at room temperature for 12 hr. After completion, the reaction mixture was quenched with saturated aq. NaHCO3, diluted with DCM, washed with saturated aq. NaHCO3 and brine. The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by chromatography yielding product as a colorless solid. Example 47. General procedure for substitution at the 4-position 2’,3’,5’-tri-O-protected 4’-halouridine, or analog version thereof, (1.03 mmol) was added DMAP (2.05 mmol), followed by the addition of dry DCM (17 mL) to give a colorless solution. The reaction flask was vacuumed and charged with argon. Then triethylamine (10.31 mmol) was added. The mixture was cooled to 0°C and then 2,4,6-triisopropylbenzenesulfonyl chloride (4.13 mmol) was added. After stirring at 0°C for 1.5 h, more triethylamine (10.31 mmol) was added, followed by DABCO (0.5200 mmol) and the desired alcohol or carboxylate (10.31 mmol). The mixture was allowed to warm up to rt gradually and stir at rt overnight. TLC showed no SM.1N HCl was added followed by more DCM. The organic layer was separated, washed once with sat NaHCO3, once with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude material was diluted with DCM and purified by ISCO column chromatography (40 g) eluting from 100% hexanes to 100% EtOAc to afford the product. This material was then deprotected using ammonium hydroxide in methanol at room temperature in a sealed tube.

Example 48. Synthesis of 4’-fluoro-2-thiouridine Preparation of 4-O-(2,6-dimethylphenyl)-2′,3′-di-O-acetyl-5′-O-(4-chl orobenzoyl)-4′- fluorouridine 2′,3′-di-O-acetyl-5′-O-(4-chlorobenzoyl)-4′-fluorour idine (1gm, 2mmol) was dissolved in anhydrous dicholoromethane (30 ml) in 100 ml RBF. Et3N (542 µL, 3.75 mmol), 2,4,6- triisopropylbenzensulfonyl chloride (690 mg, 2.26mmol), and 4-(dimethylamino)pyridine (62 mg, 0.5 mmol) were added added at 0 °C under an inert atmosphere with continued stirring at room temperature. After completion of the reaction, 2,6-dimethylphenol (300 mg, 2.45 mmol), Et ₃ N (3.45 mL, 25 mmol), and 1,4-diazabicyclo[2,2,2]octane (23 mg, 0.2 mmol) were added at 0 °C under an inert atmosphere with continued stirring at room temperature for 3-4 hr. The reaction mixture was diluted with dichloromethane (30ml) and washed once with saturated NaHCO3 (aqueous) and twice with brine. The combined organic extracts were dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography. Product was obtained as colorless solid (yield 53%). Preparation of 4-O-(2,6-Dimethylphenyl)-4′-fluorouridine To a solution of 4-O-(2,6-Dimethylphenyl)-2′,3′-di-O-acetyl-5′-O-(4-chl orobenzoyl)-4′- fluorouridine (600 mg) in anhydrous methanol (6 ml) in 25 ml RBF, 1 ml of 7N ammonia in methanol was added and stirred at room temperature for 8 hr. After completion, the reaction mixture was concentrated under reduced pressure and the crude product was obtained as colorless solid (yield 88%). Preparation of 4-O-(2,6-dimethylphenyl)-2′,3′,5′-tri-O-(t-butyldimeth ylsilyl)-4′- fluorouridine To a solution of 4-O-(2,6-dimethylphenyl)-4′-fluorouridine (720mg) in anhydrous DMF (10 ml) in a 50 ml RBF, tert-butyldimethylsilyl chloride (1185 mg, 7.8 mmol) and imidazole (670 mg, 9.8 mmol) were added at 0 °C under an inert atmosphere with continued stirring at room temperature for 12 hr. After completion the reaction mixture was concentrated under reduced pressure and the crude product was taken up in DCM and washed with saturated aq.NaHCO3 and with brine. The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to get colorless foam (yield 71%) Preparation of 4-O-(2,6-dimethylphenyl)- 2′,3′,5′-tri-O-(t-butyldimethylsilyl)-4′-fluoro-2- thiouridine To a solution of 4-O-(2,6-dimethylphenyl)- 2′,3′,5′-tri-O-(t-butyldimethylsilyl)-4′- fluorouridine (750 mg, 1 mmol) in anhydrous toluene (20 ml), Lawesson’s reagent (freshly purchased) (590 mg, 1.5 mmol) and potassium carbonate (29 mg, 0.2 mmol) were added and the reaction mixture was refluxed for 8 hr. After completion, the reaction mixture was concentrated under reduced pressure and the crude product was purified by column chromatography. Product was obtained as colorless foam (yield 74%). Preparation of 2′,3′,5′-tri-O-(t-butyldimethylsilyl)-4′-fluoro-2-th iouridine To a solution of 4-O-(2,6-dimethylphenyl)-2′,3′,5′-tri-O-(t-butyldimeth ylsilyl)-4′-fluoro- 2-thiouridine (500 mg, 0.68 mmol) in acetonitrile (10 ml), 1,1,3,3-tetramethylguanidine (260 µL, 2 mmol) and syn-o-nitrobenzaldoxime (343 mg, 2 mmol) were added and stirred at room temperature for 5 hr. After completion, the mixture was concentrated under reduced pressure. The crude product was dissolved in dichloromethane and washed with saturated aq. NaHCO ₃ and with brine. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography. Product was obtained as colorless foam (yield 67%). Preparation of 4′-fluoro-2-thiouridine To a solution of 2′,3′,5′-tri-O-(t-butyldimethylsilyl)-4′-fluoro-2-th iouridine (270 mg, 0.43 mmol) in anhydrous tetrahydrofuran (5 ml), 1M solution of tetrabutylammonium fluoride (2 ml) was added and stirred at room temperature for 5 hr. After completion, the reaction mixture was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography. Product was obtained as off white solid (yield 74%). 1H NMR 400 MHz, CD3OD, δ 8.11 (1H, d, J = 8 Hz), 6.84 (1H, s), 5.94 (1H, d, J = 8 Hz), 4.26 (2H, m), 3.78 (2H, m); 13C NMR 100 MHz δ 176.49, 159.90, 140.78, 119.46, 117.16, 107.34, 95.08, 72.83, 68.59, 59.80; 19F NMR 376 MHz δ -122.77, (1F, d, J = 18.8 Hz); LCMS: [M+1] ⁺ 279.0. Example 49. General Synthesis of 1’-Methyl Nucleosides Synthesis of compound C: Step 1: A cooled (0 °C) and stirred mixture of commercially available 2,3-O-isopropylidene-D- ribonolactone (10.0 g, 53.1 mmol) in dry THF (100 mL), was treated with sodium hydride (60% w/w oil dispersion) (2.5 g, 63.8 mmol), portion-wise over 15 min. Benzyl bromide (7.6 mL, 63.8 mmol) was then added dropwise over 20 min and the resulting mixture was stirred at room temperature for 18 h, when LCMS indicated the reaction was over. Small portions of ice were added slowly over 20 min to quench the reaction before pouring on to ice/water (200 mL). The resulting mixture was extracted with DCM (3 x 150 mL) and the combined organic phase was washed in-turn, with water and brine (150 mL each), dried (MgSO4), filtered and concentrated. Silica gel column chromatography of the residue (100 g silica cartridge; 2-20% EtOAc in PE) gave pure product A (7.3 g, 49%). Step 2: A cooled (-78 °C) and stirred solution of compound A (7.3 g, 26.2 mmol) in dry ether (150 mL), was added dropwise over 20 min a 1.6 M solution of methyl lithium in ether (23 mL, 36.2 mmol) and the resulting mixture kept at this temperature for 45 min before warming to 0 °C. A saturated solution of ammonium chloride was added and the mixture was extracted with ether (3 x 200 mL) and the combined organic phases were washed with cold water (2 x 150 mL), dried (MgSO4), filtered and concentrated to give compound B, which was used as crude in the next step. Step 3: Crude compound B (26.2 mmol) was taken up in pyridine (50 mL) and treated with acetic anhydride (20 mL), with stirring for 18 h; LCMS showed reaction to be incomplete. DMAP (1.3 mmol) was added and stirring was continued for 24 h; LCMS showed reaction to be over. Ice/water (150 mL) was added and the resulting mixture was extracted with DCM (3 x 100 mL) and the combined organic phase was washed in-turn, with cold sat. sodium bicarb., ice cold water and brine (100 mL each), dried (MgSO ₄ ), filtered and concentrated. Silica gel column chromatography of the residue (100 g silica cartridge; 0-15% EtOAc in PE) gave pure product C (3.6 g, 41%). General procedure for coupling between compound C and nucleobase: A mixture of sugar (1 eq) and nucleobase (2 eq) in dry CH ₃ CN under argon was treated with BSA (4.5 eq), with stirring until the mixture was homogeneous. Then 1.8 M solution of ethylaluminium dichloride in toluene (1 eq) was added dropwise. After sugar was consumed, the reaction mixture was added to a 1:1 biphasic mixture of DCM and cold sat. sodium bicarb. and the mixture stirred for 10 min at room temperature before passage through a pad of Celite, whereby the organic portion was collected and washed in-turn, with sat. sodium bicarb. and brine (2 x), dried (MgSO4), filtered and concentrated. Silica gel column chromatography of the residue gave the protected nucleoside. Synthesis of compound D: Following the general procedure for coupling between compound C and nucleobase, compound D (1.8 g, 68%) was obtained as a 1:4 mixture of α- and β anomers. The reaction was run with compound C (2.3 g, 6.84 mmol), uracil (1.5 g, 13.7 mmol) and BSA (7.53 mL, 30.8 mmol) in dry MeCN (80 mL), and a 1.8 M solution of ethylaluminium dichloride in toluene (3.7 mL, 6.57 mmol). General procedure for acetonide deprotection: Nucleoside (1 eq) was dissolved in 70% aqueous MeOH (0.018 M) and then treated with Dowex 50W-8X H ⁺ resin (6g/g of nucleoside). The mixture was heated to 43 °C until LCMS showed no starting material. Then the reaction was filtered and concentrated by rotary evaporation to remove MeOH and the aqueous portion freeze-dried. Silica gel column chromatography of the residue gave the deprotected nucleoside. Synthesis of compound E: Following the general procedure for acetonide deprotection, a solution of compound D (1.8 g, 4.63 mmol) in a 1:2.4 mixture of water and MeOH (255 mL) was treated with Dowex 50W-8X H ⁺ resin (10.8 g) with stirring at 43 °C until LCMS showed reaction to be complete (18 h). The reaction was filtered and concentrated by rotary evaporation to remove MeOH and the aqueous portion freeze-dried. Silica gel column chromatography of the residue (100 g silica cartridge; 0-10% MeOH in DCM) was performed twice and gave two fractions of compound E as β-anomer: fraction 1: product that was 100 % pure by LCMS (380 mg), and fraction 2: product that was 97.5% pure by LCMS (580 mg). Combined yield = 960 mg = 60%. General procedure for removal of benzyl group via hydrogenolysis: 5’-Benzyl protected nucleoside (1 eq) was dissolved in MeOH (0.015M). This was vacuumed and charged with argon. Then 10% Pd/C (0.1 eq) was added. An atmosphere of hydrogen was introduced using a H ₂ balloon. After starting material was consumed, it was filtered through Celite and the filtrate was concentrated in vacuo. The residue was freeze-dried from water to remove traces of MeOH to afford the deprotected nucleoside. The obtained nucleoside can be subjected to the reaction conditions in Examples 8, 9, and 10 to install a 4’- fluoro or 4’-chloro group. Synthesis of compound F: A solution of compound E (640 mg, 1.84 mmol) in MeOH (125 mL) under argon was treated with 10% Pd/C (200 mg). An atmosphere of hydrogen was introduced, and the mixture stirred for 35 min at room temperature. The reaction was passed through a pad of Celite and concentrated by rotary evaporation. The residue was freeze-dried from water to remove traces of MeOH to give compound F (556 mg, 98% yield). The obtained nucleoside F can be subjected to the reaction conditions in Examples 8, 9, and 10 to install a 4’-fluoro or 4’-chloro group.

Example 50. General Synthesis of 1’-CH2OH Nucleosides Synthesis of compound K: Step 1: Known compound G (synthesized according to J. Org. Chem.1976, 41, 1836-1846) (1 eq) was co-evaporated with pyridine 3 times and dissolved in pyridine (0.225 M). The solution was cooled to 0 ^o C and 4-toluoyl chloride (1.1 eq) was added dropwise under argon. After stirring for 2 h, saturated NaHCO ₃ was added, and the reaction mixture was extracted with DCM. The organic phase was washed with brine once, dried (MgSO4), evaporated and co- evaporated with toluene. Recrystallisation from MeOH afforded compound H. Step 2: Compound H (1 eq) was treated with 0.4 M methanolic HCl (2 eq) and stirred at room temperature for 2-3 h. The reaction mixture was cooled to 0 ^o C and then neutralized with triethylamine and evaporated. The crude mixture was partitioned between DCM and water. The aqueous phase was washed with DCM (3 x). The combined organic phase was dried (MgSO4), filtered and concentrated in vacuo. Silica gel column chromatography afforded compound I. Step 3: Compound I (1 eq) in dry THF (0.53 M) was cooled to 0 ^o C and treated with sodium hydride (1.2 eq, 60% w/w oil dispersion) portion-wise. Benzyl bromide (1.2 eq) was then added dropwise and the resulting mixture was stirred at room temperature overnight, when LCMS indicated the reaction was complete. Small portions of ice were added slowly to quench the reaction before pouring on to ice/water. The resulting mixture was extracted with DCM (3 x) and the combined organic phase was washed with water once and brine once, dried (MgSO ₄ ), filtered and concentrated in vacuo. Silica gel column chromatography of the residue gave compound J. Step 4: Compound J (1 eq) was stirred in a mixture of TFA/H ₂ O (95/5, v/v) at room temperature overnight. Then the solvent was removed in vacuo. The crude residue was co-evaporated with pyridine 3 times and dissolved in pyridine. The mixture was cooled to 0 ^o C and then Ac ₂ O (10 eq) was added dropwise, followed by DMAP (0.1 eq). After addition, ice-water bath was removed, and the mixture was allowed to stir at room temperature overnight. Then ice-water was added, and the mixture was extracted with DCM (3 x). The organic phase was washed with saturated NaHCO ₃ once, cold water once and brine once, dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography to afford compound K. General procedure for coupling between compound K and nucleobase: A mixture of sugar K (1 eq) and nucleobase (2 eq) in dry CH3CN under argon was treated with BSA (4.5 eq), with stirring until the mixture was homogeneous. Then 1.8 M solution of ethylaluminium dichloride in toluene (1 eq) was added dropwise. After sugar was consumed, the reaction mixture was added to a 1:1 biphasic mixture of DCM and cold sat. sodium bicarb. and the mixture stirred for 10 min at room temperature before passage through a pad of Celite, whereby the organic portion was collected and washed in-turn, with sat. sodium bicarb. and brine (2 x), dried (MgSO4), filtered and concentrated. Silica gel column chromatography of the residue gave the protected nucleoside L. General procedure to remove 4-toluoyl and acetate group: Nucleoside (1 eq) was treated with 7 N ammonia in MeOH (30 eq) at rt. After LCMS showed the starting material was fully deprotected, solvent was removed in vacuo. The crude material was triturated with Et ₂ O overnight. Solids were filtered and dried under 50 ^o C vacuum oven overnight to provide compound M. Compound M was then be subjected to the reaction conditions in examples 8, 9, and 10 to install either a 4’-fluoro or 4’-chloro group followed by deprotection with 10% Pd/C under a H ₂ atmosphere. Example 50. General Synthesis of 1’-CH2F Nucleosides Synthesis of compound O: Step 1: A solution of compound I (1 eq) dissolved in DCM was treated with Et ₃ N (2 eq). The mixture was cooled to 0 ^o C, and MsCl (1.2 eq) was added dropwise. After addition, ice-water bath was removed to allow the reaction to stir at room temperature. After starting material was consumed, reaction was quenched with water. Organic phase was washed with brine once, dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography to afford the mesylate intermediate. This intermediate (1 eq) was dissolved in THF and treated with 1.0 M TBAF in THF (2 eq). The mixture was stirred at room temperature. After TLC showed no starting material, solvent was removed in vacuo. The crude material was purified by silica gel column chromatography to afford compound N. Step 2: Compound N (1 eq) was stirred in a mixture of TFA/H2O (95/5, v/v) at room temperature overnight. Then the solvent was removed in vacuo. The crude residue was co-evaporated with pyridine 3 times and dissolved in pyridine. The mixture was cooled to 0 ^o C and then Ac2O (10 eq) was added dropwise, followed by DMAP (0.1 eq). After addition, ice-water bath was removed, and the mixture was allowed to stir at room temperature overnight. Then ice-water was added, and the mixture was extracted with DCM (3 x). The organic phase was washed with saturated NaHCO3 once, cold water once and brine once, dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography to afford compound O. General procedure for coupling between compound O and nucleobase: Nucleobase (1.5 eq) was suspended in HMDS with catalytic amount of ammonia sulfate (0.05 eq). The mixture was heated at 140 ^o C until it gave a clear solution. After cooling to room temperature rt, solvent was removed in vacuo and dried under oil pump before coupling with sugar intermediate. To the above silylated nucleobase was added dry CH3CN, followed by a CH ₃ CN solution of the sugar intermediate (1 eq). This was treated with SnCl ₄ (3.5 eq) under argon. The mixture was heated to 80 ^o C until the sugar intermediate was all consumed. After cooling to room temperature, solid NaHCO ₃ and a little water were added. The mixture was allowed to stir at room temperature for 1 h. Then it was filtered through Celite. The filtrate was concentrated in vacuo. To the residue was added DCM, and it was washed with saturated NaHCO3 once, water once and brine once. Organic phase was dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography to afford the coupling product P. Synthesis of compound Q: Nucleoside P (1 eq) was treated with 7 N ammonia in MeOH (30 eq) at rt. After LCMS showed the starting material was fully deprotected, solvent was removed in vacuo. The crude material was triturated with Et2O overnight. Solids were filtered and dried under 50 ^o C vacuum oven overnight to provide compound Q. Compound Q was then be subjected to the reaction conditions in examples 8, 9, and 10 to install either a 4’-fluoro or 4’-chloro group. Example 51. General Synthesis of 1’-CN Nucleosides Synthesis of compound S: Step 1: Commercially available 1-O-Acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (1 eq) was dissolved in DCM under argon. This was cooled to 0 ^o C, and then TMSCN (1.2 eq) was added, followed by BF3-Et2O (2 eq). After addition, ice-water bath was removed. The mixture was stirred at room temperature overnight. After reaction was complete, the mixture was cooled to 0 ^o C and saturated NaHCO3 was added. The mixture was stirred for 30 min. Organic phase was separated, washed with water once, brine once, dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography to afford compound R. Step 2: Compound R (1 eq) and NBS (2.4 eq), in a flat-bottomed Erlenmeyer flask equipped with a condenser, was heated under reflux in dry CCl ₄ (0.042 M) for 35 min over a 250 W tungsten lamp. The insoluble materials were removed from the cooled mixture by filtration and the filtrate was diluted with CHCl ₃ and washed sequentially with saturated sodium thiosulphate, saturated NaHCO3 and water. Organic layer was dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography to afford compound S as a mixture of two diastereomers (2.3/1). General procedure for coupling between compound S and nucleobase: Nucleobase (1.5 eq) was suspended in HMDS with catalytic amount of ammonia sulfate (0.05 eq). The mixture was heated at 140 ^o C until it gave a clear solution. After cooling to room temperature, solvent was removed in vacuo and dried under oil pump before coupling with sugar intermediate. To the above silylated nucleobase was added dry CH ₃ CN, followed by a CH ₃ CN solution of the sugar intermediate (1 eq). This was treated with AgOTf (1.5 eq) under argon. The mixture was heated to 80 ^o C until the sugar intermediate was all consumed. After cooling to room temperature, AgBr that precipitated out was filtered off. Solvent was removed in vacuo. To the residue was added EtOAc, and it was washed with saturated NaHCO3 once, and brine once. Organic phase was dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography to afford the coupling product T. Synthesis of compound U: Nucleoside T (1 eq) was treated with 7 N ammonia in MeOH (30 eq) at rt. After LCMS showed the starting material was fully deprotected, solvent was removed in vacuo. The crude material was triturated with Et2O overnight. Solids were filtered and dried under 50 ^o C vacuum oven overnight to provide compound U. Compound U was then be subjected to the reaction conditions in examples 8, 9, and 10 to install either a 4’-fluoro or 4’-chloro group. Example 52. General Synthesis of 1’-Ethynyl Nucleosides Step 1: Compound V was synthesized from compound M by installing either a 4’-F or a 4’-Cl according to examples 8, 9, and 10. Compound V (1 eq) was dissolved in DMF and treated with imidazole (5 eq), followed by the addition of TBSCl (4 eq). The mixture was stirred at room temperature overnight. Then it was quenched with water, followed by the addition of EtOAc. Organic phase was separated and washed with water twice and brine once. It was dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography to afford TBS protected nucleoside. This was dissolved in MeOH and treated with 10% Pd/C (0.1 eq) under argon. An atmosphere of hydrogen was introduced using a H2 balloon. After starting material was consumed, it was filtered through Celite. The filtrate was concentrated in vacuo to afford compound W. Step 2: Dimethyl sulfoxide (2 eq) was added to a solution of trichloroacetic anhydride (1.4 eq) in DCM at – 78 ^o C under argon. The mixture was stirred for 20 min at the same temperature, and a solution of compound W (1 eq) in DCM was added to the mixture, which was stirred for a further 30 min at the same temperature. After addition of Et3N (4.8 eq), the reaction mixture was allowed to warm to room temperature and stirred for 1 h. Water was added to the mixture, and the separated organic phase was washed with water once, dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography to afford compound X. Step 3: A hexane solution of nBuLi (1.6 M, 4 eq) was added to a suspension of chloromethyltriphenylphosphonium chloride (4 eq) in THF at – 78 ^o C under argon. The mixture was stirred for 50 min at -78 ^o C, and a solution of compound X (1 eq) in THF was added to the mixture. The mixture was warmed to 0 oC and stirred for 2.5 h. Saturated NH4Cl was added to the mixture, which was extracted with EtOAc once. The separated organic phase was washed brine once, dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography to afford the chloroalkene intermediate. A hexane solution of nBuLi (1.6 M, 12 eq) was added to a solution of the above intermediate (1 eq) in THF at – 78 ^o C under argon. The mixture was stirred at – 78 ^o C for 2 h, and a saturated NH4Cl was added, which was extracted with EtOAc once. The organic phase was washed with brine once, dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography to afford compound Y. Step 4: Compound Y (1 eq) was dissolved in THF and then treated with TBAF (1.0 M in THF, 4 eq). After starting material was fully deprotected, solvent was removed in vacuo. The crude material was purified by silica gel column chromatography to afford compound Z. Example 53. 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 37 ^o C with 5% CO ₂ until maximum CPE is observed in virus control wells. The plates are then stained with 0.011% neutral red for approximately two hours at 37 ^o C in a 5% CO ₂ incubator. 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 CC ₅₀ divided by EC ₅₀ 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-log ₁₀ concentrations of inhibitor are tested for antiviral activity and cytotoxicity. After sufficient virus replication occurs, 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 EC ₅₀ , CC ₅₀ , 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 log10 of 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. Example 54. Screening Assays for Lassa fever virus (LASV) Primary Lassa fever virus assay. Confluent or near-confluent cell culture monolayers in 12-well disposable cell culture plates are prepared. Cells are maintained in DMEM supplemented with 10% FBS. For antiviral assays the same medium is used but with FBS reduced to 2% or less and supplemented with 1% penicillin/streptomycin. 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 will be run in parallel with each tested compound. Further, a known active drug is tested as a positive control drug using the same experimental set-up as described for the virus and cell control. The positive control is tested with each test run. The assay is set up by first removing growth media from the 12-well plates of cells, and infecting cells with 0.01 MOI of LASV strain Josiah. Cells will be incubated for 90 min: 500 μl inoculum/M12 well, at 37°C, 5% CO2 with constant gentle rocking. The inoculums will be removed and cells will be washed 2X with medium. Then the test compound is applied in 1 ml of total volume of media. Tissue culture supernatant (TCS) will be collected at appropriate time points. TCS will then be used to determine the compounds inhibitory effect on virus replication. Virus that was replicated in the presence of test compound is titrated and compared to virus from untreated, infected controls. For titration of TCS, serial ten-fold dilutions will be prepared and used to infect fresh monolayers of cells. Cells will be overlaid with 1% agarose mixed 1:1 with 2X MEM supplemented with 10%FBS and 1%penecillin, and the number of plaques determined. Plotting the log10 of the inhibitor concentration versus log10 of virus produced at each concentration allows calculation of the 90% (one log ₁₀ ) effective concentration by linear regression. Secondary Lassa fever virus assay. The secondary assay involves similar methodology to what is described in the previous paragraphs using 12-well plates of cells. The differences are noted in this section. Cells are being infected as described above but this time overlaid with 1% agarose diluted 1:1 with 2X MEM and supplemented with 2% FBS and 1% penicillin/streptomycin and supplemented with the corresponding drug concentration. Cells will be incubated at 37 ^o C with 5% CO2 for 6 days. The overlay is then removed and plates stained with 0.05% crystal violet in 10% buffered formalin for approximately twenty minutes at room temperature. The plates are then washed, dried and the number of plaques counted. The number of plaques is in each set of compound dilution is converted to a percentage relative to the untreated virus control. The 50% effective (EC50, virus-inhibitory) concentrations are then calculated by linear regression analysis. Example 55. Screening Assays for Ebola virus (EBOV) and Nipah virus (NIV) Primary Ebola/Nipah virus assay. Four-concentration plaque reduction assays are performed. Confluent or near-confluent cell culture monolayers in 12-well disposable cell culture plates are prepared. Cells are maintained in DMEM supplemented with 10% FBS. For antiviral assays the same medium is used but with FBS reduced to 2% or less and supplemented with 1% penicillin/streptomycin. 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 will be run in parallel with each tested compound. Further, a known active drug is tested as a positive control drug using the same experimental set-up as described for the virus and cell control. The positive control is tested with each test run. The assay is set up by first removing growth media from the 12-well plates of cells. Then the test compound is applied in 0.1 ml volume to wells at 2X concentration. Virus, normally at approximately 200 plaque-forming units 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 37°C with 5% CO ₂ for one hour. Virus-compound inoculums will be removed, cells washed and overlaid with 1.6% tragacanth diluted 1:1 with 2X MEM and supplemented with 2% FBS and 1% penicillin/streptomycin and supplemented with the corresponding drug concentration. Cells will be incubated at 37°C with 5% CO2 for 10 days. The overlay is then removed and plates stained with 0.05% crystal violet in 10% buffered formalin for approximately twenty minutes at room temperature. The plates are then washed, dried and the number of plaques counted. The number of plaques is in each set of compound dilution is converted to a percentage relative to the untreated virus control. The 50% effective (EC ₅₀ , virus- inhibitory) concentrations are then calculated by linear regression analysis. Secondary Ebola/NIpah virus assay with VYR component. The secondary assay involves similar methodology to what is described in the previous paragraphs using 12-well plates of cells. The differences are noted in this section. Eight half-log ₁₀ concentrations of inhibitor are tested for antiviral activity. One positive control drug is tested per batch of compounds evaluated. For this assay, cells are infected with virus. Cells are being infected as described above but this time incubated with DMEM supplemented with 2% FBS and 1% penicillin/streptomycin and supplemented with the corresponding drug concentration. Cells will be incubated for 10 days at 37°C with 5% CO2, daily observed under microscope for the number of green fluorescent cells. Aliquots of supernatant from infected cells will be taken daily and the three replicate wells are pooled. The pooled supernatants are then used to determine the compounds inhibitory effect on virus replication. Virus that was replicated in the presence of test compound is titrated and compared to virus from untreated, infected controls. For titration of pooled viral samples, serial ten-fold dilutions will be prepared and used to infect fresh monolayers of cells. Cells are overlaid with tragacanth and the number of plaques determined. Plotting the log10 of the inhibitor concentration versus log10 of virus produced at each concentration allows calculation of the 90% (one log ₁₀ ) effective concentration by linear regression. Example 56. 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 10 ³ (5 x 10 ⁵ for 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 57. 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 10 ⁴ 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. 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 58. 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 10 ⁴ 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. 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 59. 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 I ₃₈₉ luc-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 10 ³ cells per well and incubated at 37˚C 5% C02 for 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 1450Microbeta 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 60. 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 10 ⁴ 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. 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% C02 incubator, the test plates were stained with the tetrazolium dye XTT (2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)ca rbonyl]-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 61. 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- ³² P] 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- ³² P] 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 62. HCV Polymerase Inhibition Assay Activity of compounds for inhibition of HCV polymerase was evaluated using methods previously described (Lam et al.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 MgCl ₂ , 0.75 mM MnCl ₂ , 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 63. 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 [ ³² P]-CTP or [ ³² P]-UTP. Assay plates were incubated at 27˚C for 1 hour before quench. [ ³² P] incorporation into macromolecular product was assessed by filter binding. Example 64. 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 MgCl ₂ , 0.4 mg/mL BSA, 1 mM DTT, 15% glycerol, 0.05 mM of dCTP, dTTP, and dATP, 10 uCi [ ³² P]-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 [ ³² P]-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 65. 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 TCID50 of 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 dH ₂ O, 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 MgCl ₂ . For each reaction, 1 uL of TTP, 4 uL of dH ₂ O, 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 66. HBV 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 10 ⁴ cells 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, HBV-AD38-qR1, and HBV-AD38-qP1 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 67. 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 MnCl ₂ , 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 MgCl ₂ , 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 68. 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 37 ^o /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 37 ^o /5% CO ₂ for 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 4 ^o C. Samples were analyzed by LC- MS/MS using an ABSCIEX 5500 QTRAP LC-MS/MS system with a Hypercarb (PGC) column. Example 69. 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 70. 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 10 ³ cells 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 71. 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. MgCl ₂ 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 MgCl ₂ , 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. 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 K _1/2 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 MgCl ₂ , 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 72. Protocol for Determining Plasma Stability Test article was incubated in triplicate at 1.00 µM in pooled mixed gender human plasma (BioIVT, K ₂ EDTA), in pooled male CD-1 mouse plasma (BioIVT, K ₂ EDTA), 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). Example 73. 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. 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 were 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 (t _1/2 ) (min) =- 0.693/ (slope). Example 74. Protocol for Determining pH Stability Test article in methanol, water, 0.1N HCl, PBS or pH9 buffer were placed in the HPLC autosampler set at 25°C or 4°C. Samples were injected on the LC-MS/MS at times: 0, 1, 2, 3, 4, 6 and 24 hours. 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 (100 x 4.6 mm, 5 µm) column (ThermoFisher, Waltham, MA USA) was used for the separation. Mobile Phase A consisted of 25 mM ammonium bicarbonate buffer in HPLC grade water (pH 9.4) and Mobile phase B consisted of neat acetonitrile. Initial mobile phase conditions of 5%B were held for a minute. A gradient 5-60% of B was run for next 7 minutes, followed by re-equilibration of the column, was used. Mass Spectrometry analysis was performed on a QTRAP 5500 Mass Spectrometer (AB Sciex, Framingham, MA, USA) using Negative Mode Electrospray Ionization (ESI) in Multiple Reaction Monitoring (MRM) Mode and UV at 260 nm. Data analysis was performed using Analyst Software (AB Sciex, Framingham, MA, USA). Stability was determined by the % UV peak area change from the time-zero samples. Example 75. Mouse PK protocol Female ICR (CD-1) mice (from Envigo) between the ages of 7 to 8 weeks were acclimated to their environment for at least three days prior to dosing. Mice were weighed at least once before dosing to determine the dosing volume. Test article was dissolved in sterile saline at 1 mg/mL for IP dosing. For oral dosing, test article was resuspended in 10 mM trisodium citrate/0.5% Tween 80/Water. For IP dosing mice were dosed with a 10 mL/kg dose volume and mice dosed PO were dosed with a 10 mL/kg dose volume. Blood samples collected from mice dosed by oral gavage were collected pre-dose, 0.25, 0.50, 1, 2, 3, 4, 8, and 24 hours post-dose. Blood samples collected from mice dosed by intraperitoneal injection were collected pre-dose, 0.08, 0.25, 0.50, 1, 2, 3, 4, and 8 hours post- dose. Blood samples were collected by reto-orbital bleeding under isoflurane anesthesia into lithium-heparin microtainer tubes, centrifuged at 2000 x g for 10 min at 5 ^C, and the plasmas were transferred into fresh tubes and stored at -80^C before processing for quantitation by LC- MS/MS. 50 µL aliquots of mouse plasma were extracted with 950 µL of acetonitrile that included EIDD-2216 as an Internal Standard. Samples were clarified by centrifugation at 20,000 x g at 4 °C for 10 min. The clarified supernatants were transferred to HPLC vials for analysis. Samples were maintained at 4 °C in a Leap Pal Autosampler (CTC Analytics AG, Zwingen, Switzerland). 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. An Agilent SB-Phenyl (150 x 4.6 mm, 5 µm) column (Agilent technologies, Santa Clara, CA, USA) was used for the separation. Mobile Phase A consisted of 100 mM Ammonium Formate buffer in HPLC grade Water and Mobile phase B consisted of pure acetonitrile. An initial 1 minute isocratic step was used at 5% Mobile Phase B followed by a 1.5 minute gradient to 100% Mobile Phase B, which was held for 1.5 minutes before returning to starting conditions for 1.5 minutes. Mass Spectrometry analysis was performed on an QTRAP 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). PK parameters are calculated using the Phoenix WinNonLin 6.4 (Build 6.4.0.768) Non- compartmental analysis tool (Certara, Princeton, NJ, USA). Bioavailability is calculated by comparing the exposure (AUCinf) after oral dosing with the exposure after intraperitoneal dosing. Example 76. Mouse MTD protocol Mice were treated by oral gavage (p.o.) once daily from day 0 to day 9 (10 days). The vehicle used for this study was 10 mM trisodium citrate with 0.5% Tween-80 in sterile water. The test article was formulated fresh in vehicle daily. The treatment volume was 0.1 mL per 20 grams of mouse body weight. End-points were mortality, whole-body weights, and adverse signs. Mice were euthanized at day 10. No tissue samples were collected from these mice. Example 77. Norovirus Activity for EIDD-02749 Example 78. Togaviridae Activity for EIDD-02749 Example 79. Flaviviridae Activity for EIDD-02749 Example 80. Picornaviridae Activity for EIDD-02749 Example 81. Respiratory Virus Activity for EIDD-02749 Example 82. Coronavirus Activity for EIDD-02749 Example 83. Bunyaviridae Activity for EIDD-02749 Example 84. Arenaviridae Activity for EIDD-02749 Example 85. Filovirus Activity for EIDD-02749 Example 86. EIDD-02749 Cytotoxicity Example 87. Synthesis of EIDD-2919 To a 25 mL pear-shaped flask charged with [2,2- dimethylpropanoyloxymethoxy(hydroxy)phosphoryl]oxymethyl 2,2-dimethylpropanoate 2 (0.19 g, 0.58 mmol) was added dry THF (3.5 mL) to give a colorless solution under argon. Then Et ₃ N (0.09 mL, 0.63 mmol) was added. After stirring at rt for 30 min, 1-[(2R,5R)-3,4-dihydroxy-5- (hydroxymethyl)-2-methyl-tetrahydrofuran-2-yl]pyrimidine-2,4 -dione 1 (60 mg, 0.23 mmol) was added all at once, followed by the addition of DIPEA (0.16 mL, 0.93 mmol). This was cooled to 0 ^o C and then a mixture of 3-nitro-1H-1,2,4-triazole (66 mg, 0.58 mmol) and BOPCl (0.15 g, 0.58 mmol) was added all at once. The mixture was allowed to stir overnight with the temperature warming to rt gradually. After overnight reaction, it was quenched with MeOH and Celite was added. The mixture was concentrated in vacuo. The crude material was purified by ISCO column chromatography (24 g) eluting from 100% DCM to 15% MeOH in DCM to afford the desired product with some impurity. This impure material was repurified by ISCO column chromatography (24 g) eluting from 100% EtOAc to 10% EtOH in EtOAc to afford [2,2- dimethylpropanoyloxymethoxy-[[(2R,5R)-5-(2,4-dioxopyrimidin- 1-yl)-3,4-dihydroxy-5-methyl- tetrahydrofuran-2-yl]methoxy]phosphoryl]oxymethyl 2,2-dimethylpropanoate 3 (23 mg, 17.5%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.07 (d, J = 8.3 Hz, 1H), 6.13 – 5.50 (m, 5H), 4.70 (d, J = 4.7 Hz, 1H), 4.39 (ddd, J = 10.6, 6.6, 3.5 Hz, 1H), 4.31 – 4.18 (m, 2H), 4.05 (dd, J = 7.3, 4.8 Hz, 1H), 1.67 (s, 3H), 1.24 (dd, J = 3.2, 0.4 Hz, 18H). ¹³ C NMR (101 MHz, CD3OD) δ 178.11, 166.87, 152.37, 142.53, 102.02, 101.37, 84.52, 82.73, 76.03, 71.13, 68.37, 39.91, 27.39, 21.98. ³¹ P NMR (162 MHz, CD3OD) δ -4.43. LCMS Calculated for C ₂₂ H ₃₅ N ₂ NaO ₁₃ P [M+Na ⁺ ]: 589.18; found: 589.2. Example 88. Synthesis of EIDD-2922 To a 25 mL pear-shaped flask charged with 1-[(2R,5R)-3,4-dihydroxy-5- (hydroxymethyl)-2-methyl-tetrahydrofuran-2-yl]pyrimidine-2,4 -dione 1 (0.30 g, 1.16 mmol) was added dry pyridine (2.9 mL) to give a colorless solution under argon. Then DMAP (28 mg, 0.23 mmol) was added. The mixture was cooled to 0 ^o C and Ac ₂ O (1.1 mL, 11.62 mmol) was added drop wise. After addition, ice-water bath was removed, and the mixture was stirring at rt overnight. After stirring 19 h, the reaction was quenched with water and concentrated in vacuo. To the residue was added EtOAc and water. Organic layer was separated and washed once with brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The crude material was purified by ISCO column chromatography (24 g) eluting from 100% hexanes to 100% EtOAc to afford [(2R,5R)-3,4-diacetoxy-5-(2,4-dioxopyrimidin-1-yl)-5-methyl- tetrahydrofuran-2- yl]methyl acetate 4 (0.45 g, 100%). 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 7.89 (d, J = 8.4 Hz, 1H), 6.08 (d, J = 5.0 Hz, 1H), 5.72 (dd, J = 8.3, 2.1 Hz, 1H), 5.28 (dd, J = 6.8, 5.0 Hz, 1H), 4.46 (dt, J = 6.7, 3.4 Hz, 1H), 4.37 – 4.19 (m, 2H), 2.19 (s, 3H), 2.10 (s, 3H), 2.07 (d, J = 0.8 Hz, 3H), 1.72 (s, 3H). To a 200 mL pear-shaped flask charged with [(2R,5R)-3,4-diacetoxy-5-(2,4- dioxopyrimidin-1-yl)-5-methyl-tetrahydrofuran-2-yl]methyl acetate 4 (0.45 g, 1.16 mmol) and 1,2,4-triazole (0.58 g, 8.36 mmol) was added dry MeCN (4.6 mL) to give a suspension under argon. Then POCl3 (0.16 mL, 1.74 mmol) was added to give a clear solution. This was cooled to 0 ^o C and then Et ₃ N (1.29 mL, 9.28 mmol) was added drop wise. The reaction was allowed to stir overnight with the temperature warms up to rt gradually. After overnight stirring, the red suspension was concentrated in vacuo. The residue was treated with EtOAc and water. Aqueous layer was separated and re-extracted with DCM twice. The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The crude material was purified by ISCO column chromatography (40 g) eluting from 100% DCM to 15% MeOH in DCM to afford [(2R,5R)-3,4-diacetoxy-5-methyl-5-[2-oxo-4-(1,2,4-triazol-1- yl)pyrimidin-1- yl]tetrahydrofuran-2-yl]methyl acetate 5 (0.24 g, 47.5%). 1H NMR (400 MHz, CDCl3) δ 9.26 (d, J = 0.9 Hz, 1H), 8.54 (d, J = 7.4 Hz, 1H), 8.14 (d, J = 1.0 Hz, 1H), 7.20 – 6.85 (m, 1H), 6.09 (d, J = 5.1 Hz, 1H), 5.27 – 5.22 (m, 1H), 4.52 (dt, J = 6.7, 3.5 Hz, 1H), 4.29 (qd, J = 12.7, 3.2 Hz, 2H), 2.22 (s, 3H), 2.07 (s, 3H), 2.03 (s, 3H), 1.84 (s, 3H). To a 25 mL pear-shaped flask charged with [(2R,5R)-3,4-diacetoxy-5-methyl-5-[2-oxo- 4-(1,2,4-triazol-1-yl)pyrimidin-1-yl]tetrahydrofuran-2-yl]me thyl acetate 5 (0.24 g, 0.55 mmol) was added MeCN (5.5 mL) to give a colorless solution. This was treated with 50% aqueous hydroxylamine solution (0.34 mL, 5.51 mmol). After 4.5 h, more 50% aqueous hydroxylamine solution (0.34 mL, 5.51 mmol) was added, and this was allowed to stir at rt overnight. After overnight reaction, TLC still showed a lot of mono-deprotected product, then some MeCN was removed in vacuo and more 50% aqueous hydroxylamine solution (2 mL) was added. The mixture was allowed to stir over the weekend. Then Celite was added, and the mixture was concentrated in vacuo. The crude material was purified by ISCO column chromatography (24 g) eluting from 100% DCM to 20% MeOH in DCM to afford the product with some impurity. It was repurified by ISCO column chromatography (24 g) eluting from 100% EtOAc to 15% EtOH in EtOAc to afford 1-[(2R,5R)-3,4-dihydroxy-5-(hydroxymethyl)-2- methyl-tetrahydrofuran-2-yl]-4-(hydroxyamino)pyrimidin-2-one 6 (28 mg, 18.6%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.48 (d, J = 8.5 Hz, 1H), 5.51 (d, J = 8.5 Hz, 1H), 4.61 (d, J = 3.9 Hz, 1H), 4.04 (dd, J = 3.3, 1.9 Hz, 2H), 3.75 (dd, J = 11.7, 2.4 Hz, 1H), 3.61 (dd, J = 12.3, 4.6 Hz, 1H), 1.60 (d, J = 0.9 Hz, 3H). ¹³ C NMR (101 MHz, CD3OD) δ 152.01, 147.42, 132.76, 100.14, 97.77, 85.64, 77.08, 72.17, 62.59, 22.05. LCMS Calculated for C10H14N3O6 [M-H ⁺ ]: 272.09; found: 272.1. Example 89. Synthesis of EIDD-3216 To a 50 mL pear-shaped flask charged with uracil (0.98 g, 8.74 mmol) was added HMDS (6.72 mL, 32.04 mmol) under argon. Then TMSCl (1.1 mL, 8.45 mmol) was added drop wise. The mixture was heated to 130 ^o C for 4 h. Then solvent was removed in vacuo. The cloudy oily residue was further dried under oil pump. Then dry MeCN (11.3 mL) was added, and this was added to a 50 mL round-bottomed flask charged with [(3'aR,4S,6'R,6'aR)-2,2,2',2'- tetramethylspiro[1,3-dioxolane-4,4'-6,6a-dihydro-3aH-furo[3, 4-d][1,3]dioxole]-6'-yl]methyl 4- methylbenzoate 7 (1.88 g, 4.97 mmol) (prepared according to Org. Biomol. Chem.2005, 3, 4362-4372). The flask was then cooled to 0 ^o C and TMSOTf (1.1 mL, 5.96 mmol) was added drop wise. The mixture was allowed to warm up to rt gradually and stir overnight. After overnight reaction, the mixture was treated with sat NaHCO ₃ drop wise. After stirring for 30 min, it was extracted with EtOAc (3X). The combined organic layers were washed with brine once, dried (Na2SO4), filtered and concentrated in vacuo. The crude material was purified by ISCO column chromatography (40 g) eluting from 100% DCM to 10% MeOH in DCM to afford [(3aR,4R,6R,6aR)-4-(2,4-dioxopyrimidin-1-yl)-4-(hydroxymethy l)-2,2-dimethyl-6,6a- dihydro-3aH-furo[3,4-d][1,3]dioxol-6-yl]methyl 4-methylbenzoate 8 (1.2 g, 56%) as a 1:1 mixture of anomers. To a 100 mL pear-shaped flask charged with dry DCM (18 mL) under argon was added oxalyl chloride (0.30 mL, 3.5 mmol). This was cooled to -60 ^o C and then a dry DCM (2.6 mL) solution of DMSO (0.49 mL, 6.94 mmol) was added drop wise. After stirring at -60 ^o C for 20 min, a dry DCM (7 mL) solution of [(3aR,4R,6R,6aR)-4-(2,4-dioxopyrimidin-1-yl)-4- (hydroxymethyl)-2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1, 3]dioxol-6-yl]methyl 4- methylbenzoate 8 (1.20 g, 2.78 mmol) was added drop wise. After stirring at -60 ^o C for 37 min, Et3N (1.93 mL, 13.88 mmol) was added drop wise. After 10 min, dry-ice acetone bath was removed, and the mixture was allowed to stir at rt for 100 min. Aliquot 1H NMR showed no starting material, then it was quenched by adding water (30 mL). The mixture was extracted with DCM (2 X 100 mL). The combined organic layers were washed with 1% HCl (75 mL), 5% NaHCO3 (75 mL), brine (100 mL), dried (Na2SO4), filtered and concentrated in vacuo to afford [(3aR,4S,6R,6aR)-4-(2,4-dioxopyrimidin-1-yl)-4-formyl-2,2-di methyl-6,6a-dihydro-3aH- furo[3,4-d][1,3]dioxol-6-yl]methyl 4-methylbenzoate 9 (1.14 g, 95.4%) as an off-white glassy solid as a 1:1 mixture of two anomeric aldehydes, which was used directly in the next step. To a 200 mL pear-shaped flask charged with [(3aR,4S,6R,6aR)-4-(2,4-dioxopyrimidin-1- yl)-4-formyl-2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]d ioxol-6-yl]methyl 4- methylbenzoate 9 (1.14 g, 2.65 mmol) was added dry pyridine (22 mL) to give a light orange solution under argon. Then hydroxylamine hydrochloride (0.74 g, 10.59 mmol) was added all at once, and the mixture was allowed to stir at rt. After 4 h, water was added, and solvent was removed in vacuo. To the residue was added DCM and water. Organic layer was separated from the aqueous layer, which was re-extracted with DCM twice. The combined organic layers were washed with brine once, dried (Na2SO4), filtered and concentrated in vacuo to afford [(3aR,4R,6R,6aR)-4-(2,4-dioxopyrimidin-1-yl)-4-[(Z)-hydroxyi minomethyl]-2,2- dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-6-yl]methyl 4-methylbenzoate 10 (1.24 g, 105%) as a white solid as a 1:1 anomeric mixture. The crude material was used directly in the next step. To a 100 mL pear-shaped flask charged with [(3aR,4R,6R,6aR)-4-(2,4-dioxopyrimidin- 1-yl)-4-[(Z)-hydroxyiminomethyl]-2,2-dimethyl-6,6a-dihydro-3 aH-furo[3,4-d][1,3]dioxol-6- yl]methyl 4-methylbenzoate 10 (0.54 g, 1.21 mmol) was added dry DCM (8.6 mL) to give a white suspension under argon. Then the mixture was cooled to 0 ^o C and Et3N (0.51 mL, 3.62 mmol) was added to give a clear colorless solution. Then MsCl (0.19 mL, 2.42 mmol) was added drop wise to give a light-yellow suspension. After 14 min, ice-water bath was removed, and the mixture was allowed to stir at rt. After 4 h, the reaction was quenched with 5 mL cold water. Organic layer was separated from the aqueous layer, which was re-extracted with DCM twice. The combined organic layers were washed with brine once, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The crude material was purified by ISCO column chromatography (24 g) eluting from 100% hexanes to 50% EtOAc in hexanes to afford [(3aR,4R,6R,6aR)-4-cyano-4- (2,4-dioxopyrimidin-1-yl)-2,2-dimethyl-6,6a-dihydro-3aH-furo [3,4-d][1,3]dioxol-6-yl]methyl 4- methylbenzoate 11 (0.48 g, 92.9%) as a white glassy solid as a 1:1 anomeric mixture. To a 100 mL pear-shaped flask charged with [(3aR,4R,6R,6aR)-4-cyano-4-(2,4- dioxopyrimidin-1-yl)-2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4- d][1,3]dioxol-6-yl]methyl 4- methylbenzoate 11 (0.48 g, 1.12 mmol) was added freshly prepared 80% formic acid (6.0 mL, 126.9 mmol) to give a colorless solution. This was allowed to stir at rt. After 4.5 h, more 80% formic acid (6.0 mL, 126.9 mmol) was added and allowed to stir at rt overnight. After overnight reaction, solvent was removed in vacuo and co-evaporated with MeOH twice. To the residue, MeOH and Celite added, and the mixture was concentrated in vacuo. The crude material was purified twice by ISCO column chromatography (40 g) eluting from 100% DCM to 25% MeOH in DCM to afford [(2R,3S,4R,5R)-5-cyano-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihyd roxy- tetrahydrofuran-2-yl]methyl 4-methylbenzoate 12 (150 mg, 34.5%) as a white glassy solid. 1H NMR (400 MHz, CDCl ₃ ) δ 8.38 (s, 1H), 7.78 – 7.71 (m, 2H), 7.66 (dd, J = 8.4, 0.5 Hz, 1H), 7.26 – 7.21 (m, 2H), 5.72 (dd, J = 8.4, 1.8 Hz, 1H), 5.25 (s, 1H), 4.89 (q, J = 2.7 Hz, 1H), 4.78 (dd, J = 12.9, 3.1 Hz, 1H), 4.62 (d, J = 4.9 Hz, 1H), 4.51 (d, J = 4.6 Hz, 1H), 4.43 (dd, J = 12.9, 2.8 Hz, 1H), 3.29 (s, 1H), 2.42 (s, 3H). To a 100 mL pear-shaped flask charged with [(2R,3S,4R,5R)-5-cyano-5-(2,4- dioxopyrimidin-1-yl)-3,4-dihydroxy-tetrahydrofuran-2-yl]meth yl 4-methylbenzoate 12 (150 mg, 0.39 mmol) was added 7 N ammonia in MeOH (3 mL, 21 mmol). The flask was capped tightly and allowed to stir at rt. After 1.5 h, more 7 N ammonia in MeOH (3 mL) was added. This was allowed to stir at rt overnight. After stirring 20.5 h, solvent was removed in vacuo. The crude material was purified by ISCO column chromatography (12 g) eluting from 100% DCM to 15% MeOH in DCM to afford (2R,3R,4S,5R)-2-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-carbonitrile 13 (56 mg, 53.7%) as a white solid. ¹ H NMR matches with what was reported in the literature (Nucleosides, Nucleotides and Nucleic Acids, 2015, 34:763-785, compound 3). 1H NMR (400 MHz, DMSO-d6) δ 11.56 (s, 1H), 8.04 (d, J = 8.3 Hz, 1H), 6.69 (d, J = 5.8 Hz, 1H), 5.60 (d, J = 8.3 Hz, 1H), 5.40 – 5.03 (m, 2H), 4.33 (dd, J = 5.8, 4.3 Hz, 1H), 4.17 – 4.02 (m, 1H), 3.96 – 3.71 (m, 2H), 3.53 (ddd, J = 13.0, 5.0, 2.9 Hz, 1H). ¹³ C NMR (101 MHz, CD3OD) δ 166.10, 151.71, 140.25, 115.53, 102.69, 92.94, 86.99, 77.95, 68.82, 60.05. LCMS Calculated for C ₁₀ H ₁₀ N ₃ O ₆ [M-H ⁺ ]: 268.06; found: 267.8. Example 90. Synthesis of EIDD-3270 To a 100 mL pear-shaped flask charged with uracil (6.15 g, 54.89 mmol) was added MeCN (100 mL), followed by trimethylsilyl (1Z)-N-trimethylsilylethanimidate (33.5 mL, 137.22 mmol). The mixture was heated to 60 ^o C and after heating 2 h, heat was removed. After cooling to 0 ^o C, [rac-(3'aR,6'R,6'aR)-2,2,2',2'-tetramethylspiro[1,3-dioxolan e-4,4'-6,6a-dihydro- 3aH-furo[3,4-d][1,3]dioxole]-6'-yl]methyl benzoate 14 (10 g, 27.44 mmol) (prepared according to Chem. Eur.J.2014, 20, 11685-11689) was added and the rest of the sugar 14 was diluted with dry MeCN (50 mL). The mixture was sonicated to make a clear solution. Then TMSOTf (9.93 mL, 54.89 mmol) was added drop wise over 8 min. After 10 min, ice-water bath was removed and allowed to stir at rt. TLC showed some unreacted starting material, then the mixture was cooled to 0 ^o C and more TMSOTf (5 mL) was added. After addition, ice-water bath was removed. The mixture was allowed to stir at rt overnight. After overnight reaction, TLC still showed some starting material. The mixture was treated with solid NaHCO3 (15 g), followed by 15 mL water. After stirring at rt for 1 h, it was filtered through Celite, and the solids were washed with MeCN. Filtrate was concentrated in vacuo. To the residue, 100 mL water was added, and it was extracted with DCM (2 X 150 mL). The combined organic layers were washed with water once, dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with a mixture of hexanes and EtOAc to afford [rac-(3aR,4R,6R,6aR)-4-(2,4-dioxopyrimidin-1-yl)-4-(hydroxym ethyl)-2,2-dimethyl-6,6a- dihydro-3aH-furo[3,4-d][1,3]dioxol-6-yl]methyl benzoate 15 (2.5 g, 21.8%) as a white solid. 1H NMR (400 MHz, CDCl ₃ ) δ 8.86 (s, 1H), 7.88 – 7.74 (m, 2H), 7.64 (dd, J = 8.3, 0.6 Hz, 1H), 7.57 (ddt, J = 8.1, 7.1, 1.3 Hz, 1H), 7.42 (td, J = 7.6, 1.0 Hz, 2H), 5.45 – 5.39 (m, 2H), 4.88 (dd, J = 6.2, 1.3 Hz, 1H), 4.84 – 4.75 (m, 1H), 4.59 (dd, J = 12.6, 2.8 Hz, 1H), 4.35 (dd, J = 12.5, 3.5 Hz, 1H), 4.18 (d, J = 12.4 Hz, 1H), 3.80 (d, J = 12.4 Hz, 1H), 2.20 (bs, 1H), 1.59 (s, 3H), 1.39 (s, 3H). To a 500 mL pear-shaped flask charged with dry DCM (74 mL) under argon was added oxalyl chloride (1.28 mL, 14.94 mmol). This was cooled to -70 ^o C and then a dry DCM (24.8 mL) solution of DMSO (2.11 mL, 29.64 mmol) was added drop wise over 28 min. After 30 min, a cloudy mixture of [(3aR,4R,6R,6aR)-4-(2,4-dioxopyrimidin-1-yl)-4-(hydroxymethy l)- 2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-6-yl]me thyl benzoate 15 (4.96 g, 11.85 mmol) in 80 mL DCM was added over 45 min at -60 ^o C. After 25 min, Et ₃ N (8.71 mL, 62.47 mmol) was added drop wise at -60 ^o C. After addition, dry ice-acetone bath was removed, and the white cloudy mixture became a yellow solution. After 4 h, the mixture was quenched with cold water, and re-extracted with DCM twice. Organic layers were washed with sat NH4Cl once, 5% NaHCO ₃ once, brine once, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to afford [(3aR,4S,6R,6aR)-4-(2,4-dioxopyrimidin-1-yl)-4-formyl-2,2-di methyl-6,6a-dihydro-3aH- furo[3,4-d][1,3]dioxol-6-yl]methyl benzoate 16 (3.86 g, 78.2%) as a light orange glassy solid, which was used directly in the next step. 1H NMR (400 MHz,DMSO-d6) δ 11.38 (d, J = 2.2 Hz, 1H), 9.47 (d, J = 0.6 Hz, 1H), 7.84 – 7.74 (m, 2H), 7.69 – 7.61 (m, 1H), 7.59 (dd, J = 8.2, 0.6 Hz, 1H), 7.47 (t, J = 7.8 Hz, 2H), 5.56 (d, J = 5.8 Hz, 1H), 5.36 – 5.28 (m, 1H), 5.14 (dd, J = 5.8, 1.1 Hz, 1H), 5.08 – 5.01 (m, 1H), 4.56 (dd, J = 12.6, 2.9 Hz, 1H), 4.45 (dd, J = 12.6, 3.8 Hz, 1H), 1.52 (s, 3H), 1.35 (s, 3H). To a 500 mL round-bottomed flask charged with [(3aR,4S,6R,6aR)-4-(2,4- dioxopyrimidin-1-yl)-4-formyl-2,2-dimethyl-6,6a-dihydro-3aH- furo[3,4-d][1,3]dioxol-6- yl]methyl benzoate (3.86 g, 9.27 mmol) 16 was added dry pyridine (46 mL) to give a light orange solution under argon. The flask was cooled to 0 ^o C and then hydroxylamine hydrochloride (1.29 g, 18.54 mmol) was added to give a yellow solution. The mixture was allowed to stir at 0 ^o C for 10 min, then ice-water bath was removed. After another 4.5 h, solvent was removed in vacuo and further dried under oil pump. To the residue was added 100 mL DCM, followed by 30 mL water. Organic layer was separated and washed with brine (30 mL) once. The aqueous layer was re-extracted with DCM (50 mL) once. The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The crude material was purified by ISCO column chromatography (40 g) eluting from 100% DCM to 15% MeOH in DCM to afford [(3aR,4R,6R,6aR)-4-(2,4-dioxopyrimidin-1-yl)-4-[(Z)-hydroxyi minomethyl]-2,2- dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-6-yl]methyl benzoate 17 (2.27 g, 56.8%) as a yellow glassy solid. 1H NMR (400 MHz, DMSO-d6) δ 11.37 (s, 1H), 11.19 (s, 1H), 8.65 – 8.53 (m, 1H), 7.82 – 7.75 (m, 2H), 7.72 (d, J = 8.2 Hz, 1H), 7.50 – 7.43 (m, 1H), 7.41 – 7.36 (m, 2H), 5.47 (d, J = 5.9 Hz, 1H), 5.28 (dd, J = 8.3, 2.3 Hz, 1H), 5.06 (dd, J = 5.9, 0.8 Hz, 1H), 4.90 (t, J = 3.5 Hz, 1H), 4.52 (dd, J = 12.5, 2.9 Hz, 1H), 4.40 (dd, J = 12.5, 4.1 Hz, 1H), 1.52 (s, 3H), 1.35 (s, 3H). To a 200 mL pear-shaped flask charged with [(3aR,4R,6R,6aR)-4-(2,4-dioxopyrimidin- 1-yl)-4-[(Z)-hydroxyiminomethyl]-2,2-dimethyl-6,6a-dihydro-3 aH-furo[3,4-d][1,3]dioxol-6- yl]methyl benzoate 17 (0.94 g, 2.18 mmol) was added dry DCM (11 mL) to give a yellow solution under argon. Then Et3N (0.91 mL, 6.54 mmol) was added drop wise. The flask was cooled to 0 ^o C and then Ms ₂ O (0.57 g, 3.27 mmol) was added portion wise. After stirring for 2h20 min, the reaction was quenched with 10 mL water and diluted with DCM. Organic layer was separated, and the aqueous layer was re-extracted with DCM once. The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo with Celite. The crude material was purified by ISCO column chromatography (40 g) eluting from 100% hexanes to 100% EtOAc to afford the product, which was triturated with a mixture of EtOAc and TBME. The solids were filtered and washed with TBME to afford [(3aR,4R,6R,6aR)-4-cyano-4-(2,4- dioxopyrimidin-1-yl)-2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4- d][1,3]dioxol-6-yl]methyl benzoate 18 (0.37 g, 41.1%) as a tan-colored solid. 1H NMR (400 MHz, CDCl ₃ ) δ 7.85 (s, 1H), 7.84 – 7.76 (m, 2H), 7.67 – 7.58 (m, 1H), 7.54 (dd, J = 8.4, 1.7 Hz, 1H), 7.45 (dddd, J = 7.8, 7.2, 1.3, 0.8 Hz, 2H), 5.63 – 5.50 (m, 1H), 5.20 (d, J = 5.6 Hz, 1H), 5.10 (s, 1H), 4.97 (ddd, J = 5.6, 1.7, 1.2 Hz, 1H), 4.79 – 4.66 (m, 1H), 4.45 (ddd, J = 12.9, 2.8, 1.4 Hz, 1H), 1.79 (s, 3H), 1.50 – 1.42 (m, 3H). To a 200 mL pear-shaped flask charged with [(3aR,4R,6R,6aR)-4-cyano-4-(2,4- dioxopyrimidin-1-yl)-2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4- d][1,3]dioxol-6-yl]methyl benzoate 18 (0.20 g, 0.48 mmol) was added dry DCM (7 mL) to give a suspension under argon. This was cooled to 0 ^o C and then DMAP (6 mg, 0.05 mmol) was added, followed by drop wise addition of DIPEA (0.42 mL, 2.38 mmol) to give a clear solution. After 10 min, 2,4,6- triisopropylbenzenesulfonyl chloride (0.29 g, 0.95 mmol) was added portion wise. After 8 min, ice-water bath was removed, and the mixture was allowed to stir at rt overnight. After overnight stirring, TLC showed no starting material. Then the mixture was cooled to 0 ^o C and then DIPEA (0.33 mL, 1.91 mmol) was added. After 15 min, hydroxylamine ^{hydrochloride} (0.13 g, 1.91 mmol) was added all at once. After addition, ice-water bath was removed. After 4h20min, 5 mL cold water was added, followed by more DCM. Organic layer was separated and washed once with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude material was purified by ISCO column chromatography (24 g) eluting from 100% DCM to 25% MeOH in DCM to afford [(3aR,4R,6R,6aR)-4-cyano-4-[4-(hydroxyamino)-2-oxo-pyrimidin -1-yl]-2,2-dimethyl- 6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-6-yl]methyl benzoate 19 (0.09 g, 44.1 % yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.92 – 7.79 (m, 2H), 7.67 – 7.56 (m, 1H), 7.50 – 7.34 (m, 2H), 7.06 (d, J = 8.4 Hz, 1H), 5.39 (d, J = 8.5 Hz, 1H), 5.23 (d, J = 5.4 Hz, 1H), 5.13 – 5.08 (m, 2H), 4.65 (dd, J = 12.9, 2.3 Hz, 1H), 4.46 (dd, J = 12.9, 2.8 Hz, 1H), 1.68 (s, 3H), 1.43 (s, 3H). To a 25 mL pear-shaped flask charged with [(3aR,4R,6R,6aR)-4-cyano-4-[4- (hydroxyamino)-2-oxo-pyrimidin-1-yl]-2,2-dimethyl-6,6a-dihyd ro-3aH-furo[3,4-d][1,3]dioxol- 6-yl]methyl benzoate 19 (0.08 g, 0.19 mmol) cooled to 0 ^o C was added freshly made cold aqueous TFA solution (2 mL,1/1 v/v, TFA/H2O) drop wise. The mixture was allowed to stir at 0 ^o C for 1 h. Then ice-water bath was removed, and the reaction was allowed to stir at rt. After 5h40min, more aqueous TFA solution (2 mL, 1/1 v/v) was added and allowed to stir at rt overnight. After stirring overnight for 17h20min, more aqueous TFA solution (1 mL, 1/1 v/v) was added. After 1 h, solvent was removed by co-evaporating with EtOH twice. The residue was diluted with EtOH and Celite was added. The mixture was concentrated in vacuo and purified by ISCO column chromatography (12 g) eluting from 100% DCM to 25% MeOH in DCM to afford [1-[(2R,3R,4S,5R)-5-(benzoyloxymethyl)-2-cyano-3,4-dihydroxy -tetrahydrofuran-2-yl]-2-oxo- pyrimidin-4-yl]-hydroxy-ammonium;2,2,2-trifluoroacetate 20 (60 mg, 64%) as a TFA salt as an off-white solid. 1H NMR (400 MHz, CD ₃ OD) δ 8.11 – 7.93 (m, 2H), 7.69 – 7.58 (m, 1H), 7.56 – 7.44 (m, 2H), 7.21 (dd, J = 8.5, 1.1 Hz, 1H), 5.42 (dd, J = 8.5, 1.1 Hz, 1H), 4.78 – 4.70 (m, 1H), 4.65 (dd, J = 4.4, 1.1 Hz, 1H), 4.62 – 4.54 (m, 2H), 4.19 (ddd, J = 7.9, 4.6, 1.1 Hz, 1H). ¹⁹ F NMR (376 MHz, CD3OD) δ -77.09. To a 100 mL pear-shaped flask charged with [1-[(2R,3R,4S,5R)-5-(benzoyloxymethyl)- 2-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]-2-oxo-pyrimidin- 4-yl]-hydroxy-ammonium;2,2,2- trifluoroacetate 20 (66 mg, 0.13 mmol) cooled to 0 ^o C was added 7 N ammonia in MeOH (2.4 mL, 17 mmol) to give a light orange solution. After stirring for 40 min, ice-water bath was removed. After stirring at rt for 1.5 h, more 7 N ammonia in MeOH (4 mL, 28 mmol) was added at rt. After overnight stirring, solvent was removed in vacuo. The crude material was purified by ISCO reverse phase column chromatography (50 g, flow rate 40 mL/min) eluting from 100% water to 100% CH3CN to 80% CH3CN in water to afford (2R,3R,4S,5R)-3,4-dihydroxy-2-[4- (hydroxyamino)-2-oxo-pyrimidin-1-yl]-5-(hydroxymethyl)tetrah ydrofuran-2-carbonitrile 21 (9.4 mg, 19.5%) as a white solid. 1H NMR (400 MHz, CD ₃ OD) δ 7.43 (d, J = 8.5 Hz, 1H), 5.59 (d, J = 8.5 Hz, 1H), 4.50 (d, J = 4.7 Hz, 1H), 4.24 (ddd, J = 8.6, 3.4, 2.3 Hz, 1H), 4.06 (dd, J = 8.6, 4.7 Hz, 1H), 3.94 (dd, J = 12.9, 2.4 Hz, 1H), 3.73 (dd, J = 12.9, 3.5 Hz, 1H). ¹³ C NMR (101 MHz, CD3OD) δ 151.08, 146.00, 129.89, 116.10, 99.22, 92.73, 86.81, 78.28, 69.38, 60.56. LCMS Calculated for C10H13N4O6 [M+H ⁺ ]: 285.06; found: 285.0. Example 91. Synthesis of EIDD-3190 5-O-benzyl-2,3-O-isopropylidene-D-ribono-1,4-lactone An oven-dried 200 mL round-bottomed flask was charged with 2,3-O-isopropylidene-D- ribono-1,4-lactone (8.45 g, 44.90 mmol) and anhydrous DMF (40 mL). After cooling to 0 ^o C, the solution was treated with benzyl bromide (6.41 mL, 53.89 mmol) followed by sodium hydride (2.16 g of 60% in mineral oil dispersion, 53.89 mmol) added in 4 portions. The mixture was stirred for 1h at 0 ^o C and then at rt for 16h. After quenching with aqueous 0.1N HCl (40 mL), the mixture was extracted into ethyl acetate (150 mL) and washed with saturated sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate, filtered, concentrated, and purified by column chromatography over silica gel (120 g) to give 5-O-benzyl-2,3-O- isopropylidene-D-ribono-1,4-lactone (9.92 g, 79%). 1H NMR (400 MHz, CDCl3) δ 7.60 – 7.08 (m, 5H), 4.79 (d, J = 5.5 Hz, 1H), 4.71 (d, J = 5.5 Hz, 1H), 4.65 (t, J = 2.0 Hz, 1H), 4.56 (d, J = 11.8 Hz, 1H), 4.47 (d, J = 11.8 Hz, 1H), 3.76 – 3.64 (m, 2H), 1.47 (d, J = 0.7 Hz, 3H), 1.37 (q, J = 0.6 Hz, 3H). 5-O-benzyl-2,3-O,O-isopropylidene-1-C-methyl-D-ribose An oven-dried 250 mL round-bottomed flask was charged with 5-O-benzyl-2,3-O- isopropylidene-D-ribono-1,4-lactone and anhydrous THF (60 mL). After cooling to -78°C, the solution was treated dropwise over a 30 min period with a THF solution of 1.6 M methyllithium (13 mL, 20.87 mmol). The mixture continued to stir for 4h at -78°C. After removing the cooling bath, the mixture was treated with saturated sodium bicarbonate solution (20 mL) and ethyl acetate (100 mL). The organic layer was collected and dried over sodium sulfate, filtered and concentrated. The resulting gum was purified by column chromatography over silica gel (80g) eluting with an ethyl acetate/hexanes mobile phase gradient to give an anomeric mixture of 5-O- benzyl-2,3-O-isopropylidene-1-C-methyl-D-ribose as a colorless oil. 1H NMR (400 MHz, CDCl3, anomeric mixture) δ 7.45 – 7.28 (m, 6H), 4.84 (dd, J = 5.9, 1.4 Hz, 1H, anomer 1), 4.79 (d, J = 5.5 Hz, 1H, anomer 2), 4.73 – 4.70 (m, 1H), 4.65 (d, J = 11.5 Hz, 1H, anomer 1), 4.54 (d, J = 11.5 Hz, 1H, anomer 1), 4.43 (d, J = 5.9 Hz, 1H, anomer 1), 4.29 (q, J = 2.2 Hz, 1H, anomer 1), 3.72 – 3.49 (m, 4H, anomer 1 and 2), 1.50 (s, 3H, anomer 1), 1.49 (s, 3H, anomer 1), 1.47 (s, 3H, anomer 2), 1.37 (t, J = 0.6 Hz, 3H, anomer 2), 1.32 (d, J = 0.8 Hz, 3H, anomer1). 1-O-acetyl-5-O-benzyl-2,3-O,O-isopropylidene-1-C-methyl-D-ri bose An oven-dried 250 mL round-bottomed flask was charged with 5-O-benzyl-2,3-O- isopropylidene-1-C-methyl-D-ribose (4.25 g, 14.439 mmol), 4-dimethylaminopyridine (176 mg, 1.444 mmol) and anhydrous pyridine (50 mL). The mixture was treated dropwise with acetic anhydride (6.81 mL, 72.195 mmol) and allowed to stir for 12 h at rt. After cooled with ice bath, the mixture was treated with treated with cold saturated sodium bicarbonate solution followed by extraction into methylene chloride (150 mL). The organic layer was washed with brine, concentrated, and purified by column chromatography over silica gel (80 g) eluting with an ethyl acetate/hexanes mobile phase gradient to give 1-O-acetyl-5-O-benzyl-2,3-O,O-isopropylidene-1- C-methyl-D-ribose (2.15 g, 44%) as a single anomer and 1-O-acetyl-5-O-benzyl-2,3-O,O- isopropylidene-1-C-methyl-D-ribose (1.95 g, 40%) as a mixture of anomers 1H NMR (400 MHz, cdcl3) δ 7.46 – 7.22 (m, 5H), 4.87 – 4.68 (m, 2H), 4.64 – 4.50 (m, 2H), 4.39 (ddd, J = 7.5, 5.9, 1.7 Hz, 1H), 3.55 (dd, J = 9.9, 5.9 Hz, 1H), 3.47 (dd, J = 9.9, 7.3 Hz, 1H), 1.89 (d, J = 0.4 Hz, 3H), 1.76 (s, 3H), 1.50 (d, J = 0.7 Hz, 3H), 1.34 (d, J = 0.8 Hz, 3H). 5’-O-benzyl-2’,3’-O,O-isopropylidene-1’-C-methylurid ine An oven-dried 200 mL round-bottomed flask was charged with 1-O-acetyl-5-O-benzyl- 2,3-O,O-isopropylidene-1-C-methyl-D-ribose (4.5 g, 13.38 mmol), uracil, and anhydrous acetonitrile (40 mL). This suspension was treated dropwise with N,O- bis(trimethylsilyl)acetamide (16.53 mL, 66.89 mmol) at rt. After 1.5 h, the homogeneous was treated dropwise over a 5 min period with ethylaluminum dichloride (7.43 mL of a 1.8M solution in toluene, 13.38 mmol). The mixture was allowed to stir at rt for 2 h and then poured into an ice-cold mixture of 1:1 methylene chloride: saturated sodium bicarbonate. After stirring for 30 min, the mixture was filtered, and the organic layer washed with saturated sodium bicarbonate solution (50 mL) and brine (50 mL) followed by concentrating to dryness. The crude mixture of 4:1 mixture of b:a-anomers was purified by column chromatography to give the b- anomer of 5’-O-benzyl-2’,3’-O,O-isopropylidene-1’-C-methylurid ine (3.55 g, 68%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.3 Hz, 1H), 7.41 – 7.28 (m, 3H), 7.24 – 7.14 (m, 2H), 5.54 (dd, J = 8.3, 2.3 Hz, 1H), 5.14 (d, J = 6.0 Hz, 1H), 4.69 (dd, J = 6.0, 1.2 Hz, 1H), 4.65 – 4.48 (m, 1H), 4.40 (s, 2H), 3.58 (dd, J = 10.6, 2.8 Hz, 1H), 3.49 (dd, J = 10.6, 4.2 Hz, 1H), 1.61 (s, 1H), 1.59 (s, 3H), 1.38 (s, 3H). 5’-O-benzyl-1’-C-methyluridine A 1L round-bottomed flask was charged with 5’-O-benzyl-2’,3’-O,O-isopropylidene-1’- C-methyluridine (3.55 g, 9.14 mmol), methanol (350 mL), and water (150 mL). This solution was treated with Dowex 50W-8x [H+] (21.6 g) and then heated to 43°C with gentle stirring. After 18h, the mixture was filtered and the collected Dowex washed with methanol (2x 40 mL). Combined filtrates were concentrated, and the resulting crude residue purified by column chromatography over silica gel (120 g) eluting with a methylene chloride/methanol gradient. Isolated 5’-O-benzyl-1’-C-methyluridine (2.08 g, 65.3%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.90 (s, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.39 – 7.25 (m, 3H), 7.16 (dd, J = 7.8, 1.7 Hz, 2H), 5.62 (dd, J = 8.3, 1.7 Hz, 1H), 4.53 (d, J = 5.1 Hz, 1H), 4.46 – 4.34 (m, 3H), 4.31 (dd, J = 5.1, 1.2 Hz, 1H), 3.59 (dd, J = 10.5, 3.0 Hz, 1H), 3.53 (dd, J = 10.5, 3.1 Hz, 1H), 1.60 (s, 3H), 1.19 (s, 3H). 1’-C-Methyluridine A two-neck round-bottomed flask equipped with two stopcock gas inlet adapters was charged with 5’-O-benzyl-1’-C-methyluridine (1.85 g, 5.31 mmol) and methanol (175 mL). The mixture was degassed by pump-fill with argon and then treated with palladium on carbon (0.6 g, 0.56 mmol). After pump-fill with hydrogen (3 x), the mixture was stirred under atm. hydrogen for 30 min and then filtered through a pad of Celite. The collected palladium was rinsed with methanol (25 mL), and combined filtrates concentrated to dryness to give 1’-C-methyluridine (1.27 g, 92.6%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.22 (d, J = 8.3 Hz, 1H), 5.62 (d, J = 8.3 Hz, 1H), 4.62 (d, J = 4.6 Hz, 1H), 4.12 – 4.00 (m, 2H), 3.81 (dd, J = 12.4, 2.8 Hz, 1H), 3.63 (dd, J = 12.4, 4.3 Hz, 1H), 1.65 (s, 3H). 5’-Deoxy-5’-iodo-1’-C-methyluridine An oven-dried 100 mL two-neck round-bottomed flask equipped with a thermometer was charged with 1’-C-methyluridine (1.20 g, 4.65 mmol), triphenylphosphine (1.83 g, 6.97 mmol), imidazole (0.47 g, 6.97 mmol) and anhydrous THF (18 mL). The suspension was stirred vigorously for 30 min and then treated over a 10 min period with a THF (5 mL) solution of iodine (142.91g, 563.06mmol) while maintaining a reaction temperature below 20°C. After 16 h at rt, tlc (10% methanol in DCM) indicated complete reaction. Solvent was removed in vacuo, and the resulting crude solid purified by column chromatography over silica gel (80g) eluting with a hexanes/ethyl acetate gradient to give 5’-deoxy-5’-iodo-1’-C-methyluridine (0.88g, 51%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.3 Hz, 1H), 5.77 (d, J = 8.3 Hz, 1H), 4.47 (d, J = 5.8 Hz, 1H), 4.33 (td, J = 5.8, 2.1 Hz, 1H), 4.24 (dd, J = 5.8, 2.1 Hz, 1H), 3.32 – 3.21 (m, 2H), 1.62 (s, 3H). 2’,3’-Di-O-acetyl-4’,5’-didehydro-5’-deoxy-1’-C- methyluridine A 100 mL round-bottomed flask was charged with 5’-deoxy-5’-iodo-1’-C-methyluridine (1.10 g, 2.99 mmol) and methanol (15 mL). The solution was treated with sodium methoxide (1.33 mL of a 4.5M solution in methanol) and then heated to 60 ^o C. After 5h, tlc (10% methanol in methylene chloride) indicated complete conversion. The mixture was concentrated, and the resulting residue co-evaporated with anhydrous acetonitrile (3 x 40 mL). The solid was suspended in anhydrous acetonitrile (20 mL) and treated with acetic anhydride (0.85 mL, 8.96 mmol) and 4-dimethylaminopyridine (36 mg, 0.29 mmol). After 16 h at 50 ^o C, the mixture was cooled to rt, concentrated, suspended in methylene chloride (50 mL) and treated with saturated sodium bicarbonate solution (5 mL). The mixture was stirred for 1h and then the organic layer concentrated. The resulting crude residue was purified by column chromatography over silica gel (24 g) eluting with an hexanes/ethyl acetate gradient to give 2’,3’-di-O-acetyl-4’,5’-didehydro- 5’-deoxy-1’-C-methyluridine (740 mg, 76%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 6.2 Hz, 1H), 7.50 (dd, J = 8.3, 0.5 Hz, 1H), 6.03 (dd, J = 5.2, 0.6 Hz, 1H), 5.75 (d, J = 8.4 Hz, 1H), 5.72 (dt, J = 5.3, 2.0 Hz, 1H), 4.77 (ddd, J = 3.0, 2.1, 0.8 Hz, 1H), 4.37 (dd, J = 3.0, 1.8 Hz, 1H), 2.17 (s, 3H), 2.08 (s, 3H). 4’,5’-Didehydro-5’-deoxy-1’-C-methyluridine A 75 mL thick-wall sealed vessel was charged with 2’,3’-di-O-acetyl-4’,5’-didehydro-5’- deoxy-1’-C-methyluridine (740 mg, 2.28 mmol) and 7N ammonia in methanol (14.8 mL, 684.87 mmol). After 12h at rt, tlc (10% methanol in methylene chloride) indicated complete conversion. The mixture was concentrated, and the resulting residue purified by column chromatography over silica gel (24 g) eluting with a methanol/methylene chloride gradient. Isolated 4’,5’- didehydro-5’-deoxy-1’-C-methyluridine (500 mg, 91%) as a white solid. 1H NMR (400 MHz, CD ₃ OD) δ 7.64 (dd, J = 8.3, 0.5 Hz, 1H), 5.68 (dd, J = 8.2, 0.4 Hz, 1H), 4.69 – 4.64 (m, 1H), 4.61 (td, J = 2.2, 0.8 Hz, 1H), 4.45 (dt, J = 5.0, 2.1 Hz, 1H), 4.34 (t, J = 2.1 Hz, 1H), 1.77 (s, 3H). 5’-Deoxy-4’-fluoro-5’-iodo-1’-C-methyluridine An oven-dried 100 mL round-bottomed flask was charged with 4’,5’-didehydro-5’- deoxy-1’-C-methyluridine (480 mg, 1.99 mmol) and anhydrous acetonitrile (10 mL). After cooled to 0 ^o C, the solution was treated with triethylamine-trihydrofluoride (160 mL, 1.00 mmol) followed by iodosuccinimide (584 mg, 2.60 mmol). The mixture was stirred at 0 ^o C for 3.5 h after which time LCMS indicated complete conversion. The mixture was purified by dry-loading with Celite onto a column of silica gel (24 g) and eluting with a methylene chloride/methanol gradient to give 5’-deoxy-4’-fluoro-5’-iodo-1’-C-methyluridine (495 mg, 64%). 1H NMR (400 MHz, CD ₃ OD) δ 7.83 (dd, J = 8.3, 0.4 Hz, 1H), 4.76 (d, J = 6.4 Hz, 1H), 4.24 (dd, J = 19.9, 6.4 Hz, 1H), 3.66 (dd, J = 11.6, 5.6 Hz, 1H), 3.61 – 3.46 (m, 1H), 1.75 (s, 3H). 1 ⁹ F NMR (376 MHz, CD3OD) δ -108.45 (td, J = 20.4, 5.5 Hz). 2’,3’-Di-O-benzyloxycarbonyl-5’-deoxy-4’-fluoro-5’ -iodo-1’-C-methyluridine An oven-dried 100 mL round-bottomed flask was charged with 5’-deoxy-4’-fluoro-5’- iodo-1’-C-methyluridine (495 mg, 1.28 mmol) and methylene chloride (10 mL). After cooled to 0 ^o C, the solution was treated with 1-methylimidazole (280 mL, 3.53 mmol) followed by dropwise addition of benzyl chloroformate (460 mL, 3.20 mmol). The mixture was stirred an additional 2 h at 0 ^o C and then allowed to gradually warm to rt. After 16 h, the mixture was quenched with saturated ammonium chloride solution (50 mL) followed by extraction into ethyl acetate (100 mL). The organic later was dried over sodium sulfate, filtered, and concentrated. The resulting crude residue was purified by column chromatography over silica gel (24 g) eluting with a methylene chloride/methanol gradient to give 2’,3’-di-O-benzyloxycarbonyl-5’- deoxy-4’-fluoro-5’-iodo-1’-C-methyluridine (700 mg, 76%) with a 91% purity as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.74 (dd, J = 8.4, 0.6 Hz, 1H), 7.43 – 7.30 (m, 10H), 5.96 (d, J = 6.9 Hz, 1H), 5.80 – 5.71 (m, 1H), 5.62 – 5.46 (m, 1H), 5.22 – 5.14 (m, 2H), 5.10 (d, J = 1.7 Hz, 2H), 3.63 (dd, J = 11.8, 7.6 Hz, 1H), 3.51 – 3.39 (m, 1H), 1.83 (s, 3H). 1 ⁹ F NMR (376 MHz, CDCl3) δ -103.41 – -103.55 (m). 2’,3’-Di-O-benzyloxycarbonyl-4’-fluoro-1’-C-methylur idine A 50 mL round-bottomed flask was charged with tetrabutylammonium hydroxide (1.38 mL of 55% aqueous solution, 2.92 mmol) and DI water (2 mL). With vigorous stirring, the solution was adjusted to pH 3.5 with dropwise treatment with trifluoroacetic acid (220 mL, 2.92 mmol). The mixture was then treated with a methylene chloride (10 mL) solution of 2’,3’-di-O- benzyloxycarbonyl-5’-deoxy-4’-fluoro-5’-iodo-1’-C-me thyluridine (700 mg, 0.97 mmol) followed by the addition of 3-chloroperoxybenzoic acid (840 mg, 4.87 mmol) in portions over a 50 min period. The reaction mixture drifted to more acidic pH and required treatment periodically with 2N sodium hydroxide solution to maintain above pH 2.5. After 18 h, tlc (10% methanol in methylene chloride) indicated complete conversion. The mixture was diluted with methylene chloride (100 mL) and treated with a 1:1 mixture of saturated sodium thiosulfate and sodium bicarbonate solution (35 mL). After stirring at rt for 30 min, the methylene chloride layer was dried over sodium sulfate, filtered and concentrated. The resulting gum was purified by column chromatography over silica gel (24 g) eluting with a methylene chloride/methanol gradient to give 2’,3’-di-O-benzyloxycarbonyl-4’-fluoro-1’-C-methylur idine (350 mg, 66%) as a faint yellow solid. 1H NMR (400 MHz, CDCl ₃ ) δ 7.90 (d, J = 8.4 Hz, 1H), 7.45 – 7.28 (m, 10H), 6.01 (d, J = 6.1 Hz, 1H), 5.70 (dd, J = 8.4, 1.3 Hz, 1H), 5.34 (dd, J = 19.2, 6.1 Hz, 1H), 5.25 – 5.09 (m, 4H), 3.90 (dd, J = 12.5, 2.3 Hz, 1H), 3.81 (dd, J = 12.4, 2.0 Hz, 1H), 1.86 (s, 3H). 1 ⁹ F NMR (376 MHz, CDCl3) δ -118.07 (dt, J = 19.3, 2.4 Hz). 4’-Fluoro-1’-C-methyluridine A two-neck round-bottomed flask equipped with two stopcock gas inlet adapters was charged with 2’,3’-di-O-benzyloxycarbonyl-4’-fluoro-1’-C-methylur idine (350 mg, 0.61 mmol) and methanol (7 mL). The mixture was degassed by pump-fill with argon and then treated with 10% palladium on carbon (129 mg, 0.12 mmol). After cooled to 0 ^o C, the mixture was pump- filled with hydrogen (3x) and then stirred under atm hydrogen for 45 min. After tlc (10% methanol in methylene chloride) indicated complete conversion, the mixture was filtered, and the collected palladium washed with methanol (10 mL). Combined filtrates were concentrated and purified by column chromatography over silica gel (12 g) eluting with a methylene chloride/methanol gradient to give 4’-fluoro-1’-C-methyluridine (31 mg, 17 %) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.18 (d, J = 8.3 Hz, 1H), 5.60 (d, J = 8.3 Hz, 1H), 4.64 (d, J = 6.0 Hz, 1H), 4.15 (dd, J = 21.7, 6.0 Hz, 1H), 3.74 (t, J = 3.2 Hz, 2H), 1.79 (s, 3H). 1 ⁹ F NMR (376 MHz, CD3OD) δ -121.36 (dt, J = 21.9, 3.7 Hz). 1 ³ C NMR (101 MHz, CD ₃ OD) δ 165.27, 150.48, 140.84, 116.94 (dd, J = 2197.9, 230.8 Hz), 100.61, 99.86, 72.69, 68.27 (d, J = 20.7 Hz), 58.99 (d, J = 46.0 Hz), 20.90. LCMS Calculated for C ₁₀ H ₁₂ FN ₂ NaO ₆ [M+Na ⁺ ]: 299.06; found: 298.8 Example 92. Synthesis of EIDD-3217 5-O-tert-Butyldimethylsilyl-2,3-O-isopropylidene-D-ribono-1, 4-lactone An oven-dried 200 mL round-bottomed flask was charged with 2,3-O-isopropylidene-D- ribono-1,4-lactone (7.75 g, 41.18 mmol), imidazole (3.08 g, 45.30 mmol) and anhydrous methylene chloride (100 mL). The mixture was treated in portions with tert-butyldimethylsilyl chloride (6.21 g, 41.18 mmol). After 16 h at rt, the mixture was treated with saturated sodium bicarbonate solution (80 mL). The aqueous layer was back-extracted with methylene chloride (100 mL), and combined organic layers dried over sodium sulfate, filtered, and concentrated. The resulting crude gum was purified by column chromatography over silica gel (80 g) eluting with a hexanes/ethyl acetate gradient to give 5-O-tert-butyldimethylsilyl-2,3-O-isopropylidene- D-ribono-1,4-lactone (9.92 g, 79%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.76 -4.67 (m, 2H), 4.60 (dd, J = 2.1, 1.4 Hz, 1H), 3.89 (dd, J = 11.3, 2.1 Hz, 1H), 3.80 (dd, J = 11.3, 1.4 Hz, 1H), 1.47 (d, J = 0.8 Hz, 3H), 1.39 (d, J = 0.8 Hz, 3H), 0.87 (s, 9H), 0.06 (d, J = 6.6 Hz, 6H). 5-O-tert-Butyldimethylsilyl-2,3-O,O-isopropylidene-1-C-(trim ethylsilyl)ethynyl-D-ribose In an oven-dried 200 mL round-bottomed flask, a THF (35 mL) solution of trimethylsilylacetylene (3.01 mL, 21.48 mmol) cooled to -78 ^o C was treated dropwise over a 20 min period with butyllithium (9.16 mL of a 2.5 M solution in hexanes, 22.91 mmol). After an additional 30 min at -78 ^o C, the mixture was treated dropwise over a 30 min period with a THF (5 mL) solution of 5-O-tert-butyldimethylsilyl-2,3-O-isopropylidene-D-ribono-1, 4-lactone (4.33 g, 14.32 mmol). The reaction mixture continued at -78 ^o C for 3 h and then quenched with saturated ammonium chloride solution (50 mL). The mixture was extracted with ethyl acetate (2 x 50 mL), and combined organic layers dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography over silica gel (40 g) eluting with a hexanes/ethyl acetate gradient to give 5-O-tert-butyldimethylsilyl-2,3-O,O-isopropylidene-1-C- (trimethylsilyl)ethynyl-D-ribose (5.2 g, 90%) as an inseparable 3:1 mixture of anomers. 1H NMR (400 MHz, CDCl3, mixture of anomers) δ 4.84 (dd, J = 6.7, 2.3 Hz, 1H, anomer 2), 4.76 (dd, J = 5.7, 1.0 Hz, 1H, anomer 1), 4.72 (d, J = 6.7 Hz, 1H, anomer 2), 4.53 (d, J = 5.7 Hz, 1H, anomer 1), 4.39 (tdd, J = 2.3, 1.5, 0.8 Hz, 1H, anomer 1), 4.21 (s, 1H, anomer 2), 4.16 (m, 1H, anomer 2), 3.83 – 3.71 (m, 3H, anomers 1and 2), 1.59 (s, 1H, anomer 2), 1.54 (s, 3H, anomer 1), 1.40 (s, 3H, anomer 2), 1.37 (s, 3H, anomer 1), 0.91 (s, 9H, anomer 1), 0.90 (s,9H, anomer 2), 0.20 (s, 9H, anomer 1), 0.17 (s, 9H, anomer 2), 0.13 (d, J = 3.2 Hz, 6H, anomer 1), 0.08 (d, J = 1.2 Hz, 6H, anomer 2). 1-O-Acetyl-5-O-tert-butyldimethylsilyl-2,3-O,O-isopropyliden e-1-C-(trimethylsilyl)ethynyl- D-ribose An oven-dried 200 mL round-bottomed flask was charged with 5-O-tert- butyldimethylsilyl-2,3-O,O-isopropylidene-1-C-(trimethylsily l)ethynyl-D-ribose (5.20 g, 12.98 mmol) and anhydrous acetonitrile (65 mL). After cooled to 0 ^o C, the solution was treated sequentially with acetic anhydride (3.06 mL, 32.45 mmol), triethylamine (2.17 mL, 15.57 mmol), and 4-dimethylaminopyridine (0.40 g, 3.24 mmol). The mixture was stirred for 1 h at 0 ^o C and then allowed to warm to rt. After 16 h, the mixture was treated with ice (50 g) and stirred for an additional 1 h. Acetonitrile was removed under vacuum, and the resulting aqueous mixture extracted into ethyl acetate (150 mL). The organic layer was washed with saturated sodium bicarbonate solution (50 mL) followed by brine (50 mL), dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography over silica gel (40 g) eluting with a hexanes/ethyl acetate gradient to give 1-O-acetyl-5-O-tert- butyldimethylsilyl-2,3-O,O-isopropylidene-1-C-(trimethylsily l)ethynyl-D-ribose (3.8 g, 66%). 1H NMR (400 MHz, CDCl3) δ 4.84 – 4.75 (m, 2H), 4.36 (ddd, J = 8.4, 4.7, 1.0 Hz, 1H), 3.70 (dd, J = 10.5, 4.7 Hz, 1H), 2.04 (s, 3H), 1.56 (s, 3H), 1.37 (s, 3H), 0.89 (s, 8H), 0.19 (s, 9H), 0.06 (d, J = 2.4 Hz, 6H). 5’-O-tert-Butyldimethylsilyl-2’,3’-O,O-isopropylidene- 1’-C-(trimethylsilyl)ethynyluridine An oven-dried 200 mL round-bottomed flask was charged with 1-O-acetyl-5-O-tert- butyldimethylsilyl-2,3-O,O-isopropylidene-1-C-(trimethylsily l)ethynyl-D-ribose (1.4 g, 3.16 mmol), uracil (709 mg, 6.32 mmol), and anhydrous acetonitrile (22 mL). The slurry was treated with N,O-bis(trimethylsilyl)acetamide (3.91 mL, 15.81 mmol). After 2 h at rt, the homogeneous mixture was treated dropwise over a 5 min period with aluminumethyldichloride (3.46 mL of a 25% solution in toluene, 6.32 mmol). After 8 h at rt, tlc (20% ethyl acetate in hexanes) indicated complete conversion. The mixture was cooled with ice bath and treated slowly with a saturated sodium bicarbonate solution (100 mL). After stirring for 30 min, the mixture was extracted with methylene chloride (2 x 100 mL). Combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography over silica gel (80 g) eluting with a hexanes/ethyl acetate gradient to give 5’-O- tert-butyldimethylsilyl-2’,3’-O,O-isopropylidene-1’-C- (trimethylsilyl)ethynyluridine (1.45 g, 92.68 mmol) as an inseparable 1:1 anomeric mixture. 1H NMR (400 MHz, CDCl ₃ ) δ 7.94 (s, 1H, anomer 1 and 2), 7.83 (d, J = 8.3 Hz, 1H, anomer 2), 7.71 (dd, J = 8.4, 0.5 Hz, 1H, anomer 1), 5.67 (ddd, J = 8.0, 5.5, 2.4 Hz, 2H, anomer 1 and 2), 5.24 (d, J = 5.8 Hz, 1H, anomer 1), 5.04 (d, J = 5.8 Hz, 1H, anomer 2), 4.88 (dd, J = 5.8, 1.5 Hz, 1H, anomer 1), 4.68 (dd, J = 5.8, 1.3 Hz, 1H, anomer 2), 4.60 (s, 1H, anomer 2), 4.43 – 4.34 (m, 1H, anomer 1), 3.91 (dd, J = 10.6, 8.3 Hz, 1H, anomer 1), 3.83 (dd, J = 10.6, 5.2 Hz, 1H, anomer 1), 3.78 (dd, J = 11.6, 2.6 Hz, 1H, anomer 2), 3.69 (dd, J = 11.7, 3.6 Hz, 1H, anomer 2), 1.68 (s, 3H, anomer 2), 1.38 (s, 3H, anomer 2), 1.32 (d, J = 1.6 Hz, 6H, anomer 1), 0.92 (s, 9H, anomer 1), 0.83 s, 9H, anomer 2), 0.18 (s, 9H, anomer 2), 0.17 (s, 9H, anomer 1), 0.11 (d, J = 0.5 Hz, 6H, anomer 1), 0.01 (d, J = 9.0 Hz, 6H, anomer2). 2’,3’-O,O-isopropylidene-1’-C-ethynyl-b-uridine A 100 mL round-bottomed flask was charged with 5’-O-tert-butyldimethylsilyl-2’,3’- O,O-isopropylidene-1’-C-(trimethylsilyl)ethynyluridine (1.45 g, 2.93 mmol) and THF (20 mL). The solution was cooled to 0 ^o C and treated with acetic acid (0.59 mL, 10.26 mmol) followed by tetrabutylammonium fluoride (5.86 mL of 1 M solution in THF, 5.86 mmol). The mixture was allowed to warm to rt. After 3.5 h, tlc (10% methanol in methylene chloride) indicated complete conversion. The mixture was concentrated, and the resulting crude gum purified by column chromatography over silica gel (40 g) eluting with a hexanes/ethyl acetate gradient to give 2’,3’- O,O-isopropylidene-1’-C-ethynyl-b-uridine (340 mg, 38%) as the slower moving anomer. 1H NMR (400 MHz, CDCl3) δ 9.47 (s, 1H), 7.99 (d, J = 8.3 Hz, 1H), 5.68 (dd, J = 8.3, 1.6 Hz, 1H), 5.19 (d, J = 6.3 Hz, 1H), 4.92 (dd, J = 6.3, 2.4 Hz, 1H), 4.52 (q, J = 2.8 Hz, 1H), 3.87 (dd, J = 12.1, 2.6 Hz, 1H), 3.76 (dd, J = 12.1, 3.4 Hz, 1H), 3.03 – 2.98 (m, 1H), 1.64 (s, 3H), 1.36 (s, 3H). LCMS Calculated for C ₁₄ H ₁₅ N ₂ O ₆ [M-H ⁺ ]: 307.09; found: 306.9 1’-C-ethynyl-b-uridine A 25 mL round-bottomed flask was charged with 2’,3’-O,O-isopropylidene-1’-C- ethynyl-b-uridine (340 mg, 1.10 mmol) and 80% aqueous formic acid (6.08 mL, 126.83 mmol). After 18 h at rt, the reaction mixture was concentrated to dryness, and the resulting residue co- evaporated with methanol (3 x 25 mL). The crude solid was purified by column chromatography over silica gel (24 g) eluting with a methylene chloride/methanol gradient followed by column chromatography over C-18 (50 g) eluting with a water/acetonitrile gradient. After lyophilization isolated 1’-C-ethynyl-b-uridine (65 mg, 22%) as a white solid. 1H NMR (400 MHz, CD ₃ OD) δ 8.01 (d, J = 8.3 Hz, 1H), 5.71 (d, J = 8.4 Hz, 1H), 4.72 (d, J = 4.9 Hz, 1H), 4.54 – 4.35 (m, 2H), 4.05 (dd, J = 8.0, 4.9 Hz, 1H), 3.27 (s, 1H). ¹³ C NMR (101 MHz, CD ₃ OD) δ 165.31, 149.84, 140.40, 99.61, 89.74, 83.34, 79.65, 76.74, 75.22, 70.48, 61.59. LCMS Calculated for C14H15N2O6 [M-H ⁺ ]: 267.09; found: 266.9 Example 93. Activity for EIDD-2918 Example 94. Activity for EIDD-2919 Example 95. Activity for EIDD-2922 Example 96. Activity for EIDD-3190 Example 97. Activity for EIDD-3216 Example 98. Activity for EIDD-3217 Example 99. Ferret Model of SARS-CoV-2 Infections Protocol 6-10–month old female ferrets (Mustela putorius furo; Triple F Farms) were used as an in vivo model to examine the therapeutic efficacy of orally administered EIDD-2749 against SARS-CoV-23 infection. Group sizes of 3-4 ferrets were used for efficacy studies. Animals were randomly assigned to the different study groups. No blinding was performed. Viruses were administered to animals through intranasal inoculation. Ferrets were inoculated with SARS- CoV-2 (1 × 10 ⁵ pfu of SARS-CoV-2WA1 or VoC alpha, beta, or gamma) in 1 ml (0.5 ml per nare). At 12 hours after infection, a group of ferrets was treated once daily (q.d.) with vehicle (10 mM sodium citrate with 0.5% (v/v) Tween 80) or EIDD-2749 at a dosage of 20 mg/kg, respectively. Nasal lavages were collected every 12 hours for all ferrets. Once daily dosing was continued for 4 days post infection. All animals were euthanized 4 days after the infection was started. Organs and tissues were harvested and stored at -80°C until processed. For virus titration, samples were weighed and homogenized in sterile PBS. Tissue homogenates were clarified by centrifugation (2,000×g for 5 minutes at 4°C). The clarified supernatants were then harvested and used in plaque assays. For detection of viral RNA, total RNA was extracted from organs using a RNeasy mini kit (Qiagen), in accordance with the manufacturer’s protocol. Total RNA was extracted from nasal lavages using a ZR viral RNA kit (Zymo Research) in accordance with the manufacturer’s protocols. Virus titers were determined by plaque assays and viral RNA copy numbers were determined by RT–qPCR quantitation. Example 100. Measurement of SARS-CoV-2 RNA Levels Detection of SARS-CoV-2 RNA was performed using the nCoV_IP2 primer–probe set (National Reference Center for Respiratory Viruses, Pasteur Institute). RT–qPCR reactions were performed on an Applied Biosystems 7500 real-time PCR system using the StepOnePlus real- time PCR system. Viral RNA was detected using the nCoV_IP2 primer–probe set in combination with TaqMan fast virus 1-step master mix (Thermo Fisher Scientific). Viral RNA copy numbers were determined based on a standard curve created using a PCR fragment (nucleotides 12669– 14146 of the SARS-CoV-2 genome) as previously described. The RNA values were normalized to the weights of the tissues used. Example 101. Mouse Model of Oropouche virus Infection Protocol Male and female 7- to 8-week-old IFNAR-/- mice were obtained from the breeding colony at Utah State University and were fed irradiated Harlan Lab Block and autoclaved tap water ad libitum. The Oropouche virus (OROV) strain (BeAn19991) used was passaged once in Vero E6 cells. The virus stock (1.5 x 10 ⁷ 50% cell culture infectious dose (CCID50/mL) was diluted in sterile minimal essential medium (MEM) and inoculated by subcutaneous (SC) injection of 0.2 mL for a total challenge dose of approximately 30 CCID50. EIDD-2749 was weighed out for each treatment day and stored at -20°C until use. Just prior to administration, EIDD-2749 was prepared in 10 mM trisodium citrate (Amresco), 0.5% Tween 80 (Sigma), and sterile injection-grade water at the desired concentration. Mice were weighed three days before the infection and assigned to treatment groups so that sex and weight were evenly distributed among the groups. The average weight per treatment group across the entire experiment varied by less than 2 g. Animals in each group were treated with EIDD-2749 by oral gavage (PO; 0.1 mL) and continued once daily for 7 days. Sham-infected, untreated mice were included as normal controls. Four animals from each treatment group were preselected for sacrifice on day 4 p.i. for determination of serum, liver, and spleen viral titers. The remaining animals were observed 21 days for morbidity and mortality. Virus titers were assayed using an infectious cell culture assay as previously described. Briefly, a specific volume of tissue homogenate or serum was serially diluted and added to quadruplicate wells of Vero E6 (African green monkey kidney) cell monolayers in 96-well microtiter plates. The viral cytopathic effect (CPE) was determined 7 days after plating and the 50% endpoints were calculated as described. The assay lower limits of detection were 1.67 log10 CCID50/mL serum and 2.27 log10 CCID50/g tissue. The Mantel-Cox log-rank test was used for analysis of Kaplan-Meier survival curves. A one-way analysis of variance (ANOVA) and Dunnett's test for multiple comparisons was used to compare differences in day 4 virus titers compared to the placebo treatment group. All statistical evaluations were performed using Prism 9 (GraphPad Software). Example 102. Dose Range Finding in the Mouse Model of Oropouche Virus Infection A mouse Oropouche infection model was conducted with animals in each group receiving 10 mg/kg, 3 mg/kg, 1 mg/kg, or 0.3 mg/kg of EIDD-2749, or the vehicle placebo, by oral gavage (PO; 0.1 mL) beginning 2 h post-infection (p.i.) and continuing once daily for 7 days. As the positive control, 100 mg/kg/day favipiravir was initiated 2 h pre-infection and administered by intraperitoneal (IP) injection twice daily (bid) for 7 days. Sham-infected, untreated mice were included as normal controls. Four animals from each treatment group, and 5 from the placebo-treated group, were preselected for sacrifice on day 4 p.i. for determination of serum, liver, and spleen viral titers. The remaining animals were observed 21 days for morbidity and mortality. As shown in Figure 2, all the EIDD-2749-treated mice, except one animal in the lowest dose group, survived the infection while all placebo-treated animals succumbed within 7 days of challenge. Mice treated with the positive control drug, favipiravir, were also protected against the lethal OROV challenge. In contrast to mice that were treated with placebo, all EIDD- 2749 treatments resulted in undetectable infectious virus in serum and spleen samples (Figure 3). All doses of EIDD-2749 also significantly reduced viral loads (***P < 0.001) in the liver (Figure 3). Favipiravir performed as expected significantly reducing virial titers in serum, spleen (***P < 0.001) and liver (*P < 0.05) tissue. Example 103. Post Exposure Dosing in the Mouse Model of Oropouche Virus Infection A mouse Oropouche infection model was conducted with animals in each group receiving 3 mg/kg EIDD-2749 by oral gavage (PO; 0.1 mL) beginning on day 1, 2, 3 or 4 post- infection (p.i.) and continuing once daily for 7 days. As the positive control, 3 mg/kg EIDD- 2749 was initiated 2 h pre-infection and administered PO once daily for 7 days. Sham-infected, untreated mice were included as normal controls. Four animals from each treatment group, except the initiated treatment on day 4, were preselected for sacrifice on day 4 p.i. for determination of serum, liver, and spleen viral titers. The remaining animals were observed 21 days for morbidity and mortality. As shown in Figure 4, all the mice treated with 3 mg/kg EIDD-2749 beginning on days 1, 2, or 3 p.i. survived the infection while all placebo-treated animals succumbed within 6 days of challenge. Mice treated with 3 mg/kg EIDD-2749 beginning on day 4 p.i. had 70% protection (*P < 0.05) from the lethal OROV challenge. Excluding the group whose treatment was initiated on day 4 p.i., four mice in each treatment group were sacrificed on day 4 p.i. to assess the impact of treatment on viremia and tissue viral loads (Figure 5). All the mice that were treated with placebo had viremia over 3.5 log10 CCID50/ml. Example 104. Guinea pig Model of Junin Virus Infection Protocol Male and female 300-350 g Hartley guinea pigs were purchased from Charles River Laboratories (Willimantic, CT) and acclimated for 10 days prior to virus challenge. Animals were fed Harlan Lab Block and tap water ad libitum. EIDD-02749 in powder form was stored at -20°C. The compound was prepared fresh daily in Gerber brand Stage 1 baby carrot food for oral delivery. The molecular clone of the Romero strain of Junin virus (JUNV) was rescued in BHK- 21 cells. The stock used was prepared from a single passage in Vero cells. The virus stock was diluted in sterile medium and inoculated by intraperitoneal (IP) injection of 0.1 ml containing approximately 5 PFU (ventral, left side of the abdomen). Guinea pigs were weighed 7 days prior to the infection then grouped (n=6, 3 males and 3 females per treatment group, with 1 male and 1 female sham-infected controls) to minimize weight variation across the cohorts. Each animal was implanted subcutaneously (SC) with an IPTT-300 programmable temperature transponder (Biomedic Data Systems, Seaford, DE). EIDD-02749 treatment was continued once daily for 14 days. Carrot food vehicle was administered to the placebo group. Blood was obtained from each animal on day 12 of the infection by cranial vena cava sampling under deep isoflurane anesthesia, and the serum was analyzed for viral load. Animals were observed for a total of 28 days for morbidity and mortality. Virus titers were assayed using an infectious cell culture assay. Briefly, serum samples were serially diluted and added to triplicate wells of Vero cell monolayers in 96-well microplates. The viral cytopathic effect was determined 11 days p.i. and 50% endpoints were calculated and represented as log10 fifty percent cell culture infectious dose (CCID ₅₀ ) units per ml. The assay limit of detection for serum virus was 1.49 CCID ₅₀ /ml. The Mantel-Cox log-rank test was used for analysis of Kaplan-Meier survival curves. A one-way analysis of variance (ANOVA) with a Dunnett’s posttest to correct for multiple comparisons was performed to compare differences in virus titers. All statistical evaluations were done using Prism (GraphPad Software, La Jolla, CA). Example 105. Dose Range Finding in the Guinea pig Model of Junin Virus Infection A guinea pig JUNV infection model was conducted to evaluate the efficacy of EIDD- 02749 dosed at 10, 3, or 1 mg/kg/day by oral instillation in baby carrot food once daily (qd) for 14 days beginning 1 h post-infection with the pathogenic Romero strain of JUNV. As shown in Figure 6, all 3 doses of EIDD-02749 provided 100% protection compared to 33% survival in the placebo group. The impact of the EIDD-02749 treatments on preventing viremia on day 12 following challenge is displayed in Figure 7. Virus was undetectable in all of the EIDD-02749- treated animals. Only the 3 placebo-treated animals that succumbed between days 14-21 were found to be viremic with titers ranging from 10 ² -10 ⁴ CCID50/ml of serum. Example 106. Post Exposure Dosing in the Guinea pig Model of Junin Virus Infection A guinea pig JUNV infection model was conducted to evaluate the therapeutic efficacy of EIDD-2749 dosed at 10 mg/kg by oral instillation in baby carrot food once daily for 14 days beginning on days 3, 7 or 11 p.i. with the pathogenic Romero strain of JUNV. As shown in Figure 8, EIDD-2749 treatment initiated 3 or 7 days p.i. significantly (P < 0.01 compared to placebo;100% survival) protected animals against a JUNV challenge dose that resulted in 86% mortality in guinea pigs treated with placebo. When EIDD-2749 therapy was withheld until day 11 p.i., 5 of 7 (71%; P = 0.07 compared to placebo) guinea pigs were protected. The impact of the EIDD-2749 treatments on preventing viremia was assessed on day 12 p.i. Virus was undetectable in both the day-3 and day-7 treatment groups (Figure 9). The day-11 guinea pigs had only received a single treatment approximately 24 h prior to the collection of blood samples on day 12. Example 107. Dose Down Treatment in the Guinea pig Model of Junin Virus Infection A guinea pig JUNV infection model was conducted to evaluate the effect of reduction in dose levels for daily dosing as well as every other day dosing with EIDD-2749 to guinea pigs after intraperitoneal injection with a lethal dose of JUNV. The treatment with EIDD-2749 was initiated 7 days post-infection with reduced daily dose levels for 14 days and a high dose level for every other day dosing for 14 days. As shown in Figure 10, all of the treatment doses and both QD and QOD treatment regimens completely (***P < 0.001) protected the animals from mortality. All of the placebo-treated animals succumbed by day 15 p.i. Example 108. Mouse Model of Ebolavirus Infection Protocol For this portion of the study, 50 experimentally-naïve BALB/c mice (equal sex, 8-9 weeks old at the time of infection) were obtained from Envigo Laboratories and were assigned into five groups (3-5 per cage) under specific pathogen-free conditions. Food, water, and bedding were routinely supplied, changed, and monitored. Virus challenge day was defined as Study Day 0. Stock virus, mouse-adapted EBOV, was removed from frozen storage and allowed to thaw under ambient conditions. The thawed suspension was diluted in Minimum Essential Medium (MEM) to a target challenge dose concentration of 1,000 PFU/mL such that animals received a target of 100 PFU per 100 μL dose. Virus administration was performed via intraperitoneal (i.p.) injection. The viral dose administered was verified through plaque assay analysis of the prepared virus suspension. Mice were anesthetized for dosing (including challenge) via isoflurane inhalation. Animals were dosed via oral gavage (0.1 mL). Mice were observed at least once daily and scored for 28 days. Example 109. Dose Range Finding in the Mouse Model of Ebolavirus Infection A mouse EBOV infection model was conducted to evaluate the efficacy of EIDD-02749 dosed orally at 30, 15, or 5 mg/kg/day for 8 days starting 1 hour post virus challenge. As shown in Figure 11, all mice challenged with virus followed by daily oral gavage dosing of vehicle control beginning one hour post-challenge (Group 1) succumbed on Study Day 6. All animals in Groups 2-4 survived the 28-day post-challenge study period. In the remaining group (Group 5; dosed daily at 30 mg/kg EIDD-2749), three (3) female mice were euthanized on Study Day 13. Example 110. Post Exposure Dosing in the Mouse Model of Ebolavirus Infection A mouse EBOV infection model was conducted to evaluate the efficacy of EIDD-02749 dosed orally at 15 mg/kg/day for 8 days starting 6, 12, and 24 hours post virus challenge. As Figure 12 shows, all mice challenged with virus followed by daily oral gavage dosing of vehicle control beginning six hours post-challenge (Group 1) succumbed between Study Days 5 and 7. All animals in Groups 2-5 survived the 28-day post-challenge study period. Example 111. Mouse Model of Rift Valley Fever Virus Infection Protocol Male and female BALB/c mice were obtained from Charles River (Wilmington, MA) and quarantined for 9 days. They were fed Harlan Lab Block and tap water ad libitum. The molecular clone of RVFV, strain ZH501, was obtained from Dr. Stuart Nichol (CDC, Atlanta, GA). The virus stock (1.1 × 10 ⁸ plaque-forming units (PFU)/ml; 1 passage in BSR-T7/5 cells, 3 passages in Vero E6 cells), from a clarified cell culture lysate preparation, was diluted in sterile minimal essential medium and inoculated by subcutaneous (SC) injection of 0.1 ml containing approximately 300 PFU of RVFV. EIDD-2749 was weighed out for each treatment day and stored at -20°C. Just prior to administration, the drug was prepared in 10 mM trisodium citrate (Amresco), 0.5% Tween 80 (Sigma), and sterile injection-grade water at the desired concentration. Mice were weighed the day before the infection and assigned to treatment groups so that sex and weight differences were minimized across the groups. The average weight per treatment group across the entire experiment varied by less than 0.3 g. Animals in each group were treated with EIDD-2749 or the vehicle placebo by oral gavage (PO) and continued qd for 7 days. Favipiravir, dosed twice daily at 200 mg/kg/day, was included as the positive control. Four animals from each drug treatment group were selected prior to infection and sacrificed on day 4 for determination of serum, liver, and spleen viral titers. The remaining animals were observed 21 days for morbidity and mortality. Virus titers were assayed using an infectious cell culture assay. Briefly, a specific volume of tissue homogenate or serum was serially diluted and added to quadruplicate wells of Vero (African green monkey kidney) cell monolayers in 96-well microtiter plates. The viral cytopathic effect (CPE) was determined 7 days after plating and the 50% endpoints were calculated. The assay lower limits of detection were 1.49 log10 CCID50/ml serum and 2.1 log10 CCID ₅₀ /g tissue. In samples presenting with virus below the limit of detection, a value representative of the limit of detection was assigned for statistical analysis. The Mantel-Cox log-rank test was used for analysis of Kaplan-Meier survival curves. A one-way analysis of variance (ANOVA) with Dunnett’s method to correct for multiple comparisons was used to compare differences in day 4 viral titers and percent weight change. All statistical evaluations were done using Prism 8 (GraphPad Software, La Jolla, CA). Example 112. Dose Range Finding in the Mouse Model of Rift Valley Fever Virus Infection Animals in each group were treated with 15, 5, 1.5, or 0.5 mg/kg of EIDD-2749 or the vehicle placebo by oral gavage (PO) beginning 1 h prior to infection and continued qd for 7 days. All animals treated with 15 or 5 mg/kg doses of EIDD-2749 were completely protected against a 90% lethal challenge dose of RVFV (Figure 13). A clear doseresponse was observed with 1.5 and 0.5 mg/kg treatments providing 50 and 20% protection, respectively, with extended survival times observed in many of the mice that succumbed to the infection (Figure 13). Example 113. Post Exposure Dosing in the Mouse Model of Rift Valley Fever Virus Infection The post-exposure therapeutic efficacy of EIDD-2749 was evaluated with EIDD-2749 administered PO beginning on days 1, 2 or 3 post-virus challenge, to protect BALB/c mice against lethal RVFV challenge. EIDD-2749 dosed at 10 mg/kg beginning 1 day p.i. provided 90% protection (***P < 0.001) and when treatment was delayed until 2 days p.i., 70% protection (***P < 0.001) was observed (Figure 15). Further delaying EIDD-2749 treatment until day 3 p.i., when many mice were sick and showing signs of disease, still provided statistically significant protection (*P < 0.05) with 40% survival observed in groups treated with 10 or 15 mg/kg of compound. All placebo-treated mice succumbed by day 14 p.i. The day 3 p.i. serum and tissue viral titers are shown in Figure 16. No infectious virus was detectable in the serum collected from the mice treated with EIDD-2749 beginning on day 1 or from the positive control favipiravir group, and only a single animal from the EIDD-2749 day 2 group had a minimally detectable titer. Viral titers in the liver tissue homogenates were only detectable in the placebo- treated mice and, to significantly lesser extent, in the positive control favipiravir-treated animals. The spleen tissue samples were less distinct and infectious virus was detectable in all experimental groups, with the placebo-treated mice having the highest viral titers. EIDD-2749 was comparable or superior to favipiravir in reducing viral loads in liver and spleen. Example 114. Mouse Model of Heartland Virus Infection Protocol Male and female AG129 IFN-α/β and γ receptor deficient mice were obtained from the breeding colony at Utah State University. They were fed irradiated Harlan Lab Block and autoclaved tap water ad libitum. The mouse-adapted HRTV (MA-HRTV) strain used was derived from the MO-4 strain obtained from Dr. Robert Tesh (WRCEVA at the University of Texas Medical Branch, Galveston, TX) and passaged 5 times in AG129 mice. The virus stock (4.7 x 10 ⁸ 50% cell culture infectious dose (CCID50/ml); 1 passage in Vero E6 cells, 5 passages in AG129 mice) used was prepared from a clarified liver homogenate. The virus stock was diluted in sterile minimal essential medium (MEM) and inoculated bilaterally in two intraperitoneal (IP) injections of 0.1 ml each for a total inoculation of 40 CCID50. EIDD-2749 was provided by Dr. Gregory Bluemling (Emory University) as a solid. The compound was weighed out for each treatment day and stored at -20°C until use. Just prior to administration, EIDD-2749 was prepared in 10 mM trisodium citrate (Amresco), 0.5% Tween 80 (Sigma), and sterile injection-grade water at the desired concentration. Mice were weighed three days before the infection and assigned to treatment groups so that sex and weight were evenly distributed among the groups. The average weight per treatment group across the entire experiment varied by less than 2 g. Animals in each group were treated with EIDD-2749 or the vehicle placebo by oral gavage (PO; 0.1 ml) and continued once-daily for 7 days. As the positive control, a group of animals was treated twice-daily, PO, with 100 mg/kg/day favipiravir. Four animals from each drug treatment group were preselected for sacrifice on day 5 postinfection (p.i.) for determination of serum, liver, and spleen viral titers. The remaining animals were observed 21 days for morbidity and mortality. Virus titers were assayed using an infectious cell culture assay as previously described1. Briefly, a specific volume of tissue homogenate or serum was serially diluted and added to quadruplicate wells of Vero E6 (African green monkey kidney) cell monolayers in 96-well microtiter plates. The viral cytopathic effect (CPE) was determined 7 days after plating and the 50% endpoints were calculated. The assay lower limits of detection were 1.67 log10 CCID ₅₀ /ml serum and 2.27 log10 CCID ₅₀ /g tissue. The Mantel-Cox log-rank test was used for analysis of Kaplan-Meier survival curves. A one-way analysis of variance (ANOVA) with Dunnett’s posttest to correct for multiple comparisons was used to compare differences in day 5 virus titers. All statistical evaluations were performed using Prism 9 (GraphPad Software, La Jolla, CA). Example 115. Dose Range Finding in the Mouse Model of Heartland Virus Infection Efficacy of 10, 3, and 1 EIDD-2749 treatments administered orally once daily starting 2 h pre-infection and continuing for 7 days against HRTV infection in AG129 mice was evaluated. Sd shown in Figure 17, all of the tested doses of EIDD-2749 completely protected the animals against lethal HRTV challenge (***P < 0.001). All of the placebo-treated mice succumbed by day 8 p.i. As expected, the positive control favipiravir-treated animals survived infection. EIDD- 2749 significantly reduced viral loads (***P < 0.001) in the serum, liver and Spleen (Figure 18). Although 3 or 4 mice treated with the lowest dose of 1 mg/kg had 4-6.3 log10 CCID50 of virus per g of spleen tissue, this level was significantly less compared to the high viral loads present in the placebo-treated mice. Example 116. Post Exposure Dosing in the Mouse Model of Heartland Virus Infection Post-exposure EIDD-2749 treatment was evaluated against lethal disease associated with MA-HRTV infection in AG129 mice and impact on viral replication in the blood and selected target organs. As shown in Figure 19, all of the test groups in which 3 mg/kg/day EIDD-2749 treatment was initiated starting on day 4 p.i. or later and the placebo-treated animals succumbed by day 6 of the infection. By comparison, all of the positive control group mice that began EIDD-2749 treatment on day 2 p.i. survived the lethal MA-HRTV challenge (***P < 0.001). Four mice in each of the day 2, day 4 and placebo treatment groups were preselected for day 5 p.i. sacrifice for analysis of viremia and tissue viral loads. As shown in Figure 20, EIDD-2749 initiated on day 2 p.i. significantly reduced viral loads (*P < 0.05) in the liver and spleen. Example 117. Mouse Model of VEEV Infection Protocol Seven to eight-week-old ICR (Crl:CD1) female mice were used in all studies. The Trinidad donkey (TrD) strain of VEEV was originally obtained from the Centers for Disease Control and Prevention (CDC) and had the following history of passaging: the 1943 TrD isolate was passaged (i) once on guinea pig brains, then (ii) six times on Vero cells (including one plaque purification), and (iii) once in BHK21 cells. The last virus was additionally passaged once on Vero cells to expand the virus and was titrated by plaque assay. Nasal challenge consisted of intranasal application of ~100 PFU of virus, corresponding to ~100 LD ₅₀ , in 25 μl volume of PBS split into two nostrils and delivered under ketamine-xylazine anesthesia. The residual inoculum used for each experiment was back titrated after the challenge to confirm the dose delivered. After EIDD-2749 treatment initiation, EIDD-2749 was dosing continued once- daily (q.d.) for seven consecutive days. Example 118. Dose Range Finding in the Mouse Model of VEEV Infection Treatment with EIDD-2749 at 10, 5, 3 and 1.5 mg/kg/day initiated 6 hours after the virus challenge and continued once-daily (q.d.) for seven consecutive days was compared to a vehicle treatment control. All vehicle-treated, VEEV infected control animals were euthanized on days 6-7 (Figure 21). Very high virus titers in brain (8.7 ± 0.3 log10 pfu/g) were detected in these mice. Treatment with 10 mg/kg/day dose of EIDD-2749 resulted in complete protection of treated mice from the disease and death (p<0.0001). Treatment with 5 mg/kg/day of EIDD-2749 resulted in 90% protection (p<0.0001), and treatment with 3 mg/kg/day dose of EIDD-2749 resulted in 30% protection (p<0.01). No survival benefit was observed in mice treated with 1.5 mg/kg dose. All treated mice that survived to the end of the experiment (day 14) had no measurable virus titers in their brains. Example 119. Post Exposure Dosing in the Mouse Model of VEEV Infection Treatment with EIDD-274910 mg/kg/day initiated 6 hours post-challenge completely protected mice from lethal infection (Figure 22). The delay of treatment for 24 hours similarly resulted in 100% protection. The 48 hours delay in treatment initiation resulted in 70% mouse survival (p<0.0001). No mice survived when treatment initiation was delayed by 72 hours post- challenge. All Control (vehicle-treated) mice succumbed to the infection by study day 5, which is earlier than the typical time of ~6 days post-challenge. Example 120. Mouse Model of EV Infection Protocol Four-week-old male and female AG129 mice from a specific-pathogen-free colony maintained at the Utah Science Technology and Research (USTAR) building at Utah State University. The mice were bred and maintained on irradiated Teklad Rodent Diet (Harlan Teklad) and autoclaved tap water at the USTAR building of Utah State University. EIDD-02749 was prepared in 10 mM trisodium citrate, 0.5% Tween-80 in sterile water. Intravenous immunoglobulin (IVIg, Carimune, CSL Behring, King of Prussia, PA) was purchased from a local pharmacy and was used as a positive control. Enterovirus 71 MP4 was obtained from the NIH Biodefense and Emerging Infection Research Resources Repository, NIAID, NIH: Human Enterovirus 71 (HEV-71), MP4, NR-472. The virus was serially passaged another six times in the brains of 4-week-old AG129 mice and then plaque-purified three times in Rhabdomyosarcoma (RD) cells obtained from the American Type Culture Collection (Manassas, VA). The resulting virus stock was amplified twice in RD cells to create a working stock. The virus used for infection was designated EV71 MP10 PP. Mice were treated once daily for nine days per os (PO) with EIDD-02749 at a fixed dose of 10 mg/kg/day beginning on day 3, 5, or 7 post-infection. One group of mice was treated with IVIg 3 days post-infection by a single intraperitoneal (IP) administration at a dose of 100 mg/kg. Each mouse was infected via intraperitoneal (IP) injection of 1 x 10 ^6.3 CCID50 of EV71 MP10 PP in 0.2 mls of MEM. Mice were weighed prior to treatment and daily thereafter. All mice were observed daily for morbidity, mortality, and neurological scores through day 21. Kaplan-Meier survival curves were generated in Prism 8.2.0. (GraphPad Software Inc.). Mean body weights for each treatment group were graphed and compared using Prism through a one-way analysis of variance (ANOVA). Neurological scores were graphed and evaluated using a Kruskal-Wallis test with a Dunn’s post-test for statistical significance compared to placebo-treated mice. Example 121. Post Exposure Dosing in the Mouse Model of EV71 Infection Figure 23 shows Kaplan-Meier survival curves for groups of mice infected with EV71 and treated after infection with EIDD-02749. A dose 10 mg/kg/day of EIDD-02749 completely protected mice from mortality when treatment started 3, 5, or 7 days after infection. A single administration of IVIg at a dose of 100 mg/kg administered 3 days after infection protected four of ten mice from mortality. One mouse in the placebo-treated group survived the infection.