Methods for treating viral infections including SARS-COV-2

Abstract

The present disclosure relates to methods for treating viral infections in non-pregnant patients. Combination treatments directed against viral infections in humans in need thereof are also provided.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 349,531, filed on June 6, 2022, and U.S. Provisional Application No. 63 / 461,218, filed on April 21, 2023. The entire contents of these applications are incorporated herein by reference in their entirety. Technical Field

[0003] The present disclosure relates to methods for treating viral infections. Background Art

[0004] Compounds and methods for treating viral infections, such as paramyxoviridae, pneumoviridae, picornaviridae, flaviviridae, filoviridae, arenaviridae, orthomyxovirus, and coronaviridae infections, are needed. Summary of the invention

[0005] Provided herein is a method of treating a viral infection in a patient in need thereof, wherein the method comprises administering to the patient a compound of Formula A:

[0006]

[0007] 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 a base as defined herein, wherein upon administration of a prodrug of a compound of Formula A, a prodrug of a deuterated compound of Formula A, or a pharmaceutically acceptable salt thereof, 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 into a compound of Formula A or a deuterated compound of Formula A, and wherein the patient is not a pregnant individual.

[0008] Also provided herein is a method of treating a viral infection in a human in need thereof, the method comprising administering to the human

[0009] (i) Compound 1:

[0010] Deuterated Compound 1, a prodrug of Compound 1, a prodrug of deuterated Compound 1, or a pharmaceutically acceptable salt thereof; and

[0011] (ii) namatevir, ritonavir, or a combination of namatevir and ritonavir;

[0012] Wherein when the prodrug of Compound 1, the deuterated prodrug of Compound 1, or a pharmaceutically acceptable salt thereof is administered to a human, the prodrug of Compound 1, the deuterated prodrug of Compound 1, or a pharmaceutically acceptable salt thereof is substantially converted into Compound 1 or the deuterated Compound 1. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 Representative two-drug combination bliss independent action consistency plots for A549-hACE-2 SARS-CoV-2FLUC antiviral analysis of compound 1 and nematevir are shown.

[0014] Figure 2 A representative three-drug combination bliss independent action consistency plot of the A549-hACE-2 SARS-CoV-2 fluc antiviral assay of compound 1, namatevir, and ritonavir is shown. DETAILED DESCRIPTION

[0015] Unless otherwise indicated, the following terms and phrases as used herein are intended to have the following meanings:

[0016] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. For example, an alkyl group can have 1 to 20 carbon atoms (i.e., C1-C 20Examples of suitable alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, isopropyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, isobutyl, -CH2CH(CH3)2), 2-butyl (s-Bu, sec-butyl, -C1-C8 alkyl), 1-propyl (i-Bu, isobutyl, -CH2CH(CH3)2), 2-butyl (s-Bu, sec-butyl, -C1-C6 alkyl), 1-propyl (i-Bu, isobutyl, -CH2CH(CH3)2), 2-propyl (i-Pr, isopropyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, isobutyl, -CH2CH(CH3)2), 2-butyl (s-Bu, sec-butyl, -C H(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, tert-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) and 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3).

[0017] "Alkenyl" refers to a group containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C 2-20 alkenyl), 2 to 8 carbon atoms (i.e., C 2-8 alkenyl), 2 to 6 carbon atoms (i.e., C 2-6 alkenyl) or 2 to 4 carbon atoms (i.e. C 2-4 Examples of the alkenyl group include vinyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0018] "Alkynyl" refers to a group containing at least one carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C 2-20 Alkynyl), 2 to 8 carbon atoms (i.e., C 2-8 Alkynyl), 2 to 6 carbon atoms (i.e., C 2-6 Alkynyl) or 2 to 4 carbon atoms (i.e. C 2-4 The term "alkynyl" also includes those groups having one triple bond and one double bond.

[0019] "Haloalkyl" is an alkyl group as defined above in which one or more of the hydrogen atoms of the alkyl group is replaced by a halogen atom. The alkyl portion of the haloalkyl group may have 1 to 20 carbon atoms (i.e., C1-C 20 haloalkyl), 1 to 12 carbon atoms (i.e., C1-C 12 The alkyl group may be any of a plurality of carbon atoms, such as -CF3, -CHF2, -CFH2, -CH2CF3, etc. The alkyl group may be any of a plurality of carbon atoms, such as -CF3, -CHF2, -CFH2, -CH2CF3, etc.

[0020] "Aryl" means an aromatic hydrocarbon radical derived by removing a 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 benzenes, naphthalene, anthracene, biphenyl, and the like.

[0021] "Heteroaryl" refers to an aromatic group with a single ring, multiple rings or multiple fused rings, wherein one or more ring heteroatoms are independently selected from nitrogen, oxygen and sulfur. As used herein, heteroaryl includes 1 to 20 ring atoms (i.e., 1 to 20 heteroaromatic rings), 3 to 12 ring atoms (i.e., 3 to 12 heteroaromatic rings) or 3 to 8 carbon ring atoms (i.e., 3 to 8 heteroaromatic rings) or 5 to 6 ring atoms (i.e., 5 to 6 heteroaromatic rings). Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl and pyrazolyl. Heteroaryl does not encompass or overlap aryl as defined above.

[0022] "Carbocyclyl" or "carbocycle" refers to a non-aromatic hydrocarbon ring consisting of carbon atoms and hydrogen atoms, having three to twenty carbon atoms, in certain embodiments three to fifteen carbon atoms, in certain embodiments three to ten carbon atoms, three to eight carbon atoms, three to seven carbon atoms, or 3 to 6 carbon atoms, and being saturated or partially unsaturated and connected to the rest of the molecule by a single bond. Carbocycles include, for example, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, cycloheptane, cycloheptene, and cyclooctane. Carbocycles include cycloalkyl groups.

[0023] "Cycloalkyl" refers to a saturated cyclic alkyl group having a single ring or multiple rings including fused, bridged and spiro ring systems. As used herein, a cycloalkyl group 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 Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0024] As used herein, "heterocycle" or "heterocyclyl" includes those heterocycles described in the following as examples and not limitations: Paquette, Leo A.; Principles of Modern Heterocyclic Chemistry (WA Benjamin, New York, 1968), especially Chapter 1, Chapter 3, Chapter 4, Chapter 6, Chapter 7 and Chapter 9; "The Chemistry of Heterocyclic Compounds, A Series of Monographs" (John Wiley & Sons, New York, 1950 to date), especially Volumes 13, 14, 16, 19 and 28; and J. Am. Chem. Soc. (1960) 82: 5566. For example, "heterocycle" includes "carbocycles" as defined herein, in which one or more (e.g., 1, 2, 3 or 4) carbon atoms have been replaced by heteroatoms (e.g., O, N or S). As used herein, heterocycles or heterocyclic groups have 3 to 20 ring atoms, 3 to 12 ring atoms, 3 to 10 ring atoms, 3 to 8 ring atoms, or 3 to 6 ring atoms. The term "heterocycle" or "heterocyclyl" includes saturated rings and partially unsaturated rings. Substituted heterocyclic groups include, for example, heterocycles substituted with any substituent described herein including a carbonyl group. Non-limiting examples of carbonyl-substituted heterocyclic groups are:

[0025]

[0026] Exemplary heterocycles include, but are not limited to, tetrahydrofuranyl, azetidinyl, and 2-oxo-1,3-dioxol-4-yl.

[0027] The term "optionally substituted" with respect to a particular moiety of a compound described herein (such as a compound of Formula A or Formula I) (e.g., an optionally substituted aryl group) refers to a moiety wherein all substituents are hydrogen or wherein one or more hydrogens of the moiety may be replaced with a listed substituent.

[0028] Unless otherwise indicated, carbon atoms of compounds of Formula I are intended to have a valence of four. If in some chemical structure representations a carbon atom is not attached to a sufficient number of variables to produce a valence of four, then the remaining carbon substituents required to provide the four valences are assumed to be hydrogen.

[0029] Any reference to a compound described herein also includes a reference to a pharmaceutically acceptable salt thereof. Examples of pharmaceutically acceptable salts of compounds described herein include those derived from a suitable base such as an alkali metal or alkaline earth metal (e.g., Na + , Li + , K + , Ca +2 and Mg +2 ), ammonium and NR4 + (wherein R is defined herein). Pharmaceutically acceptable salts of nitrogen atoms or amino groups include: (a) acid addition salts formed with inorganic acids (e.g., 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, polygalactonic acid, malonic acid, sulfosalicylic acid, glycolic acid, 2-hydroxy-3-naphthoate, pamoate, salicylic acid, stearic acid, phthalic acid, amygdallic acid, lactic acid, ethanesulfonic acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine, leucine, etc.; and (c) salts formed with elemental anions such as chlorine, bromine and iodine. Pharmaceutically acceptable salts of hydroxy compounds include anions of the compounds with suitable cations such as Na + and NR4 + In some embodiments, R4 is H, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, C6-C 20 Aryl or C2-C 20 Heterocyclic group.

[0030] For therapeutic use, the salts of the active ingredients of the compounds described herein will be pharmaceutically acceptable, i.e., they will be salts derived from pharmaceutically acceptable acids or bases. It should also be understood that the compositions herein include the compounds described herein in non-ionized form and zwitterionic form and in combination with a stoichiometric amount of water in a hydrate. It should be noted that the present disclosure encompasses 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 pharmaceutically acceptable salts thereof. All mixtures of such enantiomers and diastereomers are within the scope of the present disclosure.

[0031] Compounds described herein may have chiral centers, such as chiral carbon atoms or phosphorus atoms. Therefore, compounds described herein include racemic mixtures of all stereoisomers, including enantiomers, diastereomers and atropisomers. In addition, compounds described herein include optical isomers enriched or split at any or all asymmetric, chiral atoms. In other words, chiral centers that are obvious from the description are provided as chiral isomers or racemic mixtures. Both racemic mixtures and diastereomeric mixtures and separated or synthesized individual optical isomers (substantially free of their enantiomers or diastereomeric partners) are within the scope of the present disclosure. Racemic mixtures are separated into their individual, substantially optically pure isomers by suitable techniques, such as separation and optically active auxiliary agents (such as acids or bases) formed diastereomeric salts, and then the diastereomeric salts are converted back to optically active substances. In most cases, the desired optical isomers are synthesized by stereospecific reactions, starting from the appropriate stereoisomers of the desired raw materials.

[0032] The stereochemical definitions and conventions used herein generally follow those of SP Parker, ed., "McGraw-Hill Dictionary of Chemical Terms" (1984) McGraw-Hill Book Company, New York; and Eliel, E and Wilen, S, "Stereochemistry of Organic Compounds" (1994) John Wiley & Sons, Inc., New York. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule around its chiral center. The prefixes d and l, D and L or (+) and (-) are used to indicate the sign of rotation of plane polarized light of the compound, where S, (-) or 1 indicates that the compound is left-handed, while compounds prefixed with R, (+) or d are right-handed. For a given chemical structure, these stereoisomers are identical, except that they are mirror images of each other. Specific stereoisomers may also be referred to as enantiomers, and mixtures of such isomers are often referred to as enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur in a chemical reaction or process without stereoselection or stereospecificity. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

[0033] In some cases, the compounds described herein may also exist as tautomeric isomers. Although only one delocalized resonance structure can be described, all such forms are considered within the scope of the present invention. For example, for purines, pyrimidines, imidazoles, guanidines, amidines, and tetrazole systems, ene-amine tautomers may exist, and all possible tautomeric forms thereof are within the scope of the present invention.

[0034] Any formula or structure described herein, including compounds of Formula A and Formula I, is also intended to represent unlabeled forms of the compounds as well as isotopically labeled forms. An isotopically labeled compound has a structure depicted by a formula given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, but not limited to, 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. Various isotopically labeled compounds of the present disclosure, for example, wherein a radioactive isotope such as 3 H. 13 C and 14 Such isotopically labeled compounds are useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as 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.

[0035] The present disclosure also includes compounds (e.g., compounds of Formula A or Formula I) in which 1 to x hydrogens attached to a carbon atom are replaced by deuterium, where x is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and are therefore useful for extending the half-life of any compound described herein (e.g., compounds of Formula A and Formula I) when administered to a mammal (particularly a human). See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol. Sci. 5(12): 524-527 (1984). In view of the present disclosure, such compounds are synthesized by methods known in the art, such as by using a starting material in which one or more hydrogens have been replaced by deuterium.

[0036] Deuterium-labeled or substituted therapeutic compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, which relate to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes (such as deuterium) may provide certain therapeutic advantages resulting from greater metabolic stability, such as increased half-life in vivo, reduced dosage requirements and / or improved therapeutic index. 18 F-labeled compounds can be used for PET or SPECT studies. Isotopically labeled compounds and prodrugs thereof disclosed herein can generally be prepared by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents to carry out the procedures disclosed in the schemes or the examples and formulations described below. It should be understood that deuterium in this context is considered a substituent in the compounds described herein.

[0037] For example, in the deuterated compounds of Formula A, one or more hydrogen atoms attached to one or more carbon atoms of Formula A are replaced with deuterium. In some embodiments of the deuterated compounds of Formula A, one hydrogen atom attached to one carbon atom of Formula A is replaced with deuterium. In some embodiments of the deuterated compounds of Formula A, two hydrogen atoms attached to one carbon atom of Formula A are replaced with deuterium. In some embodiments of the deuterated compounds of Formula A, two or more hydrogen atoms attached to two carbon atoms of Formula A are replaced with deuterium.

[0038] The concentration of such heavier isotopes, particularly deuterium, can be defined by an isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise indicated, when a position is specifically designated as "H" or "hydrogen", then that position is understood to be a hydrogen having its natural abundance isotopic composition. Therefore, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is meant to represent deuterium.

[0039] Whenever a compound described herein is substituted with more than one of the same designated group (eg, "R" or "R"), it is understood that these groups may be the same or different, i.e., each group is independently selected.

[0040] Wave line, Indicates the locations of covalent bonds to adjacent substructures, groups, moieties, or atoms.

[0041] Unless otherwise indicated, as used herein, the term "treat" means reversing, alleviating or inhibiting the progression of the disorder or condition to which the term applies, or one or more symptoms of such disorder or condition. As used herein, the term "treat" refers to the act of treating, as "treating" is defined above.

[0042] "Prevention" means any treatment of any disease or condition that does not develop clinical symptoms of a disease or condition. In some embodiments, the compounds and compositions described herein may be applied to subjects (including people) at risk of suffering from a disease or condition. As used herein, the term "prevention" covers the administration of compounds, compositions or pharmaceutically acceptable salts according to the embodiments described herein before or after an individual is exposed to a virus but before symptoms of a viral infection appear and / or before the virus is detected in the blood. The term also refers to preventing the occurrence of disease symptoms and / or preventing the virus from reaching a detectable level in the blood. The term includes pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP) and event-driven or "on-demand" prevention. The term also refers to the prevention of perinatal transmission of viruses from mother to baby by administering to the mother before delivery and to the child within the first few days of life. The term also refers to the prevention of the spread of viruses through blood transfusions.

[0043] 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 that is required to provide the desired level of drug in the secretions and tissues of the airways and lungs, or alternatively, when such a composition is administered by a selected route of administration, the desired physiological response or desired biological effect in the bloodstream of the subject to be treated. The exact amount will depend on many factors, such as the specific compound described herein (e.g., a compound of Formula A or Formula I), the specific activity of the composition, the delivery device employed, the physical properties of the composition, its intended use, and patient considerations such as the severity of the disease state, patient cooperation, etc., and the exact amount can be readily determined by those skilled in the art based on the information provided herein.

[0044] As used herein, the term "prodrug" refers to a biologically inactive derivative of a drug that can be converted to the parent drug according to some chemical or enzymatic pathway after 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 a pharmaceutically acceptable salt thereof can be converted to a 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 a pharmaceutically acceptable salt thereof can be converted to a deuterated compound of Formula A.

[0045] As used herein, the term "substantially converted" with respect to a prodrug means that greater 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) is converted to the parent compound (e.g., a compound of Formula A or a deuterated compound of Formula A). For example, the term "substantially converted" may mean that greater than 50%, greater than 60%, greater than 70%, greater than 80%, greater than 90%, greater than 95%, or greater than 99% of the prodrug of a compound of Formula A, a prodrug of a deuterated compound of Formula A, or a pharmaceutically acceptable salt thereof is converted to a compound of Formula A or a deuterated compound of Formula A.

[0046] The term "symptoms" as used herein may include symptoms of viral infection including, for example, fever, chills, cough, shortness of breath, fatigue, myalgia, headache, diarrhea, loss of taste, loss of smell, sore throat, congestion, nausea and vomiting.

[0047] Now will specifically refer to specific embodiments of the present invention, their examples are shown in the attached description. Although the present invention will be described in conjunction with the embodiments listed, it should be understood that they are not intended to limit the present invention to those embodiments. On the contrary, the present invention is intended to cover all alternatives, modifications and equivalents that may be included within the scope of the present invention.

[0048] A method of treating a viral infection in a patient in need thereof is provided, wherein the method comprises administering to the patient a compound of formula A:

[0049]

[0050] 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:

[0051] R 1 -OH, -OC(=O)R 4 OR-OC(=O)OR 4 ;

[0052] R 2 -OH, -OC(=O)R 5 OR-OC(=O)OR 5 ;or

[0053] R 1 and R 2 Together they form -OC(=O)O-, -OP(=O)(OH)O- or -OCHR 6 O-;

[0054] R 4 and R 5 are independently H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclyl, C6-C 10 aryl, a 4- to 6-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O and S, or a 5- to 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S; wherein R 4 and R 5 Each 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 and optionally substituted by one, two or three R a Substituent substitution;

[0055] R 6 is H, C1-C6 alkyl, C1-C6 alkoxy, a 5- to 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S, or a C6-C 10 Aryl; wherein R 6 Each 5- to 6-membered heteroaryl and C6-C 10 Aryl is independently and optionally substituted by one, two or three R b Substituent substitution;

[0056] Alkali is

[0057] R 11 is optionally substituted with -OP(=O)(OH)(OR14 ) substituted C1-C6 alkyl;

[0058] R 12 is H, C1-C6 alkyl, -C(=O)R 13 OR -C(=O)OR 13 ;

[0059] Each R 13 independently H, C1-C 10 Alkyl, C6-C 10 Aryl, -O-C6-C 10 Aryl or -O-C1-C 10 Alkyl; wherein R 13 Each C1-C 10 Alkyl, C6-C 10 Aryl, -O-C6-C 10 Aryl and -O-C1-C 10 The alkyl group is independently and optionally substituted by one, two or three R c Substituent substitution;

[0060] Each R a are independently halo, cyano, C1-C6 alkyl, carbonyl, -N3, -OR 8 、-NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic group, 4- to 6-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O and S, 5- to 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S, or phenyl; wherein R a Each 4- to 6-membered heterocyclic group is independently, optionally, substituted by one, two or three R d Substituent substitution; wherein R a Each phenyl group is independently, optionally, substituted by one, two or three R e Substituent substitution;

[0061] R 8 , R 9 and R 10 Each is independently H, C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl

[0062] Each R b are independently halo, cyano, C1-C6 alkoxy or C1-C6 alkyl;

[0063] Each R c are independently halo, cyano, -OP(=O)(OH)(OR 14 ) or phenyl; wherein R cEach phenyl group of 14 )replace;

[0064] Each R 14 are independently H, C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10 aryl, or a 5- to 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S; wherein R 14 Each C1-C8 alkyl group is independently, optionally substituted by one, two or three R f Substituent substitution;

[0065] Each R d are independently carbonyl or C1-C6 alkyl;

[0066] Each R e are independently halo, cyano or C1-C6 alkyl; and

[0067] Each R f are independently halo, cyano or phenyl;

[0068] wherein 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

[0069] Wherein the patient is not a pregnant individual.

[0070] In some embodiments, greater than 60% of the prodrugs of the compounds of Formula A, the prodrugs of the deuterated compounds of Formula A, or their pharmaceutically acceptable salts are converted to the compounds of Formula A or the deuterated compounds of Formula A after administration to a patient. In some embodiments, greater than 70% of the prodrugs of the compounds of Formula A, the prodrugs of the deuterated compounds of Formula A, or their pharmaceutically acceptable salts are converted to the compounds of Formula A or the deuterated compounds of Formula A after administration to a patient. In some embodiments, greater than 80% of the prodrugs of the compounds of Formula A, the prodrugs of the deuterated compounds of Formula A, or their pharmaceutically acceptable salts are converted to the compounds of Formula A or the deuterated compounds of Formula A after administration to a patient. In some embodiments, greater than 90% of the prodrugs of the compounds of Formula A, the prodrugs of the deuterated compounds of Formula A, or their pharmaceutically acceptable salts are converted to the compounds of Formula A or the deuterated compounds of Formula A after administration to a patient. In some embodiments, after administration to a patient, greater than 95% of the prodrug of a compound of Formula A, the prodrug of a deuterated compound of Formula A, or a pharmaceutically acceptable salt thereof is converted to a compound of Formula A or a deuterated compound of Formula A. In some embodiments, after administration to a patient, greater than 95% of the prodrug of a compound of Formula A, the prodrug of a deuterated compound of Formula A, or a pharmaceutically acceptable salt thereof is converted to a compound of Formula A or a deuterated compound of Formula A.

[0071] In some embodiments, the carbon at the 5-position of the tetrahydrofuranyl ring bonded to the deuterated compound of Formula A is substituted with one or two deuterium atoms. In some embodiments, the deuterated compound of Formula A is

[0072] 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 In some embodiments, the base is In some embodiments, the base is In some embodiments, the base is In some embodiments, the base of the deuterated compound of Formula A has R 12 The carbon of the deuterated compound of Formula A is replaced by one or more deuterium atoms, such as one or two deuterium atoms. 11 The carbon atoms on the carbon atoms are substituted with one or more deuterium atoms, such as one or two deuterium atoms.

[0073] In some embodiments, R of the deuterated compound of Formula A is 1 The carbon of the deuterated compound of Formula A is substituted with one or more deuterium atoms, such as one or two deuterium atoms. 2 The carbon atoms are replaced by one or more deuterium atoms, such as one or two deuterium atoms.

[0074] In some embodiments, the compound of Formula A is or a pharmaceutically acceptable salt thereof.

[0075] In some embodiments, the deuterated compound of Formula A is or pharmaceutically acceptable salts thereof.

[0076] In some embodiments, the method comprises administering to the patient a prodrug of Formula A having Formula I:

[0077]

[0078] Or a deuterated compound of formula I or a pharmaceutically acceptable salt thereof, wherein:

[0079] R 3 Yes -C(=O)OR 7 or -C(=O)R 7 ;and

[0080] R 7 is H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, C6-C 10 aryl, a 4- to 6-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O and S, or a 5- to 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S; wherein R 7 C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, C6-C 10 Aryl, 4- to 6-membered heterocyclyl and 5- to 6-membered heteroaryl are optionally substituted by one, two or three R a Substituent substitution.

[0081] In some embodiments, R of the deuterated compound of Formula I 3 The carbon of the deuterated compound of Formula I is substituted with one or more deuterium atoms, such as one or two deuterium atoms. 7 The carbon atoms are replaced by one or more deuterium atoms, such as one or two deuterium atoms.

[0082] In some embodiments, R 1 In some embodiments, R 1 Yes-OC(=O)R 4 In some embodiments, R 1 Yes-OC(=O)OR 4 .

[0083] In some embodiments, R 2 In some embodiments, R2 Yes-OC(=O)R 5 In some embodiments, R 2 Yes-OC(=O)OR 5 .

[0084] In some embodiments, R 1 and R 2 In some embodiments, R 1 Yes-OC(=O)R 4 And R 2 Yes-OC(=O)R 5 In some embodiments, R 1 is OH and R 2 Yes-OC(=O)R 5 OR-OC(=O)OR 5 In some embodiments, R 1 Yes-OC(=O)R 4 OR-OC(=O)OR 4 And R 2 is OH. In some embodiments, R 1 and R 2 Together they form -OC(=O)O-. In some embodiments, R 1 and R 2 Together they form -OP(=O)(OH)O-. In some embodiments, R 1 and R 2 Together we form - OCHR 6 O-.

[0085] In some embodiments,

[0086] R 1 is OH, OC(O)CH(CH3)2 or OC(O)CH3,

[0087] R 2 is OH, OC(O)CH(CH3)2 or OC(O)CH3, or

[0088] R 1 and R 2 Together they form -OC(=O)O-.

[0089] In some embodiments, R 4 is C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl. 4 is C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl, each of which is optionally substituted by one, two or three independently selected from halo, cyano, -N3, -OR 8 、-NR9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic group and phenyl group a Substituent substitution.

[0090] In some embodiments, R 4 is C1-C8 alkyl. 4 is optionally substituted by one, two or three independently selected from halo, cyano, -N3, -OR 8 、-NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic group and phenyl group a In some embodiments, R 4 is an unsubstituted C1-C8 alkyl. 4 is an unsubstituted C1-C6 alkyl. 4 is an unsubstituted C1-C3 alkyl. 4 is -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3 or -C(CH3)3. In some embodiments, R 4 It is -CH3 or -CH(CH3)2.

[0091] In some embodiments, R 5 is C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl. 5 is C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl, each of which is optionally substituted by one, two or three independently selected from halo, cyano, -N3, -OR 8 、-NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic group and phenyl group a Substituent substitution.

[0092] In some embodiments, R 5 is C1-C8 alkyl. 5 is optionally substituted by one, two or three independently selected from halo, cyano, -N3, -OR 8 、-NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic group and phenyl group a In some embodiments, R 5is an unsubstituted C1-C8 alkyl. 5 is an unsubstituted C1-C6 alkyl. 5 is an unsubstituted C1-C3 alkyl. 5 is -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3 or -C(CH3)3. In some embodiments, R 5 It is -CH3 or -CH(CH3)2.

[0093] In some embodiments, R 4 and R 5 In some embodiments, R 4 and R 5 In some embodiments, R 4 is a C1-C8 alkyl group and R 5 is C1-C8 alkyl. 4 is an unsubstituted C1-C8 alkyl group and R 5 is an unsubstituted C1-C8 alkyl. 4 is -CH3 or -CH(CH3)2 and R 5 is -CH3 or -CH(CH3)2. In some embodiments, R 4 is -CH3 and R5 is -CH3. 4 is -CH(CH3)2 and R 5 It is -CH(CH3)2.

[0094] In some embodiments, R 6 is H. In some embodiments, R 6 is C1-C6 alkyl. 6 is -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3 or -C(CH3)3. In some embodiments, R 6 It is a C1-C6 alkoxy group.

[0095] In some embodiments, R 6 is a 5- to 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S. In some embodiments, R 6 Is it one, two or three R b A 5- to 6-membered heteroaryl group substituted with a substituent containing 1, 2 or 3 heteroatoms selected from N, O and S. In some embodiments, R 6is a 5- to 6-membered heteroaryl group 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 group containing 1, 2 or 3 heteroatoms selected from N, O and S.

[0096] In some embodiments, R 6 It is C6-C 10 In some embodiments, R 6 Is it one, two or three R b Substituent-substituted C6-C 10 In some embodiments, R 6 It is an unsubstituted C6-C 10 In some embodiments, R 6 In some embodiments, R 6 It is an unsubstituted phenyl group.

[0097] In some embodiments, R 3 Yes -C(=O)OR 7 In some embodiments, R 3 Yes-C(=O)R 7 .

[0098] In some embodiments, R 7 It is C1-C8 alkyl, C3-C8 carbocyclic group, C6-C 10 aryl, 4 to 6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S, or 5 to 6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S. In some embodiments, R 7 It is C1-C8 alkyl, C3-C8 carbocyclic group, C6-C 10 aryl, 4 to 6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S, or 5 to 6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S, each of which is optionally substituted by one, two or three independently selected from -OR 8 , -OP(=O)(OH)2, C3-C8 carbocyclic group and phenyl group a Substituent substitution.

[0099] In some embodiments, R 7 is C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl. 7 is C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl, each of which is optionally substituted by one, two or three independently selected from halo, cyano, -N3, -OR 8 、-NR 9 R 10, -OP(=O)(OH)2, C3-C8 carbocyclic group and phenyl group a In some embodiments, R 7 is C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl, each of which is optionally substituted by one, two or three independently selected from halo, cyano, -N3, -OR 8 、-NR 9 R 10 and phenyl R a Substituent substitution.

[0100] In some embodiments, R 7 is C1-C8 alkyl. 7 is optionally substituted by one, two or three independently selected from halo, cyano, -N3, -OR 8 、-NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic group and phenyl group a In some embodiments, R 7 is optionally selected from -OR 8 , -OP(=O)(OH)2, C3-C8 carbocyclic group and unsubstituted phenyl group a In some embodiments, R 7 is optionally substituted by one, two or three independently selected from halo, cyano, -N3, -OR 8 、-NR 9 R 10 and phenyl R a In some embodiments, R 7 is optionally substituted by one, two or three independently selected from halo, cyano, -N3, -OR 8 、-NR 9 R 10 and unsubstituted phenyl R a In some embodiments, R 7 is-OR 8 In some embodiments, R 7 is a C1-C8 alkyl group substituted with a phenyl group. 7 is a C1-C8 alkyl group substituted with a C3-C8 carbocyclyl group. 7 It is a C1-C8 alkyl group substituted by -OP(=O)(OH)2.

[0101] In some embodiments, R7 is C1-C6 alkyl. 7 is optionally substituted by one, two or three independently selected from halo, cyano, -N3, -OR 8 、-NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic group and phenyl group a In some embodiments, R 7 is optionally selected from -OR 8 , -OP(=O)(OH)2, C3-C8 carbocyclic group and unsubstituted phenyl group a The substituent is a C1-C6 alkyl group substituted with a substituent.

[0102] In some embodiments, R 7 is a C1-C4 alkyl group substituted with a phenyl group. 7 It is a C1-C4 alkyl group substituted by a phenyl group. 7 It is a C1-C4 alkyl group substituted by -OP(=O)(OH)2.

[0103] In some embodiments, R 7 is C2-C4 alkyl. 7 is-OR 8 In some embodiments, R 7 is a C2-C4 alkyl group substituted with -OCH3. 7 is a C2-C4 alkyl substituted with a C4-C7 carbocyclyl. 7 is Substituted C2-C4 alkyl.

[0104] In some embodiments, R 7 It is -CH3, -CH2CH3, In some embodiments, R 7 It is -CH3, -CH2CH3, In some embodiments, R 7 It is -CH3, -CH2CH3,

[0105] In some embodiments, R 7 yes

[0106] In some embodiments, R7 yes In some embodiments, R 7 yes In some embodiments, R 7 yes In some embodiments, R 7 yes In some embodiments, R 7 yes

[0107] In some embodiments, R 7 is a C3-C8 carbocyclyl. 7 is optionally substituted by one, two or three independently selected from halogen, cyano, -N3, -OR 8 、-NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic group and phenyl group a In some embodiments, R 7 is optionally substituted by one, two or three independently selected from halogen, cyano, -N3, -OR 8 、-NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic group and unsubstituted phenyl group a In some embodiments, R 7 is optionally selected from one, two or three independently selected from -OR 8 、-NR 9 R 10 , a C3-C8 carbocyclic group and a C3-C8 carbocyclic group substituted with a substituent of an unsubstituted phenyl group.

[0108] In some embodiments, R 7 yes

[0109] In some embodiments, R 7 It is C6-C 10 In some embodiments, R 7 is optionally substituted by one, two or three independently selected from halogen, cyano, -N3, -OR 8 、-NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic group and phenyl group a Substituent-substituted C6-C 10 In some embodiments, R 7is optionally substituted by one, two or three independently selected from halogen, cyano, -N3, -OR 8 、-NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic group and unsubstituted phenyl group a Substituent-substituted C6-C 10 Aryl.

[0110] In some embodiments, R 7 is phenyl or naphthyl. In some embodiments, R 7 is phenyl or naphthyl OR, each of which is optionally substituted by one, two or three independently selected from halogen, cyano, -N3, -OR 8 、-NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic group and unsubstituted phenyl group a In some embodiments, R 7 In some embodiments, R 7 is optionally substituted by one, two or three independently selected from halogen, cyano, -N3, -OR 8 、-NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic group and unsubstituted phenyl group a Substituents: phenyl substituted.

[0111] In some embodiments, R 7 yes

[0112] In some embodiments, R 7 is a 4- to 6-membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S. In some embodiments, R 7 is optionally substituted by one, two or three independently selected from halogen, cyano, -N3, -OR 8 、-NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic group and phenyl group a A 4- to 6-membered heterocyclic group substituted with a substituent group containing 1, 2 or 3 heteroatoms selected from N, O and S. In some embodiments, R 7 is optionally substituted by one, two or three independently selected from halogen, cyano, -N 3 、-OR 8 、-NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic group and unsubstituted phenyl groupa The substituents are substituted 4- to 6-membered heterocyclic groups containing 1, 2 or 3 heteroatoms selected from N, O and S.

[0113] 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 optionally substituted by one, two or three independently selected from halogen, cyano, -N3, -OR 8 、-NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic group and unsubstituted phenyl group a The substituent is a 6-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O and S.

[0114] 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 optionally substituted by one, two or three independently selected from halogen, cyano, -N3, -OR 8 、-NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic group and unsubstituted phenyl group a A 5-membered heterocyclic group substituted with a substituent containing 1, 2 or 3 heteroatoms selected from N, O and S. In some embodiments, R 7 is an unsubstituted 5-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O and S.

[0115] In some embodiments, R 7 yes

[0116] In some embodiments, R 7 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 heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O and S.

[0117] In some embodiments, R 7 yes

[0118] In some embodiments, R 7 is a 5- to 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S. In some embodiments, R 7 is optionally substituted by one, two or three independently selected from halogen, cyano, -N3, -OR 8、-NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic group and phenyl group a A 5- to 6-membered heteroaryl group substituted with a substituent containing 1, 2 or 3 heteroatoms selected from N, O and S. In some embodiments, R 7 is optionally substituted by one, two or three independently selected from halogen, cyano, -N3, -OR 8 、-NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic group and unsubstituted phenyl group a The substituents are 5- to 6-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S.

[0119] In some embodiments, R 7 is a 5-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S. In some embodiments, R 7 is optionally substituted by one, two or three independently selected from halogen, cyano, -N3, -OR 8 、-NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic group and unsubstituted phenyl group a A 5-membered heteroaryl group substituted with a substituent containing 1, 2 or 3 heteroatoms selected from N, O and S. In some embodiments, R 7 is an unsubstituted 5-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S.

[0120] In some embodiments, R 7 is a 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S. In some embodiments, R 7 is optionally substituted by one, two or three independently selected from halogen, cyano, -N3, -OR 8 、-NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic group and unsubstituted phenyl group a A 6-membered heteroaryl group substituted with a substituent containing 1, 2 or 3 heteroatoms selected from N, O and S. In some embodiments, R 7 is optionally substituted by one, two or three independently selected from halogen, cyano and -NR 9 R 10 R a A 6-membered heteroaryl group substituted with a substituent containing 1, 2 or 3 heteroatoms selected from N, O and S. In some embodiments, R 7is an unsubstituted 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S.

[0121] In some embodiments, R 7 yes

[0122] In some embodiments, R 7 yes

[0123]

[0124] In some embodiments, R 7 yes

[0125] In some embodiments, R 7 yes

[0126] In some embodiments, R 8 is H. In some embodiments, R 8 is C1-C6 alkyl. 8 is -CH3. In some embodiments, R 8 is C1-C6 haloalkyl. 8 It is a C3-C6 cycloalkyl group.

[0127] In some embodiments, R 9 is H. In some embodiments, R 9 is C1-C6 alkyl. 9 is -CH3. In some embodiments, R 9 is C1-C6 haloalkyl. 9 It is a C3-C6 cycloalkyl group.

[0128] In some embodiments, R 10 is H. In some embodiments, R 10 is C1-C6 alkyl. 10 is -CH3. In some embodiments, R 10 is C1-C6 haloalkyl. 10 It is a C3-C6 cycloalkyl group.

[0129] In some embodiments, the base is In some embodiments, the base is

[0130] In some embodiments, the base is In some embodiments, the base is In some embodiments, the base is In some embodiments, the base is

[0131] In some embodiments, R 11 is -OP(=O)(OH)(OR 14 ) substituted C1-C3 alkyl. In some embodiments, R 11 is -(CH2)OP(=O)(OH)(OR 14 ).

[0132] In some embodiments, R 14 It's H.

[0133] In some embodiments, R 14 is H or C1-C8 alkyl; wherein R 14 The C1-C8 alkyl is optionally substituted with one, two or three substituents independently selected from halogen, cyano and phenyl.

[0134] In some embodiments, R 14 is a C1-C8 alkyl group optionally substituted by one, two or three substituents independently selected from halogen, cyano and phenyl. 14 is C1-C3 alkyl optionally substituted by one, two or three substituents independently selected from halogen, cyano and phenyl. 14 is a C1-C3 alkyl group substituted with one phenyl group. 14 yes

[0135] In some embodiments, R 11 is -(CH2)OP(=O)(OH)2. In some embodiments, R 11 yes

[0136] In some embodiments, R 12 is H. In some embodiments, R 12 is C1-C6 alkyl. 12 Yes-C(=O)R 13 In some embodiments, R 12 is -C(=O)(CH2)2CH3. In some embodiments, R 12 Yes -C(=O)OR 13In some embodiments, R 12 is -C(=O)OCH2CH(CH3)2. In some embodiments, R 12 is -C(=O)OCH2CH(CH3)2 or -C(=O)(CH2)2CH3. In some embodiments, R 12 yes

[0137] In some embodiments, R 13 is H. In some embodiments, R 13 It is C1-C 10 In some embodiments, R 13 is C1-C8 alkyl. 13 is optionally substituted by one, two or three independently selected from halogen, cyano, -OP(=O)(OH)(OR 14 ) and phenyl R c In some embodiments, R 13 is optionally substituted by one, two or three R independently selected from halogen, cyano and phenyl c In some embodiments, R 13 is optionally substituted by one, two or three R independently selected from halogen, cyano and unsubstituted phenyl c In some embodiments, R 13 is C1-C8 alkyl. 13 is -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3 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 It is C6-C 10 In some embodiments, R 13 In some embodiments, R 13 Yes-O-C6-C 10 In some embodiments, R 13 In some embodiments, R 13 Yes-O-C1-C 10 In some embodiments, R 13is -O-CH3, -O-CH2CH3, -O-(CH2)2CH3, -O-(CH2)4CH3 or -O-(CH2)6CH3.

[0138] In some embodiments, R 13 yes

[0139] In some embodiments, the base is

[0140] In some embodiments, the method comprises administering to the patient a compound of formula A or a prodrug thereof or a pharmaceutically acceptable salt thereof, wherein

[0141] R 1 -OH, -OC(=O)R 4 OR-OC(=O)OR 4 ;

[0142] R 2 -OH, -OC(=O)R 5 OR-OC(=O)OR 5 ;or

[0143] R 1 and R 2 together to form -OC(=O)O-; and

[0144] R 4 and R 5 are each independently an unsubstituted C1-C8 alkyl, an unsubstituted C3-C8 carbocyclic group, an unsubstituted C6-C 10 aryl, an unsubstituted 4- to 6-membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S, or an unsubstituted 5- to 6-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S.

[0145] In some embodiments, the base is

[0146] In some embodiments, R 4 and R 5 Each is independently an unsubstituted C1-C8 alkyl. 4 and R 5 Each is independently an unsubstituted C1-C6 alkyl. 1 is -OH or -OC(=O)R 4 And R 2 is -OH or -OC(=O)R 5 In some embodiments, R 1 and R2 Each is independently -OH, OC(=O)CH(CH3)2 or OC(=O)CH3. 1 and R 2 Together they form -OC(=O)O-.

[0147] In some embodiments, the method comprises administering to the patient a deuterated compound of formula A having formula A1

[0148]

[0149] or a prodrug thereof or a pharmaceutically acceptable salt thereof, wherein

[0150] R 1 -OH, -OC(=O)R 4 OR-OC(=O)OR 4 ;

[0151] R 2 -OH, -OC(=O)R 5 OR-OC(=O)OR 5 ;or

[0152] R 1 and R 2 together to form -OC(=O)O-; and

[0153] R 4 and R 5 are each independently an unsubstituted C1-C8 alkyl, an unsubstituted C3-C8 carbocyclic group, an unsubstituted C6-C 10 aryl, an unsubstituted 4- to 6-membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S, or an unsubstituted 5- to 6-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S.

[0154] In some embodiments, R 4 and R 5 Each is independently an unsubstituted C1-C8 alkyl. 4 and R 5 Each is independently an unsubstituted C1-C6 alkyl. 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 Each is independently -OH, OC(=O)CH(CH3)2 or OC(=O)CH3. 1 and R2 Together they form -OC(=O)O-.

[0155] In some embodiments, the method comprises administering to the patient a deuterated compound of formula A having formula A2

[0156]

[0157] or a prodrug thereof or a pharmaceutically acceptable salt thereof, wherein

[0158] R 1 -OH, -OC(=O)R 4 OR-OC(=O)OR 4 ;

[0159] R 2 -OH, -OC(=O)R 5 OR-OC(=O)OR 5 ;or

[0160] R 1 and R 2 together to form -OC(=O)O-; and

[0161] R 4 and R 5 are each independently an unsubstituted C1-C8 alkyl, an unsubstituted C3-C8 carbocyclic group, an unsubstituted C6-C 10 aryl, an unsubstituted 4- to 6-membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S, or an unsubstituted 5- to 6-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S.

[0162] In some embodiments, R 4 and R 5 Each is independently an unsubstituted C1-C8 alkyl. 4 and R 5 Each is independently an unsubstituted C1-C6 alkyl. 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 Each is independently -OH, OC(=O)CH(CH3)2 or OC(=O)CH3. 1 and R 2 Together they form -OC(=O)O-.

[0163] In some embodiments, the method comprises administering to the patient a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein

[0164] R 1 -OH, -OC(=O)R 4 OR-OC(=O)OR 4 ;

[0165] R 2 -OH, -OC(=O)R 5 OR-OC(=O)OR 5 ;or

[0166] R 1 and R 2 Together they form -OC(=O)O-;

[0167] R 3 Yes -C(=O)OR 7 or -C(=O)R 7 ;and

[0168] R 4 , R 5 and R 7 are each independently an unsubstituted C1-C8 alkyl, an unsubstituted C3-C8 carbocyclic group, an unsubstituted C6-C 10 aryl, an unsubstituted 4- to 6-membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S, or an unsubstituted 5- to 6-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S.

[0169] In some embodiments, the base is

[0170] In some embodiments, R 4 , R 5 and R 7 Each is independently an unsubstituted C1-C8 alkyl. 4 , R 5 and R 7 Each is independently an unsubstituted C1-C6 alkyl. 1 is -OH or -OC(=O)R 4 , R 2 is -OH or -OC(=O)R 5 , and R 3 Yes-C(=O)R 7 In some embodiments, R 1 and R 2 are each independently -OH, OC(=O)CH(CH3)2 or OC(=O)CH3, and R 7is -CH(CH3)2 or -CH3. In some embodiments, R 1 and R 2 Together they form -OC(=O)O-, and R 7 It is -CH(CH3)2 or -CH3.

[0171] In some embodiments, the method comprises administering to the patient a deuterated compound of Formula I having Formula Ia

[0172]

[0173] or a pharmaceutically acceptable salt thereof, wherein

[0174] R 1 -OH, -OC(=O)R 4 OR-OC(=O)OR 4 ;

[0175] R 2 -OH, -OC(=O)R 5 OR-OC(=O)OR 5 ;or

[0176] R 1 and R 2 Together they form -OC(=O)O-;

[0177] R 3 Yes -C(=O)OR 7 or -C(=O)R 7 ;and

[0178] R 4 , R 5 and R 7 are each independently an unsubstituted C1-C8 alkyl, an unsubstituted C3-C8 carbocyclic group, an unsubstituted C6-C 10 aryl, an unsubstituted 4- to 6-membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S, or an unsubstituted 5- to 6-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S.

[0179] In some embodiments, R 4 , R 5 and R 7 Each is independently an unsubstituted C1-C8 alkyl. 4 , R 5 and R 7 Each is independently an unsubstituted C1-C6 alkyl. 1 is -OH or -OC(=O)R 4 , R 2is -OH or -OC(=O)R 5 , and R 3 Yes-C(=O)R 7 In some embodiments, R 1 and R 2 are each 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 they form -OC(=O)O-, and R 7 It is -CH(CH3)2 or -CH3.

[0180] In some embodiments, the method comprises administering to the patient a deuterated compound of Formula I having Formula Ib

[0181]

[0182] or a pharmaceutically acceptable salt thereof, wherein

[0183] R 1 -OH, -OC(=O)R 4 OR-OC(=O)OR 4 ;

[0184] R 2 -OH, -OC(=O)R 5 OR-OC(=O)OR 5 ;or

[0185] R 1 and R 2 Together they form -OC(=O)O-;

[0186] R 3 Yes -C(=O)OR 7 or -C(=O)R 7 ;and

[0187] R 4 , R 5 and R 7 are each independently an unsubstituted C1-C8 alkyl, an unsubstituted C3-C8 carbocyclic group, an unsubstituted C6-C 10 aryl, an unsubstituted 4- to 6-membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S, or an unsubstituted 5- to 6-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S.

[0188] In some embodiments, R 4 , R 5 and R 7Each is independently an unsubstituted C1-C8 alkyl. 4 , R 5 and R 7 Each is independently an unsubstituted C1-C6 alkyl. 1 is -OH or -OC(=O)R 4 , R 2 is -OH or -OC(=O)R 5 , and R 3 Yes-C(=O)R 7 In some embodiments, R 1 and R 2 are each 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 they form -OC(=O)O-, and R 7 It is -CH(CH3)2 or -CH3.

[0189] 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.

[0190] Table 1

[0191]

[0192] In some embodiments, the compound of Formula I is a compound of Table 2 or a pharmaceutically acceptable salt thereof.

[0193] Table 2

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206]

[0207]

[0208]

[0209] In some embodiments, the deuterated compound of Formula A, a prodrug of a compound of Formula A, or a prodrug of a deuterated compound of Formula A is a compound of Table 3 or a pharmaceutically acceptable salt thereof.

[0210] Table 3

[0211]

[0212]

[0213]

[0214]

[0215]

[0216]

[0217]

[0218]

[0219]

[0220]

[0221]

[0222]

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237] In some embodiments, the compound of Formula I is a compound of Table 4 or a pharmaceutically acceptable salt thereof.

[0238] Table 4

[0239]

[0240]

[0241] In some embodiments, the compound of Formula I is or a pharmaceutically acceptable salt thereof.

[0242] In some embodiments, the deuterated compound of Formula I is or a pharmaceutically acceptable salt thereof.

[0243] In some embodiments, the compound of Formula I is or a pharmaceutically acceptable salt thereof.

[0244] The compounds described herein can be formulated with conventional carriers and excipients. For example, tablets will contain excipients, glidants, fillers, binders, etc. Aqueous preparations are prepared in a sterile form and will generally be isotonic when intended to be delivered by non-oral administration. All preparations 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 dextrin, hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose, stearic acid, etc. In some embodiments, the preparation comprises one or more pharmaceutically acceptable excipients. The pH range of the preparation is from about 3 to about 11, but is generally from about 7 to 10. In some embodiments, the pH range of the preparation is from about 2 to about 5, but is generally from about 3 to 4.

[0245] Although the compounds of the present disclosure ("active ingredients") can be administered alone, it is preferred to provide them as pharmaceutical formulations. Both veterinary and human formulations of the present invention include at least one active ingredient as defined above, together with one or more acceptable carriers therefor and optionally other therapeutic ingredients, especially those additional therapeutic ingredients discussed herein. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not physiologically harmful to the recipient thereof.

[0246] These preparations include those suitable for the aforementioned routes of administration. The preparations can be conveniently provided in unit dosage form and can be prepared by any suitable method known in the pharmaceutical field. Technology and preparations are generally found in "Remington's Pharmaceutical Sciences" (Mack Publishing Co., Easton, PA). Such methods include the step of associating the active ingredient with a carrier constituting one or more auxiliary ingredients. Generally speaking, the preparation is prepared by uniformly and closely associating the active ingredient with a liquid carrier or a subdivided solid carrier or both, and then, if necessary, shaping the product.

[0247] In some embodiments, the pharmaceutical formulation is for subcutaneous, intramuscular, intravenous, oral, or inhalation administration.

[0248] In some embodiments, the compounds described herein, e.g., compounds of Formula A, deuterated compounds of Formula A, prodrugs of compounds of Formula A, prodrugs of deuterated compounds of Formula A, compounds of Formula I, deuterated compounds of Formula I, or pharmaceutically acceptable salts thereof, described herein, have optimized / improved pharmacokinetic properties and are suitable for oral administration. For example, compounds of Formula I have improved bioavailability and can therefore be administered by oral administration.

[0249] In some embodiments, formulations of the invention suitable for oral administration may be provided 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 may also be administered as a pill, elixir, or paste.

[0250] In some embodiments, tablets are prepared by optionally compressing or molding with one or more auxiliary components. Compressed tablets can be prepared by compressing the active ingredient of a free-flowing form (such as powdered or granular) in a suitable machine, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant or dispersant. Molded tablets can be prepared by molding a mixture of powdered active ingredients moistened with an inert liquid diluent in a suitable machine. Tablets can be optionally coated or scored, and are optionally formulated to provide slow or controlled release of active ingredients therefrom.

[0251] For infections of the eye or other external tissues (e.g., oral cavity and skin), the formulation is applied as an external ointment or cream containing the active ingredient in an amount of, for example, 0.075% w / w to 20% w / w (including active ingredients in a range between 0.1% and 20% in increments of 0.1% w / w, such as 0.6% w / w, 0.7% w / w, etc.), preferably 0.2% w / w to 15% w / w, and most preferably 0.5% w / w to 10% w / w. When formulated into an ointment, the active ingredient may be used with a paraffin base or a water-miscible ointment base. Alternatively, the active ingredient may be formulated into a cream with an oil-in-water cream base.

[0252] If desired, the aqueous phase of the cream base may contain, for example, at least 30% w / w of a polyol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol, and polyethylene glycol (including PEG 400), and mixtures thereof. Topical formulations may desirably include compounds that enhance 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.

[0253] The oil phase of the emulsion of the present invention can be composed of known ingredients in a known manner. Although this phase can only include emulsifiers (or called emulsifiers), it ideally includes a mixture of at least one emulsifier with fat or oil or with both fat and oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. It is also preferred to include both oil and fat. Emulsifiers with or without stabilizers together constitute the so-called emulsifying wax, and wax together with oil and fat constitute the so-called emulsifying ointment base, which forms the oily dispersed phase of the cream formulation.

[0254] Emulsifiers and emulsion stabilizers suitable for use in the formulations of the present invention include 60. 80, cetearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate. Additional emulsifiers and emulsion stabilizers suitable for the formulation of the present invention include 80.

[0255] The cosmetic properties required for the preparation are selected to be suitable oil or fat. Emulsifiable paste should preferably be a non-greasy, non-staining and washable product with a suitable consistency to avoid leakage from a tube or other containers. Straight or branched monoalkyl esters or dialkyl esters can be used, such as diisoadipate, isohexadecyl stearate, propylene glycol diester of coconut fatty acid, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, palmitic acid-2-ethylhexyl or a mixture of branched esters called Crodamol CAP, the last three being preferred esters. These esters can be used alone or in combination, specifically depending on the desired properties. Alternatively, high melting point lipids are used, such as white soft paraffin and / or liquid paraffin or other mineral oils.

[0256] The pharmaceutical preparation according to the present invention comprises a compound according to the present invention and one or more pharmaceutically acceptable carriers or excipients and optional other therapeutic agents. The pharmaceutical preparation containing the active ingredient may be in any form suitable for the intended method of administration. For example, when used for oral use, tablets, lozenges, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known in the art for making pharmaceutical compositions, and such compositions may include one or more medicaments, including sweeteners, flavoring agents, colorants and preservatives, so as to provide a palatable preparation. Tablets containing active ingredients mixed with non-toxic pharmaceutically acceptable excipients suitable for making tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium carbonate or sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrants, such as corn starch or alginic acid; binding agents, such as starch, gelatin or gum arabic; and lubricants, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be used alone or with a wax.

[0257] Formulations for oral use may also be provided as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, such as calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.

[0258] The aqueous suspension of the present invention contains an active substance mixed with an excipient suitable for making an aqueous suspension. Such excipients include suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth and gum arabic; and dispersants or wetting agents, such as naturally occurring phospholipids (e.g., lecithin), condensation products of alkylene oxides and fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide and long-chain fatty alcohols (e.g., heptadecaethyleneoxycetanol), 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 p-hydroxybenzoate or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweeteners such as sucrose or saccharin. Other non-limiting examples of suspending agents include cyclodextrins. In some examples, the suspending agent is sulfobutyl ether β-cyclodextrin (SEB-β-CD), e.g.

[0259] Oily suspensions can be prepared 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. Oral suspensions can contain thickeners such as beeswax, hard paraffin or cetyl alcohol. Sweeteners such as those described above and flavoring agents can be added to provide a palatable oral preparation. These compositions can be preserved by adding an antioxidant such as ascorbic acid.

[0260] The dispersible powders and granules of the present invention suitable for preparing aqueous suspensions by adding water provide the active ingredient mixed with a dispersant or wetting agent, a suspending agent and one or more preservatives. Suitable dispersants or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients such as sweeteners, flavoring agents and coloring agents may also be present.

[0261] 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 gum arabic and tragacanth; naturally occurring phospholipids such as soy 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. Emulsions may also contain sweeteners and flavoring agents. Syrups and elixirs may be formulated with sweeteners such as glycerol, sorbitol or sucrose. Such preparations may also contain a demulcent, a preservative, a flavoring agent or a coloring agent.

[0262] The pharmaceutical composition of the present invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oily suspension. The suspension may be prepared according to known techniques using those suitable dispersants or wetting agents and suspending agents already mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent (such as a solution in 1,3-butanediol), or may be prepared as a lyophilized powder. Acceptable solvents and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile non-volatile oils may be used generally as solvents or suspension media. For this purpose, any mild non-volatile oil may be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid may also be used to prepare injections. Acceptable solvents and solvents that may be used are water, Ringer's solution, isotonic sodium chloride solution, and hypertonic sodium chloride solution.

[0263] The amount of active ingredient that can be combined with carrier material to produce single dosage form will vary according to the treated host and specific mode of administration. For example, a sustained release formulation intended for oral administration to a human being may contain about 1 mg to 1000 mg of active material, which is compounded with a suitable and convenient amount of carrier material, which may vary between about 5% to about 95% (weight: weight) of the total composition. Pharmaceutical compositions may be prepared to provide an application amount that is easy to measure. For example, an aqueous solution intended for intravenous infusion may contain about 3 mg to 500 mg of active ingredient per milliliter of solution, so as to infuse a suitable volume at a rate of about 30 mL / hr.

[0264] 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 0.5% to 20%, advantageously 0.5% to 10%, and especially about 1.5% w / w.

[0265] Formulations suitable for topical administration in the mouth include lozenges containing the active ingredient in a flavored form, usually sucrose and acacia or tragacanth; lozenges containing an inert active ingredient such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

[0266] Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.

[0267] In some embodiments, the compounds described herein are administered by inhalation. In some embodiments, preparations suitable for intrapulmonary or intranasal administration have, for example, a particle size in the range of 0.1 micron to 500 microns, such as 0.5 micron, 1 micron, 30 microns, 35 microns, etc., and the preparation is administered by rapid inhalation of the nasal passage or by inhalation into the oral cavity to reach the alveolar sacs. Suitable preparations include aqueous or oily solutions of active ingredients. Preparations suitable for aerosol or dry powder administration can be prepared according to conventional methods and can be delivered with other therapeutic agents. In some embodiments, the compounds used herein are formulated and administered as dry powders. In some embodiments, the compounds used herein are formulated and administered as atomized preparations. In some embodiments, the compounds used herein are formulated for delivery by a mask. In some embodiments, the compounds used herein are formulated for delivery by a mask inhaler.

[0268] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

[0269] 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 agents and thickening agents.

[0270] The preparation is present in unit dose or multi-dose containers, such as sealed ampoules and vials, and can be stored under freeze-dried (lyophilized) conditions, requiring only the addition of a sterile liquid carrier, such as water for injection, immediately before use. Extemporaneous injections and suspensions are prepared from sterile powders, granules and tablets of the aforementioned type. A preferred unit dose preparation is a preparation containing a daily dose or unit daily subdose of the active ingredient as described above, or an appropriate portion thereof.

[0271] It should be understood that in addition to the ingredients particularly mentioned above, the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

[0272] The present invention further provides a veterinary composition comprising at least one active ingredient as defined above and a veterinary carrier thereof.

[0273] Veterinary carriers are materials useful for administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally or by any other desired route.

[0274] The compounds described herein are useful in providing controlled release pharmaceutical formulations containing one or more compounds described herein as an active ingredient ("controlled release formulations"), wherein the release of the active ingredient is controlled and regulated to allow less frequent dosing or to improve the pharmacokinetic or toxicity profile of a given active ingredient.

[0275] Also provided herein are kits comprising the compounds described herein. In some embodiments, the kits described herein may include labels and / or instructions for using the compounds to treat a disease or condition in a non-pregnant patient in need thereof. In some embodiments, the disease or condition is a viral infection.

[0276] In some embodiments, the kit may also include one or more additional therapeutic agents and / or instructions for using the additional therapeutic agents in combination with a compound 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 to treat a disease or condition in a subject (e.g., a human) in need thereof.

[0277] In some embodiments, the kits provided herein contain 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 may 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, a kit may contain a single dosage unit, and in other embodiments there are multiple dosage units, such as the number of dosage units required for a given regimen or cycle.

[0278] One or more compounds described herein are administered by any route suitable 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), etc. In some embodiments, the compounds described herein are administered by inhalation or intravenous. In some embodiments, the compounds described herein are administered orally. It should be understood that the preferred route may vary with, for example, the condition of the recipient.

[0279] In the methods for treating viral infections described herein, the compounds described herein can be applied to people who may be exposed to viruses or already have viral infections at any time. In some embodiments, the compounds described herein can be applied prophylactically to people who are in contact with people suffering from viral infections or are at risk of contacting people suffering from viral infections, such as health care providers. In some embodiments, the administration of the compounds described herein can be applied to people who are positive for viral infection tests but have not yet shown symptoms of viral infection. In some embodiments, the compounds described herein can be applied to people at the beginning of symptoms of viral infection.

[0280] In some embodiments, the methods described herein comprise event-driven administration of 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, to a subject.

[0281] As used herein, the term "event-driven" or "event-driven administration" refers to administration of 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) prior to an event that will expose an individual to a virus (or will otherwise increase the risk of an individual acquiring a viral infection) (e.g., 2 hours, 1 day, 2 days, 5 days, or 7 days or more prior to the event); and / or (2) during an event (or more than one repetitive event) that will expose an individual to a virus (or will otherwise increase the risk of an individual acquiring a viral infection); and / or (3) after an event (or after the final event in a series of repetitive events) that will expose an individual to a virus (or will otherwise increase the risk of an individual acquiring a viral infection). In some embodiments, event-driven administration is performed before the subject is exposed to the virus. In some embodiments, event-driven administration is performed after the subject is exposed to the virus. In some embodiments, event-driven administration occurs before the subject is exposed to the virus and after exposure to the virus.

[0282] In certain embodiments, the methods described herein involve administration before and / or after an event that will expose an individual to a virus or otherwise increase the risk of an individual acquiring a viral infection, e.g., as pre-exposure prophylaxis (PrEP) and / or as 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).

[0283] 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 prior to exposing the subject to the virus.

[0284] 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 exposing the subject to the virus.

[0285] 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 exposing the subject to the virus.

[0286] 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 24 hours to 2 hours prior to the virus, 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 every 24 hours during the exposure period. An acceptable salt of the 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 further after the last exposure, and then 24 hours later, a final 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 is administered.

[0287] Another example of an event-driven dosing regimen includes 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 hours prior to viral exposure, then daily during exposure, and then a final administration (which may be in increasing doses, such as double doses) approximately 24 hours after the last exposure.

[0288] The specific dosage level of the compounds described herein for any particular subject will depend on a variety of factors, including the activity of the specific compound used, the age, weight, general health, sex, diet, administration time, route of administration and excretion rate, drug combination and the severity of a specific disease of the subject receiving therapy. For example, the dosage can be expressed as milligrams (mg / kg) of the compound described herein per kilogram of subject body weight. A dosage between about 0.1 mg / kg and 150 mg / kg may be appropriate. In some embodiments, a dosage between about 0.1 mg / kg and 100 mg / kg may be appropriate. In other embodiments, a dosage between 0.5 mg / kg and 60 mg / kg may be appropriate. Normalization according to the subject's weight is particularly useful when adjusting the dosage between subjects with large size differences (such as when using drugs in children and adults, or when converting the effective dose of non-human subjects such as dogs to a dosage suitable for human subjects).

[0289] The daily dose may also be described as the total amount of the compound described herein administered per dose or per day. The daily dose 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 may be between about 1 mg and 4,000 mg, between about 2,000 mg / day to 4,000 mg / day, between about 1 mg / day to 2,000 mg / day, between about 1 mg / day to 1,000 mg / day, between about 10 mg / day to 500 mg / day, between about 20 mg / day to 500 mg / day, between about 50 mg / day to 300 mg / day, between about 75 mg / day to 200 mg / day, or between about 15 mg / day to 150 mg / day.

[0290] The dosage or administration frequency of the compounds described herein may be adjusted during the course of treatment according to the judgment of the administering physician.

[0291] 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.

[0292] Compounds described herein can be administered by any available route and means, such as by oral or parenteral (e.g., intravenous) administration. The therapeutically effective amount of a compound may include about 0.00001 mg / kg body weight / day to about 10 mg / kg body weight / day, such as about 0.0001 mg / kg body weight / day to about 10 mg / kg body weight / day, or such as about 0.001 mg / kg body weight / day to about 1 mg / kg body weight / day, or such as about 0.01 mg / kg body weight / day to about 1 mg / kg body weight / day, or such as about 0.05 mg / kg body weight / day to about 0.5 mg / kg body weight / day. In some embodiments, the therapeutically effective amount of a compound described herein includes about 0.3 mg / day to about 30 mg / day, or about 30 mg / day to about 300 mg / day, or about 0.3 mg / day to about 30 mg / day, or about 30 mg / day to about 300 mg / day.

[0293] Compounds described herein can be combined with one or more additional therapeutic agents in any dose of compounds described herein (e.g., 1 mg to 1000 mg compound). A therapeutically effective amount may include about 0.1 mg / agent to about 1000 mg / agent, such as about 50 mg / agent to about 500 mg / agent, or such as about 100 mg / agent to about 400 mg / agent, or such as about 150 mg / agent to about 350 mg / agent, or such as about 200 mg / agent to about 300 mg / agent, or such as about 0.01 mg / agent to about 1000 mg / agent, or such as about 0.01 mg / agent to about 100 mg / agent, or such as about 0.1 mg / agent to about 100 mg / agent, or such as about 1 mg / agent to about 100 mg / agent, or such as about 1 mg / agent to about 10 mg / agent, or such as about 1 mg / agent to about 1000 mg / agent. Other therapeutically effective amounts 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 are about 1 mg / dose, or about 2 mg / dose, 3 mg / dose, 4 mg / dose, 5 mg / dose, 6 mg / dose, 7 mg / dose, 8 mg / dose, 9 mg / dose, 10 mg / dose, 15 mg / dose, 20 mg / dose, 25 mg / dose, 30 mg / dose, 35 mg / dose, 40 mg / dose, 45 mg / dose, 50 mg / dose, 55 mg / dose, 60 mg / dose, 65 mg / dose, 70 mg / dose, 75 mg / dose, 80 mg / dose, 85 mg / dose, 90 mg / dose, 95 mg / dose, or about 100 mg / dose. Other therapeutically effective amounts of the compounds described herein are about 100 mg / dose, 125 mg / dose, 150 mg / dose, 175 mg / dose, 200 mg / dose, 225 mg / dose, 250 mg / dose, 275 mg / dose, 300 mg / dose, 325 mg / dose, 350 mg / dose, 375 mg / dose, 400 mg / dose, 425 mg / dose, 450 mg / dose, 475 mg / dose, 500 mg / dose, 525 mg / dose, g / dose, 550 mg / dose, 575 mg / dose, 600 mg / dose, 625 mg / dose, 650 mg / dose, 675 mg / dose, 700 mg / dose, 725 mg / dose, 750 mg / dose, 775 mg / dose, 800 mg / dose, 825 mg / dose, 850 mg / dose, 875 mg / dose, 900 mg / dose, 925 mg / dose, 950 mg / dose, 975 mg / dose or about 1000 mg / dose.

[0294] In some embodiments, the methods described herein include administering to a subject an initial daily dose of about 1 mg to 500 mg of a compound described herein, and gradually increasing the dose until clinical efficacy is achieved. Increments of about 5 mg, 10 mg, 25 mg, 50 mg, or 100 mg may be used to increase the dose. The dose may be increased daily, every other day, twice a week, once a week, once every two weeks, once every three weeks, or once a month.

[0295] When administered orally, the total daily dosage for a human subject can be between about 1 mg / day-4,000 mg / day, between about 1 mg / day-3,000 mg / day, between 1 mg / day-2,000 mg / day, between about 1 mg / day-1,000 mg / day, between about 10 mg / day-500 mg / day, between about 50 mg / day-300 mg / day, between about 75 mg / day-200 mg / day, or between about 100 mg / day-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 in 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 in a single dose. In some embodiments, the total daily dosage for a human subject may be about 300 mg / day, 400 mg / day, 500 mg / day, or 600 mg / day administered in 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 dose for a human subject can be about 100 mg / day to 200 mg / day, 100 mg / day to 300 mg / day, 100 mg / day to 400 mg / day, 100 mg / day to 500 mg / day, 100 mg / day to 600 mg / day, 100 mg / day to 700 mg / day, 100 mg / day to 800 mg / day, 100 mg / day to 900 mg / day, 100 mg / day to 1000 mg / day, 500 mg / day -1100mg / day, 500mg / day-1200mg / day, 500mg / day-1300mg / day, 500mg / day-1400mg / day, 500mg / day-1500mg / day, 500mg / day-1600mg / day, 500mg / day-1700mg / day, 500mg / day-1800mg / day, 500mg / day-1900mg / day, 500mg / day-2000mg / day, 1500mg / day-21 00mg / day, 1500mg / day-2200mg / day, 1500mg / day-2300mg / day, 1500mg / day-2400mg / day, 1500mg / day-2500mg / day, 2000mg / day-2600mg / day, 2000mg / day-2700mg / day, 2000mg / day-2800mg / day, 2000mg / day-2900mg / day, 2000mg / day-3000mg / day, 2500mg / day g / day-3100 mg / day, 2500 mg / day-3200 mg / day, 2500 mg / day-3300 mg / day, 2500 mg / day-3400 mg / day, 2500 mg / day-3500 mg / day, 3000 mg / day-3600 mg / day, 3000 mg / day-3700 mg / day, 3000 mg / day-3800 mg / day, 3000 mg / day-3900 mg / day or 3000 mg / day-4000 mg / day.

[0296] In some embodiments, the total daily dose for a human subject may be about 100 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject may be about 150 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject may be about 200 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject may be about 250 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject may be about 300 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject may be about 350 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject may be about 400 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject may be about 450 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject may be about 500 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject may be about 550 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject may be about 600 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject may be about 650 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject may be about 700 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject may be about 750 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject may be about 800 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject may be about 850 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject may be about 900 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject may be about 950 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject may be about 1000 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject may be about 1500 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject may be about 2000 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject may be about 2500 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject may be about 3000 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject may be about 4000 mg / day administered in a single dose.

[0297] A single dose can be administered hourly, daily, weekly, or monthly. For example, a single dose can be administered once every 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 16 hours, or once every 24 hours. A single dose can also be administered once every 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or once every 7 days. A single dose can also be administered once every 1 week, 2 weeks, 3 weeks, or once every 4 weeks. In certain embodiments, a 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 in the methods described herein. In some embodiments, the compounds described herein are administered twice a day in the methods described herein. In some embodiments, the compounds described herein are administered three times a day in the methods described herein.

[0298] In some embodiments, the compounds described herein are administered once a day at a total daily dose of 100 mg / day-4000 mg / day. In some embodiments, the compounds described herein are administered twice a day at a total daily dose of 100 mg / day-4000 mg / day. In some embodiments, the compounds described herein are administered three times a day at a total daily dose of 100 mg / day-4000 mg / day.

[0299] The dosage frequency of the compounds described herein will be determined by the needs of the individual patient, and may be, for example, once a day or twice a day or more. The administration of the compounds is continued as long as the treatment of the viral infection requires. For example, the compounds may be administered to a person 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.

[0300] Administration can be intermittent, with the patient receiving a daily dose of a compound as described herein over a period of several or more days, followed by a period of several or more days in which the patient does not receive a daily dose of the compound. For example, the patient may receive a dose of the compound every other day or three times a week. Again by way of example, the patient may receive a dose of the compound every day over a period of 1 to 14 days, followed by a period of 7 to 21 days in which the patient does not receive a dose of the compound, followed by a period of 1 to 14 days in which the patient again receives a dose of the compound. Depending on the clinical needs of the patient being treated, the alternating time periods of the compound followed by the non-administration of the compound may be repeated.

[0301] The compounds of the present disclosure or pharmaceutical compositions thereof can be administered once, twice, three times, or four times per day using any suitable mode described above. Moreover, administration or treatment with the compounds can continue for multiple days; for example, for one treatment cycle, treatment will typically continue for at least 7 days, 14 days, or 28 days. Treatment cycles are well known in cancer chemotherapy and are typically alternating with a rest period of about 1 to 28 days, typically about 7 days or about 14 days, between cycles. In other embodiments, treatment cycles may also be continuous.

[0302] In some embodiments, the compound is administered continuously for 1 to 30 days, such as 1 to 28 days, 1 to 21 days, 1 to 14 days, 1 to 7 days, 1 to 5 days, 3 to 30 days, 3 to 28 days, 3 to 21 days, 3 to 14 days, 3 to 7 days, 5 to 30 days, 5 to 28 days, 5 to 21 days, 5 to 14 days, or 5 to 7 days. In some embodiments, the compound is administered once a day or twice a day. In some embodiments, the compound is administered once a day. In some embodiments, the compound is administered twice a day.

[0303] In some embodiments, the compound is administered once a day for 2 consecutive days, 3 consecutive days, 4 consecutive days, 5 consecutive days, 6 consecutive days, 7 consecutive days, 8 consecutive days, 9 consecutive days, 10 consecutive days, 11 consecutive days, 12 consecutive days, 13 consecutive days, or 14 consecutive 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 consecutive days, 3 consecutive days, 4 consecutive days, 5 consecutive days, 6 consecutive days, 7 consecutive days, 8 consecutive days, 9 consecutive days, 10 consecutive days, 11 consecutive days, 12 consecutive days, 13 consecutive days, or 14 consecutive 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.

[0304] In some embodiments, the compounds described herein are administered to a human via oral, intramuscular, intravenous, subcutaneous, or inhalation administration. In some embodiments, the compound is administered orally.

[0305] 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 pregnancy from the first day of administration to 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 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 pregnancy from the first day of administration to at least 2 days after 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 pregnancy from the first day of administration to at least 4 days after 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 pregnancy from the first day of administration to at least 7 days after 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 pregnancy from the first day of administration to at least 14 days after administration. In some embodiments, the patient is not pregnant on the first day of administration 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, and the patient avoids pregnancy from the first day of administration to at least 1 month after administration.

[0306] In some embodiments, the patient is a lactating individual and the patient avoids breastfeeding 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 to 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 a lactating individual and the patient avoids breastfeeding 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 to at least 2 days after administration. In some embodiments, the patient is a lactating individual, and the patient avoids breastfeeding 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 to at least 4 days after administration. In some embodiments, the patient is a lactating individual, and the patient avoids breastfeeding 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 to at least 7 days after administration. In some embodiments, the patient is a lactating individual, and the patient avoids breastfeeding 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 to at least 14 days after administration. In some embodiments, the patient is a lactating individual and the patient avoids breastfeeding from the first day of administration 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, to at least 1 month after administration.

[0307] In some embodiments, the patient is not a lactating individual.

[0308] In some embodiments, the method further comprises determining that the patient is not pregnant prior to administering 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. In some embodiments, the determination comprises classifying the patient as a patient of fertile potential or a patient of non-fertile potential, and administering a pregnancy test to the patient of fertile potential.

[0309] In some embodiments, the patient is a patient of childbearing potential and the patient has had at least one negative pregnancy test, which was performed at least one 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 a patient of childbearing potential and the patient has had at least two negative pregnancy tests, which were each performed at least one 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.

[0310] In some embodiments, the patient has had a first negative pregnancy test 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, at least 14 days, at least 3 weeks, or at least 4 weeks prior to administration. In some embodiments, the patient has had a second negative pregnancy test after the first pregnancy test and at least one day prior to administration. In some embodiments, the patient has had a first negative pregnancy test at least 7 days prior to administration, and has had a second negative pregnancy test after the first pregnancy test and at least one day prior to administration. In some embodiments, the patient has had a first negative pregnancy test at least 14 days prior to administration, and has had a second negative pregnancy after the first pregnancy test and at least one day prior to administration.

[0311] In some embodiments, the patient has had a second negative 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 the menstrual period immediately before administration. In some embodiments, the patient has had a second negative pregnancy test during the first 5 days of the menstrual period immediately before administration. In some embodiments, the patient has amenorrhea, and the patient has had a second negative 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 sexual intercourse. In some embodiments, the patient has amenorrhea, and the patient has had a second negative pregnancy test at least 11 days after the last unprotected sexual intercourse.

[0312] In some embodiments, each pregnancy test is independently a urine pregnancy test or a serum pregnancy test. In some embodiments, each pregnancy test independently has a sensitivity of at least 10mIU / mL, at least 15mIU / mL, at least 20mIU / mL, or at least 25mIU / mL. In some embodiments, each pregnancy test independently has a sensitivity of at least 25mIU / mL.

[0313] In some embodiments, the patient is of childbearing potential 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 to 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 of childbearing potential 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, to 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.

[0314] In some embodiments, the patient uses contraception from at least one week, at least two weeks, at least three weeks, at least four weeks, or at least one month before the first day of administration. In some embodiments, the patient uses contraception from at least 1 month before the first day of administration. In some embodiments, the patient uses contraception until at least one week, at least two weeks, at least three weeks, at least four weeks, or at least one month after administration. In some embodiments, the patient uses contraception until at least one month after administration.

[0315] In some embodiments, the patient uses at least one form of contraception selected from tubal ligation, partner vasectomy, intrauterine contraceptive device, contraceptive pills, and injectable, implantable, and insertable hormonal birth control products. In some embodiments, the patient uses at least one form of contraception selected from contraceptive diaphragms, latex condoms, and cervical caps. In some embodiments, contraceptive diaphragms, latex condoms, and cervical caps are used with spermicides.

[0316] 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 viral infection (such as severe COVID-19) (including hospitalization or death). Risk factors for progressing to hospitalization include, for example, age ≥ 60 years old, obesity (BMI ≥ 30), chronic lung disease, hypertension, cardiovascular or cerebrovascular disease, diabetes, immune disability, chronic mild or moderate kidney disease, chronic liver disease, current cancer, and sickle cell disease. In some embodiments, the age of high-risk patients is 50 years old or older. In some embodiments, the age of high-risk patients is 65 years old or older. In some embodiments, high-risk patients are immune disabled. In some embodiments, high-risk patients have a weak immune system. In some embodiments, high-risk patients are taking drugs that weaken the immune system. In some embodiments, high-risk patients suffer from obesity. In some embodiments, high-risk patients suffer from chronic obstructive pulmonary disease. In some embodiments, high-risk patients suffer from severe heart disease. In some embodiments, high-risk patients suffer from hypertension.

[0317] In some embodiments, the disclosure provides methods of treating or preventing a viral infection in a subject (eg, 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.

[0318] In some embodiments, the disclosure provides methods of treating a viral infection in a subject (eg, 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.

[0319] In one embodiment, the disclosure provides methods of inhibiting viral polymerase in a cell, the methods comprising contacting a cell infected with a virus with a compound described herein, thereby inhibiting the viral polymerase.

[0320] In one embodiment, the disclosure provides methods of inhibiting viral polymerase in a cell, the methods comprising contacting a cell infected with a virus with a compound described herein and at least one additional active therapeutic agent, thereby inhibiting the viral polymerase.

[0321] Also provided herein are uses of the compounds described herein for treating or preventing viral infections in subjects in need thereof. For example, provided herein are uses of the compounds described herein for treating viral infections in subjects in need thereof.

[0322] In some embodiments, the viral infection is a Paramyxoviridae virus infection. Therefore, in some embodiments, the present disclosure provides a method for treating a Paramyxoviridae infection in a subject (e.g., a human) in need thereof, the method comprising administering a compound as described herein to the subject. Paramyxoviridae viruses include, but are not limited to, Nipah virus, Hendra virus, measles, mumps, and parainfluenza virus.

[0323] In some embodiments, the viral infection is human parainfluenza virus, Nipah virus, Hendra virus, measles, or mumps infection.

[0324] In some embodiments, the viral infection is a Pneumoviridae viral infection. Thus, in some embodiments, the present disclosure provides a method of treating a Pneumoviridae viral infection in a person in need thereof, the method comprising administering to the person a compound as described herein. Pneumoviridae viruses include, but are not limited to, respiratory syncytial virus and human metapneumovirus. In some embodiments, the Pneumoviridae viral infection is a respiratory syncytial virus infection. In some embodiments, the Pneumoviridae viral infection is a human metapneumovirus infection.

[0325] In some embodiments, the disclosure provides a compound as 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.

[0326] In some embodiments, the present disclosure provides a method for treating RSV infection in a person in need thereof, the method comprising administering a compound as described herein to the person. In some embodiments, the person suffers from chronic respiratory syncytial virus infection. In some embodiments, the person is acutely infected with RSV.

[0327] In some embodiments, a method of inhibiting RSV replication is provided, wherein the method comprises administering a compound described herein to a human in need thereof, wherein the administration is by inhalation.

[0328] In some embodiments, the present disclosure provides methods for reducing viral load associated with RSV infection, wherein the method comprises administering a compound described herein to a human infected with RSV.

[0329] In some embodiments, the viral infection is a Picornaviridae virus infection. Therefore, in some embodiments, the present disclosure provides a method for treating a Picornaviridae virus infection in a person in need, the method comprising administering a compound as described herein to the person. Picornaviridae viruses are enteroviruses that cause heterogeneous infections including herpangina, aseptic meningitis, common cold-like syndrome (human rhinovirus infection), non-paralytic poliomyelitis-like syndrome, epidemic chest pain (acute, febrile, infectious diseases that usually occur in epidemics), hand, foot and mouth syndrome, pediatric and adult pancreatitis and severe myocarditis. In some embodiments, Picornaviridae virus infection is human rhinovirus infection (HRV). In some embodiments, Picornaviridae virus infection is HRV-A, HRV-B or HRV-C infection.

[0330] In some embodiments, the viral infection is selected from the group consisting of: coxsackie A virus infection, coxsackie A virus infection, enterovirus D68 infection, enterovirus B69 infection, enterovirus D70 infection, enterovirus A71 infection, and poliovirus infection.

[0331] In some embodiments, the present disclosure provides compounds for use in treating a Picornaviridae viral infection in a human in need thereof. In some embodiments, the Picornaviridae viral infection is a human rhinovirus infection.

[0332] In some embodiments, the viral infection is a Flaviviridae virus infection. Therefore, in some embodiments, the present disclosure provides a method for treating a Flaviviridae virus infection in a person in need thereof, the method comprising administering a compound as described herein to the person. Representative Flaviviridae viruses include, but are not limited to, dengue fever, yellow fever, West Nile virus, Zika virus, Japanese encephalitis virus, and hepatitis C virus (HCV). In some embodiments, the Flaviviridae virus infection is a dengue virus infection. In some embodiments, the Flaviviridae virus infection is a yellow fever virus infection. In some embodiments, the Flaviviridae virus infection is a West Nile virus infection. In some embodiments, the Flaviviridae virus infection is a Zika virus infection. In some embodiments, the Flaviviridae virus infection is a Japanese encephalitis virus infection. In some embodiments, the Flaviviridae virus infection is a hepatitis C virus infection.

[0333] In some embodiments, the Flaviviridae virus infection is a dengue virus infection, a yellow fever virus infection, a West Nile virus infection, tick-borne encephalitis, Kunjin Japanese encephalitis, St. Louis encephalitis, Murray Valley encephalitis, Omsk hemorrhagic fever, bovine viral diarrhea, a Zika virus infection, or an HCV infection.

[0334] In some embodiments, the present disclosure provides for the use of a compound as described herein for treating a Flaviviridae virus infection in a human in need thereof. In some embodiments, the Flaviviridae virus infection is a dengue virus infection. In some embodiments, the Flaviviridae virus infection is a yellow fever virus infection. In some embodiments, the Flaviviridae virus infection is a West Nile virus infection. In some embodiments, the Flaviviridae virus infection is a Zika virus infection. In some embodiments, the Flaviviridae virus infection is a hepatitis C virus infection.

[0335] In some embodiments, the viral infection is a Filoviridae virus infection. Therefore, in some embodiments, provided herein is a method for treating a Filoviridae virus infection in a person in need thereof, the method comprising administering a compound as described herein to the person. Representative Filoviridae viruses include, but are not limited to, Ebola virus (variants Zaire, Bundibugio, Sudan, Tai Forest or Reston) 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.

[0336] In some embodiments, the present disclosure provides a compound for use in treating a Filoviridae viral infection in a human in need thereof. In some embodiments, the Filoviridae viral infection is an Ebola virus infection. In some embodiments, the Filoviridae viral infection is a Marburg virus infection.

[0337] In some embodiments, the viral infection is a coronavirus infection. Therefore, in some embodiments, provided herein is a method for treating a coronavirus infection in a person in need, wherein the method includes administering a compound as described herein to the person. In some embodiments, coronavirus infection is severe acute respiratory syndrome (SARS-CoV) infection, Middle East respiratory syndrome (MERS) infection, SARS-CoV-2 infection, other human coronaviruses (229E, NL63, OC43, HKU1 or WIV1) infection, zoonotic coronavirus (PEDV or HKU CoV isolates, such as HKU3, HKU5 or HKU9) infection. In some embodiments, the viral infection is severe acute respiratory syndrome (SARS) infection. In some embodiments, the viral infection is Middle East respiratory syndrome (MERS) infection. In some embodiments, the viral infection is 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 with 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 with 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 with 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 with a viral polymerase selected from SARS CoV polymerase, MERS CoV polymerase, and SARS-CoV-2.

[0338] In some embodiments, the viral infection is caused by a variant of SARS-CoV-2, such as a B.1.1.7 variant (British variant), a B.1.351 variant (South African variant), a P.1 variant (Brazilian variant), a B.1.1.7 and E484K variant, a B.1.1.207 variant, a B.1.1.317 variant, a B.1.1.318 variant, a B.1.429 variant, a B.1.525 variant, or a P.3 variant. In some embodiments, the viral infection is caused by a B.1.1.7 variant of SARS-CoV-2. In some embodiments, the viral infection is caused by a B.1.351 variant of SARS-CoV-2. In some embodiments, the viral infection is caused by a P.1 variant of SARS-CoV-2.

[0339] In some embodiments, the disclosure provides compounds for treating coronavirus infections in people in need. In some embodiments, coronavirus infection is severe acute respiratory syndrome (SARS) infection, Middle East respiratory syndrome (MERS) infection, SARS-CoV-2 infection, other human coronaviruses (229E, NL63, OC43, HKU1 or WIV1) infection, and zoonotic coronavirus (PEDV or HKU CoV isolates, such as HKU3, HKU5 or HKU9) infection. In some embodiments, viral infection is severe acute respiratory syndrome (SARS) infection. In some embodiments, viral infection is Middle East respiratory syndrome (MERS) infection. In some embodiments, viral infection is SARS-CoV-2 infection (COVID19).

[0340] In some embodiments, the viral infection is an Arenaviridae viral infection. Thus, in some embodiments, the disclosure provides a method of treating an Arenaviridae viral infection in a human in need thereof, the method comprising administering to the human a compound described herein. In some embodiments, the Arenaviridae viral infection is a Lassa virus infection or a Junin virus infection.

[0341] In some embodiments, the disclosure provides compounds for use in treating an Arenaviridae viral infection in a human in need thereof. In some embodiments, the Arenaviridae viral infection is a Lassa virus infection or a Junin virus infection.

[0342] 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 virus A, influenza virus B, or influenza virus C infection.

[0343] As described more fully herein, the compounds described herein can be administered to individuals (e.g., humans) infected with a virus together with one or more additional therapeutic agents. Additional therapeutic agents can be administered to infected individuals simultaneously with the compounds described herein or before or after administration of the compounds described herein.

[0344] The compounds described herein may also be used in combination with one or more additional therapeutic agents. Thus, methods of treating viral infections in subjects in need thereof are also provided herein, wherein the methods comprise administering to the subject a compound disclosed herein and a therapeutically effective amount of one or more additional therapeutic or prophylactic agents.

[0345] In some embodiments, the additional therapeutic agent is 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, anti-mitotic inhibitors and combinations thereof.

[0346] In some embodiments, the additional therapeutic agent is a 5-substituted 2'-deoxyuridine analog. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of iodouridine, trifluridine, brivudine [BVDU], and combinations thereof.

[0347] 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), telmivudine, 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 a combination thereof.

[0348] In some embodiments, the additional therapeutic agent is a pyrophosphate analog. For example, in some embodiments, the additional therapeutic agent is foscarnet or phosphonoacetic acid. In some embodiments, the additional therapeutic agent is foscarnet.

[0349] 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.

[0350] In some embodiments, the additional therapeutic agent is a non-nucleoside reverse transcriptase inhibitor. In some embodiments, the antiviral agent is selected from the group consisting of: nevirapine, delavirdine, efavirenz, etravirine, rilpivirine, and combinations thereof.

[0351] 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 the group consisting of: voxiprevir, anaprevir, boceprevir, paritaprevir, simeprevir, telaprevir, vanirepvir, gezoprevir, ribavirin, danoprevir, fadaprevir, vedoprevir, sovaprevir, deprevir, naraprevir, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of: voxiprevir, anaprevir, boceprevir, paritaprevir, simeprevir, telaprevir, vanirepvir, gezoprevir, and combinations thereof.

[0352] 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: bicagevir, raltegravir, dolutegravir, cabotegravir, elvitegravir, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from: bicagevir, dolutegravir, cabotegravir, and combinations thereof. In some embodiments, the additional therapeutic agent is bicagevir.

[0353] In some embodiments, the additional therapeutic agent is an entry inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of docosanol, enfuvirtide, maraviroc, ibalizumab, fotexavir, lelizumab, ibalizumab, fotexavir, lelizumab, palivizumab, respiratory syncytial virus immune globulin for intravenous administration [RSV-IGIV], varicella zoster immune globulin [VariZIG], varicella zoster immune globulin [VZIG]) and combinations thereof.

[0354] In some embodiments, the additional therapeutic agent is an acyclovir analog. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of acyclovir, ganciclovir, valacyclovir (also known as valacyclovir), valganciclovir, penciclovir, famciclovir, and combinations thereof.

[0355] 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: 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, adefovir dipivoxil, tenofovir, TDF and combinations thereof.

[0356] 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 protease 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: daclatasvir, ledipasvir, velpatasvir, ombitasvir, elbasvir, sofosbuvir, dasabuvir, ribavirin, anaprevir, simeprevir, paritaprevir, ritonavir, elbasvir, gezoprevir, 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.

[0357] 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 (uminovir), baloxavir mapositate, oseltamivir, peramivir, ingavirin, laninamivir octanoate, zanamivir, favipiravir, ribavirin and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of amantadine, rimantadine, zanamivir, oseltamivir, peramivir, laninamivir octanoate, ribavirin, favipiravir, and combinations thereof.

[0358] In some embodiments, the additional therapeutic agent is interferon. In some embodiments, the additional therapeutic agent is selected from: interferon alfacon 1, interferon α1b, interferon α2a, interferon α2b, pegylated interferon alfacon 1, pegylated interferon α1b, pegylated interferon α2a (PegIFNα-2a) and PegIFNα-2b. In some embodiments, the additional therapeutic agent is selected from: interferon alfacon 1, interferon α1b, interferon α2a, interferon α2b, pegylated interferon α2a (PegIFNα-2a) and PegIFNα-2b. In some embodiments, the additional therapeutic agent is selected from: interferon alfacon 1, pegylated interferon α2a (PegIFNα-2a), PegIFNα-2b and ribavirin. In some embodiments, the additional therapeutic agent is pegylated interferon alpha-2a, pegylated interferon alpha-2b, or a combination thereof.

[0359] 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 an anti-mitotic inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from: fomivirsen, podafilox, imiquimod, pheniramine, and combinations thereof.

[0360] In some embodiments, the additional therapeutic agent is selected from the group consisting of: besifovir, nitazoxanide, REGN2222, doravirine, sofosbuvir, velpatasvir, daclatasvir, anaprevir, becabuvir, FV100, and letermovir, and combinations thereof.

[0361] In some embodiments, the additional therapeutic agent is an agent used to treat RSV. For example, in some embodiments, the antiviral agent is ribavirin, ALS-8112, or prutovir. For example, in some embodiments, the antiviral agent is ALS-8112 or prutovir.

[0362] In some embodiments, the additional therapeutic agent is an agent for treating picornaviruses. 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 lupintravir.

[0363] In some embodiments, the additional therapeutic agent is an agent used to treat malaria. In some embodiments, the additional therapeutic agent is chloroquine.

[0364] In some embodiments, the additional therapeutic agent is selected from the group consisting of hydroxychloroquine, chloroquine, artemether, lumefantrine, atovaquone, proguanil, tafenoquine, pyronaridine, artesunate, dihydroartemisinin, piperaquine, artesunate, amodiaquine, pyronaridine, artesunate, halofantrine, quinine sulfate, mefloquine, solithromycin, pyrimethamine, MMV-390048, ferrocenechloroquine, artemisinin mesylate, ganaplacide, DSM-265, sipagamine, artemether, and combinations thereof.

[0365] In some embodiments, the additional therapeutic agent is an agent for treating coronavirus. In some embodiments, the additional therapeutic agent is selected from: IFX-1, FM-201, CYNK-001, DPP4-Fc, ranpirnase, nafamostat, LB-2, AM-1, antiviral porin, and combinations thereof.

[0366] In some embodiments, the additional therapeutic agent is an agent used to treat Ebola virus. For example, in some embodiments, the additional therapeutic agent is selected from: ribavirin, palivizumab, motavizumab, RSV-IGIV 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-dimethylquinolinol[8,7-h]quinolone-1,7-diamine), JK-05, TKM-Ebola, ZMapp, rNAPc2, VRC-EBOADC076-00-VP, OS-2966, MVA-BN filo, bromcidofovir, Ebola vaccine based on Vaxart adenovirus vector 5, 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.

[0367] In some embodiments, the additional therapeutic agent is a medicament for treating HCV. In some embodiments, the additional therapeutic agent is an HCV polymerase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from: sofosbuvir, GS-6620, PSI-938, ribavirin, tergobuvir, remdabuvir, MK-0608 and combinations thereof. In some embodiments, the additional therapeutic agent is an HCV protease inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from: such as GS-9256, vedoprevir, voxiprevir and combinations thereof.

[0368] In some embodiments, the additional therapeutic agent is an NS5A inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of ledipasvir, velpatasvir, and combinations thereof.

[0369] 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, but are not limited to, α-hydroxytropolone, amidosvir, antroquinol, β-hydroxycytidine, ARB-199, CCC-0975, ccc-R08, efcitabine, ezetimibe, cyclosporin A, gentioside (gentiopicroside), HH-003, hepalatide, JNJ-56136379, nitazoxanide, birenapa, NJK14047, NOV-205 (molixan, BAM-205), oligonucleotides, mivotilide, feron, GST-HG-131, levamisole, Ka Shu Ning, alloferon, WS-007, Y-101 (Ti Fen Tai), rSIFN-co, PEG-IIFNm, KW-3, BP-Inter-014, caryophyllin, HepB-nRNA, cTP-5(rTP-5), HSK-II-2, HEISCO-106-1, HEISCO-106, Hepbarna, IBPB-006IA, Hepuyinfen, DasKloster 0014-01, ISA-204, Jiangantai (Ganxikang), MIV-210, OB-AI-004, PF-06, picroside, DasKloster-0039, hepulantai, IMB-2613, TCM-800B, reduced glutathione, RO-6864018, RG-7834, QL-007, sofosbuvir, ledipasvir, UB-551 and ZH-2N, and US20150210682 (Roche), US2016 / 0122344 (Roche), WO2015173164, WO2016023 877, US2015252057A (Roche), WO16128335A1 (Roche), WO16120186A1 (Roche), US2016237090A (Roche), WO16107833A1 (Roche), WO16107832A1 (Roche), US2016176899A (Roche), WO16102438A1 (Roche), WO16012470A1 (Roche), US2016220586A (Roche) and US2015031687A (Roche). In some embodiments, the additional therapeutic agent is an HBV polymerase inhibitor. Examples of HBV DNA polymerase inhibitors include, but are not limited to, adefovir. Emtricitabine Tenofovir Disoproxil Fumarate Tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil fumarate, tenofovir disoproxil fumarate, tenofovir octadecyloxyethyl ester, CMX-157, tenofovir exalidex, besifovir, entecavir Entecavir Maleate, Telbivudine Feloxivir, pradefovir, clavudine, ribavirin, lamivudine Phosphorus azide, famciclovir, fusolin, metakavir, SNC-019754, FMCA, AGX-1009, AR-II-04-26, HIP-1302, tenofovir disoproxil aspartate, tenofovir disoproxil orotate, and HS-10234. In some embodiments, the additional therapeutic agent is an HBV capsid inhibitor.

[0370] In some embodiments, the additional therapeutic agent is an agent used to treat HIV. In some embodiments, the additional therapeutic agent is selected from HIV protease inhibitors, HIV integrase inhibitors, entry inhibitors, HIV nucleoside reverse transcriptase inhibitors, HIV non-nucleoside reverse transcriptase inhibitors, acyclic nucleoside phosphonate analogs, and combinations thereof.

[0371] In some embodiments, the additional therapeutic agent is selected from: HIV protease inhibitors, HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitors, HIV nucleoside or nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, immunomodulators, immunotherapeutics, antibody-drug conjugates, gene modifiers, gene editing agents (such as CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs) and cell therapies (such as chimeric antigen receptor T cells, CAR-T and engineered T cell receptors, TCR-T, autologous T cell therapy).

[0372] In some embodiments, the additional therapeutic agent is selected from: combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversal agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies and bispecific antibodies and "antibody-like" therapeutic proteins, and combinations thereof.

[0373] In some embodiments, the additional therapeutic agent is an HIV combination drug. Examples of HIV combination drugs include, but are not limited to (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); (bicagvir, emtricitabine, and tenofovir alafenamide); ( rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); (tenofovir alafenamide and emtricitabine); (tenofovir alafenamide, emtricitabine, and rilpivirine); (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); (darunavir, tenofovir alafenamide hemifumarate, emtricitabine, and cobicistat); SYMFI TM (efavirenz, lamivudine, and tenofovir disoproxil fumarate); CIMDU TM (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; (zidovudine and lamivudine; AZT+3TC); ( abacavir sulfate and lamivudine; ABC+3TC); ( lopinavir and ritonavir); (dolutegravir, abacavir, and lamivudine); (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 fumarate; dapivirine + levonorgestrel, dolutegravir + lamivudine, Dolutegravir + emtricitabine + tenofovir alafenamide, efavirenz + 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.

[0374] 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 the group consisting of amprenavir, atazanavir, brecanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir, saquinavir mesylate, tipranavir, DG-17, TMB-657 (PPL-100), T-169, BL-008, MK-8122, TMB-607, TMC-310911, and combinations thereof.

[0375] In some embodiments, the additional therapeutic agent is an HIV integrase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of: raltegravir, elvitegravir, dolutegravir, abacavir, lamivudine, bicagevir, and combinations thereof. In some embodiments, the additional therapeutic agent is bicagevir. In some embodiments, the additional therapeutic agent is selected from the group consisting of: bicagevir, elvitegravir, curcumin, a derivative of curcumin, chicoric acid, a derivative of chicoric acid, 3,5-dicaffeoylquinic acid, a derivative of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, a derivative of aurintricarboxylic acid, caffeic acid phenethyl ester, a derivative of caffeic acid phenethyl ester, a tyrosine kinase inhibitor, a derivative of a tyrosine kinase inhibitor, a quercetin, a derivative of quercetin, raltegravir, dolutegravir, JTK-351, bicagevir, AVX-15567, BMS- 986197, cabotegravir (long-acting injection), diketoquinoline-4-1 derivatives, integrase-LEDGF inhibitors, ledgins, M-522, M-532, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, distilbenesulphonic acid, T-169, VM-3500, cabotegravir and combinations thereof.

[0376] 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. Other examples of HIV entry inhibitors include, but are not limited to, cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 connection inhibitors, DS-003 (BMS-599793), gp120 inhibitors and CXCR4 inhibitors. Examples of CCR5 inhibitors include apraviroc, vicoviroc, maraviroc, cenicriviroc, lelimonab (PRO-140), adatasvir (RAP-101), nifeviroc (TD-0232), anti-GP120 / CD4 or CCR5 bispecific antibodies, B-07, MB-66, polypeptide C25P, TD-0680 and vMIP (Haimipu). Examples of CXCR4 inhibitors include plerixafor, ALT-1188, N15 peptide and vMIP (Haimipu).

[0377] 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.

[0378] In some embodiments, the additional therapeutic agent is an HIV nucleoside or nucleotide reverse transcriptase inhibitor. For example, the additional therapeutic agent is selected from: adefovir, adefovir dipivoxil, azvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, and (didanosine, ddl), abacavir, abacavir sulfate, alovudine, aritibine, sinavudine, didanosine, efavirenz, festinavir, fosalvudine tidoxil, CMX-157, dapivirine, doravirine, etravirine, OCR-5753, tenofovir disoproxil orotate, fosalvudine tidoxil, islatravir, lamivudine, phosphazid, stavudine, zalcitabine, zidovudine, rovafavir-etafovir amide (GS-9131), GS-9148, MK-8504, MK-8591, MK-858, VM-2500, KP-1461, and combinations thereof.

[0379] In some embodiments, the additional therapeutic agent is a HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitor. For example, the additional agent is selected from: dapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz, etravirine, lentinan, MK-8583, nevirapine, rilpivirine, TMC-278LA, ACC-007, AIC-292, KM-023, PC-1005, efavirenz rilp (VM-1500) and combinations thereof.

[0380] In some embodiments, the additional therapeutic agent is selected from (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); ( rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); (tenofovir alafenamide and emtricitabine); (tenofovir alafenamide, emtricitabine, and rilpivirine); (tenofovir alafenamide, emtricitabine, cobicistat and elvitegravir); adefovir; adefovir disoproxil; cobicistat; emtricitabine; tenofovir; tenofovir disoproxil; tenofovir disoproxil fumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate; (dulutegravir, abacavir, and lamivudine); dolutegravir, abacavir sulfate, and lamivudine; raltegravir; raltegravir and lamivudine; maraviroc; enfuvirtide; ( lopinavir and ritonavir); (zidovudine and lamivudine; AZT+3TC); ( abacavir sulfate and lamivudine; ABC+3TC); (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; platinum; fosamprenavir; fosamprenavir calcium efavirenz; etravirine; nelfinavir; nelfinavir mesylate; interferon; didanosine; stavudine; indinavir; indinavir sulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir; delavirdine; delavirdine mesylate; Radha-108 (receptor alcohol); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovir disoproxil fumarate; phosphinothricin; lamivudine, nevirapine, and zidovudine; abacavir; and abacavir sulfate.

[0381] In some embodiments, the additional therapeutic agent is selected from the group consisting of colistin, valrubicin, icatibant, bepotastine, epirubicin, epoprosetnol, vapreotide, aprepitant, caspofungin, perphenazine, atazanavir, efavirenz, ritonavir, acyclovir, ganciclovir, penciclovir, prulifloxacin, bicarbvir, nelfinavir, tegobuvi, nelfinavir, praziquantel, pitavastatin, perampanel, eszopiclone, and zopiclone.

[0382] In some embodiments, the additional therapeutic agent is Bruton's tyrosine kinase (BTK, AGMX1, AT, ATK, BPK, IGHD3, IMD1, PSCTK1, XLA; NCBI Gene ID: 695). For example, in some embodiments, the additional therapeutic agent is selected from: (S)-6-amino-9-(1-(but-2-ynyl)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, sepretinib (CC-292), TAK-020, vecabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, TAS-5315, AZD6738, acalabrutinib, danvastatin, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of: tilarutinib, ibrutinib, acalabrutinib, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of: tilarutinib, ibrutinib, and combinations thereof. In some embodiments, the additional therapeutic agent is the tyrosine kinase inhibitor A9 (A9).

[0383] 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 (RasGTP), RT11, MRTX-849 (G12C), and K-Ras (G12D) selective inhibitory peptides, including KRpep-2 (Ac-RRCPLYISYDPVCRR-NH2), KRpep-2d (Ac-RRRRCPLYISYDPVCRRRR-NH2) and combinations thereof.

[0384] 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.

[0385] In some embodiments, the additional therapeutic agent is a vaccine. For example, in some embodiments, the additional therapeutic agent is a DNA vaccine, an RNA vaccine, a live attenuated vaccine, a therapeutic vaccine, a preventive vaccine, a protein-based vaccine, or a combination thereof. In some embodiments, the additional therapeutic agent is mRNA-1273. In some embodiments, the additional therapeutic agent is INO-4800 or INO-4700. In some embodiments, the additional therapeutic agent is a live attenuated RSV vaccine MEDI-559, a human monoclonal antibody REGN2222 against RSV, palivizumab, respiratory syncytial virus immunoglobulin, intravenous respiratory syncytial virus immunoglobulin [RSV-IGIV], and a combination thereof. In some embodiments, the additional therapeutic agent is an HBV vaccine, such as pediarix, engerix-B, and recombivax HB. In some embodiments, the additional therapeutic agent is a VZV vaccine, such as zostavax and varivax. In some embodiments, the additional therapeutic agent is an HPV vaccine, such as cervarix, gardasil9, and gardasil. In some embodiments, the additional therapeutic agent is an influenza virus vaccine. For example, (i) influenza A monovalent vaccine (e.g., influenza A [H5N1] virus monovalent vaccine and influenza A [H1N1] 2009 virus monovalent vaccine), (ii) influenza A and B virus trivalent vaccine (e.g., Afluria, Agriflu, Fluad, Fluarix, Flublok, Flucelvax, FluLaval, Fluvirin and Fluzone), and (iii) influenza A and B virus quadrivalent vaccine (FluMist, Fluarix, Fluzone and FluLaval). In some embodiments, the additional therapeutic agent is a human adenovirus vaccine (e.g., adenovirus type 4 and type 7 vaccine, live, oral). In some embodiments, the additional therapeutic agent is a rotavirus vaccine (e.g., Rotarix for rotavirus serotypes G1, G3, G4 or G9 and RotaTeq for rotavirus serotypes G1, G2, G3 or G4). In some embodiments, the additional therapeutic agent is a hepatitis A virus vaccine (e.g., Havrix and Vaqta). In some embodiments, the additional therapeutic agent is a polio virus vaccine (e.g., Kinrix, Quadracel, and Ipol). In some embodiments, the additional therapeutic agent is a yellow fever virus vaccine (e.g., YF-Vax). In some embodiments, the additional therapeutic agent is a Japanese encephalitis virus vaccine (e.g., Ixiaro and JE-Vax). In some embodiments, the additional therapeutic agent is a measles vaccine (e.g., MMR II and ProQuad). In some embodiments, the additional therapeutic agent is a mumps vaccine (e.g., MMR II and ProQuad).In some embodiments, the additional therapeutic agent is a rubella vaccine (e.g., MMR II and ProQuad). In some embodiments, the additional therapeutic agent is a 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.

[0386] In some embodiments, the additional therapeutic agent is an antibody, such as a monoclonal antibody. For example, the additional therapeutic agent is an anti-2019-nCov antibody selected from the following: Regeneron antibody, Wuxi antibody, Vir Biotechnology antibody, antibody targeting SARS-CoV-2 spike protein, antibody that can neutralize SARS-CoV-2 (SARS-CoV-2 neutralizing antibody), and combinations thereof. In some embodiments, the additional therapeutic agent is the anti-SARS-CoV antibody CR-3022. In some embodiments, the additional therapeutic agent is an aPD-1 antibody.

[0387] In some embodiments, the additional therapeutic agent is an injection of a protein derived from a recombinant cytokine gene.

[0388] 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, pimaudid, and combinations thereof.

[0389] In some embodiments, the additional therapeutic agent is selected from the group consisting of lopinavir, ritonavir, interferon alpha-2b, ritonavir, arbidol, hydroxychloroquine, darunavir and cobicistat, arbidol hydrochloride, oseltamivir, litonavir, emtricitabine, tenofovir alafenamide fumarate, baloxavir mapositol, ruxolitinib, and combinations thereof.

[0390] In some embodiments, the additional therapeutic agent is selected from: 6'-fluorinated manrene analogs, acyclovir fleximer analogs, disulfiram, thiopurine analogs, ASC09F, GC376, GC813, phenylisoserine derivatives, neuraminidase inhibitor analogs, pyrithione derivatives, bananin and 5-hydroxychromone derivatives, SSYA10-001, griffithsin, HR2P-M1, HR2P-M2, P21S10, dihydrotanshinone E-64-C and E-64-D, OC43-HR2P, MERS-5 HB, 229E-HR1P, 229E-HR2P, resveratrol, 1-thiophene-4-azaspiro[4.5]decan-3-one derivatives, gemcitabine hydrochloride, loperamide, recombinant interferon, cyclosporine A, alisporivir, imatinib mesylate, dasatinib, selumetinib, trametinib, rapamycin, sacatinib, chlorpromazine, triflupromazine, fluphenazine, thiethylperazine, promethazine, cyclophilin inhibitors, K11777, camostat, k22, teicoplanin derivatives, benzoheterocyclic amine derivative N30, mycophenolic acid, silvestrol and combinations thereof.

[0391] 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 2019-nCoV virus antibody.

[0392] The composition of the present invention is also used in combination with other active ingredients. For the treatment of 2019-nCoV virus infection, preferably, other active therapeutic agents have activity against coronavirus infection, such as activity against 2019-nCoV virus infection. The compounds and compositions of the present invention are also intended to be used for general care provided to patients with 2019-nCoV virus infection, including parenteral fluids (including glucose saline and Ringer's lactate) and nutrients, antibiotics (including metronidazole and cephalosporin antibiotics, such as ceftriaxone and cefuroxime) and / or antifungal prophylaxis, fever and pain medications, antiemetics (such as metoclopramide) and / or antidiarrheals, vitamins and mineral supplements (including vitamin K and zinc sulfate), anti-inflammatory agents (such as ibuprofen or steroids), corticosteroids such as methylprednisolone, immunomodulatory drugs (e.g., dry Interferon), other small molecules or biologics antiviral agents targeting 2019-nCoV (such as, but not limited to, lopinavir / ritonavir, EIDD-1931, favipiravir, ribavirin, neutralizing antibodies, etc.), vaccines, pain medications, and medications for other common diseases in patient populations, such as antimalarials (including artemether and artesunate-lumefantrine combination therapy), typhoid vaccines (including quinolone antibiotics such as ciprofloxacin, macrolide antibiotics such as azithromycin, cephalosporin antibiotics such as ceftriaxone, or aminopenicillins such as ampicillin) or shigellosis vaccines. In some embodiments, the additional therapeutic agent is dihydroartemisinin / piperaquine. In some embodiments, the additional therapeutic agent is EIDD-2801 (MH-4482, monoupivir).

[0393] In some embodiments, the additional therapeutic agent is an immunomodulator. Examples of immune-based therapies include toll-like receptor modulators, such as tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12, and tlr13; programmed cell death protein 1 (PD-1) modulators; programmed death ligand 1 (PD-L1) modulators; IL-15 modulators; DermaVir; interleukin-7; plaquenil (hydroxychloroquine); prilocaine (aldesleukin, IL-2); interferon alpha; interferon alpha-2b; interferon alpha-n3; pegylated interferon alpha; interferon gamma; hydroxyurea; mycophenolate mofetil (MPA) and its ester derivatives In some embodiments, the additional therapeutic agent is fingolimod, leflunomide, or a combination thereof. In some embodiments, the additional therapeutic agent is thalidomide.

[0394] In some embodiments, the additional therapeutic agent is an IL-6 inhibitor, such as tocilizumab, salilumab, or a combination thereof.

[0395] 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.

[0396] In some embodiments, the additional therapeutic agent is a JAK inhibitor, for example, the additional therapeutic agent is baricitinib, filgotinib, baricitinib, or a combination thereof.

[0397] In some embodiments, the additional therapeutic agent is an inflammatory inhibitor, such as pirfenidone.

[0398] 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 pneumoniae), a fluoroquinolone (e.g., ciprofloxacin and levofloxacin), a tetracycline (e.g., doxycycline and tetracycline), or a combination thereof.

[0399] In some embodiments, the compounds described herein are used in combination with standard of care for pneumonia (see, e.g., Pediatric Community Pneumonia Guidelines, CID 2011:53 (Oct. 1)). Treatment of pneumonia generally involves curing the infection and preventing complications. The specific treatment will depend on several factors, including the type and severity of pneumonia, the age and overall health of the individual. Options include: (i) antibiotics, (ii) cough medicines, and (iii) antipyretics / pain relievers (e.g., aspirin, ibuprofen (Advil, Motrin IB, etc.) and acetaminophen (Tylenol, etc.)). In some embodiments, the additional therapeutic agent is a bromhexine cough suppressant.

[0400] In some embodiments, the compounds described herein are used in combination with immunoglobulins from cured COVID-19 patients. In some embodiments, the compounds described herein are used in combination with plasma infusions. In some embodiments, the compounds described herein are used in combination with stem cells.

[0401] In some embodiments, the additional therapeutic agent is a TLR agonist. Examples of TLR agonists include, but are not limited to, visamod (GS-9620), GS-986, IR-103, lefimod, tilsotolimod, rintatlimod, DSP-0509, AL-034, G-100, cobitolimod, AST-008, motolimod, GSK-1795091, GSK-2245035, VTX-1463, GS-9688, LHC-165, BDB-001, RG-7854, telratolimod, and RO-7020531.

[0402] In some embodiments, the additional therapeutic agent is selected from the group consisting of bortezomib, flurazepam, ponatinib, sorafenib, paramethasone, clocortolone, flucloxacillin, sertindole, clevidipine, atorvastatin, cinoxazepam, clofazimine, fosaprepitant, and combinations thereof.

[0403] In some embodiments, the additional therapeutic agent is carlimycin, suramin, triazolin, dipyridamole, bevacizumab, mepozumab, GD31 (Rhizobium), NLRP inflammasome inhibitor or alpha-ketoamine. In some embodiments, the additional therapeutic agent is recombinant human angiotensin converting enzyme 2 (rhACE2). In some embodiments, the additional therapeutic agent is viral macrophage inflammatory protein (vMIP).

[0404] In some embodiments, the additional therapeutic agent is an antiviral porin 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. Additional examples of additional therapeutic agents include those described in WO-2004112687, WO-2006135978, WO-2018145148, and WO-2009018609.

[0405] In some embodiments, the additional therapeutic or prophylactic agent is monupirvir, oseltamivir, nirmatrelvir, or ritonavir. In some embodiments, the additional therapeutic or prophylactic agent is ritonavir or cobicistat.

[0406] In some embodiments, the additional therapeutic agent is a 2,5-oligoadenylate synthetase stimulator, a 5-HT 2a receptor antagonist, a 5-lipoxygenase inhibitor, an ABL family tyrosine kinase inhibitor, an Abl tyrosine kinase inhibitor, an acetaldehyde dehydrogenase inhibitor, an acetyl-CoA carboxylase inhibitor, an actin antagonist, an actin modulator, an activity-dependent neuroprotectant modulator, an adenosine A3 receptor agonist, an adrenergic receptor antagonist, an adrenomedullin ligand, an adrenomedullin ligand inhibitor, an advanced glycosylation product receptor antagonist, an advanced glycosylation product receptor modulator, an AKT protein kinase inhibitor, a stimulator of alanine proline-rich secretory protein, an aldose reductase inhibitor, an alkaline phosphatase stimulator, an alpha 2 adrenergic receptor antagonist, an alpha 2B adrenergic receptor agonist, an AMP-activated protein kinase stimulator, an AMPA receptor modulator, an amyloid deposition inhibitor, an androgen receptor antagonist, an angiotensin II AT-1 receptor antagonist, an angiotensin II AT-2 receptor agonists, angiotensin II receptor modulators, angiotensin converting enzyme 2 inhibitors, angiotensin converting enzyme 2 modulators, angiotensin converting enzyme 2 stimulators, angiotensin receptor modulators, annexin A5 stimulators, Anoctamin 1 inhibitors, anticoagulants, antihistamines, antihypoxic drugs, antithrombotic drugs, AP1 transcription factor regulators, apelin receptor agonists, APOA1 gene stimulators, apolipoprotein A1 agonists, apolipoprotein B antagonists, apolipoprotein B regulators, apolipoprotein C3 antagonists, aryl hydrocarbon receptor agonists, aryl hydrocarbon receptor antagonists, ATP-binding cassette transporter B5 regulators, Axl tyrosine kinase receptor inhibitors, bactericidal permeability protein inhibitors, Basigin inhibitors, Basigin regulators, BCL2 gene inhibitors, BCL2L11 gene stimulators, Bcr protein inhibitors, β1 adrenergic regulators, β2 adrenergic agonists, β-adrenergic agonists, β-arrestin stimulators, blood coagulation regulators, BMP10 gene inhibitors, BMP15 gene inhibitors agents, bone morphogenetic protein-10 ligand inhibitors, bone morphogenetic protein-15 ligand inhibitors, bradykinin B2 receptor antagonists, brain-derived neurotrophic factor ligands, bromodomain-containing protein 2 inhibitors, bromodomain-containing protein 4 inhibitors, Btk tyrosine kinase inhibitors, C-reactive protein modulators, Ca2+ release-activated Ca2+ channel 1 inhibitors, cadherin-5 modulators, calcium-activated chloride channel inhibitors, calcium channel modulators, calpain-I inhibitors, calpain-II inhibitors, calpain-IX inhibitors, cannabinoid CB2 receptor agonists, cannabinoid receptor modulators, casein kinase II inhibitors, CASP8-FADD-like regulator inhibitors, caspase inhibitors, catalase stimulators, CCL26 gene inhibitors, CCR2 chemokine antagonists,CCR5 chemokine antagonist, CD11a agonist, CD122 agonist, CD3 antagonist, CD4 agonist, CD40 ligand, CD40 ligand modulator, CD40 ligand receptor agonist, CD40 ligand receptor modulator, CD49d agonist, CD70 antigen modulator, CD73 agonist, CD73 antagonist, CD95 antagonist, CFTR inhibitor, CGRP receptor antagonist, chemokine receptor-like 1 agonist, chloride channel inhibitor, chloride channel modulator, cholera toxin subunit B inhibitor, cholesterol ester transfer protein inhibitor, glue Pro-modulators, complement C1s subcomponent inhibitors, complement C3 inhibitors, complement C5 factor inhibitors, complement C5a factor inhibitors, complement factor H stimulators, complement cascade inhibitors, complement factor C2 inhibitors, complement factor D inhibitors, connective tissue growth factor ligand inhibitors, coronavirus nucleoprotein modulators, coronavirus small envelope protein modulators, coronavirus spike glycoprotein inhibitors, coronavirus spike glycoprotein modulators, COVID19 envelope small membrane protein modulators, COVID19 non-structural protein 8 modulators, COVID19 nucleoprotein modulators, COVID19 protein COVID19 replicase polyprotein 1a inhibitors, COVID19 replicase polyprotein 1a modulators, COVID19 replicase polyprotein 1ab inhibitors, COVID19 replicase polyprotein 1ab modulators, COVID19 spike glycoprotein inhibitors, COVID19 spike glycoprotein modulators, COVID19 structural glycoprotein modulators, CRF-2 receptor agonists, CSF-1 agonists, CSF-1 antagonists, CX3CR1 chemokine antagonists, CXC10 chemokine ligand inhibitors, CXC5 chemokine ligand inhibitors Preparations, CXCL1 gene modulators, CXCL2 gene modulators, CXCL3 gene modulators, CXCR1 chemokine antagonists, CXCR2 chemokine antagonists, CXCR4 chemokine antagonists, cyclin D1 inhibitors, cyclin E inhibitors, cyclin-dependent kinase-1 inhibitors, cyclin-dependent kinase-2 inhibitors, cyclin-dependent kinase-5 inhibitors, cyclin-dependent kinase-7 inhibitors, cyclin-dependent kinase-9 inhibitors, cyclooxygenase 2 inhibitors, cyclooxygenase inhibitors, cyclophilin inhibitors, cysteine ​​protease inhibitors, cytochrome P450 3A4 inhibitors, cytokine receptor antagonists, cytotoxic T-lymphocyte protein gene regulators, cytotoxic T-lymphocyte protein-4 inhibitors, cytotoxic T-lymphocyte protein-4 stimulators, DDX3 inhibitors, dehydrogenase inhibitors, dehydrogenase-1 regulators, deoxyribonuclease I stimulators, deoxyribonuclease gamma stimulators, deoxyribonuclease stimulators, deoxyribonuclease delta 4 desaturase inhibitors, dihydroorotate dehydrogenase inhibitors, dipeptidyl peptidase I inhibitors, dipeptidyl peptidase III inhibitors, diuretics,DNA binding protein inhibitors, DNA methyltransferase inhibitors, dopamine transporter inhibitors, E-selectin antagonists, Ecto NOX disulfide thiol exchanger 2 inhibitors, EGFR gene inhibitors, elongation factor 1α2 modulators, endosomal modulators, endoribonuclease DICER modulators, endothelin ET-A receptor antagonists, epidermal growth factor receptor antagonists, E-selectin antagonists, estrogen receptor beta agonists, estrogen receptor modulators, eukaryotic initiation factor 4A-I inhibitors, exo-alpha sialidase modulators, exportin 1 inhibitors, factor Ia modulators, factor IIa modulators, factor VII antagonists, factor Xa antagonists, factor XI a 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 modulators, galectin-3 inhibitors, γ-secretase inhibitors, GDF agonists, gelsolin stimulators, glial cell neurotrophic factor ligands, glucocorticoid receptor agonists, glutathione peroxidase stimulators, GM-CSF ligand inhibitors, GM-CSF receptor agonists, GM-CSF receptor modulators, Griffithsin modulators, growth regulatory protein α ligand inhibitors, Grp78 calcium binding protein inhibitors, heat shock protein HSP90α inhibitors, heat shock protein HSP90β inhibitors, heat shock protein inhibitors, heat shock protein stimulators , hemagglutinin regulators, hemoglobin regulators, hemolysin α inhibitors, heparanase inhibitors, heparin agonists, hepatitis B structural protein inhibitors, hepatitis C virus NS5B polymerase inhibitors, HIF prolyl hydroxylase inhibitors, HIF prolyl hydroxylase-2 inhibitors, high mobility group histone B1 inhibitors, histamine H1 receptor antagonists, histamine H2 receptor antagonists, histone deacetylase-6 inhibitors, histone inhibitors, HIV protease inhibitors, HIV-1gp120 protein inhibitors, HIV-1 protease inhibitors, HIV-1 reverse transcriptase inhibitors, HLA Class I antigen modulators, HLA class II antigen modulators, host cytokine modulators, Hsp 90 inhibitors, human papillomavirus E6 protein modulators, human papillomavirus E7 protein modulators, hypoxia-inducible factor suppressor gene inhibitors, hypoxia-inducible factor-2α modulators, I-κB kinase inhibitors, I-κB kinase modulators, ICAM-1 stimulators, IgG receptor FcRn large subunit p51 modulators, IL-12 receptor antagonists, IL-15 receptor agonists,IL-15 receptor modulator, 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 modulator, IL-7 receptor agonist, IL-8 receptor antagonist, IL12 gene stimulator, IL8 gene modulator, immunoglobulin G modulator, immunoglobulin G1 agonist, immunoglobulin G1 modulator, immunoglobulin agonist, immunoglobulin gamma Fc receptor I modulator, immunoglobulin kappa modulator, inosine monophosphate dehydrogenase inhibitor, insulin sensitizer, integrin agonist, integrin alpha-4 / beta-7 antagonist, integrin alpha-V / beta-1 antagonist, integrin alpha-V / beta-6 antagonist, interferon agonist, interferon alpha 14 ligand, interferon alpha 2 ligand , interferon alpha 2 ligand modulators, interferon alpha ligands, interferon alpha ligand inhibitors, interferon alpha ligand modulators, interferon beta ligands, interferon gamma ligand inhibitors, interferon gamma receptor agonists, interferon gamma receptor antagonists, interferon receptor modulators, interferon type I receptor agonists, interleukin 17A ligand inhibitors, interleukin 17F ligand inhibitors, interleukin 18 ligand inhibitors, interleukin 22 ligands, interleukin-1β ligand inhibitors, interleukin-1β ligand modulators, interleukin-1 ligand inhibitors, interleukin-2 ligands, interleukin-29 ligands, interleukin-6 ligand inhibitors, interleukin-7 ligands, interleukin-8 ligand inhibitors, IRAK-4 protein kinase inhibitors, JAK tyrosine kinase inhibitors, Jak1 tyrosine kinase inhibitors, Jak2 tyrosine kinase inhibitors, Jak3 tyrosine kinase inhibitors, Jun N-terminal kinase inhibitors, Jun N-terminal kinase modulators, kallikrein modulators, Kelch-like ECH-related protein 1 modulators, Kit tyrosine kinase inhibitors, KLKB1 gene inhibitors, lactoferrin stimulators, lanosterol-14 demethylase inhibitors, Lck tyrosine kinase inhibitors, leukocyte Ig-like receptor A4 modulators, leukocyte elastase inhibitors, leukotriene BLT receptor antagonists, leukotriene D4 antagonists, leukotriene receptor antagonists, listeriolysin stimulators, liver X receptor antagonists, low molecular weight heparin, pulmonary surfactant-associated protein B stimulators, pulmonary surfactant-associated protein D modulators, Lyn tyrosine kinase inhibitors, Lyn tyrosine kinase stimulators, lysine-specific histone demethylase 1 inhibitors, macrophage migration inhibitory factor inhibitors, mannan-binding lectin serine protease inhibitors, mannan-binding lectin serine protease-2 inhibitors, MAO B inhibitors, MAP kinase inhibitors, MAPK gene modulators, matrix metalloproteinase modulators, Maxi K potassium channel inhibitors, MCL1 gene inhibitors, MEK protein kinase inhibitors, MEK-1 protein kinase inhibitors, melanocortin MC1 receptor agonists,Melanocortin MC3 receptor agonist, metalloproteinase-12 inhibitor, METTL3 gene inhibitor, moesin inhibitor, moesin modulator, monocyte chemoattractant protein 1 ligand inhibitor, monocyte differentiation antigen CD14 inhibitor, mRNA cap guanine N7 methyltransferase modulator, mTOR complex 1 inhibitor, mTOR complex 2 inhibitor, mTOR inhibitor, mucolipin modulator, muscarinic receptor antagonist, myeloperoxidase inhibitor, NACHT LRR PYD domain protein 3 inhibitors, NAD synthetase modulators, NADPH oxidase inhibitors, neuropilin 2 modulators, Neuroplastin inhibitors, NFE2L2 gene stimulators, NK cell receptor agonists, NK1 receptor antagonists, NMDA receptor antagonists, NMDA receptor ε2 subunit inhibitors, non-receptor tyrosine kinase TYK2 antagonists, non-nucleotide reverse transcriptase inhibitors, nsp12 polymerase inhibitors, nuclear factor erythroid 2-related factor 2 stimulators, nuclear factor κB inhibitors, nuclear factor κB modulators, nuclease stimulators, nucleolin inhibitors, nucleoprotein inhibitors, nucleoprotein modulators, nucleoside reverse transcriptase inhibitors, opioid receptor agonists, opioid receptor antagonists, opioid receptor μ modulators, opioid receptor σ antagonist 1, ORF1ab multiprotein inhibitors, ornithine decarboxylase inhibitors, outer membrane protein inhibitors, OX40 ligands, p38 MAP kinase α inhibitors, p38 MAP kinase inhibitors, p38 MAP kinase modulators, p53 tumor suppressor protein stimulators, palmitoyl protein thioesterase 1 inhibitors, papain inhibitors, PARP inhibitors, PARP modulators, PDE 10 inhibitors, PDE 3 inhibitors, PDE 4 inhibitors, PDGF receptor alpha antagonists, PDGF receptor antagonists, PDGF receptor beta antagonists, peptidyl prolyl cis-trans isomerase A inhibitors, peroxiredoxin 6 modulators, PGD2 antagonists, PGI2 agonists, P-glycoprotein inhibitors, phosphoinositide 3-kinase inhibitors, phosphoinositide-3 kinase delta inhibitors, phosphoinositide-3 kinase gamma inhibitors, phospholipase A2 inhibitors, PIKfyve inhibitors, plasma kallikrein inhibitors, plasminogen activator inhibitor 1 inhibitors, platelet inhibitors, platelet glycoprotein VI inhibitors, Polo-like kinase 1 inhibitor, poly ADP ribose polymerase 1 inhibitor, poly ADP ribose polymerase 2 inhibitor, polymerase cofactor VP35 inhibitor, PPARα 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 β inhibitor, protein tyrosine phosphatase-2C inhibitor, proto-oncogene Mas agonist, purine receptor antagonist, Raf protein kinase inhibitor,RANTES ligand, Ras gene inhibitor, retinoic acid receptor response protein 2 stimulator, Rev protein modulator, ribonuclease stimulator, RIP-1 kinase inhibitor, RNA helicase inhibitor, RNA polymerase inhibitor, RNA polymerase modulator, 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 modulator, signal transduction protein CD24 stimulator, deacetylase inhibitor, sodium channel stimulator, sodium glucose transporter-2 inhibitor, sphingosine kinase 1 inhibitor, sphingosine Sphingosine kinase 2 inhibitors, sphingosine kinase inhibitors, sphingosine-1-phosphate receptor-1 agonists, sphingosine-1-phosphate receptor-1 antagonists, sphingosine-1-phosphate receptor-1 modulators, sphingosine-1-phosphate receptor-5 agonists, sphingosine-1-phosphate receptor-5 modulators, spike glycoprotein inhibitors, Src tyrosine kinase inhibitors, STAT-1 modulators, STAT-3 inhibitors, STAT-5 inhibitors, STAT3 gene inhibitors, stem cell antigen-1 inhibitors, interferon gene stimulator protein stimulators, sulfatase inhibitors, superoxide dismutase modulators, superoxide dismutase stimulators, Syk tyrosine kinase inhibitors, T cell immunoreceptor Ig ITIM protein inhibitors, T cell receptor agonists, T cell surface glycoprotein CD28 inhibitors, T-cell differentiation antigen CD6 inhibitors, T-cell surface glycoprotein CD8 stimulators, T-cell transcription factor NFAT regulators, tankyrase-1 inhibitors, tankyrase-2 inhibitors, Tek tyrosine kinase receptor stimulators, telomerase regulators, tetanus toxin regulators, TGFβ receptor antagonists, TGFB2 gene inhibitors, thymosin β4 ligands, thyroid hormone receptor β agonists, tissue factor inhibitors, tissue plasminogen activator regulators, tissue plasminogen activator stimulators, TLR agonists, TLR regulators, TLR-2 agonists, TLR-2 antagonists, TLR-3 agonists, TLR-4 agonists, TLR-4 antagonists, TLR-6 agonists, TLR-7 agonists, TLR-7 antagonists, TLR-8 antagonists, TLR-9 agonists, TMPRSS2 gene inhibitors, TNFα ligand inhibitors, TNFα ligand modulators, TNF binders, TNF gene inhibitors, topoisomerase inhibitors, transcription factor EB stimulators, transferrin modulators, transketolase inhibitors, translocation-associated protein inhibitors, transmembrane serine protease 2 inhibitors, transthyretin modulators, TREM receptor 1 antagonists, TRP cation channel C1 modulators, TRP cation channel C6 inhibitors, TRP cation channel V6 inhibitors, trypsin 1 inhibitors, trypsin 2 inhibitors, trypsin 3 inhibitors, trypsin inhibitors,Tubulin 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, ubiquitin cytochrome c reductase 14kDa inhibitor, ubiquitin ligase modulator, non-specified GPCR agonist, non-specified cytokine receptor modulator, non-specified enzyme stimulator, non-specified gene inhibitor, non-specified receptor modulator, urokinase plasminogen activator inhibitor, vascular cell adhesion protein 1 agonist, vasodilator, VEGF ligand inhibitor, VEGF receptor antagonist, VEGF-1 receptor antagonist, VEGF-1 receptor modulator, VEGF-2 receptor antagonist, VEGF-3 receptor antagonist, vimentin inhibitor, vimentin modulator, VIP receptor agonist, viral envelope protein inhibitor, viral protease inhibitor, viral protease modulator, viral protein target modulator, viral ribonuclease inhibitor, viral structural protein modulator, vitamin D3 receptor agonist, X-linked apoptosis inhibitor protein inhibitor, xanthine oxidase inhibitor or zonulin inhibitor.

[0407] In some embodiments, the compounds and compositions of the present disclosure may be administered in combination with Sars-Cov-2 treatments such as parenteral fluids (including dextrose saline and Ringer's lactate), nutrients, antibiotics (including azithromycin, metronidazole, amphotericin B, amoxicillin / clavulanic acid, trimethoprim / sulfamethoxazole, R-327, and cephalosporin antibiotics such as ceftriaxone and cefuroxime), antifungal prophylactics, antipyretics and analgesics, antiemetics (such as metoclopramide) and / or antidiarrheals, vitamin and mineral supplements (including vitamin K, vitamin D, cholecalciferol, vitamin C, and zinc sulfate), anti-inflammatory agents (such as ibuprofen or steroids), corticosteroids (such as dexamethasone, methylprednisolone, prednisone, mometasone), immunomodulatory drugs (e.g., interferons), vaccines, and analgesics.

[0408] In some embodiments, the additional therapeutic agent is an Abl tyrosine kinase inhibitor, such as radotinib or imatinib.

[0409] In some embodiments, the additional therapeutic agent is an aldehyde dehydrogenase inhibitor, such as ADX-629.

[0410] In some embodiments, the additional therapeutic agent is an adenosine A3 receptor agonist, such as piclidenoson.

[0411] In some embodiments, the additional therapeutic agent is an adrenomedullin ligand, such as adrenomedullin.

[0412] In some embodiments, the additional therapeutic agent is a p38 MAPK+PPARγ agonist / insulin sensitizer, such as KIN-001.

[0413] In some embodiments, the additional therapeutic agent is a PPARα agonist, such as DWTC-5101 (fenofibrate choline).

[0414] In some embodiments, the additional therapeutic agent is a cyclophilin inhibitor, such as rencofilstat.

[0415] In some embodiments, the additional therapeutic agent is a p38 MAP kinase inhibitor, such as PRX-201 or Gen-1124.

[0416] In some embodiments, the additional therapeutic agent is an aldose reductase inhibitor, such as caficrestat.

[0417] In some embodiments, the additional therapeutic agent is an AMPA receptor modulator, such as traneurocin.

[0418] In some embodiments, the additional therapeutic agent is an Annexin A5 stimulator, such as AP-01 or SY-005.

[0419] In some embodiments, the additional therapeutic agent is an apelin receptor agonist, such as CB-5064MM.

[0420] In some embodiments, the additional therapeutic agent is an anticoagulant, such as heparins (heparin and low molecular weight heparin), aspirin, apixaban, dabigatran, edoxaban, argatroban, enoxaparin, or fondaparinux.

[0421] In some embodiments, the additional therapeutic agent is an androgen receptor antagonist, such as bicalutamide, dunlutamide, enzalutamide, or paxlovid.

[0422] In some embodiments, the additional therapeutic agent is an anti-hypoxic drug, such as crocetin disodium salt.

[0423] In some embodiments, the additional therapeutic agent is an antithrombotic agent such as defibrotide, rivaroxaban, alteplase, tirofiban, clopidogrel, prasugrel, bemiparin, bivalirudin, sulodexide, or tenecteplase.

[0424] In some embodiments, the additional therapeutic agent is an antihistamine, such as cloperastine or clemastine.

[0425] In some embodiments, the additional therapeutic agent is an apolipoprotein A1 agonist, such as CER-001.

[0426] In some embodiments, the additional therapeutic agent is a phospholipase A2 inhibitor, such as icosapent ethyl.

[0427] In some embodiments, the additional therapeutic agent is an axl tyrosine kinase receptor inhibitor, such as besentinib.

[0428] In some embodiments, the additional therapeutic agent is a corticosteroid / β2 adrenergic receptor agonist, such as budesonide + formoterol fumarate.

[0429] In some embodiments, the additional therapeutic agent is a BET bromodomain inhibitor / APOA1 gene stimulator, such as apabetalone.

[0430] In some embodiments, the additional therapeutic agent is a blood coagulation regulator, such as lanarumab.

[0431] In some embodiments, the additional therapeutic agent is a bradykinin B2 receptor antagonist, such as icatibant.

[0432] In some embodiments, the additional therapeutic agent is an EGFR gene inhibitor / Btk tyrosine kinase inhibitor, such as abivertinib.

[0433] In some embodiments, the additional therapeutic agent is a Btk tyrosine kinase inhibitor, such as ibrutinib or zanubrutinib.

[0434] In some embodiments, the additional therapeutic agent is a calpain-I / II / IX inhibitor, such as BLD-2660.

[0435] In some embodiments, the additional therapeutic agent is a cannabinoid CB2 receptor agonist, such as onternabez or PPP-003.

[0436] In some embodiments, the additional therapeutic agent is a Ca2+ release-activated Ca2+ channel 1 inhibitor, such as zegocractin (CM-4620).

[0437] In some embodiments, the additional therapeutic agent is an ATR inhibitor, such as berzosertib.

[0438] In some embodiments, the additional therapeutic agent is a Cadherin-5 modulator, such as FX-06.

[0439] In some embodiments, the additional therapeutic agent is a casein kinase II inhibitor, such as silmitasertib.

[0440] In some embodiments, the additional therapeutic agent is a caspase inhibitor, such as emricasan.

[0441] In some embodiments, the additional therapeutic agent is a catalase stimulator / superoxide dismutase stimulator, such as MP-1032.

[0442] In some embodiments, the additional therapeutic agent is a CCR2 chemokine antagonist / CCR5 chemokine antagonist, such as cenikvir.

[0443] In some embodiments, the additional therapeutic agent is a CCR5 chemokine antagonist, such as maraviroc or levitra.

[0444] In some embodiments, the additional therapeutic agent is a CD122 agonist / IL-2 receptor agonist, such as bempegaldesleukin.

[0445] In some embodiments, the additional therapeutic agent is a CD73 agonist / interferon beta ligand, such as FP-1201.

[0446] In some embodiments, the additional therapeutic agent is a cholesteryl ester transport protein inhibitor, such as dalcetrapib.

[0447] In some embodiments, the additional therapeutic agent is a mannan-binding lectin serine protease / complement C1s subcomponent inhibitor / myeloperoxidase inhibitor, such as RLS-0071.

[0448] In some embodiments, the additional therapeutic agent is a complement factor C5 inhibitor / leukotriene BLT receptor antagonist, such as nomacopan.

[0449] In some embodiments, the additional therapeutic agent is a complement factor C5 inhibitor, such as eculizumab, STSA-1002, zilucoplan.

[0450] In some embodiments, the additional therapeutic agent is a CXCR4 chemokine antagonist, such as plerixafor or motexafortide.

[0451] In some embodiments, the additional therapeutic agent is a cytochrome P450 3A4 inhibitor / peptidylprolyl cis-trans isomerase A inhibitor, such as alisporivir.

[0452] In some embodiments, the additional therapeutic agent is a cysteine ​​protease inhibitor, such as SLV-213.

[0453] In some embodiments, the additional therapeutic agent is a dihydroorotate dehydrogenase inhibitor, such as Meds-433, brequinar, RP-7214, farudostat, or emvododstat.

[0454] In some embodiments, the additional therapeutic agent is a dehydropeptidase-1 modulator, such as Metablok.

[0455] In some embodiments, the additional therapeutic agent is a dihydroorotate dehydrogenase inhibitor / IL-17 antagonist, such as vedofluradimol.

[0456] In some embodiments, the additional therapeutic agent is a diuretic, such as an aldosterone antagonist, such as spironolactone.

[0457] In some embodiments, the additional therapeutic agent is a deoxyribonuclease I stimulator, such as GNR-039 or dornase alfa.

[0458] In some embodiments, the additional therapeutic agent is a NET inhibitor, such as NTR-441.

[0459] In some embodiments, the additional therapeutic agent is a dihydroceramide delta 4 desaturase inhibitor / sphingosine kinase 2 inhibitor, such as opaganib.

[0460] In some embodiments, the additional therapeutic agent is a DNA methyltransferase inhibitor, such as azacytidine.

[0461] In some embodiments, the additional therapeutic agent is an LXR antagonist, such as larsucosterol.

[0462] In some embodiments, the additional therapeutic agent is a dipeptidyl peptidase I inhibitor, such as brensocatib.

[0463] In some embodiments, the additional therapeutic agent is a protein arginine deiminase IV inhibitor, such as JBI-1044.

[0464] In some embodiments, the additional therapeutic agent is an elongation factor 1 α2 modulator, such as prilotide.

[0465] In some embodiments, the additional therapeutic agent is a eukaryotic initiation factor 4A-I inhibitor, such as zotatifin.

[0466] In some embodiments, the additional therapeutic agent is an exo-alpha sialidase modulator, such as DAS-181.

[0467] In some embodiments, the additional therapeutic agent is an exportin 1 inhibitor, such as selinexor.

[0468] In some embodiments, the additional therapeutic agent is a fractalkine ligand inhibitor, such as KAND-567.

[0469] In some embodiments, the additional therapeutic agent is a FYVE finger phosphoinositide kinase inhibitor / IL-12 receptor antagonist / IL-23 antagonist, such as apimod dimesylate.

[0470] In some embodiments, the additional therapeutic agent is a GABA A receptor modulator, such as brexanolone.

[0471] In some embodiments, the additional therapeutic agent is a glucocorticoid receptor agonist, such as ciclesonide, hydrocortisone, dexamethasone, dexamethasone phosphate, or 101-PGC-005.

[0472] In some embodiments, the additional therapeutic agent is a GM-CSF receptor agonist, such as sargramostim.

[0473] In some embodiments, the additional therapeutic agent is a GPCR agonist, such as esuberaprost sodium.

[0474] In some embodiments, the additional therapeutic agent is a Griffithsin modulator, such as Q-Griffithsin.

[0475] In some embodiments, the additional therapeutic agent is a leukotriene D4 antagonist, such as montelukast.

[0476] In some embodiments, the additional therapeutic agent is a histamine H1 receptor antagonist, such as ebastine, tranilast, levocetirizine hydrochloride.

[0477] In some embodiments, the additional therapeutic agent is a histamine H2 receptor antagonist, such as famotidine.

[0478] In some embodiments, the additional therapeutic agent is a heat shock protein stimulator / insulin sensitizer / PARP inhibitor, such as BGP-15.

[0479] In some embodiments, the additional therapeutic agent is a histone inhibitor, such as STC-3141.

[0480] In some embodiments, the additional therapeutic agent is a histone deacetylase-6 inhibitor, such as CKD-506.

[0481] In some embodiments, the additional therapeutic agent is a HIF prolyl hydroxylase-2 inhibitor, such as depo-statin.

[0482] In some embodiments, the additional therapeutic agent is a HIF prolyl hydroxylase inhibitor, such as valdostat.

[0483] In some embodiments, the additional therapeutic agent is an IL-8 receptor antagonist, such as reparixin.

[0484] In some embodiments, the additional therapeutic agent is an IL-7 receptor agonist, such as CYT-107.

[0485] In some embodiments, the additional therapeutic agent is an IL-7 receptor agonist / interleukin-7 ligand, such as efineptakin alfa.

[0486] In some embodiments, the additional therapeutic agent is an IL-22 agonist, such as efmarodocokin alfa.

[0487] In some embodiments, the additional therapeutic agent is an IL-22 agonist / interleukin 22 ligand, such as F-652.

[0488] In some embodiments, the additional therapeutic agent targets IL-33, such as torelikizumab.

[0489] In some embodiments, the additional therapeutic agent is an IL-15 agonist, such as nogapendekin alfa.

[0490] In some embodiments, the additional therapeutic agent is an integrin α-V / β-1 antagonist / integrin α-V / β-6 antagonist, such as bexotegrast.

[0491] In some embodiments, the additional therapeutic agent is an interferon alpha 2 ligand, such as interferon alpha-2b or Virafin.

[0492] In some embodiments, the additional therapeutic agent is an interferon beta ligand, such as interferon beta-1a follow-on biologic, interferon beta-1b, or SNG-001.

[0493] In some embodiments, the additional therapeutic agent is an interferon receptor modulator, such as peginterferon lambda-1a.

[0494] In some embodiments, the additional therapeutic agent is an interleukin-2 ligand, such as aldesleukin.

[0495] In some embodiments, the additional therapeutic agent is an IRAK-4 protein kinase inhibitor, such as zimlovisertib.

[0496] In some embodiments, the additional therapeutic agent is a JAK inhibitor, for example, the additional therapeutic agent is baricitinib, filgotinib, jaktinib, tofacitinib, or nezulcitinib (TD-0903).

[0497] In some embodiments, the additional therapeutic agent is a neutrophil elastase inhibitor, such as alvilestat.

[0498] In some embodiments, the additional therapeutic agent is a pulmonary surfactant-associated protein D modulator, such as AT-100.

[0499] In some embodiments, the additional therapeutic agent is a plasma kallikrein inhibitor, such as donidalorsen.

[0500] In some embodiments, the additional therapeutic agent is a lysine-specific histone demethylase 1 / MAO B inhibitor, such as vafidostat.

[0501] In some embodiments, the additional therapeutic agent is a mannan-binding lectin serine protease inhibitor, such as conestat alfa.

[0502] In some embodiments, the additional therapeutic agent is a maxi K potassium channel inhibitor, such as ENA-001.

[0503] In some embodiments, the additional therapeutic agent is a MEK protein kinase inhibitor, such as zapnometinib.

[0504] In some embodiments, the additional therapeutic agent is a MEK-1 protein kinase inhibitor / Ras gene inhibitor, such as androquinol.

[0505] In some embodiments, the additional therapeutic agent is a melanocortin MC1 receptor agonist, such as PL-8177

[0506] In some embodiments, the additional therapeutic agent is a melanocortin MC1 / MC3 receptor agonist, such as resommelegol acetate.

[0507] In some embodiments, the additional therapeutic agent is a matrix metalloproteinase-12 inhibitor, such as FP-025.

[0508] In some embodiments, the additional therapeutic agent is a NACHT LRR PYD domain protein 3 inhibitor, such as dapansutrile, DFV-890, or ZYIL-1.

[0509] In some embodiments, the additional therapeutic agent is a NADPH oxidase inhibitor, such as isuzinaxib.

[0510] In some embodiments, the additional therapeutic agent is a neuropilin 2 modulator, such as efzofitimod.

[0511] In some embodiments, the additional therapeutic agent is a NK1 receptor antagonist, such as aprepitant or tredipitant.

[0512] In some embodiments, the additional therapeutic agent is an NMDA receptor antagonist, such as crocetin or ifenprodil.

[0513] In some embodiments, the additional therapeutic agent is a nuclear factor κB inhibitor / p38 MAP kinase inhibitor, such as zenuzolac.

[0514] In some embodiments, the additional therapeutic agent is an ornithine decarboxylase inhibitor, such as eflornithine.

[0515] In some embodiments, the additional therapeutic agent is an opioid receptor sigma antagonist 1, such as MR-309.

[0516] In some embodiments, the additional therapeutic agent is a PGD2 antagonist, such as asapiprant.

[0517] In some embodiments, the additional therapeutic agent is a PDGF receptor antagonist / TGF[beta] receptor antagonist / p38 MAP kinase inhibitor, such as deupirfenidone.

[0518] In some embodiments, the additional therapeutic agent is a phospholipase A2 inhibitor, such as methylvarespladib.

[0519] In some embodiments, the additional therapeutic agent is a phosphoinositide 3-kinase inhibitor / mTOR complex inhibitor, such as dactolisib.

[0520] In some embodiments, the additional therapeutic agent is an mTOR inhibitor, such as sirolimus.

[0521] In some embodiments, the additional therapeutic agent is a phosphoinositide 3-kinase delta / gamma inhibitor, such as duvelisib.

[0522] In some embodiments, the additional therapeutic agent is a PIKfyve inhibitor, such as VRG-101.

[0523] In some embodiments, the additional therapeutic agent is a plasminogen activator inhibitor 1 inhibitor, such as TM-5614.

[0524] In some embodiments, the additional therapeutic agent is a protein tyrosine phosphatase beta inhibitor, such as ralostadil.

[0525] In some embodiments, the additional therapeutic agent is a RIP-1 kinase inhibitor, such as eclitasertib (DNL-758) or SIR-0365.

[0526] In some embodiments, the additional therapeutic agent is a Rev protein modulator, such as obefazimod.

[0527] 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.

[0528] In some embodiments, the additional therapeutic agent is a signaling protein CD24 stimulator, such as EXO-CD24.

[0529] In some embodiments, the additional therapeutic agent is a sodium glucose transporter-2 inhibitor, such as dapagliflozin propylene glycol.

[0530] In some embodiments, the additional therapeutic agent is a sodium channel inhibitor, such as solnatide.

[0531] In some embodiments, the additional therapeutic agent is a sphingosine-1-phosphate-1 agonist / sphingosine-1-phosphate-5 agonist, such as ozanimod.

[0532] In some embodiments, the additional therapeutic agent is a nonsteroidal anti-inflammatory drug, such as Ampion.

[0533] In some embodiments, the additional therapeutic agent is a superoxide dismutase agonist, such as avasopasem manganese.

[0534] In some embodiments, the additional therapeutic agent is a Syk tyrosine kinase inhibitor, such as fostamatinib disodium salt.

[0535] In some embodiments, the additional therapeutic agent is a Tie2 tyrosine kinase receptor agonist, such as AV-001.

[0536] In some embodiments, the additional therapeutic agent is a TGFB2 gene inhibitor, such as trabedocranolol.

[0537] In some embodiments, the additional therapeutic agent is a tissue factor inhibitor, such as AB-201.

[0538] In some embodiments, the additional therapeutic agent is a TLR-3 agonist, such as rentatimod.

[0539] In some embodiments, the additional therapeutic agent is a TLR-4 antagonist, such as ApTLR-4FT, EB-05, or eritoran.

[0540] In some embodiments, the additional therapeutic agent is a TLR-7 / 8 antagonist, such as enpatoran.

[0541] In some embodiments, the additional therapeutic agent is a TLR-2 / 6 agonist, such as INNA-051.

[0542] In some embodiments, the additional therapeutic agent is a TLR-7 agonist, such as PRTX-007 or APR-002.

[0543] In some embodiments, the additional therapeutic agent is a TLR agonist, such as PUL-042.

[0544] In some embodiments, the additional therapeutic agent is a TLR-4 agonist, such as REVTx-99.

[0545] In some embodiments, the additional therapeutic agent is a TLR-2 / 4 antagonist, such as VB-201.

[0546] In some embodiments, the additional therapeutic agent is a TNFα ligand inhibitor, such as pegipanermin.

[0547] In some embodiments, the additional therapeutic agent is a type I IL-1 receptor antagonist, such as anakinra.

[0548] In some embodiments, the additional therapeutic agent is a TREM receptor 1 antagonist, such as nangibotide.

[0549] In some embodiments, the additional therapeutic agent is a trypsin inhibitor, such as ulinastatin.

[0550] In some embodiments, the additional therapeutic agent is a tubulin inhibitor, such as sabizabulin, CCI-001, PCNT-13, CR-42-24, albendazole, entabulin, SAR-132885, or ON-24160.

[0551] In some embodiments, the additional therapeutic agent is a VIP receptor agonist, such as aviptadil.

[0552] In some embodiments, the additional therapeutic agent is a xanthine oxidase inhibitor, such as oxypurinol.

[0553] In some embodiments, the additional therapeutic agent is a vasodilator such as iloprost, VentaProst, vazegepant, TXA-127, USB-002, ambrisentan, nitric oxide nasal spray (NORS), pentoxifylline, propranolol, RESP301, sodium nitrite, or dipyridamole.

[0554] In some embodiments, the additional therapeutic agent is a vitamin D3 receptor agonist, such as cholecalciferol.

[0555] In some embodiments, the additional therapeutic agent is a zonulin inhibitor, such as larazotideacetate.

[0556] In some embodiments, the additional therapeutic agent is a synthetic retinoid derivative, such as fenretinide.

[0557] In some embodiments, the additional therapeutic agent is a glucose metabolism inhibitor, such as WP-1122 or WP-1096.

[0558] In some embodiments, the additional therapeutic agent is adalimumab, AT-H201, 2-deoxy-D-glucose, AD-17002, AIC-649, AMTX-100, astodrimer, AZD-1656, belapectin, bitespiramycin, bucillamine, budesonide, CNM-AgZn-17, Codivir, CT-38, danicopan, didodecyl methotrexate, DW-2008S (DW-2008), EDP-1815, EG-009A, Fabencov, Gamunex, genistein, GLS-1200, hzVSF-v13, imidazole acetamide glutarate, IMM-101, M AS-825, MRG-001, Nasitrol, Nylexa, Olebatinib, OP-101, OPN-019, Orynotide rhesus theta defensin-1, pyronaridine + artesunate, dapsone, RPH-104, sodium pyruvate, Sulforadex, tafenoquine, TB-006, telacebec, Tempol, TL-895, thimerosal, trimodulin, XC-221, XC-7, santol, glycine metformin, lucinactant, EOM-613, mosmod, ivermectin, leflunomide, ibudilast, RBT-9, raloxifene, prothione, gemcabene or idronoxil.

[0559] In some embodiments, the additional therapeutic agent is a CD73 antagonist, such as AK-119.

[0560] In some embodiments, the additional therapeutic agent is a CD95 protein fusion, such as asunercept.

[0561] In some embodiments, the additional therapeutic agent is a complement factor C2 modulator, such as ARGX-117.

[0562] In some embodiments, the additional therapeutic agent is a complement C3 inhibitor, such as AMY-101 or NGM-621.

[0563] In some embodiments, the additional therapeutic agent is a CXC10 chemokine ligand inhibitor, such as EB-06.

[0564] In some embodiments, the additional therapeutic agent is a cytotoxic T-lymphocyte protein-4 fusion protein, such as abatacept

[0565] In some embodiments, the additional therapeutic agent is an anti-S. aureus antibody, such as tosatoxumab.

[0566] In some embodiments, the additional therapeutic agent is an anti-LPS antibody, such as IMM-124-E.

[0567] In some embodiments, the additional therapeutic agent is an adrenomedullin ligand inhibitor, such as embaricimab.

[0568] In some embodiments, the additional therapeutic agent is a basigin inhibitor, such as mepentizumab.

[0569] In some embodiments, the additional therapeutic agent is a CD3 antagonist, such as foramicin.

[0570] In some embodiments, the additional therapeutic agent is a connective tissue growth factor ligand inhibitor, such as PRS-220, panrelumab.

[0571] In some embodiments, the additional therapeutic agent is a complement factor C5a inhibitor, such as BDB-1 or veloxazolizumab.

[0572] In some embodiments, the additional therapeutic agent is a complement factor C5 inhibitor, such as eculizumab.

[0573] In some embodiments, the additional therapeutic agent is a mannan-binding lectin serine protease-2 inhibitor, such as nasolizumab.

[0574] In some embodiments, the additional therapeutic agent is a GM-CSF modulator, such as STSA-1005, netilumab, namecirumab, punalimab, otelimumab, or renzilumab.

[0575] In some embodiments, the additional therapeutic agent is a heat shock protein inhibitor / IL-6 receptor antagonist, such as siltuximab.

[0576] In some embodiments, the additional therapeutic agent is an IL-6 receptor antagonist, such as clazakizumab, levilimab, olokizumab, tocilizumab, or sirukumab.

[0577] In some embodiments, the additional therapeutic agent is an IL-8 receptor antagonist, such as BMS-986253.

[0578] In some embodiments, the additional therapeutic agent is an interleukin-1 β ligand inhibitor, such as canakinumab.

[0579] In some embodiments, the additional therapeutic agent is an interferon gamma ligand inhibitor, such as epavacumab.

[0580] In some embodiments, the additional therapeutic agent is an anti-ILT7 antibody, such as daxdilimab.

[0581] In some embodiments, the additional therapeutic agent is a monocyte differentiation antigen CD14 inhibitor, such as atibuclimab.

[0582] In some embodiments, the additional therapeutic agent is a plasma kallikrein inhibitor, such as lanarumab.

[0583] In some embodiments, the additional therapeutic agent is a platelet glycoprotein VI inhibitor, such as glenzocimab.

[0584] In some embodiments, the additional therapeutic agent is an inhibitor of T-cell differentiation antigen CD6, such as itolizumab.

[0585] In some embodiments, the additional therapeutic agent is a TNFα ligand inhibitor / TNF binder, such as infliximab.

[0586] In some embodiments, the additional therapeutic agent is an anti-LIGHT antibody, such as AVTX-002.

[0587] In some embodiments, the additional therapeutic agent is IMC-2 (valacyclovir + celecoxib) or AXA-1125.

[0588] In some embodiments, the additional therapeutic agent is COVID-HIG.

[0589] In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with one or more agents useful for treating and / or preventing COVID-19.

[0590] 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 salilumab; Janus kinase (JAK) inhibitors such as baricitinib, ruxolitinib, or tofacitinib; and antiviral agents such as monoprevir, sotrovimab, or remdesivir.

[0591] In another embodiment, the compounds of the present disclosure or pharmaceutically acceptable salts thereof are co-administered with two or more agents useful for treating COVID-19. Agents useful for treating and / or preventing COVID-19 include, but are not limited to, compounds of the present disclosure and two additional therapeutic agents, such as namatevir and ritonavir, carrivimab and idevimab, or ruxolitinib and tofacitinib.

[0592] In some embodiments, the additional therapeutic agent is 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.

[0593] In some embodiments, the antiviral agent is selected from angiotensin converting enzyme 2 inhibitors, angiotensin converting enzyme 2 modulators, angiotensin converting enzyme 2 stimulators, angiotensin II AT-2 receptor agonists, angiotensin II AT-2 receptor antagonists, angiotensin II receptor modulators, coronavirus nucleoprotein modulators, coronavirus small envelope protein modulators, coronavirus spike glycoprotein inhibitors, coronavirus spike glycoprotein modulators, SARS-CoV-2 small envelope membrane protein inhibitors, SARS-CoV-2 small envelope membrane protein modulators, SARS-CoV-2 MPro inhibitors, SARS-CoV-2 nonstructural protein 8 modulators, SARS-CoV-2 nucleoprotein inhibitors, SARS-CoV-2 nucleoprotein modulators, SARS-CoV-2 protein 3a inhibitors, SARS-CoV-2 replicase polyprotein 1a inhibitors, SARS-CoV-2 replicase polyprotein 1a modulators, SARS-CoV-2 replicase polyprotein 1ab inhibitors, SARS-CoV-2 replicase Polyprotein 1ab modulators, SARS-CoV-2 spike glycoprotein inhibitors, SARS-CoV-2 spike glycoprotein modulators, SARS-CoV-2 structural glycoprotein modulators, papain inhibitors, protease inhibitors, protease modulators, RNA polymerase inhibitors, RNA polymerase modulators, RNA-dependent RNA polymerase (RdRp) inhibitors, SARS coronavirus 3C protease-like inhibitors, SARS-CoV-2 nsp14 methyltransferase inhibitors, 3CLpro / Mpro inhibitors, serine protease inhibitors, transmembrane serine protease 2 inhibitors, transmembrane serine protease 2 modulators, viral envelope protein inhibitors, viral protease inhibitors, viral protease modulators, viral protein target modulators, viral ribonuclease inhibitors, and viral structural protein modulators.

[0594] 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.

[0595] In some embodiments, the additional therapeutic agent is an angiotensin converting enzyme 2 inhibitor, such as SBK-001.

[0596] In some embodiments, the additional therapeutic agent is an angiotensin converting enzyme 2 modulator, such as neumifil or JN-2019.

[0597] In some embodiments, the additional therapeutic agent is an entry inhibitor, such as MU-UNMC-1 or SAI-4.

[0598] In some embodiments, the additional therapeutic agent is an angiotensin converting enzyme 2 stimulator, such as alunacedase alfa.

[0599] In some embodiments, the additional therapeutic agent is an angiotensin II AT-2 receptor agonist, such as VP-01.

[0600] In some embodiments, the additional therapeutic agent is an ACE II receptor antagonist, such as DX-600.

[0601] In some embodiments, the additional therapeutic agent is an angiotensin II receptor modulator, such as TXA-127.

[0602] In some embodiments, the additional therapeutic agent is a transmembrane serine protease 2 modulator, such as BC-201, N-0385.

[0603] In some embodiments, the additional therapeutic agent is a viral envelope protein inhibitor, such as MXB-9 or MXB-004.

[0604] In some embodiments, the additional therapeutic agent is a RNAi agent, such as ARO-COV or SNS-812.

[0605] 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 cellular vaccine, or a dendritic cell vaccine.

[0606] In some embodiments, the additional therapeutic agent is a vaccine, such as tozinameran, NVX-CoV2373, elasomeran, 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 protein subunit recombinant vaccine, Sputnik M, ZyCoV-D, COVID-19XWG-03, mRNA-1273.529, mRNA-1010, CoronaVac, AZD-2816, Sputnik V, inactivated SARS-CoV-2 vaccine (Vero cells, COVID-19), DS-5670, PHH-1V, INO-4800, UB-612, coronavirus vaccine (whole virus particles, inactivated / purified), ReCOV, MT-2766, ARCT-154, SP-0253, CORBEVAX, mRNA-1273.211, ZF-2001, SputnikLight, Recombinant protein vaccine (COVID-19 / SARS-CoV-2 infection), VSV vector-based 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 cells, COVID-19), BBV-154, RAZICov Pars, COVID-19 vaccine (inactivated / Vero cells / intramuscular, SARS-CoV-2 infection), COVID-19 vaccine (inactivated, Vero cells / 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. .

[0607] 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 known as main protease, Mpro), a papain-like protease inhibitor (PLpro), a serine protease inhibitor, or a transmembrane serine protease 2 inhibitor (TMPRSS2).

[0608] 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, bofutrelvir (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, namatevir, enrofloxacin, Seravir, ASC-11, ASC-11+ritonavir, EDDC-2214, SIM-0417, PF-07817883, senotevir, senotevir+ritonavir, SYH-2055, ISM-3312, CDI-45205, LHP-803 (COR-803), ALG-097111, TJC-642, CVD-0013943, olgotrelvir (STI-1558), eravacycline, cynarine, WPV-01, or prexasertib.

[0609] In some embodiments, the additional therapeutic agent is a papain-like protease inhibitor (PLpro), such as SBFM-PL4 or GRL-0617.

[0610] In some embodiments, the additional therapeutic agent is an inhibitor of the SARS-CoV-2 helicase Nsp13, such as EIS-4363.

[0611] In some embodiments, the additional therapeutic agent is an inhibitor of the SARS-CoV-2 helicase Nsp14, such as TO-507.

[0612] In some embodiments, the additional therapeutic agents are the SARS-CoV-2 spike protein (S) and a protease modulator, such as ENU-200.

[0613] In some embodiments, the additional therapeutic agent is a protease inhibitor, such as ALG-097558 or MRX-18.

[0614] In some embodiments, the additional therapeutic agent is a serine protease inhibitor, such as upastat, nafamostat, camostat mesylate, nafamostat mesylate, or camostat.

[0615] In some embodiments, the additional therapeutic agent is a 3CLpro / transmembrane serine protease 2 inhibitor, such as SNB-01 (pentarlandir) or SNB-02.

[0616] In some embodiments, the additional therapeutic agent is a viral protease inhibitor such as Pan-Corona, Cov-X, or Bepridil.

[0617] 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.

[0618] 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, deuterated remdesivir (VV-116), LGN-20, CMX-521, SHEN-26, MB-905, and compounds disclosed in WO2022142477, WO2021213288, and WO2022047065.

[0619] In some embodiments, the additional therapeutic agent is an RNA polymerase inhibitor, such as monuprivir (EIDD-2801), favipiravir, bemnifosbuvir, sofosbuvir, ASC-10, or galidesivir.

[0620] In some embodiments, the additional therapeutic agent is a viral entry inhibitor, such as brilacidin.

[0621] In some embodiments, the additional therapeutic agent is an antibody that binds to a coronavirus, such as an antibody that binds to SARS or MERS.

[0622] 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 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).

[0623] 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).

[0624] In some embodiments, the additional therapeutic agent is a SARS-CoV-2 viral antibody.

[0625] 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 sotretinoin (VIR-7831), carrevizumab + idevizumab (REGN-COV2 or REGN10933 + RGN10987), BAT2020, BAT2019, 47D11, YBSW-015, or PA-001.

[0626] In some embodiments, the additional therapeutic agent is STI-9199 (COVI-SHIELD), STI-9167, or AR-701 (AR-703 and AR-720).

[0627] 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, sotretinoin (GSK-4182136), tesategravir + segavir (AZD-7442), regdanilimab (regd anvimab), SAB-301, AOD-01, plutavimab (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-038 20), enuzovimab (HFB-30132A), INM-005, SCTA01, TY-027, XAV-19, ambavir monoclonal antibody + romisvir monoclonal antibody, SCTA-01, bebtelovimab, beludavir monoclonal antibody, IBI-O123, IGM-6268, FYB-207, FS-2101, RBT-0813, RE GN-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.

[0628] In some embodiments, the additional therapeutic agent is an engineered ACE-2-IgG1-Fc fusion protein that targets the SARS-Cov-2 RBD, such as EU-129, a bivalent ACE2-IgG Fc null fusion protein (SI-F019).

[0629] In some embodiments, the additional therapeutic agent is an ACE2-Fc receptor fusion protein, such as HLX-71.

[0630] In some embodiments, the additional therapeutic agent is ensovibep.

[0631] In some embodiments, the additional therapeutic agent is SYZJ-001.

[0632] In some embodiments, the additional therapeutic agent is an HIV-1 protease inhibitor, such as ASC-09F (ASC-09 + ritonavir) or lopinavir + ritonavir.

[0633] In some embodiments, the additional therapeutic agent is a non-nucleoside reverse transcriptase inhibitor, such as elfavirine.

[0634] In some embodiments, the additional therapeutic agent is a nucleoside reverse transcriptase inhibitor, such as azithromycin.

[0635] In some embodiments, the additional therapeutic agent is 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, clofocol, CR-405, delcetravir, D4-102-01, D4-102-02, ESFAM-289, ENOB-CV-01, ENOB-CV-11, EIS-10700, EV-300, β-521, GEA-001, SIM-0417, monoprevir, Pan-Corona, Tollovir, namatevir + ritonavir JTBC-00201, Favipiravir, Favipiravir + cathepsin inhibitor (TNX-3900), GC-376, Upastat, LeSoleil-01, LeSoleil-02+, Benfovir, VV-116, VV-993, SNB-01, EDP-235, Cov-X, Enstevir, MPI-8, Masitinib, ALG-097558, ASC-11, PBI-0451, Nafamostat, Nafamostat mesylate, CDI-45205, LHP-803 (COR-803), ALG-097111, BC-201, SH-879, CDI- 873, CDI-988, remdesivir, NV-CoV-2-R, NV-CoV-1 encapsulated remdesivir, NA-831+remdesivir, DEP remdesivir, GS-621763, GS-5245, GLS-5310, benifosbuvir, QLS-1128, ASC-10, SBFM-PL4, camostat mesylate, UCI-1, FB-2001 (DC-402234), ebselen, SH-580, LeSoleil-01, LeSoleil-02+, MRX-18, MXB-9, MI-09, MI-30, SNB-02, SJP-0 02C, TJC-642, ENU-200, CVD-0013943, GS-441524, Bepridil, MXB-004, Eracycline, GRL-0617, GST-HG171, GST-HG171+ritonavir, Camostat, GC-373, KD-1, Nitazoxanide, Cinaline, Presertib, PL-M, RAY-1216, SACT-COVID-19, MP-18, EIDD-1931, EDDC-2214, Nitric Oxide, Apaberone, AnQlar, SBK-001, LQ-050, CG-SpikeDown, Baminivir, JTBC-001 01, HLX-71, HT-002, HY-209, HY-3000, HSC-1553, FYB-207, Ensovipu, SYZJ-001, EU-129, neumifil, JN-2019 (KG-2019), LCB-99, AR-701, vostesyl, 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 (AnixaBiosciences), PBF-4554, alunase alfa, VP-01, TRV-027, DX-600, TXA-127, NVX-CoV2515, rapamycin, RCYM-002, RCYM-003, riamilovir, SARS-Cov-2PL pro inhibitor (Enanta), SBP-502, SM-4, STB-R040, THY-01, tozinamethron, irasomerase, Ad5-nCoV, BBIBP-CorV, CoronaVac, MVC-COV1901, NVX-CoV2373, sotrimab, Sputnik V, TEE-001, Tyme-19, Vaxzevria, XW-001, ZF-2001, or ZyCoV-D.

[0636] In some embodiments, the additional therapeutic agent or prophylactic agent is a SARS-CoV-2 MPro inhibitor. In some embodiments, the SARS-CoV-2 MPro inhibitor is namatevir. In some embodiments, the SARS-CoV-2 MPro inhibitor is ritonavir.

[0637] Any compound of the invention may also be combined with one or more additional active therapeutic agents in a single dosage form for simultaneous or sequential administration to a patient. Combination therapy may be administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations.

[0638] Co-administration of a compound of the invention and one or more other active therapeutic agents generally refers to administering the compound of the invention and the one or more other active therapeutic agents simultaneously or sequentially such that therapeutically effective amounts of the compound of the invention and the one or more other active therapeutic agents are both present in the patient's body.

[0639] Co-administration includes administering a unit dose of a compound described herein before or after administering a unit dose of one or more other active therapeutic agents, for example, administering a compound described herein within seconds, minutes, or hours of administering one or more other active therapeutic agents. For example, a unit dose of the compound of the present invention may be administered first, and then a unit dose of one or more other active therapeutic agents may be administered within seconds or minutes. Alternatively, a unit dose of one or more other therapeutic agents may be administered first, and then a unit dose of the compound of the present invention may be administered within seconds or minutes. In some cases, it may be necessary to first administer a unit dose of the compound of the present invention, and then administer a unit dose of one or more other active therapeutic agents after a few hours (e.g., 1-12 hours). In other cases, it may be necessary to first administer a unit dose of one or more other active therapeutic agents, and then administer a unit dose of the compound of the present invention after a few hours (e.g., 1-12 hours).

[0640] Combination therapy can provide "synergy" and "synergy", that is, the effect achieved when the active ingredients are used together is greater than the sum of the effects produced by the compounds used alone. A synergistic effect can be obtained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combination formulation; (2) delivered alternatingly or in parallel as separate formulations; or (3) by some other regimen. When delivered in alternation therapy, a synergistic effect can be obtained when the compounds are administered or delivered sequentially, for example, in separate tablets, pills, or capsules or by different injections in separate syringes. In general, during alternation therapy, an effective dose of each active ingredient is administered sequentially (i.e., continuously), whereas in combination therapy, effective doses of two or more active ingredients are administered together. A synergistic antiviral effect means that the antiviral effect is greater than the predicted purely additive effect of the individual compounds in the combination.

[0641] The compounds described herein are also used in combination with other active therapeutic agents. For the treatment of Pneumoviridae virus infection, preferably, the other active therapeutic agent has activity against Pneumoviridae virus infection, particularly respiratory syncytial virus infection and / or metapneumovirus infection. Non-limiting examples of these other active therapeutic agents with anti-RSV activity are ribavirin, palivizumab, movizumab, RSV-IGIV 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 with anti-respiratory syncytial virus infection activity include respiratory syncytial virus protein F inhibitors, such as AK-0529; RV-521, ALX-0171, JNJ-53718678, BTA-585, and prutovir; RNA polymerase inhibitors, such as lumicitabine and ALS-8112; anti-RSV G protein antibodies, such as anti-G protein mAb; viral replication inhibitors, such as nitazoxanide.

[0642] In some embodiments, the other active therapeutic agent may be a vaccine for the treatment or prevention of RSV, including but not limited to MVA-BN RSV, RSV-F, MEDI-8897, JNJ-64400141, DPX-RSV, SynGEM, GSK-3389245A, GSK-300389-1A, RSV-MEDI deltaM2-2 vaccine, VRC-RSVRGP084-00VP, Ad35-RSV-FA2, Ad26-RSV-FA2, and RSV fusion glycoprotein subunit vaccine.

[0643] 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 treating metapneumovirus infection, such as EV-046113.

[0644] In some embodiments, the other active therapeutic agent may be a vaccine for treating or preventing metapneumovirus infection, including but not limited to mRNA-1653 and rHMPV-Pa vaccines.

[0645] The compounds described herein are also used in combination with other active therapeutic agents. For the treatment of Picornaviridae virus infection, preferably, the other active therapeutic agents have activity against Picornaviridae virus infection, particularly enterovirus infection. Non-limiting examples of these other active therapeutic agents are capsid binding inhibitors such as pleconaril, BTA-798 (vapendavir) and other compounds disclosed by Wu et al. (US 7,078,403) and Watson (US 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; anti-EV71 antibodies.

[0646] In some embodiments, the other active therapeutic agent may be a vaccine for treating or preventing infection with a Picornaviridae virus, including but not limited to EV71 vaccine, TAK-021, and EV-D68 adenovirus vector-based vaccines.

[0647] Many infections with Pneumoviridae, Picornaviridae, and Coronaviridae viruses are respiratory infections. Therefore, additional active therapeutic agents for treating respiratory symptoms and sequelae of infection can be used in combination with the compounds described herein. The additional therapeutic agent is preferably administered orally or by direct inhalation. For example, other preferred additional therapeutic agents for treating viral respiratory infections in combination with the compounds described herein include, but are not limited to, bronchodilators and corticosteroids.

[0648] Glucocorticoids, first introduced as an asthma treatment in 1950 (Carryer, Journal of Allergy, 21, 282-287, 1950), remain the most effective and sustained therapy for this disease, but their mechanism of action is not yet fully understood (Morris, J. Allergy Clin. Immunol., 75 (1 Pt) 1-13, 1985). Unfortunately, oral glucocorticoid therapy is associated with serious adverse side effects, such as truncal obesity, hypertension, glaucoma, glucose intolerance, accelerated cataract formation, bone mineral loss and psychological effects, all of which limit its use as a long-term therapeutic agent (Goodman and Gilman, 10th edition, 2001). The solution to systemic side effects is to deliver steroid drugs directly to the site of inflammation. Inhaled corticosteroids (ICS) have been developed to alleviate the serious side effects of oral steroids. Non-limiting examples of corticosteroids that can be used in combination with the compounds described herein are dexamethasone, dexamethasone sodium phosphate, fluorometholone, fluorometholone acetate, loteprednol, loteprednol etabonate, hydrocortisone, prednisolone, fludrocortisone, triamcinolone, triamcinolone acetonide, betamethasone, beclomethasone dipropionate, methylprednisolone, fluocinolone acetonide, fluocinolone acetonide, flunisolide, fluocortidine-21-butyrate, flumethasone, flumethasone pivalate, budesonide, halobetasol propionate, mometasone furoate, fluticasone, AZD-7594, ciclesonide; or pharmaceutically acceptable salts thereof.

[0649] Other anti-inflammatory agents that work through the anti-inflammatory cascade mechanism can also be used as additional therapeutic agents in combination with the compounds described herein for the treatment of viral respiratory infections. Application of "anti-inflammatory signal transduction regulators" (referred to as AIS™ in this text), such as phosphodiesterase inhibitors (e.g., PDE-4, PDE-5 or PDE-7 specific), transcription factor inhibitors (e.g., blocking NFκB by IKK inhibition) or kinase inhibitors (e.g., blocking P38 MAP, JNK, PI3K, EGFR or Syk) is a logical approach to cut off inflammation, because these small molecules target a limited number of common intracellular pathways - those signal transduction pathways that are key points of anti-inflammatory therapeutic intervention (see PJ Barnes, 2006 for a review). 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 [(methylsulfonyl)amino]-1-dibenzofurancarboxamide (PDE-4 inhibitor Oglemilast); N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxo-acetamide (PDE-4 inhibitor AWD 12-281); 8-methoxy-2-trifluoromethyl-quinoline-5-carboxylic acid (3,5-dichloro-1-oxy-pyridin-4-yl)-amide (PDE-4 inhibitor Sch 351591); 4-[5-(4-fluorophenyl)-2-(4-methanesulfinyl-phenyl)-1H-imidazol-4-yl]-pyridine (P38 inhibitor SB-203850); 4-[4-(4-fluorophenyl)-1-(3-phenylpropyl)-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 (2-diethyl-ethyl ester prodrug of cilomilast, 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).

[0650] Combinations comprising an inhaled β2-adrenergic receptor agonist bronchodilator such as formoterol, salbutamol or salmeterol and a compound described herein are also suitable but non-limiting combinations useful for treating respiratory viral infections.

[0651] Combinations of inhaled β2-adrenergic agonist bronchodilators such as formoterol or salmeterol with ICS are also used to treat bronchoconstriction and inflammation ( and Combinations comprising these ICS and β2-adrenergic receptor agonist combinations and the compounds described herein are also suitable but non-limiting combinations useful for treating respiratory viral infections.

[0652] Other examples of beta2 adrenergic receptor agonists are bedoradrine, vilanterol, indacaterol, olodaterol, tulobuterol, formoterol, abitirol, albuterol, arformoterol, levalbuterol, fenoterol, and TD-5471.

[0653] Anticholinergics have potential use for the treatment or prevention of pulmonary bronchoconstriction and thus may be used as additional therapeutic agents in combination with the compounds described herein to treat viral respiratory infections.These anticholinergic agents include, but are not limited to, antagonists of muscarinic receptors (particularly the M3 subtype), which have demonstrated therapeutic efficacy in humans for controlling cholinergic tone in COPD (Witek, 1999); 1-{4-hydroxy-1-[3,3,3-tris-(4-fluorophenyl)-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- 1-Aza-bicyclo[2.2.2]oct-3-yl formate (Sofenacin); 1-Aza-bicyclo[2.2.2]oct-3-yl 2-hydroxymethyl-4-methanesulfinyl-2-phenyl-butyrate (Revatropate); 2-{1-[2-(2,3-dihydro-benzofuran-5-yl)-ethyl]-pyrrolidin-3-yl}-2,2-diphenyl-acetamide (Darifenacin); 4-Azacycloheptane-1-yl-2,2-diphenyl-butyramide (Buzepide); 7-[3-(2-diethylamino-acetoxy)-2-phenyl-propionyloxy]-9-ethyl-9-methyl-3-oxa-9-azonia-tricyclo[3.3.1.02,4]nonane (Oxytropine-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); dimethylamino-acetic acid 2-(3-diisopropylamino-1-phenyl-propyl)-4-methyl-phenyl ester (tolterodine-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-aza-bicyclo[2.2.2]oct-3-yl)-1-phenyl-prop-2-yn-1-ol; 3-[2-(2-diethylamino-acetoxy)-2,2-dithiophen-2-yl-acetoxy]-1-(3-phenoxy-propyl)-1-azonia-bicyclo[2.2.2]octane (Aclidinium bromide-N,N-diethylglycinate); or (2-diethylamino-acetoxy)-dithiophen-2-yl-acetic acid 1-methyl-1-(2-phenoxy-ethyl)-piperidin-4-yl ester; revenacin, glycopyrrolate, umeclidinium bromide, tiotropium bromide, aclidinium bromide, bencyclidine bromide.

[0654] The compounds described herein may also be combined with mucolytics to treat symptoms of infection and respiratory tract infection. A non-limiting example of a mucolytic is ambroxol. Similarly, the compounds may be combined with expectorants to treat symptoms of infection and respiratory tract infection. A non-limiting example of an expectorant is guaifenesin.

[0655] Nebulized hypertonic saline is used to improve immediate and long-term clearance of the small airways in patients with lung disease (Kuzik, J. Pediatrics 2007, 266). Therefore, the compounds described herein may also be combined with nebulized hypertonic saline, particularly when viral infection is complicated by bronchiolitis. The combination of the compounds described herein with hypertonic saline may also include any of the additional agents discussed above. In one embodiment, nebulized about 3% hypertonic saline is used.

[0656] The compounds and compositions provided herein are also useful in combination with other active therapeutic agents. For the treatment of Flaviviridae infections, preferably, the other active therapeutic agent has anti-Flavviridae infection activity.

[0657] For the treatment of dengue virus infection, non-limiting examples of other active therapeutic agents are host cytokine 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 modipaban; 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.

[0658] In some embodiments, the other active therapeutic agent may be a vaccine for the treatment or prevention of dengue fever, including but not limited to TetraVax-DV, DPIV-001, TAK-003, live attenuated dengue vaccine, quadrivalent dengue vaccine, quadrivalent DNA vaccine, rDEN2delta30-7169, and DENV-1PIV.

[0659] The compounds described herein are also used in combination with other active therapeutic agents. For the treatment of Filoviridae infections, preferably, the other active therapeutic agent has activity against Filoviridae infections, particularly Marburg virus, Ebola virus and Queva virus infections. Non-limiting examples of these other active therapeutic agents are: 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-(di methylamino)propyl]-3,9-dimethylquinolino[8,7-h]quinolone-1,7-diamine), rNAPc2, OS-2966, brincidofovir, remdesivir; RNA polymerase inhibitors such as galidesivir, favipiravir (also known as T-705 or Avigan), JK-05; host cytokine regulators such as GMV-006; cadherin-5 / factor Ia regulators such as FX-06; and antibodies for the treatment of Ebola such as REGN-3470-3471-3479 and ZMapp.

[0660] Other non-limiting active therapeutic agents with anti-Ebola activity include alpha-glucosidase 1 inhibitors, cathepsin B inhibitors, CD29 antagonists, dendritic ICAM-3 grasping non-integrin 1 inhibitors, estrogen receptor antagonists, factor VII antagonists, HLA class II antigen modulators, host cytokine modulators, interferon alpha ligands, neutral alpha glucosidase AB inhibitors, Niemann-Pick C1 protein inhibitors, nucleoprotein inhibitors, polymerase cofactor VP35 inhibitors, serine protease inhibitors, tissue factor inhibitors, TLR-3 agonists, viral envelope glycoprotein inhibitors and Ebola virus entry inhibitors (NPC1 inhibitors).

[0661] 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, adenovirus-based Ebola vaccine, rVSV-EBOV, rVSVN4CT1-EBOVGP, MVA-BN Filo+Ad26-ZEBOV regimen, INO-4212, VRC-EBODNA023-00-VP, VRC-EBOADC069-00-VP, GamEvac-combi vaccine, SRC VB vector, HPIV3 / EboGP vaccine, MVA-EBOZ, Ebola recombinant glycoprotein vaccine, Ebola vaccine based on Vaxart adenovirus vector 5, FiloVax vaccine, GOVX-E301 and GOVX-E302.

[0662] 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.

[0663] The compounds described herein are also intended for use with general care provided to patients with Filoviridae infections, including parenteral fluids (including dextrose saline and Ringer's lactate) and nutrients, antibiotics (including metronidazole and cephalosporin antibiotics such as ceftriaxone and cefuroxime) and / or antifungal prophylaxis, fever and pain medications, antiemetics (such as metoclopramide) and / or antidiarrheal medications, vitamin and mineral supplements (including vitamin K and zinc sulfate), anti-inflammatory agents (such as ibuprofen), pain medications, and medications for other common diseases in the patient population, such as antimalarials (including artemether and artesunate-lumefantrine combination therapy), typhoid vaccines (including quinolone antibiotics such as ciprofloxacin, macrolide antibiotics such as azithromycin, cephalosporin antibiotics such as ceftriaxone, or aminopenicillins such as ampicillin) or shigellosis vaccines.

[0664] Also provided herein is a method of treating a viral infection in a human in need thereof, the method comprising administering to the human

[0665] (i) Compound 1:

[0666] Deuterated Compound 1, a prodrug of Compound 1, a prodrug of deuterated Compound 1, or a pharmaceutically acceptable salt thereof; and

[0667] (ii) one or more SARS-CoV-2 MPro inhibitors;

[0668] Wherein when the prodrug of Compound 1, the deuterated prodrug of Compound 1, or a pharmaceutically acceptable salt thereof is administered to a human, the prodrug of Compound 1, the deuterated prodrug of Compound 1, or a pharmaceutically acceptable salt thereof is substantially converted into Compound 1 or the deuterated Compound 1.

[0669] In some embodiments, the SARS-CoV-2 MPro inhibitor is namatevir, ritonavir, or a combination thereof.

[0670] Also provided herein is a method of treating a viral infection in a human in need thereof, the method comprising administering to the human

[0671] (i) Compound 1:

[0672] Deuterated Compound 1, a prodrug of Compound 1, a prodrug of deuterated Compound 1, or a pharmaceutically acceptable salt thereof; and

[0673] (ii) namatevir, ritonavir, or a combination of namatevir and ritonavir;

[0674] Wherein when the prodrug of Compound 1, the deuterated prodrug of Compound 1, or a pharmaceutically acceptable salt thereof is administered to a human, the prodrug of Compound 1, the deuterated prodrug of Compound 1, or a pharmaceutically acceptable salt thereof is substantially converted into Compound 1 or the deuterated Compound 1.

[0675] In some embodiments, the method includes administering to a human (i) Compound 1 or a prodrug or a pharmaceutically acceptable salt of Compound 1 and (ii) Namatevir, Ritonavir, or a combination of Namatevir and Ritonavir. In some embodiments, the method includes administering Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the method includes administering Compound 1. In some embodiments, the method includes administering deuterated Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the method includes administering deuterated Compound 1. In some embodiments, the method includes administering a prodrug of deuterated Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the method includes administering a prodrug of deuterated Compound 1. In some embodiments, the method includes administering a prodrug of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the method includes administering a prodrug of deuterated Compound 1. In some embodiments, the method includes administering a prodrug of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the method includes administering a prodrug of Compound 1.

[0676] In some embodiments, a prodrug of Compound 1 is:

[0677]

[0678] In some embodiments, when applied to humans, (i) Compound 1 or its pharmaceutically acceptable salt or prodrug and (ii) Namatevir, ritonavir, or a combination of Namatevir and ritonavir has a synergistic effect. In some embodiments, when applied to humans, (i) Compound 1 or its pharmaceutically acceptable salt or prodrug and (ii) Namatevir, ritonavir, or a combination of Namatevir and ritonavir has an additive effect. In some embodiments, when applied to humans, (i) Compound 1 or its pharmaceutically acceptable salt or prodrug and (ii) Namatevir, ritonavir, or a combination of Namatevir and ritonavir has a non-antagonistic effect.

[0679] In some embodiments, the human is not a pregnant individual. In some embodiments, the human is not hospitalized. In some embodiments, the human is hospitalized.

[0680] In some embodiments, nematevir is administered to the human being without ritonavir. In some embodiments, ritonavir is administered to the human being without nematevir. In some embodiments, both ritonavir and nematevir are administered to the human being.

[0681] In some embodiments, Naimategravir is administered orally. In some embodiments, Naimategravir is administered twice a day. In some embodiments, Naimategravir is administered twice a day for a period of at least five days. In some embodiments, Naimategravir is administered twice a day for a period of five days. In some embodiments, Naimategravir is administered within 5 days of symptom onset. In some embodiments, Naimategravir is administered within 1 day, 2 days, 3 days, 4 days or 5 days of symptom onset. In some embodiments, Naimategravir is administered at a dosage of 100mg to 1,600mg, 100mg to 900mg, 100mg to 700mg, 100mg to 500mg, 100mg to 400mg / dose, 200mg to 1,600mg, 200mg to 900mg, 200mg to 800mg, 200mg to 700mg, 200mg to 500mg or 200mg to 400mg. In some embodiments, namatevir is administered at a dose of about 300 mg. In some embodiments, the dose includes two tablets of about 150 mg. In some embodiments, a dose of about 300 mg is administered twice a day. In some embodiments, 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 namatevir is administered to the person. In some embodiments, about 600 mg of namatevir is administered to the person every day.

[0682] In some embodiments, ritonavir is administered orally. In some embodiments, ritonavir is administered twice a day. In some embodiments, ritonavir is administered twice a day for a period of at least five days. In some embodiments, ritonavir is administered twice a day for a period of five days. In some embodiments, ritonavir is administered within 5 days of symptom onset. In some embodiments, ritonavir is administered within 1 day, 2 days, 3 days, 4 days or 5 days of symptom onset. In some embodiments, ritonavir is administered at a dosage of 25mg to 800mg, 25mg to 600mg, 25mg to 400mg, 25mg to 300mg, 25mg to 150mg, 50mg to 800mg, 50mg to 700mg, 50mg to 600mg, 50mg to 400mg, 50mg to 300mg or 50mg to 150mg. In some embodiments, ritonavir is administered at a dosage of about 100mg. In some embodiments, the dosage includes a tablet of about 100mg. In some embodiments, a dose of about 100 mg is administered twice daily. In some embodiments, 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 is administered to the human daily. In some embodiments, about 200 mg of ritonavir is administered to the human daily.

[0683] In some embodiments, namatevir and ritonavir are administered orally. In some embodiments, namatevir and ritonavir are administered twice a day. In some embodiments, namatevir and ritonavir are administered twice a day for at least a five-day period. In some embodiments, namatevir and ritonavir are administered twice a day for a five-day period. In some embodiments, namatevir and ritonavir are administered within 5 days of symptom onset. In some embodiments, namatevir and ritonavir are administered within 1 day, 2 days, 3 days, 4 days, or 5 days of symptom onset. In some embodiments, namatevir 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, namatevir is administered at a dose of about 300 mg and ritonavir is administered at a dose of about 100 mg. In some embodiments, the namatevir dose includes two tablets of about 150 mg and the ritonavir dose includes one tablet of about 100 mg. In some embodiments, the namatevir dose of about 300 mg and the ritonavir dose of about 100 mg are administered twice a day. In some embodiments, the 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 / dose per day. In some embodiments, the human is administered about 600 mg of namatevir per day and about 200 mg of ritonavir per day.

[0684] 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 (COVID19). In some embodiments, the viral infection is a SARS-CoV-2 infection (COVID19).

[0685] The present invention will be described in more detail by specific examples. The following examples are provided for illustrative purposes and are not intended to limit the present invention in any way. Those skilled in the art will readily recognize that various non-critical parameters that can be changed or modified to produce substantially the same result.

[0686] Example

[0687] The present invention is further described in the following examples, which do not limit the scope of the invention described in the claims.

[0688] Example 1. Nonclinical studies - Toxicology studies: Administration of compounds by gavage in Wistar Han rats 16Conduct dose-ranging enhancement-discovery studies and toxicokinetic embryo-fetal development studies

[0689] The effects of compound 16 on pregnant Wistar Han rats and embryonic development from implantation to hard palate closure caused by exposure of female rats were evaluated. Compound 16 was administered to 4 groups of presumed pregnant rats (8 / group) at a dose of 0 (vehicle) mg / kg / day, 125 mg / kg / day, 250 mg / kg / day and 500 mg / kg / day via once-daily gavage at a dose volume of 5 mL / kg during organ formation (gestational day [GD] 6 to 17). Other pregnant rats were administered in a similar manner to perform toxicokinetic evaluations of compound 16 and compound 1. The evaluation of toxicity in pregnant rats was based on mortality, clinical observations, body weight and food intake. The rats were autopsied at GD 21 and delivered by cesarean section. The external features of the corpse were examined; external body orifices; abdominal cavity, thoracic cavity, pelvic cavity and oral cavity; organs; and tissues. Note any macroscopic abnormalities. Determine the state of pregnancy. The uterus of each pregnant animal was removed, weighed, and examined for the number and location of live and dead fetuses, the number of early or late resorptions, and any abnormalities. The number of corpora lutea from the right and left ovaries of each pregnant female was examined. Each fetus was sexed, weighed, and examined for external abnormalities. The head of each fetus was removed, frozen on dry ice, and cross-sectioned using the Wilson sectioning technique (Astroff et al., 2002). The internal organs of the thoracic and abdominal cavities were examined in a fresh state using a modified Staple technique (Stuckhardt and Poppe, 1984). Fetal findings were classified as deformed or malformed.

[0690] The dose level of 500 mg / kg / day was not tolerated, and the toxic dose group was terminated as early as gestational day (GD) 16. Mortality, severe clinical signs, macroscopic observation of enlarged and discolored kidneys and enlarged and discolored adrenal glands at autopsy were expected findings as these findings had been observed in previous toxicology studies in female rats. Fetal parameters in this group were not evaluated due to excessive maternal toxicity.

[0691] There were no significant clinical signs or significant effects on body weight, food intake or macroscopic observations at 125 mg / kg / day or 250 mg / kg / day. No compound 16-related effects were observed for embryo-fetal viability parameters, litter size and fetal weight or fetal pathology at 125 mg / kg / day or 250 mg / kg / day. The no observed adverse effect level (NOAEL) for maternal toxicity and embryo-fetal development was 250 mg / kg / day, which was associated with a compound 1 AUC0-24h exposure of 183,000 ng*h / mL at GD 17.

[0692] Example 2. Nonclinical studies - Toxicology studies: Administration of compounds by gavage in Wistar Han rats 16 Conduct embryo-fetal development research

[0693] The potential of Compound 16 to induce developmental toxicity following maternal exposure during the critical period of organogenesis (GD 6 to 17) was evaluated, maternal toxicity at the exposure levels tested was characterized, and no observed adverse effect levels (NOAELs) for maternal and developmental toxicity were determined following oral administration in Wistar Han rats.

[0694] Compound 16 was administered to 3 groups of presumed pregnant rats (25 / group) at doses of 0 (vehicle) mg / kg / day, 125 mg / kg / day, and 250 mg / kg / day via gavage once daily at a dose volume of 5 mL / kg during organogenesis (gestational day [GD] 6 to 17). The toxicity of pregnant rats was assessed based on mortality, clinical observations, body weight, and food intake. Rats were autopsied at GD 21 and cesarean sections were performed. The external features of the corpse were examined; external body orifices; abdominal, thoracic, pelvic, and oral cavities; organs; and tissues. Any macroscopic abnormalities were noted. Determine the state of pregnancy. The uterus of each pregnant animal was excised, weighed, and examined for the number and location of surviving and dead fetuses, the number of early or late resorptions, and any abnormalities. The number of corpora lutea from the right and left ovaries of each pregnant female animal was examined. Each fetus was sexed, weighed, and examined for external abnormalities. Approximately half of the fetuses from each litter were examined for visceral abnormalities in the fresh state by dissection. The thoracic and abdominal cavities were opened and dissected using the technique described by Stuckhardt and Poppe (1984). The fetal kidneys were examined and the renal papillary development was graded (Woo and Hoar, 1972). The heads of these fetuses were removed and placed in Davidson's fixative for soft tissue examination using the Wilson sectioning technique (Wilson, 1965). The remaining fetuses (approximately half of each litter) were eviscerated, fixed in 100% ethanol, immersed in potassium hydroxide, and stained with Alizarin Red S for subsequent skeletal examination by a method similar to that described by Dawson (1926).

[0695] No effects on intrauterine growth or survival were noted related to Compound 16. No external, visceral, or skeletal malformations or deformations were noted related to Compound 16. The no observed adverse effect level (NOAEL) for maternal toxicity and embryo-fetal development was 250 mg / kg / day.

[0696] Example 3. Nonclinical studies - toxicology studies: gavage embryo-fetal development in rabbits with compound 16 and toxicokinetic studies

[0697] The effects of compound 16 on pregnant New Zealand white rabbits (NZW) and embryonic development from implantation to hard palate closure (gestational day [GD] 7 to 19) caused by exposure of female rabbits were evaluated. Compound 16 was administered to 4 groups of pregnant rabbits (20 / group) at doses of 0 (0.5% methylcellulose solution in deionized water) mg / kg / day, 125 mg / kg / day, 250 mg / kg / day and 500 mg / kg / day via gavage once daily during organogenesis (GD 7 to 19). Toxicity assessments were based on mortality, clinical observations, body weight, food intake, and autopsy and cesarean section findings. In addition, blood samples were collected from animals (4 / group) administered in a similar manner for toxicokinetic evaluation of compound 16 and compound 1. Due to excessive maternal toxicity observed at a dose of 500 mg / kg / day, the toxic dose group was terminated as early as between GD 17 and 22, and the fetal parameters of this group were not evaluated.

[0698] For animals administered at 250 mg / kg / day or 500 mg / kg / day, a decrease in food intake was noted compared to the control, with a decrease in mean maternal weight gain relative to the control in animals administered at 250 mg / kg / day, and a decrease in mean body weight relative to GD 7 body weight in animals administered at 500 mg / kg / day. An increase in the rate of post-implantation weight loss was noted in animals administered at 250 mg / kg / day. For animals administered at 250 mg / kg / day, the increase in the rate of post-implantation weight loss was associated with an increase in the mean number of early resorptions and a decrease in the mean number of surviving fetuses. An increase in the rate of ventricular septal defects, large or small ventricles, dilation or misalignment of the aorta, retroesophageal aortic arch, retroesophageal subclavian artery, and abnormal lobulation of the liver was noted in fetuses from animals administered at 250 mg / kg / day. No skeletal malformations associated with Compound 16 were noted. Based on these findings, the NOAEL of compound 16 for embryo-fetal development in rabbits was 125 mg / kg / day, which correlated with a compound 1 AUC0-24h exposure of 64,100 ng*h / mL at GD 17.

[0699] Example 4. In vitro combination analysis of clinically used SARS-CoV-2 antiviral drugs and compound 1 / compound 16

[0700] Materials and methods

[0701] Compound

[0702] All compounds were synthesized by known methods or purchased. Confirmation of chemical species was determined by NMR and LCMS, and purity was >95% as assessed by HPLC. Compounds were dissolved in 100% dimethyl sulfoxide (DMSO) at a concentration of 10 mM.

[0703] cell

[0704] A549-hACE2 cells stably expressing human angiotensin converting enzyme 2 (hACE2) were established and provided by University ofTexas Medical Branch (Mossel, EC 2005). A549-hACE2 cells were maintained in Dulbecco's Minimum Essential Medium (DMEM) (Gibco catalog number 10569-010) containing GlutaMAX at 37°C and 5% CO2, and the culture medium was supplemented with 10% heat-inactivated fetal bovine serum (FBS) (Hyclone catalog number SH30396.03), 100 units / mL penicillin, 100 μg / mL streptomycin (Gibco catalog number 15140-122) and selection agent-10 μg / mL blasticidin. The A549-hACE2 cells used in all experimental settings were between the 5th and 30th generations.

[0705] Virus proliferation

[0706] Recombinant firefly luciferase WA SARS-CoV-2 virus (SARS-CoV-2Fluc) was amplified from a stock obtained from the University of Texas Medical Branch (UTMB; Galveston, TX) 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-2Fluc was propagated as a high titer stock in Vero-TMPRSS2 cells as follows: 1×10 7 Vero-TMPRSS2 cells were inoculated into Vero-TMPRSS2 maintenance medium in a T225 flask and incubated overnight at 37°C + 5% CO2. The next day, the culture medium was aspirated, replaced with 25 mL of DMEM (infection medium) supplemented with 2% FBS, and infected with 10 μL P0 SARS-CoV-2Fluc stock solution. The flask was returned to 37°C + 5% CO2 until only 10%-20% of viable cells remained (usually 36 hours -72 hours (hpi) after infection). The supernatant was harvested into a 50 mL falcon tube and centrifuged at 2000 × g for 5 minutes to precipitate cell debris. The clarified supernatant was then divided into 250 μL aliquots as a working P1 stock solution and frozen at -80°C. The titer of the working P1 stock solution was determined by plaque formation assay (PFA).

[0707] SARS-CoV-2 Fluc Antiviral Assay

[0708] A549-hACE2 cells were seeded in 100 μL volume of maintenance medium in 96-well plates at 12,000 cells / well and incubated overnight at 37 ° C and 5% CO2. The next day, the spent culture medium was aspirated and 100 μL infection medium (supplemented with 2% FBS DMEM) was added to each well. The compound was added directly to the culture using an HP D300e digital liquid dispenser, where the DMSO volume was normalized to the volume of the highest compound concentration (final DMSO concentration <0.1%). The plates (each combination in quadruplicate) were arranged in an array format, where the concentrations of the two drugs to be evaluated were gradually increased across rows and columns, and then compound dilutions were randomly placed on each plate to reduce the variability caused by edge effects. Compound 16, compound 1 and Monupivir were respectively distributed to the plate at starting concentrations of 4000nM, 5000nM and 10,000nM, and titrated by the pre-determined optimal serial dilutions of each compound. Namatevir was distributed to the plate at a starting concentration or 600nM and serially diluted at 1:2. For the three-drug combination, the compound was distributed as described above, but for the entire single plate, ritonavir was distributed at 0nM, 300nM, 600nM, 1200nM or 2400nM, and 2 other compounds (compound 16 and Namatevir or compound 1 and Namatevir) were evaluated in addition. 50 μL of recombinant WA SARS-CoV-2Fluc was added with an MOI of 1, and 50 μL of infection culture medium was added to a column for uninfected control wells, and the culture was incubated at 37°C and 5% CO2. At 24hpi, the culture was removed from the incubator, and 50 μL of Promega One-Glo luciferase assay system (CAT#E6120) was added to all wells. The plate was placed on an orbital shaker for 10 minutes and luminescence was read on a Perkin Elmer Envision plate reader.

[0709] SynergyFinder3.0 Analysis

[0710] After derandomization of the raw luminescence data from the Envision plate reader in Microsoft Excel, the dose-dependent inhibition percentage of WA SARS-CoV-2Fluc was calculated (inhibition % = 100 × (1-(X-min) / (max-min)), and the data matrix was uploaded into the Synergy Finder (version 3.0) (https: / / synergyfinder.fimm.fi) analysis software {Ianevski, A 2022#67038}. The Bliss independent action (background correction) mathematical model was used to quantify the drug combination effect. A synergy report was generated for each drug combination, and the score was reported as the median of all four biological parallel determinations using a conventional synergy scoring method. This method defines a synergy score between -10 and 10 as an additive effect, and considers a synergistic effect below -10 as an antagonistic effect and a synergistic effect above 10 {Ianevski, A 2022#67038}.

[0711] result

[0712] The following drug combinations were evaluated using the Bliss independent action consistency score by interpreting any score between -10 and 10 as an additive effect, greater than 10 as a synergistic effect, and less than 10 as an antagonistic effect. An overview of the Bliss consistency scores for the combination of the two drugs is reported in Table 4.1 and Table 4.2. For the combination of the two drugs of Compound 1 and Namatevir, an additive effect with an average Bliss score of 0.96 ± 0.67 was observed for four replicates (a representative Bliss independent action diagram is shown in Figure 1 In). For compound 16 and namatevir, an additive effect was observed in parallel determinations, and the average Bliss score was 2.77 ± 0.07. For the combination of compound 1 and Monupivir and the combination of compound 16 and Monupivir, an additive effect was observed, which was confirmed by the average Bliss scores of -0.22 ± 0.20 and -1.36 ± 1.44, respectively. Together with the combination of these 2 drugs, compound 1, compound 16, namatevir and Monupivir were tested as a combination of themselves and themselves to be used as a determination validation control. The compounds cannot synergize or antagonize with themselves, and for all drugs evaluated, the determination confirmed the additive effect of the drug itself and its combination. Additive effects were observed for Compound 1, Compound 16, Nematevir, and Monouprivir by themselves and in combination with themselves, 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.

[0713] The Bliss consistency scores for the three-drug combinations are summarized in Tables 4.3 and 4.4. For the three-drug combination of Compound 1, Nematevir, and Ritonavir, an additive effect with a mean Bliss score of 2.80 ± 3.95 was observed. Figure 2 The representative Bliss independent action diagram of the combination is shown. Together with the triple drug combination, the combination of namatevir and ritonavir, compound 1 and ritonavir and compound 1 and namatevir's 2 kinds of drugs also confirmed the additive effect, wherein the average Bliss score was 0.63 ± 5.65, -2.47 ± 3.00 and 1.67 ± 0.53 respectively. Similarly, the three-drug combination of compound 16, namatevir and ritonavir confirmed the additive effect, wherein the average Bliss score was observed to be 5.33 ± 4.76 in parallel determination. Together with the three-drug combination, the combination of namatevir and ritonavir, compound 16 and ritonavir and compound 16 and namatevir's 2 kinds of drugs also confirmed the additive effect, wherein the average Bliss score was observed to be 6.31 ± 5.38, 0.75 ± 6.96 and 2.01 ± 0.79 respectively.

[0714] Table 4.1. Dual-drug combination Bliss-independent effects for A549-hACE-2 SARS-CoV-2 Fluc antiviral analysis Consistency score

[0715]

[0716] Table 4.2. Dual-drug and self-combination for A549-hACE-2 SARS-CoV-2 Fluc antiviral analysis Bliss independent action consistency score

[0717]

[0718] Table 4.3. Three-drug combination compound 1 Bliss unique for A549-hACE-2 SARS-CoV-2 Fluc antiviral analysis Consistency score

[0719]

[0720]

[0721] Table 4.4. Three-drug combination compound 16Bliss for A549-hACE-2SARS-CoV-2Fluc antiviral analysis Independent Action Consistency Score

[0722]

[0723] In A549-hACE-2 cells, drug combinations of compound 1 or compound 16 with monoupivir, namatevir and / or ritonavir all demonstrated additive effects against SARS-CoV-2.

[0724] Example 5. Dual-drug combination Loewe model for A549-hACE-2 SARS-CoV-2 Fluc antiviral analysis score

[0725] Materials and methods

[0726] Compound

[0727] All compounds were synthesized by known methods or purchased. Confirmation of chemical species was determined by NMR and LCMS, and purity was >95% as assessed by HPLC. Compounds were dissolved in 100% dimethyl sulfoxide (DMSO) at a concentration of 10 mM.

[0728] cell

[0729] A549-hACE2 cells stably expressing human angiotensin converting enzyme 2 (hACE2) were established and provided by University ofTexas Medical Branch (Mossel, EC 2005). A549-hACE2 cells were maintained in Dulbecco's Minimum Essential Medium (DMEM) (Gibco catalog number 10569-010) containing GlutaMAX at 37°C and 5% CO2, and the culture medium was supplemented with 10% heat-inactivated fetal bovine serum (FBS) (Hyclone catalog number SH30396.03), 100 units / mL penicillin, 100 μg / mL streptomycin (Gibco catalog number 15140-122) and selection agent-10 μg / mL blasticidin. The A549-hACE2 cells used in all experimental settings were between the 5th and 30th generations.

[0730] Virus proliferation

[0731] Recombinant firefly luciferase WA SARS-CoV-2 virus (SARS-CoV-2Fluc) was amplified from a stock obtained from the University of Texas Medical Branch (UTMB; Galveston, TX) 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-2Fluc was propagated as a high titer stock in Vero-TMPRSS2 cells as follows: 1×10 7Vero-TMPRSS2 cells were inoculated into Vero-TMPRSS2 maintenance medium in a T225 flask and incubated overnight at 37°C + 5% CO2. The next day, the culture medium was aspirated, replaced with 25 mL of DMEM (infection medium) supplemented with 2% FBS, and infected with 10 μL P0 SARS-CoV-2Fluc stock solution. The flask was returned to 37°C + 5% CO2 until only 10%-20% of viable cells remained (usually 36 hours -72 hours (hpi) after infection). The supernatant was harvested into a 50 mL Falcon tube and centrifuged at 2000 × g for 5 minutes to precipitate cell debris. The clarified supernatant was then divided into 250 μL aliquots as a working P1 stock solution and frozen at -80°C. The titer of the working P1 stock solution was determined by plaque formation assay (PFA).

[0732] SARS-CoV-2 Fluc Antiviral Assay

[0733] A549-hACE2 cells were seeded at 12,000 cells / well in a 96-well plate in a 100 μL volume of maintenance medium and incubated overnight at 37 ° C and 5% CO2. The next day, the spent medium was aspirated and 100 μL of infection medium (DMEM supplemented with 2% FBS) was added to each well. The compound was added directly to the culture using an HP D300e digital liquid dispenser, with the DMSO volume normalized to the volume of the highest compound concentration (final DMSO concentration <0.1%). The plates (four replicates for each combination) were arranged in an array format, where the concentrations of the two drugs to be evaluated were gradually increased across rows and columns, and then the compound dilutions were randomly placed on each plate to reduce the variability caused by edge effects. 50 μL of recombinant WA SARS-CoV-2Fluc was added at an MOI of 1, and 50 μL of infection medium was added to one column for the uninfected control wells, and the culture was incubated at 37 ° C and 5% CO2. At 24 hpi, cultures were removed from the incubator and 50 μL of Promega One-Glo Luciferase Assay System (CAT# E6120) was added to all wells. Plates were placed on an orbital shaker for 10 minutes and luminescence was read on a Perkin Elmer Envision plate reader.

[0734] SynergyFinderPlus Analysis

[0735] After the raw luminescence data from the Envision plate reader were derandomized in Microsoft Excel, the dose-dependent inhibition percentage of WA SARS-CoV-2Fluc was calculated (inhibition % = 100 × (1-(X-min) / (max-min)), and the data matrix was uploaded to 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 synergistic effect report was generated for each drug combination. This method defines the synergistic effect score between -10 and 10 as an additive effect, and considers that less than -10 is an antagonistic effect, and more than 10 is a synergistic effect {Ianevski, A 2022 # 67038}. The results are shown in Table 5.1.

[0736] Table 5.1: Loewe model scoring of dual drug combinations for A549-hACE-2SARS-CoV-2Fluc antiviral analysis

[0737]

[0738] Example 6. Use in non-infectious BHK-SARS-2R_GFP_NeoR_NL (SCL414) replicon cells Loewe model scoring of dual-drug combination for A549-hACE-2SARS-CoV-2Fluc antiviral analysis

[0739] Materials and methods

[0740] Cell culture

[0741] The non-infectious BHK-SARS-2R_GFP_NeoR_NL (SCL414) replicon cell line was authorized for use by Emory University (Lan et al. 2021). These cell lines are stable cell lines expressing SARS-CoV-2 replicon DNA and sNLuc reporter genes. Cells were maintained in Dulbecco's Modified Eagle Medium (ThermoFisher, catalog number 10566016) supplemented with 10% fetal bovine serum (ThermoFisher, catalog number SH3040602HI), 100U / mL penicillin / 100μg / mL streptomycin (ThermoFisher, catalog number 15140122), and 1mg / mL Geneticine TM (ThermoFisher, catalog number 10131027).

[0742] Drug combination assay

[0743] 50 μL of BHK-SARS-2R_GFP_NeoR_NL replicon cell line in assay medium (DMEM supplemented with 10% FBS) was added to a white clear 96-well bottom plate (ThermoFisher, catalog number 07-200-566). Serial dilutions of compound 1 and namatevir were added in matrix form to wells with assay medium using an HP D300e digital dispenser and standardized to DMSO (ATCC 4-X TM ) at the highest concentration (>0.1% final volume). The starting concentration of compound 1 was 12 μM and the starting concentration of nematevir was 1.2 μM. For the negative control, puromycin dissolved in DMSO was added to a final concentration of 10 μM. Untreated wells were used as positive controls. For this assay, drug combination matrices of compound 1 with nematevir and nematevir with compound 1 itself (internal control) were tested. The cells were then incubated at 8.0×10 4 Cells / mL were seeded in the same plate in a total volume of 100 μL / well and incubated at 37°C and 5% CO2 for three days. 50 μL / well of room temperature Luciferase reagent (Promega, catalog number N1110) is added to the plate. The plate is incubated on a shaker at room temperature for 1 minute-2 minutes, and the luminescence is measured using an Envision plate reader (PerkinElmer, catalog number 2105-0010). Three replicates are performed for each combination. The average value of the three replicates is used for analysis. The drug response data is normalized to positive and negative controls to determine the percentage of inhibition.

[0744] SynergyFinderPlus Analysis

[0745] After the raw luminescence data from the Envision plate reader were derandomized in Microsoft Excel, the dose-dependent inhibition percentage of WA SARS-CoV-2Fluc was calculated (inhibition % = 100 × (1-(X-min) / (max-min)), and the data matrix was uploaded to 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 synergistic effect report was generated for each drug combination. This method defines the synergistic effect score between -10 and 10 as an additive effect, and considers that less than -10 is an antagonistic effect, and more than 10 is a synergistic effect {Ianevski, A 2022 # 67038}. The results are shown in Table 6.1.

[0746] Table 6.1: Loewe model scoring of dual drug combinations for A549-hACE-2 SARS-CoV-2 Fluc antiviral analysis

[0747]

[0748] All references, including publications, patents and patent documents are incorporated herein by reference, as if separately incorporated by reference. The disclosure provides references to various embodiments and technologies. However, it should be understood that many changes and modifications can be made while remaining within the spirit and scope of the disclosure. It should be understood that when this description is made, it is considered to be an illustration of the claimed subject matter and is not intended to limit the attached claims to the specific embodiments described.

Claims

1. A method of treating a viral infection in a patient in need thereof, wherein the method comprises administering to the patient a compound of formula A: A deuterated compound of formula A, a prodrug of the compound of formula A, a prodrug of the 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 ; R 2 -OH, -OC(=O)R 5 OR-OC(=O)OR 5 ;or R 1 and R 2 Together they form -OC(=O)O-, -OP(=O)(OH)O- or -OCHR 6 O-; R 4 and R 5 are independently H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclyl, C6-C 10 aryl, a 4- to 6-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O and S, or a 5- to 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S; wherein R 4 and R 5 Each 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 and optionally substituted by one, two or three R a Substituent substitution; R 6 is H, C1-C6 alkyl, C1-C6 alkoxy, a 5- to 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S, or a C6-C 10 Aryl; wherein R 6 Each 5- to 6-membered heteroaryl and C6-C 10 Aryl is independently and optionally substituted by one, two or three R b Substituent substitution; Alkali is R 11 is optionally substituted with -OP(=O)(OH)(OR 14 ) substituted C1-C6 alkyl; R 12 is H, C1-C6 alkyl, -C(=O)R 13 OR -C(=O)OR 13 ; Each R 13 independently H, C1-C 10 Alkyl, C6-C 10 Aryl, -O-C6-C 10 Aryl or -O-C1-C 10 Alkyl; wherein R 13 Each C1-C 10 Alkyl, C6-C 10 Aryl, -O-C6-C 10 Aryl and -O-C1-C 10 The alkyl group is independently and optionally substituted by one, two or three R c Substituent substitution; Each R a are independently halo, cyano, C1-C6 alkyl, carbonyl, -N3, -OR 8 、-NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic group, 4- to 6-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O and S, 5- to 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S, or phenyl; wherein R a Each 4- to 6-membered heterocyclic group is independently, optionally, substituted by one, two or three R d Substituent substitution; wherein R a Each phenyl group is independently, optionally, substituted by one, two or three R e Substituent substitution; R 8 , R 9 and R 10 Each is independently H, C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl Each R b are independently halo, cyano, C1-C6 alkoxy or C1-C6 alkyl; Each R c are independently halo, cyano, -OP(=O)(OH)(OR 14 ) or phenyl; wherein R c Each phenyl group of 14 )replace; Each R 14 are independently H, C1-C8 alkyl, C3-C8 carbocyclic, C6-C 10 aryl, or a 5- to 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S; wherein R 14 Each C1-C8 alkyl group is independently, optionally substituted by one, two or three R f Substituent substitution; Each R d are independently carbonyl or C1-C6 alkyl; Each R e are independently halo, cyano or C1-C6 alkyl; and Each R f are independently halo, cyano or phenyl; wherein when the prodrug of the compound of formula A, the prodrug of the deuterated compound of formula A, or the pharmaceutically acceptable salt thereof is administered, the prodrug of the compound of formula A, the prodrug of the deuterated compound of formula A, or the pharmaceutically acceptable salt thereof is substantially converted to the compound of formula A or the deuterated compound of formula A; and wherein the patient is not a pregnant individual.

2. The method of claim 1, wherein after administration to the patient, greater than 60% of the prodrug of the compound of Formula A, the prodrug of the deuterated compound of Formula A, or the pharmaceutically acceptable salts thereof are converted to the compound of Formula A or the deuterated compound of Formula A.

3. The method of claim 1, wherein after administration to the patient, greater than 70% of the prodrug of the compound of Formula A, the prodrug of the deuterated compound of Formula A, or the pharmaceutically acceptable salts thereof are converted to the compound of Formula A or the deuterated compound of Formula A.

4. The method of claim 1, wherein after administration to the patient, greater than 80% of the prodrug of the compound of Formula A, the prodrug of the deuterated compound of Formula A, or the pharmaceutically acceptable salts thereof are converted to the compound of Formula A or the deuterated compound of Formula A.

5. The method of claim 1, wherein after administration to the patient, greater than 90% of the prodrug of the compound of Formula A, the prodrug of the deuterated compound of Formula A, or the pharmaceutically acceptable salts thereof are converted to the compound of Formula A or the deuterated compound of Formula A.

6. The method of claim 1, wherein after administration to the patient, greater than 95% of the prodrug of the compound of Formula A, the prodrug of the deuterated compound of Formula A, or the pharmaceutically acceptable salts thereof are converted to the compound of Formula A or the deuterated compound of Formula A.

7. The method of claim 1, wherein after administration to the patient, greater than 99% of the prodrug of the compound of Formula A, the prodrug of the deuterated compound of Formula A, or the pharmaceutically acceptable salts thereof are converted to the compound of Formula A or the deuterated compound of Formula A.

8. The method according to any one of claims 1 to 7, wherein 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, or a pharmaceutically acceptable salt thereof is administered orally.

9. The method of any one of claims 1 to 8, wherein 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, or a pharmaceutically acceptable salt thereof is administered once a day.

10. The method of any one of claims 1 to 8, wherein 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, or a pharmaceutically acceptable salt thereof is administered twice daily.

11. The method according to claim 9 or 10, wherein 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, or a pharmaceutically acceptable salt thereof is administered continuously for 1 to 30 days.

12. The method according to claim 9 or 10, wherein 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, or a pharmaceutically acceptable salt thereof is administered continuously for 1 to 14 days.

13. The method according to claim 9 or 10, wherein 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, or a pharmaceutically acceptable salt thereof is administered continuously for 3 to 14 days.

14. The method of any one of claims 1 to 8, wherein 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, or a pharmaceutically acceptable salt thereof is administered once a day for three consecutive days.

15. The method of any one of claims 1 to 8, wherein 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, or a pharmaceutically acceptable salt thereof is administered twice a day for three consecutive days.

16. The method of any one of claims 1 to 8, wherein 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, or a pharmaceutically acceptable salt thereof is administered once a day for five consecutive days.

17. The method of any one of claims 1 to 8, wherein 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, or a pharmaceutically acceptable salt thereof is administered twice a day for five consecutive days.

18. The method of any one of claims 1 to 17, wherein the patient is not pregnant on the first day of administration 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, or a pharmaceutically acceptable salt thereof, and the patient avoids pregnancy from the first day to at least 2 days after the administration.

19. The method of any one of claims 1 to 17, wherein the patient is not pregnant on the first day of administration 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, or a pharmaceutically acceptable salt thereof, and the patient avoids pregnancy from the first day until at least 4 days after the administration.

20. The method of any one of claims 1 to 17, wherein the patient is not pregnant on the first day of administration 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, or a pharmaceutically acceptable salt thereof, and the patient avoids pregnancy from the first day until at least 7 days after the administration.

21. The method of any one of claims 1 to 17, wherein the patient is not pregnant on the first day of administration 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, or a pharmaceutically acceptable salt thereof, and the patient avoids pregnancy from the first day until at least 14 days after the administration.

22. The method of any one of claims 1 to 17, wherein the patient is not pregnant on the first day of administration 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, or a pharmaceutically acceptable salt thereof, and the patient avoids pregnancy from the first day to at least one month after the administration.

23. The method of any one of claims 1 to 22, wherein the patient is a lactating individual and the patient refrains from breastfeeding from the first day of administration 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, or a pharmaceutically acceptable salt thereof to at least 2 days after the administration.

24. The method of any one of claims 1 to 22, wherein the patient is a lactating individual and the patient refrains from breastfeeding from the first day of administration 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, or a pharmaceutically acceptable salt thereof to at least 4 days after the administration.

25. The method of any one of claims 1 to 22, wherein the patient is a lactating individual and the patient refrains from breastfeeding from the first day of administration 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, or a pharmaceutically acceptable salt thereof to at least 7 days after the administration.

26. The method of any one of claims 1 to 22, wherein the patient is a lactating individual and the patient refrains from breastfeeding from the first day of administration 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, or a pharmaceutically acceptable salt thereof to at least 14 days after the administration.

27. The method of any one of claims 1 to 22, wherein the patient is a lactating individual and the patient refrains from breastfeeding from the first day of administration 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, or a pharmaceutically acceptable salt thereof to at least one month after the administration.

28. The method of any one of claims 1 to 22, wherein the patient is not a lactating individual.

29. The method of any one of claims 1 to 28, further comprising determining that the patient is not pregnant prior to administering 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, or a pharmaceutically acceptable salt thereof.

30. The method of claim 29, wherein the determining comprises classifying the patient as a patient of childbearing potential or a patient of non-childbearing potential, and administering a pregnancy test to a patient of childbearing potential.

31. The method of claim 30, wherein said determining comprises administering a first pregnancy test 7 days to 1 month prior to said administering and administering a second pregnancy test 1 day to 3 days prior to said administering.

32. The method of any one of claims 1 to 28, wherein the patient is a patient of fertility potential, and wherein the patient has had at least one negative pregnancy test performed at least one day prior to administering 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, or a pharmaceutically acceptable salt thereof.

33. The method of claim 32, wherein the patient has had at least two negative pregnancy tests, each independently performed at least one day prior to the administering.

34. The method of claim 33, wherein the patient has had a first negative pregnancy test at least 7 days prior to the administering, and has had a second negative pregnancy test subsequent to the first pregnancy test and at least one day prior to the administering.

35. The method of claim 33, wherein the patient has had a first negative pregnancy test at least 14 days prior to the administering and has had a second negative pregnancy test subsequent to the first pregnancy test and at least one day prior to the administering.

36. The method of claim 34 or 35, wherein the patient has had the second negative pregnancy test during the first five days of the menstrual period immediately preceding the administering.

37. The method of claim 34 or 35, wherein the patient suffers from amenorrhea and the patient has had the second negative pregnancy test at least 11 days after the last act of unprotected sexual intercourse.

38. The method of any one of claims 30 to 37, wherein each pregnancy test is independently a urine pregnancy test or a serum pregnancy test.

39. The method of claim 38, wherein each pregnancy test independently has a sensitivity of at least 25 mIU / mL.

40. The method of any one of claims 1 to 39, wherein the patient is a patient of fertility potential, and wherein the patient uses at least one form of contraception from the first day of administration 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, or a pharmaceutically acceptable salt thereof to at least 2 days after the administration.

41. The method of any one of claims 1 to 39, wherein the patient is a patient of fertile potential, and wherein the patient uses at least two forms of contraception from the first day of administration 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, or a pharmaceutically acceptable salt thereof to at least 2 days after said administration.

42. The method of claim 40 or 41, wherein the patient has used the contraception for at least one month from before the first day of the administering.

43. The method of any one of claims 40 to 42, wherein the patient uses the contraception until at least one month after the administering.

44. The method of any one of claims 40 to 43, wherein the patient uses at least one form of contraception selected from tubal ligation, partner vasectomy, intrauterine contraceptive devices, birth control pills, and injectable, implantable, and insertable hormonal birth control products.

45. The method of any one of claims 40 to 44, wherein the patient uses at least one form of contraception selected from a contraceptive diaphragm, a latex condom, and a cervical cap.

46. ​​The method of claim 45, wherein the contraception is used with a spermicide.

47. The method according to any one of claims 1 to 46, wherein the compound of formula A is: or a pharmaceutically acceptable salt thereof.

48. The method of any one of claims 1 to 46, wherein the deuterated compound of formula A is: or pharmaceutically acceptable salts thereof.

49. The method of any one of claims 1 to 48, wherein the method comprises administering to the patient a prodrug of formula A having formula I: Or a deuterated compound of formula I or a pharmaceutically acceptable salt thereof, wherein: R 3 Yes -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- to 6-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O and S, or a 5- to 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S; wherein R 7 C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, C6-C 10 Aryl, 4- to 6-membered heterocyclyl and 5- to 6-membered heteroaryl are optionally substituted by one, two or three R a Substituent substitution.

50. The method according to any one of claims 1 to 49, wherein R 1 It is -OH.

51. The method according to any one of claims 1 to 49, wherein R 1 Yes-OC(=O)R 4 .

52. The method according to any one of claims 1 to 49, wherein R 1 Yes-OC(=O)OR 4 .

53. The method according to any one of claims 1 to 49, wherein R 2 It is -OH.

54. The method according to any one of claims 1 to 49, wherein R 2 Yes-OC(=O)R 5 .

55. The method according to any one of claims 1 to 49, wherein R 2 Yes-OC(=O)OR 5 .

56. The method according to any one of claims 1 to 49, wherein R 1 and R 2 All are -OH.

57. The method according to any one of claims 1 to 49, wherein R 1 Yes-OC(=O)R 4 And R 2 Yes-OC(=O)R 5 .

58. The method according to any one of claims 1 to 49, wherein R 1 is -OH, and R 2 Yes-OC(=O)R 5 OR-OC(=O)OR 5 .

59. The method according to any one of claims 1 to 49, wherein R 1 Yes-OC(=O)R 4 OR-OC(=O)OR 4 , and R 2 It is -OH.

60. The method according to any one of claims 1 to 49, wherein R 1 and R 2 Together they form -OC(=O)O-.

61. The method according to any one of claims 1 to 49, wherein R 1 and R 2 Together they form -OP(=O)(OH)O-.

62. The method according to any one of claims 1 to 49, wherein R 1 and R 2 Together we form - OCHR 6 O-.

63. The method according to any one of claims 1 to 49, wherein: 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 Together they form -OC(=O)O-.

64. The method of any one of claims 1 to 49, 51 to 55, 57 and 59, wherein R 4 is C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl, each of which is optionally substituted by one, two or three independently selected from halo, cyano, -N3, -OR 8 、-NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic group and phenyl group a Substituent substitution.

65. The method of any one of claims 1 to 49, 51 to 55, 57 and 59, wherein R 4 is optionally substituted by one, two or three independently selected from halo, cyano, -N3, -OR 8 、-NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic group and phenyl group a The substituent is a C1-C8 alkyl substituted with a substituent.

66. The method of any one of claims 1 to 49, 51 to 55, 57 and 59, wherein R 4 It is an unsubstituted C1-C8 alkyl group.

67. The method of any one of claims 1 to 49, 51 to 55, 57 and 59, wherein R 4 It is an unsubstituted C1-C6 alkyl group.

68. The method of any one of claims 1 to 49, 51 to 55, 57 and 59, wherein R 4 It is an unsubstituted C1-C3 alkyl group.

69. The method of any one of claims 1 to 49, 51 to 55, 57 and 59, wherein R 4 It is -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3 or -C(CH3)3.

70. The method of any one of claims 1 to 49, 51 to 55, 57 and 59, wherein R 4 It is -CH3 or -CH(CH3)2.

71. The method of any one of claims 1 to 55, 57, 58 and 64 to 70, wherein R 5 is C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl, each of which is optionally substituted by one, two or three independently selected from halo, cyano, -N3, -OR 8 、-NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic group and phenyl group a Substituent substitution.

72. The method of any one of claims 1 to 55, 57, 58 and 64 to 70, wherein R 5 is optionally substituted by one, two or three independently selected from halo, cyano, -N3, -OR 8 、-NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic group and phenyl group a The substituent is a C1-C8 alkyl substituted with a substituent.

73. The method of any one of claims 1 to 55, 57, 58 and 64 to 70, wherein R 5 It is an unsubstituted C1-C8 alkyl group.

74. The method of any one of claims 1 to 55, 57, 58 and 64 to 70, wherein R 5 It is an unsubstituted C1-C6 alkyl group.

75. The method of any one of claims 1 to 55, 57, 58 and 64 to 70, wherein R 5 It is an unsubstituted C1-C3 alkyl group.

76. The method of any one of claims 1 to 55, 57, 58 and 64 to 70, wherein R 5 It is -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3 or -C(CH3)3.

77. The method of any one of claims 1 to 55, 57, 58 and 64 to 70, wherein R 5 It is -CH3 or -CH(CH3)2.

78. The method of any one of claims 1 to 49, 51, 52, 54, 55, 57, and 64 to 77, wherein R 4 and R 5 same.

79. The method of any one of claims 1 to 49, 51, 52, 54, 55, 57, and 64 to 77, wherein R 4 and R 5 different.

80. The method of any one of claims 1 to 49, 51, 52, 54, 55, 57, and 64 to 77, wherein R 4 is an unsubstituted C1-C8 alkyl group and R 5 It is an unsubstituted C1-C8 alkyl group.

81. The method of any one of claims 1 to 49, 51, 52, 54, 55, 57, and 64 to 77, wherein R 4 is -CH3 or -CH(CH3)2 and R 5 It is -CH3 or -CH(CH3)2.

82. The method of any one of claims 1 to 49, 51, 52, 54, 55, 57, and 64 to 77, wherein R 4 is -CH3 and R 5 It is -CH3.

83. The method of any one of claims 1 to 49, 51, 52, 54, 55, 57, and 64 to 77, wherein R 4 is -CH(CH3)2 and R5 is -CH(CH3)2.

84. The method of any one of claims 1 to 49 or 62, wherein R 6 It's H.

85. The method of any one of claims 1 to 49 or 62, wherein R 6 It is a C1-C6 alkyl group.

86. The method of any one of claims 1 to 49 or 62, wherein R 6 It is -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3 or -C(CH3)3.

87. The method of any one of claims 1 to 49 or 62, wherein R 6 It is a C1-C6 alkoxy group.

88. The method of any one of claims 1 to 49 or 62, wherein R 6 It is C6-C 10 Aryl.

89. The method of any one of claims 1 to 49 or 62, wherein R 6 It is an unsubstituted phenyl group.

90. The method according to any one of claims 49 to 89, wherein R 3 Yes -C(=O)OR 7 .

91. The method of any one of claims 49 to 89, wherein R 3 Yes-C(=O)R 7 .

92. The method according to any one of claims 49 to 91, wherein R 7 It is C1-C8 alkyl, C3-C8 carbocyclic group, C6-C 10 aryl, 4 to 6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S, or 5 to 6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S, each of which is optionally substituted by one, two or three independently selected from -OR 8 , -OP(=O)(OH)2, C3-C8 carbocyclic group and phenyl group a Substituent substitution.

93. The method according to any one of claims 49 to 91, wherein R 7 is C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl, each of which is optionally substituted by one, two or three independently selected from halo, cyano, -N3, -OR 8 、-NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic group and phenyl group a Substituent substitution.

94. The method according to any one of claims 49 to 91, wherein R 7 is optionally substituted by one, two or three independently selected from halo, cyano, -N3, -OR 8 、-NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic group and phenyl group a The substituent is a C1-C8 alkyl substituted with a substituent.

95. The method according to any one of claims 49 to 91, wherein R 7 is optionally substituted by one, two or three independently selected from halo, cyano, -N3, -OR 8 、-NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic group and phenyl group a The substituent is a C1-C6 alkyl group substituted with a substituent.

96. The method of any one of claims 49 to 91, wherein R 7 is optionally selected from -OR 8 , -OP(=O)(OH)2, C3-C8 carbocyclic group and unsubstituted phenyl group a The substituent is a C1-C8 alkyl substituted with a substituent.

97. The method of any one of claims 49 to 91, wherein R 7 is optionally selected from -OR 8 , -OP(=O)(OH)2, C3-C8 carbocyclic group and unsubstituted phenyl group a The substituent is a C1-C6 alkyl group substituted with a substituent.

98. The method of any one of claims 49 to 91, wherein R 7 is C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl, each of which is optionally substituted by one, two or three independently selected from halo, cyano, -N3, -OR 8 、-NR 9 R 10 and phenyl R a Substituent substitution.

99. The method of any one of claims 49 to 91, wherein R 7 is optionally substituted by one, two or three independently selected from halo, cyano, -N3, -OR 8 、-NR 9 R 10 and phenyl R a The substituent is a C1-C8 alkyl substituted with a substituent.

100. The method according to any one of claims 49 to 91, wherein R 7 is optionally substituted by one, two or three independently selected from halo, cyano, -N3, -OR 8 、-NR 9 R 10 and unsubstituted phenyl R a The substituent is a C1-C8 alkyl substituted with a substituent.

101. The method according to any one of claims 49 to 91, wherein R 7 is-OR 8 Substituted C1-C8 alkyl.

102. The method of any one of claims 49 to 91, wherein R 7 is-OR 8 Substituted C2-C4 alkyl.

103. The method according to any one of claims 49 to 91, wherein R 7 It is a C2-C4 alkyl group substituted by -OCH3.

104. The method of any one of claims 49 to 91, wherein R 7 yes 105. The method of any one of claims 49 to 91, wherein R 7 It is a C1-C8 alkyl group substituted by a phenyl group.

106. The method of any one of claims 49 to 91, wherein R 7 It is a C1-C4 alkyl group substituted by a phenyl group.

107. The method of any one of claims 49 to 91, wherein R 7 yes 108. The method of any one of claims 49 to 91, wherein R 7 It is a C1-C8 alkyl group substituted by a C3-C8 carbocyclic group.

109. The method of any one of claims 49 to 91, wherein R 7 It is a C2-C4 alkyl group substituted by a C4-C7 carbocyclic group.

110. The method according to any one of claims 49 to 91, wherein R 7 is Substituted C2-C4 alkyl.

111. The method according to any one of claims 49 to 91, wherein R 7 yes 112. The method according to any one of claims 49 to 91, wherein R 7 It is a C1-C8 alkyl group substituted by -OP(=O)(OH)2.

113. The method according to any one of claims 49 to 91, wherein R 7 It is a C1-C4 alkyl group substituted by -OP(=O)(OH)2.

114. The method according to any one of claims 49 to 91, wherein R 7 yes 115. The method according to any one of claims 49 to 91, wherein R 7 It is a C1-C8 alkyl group.

116. The method according to any one of claims 49 to 91, wherein R 7 It is a C1-C6 alkyl group.

117. The method according to any one of claims 49 to 91, wherein R 7 yes 118. The method according to any one of claims 49 to 91, wherein R 7 yes 119. The method according to any one of claims 49 to 91, wherein R 7 is optionally substituted by one, two or three independently selected from halo, cyano, -N3, -OR 8 、-NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic group and phenyl group a The substituent is a C3-C8 carbocyclic group substituted with a substituent.

120. The method according to any one of claims 49 to 91, wherein R 7 is optionally substituted by one, two or three independently selected from halo, cyano, -N3, -OR 8 、-NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic group and unsubstituted phenyl group a The substituent is a C3-C8 carbocyclic group substituted with a substituent.

121. The method according to any one of claims 49 to 91, wherein R 7 is optionally selected from one, two or three independently selected from -OR 8 、-NR 9 R 10 , C3-C8 carbocyclic group and unsubstituted phenyl group R a The substituent is a C3-C8 carbocyclic group substituted with a substituent.

122. The method of any one of claims 49 to 91, wherein R 7 yes 123. The method according to any one of claims 49 to 91, wherein R 7 is optionally substituted by one, two or three independently selected from halo, cyano, -N3, -OR 8 、-NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic group and phenyl group a Substituent-substituted C6-C 10 Aryl.

124. The method of any one of claims 49 to 91, wherein R 7 is optionally substituted by one, two or three independently selected from halo, cyano, -N3, -OR 8 、-NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic group and unsubstituted phenyl group a Substituent-substituted C6-C 10 Aryl.

125. The method of any one of claims 49 to 91, wherein R 7 is phenyl or naphthyl, each of which is optionally substituted by one, two or three independently selected from halo, cyano, -N3, -OR 8 、-NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic group and unsubstituted phenyl group a Substituent substitution.

126. The method of any one of claims 49 to 91, wherein R 7 is optionally substituted by one, two or three independently selected from halo, cyano, -N3, -OR 8 、-NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic group and unsubstituted phenyl group a Substituents: phenyl substituted.

127. The method of any one of claims 49 to 91, wherein R 7 yes 128. The method of any one of claims 49 to 91, wherein R 7 is a 1, 2 or 3 heteroatoms selected from N, O and S, optionally substituted by one, two or three independently selected from halo, cyano, -N 3 、-OR 8 、-NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic group and phenyl group a The substituent is a 4- to 6-membered heterocyclic group substituted by the substituent.

129. The method of any one of claims 49 to 91, wherein R 7 is a 1, 2 or 3 heteroatoms selected from N, O and S, optionally substituted by one, two or three independently selected from halo, cyano, -N3, -OR 8 、-NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic group and unsubstituted phenyl group a The substituent is a 4- to 6-membered heterocyclic group substituted by the substituent.

130. The method of any one of claims 49 to 91, wherein R 7 is a 1, 2 or 3 heteroatoms selected from N, O and S, optionally substituted by one, two or three independently selected from halo, cyano, -N3, -OR 8 、-NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic group and unsubstituted phenyl group a The substituent is a 6-membered heterocyclic group substituted by the substituent.

131. The method of any one of claims 49 to 91, wherein R 7 is a 1, 2 or 3 heteroatoms selected from N, O and S, optionally substituted by one, two or three independently selected from halo, cyano, -N3, -OR 8 、-NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic group and unsubstituted phenyl group a The substituent is a 5-membered heterocyclic group substituted by the substituent.

132. The method of any one of claims 49 to 91, wherein R 7 is an unsubstituted 5-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O and S.

133. The method according to any one of claims 49 to 91, wherein R 7 yes 134. The method of any one of claims 49 to 91, wherein R 7 is a 1, 2 or 3 heteroatoms selected from N, O and S, optionally substituted by one, two or three independently selected from halo, cyano, -N3, -OR 8 、-NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic group and unsubstituted phenyl group a The substituent is a 4-membered heterocyclic group substituted by the substituent.

135. The method of any one of claims 49 to 91, wherein R 7 is an unsubstituted 4-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O and S.

136. The method of any one of claims 49 to 91, wherein R 7 yes 137. The method of any one of claims 49 to 91, wherein R 7 is a 1, 2 or 3 heteroatoms selected from N, O and S, optionally substituted by one, two or three independently selected from halo, cyano, -N3, -OR 8 、-NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic group and phenyl group a The substituent is a 5- to 6-membered heteroaryl group substituted with a substituent.

138. The method of any one of claims 49 to 91, wherein R 7 is a 1, 2 or 3 heteroatoms selected from N, O and S, optionally substituted by one, two or three independently selected from halo, cyano, -N3, -OR 8 、-NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic group and unsubstituted phenyl group a The substituent is a 5- to 6-membered heteroaryl group substituted with a substituent.

139. The method of any one of claims 49 to 91, wherein R 7 is a 1, 2 or 3 heteroatoms selected from N, O and S, optionally substituted by one, two or three independently selected from halo, cyano, -N3, -OR 8 、-NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic group and unsubstituted phenyl group a The substituent is a 5-membered heteroaryl substituted with a substituent.

140. The method of any one of claims 49 to 91, wherein R 7 is a 1, 2 or 3 heteroatoms selected from N, O and S, optionally substituted by one, two or three independently selected from halo, cyano, -N3, -OR 8 、-NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclic group and unsubstituted phenyl group a The substituent is a 6-membered heteroaryl substituted with a substituent.

141. The method of any one of claims 49 to 91, wherein R 7 is a group containing 1, 2 or 3 heteroatoms selected from N, O and S, optionally substituted by one, two or three independently selected from halo, cyano and -NR 9 R 10 R a The substituent is a 6-membered heteroaryl substituted with a substituent.

142. The method of any one of claims 49 to 91, wherein R 7 yes 143. The method of any one of claims 49 to 91, wherein R 7 yes 144. The method of any one of claims 49 to 91, wherein R 7 yes 145. The method of any one of claims 1 to 58, 75 to 77, 79 to 82, 84 to 87, 90 and 93 to 96, wherein R 8 It's H.

146. The method of any one of claims 1 to 102, 119 to 121, 123 to 126, 128 to 131, 134, and 137 to 140, wherein R 8 It is a C1-C6 alkyl group.

147. The method of any one of claims 1 to 102, 119 to 121, 123 to 126, 128 to 131, 134, and 137 to 140, wherein R 8 It is -CH3.

148. The method of any one of claims 1 to 102, 119 to 121, 123 to 126, 128 to 131, 134, and 137 to 140, wherein R 8 It is a C1-C6 haloalkyl group.

149. The method of any one of claims 1 to 102, 119 to 121, 123 to 126, 128 to 131, 134, and 137 to 140, wherein R 8 It is a C3-C6 cycloalkyl group.

150. The method of any one of claims 1 to 91, 93 to 95, 98 to 100, 119 to 121, 123 to 126, 128 to 131, 134, 137 to 141, and 145 to 149, wherein R 9 It's H.

151. The method of any one of claims 1 to 91, 93 to 95, 98 to 100, 119 to 121, 123 to 126, 128 to 131, 134, 137 to 141, and 145 to 149, wherein R 9 It is a C1-C6 alkyl group.

152. The method of any one of claims 1 to 91, 93 to 95, 98 to 100, 119 to 121, 123 to 126, 128 to 131, 134, 137 to 141, and 145 to 149, wherein R 9 It is -CH3.

153. The method of any one of claims 1 to 91, 93 to 95, 98 to 100, 119 to 121, 123 to 126, 128 to 131, 134, 137 to 141, and 145 to 149, wherein R 9 It is a C1-C6 haloalkyl group.

154. The method of any one of claims 1 to 91, 93 to 95, 98 to 100, 119 to 121, 123 to 126, 128 to 131, 134, 137 to 141, and 145 to 149, wherein R 9 It is a C3-C6 cycloalkyl group.

155. The method of any one of claims 1 to 91, 93 to 95, 98 to 100, 119 to 121, 123 to 126, 128 to 131, 134, 137 to 141, and 145 to 154, wherein R 10 It's H.

156. The method of any one of claims 1 to 91, 93 to 95, 98 to 100, 119 to 121, 123 to 126, 128 to 131, 134, 137 to 141, and 145 to 154, wherein R 10 It is a C1-C6 alkyl group.

157. The method of any one of claims 1 to 91, 93 to 95, 98 to 100, 119 to 121, 123 to 126, 128 to 131, 134, 137 to 141, and 145 to 154, wherein R 10 It is -CH3.

158. The method of any one of claims 1 to 91, 93 to 95, 98 to 100, 119 to 121, 123 to 126, 128 to 131, 134, 137 to 141, and 145 to 154, wherein R 10 It is a C1-C6 haloalkyl group.

159. The method of any one of claims 1 to 91, 93 to 95, 98 to 100, 119 to 121, 123 to 126, 128 to 131, 134, 137 to 141, and 145 to 154, wherein R 10 It is a C3-C6 cycloalkyl group.

160. The process of any one of claims 1 to 159, wherein the base is 161. The method according to any one of claims 1 to 159, wherein the base is 162. The method according to any one of claims 1 to 159, wherein the base is 163. The method according to any one of claims 1 to 162, wherein R 12 It's H.

164. The method of any one of claims 1 to 162, wherein R 12 It is a C1-C6 alkyl group.

165. The method of any one of claims 1 to 162, wherein R 12 Yes-C(=O)R 13 .

166. The method of any one of claims 1 to 162, wherein R 12 yes- C(=O)OR 13 。 167. The method of any one of claims 1 to 162, 165 and 166, wherein R 13 It's H.

168. The method of any one of claims 1 to 162, 165 and 166, wherein R 13 is optionally substituted by one, two or three R independently selected from halo, cyano and phenyl c The substituent is a C1-C8 alkyl substituted with a substituent.

169. The method of any one of claims 1 to 162, 165 and 166, wherein R 13 is optionally substituted by one, two or three R independently selected from halo, cyano and unsubstituted phenyl c The substituent is a C1-C8 alkyl substituted with a substituent.

170. The method of any one of claims 1 to 162, 165 and 166, wherein R 13 It is a C1-C8 alkyl group.

171. The method of any one of claims 1 to 162, 165 and 166, wherein R 13 It is -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH3 or -C(CH3)3.

172. The method of any one of claims 1 to 162, 165 and 166, wherein R 13 It is -CH2CH(CH3)2 or -(CH2)2CH3.

173. The method of any one of claims 1 to 162, wherein R 12 yes- C(=O)(CH2)2CH3.

174. The method of any one of claims 1 to 162, wherein R 12 yes- C(=O)OCH2CH(CH3)2.

175. The method of any one of claims 1 to 162, wherein R 12 yes- C(=O)OCH2CH(CH3)2 or -C(=O)(CH2)2CH 3。 176. The method of any one of claims 1 to 159, wherein the base is 177. The method according to any one of claims 1 to 159, wherein the base is 178. The method of any one of claims 1 to 159, 176 and 177, wherein R 11 is -OP(=O)(OH)(OR 14 ) substituted C1-C3 alkyl.

179. The method of any one of claims 1 to 159, 176 and 177, wherein R 11 is -(CH2)OP(=O)(OH)(OR 14 ).

180. The method of any one of claims 1 to 159 and 176 to 179, wherein R 14 It's H.

181. The method of any one of claims 1 to 159 and 176 to 179, wherein R 14 is H or optionally substituted by one, two or three R independently selected from halo, cyano and phenyl f The substituent is a C1-C8 alkyl substituted with a substituent.

182. The method of any one of claims 1 to 159 and 176 to 179, wherein R 14 is optionally substituted by one, two or three R independently selected from halo, cyano and phenyl f The substituent is a C1-C8 alkyl substituted with a substituent.

183. The method of any one of claims 1 to 159 and 176 to 179, wherein R 14 is optionally substituted by one, two or three R independently selected from halo, cyano and phenyl f Substituent: C1-C3 alkyl substituted with a substituent.

184. The method of any one of claims 1 to 159 and 176 to 179, wherein R 14 It is a C1-C3 alkyl group substituted with a phenyl group.

185. The method according to any one of claims 1 to 159 and 176 to 179, wherein R 14 is 186. The method of any one of claims 1 to 159, 176 and 179, wherein R 11 It is -(CH2)OP(=O)(OH)2.

187. The method of any one of claims 1 to 159, 176 and 179, wherein R 11 yes 188. The method of any one of claims 1 to 46, comprising administering to the 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 ; R 2 -OH, -OC(=O)R 5 OR-OC(=O)OR 5 ;or R 1 and R 2 together to form -OC(=O)O-; and R 4 and R 5 are each independently an unsubstituted C1-C8 alkyl, an unsubstituted C3-C8 carbocyclic group, an unsubstituted C6-C 10 aryl, an unsubstituted 4- to 6-membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S, or an unsubstituted 5- to 6-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S.

189. The method of claim 188, wherein the base is 190. The method according to any one of claims 1 to 46, comprising administering to the patient a deuterated compound of formula A having formula A1 or a prodrug thereof or a pharmaceutically acceptable salt thereof, wherein R 1 is -OH, -OC(=O)R 4 or -OC(=O)OR 4 ; R 2 -OH, -OC(=O)R 5 OR-OC(=O)OR 5 ;or R 1 and R 2 together to form -OC(=O)O-; and R 4 and R 5 are each independently an unsubstituted C1-C8 alkyl, an unsubstituted C3-C8 carbocyclic group, an unsubstituted C6-C 10 aryl, an unsubstituted 4- to 6-membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S, or an unsubstituted 5- to 6-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S.

191. The method of any one of claims 1 to 46, comprising administering to the patient a deuterated compound of formula A having formula A2 or a prodrug thereof or a pharmaceutically acceptable salt thereof, wherein R 1 is -OH, -OC(=O)R 4 or -OC(=O)OR 4 ; R 2 -OH, -OC(=O)R 5 OR-OC(=O)OR 5 ;or R 1 and R 2 together to form -OC(=O)O-; and R 4 and R 5 are each independently an unsubstituted C1-C8 alkyl, an unsubstituted C3-C8 carbocyclic group, an unsubstituted C6-C 10 aryl, an unsubstituted 4- to 6-membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S, or an unsubstituted 5- to 6-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S.

192. The method of any one of claims 188 to 191, wherein R 4 and R 5 Each is independently an unsubstituted C1-C8 alkyl group.

193. The method of any one of claims 188 to 191, wherein R 4 and R 5 Each is independently an unsubstituted C1-C6 alkyl group.

194. The method of any one of claims 188 to 193, wherein R 1 is -OH or - OC(=O)R 4 And R 2 is -OH or -OC(=O)R 5 .

195. The method of any one of claims 188 to 193, wherein R 1 and R 2 Each is independently -OH, OC(=O)CH(CH3)2 or OC(=O)CH3.

196. The method of any one of claims 188 to 191, wherein R 1 and R 2 Together they form -OC(=O)O-.

197. The method of claim 49, comprising administering to the 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 ; R 2 -OH, -OC(=O)R 5 OR-OC(=O)OR 5 ;or R 1 and R 2 Together they form -OC(=O)O-; R 3 Yes-C(=O)R 7 ;and R 4 , R 5 and R 7 are each independently an unsubstituted C1-C8 alkyl, an unsubstituted C3-C8 carbocyclic group, an unsubstituted C6-C 10 aryl, an unsubstituted 4- to 6-membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S, or an unsubstituted 5- to 6-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S.

198. The method of claim 198, wherein the base is 199. The method of claim 49, comprising administering to the patient a deuterated compound of Formula I having Formula Ia or a pharmaceutically acceptable salt thereof, wherein R 1 is -OH, -OC(=O)R 4 or -OC(=O)OR 4 ; R 2 -OH, -OC(=O)R 5 OR-OC(=O)OR 5 ;or R 1 and R 2 Together they form -OC(=O)O-; R 3 Yes-C(=O)R 7 ;and R 4 , R 5 and R 7 are each independently an unsubstituted C1-C8 alkyl, an unsubstituted C3-C8 carbocyclic group, an unsubstituted C6-C 10 aryl, an unsubstituted 4- to 6-membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S, or an unsubstituted 5- to 6-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S.

200. The method of claim 49, comprising administering to the patient a deuterated compound of Formula I having Formula Ib or a pharmaceutically acceptable salt thereof, wherein R 1 is -OH, -OC(=O)R 4 or -OC(=O)OR 4 ; R 2 -OH, -OC(=O)R 5 OR-OC(=O)OR 5 ;or R 1 and R 2 Together they form -OC(=O)O-; R 3 Yes-C(=O)R 7 ;and R 4 , R 5 and R 7 are each independently an unsubstituted C1-C8 alkyl, an unsubstituted C3-C8 carbocyclic group, an unsubstituted C6-C 10 aryl, an unsubstituted 4- to 6-membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S, or an unsubstituted 5- to 6-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S.

201. The method of any one of claims 197 to 200, wherein R 4 , R 5 and R 7 Each is independently an unsubstituted C1-C8 alkyl group.

202. The method of any one of claims 197 to 200, wherein R 4 , R 5 and R 7 Each is independently an unsubstituted C1-C6 alkyl group.

203. The method of any one of claims 197 to 202, wherein R 1 is -OH or -OC(=O)R 4 , R 2 is -OH or -OC(=O)R 5 , and R 3 Yes-C(=O)R 7 .

204. The method of any one of claims 197 to 202, wherein R 1 and R 2 are each independently -OH, OC(=O)CH(CH3)2 or OC(=O)CH3, and R 7 It is -CH(CH3)2 or -CH3.

205. The method according to any one of claims 197 to 200, wherein R 1 and R 2 Together they form -OC(=O)O-, and R 7 It is -CH(CH3)2 or -CH3.

206. The method according to any one of claims 1 to 46, wherein the compound of formula A or the prodrug of the compound of formula A is selected from the following compounds and pharmaceutically acceptable salts thereof:

207. The method of any one of claims 1 to 46, wherein 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 selected from the following compounds and pharmaceutically acceptable salts thereof:

208. The method of claim 49, wherein the compound of formula I is: or a pharmaceutically acceptable salt thereof.

209. The method of claim 49, wherein the compound of formula I is: or a pharmaceutically acceptable salt thereof.

210. The method of claim 49, wherein the compound of formula I is: or a pharmaceutically acceptable salt thereof.

211. A method of treating a viral infection in a human in need thereof, the method comprising administering to the human (i) Compound 1: Deuterated Compound 1, a prodrug of Compound 1, a prodrug of deuterated Compound 1, or a pharmaceutically acceptable salt thereof; and (ii) namatevir, ritonavir, or a combination of namatevir and ritonavir; Wherein when the prodrug of Compound 1, the prodrug of deuterated Compound 1, or the 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 into Compound 1 or deuterated Compound 1.

212. The method of claim 211, comprising administering to the human (i) Compound 1 or the prodrug or pharmaceutically acceptable salt of Compound 1 and (ii) namatevir, ritonavir, or a combination of namatevir and ritonavir.

213. The method of claim 211 or 212, comprising administering Compound 1 or a pharmaceutically acceptable salt thereof.

214. The method of any one of claims 211 to 213, comprising administering Compound 1.

215. The method of claim 211 or 212, comprising administering deuterated Compound 1 or a pharmaceutically acceptable salt thereof.

216. The method of any one of claims 211, 212 and 215, comprising administering deuterated Compound 1.

217. The method of claim 211 or 212, comprising administering a prodrug of deuterated Compound 1 or a pharmaceutically acceptable salt thereof.

218. The method of any one of claims 211, 212, and 217, comprising administering a deuterated prodrug of Compound 1.

219. The method of claim 211 or 212, comprising administering a prodrug of Compound 1 or a pharmaceutically acceptable salt thereof.

220. The method of any one of claims 211, 212 and 218, comprising administering a prodrug of Compound 1.

221. The method of any one of claims 211, 212, 219, and 220, wherein the prodrug of Compound 1 is:

222. The method of any one of claims 211 to 221, wherein the human is not a pregnant individual.

223. The method of any one of claims 211 to 222, wherein (i) Compound 1, or a pharmaceutically acceptable salt or prodrug thereof, and (ii) namatevir, ritonavir, or a combination of namatevir and ritonavir have a synergistic effect when administered to the human.

224. The method of any one of claims 211 to 222, wherein (i) Compound 1, or a pharmaceutically acceptable salt or prodrug thereof, and (ii) namatevir, ritonavir, or a combination of namatevir and ritonavir have an additive effect when administered to the human.

225. The method of any one of claims 211 to 221, wherein (i) Compound 1, or a pharmaceutically acceptable salt or prodrug thereof, and (ii) namatevir, ritonavir, or a combination of namatevir and ritonavir have a non-antagonistic effect when administered to the human.

226. The method of any one of claims 211 to 225, wherein the human is not hospitalized.

227. The method of any one of claims 211 to 225, wherein the human is hospitalized.

228. The method of any one of claims 211 to 227, wherein nematevir is administered to the human without ritonavir.

229. The method of any one of claims 211 to 227, wherein ritonavir is administered to the human without nematevir.

230. The method of any one of claims 211 to 227, wherein both ritonavir and nematevir are administered to the human.

231. The method of any one of claims 211 to 228 and 230, wherein namatevir is administered orally.

232. The method of any one of claims 211 to 228, 230 and 231, wherein namatevir is administered twice daily.

233. The method of any one of claims 211 to 228 and 230 to 232, wherein namatevir is administered twice daily for a period of at least five days.

234. The method of any one of claims 211 to 228 and 230 to 233, wherein namatevir is administered twice daily for a period of five days.

235. The method of any one of claims 211 to 228 and 230 to 234, wherein namatevir is administered within 5 days of symptom onset.

236. The method of any one of claims 211 to 228 and 230 to 235, wherein namatevir is administered within 1 day, 2 days, 3 days, 4 days or 5 days of symptom onset.

237. The method of any one of claims 211 to 228 and 230 to 236, wherein namatevir 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.

238. The method of any one of claims 211 to 228 and 230 to 237, wherein namatevir is administered at a dose of about 300 mg.

239. The method of any one of claims 211 to 228 and 230 to 238, wherein the dose comprises two tablets of approximately 150 mg.

240. The method of any one of claims 211 to 228 and 230 to 239, wherein the dose of about 300 mg is administered twice a day.

241. The method of any one of claims 211 to 228 and 230 to 240, wherein 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 namatevir per day is administered to the human.

242. The method of any one of claims 211 to 228 and 230 and 241, wherein about 600 mg of namatevir per day is administered to the human.

243. The method of any one of claims 211 to 227 and 230, wherein ritonavir is administered orally.

244. The method of any one of claims 211 to 227, 230 and 243, wherein ritonavir is administered twice daily.

245. The method of any one of claims 211 to 227, 230, 243 and 244, wherein ritonavir is administered twice daily for a period of at least five days.

246. The method of any one of claims 211 to 227, 230, and 243 to 245, wherein ritonavir is administered twice daily for a period of five days.

247. The method of any one of claims 211 to 227, 230, and 243 to 246, wherein ritonavir is administered within 5 days of symptom onset.

248. The method of any one of claims 211 to 227, 230, and 243 to 247, wherein ritonavir is administered within 1 day, 2 days, 3 days, 4 days, or 5 days of symptom onset.

249. The method of any one of claims 211 to 227, 230, and 243 to 248, wherein ritonavir is administered in an amount of 25 mg to 800 mg, 25 mg to 600 mg, 25 mg to 400 mg, A dosage of 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 is administered.

250. The method of any one of claims 211 to 227, 230, and 243 to 249, wherein ritonavir is administered at a dose of about 100 mg.

251. The method of any one of claims 211 to 227, 230, and 243 to 250, wherein the dose comprises one tablet of about 100 mg.

252. The method of any one of claims 211 to 227, 230, and 243 to 251, wherein the dose of about 100 mg is administered twice a day.

253. The method of any one of claims 211 to 227, 230, and 243 to 252, wherein 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, 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.

254. The method of any one of claims 211 to 227, 230, and 243 to 253, wherein about 200 mg of ritonavir per day is administered to the human.

255. The method of any one of claims 211 to 227 and 230, wherein namatevir and ritonavir are administered orally.

256. The method of any one of claims 211 to 227, 230 and 255, wherein namatevir and ritonavir are administered twice daily.

257. The method of any one of claims 211 to 227, 230, 255 and 256, wherein nematevir and ritonavir are administered twice daily for a period of at least five days.

258. The method of any one of claims 211 to 227, 230, and 255 to 257, wherein nematevir and ritonavir are administered twice daily for a period of five days.

259. The method of any one of claims 211 to 227, 230, and 255 to 258, wherein namatevir and ritonavir are administered within 5 days of symptom onset.

260. The method of any one of claims 211 to 227, 230, and 255 to 259, wherein namatevir and ritonavir are administered within 1 day, 2 days, 3 days, 4 days, or 5 days of symptom onset.

261. The method of any one of claims 211 to 227, 230, and 255 to 260, wherein namatevir is administered at 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, 2 00 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.

262. The method of any one of claims 211 to 227, 230, and 255 to 262, wherein nematevir is administered at a dose of about 300 mg and ritonavir is administered at a dose of about 100 mg.

263. The method of any one of claims 211 to 227, 230, and 255 to 262, wherein the namatevir dose comprises two tablets of about 150 mg and the ritonavir dose comprises one tablet of about 100 mg.

264. The method of any one of claims 211 to 227, 230, and 255 to 263, wherein the nematevir dose of about 300 mg and the ritonavir dose of about 100 mg are administered twice daily.

265. The method of any one of claims 211 to 227, 230, and 255 to 264, wherein the 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 per 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 namatevir and 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 of ritonavir per day.

266. The method of any one of claims 211 to 227, 230, and 255 to 265, wherein about 600 mg of nematevir per day and about 200 mg of ritonavir per day are administered to the human.

267. The method of any one of claims 211 to 266, wherein the viral infection is a coronavirus infection.

268. The method of any one of claims 211 to 267, wherein 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 (COVID19).

269. The method of any one of claims 211 to 268, wherein the viral infection is SARS-CoV-2 infection (COVID19).

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