Compounds and methods for the treatment of viral infections

Abstract

Disclosed are compounds, methods of using the compounds alone or in combination with additional agents, and salts or pharmaceutical compositions of the compounds for the treatment of viral infections.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 315,919, filed March 2, 2022, and U.S. Provisional Application No. 63 / 413,748, filed October 6, 2022, the entire contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] There is a need for compounds and methods for treating viral infections, such as those of the Paramyxoviridae, Pneumoviridae, Picornaviridae, Flaviviridae, Filoviridae, Arenaviridae, Orthomyxovirus, and Coronaviridae families. The present disclosure addresses these and other needs.

[0003] The oral route is the preferred route for daily drug administration due to its advantages such as non-invasiveness, patient compliance, and ease of drug administration. Nevertheless, oral administration may be limited due to poor physicochemical properties of drug molecules, including low water solubility at pH 2-7, instability, low permeability, and rapid metabolism, all of which may combine to result in low and erratic oral bioavailability. Oral bioavailability (F%) is the percentage of orally administered drug that reaches the systemic circulation for the same dose delivery by intravenous administration. After intravenous administration, the drug is directly and completely available in the bloodstream and can be distributed through the systemic circulation to the point where a pharmacological effect occurs. When a drug is administered orally, it must survive intestinal fluids, pass through additional barriers such as gastro-intestinal (GI) cell layers, and then pass through the liver to reach the systemic circulation, which may significantly reduce the amount of administered drug that reaches the bloodstream. Thus, oral bioavailability is an important property in drug design and development. High oral bioavailability reduces the required amount of administered drug required to achieve the desired pharmacological effect, and therefore may reduce the risk of side effects and toxicity during the absorption process. The present disclosure also provides compounds with a combination of solubility, stability, and permeability properties that lead to improved oral bioavailability. Summary of the Invention

[0004] The present disclosure relates to a compound of formula A: [ka] or a pharma- ceutically acceptable salt thereof, 1 , R 2 , R 3 and Base A is defined herein, or a pharma- ceutically acceptable salt thereof.

[0005] As used herein, a compound of formula B: [ka] or a pharma- ceutically acceptable salt thereof, A , R B , R C Also provided is a compound of formula B, or a pharma- ceutically acceptable salt thereof, wherein: and Base B is as defined herein.

[0006] Also provided herein are pharmaceutical compositions comprising a compound disclosed herein (e.g., a compound of Formula A or Formula B), or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable excipients.

[0007] Also provided herein is a method of treating or preventing a viral infection in a human in need thereof, the method comprising administering to the human a compound disclosed herein (e.g., a compound of Formula A or Formula B), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0008] Also provided herein is the use of a compound disclosed herein (e.g., a compound of Formula A or Formula B), or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a viral infection in a human in need thereof.

[0009] Also provided herein is a composition comprising a compound as described herein (e.g., a compound of Formula A or Formula B), or a pharma- ceutically acceptable salt thereof, for use in treating or preventing a viral infection in a human in need thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] I. Overview The present invention relates generally to methods and compounds for treating or preventing viral infections, such as those of the Paramyxoviridae, Pneumoviridae, Picornaviridae, Flaviviridae, Filoviridae, Arenaviridae, Orthomyxovirus, and Coronaviridae families.

[0011] II. Definition Unless otherwise stated, the following terms and phrases are intended to have the following meanings as used herein:

[0012] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. For example, an alkyl group can be any group having 1 to 20 carbon atoms (i.e., C 1 ~C 20 alkyl), 1 to 8 carbon atoms (i.e., C 1 ~C 8 alkyl), 1 to 6 carbon atoms (i.e., C 1 ~C 6 alkyl), or 1 to 3 carbon atoms (i.e., C 1 ~C 3 Examples of suitable alkyl groups include methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), 1-propyl (n-Pr, n-propyl, -CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, i-propyl, -CH(CH 3 ) 2 ), 1-Butyl (n-Bu, n-Butyl, -CH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propyl (i-Bu, i-butyl, -CH 2 CH(CH 3 ) 2 ), 2-Butyl (s-Bu, s-Butyl, -CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH 3 ) 3 ), 1-pentyl (n-pentyl, -CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH2 CH 3 ) 2 ), 2-methyl-2-butyl (-C(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl (-CH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1-butyl (-CH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butyl (-CH 2 CH(CH 3 )CH 2 CH 3 ), 1-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-hexyl (-CH(CH 3 )CH 2 CH 2 CH 2 CH 3 ), 3-hexyl (-CH(CH 2 CH 3 )(CH 2 CH 2 CH 3 )), 2-methyl-2-pentyl (-C(CH 3 ) 2 CH 2 CH 2 CH 3 ), 3-methyl-2-pentyl (-CH(CH 3 )CH(CH 3 )CH 2 CH 3 ), 4-methyl-2-pentyl (-CH(CH 3 )CH 2 CH(CH 3 ) 2 ), 3-methyl-3-pentyl (-C(CH 3 )(CH 2 CH 3 ) 2 ), 2-methyl-3-pentyl (-CH(CH 2 CH3 )CH(CH 3 ) 2 ), and 2,3-dimethyl-2-butyl (-C(CH 3 ) 2 CH(CH 3 ) 2 ), 3,3-dimethyl-2-butyl (-CH(CH 3 )C(CH 3 ) 3 These include, but are not limited to:

[0013] "Alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C 2~20 alkenyl), 2 to 8 carbon atoms (i.e., C 2~8 alkenyl), 2 to 6 carbon atoms (i.e., C 2~6 alkenyl), or 2 to 4 carbon atoms (i.e., C 2~4 Alkenyl refers to an aliphatic group having an alkyl group. Examples of alkenyl groups include ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0014] "Alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C 2~20 alkynyl), 2 to 8 carbon atoms (i.e., C 2~8 alkynyl), 2 to 6 carbon atoms (i.e., C 2~6 alkynyl), or 2 to 4 carbon atoms (i.e., C 2~4 The term "alkynyl" also includes alkynyl groups having one triple bond and one double bond.

[0015] "Haloalkyl" refers to an alkyl group as defined above in which one or more hydrogen atoms of the alkyl group are replaced by a halogen atom. The alkyl portion of a haloalkyl group has 1 to 20 carbon atoms (i.e., C 1 ~C 20 haloalkyl), 1 to 12 carbon atoms (i.e., C 1 ~C 12haloalkyl), 1 to 8 carbon atoms (i.e., C 1 ~C 8 haloalkyl), 1 to 6 carbon atoms (i.e., C 1 ~C 6 alkyl), or 1 to 3 carbon atoms (i.e., C 1 ~C 3 Examples of suitable haloalkyl groups include -CF 3 , -CHF 2 , -CFH 2 , -CH 2 CF 3 etc.

[0016] "Alkoxy" refers to a group of the formula -O-alkyl. Example alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), butoxy (e.g., n-butoxy and tert-butoxy), and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0017] "Aryl" means 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 from 6 to 20 carbon atoms, from 6 to 14 carbon atoms, or from 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.

[0018] "Aryloxy" refers to a group of the formula -O-aryl. Examples of alkoxy groups include, but are not limited to, phenoxy and naphthyloxy. In some embodiments, the aryl group has 6 or 10 carbon atoms.

[0019] "Heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl contains 1-20 ring atoms (i.e., 1-20 membered heteroaryl), 3-12 ring atoms (i.e., 3-12 membered heteroaryl), or 3-8 carbon ring atoms (3-8 membered heteroaryl), or 5-6 ring atoms (5-6 membered heteroaryl). Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Heteroaryl does not encompass and does not overlap with aryl as defined above.

[0020] "Carbocyclyl" or "carbocyclic ring" refers to a non-aromatic hydrocarbon ring consisting of carbon and hydrogen atoms, having 3 to 20 carbon atoms, in certain embodiments having 3 to 15 carbon atoms, and in certain embodiments having 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 7 carbon atoms, or 3 to 6 carbon atoms, which is saturated or partially unsaturated and is attached to the remainder of the molecule by a single bond. Examples of carbocyclic rings include cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, cycloheptane, cycloheptene, and cyclooctane. Examples of carbocyclic rings include cycloalkyl groups.

[0021] "Cycloalkyl" refers to saturated cyclic alkyl groups having single or multiple rings, including fused, bridged, and spiro ring systems. As used herein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C 3~20 cycloalkyl), having 3 to 12 ring carbon atoms (i.e., C 3~12 cycloalkyl), having 3 to 10 ring carbon atoms (i.e., C 3~10 cycloalkyl), having 3 to 8 ring carbon atoms (i.e., C 3~8 cycloalkyl), or having 3 to 6 ring carbon atoms (i.e., C 3~6Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0022] As used herein, "heterocycle" or "heterocyclyl" includes, by way of example and not limitation, those heterocycles described in Paquette, Leo A.; Principles of Modern Heterocyclic Chemistry (WA Benjamin, New York, 1968), particularly chapters 1, 3, 4, 6, 7, and 9; The Chemistry of Heterocyclic Compounds, A Series of Monographs (John Wiley & Sons, New York, 1950 to present), particularly volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566. For example, "heterocycle" includes "carbocycle" as defined herein, in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced with a heteroatom (e.g., O, N, or S). As used herein, a heterocycle or heterocyclyl has 3 to 20 ring atoms, 3 to 12 ring atoms, 3 to 10 ring atoms, 3 to 8 ring atoms, or 3 to 6 ring atoms. The term "heterocycle" or "heterocyclyl" includes saturated and partially unsaturated rings. Substituted heterocyclyls include, for example, heterocyclic rings substituted with any of the substituents disclosed herein, including a carbonyl group. Non-limiting examples of carbonyl-substituted heterocyclyls are: [ka] Examples of heterocycles include, but are not limited to, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, and piperidinyl.

[0023] The term "optionally substituted" with respect to a particular moiety of the compounds described herein, such as compounds of Formula A or Formula B (e.g., an optionally substituted aryl group), refers to a moiety in which all of the substituents are hydrogen or where one or more of the hydrogens of the moiety can be replaced with a substituent as listed.

[0024] Unless otherwise indicated, the carbon atoms of the compounds described herein (e.g., compounds of Formula A or Formula B) are intended to have a valence of 4. When a carbon atom in some chemical structure representation does not have a sufficient number of variables to produce a valence of 4, the remaining carbon substituents necessary to provide a valence of 4 should be assumed to be hydrogen.

[0025] As used herein, unless otherwise indicated, the term "treat" means to reverse, alleviate, or inhibit the progression of the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. As used herein, the term "treatment" refers to the act of treating, as "treating" is defined immediately above.

[0026] "Prevention" or "preventing" refers to any treatment of a disease or condition that does not result in the development of clinical symptoms of the disease or condition. The compounds and compositions disclosed herein may, in some embodiments, be administered to a subject (including a human) at risk of having a disease or condition. As used herein, the terms "preventing" and "prevention" include administering a compound, composition, or pharma- ceutically acceptable salt according to an embodiment disclosed herein before or after an individual is exposed to a virus, but before symptoms of viral infection appear and / or before the virus is detected in the blood. The term also refers to preventing symptoms of a disease from appearing and / or preventing the virus from reaching detectable levels in the blood. The term includes both pre-exposure prophylaxis (PrEP), as well as post-exposure prophylaxis (PEP) and event-driven or "on-demand" prophylaxis. These terms also refer to preventing perinatal transmission of the virus from mother to infant by administration to the mother before birth and to the child within the first few days of life. The term also refers to preventing transmission of the virus through blood transfusions.

[0027] As used herein, the term "therapeutically effective amount" refers to the amount of a compound of formula A or formula B present in a composition described herein required to provide a desired level of drug in the secretions and airway and lung tissues of a subject, or alternatively in the bloodstream of a subject being treated, that will provide an expected physiological response or desired biological effect when such composition is administered by a selected route of administration. The exact amount will depend on a number of factors, such as the particular compound of formula A or formula B, the particular activity of the composition, the delivery device used, the physical properties of the composition, its intended use, and patient considerations such as the severity of the disease state, patient interaction, and can be readily determined by one of ordinary skill in the art based on the information provided herein.

[0028] III.Compound Any reference to a compound of the invention described herein also includes a reference to a pharma- ceutically acceptable salt thereof. Examples of pharma- ceutically acceptable salts of the compounds of the invention include alkali metal or alkaline earth salts (e.g., Na + , Li + , K + , Ca +2 , and Mg +2 ), ammonium and NR 4 + Pharmaceutically acceptable salts of nitrogen atoms or amino groups include salts derived from appropriate bases, such as (a) acid addition salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; (b) acid addition salts formed with acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, isethionic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, and the like; Examples of hydroxyl groups include salts formed with organic acids such as benzenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, malonic acid, sulfosalicylic acid, glycolic acid, 2-hydroxy-3-naphthoate, pamoate, salicylic acid, stearic acid, phthalic acid, mandelic acid, lactic acid, ethanesulfonic acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine, and leucine; and (c) salts formed with elemental anions such as chlorine, bromine, and iodine. Pharmaceutically acceptable salts of hydroxyl groups include salts formed with Na + and N.R. 4 + Examples of suitable cations include the anions of the compounds in combination with suitable cations such as:

[0029] In some embodiments, R is H, (C 1 ~C 8 ) alkyl, (C 2 ~C 8 ) alkenyl, (C 2 ~C 8 ) alkynyl, C 6 ~C 20 Aryl or C 2 ~C20 It is a heterocyclyl.

[0030] For therapeutic use, the salts of the active ingredients of the compounds of the present invention are pharmaceutically acceptable. That is, they are salts derived from pharmaceutically acceptable acids or bases. However, salts of non-pharmaceutically acceptable acids or bases may also find use, for example, in the preparation or purification of pharmaceutically acceptable compounds. All salts are within the scope of the present invention, whether derived from pharmaceutically acceptable acids or bases or not.

[0031] It should also be understood that the compositions herein include compounds of the invention in their non-ionized, as well as zwitterionic forms, as well as combinations with a stoichiometric amount of water in hydrates.

[0032] It should be noted that all enantiomers, diastereomers, racemic mixtures, tautomers, polymorphs, and pseudopolymorphs of the compounds within the scope of Formula A and Formula B, as well as pharma- ceutically acceptable salts thereof, are encompassed by the present invention. All mixtures of such enantiomers and diastereomers are within the scope of the present invention.

[0033] The compounds of the present invention exemplified by Formula A and Formula B may have chiral centers, such as chiral carbon or phosphorus atoms. Thus, the compounds of the present invention include racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and atropisomers. In addition, the compounds of the present invention include optical isomers enriched or resolved at any or all asymmetric chiral atoms. In other words, the chiral centers evident from the depiction are provided as chiral isomers or racemic mixtures. Both racemic and diastereomeric mixtures, as well as individual isolated or synthesized optical isomers substantially free of their enantiomeric or diastereomeric partners, are all within the scope of the present invention. The racemic mixtures are separated into their individual substantially optically pure isomers by suitable techniques, such as, for example, separation of diastereomeric salts formed with optically active auxiliaries, such as acids or bases, followed by conversion back to optically active substances. In most cases, the desired optical isomers are synthesized by stereospecific reactions beginning with the appropriate stereoisomer of the desired starting material.

[0034] Stereochemical definitions and rules used herein generally follow S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York, and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., New York. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule about its chiral center. The prefixes d and l, D and L, or (+) and (-) are used to indicate the indication of the rotation of plane polarized light by the compound, with S, (-), or 1 meaning that the compound is levorotatory, while a compound with an R, (+), or d prefix is ​​dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A specific stereoisomer may be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

[0035] The compounds of the present invention may also exist as tautomers in certain cases.Although only one delocalized resonance structure may be depicted, all such forms are contemplated within the scope of the present invention.For example, ene-amine tautomers may exist for purine, pyrimidine, imidazole, guanidine, amidine, and tetrazole systems, and all of their possible tautomers are within the scope of the present invention.

[0036] Any formula or structure given herein, including compounds of formula A and formula B, is also intended to represent unlabeled and isotopically labeled forms of the compounds. Isotopically labeled compounds have the structure shown by the formula given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, e.g., 2 H (deuterium, D), 3 H (tritium), 11 C. 13 C. 14 C. 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 Various isotopically labeled compounds of the present disclosure include, but are not limited to, 3 H, 13 C and 14 C. Such isotopically labeled compounds may be useful in detection or imaging techniques such as metabolism studies, reaction kinetic studies, positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radiation treatment of patients.

[0037] The present disclosure also includes compounds described herein (e.g., compounds of formula A and formula B) in which 1 to x hydrogens attached to a carbon atom have been replaced by deuterium, where x is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and are therefore useful for extending the half-life of any of the compounds described herein (e.g., compounds of formula A and formula B) when administered to a mammal, particularly a human. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol.Sci.5(12):524-527 (1984). In view of the present disclosure, such compounds are synthesized by means known in the art, e.g., by using starting materials in which one or more hydrogens have been replaced by deuterium.

[0038] Deuterium-labeled or deuterium-substituted therapeutic compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties with respect to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may confer certain therapeutic advantages due to greater metabolic stability, e.g., increased in vivo half-life, reduced dosage requirements, and / or improved therapeutic index. 18 F-labeled compounds can be useful in PET or SPECT studies.The isotopically labeled compounds of the present disclosure and their prodrugs can generally be prepared by carrying out the procedures disclosed in the schemes or the examples and preparations described below, by replacing readily available isotopically labeled reagents with non-isotopically labeled reagents.It is understood that deuterium in this context is considered as a substituent in the compound of formula A or formula B.

[0039] In some embodiments, the carbon attached to the 5-position on the tetrahydrofuranyl ring of formula A is substituted with one or two deuterium atoms. [ka] In some embodiments, the compound of formula A is [ka] In some embodiments, the carbon of Base A of formula A is substituted with one or more deuterium atoms. In some embodiments, Base A is [ka] In some embodiments, R of Base of formula A is 12 In some embodiments, the R of Base of formula A is substituted with one or more deuterium atoms. 11 In some embodiments, the R 1 In some embodiments, the R 2 In some embodiments, the R 3 The top carbon is replaced with one or more deuterium atoms.

[0040] In some embodiments, the carbon attached to the 5-position on the tetrahydrofuranyl ring of formula B is substituted with one or two deuterium atoms. [ka] In some embodiments, the compound of formula B is [ka] In some embodiments, the carbon of Base B in formula B is substituted with one or more deuterium atoms. In some embodiments, Base B is [ka] In some embodiments, the R of Base in formula B is K In some embodiments, the R A In some embodiments, the R B In some embodiments, the R C The top carbon is replaced with one or more deuterium atoms.

[0041] The concentration of such heavier isotopes, specifically deuterium, can be defined by the isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen", the position is understood to have hydrogen at the natural abundance isotopic composition of hydrogen. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is meant to represent deuterium.

[0042] Whenever a compound described herein is substituted with more than one of the same group, e.g., designated "R" or "R", it will be understood that the groups can be the same or different, i.e., each group is independently selected.

[0043] Wavy Line [ka] indicates the site of covalent attachment to an adjacent substructure, group, moiety, or atom.

[0044] IV.Compound In certain embodiments, the compounds of formula A are provided herein: [ka] or a pharma- ceutically acceptable salt thereof, In the formula, R 1 and R2 Together, they form -OC(=O)O- and -OCHR. 6 O-, or -OP(=O)(OR 14 )O-, R 6 But, H, C 1 ~C 6 Alkyl, C 6 ~C 10 Aryloxy or C 1 ~C 6 is an alkoxy; R 3 But -C(=O)R 7 and R 7 But, C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenyl, C 2 ~C 8 Alkynyl, C 3 ~C 8 Carbocyclyl, C 6 ~C 10 aryl or a 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, and S; R 7 Each C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenyl, C 2 ~C 8 Alkynyl, C 3 ~C 8 Carbocyclyl, C 6 ~C 10 Aryl or 5-6 membered heteroaryl is halogen, cyano, -N 3 , -OR 8 , -NR 9 R 10 and phenyl, wherein the phenyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, cyano, and C 1 ~C 6 optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; Each R 8 However, independently, H, C 1~C 6 Alkyl, C 1 ~C 6 Haloalkyl and C 3 ~C 6 is cycloalkyl, Each R 9 However, independently, H, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl and C 3 ~C 6 is cycloalkyl, Each R 10 However, independently, H, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl and C 3 ~C 6 is cycloalkyl, Base A is [ka] and R 11 But -OP(=O)(OH) 2 C replaced with 1 ~C 6 is alkyl, R 12 But, H, C 1 ~C 6 Alkyl, -C(=O)R 13 , or -C(=O)OR 13 and Each R 13 are independently H or C 1 ~C 8 is alkyl, R 13 C 1 ~C 8 The alkyl is optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and phenyl, and the phenyl is -OP(=O)(OH)(OR 14 ), and Each R 14 But, H, C 1 ~C 8 Alkyl, C3 ~C 8 Carbocyclyl, C 6 ~C 10 aryl or a 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, and S; R 14 C 1 ~C 8 Provided is a compound of formula A, or a pharma- ceutically acceptable salt thereof, wherein alkyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, and phenyl.

[0045] In some embodiments, R 1 and R 2 together form -OC(=O)O- or -OCHR 6 In some embodiments, R 1 and R 2 taken together form -OC(=O)O-. In some embodiments, R 1 and R 2 Together, -OCHR 6 In some embodiments, R 1 and R 2 together, -OCH(OCH 3 In some embodiments, R 1 and R 2 Together, -OP(=O)(OR 14 In some embodiments, R 1 and R 2 taken together form -OP(=O)(OH)O-. In some embodiments, R 1 and R 2 together, -OC(=O)O-, -OCH(OCH 3 )O-, or -OP(=O)(OH)O-. In some embodiments, R 1 and R 2 together form -OC(=O)O- or -OCH(OCH 3 )O- is formed.

[0046] In some embodiments, R 6 is H. In some embodiments, R 6 is C 1 ~C 6 In some embodiments, R 6 is C 1 ~C 3 In some embodiments, R 6 is -CH 3 In some embodiments, R 6 is C 6 ~C 10 In some embodiments, R 6 teeth, [ka] In some embodiments, R 6 is C 1 ~C 6 In some embodiments, R 6 is C 1 ~C 3 In some embodiments, R 6 -OCH 2 CH 3 , -OCH(CH 3 ) 2 , or -OCH 3 In some embodiments, R 6 -OCH 3 It is.

[0047] In some embodiments, R 7 is C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenyl, or C 2 ~C 8 alkynyl, R 7 Each C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenyl, and C 2 ~C 8 Alkynyl is halogen, cyano, -N 3, -OR 8 , -NR 9 R 10 and phenyl, wherein the phenyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, cyano, and C 1 ~C 6 Optionally substituted with 1, 2, or 3 substituents independently selected from alkyl.

[0048] In some embodiments, R 7 But halogen, cyano, -N 3 , -OR 8 , -NR 9 R 10 C optionally substituted with one, two, or three substituents independently selected from the group consisting of phenyl, 1 ~C 8 alkyl, phenyl, halo, cyano, and C 1 ~C 6 Optionally substituted with 1, 2, or 3 substituents independently selected from alkyl.

[0049] In some embodiments, R 7 is halogen, cyano, -N 3 , -OR 8 , -NR 9 R 10 C optionally substituted with one, two, or three substituents independently selected from the group consisting of phenyl, 1 ~C 8 It is an alkyl.

[0050] In some embodiments, R 8 is H. In some embodiments, R 8 is C 1 ~C 6 In some embodiments, R 8 is -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , or -CH(CH 3) 2 In some embodiments, R 8 is -CH 3 In some embodiments, R 8 is C 1 ~C 6 In some embodiments, R 8 is C 3 ~C 6 It is cycloalkyl.

[0051] In some embodiments, R 9 is H. In some embodiments, R 9 is C 1 ~C 6 In some embodiments, R 9 is -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , or -CH(CH 3 ) 2 In some embodiments, R 9 is -CH 3 In some embodiments, R 9 is C 1 ~C 6 In some embodiments, R 9 is C 3 ~C 6 It is cycloalkyl.

[0052] In some embodiments, R 10 is H. In some embodiments, R 10 is C 1 ~C 6 In some embodiments, R 10 is -CH 3 In some embodiments, R 10 is -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , or -CH(CH3 ) 2 In some embodiments, R 10 is C 1 ~C 6 In some embodiments, R 10 is C 3 ~C 6 It is cycloalkyl.

[0053] In some embodiments, R 7 is C 1 ~C 8 In some embodiments, R 7 is C 1 ~C 6 In some embodiments, R 7 is -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -CH(CH 3 ) 2 , -(CH 2 ) 3 CH 3 , or -C(CH 3 ) 3 In some embodiments, R 7 is -CH(CH 3 ) 2 It is.

[0054] In some embodiments, Base A is [ka] In some embodiments, Base A is [ka] It is.

[0055] In some embodiments, R 11 is -OP(=O)(OH) 2 C replaced with 1 ~C 3In some embodiments, R 11 is -(CH 2 )OP(=O)(OH) 2 It is.

[0056] In some embodiments, Base A is [ka] It is.

[0057] In some embodiments, R 12 is -C(=O)R 13 is 。 In some embodiments, R 12 is -C(=O)OR 13 It is.

[0058] In some embodiments, R 13 is optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and phenyl; 1 ~C 8 alkyl and phenyl is -OP(=O)(OH)(OR 14 ) is optionally replaced.

[0059] In some embodiments, R 14 is H. In some embodiments, R 14 is H or C 1 ~C 8 is alkyl, R 14 C 1 ~C 8 The alkyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, and phenyl. In some embodiments, R 14 is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, and phenyl; 1 ~C 8 In some embodiments, R 14is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, and phenyl; 1 ~C 3 In some embodiments, R 14 is a C substituted with one phenyl 1 ~C 3 In some embodiments, R 14 teeth, [ka] It is.

[0060] In some embodiments, R 13 is H. In some embodiments, R 13 is optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and phenyl; 1 ~C 8 In some embodiments, R 13 is C 1 ~C 8 In some embodiments, R 13 is -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -CH(CH 3 ) 2 , -(CH 2 ) 3 CH 3, , or -C(CH 3 ) 3 In some embodiments, R 13 is -CH 2 CH(CH 3 ) 2 or -(CH 2 ) 2 CH 3 It is.

[0061] In some embodiments, R 12 is H. In some embodiments, R 12 is C1 ~C 6 In some embodiments, R 12 is -C(=O)(CH 2 ) 2 CH 3 In some embodiments, R 12 is -C(=O)OCH 2 CH(CH 3 ) 2 In some embodiments, R 12 is -C(=O)OCH 2 CH(CH 3 ) 2 or -C(=O)(CH 2 ) 2 CH 3 It is.

[0062] In some embodiments, the compound of formula A is [Table 1] or a pharma- ceutically acceptable salt thereof.

[0063] In some embodiments, the compound of formula A is [Table 2] or a pharma- ceutically acceptable salt thereof.

[0064] As used herein, a compound of formula B: [ka] or a pharma- ceutically acceptable salt thereof, In the formula, R A -OH, -OC(=O)R D , or -OC(=O)OR D or R B -OH, -OC(=O)R E , or -OC(=O)OR E or R A and R BTogether, they form -OC(=O)O- or -OCHR F Forming O- R F But, H, C 1 ~C 6 Alkyl or C 6 ~C 10 is aryl, R C But -C(=O)R G and R D and R E However, each independently, C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenyl, C 2 ~C 8 Alkynyl, C 3 ~C 8 Carbocyclyl, C 6 ~C 10 aryl or a 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, and S; R D and R E C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenyl, C 2 ~C 8 Alkynyl, C 3 ~C 8 Carbocyclyl, C 6 ~C 10 Aryl or 5- to 6-membered heteroaryl are each independently selected from halogen, cyano, -N 3 , -OR H , -NR I R J and phenyl, wherein the phenyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, cyano, and C 1 ~C 6 optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; R G But, H, C 1 ~C 8 Alkyl, C 2~C 8 Alkenyl, C 2 ~C 8 Alkynyl, C 3 ~C 8 Carbocyclyl, C 6 ~C 10 aryl or a 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, and S; R G C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenyl, C 2 ~C 8 Alkynyl, C 3 ~C 8 Carbocyclyl, C 6 ~C 10 Aryl or 5- to 6-membered heteroaryl are each independently selected from halogen, cyano, -N 3 , -OR H , -NR I R J , -OP(=O)(OH)(OR L ), and phenyl, wherein phenyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, cyano, and C 1 ~C 6 optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; Each R H However, independently, H, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl and C 3 ~C 6 is cycloalkyl, Each R I However, independently, H, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl and C 3 ~C 6 is cycloalkyl, Each R J However, independently, H, C 1 ~C 6Alkyl, C 1 ~C 6 Haloalkyl and C 3 ~C 6 is cycloalkyl, Base B, [ka] and R K But, C 6 ~C 10 Aryl, -OC 6 ~C 10 Aryl, -OC 1 ~C 10 Alkyl, or -OP(=O)(OH)(OR L ) optionally replaced by 1 ~C 10 is alkyl, and R L But, H, C 1 ~C 8 Alkyl, C 3 ~C 8 Carbocyclyl, C 6 ~C 10 aryl or a 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, and S; R L C 1 ~C 8 The alkyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, and phenyl; However, if Base B is [ka] and R G One, two or three -OP(=O)(OH)(OR L ) replaced by C 1 ~C 8 Also provided are compounds of formula B, or a pharma- ceutically acceptable salt thereof, provided that: B is alkyl.

[0065] As used herein, a compound of formula B: [ka] or a pharma- ceutically acceptable salt thereof, In the formula, R A -OH, -OC(=O)R D , or -OC(=O)OR D or R B -OH, -OC(=O)R E , or -OC(=O)OR E or R A and R B Together, they form -OC(=O)O- or -OCHR F Forming O- R F But, H, C 1 ~C 6 Alkyl or C 6 ~C 10 is aryl, R C But -C(=O)R G and R D and R E However, each independently, C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenyl, C 2 ~C 8 Alkynyl, C 3 ~C 8 Carbocyclyl, C 6 ~C 10 aryl or a 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, and S; R D and R E C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenyl, C 2 ~C 8 Alkynyl, C 3 ~C 8 Carbocyclyl, C 6 ~C 10Aryl or 5- to 6-membered heteroaryl are each independently selected from halogen, cyano, -N 3 , -OR H , -NR I R J and phenyl, wherein the phenyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, cyano, and C 1 ~C 6 optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; R G But, H, C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenyl, C 2 ~C 8 Alkynyl, C 3 ~C 8 Carbocyclyl, C 6 ~C 10 aryl or a 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, and S; R G C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenyl, C 2 ~C 8 Alkynyl, C 3 ~C 8 Carbocyclyl, C 6 ~C 10 Aryl or 5- to 6-membered heteroaryl are each independently selected from halogen, cyano, -N 3 , -OR H , -NR I R J , -OP(=O)(OH)(OR L ), and phenyl, wherein phenyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, cyano, and C 1 ~C 6 optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; Each R H However, independently, H, C 1 ~C6 Alkyl, C 1 ~C 6 Haloalkyl and C 3 ~C 6 is cycloalkyl, Each R I However, independently, H, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl and C 3 ~C 6 is cycloalkyl, Each R J However, independently, H, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl and C 3 ~C 6 is cycloalkyl, Base B, [ka] and R K But, C 6 ~C 10 Aryl, -OC 6 ~C 10 Aryl, -OC 1 ~C 10 Alkyl, or -OP(=O)(OH)(OR L ) optionally replaced by 1 ~C 10 is alkyl, and R L But, H, C 1 ~C 8 Alkyl, C 3 ~C 8 Carbocyclyl, C 6 ~C 10 aryl or a 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, and S; R L C 1 ~C 8Also provided is a compound of formula B, or a pharma- ceutically acceptable salt thereof, wherein alkyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, and phenyl.

[0066] In some embodiments, R A is -OC(=O)R D In some embodiments, R A is -OC(=O)OR D It is.

[0067] In some embodiments, R B is -OC(=O)R E In some embodiments, R B is -OC(=O)OR E It is.

[0068] In some embodiments, R A is -OC(=O)R D and R B is -OC(=O)R E In some embodiments, R A is -OH, and R B is -OC(=O)R E Or -OC(=O)OR E In some embodiments, R A is -OC(=O)R D Or -OC(=O)OR D and R B is -OH.

[0069] In some embodiments, R D is C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenyl, or C 2 ~C 8 alkynyl, R 4 C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenyl, and C 2 ~C8 Each alkynyl is independently halogen, cyano, -N 3 , -OR H , -NR I R J , -OP(=O)(OH) 2 , C 3 ~C 8 carbocyclyl, and phenyl, wherein the phenyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, cyano, and C 1 ~C 6 In some embodiments, R is optionally substituted with 1, 2, or 3 substituents independently selected from alkyl. D is halogen, cyano, -N 3 , -OR H , -NR I R J , -OP(=O)(OH) 2 , C 3 ~C 8 C optionally substituted with one, two, or three substituents independently selected from the group consisting of carbocyclyl, and phenyl. 1 ~C 8 In some embodiments, R D is C 1 ~C 8 In some embodiments, R D is C 1 ~C 6 In some embodiments, R D is C 1 ~C 3 In some embodiments, R D is -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -CH(CH 3 ) 2 , -(CH 2 ) 3 CH 3 , or -C(CH 3 ) 3 In some embodiments, RD is -CH 3 or -CH(CH 3 ) 2 It is.

[0070] In some embodiments, R E is C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenyl, or C 2 ~C 8 alkynyl, R 4 C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenyl, and C 2 ~C 8 Each alkynyl is independently halogen, cyano, -N 3 , -OR H , -NR I R J , -OP(=O)(OH) 2 , C 3 ~C 8 carbocyclyl, and phenyl, wherein the phenyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, cyano, and C 1 ~C 6 In some embodiments, R is optionally substituted with 1, 2, or 3 substituents independently selected from alkyl. E is halogen, cyano, -N 3 , -OR H , -NR I R J , -OP(=O)(OH) 2 , C 3 ~C 8 C optionally substituted with one, two, or three substituents independently selected from the group consisting of carbocyclyl, and phenyl. 1 ~C 8 In some embodiments, R E is C 1 ~C 8 In some embodiments, R E is C 1 ~C6 In some embodiments, R E is C 1 ~C 3 In some embodiments, R E is -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -CH(CH 3 ) 2 , -(CH 2 ) 3 CH 3 , or -C(CH 3 ) 3 In some embodiments, R E is -CH 3 or -CH(CH 3 ) 2 It is.

[0071] In some embodiments, R A is -OH. In some embodiments, R B is -OH. In some embodiments, R A or R B are both -OH. In some embodiments, R A OH, OC(O)CH(CH 3 ) 2 , or OC(O)CH 3 and R B OH, OC(O)CH(CH 3 ) 2 , or OC(O)CH 3 In some embodiments, R A and R B Both are OC(O)CH 3 It is.

[0072] In some embodiments, R A and R B taken together form -OC(=O)O-. In some embodiments, R A and R B Together, -OCHR F Forms O-.

[0073] In some embodiments, R F is H. In some embodiments, R F is C 1 ~C 6 In some embodiments, R F is C 6 ~C 10 It is aryl.

[0074] In some embodiments, R G are each independently a halogen, a cyano, or -N 3 , -OR H , -NR I R J , -OP(=O)(OH)(OR L ), and C optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of phenyl. 3 ~C 8 carbocyclyl, phenyl is halo, cyano, and C 1 ~C 6 Optionally substituted with 1, 2, or 3 substituents independently selected from alkyl.

[0075] In some embodiments, R G are each independently a halogen, a cyano, or -N 3 , -OR H , -NR I R J , -OP(=O)(OH)(OR L ), and C optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of phenyl. 6 ~C 10 aryl, phenyl, halo, cyano, and C 1 ~C 6 Optionally substituted with 1, 2, or 3 substituents independently selected from alkyl.

[0076] In some embodiments, R G are each independently a halogen, a cyano, or -N 3 , -ORH , -NR I R J , -OP(=O)(OH)(OR L ), and phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, cyano, and C 1 ~C 6 Optionally substituted with 1, 2, or 3 substituents independently selected from alkyl.

[0077] In some embodiments, R G are each independently 1 ~C 8 Alkyl, C 2 ~C 8 Alkenyl, or C 2 ~C 8 alkynyl, R G C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenyl, and C 2 ~C 8 Each alkynyl is independently halogen, cyano, -N 3 , -OR H , -NR I R J , -OP(=O)(OH)(OR L ), and phenyl, wherein phenyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, cyano, and C 1 ~C 6 Optionally substituted with 1, 2, or 3 substituents independently selected from alkyl.

[0078] In some embodiments, R G are each independently 1 ~C 8 Alkyl, C 2 ~C 8 Alkenyl, or C 2 ~C 8 alkynyl, RG C 1 ~C 8 Alkyl, C 2 ~C 8 Alkenyl, and C 2 ~C 8 Each alkynyl is independently halogen, cyano, -N 3 , -OR H , -NR I R J , -OP(=O)(OH)(OR L ), and phenyl.

[0079] In some embodiments, R G is halogen, cyano, -N 3 , -OR H , -NR I R J , -OP(=O)(OH)(OR L ), and C optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of phenyl. 1 ~C 8 alkyl, phenyl, halo, cyano, and C 1 ~C 6 Optionally substituted with 1, 2, or 3 substituents independently selected from alkyl.

[0080] In some embodiments, R G is C 1 ~C 8 In some embodiments, R G is -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -CH(CH 3 ) 2 , -(CH 2 ) 3 CH 3 , or -C(CH 3 ) 3 In some embodiments, R G is C1 ~C 4 In some embodiments, R G is -(CH 2 ) 2 CH 3 and -CH(CH 3 ) 2 In some embodiments, R G is -CH(CH 3 ) 2 In some embodiments, R G is H. In some embodiments, R G is -(CH 2 )OP(=O)(OH) 2 It is.

[0081] In some embodiments, R H is H. In some embodiments, R H is C 1 ~C 6 In some embodiments, R H is -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , or -CH(CH 3 ) 2 In some embodiments, R H is -CH 3 In some embodiments, R H is C 1 ~C 6 In some embodiments, R H is C 3 ~C 6 It is cycloalkyl.

[0082] In some embodiments, R I is H. In some embodiments, R I is C 1 ~C 6 In some embodiments, R I is -CH 3 , -CH 2 CH3 , -(CH 2 ) 2 CH 3 , or -CH(CH 3 ) 2 In some embodiments, R I is -CH 3 In some embodiments, R I is C 1 ~C 6 In some embodiments, R I is C 3 ~C 6 It is cycloalkyl.

[0083] In some embodiments, R J is H. In some embodiments, R J is C 1 ~C 6 In some embodiments, R J is -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , or -CH(CH 3 ) 2 In some embodiments, R J is -CH 3 In some embodiments, R J is C 1 ~C 6 In some embodiments, R J is C 3 ~C 6 It is cycloalkyl.

[0084] In some embodiments, Base B is [ka] In some embodiments, Base B is [ka] In some embodiments, Base B is [ka] It is.

[0085] In some embodiments, Base B is [ka] In some embodiments, Base B is [ka] and R G is -(CH 2 )OP(=O)(OH)(OR L In some embodiments, Base B is [ka] and R G is -(CH 2 )OP(=O)(OH 2 ).

[0086] In some embodiments, R K is -OP(=O)(OH)(OR L ) replaced by C 1 ~C 6 In some embodiments, R K is -(CH 2 )OP(=O)(OH)(OR L ) or -(CH 2 ) 2 OP(=O)(OH)(OR L ).

[0087] In some embodiments, R L is H. In some embodiments, R L is H or C 1 ~C 8 is alkyl, R 14 C 1 ~C 8The alkyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, and phenyl. In some embodiments, R L is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, and phenyl; 1 ~C 8 In some embodiments, R L is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, and phenyl; 1 ~C 3 In some embodiments, R L is a C substituted with one phenyl 1 ~C 3 In some embodiments, R L teeth, [ka] It is.

[0088] In some embodiments, R K teeth, [ka] In some embodiments, R K is C 1 ~C 10 In some embodiments, R K is C 1 ~C 7 In some embodiments, R K is -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , -(CH 2 ) 4 CH 3 , or -(CH 2 ) 6 CH 3 In some embodiments, R Kis C 6 ~C 10 In some embodiments, R K is phenyl. In some embodiments, R K -OC 6 ~C 10 In some embodiments, R K is -O-phenyl. In some embodiments, R K -OC 1 ~C 10 In some embodiments, R K is -O-CH 3 , -O-CH 2 CH 3 , -O-(CH 2 ) 2 CH 3 , -O-(CH 2 ) 4 CH 3 , or -O-(CH 2 ) 6 CH 3 It is.

[0089] In some embodiments, Base B is [ka] It is.

[0090] In some embodiments, Base B is [ka] It is.

[0091] In some embodiments, the compound of formula B is [Table 3-1] [Table 3-2] or a pharma- ceutically acceptable salt thereof.

[0092] In some embodiments, the compound of formula B is [Table 4] or a pharma- ceutically acceptable salt thereof.

[0093] V. Pharmaceutical Preparations The compounds disclosed herein may be formulated with conventional carriers and excipients. For example, tablets contain excipients, lubricants, fillers, binders, etc. Aqueous formulations are prepared in sterile form and are generally isotonic if intended for delivery other than by oral administration. All formulations may optionally include excipients such as those described in the "Handbook of Pharmaceutical Excipients" (1986). Pharmaceutically acceptable excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextran, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, and stearic acid. In some embodiments, the formulation includes one or more pharma-ceutically acceptable excipients. The pH of the formulation ranges from about 3 to about 11, but is usually about 7 to 10. In some embodiments, the pH of the formulation ranges from about 2 to about 5, but is usually about 3 to 4.

[0094] While it is possible for the compounds of the present disclosure ("active ingredients") to be administered alone, it may be preferable to present them as pharmaceutical formulations. The formulations of the present invention, both for veterinary and human use, comprise at least one active ingredient, as defined above, together with one or more acceptable carriers therefor and optionally other therapeutic ingredients, particularly additional therapeutic ingredients discussed herein. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and physiologically non-toxic to the recipient thereof.

[0095] Formulations include those suitable for the aforementioned routes of administration. Formulations may conveniently be presented in unit dosage form and may be prepared by any suitable method known in the pharmaceutical art. Techniques and formulations are generally found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0096] In some embodiments, the pharmaceutical formulation is for subcutaneous, intramuscular, intravenous, oral, or inhaled administration.

[0097] In some embodiments, the compounds described herein, such as compounds of formula A or formula B, or pharma- ceutically acceptable salts thereof described herein, have optimized / improved pharmacokinetic properties and are suitable for oral administration. For example, compounds of formula A or formula B have improved bioavailability and therefore can be administered by oral administration.

[0098] In some embodiments, formulations of the invention suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets each containing a predetermined amount of the active ingredient, as a powder or granules, as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion. The active ingredient may also be administered as a bolus, electuary, or paste.

[0099] In some embodiments, the tablet is made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form, such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active agent, or dispersing agent, in a suitable machine. Molded tablets can be made by molding a mixture of the powdered active ingredient moistened with an inert liquid diluent in a suitable machine. The tablet can be optionally coated or scored, and is optionally formulated to provide a slow or controlled release of the active ingredient therefrom.

[0100] For infections of the eye or other external tissues, e.g., mouth and skin, the formulations are applied as a topical ointment or cream containing, for example, the active ingredient in an amount of 0.075 to 20% weight / weight (including active ingredient in the range of 0.1% to 20% in increments of 0.1% weight / weight, e.g., 0.6% weight / weight, 0.7% weight / weight, etc.), preferably 0.2 to 15% weight / weight, and most preferably 0.5 to 10% weight / weight. When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base.

[0101] If desired, the aqueous phase of the cream base may contain, for example, at least 30% weight / weight of a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups, such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol, and polyethylene glycol (including PEG 400), and mixtures thereof. Topical formulations may desirably contain a compound that enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such skin penetration enhancers include dimethylsulfoxide and related analogues.

[0102] The oily phase of the emulsion of the present invention can be composed of known ingredients in a known manner. The phase can simply comprise an emulsifier (otherwise known as emulsion), but desirably comprises at least one emulsifier mixed with fat or oil, or with both fat and oil. Preferably, a hydrophilic emulsifier is comprised together with a lipophilic emulsifier acting as a stabilizer. It is also preferred to comprise both oil and fat. Together, the emulsifier with or without stabilizer constitutes the so-called emulsifying wax, which, together with oil and fat, constitutes the so-called emulsifying ointment base, which forms the oily dispersed phase of cream formulations.

[0103] Emulgents and emulsion stabilizers suitable for use in the formulations of the present invention include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate. Further emulgents and emulsion stabilizers suitable for use in the formulations of the present invention include Tween® 80.

[0104] The selection of suitable oils or fats for the formulation is based on achieving the desired aesthetic properties. The cream should preferably be a non-greasy, non-staining, washable product with a suitable consistency to avoid leakage from tubes or other containers. Linear or branched, mono- or dibasic alkyl esters may be used, such as diisoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acid, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate, or a blend of branched esters known as Crodamol CAP, the last three being the preferred esters. These may be used alone or in combination, depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils are used.

[0105] The pharmaceutical preparation according to the present invention comprises a compound according to the present invention together with one or more pharma- ceutically acceptable carriers or excipients and optionally other therapeutic agents. The pharmaceutical preparation containing the active ingredient may be in any form suitable for the intended method of administration. For example, when used for oral use, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs can be prepared. Compositions intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents, including sweeteners, flavoring agents, coloring agents, and preservatives, to provide a palatable preparation. Tablets containing the active ingredient in a mixture with non-toxic pharma- ceutically acceptable excipients suitable for the manufacture of tablets are acceptable. These excipients may be, for example, inert diluents such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binding agents such as starch, gelatin, or acacia, and lubricants such as magnesium stearate, stearic acid, or talc. The tablets may be uncoated or may be coated by known techniques, including microencapsulation, to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be used alone or with a wax.

[0106] Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin, or olive oil.

[0107] Aqueous suspensions of the present invention contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, as well as dispersing or wetting agents such as naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearates), condensation products of ethylene oxide with long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide with partial esters derived from fatty acids, and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxy-benzoates, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. Further non-limiting examples of suspending agents include cyclodextrins. In some examples, the suspending agent is sulfobutyl ether β-cyclodextrin (SEB-β-CD), such as Captisol®.

[0108] Oil suspensions can be formulated by suspending the active ingredient in vegetable oils such as peanut oil, olive oil, sesame oil or coconut oil, or in mineral oils such as liquid paraffin. Oral suspensions can contain thickening agents such as beeswax, hard paraffin or cetyl alcohol. Sweeteners and flavoring agents such as those mentioned above can be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid.

[0109] The dispersible powders and granules of the present invention suitable for preparing an aqueous suspension by adding water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives.Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above.Additional excipients, such as sweeteners, flavoring agents, and coloring agents, may also be present.

[0110] The pharmaceutical composition of the present invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, such as olive oil or peanut oil, a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifiers include naturally occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids, and hexitol anhydrides, such as sorbitan monooleate, and the condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavoring agents. Syrups and elixirs may be formulated with sweeteners, such as glycerol, sorbitol, or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring, or a coloring agent.

[0111] The pharmaceutical compositions of the present invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol, or may be prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be used as a solvent or suspending medium. For this purpose, any solventless fixed oil may be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may also be used in the preparation of injectables. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, isotonic sodium chloride solution, and hypertonic sodium chloride solution.

[0112] The amount of active ingredient that may be combined with a carrier material to produce a single dosage form will vary depending on the host treated and the particular mode of administration. For example, a sustained release formulation intended for oral administration to humans may contain about 1 to about 1000 mg of active ingredient combined with an appropriate and convenient amount of carrier material, which may vary from about 5 to about 95% (weight:weight) of the total composition. Pharmaceutical compositions can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain about 3 to 500 mg of active ingredient per milliliter of solution to allow for the infusion of a suitable volume at a rate of about 30 mL / hour.

[0113] Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10%, especially about 1.5% w / w.

[0114] Formulations suitable for topical administration in the mouth include lozenges which comprise the active ingredient in a flavored base, usually sucrose and acacia or tragacanth, pastilles which comprise the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes which comprise the active ingredient in a suitable liquid carrier.

[0115] Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

[0116] In some embodiments, the compounds disclosed herein are administered by inhalation. In some embodiments, formulations suitable for pulmonary or nasal administration have a particle size in the range of, for example, 0.1 to 500 micrometers, for example, 0.5, 1, 30, 35, etc., and are administered by rapid inhalation through the nasal passage or by inhalation through the mouth to reach the alveoli. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration can be prepared according to conventional methods and can be delivered with other therapeutic agents. In some embodiments, the compounds used herein are formulated and administered as dry powders. In some embodiments, the compounds used herein are formulated and administered as a spray formulation. In some embodiments, the compounds used herein are formulated for delivery by a face mask. In some embodiments, the compounds used herein are formulated for delivery by a face tent.

[0117] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing, in addition to the active ingredient, such carriers as are known in the art to be appropriate.

[0118] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

[0119] The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules, and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, of the active ingredient, or an appropriate fraction thereof.

[0120] It will be understood that in addition to the ingredients specifically mentioned above, the formulations of the invention may include other agents conventional in the art having regard to the type of formulation in question; for example, those suitable for oral administration may include flavoring agents.

[0121] The present invention further provides veterinary compositions comprising at least one active ingredient as defined above together with a veterinary carrier therefor.

[0122] A veterinary carrier may be a solid, liquid, or gaseous substance that is useful for the purpose of administering the composition and is otherwise inert or acceptable in the veterinary field and compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally, or by any other desired route.

[0123] The compounds of the present invention are used to provide controlled release pharmaceutical formulations ("controlled release formulations") containing one or more compounds of the present invention as active ingredients, in which release of the active ingredient is controlled and regulated to allow less frequent administration or to improve the pharmacokinetic or toxicity profile of a given active ingredient.

[0124] VI. Kit Also provided herein are kits comprising the compounds disclosed herein, pharma- ceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or tautomers thereof. In some embodiments, the kits described herein may include labels and / or instructions for use of the compounds in treating a disease or condition in a subject (e.g., a human) in need of such treatment. In some embodiments, the disease or condition is a viral infection.

[0125] In some embodiments, the kit may also include one or more additional therapeutic agents and / or instructions for using the additional therapeutic agents in combination with a compound described herein, e.g., a compound of Formula A or Formula B, in treating a disease or condition in a subject (e.g., a human) in need of such treatment.

[0126] In some embodiments, the kits provided herein contain individual unit doses of the compounds described herein, or pharma- ceutically acceptable salts, racemates, enantiomers, diastereomers, tautomers, polymorphs, pseudopolymorphs, amorphous forms, hydrates, or solvates. Examples of individual dosage units include pills, tablets, capsules, pre-filled syringes or syringe cartridges, IV bags, inhalers, nebulizers, etc., each of which may contain a therapeutically effective amount of the compound in question, or a pharma- ceutically acceptable salt, racemate, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, amorphous form, hydrate, or solvate. In some embodiments, the kits may contain a single dosage unit, such as the number of dosage units required for a particular regimen or time period, or in others, there are multiple dosage units.

[0127] Also provided is an article of manufacture that includes a compound described herein, e.g., a compound of Formula A or Formula B, or a pharma- ceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof, and a container. In some embodiments, the article of manufacture container is a vial, bottle, ampoule, pre-filled syringe, blister package, tin, can, bottle, box, intravenous bag, inhaler, or nebulizer.

[0128] VII. Administration One or more compounds of the present invention are administered by any route appropriate for the condition to be treated. Suitable routes include oral, rectal, inhalation, pulmonary, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. In some embodiments, the compounds disclosed herein are administered by inhalation or intravenously. In some embodiments, the compounds disclosed herein are administered orally. It will be understood that the preferred route may vary, for example, depending on the condition of the recipient.

[0129] In the method of the present invention for treating viral infection, the compound of the present invention can be administered at any time to a human who may have come into contact with the virus or who is already suffering from the viral infection. In some embodiments, the compound of the present invention can be administered prophylactically to a human who comes into contact with a human suffering from a viral infection or is at risk of coming into contact with a human suffering from a viral infection, such as a health care provider. In some embodiments, the administration of the compound of the present invention can be to a human who tests positive for a viral infection but does not yet show symptoms of the viral infection. In some embodiments, the administration of the compound of the present invention can be to a human at the onset of symptoms of a viral infection.

[0130] In some embodiments, the methods disclosed herein include event-driven administration of a compound of Formula A or Formula B, or a pharma- ceutically acceptable salt thereof, to a subject.

[0131] As used herein, the term "event-driven" or "event-driven administration" refers to administering a compound described herein, e.g., a compound of Formula A or Formula B, or a pharma- ceutically acceptable salt thereof, (1) before an event (e.g., 2 hours, 1 day, 2 days, 5 days, or 7 days or more before the event) that exposes the individual to the virus (or otherwise increases the individual's risk of being infected with the virus), and / or (2) during an event (or two or more recurring events) that exposes the individual to the virus (or otherwise increases the individual's risk of being infected with the virus), and / or (3) after an event (or after the last event in a series of recurring events) that exposes the individual to the virus (or otherwise increases the individual's risk of being infected with the virus). In some embodiments, the event-driven administration is performed before the subject's exposure to the virus. In some embodiments, the event-driven administration is performed after the subject's exposure to the virus. In some embodiments, the event-driven administration is performed before the subject's exposure to the virus and after the subject's exposure to the virus.

[0132] In certain embodiments, the methods disclosed herein include administration before and / or after an event that exposes an individual to the virus or that otherwise increases the individual's risk of infection with the virus, e.g., as pre-exposure prophylaxis (PrEP) and / or post-exposure prophylaxis (PEP). In some embodiments, the methods disclosed herein include pre-exposure prophylaxis (PrEP). In some embodiments, the methods disclosed herein include post-exposure prophylaxis (PEP).

[0133] In some embodiments, the compound of Formula A or Formula B, or a pharma- ceutically acceptable salt thereof, is administered prior to exposure of the subject to the virus.

[0134] In some embodiments, the compound of Formula A or Formula B, or a pharma- ceutically acceptable salt thereof, is administered before and after exposure of the subject to the virus.

[0135] In some embodiments, the compound of Formula A or Formula B, or a pharma- ceutically acceptable salt thereof, is administered after exposure of the subject to the virus.

[0136] An example of an event-driven dosing regimen includes administering a compound of Formula A or Formula B, or a pharma- ceutically acceptable salt thereof, within 24 hours to 2 hours prior to the virus, followed by administration of a compound of Formula A or Formula B, or a pharma- ceutically acceptable salt thereof, every 24 hours during the exposure period, followed by another dose of a compound of Formula A or Formula B, or a pharma- ceutically acceptable salt thereof, after the last exposure, and finally one more dose of a compound of Formula A or Formula B, or a pharma- ceutically acceptable salt thereof, 24 hours later.

[0137] A further example of an event-driven dosing regimen includes administering a compound of Formula A or Formula B, or a pharma- ceutically acceptable salt thereof, within 24 hours prior to exposure to the virus, followed by daily dosing for the duration of exposure, followed by a final dose (which may be an increased dose, such as a double dose) approximately 24 hours after the last exposure.

[0138] The specific dose level of the compounds of the present disclosure for any particular subject will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination, and the severity of the particular disease in the subject undergoing therapy. For example, dosages may be expressed as milligrams of the compounds described herein per kilogram of subject body weight (mg / kg). Doses of about 0.1 to 150 mg / kg may be appropriate. In some embodiments, between about 0.1 and 100 mg / kg may be appropriate. In other embodiments, doses of 0.5 to 60 mg / kg may be appropriate. Normalizing by subject body weight is particularly useful when adjusting dosages between subjects of widely differing sizes, such as occurs when using drugs in both pediatric and adult humans, or when converting effective dosages in non-human subjects, such as dogs, to dosages suitable for human subjects.

[0139] A daily dose may also be described as the total amount of a compound described herein administered per administration or per day. The daily dose of a compound of formula A or formula B, or a pharma- ceutically acceptable salt thereof, may be about 1 mg to 4,000 mg, about 2,000 to 4,000 mg / day, about 1 to 2,000 mg / day, about 1 to 1,000 mg / day, about 10 to 500 mg / day, about 20 to 500 mg / day, about 50 to 300 mg / day, about 75 to 200 mg / day, or about 15 to 150 mg / day.

[0140] The dosage or frequency of administration of a compound of the present disclosure may be adjusted over the course of treatment, based on the judgment of the administering physician.

[0141] The compounds of the present disclosure may be administered to an individual (e.g., a human) in a therapeutically effective amount. In some embodiments, the compounds are administered once a day.

[0142] The compounds provided herein may be administered by any useful route and means, such as oral or parenteral (e.g., intravenous) administration. A therapeutically effective amount of a compound may include from about 0.00001 mg / kg body weight per day to about 10 mg / kg body weight per day, e.g., from about 0.0001 mg / kg body weight per day to about 10 mg / kg body weight per day, or from about 0.001 mg / kg body weight per day to about 1 mg / kg body weight per day, or from about 0.01 mg / kg body weight per day to about 1 mg / kg body weight per day, or from about 0.05 mg / kg body weight per day to about 0.5 mg / kg body weight per day. In some embodiments, a therapeutically effective amount of a compound provided herein may include from about 0.3 mg to about 30 mg per day, or from about 30 mg to about 300 mg per day, or from about 0.3 mg to about 30 mg per day, or from about 30 mg to about 300 mg per day.

[0143] The compounds of the present disclosure can be combined with one or more additional therapeutic agents at any dosage of the compounds of the present disclosure (e.g., 1 mg to 1000 mg of compound). Therapeutically effective amounts can include from about 0.1 mg per dose to about 1000 mg per dose, e.g., from about 50 mg per dose to about 500 mg per dose, or, e.g., from about 100 mg per dose to about 400 mg per dose, or, e.g., from about 150 mg per dose to about 350 mg per dose, or, e.g., from about 200 mg per dose to about 300 mg per dose, or, e.g., from about 0.01 mg per dose to about 1000 mg per dose, or, e.g., from about 0.01 mg per dose to about 100 mg per dose, or, e.g., from about 0.1 mg per dose to about 100 mg per dose, or, e.g., from about 1 mg per dose to about 100 mg per dose, or, e.g., from about 1 mg per dose to about 10 mg per dose, or, e.g., from about 1 mg per dose to about 1000 mg per dose. Other therapeutically effective amounts of a compound of Formula A or Formula B are about 1 mg per dose, or about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or about 100 mg per dose. Other therapeutically effective amounts of a compound of the present disclosure are about 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, or about 1000 mg per dose.

[0144] In some embodiments, the method includes administering to a subject an initial daily dose of about 1-500 mg of a compound provided herein, and increasing the dose in increments until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dose. The dosage can be increased daily, daily, twice weekly, weekly, biweekly, triweekly, or monthly.

[0145] When administered orally, the total daily dosage for a human subject may be about 1-4,000 mg / day, about 1-3,000 mg / day, 1-2,000 mg / day, about 1-1,000 mg / day, about 10-500 mg / day, about 50-300 mg / day, about 75-200 mg / day, or about 100-150 mg / day. In some embodiments, the total daily dosage for a human subject may be about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, or 3000 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 200, 300, 400, 500, 600, 700, or 800 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 300, 400, 500, or 600 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800, 3900, or 4000 mg / day.In some embodiments, the total daily dosage for a human subject is about 100-200, 100-300, 100-400, 100-500, 100-600, 100-700, 100-800, 100-900, 100-1000, 500-1100, 500-1200, 500-1300, 500-1400, 500-1500, 500-1600, 500-1700, 500-1800, 500-1900, 500-2000, 1500-2100, It may be 1500 to 2200, 1500 to 2300, 1500 to 2400, 1500 to 2500, 2000 to 2600, 2000 to 2700, 2000 to 2800, 2000 to 2900, 2000 to 3000, 2500 to 3100, 2500 to 3200, 2500 to 3300, 2500 to 3400, 2500 to 3500, 3000 to 3600, 3000 to 3700, 3000 to 3800, 3000 to 3900, or 3000 to 4000 mg / day.

[0146] In some embodiments, the total daily dosage for a human subject may be about 100 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 150 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 200 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 250 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 300 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 350 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 400 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 450 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 500 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 550 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 600 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 650 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 700 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 750 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 800 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 850 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 900 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 950 mg / day administered in a single dose.In some embodiments, the total daily dosage for a human subject may be about 1000 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 1500 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 2000 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 2500 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 3000 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 4000 mg / day administered in a single dose.

[0147] The single dose can be administered hourly, daily, weekly, or monthly. For example, the single dose can be administered once every 1, 2, 3, 4, 6, 8, 12, 16 hours, or once every 24 hours. The single dose can also be administered once every 1, 2, 3, 4, 5, 6 days, or once every 7 days. The single dose can also be administered once every 1, 2, 3 weeks, or once every 4 weeks. In certain embodiments, the single dose can be administered once every week. The single dose can also be administered once every month. In some embodiments, the compounds disclosed herein are administered once a day in the methods disclosed herein. In some embodiments, the compounds disclosed herein are administered twice a day in the methods disclosed herein. In some embodiments, the compounds disclosed herein are administered three times a day in the methods disclosed herein.

[0148] In some embodiments, the compounds disclosed herein are administered once daily at a total daily dose of 100-4000 mg / day. In some embodiments, the compounds disclosed herein are administered twice daily at a total daily dose of 100-4000 mg / day. In some embodiments, the compounds disclosed herein are administered three times daily at a total daily dose of 100-4000 mg / day.

[0149] The frequency of administration of the compounds of the present disclosure is determined by the needs of an individual patient, and can be, for example, once a day or twice a day or more. Administration of the compounds continues as long as necessary to treat the viral infection. For example, the compounds can be administered to a human infected with a virus for a period of 20 to 180 days, or for example, for a period of 20 to 90 days, or for example, for a period of 30 to 60 days.

[0150] Administration can be intermittent, with a period of several days or more during which the patient receives a daily dose of the disclosed compound, followed by a period of several days or more during which the patient does not receive a daily dose of the compound. For example, the patient can receive a dose of the compound every other day, or three times per week. As a further example, the patient can receive a dose of the compound daily for a period of 1-14 days, followed by a period of 7-21 days during which the patient does not receive a dose of the compound, followed by a subsequent period (e.g., 1-14 days) during which the patient again receives a daily dose of the compound. The alternating periods of administration of the compound followed by non-administration of the compound can be repeated as clinically required to treat the patient.

[0151] The disclosed compound or pharmaceutical composition thereof may be administered once, twice, three times, or four times a day using any suitable mode described above. Also, administration or treatment with the compound may continue for several days, for example, treatment will usually continue for at least 7 days, 14 days, or 28 days for one treatment cycle. Treatment cycles are well known in cancer chemotherapy and frequently alternate with rest periods of about 1 to 28 days, generally about 7 days or about 14 days, between cycles. Treatment cycles may also be continuous in other embodiments.

[0152] VIII.How to use The disclosure also provides a method of treating or preventing a viral infection in a subject (e.g., a human) in need thereof, the method comprising administering to the subject a compound described herein.

[0153] In some embodiments, the disclosure provides a method of treating or preventing a viral infection in a subject (e.g., a human) in need thereof, the method comprising administering to the subject in need of treatment or prevention a compound described herein.

[0154] In some embodiments, the compounds described herein are administered to humans via oral, intramuscular, intravenous, subcutaneous, or inhaled administration.

[0155] In some embodiments, the disclosure provides a method of treating or preventing a viral infection in a subject (e.g., a human) in need thereof, the method comprising administering to the subject a compound disclosed herein and at least one additional active therapeutic or prophylactic agent.

[0156] In some embodiments, the disclosure provides a method of treating a viral infection in a subject (e.g., a human) in need thereof, comprising administering to the subject a compound disclosed herein and at least one additional active therapeutic or prophylactic agent.

[0157] In one embodiment, the disclosure provides a method of inhibiting a viral polymerase in a cell, comprising contacting a cell infected with a virus with a compound disclosed herein, thereby inhibiting the viral polymerase.

[0158] In one embodiment, the disclosure provides a method of inhibiting a viral polymerase in a cell, comprising contacting a virally infected cell with a compound disclosed herein and at least one additional active therapeutic agent, thereby inhibiting the viral polymerase.

[0159] Also provided is the use of a compound disclosed herein for use in treating or preventing a viral infection in a subject in need thereof. For example, provided herein is the use of a compound disclosed herein for use in treating a viral infection in a subject in need thereof.

[0160] In some embodiments, the viral infection is a Paramyxoviridae virus infection. Thus, in some embodiments, the present disclosure provides a method for treating a Paramyxoviridae virus infection in a subject (e.g., a human) in need thereof, comprising administering to the subject a compound disclosed herein. Paramyxoviridae viruses include, but are not limited to, Nipah virus, Hendra virus, measles virus, mumps virus, and parainfluenza virus.

[0161] In some embodiments, the viral infection is a human parainfluenza virus infection, a Nipah virus infection, a Hendra virus infection, a measles virus infection, or a mumps virus infection.

[0162] In some embodiments, the viral infection is a Pneumoviridae virus infection. Thus, in some embodiments, the disclosure provides a method of treating a Pneumoviridae virus infection in a human in need thereof, comprising administering to the human a compound provided herein. Pneumoviridae viruses include, but are not limited to, respiratory syncytial virus and human metapneumovirus. In some embodiments, the Pneumoviridae virus infection is a respiratory syncytial virus infection. In some embodiments, the Pneumoviridae virus infection is a human metapneumovirus infection.

[0163] In some embodiments, the disclosure provides a compound disclosed herein for use in treating a Pneumoviridae virus infection in a human in need thereof. In some embodiments, the Pneumoviridae virus infection is a respiratory syncytial virus infection. In some embodiments, the Pneumoviridae virus infection is a human metapneumovirus infection.

[0164] In some embodiments, the present disclosure provides a method for treating a RSV infection in a human in need thereof, comprising administering to the human a compound provided herein. In some embodiments, the human suffers from a chronic respiratory syncytial virus infection. In some embodiments, the human suffers from an acute RSV infection.

[0165] In some embodiments, a method of inhibiting RSV replication is provided, comprising administering to a human in need thereof a compound disclosed herein, wherein the administration is by inhalation.

[0166] In some embodiments, the disclosure provides a method for reducing the viral load associated with a RSV infection, the method comprising administering to a human infected with RSV a compound disclosed herein.

[0167] In some embodiments, the viral infection is a Picornaviridae virus infection. In some embodiments, the disclosure provides a method of treating a Picornaviridae virus infection in a human in need thereof, the method comprising administering a compound of the disclosure to the human. Picornaviridae viruses are enteroviruses that cause a heterogeneous group of infections, including herpangina, aseptic meningitis, common cold-like syndrome (human rhinovirus infection), non-paralytic polio-like syndrome, epidemic pleurodynia (an acute, febrile, infectious illness that typically occurs during epidemics), hand, foot and mouth disease, pediatric and adult pancreatitis, and severe myocarditis. In some embodiments, the Picornaviridae virus infection is a human rhinovirus infection (HRV). In some embodiments, the Picornaviridae virus infection is an HRV-A, HRV-B, or HRV-C infection.

[0168] In some embodiments, the viral infection is selected from the group consisting of a Coxsackie A virus infection, a Coxsackie A virus infection, an Enterovirus D68 infection, an Enterovirus B69 infection, an Enterovirus D70 infection, an Enterovirus A71 infection, and a poliovirus infection.

[0169] In some embodiments, the disclosure provides a compound for use in treating a Picornaviridae virus infection in a human in need thereof, hi some embodiments, the Picornaviridae virus infection is a human rhinovirus infection.

[0170] In some embodiments, the viral infection is a Flaviviridae virus infection. Thus, in some embodiments, the disclosure provides a method of treating a Flaviviridae virus infection in a human in need thereof, the method comprising administering to the human a compound described herein. Representative Flaviviridae viruses include, but are not limited to, Dengue, Yellow Fever, West Nile, Zika, Japanese Encephalitis Virus, and Hepatitis C (HCV). In some embodiments, the Flaviviridae virus infection is a Dengue virus infection. In some embodiments, the Flaviviridae virus infection is a Yellow Fever virus infection. In some embodiments, the Flaviviridae virus infection is a West Nile virus infection. In some embodiments, the Flaviviridae virus infection is a Zika virus infection. In some embodiments, the Flaviviridae virus infection is a Japanese Encephalitis virus infection. In some embodiments, the Flaviviridae virus infection is a Hepatitis C virus infection.

[0171] In some embodiments, the Flaviviridae virus infection is Dengue virus infection, Yellow fever virus infection, West Nile virus infection, Tick-borne encephalitis, Kunjin Japanese encephalitis, St. Louis encephalitis, Murray Valley encephalitis, Omsk hemorrhagic fever, Bovine viral diarrhea, Zika virus infection, or HCV infection.

[0172] In some embodiments, the disclosure provides for the use of a compound of the disclosure for the treatment of a Flaviviridae virus infection in a human in need thereof. In some embodiments, the Flaviviridae virus infection is a Dengue virus infection. In some embodiments, the Flaviviridae virus infection is a Yellow Fever virus infection. In some embodiments, the Flaviviridae virus infection is a West Nile virus infection. In some embodiments, the Flaviviridae virus infection is a Zika virus infection. In some embodiments, the Flaviviridae virus infection is a Hepatitis C virus infection.

[0173] In some embodiments, the viral infection is a Filoviridae virus infection. Thus, in some embodiments, the present disclosure provides a method of treating a Filoviridae virus infection in a human in need thereof, comprising administering to the human a compound disclosed herein. Representative Filoviridae viruses include, but are not limited to, Ebola virus (Zaire, Bundibugyo, Sudan, Tai forest, or Reston variant) and Marburg virus. In some embodiments, the Filoviridae virus infection is an Ebola virus infection. In some embodiments, the Filoviridae virus infection is a Marburg virus infection.

[0174] In some embodiments, the disclosure provides a compound for use in treating a Filoviridae virus infection in a human in need thereof. In some embodiments, the Filoviridae virus infection is an Ebola virus infection. In some embodiments, the Filoviridae virus infection is a Marburg virus infection.

[0175] In some embodiments, the viral infection is a coronavirus infection. Thus, in some embodiments, the present disclosure provides a method of treating a coronavirus infection in a human in need thereof, the method comprising administering a compound provided herein to the human. In some embodiments, the coronavirus infection is a Severe Acute Respiratory Syndrome (SARS-CoV) infection, a Middle Eastern Respiratory Syndrome (MERS) infection, a SARS-CoV-2 infection, another human coronavirus (229E, NL63, OC43, HKU1, or WIV1) infection, a zoonotic coronavirus (PEDV or HKU CoV isolate, e.g., HKU3, HKU5, or HKU9) infection. In some embodiments, the viral infection is a Severe Acute Respiratory Syndrome (SARS) infection. In some embodiments, the viral infection is a Middle East Respiratory Syndrome (MERS) infection. In some embodiments, the viral infection is a SARS-CoV-2 infection. In some embodiments, the viral infection is a zoonotic coronavirus infection, and in some embodiments, the viral infection is caused by a virus with at least 70% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2. In some embodiments, the viral infection is caused by a virus with at least 80% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2. In some embodiments, the viral infection is caused by a virus with at least 90% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2.In some embodiments, the viral infection is caused by a virus having at least 95% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2.

[0176] In some embodiments, the viral infection is caused by a SARS-CoV-2 variant, such as the B.1.1.7 variant (UK variant), the B.1.351 variant (South African variant), the P.1 variant (Brazilian variant), the B.1.1.7 with the E484K mutation, the B.1.1.207 variant, the B.1.1.317 variant, the B.1.1.318 variant, the B.1.429 variant, the B.1.525 variant, or the P.3 variant. In some embodiments, the viral infection is caused by the B.1.1.7 variant of SARS-CoV-2. In some embodiments, the viral infection is caused by the B.1.351 variant of SARS-CoV-2. In some embodiments, the viral infection is caused by the P.1 variant of SARS-CoV-2.

[0177] In some embodiments, the disclosure provides a compound for use in treating a coronavirus infection in a human in need thereof. In some embodiments, the coronavirus infection is a severe acute respiratory syndrome (SARS) infection, a Middle East respiratory syndrome (MERS) infection, a SARS-CoV-2 infection, other human coronaviruses (229E, NL63, OC43, HKU1, or WIV1) infection, and a zoonotic coronavirus (PEDV or HKU CoV isolate, e.g., HKU3, HKU5, or HKU9) infection. In some embodiments, the viral infection is a severe acute respiratory syndrome (SARS) infection. In some embodiments, the viral infection is a Middle East respiratory syndrome (MERS) infection. In some embodiments, the viral infection is a SARS-CoV-2 infection (COVID19).

[0178] In some embodiments, the viral infection is an Arenaviridae virus infection. Thus, in some embodiments, the disclosure provides a method of treating an Arenaviridae virus infection in a human in need thereof, the method comprising administering to the human a compound disclosed herein. In some embodiments, the Arenaviridae virus infection is a Lassa infection or a Junin infection.

[0179] In some embodiments, the disclosure provides a compound for use in treating an Arenaviridae virus infection in a human in need thereof, hi some embodiments, the Arenaviridae virus infection is a Lassa infection or a Junin infection.

[0180] In some embodiments, the viral infection is an orthomyxovirus infection, e.g., an influenza virus infection. In some embodiments, the viral infection is an influenza virus A, influenza virus B, or influenza virus C infection.

[0181] As described more fully herein, the compounds described herein can be administered to an individual (e.g., a human) infected with a viral infection along with one or more additional therapeutic agents. The additional therapeutic agents can be administered to the infected individual simultaneously with the compounds of the present disclosure, or prior to or after administration of the compounds of the present disclosure.

[0182] IX. Combination Therapy The compounds described herein can also be used in combination with one or more additional therapeutic agents.Therefore, also provided herein is a method for treating a viral infection in a subject in need thereof, comprising administering to the subject a compound disclosed herein and a therapeutically effective amount of one or more additional therapeutic or prophylactic agents.

[0183] In some embodiments, the additional therapeutic agent comprises an antiviral agent. Any suitable antiviral agent can be used in the methods described herein. In some embodiments, the antiviral agent is selected from the group consisting of 5-substituted 2'-deoxyuridine analogs, nucleoside analogs, pyrophosphate analogs, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, entry inhibitors, acyclic guanosine analogs, acyclic nucleoside phosphonate analogs, HCV NS5A / NS5B inhibitors, influenza virus inhibitors, interferons, immunostimulants, oligonucleotides, mitotic inhibitors, and combinations thereof.

[0184] In some embodiments, the additional therapeutic agent is a 5-substituted 2'-deoxyuridine analog, for example, in some embodiments, the additional therapeutic agent is selected from the group consisting of idoxuridine, trifluridine, brivudine [BVDU], and combinations thereof.

[0185] In some embodiments, the additional therapeutic agent is a nucleoside analog. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of vidarabine, entecavir (ETV), telbivudine, lamivudine, adefovir dipivoxil, tenofovir disoproxil fumarate (TDF), and combinations thereof. In some embodiments, the additional therapeutic agent is favipiravir, ribavirin, galidesivir, β-D-N4-hydroxycytidine, or combinations thereof.

[0186] In some embodiments, the additional therapeutic agent is a pyrophosphate analog. For example, in some embodiments, the additional therapeutic agent is foscarnet or phosphonoacetic acid. In some embodiments, the additional therapeutic agent is foscarnet.

[0187] In some embodiments, the additional therapeutic agent is a nucleoside reverse transcriptase inhibitor, hi some embodiments, the antiviral agent is zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine, and combinations thereof.

[0188] In some embodiments, the additional therapeutic agent is a non-nucleoside reverse transcriptase inhibitor. In some embodiments, the antiviral agent is selected from the group consisting of nevirapine, delavirdine, efavirenz, etravirine, rilpivirine, and combinations thereof.

[0189] In some embodiments, the additional therapeutic agent is a protease inhibitor. In some embodiments, the protease inhibitor is an HIV protease inhibitor. For example, in some embodiments, the antiviral agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, cobicistat, and combinations thereof. In some embodiments, the antiviral agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, and combinations thereof. In some embodiments, the protease inhibitor is an HCV NS3 / 4A protease inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of voxilaprevir, asunaprevir, boceprevir, paritaprevir, simeprevir, telaprevir, vaniprevir, grazoprevir, ribavirin, danoprevir, faldaprevir, vedroprevir, sovaprevir, deldeprevir, naraprevir, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of voxilaprevir, asunaprevir, boceprevir, paritaprevir, simeprevir, telaprevir, vaniprevir, grazoprevir, and combinations thereof.

[0190] In some embodiments, the additional therapeutic agent is an integrase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of raltegravir, dolutegravir, elvitegravir, abacavir, lamivudine, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of bictegravir, raltegravir, dolutegravir, cabotegravir, elvitegravir, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of bictegravir, dolutegravir, and cabotegravir, and combinations thereof. In some embodiments, the additional therapeutic agent is bictegravir.

[0191] In some embodiments, the additional therapeutic agent is an entry inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of docosanol, enfuvirtide, maraviroc, ibalizumab, fostemsavir, leronlimab, ibalizumab, fostemsavir, leronlimab, palivizumab, respiratory syncytial virus immune globulin, intravenous (RSV-IGIV), varicella-zoster immunoglobulin (VariZIG), varicella-zoster immune globulin (VZIG), and combinations thereof.

[0192] In some embodiments, the additional therapeutic agent is an acyclic guanosine analog, for example, in some embodiments, the additional therapeutic agent is selected from the group consisting of acyclovir, ganciclovir, valacyclovir (also known as valacyclovir), valganciclovir, penciclovir, famciclovir, and combinations thereof.

[0193] In some embodiments, the additional therapeutic agent is an acyclic nucleoside phosphonate analog. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of cidofovir, adefovir, adefovir dipivoxil, tenofovir, TDF, emtricitabine, efavirenz, rilpivirine, elvitegravir, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of cidofovir, adefovir, adefovir dipivoxil, tenofovir, TDF, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of cidofovir, adefovir dipivoxil, TDF, and combinations thereof.

[0194] In some embodiments, the additional therapeutic agent is an HCV NS5A / NS5B inhibitor. In some embodiments, the additional therapeutic agent is an NS3 / 4A protease inhibitor. In some embodiments, the additional therapeutic agent is an NS5A protein inhibitor. In some embodiments, the additional therapeutic agent is a nucleoside / nucleotide NS5B polymerase inhibitor. In some embodiments, the additional therapeutic agent is a non-nucleoside NS5B polymerase inhibitor. In some embodiments, the additional therapeutic agent is selected from the group consisting of daclatasvir, ledipasvir, velpatasvir, ombitasvir, elbasvir, sovosbuvir, dasabuvir, ribavirin, asunaprevir, simeprevir, paritaprevir, ritonavir, elbasvir, grazoprevir, AT-527, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of daclatasvir, ledipasvir, velpatasvir, ombitasvir, elbasvir, sovosbuvir, dasabuvir, and combinations thereof.

[0195] In some embodiments, the additional therapeutic agent is an influenza virus inhibitor. In some embodiments, the additional therapeutic agent is a matrix 2 inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of amantadine, rimantadine, and combinations thereof. In some embodiments, the additional therapeutic agent is a neuraminidase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of zanamivir, oseltamivir, peramivir, laninamivir octanoate, and combinations thereof. In some embodiments, the additional therapeutic agent is a polymerase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of ribavirin, favipiravir, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of amantadine, rimantadine, arbidol (umifenovir), baloxavir marboxil, oseltamivir, peramivir, ingavirin, laninamivir octanoate, zanamivir, favipiravir, ribavirin, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of amantadine, rimantadine, zanamivir, oseltamivir, peramivir, laninamivir octanoate, ribavirin, favipiravir, and combinations thereof.

[0196] In some embodiments, the additional therapeutic agent is an interferon. In some embodiments, the additional therapeutic agent is selected from the group consisting of interferon alfacon1, interferon alfa 1b, interferon alfa 2a, interferon alfa 2b, pegylated interferon alfacon1, pegylated interferon alfa 1b, pegylated interferon alfa 2a (PegIFNα-2a), and PegIFNα-2b. In some embodiments, the additional therapeutic agent is selected from the group consisting of interferon alfacon1, interferon alfa 1b, interferon alfa 2a, interferon alfa 2b, and pegylated interferon alfa 2a (PegIFNα-2a), and PegIFNα-2b. In some embodiments, the additional therapeutic agent is selected from the group consisting of interferon alfacon1, pegylated interferon alfa 2a (PegIFNα-2a), PegIFNα-2b, and ribavirin. In some embodiments, the additional therapeutic agent is pegylated interferon alpha-2a, pegylated interferon alpha-2b, or a combination thereof.

[0197] In some embodiments, the additional therapeutic agent is an immunostimulant. In some embodiments, the additional therapeutic agent is an oligonucleotide. In some embodiments, the additional therapeutic agent is a mitotic inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of fomivirsen, podofilox, imiquimod, sinecatechin, and combinations thereof.

[0198] In some embodiments, the additional therapeutic agent is selected from the group consisting of besifovir, nitazoxanide, REGN2222, doravirine, sovosbuvir, velpatasvir, daclatasvir, asunaprevir, beclabuvir, FV100, and letermovir, and combinations thereof.

[0199] In some embodiments, the additional therapeutic agent is an agent for the treatment of RSV. For example, in some embodiments, the antiviral agent is ribavirin, ALS-8112, or presatovir. For example, in some embodiments, the antiviral agent is ALS-8112 or presatovir.

[0200] In some embodiments, the additional therapeutic agent is an agent for the treatment of picornavirus. In some embodiments, the additional therapeutic agent is selected from the group consisting of hydantoin, guanidine hydrochloride, l-buthionine sulfoximine, Py-11, and combinations thereof. In some embodiments, the additional therapeutic agent is a picornavirus polymerase inhibitor. In some embodiments, the additional therapeutic agent is rupintrivir.

[0201] In some embodiments, the additional therapeutic agent is an agent for the treatment of malaria, hi some embodiments, the additional therapeutic agent is chloroquine.

[0202] In some embodiments, the additional therapeutic agent is selected from the group consisting of hydroxychloroquine, chloroquine, artemether, lumefantrine, atovaquone, proguanil, tafenoquine, pyronaridine, artesunate, artenimol, piperaquine, artesunate, amodiaquine, pyronaridine, artesunate, halofantrine, quinine sulfate, mefloquine, solithromycin, pyrimethamine, MMV-390048, ferroquine, artefenomer mesylate, ganaplacid, DSM-265, cypargamine, artemison, and combinations thereof.

[0203] In some embodiments, the additional therapeutic agent is an agent for the treatment of coronavirus, hi some embodiments, the additional therapeutic agent is selected from the group consisting of IFX-1, FM-201, CYNK-001, DPP4-Fc, ranpirnase, nafamostat, LB-2, AM-1, antiviroporin, and combinations thereof.

[0204] In some embodiments, the additional therapeutic agent is an agent for the treatment of Ebola virus. For example, in some embodiments, the additional therapeutic agent is ribavirin, palivizumab, motavizumab, RSV-IGIV (RespiGam®), MEDI-557, A-60444, MDT-637, BMS-433771, amiodarone, dronedarone, verapamil, Ebola Convalescent Plasma, Plasma, ECP), TKM-100201, BCX4430 ((2S,3S,4R,5R)-2-(4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-5-(hydroxymethyl)pyrrolidine-3,4-diol), Favipiravir (also known as T-705 or Avigan), T-705 monophosphate, T-705 diphosphate, T-705 triphosphate, FGI-106 (1-N,7-N-bis[3-(dimethylamino)propyl]-3,9-dimethylquinolin[8,7 [-h]quinolone-1,7-diamine), JK-05, TKM-Ebola, ZMapp, rNAPc2, VRC-EBOADC076-00-VP, OS-2966, MVA-BN filo, brincidofovir, Vaxart adenoviral vector 5-based Ebola vaccine, Ad26-ZEBOV, FiloVax vaccine, GOVX-E301, GOVX-E302, Ebola virus entry inhibitor (NPC1 inhibitor), rVSV-EBOV, and combinations thereof. In some embodiments, the additional therapeutic agent is ZMapp, mAB114, REGEN-EB3, and combinations thereof.

[0205] In some embodiments, the additional therapeutic agent is an agent for the treatment of HCV. In some embodiments, the additional therapeutic agent is an HCV polymerase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of sofosbuvir, GS-6620, PSI-938, ribavirin, tegobuvir, ladarbuvir, MK-0608, and combinations thereof. In some embodiments, the additional therapeutic agent is an HCV protease inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of GS-9256, vedroprevir, voxilaprevir, and combinations thereof.

[0206] In some embodiments, the additional therapeutic agent is an NS5A inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of ledipasvir, velpatasvir, and combinations thereof.

[0207] In some embodiments, the additional therapeutic agent is an anti-HBV agent, for example, in some embodiments, the additional therapeutic agent is tenofovir disoproxil fumarate and emtricitabine, or a combination thereof. Examples of additional anti-HBV agents include α-hydroxytropolone, amdoxovir, antroquinonol, β-hydroxycytosine nucleosides, ARB-199, CCC-0975, ccc-R08, elvucitabine, ezetimibe, cyclosporine A, gentiopicrin (gentiopicroside), HH-003, heparatide, JNJ-56136379, nitazoxanide, birinapant, NJK14047, NOV-205 (Mollixan, BAM-205), oligotide, mibotylate, feron, GST-HG-131, levamisole, Ka Shu Ning, alloferon, WS-007, Y-101 (Ti Fen Tai), rSIFN-co, PEG-IIFNm, KW-3, BP-Inter-014, oleanolic acid, HepB-nRNA, cTP-5 (rTP-5), HSK-II-2, HEISCO-106-1, HEISCO-106, Hepbarna, IBPB-006IA, Hepuyinfen, DasKloster0014-01, ISA-204, Jiangantai (Ganxikang), MIV-210, OB-AI-004, PF-06, picroside, DasKloster-0039, Heplantai, IMB-2613, TCM-800B, reduced glutathione, RO-6864018, RG-7834, QL-007 sovosbuvir, ledipasvir, UB-551, and ZH-2N, as well as U.S. Patent Application Publication No. 20150210682 (Roche), U.S. Patent Application Publication No. 2016 / 0122344 (Roche), WO 2015173164, WO 2016023877, U.S. Patent Application Publication No. 2015252057(A) (Roche), WO 2015252057(B) (Roche), WO 2015252057(C) (Roche), WO 2015252057(D) (Roche), WO 2015252057(E) (Roche), WO 2015252057(F) (Roche), WO 2015252057(G) (Roche), WO 2015252057(H) (Roche), WO 2015252057(I ... The additional therapeutic agent includes, but is not limited to, compounds disclosed in Publication No. 16128335(A1) (Roche), Publication No. 16120186(A1) (Roche), US Patent Publication No. 2016237090(A) (Roche), WO 16107833(A1) (Roche), WO 16107832(A1) (Roche), US Patent Publication No. 2016176899(A) (Roche), WO 16102438(A1) (Roche), WO 16012470(A1) (Roche), US Patent Publication No. 2016220586(A) (Roche), and WO 2015031687(A) (Roche). In some embodiments, the additional therapeutic agent is an HBV polymerase inhibitor. HBVExamples of DNA polymerase inhibitors include adefovir (HEPSERA®), emtricitabine (EMTRIVA®), tenofovir disoproxil fumarate (VIREAD®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir dipivoxil, tenofovir dipivoxil fumarate, tenofovir octadecyloxyethyl ester, CMX-157, tenofovir exalidex, bicifovir, and entecavir. These include, but are not limited to, HBV capsid inhibitors, such as, but not limited to, HBV serovar IgE ...

[0208] In some embodiments, the additional therapeutic agent is an agent for the treatment of HIV, hi some embodiments, the additional therapeutic agent is selected from the group consisting of an HIV protease inhibitor, an HIV integrase inhibitor, an entry inhibitor, an HIV nucleoside reverse transcriptase inhibitor, an HIV non-nucleoside reverse transcriptase inhibitor, an acyclic nucleoside phosphonate analog, and combinations thereof.

[0209] In some embodiments, the additional therapeutic agent is selected from the group consisting of HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, immune modulators, immunotherapeutics, antibody-drug conjugates, gene modulating agents, gene editing agents (CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs, etc.), and cell therapy (e.g., chimeric antigen receptor T cells, CAR-T, and engineered T cell receptors, TCR-T, autologous T cell therapy).

[0210] In some embodiments, the additional therapeutic agent is selected from the group consisting of HIV combination medications, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latent reactivators, capsid inhibitors, immune system therapies, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and "antibody-like" therapeutic proteins, and combinations thereof.

[0211] In some embodiments, the additional therapeutic agent is an HIV combination medication. Examples of HIV combination medications include ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); BIKTARVY® bictegravir, emtricitabine, and tenofovir alafenamide; COMPLERA® (EVIPLERA®, rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine). ); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); SYMTUZA® (darunavir, tenofovir alafenamide hemifumarate, emtricitabine, tenofovir alafenamide and emtricitabine; tenofovir alafenamide hemifumarate and emtricitabine; tenofovir alafenamide hemifumarate, emtricitabine, and rilpivirine; tenofovir alafenamide hemifumarate, emtricitabine, cobicistat, and ervivir; Tegravir; COMBIVIR® (zidovudine and lamivudine, AZT+3TC); EPZICOM® (LIVEXA®, abacavir sulfate and lamivudine, ABC+3TC); KALETRA® (ALUVIA®, lopinavir and ritonavir); TRIUMEQ® (dolutegravir, abacavir, and lamivudine); TRIZIVIR® (abacavir sulfate, zidovudine, and lamivudine, ABC+AZT+3TC); atazanavir and cobicistat;Atazanavir sulfate and cobicistat; Atazanavir sulfate and ritonavir; Darunavir and cobicistat; Dolutegravir and rilpivirine; Dolutegravir and rilpivirine hydrochloride; Dolutegravir, abacavir sulfate, and lamivudine; Lamivudine, nevirapine, and zidovudine; Raltegravir and lamivudine; Doravirine, lamivudine, and tenofovir disoproxil fumarate; Doravirine, lamivudine, and tenofovir disoproxil; Dapivirine + levonorgestrel, dolutegravir + lamivudine, dolutegravir + emtricitabine + tenofovir alafena In some embodiments, the vasodilators include, but are not limited to, ersulfavirine + emtricitabine + tenofovir disoproxil, lamivudine + abacavir + zidovudine, lamivudine + abacavir, lamivudine + tenofovir disoproxil fumarate, lamivudine + zidovudine + nevirapine, lopinavir + ritonavir, lopinavir + ritonavir + abacavir + lamivudine, lopinavir + ritonavir + zidovudine + lamivudine, tenofovir + lamivudine, and tenofovir disoproxil fumarate + emtricitabine + rilpivirine hydrochloride, lopinavir, ritonavir, zidovudine, and lamivudine;

[0212] In some embodiments, the additional therapeutic agent is an HIV protease inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, cobicistat, ASC-09, AEBL-2, MK-8718, GS-9500, GS-1156, and combinations thereof. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, cobicistat. In some embodiments, the additional therapeutic agent is selected from the group consisting of amprenavir, atazanavir, brecanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir, saquinavir mesylate, tipranavir, DG-17, TMB-657 (PPL-100), T-169, BL-008, MK-8122, TMB-607, TMC-310911, and combinations thereof.

[0213] In some embodiments, the additional therapeutic agent is an HIV integrase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of raltegravir, elvitegravir, dolutegravir, abacavir, lamivudine, bictegravir, and combinations thereof. In some embodiments, the additional therapeutic agent is bictegravir. In some embodiments, the additional therapeutic agent is bictegravir, elvitegravir, curcumin, curcumin derivatives, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, raltegravir, dolutegravir, JTK-351, bictegravir, A Selected from the group consisting of VX-15567, BMS-986197, cabotegravir (long acting injectable), diketoquinoline 4-1 derivatives, integrase-LEDGF inhibitors, ledgin, M-522, M-532, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbene disulfonic acid, T-169, VM-3500, cabotegravir, and combinations thereof.

[0214] In some embodiments, the additional therapeutic agent is an HIV entry inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of enfuvirtide, maraviroc, and combinations thereof. Further examples of HIV entry inhibitors include, but are not limited to, cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 adhesion inhibitors, DS-003 (BMS-599793), gp120 inhibitors, and CXCR4 inhibitors. Examples of CCR5 inhibitors include aplaviroc, vicriviroc, maraviroc, cenicriviroc, leronlimab (PRO-140), adaptavir (RAP-101), nifeviroc (TD-0232), anti-GP120 / CD4 or CCR5 bispecific antibodies, B-07, MB-66, polypeptide C25P, TD-0680, and vMIP (Haimipu). Examples of CXCR4 inhibitors include plerixafor, ALT-1188, N15 peptide, and vMIP (Haimipu).

[0215] In some embodiments, the additional therapeutic agent is an HIV nucleoside reverse transcriptase inhibitor. In some embodiments, the additional therapeutic agent is an HIV non-nucleoside reverse transcriptase inhibitor. In some embodiments, the additional therapeutic agent is an acyclic nucleoside phosphonate analog. In some embodiments, the additional therapeutic agent is an HIV capsid inhibitor.

[0216] In some embodiments, the additional therapeutic agent is a nucleoside or nucleotide inhibitor of HIV reverse transcriptase, for example, adefovir, adefovir dipivoxil, azuvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, VIDEX®, and VIDEX®. EC® (didanosine, ddl), abacavir, abacavir sulfate, alovudine, apricitabine, censavudine, didanosine, elvucitabine, festinavir, fosalvudine tidoxyl, CMX-157, dapivirine, doravirine, etravirine, OCR-5753, tenofovir disoproxil orotate, fozivudine tidoxyl, islatravir, lamivudine, phosphazide, stavudine, zalcitabine, zidovudine, lobafovir etalafenamid (GS-9131), GS-9148, MK-8504, MK-8591, MK-858, VM-2500, KP-1461, and combinations thereof.

[0217] In some embodiments, the additional therapeutic agent is a non-nucleoside or non-nucleotide inhibitor of HIV reverse transcriptase, for example, the additional agent is selected from the group consisting of dapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz, etravirine, lentinan, MK-8583, nevirapine, rilpivirine, TMC-278LA, ACC-007, AIC-292, KM-023, PC-1005, elsulfavirine rilp (VM-1500), and combinations thereof.

[0218] In some embodiments, the additional therapeutic agent is ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®, rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF+FT C; DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); Adefovir, adefovir dipivoxil; cobicistat; emtricitabine; tenofovir; tenofovir disoproxil; tenofovir disoproxil fumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate; T RIUMEQ® (dolutegravir, abacavir, and lamivudine); dolutegravir, abacavir sulfate, and lamivudine; raltegravir; raltegravir and lamivudine; maraviroc; enfuvirtide; ALUVIA® (KALETRA®, lopinavir and ritonavir); COMBIVIR® (zidovudine and lamivudine, AZT+3TC); EPZICOM® (LIVEXA®, abacavir sulfate and lamivudine, ABC+3TC); TRIZIVIR® (abacavir sulfate salts, zidovudine, and lamivudine, ABC+AZT+3TC);rilpivirine;rilpivirine hydrochloride;atazanavir sulfate and cobicistat;atazanavir and cobicistat;darunavir and cobicistat;atazanavir;atazanavir sulfate;dolutegravir;elvitegravir;ritonavir;atazanavir sulfate and ritonavir;darunavir;lamivudine;prolastin;fosamprenavir;fosamprenavir calcium efavirenz;etravirine;nelfinavir;nelfinavir mesylate;interferon;didanosine;Selected from stavudine; indinavir; indinavir sulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir; delavirdine; delavirdine mesylate; Radha-108 (Receptor); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovir disoproxil fumarate; phosphazide; lamivudine, nevirapine, and zidovudine; abacavir; and abacavir sulfate.

[0219] In some embodiments, the additional therapeutic agent is selected from the group consisting of colistin, barbicin, icatibant, bepotastine, epirubicin, epoprocetonol, vapreotide, aprepitant, caspofungin, perphenazine, atazanavir, efavirenz, ritonavir, acyclovir, ganciclovir, penciclovir, prulifloxacin, bictegravir, nelfinavir, tegovubi, nelfinavir, praziquantel, pitavastatin, perampanel, eszopiclone, and zopiclone.

[0220] In some embodiments, the additional therapeutic agent is an inhibitor of Bruton's tyrosine kinase (BTK, AGMX1, AT, ATK, BPK, IGHD3, IMD1, PSCTK1, XLA, NCBI Gene ID: 695). For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of (S)-6-amino-9-(1-(but-2-ynoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one, acalabrutinib (ACP-196), BGB-3111, CB988, HM71224, ibrutinib (Imbruvica), M-2951 (evobrutinib), M7583, tirabrutinib (ONO-4059), PRN-1008, spebrutinib (CC-292), TAK-020, becabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, TAS-5315, AZD6738, calquence, dambatricene, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of tirabrutinib, ibrutinib, acalabrutinib, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of tirabrutinib, ibrutinib, and combinations thereof. In some embodiments, the additional therapeutic agent is tyrphostin A9 (A9).

[0221] In some embodiments, the additional therapeutic agent is a KRAS inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of MRTX-849(G12C) and K-Ras(G12D) selective inhibitory peptides, including AMG-510, COTI-219, MRTX-1257, ARS-3248, ARS-853, WDB-178, BI-3406, BI-1701963, ARS-1620(G12C), SML-8-73-1(G12C), compound 3144(G12D), Kobe0065 / 2602(Ras GTP), RT11, KRpep-2(Ac-RRCPLYISYDPVCRR-NH2), KRpep-2d(Ac-RRRRCPLYISYDPVCRRRR-NH2), and combinations thereof.

[0222] In some embodiments, the additional therapeutic agent is a proteasome inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of ixazomib, carfilzomib, marizomib, bortezomib, and combinations thereof. In some embodiments, the additional therapeutic agent is carfilzomib.

[0223] In some embodiments, the additional therapeutic agent is a vaccine. For example, in some embodiments, the additional therapeutic agent is a DNA vaccine, an RNA vaccine, a live attenuated vaccine, a therapeutic vaccine, a prophylactic vaccine, a protein-based vaccine, or a combination thereof. In some embodiments, the additional therapeutic agent is mRNA-1273. In some embodiments, the additional therapeutic agent is INO-4800 or INO-4700. In some embodiments, the additional therapeutic agent is a live attenuated RSV vaccine MEDI-559, a human monoclonal antibody against RSV REGN2222, palivizumab, respiratory syncytial virus immune globulin, intravenous (RSV-IGIV), and combinations thereof. In some embodiments, the additional therapeutic agent is an HBV vaccine, e.g., Pedialix, Angelix-B, and RecombiVax HB. In some embodiments, the additional therapeutic agent is a VZV vaccine, e.g., Zostavix and Varivax. In some embodiments, the additional therapeutic agent is an HPV vaccine, e.g., cervical, Gardasil 9, and Gardasil. In some embodiments, the additional therapeutic agent is an influenza virus vaccine, such as (i) a monovalent influenza A vaccine (e.g., influenza A [H5N1] virus monovalent vaccine and influenza A [H1N1] 2009 virus monovalent vaccine), (ii) a trivalent vaccine for influenza A and B viruses (e.g., Afluria, Agriflu, Flude, Fluarix, Flublock, Flucervax, Flulaval, Fluvirin, and Fluzone), and (iii) a quadrivalent vaccine for influenza A and B viruses (Flumist, Fluarix, Fluzone, and Flulaval). In some embodiments, the additional therapeutic agent is a human adenovirus vaccine (e.g., adenovirus types 4 and 7 vaccine, live, oral). In some embodiments, the additional therapeutic agent is a rotavirus vaccine (e.g., Rotarix for rotavirus serotypes G1, G3, G4, or G9, and RotaTeq for rotavirus serotypes G1, G2, G3, or G4).In some embodiments, the additional therapeutic agent is a Hepatitis A virus vaccine (e.g., Havrix and Vaqta). In some embodiments, the additional therapeutic agent is a poliovirus vaccine (e.g., Kinrix, Quadracel, and Ipol). In some embodiments, the additional therapeutic agent is a Yellow Fever virus vaccine (e.g., YF-Vax). In some embodiments, the additional therapeutic agent is a Japanese Encephalitis virus vaccine (e.g., Ixiaro and JE-Vax). In some embodiments, the additional therapeutic agent is a Measles vaccine (e.g., MMR II and ProQuad). In some embodiments, the additional therapeutic agent is a Mumps vaccine (e.g., MMR II and ProQuad). In some embodiments, the additional therapeutic agent is a Rubella vaccine (e.g., MMR II and ProQuad). In some embodiments, the additional therapeutic agent is a Chickenpox vaccine (e.g., ProQuad). In some embodiments, the additional therapeutic agent is a Rabies vaccine (e.g., Imovax and RabAvert). In some embodiments, the additional therapeutic agent is a variola virus (smallpox) vaccine (ACAM2000). In some embodiments, the additional therapeutic agent is a hepatitis E virus (HEV) vaccine (e.g., HEV239). In some embodiments, the additional therapeutic agent is a 2019-nCov vaccine.

[0224] In some embodiments, the additional therapeutic agent is an antibody, e.g., a monoclonal antibody. For example, the additional therapeutic agent is an antibody against 2019-nCov selected from the group consisting of a Regeneron antibody, a Wuxi antibody, a Vir Biotechnology antibody, an antibody targeting the SARS-CoV-2 spike protein, an antibody capable of neutralizing SARS-CoV-2 (SARS-CoV-2 neutralizing antibody), and combinations thereof. In some embodiments, the additional therapeutic agent is the anti-SARS-CoV antibody CR-3022. In some embodiments, the additional therapeutic agent is an aPD-1 antibody.

[0225] In some embodiments, the additional therapeutic agent is a recombinant cytokine gene-derived protein injection.

[0226] In some embodiments, the additional therapeutic agent is a polymerase inhibitor. In some embodiments, the additional therapeutic agent is a DNA polymerase inhibitor. For example, in some embodiments, the additional therapeutic agent is cidofovir. In some embodiments, the additional therapeutic agent is an RNA polymerase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of ribavirin, favipiravir, lamivudine, pimodivir, and combinations thereof.

[0227] In some embodiments, the additional therapeutic agent is selected from the group consisting of lopinavir, ritonavir, interferon-alpha-2b, ritonavir, arbidol, hydroxychloroquine, darunavir and cobicistat, abidol hydrochloride, oseltamivir, ritonavir, emtricitabine, tenofovir alafenamide fumarate, baloxavir marboxil, ruxolitinib, and combinations thereof.

[0228] In some embodiments, the additional therapeutic agent is a 6'-fluorinated aristemicin analog, an acyclovir fleximer analog, disulfiram, a thiopurine analog, ASC09F, GC376, GC813, a phenylisoserine derivative, a neuroimidase inhibitor analog, a pyrithiobac derivative, a bananine and a 5-hydroxychromone derivative, SSYA10-001, a griffithsin, a HR2P-M1, a HR2P-M2, a P21S10, a dihydrotanshinone E-64-C and a E-64-D, an OC43-HR2P, a MERS-5HB, a 229E-HR1P, a 229E-HR2P, a resveratrol, rol, 1-thia-4-azaspiro[4.5]decan-3-one derivatives, gemcitabine hydrochloride, loperamide, recombinant interferon, cyclosporin A, alisporivir, imatinib mesylate, dasatinib, selumetinib, trametinib, rapamycin, saracatinib, chlorpromazine, triflupromazine, fluphenazine, thiethylperazine, promethazine, cyclophilin inhibitors, K11777, camostat, k22, teicoplanin derivatives, benzoheterocyclic amine derivative N30, mycophenolic acid, silvestrol, and combinations thereof.

[0229] In some embodiments, the additional therapeutic agent is an antibody. In some embodiments, the additional therapeutic agent is an antibody that binds to a coronavirus, e.g., an antibody that binds to SARS-CoV or MERS-CoV. In some embodiments, the additional therapeutic agent is a viral antibody for 2019-nCoV.

[0230] The compositions of the present invention are also used in combination with other active ingredients. For the treatment of 2019-nCoV viral infection, preferably the other active therapeutic agent is active against coronavirus infection, e.g., 2019-nCoV viral infection. The compounds and compositions of the present invention may also be used in combination with parenteral fluids (including dextrose saline and lactated Ringer's solution) and nutrients, antibiotics (including metronidazole and cephalosporin antibiotics such as ceftriaxone and cefuroxime) and / or antifungal prophylaxis, fever and analgesics, antiemetics (such as metoclopramide) and / or antidiarrheal medications, vitamin and mineral supplements (including vitamin K and zinc sulfate), anti-inflammatory agents (such as ibuprofen or steroids), corticosteroids such as methylprednisolone, immunomodulatory agents (e.g., interferons), other small molecule or biological antivirals targeting 2019-nCoV. The additional therapeutic agent is intended for use with the general care provided to patients with 2019-nCoV virus infection, including drugs (such as, but not limited to, lopinavir / ritonavir, EIDD-1931, favipiravir, ribavirin, neutralizing antibodies), vaccines, analgesics, and drugs for other common illnesses in the patient population, such as antimalarials (including artemether and artemether-lumefantrine combination therapy), typhoid (quinolone antibiotics such as ciprofloxacin, macrolide antibiotics such as azithromycin, cephalosporin antibiotics such as ceftriaxone, or aminopenicillins such as ampicillin), or shigellosis. In some embodiments, the additional therapeutic agent is dihydroartemisinin / piperaquine. In some embodiments, the additional therapeutic agent is EIDD-2801 (MH-4482, molnupiravir).

[0231] In some embodiments, the additional therapeutic agent is an immune modulator. Examples of immune system therapies include toll-like receptor modulators, such as tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12, and tlr13, programmed cell death protein 1 (Pd-1) modulators, programmed death-ligand 1 (Pd-L1) modulators, IL-15 modulators, DermaVir, interleukin-7, Plaquenil (hydroxychloroquine), Proleukin (aldesleukin, IL-2), interferon alpha, interferon alpha-2b, interferon alpha-n3, pegylated interferon alpha, interferon gamma, hydroxyurea, mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MPA), ... mofetil, MMF), ribavirin, polymer polyethyleneimine (PEI), gepon, IL-12, WF-10, VGV-1, MOR-22, BMS-936559, CYT-107, interleukin-15 / Fc fusion protein, AM-0015, ALT-803, NIZ-985, NKTR-255, NKTR-262, NKTR-214, normferon, pegylated interferon alpha-2a, pegylated interferon alpha-2b, recombinant interleukin-15, Xmab-24306, RPI-MN, STING modulators, RIG-I modulators, NOD2 modulators, SB-9200, and IR-103. In some embodiments, the additional therapeutic agent is fingolimod, leflunomide, or a combination thereof. In some embodiments, the additional therapeutic agent is thalidomide.

[0232] In some embodiments, the additional therapeutic agent is an IL-6 inhibitor, e.g., tocilizumab, sarilumab, or a combination thereof.

[0233] In some embodiments, the additional therapeutic agent is an anti-TNF inhibitor, e.g., the additional therapeutic agent is adalimumab, etanercept, golimumab, infliximab, or a combination thereof.

[0234] In some embodiments, the additional therapeutic agent is a JAK inhibitor, for example, the additional therapeutic agent is baricitinib, filgotinib, Olumiant, or a combination thereof.

[0235] In some embodiments, the additional therapeutic agent is an inflammation inhibitor, e.g., pirfenidone.

[0236] In some embodiments, the additional therapeutic agent is an antibiotic for secondary bacterial pneumonia, for example, the additional therapeutic agent is a macrolide antibiotic (e.g., azithromycin, clarithromycin, and mycoplasma pneumonia), a fluoroquinolone (e.g., ciprofloxacin and levofloxacin), a tetracycline (e.g., doxycycline and tetracycline), or a combination thereof.

[0237] In some embodiments, the compounds disclosed herein are used in combination with standard treatments for pneumonia (see, e.g., Pediatric Community Pneumonia Guidelines, CID 2011:53 (October 1)). Treatment of pneumonia generally involves curing the infection and preventing complications. The specific treatment depends on several factors, including the type and severity of the pneumonia, the age, and the overall health of the individual. The options include (i) antibiotics, (ii) cough suppressants, and (iii) antipyretics / pain relievers (e.g., aspirin, ibuprofen (Advil, Motrin IB, etc.), and acetaminophen (Tylenol, etc.)). In some embodiments, the additional therapeutic agent is a bromhexine cough suppressant.

[0238] In some embodiments, the compounds disclosed herein are used in combination with immunoglobulin from cured COVID-19 patients. In some embodiments, the compounds disclosed herein are used in combination with plasma transfusions. In some embodiments, the compounds disclosed herein are used in combination with stem cells.

[0239] In some embodiments, the additional therapeutic agent is a TLR agonist. Examples of TLR agonists include, but are not limited to, vesatolimod (GS-9620), GS-986, IR-103, lefitolimod, tilsotolimod, lintatolimod, DSP-0509, AL-034, G-100, cobitolimod, AST-008, motolimod, GSK-1795091, GSK-2245035, VTX-1463, GS-9688, LHC-165, BDB-001, RG-7854, tellulatorimod, and RO-7020531.

[0240] In some embodiments, the additional therapeutic agent is selected from the group consisting of bortezomib, flurazepam, ponatinib, sorafenib, paramethasone, clocortolone, flucloxacillin, sertindole, crividipine, atorvastatin, cinolazepam, clofazimine, fosaprepitant, and combinations thereof.

[0241] In some embodiments, the additional therapeutic agent is kalimycin, suramin, triazavirine, dipyridamole, bevacizumab, meplasmab, GD31 (Rhizobium), an NLRP inflammasome inhibitor, or an alpha-ketoamine. In some embodiments, the additional therapeutic agent is recombinant human angiotensin-converting enzyme 2 (rhACE2). In some embodiments, the additional therapeutic agent is viral macrophage inflammatory protein (vMIP).

[0242] In some embodiments, the additional therapeutic agent is an anti-viroporin therapeutic agent. For example, the additional therapeutic agent is BIT-314 or BIT-225. In some embodiments, the additional therapeutic agent is a coronavirus E protein inhibitor. For example, the additional therapeutic agent is BIT-009. Further examples of additional therapeutic agents include those described in WO2004112687, WO2006135978, WO2018145148, and WO2009018609.

[0243] In some embodiments, the additional therapeutic or prophylactic agent is molnupiravir, oseltamivir, nilmatreorvir, or ritonavir. In some embodiments, the additional therapeutic or prophylactic agent is ritonavir or cobicistat.

[0244] Any compound of the present invention may also be combined with one or more additional active therapeutic agents in a single dosage form for simultaneous or sequential administration to a patient. The combination therapy may be administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more doses.

[0245] Co-administration of a compound of the invention with one or more other active therapeutic agents generally refers to the simultaneous or sequential administration of a compound of the invention and one or more other active therapeutic agents such that therapeutically effective amounts of both the compound of the invention and the one or more other active therapeutic agents are present in the patient's body.

[0246] Co-administration includes administration of a unit dose of a compound of the invention before or after administration of a unit dose of one or more other active therapeutic agents, e.g., within seconds, minutes, or hours of administration of a compound of the invention. For example, a unit dose of a compound of the invention can be administered first, followed within seconds or minutes by a unit dose of one or more other active therapeutic agents. Alternatively, a unit dose of one or more other therapeutic agents can be administered first, followed within seconds or minutes by a unit dose of a compound of the invention. In some cases, it may be desirable to administer a unit dose of a compound of the invention first, followed several hours (e.g., 1-12 hours) later by a unit dose of one or more other active therapeutic agents. In other cases, it may be desirable to administer a unit dose of one or more other active therapeutic agents first, followed several hours (e.g., 1-12 hours) later by a unit dose of a compound of the invention.

[0247] Combination therapy can provide "synergistic" and "synergistic", i.e., an effect achieved when the active ingredients used together are greater than the sum of the effects resulting from using the compounds separately. Synergistic effects can be achieved when the active ingredients are (1) co-formulated and administered or delivered simultaneously in a combined formulation, (2) delivered alternately or in parallel as separate formulations, or (3) by some other regimen. When delivered in alternation therapy, synergistic effects can be achieved when the compounds are administered or delivered sequentially, for example, by separate tablets, pills, capsules, or different injections in separate syringes. Generally, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, i.e., sequentially, whereas in combination therapy, effective dosages of two or more active ingredients are administered together. A synergistic antiviral effect indicates an antiviral effect that is greater than the expected purely additive effect of the individual compounds of the combination.

[0248] 1. Combination Therapies for the Treatment of Pneumoviridae The compounds provided herein can also be used in combination with other active therapeutic agents.When treating Pneumoviridae virus infection, preferably, the other active therapeutic agent is active against Pneumoviridae virus infection, particularly respiratory syncytial virus infection and / or metapneumovirus infection.Non-limiting examples of these other active therapeutic agents against RSV are ribavirin, palivizumab, motavizumab, RSV-IGIV (RespiGam®), MEDI-557, A-60444 (also known as RSV604), MDT-637, BMS-433771, ALN-RSV0, ALX-0171, and mixtures thereof. Other non-limiting examples of other active therapeutic agents active against respiratory syncytial virus infection include respiratory syncytial virus protein F inhibitors such as AK-0529; RV-521, ALX-0171, JNJ-53718678, BTA-585, and presatovir; RNA polymerase inhibitors such as lumicitabine and ALS-8112; anti-RSV G protein antibodies such as anti-G protein mAb; and viral replication inhibitors such as nitazoxanide.

[0249] In some embodiments, the other active therapeutic agent may be a vaccine for the treatment or prevention of RSV, including, but not limited to, MVA-BN RSV, RSV-F, MEDI-8897, JNJ-64400141, DPX-RSV, SynGEM, GSK-3389245A, GSK-300389-1A, RSV-MEDI δM2-2 vaccine, VRC-RSVRGP084-00VP, Ad35-RSV-FA2, Ad26-RSV-FA2, and RSV fusion glycoprotein subunit vaccine.

[0250] Non-limiting examples of other active therapeutic agents active against metapneumovirus infection include sialidase modulators such as DAS-181, RNA polymerase inhibitors such as ALS-8112; and antibodies for the treatment of metapneumovirus infection, such as EV-046113.

[0251] In some embodiments, the other active therapeutic agent may be a vaccine for the treatment or prevention of metapneumovirus infection, including but not limited to mRNA-1653 and rHMPV-Pa vaccines.

[0252] 2. Combination Therapies for the Treatment of Picornaviridae The compounds provided herein can also be used in combination with other active therapeutic agents.When treating Picornaviridae virus infection, preferably, the other active therapeutic agent is active against Picornaviridae virus infection, particularly against Enterovirus infection.Non-limiting examples of these other active therapeutic agents are capsid binding inhibitors, such as pleconaril, BTA-798 (Vapendavir), and other compounds disclosed by Wu et al. (US Pat. No. 7,078,403) and Watson (US Pat. No. 7,166,604), fusion sialidase proteins such as DAS-181, capsid protein VP1 inhibitors such as VVX-003 and AZN-001, viral protease inhibitors such as CW-33, phosphatidylinositol 4 kinase beta inhibitors such as GSK-480 and GSK-533, and anti-EV71 antibodies.

[0253] In some embodiments, the other active therapeutic agent may be a vaccine for the treatment or prevention of Picornaviridae virus infection, including but not limited to, EV71 vaccine, TAK-021, and EV-D68 adeno-vector-based vaccine.

[0254] 3. Combination therapy for respiratory infections Many of the infections of Pneumoviridae, Picornaviridae, and Coronaviridae viruses are respiratory infections.Therefore, additional active therapeutic agents used to treat respiratory symptoms and sequelae of infections can be used in combination with the compounds provided herein.The additional agents are preferably administered orally or by direct inhalation.For example, other preferred additional therapeutic agents that are combined with the compounds provided herein for the treatment of viral respiratory infections include, but are not limited to, bronchodilators and corticosteroids.

[0255] Glucocorticoids Glucocorticoids, first introduced in 1950 as an asthma therapy (Carryer, Journal of Allergy, 21, 282-287, 1950), remain the most potent and consistently effective therapy for the disease, although their mechanism of action is still not fully understood (Morris, J. Allergy Clin. Immunol., 75(1 Pt)1-13, 1985). Unfortunately, oral glucocorticoid therapy is associated with significant undesirable side effects, such as truncal obesity, hypertension, glaucoma, glucose intolerance, accelerated cataract formation, bone mineral loss, and psychological effects, all of which limit their use as long-term therapeutic agents (Goodman and Gilman, 10th edition, 2001). The solution to the systemic side effects is to deliver steroid drugs directly to the site of inflammation. To reduce the severe adverse effects of oral steroids, inhaled corticosteroids (ICS) have been developed. Non-limiting examples of corticosteroids that may be used in combination with the compounds provided herein are dexamethasone, dexamethasone sodium phosphate, fluorometholone, fluorometholone acetate, loteprednol, loteprednol etabonate, hydrocortisone, prednisolone, fludrocortisone, triamcinolone, triamcinolone acetonide, betamethasone, beclomethasone diproprionate, methylprednisolone, fluocinolone, fluocinolone acetonide, flunisolide, fluocortin-21-butyrate, flumethasone, flumethasone pivalate, budesonide, halobetasol propionate, mometasone furoate, fluticasone, AZD-7594, ciclesonide, or a pharma- ceutically acceptable salt thereof.

[0256] Anti-inflammatory agents Other anti-inflammatory agents that act through anti-inflammatory cascade mechanisms are also useful as additional therapeutic agents combined with the compounds provided herein for the treatment of viral respiratory infections.Applying "anti-inflammatory signaling modulators" (herein referred to as AISTM), such as phosphodiesterase inhibitors (e.g., PDE-4, PDE-5, or PDE-7 specific), transcription factor inhibitors (e.g., blocking NFκB through IKK inhibition), or kinase inhibitors (e.g., P38 MAP, JNK, PI3K, EGFR, or Syk), is a logical approach to stop inflammation, because these small molecules target a limited number of common intracellular pathways, signaling pathways that are the key points of anti-inflammatory therapeutic intervention (see review by PJBarnes, 2006).These additional therapeutic agents include, but are not limited to, 5-(2,4-difluoro-phenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (2-dimethylamino-ethyl)-amide (P38 MAP kinase inhibitor ARRY-797), 3-cyclopropylmethoxy-N-(3,5-dichloro-pyridin-4-yl)-4-difluoromethoxy-benzamide (PDE-4 inhibitor roflumilast), 4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenyl-ethyl]-pyridine (PDE-4 inhibitor CDP-840), N-(3,5-dichloro-4-pyridinyl)-4-(difluoromethoxy)-8-[(methylsulfonyl)amino]-1-dibenzofurancarboxamide (PDE-4 inhibitor oglemilast), N-(3,5-dichloro-pyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxo-acetamide (PDE-4 inhibitor AWD 12-281), 8-Methoxy-2-trifluoromethyl-quinoline-5-carboxylic acid (3,5-dichloro-1-oxy-pyridin-4-yl)-amide (PDE-4 inhibitor Sch 351591), 4-[5-(4-fluorophenyl)-2-(4-methanesulfinyl-phenyl)-1H-imidazol-4-yl]-pyridine (P38 inhibitor SB-203850), 4-[4-(4-fluoro-phenyl)-1-(3-phenyl-propyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-but-3-yn-1-ol (P38 inhibitor RWJ-67657), 4-cyano-4-(3-cyclopentyloxy-4-methoxy-phenyl)-cyclohexane carboxylic acid 2-diethyl 2-Diethyl-ethyl ester prodrug of a PDE-4 inhibitor (cilomilast, a 2-diethyl-ethyl ester prodrug of a PDE-4 inhibitor), (3-chloro-4-fluorophenyl)-[7-methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-yl]-amine (gefinib, an EGFR inhibitor), and 4-(4-methyl-piperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide (imatinib, an EGFR inhibitor).

[0257] β2-adrenergic receptor agonist bronchodilators Combinations including an inhaled β2-adrenergic receptor agonist bronchodilator, such as formoterol, albuterol, or salmeterol, along with a compound provided herein are also suitable, but non-limiting, combinations useful for treating respiratory viral infections.

[0258] Combinations of inhaled β2-adrenergic receptor agonist bronchodilators, such as formoterol or salmeterol, with ICS are also used to treat both bronchial constriction and inflammation (Symbicort® and Advair®, respectively). Combinations including these ICS and β2-adrenergic receptor agonists with the compounds provided herein are also suitable, but not limited to, combinations useful in treating respiratory viral infections.

[0259] Other examples of β2 adrenergic receptor agonists are bedoradrine, vilanterol, indacaterol, olodaterol, tulobuterol, formoterol, avesiterol, salbutamol, arformoterol, levalbuterol, fenoterol, and TD-5471.

[0260] Anticholinergic drugs Anticholinergics may be useful for the treatment or prevention of pulmonary bronchoconstriction and therefore are useful as additional therapeutic agents in combination with the compounds provided herein for the treatment of viral respiratory infections. These anticholinergic drugs include antagonists of muscarinic receptors (especially of the M3 subtype) that have shown therapeutic efficacy in humans for controlling cholinergic tone in COPD (Witek, 1999); 1-{4-hydroxy-1-[3,3,3-tris-(4-fluoro-phenyl)-propionyl]-pyrrolidine-2-carbonyl}-pyrrolidine-2-carboxylic acid (1-methyl-piperidin-4-ylmethyl)-amide, 3-[3-(2-diethylamino-acetoxy)-2-phenyl-propionyloxy]-8-isopropyl-8-methyl-8-azonia-bicyclo[3.2.1]octane (ipratropium-N,N-diethylglycinate), 1-cyclohexyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester (solifenacin). ), 2-hydroxymethyl-4-methanesulfinyl-2-phenyl-butyric acid 1-aza-bicyclo[2.2.2]oct-3-yl ester (revatropate), 2-{1-[2-(2,3-dihydro-benzofuran-5-yl)-ethyl]-pyrrolidin-3-yl}-2,2-diphenyl-acetamide (darifenacin), 4-azepan-1-yl-2,2-diphenyl-butyramide (buzepide), 7-[3-( 2-Diethylamino-acetoxy)-2-phenyl-propionyloxy]-9-ethyl-9-methyl-3-oxa-9-azonia-tricyclo[3.3.1.02,4]nonane (oxitropium-N,N-diethylglycinate), 7-[2-(2-diethylamino-acetoxy)-2,2-di-thiophen-2-yl-acetoxy]-9,9-dimethyl-3-oxa-9-azonia-tricyclo[3.3.1.02,4]nonane (tiotropium-N,N-diethylglycinate), dimethylaminoacetic acid 2-(3-diisopropylamino-1-phenyl-propyl)-4-methyl-phenyl ester (tolterodine-N,N-dimethylglycinate), 3-[4,4-bis-(4-fluoro-phenyl)-2-oxo-imidazolidin-1-yl]-1-methyl-1-(2-oxo-2-pyridin-2-yl-ethyl)-pyrrolidinium, 1-[1-(3-fluoro-benzyl)-piperidin-4-yl]-4,4-bis-(4-fluoro-phenyl)-imidazolidin-2-one, 1-cyclooctyl-3-(3-methoxy-1-aza-bicyclo[2.2.2] oct-3-yl)-1-phenyl-prop-2-yn-1-ol, 3-[2-(2-diethylamino-acetoxy)-2,2-di-thiophen-2-yl-acetoxy]-1-(3-phenoxy-propyl)-1-azonia-bicyclo[2.2.2]octane (acridinium-N,N-diethylglycinate), or (2-diethylamino-acetoxy)-di-thiophen-2-yl-acetic acid 1-methyl-1-(2-phenoxy-ethyl)-piperidin-4-yl ester, rebefenacin, glycopyrronium bromide, umeclidinium bromide, tiotropium bromide, acridinium bromide, bencycloquidium bromide, but are not limited thereto.

[0261] Mucolytic agents The compounds provided herein can also be combined with mucolytic agents to treat both infection and symptoms of respiratory infection.A non-limiting example of a mucolytic agent is ambroxol.Similarly, the compounds can be combined with expectorants to treat both infection and symptoms of respiratory infection.A non-limiting example of an expectorant is guaifenesin.

[0262] Nebulized hypertonic saline is used to improve the immediate and long-term clearance of small airways in patients with pulmonary disease (Kuzik, J. Pediatrics 2007,266). Thus, the compounds provided herein can also be combined with nebulized hypertonic saline, especially when viral infections are coexisting with bronchiolitis. The combination of the compounds provided herein with hypertonic saline can also include any of the additional agents discussed above. In one embodiment, about 3% nebulized hypertonic saline is used.

[0263] 4. Combination Therapy for the Treatment of Flaviviridae Infections The compounds and compositions provided herein are also used in combination with other active therapeutic agents. In the case of the treatment of Flaviviridae viral infections, preferably the other active therapeutic agent is active against Flaviviridae viral infections.

[0264] For the treatment of Dengue virus infection, non-limiting examples of other active therapeutic agents are host cell factor modulators such as GBV-006; alpha-glucosidase 1 inhibitors such as fenretinide ABX-220, BRM-211, celgosivir, platelet activating factor receptor (PAFR) antagonists such as modipafant, cadherin-5 / factor Ia modulators such as FX-06, NS4B inhibitors, e.g., JNJ-8359, viral RNA splicing modulators such as ABX-202, NS5 polymerase inhibitors, NS3 protease inhibitors, and TLR modulators.

[0265] In some embodiments, the other active therapeutic agent may be a vaccine for the treatment or prevention of dengue fever, including, but not limited to, TetraVax-DV, Dengvaxia®, DPIV-001, TAK-003, live attenuated dengue vaccine, tetravalent dengue vaccine, tetravalent DNA vaccine, rDEN2δ30-7169; and DENV-1 PIV.

[0266] 5. Combination Therapy for the Treatment of Filoviridae Infections The compounds provided herein may also be used in combination with other active therapeutic agents. In the case of treatment of Filoviridae virus infections, preferably the other active therapeutic agent is active against Filoviridae virus infections, particularly Marburg virus infections, Ebola virus infections, and Cueva virus infections. Non-limiting examples of these other active therapeutic agents include ribavirin, amiodarone, dronedarone, verapamil, Ebola Convalescent Plasma, and cyclosporine. Plasma, ECP), TKM-100201, BCX4430 ((2S,3S,4R,5R)-2-(4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-5-(hydroxymethyl)pyrrolidine-3,4-diol), TKM-Ebola, T-705 monophosphate, T-705 diphosphate, T-705 triphosphate, FGI-106 (1-N,7-N-bis[3-(dimethylamino)propyl]-3,9-dimethylquinolino[8,7-h] quinolone-1,7-diamines), rNAPc2, OS-2966, brincidofovir, remdesivir, galidesivir, favipiravir (also known as T-705 or Avigan), RNA polymerase inhibitors such as JK-05, host cell factor modulators such as GMV-006, cadherin-5 / factor Ia modulators such as FX-06; and antibodies for the treatment of Ebola such as REGN-3470-3471-3479 and ZMapp.

[0267] Other non-limiting active therapeutic agents active against Ebola include alpha-glucosidase 1 inhibitors, cathepsin B inhibitors, CD29 antagonists, dendritic ICAM-3 binding nonintegrin 1 inhibitors, estrogen receptor antagonists, factor VII antagonists HLA class II antigen modulators, host cell factor modulators, interferon alpha ligands, neutral alpha glucosidase AB inhibitors, Niemann-Pick C1 protein inhibitors, nucleoprotein inhibitors, polymerase cofactor VP35 inhibitors, serine protease inhibitors, tissue factor inhibitors, TLR-3 agonists, viral envelope glycoprotein inhibitors, and Ebola virus entry inhibitors (NPC1 inhibitors).

[0268] In some embodiments, the other active therapeutic agent may be a vaccine for the treatment or prevention of Ebola, including, but not limited to, VRC-EBOADC076-00-VP, adenovirus-based Ebola vaccine, rVSV-EBOV, rVSVN4CT1-EBOVGP, MVA-BN Filo+Ad26-ZEBOV regimen, INO-4212, VRC-EBODNA023-00-VP, VRC-EBOADC069-00-VP, GamEvac-combi vaccine, SRC VB vector, HPIV3 / EboGP vaccine, MVA-EBOZ, Ebola recombinant glycoprotein vaccine, Vaxart adenovirus vector 5-based Ebola vaccine, FiloVax vaccine, GOVX-E301, and GOVX-E302.

[0269] The compounds provided herein can also be used in combination with phosphoramidate morpholino oligomers (PMOs), which are synthetic antisense oligonucleotide analogues designed to interfere with the translation process by forming base-pair duplexes with specific RNA sequences.Examples of PMOs include, but are not limited to, AVI-7287, AVI-7288, AVI-7537, AVI-7539, AVI-6002 and AVI-6003.

[0270] The compounds provided herein are also intended for use in combination with the general care provided to patients with Filoviridae virus infections, including parenteral fluids (including dextrose saline and lactated Ringer's solution) and nutrients, antibiotics (including metronidazole and cephalosporin antibiotics such as ceftriaxone and cefuroxime) and / or antifungal prophylaxis, antipyretics and analgesics, antiemetics (such as metoclopramide) and / or antidiarrheal medications, vitamin and mineral supplements (including vitamin K and zinc sulfate), anti-inflammatories (such as ibuprofen), analgesics, and antimalarials (including artemether and artesunate-lumefantrine combination therapy), typhoid (including quinolone antibiotics such as ciprofloxacin, macrolide antibiotics such as azithromycin, cephalosporin antibiotics such as ceftriaxone, or aminopenicillins such as ampicillin), or medications for other common illnesses in the patient population, such as shigellosis.

[0271] The present invention will be described in more detail by specific examples. The following examples are provided for illustrative purposes and are not intended to limit the present invention in any manner. Those skilled in the art will easily recognize various non-critical parameters that can be changed or modified to produce essentially the same results. EXAMPLES

[0272] X. Example Example 1: Synthesis of intermediate 2 [ka] To a solution of (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile, intermediate 1 (2000 mg, 6.0 mmol) (Siegel et.al. J. Med. Chem. 2017,60,1648-1661) in tetrahydrofuran (THF), N,N-dimethylaminopyridine (DMAP) (0.03 equiv.) was added. Isobutyric anhydride (1.1 equiv.) was slowly added to the reaction mixture. After completion of the starting material, the reaction mixture was concentrated and purified by flash chromatography using 20% ​​methanol in DCM as eluent to give ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl isobutyrate, intermediate 1a. LCMS: MS m / z: 402.2 (M+1).

[0273] Concentrated HCl (5 eq, 1 mL) was added to a solution of intermediate 1a (1000 mg) in acetonitrile (10 mL), which was then stirred at room temperature for 2 h. LCMS showed the formation of the product. After 4 h, the reaction was stopped. The reaction mixture was diluted with ethyl acetate and quenched with bicarbonate. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography using 30% methanol DCM as eluent. The collected fractions were concentrated to give intermediate 2. 1 H NMR (400MHz, methanol-d4) δ7.88(s,1H),6.96-6.85(m,2H),4.50-4.27(m,4H),4.16( dd,J=6.2,5.3Hz,1H),2.56(p,J=7.0Hz,1H),1.14(dd,J=7.0,3.8Hz,6H);LCMS:MS m / z:362.1(M+1).

[0274] Example 2: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2-oxotetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl isobutyrate (compound 3) [ka] Diphenyl carbonate (1423 mg, 6.6 mmol) and triethylamine (560 mg, 5.5 mmol) were added to a solution of intermediate 2 (2000 mg, 5.5 mmol) in DMF (5 mL) and then heated at 130° C. and stirred for 2 h. LCMS showed complete conversion to the product. The reaction mixture was diluted with ethyl acetate, washed with bicarbonate, water, brine, dried over sodium sulfate, concentrated, and purified by flash chromatography using dichloromethane and ethyl acetate as eluents to give compound 3. 1 H NMR(400MHz,DMSO-d6)δ7.98(s,2H),6.98-6.87(m,2H),5.99(d,J=7.7Hz,1H),5.49(dd,J=7.6,3.7Hz,1H),4.81(q,J=4.2Hz, 1H),4.34(dd,J=12.2,4.0Hz,1H),4.23(dd,J=12.2,5.2Hz,1H),2.44(p,J=7.0Hz,1H),1.00(dd,J=13.3,7.0Hz,6H);LCMS:MS m / z:388.1(M+1).

[0275] Example 3: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2-methoxytetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl isobutyrate (compound 4) [ka] To a solution of intermediate 2 (250 mg, 0.67 mmol) in dichloromethane (10 mL), trimethyl orthoformate (220 mg, 2.1 mmol) was added followed by pyridinium p-toluenesulfonate (174 mg, 0.7 mmol) and the reaction mixture was stirred at room temperature for 18 hours. After completion of the starting material, the reaction mixture was diluted with dichloromethane (50 mL), washed with saturated sodium bicarbonate solution, water, brine, dried and concentrated. The residue was purified by slash chromatography using DCM / ethyl acetate as eluent to give compound 4. 1 H NMR (400 MHz, chloroform-d) δ 7.98 (s, 1H), 7.04 (d, J = 4.6 Hz, 1H), 6.65 (d, J = 4.6 Hz, 1H), 6.07 (s, 1H), 5.67 (s, 2H), 5.37 (d, J = 7.2 Hz, 1H), 5.05 (dd, J = 7.2, 6.2 Hz, 1H), 4.82 (td, J = 6.1 ,4.3Hz,1H),4.45(dd,J=11.9,4.4Hz,1H),4.28(dd,J=11.9,6.1Hz,1H),3.70(d,J=0.7H z,1H),3.57(d,J=0.7Hz,3H),2.57(p,J=7.0Hz,1H),1.16(dd,J=7.0,1.0Hz,6H);LCMS:MS m / z:404.1

[0276] Example 4: ((2R,3S,4R,5R)-5-(3-((((benzyloxy)(hydroxy)phosphoryl)oxy)methyl)-4-imino-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl isobutyrate (compound 5) [ka] Dibenzyl chloromethyl phosphate (1805 mg, 5.5 mmol) in acetone (5 mL) was slowly added to a solution of intermediate 2 (1000 mg, 2.8 mmol) and sodium iodide (830 mg, 5.5 mmol) in acetone (20 mL), which was then stirred at room temperature for 48 hours. After completion of the reaction, the solvent was evaporated and the residue was loaded onto a flash column and eluted with dichloromethane and methanol as eluents to give compound 5. 1 H NMR(400MHz,DMSO-d6)δ10.53(s,1H),8.52(s,1H),7.49(d,J=4.7Hz,1H),7. 34-7.17(m,5H),7.01(d,J=4.7Hz,1H),5.69(d,J=11.2Hz,2H),4.80(d,J=7.1 Hz,2H),4.58(d,J=4.8Hz,1H),4.36-4.24(m,2H),4.18(dd,J=13.0,5.9Hz,1 H),3.93(dd,J=6.5,4.8Hz,1H),2.56(d,J=7.0Hz,1H),1.06(d,J=7.0Hz,6H), 31P NMR (162MHz, DMSO-d6) δ 0.02; 19F NMR(376 MHz,DMSO-d6)δ-74.94;LCMS:MS m / z:562.2(M+1)

[0277] Example 5: ((2R,3S,4R,5R)-5-cyano-3,4-dihydroxy-5-(4-imino-3-((phosphonooxy)methyl)-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-2-yl)methyl isobutyrate (compound 6) [ka] To a solution of compound 5 (600 mg, 1.1 mmol) in ethanol was added 5% palladium on carbon (30 mg). The resulting mixture was stirred under a hydrogen balloon for 48 hours. The reaction was quenched. The mixture was filtered and washed with ethyl acetate. The reaction was concentrated to give a residue. The residue was purified by preparative HPLC using 0.1% trifluoroacetate (TFA) in acetonitrile and 0.1% TFA in water as eluents to give compound 6 as a TFA salt. 1 H NMR(400MHz,DMSO-d6)δ10.56(s,1H),8.52(s,1H),7.53(d,J=4.7Hz,1H),7.02(d,J=4.7Hz,1H),5.74(d,J=11.6Hz,2H),4.59(d,J=4.9H) z,1H),4.36-4.24(m,2H),4.17(dd,J=12.9,5.7Hz,1H),3.93(dd,J=6.4,4.8Hz,1H),2.56(d,J=7.0Hz,1H),1.06(dd,J=6.9,0.8Hz,5H); 31P NMR (162MHz, DMSO-d6) δ-0.12; 19 F NMR(376MHz,DMSO-d6)δ-74.47;LCMS:MS m / z:472.1(M+1)

[0278] Example 6: (2R,3R,4R,5R)-2-(4-acetamidopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-(acetoxymethyl)-2-cyanotetrahydrofuran-3,4-diyl diacetate (compound 7) [ka] To a suspension of (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile (100 mg, 3.4 mmol) and DMAP (419 mg, 3.4 mmol) in anhydrous dimethylformamide (DMF) (5 mL), acetic anhydride (2804 mg, 27 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 30 minutes. After completion of the starting material, the reaction mixture was concentrated under high vacuum to remove DMF. The resulting residue was dissolved in ethyl acetate (200 mL) and washed with saturated NaHCO 3 (75 mL x 3), dried, concentrated in vacuo, and purified by flash chromatography using hexane and ethyl acetate as eluents to isolate intermediate 7a and compound 7. Intermediate 7a: LCMS: MS m / z: 418.1 (M+1). Compound 7: 1 H NMR (400MHz, methanol-d4) δ8.28(s,1H),7.27(d,J=4.8Hz,1H),7.12(d,J=4.8Hz,1H),6.25(d,J=5.8Hz,1H),5.53-5.46(m,1H),4.66(td,J= LCMS:MS m / z:460.1(M+1)

[0279] Example 7: (2R,3R,4R,5R)-5-(acetoxymethyl)-2-(4-butylamidopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyanotetrahydrofuran-3,4-diyl diacetate (compound 8) [ka] To a solution of intermediate 7a (600 mg, 1.4 mmol) in DMF (5 mL) was added butanoic acid (253 mg, 2.9 mmol). To this solution, N,N'-diisopropylcarbodiimide (218 mg, 1.7 mmol) was slowly added at room temperature followed by DMAP (176 mg, 1.4 mmol) and stirred for 18 h. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water and brine, dried and concentrated. The resulting residue was purified by flash chromatography using 20% ​​methanol in DCM as eluent to give compound 8. 1 H NMR(400MHz,DMSO-d6)δ10.95(s,1H),8.42(s,1H),7.31(d,J=4.8Hz,1H),7.05(d,J=4. 8Hz,1H),6.06(d,J=5.9Hz,1H),5.40(dd,J=5.9,4.6Hz,1H),4.63(td,J=4.7,3.2Hz,1H ),4.38(dd,J=12.4,3.3Hz,1H),4.24(dd,J=12.4,4.8Hz,1H),2.70(t,J=7.2Hz,2H),2. 12(d,J=3.6Hz,6H),1.99(s,3H),1.64(h,J=7.4Hz,2H),0.94(t,J=7.4Hz,3H);LCMS:MS m / z:488.1(M+1)

[0280] Example 8: ((2R,3S,4R,5R)-5-(4-butylamidopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl isobutyrate (compound 9) [ka] To a mixture of intermediate 1a (1100 mg, 2.74 mmol) and butyric acid (0.654 mL, 7.12 mmol) in acetonitrile (CAN) (10 mL) was added DMAP (870 mg, 7.12 mmol) followed by 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (1370 mg, 7.12 mmol) at room temperature. The resulting mixture was stirred at room temperature for 15 h, quenched with MeOH, concentrated in vacuo, and purified by silica gel column chromatography (0-70% EtOAc in hexanes) to give intermediate 9a. LCMS: MS m / z: 472 (M+1).

[0281] To a solution of intermediate 9a (1200 mg, 2.55 mmol) in ACN (15 mL) was added concentrated HCl (12 mL) at room temperature. The mixture was stirred at room temperature for 1 h, diluted with ethyl acetate (100 mL) and neutralized with saturated sodium bicarbonate (30 mL). The resulting mixture was stirred at room temperature for 5 min. The phases were separated and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layers were dried under sodium sulfate, concentrated in vacuo and purified by flash chromatography using dichloromethane and methanol as eluents to give compound 9. 1 H NMR(400MHz,DMSO-d6)δ10.89(s,1H),8.40(s,1H),7.29(d,J=4.8Hz,1H),7.06(d,J=4.8 Hz,1H),6.43(d,J=6.0Hz,1H),5.44(d,J=5.9Hz,1H),4.69(t,J=5.4Hz,1H),4.36-4.25( m,2H),4.19(dd,J=11.5,4.4Hz,1H),3.97(q,J=5.8Hz,1H),2.70(t,J=7.3Hz,2H),2.50( m,1H),1.65(h,J=7.3Hz,2H),1.05(dd,J=7.0,3.5Hz,6H),0.94(t,J=7.4Hz,3H);LCMS:MS m / z:432(M+1)

[0282] Example 9: ((2R,3S,4R,5R)-5-cyano-5-(4-hexanamidopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl isobutyrate (compound 10) [ka] To a mixture of intermediate 1a (150 mg, 0.374 mmol) and hexanoic acid (0.121 mL, 0.972 mmol) in ACN (2 mL) was added DMAP (119 mg, 0.972 mmol) followed by EDCI (186 mg, 0.972 mmol) at room temperature. The resulting mixture was stirred at room temperature for 15 h, quenched with MeOH, concentrated in vacuo, and purified by silica gel column chromatography (0-5% MeOH in DCM) to give intermediate 10a. LCMS: MS m / z: 500.2 (M+1)

[0283] To a solution of intermediate 10a (160 mg, 0.32 mmol) in ACN (2 mL) was added concentrated HCl (0.16 mL) at room temperature. The mixture was stirred at room temperature for 1 h, neutralized with triethanolamine (TEA) (0.4 mL) in a water bath, and purified by HPLC (10% to 100% ACN in water for 15 min, then 100% ACN for 3 min, total run 20 min) to give compound 10. 1 H NMR(400MHz,DMSO-d6)δ10.89(s,1H),8.40(s,1H),7.29(d,J=4.8Hz,1H),7.06(d,J=4.7Hz,1H), 6.43(d,J=6.1Hz,1H),5.44(d,J=5.9Hz,1H),4.68(t,J=5.5Hz,1H),4.38-4.24(m,2H),4.18(dd,J =11.6,4.5Hz,1H),3.96(q,J=5.8Hz,1H),2.71(t,J=7.4Hz,2H),2.51(m,1H),1.62(td,J=12.2,9. 7,5.1Hz,2H),1.32(h,J=4.7,3.9Hz,4H),1.05(dd,J=7.0,3.6Hz,6H),0.93-0.83(m,3H);LCMS:MS m / z:460.3(M+1)

[0284] Example 10: ((2R,3S,4R,5R)-5-cyano-3,4-dihydroxy-5-(4-octanamidopyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-2-yl)methyl isobutyrate (compound 11) [ka] To a mixture of intermediate 1a (1100 mg, 2.74 mmol) and butyric acid (0.654 mL, 7.12 mmol) in ACN (10 mL) was added DMAP (870 mg, 7.12 mmol) followed by EDCI (1370 mg, 7.12 mmol) at room temperature. The resulting mixture was stirred at room temperature for 15 h, quenched with MeOH, concentrated under vacuum and purified by silica gel column chromatography (0-5% MeOH in DCM) to give intermediate 11a. LCMS: MS m / z: 528.2 (M+1)

[0285] To a solution of intermediate 11a (90 mg, 0.171 mmol) in ACN (1 mL) was added concentrated HCl (0.10 mL) at room temperature. The mixture was stirred at room temperature for 1 h, neutralized with TEA (0.4 mL) in a water bath, and purified by HPLC (10% to 100% ACN in water for 15 min, then 100% ACN for 3 min, total run 20 min) to give compound 11. 1 H NMR(400MHz,DMSO-d6)δ10.89(s,1H),8.40(s,1H),7.28(d,J=4.7Hz,1H),7.06(d,J=4.7 Hz,1H),6.43(d,J=6.0Hz,1H),5.44(d,J=5.9Hz,1H),4.68(t,J=5.4Hz,1H),4.36-4.23( m,2H),4.23(s,0H),3.96(q,J=5.5Hz,1H),2.71(t,J=7.4Hz,2H),2.51(m,1H),1.62(t,J =7.3Hz,2H), 1.39-1.21(m,8H),1.05(dd,J=7.0,3.7Hz,6H),0.92-0.78(m,3H) m / z:488.2(M+1)

[0286] Example A: HEp-2 RSV-Luc5 384-well assay The HEp-2 cell line was purchased from ATCC (Manassas, VA, catalog number CCL-23) and maintained in Dulbecco's Minimum Essential Medium (DMEM) (Corning, New York, NY, catalog number 15-018CM) supplemented with 10% fetal bovine serum (FBS) (Hyclone, Logan, UT, catalog number SH30071-03) and 1x penicillin-streptomycin-L-glutamine (Corning, New York, NY, catalog number 30-009-CI). Cells were passaged twice weekly to maintain subconfluent density and used for experiments at passages 5–20. Respiratory syncytial virus recombinant for luciferase (RSV-Luc5) (≥1×107, TCID50 / ml) was purchased from Microbiologics (Saint Cloud, MN). Viral replication was determined in HEp-2 cells in the following manner.

[0287] Compounds are prepared in 100% DMSO in 384-well polypropylene plates (Greiner, Monroe, NC, Cat. No. 784201) with eight compounds per plate with four replicates grouped in 10 serially diluted concentrations (1:3). Serially diluted compounds are transferred to low dead volume Echo plates (Labcyte, Sunnyvale, CA, Cat. No. LP-0200).

[0288] Test compounds were spotted onto 384-well assay plates (Greiner, Monroe, NC, Cat. No. 781091) at 200 nL / well. HEp-2 cells were harvested, suspended in DMEM (supplemented with 10% FBS and 1x Penicillin-Streptomycin-L-Glutamine) and seeded into pre-spotted assay plates at 4,000 cells per well in 30 μL. RSV-Luc5 virus was diluted at 200,000 infectious units (IU) / mL in DMEM (supplemented with 10% FBS and 1x Penicillin-Streptomycin-L-Glutamine) and 10 μL / well was added to the assay plates containing cells and compounds to give an MOI=0.5. The assay plates were incubated at 37°C and 5% CO. 2 The plates were incubated at 4°C for 3 days. At the end of the incubation, One-Glo reagent (Promega, Madison, WI, Cat. No. E6120) was prepared. The assay plate and One-Glo reagent were equilibrated at room temperature for at least 15 minutes. 40 μL / well of One-Glo reagent was added and the plate was incubated at room temperature for 15 minutes before reading the luminescence signal on an EnVision multimode plate reader (Perkin Elmer, Waltham, MA). Remdesivir was used as a positive control and DMSO was used as a negative control. Values ​​were normalized to the positive and negative controls (as 0% and 100% replicates, respectively) and the data was fitted using nonlinear regression analysis by Gilead's dose-response tool. The EC 50 Values ​​were determined as the concentration that reduced viral replication by 50%.

[0289] Example B: A549-hACE2 SARS-CoV2-NLuc 384-well assay The A549-hACE2 cell line was maintained in Dulbecco's Minimum Essential Medium (DMEM) (Corning, New York, NY, catalog number 15-018CM) supplemented with 10% fetal bovine serum (FBS) (Hyclone, Logan, UT, catalog number SH30071-03), 1x penicillin-streptomycin-L-glutamine (Corning, New York, NY, catalog number 30-009-CI), and 10 μg / mL blasticidin (Life Technologies Corporation, Carlsbad, CA, catalog number A11139-03). Cells were passaged twice a week to maintain subconfluent density and used for experiments at passages 5–20. SARS-coronavirus 2 recombinant with NanoLuc (SARS-CoV2-NLuc) was obtained from the University of Texas Medical Branch (Galveston, TX). Viral replication was determined in A549-hACE2 cells in the following manner.

[0290] Compounds are prepared in 100% DMSO in 384-well polypropylene plates (Greiner, Monroe, NC, Cat. No. 784201) with eight compounds per plate with four replicates grouped in 10 serially diluted concentrations (1:3). Serially diluted compounds are transferred to low dead volume Echo plates (Labcyte, Sunnyvale, CA, Cat. No. LP-0200).

[0291] Test compounds were spotted at 200 nL / well onto 384-well assay plates (Greiner, Monroe, NC, Cat. No. 781091) using an Echo acoustic dispenser (Labcyte, Sunnyvale, CA). A549-hACE2 cells were harvested, suspended in DMEM (supplemented with 2% FBS and 1x Penicillin-Streptomycin-L-Glutamine) and seeded into pre-spotted assay plates at 10,000 cells / well in 30 μL. SARS-CoV2-NLuc virus was diluted at 350,000 infectious units (IU) / mL in DMEM (supplemented with 2% FBS and 1x Penicillin-Streptomycin-L-Glutamine) and 10 μL / well was added to the assay plates containing cells and compounds for an MOI of 0.35. The assay plates were incubated at 37°C and 5% CO. 2 The plates were incubated at 4°C for 2 days. At the end of the incubation, Nano-Glo reagent (Promega, Madison, WI, Cat. No. N1150) was prepared. The assay plates and Nano-Glo reagent were equilibrated at room temperature for at least 15 minutes. 40 μL / well of Nano-Glo reagent was added and the plates were incubated at room temperature for 15 minutes before reading the luminescence signal on an EnVision multimode plate reader (Perkin Elmer, Waltham, MA). Remdesivir was used as a positive control and DMSO was used as a negative control. Values ​​were normalized to the positive and negative controls (as 0% and 100% replicates, respectively) and the data was fitted using nonlinear regression analysis by Gilead's dose-response tool. The EC 50 Values ​​were defined as the concentration that reduced viral replication by 50%.

[0292] Example C: NHBE RSV-Luc5 384-well assay Normal Human Bronchial Epithelial (NHBE) cells were purchased from Lonza (Walkersville, MD catalog number CC2540) and maintained in BEGM Bronchial Epithelial Cell Growth Medium BulletKit (Lonza CC-3170).

[0293] Cells were thawed, expanded, and used for experiments at passage 2. Respiratory syncytial virus recombinant carrying luciferase (RSV-Luc5) (TCID 50 Determined by >1×10 7 Infectious Units / ml (IU / ml) were purchased from Microbiologics (Saint Cloud, Minn.) Viral replication was determined in NHBE cells in the following manner.

[0294] Compounds are prepared in 100% DMSO in 384-well polypropylene plates (Greiner, Monroe, NC, Cat. No. 784201) with eight compounds per plate with four replicates grouped in 10 serially diluted concentrations (1:3). Serially diluted compounds are transferred to low dead volume Echo plates (Labcyte, Sunnyvale, CA, Cat. No. LP-0200).

[0295] Test compounds were spotted onto 384-well assay plates (Greiner, Monroe, NC, Catalog #781091) at 200 nL / well. NHBE cells were harvested, suspended in BEGM Bronchial Epithelial Cell Growth Medium BulletKit, and seeded into pre-spotted assay plates at 5,000 cells / well in 30 μL. RSV-Luc5 virus was diluted at 500,000 infectious units (IU) / mL in BEGM Bronchial Epithelial Cell Growth Medium BulletKit and 10 μL / well was added to the assay plates containing cells and compound to give an MOI of 1. Assay plates were incubated at 37°C and 5% CO. 2 The plates were incubated at 4°C for 3 days. At the end of the incubation, One-Glo reagent (Promega, Madison, WI, Cat. No. E6120) was prepared. The assay plate and One-Glo reagent were equilibrated at room temperature for at least 15 minutes. 40 μL / well of One-Glo reagent was added and the plate was incubated at room temperature for 15 minutes before reading the luminescence signal on an EnVision multimode plate reader (Perkin Elmer, Waltham, MA). Remdesivir was used as a positive control and DMSO was used as a negative control. Values ​​were normalized to the positive and negative controls (as 0% and 100% replicates, respectively) and the data was fitted using nonlinear regression analysis by Gilead's dose-response tool. The EC 50 Values ​​were defined as the concentration that reduced viral replication by 50%.

[0296] Example D: CC50 MT4 Cytotoxicity of compounds was determined in uninfected cells using cell viability reagents in a manner similar to that previously described for other cell types (Cihlar et al., Antimicrob Agents Chemother. 2008, 52(2):655-65). HEp-2 (1.5×103 cells / well) and MT-4 (2×103 cells / well) cells were seeded in 384-well plates and incubated with appropriate media containing 3-fold serially diluted compounds ranging from 15 nM to 100,000 nM. Cells were cultured at 37°C for 4-5 days. After incubation, cells were equilibrated to 25°C and cell viability was determined by adding Cell-Titer Glo viability reagent. The mixture was incubated for 10 min and luminescence signal was quantified using an Envision plate reader. Untreated cells and cells treated with 2 μM puromycin (Sigma, St. Louis, MO) served as 100% and 0% cell viability controls, respectively. Percentage of cell viability was calculated for each compound concentration tested relative to the 0% and 100% controls and CC 50 Values ​​were determined by nonlinear regression as the compound concentration that reduced cell viability by 50%. [Table 5]

[0297] Example E: Rat Pharmacokinetic Assay The ester reference compound, compound 3, and compound 6 were administered orally by gavage to male Sprague-Dawley rats (n=3 / group); 6 mg / kg of the ester reference compound in 2.5% dimethyl sulfoxide; 10% Kolliphor HS-15; 10% Labrasol; 2.5% propylene glycol and 75% water (pH 2.5); 6.65 mg / kg of compound 3 in 10% dimethyl sulfoxide; 40% Kolliphor HS-15; 40% Labrasol and 10% propylene glycol, and 8.1 mg / kg of compound 6 in 2.5% dimethyl sulfoxide; 10% Kolliphor HS-15; 10% Labrasol; 2.5% propylene glycol and 75% water (pH 2.8). Blood samples were collected at 100 mL / min and 100 mL / min.2 Blood samples were collected in pre-chilled collection tubes containing EDTA and processed to plasma at 10 time points spanning the pre-dose to 24-hour post-dose period. Blood samples were subjected to protein precipitation with 12.5 volumes of methanol, vortexed, and centrifuged. Supernatants were transferred under nitrogen, evaporated to dryness, and reconstituted in 5% acetonitrile in water. Separation was achieved on a Phenomenex Synergi Polar-RP column, mobile phase A of 10 mM ammonium formate with 0.1% formic acid in water, and mobile phase B of 0.1% formic acid in acetonitrile, with a stepwise linear gradient from 5 to 95% mobile phase B. An LC-MS / MS method was used to measure the concentrations of reference compound A and either the ester reference compound, compound 3, or compound 6, in plasma. Data for reference compound A following oral administration of either the ester reference compound, compound 3, or compound 6 are shown in the table below. [ka] [Table 6] a Based on mg equivalent / kg dose of Reference Compound A, using IV data from a 1 mg / kg dose of Reference Compound A

[0298] Example F: Monkey Pharmacokinetic Assay The ester reference compound, compound 3, and compound 6 were administered orally by gavage to male and female rhesus monkeys (n=3 / group); ester reference compound at 12.4 mg / kg in 2.5% DMSO; 10% Kolliphor HS-15; 10% Labrasol; 2.5% propylene glycol and 75% water (pH 2.2); compound 3 at 13.3 mg / kg in 10% dimethyl sulfoxide; 40% Kolliphor HS-15; 40% Labrasol and 10% propylene glycol, and compound 6 at 9.3 mg / kg in 2.5% dimethyl sulfoxide; 10% Kolliphor HS-15; 10% Labrasol; 2.5% propylene glycol and 75% water (pH 2.3). Blood samples were then diluted with dichlorvos and diluted with K 2Blood samples were collected in pre-chilled collection tubes containing EDTA (2 mM final concentration spiked with blood) and processed to plasma at 10 time points spanning the pre-dose to 24 hour post-dose period. Blood samples were subjected to protein precipitation with 12.5 volumes of methanol, vortexed, and centrifuged. Supernatants were transferred under nitrogen, evaporated to dryness, and reconstituted in 5% acetonitrile in water. Separation was achieved on a Phenomenex Synergi Polar-RP column, mobile phase A of 10 mM ammonium formate with 0.1% formic acid in water, and mobile phase B of 0.1% formic acid in acetonitrile, with a stepwise linear gradient from 5 to 95% mobile phase B. An LC-MS / MS method was used to measure the concentrations of reference compound A and either the ester reference compound, compound 3, or compound 6, in plasma. Data for reference compound A following oral administration of either the ester reference compound, compound 3, or compound 6 are shown in the table below. [ka] [Table 7] a Based on mg equivalent / kg dose of Reference Compound A, use IV data from the 1 mg / kg dose in the Reference Compound A study

[0299] Example G: GI S9 Stability Duplicate aliquots of test compounds or positive control substrate (GS-7340) were added to S9 stock diluted in 100 mM phosphate buffered saline (pH 7.4) to obtain a protein concentration of 1.0 mg / mL. The S9 metabolic reaction was initiated by adding substrate to the S9 reaction mixture to a final concentration of 2 μM. At 0, 10, 20, 30, 60, and 120 min, 25 μL aliquots of the reaction mixture were transferred to a plate containing 225 μl of IS / Q solution. After quenching, the plate was centrifuged at 3000×g for 30 min, and a 150 μL aliquot of each supernatant was diluted with 150 μL of water. Aliquots (10 μL) of the diluted supernatants were analyzed on a Thermo Q-Exactive mass spectrometer as described below.

[0300] Example H: Plasma Stability Duplicate aliquots of plasma were warmed to 37° C. and metabolic reactions were initiated by the addition of test compound (6 μL of 0.1 mM DMSO stock) or plasma stability standard (GS-7340) to give a final substrate concentration of 2 μM. At 0.05, 0.5, 1, 2, 3 and 4 hours, 25 μL aliquots of the reaction mixture were transferred to a plate containing 225 μl of IS / Q quenching solution. After quenching, the plate was centrifuged at 3000×g for 30 min and 150 μL of the supernatant was diluted with 150 μL of water. Aliquots (10 μL) of the diluted supernatant were analyzed on a Thermo Q-Exactive mass spectrometer as described below.

[0301] Example I: CES1 / 2 Stability Test compounds or positive control substrates (oseltamivir for CES1 enzyme or procaine for CES2) are incubated with the respective supersome preparations (final CES concentration 1.5 mg / ml) in 0.1 M potassium phosphate buffer (pH 7.4) at 37° C. Substrate is added to a final concentration of 2 μM to initiate the reaction. The final incubation volume is 250 μL. Aliquots are removed after 0, 10, 30, 60, and 120 minutes of incubation. The reaction is stopped by addition of IS / Q. After protein precipitation and centrifugation, 150 μL of the supernatant is diluted with an equal volume of water before LC-MS analysis. For procaine, 150 μL of the supernatant is dried and reconstituted in 250 μL of water. All samples are analyzed by LC-MS and PAR values ​​are used for quantification.

[0302] Example J: Hepatic S9 Stability Duplicate aliquots of test compounds or positive control substrate (GS-7340) were added to S9 stock diluted in 100 mM potassium phosphate buffer (pH 7.4) to obtain a protein concentration of 2.4 mg / mL. The S9 metabolic reaction was initiated by adding substrate to the S9 reaction mixture to a final concentration of 2 μM. At 2, 12, 25, 45, 65, and 90 min, 25 μL aliquots of the reaction mixture were transferred to a plate containing 225 μl of IS / Q solution. After quenching, the plate was centrifuged at 3000×g for 30 min, and a 150 μL aliquot of each supernatant was diluted with 150 μL of water. Aliquots (10 μL) of the diluted supernatants were analyzed on a Thermo Q-Exactive mass spectrometer as described below. Example K: Liquid Chromatography / Mass Spectrometry Method for S9 and Plasma Stability Quantification of test compounds and controls was performed by analyte / internal standard peak area ratio (PAR) values ​​measured on a Thermo Q-Exactive mass spectrometer coupled to a Dionex UltiMate 3000 HPLC equipped with a Leap Technologies HTC PAL autosampler. The column used was Thermo Hypersil GOLD (1.9 μm particle size, 2.1×50 mm). Mobile phase A consisted of 0.1% (v / v) formic acid in water. Mobile phase B consisted of 0.1% (v / v) formic acid in acetonitrile. Elution of the analytes was achieved by a series of linear gradients of acetonitrile in water containing 0.1% (v / v) formic acid. The mass spectrometer was calibrated weekly and a mass tolerance of 5 ppm was used.

[0303] All references, including publications, patents, and patent documents, are incorporated herein by reference as if individually incorporated by reference. The present disclosure refers to various embodiments and techniques. However, it should be understood that many variations and modifications can be made while remaining within the spirit and scope of the present disclosure. The description should be considered as illustrative of the claimed subject matter, with the understanding that it is not intended to limit the scope of the appended claims to the specific embodiments illustrated.

Claims

1. A compound of formula A, 【Chemistry 51】 or a pharmaceutically acceptable salt thereof, In the formula, R １ and R ２ Together, they form -OC(=O)O-, -OCHR ６ O-, or -OP(=O)(OR １４ )O—, R ６ But H, C １ ~C ６ Alkyl, C ６ ~C １０ Aryloxy, or C １ ~C ６ is an alkoxy; R ３ But -C(=O)R ７ and R ７ But C １ ~C ８ Alkyl, C ２ ~C ８ Alkenyl, C ２ ~C ８ Alkynyl, C ３ ~C ８ Carbocyclyl, C ６ ~C １０ aryl or a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R ７ Each C １ ~C ８ Alkyl, C ２ ~C ８ Alkenyl, C ２ ~C ８ Alkynyl, C ３ ~C ８ Carbocyclyl, C ６ ~C １０ The aryl or 5- to 6-membered heteroaryl is selected from the group consisting of halogen, cyano, -N ３ , -OR ８ , -NR ９ R １０ and phenyl, wherein phenyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, cyano, and C １ ~C ６ optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; Each R ８ However, independently, H, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, and C ３ ~C ６ is cycloalkyl, Each R ９ However, independently, H, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, and C ３ ~C ６ is cycloalkyl, Each R １０ However, independently, H, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, and C ３ ~C ６ is cycloalkyl, Base A is 【Chemistry 52】 and R １１ -OP(=O)(OH) ２ C optionally substituted with １ ~C ６ is alkyl, R １２ But H, C １ ~C ６ Alkyl, —C(═O)R １３ , or -C(=O)OR １３ and Each R １３ are independently H or C １ ~C ８ alkyl, and R １３ C １ ~C ８ alkyl is optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and phenyl, and phenyl is -OP(=O)(OH)(OR １４ ), and Each R １４ However, independently, H, C １ ~C ８ Alkyl, C ３ ~C ８ Carbocyclyl, C ６ ~C １０ aryl or a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R １４ C １ ~C ８ A compound of Formula A, or a pharmaceutically acceptable salt thereof, wherein alkyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, and phenyl.

2. R １ and R ２ together to form -OC(=O)O- or -OCHR ６ forming O- Alternatively, R 1 and R 2 together form —OCHR 6 O—; 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

3. R １ and R ２ together to form -OC(=O)O-, Alternatively, R 1 and R 2 together form —OCH(OCH 3 )O—; Alternatively, R 1 and R 2 together form —OP(═O)(OR 14 )O—; Alternatively, R 1 and R 2 together form —OP(═O)(OH)O—; Alternatively, R 1 and R 2 together form —OC(═O)O—, —OCH(OCH 3 )O—, or —OP(═O)(OH)O—; Alternatively, R 1 and R 2 together form —OC(═O)O— or —OCH(OCH 3 )O—; 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

4. R ６ is H, Alternatively, R 6 is C 1 -C 6 alkyl; Alternatively, R 6 is C 1 -C 3 alkyl; Alternatively, R 6 is —CH 3 ; Alternatively, R 6 is C 6 -C 10 aryloxy; Alternatively, R 6 is 【Chemistry 53】 That is, Alternatively, R 6 is C 1 -C 6 alkoxy; Alternatively, R 6 is C 1 -C 3 alkoxy; Alternatively, R 6 is —OCH 2 CH 3 , —OCH(CH 3 ) 2 , or —OCH 3 ; Alternatively, R 6 is —OCH 3 ; 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

5. (a) R ７ But C １ ~C ８ Alkyl, C ２ ~C ８ Alkenyl, or C ２ ~C ８ alkynyl, and R ７ Each C １ ~C ８ Alkyl, C ２ ~C ８ Alkenyl, and C ２ ~C ８ Alkynyl is selected from halogen, cyano, -N ３ , -OR ８ , -NR ９ R １０ and phenyl, wherein phenyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, cyano, and C １ ~C ６ optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; or R 7 is C 1 -C 8 alkyl optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, —N 3 , —OR 8 , —NR 9 R 10 , and phenyl, wherein phenyl is optionally substituted with one, two, or three substituents independently selected from halo, cyano, and C 1 -C 6 alkyl; Alternatively, R 7 is C 1 -C 8 alkyl optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, —N 3 , —OR 8 , —NR 9 R 10 , and phenyl; and / or (a)(i) R 8 is H; Alternatively, R 8 is C 1 -C 6 alkyl; Alternatively, R 8 is —CH 3 , —CH 2 CH 3 , —(CH 2 ) 2 CH 3 , or —CH(CH 3 ) 2 ; Alternatively, R 8 is —CH 3 ; Alternatively, R 8 is C 1 -C 6 haloalkyl; Alternatively, R 8 is C 3 -C 6 cycloalkyl; and / or (a)(i)' R 9 is H; Alternatively, R 9 is C 1 -C 6 alkyl; Alternatively, R 9 is —CH 3 , —CH 2 CH 3 , —(CH 2 ) 2 CH 3 , or —CH(CH 3 ) 2 ; Alternatively, R 9 is —CH 3 ; Alternatively, R 9 is C 1 -C 6 haloalkyl; Alternatively, R 9 is C 3 -C 6 cycloalkyl; and / or (a)(i)''R 10 is H; Alternatively, R 10 is C 1 -C 6 alkyl; Alternatively, R 10 is —CH 3 ; Alternatively, R 10 is —CH 3 , —CH 2 CH 3 , —(CH 2 ) 2 CH 3 , or —CH(CH 3 ) 2 ; Alternatively, R 10 is C 1 -C 6 haloalkyl; Alternatively, R 10 is C 3 -C 6 cycloalkyl; or, (b) R 7 is C 1 -C 8 alkyl; Alternatively, R 7 is C 1 -C 6 alkyl; Alternatively, R 7 is —CH 3 , —CH 2 CH 3 , —(CH 2 ) 2 CH 3 , —CH(CH 3 ) 2 , —(CH 2 ) 3 CH 3 , or —C(CH 3 ) 3 ; Alternatively, R 7 is —CH(CH 3 ) 2 ; 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

6. (a) Base A is 【Chemistry 54】 That is, Alternatively, Base A is 【Transformation 55】 That is, and / or (a)(i) R 11 is C 1 -C 3 alkyl substituted with —OP(═O)(OH) 2 ; Alternatively, R 11 is —(CH 2 )OP(═O)(OH) 2 ; or, (b) Base A is 【Transformation 56】 That is, 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

7. (a) R １２ But -C(=O)R １３ or R 12 is —C(═O)OR 13 ; and / or (a)(i) R 13 is C 1 -C 8 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from halogen, cyano, and phenyl, wherein phenyl is optionally substituted with —OP(═O)(OH)(OR 14 ); and / or (a)(i)' R 14 is H; Alternatively, R 14 is H or C 1 -C 8 alkyl, wherein the C 1 -C 8 alkyl of R 14 is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, and phenyl; Alternatively, R 14 is C 1 -C 8 alkyl optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, and phenyl; Alternatively, R 14 is C 1 -C 3 alkyl optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, and phenyl; Alternatively, R 14 is C 1 -C 3 alkyl substituted with one phenyl; Alternatively, R 14 is 【Chemistry 57】 That is, or, (a)(ii) R 13 is H; Alternatively, R 13 is C 1 -C 8 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from halogen, cyano, and phenyl; Alternatively, R 13 is C 1 -C 8 alkyl; Alternatively, R 13 is —CH 3 , —CH 2 CH 3 , —(CH 2 ) 2 CH 3 , —CH(CH 3 ) 2 , —(CH 2 ) 3 CH 3 , or —C(CH 3 ) 3 ; Alternatively, R 13 is —CH 2 CH(CH 3 ) 2 or —(CH 2 ) 2 CH 3 ; or, (b) R 12 is H; Alternatively, R 12 is C 1 -C 6 alkyl; Alternatively, R 12 is —C(═O)(CH 2 ) 2 CH 3 ; Alternatively, R 12 is —C(═O)OCH 2 CH(CH 3 ) 2 ; Alternatively, R 12 is —C(═O)OCH 2 CH(CH 3 ) 2 or —C(═O)(CH 2 ) 2 CH 3 ; 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

8. The compound of formula A is Table 8 2. The compound of claim 1, wherein:

9. A compound of formula B: 【Chemistry 58】 or a pharmaceutically acceptable salt thereof, In the formula, R Ａ is -OH, -OC(=O)R Ｄ , or —OC(═O)OR Ｄ Or R Ｂ is -OH, -OC(=O)R Ｅ , or —OC(═O)OR Ｅ or R Ａ and R Ｂ together to form -OC(=O)O- or -OCHR Ｆ O- is formed, R Ｆ But H, C １ ~C ６ Alkyl, or C ６ ~C １０ is aryl, R Ｃ But -C(=O)R Ｇ and R Ｄ and R Ｅ However, each independently, C １ ~C ８ Alkyl, C ２ ~C ８ Alkenyl, C ２ ~C ８ Alkynyl, C ３ ~C ８ Carbocyclyl, C ６ ~C １０ aryl or a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R Ｄ and R Ｅ C １ ~C ８ Alkyl, C ２ ~C ８ Alkenyl, C ２ ~C ８ Alkynyl, C ３ ~C ８ Carbocyclyl, C ６ ~C １０ Each of the aryl or 5- to 6-membered heteroaryl groups is independently selected from halogen, cyano, -N ３ , -OR Ｈ , -NR Ｉ R Ｊ and phenyl, wherein phenyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, cyano, and C １ ~C ６ optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; R Ｇ But H, C １ ~C ８ Alkyl, C ２ ~C ８ Alkenyl, C ２ ~C ８ Alkynyl, C ３ ~C ８ Carbocyclyl, C ６ ~C １０ aryl or a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R Ｇ C １ ~C ８ Alkyl, C ２ ~C ８ Alkenyl, C ２ ~C ８ Alkynyl, C ３ ~C ８ Carbocyclyl, C ６ ~C １０ The aryl or 5- or 6-membered heteroaryl is independently selected from halogen, cyano, -N ３ , -OR Ｈ , -NR Ｉ R Ｊ , -OP(=O)(OH)(OR Ｌ ), and phenyl, wherein phenyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, cyano, and C １ ~C ６ optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; Each R Ｈ However, independently, H, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, and C ３ ~C ６ is cycloalkyl, Each R Ｉ However, independently, H, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, and C ３ ~C ６ is cycloalkyl, Each R Ｊ However, independently, H, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, and C ３ ~C ６ is cycloalkyl, Base B is 【Chemistry 59】 and R Ｋ But C ６ ~C １０ Aryl, —O—C ６ ~C １０ Aryl, —O—C １ ~C １０ Alkyl, or -OP(=O)(OH)(OR Ｌ ) optionally substituted with １ ~C １０ alkyl, and R Ｌ But H, C １ ~C ８ Alkyl, C ３ ~C ８ Carbocyclyl, C ６ ~C １０ aryl or a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R Ｌ C １ ~C ８ A compound of Formula B, or a pharmaceutically acceptable salt thereof, wherein alkyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, and phenyl.

10. A compound of formula B: 【Transformation 60】 or a pharmaceutically acceptable salt thereof, In the formula, R Ａ is -OH, -OC(=O)R Ｄ , or —OC(═O)OR Ｄ Or R Ｂ is -OH, -OC(=O)R Ｅ , or —OC(═O)OR Ｅ or R Ａ and R Ｂ together to form -OC(=O)O- or -OCHR Ｆ O- is formed, R Ｆ But H, C １ ~C ６ Alkyl, or C ６ ~C １０ is aryl, R Ｃ But -C(=O)R Ｇ and R Ｄ and R Ｅ However, each independently, C １ ~C ８ Alkyl, C ２ ~C ８ Alkenyl, C ２ ~C ８ Alkynyl, C ３ ~C ８ Carbocyclyl, C ６ ~C １０ aryl or a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R Ｄ and R Ｅ C １ ~C ８ Alkyl, C ２ ~C ８ Alkenyl, C ２ ~C ８ Alkynyl, C ３ ~C ８ Carbocyclyl, C ６ ~C １０ Each of the aryl or 5- to 6-membered heteroaryl groups is independently selected from halogen, cyano, -N ３ , -OR Ｈ , -NR Ｉ R Ｊ and phenyl, wherein phenyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, cyano, and C １ ~C ６ optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; R Ｇ But H, C １ ~C ８ Alkyl, C ２ ~C ８ Alkenyl, C ２ ~C ８ Alkynyl, C ３ ~C ８ Carbocyclyl, C ６ ~C １０ aryl or a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R Ｇ C １ ~C ８ Alkyl, C ２ ~C ８ Alkenyl, C ２ ~C ８ Alkynyl, C ３ ~C ８ Carbocyclyl, C ６ ~C １０ Each of the aryl or 5- to 6-membered heteroaryl groups is independently selected from halogen, cyano, -N ３ , -OR Ｈ , -NR Ｉ R Ｊ , -OP(=O)(OH)(OR Ｌ ), and phenyl, wherein phenyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, cyano, and C １ ~C ６ optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; Each R Ｈ However, independently, H, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, and C ３ ~C ６ is cycloalkyl, Each R Ｉ However, independently, H, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, and C ３ ~C ６ is cycloalkyl, Each R Ｊ However, independently, H, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, and C ３ ~C ６ is cycloalkyl, Base B is 【Chemistry 61】 and R Ｋ But C ６ ~C １０ Aryl, —O—C ６ ~C １０ Aryl, —O—C １ ~C １０ Alkyl, or -OP(=O)(OH)(OR Ｌ ) optionally substituted with １ ~C １０ alkyl, and R Ｌ But H, C １ ~C ８ Alkyl, C ３ ~C ８ Carbocyclyl, C ６ ~C １０ aryl or a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R Ｌ C １ ~C ８ alkyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, and phenyl; However, Base B is 【Transformation 62】 and R Ｇ One, two, or three -OP(=O)(OH)(OR Ｌ ) substituted with C １ ~C ８ A compound of formula B, or a pharmaceutically acceptable salt thereof, provided that: R is alkyl.

11. R Ａ But -OC(=O)R Ｄ 11. The compound of claim 10, wherein:

12. R Ａ -OC(=O)OR Ｄ 11. The compound of claim 10, wherein:

13. R Ｂ But -OC(=O)R Ｅ That is, Alternatively, R B is —OC(═O)ORE; 11. The compound of claim 10, or a pharmaceutically acceptable salt thereof.

14. R Ａ But -OC(=O)R Ｄ and R Ｂ But -OC(=O)R Ｅ 11. The compound of claim 10, wherein:

15. R Ａ is —OH, and R Ｂ But -OC(=O)R Ｅ or -OC(=O)OR Ｅ 11. The compound of claim 10, wherein:

16. R Ａ But -OC(=O)R Ｄ or -OC(=O)OR Ｄ and R Ｂ The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein is -OH.

17. R Ｄ But C １ ~C ８ Alkyl, C ２ ~C ８ Alkenyl, or C ２ ~C ８ alkynyl, and R ４ C １ ~C ８ Alkyl, C ２ ~C ８ Alkenyl, and C ２ ~C ８ Each alkynyl is independently selected from halogen, cyano, -N ３ , -OR Ｈ , -NR Ｉ R Ｊ , -OP(=O)(OH) ２ , C ３ ~C ８ carbocyclyl, and phenyl, wherein phenyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, cyano, and C １ ~C ６ optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; or R D is C 1 -C 8 alkyl optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, —N 3 , —OR H , —NR I R J , —OP(═O)(OH) 2 , C 3 -C 8 carbocyclyl, and phenyl; Alternatively, R D is C 1 -C 8 alkyl; Alternatively, R D is C 1 -C 6 alkyl; Alternatively, R D is C 1 -C 3 alkyl; Alternatively, R D is —CH 3 , —CH 2 CH 3 , —(CH 2 ) 2 CH 3 , —CH(CH 3 ) 2 , —(CH 2 ) 3 CH 3 , or —C(CH 3 ) 3 ; Alternatively, R D is —CH 3 or —CH(CH 3 ) 2 ; 11. The compound of claim 10, or a pharmaceutically acceptable salt thereof.

18. R Ｅ But C １ ~C ８ Alkyl, C ２ ~C ８ Alkenyl, or C ２ ~C ８ alkynyl, and R ４ C １ ~C ８ Alkyl, C ２ ~C ８ Alkenyl, and C ２ ~C ８ Each alkynyl is independently selected from halogen, cyano, -N ３ , -OR Ｈ , -NR Ｉ R Ｊ , -OP(=O)(OH) ２ , C ３ ~C ８ carbocyclyl, and phenyl, wherein phenyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, cyano, and C １ ~C ６ optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; or R E is C 1 -C 8 alkyl optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, —N 3 , —OR H , —NR I R J , —OP(═O)(OH) 2 , C 3 -C 8 carbocyclyl, and phenyl; Alternatively, R E is C 1 -C 8 alkyl; Alternatively, R E is C 1 -C 6 alkyl; Alternatively, R E is C 1 -C 3 alkyl; Alternatively, R E is —CH 3 , —CH 2 CH 3 , —(CH 2 ) 2 CH 3 , —CH(CH 3 ) 2 , —(CH 2 ) 3 CH 3 , or —C(CH 3 ) 3 ; Alternatively, R E is —CH 3 or —CH(CH 3 ) 2 ; 12. The compound of claim 11, or a pharmaceutically acceptable salt thereof.

19. R Ａ The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein is -OH.

20. R Ｂ The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein is -OH.

21. R Ａ and R Ｂ are both —OH; Alternatively, R A is OH, OC(O)CH(CH 3 ) 2 , or OC(O)CH 3 , and R B is OH, OC(O)CH(CH 3 ) 2 , or OC(O)CH 3 ; Alternatively, both R A and R B are OC(O)CH 3 ; Alternatively, R A and R B together form —OC(═O)O—; 11. The compound of claim 10, or a pharmaceutically acceptable salt thereof.

22. R Ａ and R Ｂ Together, -OCHR Ｆ 11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, which forms O-.

23. R Ｆ is H, Alternatively, R F is C 1 -C 6 alkyl; Alternatively, R F is C 6 -C 10 aryl; 11. The compound of claim 10, or a pharmaceutically acceptable salt thereof.

24. R Ｇ each independently represents a halogen, a cyano, or a —N ３ , -OR Ｈ , -NR Ｉ R Ｊ C optionally substituted with one, two, or three substituents independently selected from the group consisting of phenyl, ３ ~C ８ carbocyclyl, and phenyl is halo, cyano, and C １ ~C ６ optionally substituted with 1, 2, or 3 substituents independently selected from alkyl; Alternatively, each R G is independently C 6 -C 10 aryl optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, —N 3 , —OR H , —NR I R J , —OP(═O)(OH)(OR L ), and phenyl, wherein phenyl is optionally substituted with one, two, or three substituents independently selected from halo, cyano, and C 1 -C 6 alkyl; Alternatively, each R G is independently a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, cyano, —N 3 , —OR H , —NR I R J , —OP(═O)(OH)(OR L ), and phenyl, wherein phenyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C 1 -C 6 alkyl; Alternatively, each R G is independently C 1 -C 8 alkyl, C 2 -C 8 alkenyl, or C 2 -C 8 alkynyl, and the C 1 -C 8 alkyl, C 2 -C 8 alkenyl, and C 2 -C 8 alkynyl of R G are each independently optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, —N 3 , —OR H , —NR I R J , —OP(═O)(OH)(OR L ), and phenyl, and the phenyl is optionally substituted with one, two, or three substituents independently selected from halo, cyano, and C 1 -C 6 alkyl; Alternatively, each R G is independently C 1 -C 8 alkyl, C 2 -C 8 alkenyl, or C 2 -C 8 alkynyl, and the C 1 -C 8 alkyl, C 2 -C 8 alkenyl, and C 2 -C 8 alkynyl of R G are each independently optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, —N 3 , —OR H , —NR I R J , —OP(═O)(OH)(OR L ), and phenyl; or R G is C 1 -C 8 alkyl optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, —N 3 , —OR H , —NR I R J , —OP(═O)(OH)(OR L ), and phenyl, wherein phenyl is optionally substituted with one, two, or three substituents independently selected from halo, cyano, and C 1 -C 6 alkyl; 11. The compound of claim 10, or a pharmaceutically acceptable salt thereof.

25. R Ｇ But C １ ~C ８ is alkyl, Alternatively, R G is —CH 3 , —CH 2 CH 3 , —(CH 2 ) 2 CH 3 , —CH(CH 3 ) 2 , —(CH 2 ) 3 CH 3 , or —C(CH 3 ) 3 ; Alternatively, R G is C 1 -C 4 alkyl; Alternatively, R G is —(CH 2 ) 2 CH 3 and —CH(CH 3 ) 2 ; Alternatively, R G is —CH(CH 3 ) 2 ; Alternatively, R G is H; Alternatively, R G is —(CH 2 )OP(═O)(OH) 2 ; 11. The compound of claim 10, or a pharmaceutically acceptable salt thereof.

26. R Ｈ is H, Alternatively, R H is C 1 -C 6 alkyl; Alternatively, R H is —CH 3 , —CH 2 CH 3 , —(CH 2 ) 2 CH 3 , or —CH(CH 3 ) 2 ; Alternatively, R H is —CH 3 ; Alternatively, R H is C 1 -C 6 haloalkyl; Alternatively, R H is C 3 -C 6 cycloalkyl; 11. The compound of claim 10, or a pharmaceutically acceptable salt thereof.

27. R Ｉ is H, Alternatively, R I is C 1 -C 6 alkyl; Alternatively, R I is —CH 3 , —CH 2 CH 3 , —(CH 2 ) 2 CH 3 , or —CH(CH 3 ) 2 ; Alternatively, R I is —CH 3 ; Alternatively, R I is C 1 -C 6 haloalkyl; Alternatively, R I is C 3 -C 6 cycloalkyl; 11. The compound of claim 10, or a pharmaceutically acceptable salt thereof.

28. R Ｊ is H, Alternatively, R J is C 1 -C 6 alkyl; Alternatively, R J is —CH 3 , —CH 2 CH 3 , —(CH 2 ) 2 CH 3 , or —CH(CH 3 ) 2 ; Alternatively, R J is —CH 3 ; Alternatively, R J is C 1 -C 6 haloalkyl; Alternatively, R J is C 3 -C 6 cycloalkyl; 11. The compound of claim 10, or a pharmaceutically acceptable salt thereof.

29. (a) Base B is 【Transformation 63】 That is, Alternatively, Base B is 【Chemistry 64】 That is, Alternatively, Base B is 【Transformation 65】 That is, and / or (a)(i) R K is C 1 -C 6 alkyl substituted with —OP(═O)(OH)(OR L ); Alternatively, R K is —(CH 2 )OP(═O)(OH)(OR L ); and / or (a)(i)'R L is H; Alternatively, R L is H or C 1 -C 8 alkyl, and the C 1 -C 8 alkyl of R 14 is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, and phenyl; Alternatively, R L is C 1 -C 8 alkyl optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, and phenyl; Alternatively, R L is C 1 -C 3 alkyl optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, and phenyl; Alternatively, R L is C 1 -C 3 alkyl substituted with one phenyl; Alternatively, R L is 【Chemical Formula 66】 That is, or, (a)(ii) R K is 【Transformation 67】 That is, Alternatively, R K is C 1 -C 10 alkyl; Alternatively, R K is C 1 -C 7 alkyl; Alternatively, R K is —CH 3 , —CH 2 CH 3 , —(CH 2 ) 2 CH 3 , —(CH 2 ) 4 CH 3 , or —(CH 2 ) 6 CH 3 ; Alternatively, R K is C 6 -C 10 aryl; Alternatively, R K is phenyl; Alternatively, R K is —O—C 6 -C 10 aryl; Alternatively, R K is —O-phenyl; Alternatively, R K is —O—C 1 -C 10 alkyl; Alternatively, R K is —O—CH 3 , —O—CH 2 CH 3 , —O—(CH 2 ) 2 CH 3 , —O—(CH 2 ) 4 CH 3 , or —O—(CH 2 ) 6 CH 3 ; or, (b) Base B is 【Transformation 68】 That is, Alternatively, Base B is 【Transformation 69】 That is, 11. The compound of claim 10, or a pharmaceutically acceptable salt thereof.

30. The compound of formula B is Table 9-1 Table 9-2 11. The compound of claim 10, wherein:

31. 31. A pharmaceutical composition comprising a compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, optionally wherein the pharmaceutical composition is for subcutaneous, intramuscular, intravenous, oral, or inhalation administration, preferably wherein the pharmaceutical composition is for oral administration.

32. A composition comprising a compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, for the treatment or prevention of a viral infection in a human being in need thereof, Optionally, the composition or pharmaceutical composition is administered to the human via oral, intramuscular, intravenous, subcutaneous, or inhalation administration; Additionally, optionally, the composition or pharmaceutical composition is for administration to a human in combination with at least one additional therapeutic or prophylactic agent, optionally wherein the additional therapeutic or prophylactic agent is molnupiravir, oseltamivir, nilmatrervir, or ritonavir; and / or The viral infection is a coronavirus infection. Alternatively, the viral infection is a zoonotic coronavirus infection. Alternatively, the viral infection is caused by a virus having at least 70% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2. Alternatively, the viral infection is caused by a virus having at least 80% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2. Alternatively, the viral infection is caused by a virus having at least 90% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2. Alternatively, the viral infection is caused by a virus having at least 95% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2. Alternatively, the viral infection is selected from the group consisting of 229E viral infection, NL63 viral infection, OC43 viral infection, and HKU1 viral infection. Alternatively, the viral infection is SARS-CoV-2 infection (COVID-19). Alternatively, the viral infection is SARS-CoV viral infection. Alternatively, the viral infection is a MERS-CoV viral infection. Alternatively, the viral infection is a Pneumoviridae virus infection, optionally wherein the Pneumoviridae virus infection is a respiratory syncytial virus infection, or optionally wherein the Pneumoviridae virus infection is a human metapneumovirus infection. Alternatively, the viral infection is a Picornaviridae virus infection, optionally wherein the Picornaviridae virus infection is a human rhinovirus infection (HRV); or optionally wherein the Picornaviridae virus infection is an HRV-A, HRV-B, or HRV-C infection; Alternatively, the viral infection is an enterovirus infection. Alternatively, the viral infection is selected from the group consisting of Coxsackie A virus infection, Coxsackie A virus infection, Enterovirus D68 infection, Enterovirus B69 infection, Enterovirus D70 infection, Enterovirus A71 infection, and Poliovirus infection. Alternatively, the viral infection is a Flaviviridae virus infection, and optionally the Flaviviridae virus infection is Dengue virus infection, Yellow fever virus infection, West Nile virus infection, Tick-borne encephalitis, Kunjin Japanese encephalitis, St. Louis encephalitis, Murray Valley encephalitis, Omsk hemorrhagic fever, Bovine viral diarrhea, Zika virus infection, or HCV infection; Alternatively, the viral infection is a Filoviridae virus infection, optionally wherein the Filoviridae virus infection is Ebola virus infection or Marburg virus infection. Alternatively, the viral infection is an orthomyxovirus infection. Alternatively, the viral infection is an influenza virus infection. Alternatively, the viral infection is influenza A virus infection or influenza B virus infection. Alternatively, the viral infection is a Paramyxoviridae virus infection. Alternatively, the composition or pharmaceutical composition, wherein the viral infection is human parainfluenza virus infection, Nipah virus infection, Hendra virus infection, measles virus infection, or mumps virus infection.

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