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WO2025128749A1 - Hydroxymethyl dihydrogen phosphate prodrugs of c-nucleosides - Google Patents

Hydroxymethyl dihydrogen phosphate prodrugs of c-nucleosides Download PDF

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Publication number
WO2025128749A1
WO2025128749A1 PCT/US2024/059655 US2024059655W WO2025128749A1 WO 2025128749 A1 WO2025128749 A1 WO 2025128749A1 US 2024059655 W US2024059655 W US 2024059655W WO 2025128749 A1 WO2025128749 A1 WO 2025128749A1
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Prior art keywords
formula
compound
c8alkyl
alkyl
mixture
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French (fr)
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Eugene J. Eisenberg
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Promedy LLC
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Promedy LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Definitions

  • RNA viruses which are responsible for infections ranging from the common cold to life-threatening hemorrhagic fevers, are a leading cause of worldwide human infectious diseases. Despite the benefit of vaccinations for many RNA viral infections, RNA viruses are a major global threat. This is due in part to the high evolution rate and high capacity to spread from animals to humans (Woolhouse MEJ, et al., Emerging Infectious Diseases 2016, 22:2037–2044).
  • nucleosides and nucleotides are metabolized to a monophosphate derivative, which is highly polar and cannot diffuse across the cell membrane.
  • the monophosphate derivative is then converted stepwise to the triphosphate derivative.
  • One nucleoside in particular that has been widely investigated is GS-441524, a 1’-cyano 4-aza-7,9-dideazaadenosine C-nucleoside that has shown activity against a range of viruses, including Yellow Fever, Dengue Fever, Parainfluenza 3, MERS, SARS, SARS-CoV, Ebola 1 1103197127 ⁇ 3 ⁇ AMERICAS Attorney Ref.
  • GS-441524 has poor oral bioavailability in several species, including non-human primates (Mackman, R. L. et al. J. Med. Chem. 2021, 64: 5001–5017; Li, Y. et al. J. Med. Chem., 2022, 65:2785-2793; Wei, D. et al. Bioorg. Med. Chem., 2001, 46, 116364). For this reason, various 5’-, 4’-, and 3’-prodrugs of GS-441524 have been studied and developed in an attempt to obtain higher exposures of GS-441524.
  • remdesivir had no significant effect on patients with COVID-19 who were already being ventilated (WHO Solidarity Trial Consortium, Lancet, 2022, 399:10339). [0009] In addition to its unclear benefit against COVID-19 in certain circumstances, remdesivir exhibits poor water solubility and must be administered as an intravenous solution. This is most beneficial for a hospital setting, but limits its outpatient use and broad patient access. While currently approved for outpatient settings where a healthcare provider has immediate access to medication to treat an allergic reaction (VEKLURY. Prescribing Information.
  • Obeldesivir was studied in a Phase III clinical trial for patients who had a high risk of developing severe COVID-19, but this study was terminated when it was determined that that there would not be a statistically significant treatment effect (NCT05603143).
  • a Phase II clinical trial is currently ongoing to study the effect of obeldesivir in nonhospitalized adults with acute respiratory syncytial virus (RSV) (NCT06585150). While obeldesivir is being developed as an oral pill, it is lipophilic, and often poorly water-soluble lipophilic molecules require additional excipients for consistent bioavailability and dissolution in the GI tract fluids at efficacious doses.
  • Described herein are hydroxymethyl dihydrogen prodrugs of C-nucleotides, including of GS-441524. It has been surprisingly discovered that in certain embodiments, the prodrugs described herein exhibit unexpected and advantageous properties, including enhanced oral bioavailability compared to GS-441524. As described in Example 2, Compound 1 and Compound 2, prodrugs of Formula I, were administered orally and intravenously to mice. Certain PK parameters were measured, and these results were compared to the parameters measured following GS-441524 administration.
  • the PK parameters were obtained using a saline dose without organic solvents, which is especially advantageous for therapy and formulation.
  • the prodrugs described herein potentially can be compatible with common IV solutions and can be administered safely via an intravenous, intramuscular, or subcutaneous route. This is especially advantageous over remdesivir, which is administrated with sulfobutylether- ⁇ -cyclodextrin as vehicle. Sulfobutylether- ⁇ -cyclodextrin causes a site reaction and can accumulate in patients with impaired renal function, causing additional toxicity. [0014] Due to the superior PK, tablets of the prodrugs described herein could potentially reduce tablet size over GS-441524.
  • enhanced solubility could potentially reduce the tablet size over obeldesivir because minimal excipients may be required for formulation. This could allow for lower pill burden, the potential for formulating combination products, and/or increased dose-range interrogation of the target.
  • the ability of the prodrugs described herein to be formulated for both oral and parenteral administration is advantageous.
  • An oral formulation, such as a pill can be widely distributed and administrated, while a parenteral 4 1103197127 ⁇ 3 ⁇ AMERICAS Attorney Ref. No.127531.00009 formulation, for example, an intravenous solution, is most beneficial for patients that are severely ill and must be treated in a hospital.
  • the prodrugs described herein exhibit superior bioavailability compared to GS-441524 and have the additional benefit of enhanced solubility, which potentially allows for advantageous formulations compared to formulations of remdesivir and obeldesivir.
  • R 1 and R 2 are each independently hydrogen, N(R a )2, N3, CN, NO2, S(O)nR 3a , halogen, C1-C8alkyl, C3-C8cycloalkyl, C2-C8alkenyl, C2-C8alkynyl, or arylC1-C8alkyl;
  • R 3 is hydrogen, OR a , N(R a ) 2 , N 3 , CN, NO 2 , S(O) n R 3a , halogen, C 1 -C 8 alkyl, C 3 - C8cycloalkyl, C2-C8alkenyl, C2-C8alkynyl
  • X 1 and X 2 are each independently CR 11 or N;
  • the prodrug of Formula I is a prodrug of Formula IA: or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers thereof and/or an anomer thereof; wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 10 , X 1 , and X 2 are as defined herein.
  • the prodrug of Formula I is a prodrug of Formula IB: 6 1103197127 ⁇ 3 ⁇ AMERICAS Attorney Ref.
  • the prodrug of Formula I is a prodrug of Formula IC: or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers thereof and/or an anomer thereof; wherein R 1 , R 2 , R 3 , R 4 , R 6 , R 10 , X 1 , X 2 , and X 4 are as defined herein.
  • the prodrug of Formula IC is a prodrug of Formula IC-1: or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers thereof and/or an anomer thereof; wherein R 1 , R 2 , R 3 , R 4 , R 6 , R 10 , X 1 , and X 2 are as defined herein.
  • the prodrug of Formula IC is a prodrug of Formula IC-2: or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers thereof and/or an anomer thereof; wherein R 1 , R 2 , R 3 , R 4 , R 6 , R 10 , X 1 , and X 2 are as defined herein. 7 1103197127 ⁇ 3 ⁇ AMERICAS Attorney Ref.
  • the prodrug of Formula I is a prodrug of Formula ID: or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers thereof and/or an anomer thereof; wherein R 1 , R 2 , R 3 , R 4 , R 6 , R 10 , X 1 , and X 2 are as defined herein.
  • compositions comprising a prodrug of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID, or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers thereof and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof.
  • the pharmaceutical composition is in a dosage form suitable for parenteral administration. In other embodiments, the dosage form is suitable for oral administration.
  • Also provided herein is a method to treat an RNA viral infection in a host in need thereof comprising administering a prodrug of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID, or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers thereof and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof, optionally in a pharmaceutically acceptable carrier.
  • the method is to treat an RNA viral infection in a host in need thereof.
  • the method is to prevent an RNA viral infection in a host in need thereof.
  • the RNA viral infection is a Coronaviridae viral infection, for example a betacoronavirus viral infection, such as COVID-19 caused by the SARS-CoV (severe acute respiratory syndrome coronavirus) virus or the SARS-CoV-2 (severe acute respiratory syndrome coronavirus) virus.
  • FIG. 1A is a profile of GS-441524 in plasma after oral administration of GS-441524 (10 mg/kg), Compound 1 (94 mg-eq/kg), and Compound 2 (10 mg-eq/kg) as described in Example 2.
  • the dose for Compound 1 and Compound 2 is the mg-equivalent GS-441524/kg dose.
  • FIG. 1B is a profile of GS-441524 in plasma after intravenous administration of Compound 2 (10 mg-eq/kg) as described in Example 2.
  • DETAILED DESCRIPTION Definitions [0027] When referring to the prodrugs and compositions provided herein, the following terms have the following meanings unless indicated otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.
  • monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, triazolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, and triazinyl.
  • tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl.
  • Halogen or “halo” means fluoro, bromo, chloro, or iodo.
  • “Patient” or “subject” includes humans and other animals, particularly mammals, and other organisms. Thus, the methods are applicable to both human therapy and veterinary applications.
  • the patient is a mammal, and in other embodiments, the patient is human.
  • the terms “subject” and “patient” are used interchangeably.
  • the terms “subject” and “subjects” refer to an animal, such as a mammal including a non- primate (e.g., a cow, pig, horse, cat, dog, rat, and mouse) and a primate (e.g., a monkey such as a cynomolgous monkey, a chimpanzee, and a human), and in certain embodiments, a human.
  • the subject is a farm animal (e.g., a horse, a cow, a pig, etc.) or a pet (e.g., a dog or a cat).
  • the subject is a human.
  • a “pharmaceutically acceptable salt” of a prodrug means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent prodrug. It is 11 1103197127 ⁇ 3 ⁇ AMERICAS Attorney Ref. No.127531.00009 understood that the pharmaceutically acceptable salts are non-toxic.
  • Examples of pharmaceutically acceptable acid addition salts include those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; as well as organic acids such as acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, 3-(4-hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,
  • Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
  • the term “substantially free of” or “substantially in the absence of” stereoisomers with respect to a composition refers to a composition that includes at least 85% or 90% by weight, 12 1103197127 ⁇ 3 ⁇ AMERICAS Attorney Ref.
  • the total weight % constitutes the weight % of the designated stereoisomer plus the weight % of the undesignated stereoisomer in the composition based on weight of the designated stereoisomer (excluding the weight of a pharmaceutically acceptable salt, if the prodrug exists as a pharmaceutically acceptable salt) plus the weight of the undesignated stereoisomer (excluding the weight of a pharmaceutically acceptable salt, if the prodrug exists as a pharmaceutically acceptable salt).
  • the prodrugs are substantially free of stereoisomers.
  • Atoms containing their natural isotopic composition may also be referred to herein as “non-enriched” atoms.
  • the atoms of the prodrugs recited herein are meant to represent any stable isotope of that atom.
  • a position is designated specifically as “H” or “hydrogen,” the position is understood to have hydrogen at its natural isotopic composition.
  • administering and variants thereof (e.g., in some embodiments, “administering” a compound) in reference to a prodrug described herein means introducing the prodrug as described herein into the system of the animal in need of treatment.
  • “administration” and its variants are each understood to include concurrent and sequential introduction of the prodrug thereof and other agents.
  • “Therapeutically effective amount” is an amount of a prodrug or composition, that when administered to a patient, is sufficient to affect such treatment for the RNA viral infection, e.g., to ameliorate a symptom of the disease.
  • the amount of a prodrug described herein which 13 1103197127 ⁇ 3 ⁇ AMERICAS Attorney Ref.
  • No.127531.00009 constitutes a “therapeutically effective amount” will vary depending on the prodrug, the RNA viral infection and its severity, the age of the patient to be treated, and the like. The therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to their knowledge and to this disclosure.
  • the terms “therapeutic agent” and “therapeutic agents” refer to any agent(s) which can be used in the treatment of an RNA viral infection described herein or one or more symptoms thereof.
  • the term “therapeutic agent” includes a prodrug provided herein.
  • a therapeutic agent is an agent that is known to be useful for, or has been or is currently being used for the treatment or prevention of an RNA viral infection or one or more symptoms thereof.
  • “Treating” or “treatment” of an RNA viral infection described herein, as used herein, includes (i) preventing the RNA viral infection from occurring in a human, i.e., causing the clinical symptoms of the virus not to develop in an animal that may be exposed to or predisposed to the RNA viral infection, but does not yet experience or display symptoms of the RNA viral infection; (ii) inhibiting the RNA viral infection, i.e., arresting its development and/or its replication; and (iii) relieving the RNA viral infection, e.g., relieving or reducing a symptom thereof.
  • Treating” or “treatment” of any RNA viral infection refers, in certain embodiments, to ameliorating a RNA viral infection that exists in a subject. In another embodiment, “treating” or “treatment” includes ameliorating at least one physical parameter, which may be indiscernible in the subject, for example, viral load.
  • “treating” or “treatment” includes modulating the RNA viral infection, either physically (e.g., stabilization of a discernible symptom) or physiologically (e.g., stabilization of a physical parameter) or both. In yet another embodiment, “treating” or “treatment” includes delaying the onset of the RNA viral infection. [0049] “Preventing” or “prevent” of the RNA viral infection, as used herein, includes the administration of a prodrug as described herein to reduce the likelihood of an occurrence or reoccurrence of the viral infection, or to minimize a new viral infection relative to a viral infection that would have occurred without such treatment.
  • prevention includes administering a prodrug as described herein to a host who has been exposed to and is thus at risk of contracting a viral infection. 14 1103197127 ⁇ 3 ⁇ AMERICAS Attorney Ref. No.127531.00009 [0050]
  • prodrug refers to any agent(s) which can be used in the prevention of a viral infection, or one or more symptoms thereof.
  • the term “prophylactic agent” includes a prodrug as provided herein. In certain other embodiments, the term “prophylactic agent” does not refer to a prodrug provided herein.
  • a prophylactic agent can be an agent that is known to be useful for, or has been or is currently being used to prevent or impede the onset, development, progression, and/or severity of the RNA viral infection.
  • prophylactically effective amount refers to the amount of a therapy (e.g., prophylactic agent) which is sufficient to result in the prevention or reduction of the development, recurrence or onset of one or more symptoms associated with an RNA viral infection, or to enhance or improve the prophylactic effect(s) of another therapy (e.g., another prophylactic agent).
  • the term “anomer” refers to a stereoisomer that differs in the configuration of the carbon bound to the base (the 2-position of the nucleoside).
  • a nucleoside can exist as either the ⁇ -anomer or the ⁇ -anomer.
  • the compounds described herein can exist as either the ⁇ -anomer, the ⁇ -anomer, or a mixture thereof. In a preferred embodiment, the compounds described herein are the ⁇ -anomers. In an alternative embodiment, the compounds described herein are the ⁇ -anomers.
  • the compound of Formula I is a compound of Formula I-1: or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers thereof and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof.
  • the compound of Formula I is a compound of Formula I-2: or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers thereof and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof. 15 1103197127 ⁇ 3 ⁇ AMERICAS Attorney Ref.
  • the compound of Formula I is a compound of Formula I-3: or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers thereof and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof.
  • Base is selected from .
  • Base is selected from [0057]
  • Formula I, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID, R 1 , R 2 , and R 3 are hydrogen.
  • Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID, R 1 , R 2 , and R 3 are independently selected from hydrogen and C1-C8alkyl.
  • Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID is hydrogen and R 1 and R 2 are independently selected from hydrogen and C1-C8alkyl.
  • R 1 , R 2 , and R 3 are independently selected from hydrogen, N(R a )2, N3, CN, and NO2, S(O)nR 3a , and halogen.
  • R 4 is OR a , N(R a )2, N3, CN, NO2, halogen, or S(O)nR 3a .
  • Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID X 2 is CH, X 1 is CR 11 , and R 11 is -CN.
  • R 5 is NR 7 R 8 .
  • R 5 is NH2.
  • R 5 is N 3 , NO, NO 2 , CHO, or CN.
  • anhydrous compositions can be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits.
  • suitable packaging includes, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs. 35 1103197127 ⁇ 3 ⁇ AMERICAS Attorney Ref. No.127531.00009 [0116]
  • pharmaceutical compositions and dosage forms that comprise one or more compounds that reduce the rate by which an active ingredient will decompose.
  • Such compounds, which are referred to herein as “stabilizers,” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.
  • compositions and single unit dosage forms can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like.
  • Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc.
  • Such compositions and dosage forms will contain a prophylactically or therapeutically effective amount of a prophylactic or therapeutic agent, in certain embodiments, in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the subject.
  • the formulation should suit the mode of administration.
  • the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, oral, intranasal or topical administration to human beings.
  • a pharmaceutical composition is formulated in accordance with routine procedures for subcutaneous administration to human beings.
  • compositions for intravenous administration are solutions in sterile isotonic aqueous buffer.
  • the composition may also include a solubilizing agent and a local anesthetic such as lignocaine to ease pain at the site of the injection.
  • dosage forms include, but are not limited to: tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; ointments; cataplasms (poultices); pastes; powders; dressings; creams; plasters; solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a subject, including suspensions (e.g., aqueous or non- aqueous liquid suspensions, oil in water emulsions, or a water in oil liquid emulsions), 36 1103197127 ⁇ 3 ⁇ AMERICAS Attorney Ref.
  • suspensions e.g., aqueous or non- aqueous liquid suspensions, oil in water emulsions, or a water in oil liquid emulsions
  • compositions suitable for parenteral administration to a subject may contain larger amounts of one or more of the active ingredients it comprises than a dosage form used in the maintenance treatment of the same infection.
  • a parenteral dosage form may contain smaller amounts of one or more of the active ingredients it comprises than an oral dosage form used to treat the RNA viral infection.
  • compositions are supplied either separately or mixed together in unit dosage form, in certain embodiments, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachet indicating the quantity of active agent.
  • a hermetically sealed container such as an ampoule or sachet indicating the quantity of active agent.
  • the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline.
  • Typical dosage forms comprise a compound provided herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof lie within the range of from about 0.1 mg to about 1000 mg per day, given as a single once-a-day dose in the morning or as divided doses throughout the day taken with food.
  • Particular dosage forms can have about 0.1, 0.2, 0.3, 0.4, 0.5, 1.0, 2.0, 2.5, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 100, 200, 250, 500 or 1000 mg of the active compound.
  • parenteral dosage forms are provided.
  • Parenteral dosage forms can be administered to subjects by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intra-arterial. Because their administration typically bypasses subjects’ natural defenses against contaminants, parenteral dosage forms are typically, sterile or capable of being sterilized prior to administration to a subject.
  • parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions. 37 1103197127 ⁇ 3 ⁇ AMERICAS Attorney Ref. No.127531.00009 [0124] Suitable vehicles that can be used to provide parenteral dosage forms are well known to those skilled in the art.
  • suitable vehicles include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer’s Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer’s Injection; water miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
  • aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer’s Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer’s Injection
  • water miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and poly
  • compositions that are suitable for oral administration can be presented as discrete dosage forms, such as, but are not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups). Such dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art. See generally, Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22 edition (September 15, 2012).
  • the oral dosage forms are solid and prepared under anhydrous conditions with anhydrous ingredients, as described in detail herein.
  • compositions provided herein extends beyond anhydrous, solid oral dosage forms. As such, further forms are described herein.
  • Typical oral dosage forms are prepared by combining the active ingredient(s) in an intimate admixture with at least one excipient according to conventional pharmaceutical compounding techniques. Excipients can take a wide variety of forms depending on the form of preparation desired for administration. In certain embodiments, excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents.
  • excipients suitable for use in solid oral dosage forms include, but are not limited to, starches, sugars, micro crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents.
  • tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid excipients are employed.
  • tablets can be coated by standard aqueous or non-aqueous techniques.
  • dosage forms can be prepared by any of the methods of pharmacy. In general, pharmaceutical compositions and 38 1103197127 ⁇ 3 ⁇ AMERICAS Attorney Ref.
  • No.127531.00009 dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary.
  • a tablet can be prepared by compression or molding.
  • Compressed tablets can be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as powder or granules, optionally mixed with an excipient.
  • Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre gelatinized starch, and mixtures thereof.
  • the binder or filler in pharmaceutical compositions is typically present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.
  • suitable forms of microcrystalline cellulose include, but are not limited to, the materials sold as AVICEL PH 101, AVICEL PH 103 AVICEL RC 581, AVICEL PH 105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA), and mixtures thereof.
  • a specific binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC 581.
  • Suitable anhydrous or low moisture excipients or additives include AVICEL PH 103TM and Starch 1500 LM.
  • Disintegrants are used in the compositions to provide tablets that disintegrate when exposed to an aqueous environment.
  • Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions.
  • a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients should be used to 39 1103197127 ⁇ 3 ⁇ AMERICAS Attorney Ref. No.127531.00009 form solid oral dosage forms.
  • the amount of disintegrant used varies based upon the type of formulation and is readily discernible to those of ordinary skill in the art.
  • Typical pharmaceutical compositions comprise from about 0.5 to about 15 weight percent of disintegrant, specifically from about 1 to about 5 weight percent of disintegrant.
  • Disintegrants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, pre gelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.
  • Lubricants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof.
  • Additional lubricants include, in certain embodiments, a syloid silica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore, MD), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Plano, TX), CAB O SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, MA), and mixtures thereof. If used at all, lubricants are typically used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated.
  • AEROSIL 200 a syloid silica gel
  • a coagulated aerosol of synthetic silica marketed by Degussa Co. of Plano, TX
  • CAB O SIL a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, MA
  • lubricants are typically used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated.
  • a prodrug of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof, optionally in a pharmaceutically acceptable carrier can be administered to a host in need thereof to treat an RNA viral infection.
  • the method is for inhibiting an RNA viral infection.
  • the method is for relieving an RNA viral infection.
  • the method is for the prevention of an RNA viral infection.
  • RNA viral infections include Coronaviridae, Flaviviridae, Filoviridae, Orthomyxoviridae, Paramyxoviridae, Pneumoviridae, and Picornaviridae.
  • the Coronaviridae infection is severe acute respiratory syndrome coronavirus (SARS-CoV) infection, Middle Eastern respiratory syndrome (MERS) coronavirus infection, severe acute respiratory coronavirus-2 (SARS-CoV- 2) infection, or another human coronavirus (229E, NL63, OC43, HKU1, or WIV1) infection.
  • SARS-CoV severe acute respiratory syndrome coronavirus
  • MERS Middle Eastern respiratory syndrome coronavirus
  • SARS-CoV- 2 severe acute respiratory coronavirus-2
  • WIV1 human coronavirus
  • the Coronaviridae infection is severe acute respiratory syndrome coronavirus (SARS-CoV) infection.
  • the Coronaviridae infection is Middle Eastern respiratory syndrome (MERS) coronavirus infection.
  • the Coronaviridae infection is severe acute respiratory coronavirus-2 (SARS- CoV-2) infection.
  • the SARS-CoV-2 viral infection is caused by a variant of SARS- CoV-2, for example an Alpha, Beta, Gamma, Delta, Epsilon, Eta, Iota, Kappa, Mu, Omicron, or Zeta variant.
  • the SARS-CoV-2 viral infection is caused an Alpha variant (Pango Lineage B.1.1.7).
  • the SARS-CoV-2 viral infection is caused a Beta variant (Pango lineages: B.1.351, B.1.351.2, B.1.351.3). In some embodiments, the SARS-CoV-2 viral infection is caused a Gamma variant (Pango Lineages: P.1, P.1.1, P.1.2). In some embodiments, the SARS-CoV-2 viral infection is caused an Epsilon variant (Pango Lineages: B.1.427, B.1.429). In some embodiments, the SARS-CoV-2 viral infection is caused an Eta variant (Pango Lineage: B.1.525). In some embodiments, the SARS-CoV-2 viral infection is caused an Iota variant (Pango Lineage: B.1.526).
  • the SARS- CoV-2 viral infection is caused a Kappa variant (Pango Lineage: B.1.617.1). In some embodiments, the SARS-CoV-2 viral infection is caused a Mu variant (Pango Lineages: B.1.621, B.1.621.1). In some embodiments, the SARS-CoV-2 viral infection is caused an Omicron variant (Pango Lineages: B.1.1.529, BA.1, BA.1.1, BA.2, BA.3, BA.4 and BA.5). In some embodiments, the SARS-CoV-2 viral infection is caused a Zeta variant (Pango Lineages: P.2).
  • a prodrug of Formula I, Formula I-1, Formula I-2, Formula I- 3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof, optionally in a pharmaceutically acceptable carrier is administered to a host in need thereof to treat a Flaviviridae virus infection.
  • Flaviviridae viral infections include, 41 1103197127 ⁇ 3 ⁇ AMERICAS Attorney Ref.
  • No.127531.00009 but are not limited to, Dengue fever, Yellow fever, West Nile fever, Zika fever, Japanese encephalitis virus, and Hepatitis C (HCV).
  • the Flaviviridae viral infection is selected from dengue fever, yellow fever, West Nile fever, Zika fever, and Japanese encephalitis virus.
  • a prodrug of Formula I, Formula I-1, Formula I-2, Formula I- 3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof, optionally in a pharmaceutically acceptable carrier is administered to a host in need thereof to treat an Orthomyxoviridae infection, for example, an influenza viral infection.
  • the Orthomyxoviridae infection is influenza type A, influenza type B, or influenza type C.
  • a prodrug of Formula I, Formula I-1, Formula I-2, Formula I- 3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof, optionally in a pharmaceutically acceptable carrier is administered to a host in need thereof to treat a Paramyxoviridae viral infection.
  • Paramyxoviridae viruses include, but are not limited to Nipah virus, Hendra virus, measles, mumps, and human parainfluenza viruses (HPIVs).
  • a prodrug of Formula I, Formula I-1, Formula I-2, Formula I- 3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof, optionally in a pharmaceutically acceptable carrier is administered to a host in need thereof to treat a Filoviridae viral infection.
  • No.127531.00009 (4) NS5B non-substrate inhibitor; (5) Interferon alfa-2a, which may be pegylated or otherwise modified, and/or ribavirin; (6) Non-substrate-based inhibitor; (7) Helicase inhibitor; (8) Antisense oligodeoxynucleotide (S-ODN); (9) Aptamer; (10) Nuclease-resistant ribozyme; (11) iRNA, including microRNA and SiRNA; (12) Antibody, partial antibody or domain antibody to the virus; (13) Viral antigen or partial antigen that induces a host antibody response; or (14) Nonsteroidal anti-inflammatory drug (NSAID) with or without a protein pump inhibitor.
  • S-ODN Antisense oligodeoxynucleotide
  • Aptamer (10) Nuclease-resistant ribozyme; (11) iRNA, including microRNA and SiRNA; (12) Antibody, partial antibody or domain antibody to the virus; (13) Vi
  • a prodrug of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof, optionally in a pharmaceutically acceptable carrier can be administered with a steroid.
  • COVID- 19-associated systemic inflammation and hypoxemic respiratory failure can be associated with heightened cytokine release, as indicated by elevated blood levels of IL-6, C-reactive protein 44 1103197127 ⁇ 3 ⁇ AMERICAS Attorney Ref. No.127531.00009 (CRP), D-dimer, and ferritin. It is thought that modulating IL-6 levels or the effects of IL-6 may reduce the duration and/or severity of COVID-19.
  • patients can be administered an IL-6- targeting monoclonal antibody, pharmaceutical inhibitor, or protein degrader, such as a bispecific compound that binds to IL-6 and also to a protein that mediates degradation.
  • a prodrug of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof, optionally in a pharmaceutically acceptable carrier is administered in combination or in alternation with Olumiant (baricitinib) or Actemra (tocilizumab).
  • immunosuppressant drugs used to treat the overreacting immune system include Janus kinase inhibitors (tofacitinib (Xeljanz)); calcineurin inhibitors (cyclosporine (Neoral, Sandimmune, SangCya)), tacrolimus (Astagraf XL, Envarsus XR, Prograf)); mTOR inhibitors (sirolimus (Rapamune), everolimus (Afinitor, Zortress)); and, IMDH inhibitors (azathioprine (Azasan, Imuran), leflunomide (Arava), mycophenolate (CellCept, Myfortic)).
  • Additional antibodies and biologies include abatacept (Orencia), adalimumab (Humira), anakinra (Kineret), certolizumab (Cimzia), etanercept (Enbrel), golimumab (Simponi), infliximab (Remicade), ixekizumab (Taltz), natalizumab (Tysabri), rituximab (Rituxan), secukinumab (Cosentyx), tocilizumab (Actemra), ustekinumab (Stelara), vedolizumab (Entyvio), basiliximab (Simulect), and daclizumab (Zinbryta)).
  • a prodrug of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof, optionally in a pharmaceutically acceptable carrier is administered in combination or in alternation with a nonsteroidal anti-inflammatory drug (NSAID) with or without a protein pump inhibitor.
  • NSAID nonsteroidal anti-inflammatory drug
  • Non-limiting examples of a protein 45 1103197127 ⁇ 3 ⁇ AMERICAS Attorney Ref. No.127531.00009 pump inhibitor include famotidine (Pepcid and Zantac), omeprazole (Prilosec), esomeprazole (Nexium), lansoprazole (Prevacid), rabeprazole (AcipHex), pantoprazole (Protonix), and dexlansoprazole (Dexilant), zegerid (omeprazole with sodium bicarbonate).
  • a prodrug of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof, optionally in a pharmaceutically acceptable carrier is administered in combination or in alternation with a NSAID, including, but not limited to, aspirin (Bayer, St.
  • a prodrug of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof, optionally in a pharmaceutically acceptable carrier, is administered in combination or in alternation with ibuprofen without a protein pump inhibitor.
  • a prodrug of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof, optionally in a pharmaceutically acceptable carrier is administered in combination or in alternation with a NSAID, including, but not limited to, aspirin (Bayer, St.
  • a prodrug of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID or a pharmaceutically 46 1103197127 ⁇ 3 ⁇ AMERICAS Attorney Ref. No.127531.00009 acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof, optionally in a pharmaceutically acceptable carrier, is administered in combination or in alternation with ibuprofen with a protein pump inhibitor.
  • 47 1103197127 ⁇ 3 ⁇ AMERICAS Attorney Ref. No.127531.00009 EXAMPLES [0155] Example 1.
  • Step 1 To a solution of compound 1-1 (3.0 g, 5.38 mmol, 1.0 eq), compound 1-2 (3.5 g, 13.45 mmol, 2.5 eq), K 2 CO 3 (2.2 g, 16.14 mmol, 3.0 eq) and KI (3.1 g, 18.84 mmol, 3.5 eq) in acetonitrile (60 mL, 20 ⁇ M) under nitrogen was stirred at 55 °C for 48h. LCMS showed the 48 1103197127 ⁇ 3 ⁇ AMERICAS Attorney Ref. No.127531.00009 reaction was completed.
  • Step 2 A solution of compounds 1-3A and 1-3B (5.21 g) in water (120 mL, 25 mM) and acetic acid (25 mL, 5 mM) was stirred at 60 o C overnight. LC-MS showed the reaction was complete. Then the mixture was cooled and extracted with ethyl acetate (100 mL x 2).
  • Step 3 To a solution of compounds 1-4A and 1-4B (250 mg, 0.37 mmol, 1.0 eq) in DCM (10 mL, 40 mM) under N2 at -68 o C was added BCl3 (1.9 mL, 1.9 mmol, 5.0 eq) dropwise and the temperature was controlled under -60 o C.
  • the reaction was stirred at -50 o C for 5h.
  • the solution was quenched with anhydrous methanol (20 mL).
  • the reaction mixture was concentrated to afford a crude product which was purified by reverse phase prep-HPLC to afford two compounds.
  • the two compounds were tentatively assigned.
  • the first eluting peak is tentatively Compound 1 and the second eluting peak is tentatively Compound 2 or the first eluting peak is tentatively one of the ⁇ -anomer and ⁇ - anomer of Compound 1 and the second eluting peak is the other of the ⁇ -anomer and ⁇ -anomer of Compound 1.
  • Compound 1 27 mg, 18%) and Compound 2 (42 mg, 28%) were off-white solids.
  • Plasma samples were collected into pre-chilled collection tubes containing K2EDTA and processed to plasma at 9 timepoints over a span of pre-dose to 49 1103197127 ⁇ 3 ⁇ AMERICAS Attorney Ref. No.127531.00009 24 h post-administration. Plasma samples were subjected to protein precipitation with a 12.5- fold volume of methanol, vortexed and centrifuged. [0161] An aliquot of 10 ⁇ L plasma samples or 10 ⁇ L working solutions mixed with 10 ⁇ L 100% ACN (100 ng/mL internal standard working solution) and 170 ⁇ L precipitant (40% methanol/40% acetonitrile/20% isopropyl alcohol (v/v/v)) were dispensed into a 96-well plate.
  • PK parameters Cmax, AUC(0-24h), and F%) for GS-441524 following oral administration of GS- 441524, Compound 1, or Compound 2 is shown in Table 1 below.
  • Table 2 provides the C max for the remaining prodrug in plasma following administration of Compound 1 or Compound 2.
  • Table 1 Pharmacokinetic Parameters for GS-441524 in Plasma Following Administration of GS-441524, Compound 1, and Compound 2 to Balb/C Mice 50 1103197127 ⁇ 3 ⁇ AMERICAS Attorney Ref. No.127531.00009 a Based on prodrug dose b Based on GS-441524 dose Table 2.
  • the C max of GS-441524 following oral and intravenous administration of Compound 2 was 3,947 nM and 27,738 nM, respectively. This compares to a Cmax of 2,049 of GS-441524 following oral administration of GS-441524.
  • the AUC(0-24h) of GS-441524 following oral administration of Compound 2 was 13,018 nM ⁇ h, which is approximately 3-fold higher than the AUC(0-24h) of GS-441524 following GS-441524 oral administration.
  • Table 2 provides the PK parameters for Compound 1 and Compound 2 following administration of Compound 1 and Compound 2, respectively.
  • FIG. 1B is a graph measuring the concentration of GS-441524 following intravenous administration of Compound 2, and as shown in the figure, Compound 2 fully converts into GS-441524 after approximately 4 hours and only a trace of Compound 2 was observed after administration.
  • GS-441524 and its current prodrugs are poorly water- soluble molecules that require additional excipients to be dissolved in GI tract fluids at efficacious doses. Because of this, the size requirement for solid preparations of these lipophilic prodrugs could limit their dose or result in a high pill burden, which may in turn reduce their efficacy and/or ability to be formulated in drug combinations for future development programs.
  • a conventional tablet of Compound 1 or Compound 2 could potentially require less excipients and effectively reduce tablet size over GS-441524 and its lipophilic prodrugs for efficacious target coverage.
  • Compound 2 could enable greater clinical target coverage to allow for increased dose-range interrogation of the target as well as the use of highly tolerable parenteral administrations when oral treatment is not viable, for example is severely ill patients.
  • Compound 1 and Compound 2 are expected to be readily converted to GS-441524 by ubiquitously distributed alkaline phosphatase, Compound 1 and Compound 2 can potentially be dosed via multiple parenteral as well as nasal and intratracheal routes in addition to the oral dosing.
  • administration of an organic-aqueous-based formulation via the intravenous route is challenging in outpatients and necessitates the use of large volumes of intravenous fluid to ensure safe drug delivery.
  • the enhanced solubility of Compound 1 and Compound 2 will potentially require less intravenous fluid.
  • Compound 1 and Compound 2 may also be compatible with common IV solutions and can be administered safely via an intravenous, intramuscular, or subcutaneous route, potentially with minimal site reaction.
  • GS-441524 prodrug remdesivir which is administrated with sulfobutylether- ⁇ -cyclodextrin as vehicle.
  • Sulfobutylether- ⁇ -cyclodextrin causes a site reaction and can accumulate in patients with impaired renal function, causing 52 1103197127 ⁇ 3 ⁇ AMERICAS Attorney Ref. No.127531.00009 additional toxicity.
  • Example 2 demonstrates, after an intravenous administration in mice of a 14 mg/kg 100% aqueous solution of Compound 2, the pharmacokinetics of GS-441524 in plasma were comparable to those of an organic-aqueous-based formulation of GS-441524 as reported in Wang, A.Q. et al.

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Abstract

Described herein are hydroxy dimethyl phosphate prodrugs and pharmaceutical compositions thereof for the treatment of RNA viral infections, including, but not limited to Coronaviridae viral infections.

Description

Attorney Ref. No.127531.00009 HYDROXYMETHYL DIHYDROGEN PHOSPHATE PRODRUGS OF C- NUCLEOSIDES CROSS-REFRENCE TO RELATED APPLICATIONS [0001] This application claims priority to and the benefit of U.S. Provisional Patent Application No.63/608,547 filed December 11, 2023, the entirety of which is incorporated by reference for all purposes. FIELD [0002] Described herein are hydroxy dimethyl phosphate prodrugs and pharmaceutical compositions thereof for the treatment of RNA viral infections, including, but not limited to Coronaviridae viral infections. BACKGROUND [0003] RNA viruses, which are responsible for infections ranging from the common cold to life-threatening hemorrhagic fevers, are a leading cause of worldwide human infectious diseases. Despite the benefit of vaccinations for many RNA viral infections, RNA viruses are a major global threat. This is due in part to the high evolution rate and high capacity to spread from animals to humans (Woolhouse MEJ, et al., Emerging Infectious Diseases 2016, 22:2037–2044). For example, outbreaks of the respiratory RNA viral infections severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) were reported in 2003 and 2016, respectively, and the 2019 outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spread quickly and was declared a global pandemic in March 2020. [0004] While nucleosides and nucleotides have long been studied as potential treatments against various RNA viruses, the compounds are most often used against the hepatitis C RNA virus. Less success has been observed with their use against respiratory RNA viral infections. Both nucleosides and nucleotides must be converted intracellularly to their corresponding active 5’-triphosphate derivatives. Once inside the cell, nucleosides and nucleotides are metabolized to a monophosphate derivative, which is highly polar and cannot diffuse across the cell membrane. The monophosphate derivative is then converted stepwise to the triphosphate derivative. [0005] One nucleoside in particular that has been widely investigated is GS-441524, a 1’-cyano 4-aza-7,9-dideazaadenosine C-nucleoside that has shown activity against a range of viruses, including Yellow Fever, Dengue Fever, Parainfluenza 3, MERS, SARS, SARS-CoV, Ebola 1 1103197127\3\AMERICAS Attorney Ref. No.127531.00009 hemorrhagic fever, Marburg hemorrhagic fever, Hepatitis C, Hepatitis E, Human metapneumovirus, Measles, Mumps, Nipah, and Respiratory syncytial virus (Cho, A. et al., Bioorganic and Medicinal Chemistry Letters, 22: 2705-2707, Lo, M. K. et al., Nature Sci. Rep., 7, 43395).
Figure imgf000003_0001
Recently, GS-441524 was also shown to inhibit SARS-CoV-2 infection in a mouse model without notable toxicity (Li, Y. et al. J. Med. Chem., 2022, 65:2785-2793). [0006] Despite its promising antiviral activity, GS-441524 has poor oral bioavailability in several species, including non-human primates (Mackman, R. L. et al. J. Med. Chem. 2021, 64: 5001–5017; Li, Y. et al. J. Med. Chem., 2022, 65:2785-2793; Wei, D. et al. Bioorg. Med. Chem., 2001, 46, 116364). For this reason, various 5’-, 4’-, and 3’-prodrugs of GS-441524 have been studied and developed in an attempt to obtain higher exposures of GS-441524. One such prodrug is remdesivir (Veklury, GS-5734) developed by Gilead Science, Inc.
Figure imgf000003_0002
[0007] Remdesivir, first studied as a potential treatment for respiratory syncytial virus (RSV), was advanced to clinical trials for the treatment of the Ebola virus in response to the West Africa outbreak in 2013. While the clinical trial was eventually halted for the treatment of Ebola after Phase 2 clinical trials, it has been shown to exhibit in vitro inhibition against other viruses of the Filovirus, Pneumovirus, Paramyxovirus, and Orthocoronavirus families (Mackman, R. L., Med. Chem. Lett.2022, 13, 3, 338–347 and Lo, M.K. et al. Scientific Reports 2017, 7, 43395; Brown, A.J. et al. Antiviral Research, 2019, 169, 104541). [0008] Following the SARS-CoV-2 outbreak, remdesivir was studied as a COVID-19 treatment and in May 2022, the United States FDA issued Emergency Use Authorization for its use. This was followed by full FDA approval in October 2022. Remdesivir is also authorized 2 1103197127\3\AMERICAS Attorney Ref. No.127531.00009 for use in the European Union. However, the benefits of remdesivir are still being studied in many clinical settings. For example, in one trial conducted among patients with moderate COVID-19 who were not receiving supplemental oxygen at enrollment, a 5-day course of remdesivir was associated with greater clinical improvement compared with standard of care when measured 11 days after initiation, but a 10-day course did not have a statistically significant difference in clinical status compared to the standard of care (Spinner, C.D., et al. JAMA 2020, 15, 324). In the Phase III DisCoVeRy clinical trial, no clinical benefit was observed from the use of remdesivir in patients who were admitted to the hospital for COVID- 19, were symptomatic for more than 7 days, and required oxygen support (Ader, F. et al. Lancet Infec Dis, 2022, 22, 209). Lastly, in the large scale WHO Solidarity trial, remdesivir had no significant effect on patients with COVID-19 who were already being ventilated (WHO Solidarity Trial Consortium, Lancet, 2022, 399:10339). [0009] In addition to its unclear benefit against COVID-19 in certain circumstances, remdesivir exhibits poor water solubility and must be administered as an intravenous solution. This is most beneficial for a hospital setting, but limits its outpatient use and broad patient access. While currently approved for outpatient settings where a healthcare provider has immediate access to medication to treat an allergic reaction (VEKLURY. Prescribing Information. Gilead Sciences, Inc.; 2022.), intravenous delivery of drugs with low solubility can be complicated and require large volumes of fluid for adequate care. Further, the remdesivir formulation includes sulfobutylether-β-cyclodextrin, which can cause a site reaction and its accumulation can cause additional toxicity in patients with impaired renal function. [0010] Gilead Sciences, Inc. is also developing a second prodrug of GS-441524 for the treatment of COVID-19. The prodrug is referred to as GS-5245 or obeldesivir, and is being developed as an oral formulation. Obeldesivir was studied in a Phase III clinical trial for patients who had a high risk of developing severe COVID-19, but this study was terminated when it was determined that that there would not be a statistically significant treatment effect (NCT05603143). A Phase II clinical trial is currently ongoing to study the effect of obeldesivir in nonhospitalized adults with acute respiratory syncytial virus (RSV) (NCT06585150). While obeldesivir is being developed as an oral pill, it is lipophilic, and often poorly water-soluble lipophilic molecules require additional excipients for consistent bioavailability and dissolution in the GI tract fluids at efficacious doses. Because of this, the formulation of lipophilic compounds can necessitate a large pill size, which can limit the dose and/or result in a high pill burden and poor patient compliance at large doses. Additionally, the isobutyric acid "leaving group" of obeldesivir could introduce gastrointestinal distress and other dose-limiting 3 1103197127\3\AMERICAS Attorney Ref. No.127531.00009 toxicities. The unpleasant taste and odor of isobutyric acid could further impact patient compliance. [0011] Therefore, there remains an outstanding medical need to develop prodrugs of GS- 441524 with potent antiviral activity that are water soluble and exhibit high bioavailability. SUMMARY [0012] Described herein are hydroxymethyl dihydrogen prodrugs of C-nucleotides, including of GS-441524. It has been surprisingly discovered that in certain embodiments, the prodrugs described herein exhibit unexpected and advantageous properties, including enhanced oral bioavailability compared to GS-441524. As described in Example 2, Compound 1 and Compound 2, prodrugs of Formula I, were administered orally and intravenously to mice. Certain PK parameters were measured, and these results were compared to the parameters measured following GS-441524 administration. Significantly, for Compound 2, whose structure was tentatively assigned, the AUC(0-24h) of GS-441524 following oral administration was 13,018 nM·h, which is approximately 3-fold higher than the AUC(0-24h) of GS-441524 following GS-441524 oral administration. The AUC(0-24h) of GS-441524 following intravenous administration of Compound 2 was 23,371 nM·h. Further, after only approximately 4 hours following intravenous administration, Compound 2 had fully converted to GS-441524 and only a trace amount of Compound 2 was observed (FIG.1B). [0013] These surprising results could not have been predicted in advance. Further, the PK parameters were obtained using a saline dose without organic solvents, which is especially advantageous for therapy and formulation. In terms of parenteral administration, the prodrugs described herein potentially can be compatible with common IV solutions and can be administered safely via an intravenous, intramuscular, or subcutaneous route. This is especially advantageous over remdesivir, which is administrated with sulfobutylether-β-cyclodextrin as vehicle. Sulfobutylether-β-cyclodextrin causes a site reaction and can accumulate in patients with impaired renal function, causing additional toxicity. [0014] Due to the superior PK, tablets of the prodrugs described herein could potentially reduce tablet size over GS-441524. Further, enhanced solubility could potentially reduce the tablet size over obeldesivir because minimal excipients may be required for formulation. This could allow for lower pill burden, the potential for formulating combination products, and/or increased dose-range interrogation of the target. The ability of the prodrugs described herein to be formulated for both oral and parenteral administration is advantageous. An oral formulation, such as a pill, can be widely distributed and administrated, while a parenteral 4 1103197127\3\AMERICAS Attorney Ref. No.127531.00009 formulation, for example, an intravenous solution, is most beneficial for patients that are severely ill and must be treated in a hospital. [0015] Therefore, the prodrugs described herein exhibit superior bioavailability compared to GS-441524 and have the additional benefit of enhanced solubility, which potentially allows for advantageous formulations compared to formulations of remdesivir and obeldesivir. [0016] Provided herein are hydroxy dimethyl phosphate prodrugs of Formula I:
Figure imgf000006_0001
or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers thereof and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof;
Figure imgf000006_0002
R1 and R2 are each independently hydrogen, N(Ra)2, N3, CN, NO2, S(O)nR3a, halogen, C1-C8alkyl, C3-C8cycloalkyl, C2-C8alkenyl, C2-C8alkynyl, or arylC1-C8alkyl; R3 is hydrogen, ORa, N(Ra)2, N3, CN, NO2, S(O)nR3a, halogen, C1-C8alkyl, C3- C8cycloalkyl, C2-C8alkenyl, C2-C8alkynyl, or arylC1-C8alkyl; R3a is independently hydrogen, N(Ra)2, C1-C8alkyl, C3-C8cycloalkyl, C2-C8alkenyl, C2-C8alkynyl, or arylC1-C8alkyl; R4 is ORa, N(Ra)2, N3, CN, NO2, S(O)nR3a, -C(=O)R7, -C(=O)OR7, -C(O)NR7R8, -C(=O)SR7, -S(O)R7, -S(O)2R7, -S(O)(OR7), -S(O)2(OR7), -SO2NR7R8, halogen, C1-C8alkyl, C3-C8cycloalkyl, C2-C8alkenyl, C2-C8alkynyl, or arylC1-C8alkyl; each n is independently 0, 1, or 2; each Ra is independently hydrogen, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, arylC1- C8alkyl, C3-C8cycloalkyl, -C(=O)R7, -C(=O)OR7, -C(=O)NR7R8, -C(=O)SR7, -S(O)R7, -S(O)2R7, -S(O)(OR7), -S(O)2(OR7), or -SO2NR7R8; 5 1103197127\3\AMERICAS Attorney Ref. No.127531.00009 X1 and X2 are each independently CR11 or N; R5 is halogen, NR7R8, N(R7)OR7a, NR7NR7aR8, N3, NO, NO2, CHO, CN, -CH(=NR7), -CH=NHNR7, -CH=N(OR7), -CH(OR7)2, -C(=O)NR7R8, -C(=S)NR7R8, -C(=O)OR7, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C8cycloalkyl, aryl, heteroaryl, -C(=O)C1-C8alkyl, -S(O)nC1-C8alkyl, arylC1-C8alkyl, OR7 or SR7; each R6, R9, and R11 are independently hydrogen, C1-C8alkyl, halogen, NR7R8, N(R7)OR7a, NR7NR7aR8, N3, NO, NO2, CHO, CN, -CH(=NR7), -CH=NHNR7, -CH=N(OR7), -CH(OR7)2, -C(=O)NR7R8, -C(=S)NR7R8, -C(=O)OR7, R7, OR7 or SR7; each R7, R8, and R7a are independently hydrogen, C1-C8alkyl, C2-C8alkenyl, C2- C8alkynyl, C3-C8cycloalkyl, aryl, heteroaryl, -C(=O)C1-C8alkyl, -S(O)nC1-C8alkyl, or arylC1- C8alkyl; or R7 and R8 taken together with a nitrogen to which they are both attached form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with -O-, -S- or -NRa-; X4 is -O- or -NH-; and R10 is -C(O)-O-PO3H2, -CHR9-O-PO3H2, or -PO3H2. [0017] In one embodiment, the prodrug of Formula I is a prodrug of Formula IA:
Figure imgf000007_0001
or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers thereof and/or an anomer thereof; wherein R1, R2, R3, R4, R5, R10, X1, and X2 are as defined herein. [0018] In one embodiment, the prodrug of Formula I is a prodrug of Formula IB:
Figure imgf000007_0002
6 1103197127\3\AMERICAS Attorney Ref. No.127531.00009 or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers thereof and/or an anomer thereof; wherein R1, R2, R3, R4, R5, R6, R10, X1, and X2 are as defined herein. [0019] In one embodiment, the prodrug of Formula I is a prodrug of Formula IC:
Figure imgf000008_0001
or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers thereof and/or an anomer thereof; wherein R1, R2, R3, R4, R6, R10, X1, X2, and X4 are as defined herein. [0020] In one embodiment, the prodrug of Formula IC is a prodrug of Formula IC-1:
Figure imgf000008_0002
or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers thereof and/or an anomer thereof; wherein R1, R2, R3, R4, R6, R10, X1, and X2 are as defined herein. [0021] In one embodiment, the prodrug of Formula IC is a prodrug of Formula IC-2:
Figure imgf000008_0003
or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers thereof and/or an anomer thereof; wherein R1, R2, R3, R4, R6, R10, X1, and X2 are as defined herein. 7 1103197127\3\AMERICAS Attorney Ref. No.127531.00009 [0022] In one embodiment, the prodrug of Formula I is a prodrug of Formula ID:
Figure imgf000009_0001
or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers thereof and/or an anomer thereof; wherein R1, R2, R3, R4, R6, R10, X1, and X2 are as defined herein. [0023] Provided herein are pharmaceutical compositions comprising a prodrug of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID, or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers thereof and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof. In certain embodiments, the pharmaceutical composition is in a dosage form suitable for parenteral administration. In other embodiments, the dosage form is suitable for oral administration. [0024] Also provided herein is a method to treat an RNA viral infection in a host in need thereof comprising administering a prodrug of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID, or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers thereof and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof, optionally in a pharmaceutically acceptable carrier. In one embodiment, the method is to treat an RNA viral infection in a host in need thereof. In another embodiment, the method is to prevent an RNA viral infection in a host in need thereof. In a preferred embodiment, the RNA viral infection is a Coronaviridae viral infection, for example a betacoronavirus viral infection, such as COVID-19 caused by the SARS-CoV (severe acute respiratory syndrome coronavirus) virus or the SARS-CoV-2 (severe acute respiratory syndrome coronavirus) virus. BRIEF DESCRIPTION OF DRAWINGS [0025] FIG. 1A is a profile of GS-441524 in plasma after oral administration of GS-441524 (10 mg/kg), Compound 1 (94 mg-eq/kg), and Compound 2 (10 mg-eq/kg) as described in Example 2. The dose for Compound 1 and Compound 2 is the mg-equivalent GS-441524/kg dose. 8 1103197127\3\AMERICAS Attorney Ref. No.127531.00009 [0026] FIG. 1B is a profile of GS-441524 in plasma after intravenous administration of Compound 2 (10 mg-eq/kg) as described in Example 2. DETAILED DESCRIPTION Definitions [0027] When referring to the prodrugs and compositions provided herein, the following terms have the following meanings unless indicated otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise. [0028] As used herein, unless specifically defined otherwise, any words of approximation such as without limitation “about,” when used in connection with various terms such as time, temperatures, doses, amounts, or weight percent of ingredients of a composition or a dosage form, mean e.g. a temperature, dose, amount, or weight percent that is recognized by those of ordinary skill in the art to provide an effect equivalent to that obtained from the specified time, temperature dose, amount, or weight percent. Specifically, the terms “about” and “approximately,” when used in this context, contemplate a time, temperature, dose, amount, or weight percent, etc. within 15%, within 10%, within 5%, within 4%, within 3%, within 2%, within 1%, or within 0.5% of the specified time, temperature, dose, amount, or weight percent, etc. In addition, any of the embodiments herein, where ranges or numbers are expressed with “about,” i.e. “about 48 wt/wt% to about 70 wt/wt%,” can be replaced with a range or number that does not recite “about,” i.e. “48 wt/wt% to 70 wt/wt%.” [0029] “Alkyl” is a straight or branched hydrocarbon. An alkyl group can have 1 to 8 carbon atoms (i.e., C1-C8 alkyl) or 1 to 6 carbon atoms (i.e., C1-C6 alkyl). Examples of suitable alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CHs)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CHs)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (- CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (- C(CHs)2CH2CH2CH3), 3-methyl-2- pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (- 9 1103197127\3\AMERICAS Attorney Ref. No.127531.00009 CH(CH3)CH2CH(CHs)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (- CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (- CH(CH3)C(CH3)3, and octyl (-(CH2)7CH3). [0030] “Alkenyl” is a hydrocarbon containing straight or branched carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon, sp2 double bond. An alkenyl group can have 2 to 8 carbon atoms (i.e., C2-C8 alkenyl) or 2 to 6 carbon atoms (i.e., C2-C6 alkenyl). Examples of suitable alkenyl groups include, but are not limited to, ethylene or vinyl (-CH=CH2), allyl (-CH2CH=CH2), cyclopentenyl (-C5H7), and 5-hexenyl (-CH2CH2CH2CH2CH=CH2). [0031] “Alkynyl” is a straight or branched hydrocarbon with at least one site of unsaturation, i.e., a carbon-carbon, sp triple bond. An alkynyl group can have 2 to 8 carbon atoms (i.e., C2- C8 alkyne) or 2 to 6 carbon atoms (i.e., C2-CG alkynyl). Examples of suitable alkynyl groups include, but are not limited to, acetylenic (-G≡CH), propargyl
Figure imgf000011_0001
the like. [0032] “Aryl” is an aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. For example, an aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 10 carbon atoms. Typical aryl groups include, but are not limited to, radicals derived from benzene (e.g., phenyl), substituted benzene, naphthalene, anthracene, biphenyl, and the like. [0033] “Arylalkyl” refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with an aryl radical. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and the like. In one embodiment, the alkyl moiety of the arylalkyl group can be 1 to 6 carbon atoms and the aryl moiety of the arylalkyl group can be 6 to 14 carbon atoms. [0034] “CHO” refers to . [0035] “Cycloalkyl” refers to a monocyclic or polycyclic saturated (i.e., cycloalkyl). Monocyclic carbocycles have 3 to 8 ring atoms or in some embodiments, 5 or 6 ring atoms. Bicyclic carbocycles have 7 to 12 ring atoms, e.g., arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as a bicyclo [5,6] or [6,6] system, or spiro-fused rings. Non-limiting examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cycIohex-2-enyl, 1-cyclohex-3-enyl, and 10 1103197127\3\AMERICAS Attorney Ref. No.127531.00009 phenyl. Non-limiting examples of bicyclo carbocycles includes naphthyl, tetrahydronaphthyl, and decalinyl. [0036] “Heteroaryl” refers to a monovalent, monocyclic aromatic group and/or multicyclic aromatic group, wherein at least one aromatic ring contains one or more heteroatoms independently selected from oxygen, sulfur, and nitrogen within the ring. Each ring of a heteroaryl group can contain one or two oxygen atoms, one or two sulfur atoms, and/or one to four nitrogen atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom. In certain embodiments, the heteroaryl has from five to twenty, from five to fifteen, or from five to ten ring atoms. A heteroaryl may be attached to the rest of the molecule via a nitrogen or a carbon atom. In some embodiments, monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, triazolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, and triazinyl. Examples of bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl, and thienopyridyl. Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl. [0037] “Halogen” or “halo” means fluoro, bromo, chloro, or iodo. [0038] “Patient” or “subject” includes humans and other animals, particularly mammals, and other organisms. Thus, the methods are applicable to both human therapy and veterinary applications. In some embodiments the patient is a mammal, and in other embodiments, the patient is human. As used herein, the terms “subject” and “patient” are used interchangeably. The terms “subject” and “subjects” refer to an animal, such as a mammal including a non- primate (e.g., a cow, pig, horse, cat, dog, rat, and mouse) and a primate (e.g., a monkey such as a cynomolgous monkey, a chimpanzee, and a human), and in certain embodiments, a human. In certain embodiments, the subject is a farm animal (e.g., a horse, a cow, a pig, etc.) or a pet (e.g., a dog or a cat). In preferred embodiments, the subject is a human. [0039] A “pharmaceutically acceptable salt” of a prodrug means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent prodrug. It is 11 1103197127\3\AMERICAS Attorney Ref. No.127531.00009 understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference, or S. M. Berge et al., “Pharmaceutical Salts,” J. Pharm. Sci.1977; 66, 1-19 which is also incorporated herein by reference. It is also understood that the prodrug can have one or more pharmaceutically acceptable salts associated with it. [0040] Examples of pharmaceutically acceptable acid addition salts include those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; as well as organic acids such as acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, 3-(4-hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4- toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4’-methylenebis-(3- hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, p-toluenesulfonic acid, salicylic acid, and the like. [0041] Examples of pharmaceutically acceptable base addition salts include those formed when an acidic proton present in the parent compound is replaced by a metal ion, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum, as salts, and the like. Preferable salts are the ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic non- toxic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins. Examples of organic bases include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, tromethamine, N-methylglucamine, polyamine resins, and the like. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. [0042] The term “substantially free of” or “substantially in the absence of” stereoisomers with respect to a composition refers to a composition that includes at least 85% or 90% by weight, 12 1103197127\3\AMERICAS Attorney Ref. No.127531.00009 or in certain embodiments 95%, 98%, 99%, or 100% by weight, of a designated stereoisomer of a prodrug in the composition based on the weight of the designated stereoisomer alone (i.e., excluding the weight of a pharmaceutically acceptable salt, if the prodrug exists as a pharmaceutically acceptable salt). In some embodiments, the total weight % constitutes the weight % of the designated stereoisomer plus the weight % of the undesignated stereoisomer in the composition based on weight of the designated stereoisomer (excluding the weight of a pharmaceutically acceptable salt, if the prodrug exists as a pharmaceutically acceptable salt) plus the weight of the undesignated stereoisomer (excluding the weight of a pharmaceutically acceptable salt, if the prodrug exists as a pharmaceutically acceptable salt). In certain embodiments, in the methods and compounds provided herein, the prodrugs are substantially free of stereoisomers. [0043] Similarly, the term “isolated” with respect to a composition refers to a composition that includes at least 85%, 90%, 95%, 98%, or 99% to 100% by weight, of a specified prodrug, the remainder comprising other chemical species or stereoisomers based on the weight of the specified prodrug alone (i.e., excluding a pharmaceutically acceptable salt, if the prodrug exists as a pharmaceutically acceptable salt). [0044] The term “isotopic composition,” as used herein, and unless otherwise specified, refers to the amount of each isotope present for a given atom, and “natural isotopic composition” refers to the naturally occurring isotopic composition or abundance for a given atom. Atoms containing their natural isotopic composition may also be referred to herein as “non-enriched” atoms. Unless otherwise designated, the atoms of the prodrugs recited herein are meant to represent any stable isotope of that atom. For example, unless otherwise stated, when a position is designated specifically as "H" or "hydrogen,” the position is understood to have hydrogen at its natural isotopic composition. [0045] “Administration” and variants thereof (e.g., in some embodiments, “administering” a compound) in reference to a prodrug described herein means introducing the prodrug as described herein into the system of the animal in need of treatment. When a prodrug described herein is provided in combination with one or more other active agents (e.g., in some embodiments, surgery, radiation, and chemotherapy, etc.), “administration” and its variants are each understood to include concurrent and sequential introduction of the prodrug thereof and other agents. [0046] “Therapeutically effective amount” is an amount of a prodrug or composition, that when administered to a patient, is sufficient to affect such treatment for the RNA viral infection, e.g., to ameliorate a symptom of the disease. The amount of a prodrug described herein which 13 1103197127\3\AMERICAS Attorney Ref. No.127531.00009 constitutes a “therapeutically effective amount” will vary depending on the prodrug, the RNA viral infection and its severity, the age of the patient to be treated, and the like. The therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to their knowledge and to this disclosure. [0047] As used herein, the terms “therapeutic agent” and “therapeutic agents” refer to any agent(s) which can be used in the treatment of an RNA viral infection described herein or one or more symptoms thereof. In certain embodiments, the term “therapeutic agent” includes a prodrug provided herein. In certain embodiments, a therapeutic agent is an agent that is known to be useful for, or has been or is currently being used for the treatment or prevention of an RNA viral infection or one or more symptoms thereof. [0048] “Treating” or “treatment” of an RNA viral infection described herein, as used herein, includes (i) preventing the RNA viral infection from occurring in a human, i.e., causing the clinical symptoms of the virus not to develop in an animal that may be exposed to or predisposed to the RNA viral infection, but does not yet experience or display symptoms of the RNA viral infection; (ii) inhibiting the RNA viral infection, i.e., arresting its development and/or its replication; and (iii) relieving the RNA viral infection, e.g., relieving or reducing a symptom thereof. As is known in the art, adjustments for systemic versus localized delivery, age, body weight, general health, sex, diet, time of administration, drug interaction and the severity of the RNA viral infection may be necessary, and will be ascertainable with routine experimentation by one of ordinary skill in the art. “Treating” or “treatment” of any RNA viral infection refers, in certain embodiments, to ameliorating a RNA viral infection that exists in a subject. In another embodiment, “treating” or “treatment” includes ameliorating at least one physical parameter, which may be indiscernible in the subject, for example, viral load. In yet another embodiment, “treating” or “treatment” includes modulating the RNA viral infection, either physically (e.g., stabilization of a discernible symptom) or physiologically (e.g., stabilization of a physical parameter) or both. In yet another embodiment, “treating” or “treatment” includes delaying the onset of the RNA viral infection. [0049] “Preventing” or “prevent” of the RNA viral infection, as used herein, includes the administration of a prodrug as described herein to reduce the likelihood of an occurrence or reoccurrence of the viral infection, or to minimize a new viral infection relative to a viral infection that would have occurred without such treatment. In one embodiment, prevention includes administering a prodrug as described herein to a host who has been exposed to and is thus at risk of contracting a viral infection. 14 1103197127\3\AMERICAS Attorney Ref. No.127531.00009 [0050] As used herein, the terms “prophylactic agent” and “prophylactic agents” refer to any agent(s) which can be used in the prevention of a viral infection, or one or more symptoms thereof. In certain embodiments, the term “prophylactic agent” includes a prodrug as provided herein. In certain other embodiments, the term “prophylactic agent” does not refer to a prodrug provided herein. In certain embodiments, a prophylactic agent can be an agent that is known to be useful for, or has been or is currently being used to prevent or impede the onset, development, progression, and/or severity of the RNA viral infection. [0051] As used herein, the phrase “prophylactically effective amount” refers to the amount of a therapy (e.g., prophylactic agent) which is sufficient to result in the prevention or reduction of the development, recurrence or onset of one or more symptoms associated with an RNA viral infection, or to enhance or improve the prophylactic effect(s) of another therapy (e.g., another prophylactic agent). [0052] As used herein, the term “anomer” refers to a stereoisomer that differs in the configuration of the carbon bound to the base (the 2-position of the nucleoside). A nucleoside can exist as either the β-anomer or the α-anomer. The compounds described herein can exist as either the β-anomer, the α-anomer, or a mixture thereof. In a preferred embodiment, the compounds described herein are the β-anomers. In an alternative embodiment, the compounds described herein are the α-anomers. Compounds [0053] In one embodiment, the compound of Formula I is a compound of Formula I-1:
Figure imgf000016_0001
or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers thereof and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof. [0054] In one embodiment, the compound of Formula I is a compound of Formula I-2:
Figure imgf000016_0002
or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers thereof and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof. 15 1103197127\3\AMERICAS Attorney Ref. No.127531.00009 [0055] In one embodiment, the compound of Formula I is a compound of Formula I-3:
Figure imgf000017_0001
or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers thereof and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof. [0056] In one embodiment, of Formula I-3, Base is selected from
Figure imgf000017_0002
Figure imgf000017_0004
. In one embodiment, of Formula I-3, Base is selected from
Figure imgf000017_0003
Figure imgf000017_0005
[0057] In one embodiment of Formula I, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID, R1, R2, and R3 are hydrogen. In one embodiment of Formula I, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID, R1, R2, and R3 are independently selected from hydrogen and C1-C8alkyl. In one embodiment of Formula I, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID, R1 and R2 are both hydrogen and R3 is ORa wherein Ra is independently selected from hydrogen, C1- C8alkyl, arylC1-C8alkyl, -C(=O)R7, and -C(=O)OR7 and R7 is independently selected from hydrogen, C1-C8alkyl, aryl, and arylC1-C8alkyl. 16 1103197127\3\AMERICAS Attorney Ref. No.127531.00009 [0058] In one embodiment of Formula I, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID, R3 is hydrogen and R1 and R2 are independently selected from hydrogen and C1-C8alkyl. [0059] In one embodiment of Formula I, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID, R1, R2, and R3 are independently selected from hydrogen, N(Ra)2, N3, CN, and NO2, S(O)nR3a, and halogen. In one embodiment of Formula I, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID, R1, R2, and R3 are independently selected from hydrogen, C1- C8alkyl, C3-C8cycloalkyl, C2-C8alkenyl, C2- C8alkynyl, and arylC1-C8alkyl. [0060] In one embodiment of Formula I, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID, R3 is hydrogen and R1 and R2 are independently selected from hydrogen, N(Ra)2, N3, CN, and NO2, S(O)nR3a, and halogen. In one embodiment of Formula I, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID, R3 is hydrogen and R1 and R2 are independently selected from hydrogen, C1-C8alkyl, C3- C8cycloalkyl, C2-C8alkenyl, C2-C8alkynyl, and arylC1-C8alkyl. [0061] In one embodiment of Formula I, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID, R4 is -CN. In one embodiment of Formula I, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID, R4 is ORa, N(Ra)2, N3, CN, NO2, halogen, or S(O)nR3a. In one embodiment of Formula I, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID, R4 is -C(=O)R7, -C(=O)OR7, or -C(O)NR7R8; R7 is selected from hydrogen, C1-C8alkyl, aryl, and arylC1- C8alkyl; and, R8 is selected from hydrogen and C1-C8alkyl. In one embodiment of Formula I, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID, R4 is -C(=O)SR7, -S(O)R7, -S(O)2R7, -S(O)(OR7), -S(O)2(OR7), or -SO2NR7R8; R7 is selected from hydrogen, C1-C8alkyl, aryl, and arylC1-C8alkyl; and, R8 is selected from hydrogen and C1- C8alkyl. In one embodiment of Formula I, Formula IA, Formula IB, Formula IC, Formula IC- 1, Formula IC-2, or Formula ID, R4 is C1-C8alkyl, C3-C8cycloalkyl, C2-C8alkenyl, C2- C8alkynyl, or arylC1-C8alkyl. In one embodiment of Formula I, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID, R1, R2, and R3 are hydrogen and R4 is CN. In one embodiment of Formula I, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID, R1, R2, and R3 are independently selected from hydrogen and C1-C8alkyl and R4 is CN. [0062] In one embodiment of Formula I, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID, R3 is hydrogen and R1 and R2 are independently selected from 17 1103197127\3\AMERICAS Attorney Ref. No.127531.00009 hydrogen and C1-C8alkyl and R4 is CN. In one embodiment of Formula I, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID, R3 is ORa and R1 and R2 are both hydrogen; Ra is independently selected from hydrogen, C1-C8alkyl, arylC1-C8alkyl, -C(=O)R7, and -C(=O)OR7; R7 is independently selected from hydrogen, C1-C8alkyl, aryl, and arylC1- C8alkyl; and R4 is CN. [0063] In one embodiment of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID, X1 is N. In one embodiment of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID, X1 is CR11. In one embodiment of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID, X1 is CR11 and R11 is -CN. In one embodiment of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID, X1 is CH. [0064] In one embodiment of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID, X2 is N. In one embodiment of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID, X2 is CR11. In one embodiment of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID, X2 is CR11 and R11 is -CN. In one embodiment of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID, X2 is CH. [0065] In one embodiment of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID, X1 is CR11 and X2 is N. In one embodiment of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID, X1 is N and X2 is CR11. In one embodiment of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID, X1 is CR11 and X2 is CR11. [0066] In one embodiment of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID, X1 is CH and X2 is N. In one embodiment of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID, X1 is N and X2 is CH. In one embodiment of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID, X1 is CH and X2 is CH. 18 1103197127\3\AMERICAS Attorney Ref. No.127531.00009 [0067] In one embodiment of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID, X1 is CR11, R11 is -CN, and X2 is N. In one embodiment of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID, X1 is N, X2 is CR11, and R11 is -CN. In one embodiment of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID, X1 is CH and X2 is CH. In one embodiment of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID, X1 is CH, X2 is CR11, and R11 is -CN. In one embodiment of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID, X2 is CH, X1 is CR11, and R11 is -CN. [0068] In one embodiment of Formula I, Formula I-1, Formula I-2, Formula IA, or Formula IB, R5 is NR7R8. In one embodiment of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, or Formula IB, R5 is NR7R8 wherein R7 and R8 are independently selected from hydrogen, C1-C8alkyl, C3-C8cycloalkyl, and -C(=O)C1-C8alkyl. In one embodiment of Formula I, Formula I-1, Formula I-2, Formula IA, or Formula IB, R5 is NH2. In one embodiment of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, or Formula IB, R5 is N(R7)OR7a or NR7NR7aR8 wherein R7, R7a, and R8 are independently hydrogen, C1- C8alkyl, C3-C8cycloalkyl, and -C(=O)C1-C8alkyl. In one embodiment of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, or Formula IB, R5 is N3, NO, NO2, CHO, or CN. In one embodiment of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, or Formula IB, R5 is -CH(=NR7), -CH=NHNR7, -CH=N(OR7), -CH(OR7)2, -C(=O)NR7R8, - C(=S)NR7R8, or -C(=O)OR7. In one embodiment of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, or Formula IB, R5 is C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3- C8cycloalkyl, aryl, or heteroaryl. In one embodiment of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, or Formula IB, R5 is -C(=O)(C1-C8)alkyl, -S(O)n(C1-C8)alkyl, aryl(C1-C8)alkyl, OR7 or SR7. In one embodiment of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, or Formula IB, R5 is OR7 wherein R7 is H, C1- C8alkyl, or-C(=O)C1-C8alkyl. [0069] In one embodiment of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IB, Formula IC, Formula IC-1, Formula IC-2, and Formula ID, R6 is hydrogen. In one embodiment of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IB, Formula IC, Formula IC-1, Formula IC-2, and Formula ID, R6 is NR7R8. In one embodiment of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IB, Formula IC, Formula IC-1, Formula IC- 19 1103197127\3\AMERICAS Attorney Ref. No.127531.00009 2, and Formula ID, R6 is NR7R8 wherein R7 and R8 are independently hydrogen, C1-C8alkyl, C3-C8cycloalkyl, and -C(=O)C1-C8alkyl. In one embodiment of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IB, Formula IC, Formula IC-1, Formula IC-2, and Formula ID, R6 is OR7 wherein R7 is hydrogen, C1-C8alkyl, C3-C8cycloalkyl, and -C(=O)C1-C8alkyl. In one embodiment of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IB, Formula IC, Formula IC-1, Formula IC-2, and Formula ID, R6 is N(R7)OR7a, NR7NR7aR8, N3, NO, is NO2. In one embodiment of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IB, Formula IC, Formula IC-1, Formula IC-2, and Formula ID, R6 is CHO, CN, -CH(=NR7), -CH=NHNR7, -CH=N(OR7), and -CH(OR7)2. In one embodiment of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IB, Formula IC, Formula IC-1, Formula IC-2, and Formula ID, R6 is -C(=O)NR7R8, -C(=S)NR7R8, -C(=O)OR7, R7, or SR7. [0070] In one embodiment of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IB, Formula IC, Formula IC-1, Formula IC-2, and Formula ID, R10 is -C(O)-O-PO3H2. In one embodiment of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IB, Formula IC, Formula IC-1, Formula IC-2, and Formula ID, R10 is -CH2-O-PO3H2. In one embodiment of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IB, Formula IC, Formula IC-1, Formula IC-2, and Formula ID, R10 is -CHR9-O-PO3H2. In one embodiment of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IB, Formula IC, Formula IC-1, Formula IC- 2, and Formula ID, R10 is -CHR9-O-PO3H2 wherein R9 is selected from halogen or C1-C8alkyl. In one embodiment of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IB, Formula IC, Formula IC-1, Formula IC-2, and Formula ID, R10 is -PO3H2. [0071] In one embodiment of Formula I, Formula I-1, Formula I-2, or Formula I-3, Base is
Figure imgf000021_0001
. 20 1103197127\3\AMERICAS Attorney Ref. No.127531.00009 [0072] In one embodiment of Formula I, Formula I-1, Formula I-2, or Formula I-3, Base is
Figure imgf000022_0001
[0073] In one embodiment of Formula I, Formula I-1, Formula I-2, or Formula I-3, Base is
Figure imgf000022_0002
[0074] In one embodiment of Formula I, Formula I-1, Formula I-2, or Formula I-3, Base is
Figure imgf000022_0003
. 21 1103197127\3\AMERICAS Attorney Ref. No.127531.00009 [0075] In one embodiment of Formula I, Formula I-1, Formula I-2, or Formula I-3, Base is
Figure imgf000023_0001
Figure imgf000023_0003
[0077] In one embodiment of Formula I, Formula I-1, Formula I-2, or Formula I-3, Base is of Formula I, Formula I-1, Formula I-2, or Formula I-3, Base is
Figure imgf000023_0002
one embodiment of Formula I, Formula I-1, Formula I-2, Formula I-3, 22 1103197127\3\AMERICAS Attorney Ref. No.127531.00009
Figure imgf000024_0005
[0079] In one embodiment of Formula I, Formula I-1, Formula I-2, or Formula I-3, Base is
Figure imgf000024_0001
. In one embodiment of Formula I, Formula I-1, Formula I-2, or Formula I-3, Base
Figure imgf000024_0002
one embodiment of Formula I, Formula I-1, Formula I-2, or Formula I-3, Base
Figure imgf000024_0003
one embodiment of Formula I, Formula I-1, Formula I-2, or Formula I-3, Base
Figure imgf000024_0004
Figure imgf000024_0006
23 1103197127\3\AMERICAS Attorney Ref. No.127531.00009
Figure imgf000025_0001
[0081] In one embodiment of Formula I, Formula I-1, Formula I-2, or Formula I-3, Base is
Figure imgf000025_0002
. [0082] In one embodiment of Formula I, Formula I-1, Formula I-2, or Formula I-3, Base is
Figure imgf000025_0003
one embodiment of Formula I, Formula I-1, Formula I-2, or Formula I-3, 24 1103197127\3\AMERICAS Attorney Ref. No.127531.00009
Figure imgf000026_0004
I- 2, or Formula I-3, Base
Figure imgf000026_0001
[0083] In one embodiment of Formula I, Formula I-1, Formula I-2, or Formula I-3, Base is
Figure imgf000026_0005
or Formula I-3, Base
Figure imgf000026_0002
one embodiment of Formula I, Formula I-1, Formula I-2, or Formula I-3, Base
Figure imgf000026_0003
25 1103197127\3\AMERICAS Attorney Ref. No.127531.00009 [0084] Non-limiting examples
Figure imgf000027_0001
include: ,
Figure imgf000027_0002
[0085] In one embodiment of Formula I, Formula I-1, Formula I-2, or Formula I-3, Base is
Figure imgf000027_0003
. [0086] In one embodiment of Formula I, Formula I-1, Formula I-2, or Formula I-3, Base is
Figure imgf000027_0004
. In one embodiment of Formula I, Formula I-1, Formula I-2, or Formula I-3, 26 1103197127\3\AMERICAS Attorney Ref. No.127531.00009
Figure imgf000028_0004
[0087] In one embodiment of Formula I, Formula I-1, Formula I-2, or Formula I-3, Base is
Figure imgf000028_0005
2, or Formula I-3, Base
Figure imgf000028_0001
[0088] Non-limiting examples
Figure imgf000028_0002
include:
Figure imgf000028_0003
27 1103197127\3\AMERICAS Attorney Ref. No.127531.00009
Figure imgf000029_0001
[0089] In one embodiment of Formula I, Formula I-1, Formula I-2, or Formula I-3, Base is
Figure imgf000029_0003
Figure imgf000029_0002
one embodiment of Formula I, Formula I-1, Formula 28 1103197127\3\AMERICAS Attorney Ref. No.127531.00009
Figure imgf000030_0001
one embodiment of Formula I, Formula I-1, Formula I-2, or Formula I-3, Base
Figure imgf000030_0002
[0091] In one embodiment of Formula I ,Formula I-1, Formula I-2, or Formula I-3, Base is
Figure imgf000030_0003
Figure imgf000030_0004
29 1103197127\3\AMERICAS Attorney Ref. No.127531.00009
Figure imgf000031_0001
[0093] In one embodiment of Formula I, Formula I-1, Formula I-2, or Formula I-3, Base is
Figure imgf000031_0005
I-1, Formula I-2, or Formula I-3, Base
Figure imgf000031_0002
one embodiment of Formula I, Formula I-1, Formula I-2, or Formula I-3, Base
Figure imgf000031_0003
Figure imgf000031_0004
. 30 1103197127\3\AMERICAS Attorney Ref. No.127531.00009 [0094] In one embodiment of Formula I, Formula I-1, Formula I-2, or Formula I-3, Base is
Figure imgf000032_0001
. [0095] In one embodiment of Formula I, Formula I-1, Formula I-2, or Formula I-3, Base is
Figure imgf000032_0002
. [0096] In one embodiment of Formula I, Formula I-1, Formula I-2, or Formula I-3, Base is of Formula I, Formula I-1, Formula I-2, or Formula I-3, Base is
Figure imgf000032_0003
. In one embodiment of Formula I, Formula I-1, Formula I-2, or Formula I-3, Base
Figure imgf000032_0004
one embodiment of Formula I, Formula I-1, Formula I-2, or Formula I-3, Base
Figure imgf000032_0005
[0098] Non-limiting examples
Figure imgf000032_0006
include: 31 1103197127\3\AMERICAS Attorney Ref. No.127531.00009
Figure imgf000033_0001
[0099] Non-limiting examples of compound of Formula I include:
Figure imgf000033_0003
[0100] In any of the foregoing embodiments, the compound is the α-anomer instead of the β- anomer as depicted. For example, in one embodiment, Compound 1 and Compound 2 are the
Figure imgf000033_0002
, 32 1103197127\3\AMERICAS Attorney Ref. No.127531.00009 Pharmaceutical compositions [0101] The prodrugs provided herein can be formulated into pharmaceutical compositions using methods available in the art and those disclosed herein. Any of the prodrugs or compounds disclosed herein can be provided in the appropriate pharmaceutical composition and be administered by a suitable route of administration. [0102] The methods provided herein encompass administering pharmaceutical compositions containing at least one prodrug as described herein, including a prodrug of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof either used alone or in the form of a combination with one or more compatible and pharmaceutically acceptable carriers, such as diluents or adjuvants, or with another agent for the treatment of an RNA viral infection. [0103] In clinical practice the active agents provided herein may be administered by any conventional route, in particular orally, parenterally, rectally or by inhalation (e.g. in the form of aerosols). In certain embodiments, the compound provided herein is administered orally. In certain embodiments, the compound provided herein is administered parenterally, for example intravenously. [0104] Use may be made, as solid compositions for oral administration, of tablets, pills, hard gelatin capsules, powders or granules. In these compositions, the active product is mixed with one or more inert diluents or adjuvants, such as sucrose, lactose or starch. [0105] These compositions can comprise substances other than diluents, for example a lubricant, such as magnesium stearate, or a coating intended for controlled release. [0106] Use may be made, as liquid compositions for oral administration, of solutions which are pharmaceutically acceptable, suspensions, emulsions, syrups and elixirs containing inert diluents, such as water or liquid paraffin. These compositions can also comprise substances other than diluents, in certain embodiments, wetting, sweetening or flavoring products. [0107] The compositions for parenteral administration can be emulsions or sterile solutions. Use may be made, as solvent or vehicle, of propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil, or injectable organic esters, in certain embodiments, ethyl oleate. These compositions can also contain adjuvants, in particular wetting, isotonizing, emulsifying, dispersing and stabilizing agents. Sterilization can be carried out in several ways, in certain embodiments, using a bacteriological filter, by radiation or by heating. They can also be 33 1103197127\3\AMERICAS Attorney Ref. No.127531.00009 prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water or any other injectable sterile medium. [0108] The compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active principle, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols. [0109] The compositions can also be formulated for inhalation. Formulations suitable for inhalation can be delivered by a wide range of passive breath driven and active power driven single/-multiple dose dry powder inhalers (DPI). The devices most commonly used for respiratory delivery include nebulizers, metered- dose inhalers, and dry powder inhalers. Several types of nebulizers are available, including jet nebulizers, ultrasonic nebulizers, and vibrating mesh nebulizers. [0110] In certain embodiments, a composition provided herein is a pharmaceutical composition or a single unit dosage form. Pharmaceutical compositions and single unit dosage forms provided herein comprise a prophylactically or therapeutically effective amount of one or more prophylactic or therapeutic agents (e.g., a prodrug provided herein, or other prophylactic or therapeutic agent), and a typically one or more pharmaceutically acceptable carriers. In a specific embodiment and in this context, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. The term “carrier” includes a diluent, adjuvant (e.g., Freund’s adjuvant (complete and incomplete)), excipient, or vehicle with which the therapeutic is administered. Any embodiment described for “excipient”. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water can be used as a carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Examples of suitable pharmaceutical carriers are described in Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22 edition (September 15, 2012). [0111] Typical pharmaceutical compositions and dosage forms comprise one or more excipients. Suitable excipients are well-known to those skilled in the art of pharmacy, and in certain embodiments, suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. Whether a particular 34 1103197127\3\AMERICAS Attorney Ref. No.127531.00009 excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art including, but not limited to, the way in which the dosage form will be administered to a subject and the specific active ingredients in the dosage form. The composition or single unit dosage form, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. [0112] Lactose free compositions provided herein can comprise excipients that are well known in the art and are listed, in certain embodiments, in the U.S. Pharmacopeia (USP 36–NF 31 S2). In general, lactose free compositions comprise an active ingredient, a binder/filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts. Exemplary lactose free dosage forms comprise an active ingredient, microcrystalline cellulose, pre gelatinized starch, and magnesium stearate. [0113] Further encompassed herein are anhydrous pharmaceutical compositions and dosage forms comprising active ingredients, since water can facilitate the degradation of some compounds. For example, the addition of water (e.g., 5%) is widely accepted in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf life or the stability of formulations over time. See, e.g., Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, New York, 1995, pp.37980. In effect, water and heat accelerate the decomposition of some compounds. Thus, the effect of water on a formulation can be of great significance since moisture and/or humidity are commonly encountered during manufacture, handling, packaging, storage, shipment, and use of formulations. [0114] Anhydrous pharmaceutical compositions and dosage forms provided herein can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms that comprise lactose and at least one active ingredient that comprises a primary or secondary amine can be anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected. [0115] An anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions can be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. In certain embodiments, suitable packaging includes, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs. 35 1103197127\3\AMERICAS Attorney Ref. No.127531.00009 [0116] Further provided are pharmaceutical compositions and dosage forms that comprise one or more compounds that reduce the rate by which an active ingredient will decompose. Such compounds, which are referred to herein as “stabilizers,” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers. [0117] The pharmaceutical compositions and single unit dosage forms can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like. Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Such compositions and dosage forms will contain a prophylactically or therapeutically effective amount of a prophylactic or therapeutic agent, in certain embodiments, in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the subject. The formulation should suit the mode of administration. In a certain embodiment, the pharmaceutical compositions or single unit dosage forms are sterile and in suitable form for administration to a subject, in certain embodiments, an animal subject, such as a mammalian subject, in certain embodiments, a human subject. [0118] A pharmaceutical composition is formulated to be compatible with its intended route of administration. In certain embodiments, routes of administration include, but are not limited to, parenteral, e.g., intravenous, intradermal, subcutaneous, intramuscular, subcutaneous, oral, buccal, sublingual, inhalation, intranasal, transdermal, topical, transmucosal, intra-tumoral, intra-synovial and rectal administration. In a specific embodiment, the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, oral, intranasal or topical administration to human beings. In an embodiment, a pharmaceutical composition is formulated in accordance with routine procedures for subcutaneous administration to human beings. Typically, compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. Where necessary, the composition may also include a solubilizing agent and a local anesthetic such as lignocaine to ease pain at the site of the injection. [0119] In certain embodiments, dosage forms include, but are not limited to: tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; ointments; cataplasms (poultices); pastes; powders; dressings; creams; plasters; solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a subject, including suspensions (e.g., aqueous or non- aqueous liquid suspensions, oil in water emulsions, or a water in oil liquid emulsions), 36 1103197127\3\AMERICAS Attorney Ref. No.127531.00009 solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a subject; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a subject. [0120] The composition, shape, and type of dosage forms provided herein will typically vary depending on their use. In certain embodiments, a dosage form used in the initial treatment of viral infection may contain larger amounts of one or more of the active ingredients it comprises than a dosage form used in the maintenance treatment of the same infection. Similarly, a parenteral dosage form may contain smaller amounts of one or more of the active ingredients it comprises than an oral dosage form used to treat the RNA viral infection. These and other ways in which specific dosage forms encompassed herein will vary from one another will be readily apparent to those skilled in the art. See, e.g., Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22 edition (September 15, 2012). [0121] Generally, the ingredients of compositions are supplied either separately or mixed together in unit dosage form, in certain embodiments, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachet indicating the quantity of active agent. Where the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration. [0122] Typical dosage forms comprise a compound provided herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof lie within the range of from about 0.1 mg to about 1000 mg per day, given as a single once-a-day dose in the morning or as divided doses throughout the day taken with food. Particular dosage forms can have about 0.1, 0.2, 0.3, 0.4, 0.5, 1.0, 2.0, 2.5, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 100, 200, 250, 500 or 1000 mg of the active compound. [0123] In certain embodiments, provided are parenteral dosage forms. Parenteral dosage forms can be administered to subjects by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intra-arterial. Because their administration typically bypasses subjects’ natural defenses against contaminants, parenteral dosage forms are typically, sterile or capable of being sterilized prior to administration to a subject. In certain embodiments, parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions. 37 1103197127\3\AMERICAS Attorney Ref. No.127531.00009 [0124] Suitable vehicles that can be used to provide parenteral dosage forms are well known to those skilled in the art. In certain embodiments, suitable vehicles include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer’s Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer’s Injection; water miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate. [0125] Compounds that increase the solubility of one or more of the active ingredients disclosed herein can also be incorporated into the parenteral dosage forms. Oral Dosage Forms [0126] Pharmaceutical compositions that are suitable for oral administration can be presented as discrete dosage forms, such as, but are not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups). Such dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art. See generally, Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22 edition (September 15, 2012). [0127] In certain embodiments, the oral dosage forms are solid and prepared under anhydrous conditions with anhydrous ingredients, as described in detail herein. However, the scope of the compositions provided herein extends beyond anhydrous, solid oral dosage forms. As such, further forms are described herein. [0128] Typical oral dosage forms are prepared by combining the active ingredient(s) in an intimate admixture with at least one excipient according to conventional pharmaceutical compounding techniques. Excipients can take a wide variety of forms depending on the form of preparation desired for administration. In certain embodiments, excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents. In certain embodiments, excipients suitable for use in solid oral dosage forms (e.g., powders, tablets, capsules, and caplets) include, but are not limited to, starches, sugars, micro crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents. [0129] Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid excipients are employed. If desired, tablets can be coated by standard aqueous or non-aqueous techniques. Such dosage forms can be prepared by any of the methods of pharmacy. In general, pharmaceutical compositions and 38 1103197127\3\AMERICAS Attorney Ref. No.127531.00009 dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary. [0130] In certain embodiments, a tablet can be prepared by compression or molding. Compressed tablets can be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as powder or granules, optionally mixed with an excipient. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. [0131] In certain embodiments, excipients that can be used in oral dosage forms include, but are not limited to, binders, fillers, disintegrants, and lubricants. Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos.2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof. [0132] In certain embodiments, fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre gelatinized starch, and mixtures thereof. The binder or filler in pharmaceutical compositions is typically present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form. [0133] In certain embodiments, suitable forms of microcrystalline cellulose include, but are not limited to, the materials sold as AVICEL PH 101, AVICEL PH 103 AVICEL RC 581, AVICEL PH 105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA), and mixtures thereof. A specific binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC 581. Suitable anhydrous or low moisture excipients or additives include AVICEL PH 103™ and Starch 1500 LM. [0134] Disintegrants are used in the compositions to provide tablets that disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients should be used to 39 1103197127\3\AMERICAS Attorney Ref. No.127531.00009 form solid oral dosage forms. The amount of disintegrant used varies based upon the type of formulation and is readily discernible to those of ordinary skill in the art. Typical pharmaceutical compositions comprise from about 0.5 to about 15 weight percent of disintegrant, specifically from about 1 to about 5 weight percent of disintegrant. [0135] Disintegrants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, pre gelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof. [0136] Lubricants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof. Additional lubricants include, in certain embodiments, a syloid silica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore, MD), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Plano, TX), CAB O SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, MA), and mixtures thereof. If used at all, lubricants are typically used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated. Methods of Treatment [0137] A prodrug of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof, optionally in a pharmaceutically acceptable carrier can be administered to a host in need thereof to treat an RNA viral infection. In one embodiment, the method is for inhibiting an RNA viral infection. In one embodiment, the method is for relieving an RNA viral infection. In one embodiment, the method is for the prevention of an RNA viral infection. Non-limiting examples of RNA viral infections include Coronaviridae, Flaviviridae, Filoviridae, Orthomyxoviridae, Paramyxoviridae, Pneumoviridae, and Picornaviridae. [0138] In some embodiments, a prodrug of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID or a 40 1103197127\3\AMERICAS Attorney Ref. No.127531.00009 pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof, optionally in a pharmaceutically acceptable carrier, is administered to a host in need thereof to treat a Coronaviridae infection. In some embodiments, the Coronaviridae infection is severe acute respiratory syndrome coronavirus (SARS-CoV) infection, Middle Eastern respiratory syndrome (MERS) coronavirus infection, severe acute respiratory coronavirus-2 (SARS-CoV- 2) infection, or another human coronavirus (229E, NL63, OC43, HKU1, or WIV1) infection. In some embodiments, the Coronaviridae infection is severe acute respiratory syndrome coronavirus (SARS-CoV) infection. In some embodiments, the Coronaviridae infection is Middle Eastern respiratory syndrome (MERS) coronavirus infection. In preferred embodiments, the Coronaviridae infection is severe acute respiratory coronavirus-2 (SARS- CoV-2) infection. [0139] In some embodiments, the SARS-CoV-2 viral infection is caused by a variant of SARS- CoV-2, for example an Alpha, Beta, Gamma, Delta, Epsilon, Eta, Iota, Kappa, Mu, Omicron, or Zeta variant. In some embodiments, the SARS-CoV-2 viral infection is caused an Alpha variant (Pango Lineage B.1.1.7). In some embodiments, the SARS-CoV-2 viral infection is caused a Beta variant (Pango lineages: B.1.351, B.1.351.2, B.1.351.3). In some embodiments, the SARS-CoV-2 viral infection is caused a Gamma variant (Pango Lineages: P.1, P.1.1, P.1.2). In some embodiments, the SARS-CoV-2 viral infection is caused an Epsilon variant (Pango Lineages: B.1.427, B.1.429). In some embodiments, the SARS-CoV-2 viral infection is caused an Eta variant (Pango Lineage: B.1.525). In some embodiments, the SARS-CoV-2 viral infection is caused an Iota variant (Pango Lineage: B.1.526). In some embodiments, the SARS- CoV-2 viral infection is caused a Kappa variant (Pango Lineage: B.1.617.1). In some embodiments, the SARS-CoV-2 viral infection is caused a Mu variant (Pango Lineages: B.1.621, B.1.621.1). In some embodiments, the SARS-CoV-2 viral infection is caused an Omicron variant (Pango Lineages: B.1.1.529, BA.1, BA.1.1, BA.2, BA.3, BA.4 and BA.5). In some embodiments, the SARS-CoV-2 viral infection is caused a Zeta variant (Pango Lineages: P.2). [0140] In certain embodiments, a prodrug of Formula I, Formula I-1, Formula I-2, Formula I- 3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof, optionally in a pharmaceutically acceptable carrier is administered to a host in need thereof to treat a Flaviviridae virus infection. Non-limiting examples of Flaviviridae viral infections include, 41 1103197127\3\AMERICAS Attorney Ref. No.127531.00009 but are not limited to, Dengue fever, Yellow fever, West Nile fever, Zika fever, Japanese encephalitis virus, and Hepatitis C (HCV). In some embodiments, the Flaviviridae viral infection is selected from dengue fever, yellow fever, West Nile fever, Zika fever, and Japanese encephalitis virus. [0141] In certain embodiments, a prodrug of Formula I, Formula I-1, Formula I-2, Formula I- 3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof, optionally in a pharmaceutically acceptable carrier is administered to a host in need thereof to treat an Orthomyxoviridae infection, for example, an influenza viral infection. In some embodiments, the Orthomyxoviridae infection is influenza type A, influenza type B, or influenza type C. [0142] In certain embodiments, a prodrug of Formula I, Formula I-1, Formula I-2, Formula I- 3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof, optionally in a pharmaceutically acceptable carrier is administered to a host in need thereof to treat a Paramyxoviridae viral infection. Non-limiting examples of Paramyxoviridae viruses include, but are not limited to Nipah virus, Hendra virus, measles, mumps, and human parainfluenza viruses (HPIVs). [0143] In certain embodiments, a prodrug of Formula I, Formula I-1, Formula I-2, Formula I- 3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof, optionally in a pharmaceutically acceptable carrier is administered to a host in need thereof to treat a Filoviridae viral infection. Non-limiting examples of Filoviridae viruses include, but are not limited to, Ebola (variants Zaire, Bundibugio, Sudan, Tai forest, or Reston) and Marburg. In some embodiments, the Filoviridae virus infection is an Ebola virus infection. [0144] In certain embodiments, a prodrug of Formula I, Formula I-1, Formula I-2, Formula I- 3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof, optionally in a pharmaceutically acceptable carrier is administered to a host in need thereof to treat a Pneumoviridae viral infection. Non-limiting examples of Pneumoviridae viruses include, but are not limited to, respiratory syncytial virus (RSV) and human metapneumovirus. In one 42 1103197127\3\AMERICAS Attorney Ref. No.127531.00009 embodiment, the prodrug of Formula I, Formula IA, or Formula IB or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof, optionally in a pharmaceutically acceptable carrier is administered to a host in need thereof to treat or prevent RSV. In one embodiment, the RSV infection is chronic. In one embodiment, the RSV infection is acute. [0145] In certain embodiments, a prodrug of Formula I, Formula I-1, Formula I-2, Formula I- 3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof, optionally in a pharmaceutically acceptable carrier is administered to a host in need thereof to treat a Picornaviridae viral infection. Non-limiting examples of Picornaviridae viruses include herpangina, aseptic meningitis, a common-cold-like syndrome (human rhinovirus infection), a non-paralytic poliomyelitis-like syndrome, epidemic pleurodynia (an acute, febrile, infectious disease generally occurring in epidemics), hand-foot-mouth syndrome, pediatric and adult pancreatitis and serious myocarditis. Combination Therapy [0146] It is well recognized that drug-resistant variants of viruses can emerge after prolonged treatment with an antiviral agent. Drug resistance most typically occurs by mutation of a gene that encodes for an enzyme used in viral replication. The efficacy of a drug against an RNA viral infection can be prolonged, augmented, or restored by administering the compound in combination or alternation with another, and perhaps even two or three other, antiviral compounds that induce a different mutation or act through a different pathway, from that of the prodrugs described herein. Alternatively, the pharmacokinetics, biodistribution, half-life, or other parameter of the prodrug can be altered by such combination therapy [0147] As described more fully herein, the prodrugs described herein can be administered with one or more additional therapeutic agent(s) to an individual (e.g., a human) infected with a viral infection. The additional therapeutic agent(s) can be administered to the infected individual at the same time as the prodrug of the present disclosure or before or after administration of the prodrug of the present disclosure. In certain embodiments, it may be useful to administer the prodrug to a host in combination with, for example a: (1) Protease inhibitor, such as an NS3/4A protease inhibitor; (2) NS5A inhibitor; (3) A polymerase inhibitor; 43 1103197127\3\AMERICAS Attorney Ref. No.127531.00009 (4) NS5B non-substrate inhibitor; (5) Interferon alfa-2a, which may be pegylated or otherwise modified, and/or ribavirin; (6) Non-substrate-based inhibitor; (7) Helicase inhibitor; (8) Antisense oligodeoxynucleotide (S-ODN); (9) Aptamer; (10) Nuclease-resistant ribozyme; (11) iRNA, including microRNA and SiRNA; (12) Antibody, partial antibody or domain antibody to the virus; (13) Viral antigen or partial antigen that induces a host antibody response; or (14) Nonsteroidal anti-inflammatory drug (NSAID) with or without a protein pump inhibitor. [0148] For Coronaviridae infections, and SARS-CoV-2 in particular, patients are commonly prescribed an anti-viral drug especially in the early stages of the infection. Therefore, in one embodiment, a prodrug of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof, optionally in a pharmaceutically acceptable carrier, can be administered in combination with interferon-β and or an additional anti-viral drug, for example Paxlovid, Ensitrelvir, or Lagevrio (molnupiravir). [0149] In later infections and for hospitalized patients, steroids are often recommended. In certain embodiments, a prodrug of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof, optionally in a pharmaceutically acceptable carrier, can be administered with a steroid. Non-limiting examples of steroids include budesonide (Entocort EC), bethamethasone, (Celestone), prednisone (Prednisone Intensol), prednisolone (Orapred, Prelone), triamcinolone (Aristospan Intra-Articular, Aristospan Intralesional, Kenalog), methylprednisolone (Medrol, Depo-Medrol, Solu-Medrol), hydrocortisone, or dexamethasone (Dexamethasone Intensol, DexPak 10 Day, DexPak 13 Day, DexPak 6 Day). [0150] Severe COVID-19 infections are often associated with hyperinflammation. COVID- 19-associated systemic inflammation and hypoxemic respiratory failure can be associated with heightened cytokine release, as indicated by elevated blood levels of IL-6, C-reactive protein 44 1103197127\3\AMERICAS Attorney Ref. No.127531.00009 (CRP), D-dimer, and ferritin. It is thought that modulating IL-6 levels or the effects of IL-6 may reduce the duration and/or severity of COVID-19. To treat this surge of an immune response, which may constitute a cytokine storm, patients can be administered an IL-6- targeting monoclonal antibody, pharmaceutical inhibitor, or protein degrader, such as a bispecific compound that binds to IL-6 and also to a protein that mediates degradation. Examples of antibodies include baricitinib, tocilizumab, sarilumab, siltuximab, olokizumab and clazakizumab. [0151] In one embodiment, a prodrug of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof, optionally in a pharmaceutically acceptable carrier, is administered in combination or in alternation with Olumiant (baricitinib) or Actemra (tocilizumab). Additional nonlimiting examples of immunosuppressant drugs used to treat the overreacting immune system include Janus kinase inhibitors (tofacitinib (Xeljanz)); calcineurin inhibitors (cyclosporine (Neoral, Sandimmune, SangCya)), tacrolimus (Astagraf XL, Envarsus XR, Prograf)); mTOR inhibitors (sirolimus (Rapamune), everolimus (Afinitor, Zortress)); and, IMDH inhibitors (azathioprine (Azasan, Imuran), leflunomide (Arava), mycophenolate (CellCept, Myfortic)). Additional antibodies and biologies include abatacept (Orencia), adalimumab (Humira), anakinra (Kineret), certolizumab (Cimzia), etanercept (Enbrel), golimumab (Simponi), infliximab (Remicade), ixekizumab (Taltz), natalizumab (Tysabri), rituximab (Rituxan), secukinumab (Cosentyx), tocilizumab (Actemra), ustekinumab (Stelara), vedolizumab (Entyvio), basiliximab (Simulect), and daclizumab (Zinbryta)). [0152] In one embodiment, a prodrug of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof, optionally in a pharmaceutically acceptable carrier, is administered in combination or in alternation with a nonsteroidal anti-inflammatory drug (NSAID) with or without a protein pump inhibitor. Non- limiting examples of a NSAID include aspirin (Bayer, St. Joseph), celecoxib (Celebrex), diclofenac (Voltaren), diflunisal, etodolac, etoricoxib, fenoprofen (Nalfon), flurbiprofen, ibuprofen (Motrin, Advil), indomethacin (Indocin), ketoprofen, ketorolac (Toradol), mefenamic acid, meloxicam, nabumetone (Relafen), naproxen (Aleve, Naprosyn), oxaprozin, piroxicam, sulindac, tolmetin and naproxen/esomeprazole. Non-limiting examples of a protein 45 1103197127\3\AMERICAS Attorney Ref. No.127531.00009 pump inhibitor include famotidine (Pepcid and Zantac), omeprazole (Prilosec), esomeprazole (Nexium), lansoprazole (Prevacid), rabeprazole (AcipHex), pantoprazole (Protonix), and dexlansoprazole (Dexilant), zegerid (omeprazole with sodium bicarbonate). [0153] In one embodiment, a prodrug of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof, optionally in a pharmaceutically acceptable carrier, is administered in combination or in alternation with a NSAID, including, but not limited to, aspirin (Bayer, St. Joseph), celecoxib (Celebrex), diclofenac (Voltaren), diflunisal, etodolac, etoricoxib, fenoprofen (Nalfon), flurbiprofen, ibuprofen (Motrin, Advil), indomethacin (Indocin), ketoprofen, ketorolac (Toradol), mefenamic acid, meloxicam, nabumetone (Relafen), naproxen (Aleve, Naprosyn), oxaprozin, piroxicam, sulindac, tolmetin and naproxen/esomeprazole, without a protein pump inhibitor. In one embodiment, a prodrug of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof, optionally in a pharmaceutically acceptable carrier, is administered in combination or in alternation with ibuprofen without a protein pump inhibitor. [0154] In one embodiment, a prodrug of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof, optionally in a pharmaceutically acceptable carrier, is administered in combination or in alternation with a NSAID, including, but not limited to, aspirin (Bayer, St. Joseph), celecoxib (Celebrex), diclofenac (Voltaren), diflunisal, etodolac, etoricoxib, fenoprofen (Nalfon), flurbiprofen, ibuprofen (Motrin, Advil), indomethacin (Indocin), ketoprofen, ketorolac (Toradol), mefenamic acid, meloxicam, nabumetone (Relafen), naproxen (Aleve, Naprosyn), oxaprozin, piroxicam, sulindac, tolmetin and naproxen/esomeprazole, with a protein pump inhibitor, including, but not limited to famotidine (Pepcid and Zantac), omeprazole (Prilosec), esomeprazole (Nexium), lansoprazole (Prevacid), rabeprazole (AcipHex), pantoprazole (Protonix), and dexlansoprazole (Dexilant), zegerid (omeprazole with sodium bicarbonate). In one embodiment, a prodrug of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula IA, Formula IB, Formula IC, Formula IC-1, Formula IC-2, or Formula ID or a pharmaceutically 46 1103197127\3\AMERICAS Attorney Ref. No.127531.00009 acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof, optionally in a pharmaceutically acceptable carrier, is administered in combination or in alternation with ibuprofen with a protein pump inhibitor. 47 1103197127\3\AMERICAS Attorney Ref. No.127531.00009 EXAMPLES [0155] Example 1. General Procedure for the Preparation of Compounds 1 and
Figure imgf000049_0001
[0156] Step 1: To a solution of compound 1-1 (3.0 g, 5.38 mmol, 1.0 eq), compound 1-2 (3.5 g, 13.45 mmol, 2.5 eq), K2CO3 (2.2 g, 16.14 mmol, 3.0 eq) and KI (3.1 g, 18.84 mmol, 3.5 eq) in acetonitrile (60 mL, 20 µM) under nitrogen was stirred at 55 °C for 48h. LCMS showed the 48 1103197127\3\AMERICAS Attorney Ref. No.127531.00009 reaction was completed. To the mixture was added water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate and concentrated to afford a crude mixture of compounds 1-3A and 1-3B (5.21 g) as a yellow oil, which was used in the next step without purification. [0157] Step 2: A solution of compounds 1-3A and 1-3B (5.21 g) in water (120 mL, 25 mM) and acetic acid (25 mL, 5 mM) was stirred at 60 oC overnight. LC-MS showed the reaction was complete. Then the mixture was cooled and extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with water (100 mL x 2) and saturated NaHCO3 to remove acetic acid. The organic phase was dried over anhydrous sodium sulfate and concentrated to get a crude product (1.4 g), which was purified by reverse phase prep-HPLC to afford compounds 1-4A and 1-4B (950 mg, 26% over two steps) as a white solid. [0158] Step 3: To a solution of compounds 1-4A and 1-4B (250 mg, 0.37 mmol, 1.0 eq) in DCM (10 mL, 40 mM) under N2 at -68 oC was added BCl3 (1.9 mL, 1.9 mmol, 5.0 eq) dropwise and the temperature was controlled under -60 oC. After the addition was completed, the reaction was stirred at -50 oC for 5h. The solution was quenched with anhydrous methanol (20 mL). The reaction mixture was concentrated to afford a crude product which was purified by reverse phase prep-HPLC to afford two compounds. The two compounds were tentatively assigned. The first eluting peak is tentatively Compound 1 and the second eluting peak is tentatively Compound 2 or the first eluting peak is tentatively one of the α-anomer and β- anomer of Compound 1 and the second eluting peak is the other of the α-anomer and β-anomer of Compound 1. Compound 1 (27 mg, 18%) and Compound 2 (42 mg, 28%) were off-white solids. LC-MS (for both compounds): 402.0 [M+1]+.1H NMR (400 MHz, CD3OD) ^ 8.31 (s, 1H), 7.48 (d, J = 8 Hz, 1H), 7.17 (d, J = 4 Hz 1H), 5.83 (d, J = 12 Hz, 1H), 4.65 (d, J = 4 Hz, 1H), 4.20 (s, 1H), 4.10 (t, J = 4 Hz, 1H), 3.85 (d, J = 4 Hz, 1H), 3.72 (d, J = 4 Hz, 1H) (the 1H NMR spectra were indistinguishable for the two compounds). [0159] Example 2. Mouse pharmacokinetics of Compound 1 and Compound 2 [0160] Compound 1 and Compound 2 are prodrugs of nucleoside compound GS-441524. Data were taken for each of these compounds. As described above, the compound structures associated with the data provided below were tentatively assigned. Compound GS-441524, Compound 1, and Compound 2 were dosed orally by gavage (PO) and Compound 2 was dosed intravenously (IV) by slow bolus to male Balb/c mice (n=3 per timepoint) at 10 mg/kg in phosphate buffered saline, pH 5. Blood samples were collected into pre-chilled collection tubes containing K2EDTA and processed to plasma at 9 timepoints over a span of pre-dose to 49 1103197127\3\AMERICAS Attorney Ref. No.127531.00009 24 h post-administration. Plasma samples were subjected to protein precipitation with a 12.5- fold volume of methanol, vortexed and centrifuged. [0161] An aliquot of 10 μL plasma samples or 10 μL working solutions mixed with 10 μL 100% ACN (100 ng/mL internal standard working solution) and 170 μL precipitant (40% methanol/40% acetonitrile/20% isopropyl alcohol (v/v/v)) were dispensed into a 96-well plate. The mixture was vortexed for 5 min and centrifuged at 4000 rpm for 5 min. An aliquot of 100 µL of each supernatant was transferred to a deep 96-well plate, then 200 µL of deionized water was added, mixed well and 2.0 μL was injected into LC-MS/MS for analysis. Separation was achieved on an Agilent, Eclipse Plus-C18, 3.5 μm, 4.6 x 100 mm column, a mobile phase A of 0.1 % ammonium acetate in water and a mobile phase B of 100% acetonitrile with a step-wise linear gradient from 10 to 90% mobile phase B. An LC-MS/MS method was used to measure the concentrations of the GS-441524 and either Compound 1 or Compound 2 in plasma. PK parameters (Cmax, AUC(0-24h), and F%) for GS-441524 following oral administration of GS- 441524, Compound 1, or Compound 2 is shown in Table 1 below. Table 2 provides the Cmax for the remaining prodrug in plasma following administration of Compound 1 or Compound 2. Table 1. Pharmacokinetic Parameters for GS-441524 in Plasma Following Administration of GS-441524, Compound 1, and Compound 2 to Balb/C Mice
Figure imgf000051_0001
50 1103197127\3\AMERICAS Attorney Ref. No.127531.00009
Figure imgf000052_0001
a Based on prodrug dose b Based on GS-441524 dose Table 2. Pharmacokinetic Parameters for the Remaining Prodrug in Plasma Following Administration of Compound 1 and Compound 2 to Balb/C Mice
Figure imgf000052_0002
a Detected only within 15 min after the IV dose (<3% of parental drug GS-441524) b Below the limit of quantitation of 1 nM [0162] Table 1 and FIG.1A show that Compound 2 demonstrated 3-fold improvement in oral bioavailability over parental drug GS-441524. No intact prodrug was detected after oral administration and only a trace amount of the intact prodrug was detected after intravenous dose (<3%). Compound 1 unexpectedly showed very low oral bioavailability with no intact prodrug detected in plasma. [0163] The Cmax of GS-441524 following oral and intravenous administration of Compound 2 was 3,947 nM and 27,738 nM, respectively. This compares to a Cmax of 2,049 of GS-441524 following oral administration of GS-441524. The AUC(0-24h) of GS-441524 following oral administration of Compound 2 was 13,018 nM·h, which is approximately 3-fold higher than the AUC(0-24h) of GS-441524 following GS-441524 oral administration. [0164] Table 2 provides the PK parameters for Compound 1 and Compound 2 following administration of Compound 1 and Compound 2, respectively. The Cmax for both Compound 1 and Compound 2 when dosed orally was below the limit of quantitation (BLQ), while the Cmax of Compound 2 when dosed intravenously was 768 nM. 51 1103197127\3\AMERICAS Attorney Ref. No.127531.00009 [0165] The AUC(0-24h) of GS-441524 following intravenous administration of Compound 2 was 23,371 nM·h. FIG. 1B is a graph measuring the concentration of GS-441524 following intravenous administration of Compound 2, and as shown in the figure, Compound 2 fully converts into GS-441524 after approximately 4 hours and only a trace of Compound 2 was observed after administration. [0166] GS-441524 and its current prodrugs, remdesivir and obeldesivir, are poorly water- soluble molecules that require additional excipients to be dissolved in GI tract fluids at efficacious doses. Because of this, the size requirement for solid preparations of these lipophilic prodrugs could limit their dose or result in a high pill burden, which may in turn reduce their efficacy and/or ability to be formulated in drug combinations for future development programs. A conventional tablet of Compound 1 or Compound 2 could potentially require less excipients and effectively reduce tablet size over GS-441524 and its lipophilic prodrugs for efficacious target coverage. This could allow for lower pill burden and the potential for formulating combination products, as well as increased dose-range interrogation of the target and the use of highly tolerable parenteral administrations. Aqueous solubility of Compound 1 and Compound 2 are significantly greater than that of GS-441524. In the mouse, a 100% aqueous solution of Compound 2 demonstrated over 30-fold improved oral bioavailability of GS-441524 compared to the GS-441524 aqueous suspension. [0167] Additionally, from a single tablet, Compound 2 could enable greater clinical target coverage to allow for increased dose-range interrogation of the target as well as the use of highly tolerable parenteral administrations when oral treatment is not viable, for example is severely ill patients. [0168] Further, because Compound 1 and Compound 2 are expected to be readily converted to GS-441524 by ubiquitously distributed alkaline phosphatase, Compound 1 and Compound 2 can potentially be dosed via multiple parenteral as well as nasal and intratracheal routes in addition to the oral dosing. For example, administration of an organic-aqueous-based formulation via the intravenous route is challenging in outpatients and necessitates the use of large volumes of intravenous fluid to ensure safe drug delivery. The enhanced solubility of Compound 1 and Compound 2 will potentially require less intravenous fluid. Compound 1 and Compound 2 may also be compatible with common IV solutions and can be administered safely via an intravenous, intramuscular, or subcutaneous route, potentially with minimal site reaction. This is especially advantageous over the GS-441524 prodrug remdesivir, which is administrated with sulfobutylether-β-cyclodextrin as vehicle. Sulfobutylether-β-cyclodextrin causes a site reaction and can accumulate in patients with impaired renal function, causing 52 1103197127\3\AMERICAS Attorney Ref. No.127531.00009 additional toxicity. As Example 2 demonstrates, after an intravenous administration in mice of a 14 mg/kg 100% aqueous solution of Compound 2, the pharmacokinetics of GS-441524 in plasma were comparable to those of an organic-aqueous-based formulation of GS-441524 as reported in Wang, A.Q. et al. Front Pharmacol.2022; 13: 918083. [0169] Lastly, since Compound 1 and Compound 2 are negatively charged at physiological pH, they have minimal permeability into the cells, and are anticipated to cause lesser toxicity than the lipophilic prodrugs of GS-441524, which may discharge potentially toxic prodrug moieties such as 2-ethylbutanol, alanine, and phenol for remdesivir and isobutyric acid for obeldesivir inside the cells. [0170] The embodiments and examples described above are intended to be merely illustrative and non-limiting. Those skilled in the art will recognize or will be able to ascertain using no more than routine experimentation, numerous equivalents of specific compounds, materials and procedures. All such equivalents are considered to be within the scope and are encompassed by the appended claims. 53 1103197127\3\AMERICAS

Claims

Attorney Ref. No.127531.00009 Claims 1. A compound of Formula I-3:
Figure imgf000055_0001
or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers thereof and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof;
Figure imgf000055_0002
X1 and X2 are each independently CR11 or N; R5 is halogen, NR7R8, N(R7)OR7a, NR7NR7aR8, N3, NO, NO2, CHO, CN, -CH(=NR7), -CH=NHNR7, -CH=N(OR7), -CH(OR7)2, -C(=O)NR7R8, -C(=S)NR7R8, -C(=O)OR7, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C8cycloalkyl, aryl, heteroaryl, -C(=O)C1-C8alkyl, -S(O)nC1-C8alkyl, arylC1-C8alkyl, OR7 or SR7; each R6, R9, and R11 are is independently hydrogen, C1-C8alkyl, halogen, NR7R8, N(R7)OR7a, NR7NR7aR8, N3, NO, NO2, CHO, CN, -CH(=NR7), -CH=NHNR7, -CH=N(OR7), -CH(OR7)2, -C(=O)NR7R8, -C(=S)NR7R8, -C(=O)OR7, R7, OR7 or SR7; each R7, R8, and R7a are independently hydrogen, C1-C8alkyl, C2-C8alkenyl, C2- C8alkynyl, C3-C8cycloalkyl, aryl, heteroaryl, -C(=O)C1-C8alkyl, -S(O)nC1-C8alkyl, or arylC1- C8alkyl; or R7 and R8 taken together with a nitrogen to which they are both attached form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with -O-, -S- or -NRa-; X4 is -O- or -NH-; and each n is independently 0, 1, or 2; R10 is -C(O)-O-PO3H2 or -CHR9-O-PO3H2, or -PO3H2. 54 1103197127\3\AMERICAS Attorney Ref. No.127531.00009 2. A compound of Formula I:
Figure imgf000056_0001
or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers thereof and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof;
Figure imgf000056_0002
R1 and R2 are each independently hydrogen, N(Ra)2, N3, CN, NO2, S(O)nR3a, halogen, C1-C8alkyl, C3-C8cycloalkyl, C2-C8alkenyl, C2-C8alkynyl, or arylC1-C8alkyl; R3 is hydrogen, ORa, N(Ra)2, N3, CN, NO2, S(O)nR3a, halogen, C1-C8alkyl, C3- C8cycloalkyl, C2-C8alkenyl, C2-C8alkynyl, or arylC1-C8alkyl; R3a is independently hydrogen, N(Ra)2, C1-C8alkyl, C3-C8cycloalkyl, C2-C8alkenyl, C2-C8alkynyl, or arylC1-C8alkyl; R4 is ORa, N(Ra)2, N3, CN, NO2, S(O)nR3a, -C(=O)R7, -C(=O)OR7, -C(O)NR7R8, -C(=O)SR7, -S(O)R7, -S(O)2R7, -S(O)(OR7), -S(O)2(OR7), -SO2NR7R8, halogen, C1-C8alkyl, C3-C8cycloalkyl, C2-C8alkenyl, C2-C8alkynyl, or arylC1-C8alkyl; each n is independently 0, 1, or 2; each Ra is independently hydrogen, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, arylC1- C8alkyl, C3-C8cycloalkyl, -C(=O)R7, -C(=O)OR7, -C(=O)NR7R8, -C(=O)SR7, -S(O)R7, -S(O)2R7, -S(O)(OR7), -S(O)2(OR7), or -SO2NR7R8; X1 and X2 are each independently CR11 or N; R5 is halogen, NR7R8, N(R7)OR7a, NR7NR7aR8, N3, NO, NO2, CHO, CN, -CH(=NR7), -CH=NHNR7, -CH=N(OR7), -CH(OR7)2, -C(=O)NR7R8, -C(=S)NR7R8, 55 1103197127\3\AMERICAS Attorney Ref. No.127531.00009 -C(=O)OR7, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C8cycloalkyl, aryl, heteroaryl, -C(=O)C1-C8alkyl, -S(O)nC1-C8alkyl, arylC1-C8alkyl, OR7 or SR7; each R6, R9, and R11 are is independently hydrogen, C1-C8alkyl, halogen, NR7R8, N(R7)OR7a, NR7NR7aR8, N3, NO, NO2, CHO, CN, -CH(=NR7), -CH=NHNR7, -CH=N(OR7), -CH(OR7)2, -C(=O)NR7R8, -C(=S)NR7R8, -C(=O)OR7, R7, OR7 or SR7; each R7, R8, and R7a are independently hydrogen, C1-C8alkyl, C2-C8alkenyl, C2- C8alkynyl, C3-C8cycloalkyl, aryl, heteroaryl, -C(=O)C1-C8alkyl, -S(O)nC1-C8alkyl, or arylC1- C8alkyl; or R7 and R8 taken together with a nitrogen to which they are both attached form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with -O-, -S- or -NRa-; X4 is -O- or -NH-; and R10 is -C(O)-O-PO3H2 or -CHR9-O-PO3H2, or -PO3H2. 3. The compound of claim 2, wherein the compound of Formula I is of Formula IA:
Figure imgf000057_0001
or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers thereof and/or an anomer thereof. 4. The compound of claim 2, wherein the compound of Formula I is of Formula IB:
Figure imgf000057_0002
or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers thereof and/or an anomer thereof. 56 1103197127\3\AMERICAS Attorney Ref. No.127531.00009 5. The compound of claim 2, wherein the compound of Formula I is of Formula IC:
Figure imgf000058_0001
or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers thereof and/or an anomer thereof. 6. The compound of claim 5, wherein the compound of Formula IC is of Formula IC-1 or Formula IC-2:
Figure imgf000058_0002
or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers thereof and/or an anomer thereof. 7. The compound of claim 2, wherein the compound of Formula I is of Formula ID:
Figure imgf000058_0003
or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers thereof and/or an anomer thereof. 8. The compound of any one of claims 2-6, wherein R1, R2, and R3 are each hydrogen. 9. The compound of any one of claims 2-6, wherein R3 is hydrogen and R1 and R2 are independently selected from hydrogen and C1-C8alkyl. 10. The compound of any one of claims 2-8, wherein R4 is CN. 11. The compound of claim 2, wherein the prodrug of Formula I is of Formula I-1: 57 1103197127\3\AMERICAS Attorney Ref. No.127531.00009
Figure imgf000059_0001
or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers thereof and/or a tautomer or a mixture of tautomers thereof and/or an anomer thereof. 12. The compound of any one of claims 1-11, wherein X1 is N and X2 is CR11. 13. The compound of any one of claims 1-11, wherein X1 is CR11 and X2 is N. 14. The compound of claim 12 or 13, wherein R11 is -CN. 15. The compound of any one of claims 1-11, wherein X1 is CH and X2 is CH. 16. The compound of any one of claims 1-4 and 8-15, wherein R5 is NR7R8 and R7 and R8 are independently selected from hydrogen, C1-C8alkyl, C3-C8cycloalkyl, and -C(=O)C1-C8alkyl. 17. The compound of claim 16, wherein R5 is NH2. 18. The compound of any one of claims 1-4 and 8-15, wherein R5 is OR7 and R7 is selected from hydrogen, C1-C8alkyl, and-C(=O)C1-C8alkyl. 19. The compound of any one of claims 1, 2, and 4-18, wherein R6 is hydrogen. 20. The compound of any one of claims 1, 2, and 4-18, wherein R6 is NR7R8 and R7 and R8 are independently selected from hydrogen, C1-C8alkyl, C3-C8cycloalkyl, and -C(=O)C1-C8alkyl. 21. The compound of claim 20, wherein R6 is NH2. 22. The compound of any one of claims 1-21, wherein R10 is -C(O)-O-PO3H2. 23. The compound of any one of claims 1-21, wherein R10 is -CHR9-O-PO3H2. 24. The compound of any one of claims 1-21, wherein R10 is -CH2-O-PO3H2. 25. The compound of any one of claims 1-21, wherein R10 is -PO3H2. 26. The compound of any one of claims 1-21, wherein X1 and X2 are both CH and R10 is -C(O)-O-PO3H2. 27. The compound of any one of claims 1-21, wherein X1 and X2 are both CH and R10 is -CH2-O-PO3H2. 28. The compound of claim 26 or 27 wherein R6 is hydrogen. 58 1103197127\3\AMERICAS Attorney Ref. No.127531.00009 29. The compound of claim 1, 2, or 11 wherein Base is selected from:
Figure imgf000060_0001
. 30. The compound of claim 1, 2 or 11 wherein Base is selected from:
Figure imgf000060_0002
. 31. The compound of claim 30, wherein R11 is -CN. 32. The compound of claim 1, 2 or 11 wherein Base is selected from:
Figure imgf000060_0003
59 1103197127\3\AMERICAS Attorney Ref. No.127531.00009 33. The compound of Formula 32, wherein Base is selected from
Figure imgf000061_0001
35. The compound of any one of claims 29-34, wherein R10 is -C(O)-O-PO3H2. 36. The compound of any one of claims 29-34, wherein R10 is -CHR9-O-PO3H2. 37. The compound of any one of claims 29-34, wherein R10 is -CH2-O-PO3H2. 38. The compound of claim 1 of the formula:
Figure imgf000061_0002
or a pharmaceutically acceptable salt thereof and/or a stereoisomer or a mixture of stereoisomers thereof and/or an anomer thereof. 39. A pharmaceutical composition comprising the compound of any one of claim 1-38 and a pharmaceutically acceptable carrier, diluent, or excipient. 40. The pharmaceutical composition of claim 39, in a dosage form suitable for oral administration. 41. The pharmaceutical composition of claim 39, wherein the dosage form is a pill or capsule. 42. The pharmaceutical composition of claim 41, in a dosage form suitable for intravenous administration. 60 1103197127\3\AMERICAS Attorney Ref. No.127531.00009 43. A method to treat an RNA viral infection in a host in need thereof comprising administering a compound of any one of claim 1-38 or a pharmaceutical composition of any one of claims 39-42. 44. The method of claims 43, wherein the method to treat an RNA viral infection is to inhibit the RNA viral infection. 45. The method of claims 43, wherein the method to treat an RNA viral infection is to relieve the RNA viral infection. 46. The method of claims 43, wherein the method to treat an RNA viral infection is to prevent the RNA viral infection. 47. The method of any one of claims 43-46, wherein the RNA viral infection is a Coronaviridae viral infection. 48. The method of claim 47, wherein the Coronaviridae infection is the severe acute respiratory syndrome coronavirus (SARS-CoV), Middle Eastern respiratory syndrome (MERS) coronavirus, or severe acute respiratory coronavirus-2 (SARS-CoV-2). 49. The method of claim 48, wherein the Coronaviridae infection is severe acute respiratory coronavirus-2 (SARS-CoV-2). 50. The method of any one of claims 43-46, wherein the RNA viral infection is a Filoviridae viral infection. 51. The method of claim 50, wherein the Filoviridae infection is Ebola. 52. The method of any one of claims 43-46, wherein the RNA viral infection is a Flaviviridae infection. 53. The method of claim 52, wherein the Flaviviridae infection is selected from dengue fever, yellow fever, West Nile fever, Zika fever, and Japanese encephalitis virus. 54. The method of any one of claims 43-46, wherein the RNA viral infection is a Pneumoviridae infection. 55. The method of claim 54, wherein the Pneumoviridae infection is respiratory syncytial virus (RSV). 56. The method of any one of claims 43-55, wherein the host in a human. 61 1103197127\3\AMERICAS
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