Method for treating viral infections including SARS-CoV-2

Abstract

The present disclosure relates to methods for treating viral infections in non-pregnant patients. Also provided is combination therapy for viral infections in humans in need of treatment.

Description

【Technical Field】 【0001】 (Cross - Reference to Related Applications) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 349,531, filed on Jun. 6, 2022, and U.S. Provisional Patent Application No. 63 / 461,218, filed on Apr. 21, 2023. The entire contents of these applications are hereby incorporated by reference in their entirety. 【0002】 (Field of the Invention) The present disclosure relates to methods for treating viral infections. 【Background Art】 【0003】 There is a need for compounds and methods for treating viral infections, such as viral infections of the Paramyxoviridae, Pneumoviridae, Picornaviridae, Flaviviridae, Filoviridae, Arenaviridae, Orthomyxovirus, and Coronaviridae families. 【Summary of the Invention】 【Means for Solving the Problems】 【0004】 Provided herein is a method for treating a viral infection in a patient in need thereof, the method comprising administering to the patient a compound of formula A, 【Chemical Formula】 a deuterated compound of formula A, a prodrug of a compound of formula A, a prodrug of a deuterated compound of formula A, or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , and the base are defined herein, and when a prodrug of a compound of formula A, a prodrug of a deuterated compound of formula A, or a pharmaceutically acceptable salt thereof is administered, the prodrug of a compound of formula A, a prodrug of a deuterated compound of formula A, or a pharmaceutically acceptable salt thereof is substantially converted to a compound of formula A or a deuterated compound of formula A, and the patient is not pregnant. 【0005】 Also provided herein is a method of treating a viral infection in a human in need thereof, the method comprising: (i) Compound 1: [Chemical formula] deuterated Compound 1, a prodrug of Compound 1, a prodrug of deuterated Compound 1, or a pharmaceutically acceptable salt thereof, and (ii) administering to the human nirmatrelvir, ritonavir, or a combination of nirmatrelvir and ritonavir, wherein when a prodrug of Compound 1, a prodrug of deuterated Compound 1, or a pharmaceutically acceptable salt thereof is administered to the human, the prodrug of Compound 1, the prodrug of deuterated Compound 1, or the pharmaceutically acceptable salt thereof is substantially converted to Compound 1 or deuterated Compound 1. 【Brief Description of the Drawings】 【0006】 【Figure 1】 Shows a representative combination of two drugs Bliss independence consensus plot in the A549-hACE-2 SARS-CoV-2 fluc antiviral assay of Compound 1 and nirmatrelvir. 【0007】 【Figure 2】 Shows a representative combination of three drugs Bliss independence consensus plot in the A549-hACE-2 SARS-CoV-2 fluc antiviral assay of Compound 1, nirmatrelvir, and ritonavir. 【Modes for Carrying Out the Invention】 【0008】 Unless otherwise specified, as used herein, the following terms and phrases are intended to have the following meanings. 【0009】 "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. For example, an alkyl group may have 1 to 20 carbon atoms (i.e., C1-C 20 alkyl), 1 to 8 carbon atoms (i.e., C1-C8 alkyl), 1 to 6 carbon atoms (i.e., C1-C6 alkyl), or 1 to 3 carbon atoms (i.e., C1-C3 alkyl). Examples of suitable alkyl groups include methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), and 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3, but are not limited thereto. 【0010】 "Alkenyl" contains at least one carbon-carbon double bond and has an aliphatic group with 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). Examples of alkenyl groups include ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl). 【0011】 "Alkynyl" contains at least one carbon-carbon triple bond and has an aliphatic group with 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 alkynyl). The term "alkynyl" also includes alkynyl groups having one triple bond and one double bond. 【0012】 "Haloalkyl" is an alkyl group as defined above in which one or more hydrogen atoms of the alkyl group are replaced by halogen atoms. The alkyl portion of the haloalkyl group can have 1 to 20 carbon atoms (i.e., C1-C 20 haloalkyl), 1 to 12 carbon atoms (i.e., C1-C 12 haloalkyl), 1 to 8 carbon atoms (i.e., C1-C8 haloalkyl), 1 to 6 carbon atoms (i.e., C1-C6 alkyl), or 1 to 3 carbon atoms (i.e., C1-C3 alkyl). Examples of suitable haloalkyl groups include -CF3, -CHF2, -CFH2, -CH2CF3, etc. 【0013】 "Aryl" means an aromatic hydrocarbon radical derived by removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. For example, an aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 10 carbon atoms. Typical aryl groups include, but are not limited to, radicals derived from benzene (e.g., phenyl), substituted benzene, naphthalene, anthracene, biphenyl, and the like. 【0014】 "Heteroaryl" refers to an aromatic group having a monocyclic, polycyclic, or fused polycyclic ring having one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl includes 1 to 20 ring atoms (i.e., 1- to 20-membered heteroaryl), 3 to 12 ring atoms (i.e., 3- to 12-membered heteroaryl), 3 to 8 carbon ring atoms (3- to 8-membered heteroaryl), or 5 to 6 ring atoms (5- to 6-membered heteroaryl). Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Heteroaryl does not include or overlap with aryl as previously defined. 【0015】 "Carbocyclic" or "carbocycle" refers to a non-aromatic hydrocarbon ring consisting of carbon and hydrogen atoms having 3 to 20 carbon atoms, in certain embodiments 3 to 15 carbon atoms, in certain embodiments 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 bonded to the remainder of the molecule by a single bond. Examples of carbocycles include, for example, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, cycloheptane, cycloheptene, and cyclooctane. Carbocycles include cycloalkyl groups. 【0016】 "Cycloalkyl" refers to a saturated cyclic alkyl group having a monocyclic or polycyclic ring including a fused ring system, a bridged ring system, and a spiro ring system. As used herein, cycloalkyl has 3 to 20 ring carbon atoms (i.e., C 3~20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3~12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3~10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3~8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C 3~6 cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. 【0017】 As used herein, "heterocyclic ring" or "heterocyclyl", by way of example and not limitation, includes those described in Paquette, Leo A.; Principles of Modern Heterocyclic Chemistry (W. A. 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, from 1950 to the present), particularly Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566. For example, "heterocyclic ring" includes "carbocyclic rings" as defined herein in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., O, N, or S). As used herein, a heterocyclic ring 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 terms "heterocyclic ring" or "heterocyclyl" include saturated rings and partially unsaturated rings. Substituted heterocyclyls include, for example, heterocyclic rings substituted with any of the substituents described herein that include a carbonyl group. Non-limiting examples of carbonyl-substituted heterocyclyls are [Chemical Formula] as follows. 【0018】 Examples of heterocyclic rings include, but are not limited to, tetrahydrofuranyl, azetidinyl, and 2-oxo-1,3-dioxol-4-yl. 【0019】 The term "optionally substituted" (e.g., an optionally substituted aryl group) with respect to a particular moiety of a compound described herein, such as a compound of Formula A or Formula I, refers to a moiety in which all substituents are hydrogen or one or more of the hydrogens are replaced with substituents such as those listed. 【0020】 Unless otherwise specified, the carbon atoms of the compounds of formulae and formula I are intended to have four valences. In some chemical structure representations, if the carbon atoms do not have a sufficient number of variables to generate four valences, the remaining carbon substituents necessary to provide four valences should be assumed to be hydrogen. 【0021】 Any reference to the compounds described herein also includes a reference to their pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts of the compounds described herein include salts derived from appropriate bases such as alkali metals or alkaline earths (e.g., Na + , Li + , K + , Ca +2 , and Mg +2 ), ammonium, and NR4 + (wherein R is as defined herein). Pharmaceutically acceptable salts of nitrogen atoms or amino groups include (a) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc., (b) salts formed with organic 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, 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, leucine, etc., (c) salts formed from elemental anions such as chlorine, bromine, iodine, etc. Pharmaceutically acceptable salts of hydroxy group-containing compounds include Na + and NR4 +Examples of anions of the above compounds in combination with suitable cations such as etc. are given. In some embodiments, R4 is H, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, C6-C 20 aryl, or C2-C 20 heterocyclyl. 【0022】 For therapeutic use, salts of the active ingredients of the compounds described herein are pharmaceutically acceptable. That is, they are salts derived from pharmaceutically acceptable acids or bases. It should also be understood that the compositions herein include the compounds described herein in their unionized, as well as zwitterionic forms, and combinations with a stoichiometric amount of water in hydrates. All enantiomers, diastereomers, racemic mixtures, tautomers, polymorphs and pseudopolymorphs of the compounds described herein (e.g., compounds within the scope of formula A or formula I) and their pharmaceutically acceptable salts are encompassed by the present disclosure. It should be noted that all mixtures of such enantiomers and diastereomers are within the scope of the present disclosure. 【0023】 The compounds described herein may have chiral centers, such as chiral carbon or phosphorus atoms. Accordingly, the compounds described herein include racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and atropisomers. In addition, the compounds described herein include optically isomers enriched or resolved at any or all asymmetric chiral atoms. In other words, chiral centers that are apparent from the depiction are provided as chiral isomers or racemic mixtures. Both racemates and mixtures of diastereomers, as well as individual isolated or synthetic optically isomers substantially free of their enantiomeric or diastereomeric partners, are all within the scope of the present disclosure. Racemic mixtures are separated into their individual substantially optically pure isomers by suitable techniques such as, for example, the separation of diastereomeric salts formed with an optically active auxiliary, such as an acid or a base, followed by the reverse conversion to the optically active substance. In most cases, the desired optically isomer is synthesized by a stereospecific reaction starting from the appropriate stereoisomer of the desired starting material. 【0024】 The stereochemical definitions and rules used in this specification 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. When 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 rotation of plane-polarized light by the compound, where the prefixes S, (-), or l mean that the compound is levorotatory while the compound with the prefixes R, (+), or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A particular stereoisomer may be referred to as an enantiomer, and a mixture of such isomers is often called a racemic mixture or racemate. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur in a chemical reaction or process when there is no stereoselectivity or stereospecificity. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species lacking optical activity. 【0025】 The compounds described in this specification may also, in certain cases, exist as tautomers. Only one delocalized resonance structure may be depicted, but all such forms are contemplated within the scope of the present invention. For example, en-amine tautomers can exist for purine, pyrimidine, imidazole, guanidine, amidine, and tetrazole systems, and all of their possible tautomers are within the scope of the present invention. 【0026】 Any formula or structure described herein that includes compounds of Formula A and Formula I is also intended to represent both unlabeled and isotopically labeled forms of the compounds. Isotopically labeled compounds have the same structure as that shown by the formulae provided herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 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 I, but are not limited thereto. Various isotopically labeled compounds of the present disclosure are, for example, 3 H, 13 C and 14 C incorporated with radioactive isotopes such as these. Such isotopically labeled compounds can be useful in detection or imaging techniques such as metabolic studies, reaction kinetics studies, positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including tissue distribution assays of drugs or substrates, or in radiation therapy of patients. 【0027】 The present disclosure also includes compounds in which 1 to x hydrogens bonded to a carbon atom are replaced with deuterium, where x is the number of hydrogens in the molecule (e.g., a compound of formula A or formula I). Such compounds exhibit increased resistance to metabolism and are thus useful for extending the half-life of any of the compounds described herein (e.g., a compound of formula A or formula I) when administered to a mammal, particularly a human. See, for example, 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 known means in the art, for example, by using starting materials in which one or more hydrogens have been exchanged with deuterium. 【0028】 The deuterium-labeled or deuterium-substituted therapeutic compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties related to distribution, metabolism, and excretion (ADME). Substitution with a heavier isotope such as deuterium can result in certain therapeutic advantages due to greater metabolic stability, e.g., increased half-life in vivo, reduced dosing requirements, and / or improved therapeutic index. 18 F-labeled compounds may be useful in PET or SPECT studies. The isotope-labeled compounds and prodrugs thereof of the present disclosure can generally be prepared by substituting readily available isotope-labeled reagents for non-isotope-labeled reagents and carrying out the procedures disclosed in the schemes or in the examples and preparations described below. It is understood that deuterium in this context is considered a substituent in the compounds described herein. 【0029】 For example, in the deuterated compound of Formula A, one or more hydrogen atoms bonded to one or more carbon atoms of Formula A are replaced by deuterium. In some embodiments of the deuterated compound of Formula A, one hydrogen atom bonded to one carbon atom of Formula A is replaced by deuterium. In some embodiments of the deuterated compound of Formula A, two hydrogen atoms bonded to one carbon atom of Formula A are replaced by deuterium. In some embodiments of the deuterated compound of Formula A, two or more hydrogen atoms bonded to two carbon atoms of Formula A are replaced by deuterium. 【0030】 The concentration of such heavier isotopes, specifically deuterium, can be defined by an isotope enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope means any stable isotope of that atom. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen", that position is understood to have hydrogen with the isotopic composition of the natural abundance of hydrogen. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) means deuterium. 【0031】 Whenever a compound described herein is substituted with, for example, more than one of the same group(s) denoted by "R" or "R", it will be understood that the groups may be the same or different, i.e., each group is independently selected. 【0032】 Wavy line 【Chemical formula】 indicates the site of a covalent bond to an adjacent substructure, group, moiety, or atom. 【0033】 As used herein, the term "treat" or "treatment," unless otherwise specified, means reversing, alleviating, or inhibiting the progression of a 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" has been previously defined above. 【0034】 "Prevent" or "prevention" means any treatment of a disease or condition that does not cause the clinical symptoms of the disease or condition to occur. The compounds and compositions described 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 "prevent" and "prevention" include administering a compound, composition, or pharmaceutically acceptable salt thereof according to the embodiments described herein before or after an individual has been exposed to a virus, but before the symptoms of viral infection appear and / or before the virus is detected in the blood. The term also refers to preventing the appearance of symptoms of a disease and / or preventing the virus from reaching a detectable level in the blood. The term includes both pre-exposure prophylaxis (PrEP), as well as post-exposure prophylaxis (PEP) and event-driven or "on-demand" prevention. These terms also refer to preventing perinatal transmission of a virus from a mother to her infant by administering to the mother before birth and to the infant within a few days after birth. The term also refers to preventing the transmission of a virus by blood transfusion. 【0035】 As used herein, the term "therapeutically effective amount" is the amount of a compound described herein (e.g., a compound of Formula A or Formula I) present in a composition described herein, which, when such composition is administered by a selected route of administration, provides a desired level of the drug in the airways and lung secretions and tissues, or alternatively, in the bloodstream of the subject being treated, to effect a predicted physiological response or desired biological effect. The exact amount depends on a number of factors, such as the particular compound described herein (e.g., a compound of Formula A or Formula I), the specific activity of the composition, the delivery device used, the physical characteristics of the composition, its intended use, as well as patient considerations such as the severity of the disease state, patient compliance, etc., and can be readily determined by one of ordinary skill in the art based on the information provided herein. 【0036】 As used herein, the term "prodrug" refers to a biologically inactive derivative of a drug that can be converted to the parent drug following several chemical or enzymatic pathways upon administration to a patient. For example, when a prodrug of a compound of Formula A or a pharmaceutically acceptable salt thereof is administered, the prodrug or its pharmaceutically acceptable salt can be converted to the compound of Formula A. In another example, when a prodrug of a deuterated compound of Formula A or a pharmaceutically acceptable salt thereof is administered, the prodrug or its pharmaceutically acceptable salt can be converted to the deuterated compound of Formula A. 【0037】 The term "substantially converted", as used herein with respect to a prodrug, refers to the conversion of more than 50% of the prodrug (e.g., a prodrug of a compound of Formula A, or a prodrug of a deuterated compound of Formula A) to the parent compound (e.g., a compound of Formula A, or a deuterated compound of Formula A). For example, the term "substantially converted" can refer to the conversion of more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, more than 95%, or more than 99% of a prodrug of a compound of Formula A, a prodrug of a deuterated compound of Formula A, or a pharmaceutically acceptable salt thereof, to the compound of Formula A or the deuterated compound of Formula A. 【0038】 As used herein, the term "symptom" can include symptoms of viral infection including, for example, fever, chills, cough, shortness of breath, fatigue, muscle pain, headache, diarrhea, loss of taste, loss of smell, pharyngolaryngitis, congestion, nausea, and vomiting. 【0039】 Reference will now be made in detail to specific embodiments of the invention, examples of which are illustrated in the accompanying description. It will be understood that the invention is not intended to be limited to the embodiments described, but on the contrary, is intended to cover all alternatives, modifications, and equivalents that may be included within the scope of the invention. 【0040】 There is provided a method of treating a viral infection in a patient in need thereof, the method comprising administering to the patient a compound of formula A, 【Chemical formula】 a deuterated compound of formula A, a prodrug of a compound of formula A, a prodrug of a deuterated compound of formula A, or a pharmaceutically acceptable salt thereof, wherein R 1 is -OH, -OC(=O)R 4 or -OC(=O)OR 4 and R 2 is -OH, -OC(=O)R 5 or -OC(=O)OR 5 alternatively, R 1 and R 2 together form -OC(=O)O-, -OP(=O)(OH)O-, or -OCHR 6 O- R 4 and R 5 are each independently C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, C6-C 10A 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from aryl, N, O, and S, or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and R 4 and R 5 each of the C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclyl, C6-C 10 aryl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl are independently optionally substituted with 1, 2, or 3 R a substituents, R 6 is H, C1-C6 alkyl, C1-C6 alkoxy, a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or C6-C 10 aryl, and each of the 5- to 6-membered heteroaryl and C6-C 6 aryl of R 10 is independently optionally substituted with 1, 2, or 3 R b substituents, The base is 【Chemical formula】 and is R 11 is C1-C6 alkyl optionally substituted with -OP(=O)(OH)(OR 14 ), R 12 is H, C1-C6 alkyl, -C(=O)R 13 , or -C(=O)OR 13 and is each R 13 is independently H, C1-C 10 alkyl, C6-C 10 aryl, -O-C6-C 10 aryl, or -O-C1-C 10 alkyl, and each of the C1-C 13 alkyl, C6-C 10 aryl, -O-C6-C 10 aryl, and -O-C1-C 10 aryl and -O-C1-C 10Alkyl is independently 1, 2, or 3 Rs c optionally substituted with substituents, each R a is independently halo, cyano, C1-C6 alkyl, carbonyl, -N3, -OR 8 , -NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic, a 4- to 6-membered heterocyclic containing 1, 2, or 3 heteroatoms selected from N, O, and S, a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or phenyl, and each 4- to 6-membered heterocyclic of R a is independently optionally substituted with 1, 2, or 3 R d substituents, and each phenyl of R a is independently optionally substituted with 1, 2, or 3 R e substituents, R 8 , R 9 , and R 10 are each independently H, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl, each R b is independently halo, cyano, C1-C6 alkoxy, or C1-C6 alkyl, each R c is independently halo, cyano, -OP(=O)(OH)(OR 14 ) or phenyl, and each phenyl of R c is optionally substituted with -OP(=O)(OH)(OR 14 ), each R 14 is independently H, C1-C8 alkyl, C3-C8 carbocyclic, C6-C 10 aryl, or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and each C1-C8 alkyl of R 14 is independently optionally substituted with 1, 2, or 3 R f substituents, each R dis independently carbonyl or C1-C6 alkyl, each R e is independently halo, cyano, or C1-C6 alkyl, each R f is independently halo, cyano, or phenyl, When a prodrug of a compound of formula A, a deuterated compound of formula A, or a pharmaceutically acceptable salt thereof is administered, the prodrug of the compound of formula A, the deuterated compound of formula A, or a pharmaceutically acceptable salt thereof is substantially converted to the compound of formula A or the deuterated compound of formula A. The patient is not a pregnant individual. 【0041】 In some embodiments, upon administration to the patient, more than 60% of the prodrug of the compound of formula A, the prodrug of the deuterated compound of formula A, or a pharmaceutically acceptable salt thereof is converted to the compound of formula A or the deuterated compound of formula A. In some embodiments, upon administration to the patient, more than 70% of the prodrug of the compound of formula A, the prodrug of the deuterated compound of formula A, or a pharmaceutically acceptable salt thereof is converted to the compound of formula A or the deuterated compound of formula A. In some embodiments, upon administration to the patient, more than 80% of the prodrug of the compound of formula A, the prodrug of the deuterated compound of formula A, or a pharmaceutically acceptable salt thereof is converted to the compound of formula A or the deuterated compound of formula A. In some embodiments, upon administration to the patient, more than 90% of the prodrug of the compound of formula A, the prodrug of the deuterated compound of formula A, or a pharmaceutically acceptable salt thereof is converted to the compound of formula A or the deuterated compound of formula A. In some embodiments, upon administration to the patient, more than 95% of the prodrug of the compound of formula A, the prodrug of the deuterated compound of formula A, or a pharmaceutically acceptable salt thereof is converted to the compound of formula A or the deuterated compound of formula A. In some embodiments, upon administration to the patient, more than 95% of the prodrug of the compound of formula A, the prodrug of the deuterated compound of formula A, or a pharmaceutically acceptable salt thereof is converted to the compound of formula A or the deuterated compound of formula A. 【0042】 In some embodiments, the carbon bonded to the 5-position on the tetrahydrofuranyl ring of the deuterated compound of formula A is substituted with one or two deuterium atoms. In some embodiments, the deuterated compound of formula A is 【Chemical formula】 is. In some embodiments, the deuterated compound of formula A is 【Chemical formula】 is. 【0043】 In some embodiments, the carbon of the base of the deuterated compound of formula A is substituted with one or more deuterium atoms. In some embodiments, the base is 【Chemical formula】 is. In some embodiments, the base is 【Chemical formula】 is. In some embodiments, the base is 【Chemical formula】 is. In some embodiments, the base is 【Chemical formula】 is. In some embodiments, the carbon of R 12 of the base of the deuterated compound of formula A is substituted with one or more deuterium atoms, for example, one or two deuterium atoms. In some embodiments, the carbon of R 11 of the base of the deuterated compound of formula A is substituted with one or more deuterium atoms, for example, one or two deuterium atoms. 【0044】 In some embodiments, R 1The carbon of [is] is substituted with one or more deuterium atoms, for example, one or two deuterium atoms. In some embodiments, the R of the deuterated compound of formula A 2 The carbon of [is] is substituted with one or more deuterium atoms, for example, one or two deuterium atoms. 【0045】 In some embodiments, the compound of formula A is 【Chemical formula】 or a pharmaceutically acceptable salt thereof. 【0046】 In some embodiments, the deuterated compound of formula A is 【Chemical formula】 or a pharmaceutically acceptable salt thereof. 【0047】 In some embodiments, the method comprises administering to a patient a prodrug of formula A having a compound of formula I, 【Chemical formula】 or a deuterated compound of formula I, or a pharmaceutically acceptable salt thereof, wherein R 3 is -C(=O)OR 7 or -C(=O)R 7 and R 7 is H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, C6-C 10 aryl, a 4-6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and the C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, C6-C 7 aryl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl of R 10 are optionally substituted with 1, 2, or 3 R aOptionally substituted with a substituent. 【0048】 In some embodiments, the carbon of the deuterated compound of Formula I at R 3 is substituted with one or more deuterium atoms, for example, one or two deuterium atoms. In some embodiments, the carbon of the deuterated compound of Formula I at R 7 is substituted with one or more deuterium atoms, for example, one or two deuterium atoms. 【0049】 In some embodiments, R 1 is -OH. In some embodiments, R 1 is -OC(=O)R 4 . In some embodiments, R 1 is -OC(=O)OR 4 . 【0050】 In some embodiments, R 2 is -OH. In some embodiments, R 2 is -OC(=O)R 5 . In some embodiments, R 2 is -OC(=O)OR 5 . 【0051】 In some embodiments, both R 1 and R 2 are -OH. In some embodiments, R 1 is -OC(=O)R 4 , and R 2 is -OC(=O)R 5 . In some embodiments, R 1 is OH, and R 2 is -OC(=O)R 5 or OC(O)OR 5 . In some embodiments, R 1 is -OC(=O)R 4 or -OC(=O)OR 4 , and R 2 is OH. In some embodiments, both R 1 and R 2combine to form -OC(=O)O-. In some embodiments, R 1 and R 2 combine to form -OP(=O)(OH)O-. In some embodiments, R 1 and R 2 combine to form, -OCHR 6 O-. 【0052】 In some embodiments, R 1 is OH, OC(O)CH(CH3)2, or OC(O)CH3, R 2 is OH, OC(O)CH(CH3)2, or OC(O)CH3, or R 1 and R 2 combine to form -OC(=O)O-. 【0053】 In some embodiments, R 4 is C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl. In some embodiments, R 4 is each independently selected from halo, cyano, -N3, -OR 8 , -NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic and phenyl, and is C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl optionally substituted with 1, 2, or 3 R a substituents. 【0054】 In some embodiments, R 4 is C1-C8 alkyl. In some embodiments, R 4 is halo, cyano, -N3, -OR 8 , -NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic and phenyl, and is C1-C8 alkyl optionally substituted with 1, 2, or 3 R a substituents. In some embodiments, R4 is unsubstituted C1-C8 alkyl. In some embodiments, R 4 is unsubstituted C1-C6 alkyl. In some embodiments, R 4 is unsubstituted C1-C3 alkyl. In some embodiments, R 4 is -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH 3、 or -C(CH3)3. In some embodiments, R 4 is -CH3 or -CH(CH3)2. 【0055】 In some embodiments, R 5 is C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl. In some embodiments, R 5 is, independently, 1, 2, or 3 R 8 substituents independently selected from halo, cyano, -N3, -OR 9 R 10 substituents independently selected from halo, cyano, -N3, -OR, -NR a R, -OP(=O)(OH)2, C3-C8 carbocyclic, and phenyl, and is optionally substituted with 1, 2, or 3 R 【0056】 In some embodiments, R 5 is C1-C8 alkyl. In some embodiments, R 5 is, independently, 1, 2, or 3 R 8 substituents independently selected from halo, cyano, -N3, -OR 9 R 10 substituents independently selected from halo, cyano, -N3, -OR, -NR a R, -OP(=O)(OH)2, C3-C8 carbocyclic, and phenyl, and is optionally substituted with 1, 2, or 3 R 5 is unsubstituted C1-C8 alkyl. In some embodiments, R 5 is unsubstituted C1-C6 alkyl. In some embodiments, R 5 is unsubstituted C1-C3 alkyl. In some embodiments, R 5is -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH 3、 or -C(CH3)3. In some embodiments, R 5 is -CH3 or -CH(CH3)2. 【0057】 In some embodiments, R 4 and R 5 are the same. In some embodiments, R 4 and R 5 are different. In some embodiments, R 4 is C1-C8 alkyl, and R 5 is C1-C8 alkyl. In some embodiments, R 4 is unsubstituted C1-C8 alkyl, and R 5 is unsubstituted C1-C8 alkyl. In some embodiments, R 4 is -CH3 or -CH(CH3)2, and R 5 is -CH3 or -CH(CH3)2. In some embodiments, R 4 is -CH3, and R 5 is -CH3. In some embodiments, R 4 is -CH(CH3)2, and R 5 is -CH(CH3)2. 【0058】 In some embodiments, R 6 is H. In some embodiments, R 6 is C1-C6 alkyl. In some embodiments, R 6 is -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH 3、 or -C(CH3)3. In some embodiments, R 6 is C1-C6 alkoxy. 【0059】 In some embodiments, R 6 is a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, R6 is a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, substituted with 1, 2, or 3 R b substituents. In some embodiments, R 6 is a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, R 6 is an unsubstituted 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S. 【0060】 In some embodiments, R 6 is C6-C 10 aryl. In some embodiments, R 6 is a C6-C b aryl substituted with 1, 2, or 3 R 10 substituents. In some embodiments, R 6 is an unsubstituted C6-C 10 aryl. In some embodiments, R 6 is phenyl. In some embodiments, R 6 is unsubstituted phenyl. 【0061】 In some embodiments, R 3 is -C(=O)OR 7 . In some embodiments, R 3 is -C(=O)R 7 . 【0062】 In some embodiments, R 7 is C1-C8 alkyl, C3-C8 carbocyclic, C6-C 10 aryl, a 4- to 6-membered heterocyclic containing 1, 2, or 3 heteroatoms selected from N, O, and S, or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, R 7 is each -OR 8, -OP(=O)(OH)2, 1, 2, or 3 Rs independently selected from C3-C8 carbocyclic and phenyl a C1-C8 alkyl, C3-C8 carbocyclic, C6-C 10 aryl, a 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, optionally substituted with substituents. 【0063】 In some embodiments, R 7 is C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl. In some embodiments, each R 7 is independently halo, cyano, -N3, -OR 8 , -NR 9 R 10 , -OP(=O)(OH)2, 1, 2, or 3 Rs independently selected from C3-C8 carbocyclic and phenyl a substituted C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl, optionally substituted with substituents. In some embodiments, each R 7 is independently halo, cyano, -N3, -OR 8 , -NR 9 R 10 , and 1, 2, or 3 Rs independently selected from phenyl a substituted C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl, optionally substituted with substituents. 【0064】 In some embodiments, R 7 is C1-C8 alkyl. In some embodiments, each R 7 is halo, cyano, -N3, -OR 8 , -NR 9 R 10 , -OP(=O)(OH)2, 1, 2, or 3 Rs independently selected from C3-C8 carbocyclic and phenyl a substituted C1-C8 alkyl, optionally substituted with substituents. In some embodiments, R 7is -OR 8 One R selected from -OP(=O)(OH)2, C3-C8 carbocyclic and unsubstituted phenyl a is C1-C8 alkyl optionally substituted with substituents. In some embodiments, R 7 is halo, cyano, -N3, -OR 8 -NR 9 R 10 and one, two or three Rs independently selected from phenyl a is C1-C8 alkyl optionally substituted with substituents. In some embodiments, R 7 is halo, cyano, -N3, -OR 8 -NR 9 R 10 and one, two or three Rs independently selected from unsubstituted phenyl a is C1-C8 alkyl optionally substituted with substituents. In some embodiments, R 7 is C1-C8 alkyl substituted with -OR 8 . In some embodiments, R 7 is C1-C8 alkyl substituted with phenyl. In some embodiments, R 7 is C1-C8 alkyl substituted with C3-C8 carbocyclic. In some embodiments, R 7 is C1-C8 alkyl substituted with -OP(=O)(OH)2. 【0065】 In some embodiments, R 7 is C1-C6 alkyl. In some embodiments, R 7 is halo, cyano, -N3, -OR 8 -NR 9 R 10 -OP(=O)(OH)2, C3-C8 carbocyclic and one, two or three Rs independently selected from phenyl a is C1-C6 alkyl optionally substituted with substituents. In some embodiments, R 7 is -OR 8, one R selected from -OP(=O)(OH)2, C3-C8 carbocyclic and unsubstituted phenyl a is C1-C6 alkyl optionally substituted with substituents. 【0066】 In some embodiments, R 7 is C1-C4 alkyl substituted with phenyl. In some embodiments, R 7 is C1-C4 alkyl substituted with phenyl. R 7 is C1-C4 alkyl substituted with -OP(=O)(OH)2. 【0067】 In some embodiments, R 7 is C2-C4 alkyl. In some embodiments, R 7 is C2-C4 alkyl substituted with -OR 8 . In some embodiments, R 7 is C2-C4 alkyl substituted with -OCH3. In some embodiments, R 7 is C2-C4 alkyl substituted with C4-C7 carbocyclic. In some embodiments, R 7 is C2-C4 alkyl substituted with. [Chemical formula] 【0068】 In some embodiments, R 7 is -CH3, -CH2CH3, [Chemical formula] and so on. In some embodiments, R 7 is -CH3, -CH2CH3, [Chemical formula] and so on. In some embodiments, R 7 is -CH3, -CH2CH3, [Chemical formula] is. 【0069】 In some embodiments, R 7 is 【Chem.】 is. In some embodiments, R 7 is 【Chem.】 is. In some embodiments, R 7 is 【Chem.】 is. In some embodiments, R 7 is 【Chem.】 is. In some embodiments, R 7 is 【Chem.】 is. In some embodiments, R 7 is 【Chem.】 is. 【0070】 In some embodiments, R 7 is C3-C8 carbocyclic. In some embodiments, R 7 is a C3-C8 carbocyclic optionally substituted with 1, 2 or 3 R 8 substituents independently selected from halogen, cyano, -N3, -OR 9 R 10 substituents independently selected from halogen, cyano, -N3, -OR a substituents independently selected from halogen, cyano, -N3, -OR 7 substituents independently selected from halogen, cyano, -N3, -OR 8 substituents independently selected from halogen, cyano, -N3, -OR9 R 10 、 -OP(=O)(OH)2, C3-C8 carbocyclic, and unsubstituted phenyl, independently selected, 1, 2, or 3 R a is a C3-C8 carbocyclic optionally substituted with substituents. In some embodiments, R 7 is -OR 8 、 -NR 9 R 10 、 C3-C8 carbocyclic, and unsubstituted phenyl, independently selected, 1, 2, or 3 substituents, optionally substituted C3-C8 carbocyclic. 【0071】 In some embodiments, R 7 is 【Chemical formula】 is. 【0072】 In some embodiments, R 7 is C6-C 10 aryl. In some embodiments, R 7 is halogen, cyano, -N3, -OR 8 、 -NR 9 R 10 、 -OP(=O)(OH)2, C3-C8 carbocyclic, and phenyl, independently selected, 1, 2, or 3 R a substituents, optionally substituted C6-C 10 aryl. In some embodiments, R 7 is halogen, cyano, -N3, -OR 8 、 -NR 9 R 10 、 -OP(=O)(OH)2, C3-C8 carbocyclic, and unsubstituted phenyl, independently selected, 1, 2, or 3 R a substituents, optionally substituted C6-C 10 aryl. 【0073】 In some embodiments, R 7 is phenyl or naphthyl. In some embodiments, R 7is each independently selected from halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic, and unsubstituted phenyl, and is 1, 2, or 3 R a substituents, and is phenyl or naphthyl optionally substituted with the substituents. In some embodiments, R 7 is phenyl. In some embodiments, R 7 is each independently selected from halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic, and unsubstituted phenyl, and is 1, 2, or 3 R a substituents, and is phenyl optionally substituted with the substituents. 【0074】 In some embodiments, R 7 is 【Chemical formula】 as shown. 【0075】 In some embodiments, R 7 is a 4-6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, R 7 is each independently selected from halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic, and phenyl, and is a 4-6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S optionally substituted with 1, 2, or 3 R a substituents. In some embodiments, R 7 is each independently selected from halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic, and unsubstituted phenyl, and is 1, 2, or 3 Ra A 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, optionally substituted with substituents. 【0076】 In some embodiments, R 7 is a 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, R 7 is independently selected from halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclyl, and unsubstituted phenyl, and is a 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, optionally substituted with 1, 2, or 3 R a substituents. 【0077】 In some embodiments, R 7 is a 5-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, R 7 is independently selected from halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclyl, and unsubstituted phenyl, and is a 5-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, optionally substituted with 1, 2, or 3 R a substituents. In some embodiments, R 7 is an unsubstituted 5-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S. 【0078】 In some embodiments, R 7 is 【Chemical formula】 as follows. 【0079】 In some embodiments, R7 is a 4-membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S. In some embodiments, R 7 is an unsubstituted 4-membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S. 【0080】 In some embodiments, R 7 is 【Chemical formula】 as follows. 【0081】 In some embodiments, R 7 is a 5- to 6-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S. In some embodiments, R 7 is a 5- to 6-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S, optionally substituted with 1, 2 or 3 R 8 substituents independently selected from halogen, cyano, -N3, -OR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclyl and phenyl. In some embodiments, R a is a 5- to 6-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S, optionally substituted with 1, 2 or 3 R 7 substituents independently selected from halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclyl and unsubstituted phenyl. a 【0082】 In some embodiments, R 7 is a 5-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S. In some embodiments, R 7 is a 5-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S, optionally substituted with 1, 2 or 3 R 8 substituents independently selected from halogen, cyano, -N3, -OR 9R 10 One, two or three Rs independently selected from -OP(=O)(OH)2, C3-C8 carbocyclic and unsubstituted phenyl a It is a 5-membered heteroaryl containing one, two or three heteroatoms selected from N, O and S, optionally substituted with substituents. In some embodiments, R 7 is an unsubstituted 5-membered heteroaryl containing one, two or three heteroatoms selected from N, O and S. 【0083】 In some embodiments, R 7 is a 6-membered heteroaryl containing one, two or three heteroatoms selected from N, O and S. In some embodiments, R 7 is halogen, cyano, -N3, -OR 8 -NR 9 R 10 One, two or three Rs independently selected from -OP(=O)(OH)2, C3-C8 carbocyclic and unsubstituted phenyl a It is a 6-membered heteroaryl containing one, two or three heteroatoms selected from N, O and S, optionally substituted with substituents. In some embodiments, R 7 is halogen, cyano, and -NR 9 R 10 One, two or three Rs independently selected from a It is a 6-membered heteroaryl containing one, two or three heteroatoms selected from N, O and S, optionally substituted with substituents. In some embodiments, R 7 is an unsubstituted 6-membered heteroaryl containing one, two or three heteroatoms selected from N, O and S. 【0084】 In some embodiments, R 7 is 【Chemical formula】 as follows. 【0085】 In some embodiments, R 7 is [Chemical formula] is as follows. 【0086】 In some embodiments, R 7 is [Chemical formula] is as follows. 【0087】 In some embodiments, R 7 is [Chemical formula] is as follows. 【0088】 In some embodiments, R 8 is H. In some embodiments, R 8 is C1-C6 alkyl. In some embodiments, R 8 is -CH3. In some embodiments, R 8 is C1-C6 haloalkyl. In some embodiments, R 8 is C3-C6 cycloalkyl. 【0089】 In some embodiments, R 9 is H. In some embodiments, R 9 is C1-C6 alkyl. In some embodiments, R 9 is -CH3. In some embodiments, R 9 is C1-C6 haloalkyl. In some embodiments, R 9 is C3-C6 cycloalkyl. 【0090】 In some embodiments, R 10 is H. In some embodiments, R 10 is C1-C6 alkyl. In some embodiments, R 10 is -CH3. In some embodiments, R 10is C1-C6 haloalkyl. In some embodiments, R 10 is C3-C6 cycloalkyl. 【0091】 In some embodiments, the base is [Chemical formula] is. In some embodiments, the base is [Chemical formula] is. 【0092】 In some embodiments, the base is [Chemical formula] is. In some embodiments, the base is [Chemical formula] is. In some embodiments, the base is [Chemical formula] is. In some embodiments, the base is [Chemical formula] is. 【0093】 In some embodiments, R 11 is C1-C3 alkyl substituted with -OP(=O)(OH)(OR 14 ). In some embodiments, R 11 is -(CH2)OP(=O)(OH)(OR 14 ). 【0094】 In some embodiments, R 14 is H. 【0095】 In some embodiments, R 14is H or C1-C8 alkyl, R 14 The C1-C8 alkyl of is optionally substituted with 1, 2 or 3 substituents independently selected from halogen, cyano and phenyl. 【0096】 In some embodiments, R 14 is C1-C8 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from halogen, cyano, and phenyl. In some embodiments, R 14 is C1-C3 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from halogen, cyano, and phenyl. In some embodiments, R 14 is C1-C3 alkyl substituted with 1 phenyl. In some embodiments, R 14 is 【Chemical formula】 is. 【0097】 In some embodiments, R 11 is -(CH2)OP(=O)(OH)2. In some embodiments, R 11 is 【Chemical formula】 is. 【0098】 In some embodiments, R 12 is H. In some embodiments, R 12 is C1-C6 alkyl. In some embodiments, R 12 is -C(=O)R 13 is. In some embodiments, R 12 is -C(=O)(CH2)2CH3. In some embodiments, R 12 is -C(=O)OR 13 is. In some embodiments, R 12 is -C(=O)OCH2CH(CH3)2. In some embodiments, R 12is -C(=O)OCH2CH(CH3)2 or -C(=O)(CH2)2CH3. In some embodiments, R 12 is [Chemical formula] as follows. 【0099】 In some embodiments, R 13 is H. In some embodiments, R 13 is C1-C 10 alkyl. In some embodiments, R 13 is C1-C8 alkyl. In some embodiments, R 13 is C1-C8 alkyl optionally substituted with one, two, or three R 14 substituents independently selected from halogen, cyano, -OP(=O)(OH)(OR c ). In some embodiments, R 13 is C1-C8 alkyl optionally substituted with one, two, or three R c substituents independently selected from halogen, cyano, and phenyl. In some embodiments, R 13 is C1-C8 alkyl optionally substituted with one, two, or three R c substituents independently selected from halogen, cyano, and unsubstituted phenyl. In some embodiments, R 13 is C1-C8 alkyl. In some embodiments, R 13 is -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH 3、 or -C(CH3)3. In some embodiments, R 13 is -CH2CH(CH3)2 or -(CH2)2CH3. In some embodiments, R 13 is -(CH2)OP(=O)(OH)2. In some embodiments, R 13 is C6-C 10 aryl. In some embodiments, R 13 is phenyl. In some embodiments, R13 is -O-C6~C 10 is aryl. In some embodiments, R 13 is -O-phenyl. In some embodiments, R 13 is -O-C1~C 10 is alkyl. In some embodiments, R 13 is -O-CH3, -O-CH2CH3, -O-(CH2)2CH3, -O-(CH2)4CH3, or -O-(CH2)6CH3. 【0100】 In some embodiments, R 13 is 【Chemical formula】 is. 【0101】 In some embodiments, the base is 【Chemical formula】 is. 【0102】 In some embodiments, the method comprises administering to a patient a compound of formula A or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is -OH, -OC(=O)R 4 or -OC(=O)OR 4 and R 2 is -OH, -OC(=O)R 5 or -OC(=O)OR 5 alternatively, R 1 and R 2 together form -OC(=O)O- and R 4 and R 5 are each independently unsubstituted C1~C8 alkyl, unsubstituted C3~C8 carbocyclic, unsubstituted C6~C 10An unsubstituted 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from aryl, N, O, and S, or an unsubstituted 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S. 【0103】 In some embodiments, the base is 【Chemical formula】 is. 【0104】 In some embodiments, R 4 and R 5 are each independently unsubstituted C1-C8 alkyl. In some embodiments, R 4 and R 5 are each independently unsubstituted C1-C6 alkyl. In some embodiments, R 1 is -OH or -OC(=O)R 4 and R 2 is -OH or -OC(=O)R 5 is. In some embodiments, R 1 and R 2 are each independently -OH, OC(=O)CH(CH3)2, or OC(=O)CH3. In some embodiments, R 1 and R 2 together form -OC(=O)O-. 【0105】 In some embodiments, the method comprises administering to a patient a deuterated compound of formula A having formula A1, 【Chemical formula】 or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is -OH, -OC(=O)R 4 , or -OC(=O)OR 4 , and R 2 is -OH, -OC(=O)R 5、or -OC(=O)OR 5 or, R 1 and R 2 together form -OC(=O)O-, R 4 and R 5 are each independently unsubstituted C1-C8 alkyl, unsubstituted C3-C8 carbocyclic, unsubstituted C6-C 10 aryl, unsubstituted 4-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S, or unsubstituted 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S. 【0106】 In some embodiments, R 4 and R 5 are each independently unsubstituted C1-C8 alkyl. In some embodiments, R 4 and R 5 are each independently unsubstituted C1-C6 alkyl. In some embodiments, R 1 is -OH or -OC(=O)R 4 and R 2 is -OH or -OC(=O)R 5 In some embodiments, R 1 and R 2 are each independently -OH, OC(=O)CH(CH3)2, or OC(=O)CH3. In some embodiments, R 1 and R 2 together form -OC(=O)O-. 【0107】 In some embodiments, the method comprises administering to a patient a deuterated compound of formula A having formula A2, 【Chemical formula】 or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is -OH, -OC(=O)R 4 or -OC(=O)OR4 and R 2 is -OH, -OC(=O)R 5 or -OC(=O)OR 5 alternatively, R 1 and R 2 together form -OC(=O)O- R 4 and R 5 are each independently unsubstituted C1-C8 alkyl, unsubstituted C3-C8 carbocyclyl, unsubstituted C6-C 10 aryl, unsubstituted 4-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S, or unsubstituted 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S. 【0108】 In some embodiments, R 4 and R 5 are each independently unsubstituted C1-C8 alkyl. In some embodiments, R 4 and R 5 are each independently unsubstituted C1-C6 alkyl. In some embodiments, R 1 is -OH or -OC(=O)R 4 and R 2 is -OH or -OC(=O)R 5 In some embodiments, R 1 and R 2 are each independently -OH, OC(=O)CH(CH3)2, or OC(=O)CH3. In some embodiments, R 1 and R 2 together form -OC(=O)O-. 【0109】 In some embodiments, the method comprises administering to a patient a compound of formula I or a pharmaceutically acceptable salt thereof, wherein R 1 is -OH, -OC(=O)R 4 or -OC(=O)OR 4 and R2 is -OH, -OC(=O)R 5 or -OC(=O)OR 5 or, R 1 and R 2 together form -OC(=O)O- R 3 is -C(=O)OR 7 or -C(=O)R 7 and R 4 R 5 and R 7 are each independently unsubstituted C1-C8 alkyl, unsubstituted C3-C8 carbocyclic, unsubstituted C6-C 10 aryl, unsubstituted 4-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S, or unsubstituted 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S. 【0110】 In some embodiments, the base is 【Chemical formula】 as follows. 【0111】 In some embodiments, R 4 R 5 and R 7 are each independently unsubstituted C1-C8 alkyl. In some embodiments, R 4 R 5 and R 7 are each independently unsubstituted C1-C6 alkyl. In some embodiments, R 1 is -OH or -OC(=O)R 4 and R 2 is -OH or -OC(=O)R 5 and R 3 is -C(=O)R 7 In some embodiments, R 1 and R 2is, independently of each other, -OH, OC(=O)CH(CH3)2, or OC(=O)CH3, and R 7 is -CH(CH3)2 or -CH3. In some embodiments, R 1 and R 2 together form -OC(=O)O-, and R 7 is -CH(CH3)2 or -CH3. 【0112】 In some embodiments, the method comprises administering to a patient a deuterated compound of formula I having formula Ia, 【Chemical formula】 or a pharmaceutically acceptable salt thereof, wherein R 1 is -OH, -OC(=O)R 4 , or -OC(=O)OR 4 , R 2 is -OH, -OC(=O)R 5 , or -OC(=O)OR 5 , or alternatively R 1 and R 2 together form -OC(=O)O-, R 3 is -C(=O)OR 7 , or -C(=O)R 7 , R 4 , R 5 , and R 7 are each independently unsubstituted C1-C8 alkyl, unsubstituted C3-C8 carbocyclyl, unsubstituted C6-C 10 aryl, unsubstituted 4-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S, or unsubstituted 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S. 【0113】 In some embodiments, R 4 , R 5 , and R 7is independently a non-substituted C1-C8 alkyl. In some embodiments, R 4 , R 5 , and R 7 are independently non-substituted C1-C6 alkyl. In some embodiments, R 1 is -OH or -OC(=O)R 4 , R 2 is -OH or -OC(=O)R 5 , R 3 is -C(=O)R 7 . In some embodiments, R 1 and R 2 are independently -OH, OC(=O)CH(CH3)2, or OC(=O)CH3, and R 7 is -CH(CH3)2 or -CH3. In some embodiments, R 1 and R 2 together form -OC(=O)O-, and R 7 is -CH(CH3)2 or -CH3. 【0114】 In some embodiments, the method comprises administering to a patient a deuterated compound of formula I having formula Ib, 【Chemical formula】 or a pharmaceutically acceptable salt thereof, wherein R 1 is -OH, -OC(=O)R 4 , or -OC(=O)OR 4 , R 2 is -OH, -OC(=O)R 5 , or -OC(=O)OR 5 , or alternatively, R 1 and R 2 together form -OC(=O)O-, R 3 is -C(=O)OR 7 , or -C(=O)R 7 , R 4 , R5 and R 7 is, independently of one another, unsubstituted C1-C8 alkyl, unsubstituted C3-C8 carbocyclyl, unsubstituted C6-C 10 aryl, unsubstituted 4-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S, or unsubstituted 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S. 【0115】 In some embodiments, R 4 , R 5 , and R 7 is, independently of one another, unsubstituted C1-C8 alkyl. In some embodiments, R 4 , R 5 , and R 7 is, independently of one another, unsubstituted C1-C6 alkyl. In some embodiments, R 1 is -OH or -OC(=O)R 4 , R 2 is -OH or -OC(=O)R 5 , R 3 is -C(=O)R 7 . In some embodiments, R 1 and R 2 are, independently of one another, -OH, OC(=O)CH(CH3)2, or OC(=O)CH3, and R 7 is -CH(CH3)2 or -CH3. In some embodiments, R 1 and R 2 together form -OC(=O)O-, and R 7 is -CH(CH3)2 or -CH3. 【0116】 In some embodiments, the compound of formula A or a prodrug of the compound of formula A is a compound of Table 1, or a pharmaceutically acceptable salt thereof. 【0117】 【Table 1】 【0118】 In some embodiments, the compound of formula I is a compound of Table 2, or a pharmaceutically acceptable salt thereof. 【0119】 【Table 2-1】 【Table 2-2】 【Table 2-3】 【Table 2-4】 【Table 2-5】 【Table 2-6】 【Table 2-7】 【Table 2-8】 【Table 2-9】 【Table 2-10】 【Table 2-11】 【Table 2-12】 【Table 2-13】 【Table 2-14】 【0120】 In some embodiments, the deuterated compound of Formula A, the prodrug of the compound of Formula A, or the prodrug of the deuterated compound of Formula A is a compound of Table 3, or a pharmaceutically acceptable salt thereof. 【0121】 【Table 3-1】 【Table 3-2】 【Table 3-3】 【Table 3-4】 【Table 3-5】 【Table 3-6】 【Table 3-7】 【Table 3-8】 【Table 3-9】 【Table 3-10】 【Table 3-11】 【Table 3-12】 【Table 3-13】 【Table 3-14】 【Table 3-15】 【Table 3-16】 【Table 3-17】 【Table 3-18】 【Table 3-19】 【Table 3-20】 【Table 3-21】 【Table 3-22】 【Table 3-23】 【Table 3-24】 【0122】 In some embodiments, the compound of formula I is a compound of Table 4, or a pharmaceutically acceptable salt thereof. 【0123】 【Table 4-1】 【0124】 In some embodiments, the compound of formula I is 【Chemical formula】 or a pharmaceutically acceptable salt thereof. 【0125】 In some embodiments, the deuterated compound of formula I is 【Chemical formula】 or a pharmaceutically acceptable salt thereof. 【0126】 In some embodiments, the compound of formula I is 【Chemical formula】 or a pharmaceutically acceptable salt thereof. 【0127】 The compounds described herein can be formulated with conventional carriers and excipients. For example, tablets contain excipients, lubricants, fillers, binders, etc. Aqueous formulations are prepared in a sterile form and are generally isotonic when delivery by means other than oral administration is intended. All formulations may optionally contain excipients such as those described in "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, stearic acid, and the like. In some embodiments, the formulation contains one or more pharmaceutically acceptable excipients. The pH of the formulation ranges from about 3 to about 11, usually about 7 to 10. In some embodiments, the pH of the formulation ranges from about 2 to about 5, usually about 3 to 4. 【0128】 Although it is possible to administer the compounds of the present disclosure (the "active ingredients") alone, it may be preferable to present them as pharmaceutical formulations. Formulations for both animal and human use of the present invention thus contain at least one active ingredient, as defined above, together with one or more acceptable carriers therefor and optionally other additional therapeutic ingredients, particularly the additional therapeutically active ingredients discussed herein. The carrier needs to be "acceptable" in the sense of being compatible with the other ingredients of the formulation and physiologically harmless to its recipient. 【0129】 The formulations include those suitable for the aforementioned routes of administration. The formulations can conveniently be presented in unit dosage form and can 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 the active ingredient into association with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product. 【0130】 In some embodiments, the pharmaceutical formulation is for subcutaneous, intramuscular, intravenous, oral, or inhalation administration. 【0131】 In some embodiments, the compounds described herein, e.g., a compound of formula A described herein, a deuterated compound of formula A, a prodrug of a compound of formula A, a prodrug of a deuterated compound of formula A, a compound of formula I, a deuterated compound of formula I, or a pharmaceutically acceptable salt thereof, have optimized / improved pharmacokinetic properties and are suitable for oral administration. For example, the compound of formula I has improved bioavailability and can thus be administered by oral administration. 【0132】 In some embodiments, the formulations of the invention suitable for oral administration can 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 liquid emulsion or a water-in-oil liquid emulsion. The active ingredient can also be administered as a bolus, a lozenge, or a paste. 【0133】 In some embodiments, the tablets are made by compressing or molding, optionally together with one or more accessory components. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant, or dispersant, 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 tablets may optionally be coated or scored and are optionally formulated to provide sustained or controlled release of the active ingredient therefrom. 【0134】 For eye or other external tissue infections, such as those of the mouth and skin, the formulation is applied as a topical ointment or cream containing the active ingredient in an amount, for example, of from 0.075 to 20% w / w (increments of 0.1% w / w, such as 0.1%, 0.6% w / w, 0.7% w / w, etc., in the range of 0.1% to 20% of the active ingredient), preferably from 0.2 to 15% w / w, and most preferably from 0.5 to 10% w / w. When formulated as an ointment, the active ingredient can be used with either a paraffin-based or water-miscible ointment base. Alternatively, the active ingredient can be formulated into a cream having an oil-in-water cream base. 【0135】 If desired, the aqueous phase of the cream base can contain, for example, at least 30% w / w 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. The topical formulation can desirably contain a compound that enhances the absorption or penetration of the active ingredient through the skin or other affected area. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogs. 【0136】 The oily phase of the emulsion of the present invention can be composed of known components in a known manner. The phase can simply contain an emulsifier (otherwise known as an emulsion), but preferably contains at least one emulsifier and a mixture of a fat or an oil, or a mixture of both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. It is also preferred to include both oils and fats. Together, the emulsifier, with or without a stabilizer, constitutes a so-called emulsifying wax, and the wax, together with the oil and fat, constitutes a so-called emulsifying ointment base that forms the oily dispersed phase of the cream formulation. 【0137】 Emulsifying agents 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 emulsifying agents and emulsion stabilizers suitable for use in the formulations of the present invention include TWEEN® 80. 【0138】 The selection of a suitable oil or fat 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 consistency suitable for avoiding leakage from a tube or other container. A straight-chain or branched-chain, mono- or dibasic alkyl ester, 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-chain esters known as Crodamol CAP may be used, with the last three being preferred esters. These may be used alone or in combination, depending on the required properties. Alternatively, high melting point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils are used. 【0139】 The pharmaceutical preparations according to the invention comprise a compound according to the invention together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. The pharmaceutical preparations containing the active ingredient can be in any form suitable for the intended method of administration. For example, when used for oral use, tablets, troches, lozenges, aqueous or oily 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 can contain one or more agents including sweetening agents, flavoring agents, coloring agents, and preservatives to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets are acceptable. These excipients can be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, calcium phosphate 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. Tablets can be uncoated or can be coated by known techniques including microencapsulation to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a long period. For example, time-delay substances such as glyceryl monostearate or glyceryl distearate can be used alone or in combination with waxes. 【0140】 Preparations for oral use can 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 an oil medium such as water or peanut oil, liquid paraffin or olive oil. 【0141】 The aqueous suspension of the present invention contains an active material, mixed with an excipient suitable for the production of an aqueous suspension. Such excipients include suspending agents such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinyl pyrrolidone, tragacanth gum and acacia gum, and dispersing agents or wetting agents such as naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides and fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide and long-chain aliphatic alcohols (e.g., heptadecaethyleneoxy cetanol), condensation products of ethylene oxide and partial esters derived from fatty acids, and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more colorants, one or more flavoring agents, and one or more sweetening agents such as sucrose or saccharin. Further non-limiting examples of suspending agents include cyclodextrin. In some examples, the suspending agent is sulfobutyl ether β-cyclodextrin (SEB-β-CD), such as Captisol®. 【0142】 The oil suspension can be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oral suspension may contain a thickening agent such as beeswax, hard paraffin, or cetyl alcohol. Sweetening agents and flavoring agents as described 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. 【0143】 The dispersible powders and granules of the present invention suitable for the preparation of an aqueous suspension by the addition of water provide an active ingredient, mixed with a dispersing agent or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing agents or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, such as sweetening agents, flavoring agents, and colorants, may also be present. 【0144】 The pharmaceutical composition of the present invention can also be in the form of an oil-in-water emulsion. The oil phase can 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 acacia gum and tragacanth gum, naturally occurring phosphatides such as soybean lecithin, esters or partial esters derived from fatty acids, and hexitol anhydrides such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsion can also contain sweetening agents and flavoring agents. Syrups and elixirs can be formulated with sweetening agents such as glycerol, sorbitol, or sucrose. Such formulations can also contain lubricants, preservatives, flavoring agents, or coloring agents. 【0145】 The pharmaceutical composition of the present invention can be in the form of a sterile injectable preparation such as a sterile aqueous or oily suspension. This suspension can be formulated according to known techniques using the suitable dispersing or wetting agents and suspending agents described above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent such as a solution in 1,3-butanediol, or can be prepared as a lyophilized powder. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, a sterile fixed oil has conventionally been used as a solvent or suspending medium. For this purpose, any solvent-free fixed oil containing synthetic monoglycerides or diglycerides can be used. In addition, fatty acids such as oleic acid can likewise be used in the preparation of injectables. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution isotonic sodium chloride solution, and hypertonic sodium chloride solution. 【0146】 The amount of active ingredient that may be combined with a carrier substance to produce a single dosage form will vary depending on the host to be treated and the particular mode of administration. For example, a sustained release formulation intended for oral administration to humans may contain from about 1 to 1000 mg of active substance formulated with a suitable and convenient amount of carrier substance that may vary in the range of about 5 to about 95% (weight:weight) of the total composition. Pharmaceutical compositions can be prepared to provide an easily measurable amount for administration. For example, an aqueous solution intended for intravenous infusion may contain from about 3 to 500 mg of active ingredient per milliliter of solution to enable infusion of a suitable volume at a rate of about 30 mL per hour. 【0147】 Formulations suitable for topical administration to the eye also include eye drops in which 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 at a concentration of from 0.5 to 20%, advantageously from 0.5 to 10%, especially about 1.5% w / w. 【0148】 Formulations suitable for topical administration in the mouth include lozenges containing the active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles containing the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes containing the active ingredient in a suitable liquid carrier. 【0149】 Formulations for rectal administration may be presented, for example, as suppositories having a suitable base containing cocoa butter or a salicylate. 【0150】 In some embodiments, the compounds described herein are administered by inhalation. In some embodiments, formulations suitable for intrapulmonary or nasal administration have a particle size in the range of, for example, 0.1 to 500 micrometers, such as 0.5, 1, 30, 35, etc., and are administered by rapid inhalation through the nasal route 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 together with other therapeutic agents. In some embodiments, the compounds used herein are formulated and administered as a dry powder. 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. 【0151】 Formulations suitable for vaginal administration can be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations, containing, in addition to the active ingredient, a carrier as is known to be appropriate in the art. 【0152】 Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes to render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions which may include suspending and thickening agents. 【0153】 The formulations are presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) state which requires only the addition of a sterile liquid carrier, for example water for injection, immediately prior to use. Immediate injection solutions and suspensions are prepared from sterile powders, granules and tablets of the above-mentioned types. Preferred unit-dose formulations contain the daily dose or unit daily sub-dose of the active ingredient as listed above herein, or appropriate fractions thereof. 【0154】 In addition to the components specifically described above, the formulations of the present invention may include other conventional drugs in the art with respect to the type of formulation in question. For example, those suitable for oral administration may be understood to include flavoring agents. 【0155】 The present invention further provides a veterinary composition comprising at least one of the above active ingredients, as defined together with a veterinary carrier therefor. 【0156】 A veterinary carrier is a substance useful for the purpose of administering the composition and is otherwise inert or acceptable in veterinary art and compatible with the active ingredient, and can be a solid, liquid, or gaseous substance. These veterinary compositions can be administered orally, parenterally, or by any other desired route. 【0157】 The compounds described herein are used to provide a controlled release pharmaceutical formulation (a "controlled release formulation") containing one or more of the compounds described herein as active ingredients, in which the release of the active ingredient is controlled and regulated to allow for less frequent dosing or to improve the pharmacokinetics or toxicity profile of a given active ingredient. 【0158】 Also provided herein are kits containing the compounds described herein. In some embodiments, the kits described herein may include a label and / or instructions for use of the compounds in the treatment of a disease or condition in a non-pregnant patient in need thereof. In some embodiments, the disease or condition is a viral infection. 【0159】 In some embodiments, the kit may also include one or more additional therapeutic agents and / or instructions for use of the additional therapeutic agents, in combination with a compound of formula A, a deuterated compound of formula A, a prodrug of a compound of formula A, a prodrug of a deuterated compound of formula A, a compound of formula I, a deuterated compound of formula I, or a pharmaceutically acceptable salt thereof, in the treatment of a disease or condition in a subject (e.g., a human) in need thereof. 【0160】 In some embodiments, the kits provided herein include individual dosage units of a compound of Formula A, a deuterated compound of Formula A, a prodrug of a compound of Formula A, a prodrug of a deuterated compound of Formula A, a compound of Formula I, a deuterated compound of Formula I, or a pharmaceutically acceptable salt thereof. Examples of individual dosage units can include pills, tablets, capsules, prefilled syringes or syringe cartridges, IV bags, inhalers, nebulizers, etc., each of which contains a therapeutically effective amount of a compound of Formula A, a deuterated compound of Formula A, a prodrug of a compound of Formula A, a prodrug of a deuterated compound of Formula A, a compound of Formula I, a deuterated compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the kit can have a single dosage unit and other multiple dosage units, such as the number of dosage units required for a particular regimen or period. 【0161】 One or more of the compounds described herein 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). In some embodiments, the compounds described herein are administered by inhalation or intravenously. In some embodiments, the compounds described herein are administered orally. It will be understood that the preferred route can vary, for example, depending on the condition of the recipient. 【0162】 In the methods described herein for the treatment of viral infections, the compounds described herein can be administered to a human who may have come into contact with the virus or who is already suffering from the viral infection at any point in time. In some embodiments, the compounds described herein can be prophylactically administered to a human who has come into contact with a human suffering from a viral infection or who is at risk of coming into contact with a human suffering from a viral infection, such as a healthcare provider. In some embodiments, the administration of the compounds described herein can be to a human who tests positive for a viral infection but who has not yet shown symptoms of the viral infection. In some embodiments, the administration of the compounds described herein can be to a human at the onset of symptoms of a viral infection. 【0163】 In some embodiments, the methods described herein include event-driven administration to a subject of a compound described herein, such as a compound of formula A, a deuterated compound of formula A, a prodrug of a compound of formula A, a prodrug of a deuterated compound of formula A, a compound of formula I, a deuterated compound of formula I, or a pharmaceutically acceptable salt thereof. 【0164】 As used herein, the terms "event-driven" or "event-driven administration" refer to administering a compound described herein (e.g., a compound of formula A, a deuterated compound of formula A, a prodrug of a compound of formula A, a prodrug of a deuterated compound of formula A, a compound of formula I, a deuterated compound of formula I, or a pharmaceutically acceptable salt thereof), or a pharmaceutically acceptable salt thereof, (1) before an event that exposes an individual to a virus (or otherwise increases the risk of an individual becoming infected with that virus) (e.g., 2 hours, 1 day, 2 days, 5 days, or more than 7 days before the event), and / or (2) during an event that exposes an individual to a virus (or otherwise increases the risk of an individual becoming infected with that virus) (or two or more repeating events), and / or (3) after an event that exposes an individual to a virus (or otherwise increases the risk of an individual becoming infected with that virus) (or after the last event of a series of repeating events). In some embodiments, event-driven administration is performed before exposure of the subject to the virus. In some embodiments, event-driven administration is performed after exposure of the subject to the virus. In some embodiments, event-driven administration is performed before and after exposure of the subject to the virus. 【0165】 In certain embodiments, the methods described herein include administering, before and / or after an event that exposes an individual to a virus or otherwise increases the risk of an individual becoming infected with that virus, for example, as pre-exposure prophylaxis (PrEP) and / or post-exposure prophylaxis (PEP). In some embodiments, the methods described herein include pre-exposure prophylaxis (PrEP). In some embodiments, the methods described herein include post-exposure prophylaxis (PEP). 【0166】 In some embodiments, a compound of formula A, a deuterated compound of formula A, a prodrug of a compound of formula A, a prodrug of a deuterated compound of formula A, a compound of formula I, a deuterated compound of formula I, or a pharmaceutically acceptable salt thereof is administered before the subject is exposed to the virus. 【0167】 In some embodiments, a compound of formula A, a deuterated compound of formula A, a prodrug of a compound of formula A, a prodrug of a deuterated compound of formula A, a compound of formula I, a deuterated compound of formula I, or a pharmaceutically acceptable salt thereof is administered before and after exposure of the subject to the virus. 【0168】 In some embodiments, a compound of formula A, a deuterated compound of formula A, a prodrug of a compound of formula A, a prodrug of a deuterated compound of formula A, a compound of formula I, a deuterated compound of formula I, or a pharmaceutically acceptable salt thereof is administered after the subject has been exposed to the virus. 【0169】 Examples of event-driven dosing regimens include administering a compound of formula A, a deuterated compound of formula A, a prodrug of a compound of formula A, a prodrug of a deuterated compound of formula A, a compound of formula I, a deuterated compound of formula I, or a pharmaceutically acceptable salt thereof within 24 to 2 hours before the virus, then administering a compound of formula A, a deuterated compound of formula A, a prodrug of a compound of formula A, a prodrug of a deuterated compound of formula A, a compound of formula I, a deuterated compound of formula I, or a pharmaceutically acceptable salt thereof every 24 hours during the exposure period, then administering a compound of formula A, a deuterated compound of formula A, a prodrug of a compound of formula A, a prodrug of a deuterated compound of formula A, a compound of formula I, a deuterated compound of formula I, or a pharmaceutically acceptable salt thereof again after the last exposure, and then administering a compound of formula A, a deuterated compound of formula A, a prodrug of a compound of formula A, a prodrug of a deuterated compound of formula A, a compound of formula I, a deuterated compound of formula I, or a pharmaceutically acceptable salt thereof one last time 24 hours later. 【0170】 As a further example of an event-driven dosing regimen, a compound of formula A, a deuterated compound of formula A, a prodrug of a compound of formula A, a prodrug of a deuterated compound of formula A, a compound of formula I, a deuterated compound of formula I, or a pharmaceutically acceptable salt thereof is administered within 24 hours prior to viral exposure, then daily during the exposure period, and then a final dose (which may be an increased dose such as a double dose) is administered approximately 24 hours after the last exposure. 【0171】 The specific dosage levels of the compounds described herein for any particular subject will depend on a variety of factors including the activity of the specific compound being used, age, 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 being treated. For example, the dosage can be expressed as milligrams of the compound described herein per kilogram of subject body weight (mg / kg). Dosages of about 0.1 - 150 mg / kg may be appropriate. In some embodiments, dosages of about 0.1 and 100 mg / kg may be appropriate. In other embodiments, dosages of 0.5 - 60 mg / kg may be appropriate. Normalizing by subject body weight is particularly useful when adjusting dosages between subjects of widely different sizes, such as when using a drug in both pediatric and adult humans or when converting an effective dosage in a non-human subject such as a dog to a dosage suitable for a human subject. 【0172】 The daily dosage can also be described as the total amount of the compound described herein administered per administration or per day. The daily dosage of a compound of formula A, a deuterated compound of formula A, a prodrug of a compound of formula A, a prodrug of a deuterated compound of formula A, a compound of formula I, a deuterated compound of formula I, or a pharmaceutically acceptable salt thereof can be about 1 mg - 4,000 mg, about 2,000 - 4,000 mg / day, about 1 - 2,000 mg / day, about 1 - 1,000 mg / day, about 10 - 500 mg / day, about 20 - 500 mg / day, about 50 - 300 mg / day, about 75 - 200 mg / day, or about 15 - 150 mg / day. 【0173】 The dosage or dosing frequency of the compounds described herein can be adjusted over the course of treatment based on the judgment of the prescribing physician. 【0174】 The compounds of the present disclosure can be administered to an individual (e.g., a human) in a therapeutically effective amount. In some embodiments, the compound is administered once a day. In some embodiments, the compound is administered twice a day. 【0175】 The compounds described herein can be administered by any useful route and means, such as oral or parenteral (e.g., intravenous) administration. The therapeutically effective amount of the compound can include from about 0.00001 mg / kg body weight per day to about 10 mg / kg body weight per day, such as from about 0.0001 mg / kg body weight per day to about 10 mg / kg body weight per day, or for example from about 0.001 mg / kg body weight per day to about 1 mg / kg body weight per day, or for example 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, the therapeutically effective amount of the compounds described herein includes from about 0.3 mg to about 30 mg / day, or from about 30 mg to about 300 mg / day, or from about 0.3 mg to about 30 mg / day, or from about 30 mg to about 300 mg / day. 【0176】 The compounds described herein can be combined with one or more additional therapeutic agents at any dosage of the compounds described herein (e.g., 1 mg to 1000 mg of the compound). Therapeutically effective amounts can include from about 0.1 mg per dose to about 1000 mg per dose, such as from about 50 mg per dose to about 500 mg per dose, or for example from about 100 mg per dose to about 400 mg per dose, or for example from about 150 mg per dose to about 350 mg per dose, or for example from about 200 mg per dose to about 300 mg per dose, or for example from about 0.01 mg per dose to about 1000 mg per dose, or for example from about 0.01 mg per dose to about 100 mg per dose, or for example from about 0.1 mg per dose to about 100 mg per dose, or for example from about 1 mg per dose to about 100 mg per dose, or for example from about 1 mg per dose to about 10 mg per dose, or for example from about 1 mg per dose to about 1000 mg per dose. Other therapeutically effective amounts of the compound of formula A, the deuterated compound of formula A, the prodrug of the compound of formula A, the prodrug of the deuterated compound of formula A, the compound of formula I, the deuterated compound of formula I, or a pharmaceutically acceptable salt thereof 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 the compounds described herein 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. 【0177】 In some embodiments, the methods described herein involve administering to a subject an initial daily dose of from about 1 to 500 mg of a compound described herein and increasing the dose incrementally until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dose. The dose can be increased daily, every other day, twice a week, once a week, once every two weeks, once every three weeks, or once a month. 【0178】 When administered orally, the total daily dose for a human subject may be about 1 to 4,000 mg / day, about 1 to 3,000 mg / day, 1 to 2,000 mg / day, about 1 to 1,000 mg / day, about 10 to 500 mg / day, about 50 to 300 mg / day, about 75 to 200 mg / day, or about 100 to 150 mg / day. In some embodiments, the total daily dose 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 as a single dose. In some embodiments, the total daily dose for a human subject may be about 200, 300, 400, 500, 600, 700, or 800 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 300, 400, 500, or 600 mg / day administered as a single dose. In some embodiments, the total daily dose 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 may be 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, 1500 - 2200, 1500 - 2300, 1500 - 2400, 1500 - 2500, 2000 - 2600, 2000 - 2700, 2000 - 2800, 2000 - 2900, 2000 - 3000, 2500 - 3100, 2500 - 3200, 2500 - 3300, 2500 - 3400, 2500 - 3500, 3000 - 3600, 3000 - 3700, 3000 - 3800, 3000 - 3900, or 3000 - 4000 mg / day. 【0179】 In some embodiments, the total daily dose for a human subject may be about 100 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 150 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 200 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 250 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 300 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 350 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 400 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 450 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 500 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 550 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 600 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 650 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 700 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 750 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 800 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 850 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 900 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 950 mg / day administered as a single dose.In some embodiments, the total daily dose for a human subject may be about 1000 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 1500 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 2000 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 2500 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 3000 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 4000 mg / day administered as a single dose. 【0180】 The single dose can be administered hourly, daily, weekly, or monthly. For example, a single dose can be administered once every 1, 2, 3, 4, 6, 8, 12, 16 hours, or once every 24 hours. A single dose can also be administered once every 1, 2, 3, 4, 5, 6 days, or once every 7 days. A 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 a week. A single dose can also be administered once a month. In some embodiments, the compounds described herein are administered once a day by the methods described herein. In some embodiments, the compounds described herein are administered twice a day by the methods described herein. In some embodiments, the compounds described herein are administered three times a day by the methods described herein. 【0181】 In some embodiments, the compounds described herein are administered once a day at a total daily dose of 100 - 4000 mg / day. In some embodiments, the compounds described herein are administered twice a day at a total daily dose of 100 - 4000 mg / day. In some embodiments, the compounds described herein are administered three times a day at a total daily dose of 100 - 4000 mg / day. 【0182】 The frequency of dosing of the compounds described herein is determined by the needs of the individual patient and can be, for example, once a day, or twice a day, or more times per day. Administration of the compound continues as long as necessary to treat the viral infection. For example, the compound can be administered to a human infected with the virus for a period of 20 to 180 days, or for example, a period of 20 to 90 days, or for example, a period of 30 to 60 days. 【0183】 Administration can be intermittent, with the patient receiving a daily dose of the compound described herein for a period of several days, followed by the patient not receiving a daily dose of the compound for a period of several days. 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 to 14 days, followed by a period of 7 to 21 days during which the patient does not receive a dose of the compound, followed by a subsequent period (e.g., 1 to 14 days) during which the patient can again receive 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 necessary to treat the patient. 【0184】 The compounds or pharmaceutical compositions thereof of the present disclosure can be administered once, twice, three times, or four times a day using any of the above - suitable modes. Also, administration or treatment with the compound can be continued for several days. For example, typically, treatment will continue for at least 7 days, 14 days, or 28 days for one treatment cycle. Treatment cycles are well - known in cancer chemotherapy and are frequently alternated with a rest period of about 1 to 28 days, generally about 7 days or about 14 days, between cycles. Treatment cycles can also be continuous in other embodiments. 【0185】 In some embodiments, the compound is administered continuously for 1 to 30 days, for example, continuously for 1 to 28 days, continuously for 1 to 21 days, continuously for 1 to 14 days, continuously for 1 to 7 days, continuously for 1 to 5 days, continuously for 3 to 30 days, continuously for 3 to 28 days, continuously for 3 to 21 days, continuously for 3 to 14 days, continuously for 3 to 7 days, continuously for 5 to 30 days, continuously for 5 to 28 days, continuously for 5 to 21 days, continuously for 5 to 14 days, or continuously for 5 to 7 days. In some embodiments, the compound is administered once or twice a day. In some embodiments, the compound is administered once a day. In some embodiments, the compound is administered twice a day. 【0186】 In some embodiments, the compound is administered continuously for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days. In some embodiments, the compound is administered once a day for 3 consecutive days. In some embodiments, the compound is administered once a day for 5 consecutive days. In some embodiments, the compound is administered twice a day for 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days. In some embodiments, the compound is administered twice a day for 3 consecutive days. In some embodiments, the compound is administered twice a day for 5 consecutive days. 【0187】 In some embodiments, the compounds described herein are administered to humans via oral, intramuscular, intravenous, subcutaneous, or inhalation administration. In some embodiments, the compound is administered orally. 【0188】 In some embodiments, the patient is not pregnant on the first day of administration of a compound of formula A, a deuterated compound of formula A, a prodrug of a compound of formula A, a prodrug of a deuterated compound of formula A, a compound of formula I, a deuterated compound of formula I, or a pharmaceutically acceptable salt thereof, and the patient avoids becoming pregnant for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, or at least 1 month after the first day of administration. In some embodiments, the patient is not pregnant on the first day of administration of a compound of formula A, a deuterated compound of formula A, a prodrug of a compound of formula A, a prodrug of a deuterated compound of formula A, a compound of formula I, a deuterated compound of formula I, or a pharmaceutically acceptable salt thereof, and the patient avoids becoming pregnant for at least 2 days after the first day of administration. In some embodiments, the patient is not pregnant on the first day of administration of a compound of formula A, a deuterated compound of formula A, a prodrug of a compound of formula A, a prodrug of a deuterated compound of formula A, a compound of formula I, a deuterated compound of formula I, or a pharmaceutically acceptable salt thereof, and the patient avoids becoming pregnant for at least 4 days after the first day of administration. In some embodiments, the patient is not pregnant on the first day of administration of a compound of formula A, a deuterated compound of formula A, a prodrug of a compound of formula A, a prodrug of a deuterated compound of formula A, a compound of formula I, a deuterated compound of formula I, or a pharmaceutically acceptable salt thereof, and the patient avoids becoming pregnant for at least 7 days after the first day of administration. In some embodiments, the patient is not pregnant on the first day of administration of a compound of formula A, a deuterated compound of formula A, a prodrug of a compound of formula A, a prodrug of a deuterated compound of formula A, a compound of formula I, a deuterated compound of formula I, or a pharmaceutically acceptable salt thereof, and the patient avoids becoming pregnant for at least 14 days after the first day of administration. In some embodiments, the patient is not pregnant on the first day of administration of a compound of formula A, a deuterated compound of formula A, a prodrug of a compound of formula A, a prodrug of a deuterated compound of formula A, a compound of formula I, a deuterated compound of formula I, or a pharmaceutically acceptable salt thereof, and the patient avoids becoming pregnant for at least 1 month after the first day of administration. 【0189】 In some embodiments, the patient is a lactating individual, and the patient avoids lactating for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, or at least 1 month after administration, starting from the first day of administration of a compound of formula A, a deuterated compound of formula A, a prodrug of a compound of formula A, a prodrug of a deuterated compound of formula A, a compound of formula I, a deuterated compound of formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the patient is a lactating individual, and the patient avoids lactating for at least 2 days after administration, starting from the first day of administration of a compound of formula A, a deuterated compound of formula A, a prodrug of a compound of formula A, a prodrug of a deuterated compound of formula A, a compound of formula I, a deuterated compound of formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the patient is a lactating individual, and the patient avoids lactating for at least 4 days after administration, starting from the first day of administration of a compound of formula A, a deuterated compound of formula A, a prodrug of a compound of formula A, a prodrug of a deuterated compound of formula A, a compound of formula I, a deuterated compound of formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the patient is a lactating individual, and the patient avoids lactating for at least 7 days after administration, starting from the first day of administration of a compound of formula A, a deuterated compound of formula A, a prodrug of a compound of formula A, a prodrug of a deuterated compound of formula A, a compound of formula I, a deuterated compound of formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the patient is a lactating individual, and the patient avoids lactating for at least 14 days after administration, starting from the first day of administration of a compound of formula A, a deuterated compound of formula A, a prodrug of a compound of formula A, a prodrug of a deuterated compound of formula A, a compound of formula I, a deuterated compound of formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the patient is a lactating individual, and the patient avoids lactating for at least 1 month after administration, starting from the first day of administration of a compound of formula A, a deuterated compound of formula A, a prodrug of a compound of formula A, a prodrug of a deuterated compound of formula A, a compound of formula I, a deuterated compound of formula I, or a pharmaceutically acceptable salt thereof. 【0190】 In some embodiments, the patient is not breastfeeding. 【0191】 In some embodiments, the method further comprises determining that the patient is not pregnant before administering a compound of formula A, a deuterated compound of formula A, a prodrug of a compound of formula A, a prodrug of a deuterated compound of formula A, a compound of formula I, a deuterated compound of formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, determining comprises classifying the patient as being capable or not capable of pregnancy and administering a pregnancy test to a patient capable of pregnancy. 【0192】 In some embodiments, the patient is capable of pregnancy and the patient is negative in at least one pregnancy test at least 1 day prior to administration of a compound of formula A, a deuterated compound of formula A, a prodrug of a compound of formula A, a prodrug of a deuterated compound of formula A, a compound of formula I, a deuterated compound of formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the patient is capable of pregnancy and the patient is negative in at least two pregnancy tests at least 1 day prior to each individual administration of a compound of formula A, a deuterated compound of formula A, a prodrug of a compound of formula A, a prodrug of a deuterated compound of formula A, a compound of formula I, a deuterated compound of formula I, or a pharmaceutically acceptable salt thereof. 【0193】 In some embodiments, the patient is negative in a first pregnancy test at least 7 days prior, at least 8 days prior, at least 9 days prior, at least 10 days prior, at least 11 days prior, at least 12 days prior, at least 13 days prior, at least 14 days prior, at least 3 weeks prior, or at least 4 weeks prior to administration. In some embodiments, the patient is negative in a second pregnancy test after the first pregnancy test and at least 1 day prior to administration. In some embodiments, the patient is negative in a first pregnancy test at least 7 days prior to administration and negative in a second pregnancy test after the first pregnancy test and at least 1 day prior to administration. In some embodiments, the patient is negative in a first pregnancy test at least 14 days prior to administration and negative in a second pregnancy test after the first pregnancy test and at least 1 day prior to administration. 【0194】 In some embodiments, the patient is negative on a second pregnancy test during the first 10 days, first 9 days, first 8 days, first 7 days, first 6 days, first 5 days, first 4 days, or first 3 days of menstruation immediately prior to administration. In some embodiments, the patient is negative on a second pregnancy test during the first 5 days of menstruation immediately prior to administration. In some embodiments, the patient is amenorrheic, and the patient is negative on a second pregnancy test at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, or at least 14 days after the last unprotected intercourse. In some embodiments, the patient is amenorrheic, and the patient is negative on a second pregnancy test at least 11 days after the last unprotected intercourse. 【0195】 In some embodiments, each pregnancy test is, independently, a urine pregnancy test or a serum pregnancy test. In some embodiments, each pregnancy test is, independently, sensitive at least 10 mIU / mL, at least 15 mIU / mL, at least 20 mIU / mL, or at least 25 mIU / mL. In some embodiments, each pregnancy test is, independently, sensitive at least 25 mIU / mL. 【0196】 In some embodiments, the patient is capable of pregnancy and the patient uses at least one form of contraception from the first day of administration of a compound of formula A, a deuterated compound of formula A, a prodrug of a compound of formula A, a prodrug of a deuterated compound of formula A, a compound of formula I, a deuterated compound of formula I, or a pharmaceutically acceptable salt thereof for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, or at least 1 month after administration. In some embodiments, the patient is capable of pregnancy and the patient uses at least two forms of contraception from the first day of administration of a compound of formula A, a deuterated compound of formula A, a prodrug of a compound of formula A, a prodrug of a deuterated compound of formula A, a compound of formula I, a deuterated compound of formula I, or a pharmaceutically acceptable salt thereof for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, or at least 1 month after administration. 【0197】 In some embodiments, the patient uses contraception starting at least 1 week before, at least 2 weeks before, at least 3 weeks before, at least 4 weeks before, or at least 1 month before the first day of administration. In some embodiments, the patient uses contraception starting at least 1 month before the first day of administration. In some embodiments, the patient uses contraception for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, or at least 1 month after administration. In some embodiments, the patient uses contraception for at least 1 month after administration. 【0198】 In some embodiments, the patient uses at least one form of contraception selected from tubal ligation, partner vasectomy, intrauterine contraceptive devices, oral contraceptives, and injectable, implantable, and insertable hormonal contraceptive products. In some embodiments, the patient uses at least one form of contraception selected from pessaries, latex condoms, and cervical caps. In some embodiments, pessaries, latex condoms, and cervical caps are used with a spermicide. 【0199】 In some embodiments, the patient is a high-risk patient. For example, the patient is at high risk of progressing to a severe stage of a viral infection such as severe COVID-19, including hospitalization or death. Risk factors for progression to hospitalization include, for example, age 60 years or older, obesity (BMI 30 or greater), chronic lung disease, hypertension, cardiovascular or cerebrovascular disease, type 2 diabetes, immunocompromised status, chronic mild or moderate kidney disease, chronic liver disease, ongoing cancer, and sickle cell disease. In some embodiments, the high-risk patient is 50 years or older. In some embodiments, the high-risk patient is 65 years or older. In some embodiments, the high-risk patient is immunocompromised. In some embodiments, the high-risk patient has a weakened immune system. In some embodiments, the high-risk patient is taking an agent that weakens the immune system. In some embodiments, the high-risk patient is obese. In some embodiments, the high-risk patient has chronic obstructive pulmonary disease. In some embodiments, the high-risk patient has severe heart disease. In some embodiments, the high-risk patient has hypertension. 【0200】 In some embodiments, the present 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 described herein and at least one additional active therapeutic or prophylactic agent. 【0201】 In some embodiments, the present disclosure provides a method of treating a viral infection in a subject (e.g., a human) in need thereof, the method comprising administering to the subject a compound described herein and at least one additional active therapeutic or prophylactic agent. 【0202】 In one embodiment, the present disclosure provides a method of inhibiting a viral polymerase in a cell, the method comprising contacting a cell infected with a virus with a compound described herein, whereby the viral polymerase is inhibited. 【0203】 In one embodiment, the present disclosure provides a method of inhibiting a viral polymerase in a cell, the method comprising contacting a cell infected with a virus with a compound described herein and at least one additional active therapeutic agent, whereby the viral polymerase is inhibited. 【0204】 Also provided herein is the use of a compound described 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 described herein for use in treating a viral infection in a subject in need thereof. 【0205】 In some embodiments, the viral infection is a paramyxovirus family virus infection. Thus, in some embodiments, the present disclosure provides a method for treating a paramyxovirus family virus infection in a subject (e.g., a human) in need thereof, the method comprising administering to the subject a compound described herein. Examples of paramyxovirus family viruses include, but are not limited to, Nipah virus, Hendra virus, measles virus, mumps virus, and parainfluenza virus. 【0206】 In some embodiments, the viral infection is a human parainfluenza virus, Nipah virus, Hendra virus, measles, or mumps infection. 【0207】 In some embodiments, the viral infection is a Pneumoviridae virus infection. Thus, in some embodiments, the present disclosure provides a method of treating a Pneumoviridae virus infection in a human in need thereof, the method comprising administering to the human a compound disclosed herein. Examples of 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. 【0208】 In some embodiments, the present disclosure provides a compound described 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. 【0209】 In some embodiments, the present disclosure provides a method of treating an RSV infection in a human in need thereof, the method comprising administering to the human a compound described herein. In some embodiments, the human is suffering from a chronic respiratory syncytial virus infection. In some embodiments, the human is acutely infected with RSV. 【0210】 In some embodiments, a method of inhibiting RSV replication is provided, the method comprising administering to a human in need thereof a compound described herein, wherein the administration is by inhalation. 【0211】 In some embodiments, the present disclosure provides a method for reducing viral load associated with RSV infection, the method comprising administering to a human infected with RSV a compound described herein. 【0212】 In some embodiments, the viral infection is a picornavirus family virus infection. Thus, in some embodiments, the present disclosure provides a method for treating a picornavirus family virus infection in a human in need thereof, the method comprising administering to the human a compound described herein. Picornavirus family viruses are enteroviruses that cause a mixed group of infections including herpangina, aseptic meningitis, cold-like syndromes (human rhinovirus infections), non-paralytic polio-like syndromes, epidemic pleurodynia (generally an acute, febrile, infectious disease that occurs during an epidemic), hand, foot, and mouth disease, pediatric and adult pancreatitis, and severe myocarditis. In some embodiments, the picornavirus family virus infection is a human rhinovirus infection (HRV). In some embodiments, the picornavirus family virus infection is an HRV-A, HRV-B, or HRV-C infection. 【0213】 In some embodiments, the viral infection is selected from coxsackievirus A virus infection, coxsackievirus A virus infection, enterovirus D68 infection, enterovirus B69 infection, enterovirus D70 infection, enterovirus A71 infection, and poliovirus infection. 【0214】 In some embodiments, the present disclosure provides a compound for use in treating a picornavirus family virus infection in a human in need thereof. In some embodiments, the picornavirus family virus infection is a human rhinovirus infection. 【0215】 In some embodiments, the viral infection is a Flavivirus family virus infection. Thus, in some embodiments, the present disclosure provides a method of treating a Flavivirus family virus infection in a human in need thereof, the method comprising administering to the human a compound described herein. Representative Flavivirus family viruses include, but are not limited to, dengue, yellow fever, West Nile, Zika, Japanese encephalitis virus, and hepatitis C (HCV). In some embodiments, the Flavivirus family virus infection is a dengue virus infection. In some embodiments, the Flavivirus family virus infection is a yellow fever virus infection. In some embodiments, the Flavivirus family virus infection is a West Nile virus infection. In some embodiments, the Flavivirus family virus infection is a Zika virus infection. In some embodiments, the Flavivirus family virus infection is a Japanese encephalitis virus infection. In some embodiments, the Flavivirus family virus infection is a hepatitis C virus infection. 【0216】 In some embodiments, the Flavivirus family virus infection is a 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. 【0217】 In some embodiments, the present disclosure provides for the use of the compounds described herein for the treatment of Flaviviridae virus infections in humans 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. 【0218】 In some embodiments, the viral infection is a Filoviridae virus infection. Accordingly, in some embodiments, the present specification provides a method for treating a Filoviridae virus infection in a human in need thereof, the method comprising administering to the human a compound described herein. Representative Filoviridae viruses include, but are not limited to, Ebola virus (Zaire, Bundibugyo, Sudan, Tai forest, or Reston strain) 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. 【0219】 In some embodiments, the present 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. 【0220】 In some embodiments, the viral infection is a coronavirus infection. Thus, in some embodiments, the present specification provides a method of treating a coronavirus infection in a human in need thereof, the method comprising administering to the human a compound described herein. In some embodiments, the coronavirus infection is a severe acute respiratory syndrome (SARS-CoV) infection, a Middle East respiratory syndrome (MERS) infection, a SARS-CoV-2 infection, an infection with another human coronavirus (229E, NL63, OC43, HKU1, or WIV1), 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 having at least 70% sequence homology to a viral polymerase selected from SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2. In some embodiments, the viral infection is caused by a virus having at least 80% sequence homology to a viral polymerase selected from SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2. In some embodiments, the viral infection is caused by a virus having at least 90% sequence homology to a viral polymerase selected from 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 SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2. 【0221】 In some embodiments, the viral infection is caused by a SARS-CoV-2 variant, such as the B.1.1.7 variant (UK variant), B.1.351 variant (South African variant), P.1 variant (Brazilian variant), B.1.1.7 with the E484K mutation, B.1.1.207 variant, B.1.1.317 variant, B.1.1.318 variant, B.1.429 variant, B.1.525 variant, or 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. 【0222】 In some embodiments, the present 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, an infection by another human coronavirus (229E, NL63, OC43, HKU1, or WIV1), or a zoonotic coronavirus (PEDV or HKUCoV isolate, such as 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). 【0223】 In some embodiments, the viral infection is an arenavirus family virus infection. Thus, in some embodiments, the present disclosure provides a method for treating an arenavirus family virus infection in a human in need thereof, the method comprising administering to the human a compound described herein. In some embodiments, the arenavirus family virus infection is a Lassa infection or a Junin infection. 【0224】 In some embodiments, the present disclosure provides compounds for use in treating Arenaviridae virus infections in humans in need thereof. In some embodiments, the Arenaviridae virus infection is Lassa fever or Lujo virus disease. 【0225】 In some embodiments, the viral infection is an Orthomyxovirus infection, such as an influenza virus infection. In some embodiments, the viral infection is an influenza A virus, influenza B virus, or influenza C virus infection. 【0226】 As described more fully herein, the compounds described herein can be administered to an individual (e.g., a human) infected with a viral infection, together with one or more additional therapeutic agents. The additional therapeutic agent can be administered to the infected individual simultaneously with the compounds described herein, or before or after administration of the compounds described herein. 【0227】 The compounds described herein can also be used in combination with one or more additional therapeutic agents. Accordingly, provided herein is also a method of treating a viral infection in a subject in need thereof, the method comprising administering to the subject a compound disclosed herein and a therapeutically effective amount of one or more additional therapeutic or prophylactic agents. 【0228】 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 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. 【0229】 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 idoxuridine, trifluridine, bromovinyldeoxyuridine [BVDU], and combinations thereof. 【0230】 In some embodiments, the additional therapeutic agent is a nucleoside analog. For example, in some embodiments, the additional therapeutic agent is selected from 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. 【0231】 In some embodiments, the additional therapeutic agent is a pyrophosphate analog. For example, in some embodiments, the additional therapeutic agent is phosphonoformate or phosphonoacetic acid. In some embodiments, the additional therapeutic agent is phosphonoformate. 【0232】 In some embodiments, the additional therapeutic agent is a nucleoside reverse transcriptase inhibitor. In some embodiments, the antiviral agent is zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine, and combinations thereof. 【0233】 In some embodiments, the additional therapeutic agent is a non-nucleoside reverse transcriptase inhibitor. In some embodiments, the antiviral agent is selected from nevirapine, delavirdine, efavirenz, etravirine, rilpivirine, and combinations thereof. 【0234】 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 saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, cobicistat, and combinations thereof. In some embodiments, the antiviral agent is selected from 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 boceprevir, asunaprevir, simeprevir, telaprevir, vaniprevir, grazoprevir, ribavirin, danoprevir, faldaprevir, vedroprevir, sofosbuvir, deleprevir, nalaprevir, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from boceprevir, asunaprevir, simeprevir, telaprevir, vaniprevir, grazoprevir, and combinations thereof. 【0235】 In some embodiments, the additional therapeutic agent is an integrase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from raltegravir, dolutegravir, elvitegravir, abacavir, lamivudine, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from bictegravir, raltegravir, dolutegravir, cabotegravir, elvitegravir, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from bictegravir, dolutegravir, and cabotegravir and combinations thereof. In some embodiments, the additional therapeutic agent is bictegravir. 【0236】 In some embodiments, the additional therapeutic agent is an entry inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from 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. 【0237】 In some embodiments, the additional therapeutic agent is an acyclic guanosine analogue. For example, in some embodiments, the additional therapeutic agent is selected from acyclovir, ganciclovir, valacyclovir (also known as valaciclovir), valganciclovir, penciclovir, famciclovir, and combinations thereof. 【0238】 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 cidofovir, adefovir, adefovir dipivoxil, tenofovir, TDF, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from cidofovir, adefovir dipivoxil, TDF, and combinations thereof. 【0239】 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 type NS5B polymerase inhibitor. In some embodiments, the additional therapeutic agent is a non-nucleoside type NS5B polymerase inhibitor. In some embodiments, the additional therapeutic agent is selected from the group consisting of daclatasvir, ledipasvir, velpatasvir, ombitasvir, elbasvir, sofosbuvir, dasabuvir, ribavirin, asunaprevir, simeprevir, paritaprevir, ritonavir, elbasvir, grazoprevir, AT-527, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from daclatasvir, ledipasvir, velpatasvir, ombitasvir, elbasvir, sofosbuvir, dasabuvir, and combinations thereof. 【0240】 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 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 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 ribavirin, favipiravir, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from 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 amantadine, rimantadine, zanamivir, oseltamivir, peramivir, laninamivir octanoate, ribavirin, favipiravir, and combinations thereof. 【0241】 In some embodiments, the additional therapeutic agent is interferon. In some embodiments, the additional therapeutic agent is selected from interferon alfa con 1, interferon alfa 1b, interferon alfa 2a, interferon alfa 2b, pegylated interferon alfa con 1, pegylated interferon alfa 1b, pegylated interferon alfa 2a, and PegIFNα-2b. In some embodiments, the additional therapeutic agent is selected from interferon alfa con 1, interferon alfa 1b, interferon alfa 2a, interferon alfa 2b, pegylated interferon alfa 2a (PegIFNα-2a), and PegIFNα-2b. In some embodiments, the additional therapeutic agent is selected from interferon alfa con 1, pegylated interferon alfa 2a (PegIFNα-2a), PegIFNα-2b, and ribavirin. In some embodiments, the additional therapeutic agent is pegylated interferon alfa-2a, pegylated interferon alfa-2b, or a combination thereof. 【0242】 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 homoharringtonine, podophyllotoxin, imiquimod, epigallocatechin, and combinations thereof. 【0243】 In some embodiments, the additional therapeutic agent is selected from besifovir, nitazoxanide, REGN2222, doravirine, sofosbuvir, velpatasvir, daclatasvir, asunaprevir, voxilaprevir, FV100, and ledipasvir, and combinations thereof. 【0244】 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. 【0245】 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 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. 【0246】 In some embodiments, the additional therapeutic agent is an agent for the treatment of malaria. In some embodiments, the additional therapeutic agent is chloroquine. 【0247】 In some embodiments, the additional therapeutic agent is selected from hydroxychloroquine, chloroquine, artemether, lumefantrine, atovaquone, proguanil, tafenoquine, pyronaridine, artesunate, artemisnimol, piperaquine, artesunate, amodiaquine, pyronaridine, artesunate, halofantrine, quinine sulfate, mefloquine, solithromycin, pyrimethamine, MMV-390048, ferroquine, artemfenomel mesylate, ganaplacide, DSM-265, cipargamin, artemisone, and combinations thereof. 【0248】 In some embodiments, the additional therapeutic agent is an agent for the treatment of coronavirus. In some embodiments, the additional therapeutic agent is selected from the group consisting of IFX-1, FM-201, CYNK-001, DPP4-Fc, laniporase, nafamostat, LB-2, AM-1, antiviroplorin, and combinations thereof. 【0249】 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 (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-dimethylquinolino[8,7-h]quinolone-1,7-diamine), JK-05, TKM-Ebola, ZMapp, rNAPc2, VRC-EBOADC076-00-VP, OS-2966, MVA-BN Filo, brincidofovir, Vaxart adenovirus 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. 【0250】 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 sofosbuvir, GS-6620, PSI-938, ribavirin, tegobuvir, ledipasvir, 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 GS-9256, boceprevir, telaprevir, and combinations thereof. 【0251】 In some embodiments, the additional therapeutic agent is an NS5A inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from ledipasvir, velpatasvir, and combinations thereof. 【0252】 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-hydroxy tropolone, amdoxovir, anthraquinonol, β-hydroxycytosine nucleoside, ARB-199, CCC-0975, ccc-R08, elvucitabine, ezetimibe, cyclosporine A, gentiopicrin (gentiopicroside), HH-003, heparotide, JNJ-56136379, nitazoxanide, birinapant, NJK14047, NOV-205 (molixan, BAM-205), oligonucleotide, mibolerate, feron, GST-HG-131, levamisole, Ka Shu Ning, allopheron, 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, Hepranta, IMB-2613, TCM-800B, Reduced Glutathione, RO-6864018, RG-7834, QL-007 Sofosbuvir, Ledipasvir, UB-551, and ZH-2N, and the compounds disclosed in U.S. Patent Application Publication No. 20150210682 (Roche), No. 2016 / 0122344 (Roche), International Publication No. 2015173164, No. 2016023877, U.S. Patent Application Publication No. 2015252057(A) (Roche), International Publication No. 16128335(A1) (Roche), No. 16120186(A1) (Roche), U.S. Patent Application Publication No. 2016237090(A) (Roche), International Publication No. 16107833(A1) (Roche), No. 16107832(A1) (Roche), U.S. Patent Application Publication No. 2016176899(A) (Roche), International Publication No. 16102438(A1) (Roche), No. 16012470(A1) (Roche), U.S. Patent Application Publication No. 2016220586(A) (Roche), and No. 2015031687(A) (Roche) are included, but not limited thereto. In some embodiments, the additional therapeutic agent is an HBV polymerase inhibitor. HBVExamples of DNA polymerase inhibitors include, but are not limited to, 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 octadecyl oxyethyl ester, CMX-157, tenofovir exalidex, bicifovir, entecavir (BARACLUDE®), entecavir maleate, telbivudine (TYZEKA®), filosciriv, pradefovir, clevudine, ribavirin, lamivudine (EPIVIR-HBV®), phosphazide, famciclovir, foscolin, metacavir, SNC-019754, FMCA, AGX-1009, AR-II-04-26, HIP-1302, tenofovir disoproxil aspartate, tenofovir disoproxil asparagine orotate, and HS-10234. In some embodiments, the additional therapeutic agent is an HBV capsid inhibitor. 【0253】 In some embodiments, the additional therapeutic agent is an agent for the treatment of HIV. In some embodiments, the additional therapeutic agent is selected from 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. 【0254】 In some embodiments, the additional therapeutic agent is selected from an HIV protease inhibitor, a non-nucleoside or non-nucleotide inhibitor of HIV reverse transcriptase, a nucleoside or nucleotide inhibitor of HIV reverse transcriptase, an HIV integrase inhibitor, an HIV non-catalytic site (or allosteric) integrase inhibitor, an HIV entry inhibitor, an HIV maturation inhibitor, an immune modulator, an immunotherapy agent, an antibody-drug conjugate, a gene regulator, a gene editing agent (CRISPR / Cas9, zinc finger nuclease, homing nuclease, synthetic nuclease, TALEN, etc.), and a cell therapy (e.g., chimeric antigen receptor T cells, CAR-T, and engineered T cell receptor, TCR-T, autologous T cell therapy). 【0255】 In some embodiments, the additional therapeutic agent is selected from an HIV combination drug, other HIV therapeutic drugs, an HIV protease inhibitor, an HIV reverse transcriptase inhibitor, an HIV integrase inhibitor, an HIV non-catalytic site (or allosteric) integrase inhibitor, an HIV entry (fusion) inhibitor, an HIV maturation inhibitor, a latent infection reactivator, a capsid inhibitor, an immune system therapeutic drug, a PI3K inhibitor, an HIV antibody, and a bispecific antibody, and an "antibody-like" therapeutic protein, and combinations thereof. 【0256】 In some embodiments, the additional therapeutic agent is an HIV combination drug. Examples of HIV combination drugs 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, and cobicistat); SYMFI™ (efavirenz, lamivudine, and tenofovir disoproxil fumarate); CIMDU™ (lamivudine, and tenofovir disoproxil fumarate); tenofovir and lamivudine; tenofovir alafenamide and emtricitabine; tenofovir alafenamide hemifumarate and emtricitabine; tenofovir alafenamide hemifumarate, emtricitabine, and rilpivirine; tenofovir alafenamide hemifumarate, emtricitabine, cobicistat, and elvitegravir; 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 Alafenamide, Elvitegravir + 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 are mentioned, but not limited to these.; 【0257】 In some embodiments, the additional therapeutic agent is an HIV protease inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from 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 saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, cobicistat. In some embodiments, the additional therapeutic agent is selected from 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. 【0258】 In some embodiments, the additional therapeutic agent is an HIV integrase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from 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 selected from the group consisting of bictegravir, elvitegravir, curcumin, curcumin derivatives, cholic acid, cholic acid derivatives, 3,5-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid derivatives, aurintricarboxylic acid, aurintricarboxylic acid derivatives, caffeic acid phenethyl ester, caffeic acid phenethyl ester derivatives, tilorone, tilorone derivatives, quercetin, quercetin derivatives, raltegravir, dolutegravir, JTK-351, bictegravir, AVX-15567, BMS-986197, cabotegravir (long-acting injection), 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, stilbenedisulfonic acid, T-169, VM-3500, cabotegravir, and combinations thereof. 【0259】 In some embodiments, the additional therapeutic agent is an HIV entry inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from 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), adapterovir (RAP-101), nevirac (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). 【0260】 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. 【0261】 In some embodiments, the additional therapeutic agent is a nucleoside or nucleotide inhibitor of HIV reverse transcriptase. For example, the additional therapeutic agent is selected from adefovir, adefovir dipivoxil, azidothymidine, 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 tiboxil, CMX-157, dapivirine, delavirdine, etravirine, OCR-5753, tenofovir disoproxil orotate, fozivudine tiboxil, islatravir, lamivudine, phosphazide, stavudine, zalcitabine, zidovudine, lobucavir etalafenamide (GS-9131), GS-9148, MK-8504, MK-8591, MK-858, VM-2500, KP-1461, and combinations thereof. 【0262】 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 dapivirine, delavirdine, delavirdine mesylate, delavirdine, efavirenz, etravirine, lenacapavir, MK-8583, nevirapine, rilpivirine, TMC-278LA, ACC-007, AIC-292, KM-023, PC-1005, elsulfavirine rilp (VM-1500), and combinations thereof. 【0263】 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+FTC); DESCCOVY® (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; TRIUMEQ® (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, 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; prolasmin; fosamprenavir; fosamprenavir calcium efavirenz; etravirine; nelfinavir; nelfinavir mesylate; interferon; didanosine; stavudine;Selected from indinavir; indinavir sulfate; tenofovir and lamivudine; didobuzine; nevirapine; saquinavir; saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir; delavirdine; delavirdine mesylate; Radha-108 (receptol); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovir disoproxil fumarate; phosphazide; lamivudine, nevirapine, and didobuzine; abacavir; and abacavir sulfate.; 【0264】 In some embodiments, the additional therapeutic agent is selected from colistin, barbicycline, icatibant, bepotastin, epirubicin, epo-procinol, vapreotide, aprepitant, caspofungin, perphenazine, atazanavir, efavirenz, ritonavir, acyclovir, ganciclovir, penciclovir, prulifloxacin, bictegravir, nelinavir, tegobuvir, nelinavir, praziquantel, pitavastatin, perampanel, eszopiclone, and zopiclone. 【0265】 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 (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, vecabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, TAS-5315, AZD6738, calquence, danvatrisen, 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 tilvestatin A9 (A9). 【0266】 In some embodiments, the additional therapeutic agent is a KRAS inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from 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), MRTX-849 (G12C), and K-Ras (G12D) selective inhibitory peptides, and combinations thereof. 【0267】 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. 【0268】 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, an attenuated live 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 the attenuated live RSV vaccine MEDI-559, the human monoclonal antibody REGN2222 against RSV, palivizumab, respiratory syncytial virus immune globulin, intravenous [RSV-IGIV], and combinations thereof. In some embodiments, the additional therapeutic agent is an HBV vaccine, for example, PedvaxHIB, Engerix-B, and Recombivax HB. In some embodiments, the additional therapeutic agent is a VZV vaccine, for example, Zostavax and Varivax. In some embodiments, the additional therapeutic agent is an HPV vaccine, for example, Cervarix, Gardasil 9, and Gardasil. In some embodiments, the additional therapeutic agent is an influenza virus vaccine. For example, (i) monovalent vaccines against influenza A (for example, monovalent vaccines against influenza A [H5N1] virus and influenza A [H1N1] 2009 virus), (ii) trivalent vaccines for influenza A and B viruses (for example, Fluarix, Agriflu, Fluzone, Fluarix, Flublok, Flucelvax, Fluviral, Fluvirin, and Fluzone), and (iii) quadrivalent vaccines for influenza A and B viruses (FluMist, Fluarix, Fluzone, and Fluviral). In some embodiments, the additional therapeutic agent is a human adenovirus vaccine (for example, adenovirus type 4 and 7 vaccine, live, oral). In some embodiments, the additional therapeutic agent is a rotavirus vaccine (for example, 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 (for example, 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., M-M-R II and ProQuad). In some embodiments, the additional therapeutic agent is a mumps vaccine (e.g., M-M-R II and ProQuad). In some embodiments, the additional therapeutic agent is a rubella vaccine (e.g., M-M-R II and ProQuad). In some embodiments, the additional therapeutic agent is a varicella 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 smallpox virus (variola) 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. 【0269】 In some embodiments, the additional therapeutic agent is an antibody, such as a monoclonal antibody. For example, the additional therapeutic agent is an antibody against 2019-nCov selected from Regeneron antibodies, Wuxi antibodies, Vir Biotechnology antibodies, antibodies targeting the SARS-CoV-2 spike protein, antibodies capable of neutralizing SARS-CoV-2 (SARS-CoV-2 neutralizing antibodies), 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. 【0270】 In some embodiments, the additional therapeutic agent is an injection of a protein derived from a recombinant cytokine gene. 【0271】 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 ribavirin, favipiravir, lamivudine, pimodivir, and combinations thereof. 【0272】 In some embodiments, the additional therapeutic agent is selected from lopinavir, ritonavir, interferon-alpha-2b, ritonavir, arbidol, hydroxychloroquine, darunavir and cobicistat, arbidol hydrochloride, oseltamivir, ritonavir, emtricitabine, tenofovir alafenamide fumarate, baloxavir marboxil, ruxolitinib, and combinations thereof. 【0273】 In some embodiments, the additional therapeutic agent is selected from 6'-fluorinated aristomycin analogs, acyclovir fleximer analogs, disulfiram, thiopurine analogs, ASC09F, GC376, GC813, phenylisoserine derivatives, neuraminidase inhibitor analogs, pyrithio back derivatives, bananine and 5-hydroxy chromone derivatives, SSYA10-001, griffithsin, HR2P-M1, HR2P-M2, P21S10, dihydrotanshinone E-64-C and E-64-D, OC43-HR2P, MERS-5HB, 229E-HR1P, 229E-HR2P, resveratrol, 1-thia-4-azaspiro[4.5]decane-3-one derivatives, gemcitabine hydrochloride, loperamide, recombinant interferon, cyclosporine A, alispovir, imatinib mesylate, dasatinib, selumetinib, trametinib, rapamycin, saracatinib, chlorpromazine, triflupromazine, fluphenazine, thietylperazine, promethazine, cyclophilin inhibitors, K11777, camostat, k22, teicoplanin derivatives, benzoheterocyclic amine derivative N30, mycophenolic acid, silvestrol, and combinations thereof. 【0274】 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, such as an antibody that binds to SARS-CoV or MERS-CoV. In some embodiments, the additional therapeutic agent is a viral antibody against 2019-nCoV. 【0275】 The compositions of the present invention are also used in combination with other active ingredients. For the treatment of 2019-nCoV virus infection, preferably, the other active therapeutic agent is active against coronavirus infections, such as 2019-nCoV virus infection. The compounds and compositions of the present invention are also parenteral fluids (including dextrose saline and lactated Ringer's solution) and nutrients, antibiotics (including antibiotics of metronidazole and cephalosporins such as ceftriaxone and cefuroxime) and / or antifungal prophylaxis agents, antipyretics and analgesics, antiemetics (such as metoclopramide) and / or antidiarrheal agents, vitamins and mineral supplements (including vitamin K and zinc sulfate), anti-inflammatory agents (such as ibuprofen or steroids), corticosteroids such as methylprednisolone, immunomodulators (e.g., interferon), other small molecules or biological antiviral agents targeting 2019-nCoV (non-limiting, lopinavir / ritonavir, EIDD-1931, favipiravir, ribavirin, neutralizing antibodies, etc.), vaccines, analgesics, and antimalarial agents (including artemether and artemether-lumefantrine combination therapy), typhoid fever (quinolone antibiotics such as ciprofloxacin, macrolide antibiotics such as azithromycin, cephalosporin antibiotics such as ceftriaxone, or aminopenicillins such as ampicillin), or drugs for other common diseases in patient populations such as bacillary dysentery, and are intended for use with general care provided to patients with 2019-nCoV virus infection. In some embodiments, the additional therapeutic drug is dihydroartemisinin / piperaquine. In some embodiments, the additional therapeutic agent is EIDD-2801 (MH-4482, molnupiravir). 【0276】 In some embodiments, the additional therapeutic agent is an immunomodulator. Examples of immunotherapies 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 (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; normiferon; peginterferon alpha-2a; peginterferon 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. 【0277】 In some embodiments, the additional therapeutic agent is an IL-6 inhibitor, such as tocilizumab, sarilumab, or a combination thereof. 【0278】 In some embodiments, the additional therapeutic agent is an anti-TNF inhibitor. For example, the additional therapeutic agent is adalimumab, etanercept, golimumab, infliximab, or a combination thereof. 【0279】 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. 【0280】 In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, such as pirfenidone. 【0281】 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. 【0282】 In some embodiments, the compounds described herein are used in combination with standard treatment for pneumonia (see, e.g., Pediatric Community Pneumonia Guidelines, CID 2011:53 (1 October)). Treatment of pneumonia generally involves curing the infection and preventing complications. The specific treatment depends on several factors including the type and severity of pneumonia, age, and the overall health of the individual. This option includes (i) antibiotics, (ii) cough suppressants, and (iii) antipyretics / analgesics (e.g., aspirin, ibuprofen (Advil, Motrin IB, etc.), and acetaminophen (Tylenol, etc.)). In some embodiments, the additional therapeutic agent is a bromhexine cough suppressant. 【0283】 In some embodiments, the compounds described herein are used in combination with immunoglobulins from recovered COVID-19 patients. In some embodiments, the compounds described herein are used in combination with plasma transfusion. In some embodiments, the compounds described herein are used in combination with stem cells. 【0284】 In some embodiments, the additional therapeutic agent is a TLR agonist. Examples of TLR agonists include, but are not limited to, besatolimod (GS-9620), GS-986, IR-103, refitremod, tilsotremod, lintetremod, DSP-0509, AL-034, G-100, cobitolimod, AST-008, motremod, GSK-1795091, GSK-2245035, VTX-1463, GS-9688, LHC-165, BDB-001, RG-7854, telratremod, and RO-7020531. 【0285】 In some embodiments, the additional therapeutic agent is selected from bortezomib, flurazepam, ponatinib, sorafenib, paramethasone, clocortolone, flucroxacillin, sertindole, clevidipine, atorvastatin, cinolazepam, clofazimine, fosaprepitant, and combinations thereof. 【0286】 In some embodiments, the additional therapeutic agent is calimycin, suramin, triazavirin, dipyridamole, bevacizumab, meplazumab, GD31 (rizobuvir), an NLRP inflammasome inhibitor, or an α-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). 【0287】 In some embodiments, the additional therapeutic agent is an antiviroplakin 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 WO 2004112687, WO 2006135978, WO 2018145148, and WO 2009018609. 【0288】 In some embodiments, the additional therapeutic or prophylactic agent is molnupiravir, oseltamivir, nirmatrelvir, or ritonavir. In some embodiments, the additional therapeutic or prophylactic agent is ritonavir or cobicistat. 【0289】 In some embodiments, the additional therapeutic agent is a 2,5-oligoadenylate synthetase stimulant, 5-HT 2a receptor antagonist, 5-lipoxygenase inhibitor, ABL family tyrosine kinase inhibitor, Abl tyrosine kinase inhibitor, acetaldehyde dehydrogenase inhibitor, acetyl-CoA carboxylase inhibitor, actin antagonist, actin regulator, activity-dependent neuroprotective agent regulator, adenosine A3 receptor agonist, adrenergic receptor antagonist, adrenomedullin ligand, adrenomedullin ligand inhibitor, advanced glycation end product receptor antagonist, advanced glycation end product receptor regulator, AKT protein kinase inhibitor, alanine proline-rich secretory protein stimulant, aldose reductase inhibitor, alkaline phosphatase stimulant, alpha2 adrenergic receptor antagonist, alpha2B adrenergic receptor agonist, AMP-activated protein kinase stimulant, AMPA receptor regulator, amyloid protein deposition inhibitor, androgen receptor antagonist, angiotensin II AT-1 receptor antagonist, angiotensin II AT-2 receptor agonist, angiotensin II receptor regulator, angiotensin-converting enzyme 2 inhibitor, angiotensin-converting enzyme 2 regulator, angiotensin-converting enzyme 2 stimulant, angiotensin receptor regulator, annexin A5 stimulant, anoctamin 1 inhibitor, anticoagulant, antihistamine, antihypoxic agent, antithrombotic agent, AP1 transcription factor regulator, apelin receptor agonist, APOA1 gene stimulant, apolipoprotein A1 agonist, apolipoprotein B antagonist, apolipoprotein B regulator, apolipoprotein C3 antagonist, aryl hydrocarbon receptor agonist, aryl hydrocarbon receptor antagonist, ATP-binding cassette transporter B5 regulator, Axl tyrosine kinase receptor inhibitor, bactericidal permeability-increasing protein inhibitor, besifloxacin inhibitor, besifloxacin regulator, BCL2 gene inhibitor, BCL2L11 gene stimulant, Bcr protein inhibitor, beta1 adrenergic receptor regulator, beta2 adrenergic receptor agonist, beta adrenergic receptor agonist, beta-arrestin stimulant, blood coagulation regulator, BMP10 gene inhibitor, BMP15 gene inhibitor, bone morphogenetic protein-10 ligand inhibitor,Bone morphogenetic protein-15 ligand inhibitor, bradykinin B2 receptor antagonist, brain-derived neurotrophic factor ligand, bromodomain-containing protein 2 inhibitor, bromodomain-containing protein 4 inhibitor, Btk tyrosine kinase inhibitor, C-reactive protein regulator, Ca2+-release-activated Ca2+ channel 1 inhibitor, cadherin-5 regulator, calcium-activated chloride channel inhibitor, calcium channel regulator, calpain-I inhibitor, calpain-II inhibitor, calpain-IX inhibitor, cannabinoid CB2 receptor agonist, cannabinoid receptor regulator, casein kinase II inhibitor, CASP8-FADD-like effector inhibitor, caspase inhibitor, catalase stimulator, CCL26 gene inhibitor, CCR2 chemokine antagonist, CCR5 chemokine antagonist, CD11a agonist, CD122 agonist, CD3 antagonist, CD4 agonist, CD40 ligand, CD40 ligand regulator, CD40 ligand receptor agonist, CD40 ligand receptor regulator, CD49d agonist, CD70 antigen regulator, CD73 agonist, CD73 antagonist, CD95 antagonist, CFTR inhibitor, CGRP receptor antagonist, chemokine receptor-like 1 agonist, chloride channel inhibitor, chloride channel regulator, cholera enterotoxin subunit B inhibitor, cholesterol ester transport protein inhibitor, collagen regulator, complement C1s subcomponent inhibitor, complement C3 inhibitor, complement C5 factor inhibitor, complement C5a factor inhibitor, complement factor H stimulator, complement cascade inhibitor, complement factor C2 inhibitor, complement factor D inhibitor, connective tissue growth factor ligand inhibitor, coronavirus nucleoprotein regulator, coronavirus small envelope protein regulator, coronavirus spike glycoprotein inhibitor, coronavirus spike glycoprotein regulator, COVID19 envelope small membrane protein regulator, COVID19 non-structural protein 8 regulator, COVID19 nucleoprotein regulator, COVID19 protein 3a inhibitor, COVID19 replicase polyprotein 1a inhibitor, COVID19 replicase polyprotein 1a regulator, COVID19 replicase polyprotein 1ab inhibitor, COVID19 replicase polyprotein 1ab regulatorCOVID-19 spike glycoprotein inhibitor, COVID-19 spike glycoprotein regulator, COVID-19 structural glycoprotein regulator, CRF-2 receptor agonist, CSF-1 agonist, CSF-1 antagonist, CX3CR1 chemokine antagonist, CXC10 chemokine ligand inhibitor, CXC5 chemokine ligand inhibitor, CXCL1 gene regulator, CXCL2 gene regulator, CXCL3 gene regulator, CXCR1 chemokine antagonist, CXCR2 chemokine antagonist, CXCR4 chemokine antagonist, cyclin D1 inhibitor, cyclin E inhibitor, cyclin-dependent kinase-1 inhibitor, cyclin-dependent kinase-2 inhibitor, cyclin-dependent kinase-5 inhibitor, cyclin-dependent kinase-7 inhibitor, cyclin-dependent kinase-9 inhibitor, cyclooxygenase 2 inhibitor, cyclooxygenase inhibitor, cyclophilin inhibitor, cysteine protease inhibitor, cytochrome P450 3A4 inhibitor, cytokine receptor antagonist, cytotoxic T lymphocyte protein gene regulator, cytotoxic T lymphocyte protein-4 inhibitor, cytotoxic T lymphocyte protein-4 stimulator, DDX3 inhibitor, dehydrogenase inhibitor, dipeptidase-1 regulator, deoxyribonuclease I stimulator, deoxyribonuclease gamma stimulator, deoxyribonuclease stimulator, dihydroceramide delta 4 desaturase inhibitor, dihydroorotate dehydrogenase inhibitor, dipeptidyl peptidase I inhibitor, dipeptidyl peptidase III inhibitor, diuretic, DNA-binding protein inhibitor, DNA methyltransferase inhibitor, dopamine transporter inhibitor, E-selectin antagonist, Ecto NOX disulfide-thiol exchanger 2 inhibitor, EGFR gene inhibitor, elongation factor 1 alpha 2 regulator, endoplasmin regulator, endoribonuclease DICER regulator, endothelin ET-A receptor antagonist, epidermal growth factor receptor antagonist, E-selectin antagonist, estrogen receptor beta agonist, estrogen receptor regulator, eukaryotic translation initiation factor 4A-I inhibitor, exo-alpha-sialidase regulator, exportin 1 inhibitor, factor Ia regulator, factor IIa regulator, factor VII antagonist, factor Xa antagonistFactor XIa antagonist, FGF receptor antagonist, FGF-1 ligand, FGF-1 ligand inhibitor, FGF-2 ligand inhibitor, FGF1 receptor antagonist, FGF2 receptor antagonist, FGF3 receptor antagonist, Flt3 tyrosine kinase inhibitor, fractalkine ligand inhibitor, free fatty acid receptor 2 agonist, free fatty acid receptor 3 agonist, furin inhibitor, Fyn tyrosine kinase inhibitor, FYVE finger phosphoinositide kinase inhibitor, G-protein-coupled bile acid receptor 1 agonist, GABA A receptor modulator, galectin-3 inhibitor, gamma-secretase inhibitor, GDF agonist, gelseolin stimulator, glial cell line-derived neurotrophic factor ligand, glucocorticoid receptor agonist, glutathione peroxidase stimulator, GM-CSF ligand inhibitor, GM-CSF receptor agonist, GM-CSF receptor modulator, Griffithsin modulator, growth regulatory protein alpha ligand inhibitor, Grp78 calcium-binding protein inhibitor, heat shock protein HSP90 alpha inhibitor, heat shock protein HSP90 beta inhibitor, heat shock protein inhibitor, heat shock protein stimulator, hemagglutinin modulator, hemoglobin modulator, hemolysin alpha inhibitor, heparanase inhibitor, heparin agonist, hepatitis B structural protein inhibitor, hepatitis C virus NS5B polymerase inhibitor, HIF prolyl hydroxylase inhibitor, HIF prolyl hydroxylase-2 inhibitor, high mobility group protein B1 inhibitor, histamine H1 receptor antagonist, histamine H2 receptor antagonist, histone deacetylase-6 inhibitor, histone inhibitor, HIV protease inhibitor, HIV-1 gp120 protein inhibitor, HIV-1 protease inhibitor, HIV-1 reverse transcriptase inhibitor, HLA class I antigen modulator, HLA class II antigen modulator, host cell factor modulator, Hsp 90 inhibitor, human papillomavirus E6 protein modulator, human papillomavirus E7 protein modulator, hypoxia-inducible factor inhibitor gene inhibitor, hypoxia-inducible factor-2 alpha modulator, I-kappaB kinase inhibitor, I-kappaB kinase modulator, ICAM-1 stimulator, IgG receptor FcRn large subunit p51 modulator,IL-12 receptor antagonist, IL-15 receptor agonist, IL-15 receptor regulator, IL-17 antagonist, IL-18 receptor accessory protein antagonist, IL-2 receptor agonist, IL-22 agonist, IL-23 antagonist, IL-6 receptor agonist, IL-6 receptor antagonist, IL-6 receptor regulator, IL-7 receptor agonist, IL-8 receptor antagonist, IL12 gene stimulator, IL8 gene regulator, immunoglobulin G regulator, immunoglobulin G1 agonist, immunoglobulin G1 regulator, immunoglobulin agonist, immunoglobulin gamma Fc receptor I regulator, immunoglobulin kappa regulator, inosine monophosphate dehydrogenase inhibitor, insulin sensitivity improver, integrin agonist, integrin alpha-4 / beta-7 antagonist, integrin alpha-V / beta-1 antagonist, integrin alpha-V / beta-6 antagonist, interferon agonist, interferon alpha14 ligand, interferon alpha2 ligand, interferon alpha2 ligand regulator, interferon alpha ligand, interferon alpha ligand inhibitor, interferon alpha ligand regulator, interferon beta ligand, interferon gamma ligand inhibitor, interferon gamma receptor agonist, interferon gamma receptor antagonist, interferon receptor regulator, interferon type I receptor agonist, interleukin 17A ligand inhibitor, interleukin 17F ligand inhibitor, interleukin 18 ligand inhibitor, interleukin 22 ligand, interleukin-1 beta ligand inhibitor, interleukin-1 beta ligand regulator, interleukin-1 ligand inhibitor, interleukin-2 ligand, interleukin-29 ligand, interleukin-6 ligand inhibitor, interleukin-7 ligand, interleukin-8 ligand inhibitor, IRAK-4 protein kinase inhibitor, JAK tyrosine kinase inhibitor, Jak1 tyrosine kinase inhibitor, Jak2 tyrosine kinase inhibitor, Jak3 tyrosine kinase inhibitor, Jun N-terminal kinase inhibitor, Jun N-terminal kinase regulator, kallikrein regulatorRegulators of Kelch-like ECH-associated protein 1, Kit tyrosine kinase inhibitors, KLKB1 gene inhibitors, lactoferrin stimulants, lanosterol-14 demethylase inhibitors, Lck tyrosine kinase inhibitors, regulators of leukocyte Ig-like receptor A4, leukocyte elastase inhibitors, leukotriene BLT receptor antagonists, leukotriene D4, Antagonist, leukotriene receptor antagonist, listeriolysin stimulant, liver X receptor antagonist, low molecular weight heparin, lung surfactant - associated protein B stimulant, lung surfactant - associated protein D regulator, Lyn tyrosine kinase inhibitor, Lyn tyrosine kinase stimulant, lysine - specific histone demethylase 1 inhibitor, macrophage migration inhibitory factor inhibitor, mannan - binding lectin serine protease inhibitor, mannan - binding lectin serine protease - 2 inhibitor, MAO B inhibitor, MAP kinase inhibitor, MAPK gene regulator, matrix metalloprotease regulator, Maxi K potassium channel inhibitor, MCL1 gene inhibitor, MEK protein kinase inhibitor, MEK - 1 protein kinase inhibitor, melanocortin MC1 receptor agonist, melanocortin MC3 receptor agonist, metalloprotease - 12 inhibitor, METTL3 gene inhibitor, moesin inhibitor, moesin regulator, monocyte chemoattractant protein 1 ligand inhibitor, monocyte differentiation antigen CD14 inhibitor, mRNA cap guanine N7 methyltransferase regulator, mTOR complex 1 inhibitor, mTOR complex 2 inhibitor, mTOR inhibitor, mucolipin regulator, muscarinic receptor antagonist, myeloperoxidase inhibitor, NACHT LRR PYD domain - containing protein 3 inhibitor, NAD synthetase regulator, NADPH oxidase inhibitor, neuropilin 2 regulator, neuroplastin inhibitor, NFE2L2 gene stimulant, NK cell receptor agonist, NK1 receptor antagonist, NMDA receptor antagonist, NMDA receptor epsilon 2 subunit inhibitor, non - receptor tyrosine kinase TYK2 antagonist, non - nucleoside reverse transcriptase inhibitor, nsp12 polymerase inhibitor, erythroid transcription factor 2 - related factor 2 stimulant, nuclear factor kappa B inhibitor, nuclear factor kappa B regulator, nuclease stimulant, nucleolin inhibitor, nuclear protein inhibitor, nuclear protein regulator, nucleoside reverse transcriptase inhibitor, opioid receptor agonist, opioid receptor antagonist, opioid receptor mu regulator, opioid receptor sigma antagonist 1, ORF1ab polyprotein inhibitor, ornithine decarboxylase inhibitor, outer membrane protein inhibitor, OX40 ligand, p38 MAP kinase alpha inhibitorp38 MAP kinase inhibitor, p38 MAP kinase regulator, p53 tumor suppressor protein stimulator, palmitoyl protein thioesterase 1 inhibitor, papain inhibitor, PARP inhibitor, PARP regulator, PDE10 inhibitor, PDE3 inhibitor, PDE4 inhibitor, PDGF receptor alpha antagonist, PDGF receptor antagonist, PDGF receptor beta antagonist, peptidyl-prolyl cis-trans isomerase A inhibitor, peroxiredoxin 6 regulator, PGD2 antagonist, PGI2 agonist, P-glycoprotein inhibitor, phosphoinositide 3-kinase inhibitor, phosphoinositide-3 kinase delta inhibitor, phosphoinositide-3 kinase gamma inhibitor, phospholipase A2 inhibitor, PIKfyve inhibitor, plasma kallikrein inhibitor, plasminogen activator inhibitor 1 inhibitor, platelet inhibitor, platelet glycoprotein VI inhibitor, polo-like kinase 1 inhibitor, poly ADP ribose polymerase 1 inhibitor, poly ADP ribose polymerase 2 inhibitor, polymerase cofactor VP35 inhibitor, PPAR alpha agonist, progesterone receptor agonist, programmed cell death protein 1 regulator, prolyl hydroxylase inhibitor, prostaglandin E synthase-1 inhibitor, protease inhibitor, proteasome inhibitor, protein arginine deiminase IV inhibitor, protein tyrosine kinase inhibitor, protein tyrosine phosphatase beta inhibitor, protein tyrosine phosphatase-2C inhibitor, oncogene Mas agonist, purine receptor antagonist, Raf protein kinase inhibitor, RANTES ligand, Ras gene inhibitor, retinoic acid receptor responder protein 2 stimulator, Rev protein regulator, ribonuclease stimulator, RIP-1 kinase inhibitor, RNA helicase inhibitor, RNA polymerase inhibitor, RNA polymerase regulator, S-phase kinase-associated protein 2 inhibitor, SARS coronavirus 3C protease-like inhibitor, serine protease inhibitor, serine threonine protein kinase ATR inhibitor, serine threonine protein kinase TBK1 inhibitor, serum amyloid A protein regulator, signal transducer CD24 stimulator, sirtuin inhibitor, sodium channel stimulator, sodium glucose transporter-2 inhibitorSphingosine kinase 1 inhibitor, sphingosine kinase 2 inhibitor, sphingosine kinase inhibitor, sphingosine-1-phosphate receptor-1 agonist, sphingosine-1-phosphate receptor-1 antagonist, sphingosine-1-phosphate receptor-1 regulator, sphingosine-1-phosphate receptor-5 agonist, sphingosine-1-phosphate receptor-5 regulator, spike glycoprotein inhibitor, Src tyrosine kinase inhibitor, STAT-1 regulator, STAT-3 inhibitor, STAT-5 inhibitor, STAT3 gene inhibitor, hepatocyte antigen-1 inhibitor, stimulator of interferon gene protein stimulator, sulfatase inhibitor, superoxide dismutase regulator, superoxide dismutase stimulator, Syk tyrosine kinase inhibitor, T cell immunoreceptor Ig ITIM protein inhibitor, T cell receptor agonist, T cell surface glycoprotein CD28 inhibitor, T cell differentiation antigen CD6 inhibitor, T cell surface glycoprotein CD8 stimulator, T cell transcription factor NFAT regulator, tankyrase-1 inhibitor, tankyrase-2 inhibitor, Tek tyrosine kinase receptor stimulator, telomerase regulator, tetanus toxin regulator, TGF beta receptor antagonist, TGFB2 gene inhibitor, thymosin beta4 ligand, thyroid hormone receptor beta agonist, tissue factor inhibitor, tissue plasminogen activator regulator, tissue plasminogen activator stimulator, TLR agonist, TLR regulator, TLR-2 agonist, TLR-2 antagonist, TLR-3 agonist, TLR-4 agonist, TLR-4 antagonist, TLR-6 agonist, TLR-7 agonist, TLR-7 antagonist, TLR-8 antagonist, TLR-9 agonist, TMPRSS2 gene inhibitor, TNF alpha ligand inhibitor, TNF alpha ligand regulator, TNF binder, TNF gene inhibitor, topoisomerase inhibitor, transcription factor EB stimulator, transferrin regulator, transketolase inhibitor, translocation-related protein inhibitor, transmembrane serine protease 2 inhibitor, transthyretin regulator, TREM receptor 1 antagonist, TRP cation channel C1 regulator, TRP cation channel C6 inhibitor, TRP cation channel V6 inhibitor, trypsin 1 inhibitor, trypsin 2 inhibitor, trypsin 3 inhibitor, trypsin inhibitorTubulin alpha inhibitor, tubulin beta inhibitor, tumor necrosis factor 14 ligand inhibitor, TYK2 gene inhibitor, type I IL-1 receptor antagonist, tyrosine protein kinase ABL1 inhibitor, ubiquinol cytochrome c reductase 14 kDa inhibitor, ubiquitin ligase regulator, unspecified GPCR agonist, unspecified cytokine receptor regulator, unspecified enzyme stimulator, unspecified gene inhibitor, unspecified receptor regulator, urokinase plasminogen activator inhibitor, vascular cell adhesion protein 1 agonist, vasodilator, VEGF ligand inhibitor, VEGF receptor antagonist, VEGF-1 receptor antagonist, VEGF-1 receptor regulator, VEGF-2 receptor antagonist, VEGF-3 receptor antagonist, vimentin inhibitor, vimentin regulator, VIP receptor agonist, viral envelope protein inhibitor, viral protease inhibitor, viral protease regulator, viral protein target regulator, viral ribonuclease inhibitor, viral structural protein regulator, vitamin D3 receptor agonist, X-linked apoptosis inhibitor protein inhibitor, xanthine oxidase inhibitor, or zonulin inhibitor. 【0290】 In some embodiments, the compounds and compositions of the present disclosure can be administered in combination with SARS-Cov-2 treatments such as parenteral fluids (including dextrose saline and lactated Ringer's solution), nutrition, antibiotics (including azithromycin, metronidazole, amphotericin B, amoxicillin / clavulanate, trimethoprim / sulfamethoxazole, R-327, and cephalosporin antibiotics such as ceftriaxone and cefuroxime), antifungal prophylaxis, antipyretics and analgesics, antiemetics (such as metoclopramide) and / or antidiarrheals, vitamins and mineral supplements (including vitamin K, vitamin D, cholecalciferol, vitamin C, and zinc sulfate), anti-inflammatory drugs (such as ibuprofen or steroids), corticosteroids such as dexamethasone, methylprednisolone, prednisone, mometasone, immunomodulators (such as interferon), vaccines, and analgesics. 【0291】 In some embodiments, the additional therapeutic agent is an Abl tyrosine kinase inhibitor (e.g., radotinib or imatinib, etc.). 【0292】 In some embodiments, the additional therapeutic agent is an aldehyde dehydrogenase inhibitor such as ADX-629. 【0293】 In some embodiments, the additional therapeutic agent is an adenosine A3 receptor agonist such as picodenoson. 【0294】 In some embodiments, the additional therapeutic agent is an adrenomedullin ligand such as adrenomedullin. 【0295】 In some embodiments, the additional therapeutic agent is a p38 MAPK+PPAR gamma agonist / insulin sensitizer such as KIN-001. 【0296】 In some embodiments, the additional therapeutic agent is a PPAR alpha agonist such as DWTC-5101 (fenofibrate choline). 【0297】 In some embodiments, the additional therapeutic agent is a cyclophilin inhibitor such as lenchofilstat. 【0298】 In some embodiments, the additional therapeutic agent is a p38 MAP kinase inhibitor such as PRX-201 or Gen-1124. 【0299】 In some embodiments, the additional therapeutic agent is an aldose reductase inhibitor such as caficrestat. 【0300】 In some embodiments, the additional therapeutic agent is an AMPA receptor modulator such as tranylcypromine. 【0301】 In some embodiments, the additional therapeutic agent is an annexin A5 stimulator, e.g., AP-01 or SY-005. 【0302】 In some embodiments, the additional therapeutic agent is an apelin receptor agonist such as CB-5064MM. 【0303】 In some embodiments, the additional therapeutic agent is an anticoagulant such as heparin (heparin and low molecular weight heparin), aspirin, apixaban, dabigatran, edoxaban, argatroban, enoxaparin, or fondaparinux. 【0304】 In some embodiments, the additional therapeutic agent is an androgen receptor antagonist such as bicalutamide, deuterated enzalutamide, enzalutamide, or purosertamide (procateramide). 【0305】 In some embodiments, the additional therapeutic agent is an antihypoxic agent such as sodium trans-croscylate. 【0306】 In some embodiments, the additional therapeutic agent is an antithrombotic agent such as defibrotide, rivaroxaban, alteplase, tirofiban, clopidogrel, prasugrel, bemiparin, bivalirudin, sodexide, or tenecteplase. 【0307】 In some embodiments, the additional therapeutic agent is an antihistamine such as chloroperastine or clemastine. 【0308】 In some embodiments, the additional therapeutic agent is an apolipoprotein A1 agonist, such as CER-001. 【0309】 In some embodiments, the additional therapeutic agent is a phospholipase A2 inhibitor such as ethyl eicosapentaenoate. 【0310】 In some embodiments, the additional therapeutic agent is an axl tyrosine kinase receptor inhibitor such as bemcentinib. 【0311】 In some embodiments, the additional therapeutic agent is a corticosteroid / beta2 adrenergic receptor agonist such as budesonide + formoterol fumarate. 【0312】 In some embodiments, the additional therapeutic agent is a BET bromodomain inhibitor / APOA1 gene stimulator, for example, apabetalone. 【0313】 In some embodiments, the additional therapeutic agent is a blood coagulation modulator such as lanadelumab. 【0314】 In some embodiments, the additional therapeutic agent is a bradykinin B2 receptor antagonist, for example, icatibant. 【0315】 In some embodiments, the additional therapeutic agent is an EGFR gene inhibitor / Btk tyrosine kinase inhibitor, for example, avibertinib. 【0316】 In some embodiments, the additional therapeutic agent is a Btk tyrosine kinase inhibitor (for example, ibrutinib or zanubrutinib, etc.). 【0317】 In some embodiments, the additional therapeutic agent is a calpain-I / II / IX inhibitor, for example, BLD-2660. 【0318】 In some embodiments, the additional therapeutic agent is a cannabinoid CB2 receptor agonist, for example, onteranabant or PPP-003. 【0319】 In some embodiments, the additional therapeutic agent is a Ca2+ release-activated Ca2+ channel 1 inhibitor, for example, zegocractin (CM-4620). 【0320】 In some embodiments, the additional therapeutic agent is an ATR inhibitor such as berzosertib. 【0321】 【0322】 In some embodiments, the additional therapeutic agent is a cadherin-5 regulator such as FX-06. 【0323】 In some embodiments, the additional therapeutic agent is a casein kinase II inhibitor such as silmitasertib. 【0324】 In some embodiments, the additional therapeutic agent is a caspase inhibitor such as emricasan. 【0325】 In some embodiments, the additional therapeutic agent is a catalase stimulator / superoxide dismutase stimulator such as MP-1032. 【0326】 In some embodiments, the additional therapeutic agent is a CCR2 chemokine antagonist / CCR5 chemokine antagonist (e.g., cenicriviroc, etc.). 【0327】 In some embodiments, the additional therapeutic agent is a CCR5 chemokine antagonist (e.g., maraviroc or leronlimab, etc.). 【0328】 In some embodiments, the additional therapeutic agent is a CD122 agonist / IL-2 receptor agonist, such as bempegaldesleukin. 【0329】 In some embodiments, the additional therapeutic agent is a CD73 agonist / interferon beta ligand (e.g., FP-1201). 【0330】 In some embodiments, the additional therapeutic agent is a cholesterol ester transport protein inhibitor such as dalcetrapib. 【0331】 In some embodiments, the additional therapeutic agent is a mannan-binding lectin serine protease / complement C1s subcomponent inhibitor / myeloperoxidase inhibitor, such as RLS-0071, etc. 【0332】 In some embodiments, the additional therapeutic agent is a complement C5 factor inhibitor / leukotriene BLT receptor antagonist, such as nomacopan. 【0333】 In some embodiments, the additional therapeutic agent is a complement C5 factor inhibitor, such as eculizumab, STSA-1002, or zilucoplan. 【0334】 In some embodiments, the additional therapeutic agent is a CXCR4 chemokine antagonist, such as plerixafor or motixafortide. 【0335】 In some embodiments, the additional therapeutic agent is a cytochrome P450 3A4 inhibitor / peptidyl-prolyl cis-trans isomerase A inhibitor, such as alisporivir. 【0336】 In some embodiments, the additional therapeutic agent is a cysteine protease inhibitor, such as SLV-213. 【0337】 In some embodiments, the additional therapeutic agent is a dihydroorotate dehydrogenase inhibitor, such as Meds-433, brequinar, RP-7214, farudostat, or emboldostat. 【0338】 In some embodiments, the additional therapeutic agent is a dipeptidase-1 regulator, such as Metablok. 【0339】 In some embodiments, the additional therapeutic agent is a dihydroorotate dehydrogenase inhibitor / IL-17 antagonist, such as vidofludimus. 【0340】 In some embodiments, the additional therapeutic agent is a diuretic, such as an aldosterone antagonist, such as spironolactone. 【0341】 In some embodiments, the additional therapeutic agent is a deoxyribonuclease I stimulant, such as GNR-039 or dornase alfa. 【0342】 In some embodiments, the additional therapeutic agent is a NET inhibitor such as NTR-441. 【0343】 In some embodiments, the additional therapeutic agent is a dihydroceramide delta 4 desaturase inhibitor / sphingosine kinase 2 inhibitor, such as opaganib. 【0344】 In some embodiments, the additional therapeutic agent is a DNA methyltransferase inhibitor, such as azacitidine. 【0345】 In some embodiments, the additional therapeutic agent is an LXR antagonist (e.g., laropiprant, etc.). 【0346】 In some embodiments, the additional therapeutic agent is a dipeptidyl peptidase I inhibitor, such as brequinar. 【0347】 In some embodiments, the additional therapeutic agent is a protein arginine deiminase IV inhibitor, such as JBI-1044. 【0348】 In some embodiments, the additional therapeutic agent is an elongation factor 1 alpha 2 regulator, such as plitidepsin. 【0349】 In some embodiments, the additional therapeutic agent is an eukaryotic initiation factor 4A-I inhibitor, such as zotatifin. 【0350】 In some embodiments, the additional therapeutic agent is an exo-alpha-sialidase regulator, such as DAS-181. 【0351】 In some embodiments, the additional therapeutic agent is an exportin 1 inhibitor, such as selinexor. 【0352】 In some embodiments, the additional therapeutic agent is a fractalkine ligand inhibitor, such as KAND-567. 【0353】 In some embodiments, the additional therapeutic agent is a FYVE finger phosphoinositide kinase inhibitor / IL-12 receptor antagonist / IL-23 antagonist, such as apilimod dimesylate. 【0354】 In some embodiments, the additional therapeutic agent is a GABA A receptor modulator, such as brexanolone. 【0355】 In some embodiments, the additional therapeutic agent is a glucocorticoid receptor agonist, such as ciclesonide, hydrocortisone, dexamethasone, dexamethasone phosphate, or 101-PGC-005. 【0356】 In some embodiments, the additional therapeutic agent is a GM-CSF receptor agonist, such as sargramostim. 【0357】 In some embodiments, the additional therapeutic agent is a GPCR agonist, such as esberaprost sodium. 【0358】 In some embodiments, the additional therapeutic agent is a glycine regulator, such as Q-glycine. 【0359】 In some embodiments, the additional therapeutic agent is a leukotriene D4 antagonist, such as montelukast. 【0360】 In some embodiments, the additional therapeutic agent is a histamine H1 receptor antagonist, such as ebastine, tranilast, or levocetirizine dihydrochloride. 【0361】 In some embodiments, the additional therapeutic agent is a histamine H2 receptor antagonist, such as famotidine. 【0362】 In some embodiments, the additional therapeutic agent is a heat shock protein stimulator / insulin sensitizer / PARP inhibitor, such as BGP-15. 【0363】 In some embodiments, the additional therapeutic agent is a histone inhibitor such as STC-3141. 【0364】 In some embodiments, the additional therapeutic agent is a histone deacetylase-6 inhibitor, such as CKD-506. 【0365】 In some embodiments, the additional therapeutic agent is a HIF prolyl hydroxylase-2 inhibitor, such as desidustat. 【0366】 In some embodiments, the additional therapeutic agent is a HIF prolyl hydroxylase inhibitor (e.g., vadadustat, etc.). 【0367】 In some embodiments, the additional therapeutic agent is an IL-8 receptor antagonist (e.g., reparixin, etc.). 【0368】 In some embodiments, the additional therapeutic agent is an IL-7 receptor agonist such as CYT-107. 【0369】 In some embodiments, the additional therapeutic agent is an IL-7 receptor agonist / interleukin-7 ligand, such as efineptakin alpha. 【0370】 In some embodiments, the additional therapeutic agent is an IL-22 agonist, such as emapalumab-lzsg alpha. 【0371】 In some embodiments, the additional therapeutic agent is an IL-22 agonist / interleukin 22 ligand, such as F-652. 【0372】 In some embodiments, the additional therapeutic agent targets IL-33 (e.g., tozakinumab, etc.). 【0373】 In some embodiments, the additional therapeutic agent is an IL-15 agonist such as nogapentin alpha. 【0374】 In some embodiments, the additional therapeutic agent is an integrin α-V / β-1 antagonist / integrin α-V / β-6 antagonist such as vixotrigast. 【0375】 In some embodiments, the additional therapeutic agent is an interferon alpha-2 ligand, such as interferon alpha-2b or virafin. 【0376】 In some embodiments, the additional therapeutic agent is an interferon beta ligand, such as a follow-on biologic of interferon beta-1a, interferon beta-1b or SNG-001. 【0377】 In some embodiments, the additional therapeutic agent is an interferon receptor modulator, such as peginterferon lambda-1a. 【0378】 In some embodiments, the additional therapeutic agent is an interleukin-2 ligand, such as aldesleukin. 【0379】 In some embodiments, the additional therapeutic agent is an IRAK-4 protein kinase inhibitor, such as deucravacitinib. 【0380】 In some embodiments, the additional therapeutic agent is a JAK inhibitor, for example, the additional therapeutic agent is baricitinib, filgotinib, jakutinib, tofacitinib or nezulcitinib (TD-0903). 【0381】 In some embodiments, the additional therapeutic agent is a neutrophil elastase inhibitor, such as alvelestat. 【0382】 In some embodiments, the additional therapeutic agent is a pulmonary surfactant-associated protein D regulator, such as AT-100. 【0383】 In some embodiments, the additional therapeutic agent is a plasma kallikrein inhibitor, such as donidalorsen. 【0384】 In some embodiments, the additional therapeutic agent is a lysine-specific histone demethylase 1 / MAO B inhibitor such as bufidemsstat. 【0385】 In some embodiments, the additional therapeutic agent is a mannan-binding lectin serine protease inhibitor, such as conestat alfa. 【0386】 In some embodiments, the additional therapeutic agent is a maxi-K potassium channel inhibitor such as ENA-001. 【0387】 In some embodiments, the additional therapeutic agent is a MEK protein kinase inhibitor (e.g., zapnometinib, etc.). 【0388】 In some embodiments, the additional therapeutic agent is a MEK-1 protein kinase inhibitor / Ras gene inhibitor, such as anthraquinonol. 【0389】 In some embodiments, the additional therapeutic agent is a melanocortin MC1 receptor agonist, such as PL-8177. 【0390】 In some embodiments, the additional therapeutic agent is a melanocortin MC1 / MC3 receptor agonist, such as resmetra gon acetate. 【0391】 In some embodiments, the additional therapeutic agent is a matrix metalloprotease-12 inhibitor, such as FP-025. 【0392】 In some embodiments, the additional therapeutic agent is an inhibitor of NACHT LRR PYD domain-containing protein 3, such as dapansutrile, DFV-890, or ZYIL-1. 【0393】 In some embodiments, the additional therapeutic agent is a NADPH oxidase inhibitor, such as iskinaxib. 【0394】 In some embodiments, the additional therapeutic agent is a neurpilin 2 regulator such as efzofitimod. 【0395】 In some embodiments, the additional therapeutic agent is an NK1 receptor antagonist such as aprepitant or trazipitant. 【0396】 In some embodiments, the additional therapeutic agent is an NMDA receptor antagonist such as translocetine or ifenprodil. 【0397】 In some embodiments, the additional therapeutic agent is a nuclear factor kappa B inhibitor / p38 MAP kinase inhibitor (e.g., zenuzolac, etc.). 【0398】 In some embodiments, the additional therapeutic agent is an ornithine decarboxylase inhibitor such as eflornithine. 【0399】 In some embodiments, the additional therapeutic agent is an opioid receptor sigma antagonist 1 such as MR-309. 【0400】 In some embodiments, the additional therapeutic agent is a PGD2 antagonist, e.g., asapiprant. 【0401】 In some embodiments, the additional therapeutic agent is a PDGF receptor antagonist / TGFβ receptor antagonist / p38 MAP kinase inhibitor (e.g., deupirfenidone, etc.). 【0402】 In some embodiments, the additional therapeutic agent is a phospholipase A2 inhibitor such as baeloprazide methyl. 【0403】 In some embodiments, the additional therapeutic agent is a phosphoinositide 3-kinase inhibitor / mTOR complex inhibitor such as ductrisib. 【0404】 In some embodiments, the additional therapeutic agent is an mTOR inhibitor such as sirolimus. 【0405】 In some embodiments, the additional therapeutic agent is a phosphoinositide-3 kinase delta / gamma inhibitor (e.g., duvelisib, etc.). 【0406】 In some embodiments, the additional therapeutic agent is a PIKfyve inhibitor such as VRG-101. 【0407】 In some embodiments, the additional therapeutic agent is a plasminogen activator inhibitor 1 inhibitor such as TM-5614. 【0408】 In some embodiments, the additional therapeutic agent is a protein tyrosine phosphatase β inhibitor, such as razuprotafib. 【0409】 In some embodiments, the additional therapeutic agent is a RIP-1 kinase inhibitor such as eclacestatib (DNL-758) or SIR-0365. 【0410】 In some embodiments, the additional therapeutic agent is a Rev protein regulator such as obergefimod. 【0411】 In some embodiments, the additional therapeutic agent is an S-phase kinase-associated protein 2 inhibitor such as niclosamide, CP-COV3, SCAI-502, or DWRX-2003. 【0412】 In some embodiments, the additional therapeutic agent is a signal transducer CD24 stimulator such as EXO-CD24. 【0413】 In some embodiments, the additional therapeutic agent is a sodium glucose transporter-2 inhibitor such as dapagliflozin propanediol. 【0414】 In some embodiments, the additional therapeutic agent is a calcium channel stimulator such as solnatide. 【0415】 In some embodiments, the additional therapeutic agent is a sphingosine-1-phosphate receptor-1 agonist / sphingosine-1-phosphate receptor-5 agonist such as ozanimod. 【0416】 In some embodiments, the additional therapeutic agent is a non-steroidal anti-inflammatory drug such as Ampion. 【0417】 In some embodiments, the additional therapeutic agent is a superoxide dismutase stimulant such as avasopasem manganese. 【0418】 In some embodiments, the additional therapeutic agent is a Syk tyrosine kinase inhibitor such as fostamatinib sodium hydrate. 【0419】 In some embodiments, the additional therapeutic agent is a Tie2 tyrosine kinase receptor agonist such as AV-001. 【0420】 In some embodiments, the additional therapeutic agent is a TGFB2 gene inhibitor, such as trabedersen. 【0421】 In some embodiments, the additional therapeutic agent is a tissue factor inhibitor such as AB-201. 【0422】 In some embodiments, the additional therapeutic agent is a TLR-3 agonist such as rintatolimod. 【0423】 In some embodiments, the additional therapeutic agent is a TLR-4 antagonist such as ApTLR-4FT, EB-05, or erythrolan. 【0424】 In some embodiments, the additional therapeutic agent is a TLR-7 / 8 antagonist (e.g., emapatran, etc.). 【0425】 In some embodiments, the additional therapeutic agent is a TLR-2 / 6 agonist such as INNA-051. 【0426】 In some embodiments, the additional therapeutic agent is a TLR-7 agonist such as PRTX-007 or APR-002. 【0427】 In some embodiments, the additional therapeutic agent is a TLR agonist, for example, PUL-042. 【0428】 In some embodiments, the additional therapeutic agent is a TLR-4 agonist such as REVTx-99. 【0429】 In some embodiments, the additional therapeutic agent is a TLR-2 / 4 antagonist such as VB-201. 【0430】 In some embodiments, the additional therapeutic agent is a TNFα ligand inhibitor such as pegylated pentoxifylline. 【0431】 In some embodiments, the additional therapeutic agent is a type I IL-1 receptor antagonist such as anakinra. 【0432】 In some embodiments, the additional therapeutic agent is a TREM receptor 1 antagonist, for example, nantibody. 【0433】 In some embodiments, the additional therapeutic agent is a trypsin inhibitor such as ulinastatin. 【0434】 In some embodiments, the additional therapeutic agent is a tubulin inhibitor such as sabizabulin, CCI-001, PCNT-13, CR-42-24, albendazole, entosbulin, SAR-132885, or ON-24160. 【0435】 In some embodiments, the additional therapeutic agent is a VIP receptor agonist such as abiptadil. 【0436】 In some embodiments, the additional therapeutic agent is a xanthine oxidase inhibitor such as oxypurinol. 【0437】 In some embodiments, the additional therapeutic agent is a vasodilator, such as iloprost, epoprostenol (VentaProst), zavegepant, TXA-127, USB-002, ambrisentan, nitric oxide nasal spray (NORS), pentoxifylline, propranolol, RESP301, sodium nitrite, or dipyridamole. 【0438】 In some embodiments, the additional therapeutic agent is a vitamin D3 receptor agonist, such as colecalciferol. 【0439】 In some embodiments, the additional therapeutic agent is a zonulin inhibitor, such as larazotide acetate. 【0440】 In some embodiments, the additional therapeutic agent is a synthetic retinoid derivative, such as fenretinide. 【0441】 In some embodiments, the additional therapeutic agent is a glucose metabolism inhibitor (e.g., WP-1122 or WP-1096, etc.). 【0442】 In some embodiments, the additional therapeutic agent is adalimumab, AT-H201, 2-deoxy-D-glucose, AD-17002, AIC-649, AMTX-100, astodrimer, AZD-1656, verapectin, viteperamycin, bucillamine, budesonide, CNM-AgZn-17, codibul, CT-38, danicopan, didecylmethotrexate, DW-2008S (DW-2008), EDP-1815, EG-009A, Fabencov, Gamunex, genistein, GLS-1200, hzVSF-v13, imidazolylethaneamide pentanedioic acid, IMM-101, MAS-825, MRG-001, Nasitrol, Nylexa, olverembatinib, OP-101, OPN-019, Orynotide rhesus theta defensin-1, pyronaridine + artesunate, dapsone, RPH-104, sodium pyruvate, sulforadex, tafenoxican, TB-006, terasebec, Tempol, TL-895, thimerosal, trimodulin, XC-221, XC-7, zunsemetinib, metformin glycinate, lucinactant, EOM-613, mosidipimod, ivermectin, leflunomide, ibudilast, RBT-9, raloxifene, prothion, gemcabene, or idronoxyl. 【0443】 In some embodiments, the additional therapeutic agent is a CD73 antagonist such as AK-119. 【0444】 In some embodiments, the additional therapeutic agent is a CD95 protein fusion such as aselcept. 【0445】 In some embodiments, the additional therapeutic agent is a complement factor C2 regulator, such as ARGX-117. 【0446】 In some embodiments, the additional therapeutic agent is a complement C3 inhibitor such as AMY-101 or NGM-621. 【0447】 In some embodiments, the additional therapeutic agent is a CXC10 chemokine ligand inhibitor (e.g., EB-06, etc.). 【0448】 In some embodiments, the additional therapeutic agent is a cytotoxic T lymphocyte protein-4 fusion protein such as abatacept. 【0449】 In some embodiments, the additional therapeutic agent is an anti-S. aureus antibody (e.g., tositumomab, etc.). 【0450】 In some embodiments, the additional therapeutic agent is an anti-LPS antibody such as IMM-124-E. 【0451】 In some embodiments, the additional therapeutic agent is an adrenomedullin ligand inhibitor (e.g., enobavumab, etc.). 【0452】 In some embodiments, the additional therapeutic agent is a basigin inhibitor such as meplazumab. 【0453】 In some embodiments, the additional therapeutic agent is a CD3 antagonist such as foralumab. 【0454】 In some embodiments, the additional therapeutic agent is a connective tissue growth factor ligand inhibitor (e.g., PRS-220, pamrevlumab, etc.). 【0455】 In some embodiments, the additional therapeutic agent is a complement C5a factor inhibitor, such as BDB-1 or vilobelimab. 【0456】 In some embodiments, the additional therapeutic agent is a complement C5 factor inhibitor, such as ravulizumab. 【0457】 In some embodiments, the additional therapeutic agent is a mannan-binding lectin serine protease-2 inhibitor (e.g., narsoplimab, etc.). 【0458】 In some embodiments, the additional therapeutic agent is a GM-CSF regulator, such as STSA-1005, gemtuzumab, namilumab, promalizumab, otilimab or lenzilumab, etc. 【0459】 In some embodiments, the additional therapeutic agent is a heat shock protein inhibitor / IL-6 receptor antagonist (such as siltuximab, etc.). 【0460】 In some embodiments, the additional therapeutic agent is an IL-6 receptor antagonist, such as clazakizumab, revilimab, orolizumab, tocilizumab, or sirukumab. 【0461】 In some embodiments, the additional therapeutic agent is an IL-8 receptor antagonist (such as BMS-986253, etc.). 【0462】 In some embodiments, the additional therapeutic agent is an interleukin-1 beta ligand inhibitor such as canakinumab. 【0463】 In some embodiments, the additional therapeutic agent is an interferon gamma ligand inhibitor such as emapalumab. 【0464】 In some embodiments, the additional therapeutic agent is an anti-ILT7 antibody, such as daxilelimab, etc. 【0465】 In some embodiments, the additional therapeutic agent is a monocyte differentiation antigen CD14 inhibitor, such as atibucumab. 【0466】 In some embodiments, the additional therapeutic agent is a plasma kallikrein inhibitor such as lanadelumab. 【0467】 In some embodiments, the additional therapeutic agent is a platelet glycoprotein VI inhibitor (such as glenzolimab, etc.). 【0468】 In some embodiments, the additional therapeutic agent is an inhibitor of the T cell differentiation antigen CD6, such as itolizumab. 【0469】 In some embodiments, the additional therapeutic agent is a TNFα ligand inhibitor / TNF binder (e.g., infliximab, etc.). 【0470】 In some embodiments, the additional therapeutic agent is an anti-LIGHT antibody such as AVTX-002. 【0471】 In some embodiments, the additional therapeutic agent is IMC-2 (valacyclovir + celecoxib) or AXA-1125. 【0472】 In some embodiments, the additional therapeutic agent is COVID-HIG. 【0473】 In some embodiments, the compounds of the present disclosure or pharmaceutically acceptable salts thereof are co-administered with one or more agents useful for the treatment and / or prevention of COVID-19. 【0474】 Non-limiting examples of such agents include corticosteroids such as dexamethasone, hydrocortisone, methylprednisolone or prednisone; interleukin-6 (IL-6) receptor blockers such as tocilizumab or sarilumab; Janus kinase (JAK) inhibitors such as baricitinib, ruxolitinib or tofacitinib; and antiviral agents such as molnupiravir, sotrovimab or remdesivir. 【0475】 In further embodiments, the compounds of the present disclosure or pharmaceutically acceptable salts thereof are co-administered with two or more agents useful for the treatment of COVID-19. Agents useful for the treatment and / or prevention of COVID-19 include, but are not limited to, the compounds of the present disclosure and two additional therapeutic agents such as nirmatrelvir and ritonavir, casirivimab and imdevimab, or ruxolitinib and tofacitinib. 【0476】 In some embodiments, the additional therapeutic agent comprises an antiviral agent. In some embodiments, the antiviral agent is an entry inhibitor. In some embodiments, the antiviral agent is a protease inhibitor. In some embodiments, the antiviral agent is an RNA polymerase inhibitor. In some embodiments, the additional therapeutic agent is an RNA-dependent RNA polymerase (RdRp) inhibitor. 【0477】 In some embodiments, the antiviral agent is selected from an angiotensin-converting enzyme 2 inhibitor, an angiotensin-converting enzyme 2 regulator, an angiotensin-converting enzyme 2 stimulator, an angiotensin II AT-2 receptor agonist, an angiotensin II AT-2 receptor antagonist, an angiotensin II receptor regulator, a coronavirus nucleoprotein regulator, a coronavirus small envelope protein regulator, a coronavirus spike glycoprotein inhibitor, a coronavirus spike glycoprotein regulator, a SARS-CoV-2 envelope small membrane protein inhibitor, a SARS-CoV-2 envelope small membrane protein regulator, a SARS-CoV-2 MPro inhibitor, a SARS-CoV-2 non-structural protein 8 regulator, a SARS-CoV-2 nucleoprotein inhibitor, a SARS-CoV-2 nucleoprotein regulator, a SARS-CoV-2 protein 3a inhibitor, a SARS-CoV-2 protease polyprotein 1a inhibitor, a SARS-CoV-2 replicase polyprotein 1a regulator, a SARS-CoV-2 replicase polyprotein 1ab inhibitor, a SARS-CoV-2 replicase polyprotein 1ab regulator, a SARS-CoV-2 glycoprotein spike inhibitor, a SARS-CoV-2 spike glycoprotein regulator, a SARS-CoV-2 structural glycoprotein regulator, a papain inhibitor, a protease inhibitor, a protease regulator, an RNA polymerase inhibitor, an RNA polymerase regulator, an RNA-dependent RNA polymerase (RdRp) inhibitor, a SARS coronavirus 3C protease-like inhibitor, a SARS-CoV-2 nsp14 methyltransferase enzyme inhibitor, a 3CLpro / Mpro inhibitor, a serine protease inhibitor, a transmembrane serine protease 2 inhibitor, a transmembrane serine protease 2 regulator, a viral envelope protein inhibitor, a viral protease inhibitor, a viral protease regulator, a viral protein target regulator, a viral ribonuclease inhibitor, and a viral structural protein regulator. 【0478】 In some embodiments, the additional therapeutic agent is an entry inhibitor. For example, in some embodiments, the additional therapeutic agent is an ACE2 inhibitor, a fusion inhibitor, or a protease inhibitor. 【0479】 In some embodiments, the additional therapeutic agent is an angiotensin-converting enzyme 2 inhibitor, such as SBK-001. 【0480】 In some embodiments, the additional therapeutic agent is an angiotensin-converting enzyme 2 modulator, such as Newmifil or JN-2019. 【0481】 In some embodiments, the additional therapeutic agent is an entry inhibitor, such as MU-UNMC-1 or SAI-4. 【0482】 In some embodiments, the additional therapeutic agent is an angiotensin-converting enzyme 2 stimulator, such as alnacetase alfa. 【0483】 In some embodiments, the additional therapeutic agent is an angiotensin II AT-2 receptor agonist, such as VP-01. 【0484】 In some embodiments, the additional therapeutic agent is an ACE II receptor antagonist, such as DX-600. 【0485】 In some embodiments, the additional therapeutic agent is an angiotensin II receptor modulator, such as TXA-127. 【0486】 In some embodiments, the additional therapeutic agent is a transmembrane serine protease 2 modulator, such as BC-201, N-0385. 【0487】 In some embodiments, the additional therapeutic agent is a viral envelope protein inhibitor, such as MXB-9 or MXB-004. 【0488】 In some embodiments, the additional therapeutic agent is an RNAi agent, such as ARO-COV or SNS-812. 【0489】 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, an inactivated vaccine (i.e., an inactivated SARS-CoV-2 vaccine), a therapeutic vaccine, a prophylactic vaccine, a protein-based vaccine, a viral vector vaccine, a cell vaccine, or a dendritic cell vaccine. 【0490】 In some embodiments, the additional therapeutic agent is a vaccine such as Tojinameran, NVX-CoV2373, Erasmelan, KD-414, Ad26.COV2-S, Vaxzevria, SCB-2019, AKS-452, VLA-2001, HDT-301, S-268019, MVC-COV1901, mRNA-1273.214, mRNA-1273.213, mRNA-1273.222, NVX-CoV2515, Covaxin, BBIBP-CorV, GBP-510, mRNA-1273.351 + mRNA-1273.617 (SARS-CoV-2 multivalent mRNA vaccine, COVID-19), Ad5-nCoV, Omicron-based COVID-19 vaccine (mRNA vaccine, COVID-19), mRNA-1073, mRNA-1273.214, mRNA-1230, mRNA-1283, Omicron-based COVID-19 vaccine, SARS-CoV-2 subunit recombinant, recombinant vaccine such as Sputnik M, ZyCoV-D, COVID-19 XWG-03, mRNA-1273.529, mRNA-1010, CoronaVac, AZD-2816, Sputnik V, inactivated SARS-CoV-2 vaccine (Vero cell, COVID-19), DS-5670, PHH-1V, INO-4800, UB-612, coronavirus vaccine (whole virion, inactivated / purified), ReCOV, MT-2766, ARCT-154, SP-0253, CORBEVAX, mRNA-1273.211, ZF-2001, Sputnik Light, Recombinant Protein Vaccine (COVID-19 / SARS-CoV-2 Infection), VSV Vector System Vaccine Targeting Spike Glycoprotein (COVID-19), VLA-2101, GRT-R912, GRAd-COV2, VPM-1002, COViran Barekat, Ad5-nCoV-IH, ARCoV, Covax-19, Recombinant SARS-CoV-2 Vaccine (Protein Subunit / CHO Cell, COVID-19), BBV-154, RAZI Cov Pars, COVID-19 Vaccine (Inactivated / Vero Cell / Intramuscular, SARS-CoV-2 Infection), COVID-19 Vaccine (Inactivated, Vero Cell / Intramuscular), BNT-162b2s01, BNT-162b4, BNT-162b5, BNT-162b2 Omi, BNT-162b2 Bivalent, CIGB-66, mRNA-1273.617, Mycobacterium w, ERUCOV-VAC, AG-0301-COVID19, fakhravac, AV-COVID-19, Peptide Vaccine (COVID-19), Nanocovax, SARS-CoV-2 Vaccine (Inactivated / Vero Cell / Intramuscular, COVID-19), QAZCOVID-IN, S-875670 Nasal Vaccine, VTP-500 or BNT162b5. 【0491】 In some embodiments, the additional therapeutic agent is a protease inhibitor. For example, in some embodiments, the additional therapeutic agent is a 3C-like cysteine protease inhibitor (3CLpro (also called main protease, Mpro)), a papain-like protease inhibitor (PLpro), a serine protease inhibitor, or a transmembrane serine protease 2 inhibitor (TMPRSS2). 【0492】 In some embodiments, the additional therapeutic agent is a 3CLpro / Mpro inhibitor such as ABBV-903, AB-343, CDI-873, GC-373, GC-376, pomotrelvir (PBI-0451), UCI-1, bebtelovimab (FB-2001, DC-402234), DC-402267, GDI-4405, HS-10517, RAY-1216, MPI-8, SH-879, SH-580, EDP-235, VV-993, CDI-988, MI-30, nirmatrelvir, ensitrelvir, ASC-11, ASC-11 + ritonavir, EDDC-2214, SIM-0417, PF-07817883, simnotrelvir, simnotrelvir + ritonavir, SYH-2055, ISM-3312, CDI-45205, LHP-803 (COR-803), ALG-097111, TJC-642, CVD-0013943, oritrelvir (STI-1558), eravacycline, cinamycin, WPV-01, or prexasertib. 【0493】 In some embodiments, the additional therapeutic agent is a papain-like protease inhibitor (PLpro), such as SBFM-PL4 or GRL-0617. 【0494】 In some embodiments, the additional therapeutic agent is a SARS-CoV-2 helicase Nsp13 inhibitor such as EIS-4363. 【0495】 In some embodiments, the additional therapeutic agent is a SARS-CoV-2 helicase Nsp14 inhibitor such as TO-507. 【0496】 In some embodiments, the additional therapeutic agent is a SARS-CoV-2 spike (S) and protease modulator, such as ENU-200. 【0497】 In some embodiments, the additional therapeutic agent is a protease inhibitor such as ALG-097558 or MRX-18. 【0498】 In some embodiments, the additional therapeutic agent is a serine protease inhibitor, such as, for example, umpastatin, nafamostat, camostat mesylate, nafamostat mesylate, or camostat. 【0499】 In some embodiments, the additional therapeutic agent is a 3CLpro / transmembrane serine protease 2 inhibitor, such as, for example, SNB-01 (pentarandil) or SNB-02. 【0500】 In some embodiments, the additional therapeutic agent is a viral protease inhibitor, such as Pan-Corona, Cov-X, or bepridil. 【0501】 In some embodiments, the additional therapeutic agent is an RNA polymerase inhibitor. For example, in some embodiments, the additional therapeutic agent is an RNA polymerase inhibitor or an RNA-dependent RNA polymerase (RdRp) inhibitor. 【0502】 In some embodiments, the additional therapeutic agent is an RNA-dependent RNA polymerase (RdRp) inhibitor, such as remdesivir, NV-CoV-2, NV-CoV-2-R, NV-CoV-1 encapsulated remdesivir, CMX-8521, GS-621763, GS-5245, GS-441524, DEP remdesivir, ATV-006, deuremidevir (VV-116), LGN-20, CMX-521, SHEN-26, MB-905, and the compounds disclosed in WO 2022142477, WO 2021213288, and WO 2022047065. 【0503】 In some embodiments, the additional therapeutic agent is an RNA polymerase inhibitor, such as, for example, molnupiravir (EIDD-2801), favipiravir, bemnifosbuvir, sofosbuvir, ASC-10, or galidesivir. 【0504】 In some embodiments, the additional therapeutic agent is a viral entry inhibitor, such as brexidine. 【0505】 In some embodiments, the additional therapeutic agent is an antibody that binds to the coronavirus, for example, an antibody that binds to SARS or MERS. 【0506】 In some embodiments, the additional therapeutic agent is an antibody, for example, a monoclonal antibody. For example, the additional therapeutic agent is an antibody against SARS-CoV-2, a neutralizing nanobody, an antibody targeting the SARS-CoV-2 spike protein, a fusion protein, a multispecific antibody, and an antibody capable of neutralizing SARS-CoV-2 (SARS-CoV-2 neutralizing antibody). 【0507】 In some embodiments, the additional therapeutic agent is an antibody that targets a specific site on ACE2. In some embodiments, the additional therapeutic agent is a polypeptide that targets the SARS-CoV-2 spike protein (S-protein). 【0508】 In some embodiments, the additional therapeutic agent is a SARS-CoV-2 virus antibody. 【0509】 In some embodiments, the antibody is ABBV-47D11, COVI-GUARD (STI-1499), C144-LS + C135-LS, DIOS-202, DIOS-203, DIOS-301, DXP-604, JMB-2002, LY-CovMab, bamlanivimab (LY-CoV555), GIGA-2050, IBI-314, S309, SAB-185, etesevimab (CB6), COR-101, JS016, VNAR, VIR-7832 and / or sotrovimab (VIR-7831), casirivimab + imdevimab (REGN-COV2 or REGN 10933 + RGN 10987), BAT2020, BAT2019, 47D11, YBSW-015 or PA-001. 【0510】 In some embodiments, the additional therapeutic agent is STI-9199 (COVI-SHIELD), STI-9167 or AR-701 (AR-703 and AR-720). 【0511】 In some embodiments, the additional therapeutic agent is BRII-196, BRII-198, ADG-10, adintrevimab (ADG-20), ABP-300, BA-7208, BI-767551, BHV-1200, CT-P63, JS-026, sotrovimab (GSK-4182136), tixagevimab + cilgavimab (AZD-7442), legdanvimab, SAB-301, AOD-01, purtabimab (COVI-AMG), 9MW-3311 (MW-33), DXP-593, BSVEQAb, anti-SARS-CoV-2 IgY, COVID-EIG, CSL-760, F-61, REGN-3048-3051, SARS-CoV-2 monoclonal antibody (COVID-19, ADM-03820), enobuvimab (HFB-30132A), INM-005, SCTA01, TY-027, XAV-19, amubarvimab + romlusevimab, SCTA-01, bebtelovimab, beldavinmab, IBI-O123, IGM-6268, FYB-207, FS-2101, RBT-0813, REGN-14256, REGN-14284, SPKM-001, XVR-011, TB202-3, TB181-36, TB339-031, LMN-301, LQ-050, COVAB-36, MAD-0004J08, STI-2099, TATX-03, TZLS-501, ZCB-11, AZD-3152, VYD-222, XVR-012, or ACV-200-17. 【0512】 In some embodiments, the additional therapeutic agent is an engineered ACE-2-IgG1-Fc fusion protein targeting the SARS-Cov-2 RBD, such as EU-129, the bivalent ACE2-IgG Fc null fusion protein (SI-F019). 【0513】 In some embodiments, the additional therapeutic agent is an ACE2-Fc receptor fusion protein such as HLX-71. 【0514】 In some embodiments, the additional therapeutic agent is ensovibep. 【0515】 In some embodiments, the additional therapeutic agent is SYZJ-001. 【0516】 In some embodiments, the additional therapeutic agent is an HIV-1 protease inhibitor, such as ASC-09F (ASC-09 + ritonavir) or lopinavir + ritonavir. 【0517】 In some embodiments, the additional therapeutic agent is a non-nucleoside reverse transcriptase inhibitor such as elsulfavirine. 【0518】 In some embodiments, the additional therapeutic agent is a nucleoside reverse transcriptase inhibitor such as azvudine. 【0519】 In some embodiments, the additional therapeutic agents are Abbv-990, ABBV-903, 2b-11, 5-aminolevulinic acid phosphate, AGP-600, AGM-380, AIP-502, ALG-150150, BAT-2022, NED-260, burfiralimab, ALG-097431, bardoxolone, BW-PS-119, croquemitol, CR-405, delstratovir, D4-102-01, D4-102-02, ESFAM-289, ENOB-CV-01, ENOB-CV-11, EIS-10700, EV-300, beta-521, GEA-001, SIM-0417, molnupiravir, Pan-corona, torbir, nirmatrelvir + ritonavir (Paxlovid (registered trademark)), JTBC-00201, favipiravir, favipiravir + cathepsin inhibitor (TNX-3900), GC-376, upamostat, Lesoreil-01, Lesoreil-02+, benforavir, VV-116, VV-993, SNB-01, EDP-235, CovX, ensitrelvir, MPI-8, masitinib, ALG-097558, ASC-11, PBI-0451, nafamostat, nafamostat mesilate, CDI-45205, LHP-803 (COR-803), ALG-097111, BC-201, SH-879, CDI-873, CDI-988, remdesivir, NV-CoV-2-R, remdesivir encapsulated in NV-CoV-1, NA-831 + remdesivir, DEP remdesivir, GS-621763, GS-5245, GLS-5310, bemnifosbuvir, QLS-1128, ASC-10, SBFM-PL4, camostat mesilate, UCI-1, FB-2001 (DC-402234), ebselen, SH-580, LeSoleil-01, LeSoleil-02+, MRX-18, MXB-9, MI-09, MI-30, SNB-02, SJP-002C, TJC-642, ENU-200, CVD-0013943, GS-441524, bepridil, MXB-004, eravacycline, GRL-0617, GST-HG171, GST-HG171 + ritonavir, camostat, GC-373, KD-1, nitazoxanide, sinarin, prexasertib, PL-M, RAY-1216, SACT-COVID-19, MP-18, EIDD-1931,EDDC-2214, nitric oxide, apabetalone, AnQlar, SBK-001, LQ-050, CG-SpikeDown, bamlanivimab, JTBC-00101, HLX-71, HT-002, HY-209, HY-3000, HSC-1553, FYB-207, ensovibep, SYZJ-001, EU-129, new mifil, JN-2019 (KG-2019), LCB-99, AR-701, bostesil, PLM-402, PJS-539, CTB-ACE2, TB181-36, TB202-3, ABP-300, XVR-011, MSP-008-22, MU-UNMC-1, MU-UNMC-2, MIC-1930, MLT-103, Mpro inhibitor (Anixa Biosciences), PBF-4554, arnase alpha, VP-01, TRV-027, DX-600, TXA-127, NVX-CoV2515, raphamin, RCYM-002, RCYM-003, riamilovir, SARS-Cov-2 PL pro inhibitor (Enanta), SBP-502, SM-4, STB-R040, THY-01, tojinameran, elastomeran, Ad5-nCoV, BBIBP-CorV, CoronaVac, MVC-COV1901, NVX-CoV2373, sotrovimab, Sputnik V, TEE-001, Tyme-19, bakis zebulia, XW-001, ZF-2001, or ZyCoV-D. 【0520】 In some embodiments, the additional therapeutic or prophylactic agent is a SARS-CoV-2 MPro inhibitor. In some embodiments, the SARS-CoV-2 MPro inhibitor is nirmatrelvir. In some embodiments, the SARS-CoV-2 MPro inhibitor is ritonavir. 【0521】 Also, for simultaneous or sequential administration to a patient, it is possible to combine any compound of the present invention with one or more additional active therapeutic agents in a single dosage form. The combination therapy can be administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in more than two administrations. 【0522】 Co - administration of a compound of the present invention with one or more other active therapeutic agents generally refers to simultaneous or sequential administration of a therapeutically effective amount of the compound of the present invention and one or more other active therapeutic agents such that both are present in the patient's body. 【0523】 Co - administration includes administration of a unit dose of the compound described herein either before or after administration of a unit dose of one or more other active therapeutic agents, e.g., administration of the compound described herein within seconds, minutes, or hours of administration of one or more other active therapeutic agents. For example, a unit dose of the compound of the present invention can be administered first, followed by administration of a unit dose of one or more other active therapeutic agents within seconds or minutes. Alternatively, a unit dose of one or more other therapeutic agents can be administered first, followed by administration of a unit dose of the compound of the present invention within seconds or minutes. In some cases, it may be desirable to administer a unit dose of the compound of the present invention first, followed by administration of a unit dose of one or more other active therapeutic agents several hours (e.g., 1 - 12 hours) later. In other embodiments, it may be desirable to administer a unit dose of one or more other active therapeutic agents first, followed by administration of a unit dose of the compound of the present invention several hours (e.g., 1 - 12 hours) later. 【0524】 Combination therapy can provide an effect, namely a "synergistic effect" and "synergistic", in which the active ingredients used together provide an effect that is greater than the sum of the effects resulting from using the compounds separately. The synergistic effect 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 by alternating therapy, a synergistic effect can be achieved when the compounds are administered or delivered sequentially, for example, by different injections in separate tablets, pills, capsules, or separate syringes. Generally, during alternating therapy, the effective dosage of each active ingredient is administered sequentially, i.e., continuously, while in combination therapy, the effective dosages of two or more active ingredients are administered together. A synergistic antiviral effect exhibits an antiviral effect that is greater than the predicted pure additive effect of the individual compounds of the combination. 【0525】 The compounds described herein are also used in combination with other active therapeutic agents. In the case of treating paramyxovirus infections, preferably, the other active therapeutic agents are active against paramyxovirus infections, particularly respiratory syncytial virus infections and / or metapneumovirus infections. Non-limiting examples of these other active therapeutic agents against RSV include 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 infections 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 virus replication inhibitors such as nitazoxanide. 【0526】 In some embodiments, other active therapeutic agents can be vaccines 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. 【0527】 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. 【0528】 In some embodiments, other active therapeutic agents can be vaccines for the treatment or prevention of metapneumovirus infection, including but not limited to mRNA-1653 and rHMPV-Pa vaccine. 【0529】 The compounds described herein are also used in combination with other active therapeutic agents. In the case of the treatment of picornavirus family virus infections, preferably, the other active therapeutic agents are active against picornavirus family virus infections, particularly enterovirus infections. 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. (U.S. Patent No. 7,078,403) and Watson (U.S. Patent 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. 【0530】 In some embodiments, the other active therapeutic agents can be vaccines for the treatment or prevention of picornavirus infections, including but not limited to EV71 vaccines, TAK-021, and EV-D68 adenovirus-based vaccines. 【0531】 Many of the infections of the Paramyxoviridae, Picornaviridae, and Coronaviridae viruses are respiratory infections. Thus, additional active therapeutic agents used to treat respiratory symptoms and sequelae of the infections can be used in combination with the compounds described herein. The additional agents are preferably administered orally or by direct inhalation. For example, other preferred additional therapeutic agents to be combined with the compounds described herein for the treatment of viral respiratory infections include, but are not limited to, bronchodilators and corticosteroids. 【0532】 Glucocorticoids, first introduced as a treatment for asthma in 1950 (Carryer, Journal of Allergy, 21, 282 - 287, 1950), remain the most potent and consistent effective therapy for this disease, although their mechanisms of action are not yet 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). A solution to systemic side effects is to deliver the steroid drug 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 can be used in combination with the compounds described herein are dexamethasone, dexamethasone sodium phosphate, fluocinolone, fluocinolone acetonide, loteprednol, loteprednol etabonate, hydrocortisone, prednisone, fludrocortisone, triamcinolone, triamcinolone acetonide, betamethasone, beclomethasone diproprionate, methylprednisolone, fluocinonide, fluocinonide acetonide, flunisolide, fluocortin - 21 - butyrate, flumethasone, flumethasone pivalate, budesonide, halobetasol propionate, mometasone furoate, fluticasone, AZD - 7594, ciclesonide, or a pharmaceutically acceptable salt thereof. 【0533】 Other anti-inflammatory agents that act through the anti-inflammatory cascade mechanism are also useful as additional therapeutic agents in combination with the compounds described herein for the treatment of viral respiratory infections. Applying "anti-inflammatory signaling modulators" (referred to herein 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 stopping inflammation because these small molecules target a limited number of common intracellular pathways, i.e., signaling pathways that are important points of anti-inflammatory therapeutic intervention (see review by P.J. Barnes, 2006).These non-limiting additional therapeutic agents include 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 AWD12-281), 8-methoxy-2-trifluoromethyl-quinoline-5-carboxylic acid (3,5-dichloro-1-oxy-pyridin-4-yl)-amide (PDE-4 inhibitor Sch351591), 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)-cyclohexanecarboxylic acid 2-diethylamino-ethyl ester (cilomilast, 2-diethyl-ethyl ester prodrug of PDE-4 inhibitor), (3-chloro-4-fluorophenyl)-[7-methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-yl]-amine (gefitinib, EGFR inhibitor), and 4-(4-methyl-piperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide (imatinib, EGFR inhibitor). 【0534】 A combination comprising an inhaled β2 - adrenergic receptor agonist bronchodilator, such as formoterol, albuterol, or salmeterol, together with a compound described herein is also a suitable but non - limiting combination useful for the treatment of respiratory viral infections. 【0535】 Combinations of inhaled β2 - adrenergic receptor agonist bronchodilators such as formoterol or salmeterol with ICS are also used to treat both bronchoconstriction and inflammation (Symbicort® and Advair®, respectively). Combinations comprising these ICS and β2 - adrenergic receptor agonists together with a compound described herein are also suitable but non - limiting combinations useful for the treatment of respiratory viral infections. 【0536】 Other examples of β2 - adrenergic receptor agonists are vedolizumab, vilanterol, indacaterol, olodaterol, tulobuterol, formoterol, abediterol, salbutamol, arformoterol, lev albuterol, fenoterol, and TD - 5471. 【0537】 For the treatment or prevention of bronchoconstriction of the lung, anticholinergic drugs are potentially useful and are therefore useful as additional therapeutic agents in combination with the compounds described herein for the treatment of viral respiratory infections. These anticholinergic drugs include antagonists of muscarinic receptors (especially the M3 subtype) for which therapeutic efficacy in humans has been shown for the control of 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 (levatropate), 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-butylamide (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), 2 - (3 - diisopropylamino - 1 - phenyl - propyl) - 4 - methyl - phenyl ester of dimethylaminoacetic acid (toltrazuril - N,N - dimethylglycinate), 3 - [4,4 - bis - (4 - fluorophenyl) - 2 - oxo - imidazolidin - 1 - yl] - 1 - methyl - 1 - (2 - oxo - 2 - pyridin - 2 - yl - ethyl) - pyrrolidinium, 1 - [1 - (3 - fluorobenzyl) - piperidin - 4 - yl] - 4,4 - bis - (4 - fluorophenyl) - imidazolidin - 2 - one, 1 - cyclooctyl - 3 - (3 - methoxy - 1 - azabicyclo[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 1 - methyl - 1 - (2 - phenoxy - ethyl) - piperidin - 4 - yl ester of (2 - diethylamino - acetoxy) - di - thiophen - 2 - yl - acetic acid, levophenacylmorphan, glycopyrronium bromide, umeclidinium bromide, tiotropium bromide, acridinium bromide, benzcyclonium bromide, and the like, but are not limited thereto. 【0538】 The compounds described herein can also be combined with a mucolytic agent to treat both the infection and symptoms of a respiratory infection. Non - limiting examples of mucolytic agents are ambroxol. Similarly, the compounds can be combined with an expectorant to treat both the infection and symptoms of a respiratory infection. Non - limiting examples of expectorants are guaifenesin. 【0539】 Nebulized hypertonic saline is used to improve the immediate and long-term clearance of the small airways in patients with lung diseases (Kuzik, J. Pediatrics 2007, 266). Thus, the compounds described herein can also be combined, in particular, with nebulized hypertonic saline when a viral infection is complicated by bronchiolitis. The combination of the compounds described herein and hypertonic saline can also include any of the additional agents discussed above. In one embodiment, about 3% nebulized hypertonic saline is used. 【0540】 The compounds and compositions provided herein are also used in combination with other active therapeutic agents. In the case of the treatment of Flaviviridae virus infections, preferably, the other active therapeutic agents are active against Flaviviridae virus infections. 【0541】 For the treatment of dengue virus infections, non-limiting examples of other active therapeutic agents are host cell factor modulators such as GBV-006, fenretinide ABX-220, BRM-211, alpha-glucosidase 1 inhibitors such as celgosivir, platelet activating factor receptor (PAFR) antagonists such as modipafant, cadherin-5 / factor Ia modulators such as FX-06, NS4B inhibitors such as JNJ-8359, viral RNA splicing modulators such as ABX-202, NS5 polymerase inhibitors, NS3 protease inhibitors, and TLR modulators. 【0542】 In some embodiments, the other active therapeutic agent can 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. 【0543】 The compounds described herein are also used in combination with other active therapeutic agents. In the case of treating filoviral infections, preferably, the other active therapeutic agents are active against filoviral infections, particularly Marburg virus infection, Ebola virus infection, and Quezon virus infection. Non-limiting examples of these other active therapeutic agents include ribavirin, amiodarone, dronedarone, verapamil, Ebola Convalescent 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-diamine), 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. 【0544】 Other non-limiting active therapeutic agents active against Ebola include α-glucosidase 1 inhibitors, cathepsin B inhibitors, CD29 antagonists, dendritic ICAM-3-binding non-integrin 1 inhibitors, estrogen receptor antagonists, factor VII antagonists HLA class II antigen modulators, host cell factor modulators, interferon α ligands, neutral α-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). 【0545】 In some embodiments, the other active therapeutic agent can be a vaccine for the treatment or prevention of Ebola, including but not limited to VRC-EBOADC076-00-VP, an 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, an Ebola recombinant glycoprotein vaccine, Vaxart adenovirus vector 5-based Ebola vaccine, FiloVax vaccine, GOVX-E301, and GOVX-E302. 【0546】 The compounds described herein can also be used in combination with phosphoramidate morpholino oligomers (PMOs), which are synthetic antisense oligonucleotide analogs 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. 【0547】 The compounds described herein are also intended for combination with general care provided to patients with filovirus family 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 antidiarrheals, vitamin and mineral supplements (including vitamin K and zinc sulfate), anti-inflammatory agents (such as ibuprofen), analgesics, and antimalarial agents (including artemether and artesunate-lumefantrine combination therapy), typhoid fever (including quinolone antibiotics such as ciprofloxacin, macrolide antibiotics such as azithromycin, cephalosporin antibiotics such as ceftriaxone, or aminopenicillins such as ampicillin), or agents for other common diseases in patient populations such as bacillary dysentery. 【0548】 Also provided herein is a method of treating a viral infection in a human in need thereof, the method comprising (i) Compound 1: [Chemical formula] deuterated Compound 1, a prodrug of Compound 1, a prodrug of deuterated Compound 1, or a pharmaceutically acceptable salt thereof, and (ii) one or more SARS-CoV-2 MPro inhibitors, administering to the human, when a prodrug of Compound 1, a prodrug of deuterated Compound 1, or a pharmaceutically acceptable salt thereof is administered to a human, the prodrug of Compound 1, the prodrug of deuterated Compound 1, or the pharmaceutically acceptable salt thereof is substantially converted to Compound 1 or deuterated Compound 1. 【0549】 In some embodiments, the SARS-CoV-2 MPro inhibitor is nirmatrelvir, ritonavir, or a combination thereof. 【0550】 Also provided herein is a method of treating a viral infection in a human in need thereof, the method comprising: (i) Compound 1: 【Chemical formula】 deuterated Compound 1, a prodrug of Compound 1, a prodrug of deuterated Compound 1, or a pharmaceutically acceptable salt thereof, and (ii) administering to the human nirmatrelvir, ritonavir, or a combination of nirmatrelvir and ritonavir, wherein when a prodrug of Compound 1, a prodrug of deuterated Compound 1, or a pharmaceutically acceptable salt thereof is administered to the human, the prodrug of Compound 1, the prodrug of deuterated Compound 1, or the pharmaceutically acceptable salt thereof is substantially converted to Compound 1 or deuterated Compound 1. 【0551】 In some embodiments, the method comprises administering to the human (i) Compound 1, or a prodrug of Compound 1, or a pharmaceutically acceptable salt, and (ii) nirmatrelvir, ritonavir, or a combination of nirmatrelvir and ritonavir. In some embodiments, the method comprises administering Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering Compound 1. In some embodiments, the method comprises administering deuterated Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering deuterated Compound 1. In some embodiments, the method comprises administering a prodrug of deuterated Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering a prodrug of deuterated Compound 1. In some embodiments, the method comprises administering a prodrug of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering a prodrug of Compound 1. 【0552】 In some embodiments, the prodrug of Compound 1 is 【Chemical formula】 is. 【0553】 In some embodiments, when administered to a human, (i) Compound 1, or a pharmaceutically acceptable salt or prodrug thereof, and (ii) nirmatrelvir, ritonavir, or a combination of nirmatrelvir and ritonavir have a synergistic effect. In some embodiments, when administered to a human, (i) Compound 1, or a pharmaceutically acceptable salt or prodrug thereof, and (ii) nirmatrelvir, ritonavir, or a combination of nirmatrelvir and ritonavir have an additive effect. In some embodiments, when administered to a human, (i) Compound 1, or a pharmaceutically acceptable salt or prodrug thereof, and (ii) nirmatrelvir, ritonavir, or a combination of nirmatrelvir and ritonavir have a non-antagonistic effect. 【0554】 In some embodiments, the human is not pregnant. In some embodiments, the human is not hospitalized. In some embodiments, the human is hospitalized. 【0555】 In some embodiments, nirmatrelvir is administered to the human and ritonavir is not administered. In some embodiments, ritonavir is administered to the human and nirmatrelvir is not administered. In some embodiments, both ritonavir and nirmatrelvir are administered to the human. 【0556】 In some embodiments, nilmatrelvir is administered orally. In some embodiments, nilmatrelvir is administered twice daily. In some embodiments, nilmatrelvir is administered twice daily for at least 5 days. In some embodiments, nilmatrelvir is administered twice daily for 5 days. In some embodiments, nilmatrelvir is administered within 5 days of symptom onset. In some embodiments, nilmatrelvir is administered within 1, 2, 3, 4, or 5 days of symptom onset. In some embodiments, nilmatrelvir is administered at a dose of 100 mg to 1,600 mg, 100 mg to 900 mg, 100 mg to 700 mg, 100 mg to 500 mg, 100 mg to 400 mg / dose, 200 mg to 1,600 mg, 200 mg to 900 mg, 200 mg to 800 mg, 200 mg to 700 mg, 200 mg to 500 mg, or 200 mg to 400 mg. In some embodiments, nilmatrelvir is administered at a dose of about 300 mg. In some embodiments, the dose comprises two tablets of about 150 mg. In some embodiments, a dose of about 300 mg is administered twice daily. In some embodiments, a human is administered 200 mg to 3,200 mg, 200 mg to 1,800 mg, 200 mg to 1,400 mg, 200 mg to 1,000 mg, 200 mg to 800 mg / dose, 400 mg to 3,200 mg, 400 mg to 1,800 mg, 400 mg to 1,600 mg, 400 mg to 1,400 mg, 400 mg to 1,000 mg, or 400 mg to 800 mg of nilmatrelvir per day. In some embodiments, a human is administered about 600 mg of nilmatrelvir per day. 【0557】 In some embodiments, ritonavir is administered orally. In some embodiments, ritonavir is administered twice daily. In some embodiments, ritonavir is administered twice daily for at least 5 days. In some embodiments, ritonavir is administered twice daily for 5 days. In some embodiments, ritonavir is administered within 5 days of symptom onset. In some embodiments, ritonavir is administered within 1, 2, 3, 4, or 5 days of symptom onset. In some embodiments, ritonavir is administered at a dosage of 25 mg to 800 mg, 25 mg to 600 mg, 25 mg to 400 mg, 25 mg to 300 mg, 25 mg to 150 mg, 50 mg to 800 mg, 50 mg to 700 mg, 50 mg to 600 mg, 50 mg to 400 mg, 50 mg to 300 mg, or 50 mg to 150 mg. In some embodiments, ritonavir is administered at a dosage of about 100 mg. In some embodiments, the dosage comprises one tablet of about 100 mg. In some embodiments, the dosage of about 100 mg is administered twice daily. In some embodiments, a human is administered 50 mg to 1,600 mg, 50 mg to 1,200 mg, 50 mg to 800 mg, 50 mg to 600 mg, 50 mg to 300 mg, 100 mg to 1,600 mg, 100 mg to 1,400 mg, 100 mg to 1,200 mg, 100 mg to 800 mg, 100 mg to 600 mg, or 100 mg to 300 mg of ritonavir per day. In some embodiments, a human is administered about 200 mg of ritonavir per day. 【0558】 In some embodiments, nirmatrelvir and ritonavir are administered orally. In some embodiments, nirmatrelvir and ritonavir are administered twice daily. In some embodiments, nirmatrelvir and ritonavir are administered twice daily for at least 5 days. In some embodiments, nirmatrelvir and ritonavir are administered twice daily for 5 days. In some embodiments, nirmatrelvir and ritonavir are administered within 5 days of symptom onset. In some embodiments, nirmatrelvir and ritonavir are administered within 1, 2, 3, 4, or 5 days of symptom onset. In some embodiments, nirmatrelvir is administered at a dose of 100 mg to 1,600 mg, 100 mg to 900 mg, 100 mg to 700 mg, 100 mg to 500 mg, 100 mg to 400 mg / dose, 200 mg to 1,600 mg, 200 mg to 900 mg, 200 mg to 800 mg, 200 mg to 700 mg, 200 mg to 500 mg, or 200 mg to 400 mg, and ritonavir is administered at a dose of 25 mg to 800 mg, 25 mg to 600 mg, 25 mg to 400 mg, 25 mg to 300 mg, 25 mg to 150 mg, 50 mg to 800 mg, 50 mg to 700 mg, 50 mg to 600 mg, 50 mg to 400 mg, 50 mg to 300 mg, or 50 mg to 150 mg. In some embodiments, nirmatrelvir is administered at a dose of about 300 mg and ritonavir is administered at a dose of about 100 mg. In some embodiments, the dose of nirmatrelvir comprises two tablets of about 150 mg each, and the dose of ritonavir comprises one tablet of about 100 mg. In some embodiments, the nirmatrelvir dose of about 300 mg and the ritonavir dose of about 100 mg are administered twice daily.In some embodiments, a human is administered nirmatrelvir at 200 mg to 3,200 mg, 200 mg to 1,800 mg, 200 mg to 1,400 mg, 200 mg to 1,000 mg, 200 mg to 800 mg / dose, 400 mg to 3,200 mg, 400 mg to 1,800 mg, 400 mg to 1,600 mg, 400 mg to 1,400 mg, 400 mg to 1,000 mg, or 400 mg to 800 mg per day and ritonavir at about 50 mg to 1,600 mg, 50 mg to 1,200 mg, 50 mg to 800 mg, 50 mg to 600 mg, 50 mg to 300 mg, 100 mg to 1,600 mg, 100 mg to 1,400 mg, 100 mg to 1,200 mg, 100 mg to 800 mg, 100 mg to 600 mg, or 100 mg to 300 mg per day. In some embodiments, a human is administered about 600 mg of nirmatrelvir and about 200 mg of ritonavir per day. 【0559】 In some embodiments, the viral infection is a coronavirus infection. In some embodiments, the viral infection is a severe acute respiratory syndrome (SARS-CoV) infection, a Middle East respiratory syndrome (MERS) infection, or a SARS-CoV-2 infection (COVID-19). In some embodiments, the viral infection is a SARS-CoV-2 infection (COVID-19). 【0560】 The present invention will be described in more detail with reference to specific examples. The following examples are provided for illustrative purposes only and are not intended to limit the present invention in any way. Those skilled in the art will readily recognize various non-essential parameters that can be changed or modified to produce essentially the same results. 【Example】 【0561】 The present invention will be further described in the following examples, which do not limit the scope of the present invention as set forth in the "claims". 【0562】 Example 1. Non-clinical trial - Toxicity test: Discovery of an enhanced dosage range of Compound 16 by forced oral administration in Wistar Han rats and a toxicokinetics embryo-fetal development test 【0563】 The effects of Compound 16 on pregnant Wistar Han rats and the development of embryos as a result of exposing females from implantation to the closure of the hard palate were evaluated. Compound 16 was administered once daily by forced administration at a dosage volume of 5 mL / kg to four groups of rats (8 rats / group) presumed to be pregnant at dosages of 0 (vehicle), 125, 250, and 500 mg / kg / day during organogenesis (gestational days 6 - 17 [GD]). Additional pregnant rats were dosed similarly for toxicokinetic evaluation of Compound 16 and Compound 1. Toxicity assessment for pregnant rats was based on mortality, symptom observation, body weight, and food intake. The rats were necropsied and cesarean section was performed on GD 21. Examination of the external characteristics of the carcass, visible orifices, abdominal cavity, thoracic cavity, pelvic cavity, and oral cavity, organs, and tissues was carried out. Any macroscopic abnormalities were recorded. The pregnancy status was determined. The uterus was removed from each pregnant animal, weighed, and the number and location of live and dead fetuses, the number of early or late resorptions, and any abnormalities were examined. The right and left ovaries of each pregnant female were examined for the number of corpora lutea. The sex of each fetus was determined, the body weight was measured, and external abnormalities were examined. The head of each fetus was removed and cryopreserved on dry ice, and cross-sectional sections were prepared using Wilson's sectioning method (Asthoff et al., 2002). The internal organs of the thoracic and abdominal cavities were examined in a fresh state using a modified Staples method (Stuckhardt and Poppe, 1984). Fetal findings were classified as mutations or malformations. 【0564】 The dosage level of 500 mg / kg / day was not tolerated, and the toxic dosage group was terminated early by GD 16. Death, severe clinical signs, and enlarged and discolored kidneys and enlarged and discolored adrenals by macroscopic observation at necropsy were expected findings as they had already been observed in previous toxicity tests in female rats. Fetal parameters were not evaluated for this group due to excessive maternal toxicity. 【0565】 At 125 or 250 mg / kg / day, there were no significant clinical signs or effects on body weight, food intake, or macroscopic observations. Effects related to Compound 16 were not observed at 125 or 250 mg / kg / day in embryo-fetal survival parameters, litter and fetal weights, or fetal pathological findings. The no-observed-adverse-effect level (NOAEL) for maternal toxicity and embryofetal development was 250 mg / kg / day, which was associated with an AUC0-24h exposure of 183,000 ng * h / mL of Compound 1 on GD17. 【0566】 Example 2. Non-clinical study - Toxicity study: Embryo-fetal development study of Compound 16 by forced oral administration in Wistar Han rats 【0567】 The ability of Compound 16 to induce developmental toxicity after maternal exposure during the important period of organogenesis (GD6 - 17) was evaluated, the maternal toxicity at the tested exposure levels was characterized, and the no-observed-adverse-effect level (NOAEL) for maternal and developmental toxicity after oral administration in Wistar Han rats was determined. 【0568】 Compound 16 was administered to three groups of rats (25 animals / group) presumed to be pregnant at doses of 0 (vehicle), 125, and 250 mg / kg / day once daily by forced gavage at a dose volume of 5 mL / kg during organogenesis (gestational days 6 - 17 [GD]). Toxicity assessment in pregnant rats was based on mortality, clinical signs, body weight, and food consumption. Rats were necropsied and cesarean section was performed on GD 21. Examination of the external features of the carcass, visible orifices, abdominal, thoracic, pelvic cavities, and oral cavity, organs, and tissues was carried out. Any macroscopic abnormalities were recorded. Pregnancy status was determined. The uterus was removed from each pregnant animal, weighed, and examined for the number and location of live and dead fetuses, number of early or late resorptions, and any abnormalities. The right and left ovaries of each pregnant female were examined for the number of corpora lutea. The sex of each fetus was determined, body weight was measured, and external abnormalities were examined. Approximately half of the fetuses from each litter were examined for visceral abnormalities by dissection immediately after removal. The thoracic and abdominal cavities were opened and incised using the method described by Stuckhardt and Poppe (1984). The fetal kidneys were examined and graded for renal papilla development (Woo and Hoar, 1972). The heads were removed from these fetuses and placed in Harrison's fixative for examination of soft tissues using Wilson's sectioning method (Wilson, 1965). The remaining fetuses (approximately half from each litter) were removed, fixed in 100% ethyl alcohol, macerated in potassium hydroxide, and stained with alizarin red S using a method similar to that described by Dawson (1926) for subsequent examination of the skeleton. 【0569】 No effects related to compound 16 on intrauterine development or survival were observed. No external, visceral, or skeletal malformations or variations related to compound 16 were observed. The no - observed - adverse - effect level (NOAEL) for maternal toxicity and embryofetal development was 250 mg / kg / day. 【0570】 Example 3. Non - clinical study - Toxicity study: Embryo - fetal development and toxicokinetics study by forced oral administration of compound 16 in rabbits 【0571】 The effects of Compound 16 on pregnant New Zealand White (NZW) rabbits and the embryonic development of the results of exposing females from implantation to hard palate closure (gestational days 7 - 19 [GD]) were evaluated. Compound 16 was administered to four groups of pregnant rabbits (20 animals / group) at doses of 0 (0.5% methylcellulose in deionized water), 125, 250, and 500 mg / kg / day by forced oral administration once daily during organogenesis (GD 7 - 19). Toxicity evaluation was based on mortality, symptom observation, body weight, food intake, and autopsy and cesarean section findings. Additionally, blood samples were collected from similarly dosed animals (4 animals / group) for toxicokinetic evaluation of Compound 16 and Compound 1. Due to the excessive maternal toxicity observed at 500 mg / kg / day, the toxic dose group was terminated early on GD 17 - 22, and fetal parameters were not evaluated for this group. 【0572】 In animals administered at 250 or 500 mg / kg / day, a decrease in food intake was observed compared to the control. In animals administered at 250 mg / kg / day, the average maternal weight gain decreased compared to the control, and in animals administered at 500 mg / kg / day, an average weight loss was observed relative to the body weight on GD 7. An increase in post - implantation mortality was observed in animals administered at 250 mg / kg / day. The increase in post - implantation mortality in animals administered at 250 mg / kg / day was correlated with an increase in the average number of early absorptions and a decrease in the average number of live fetuses. Fetuses of animals administered at 250 mg / kg / day showed an increase in the proportion of ventricular septal defects, ventricular hypertrophy or atrophy, aortic dilation or abnormal position, aortic arch posterior to the esophagus, subclavian artery posterior to the esophagus, and abnormal lobation of the liver. No skeletal malformations related to Compound 16 were observed. Based on these findings, the NOAEL of Compound 16 in rabbit embryo - fetal development was 125 mg / kg / day, associated with a Compound 1 AUC0 - 24h exposure of 64,100 ng * h / mL. 【0573】 Example 4. In Vitro Combinatorial Analysis of Compound 1 / Compound 16 and SARS - CoV - 2 Antiviral Agents in Clinical Use 【0574】 Materials and Methods 【0575】 Compounds 【0576】 All compounds were synthesized by known methods or purchased. Chemical identity was determined by NMR and LCMS, and purity >95% was evaluated by HPLC. Compounds were solubilized at a concentration of 10 mM in 100% dimethyl sulfoxide (DMSO). 【0577】 Cells 【0578】 A549-hACE2 cells stably expressing human angiotensin-converting enzyme 2 (hACE2) were established and provided by the University of Texas Medical Branch (Mossel, EC 2005). A549-hACE2 cells were maintained in Dulbecco's Minimum Essential Medium (DMEM) containing GlutaMAX (Gibco catalog #10569-010) supplemented with 10% heat-inactivated fetal bovine serum (FBS) (Hyclone catalog #SH30396.03), 100 units / mL penicillin, 100 μg / mL streptomycin (Gibco catalog #15140-122), and a selective agent (10 μg / mL blasticidin) at 37 °C and 5% CO2. A549-hACE2 cells used in all experimental settings were between passages 5 and 30. 【0579】 Virus Propagation 【0580】 Recombinant firefly luciferase WA SARS-CoV-2 virus (SARS-CoV-2 Fluc) was obtained from the University of Texas Medical Branch (UTMB, Galveston, TX) and amplified from a stock generated as previously described (Xie, X., et al. (2021). "Engineering SARS-CoV-2 using a reverse genetic system." Nat Protoc 16(3):1761-1784). SARS-CoV-2 Fluc was grown as a high-titer stock in Vero-TMPRSS2 cells as follows. 1×10 7 Vero-TMPRSS2 cells were seeded into Vero-TMPRSS2 maintenance medium in a T225 flask and incubated overnight at 37 °C + 5% CO2. The next day, the medium was aspirated and replaced with 25 mL of DMEM supplemented with 2% FBS (infection medium), and 10 μL of P0 SARS-CoV-2 Fluc stock was used to infect. The flask was returned to 37 °C + 5% CO2 until only 10 - 20% of the viable cells remained (typically 36 - 72 hours post-infection (hpi)). The supernatant was collected into a 50 mL Falcon tube and centrifuged at 2000 × g for 5 minutes to pellet cell debris. The clarified supernatant was then aliquoted into 250 μL working P1 stocks and frozen at -80 °C. The titer of the working P1 stocks was determined by plaque formation assay (PFA). 【0581】 SARS-CoV-2 Fluc antiviral assay 【0582】 A549-hACE2 cells were seeded at 12,000 cells per well in a 96-well plate in 100 μL of maintenance medium and incubated overnight at 37 °C and 5% CO2. The next day, the used medium was aspirated, and 100 μL of infection medium (DMEM supplemented with 2% FBS) was added to each well. Compounds were added directly to the cultures using an HP D300e digital liquid dispenser, and the DMSO volume was normalized to that of the highest compound concentration (final DMSO concentration < 0.1%). Plates (in quadruplicate for each combination) were arrayed such that the concentrations increased across the rows and columns of the two drugs being evaluated, and then the dilution layout of the compounds was randomized on each plate to reduce variability due to edge effects. Compound 16, Compound 1, and molnupiravir were dispensed onto the plates at starting concentrations of 4000, 5000, and 10,000 nM, respectively, and titrated at a pre-determined optimal serial dilution for each compound. Nirmatrelvir was dispensed onto the plates at a starting concentration of either 600 nM and serially diluted 1:2. For triple-drug combinations, the compounds were dispensed as described above, but for the entire individual plates, ritonavir was added to the two other compounds being evaluated (Compound 16 and nirmatrelvir or Compound 1 and nirmatrelvir) at either 0, 300, 600, 1200, or 2400 nM. 50 μL of recombinant WA SARS-CoV-2 Fluc was added at an MOI of 1, and for uninfected control wells, 50 μL of infection medium was added to one column, and the cultures were incubated at 37 °C and 5% CO2. At 24 hpi, the cultures were removed from the incubator, and 50 μL of Promega One-Glo Luciferase Assay System (Catalog #E6120) was added to all wells. The plates were placed on an orbital shaker for 10 minutes, and luminescence was read using a Perkin Elmer Envision plate reader. 【0583】 Analysis by Synergy Finder 3.0 【0584】 In Microsoft Excel, after de-randomizing the raw data of the luminescence of the Envision plate reader, the dose-dependent inhibition rate of WA SARS-CoV-2 Fluc was calculated (Inhibition % = 100×(1-(X-min) / (max-min)), and the data matrix was uploaded to the Synergy Finder (version 3.0) (https: / / synergyfinder.fimm.fi) analysis software {Ianevski, A 2022 #67038}. The drug combination effect was quantified using the Bliss independence (background-corrected) mathematical model. A synergy report was generated for each drug combination, and the score was reported as the median of all four biological replicates using the conventional synergy scoring method. This method defines additive when the synergy score is between -10 and 10, less than -10 is considered antagonistic, and greater than 10 is considered synergistic {Ianevski, A 2022 #67038}. 【0585】 Results 【0586】 Using the Bliss independence consensus score, any score between -10 and 10 was interpreted as additive, greater than 10 as multiplicative, and less than 10 as antagonistic, and the following drug combinations were evaluated. The summary of the Bliss consensus scores for combinations of two drugs is reported in Tables 4.1 and 4.2. For the combination of two drugs, compound 1 and nirmatrelvir, the average Bliss score of four replicates was 0.96 ± 0.67, and an additive effect was observed (a representative Bliss independence plot is shown in Figure 1). For compound 16 and nirmatrelvir, the average Bliss score was 2.77 ± 0.07 in the replicates, and an additive effect was observed. Additive effects were observed for the combinations of compound 1 and molnupiravir and compound 16 and molnupiravir, demonstrated by average Bliss scores of -0.22 ± 0.20 and -1.36 ± 1.44, respectively. In parallel with these two-drug combinations, compound 1, compound 16, nirmatrelvir, and molnupiravir were tested as self-self combinations and used as assay validation controls. A compound cannot be multiplicative or antagonistic with itself, and for all drugs evaluated in the assay, an additive drug self-self combination effect was verified. Additive effects were observed for the self-self combinations of compound 1, compound 16, nirmatrelvir, and molnupiravir, with Bliss scores of 8.00 ± 1.09, 6.15 ± 2.16, 0.13 ± 1.53, and -2.47 ± 2.10, respectively, as shown in Table 4.2. 【0587】 The 3-drug combination Bristol consensus scores are summarized in Tables 4.3 and 4.4. For the 3-drug combination of Compound 1, nirmatrelvir, and ritonavir, an additive effect was observed, and the average Bristol score was 2.80 ± 3.95. Figure 2 shows a representative Bristol independence plot for this combination. In parallel with the 3-drug combination, the 2-drug combinations of nirmatrelvir and ritonavir, Compound 1 and ritonavir, and Compound 1 and nirmatrelvir showed additive effects with average Bristol scores of 0.63 ± 5.65, -2.47 ± 3.00, and 1.67 ± 0.53, respectively. Similarly, the 3-drug combination of Compound 16, nirmatrelvir, and ritonavir showed an additive effect, and the observed average Bristol score was 5.33 ± 4.76 across all replicates. In parallel with this 3-drug combination, the 2-drug combinations of nirmatrelvir and ritonavir, Compound 16 and ritonavir, and Compound 16 and nirmatrelvir showed additive effects with observed average Bristol scores of 6.31 ± 5.38, 0.75 ± 6.96, and 2.01 ± 0.79, respectively. 【0588】 【Table 4-2】 【0589】 【Table 4-3】 【0590】 【Table 4-4】 【0591】 【Table 4-5】 【0592】 All drug combinations of Compound 1 or Compound 16 with molnupiravir, nirmatrelvir, and / or ritonavir showed additive effects against SARS-CoV-2 in A549-hACE-2 cells. 【0593】 Loewe model scores for combination of two drugs in the anti-viral assay of Example 5. A549-hACE-2 SARS-CoV-2 Fluc 【0594】 Materials and methods 【0595】 Compounds 【0596】 All compounds were synthesized by known methods or purchased. Chemical identity was verified by NMR and LCMS, and purity >95% was evaluated by HPLC. Compounds were solubilized at a concentration of 10 mM in 100% dimethyl sulfoxide (DMSO). 【0597】 Cells 【0598】 A549-hACE2 cells stably expressing human angiotensin-converting enzyme 2 (hACE2) were established and provided by the University of Texas Medical Branch (Mossel, EC 2005). A549-hACE2 cells were maintained at 37 °C and 5% CO2 in Dulbecco's Minimum Essential Medium (DMEM) supplemented with 10% heat-inactivated fetal bovine serum (FBS) (Hyclone catalog #SH30396.03), 100 units / mL penicillin, 100 μg / mL streptomycin (Gibco catalog #15140-122), and a selection agent (10 μg / mL blasticidin) in GlutaMAX (Gibco catalog #10569-010). A549-hACE2 cells used in all experimental settings were between passages 5 and 30. 【0599】 Virus propagation 【0600】 Recombinant firefly luciferase WA SARS-CoV-2 virus (SARS-CoV-2 Fluc) was obtained from the University of Texas Medical Branch (UTMB, Galveston, TX) and amplified from a stock generated as previously described (Xie, X., et al. (2021). "Engineering SARS-CoV-2 using a reverse genetic system." Nat Protoc 16(3):1761-1784). SARS-CoV-2 Fluc was grown as a high-titer stock in Vero-TMPRSS2 cells as follows. 1×10 7 Vero-TMPRSS2 cells were seeded into Vero-TMPRSS2 maintenance medium in a T225 flask and incubated overnight at 37 °C + 5% CO2. The next day, the medium was aspirated and replaced with 25 mL of DMEM supplemented with 2% FBS (infection medium), and 10 μL of P0 SARS-CoV-2 Fluc stock was used to infect. The flask was returned to 37 °C + 5% CO2 until only 10 - 20% of the viable cells remained (typically 36 - 72 hours post-infection (hpi)). The supernatant was collected into a 50 mL Falcon tube and centrifuged at 2000 × g for 5 minutes to pellet cell debris. The clarified supernatant was then aliquoted into 250 μL working P1 stocks and frozen at -80 °C. The titer of the working P1 stocks was determined by plaque formation assay (PFA). 【0601】 SARS-CoV-2 Fluc antiviral assay 【0602】 A549-hACE2 cells were seeded at 12,000 cells per well in a 96-well plate in 100 μL volume of maintenance medium and incubated overnight at 37 °C, 5% CO2. The next day, the used medium was aspirated and 100 μL of infection medium (DMEM supplemented with 2% FBS) was added to each well. Compounds were added directly to the cultures using an HP D300e digital liquid dispenser, and the DMSO volume was normalized to that of the highest compound concentration (final DMSO concentration <0.1%). Plates (4 replicates for each combination) were arrayed such that the concentrations increased across the rows and columns of the two drugs being evaluated, and then the dilution layout of the compounds was randomized on each plate to reduce variability due to edge effects. 50 μL of recombinant WA SARS-CoV-2 Fluc was added at an MOI of 1, and for uninfected control wells, 50 μL of infection medium was added to one column, and the cultures were incubated at 37 °C, 5% CO2. At 24 hpi, the cultures were removed from the incubator and 50 μL of Promega One-Glo Luciferase Assay System (Catalog #E6120) was added to all wells. The plates were placed on an orbital shaker for 10 minutes and luminescence was read using a Perkin Elmer Envision plate reader. 【0603】 Analysis by Synergy Finder Plus 【0604】 In Microsoft Excel, after de-randomizing the raw data of the luminescence of the Envision plate reader, the dose-dependent inhibition rate of WA SARS-CoV-2 Fluc was calculated (Inhibition % = 100×(1-(X-min) / (max-min))), and the data matrix was uploaded to the SynergyFinder Plus (DOI: 10.1016 / j.gpb.2022.01.004) analysis software {Ianevski, A 2022 #67038}. The drug combination effect was quantified by the Loewe method. A synergy report was generated for each drug combination. This method defines additivity when the synergy score is between -10 and 10, considers values less than -10 as antagonistic, and values greater than 10 as synergistic {Ianevski, A 2022 #67038}. The results are shown in Table 5.1. 【0605】 【Table 5】 【0606】 Example 6. Loewe model scores for combination of two drugs in the antiviral assay of A549-hACE-2 SARS-CoV-2 Fluc in non-infected BHK-SARS-2R_GFP_NeoR_NL (SCL414) replicon cells 【0607】 Materials and Methods 【0608】 Cell Culture 【0609】 The non-infectious BHK-SARS-2R_GFP_NeoR_NL(SCL414) replicon cell line was licensed from Emory University (Lan et al 2021). These are stable cell lines that express SARS-CoV-2 replicon DNA and the sNLuc reporter gene. Cells were maintained in Dulbecco's Modified Eagle Medium (ThermoFisher, catalog #10566016) supplemented with 10% fetal bovine serum (ThermoFisher, catalog #SH3040602HI), 100 U / mL penicillin / 100 μg / mL streptomycin (ThermoFisher, catalog #15140122), and 1 mg / mL Geneticin™ (ThermoFisher, catalog #10131027). 【0610】 Combination drug assay 【0611】 50 μL of assay medium (DMEM supplemented with 10% FBS) of the BHK-SARS-2R_GFP_NeoR_NL replicon cell line was added to a white clear-bottom 96-well plate (ThermoFisher, catalog #07-200-566). Serial dilutions of Compound 1 and nirmatrelvir were added in a matrix format to the wells containing the assay medium using an HP D300e digital dispenser and normalized to the highest concentration of DMSO (ATCC 4-X™) in all wells (>0.1% final volume). The starting concentration of Compound 1 was 12 μM and the starting concentration of nirmatrelvir was 1.2 μM. As a negative control, puromycin dissolved in DMSO was added at a final concentration of 10 μM. Untreated wells were used as positive controls. In this assay, the self-matrices (internal controls) of nirmatrelvir and Compound 1 were tested together with the drug combination matrix of Compound 1 and nirmatrelvir. The cells were then added to the same plate at 8.0×10 4Seeded at a density of cells / mL with a total volume of 100 μL / well and incubated at 37 °C and 5% CO2 for 3 days. Added 50 μL / well of room temperature Nano-Glo® Luciferase Reagent (Promega, Catalog #N1110) to the plate. Incubated the plate on a shaker at room temperature for 1 - 2 minutes and measured luminescence using an Envision plate reader (PerkinElmer, Catalog #2105-0010). Each combination was performed in triplicate. The average of the three replicates was used for analysis. Drug response data were corrected against positive and negative controls to determine the percent inhibition. 【0612】 Analysis by Synergy Finder Plus 【0613】 In Microsoft Excel, after un-randomizing the raw luminescence data from the Envision plate reader, the dose-dependent inhibition rate of WA SARS-CoV-2 Fluc was calculated (Inhibition % = 100×(1-(X-min) / (max-min)) and the data matrix was uploaded to the SynergyFinder Plus (DOI: 10.1016 / j.gpb.2022.01.004) analysis software {Ianevski,A 2022 #67038}. The drug combination effect was quantified by the Loewe method. A synergy report was generated for each drug combination. This method defines additivity when the synergy score is between -10 and 10, less than -10 is considered antagonistic, and greater than 10 is considered synergistic {Ianevski,A 2022 #67038}. The results are shown in Table 6.1. 【0614】 【Table 6】 【0615】 All references, including publications, patents, and patent documents, are incorporated herein by reference as if individually incorporated by reference. This disclosure provides references 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 this disclosure. The description should be regarded as illustrative of the claimed subject matter and is not intended to limit the appended claims to the specific embodiments illustrated.

Claims

[Claim 1] A composition for use in a method of treating or preventing a viral infection in a person in need thereof, wherein the composition comprises compound 1: 【Chemistry 92】 Deuterated compound 1, a prodrug of compound 1, a prodrug of deuterated compound 1, or a pharmaceutically acceptable salt thereof, Including nilmatrellvir, ritonavir, or a combination of nilmatrellvir and ritonavir, The method comprises administering to a human being compound 1, deuterated compound 1, a prodrug of compound 1, a prodrug of deuterated compound 1, or a pharmaceutically acceptable salt thereof, and nilmatrelvir, ritonavir, or a combination of nilmatrelvir and ritonavir. A composition in which, when the prodrug of compound 1, the prodrug of deuterated compound 1, or a pharmaceutically acceptable salt thereof is administered to a human, the prodrug of compound 1, the prodrug of deuterated compound 1, or a pharmaceutically acceptable salt thereof is substantially converted to compound 1 or deuterated compound 1. [Claim 2] The composition according to claim 1, wherein the method comprises administering to a human being (i) compound 1, or the prodrug of compound 1, or a pharmaceutically acceptable salt thereof, and (ii) nilmatrelvir, ritonavir, or a combination of nilmatrelvir and ritonavir. [Claim 3] The composition according to claim 1, wherein the method comprises administering compound 1 or a pharmaceutically acceptable salt thereof. [Claim 4] The composition according to claim 1, wherein the method comprises administering compound 1. [Claim 5] The composition according to claim 1, wherein the method comprises administering a prodrug of compound 1 or a pharmaceutically acceptable salt thereof. [Claim 6] The composition according to claim 1, wherein the method comprises administering a prodrug of compound 1. [Claim 7] The method comprises administering a prodrug of compound 1, wherein the prodrug of compound 1 is 【Chemistry 93】 The composition according to claim 1. [Claim 8] The composition according to claim 1, wherein the human being is not pregnant. [Claim 9] The composition according to claim 1, characterized in that the human being is administered both ritonavir and nilmatrelvir. [Claim 10] The composition according to claim 1, characterized in that nilmatrelvir and ritonavir are administered orally. [Claim 11] The composition according to claim 1, characterized in that nilmatrelvir and ritonavir are administered twice a day. [Claim 12] The composition according to claim 1, characterized in that nilmatrelvir and ritonavir are administered twice a day for at least 5 days. [Claim 13] The composition according to claim 1, characterized in that nilmatrelvir and ritonavir are administered within 5 days of the onset of symptoms. [Claim 14] The composition according to claim 1, characterized in that nilmatrelvir is administered in a dose of approximately 300 mg and ritonavir in a dose of approximately 100 mg, or in a dose of approximately 600 mg of nilmatrelvir and approximately 200 mg of ritonavir per day. [Claim 15] The composition according to any one of claims 1 to 14, wherein the viral infection is a coronavirus infection. [Claim 16] The composition according to any one of claims 1 to 14, wherein the viral infection is severe acute respiratory syndrome (SARS-CoV) infection, Middle East respiratory syndrome (MERS) infection, or SARS-CoV-2 infection (COVID-19). [Claim 17] The composition according to any one of claims 1 to 14, wherein the viral infection is SARS-CoV-2 infection (COVID-19).

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