Compounds and methods for the treatment of viral infections

Abstract

Disclosed are compounds and methods of using the compounds alone or in combination with additional agents, as well as salts or pharmaceutical compositions of the compounds for treating viral infections. Also provided herein are pharmaceutical compositions comprising a compound disclosed herein (e.g., a compound of Formula I) or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable excipients. Also provided herein are methods of treating or preventing a viral infection in a human in need thereof, comprising administering to the human a compound disclosed herein (e.g., a compound of Formula I) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described herein.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 315,769, filed March 2, 2022, U.S. Provisional Application No. 63 / 390,421, filed July 19, 2022, U.S. Provisional Application No. 63 / 424,083, filed November 9, 2022, and U.S. Provisional Application No. 63 / 434,993, filed December 23, 2022, the entire contents of which are incorporated herein by reference in their entirety. [Background technology]

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

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

[0004] The present disclosure provides compounds of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 and Base are defined herein.

[0005] Also provided herein are pharmaceutical compositions comprising a compound disclosed herein (e.g., a compound of Formula I) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0006] Also provided herein is a method of treating or preventing a viral infection in a human in need thereof, the method comprising administering to the human a compound disclosed herein (e.g., a compound of Formula I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0007] Also provided herein is the use of a compound disclosed herein (e.g., a compound of Formula I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a viral infection in a human in need thereof.

[0008] Also provided herein is a composition comprising a compound described herein (e.g., a compound of Formula I), or a pharmaceutically acceptable salt thereof, for use in treating or preventing a viral infection in a human in need thereof. [Brief explanation of the drawings]

[0009] [Figure 1] 1 shows the GI stability of Compound 4, Compound 128, an ester reference compound, and a third ester reference compound.

[0010] [Figure 2] 1 shows the stability of Compound 128, Compound 129, an ester reference compound, a second ester reference compound, and a third ester reference compound. DETAILED DESCRIPTION OF THE INVENTION

[0011] I. Overview The present invention relates generally to methods and compounds for treating or preventing viral infections, such as those of the Paramyxoviridae, Pneumoviridae, Picornaviridae, Flaviviridae, Filoviridae, Arenaviridae, Orthomyxovirus, and Coronaviridae families.

[0012] II. Definition Unless otherwise stated, the following terms and phrases are intended to have the following meanings as used herein:

[0013] "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 to C6). 20The alkyl group may have 1 to 8 carbon atoms (i.e., C1-C8 alkyl), 1 to 6 carbon atoms (i.e., C1-C6 alkyl), or 1 to 3 carbon atoms (i.e., C1-C3 alkyl). Examples of suitable alkyl groups include methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -C H(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH( These include, but are not limited to, 4-methyl-2-pentyl (-CH(CH)CHCH(CH)), 3-methyl-3-pentyl (-C(CH)(CHCH)), 2-methyl-3-pentyl (-CH(CHCH)CH(CH)), and 2,3-dimethyl-2-butyl (-C(CH)CH(CH)), 3,3-dimethyl-2-butyl (-CH(CH)C(CH)).

[0014] "Alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C 2-20 alkenyl), 2 to 8 carbon atoms (i.e., C2-8 alkenyl), 2 to 6 carbon atoms (i.e., C 2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C 2-4 Alkenyl refers to an aliphatic group having an alkyl group. Examples of alkenyl groups include ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0015] "Alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C 2-20 alkynyl), 2 to 8 carbon atoms (i.e., C 2-8 alkynyl), 2 to 6 carbon atoms (i.e., C 2-6 alkynyl), or 2 to 4 carbon atoms (i.e., C 2-4 The term "alkynyl" also includes alkynyl groups having one triple bond and one double bond.

[0016] A "haloalkyl" is an alkyl group as defined above in which one or more hydrogen atoms of the alkyl group are replaced with a halogen atom. The alkyl portion of a haloalkyl group has 1 to 20 carbon atoms (i.e., C1 to C6). 20 haloalkyl), 1 to 12 carbon atoms (i.e., C1 to C 12 haloalkyl), 1 to 8 carbon atoms (i.e., C1-C8 haloalkyl), 1 to 6 carbon atoms (i.e., C1-C6 alkyl), or 1 to 3 carbon atoms (i.e., C1-C3 alkyl). Examples of suitable haloalkyl groups include -CF3, -CHF2, -CFH2, -CH2CF3, and the like.

[0017] "Aryl" means an aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. For example, an aryl group can have from 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 10 carbon atoms. Typical aryl groups include, but are not limited to, radicals derived from benzene (e.g., phenyl), substituted benzene, naphthalene, anthracene, biphenyl, and the like.

[0018] "Heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl contains 1 to 20 ring atoms (i.e., 1-20 membered heteroaryl), 3 to 12 ring atoms (i.e., 3-12 membered heteroaryl), or 3 to 8 carbon ring atoms (3-8 membered heteroaryl), or 5 to 6 ring atoms (5-6 membered heteroaryl). Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Heteroaryl does not encompass and does not overlap with aryl, as defined above.

[0019] "Carbocyclyl" or "carbocyclic ring" refers to a non-aromatic hydrocarbon ring composed of carbon and hydrogen atoms, having from 3 to 20 carbon atoms, and in certain embodiments from 3 to 15 carbon atoms, and in certain embodiments from 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 7 carbon atoms, or 3 to 6 carbon atoms, which is saturated or partially unsaturated and is attached to the rest of the molecule by a single bond. Examples of carbocycles include cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, cycloheptane, cycloheptene, and cyclooctane. Carbocycles include cycloalkyl groups.

[0020] "Cycloalkyl" refers to saturated cyclic alkyl groups having single or multiple rings, including fused, bridged, and spiro ring systems. As used herein, cycloalkyl refers to groups having 3 to 20 ring carbon atoms (i.e., C 3~20 cycloalkyl), having 3 to 12 ring carbon atoms (i.e., C 3~12 cycloalkyl), having 3 to 10 ring carbon atoms (i.e., C 3~10 cycloalkyl), having 3 to 8 ring carbon atoms (i.e., C 3~8 cycloalkyl), or having 3 to 6 ring carbon atoms (i.e., C 3~6 Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0021] As used herein, "heterocycle" or "heterocyclyl" includes, by way of example and not limitation, the heterocycles described in Paquette, Leo A.; Principles of Modern Heterocyclic Chemistry (WA Benjamin, New York, 1968), especially Chapters 1, 3, 4, 6, 7, and 9; The Chemistry of Heterocyclic Compounds, A Series of Monographs (John Wiley & Sons, New York, 1950 to present), especially Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566. For example, "heterocycle" includes a "carbocycle" as defined herein in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by a heteroatom (e.g., O, N, or S). As used herein, a heterocycle or heterocyclyl has 3 to 20 ring atoms, 3 to 12 ring atoms, 3 to 10 ring atoms, 3 to 8 ring atoms, or 3 to 6 ring atoms. The ring-forming carbon atoms and heteroatoms of a heterocycle group can be optionally oxidized to form oxo or sulfido groups or other oxidized bonds (e.g., C(O), S(O), C(S), or S(O), N-oxide, etc.), or a nitrogen atom can be quaternized. The term "heterocycle" or "heterocyclyl" includes saturated and partially unsaturated rings. Substituted heterocyclyls include heterocyclic rings substituted with any of the substituents disclosed herein, including, for example, a carbonyl group. Non-limiting examples of carbonyl-substituted heterocyclyls are: [ka]

[0022] Examples of heterocycles include, but are not limited to, tetrahydrofuranylazetidinyl and 2-oxo-1,3-dioxol-4-yl.

[0023] The term "optionally substituted" with respect to certain moieties of the compounds described herein, such as compounds of Formula I (e.g., optionally substituted aryl groups), refers to a moiety in which all of the substituents are hydrogen, or in which one or more of the hydrogens of the moiety can be replaced with the listed substituents.

[0024] Unless otherwise specified, the carbon atoms of the compounds of Formula I are intended to have a valence of 4. If a carbon atom in some chemical structure representation does not have a sufficient number of variables to produce a valence of 4, the remaining carbon substituents necessary to provide a valence of 4 should be assumed to be hydrogen.

[0025] The term "treating," as used herein, unless otherwise specified, means reversing, alleviating, or inhibiting the progression of the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. As used herein, the term "treatment" refers to the act of treating, as "treating" is defined immediately above.

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

[0027] As used herein, the term "therapeutically effective amount" refers to the amount of a compound described herein (e.g., a compound of Formula I) present in a composition described herein, when such composition is administered by a selected route of administration, that is required to provide a desired level of drug in the secretions and tissues of the airways and lungs, or alternatively, in the bloodstream of a treated subject, to confer an expected physiological response or desired biological effect. The precise amount will depend on numerous factors, including the particular compound described herein (e.g., a compound of Formula I), the specific activity of the composition, the delivery device used, the physical properties of the composition, its intended use, and patient considerations such as the severity of the disease state and patient cooperation, and can be readily determined by one of ordinary skill in the art based on the information provided herein.

[0028] III.Compound Any reference to a compound of the invention described herein also includes a reference to a pharmaceutically acceptable salt thereof. Examples of pharmaceutically acceptable salts of the compounds of the invention include alkali metal or alkaline earth salts (e.g., Na + , Li + , K. + , Ca +2 , and Mg +2 ), ammonium and NR4 + (wherein R is as defined herein) Pharmaceutically acceptable salts of a nitrogen atom or an amino group include (a) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; (b) acid addition salts formed with acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, isethionic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, and the like; (c) salts formed with organic acids such as benzoic acid, benzosulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, malonic acid, sulfosalicylic acid, glycolic acid, 2-hydroxy-3-naphthoate, pamoate, salicylic acid, stearic acid, phthalic acid, mandelic acid, lactic acid, ethanesulfonic acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine, and leucine; and (c) salts formed with elemental anions such as chlorine, bromine, and iodine. Pharmaceutically acceptable salts of compounds with hydroxy groups include Na + and NR4 + Examples of suitable cations include the anions of the above compounds in combination with suitable cations such as:

[0029] In some embodiments, R is H, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, C6-C 20 Aryl, or C2-C 20 It is a heterocyclyl.

[0030] For therapeutic use, salts of the active ingredients of the compounds of the present invention are pharmaceutically acceptable. That is, they are salts derived from pharmaceutically acceptable acids or bases. However, salts of non-pharmaceutically acceptable acids or bases may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether derived from pharmaceutically acceptable acids or bases, are within the scope of the present invention.

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

[0032] It should be noted that all enantiomers, diastereomers, racemic mixtures, tautomers, polymorphs, and pseudopolymorphs of the compounds described herein (e.g., compounds within the scope of Formula I) and their pharmaceutically acceptable salts are encompassed by the present invention. All mixtures of such enantiomers and diastereomers are within the scope of the present invention.

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

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

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

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

[0037] The present disclosure also includes compounds (e.g., compounds of Formula I) in which 1 to x hydrogens bonded to carbon atoms have been replaced with deuterium, where x is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and are therefore useful for increasing the half-life of any compound described herein (e.g., compounds of 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 light of the present disclosure, such compounds are synthesized by means known in the art, for example, by using starting materials in which one or more hydrogens have been replaced with deuterium.

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

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

[0040] In some embodiments, the compound of formula I is [ka] is.

[0041] In some embodiments, Base is [ka] is.

[0042] The concentration of such heavier isotopes, specifically deuterium, can be defined by the isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise noted, when a position is specifically designated as "H" or "hydrogen," the position is understood to have hydrogen at the natural abundance isotopic composition of hydrogen. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is meant to represent deuterium.

[0043] Whenever a compound described herein is substituted with more than one of the same group, e.g., designated "R" or "R", it will be understood that the groups can be the same or different, i.e., each group is independently selected.

[0044] Wavy Line [ka] indicates the site of covalent attachment to an adjacent substructure, group, moiety, or atom.

[0045] IV.Compound In certain embodiments, provided herein are compounds of formula I: [ka] or a pharmaceutically acceptable salt thereof, R 1 -OH, -OC(=O)R 4 , -OC(=O)OR 4 , or -OP(=O)(OH)(OR 4 ) and R 2 -OH, -OC(=O)R 5 , -OC(=O)OR 5 , or -OP(=O)(OH)(OR 5 ) or R 1 and R 2together form -OC(=O)O-, -OP(=O)(OH)O-, or -OCHR 6 O- is formed, R 3 is -C(=O)OR 7 and R 4 , R 5 , and R 7 are independently C1 to C 20 Alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 10 Carbocyclyl, C6-C 10 aryl, a 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R 4 , R 5 and R 7 C1~C 20 Alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 10 Carbocyclyl, C6-C 10 The aryl, 4- to 8-membered heterocyclyl, and 5- to 6-membered heteroaryl are each independently C1 to C8 alkyl, halogen, cyano, carbonyl, -N3, -OR 8 , -NR 9 R 10 , -OP(=O)(OH)2, -OP(=O)(OR 8 )2, C3-C8 carbocyclyl, 4-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S, and phenyl; R 4 , R 5 and R 7 the substituent C3-C8 carbocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from C1-C8 alkyl, halogen, —CF3, cyano, —CH2CN, and phenyl; R 4 , R5 , and R 7 wherein the substituted 4- to 6-membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from carbonyl and C1-C6 alkyl; R 4 , R 5 , and R 7 The substituent phenyl in the formula (I) is selected from halo, cyano, C1-C6 alkyl, and -OR 8 and optionally substituted with 1, 2, or 3 substituents independently selected from R 6 is H, C1-C6 alkyl, C1-C6 alkoxy, 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or C6-C 10 is aryl, R 6 5-6 membered heteroaryl and C6-C 10 each aryl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, C1-C6 alkoxy, and C1-C6 alkyl; Each R 8 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl and 4-6 membered heterocyclyl; R 8 wherein the C1-C6 alkyl is optionally substituted with a C3-C6 cycloalkyl or a 4- to 6-membered heterocyclyl; Each R 9 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; Each R 10 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; Base is, [ka] and R 11 is -OP(=O)(OH)(OR 14 ) is C1-C6 alkyl optionally substituted with R 12 is H, C1-C6 alkyl, -C(=O)R 13 , or -C(=O)OR 13 and Each R 13 are independently H or C1-C8 alkyl, and R 13 C1-C8 alkyl is halogen, cyano, -OP(=O)(OH)(OR 14 ), and phenyl; R 13 The substituent phenyl is -OP(=O)(OH)(OR 14 ), and Each R 14 are independently H, C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10 aryl, or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R 14 wherein the C1-C8 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, cyano, and phenyl; A compound of Formula I or a pharmaceutically acceptable salt thereof:

[0046] In certain embodiments, provided herein are compounds of formula I: [ka] or a pharmaceutically acceptable salt thereof, R 1 -OH, -OC(=O)R 4 , or -OC(=O)OR 4 and R 2 -OH, -OC(=O)R 5 , or -OC(=O)OR 5 or R 1 and R 2 together form -OC(=O)O-, -OP(=O)(OH)O-, or -OCHR 6 O- is formed, R 3 is -C(=O)OR 7 and R 4 , R 5 , and R 7 are independently C1 to C 20 Alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclyl, C6-C 10 aryl, a 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R 4 , R 5 and R 7 C1~C 20 Alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclyl, C6-C 10 The aryl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl are each independently C1 to C8 alkyl, halogen, cyano, carbonyl, -N3, -OR 8 , -NR 9 R 10 , -OP(=O)(OH)2, -OP(=O)(OR 8 )2, C3-C8 carbocyclyl, 4-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S, and phenyl; R 4 , R 5 and R 7 the substituent C3-C8 carbocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from C1-C8 alkyl, halogen, —CF3, cyano, —CH2CN, and phenyl; R 4 , R 5 , and R 7wherein the substituted 4- to 6-membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from carbonyl and C1-C6 alkyl; R 4 , R 5 , and R 7 The substituent phenyl in the formula (I) is selected from halo, cyano, C1-C6 alkyl, and -OR 8 and optionally substituted with 1, 2, or 3 substituents independently selected from R 6 is H, C1-C6 alkyl, C1-C6 alkoxy, 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or C6-C 10 is aryl, R 6 5-6 membered heteroaryl and C6-C 10 each aryl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, C1-C6 alkoxy, and C1-C6 alkyl; Each R 8 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; Each R 9 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; Each R 10 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; Base is, [ka] and R 11 is -OP(=O)(OH)(OR 14 ) is C1-C6 alkyl optionally substituted with R 12 is H, C1-C6 alkyl, -C(=O)R 13 , or -C(=O)OR 13 and Each R 13are independently H or C1-C8 alkyl, and R 13 C1-C8 alkyl is halogen, cyano, -OP(=O)(OH)(OR 14 ), and phenyl; R 13 The substituent phenyl is -OP(=O)(OH)(OR 14 ), and Each R 14 are independently H, C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10 aryl, or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R 14 wherein the C1-C8 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, cyano, and phenyl; A compound of Formula I or a pharmaceutically acceptable salt thereof:

[0047] In certain embodiments, provided herein are compounds of formula I: [ka] or a pharmaceutically acceptable salt thereof, R 1 -OH, -OC(=O)R 4 , or -OC(=O)OR 4 and R 2 -OH, -OC(=O)R 5 , or -OC(=O)OR 5 or R 1 and R 2 together form -OC(=O)O-, -OP(=O)(OH)O-, or -OCHR 6 O- is formed, R 3 is -C(=O)OR 7 and R 4 , R 5 , and R 7are each independently C1 to C8 alkyl, C2 to C8 alkenyl, C2 to C8 alkynyl, C3 to C8 carbocyclyl, C6 to C 10 aryl, a 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R 4 , R 5 and R 7 C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclyl, C6-C 10 The aryl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl are each independently C1 to C8 alkyl, halogen, cyano, carbonyl, -N3, -OR 8 , -NR 9 R 10 optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of -OP(=O)(OH)2, C3-C8 carbocyclyl, 4-6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl; R 4 , R 5 and R 7 The 4-6 membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from carbonyl and C1-C6 alkyl, and R 4 , R 5 and R 7 wherein the substituent phenyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl; R 6 is H, C1-C6 alkyl, C1-C6 alkoxy, 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or C6-C 10 is aryl, R 6 5-6 membered heteroaryl and C6-C 10each aryl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, C1-C6 alkoxy, and C1-C6 alkyl; Each R 8 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; Each R 9 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; Each R 10 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; Base is, [ka] and R 11 is -OP(=O)(OH)(OR 14 ) is C1-C6 alkyl optionally substituted with R 12 is H, C1-C6 alkyl, -C(=O)R 13 , or -C(=O)OR 13 and Each R 13 are independently H or C1-C8 alkyl, and R 13 C1-C8 alkyl is halogen, cyano, -OP(=O)(OH)(OR 14 ), and phenyl; R 13 The substituent phenyl is -OP(=O)(OH)(OR 14 ), and Each R 14 are independently H, C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10 aryl, or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R 14wherein the C1-C8 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, cyano, and phenyl; A compound of Formula I or a pharmaceutically acceptable salt thereof:

[0048] In certain embodiments, provided herein are compounds of formula I: [ka] or a pharmaceutically acceptable salt thereof, R 1 -OH, -OC(=O)R 4 , or -OC(=O)OR 4 and R 2 -OH, -OC(=O)R 5 , or -OC(=O)OR 5 or R 1 and R 2 together form -OC(=O)O-, -OP(=O)(OH)O-, or -OCHR 6 O- is formed, R 3 is -C(=O)OR 7 and R 4 , R 5 , and R 7 are each independently C1 to C8 alkyl, C2 to C8 alkenyl, C2 to C8 alkynyl, C3 to C8 carbocyclyl, C6 to C 10 aryl, a 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; where R 4 , R 5 and R 7 C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclyl, C6-C 10The aryl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl are each independently selected from halogen, cyano, carbonyl, -N3, -OR 8 , -NR 9 R 10 optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of -OP(=O)(OH)2, C3-C8 carbocyclyl, 4-6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl; wherein the 4- to 6-membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from carbonyl and C1-C6 alkyl; and the phenyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl; R 6 is H, C1-C6 alkyl, C1-C6 alkoxy, 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or C6-C 10 is aryl, 5-6 membered heteroaryl and C6-C 10 each aryl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, C1-C6 alkoxy, and C1-C6 alkyl; Each R 8 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; Each R 9 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; Each R 10 are independently H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; Base is, [ka] and R11 is -OP(=O)(OH)(OR 14 ) is C1-C6 alkyl optionally substituted with R 12 is H, C1-C6 alkyl, -C(=O)R 13 , or -C(=O)OR 13 and Each R 13 are independently H or C1-C8 alkyl, and R 13 C1-C8 alkyl is halogen, cyano, -OP(=O)(OH)(OR 14 ) and phenyl, wherein phenyl is optionally substituted with 1, 2, or 3 substituents independently selected from -OP(=O)(OH)(OR 14 ), and Each R 14 are independently H, C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10 aryl, or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R 14 wherein the C1-C8 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, cyano, and phenyl; A compound of Formula I or a pharmaceutically acceptable salt thereof:

[0049] In some embodiments, R 1 is —OH. In some embodiments, R 1 is -OC(=O)R 4 In some embodiments, R 1 is -OC(=O)OR 4 is.

[0050] In some embodiments, R 1 is -OP(=O)(OH)(OR 4 )

[0051] In some embodiments, R 2 is —OH. In some embodiments, R 2is -OC(=O)R 5 In some embodiments, R 2 is -OC(=O)OR 5 is.

[0052] In some embodiments, R 2 is -OP(=O)(OH)(OR 5 )

[0053] In some embodiments, R 1 and R 2 are both —OH. In some embodiments, R 1 is -OC(=O)R 4 and R 2 is -OC(=O)R 5 In some embodiments, R 1 is OH and R 2 is -OC(=O)R 5 or OC(O)OR 5 In some embodiments, R 1 is -OC(=O)R 4 or -OC(=O)OR 4 and R 2 is OH. In some embodiments, R 1 and R 2 together form -OC(=O)O-. In some embodiments, R 1 and R 2 together form -OP(=O)(OH)O-. In some embodiments, R 1 and R 2 Together, -OCHR 6 Forms O-.

[0054] In some embodiments, R 1 is OH and R 2 is -OC(=O)R 5 In some embodiments, R 1 is OH and R 2 is OC(=O)OR 5 In some embodiments, R 1 is -OC(=O)R4 and R 2 is OH. In some embodiments, R 1 is -OC(=O)OR 4 and R 2 is OH. In some embodiments, R 1 is -OC(=O)OR 4 and R 2 is OC(=O)OR 5 In some embodiments, R 1 is -OC(=O)R 4 and R 2 is OC(=O)OR 5 In some embodiments, R 1 is -OC(=O)OR 4 and R 2 is OC(=O)R 5 is.

[0055] In some embodiments, R 1 is -OP(=O)(OH)(OR 4 ) and R 2 is -OH.

[0056] In some embodiments, R 1 is —OC(═O)CH. In some embodiments, R 2 is —OC(═O)CH. In some embodiments, R 1 and R 2 are both -OC(=O)CH3.

[0057] In some embodiments, R 1 is OH, OC(O)CH(CH3)2, or OC(O)CH3, R 2 is OH, OC(O)CH(CH3)2, or OC(O)CH3, or R 1 and R 2 together form -OC(=O)O-.

[0058] In some embodiments, R4 is C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl, and R 4 The C1-C8 alkyl, C2-C8 alkenyl, and C2-C8 alkynyl are each independently halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , —OP(═O)(OH), C-C carbocyclyl, and phenyl, wherein R 4 The substituted phenyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl.

[0059] In some embodiments, R 4 is C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl, and R 4 The C1-C8 alkyl, C2-C8 alkenyl, and C2-C8 alkynyl are each independently halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclyl, and phenyl, wherein phenyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl.

[0060] In some embodiments, R 4 is halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , —OP(═O)(OH), C-C alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of —O—P(═O)(OH), C-C carbocyclyl, and phenyl. In some embodiments, R 4 is C1-C8 alkyl. In some embodiments, R 4 is C1-C6 alkyl. In some embodiments, R 4is C1-C3 alkyl. In some embodiments, R 4 is -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH 3、 or -C(CH3)3. In some embodiments, R 4 is -CH3 or -CH(CH3)2.

[0061] In some embodiments, R 4 is -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH 3、 -C(CH3)3 or -C(CH3)2CH2CH3.

[0062] In some embodiments, R 4 is carbonyl, -OR 8 , -NR 9 R 10 and -OP(=O)(OH)2, wherein each C1-C1 is substituted with 1, 2, or 3 substituents independently selected from the group consisting of 20 In some embodiments, R 4 is a carbonyl and -OR 8 In some embodiments, R 4 teeth [ka] is.

[0063] In some embodiments, R 4 is C2-C8 alkenyl. In some embodiments, R 4 is C4 alkenyl. In some embodiments, R 4 teeth [ka] is.

[0064] In some embodiments, R 5 is C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl, and R4 The C1-C8 alkyl, C2-C8 alkenyl, and C2-C8 alkynyl are each independently halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , —OP(═O)(OH), C-C carbocyclyl, and phenyl, wherein R 5 The substituted phenyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl.

[0065] In some embodiments, R 5 is C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl, and R 4 The C1-C8 alkyl, C2-C8 alkenyl, and C2-C8 alkynyl are each independently halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclyl, and phenyl, wherein phenyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl.

[0066] In some embodiments, R 5 is halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , —OP(═O)(OH), C-C alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of —O—P(═O)(OH), C-C carbocyclyl, and phenyl. In some embodiments, R 5 is C1-C8 alkyl. In some embodiments, R 5 is C1-C6 alkyl. In some embodiments, R 5 is C1-C3 alkyl. In some embodiments, R 5is -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH 3、 or -C(CH3)3. In some embodiments, R 5 is -CH3 or -CH(CH3)2.

[0067] In some embodiments, R 5 is -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH 3、 -C(CH3)3 or -C(CH3)2CH2CH3.

[0068] In some embodiments, R 5 is carbonyl, -OR 8 , -NR 9 R 10 and -OP(=O)(OH)2, wherein each C1-C1 is substituted with 1, 2, or 3 substituents independently selected from the group consisting of 20 In some embodiments, R 5 is a carbonyl and -OR 8 In some embodiments, R 5 teeth [ka] is.

[0069] In some embodiments, R 5 is C2-C8 alkenyl. In some embodiments, R 5 is C4 alkenyl. In some embodiments, R 5 teeth [ka] is.

[0070] In some embodiments, R 4 and R 5 and are the same. In some embodiments, R 4 and R 5 In some embodiments, R4 is a C1-C8 alkyl, and R 5 is C1-C8 alkyl. In some embodiments, R 4 is -CH3 or -CH(CH3)2, and R 5 is —CH or —CH(CH). In some embodiments, R 4 is -CH3 and R 5 is -CH3. In some embodiments, R 4 is -CH(CH3)2 and R 5 is -CH(CH3)2.

[0071] In some embodiments, R 6 is H. In some embodiments, R 6 is C1-C6 alkyl. In some embodiments, R 6 is -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH 3、 or -C(CH3)3. In some embodiments, R 6 is C1-C6 alkoxy. In some embodiments, R 6 is -OCH3.

[0072] In some embodiments, R 6 is a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, C1-C6 alkoxy, and C1-C6 alkyl. In some embodiments, R 6 is a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S substituted with 1, 2, or 3 substituents independently selected from halo, cyano, C1-C6 alkoxy, and C1-C6 alkyl. In some embodiments, R 6 is a 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S.

[0073] In some embodiments, R 6is a C6-C6 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, C1-C6 alkoxy, and C1-C6 alkyl; 10 In some embodiments, R 6 is a C6-C substituted with 1, 2, or 3 substituents independently selected from halo, cyano, C1-C6 alkoxy, and C1-C6 alkyl. 10 In some embodiments, R 6 is C6~C 10 In some embodiments, R 6 is phenyl.

[0074] In some embodiments, R 7 is C1~C 20 Alkyl, C2-C8 alkenyl, C3-C 10 Carbocyclyl, C6-C 10 aryl, a 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; 7 C1~C 20 Alkyl, C3-C8 carbocyclyl, C6-C 10 Aryl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl are each selected from C1 to C8 alkyl, halogen, cyano, carbonyl, -N3, -OR 8 , -NR 9 R 10 , -OP(=O)(OH)2, -OP(=O)(OR 8 )2, C3-C8 carbocyclyl, 4-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S, and phenyl; 7 the substituent C3-C8 carbocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from C1-C8 alkyl, halogen, —CF3, cyano, —CH2CN, and phenyl;7 The 4-6 membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from carbonyl and C1-C6 alkyl, and R 7 The substituent phenyl in the formula (I) is selected from halo, cyano, C1-C6 alkyl, and OR 8 is optionally substituted with 1, 2, or 3 substituents independently selected from

[0075] In some embodiments, R 7 is C1~C 20 Alkyl, C2-C8 alkenyl, C3-C8 carbocyclyl, C6-C 10 aryl, a 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; and R 7 C1~C 20 Alkyl, C3-C8 carbocyclyl, C6-C 10 Aryl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl are each selected from C1 to C8 alkyl, halogen, cyano, carbonyl, -N3, -OR 8 , -NR 9 R 10 , -OP(=O)(OH)2, -OP(=O)(OR 8 )2, C3-C8 carbocyclyl, 4-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S, and phenyl; 7 the substituent C3-C8 carbocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from C1-C8 alkyl, halogen, —CF3, cyano, —CH2CN, and phenyl; 7 The 4-6 membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from carbonyl and C1-C6 alkyl, and R 7 The substituent phenyl in the formula (I) is selected from halo, cyano, C1-C6 alkyl, and OR8 is optionally substituted with 1, 2, or 3 substituents independently selected from

[0076] In some embodiments, R 7 is C1~C 20 Alkyl, C3-C8 carbocyclyl, C6-C 10 aryl, a 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; and R 7 C1~C 20 Alkyl, C3-C8 carbocyclyl, C6-C 10 Aryl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl are each selected from C1 to C8 alkyl, halogen, cyano, carbonyl, -N3, -OR 8 , -NR 9 R 10 , -OP(=O)(OH)2, -OP(=O)(OR 8 )2, C3-C8 carbocyclyl, 4-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S, and phenyl; 7 the substituent C3-C8 carbocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from C1-C8 alkyl, halogen, —CF3, cyano, —CH2CN, and phenyl; 7 The 4-6 membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from carbonyl and C1-C6 alkyl, and R 7 The substituent phenyl in the formula (I) is selected from halo, cyano, C1-C6 alkyl, and OR 8 is optionally substituted with 1, 2, or 3 substituents independently selected from

[0077] In some embodiments, R 7 is C1~C 20Alkyl, C3-C8 carbocyclyl, C6-C 10 aryl, a 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, wherein R 7 C1~C 20 Alkyl, C3-C8 carbocyclyl, C6-C 10 Aryl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl are each C1-C8 alkyl, -OR 8 , -NR 9 R 10 , -OP(=O)(OH)2, -OP(=O)(OR 8 )2, C3-C8 carbocyclyl, 4-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S, and phenyl; 7 the substituent C3-C8 carbocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from C1-C8 alkyl, halogen, —CF3, cyano, —CH2CN, and phenyl; 7 The 4-6 membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from carbonyl and C1-C6 alkyl, and R 7 The substituent phenyl in the formula (I) is selected from halo, cyano, C1-C6 alkyl, and OR 8 is optionally substituted with 1, 2, or 3 substituents independently selected from

[0078] In some embodiments, R 7 is C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10 aryl, a 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, wherein R 7C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10 Aryl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl are each optionally selected from C1-C8 alkyl, -OR 8 , -OP(=O)(OH)2, C3-C8 carbocyclyl, 4-6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl; 7 The 4-6 membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from carbonyl and C1-C6 alkyl, and R 7 The substituted phenyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl.

[0079] In some embodiments, R 7 is C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10 aryl, a 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; and R 7 C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10 Aryl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl are each -OR 8 , -OP(=O)(OH)2, C3-C8 carbocyclyl, 4-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S, and phenyl; R 7the substituent C3-C8 carbocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from C1-C8 alkyl, halogen, —CF3, cyano, —CH2CN, and phenyl; 7 The 4-6 membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from carbonyl and C1-C6 alkyl, and R 7 The substituent phenyl in the formula (I) is selected from halo, cyano, C1-C6 alkyl, and OR 8 is optionally substituted with 1, 2, or 3 substituents independently selected from

[0080] In some embodiments, R 7 is C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10 aryl, a 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; and R 7 C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10 Aryl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl are each -OR 8 , -OP(=O)(OH)2, C3-C8 carbocyclyl, 4-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S, and phenyl; R 7 The 4-6 membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from carbonyl and C1-C6 alkyl, and R 7 The substituted phenyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl.

[0081] In some embodiments, R 7 is C1-C8 alkyl, C3-C8 carbocyclyl, C6-C10 aryl, a 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; and R 7 C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10 Aryl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl are each -OR 8 , -OP(=O)(OH)2, C3-C8 carbocyclyl, 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl, wherein the 4- to 6-membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from carbonyl and C1-C6 alkyl, and the phenyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl.

[0082] In some embodiments, R 7 is C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10 aryl, a 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, wherein R 7 C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10 Aryl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl are each C1-C8 alkyl, -OR 8 , —OP(═O)(OH), C-C carbocyclyl, and phenyl; R 7 The substituted phenyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl.

[0083] In some embodiments, R 7 is C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10 aryl, a 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; and R 7 C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10 Aryl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl are each -OR 8 , —OP(═O)(OH), C-C carbocyclyl, and phenyl; R 7 The substituted phenyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl.

[0084] In some embodiments, R 7 is C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10 aryl, a 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; and R 7 C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10 Aryl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl are each -OR 8 , -OP(=O)(OH)2, C3-C8 carbocyclyl, and phenyl, wherein phenyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl.

[0085] In some embodiments, R 7 is C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10aryl, 4-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S, or 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S, wherein C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10 aryl, 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and R 7 Each of the 5- to 6-membered heteroaryls containing 1, 2, or 3 heteroatoms selected from N, O, and S is selected from C1-C8 alkyl, -OR 8 , -OP(=O)(OH)2, C3-C8 carbocyclyl, 4-6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl; R 7 The substituted 4-6 membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from carbonyl and C1-C6 alkyl.

[0086] In some embodiments, R 7 is C1-C8 alkyl, C3-C8 carbocyclyl, 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; C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10 aryl, 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and R 7 Each of the 5- to 6-membered heteroaryls containing 1, 2, or 3 heteroatoms selected from N, O, and S is -OR 8, -OP(=O)(OH)2, C3-C8 carbocyclyl, 4-6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl; R 7 The substituted 4-6 membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from carbonyl and C1-C6 alkyl.

[0087] In some embodiments, R 7 is C1-C8 alkyl, C3-C8 carbocyclyl, 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; C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10 Aryl, 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S are each represented by -OR 8 , -OP(=O)(OH)2, C3-C8 carbocyclyl, 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl, wherein the 4- to 6-membered heterocyclyl is optionally substituted by 1, 2, or 3 substituents independently selected from carbonyl and C1-C6 alkyl.

[0088] In some embodiments, R 7 is C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10aryl, 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, wherein C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10 aryl, 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and R 7 The 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S is, respectively, C1-C8 alkyl, -OR 8 , -OP(=O)(OH)2, C3-C8 carbocyclyl, 4-6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl.

[0089] In some embodiments, R 7 is C1-C8 alkyl, C3-C8 carbocyclyl, 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; C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10 aryl, 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and R 7 Each of the 5- to 6-membered heteroaryls containing 1, 2, or 3 heteroatoms selected from N, O, and S is -OR 8 , -OP(=O)(OH)2, C3-C8 carbocyclyl, 4-6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl.

[0090] In some embodiments, R 7 is C1-C8 alkyl, C3-C8 carbocyclyl, 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; C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10 Aryl, 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S are each represented by -OR 8 , -OP(=O)(OH)2, C3-C8 carbocyclyl, 4-6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl.

[0091] In some embodiments, R 7 is C1-C8 alkyl, C3-C8 carbocyclyl, 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, wherein C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10 aryl, 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and R 7 Each of the 5- to 6-membered heteroaryls containing 1, 2, or 3 heteroatoms selected from N, O, and S is selected from C1-C8 alkyl, -OR 8 , -OP(=O)(OH)2, C3-C8 carbocyclyl, and phenyl.

[0092] In some embodiments, R 7 is C1-C8 alkyl, C3-C8 carbocyclyl, 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, wherein C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10 aryl, 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and R 7 Each of the 5- to 6-membered heteroaryls containing 1, 2, or 3 heteroatoms selected from N, O, and S is -OR 8 , -OP(=O)(OH)2, C3-C8 carbocyclyl, and phenyl.

[0093] In some embodiments, R 7 is C1-C8 alkyl, C3-C8 carbocyclyl, 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; and C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10 Aryl, 4- to 6-membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S, and 5- to 6-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S are represented by -OR 8 , -OP(=O)(OH)2, C3-C8 carbocyclyl, and phenyl.

[0094] In some embodiments, R 7 is C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10aryl, a 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; and R 7 C1-C8 alkyl is C1-C8 alkyl, -OR 8 , -OP(=O)(OH)2, C3-C8 carbocyclyl, 4-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S, and phenyl; R 7 The substituted 4-6 membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from carbonyl and C1-C6 alkyl.

[0095] In some embodiments, R 7 is C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10 aryl, a 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, wherein R 7 C1-C8 alkyl is -OR 8 , -OP(=O)(OH)2, C3-C8 carbocyclyl, 4-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S, and phenyl; R 7 The substituted 4-6 membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from carbonyl and C1-C6 alkyl.

[0096] In some embodiments, R 7 is C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10aryl, a 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; and C1-C8 alkyl is -OR 8 , -OP(=O)(OH)2, C3-C8 carbocyclyl, 4-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S, and phenyl, wherein the 4-6 membered heterocyclyl is optionally substituted by 1, 2 or 3 substituents independently selected from carbonyl and C1-C6 alkyl.

[0097] In some embodiments, R 7 is C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10 aryl, a 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, wherein R7 is C1-C 8 Alkyl is -OR 8 , -OP(=O)(OH)2, C3-C8 carbocyclyl, 4-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S, and phenyl.

[0098] In some embodiments, R 7 is C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10 aryl, a 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; and C1-C8 alkyl is -OR 8, -OP(=O)(OH)2, C3-C8 carbocyclyl, 4-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S, and phenyl.

[0099] In some embodiments, R 7 is C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10 aryl, a 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, wherein R 7 The C1-C8 alkyl may optionally be -OR 8 , -OP(=O)(OH)2, C3-C8 carbocyclyl, and phenyl.

[0100] In some embodiments, R 7 is C1-C8 alkyl, C3-C8 carbocyclyl, C6-C 10 aryl, a 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; and C1-C8 alkyl is -OR 8 , -OP(=O)(OH)2, C3-C8 carbocyclyl, and phenyl.

[0101] In some embodiments, R 7 is C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl, wherein R 7 The C1-C8 alkyl, C2-C8 alkenyl, and C2-C8 alkynyl are each independently halogen, cyano, -N3, -OR 8 , -NR9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclyl, and phenyl, wherein phenyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl.

[0102] In some embodiments, R 7 is C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl, and each of the C1-C8 alkyl, C2-C8 alkenyl, and C2-C8 alkynyl independently represents halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclyl, and phenyl, wherein phenyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl.

[0103] In some embodiments, R 7 C1-C8 alkyl, halogen, cyano, carbonyl, -N3, -OR 8 , -NR 9 R 10 , -OP(=O)(OH)2, -OP(=O)(OR 8 )2, C1-C optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C3-C8 carbocyclyl, 4-6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl. 20 alkyl, and R 7 the substituent C3-C8 carbocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from C1-C8 alkyl, halogen, —CF3, cyano, —CH2CN, and phenyl; 7The 4-6 membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from carbonyl and C1-C6 alkyl, and R 7 The substituent phenyl in the formula (I) is selected from halo, cyano, C1-C6 alkyl, and OR 8 is optionally substituted with 1, 2, or 3 substituents independently selected from

[0104] In some embodiments, R 7 is halogen, cyano, -N3, -OR 8 , -NR 9 R 10 C1-C optionally substituted by 1, 2, or 3 substituents independently selected from the group consisting of -OP(=O)(OH), C3-C8 carbocyclyl, 4-6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl. 20 Alkyl, R 7 The 4-6 membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from carbonyl and C1-C6 alkyl, and R 7 The substituted phenyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl.

[0105] In some embodiments, R 7 is halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclyl, 4-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S, and phenyl; 7The 4-6 membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from carbonyl and C1-C6 alkyl, and R 7 The substituted phenyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl.

[0106] In some embodiments, R 7 is halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclyl, 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and C1-C8 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of phenyl, -OP(=O)(OH), C3-C8 carbocyclyl, 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and phenyl, wherein the 4- to 6-membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from carbonyl and C1-C6 alkyl, and the phenyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl.

[0107] In some embodiments, R 7 is halogen, cyano, carbonyl, -N3, -OR 8 , -NR 9 R 10 , —OP(═O)(OH), C-C carbocyclyl, and phenyl, wherein R 7 The substituent C3-C8 carbocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl, and wherein R 7 The substituted phenyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl.

[0108] In some embodiments, R 7 is halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , —OP(═O)(OH), C-C alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of —OP(═O)(OH), C-C carbocyclyl, and phenyl; R 7 The substituted phenyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl.

[0109] In some embodiments, R 7 is halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , -OP(=O)(OH)2, C1-C8 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C3-C8 carbocyclyl and phenyl, wherein phenyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl.

[0110] In some embodiments, R 7 is halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , —OP(═O)(OH) , C-C alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of —O—P(═O)(OH), C-C carbocyclyl, and phenyl; R 7 The substituted phenyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl.

[0111] In some embodiments, R 7 is halogen, cyano, -N3, -OR 8 , -NR 9 R 10, -OP(=O)(OH)2, C3-C8 carbocyclyl, and phenyl, wherein phenyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl.

[0112] In some embodiments, R 7 -OR 8 , -OP(=O)(OH)2, -OP(=O)(OR 8 )2, C1-C8 alkyl optionally substituted with one substituent selected from the group consisting of C3-C8 carbocyclyl and phenyl.

[0113] In some embodiments, R 7 -OR 8 , —OP(═O)(OH), C1-C8 alkyl optionally substituted with one substituent selected from the group consisting of C3-C8 carbocyclyl and phenyl. In some embodiments, R 7 -OR 8 , —OP(═O)(OH) 2 , C1-C6 alkyl optionally substituted with one substituent selected from the group consisting of C3-C8 carbocyclyl and phenyl.

[0114] In some embodiments, R 7 is C1-C8 alkyl substituted with halogen. In some embodiments, R 7 is C1-C8 alkyl substituted with -F or -Cl. In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] is.

[0115] In some embodiments, R 7 -OR 8 In some embodiments, R 7 -OR 8 In some embodiments, R 7 is a C2-C4 alkyl substituted with -OCH3. In some embodiments, R 7 teeth, [ka] is.

[0116] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] is.

[0117] In some embodiments, R 7 is -NR 9 R 10 In some embodiments, R 7 is a C1-C8 alkyl substituted with -N(CH3)2.

[0118] In some embodiments, R 7 is a C1-C8 alkyl substituted with a carbonyl.

[0119] In some embodiments, R 7 is a carbonyl and -OR 8 In some embodiments, R 7 is a C1-C8 alkyl substituted with carbonyl and -OCH2CH3. In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 is carbonyl and -NR 9 R 10 In some embodiments, R 7 is a C1-C8 alkyl substituted with carbonyl and -N(CH3)2. In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] is.

[0120] In some embodiments, R 7 is a C1-C8 alkyl substituted with carbonyl and -OC(CH3)3. In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 is a C1-C8 alkyl substituted with carbonyl and -OH. In some embodiments, R 7 teeth, [ka] is.

[0121] In some embodiments, R 7 is carbonyl, -NR 9 R 10 and-OR 8In some embodiments, R 7 is C1-C8 alkyl substituted with carbonyl, —N(CH3)2, and —OCH3. In some embodiments, R 7 is C1-C8 alkyl substituted with carbonyl, —N(CH3)2, and —OCH(CH3)2. In some embodiments, R 7 is C1-C8 alkyl substituted with carbonyl, —N(CH3)2, and —OCH2C(CH3)3. In some embodiments, R 7 is a carbonyl, -N(CH3)2, and [ka] In some embodiments, R 7 is a carbonyl, -N(CH3)2, and [ka] In some embodiments, R 7 is a carbonyl, -N(CH3)2, and [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] is.

[0122] In some embodiments, R 7 is a C1-C8 alkyl substituted with a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, R 7is alkyl substituted with pyridinyl, pyrimidinyl, or imidazolyl. In some embodiments, R 7 teeth, [ka] is.

[0123] In some embodiments, R 7 is a C1-C8 alkyl substituted with phenyl, where R 7 The substituent phenyl in the formula (I) is selected from halo, cyano, C1-C6 alkyl, and OR 8 In some embodiments, R 7 is R 7 The substituent phenyl is OR 8 In some embodiments, R 7 teeth, [ka] is.

[0124] In some embodiments, R 7 is C1-C8 alkyl substituted with phenyl. In some embodiments, R 7 is C1-C4 alkyl substituted with phenyl. In some embodiments, R 7 teeth, [ka] is.

[0125] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] is.

[0126] In some embodiments, R 7 is a C1-C8 alkyl substituted with a C3-C8 carbocyclyl, and R 7 The substituent C3-C8 carbocyclyl in R is optionally substituted with 1, 2, or 3 substituents independently selected from C1-C8 alkyl, halogen, —CF3, cyano, —CH2CN, and phenyl. 7 teeth, [ka] is.

[0127] In some embodiments, R 7 is C1-C8 alkyl substituted with C3-C8 carbocyclyl. In some embodiments, R 7 is a C2-C4 alkyl substituted with a C4-C7 carbocyclyl. 7 is a C2-C4 alkyl substituted with [ka] In some embodiments, R 7 teeth, [ka] is.

[0128] In some embodiments, R 7 teeth, [ka] is.

[0129] In some embodiments, R 7 teeth, [ka] C replaced with 2~4 In some embodiments, R 7teeth, [ka] is.

[0130] In some embodiments, R 7 is a C1-C8 alkyl substituted with a 4-6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, R 7 teeth [ka] In some embodiments, R 7 is a C1-C8 alkyl substituted with a 4-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S, where R 7 The substituted 4-6 membered heterocyclyl of R is substituted with 1, 2, or 3 substituents independently selected from the group consisting of C1-C8 alkyl and carbonyl. 7 teeth, [ka] is.

[0131] In some embodiments, R 7 is a C1-C8 alkyl substituted with -OP(=O)(OH). In some embodiments, R 7 is C1-C4 alkyl substituted with -OP(=O)(OH). In some embodiments, R 7 teeth, [ka] is.

[0132] In some embodiments, R 7 is -OP(=O)(OR 8 )2. In some embodiments, R 7 teeth, [ka] is.

[0133] In some embodiments, R 7 is C1~C 20 In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] is.

[0134] In some embodiments, R 7 is C1-C8 alkyl. In some embodiments, R 7 is C1-C6 alkyl. In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] is.

[0135] In some embodiments, R 7 is C1-C3 alkyl. In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] is.

[0136] In some embodiments, R7 is a C1-C3 alkyl, and R 1 and R 2 are both -OC(=O)CH3. In some embodiments, R 7 teeth [ka] and R 1 and R 2 are both -OC(=O)CH3. In some embodiments, R 7 teeth [ka] and R 1 and R 2 are both -OC(=O)CH3.

[0137] In some embodiments, R 7 teeth, [ka] [ka] is.

[0138] In some embodiments, R 7 teeth, [ka] is.

[0139] In some embodiments, R 7 teeth, [ka] is.

[0140] In some embodiments, R 7 is C2-C8 alkenyl. In some embodiments, R 7 teeth, [ka] is.

[0141] In some embodiments, R 7 is C1-C8 alkyl, halogen, cyano, -N3, -OR 8 , -NR 9 R 10 C3-C optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of -OP(=O)(OH), C3-C8 carbocyclyl, and phenyl. 10 carbocyclyl and the substituent phenyl R 7 is optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl.

[0142] In some embodiments, R 7 is C1-C8 alkyl, halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , —OP(═O)(OH) , C-C carbocyclyl, and phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: —O—P(═O)(OH) , C-C carbocyclyl, and phenyl; 7 is optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl.

[0143] In some embodiments, R 7 is halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , —OP(═O)(OH) , C-C carbocyclyl, and phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: —O—P(═O)(OH) , C-C carbocyclyl, and phenyl; 7 is optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl.

[0144] In some embodiments, R 7is halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclyl, and phenyl, wherein phenyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl.

[0145] In some embodiments, R 7 is C1-C8 alkyl, halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of -OP(=O)(OH)2, C3-C8 carbocyclyl, and phenyl.

[0146] In some embodiments, R 7 is halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of -OP(=O)(OH)2, C3-C8 carbocyclyl, and phenyl.

[0147] In some embodiments, R 7 is C1-C8 alkyl, -OR 8 , -NR 9 R 10 , C3-C8 carbocyclyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C3-C8 carbocyclyl and phenyl.

[0148] In some embodiments, R 7 -OR 8 , -NR 9 R 10, C3-C8 carbocyclyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C3-C8 carbocyclyl and phenyl.

[0149] In some embodiments, R 7 is a C3-C8 carbocyclyl substituted with 1, 2, or 3 substituents independently selected from the group consisting of C1-C8 alkyl and halogen. 7 teeth [ka] In some embodiments, R 7 teeth, [ka] is.

[0150] In some embodiments, R 7 teeth, [ka] is.

[0151] In some embodiments, R 7 is C3~C 10 In some embodiments, R 7 teeth, [ka] is.

[0152] In some embodiments, R 7 is C3-C8 carbocyclyl. In some embodiments, R 7 teeth, [ka] is.

[0153] In some embodiments, R 7 teeth, [ka] is.

[0154] In some embodiments, R 7 teeth [ka] is.

[0155] In some embodiments, R 7 teeth, [ka] is.

[0156] In some embodiments, R 7 is C1-C8 alkyl, halogen, cyano, -N3, -OR 8 , -NR 9 R 10 C6-C optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of -OP(=O)(OH), C3-C8 carbocyclyl, and phenyl. 10 aryl, and R 7 The substituted phenyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl.

[0157] In some embodiments, R 7 is halogen, cyano, N3, -OR 8 , -NR 9 R 10 C6-C optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of -OP(=O)(OH), C3-C8 carbocyclyl, and phenyl. 10 aryl, and R 7 The substituted phenyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl.

[0158] In some embodiments, R7 is halogen, cyano, N3, -OR 8 , -NR 9 R 10 C6-C optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of -OP(=O)(OH), C3-C8 carbocyclyl, and phenyl. 10 Aryl, wherein the phenyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl.

[0159] In some embodiments, R 7 is halogen, cyano, N3, -OR 8 , -NR 9 R 10 C6-C optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of -OP(=O)(OH), C3-C8 carbocyclyl, and phenyl. 10 It is aryl.

[0160] In some embodiments, R 7 is halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , -OP(=O)(OH)2, phenyl or naphthyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C3-C8 carbocyclyl and phenyl.

[0161] In some embodiments, R 7 is halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclyl, and phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: -O-P(=O)(OH)2, C3-C8 carbocyclyl, and phenyl.

[0162] In some embodiments, R 7 is C1-C8 alkyl and -OR 8In some embodiments, the phenyl is substituted with three substituents independently selected from the group consisting of: [ka] is.

[0163] In some embodiments, R 7 teeth, [ka] is.

[0164] In some embodiments, R 7 teeth, [ka] is.

[0165] In some embodiments, R 7 is halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclyl, and phenyl; R is a 4-8 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: -OP(=O)(OH), C3-C8 carbocyclyl, and phenyl; 7 The substituted phenyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl.

[0166] In some embodiments, R 7 is halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclyl, and phenyl; R is a 4-6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: -OP(=O)(OH), C3-C8 carbocyclyl, and phenyl; 7The substituted phenyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl.

[0167] In some embodiments, R 7 is halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclyl, and phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl.

[0168] In some embodiments, R 7 is halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclyl, and phenyl, and optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of phenyl, -OP(=O)(OH), C3-C8 carbocyclyl, and phenyl.

[0169] In some embodiments, R 7 is halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclyl, and phenyl, and a 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: -OP(=O)(OH), C3-C8 carbocyclyl, and phenyl.

[0170] In some embodiments, R 7 teeth, [ka] is.

[0171] In some embodiments, R 7 is halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclyl, and phenyl, and a 5-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: -OP(=O)(OH), C3-C8 carbocyclyl, and phenyl.

[0172] 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 teeth [ka] is.

[0173] In some embodiments, R 7 is halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclyl, and phenyl, and a 4-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: -OP(=O)(OH), C3-C8 carbocyclyl, and phenyl.

[0174] In some embodiments, R 7 is a 4-membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S.

[0175] In some embodiments, R 7 teeth, [ka] is.

[0176] In some embodiments, R7 teeth, [ka] is.

[0177] In some embodiments, R 7 teeth [ka] In some embodiments, R 7 teeth, [ka] is.

[0178] In some embodiments, R 7 is halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , -OP(=O)(OH), C-C carbocyclyl, and phenyl; R is a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: -OP(=O)(OH), C-C carbocyclyl, and phenyl; 7 The substituted phenyl is optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl.

[0179] In some embodiments, R 7 is halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclyl, and phenyl, optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, and C1-C6 alkyl.

[0180] In some embodiments, R 7 is halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclyl, and phenyl, and optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of N, O, and S.

[0181] In some embodiments, R 7 is halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclyl, and phenyl, and is a 5-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: -OP(=O)(OH), C3-C8 carbocyclyl, and phenyl.

[0182] In some embodiments, R 7 is a 5-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S.

[0183] In some embodiments, R 7 is halogen, cyano, -N3, -OR 8 , -NR 9 R 10 , -OP(=O)(OH)2, C3-C8 carbocyclyl, and phenyl, and is a 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of: -OP(=O)(OH), C3-C8 carbocyclyl, and phenyl.

[0184] In some embodiments, R 7 is halogen, cyano and -NR 9 R 10 and is a 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of:

[0185] In some embodiments, R 7 is a 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, R 7 teeth, [ka] is.

[0186] In some embodiments, R 7 teeth, [ka] [ka] is.

[0187] In some embodiments, R 7 teeth, [ka] [ka] is.

[0188] In some embodiments, R 7 teeth, [ka] is.

[0189] In some embodiments, R 7 teeth, [ka] is.

[0190] In some embodiments, R 7 teeth, [ka] is.

[0191] In some embodiments, R 7 teeth, [ka] is.

[0192] In some embodiments, R 8 is H. In some embodiments, R 8 is C1-C6 alkyl. In some embodiments, R 8 is -CH3. In some embodiments, R 8 is C1-C6 haloalkyl. In some embodiments, R 8 is a C3-C6 cycloalkyl.

[0193] In some embodiments, R 8 teeth, [ka] In some embodiments, R 8 is —C(CH3)3, —CH(CH3)2, or —CH2C(CH3)3. In some embodiments, R 8 is C1-C6 alkyl substituted with C3-C6 cycloalkyl. In some embodiments, R 8 teeth, [ka] In some embodiments, R 8 is a 4- to 6-membered heterocyclyl. In some embodiments, R 8 teeth, [ka] is.

[0194] In some embodiments, R 9 is H. In some embodiments, R 9is C1-C6 alkyl. In some embodiments, R 9 is -CH3. In some embodiments, R 9 is C1-C6 haloalkyl. In some embodiments, R 9 is a C3-C6 cycloalkyl.

[0195] In some embodiments, R 10 is H. In some embodiments, R 10 is C1-C6 alkyl. In some embodiments, R 10 is -CH3. In some embodiments, R 10 is C1-C6 haloalkyl. In some embodiments, R 10 is a C3-C6 cycloalkyl.

[0196] In some embodiments, Base is [ka] In some embodiments, Base is [ka] In some embodiments, Base is [ka] is.

[0197] In some embodiments, Base is [ka] is.

[0198] In some embodiments, R 11 is -OP(=O)(OH)(OR 14 In some embodiments, R 11 is -(CH2)OP(=O)(OH)(OR 14 )

[0199] In some embodiments, R 14 is H. In some embodiments, R 14 is H or C1-C8 alkyl, and R 14 The C1-C8 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, cyano, and phenyl.

[0200] In some embodiments, R 14 is C1-C8 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, cyano, and phenyl. In some embodiments, R 14 is C1-C3 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, cyano, and phenyl. In some embodiments, R 14 is C1-C3 alkyl substituted with one phenyl. In some embodiments, R 14 teeth, [ka] is.

[0201] In some embodiments, R 11 is —(CH)OP(═O)(OH). In some embodiments, R 11 teeth, [ka] is.

[0202] In some embodiments, R 12 is H. In some embodiments, R 12 is C1-C6 alkyl. In some embodiments, R 12 is -C(=O)R 13 In some embodiments, R 12 is —C(═O)(CH)CH. In some embodiments, R 12 is -C(=O)OR13 In some embodiments, R 12 is —C(═O)OCHCH(CH). In some embodiments, R 12 is —C(═O)OCHCH(CH) or —C(═O)(CH)CH. In some embodiments, R 12 teeth, [ka] In some embodiments, R 12 teeth, [ka] is.

[0203] In some embodiments, R 12 teeth, [ka] is.

[0204] In some embodiments, R 13 is a C1-C8 alkyl, wherein R 13 C1-C8 alkyl is halogen, cyano, -OP(=O)(OH)(OR 14 ) and phenyl, wherein R 13 The substituent phenyl is -OP(=O)(OH)(OR 14 In some embodiments, R 13 is C1-C8 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from halogen, cyano, and phenyl, where R 13 The substituent phenyl is -OP(=O)(OH)(OR 14 ) is optionally replaced.

[0205] In some embodiments, R 13 is H. In some embodiments, R 13 is a C1-C8 alkyl, wherein R13 C1-C8 alkyl is halogen, cyano, -OP(=O)(OH)(OR 14 ) and phenyl, wherein phenyl is optionally substituted with 1, 2, or 3 substituents independently selected from -OP(=O)(OH)(OR 14 In some embodiments, R 13 is a C1-C8 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from halogen, cyano, and phenyl, wherein phenyl is —OP(═O)(OH)(OR 14 In some embodiments, R 13 is C1-C8 alkyl optionally substituted with 1, 2, or 3 substituents independently selected from halogen, cyano, and phenyl. In some embodiments, R 13 is C1-C8 alkyl. In some embodiments, R 13 is -CH3, -CH2CH3, -(CH2)2CH3, -CH(CH3)2, -(CH2)3CH 3、 or -C(CH3)3. In some embodiments, R 13 is —CHCH(CH) or —(CH)CH. In some embodiments, R 13 is -(CH2)OP(=O)(OH)2.

[0206] In some embodiments, R 13 is -(CH2)CH(CH3)2.

[0207] In some embodiments, R 13 is C1-C8 alkyl substituted with phenyl. In some embodiments, R 13 teeth, [ka] is.

[0208] In some embodiments, Base is [ka] is.

[0209] In some embodiments, Base is [ka] is.

[0210] In some embodiments, Base is [ka] is.

[0211] In some embodiments, R 1 is -OH or -OC(=O)R 4 and R 2 is -OH or -OC(=O)R 5 and R 3 is -C(=O)OR 7 and R 4 is C1-C3 alkyl, R 5 is C1-C3 alkyl, R 7 is C1-C6 alkyl or C6-C8 carbocyclyl, Base, [ka] is.

[0212] In some embodiments, R 1 is -OC(=O)R 4 and R 2 is -OC(=O)R 5 and R 3 is -C(=O)OR 7 and R 4 is C1-C3 alkyl, R 5 is C1-C3 alkyl, R 7 is a C1-C6 alkyl, Base, [ka] is.

[0213] In some embodiments, R 1 -OH, -OC(=O)R 4 , -OC(=O)OR 4 , or -OP(=O)(OH)(OR 4 ) and R 2 -OH, -OC(=O)R 5 , or -OC(=O)OR 5 or R 1 and R 2 together form -OC(=O)O-, -OP(=O)(OH)O-, or -OCHR 6 O- is formed, R 3 is -C(=O)OR 7 and R 4 is C1-C8 alkyl or C2-C8 alkenyl, and R 4 The C1-C8 alkyl is a carbonyl and -OR 8 and optionally substituted with one or two substituents independently selected from R 5 is C1-C8 alkyl or C2-C8 alkenyl, R 7 is C1~C 20 Alkyl, C2-C8 alkenyl, C3-C 10 Carbocyclyl, C6-C 10 aryl, a 4- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R 7 C1~C20 Alkyl, C3-C 10 Carbocyclyl, C6-C 10 The aryl or 4- to 8-membered heterocyclyl is each independently C1 to C8 alkyl, halogen, carbonyl, -OR 8 , -NR 9 R 10 , -OP(=O)(OH)2, -OP(=O)(OR 8 )2, C3-C8 carbocyclyl, 4-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S, and phenyl; R 7 the substituent C3-C8 carbocyclyl is optionally substituted with one or two substituents independently selected from C1-C8 alkyl, halogen, —CF3, cyano, —CH2CN, and phenyl; R 7 The 4- to 6-membered heterocyclyl is optionally substituted with two substituents independently selected from carbonyl and C1-C6 alkyl; R 7 The substituent phenyl in the formula is -OR 8 and optionally substituted with R 6 is C1-C6 alkoxy or C6-C 10 is aryl, Each R 8 are independently H, C1-C6 alkyl, C3-C6 cycloalkyl, and 4-6 membered heterocyclyl; where R 8 wherein the C1-C6 alkyl is optionally substituted with a C3-C6 cycloalkyl; R 9 and R 10 are each independently C1 to C6 alkyl, Base is [ka] and R 11 is -OP(=O)(OH)(OR 14 ) is C1-C6 alkyl optionally substituted with R 12 is H, -C(=O)R 13 , or -C(=O)OR 13 and Each R 13 are independently phenyl or -OP(=O)(OH)(OR 14 ) and Each R 14 are independently H or C1-C8 alkyl, and R 14 The C1-C8 alkyl is optionally substituted with phenyl.

[0214] In some embodiments, R 1 -OH, -OC(=O)R 4 , or -OC(=O)OR 4 and R 2 -OH, -OC(=O)R 5 , or -OC(=O)OR 5 or R 1 and R 2 together form -OC(=O)O-, -OP(=O)(OH)O-, or -OCHR 6 O- is formed, R 3 is -C(=O)OR 7 and R 4 is C1-C8 alkyl or C2-C8 alkenyl, and R 4 The C1-C8 alkyl is a carbonyl and -OR 8 and optionally substituted with one or two substituents independently selected from R 5 is C1-C8 alkyl or C2-C8 alkenyl, R 7 is C1~C 20 Alkyl, C2-C8 alkenyl, C3-C8 carbocyclyl, C6-C 10aryl, a 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R 7 C1~C 20 Alkyl, C3-C8 carbocyclyl or C6-C 10 Each aryl is independently C1-C8 alkyl, halogen, carbonyl, -OR 8 , -NR 9 R 10 , -OP(=O)(OH)2, -OP(=O)(OR 8 )2, C3-C8 carbocyclyl, 4-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S, and phenyl; R 7 the substituent C3-C8 carbocyclyl is optionally substituted with one or two substituents independently selected from C1-C8 alkyl, halogen, —CF3, cyano, —CH2CN, and phenyl; R 7 The 4- to 6-membered heterocyclyl is optionally substituted with two substituents independently selected from carbonyl and C1-C6 alkyl; R 7 The substituent phenyl in the formula is -OR 8 and optionally substituted with R 6 is C1-C6 alkoxy or C6-C 10 is aryl, Each R 8 are independently H or C1-C6 alkyl, R 9 and R 10 are each independently C1 to C6 alkyl, Base is [ka] and R 11 is -OP(=O)(OH)(OR 14 ) is C1-C6 alkyl optionally substituted with R 12 is H, -C(=O)R 13 , or -C(=O)OR 13 and Each R 13 are independently phenyl or -OP(=O)(OH)(OR 14 ) and Each R 14 are independently H or C1-C8 alkyl, and R 14 The C1-C8 alkyl is optionally substituted with phenyl.

[0215] In some embodiments, R 1 -OH, -OC(=O)R 4 , or -OC(=O)OR 4 and R 2 -OH, -OC(=O)R 5 , or -OC(=O)OR 5 or R 1 and R 2 together form -OC(=O)O-, -OP(=O)(OH)O-, or -OCHR 6 O- is formed, R 3 is -C(=O)OR 7 and R 4 and R 5 is a C1-C8 alkyl; R 7 is C1~C 20 Alkyl, C2-C8 alkenyl, C3-C8 carbocyclyl, C6-C 10 aryl, a 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R 7 C1~C20 Alkyl, C3-C8 carbocyclyl or C6-C 10 Each aryl is independently C1-C8 alkyl, halogen, carbonyl, -OR 8 , -NR 9 R 10 , -OP(=O)(OH)2, -OP(=O)(OR 8 )2, C3-C8 carbocyclyl, 4-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S, and phenyl; R 7 the substituent C3-C8 carbocyclyl is optionally substituted with one or two substituents independently selected from C1-C8 alkyl, halogen, —CF3, cyano, —CH2CN, and phenyl; R 7 The 4- to 6-membered heterocyclyl is optionally substituted with two substituents independently selected from carbonyl and C1-C6 alkyl; R 7 The substituent phenyl in the formula is -OR 8 and optionally substituted with R 6 is C1-C6 alkoxy or C6-C 10 is aryl, Each R 8 , R 9 and R 10 are independently C1-C6 alkyl, Base is [ka] and R 11 is -OP(=O)(OH)(OR 14 ) is C1-C6 alkyl optionally substituted with R 12 is H, -C(=O)R 13 , or -C(=O)OR 13 and Each R 13 are independently -OP(=O)(OH)(OR 14 ) and C1-C8 alkyl optionally substituted with Each R 14 are independently H or C1-C8 alkyl, and R 14 The C1-C8 alkyl is optionally substituted with phenyl.

[0216] In some embodiments, R 1 is -OH or -OC(=O)R 4 and R 2 is -OH or -OC(=O)R 5 or R 1 and R 2 together form -OC(=O)O- or -OP(=O)(OH)O-, R 3 is -C(=O)OR 7 and R 4 , R 5 and R 7 are each independently C1 to C8 alkyl, C3 to C8 carbocyclyl, C6 to C 10 aryl, a 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; In the formula, R 7 The C1-C8 alkyls in each group are independently C1-C8 alkyl, -OR 8 , -OP(=O)(OH)2, C3-C8 carbocyclyl, 4-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S, and phenyl; The 4- to 6-membered heterocyclyl is optionally substituted by 1, 2, or 3 substituents independently selected from carbonyl and C1-C6 alkyl; Each R 8 are independently C1-C6 alkyl, Base is, [ka] and R 11 is -OP(=O)(OH)(OR 14 ) C1-C6 alkyl substituted with R 12 is H, -C(=O)R 13 , or -C(=O)OR 13 and R 13 is -OP(=O)(OH)(OR 14 ) and Each R 14 are independently H or C1-C8 alkyl, and R 14 The C1-C8 alkyl is optionally substituted with phenyl.

[0217] In some embodiments, R 1 is -OH or -OC(=O)R 4 and R 2 is -OH or -OC(=O)R 5 or R 1 and R 2 together form -OC(=O)O- or -OP(=O)(OH)O-, R 3 is -C(=O)OR 7 and R 4 , R 5 and R 7 are each independently C1 to C8 alkyl, C3 to C8 carbocyclyl, C6 to C 10 aryl, a 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; In the formula, R7 Each C1-C8 alkyl is independently -OR 8 , -OP(=O)(OH)2, C3-C8 carbocyclyl, 4-6 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O and S, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S, and phenyl; The 4- to 6-membered heterocyclyl is optionally substituted by 1, 2, or 3 substituents independently selected from carbonyl and C1-C6 alkyl; Each R 8 are independently C1-C6 alkyl, Base is, [ka] and R 11 is -OP(=O)(OH)(OR 14 ) C1-C6 alkyl substituted with R 12 is H, -C(=O)R 13 , or -C(=O)OR 13 and R 13 is -OP(=O)(OH)(OR 14 ) and Each R 14 are independently H or C1-C8 alkyl, and R 14 The C1-C8 alkyl is optionally substituted with phenyl.

[0218] In some embodiments, R 1 is -OH or -OC(=O)R 4 and R 2 is -OH or -OC(=O)R 5 or R 1 and R 2 together to form -OC(=O)O-, R3 is -C(=O)OR 7 and R 4 , R 5 and R 7 are each independently C1 to C8 alkyl, C3 to C8 carbocyclyl, C6 to C 10 aryl, a 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R 7 Each C1-C8 alkyl is independently -OR 8 , —OP(═O)(OH) 2 , C-C carbocyclyl, and phenyl; Each R 8 are independently C1-C6 alkyl, Base is, [ka] and R 11 is -OP(=O)(OH)(OR 14 ) C1-C6 alkyl substituted with R 12 is H, -C(=O)R 13 , or -C(=O)OR 13 and R 13 is a C1-C8 alkyl; Each R 14 are independently H or C1-C8 alkyl, and R 14 The C1-C8 alkyl is optionally substituted with phenyl.

[0219] In some embodiments, R 1 is -OH or -OC(=O)R 4 and R 2 is -OH or -OC(=O)R 5 or R 1and R 2 together to form -OC(=O)O-, R 3 is -C(=O)OR 7 and R 4 , R 5 , and R 7 are each independently C1 to C8 alkyl, C3 to C8 carbocyclyl, C6 to C 10 aryl or a 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S; R7 C1 to C 8 Each alkyl is independently -OR 8 and phenyl; Each R 8 are independently C1-C6 alkyl, Base is, [ka] and R 11 is -OP(=O)(OH)(OR 14 ) C1-C6 alkyl substituted with R 12 is H, -C(=O)R 13 , or -C(=O)OR 13 and R 13 is a C1-C8 alkyl; Each R 14 are independently H or C1-C8 alkyl, and R 14 The C1-C8 alkyl is optionally substituted with phenyl.

[0220] In some embodiments, the compound of formula I is [ka] or a pharmaceutically acceptable salt thereof.

[0221] In some embodiments, the compound of formula I is [ka] or a pharmaceutically acceptable salt thereof.

[0222] In some embodiments, the compound of formula I is [ka] or a pharmaceutically acceptable salt thereof.

[0223] In some embodiments, the compound of formula I is [ka] or a pharmaceutically acceptable salt thereof.

[0224] In some embodiments, the compound of formula I is [ka] or a pharmaceutically acceptable salt thereof.

[0225] In some embodiments, the compound of formula I is [ka] or a pharmaceutically acceptable salt thereof.

[0226] In some embodiments, the compound of formula I is [ka] or a pharmaceutically acceptable salt thereof.

[0227] In some embodiments, the compound of formula I is [ka] or a pharmaceutically acceptable salt thereof.

[0228] In some embodiments, the compound of formula I is [ka] or a pharmaceutically acceptable salt thereof.

[0229] In some embodiments, the compound of formula I is [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] or a pharmaceutically acceptable salt thereof.

[0230] In some embodiments, the compound of formula I is [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] or a pharmaceutically acceptable salt thereof.

[0231] In some embodiments, the compound of formula I is [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] or a pharmaceutically acceptable salt thereof.

[0232] In some embodiments, the compound of formula I is [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] or a pharmaceutically acceptable salt thereof.

[0233] In some embodiments, the compound of formula I is [Table 5-1] [Table 5-2] or a pharmaceutically acceptable salt thereof.

[0234] In some embodiments, the compound of formula I is [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] or a pharmaceutically acceptable salt thereof.

[0235] V. Pharmaceutical Preparations The compounds disclosed herein can be formulated with conventional carriers and excipients. For example, tablets contain excipients, lubricants, fillers, binders, etc. Aqueous formulations are prepared in sterile form and, if intended for delivery by routes other than oral administration, are generally isotonic. All formulations may optionally contain excipients such as those described in the "Handbook of Pharmaceutical Excipients" (1986). Pharmaceutically acceptable excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextran, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid, and the like. In some embodiments, the formulation contains one or more pharmaceutically acceptable excipients. The pH of the formulation ranges from about 3 to about 11, but is typically about 7 to 10. In some embodiments, the pH of the formulation ranges from about 2 to about 5, but is typically about 3 to 4.

[0236] While it is possible for the compounds of the present disclosure ("active ingredients") to be administered alone, it may be preferable to present them as pharmaceutical formulations. The formulations of the present invention, both for veterinary and human use, comprise at least one active ingredient, as defined above, together with one or more acceptable carriers therefor and optionally other additional therapeutic ingredients, particularly the additional therapeutically active ingredients discussed herein. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and physiologically non-toxic to the recipient thereof.

[0237] Formulations include those suitable for the aforementioned routes of administration. Formulations may conveniently be presented in unit dosage form and may be prepared by any suitable method known in the art of pharmacy. Techniques and formulations are generally found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with the carrier, which constitutes one or more accessory ingredients. In general, formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0238] In some embodiments, the pharmaceutical formulation is for subcutaneous, intramuscular, intravenous, oral, or inhaled administration.

[0239] In some embodiments, the compounds described herein, e.g., the compounds of Formula I described herein or pharmaceutically acceptable salts thereof, have optimized / improved pharmacokinetic properties and are suitable for oral administration. For example, the compounds of Formula I have improved bioavailability and therefore can be administered orally.

[0240] In some embodiments, formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil liquid emulsion. The active ingredient may also be administered as a bolus, electuary, or paste.

[0241] In some embodiments, tablets are made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant, or dispersant, in a suitable machine. Molded tablets can be made by molding a mixture of the powdered active ingredient moistened with an inert liquid diluent in a suitable machine. Tablets can optionally be coated or scored, and are optionally formulated to provide slow or controlled release of the active ingredient therefrom.

[0242] For infections of the eye or other external tissues, e.g., mouth and skin, formulations are applied as a topical ointment or cream containing, for example, 0.075 to 20% w / w (with active ingredient in the range of 0.1% to 20%, in increments of 0.1%, e.g., 0.6% w / w, 0.7% w / w, etc.), preferably 0.2 to 15% w / w, and most preferably 0.5 to 10% w / w. When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base.

[0243] If desired, the aqueous phase of the cream base may contain, for example, at least 30% w / w of a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups, such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol, and polyethylene glycol (including PEG 400), and mixtures thereof. Topical formulations may desirably include a compound that enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogues.

[0244] The oily phase of the emulsion of the present invention can be composed of known ingredients in a known manner. The phase can simply contain an emulsifier (otherwise known as an emulsion), but desirably contains a mixture of at least one emulsifier with a fat or oil, or a mixture of both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier, with or without a stabilizer, constitutes the so-called emulsifying wax, which, together with the oil and fat, constitutes the so-called emulsifying ointment base that forms the oily dispersed phase of the cream formulation.

[0245] Emulgents and emulsion stabilizers suitable for use in the formulations of the present invention include TWEEN® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate. Additional emulgents and emulsion stabilizers suitable for use in the formulations of the present invention include TWEEN® 80.

[0246] The selection of suitable oils or fats for the formulation is based on achieving the desired aesthetic properties. Creams should preferably be non-greasy, non-staining, and washable products with a suitable consistency to avoid leakage from tubes or other containers. Linear or branched, mono- or dibasic alkyl esters, such as diisoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acid, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate, or a blend of branched esters known as Crodamol CAP, may also be used, the last three being preferred esters. These may be used alone or in combination, depending on the desired properties. Alternatively, high-melting-point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils may be used.

[0247] The pharmaceutical formulation according to the present invention comprises a compound according to the present invention together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents.The pharmaceutical formulation containing the active ingredient can be in any form suitable for the intended method of administration.For example, when used for oral use, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs can be prepared.Compositions intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions can contain one or more agents, including sweeteners, flavoring agents, coloring agents, and preservatives, to provide a palatable preparation.Tablets containing the active ingredient in a mixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets are acceptable. These excipients may be, for example, inert diluents such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin, or acacia; 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.

[0248] Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin, or olive oil.

[0249] Aqueous suspensions of the present invention contain the active ingredient in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia, as well as dispersing or wetting agents such as naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearates), condensation products of ethylene oxide with long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide with partial esters derived from fatty acids, and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoates, one or more colorants, one or more flavoring agents, and one or more sweeteners, such as sucrose or saccharin. Further non-limiting examples of suspending agents include cyclodextrins. In some examples, the suspending agent is sulfobutyl ether β-cyclodextrin (SEB-β-CD), such as Captisol®.

[0250] Oil suspensions can be prepared by suspending the active ingredient in vegetable oils such as peanut oil, olive oil, sesame oil or coconut oil, or in mineral oils such as liquid paraffin.Oral suspensions can contain thickening agents such as beeswax, hard paraffin or cetyl alcohol.Sweeteners and flavoring agents such as those mentioned above can be added to provide a palatable oral preparation.These compositions can be preserved by adding antioxidants such as ascorbic acid.

[0251] Dispersible powders and granules of the present invention suitable for preparation of an aqueous suspension by adding water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, such as sweeteners, flavoring agents, and coloring agents, may also be present.

[0252] The pharmaceutical composition of the present invention can also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil such as olive oil or peanut oil, a mineral oil such as liquid paraffin, or a mixture thereof. Suitable emulsifiers include naturally occurring gums such as acacia gum and tragacanth gum, naturally occurring phosphatides such as soybean lecithin, esters or partial esters derived from fatty acids, and hexitol anhydrides such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. Emulsions can also contain sweeteners and flavoring agents. Syrups and elixirs can be formulated with sweeteners such as glycerol, sorbitol, or sucrose. Such formulations can also contain demulcents, preservatives, flavorings, or coloring agents.

[0253] The pharmaceutical compositions of the present invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. These suspensions may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents as described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol, or may be prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any solvent-free fixed oil, including synthetic monoglycerides or diglycerides, may be used. Additionally, fatty acids such as oleic acid may also be used in the preparation of injectables. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, isotonic sodium chloride solution, and hypertonic sodium chloride solution.

[0254] The amount of active ingredient that may be combined with a carrier material to produce a single dosage form will vary depending on the host treated and the particular mode of administration. For example, a sustained-release formulation intended for oral administration to humans may contain from about 1 to about 1000 mg of active ingredient, compounded with an appropriate and convenient amount of carrier material, which may vary from about 5 to about 95% (weight:weight) of the total composition. Pharmaceutical compositions can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain from about 3 to 500 mg of active ingredient per milliliter of solution to allow infusion of a suitable volume at a rate of about 30 mL / hour.

[0255] Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10%, especially about 1.5% w / w.

[0256] Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

[0257] Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

[0258] In some embodiments, the compounds disclosed herein are administered by inhalation. In some embodiments, formulations suitable for pulmonary or nasal administration have particle sizes ranging from, for example, 0.1 to 500 micrometers, e.g., 0.5, 1, 30, 35, etc., and are administered by rapid inhalation through the nasal passage or by inhalation through the mouth to reach the alveoli. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration can be prepared according to conventional methods and may 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 spray formulations. In some embodiments, the compounds used herein are formulated for delivery via a face mask. In some embodiments, the compounds used herein are formulated for delivery via a face tent.

[0259] 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.

[0260] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

[0261] The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example, water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules, and tablets of the kind described above. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, of the active ingredient, or an appropriate fraction thereof.

[0262] It will be understood that in addition to the ingredients specifically mentioned above, the formulations of the present 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.

[0263] The present invention further provides veterinary compositions comprising at least one active ingredient as defined above together with a veterinary carrier therefor.

[0264] A veterinary carrier may be a solid, liquid, or gaseous substance that is useful for the purpose of administering the composition and is otherwise inert or acceptable in veterinary art and compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally, or by any other desired route.

[0265] The compounds of the present invention are used to provide controlled-release pharmaceutical formulations ("controlled-release formulations") containing one or more compounds of the present invention as the active ingredient, in which release of the active ingredient is controlled and regulated to allow less frequent administration or to improve the pharmacokinetic or toxicity profile of a given active ingredient.

[0266] VI. Kit Also provided herein are kits comprising the compounds disclosed herein, pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or tautomers thereof. In some embodiments, the kits described herein may include a label and / or instructions for use of the compound in treating a disease or condition in a subject (e.g., a human) in need thereof. In some embodiments, the disease or condition is a viral infection.

[0267] 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 the compound of Formula I in the treatment of a disease or condition in a subject (e.g., a human) in need thereof.

[0268] In some embodiments, the kits provided herein contain individual unit doses of a compound described herein, or a pharmaceutically acceptable salt, racemate, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, amorphous form, hydrate, or solvate. Examples of individual dosage units include pills, tablets, capsules, pre-filled syringes or syringe cartridges, IV bags, inhalers, nebulizers, etc., each of which may contain a therapeutically effective amount of the compound of interest, or a pharmaceutically acceptable salt, racemate, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, amorphous form, hydrate, or solvate. In some embodiments, the kits may contain a single dosage unit and other multiple dosage units, such as the number of dosage units required for a particular regimen or time period.

[0269] Also provided is an article of manufacture comprising a compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof, and a container. In some embodiments, the article of manufacture container is a vial, bottle, ampoule, pre-filled syringe, blister package, tin, can, bottle, box, intravenous bag, inhaler, or nebulizer.

[0270] VII. Administration One or more compounds of the present invention are administered by any route appropriate to 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 disclosed herein are administered by inhalation or intravenously. In some embodiments, the compounds disclosed herein are administered orally. It will be understood that the preferred route may vary depending, for example, on the condition of the recipient.

[0271] In the method of the present invention for treating viral infection, the compound of the present invention can be administered at any time to a person who may have come into contact with the virus or who is already suffering from the viral infection. In some embodiments, the compound of the present invention can be administered prophylactically to a person who comes into contact with a person suffering from a viral infection or who is at risk of coming into contact with a person suffering from a viral infection, such as a healthcare provider. In some embodiments, the compound of the present invention can be administered to a person who has tested positive for a viral infection but has not yet shown symptoms of the viral infection. In some embodiments, the compound of the present invention can be administered to a person at the onset of symptoms of the viral infection.

[0272] In some embodiments, the methods disclosed herein include event-driven administration of a compound described herein, e.g., a compound of Formula I or a pharmaceutically acceptable salt thereof, to a subject.

[0273] As used herein, the terms "event-driven" or "event-driven administration" refer to administering a compound described herein (e.g., a compound of Formula I), or a pharmaceutically acceptable salt thereof, (1) before an event that exposes an individual to a virus (e.g., 2 hours, 1 day, 2 days, 5 days, or 7 days or more before the event), and / or (2) during an event (or two or more recurring events) that exposes an individual to the virus (or otherwise increases the individual's risk of being infected with the virus), and / or (3) after an event (or after the last event in a series of recurring events) that exposes an individual to the virus (or otherwise increases the individual's risk of being infected with the virus). In some embodiments, event-driven administration occurs before the subject's exposure to the virus. In some embodiments, event-driven administration occurs after the subject's exposure to the virus. In some embodiments, event-driven administration occurs before the subject's exposure to the virus and after the subject's exposure to the virus.

[0274] In certain embodiments, the methods disclosed herein involve administration before and / or after an event that exposes an individual to the virus or that otherwise increases the individual's risk of becoming infected with the virus, e.g., as pre-exposure prophylaxis (PrEP) and / or post-exposure prophylaxis (PEP). In some embodiments, the methods disclosed herein involve pre-exposure prophylaxis (PrEP). In some embodiments, the methods disclosed herein involve post-exposure prophylaxis (PEP).

[0275] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is administered prior to the subject's exposure to the virus.

[0276] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is administered before and after the subject's exposure to the virus.

[0277] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is administered after the subject's exposure to the virus.

[0278] An example of an event-driven dosing regimen includes administering a compound of Formula I, or a pharmaceutically acceptable salt thereof, within 24 hours to 2 hours prior to the virus, followed by administration of a compound of Formula I, or a pharmaceutically acceptable salt thereof, every 24 hours for the duration of exposure, followed by another administration of a compound of Formula I, or a pharmaceutically acceptable salt thereof, after the final exposure, and finally another administration of a compound of Formula I, or a pharmaceutically acceptable salt thereof, 24 hours later.

[0279] A further example of an event-driven dosing regimen includes administering a compound of formula I, or a pharmaceutically acceptable salt thereof, within 24 hours before exposure to the virus, followed by daily dosing for the duration of exposure, followed by a final dose (which may be an increased dose, such as a double dose) about 24 hours after the last exposure.

[0280] The specific dose level of a compound of the present disclosure for any particular subject will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combinations, and the severity of the particular disease in the subject receiving therapy. For example, dosages may be expressed as milligrams of a compound described herein per kilogram of subject body weight (mg / kg). Doses of about 0.1 to 150 mg / kg may be appropriate. In some embodiments, doses of about 0.1 and 100 mg / kg may be appropriate. In other embodiments, doses of 0.5 to 60 mg / kg may be appropriate. Normalizing by subject body weight is particularly useful when adjusting dosages between subjects of widely different sizes, such as occurs when using drugs in both pediatric and adult humans, or when converting effective dosages in non-human subjects, such as dogs, to dosages suitable for human subjects.

[0281] The daily dose may also be described as the total amount of the compound described herein administered per administration or per day. The daily dose of the compound of Formula I, or a pharmaceutically acceptable salt thereof, may be about 1 mg to 4,000 mg, about 2,000 to 4,000 mg / day, about 1 to 2,000 mg / day, about 1 to 1,000 mg / day, about 10 to 500 mg / day, about 20 to 500 mg / day, about 50 to 300 mg / day, about 75 to 200 mg / day, or about 15 to 150 mg / day.

[0282] The dosage or frequency of administration of a compound of the present disclosure may be adjusted over the course of treatment, based on the judgment of the administering physician.

[0283] 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 compounds are administered once daily.

[0284] The compounds provided herein can be administered by any useful route and means, such as oral or parenteral (e.g., intravenous) administration. A therapeutically effective amount of a compound can include from about 0.00001 mg / kg body weight per day to about 10 mg / kg body weight per day, e.g., from about 0.0001 mg / kg body weight per day to about 10 mg / kg body weight per day, or from about 0.001 mg / kg body weight per day to about 1 mg / kg body weight per day, or from about 0.01 mg / kg body weight per day to about 1 mg / kg body weight per day, or from about 0.05 mg / kg body weight per day to about 0.5 mg / kg body weight per day. In some embodiments, a therapeutically effective amount of a compound provided herein includes from about 0.3 mg to about 30 mg per day, or from about 30 mg to about 300 mg per day, or from about 0.3 mg to about 30 mg per day, or from about 30 mg to about 300 mg per day.

[0285] The compounds of the present disclosure can be combined with one or more additional therapeutic agents at any dosage of the compound of the present disclosure (e.g., 1 mg to 1000 mg of compound). Therapeutically effective amounts may include from about 0.1 mg per dose to about 1000 mg per dose, such as from about 50 mg per dose to about 500 mg per dose, or from about 100 mg per dose to about 400 mg per dose, or from about 150 mg per dose to about 350 mg per dose, or from about 200 mg per dose to about 300 mg per dose, or from about 0.01 mg per dose to about 1000 mg per dose, or from about 0.01 mg per dose to about 100 mg per dose, or from about 0.1 mg per dose to about 100 mg per dose, or from about 1 mg per dose to about 100 mg per dose, or from about 1 mg per dose to about 10 mg per dose, or from about 1 mg per dose to about 1000 mg per dose. Other therapeutically effective amounts of a compound of formula I are about 1 mg per dose, or about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or about 100 mg per dose. Other therapeutically effective amounts of compounds of the present disclosure are about 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, or about 1000 mg per dose.

[0286] In some embodiments, the method includes administering to a subject an initial daily dose of about 1 to 500 mg of a compound provided herein, and increasing the dose incrementally until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dose. The dose can be increased daily, daily, twice weekly, weekly, every two weeks, every three weeks, or monthly.

[0287] When administered orally, the total daily dosage for a human subject may be about 1-4,000 mg / day, about 1-3,000 mg / day, 1-2,000 mg / day, about 1-1,000 mg / day, about 10-500 mg / day, about 50-300 mg / day, about 75-200 mg / day, or about 100-150 mg / day. In some embodiments, the total daily dosage for a human subject can be about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, or 3000 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject can be about 200, 300, 400, 500, 600, 700, or 800 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 300, 400, 500, or 600 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800, 3900, or 4000 mg / day.In some embodiments, the total daily dosage for a human subject is about 100-200, 100-300, 100-400, 100-500, 100-600, 100-700, 100-800, 100-900, 100-1000, 500-1100, 500-1200, 500-1300, 500-1400, 500-1500, 500-1600, 500-1700, 500-1800, 500-1900, 500-2000, 1500-2100, It may be 1500 to 2200, 1500 to 2300, 1500 to 2400, 1500 to 2500, 2000 to 2600, 2000 to 2700, 2000 to 2800, 2000 to 2900, 2000 to 3000, 2500 to 3100, 2500 to 3200, 2500 to 3300, 2500 to 3400, 2500 to 3500, 3000 to 3600, 3000 to 3700, 3000 to 3800, 3000 to 3900, or 3000 to 4000 mg / day.

[0288] In some embodiments, the total daily dosage for a human subject may be about 100 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 150 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 200 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 250 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 300 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 350 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 400 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 450 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 500 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 550 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 600 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 650 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 700 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 750 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 800 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 850 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 900 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 950 mg / day administered in a single dose.In some embodiments, the total daily dosage for a human subject may be about 1000 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 1500 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 2000 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 2500 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 3000 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 4000 mg / day administered in a single dose.

[0289] A single dose can be administered hourly, daily, weekly, or monthly. For example, a single dose can be administered once every 1, 2, 3, 4, 6, 8, 12, 16 hours, or once every 24 hours. A single dose can also be administered once every 1, 2, 3, 4, 5, 6 days, or once every 7 days. A single dose can also be administered once every 1, 2, 3 weeks, or once every 4 weeks. In certain embodiments, a single dose can be administered once weekly. A single dose can also be administered once monthly. In some embodiments, a compound disclosed herein is administered once daily in a method disclosed herein. In some embodiments, a compound disclosed herein is administered twice daily in a method disclosed herein. In some embodiments, a compound disclosed herein is administered three times daily in a method disclosed herein.

[0290] In some embodiments, the compounds disclosed herein are administered once daily at a total daily dose of 100-4000 mg / day. In some embodiments, the compounds disclosed herein are administered twice daily at a total daily dose of 100-4000 mg / day. In some embodiments, the compounds disclosed herein are administered three times daily at a total daily dose of 100-4000 mg / day.

[0291] The frequency of administration of the compounds of the present disclosure is determined by the needs of each individual patient and can be, for example, once a day or twice a day or more. Administration of the compounds continues as long as necessary to treat the viral infection. For example, the compounds can be administered to a human infected with a virus for a period of 20 to 180 days, or for example, for a period of 20 to 90 days, or for example, for a period of 30 to 60 days.

[0292] Administration can be intermittent, with the patient receiving a daily dose of a compound of the present disclosure for a period of several days or more, followed by a period of several days or more during which the patient does not receive a daily dose of the compound. For example, the patient can receive a dose of the compound every other day or three times per week. As a further example, the patient can receive a dose of the compound daily for a period of 1 to 14 days, followed by a period of 7 to 21 days during which the patient does not receive a dose of the compound, followed by a subsequent period (e.g., 1 to 14 days) during which the patient again receives a daily dose of the compound. The alternating periods of compound administration followed by non-compound administration can be repeated as clinically needed to treat the patient.

[0293] The compounds of the present disclosure or pharmaceutical compositions thereof can be administered once, twice, three times, or four times daily using any suitable method described above. Administration or treatment with the compound can also continue for several days; for example, treatment typically lasts for at least 7, 14, or 28 days per treatment cycle. Treatment cycles are well known in cancer chemotherapy and frequently alternate with rest periods of about 1 to 28 days, typically about 7 days or about 14 days, between cycles. Treatment cycles can also be continuous in other embodiments.

[0294] VIII.How to use The present disclosure also provides a method of treating or preventing a viral infection in a subject (e.g., a human) in need thereof, the method comprising administering to the subject a compound described herein.

[0295] In some embodiments, the disclosure provides a method of treating or preventing a viral infection in a subject (e.g., a human) in need thereof, the method comprising administering to the subject in need thereof a compound described herein.

[0296] In some embodiments, the compounds described herein are administered to humans via oral, intramuscular, intravenous, subcutaneous, or inhaled administration.

[0297] In some embodiments, the present disclosure provides a method of treating or preventing a viral infection in a subject (e.g., a human) in need thereof, the method comprising administering to the subject a compound disclosed herein and at least one additional active therapeutic or prophylactic agent.

[0298] In some embodiments, the present disclosure provides a method of treating a viral infection in a subject (e.g., a human) in need thereof, the method comprising administering to the subject a compound disclosed herein and at least one additional active therapeutic or prophylactic agent.

[0299] In one embodiment, the present disclosure provides a method of inhibiting a viral polymerase in a cell, comprising contacting a virally infected cell with a compound disclosed herein, thereby inhibiting the viral polymerase.

[0300] In one embodiment, the present disclosure provides a method of inhibiting a viral polymerase in a cell, comprising contacting a virally infected cell with a compound disclosed herein and at least one additional active therapeutic agent, thereby inhibiting the viral polymerase.

[0301] Also provided is the use of a compound disclosed herein for use in treating or preventing a viral infection in a subject in need thereof. For example, provided herein is the use of a compound disclosed herein for use in treating a viral infection in a subject in need thereof.

[0302] In some embodiments, the viral infection is a Paramyxoviridae virus infection. Accordingly, in some embodiments, the present disclosure provides a method for treating a Paramyxoviridae virus infection in a subject (e.g., a human) in need thereof, the method comprising administering to the subject a compound disclosed herein. Paramyxoviridae viruses include, but are not limited to, Nipah virus, Hendra virus, measles virus, mumps virus, and parainfluenza virus.

[0303] In some embodiments, the viral infection is a human parainfluenza virus, Nipah virus, Hendra virus, measles, or mumps infection.

[0304] In some embodiments, the viral infection is a Pneumoviridae virus infection. Accordingly, in some embodiments, the present disclosure provides a method of treating a Pneumoviridae virus infection in a human in need thereof, the method comprising administering a compound provided herein to the human. Pneumoviridae viruses include, but are not limited to, respiratory syncytial virus and human metapneumovirus. In some embodiments, the Pneumoviridae virus infection is a respiratory syncytial virus infection. In some embodiments, the Pneumoviridae virus infection is a human metapneumovirus infection.

[0305] In some embodiments, the present disclosure provides a compound disclosed herein for use in treating a Pneumoviridae virus infection in a human in need thereof. In some embodiments, the Pneumoviridae virus infection is a respiratory syncytial virus infection. In some embodiments, the Pneumoviridae virus infection is a human metapneumovirus infection.

[0306] In some embodiments, the present disclosure provides a method for treating a RSV infection in a human in need thereof, the method comprising administering a compound provided herein to the human. In some embodiments, the human is suffering from a chronic respiratory syncytial virus infection. In some embodiments, the human is acutely infected with RSV.

[0307] In some embodiments, a method of inhibiting RSV replication is provided, comprising administering to a human in need thereof a compound disclosed herein, wherein the administration is by inhalation.

[0308] In some embodiments, the present disclosure provides a method for reducing the viral load associated with a RSV infection, the method comprising administering to a human infected with RSV a compound disclosed herein.

[0309] In some embodiments, the viral infection is a Picornaviridae virus infection. In some embodiments, the disclosure provides a method of treating a Picornaviridae virus infection in a human in need thereof, the method comprising administering a compound of the disclosure to the human. Picornaviridae viruses are enteroviruses that cause a heterogeneous group of infections, including herpangina, aseptic meningitis, common cold-like syndrome (human rhinovirus infection), non-paralytic polio-like syndrome, epidemic pleurodynia (an acute, febrile, infectious illness that typically occurs during epidemics), hand, foot, and mouth disease, pediatric and adult pancreatitis, and severe myocarditis. In some embodiments, the Picornaviridae virus infection is a human rhinovirus infection (HRV). In some embodiments, the Picornaviridae virus infection is an HRV-A, HRV-B, or HRV-C infection.

[0310] In some embodiments, the viral infection is selected from the group consisting of a Coxsackie A virus infection, a Coxsackie A virus infection, an Enterovirus D68 infection, an Enterovirus B69 infection, an Enterovirus D70 infection, an Enterovirus A71 infection, and a Poliovirus infection.

[0311] In some embodiments, the present disclosure provides a compound for use in treating a Picornaviridae virus infection in a human in need thereof, hi some embodiments, the Picornaviridae virus infection is a human rhinovirus infection.

[0312] In some embodiments, the viral infection is a Flaviviridae virus infection. Accordingly, in some embodiments, the present disclosure provides a method of treating a Flaviviridae virus infection in a human in need thereof, the method comprising administering to the human a compound described herein. Representative Flaviviridae viruses include, but are not limited to, Dengue fever, Yellow fever, West Nile, Zika, Japanese encephalitis virus, and Hepatitis C (HCV). In some embodiments, the Flaviviridae virus infection is a Dengue virus infection. In some embodiments, the Flaviviridae virus infection is a Yellow fever virus infection. In some embodiments, the Flaviviridae virus infection is a West Nile virus infection. In some embodiments, the Flaviviridae virus infection is a Zika virus infection. In some embodiments, the Flaviviridae virus infection is a Japanese encephalitis virus infection. In some embodiments, the Flaviviridae virus infection is a Hepatitis C virus infection.

[0313] In some embodiments, the Flaviviridae virus infection is dengue virus infection, yellow fever virus infection, West Nile virus infection, tick-borne encephalitis, Kunjin Japanese encephalitis, St. Louis encephalitis, Murray Valley encephalitis, Omsk hemorrhagic fever, bovine viral diarrhea, Zika virus infection, or HCV infection.

[0314] In some embodiments, the disclosure provides use of a compound of the disclosure for the treatment of a Flaviviridae virus infection in a human in need thereof. In some embodiments, the Flaviviridae virus infection is a Dengue virus infection. In some embodiments, the Flaviviridae virus infection is a Yellow Fever virus infection. In some embodiments, the Flaviviridae virus infection is a West Nile virus infection. In some embodiments, the Flaviviridae virus infection is a Zika virus infection. In some embodiments, the Flaviviridae virus infection is a Hepatitis C virus infection.

[0315] In some embodiments, the viral infection is a Filoviridae virus infection. Accordingly, in some embodiments, the present disclosure provides a method of treating a Filoviridae virus infection in a human in need thereof, the method comprising administering to the human a compound disclosed herein. Representative Filoviridae viruses include, but are not limited to, Ebola virus (Zaire, Bundibugyo, Sudan, Tai Forest, or Reston variant) and Marburg virus. In some embodiments, the Filoviridae virus infection is an Ebola virus infection. In some embodiments, the Filoviridae virus infection is a Marburg virus infection.

[0316] In some embodiments, the present disclosure provides a compound for use in treating a Filoviridae virus infection in a human in need thereof. In some embodiments, the Filoviridae virus infection is an Ebola virus infection. In some embodiments, the Filoviridae virus infection is a Marburg virus infection.

[0317] In some embodiments, the viral infection is a coronavirus infection. Accordingly, in some embodiments, provided herein are methods of treating a coronavirus infection in a human in need thereof, the method comprising administering a compound provided herein to the human. In some embodiments, the coronavirus infection is a severe acute respiratory syndrome (SARS-CoV) infection, a Middle East respiratory syndrome (MERS) infection, a SARS-CoV-2 infection, another human coronavirus (229E, NL63, OC43, HKU1, or WIV1) infection, or a zoonotic coronavirus (PEDV or HKU CoV isolate, e.g., HKU3, HKU5, or HKU9) infection. In some embodiments, the viral infection is a severe acute respiratory syndrome (SARS) infection. In some embodiments, the viral infection is a Middle East respiratory syndrome (MERS) infection. In some embodiments, the viral infection is a SARS-CoV-2 infection. In some embodiments, the viral infection is a zoonotic coronavirus infection, and in some embodiments, the viral infection is caused by a virus having at least 70% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2. In some embodiments, the viral infection is caused by a virus having at least 80% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2. In some embodiments, the viral infection is caused by a virus having at least 90% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2. In some embodiments, the viral infection is caused by a virus having at least 95% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2.

[0318] In some embodiments, the viral infection is caused by a SARS-CoV-2 variant, such as the B.1.1.7 variant (UK variant), the B.1.351 variant (South African variant), the P.1 variant (Brazilian variant), the B.1.1.7 with the E484K mutation, the B.1.1.207 variant, the B.1.1.317 variant, the B.1.1.318 variant, the B.1.429 variant, the B.1.525 variant, or the P.3 variant. In some embodiments, the viral infection is caused by the B.1.1.7 variant of SARS-CoV-2. In some embodiments, the viral infection is caused by the B.1.351 variant of SARS-CoV-2. In some embodiments, the viral infection is caused by the P.1 variant of SARS-CoV-2.

[0319] In some embodiments, the disclosure provides compounds for use in treating a coronavirus infection in a human in need thereof. In some embodiments, the coronavirus infection is a severe acute respiratory syndrome (SARS) infection, a Middle East respiratory syndrome (MERS) infection, a SARS-CoV-2 infection, another human coronavirus (229E, NL63, OC43, HKU1, or WIV1) infection, or a zoonotic coronavirus (PEDV or HKUCoV isolate, e.g., HKU3, HKU5, or HKU9) infection. In some embodiments, the viral infection is a severe acute respiratory syndrome (SARS) infection. In some embodiments, the viral infection is a Middle East respiratory syndrome (MERS) infection. In some embodiments, the viral infection is a SARS-CoV-2 infection (COVID19).

[0320] In some embodiments, the viral infection is an Arenaviridae virus infection. Accordingly, in some embodiments, the present disclosure provides a method of treating an Arenaviridae virus infection in a human in need thereof, the method comprising administering to the human a compound disclosed herein. In some embodiments, the Arenaviridae virus infection is a Lassa infection or a Junin infection.

[0321] In some embodiments, the present disclosure provides a compound for use in treating an Arenaviridae virus infection in a human in need thereof, hi some embodiments, the Arenaviridae virus infection is a Lassa infection or a Junin infection.

[0322] 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.

[0323] As described more fully herein, the compounds described herein can be administered to an individual (e.g., a human) infected with a viral infection along with one or more additional therapeutic agents. The additional therapeutic agents can be administered to the infected individual simultaneously with the compounds of the present disclosure, or before or after administration of the compounds of the present disclosure.

[0324] IX. Combination Therapy The compounds described herein can also be used in combination with one or more additional therapeutic agents. Accordingly, also provided herein is a method for treating a viral infection in a subject in need thereof, the method comprising administering to the subject a compound disclosed herein and a therapeutically effective amount of one or more additional therapeutic or prophylactic agents.

[0325] In some embodiments, the additional therapeutic agent comprises an antiviral agent. Any suitable antiviral agent can be used in the methods described herein. In some embodiments, the antiviral agent is selected from the group consisting of a 5-substituted 2'-deoxyuridine analog, a nucleoside analog, a pyrophosphate analog, a nucleoside reverse transcriptase inhibitor, a non-nucleoside reverse transcriptase inhibitor, a protease inhibitor, an integrase inhibitor, an entry inhibitor, an acyclic guanosine analog, an acyclic nucleoside phosphonate analog, an HCV NS5A / NS5B inhibitor, an influenza virus inhibitor, an interferon, an immunostimulant, an oligonucleotide, a mitotic inhibitor, and combinations thereof.

[0326] In some embodiments, the additional therapeutic agent is a 5-substituted 2'-deoxyuridine analog, e.g., in some embodiments, the additional therapeutic agent is selected from the group consisting of idoxuridine, trifluridine, brivudine [BVDU], and combinations thereof.

[0327] In some embodiments, the additional therapeutic agent is a nucleoside analog. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of vidarabine, entecavir (ETV), telbivudine, lamivudine, adefovir dipivoxil, tenofovir disoproxil fumarate (TDF), and combinations thereof. In some embodiments, the additional therapeutic agent is favipiravir, ribavirin, galidesivir, β-D-N4-hydroxycytidine, or a combination thereof.

[0328] 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.

[0329] In some embodiments, the additional therapeutic agent is a nucleoside reverse transcriptase inhibitor, hi some embodiments, the antiviral agent is zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine, and combinations thereof.

[0330] 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.

[0331] In some embodiments, the additional therapeutic agent is a protease inhibitor. In some embodiments, the protease inhibitor is an HIV protease inhibitor. For example, in some embodiments, the antiviral agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, cobicistat, and combinations thereof. In some embodiments, the antiviral agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, and combinations thereof. In some embodiments, the protease inhibitor is an HCV NS3 / 4A protease inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of voxilaprevir, asunaprevir, boceprevir, paritaprevir, simeprevir, telaprevir, vaniprevir, grazoprevir, ribavirin, danoprevir, faldaprevir, bedroprevir, sovaprevir, deldeprevir, naraprevir, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of voxilaprevir, asunaprevir, boceprevir, paritaprevir, simeprevir, telaprevir, vaniprevir, grazoprevir, and combinations thereof.

[0332] In some embodiments, the additional therapeutic agent is an integrase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of raltegravir, dolutegravir, elvitegravir, abacavir, lamivudine, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of bictegravir, raltegravir, dolutegravir, cabotegravir, elvitegravir, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of bictegravir, dolutegravir, and cabotegravir, and combinations thereof. In some embodiments, the additional therapeutic agent is bictegravir.

[0333] In some embodiments, the additional therapeutic agent is an entry inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of docosanol, enfuvirtide, maraviroc, ibalizumab, fostemsavir, leronlimab, ibalizumab, fostemsavir, leronlimab, palivizumab, respiratory syncytial virus immune globulin, intravenous (RSV-IGIV), varicella-zoster immunoglobulin (VariZIG), varicella-zoster immune globulin (VZIG), and combinations thereof.

[0334] In some embodiments, the additional therapeutic agent is an acyclic guanosine analog, for example, in some embodiments, the additional therapeutic agent is selected from the group consisting of acyclovir, ganciclovir, valacyclovir (also known as valaciclovir), valganciclovir, penciclovir, famciclovir, and combinations thereof.

[0335] In some embodiments, the additional therapeutic agent is an acyclic nucleoside phosphonate analog. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of cidofovir, adefovir, adefovir dipivoxil, tenofovir, TDF, emtricitabine, efavirenz, rilpivirine, elvitegravir, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of cidofovir, adefovir, adefovir dipivoxil, tenofovir, TDF, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of cidofovir, adefovir dipivoxil, TDF, and combinations thereof.

[0336] In some embodiments, the additional therapeutic agent is an HCV NS5A / NS5B inhibitor. In some embodiments, the additional therapeutic agent is an NS3 / 4A protease inhibitor. In some embodiments, the additional therapeutic agent is an NS5A protein inhibitor. In some embodiments, the additional therapeutic agent is a nucleoside / nucleotide-based NS5B polymerase inhibitor. In some embodiments, the additional therapeutic agent is a non-nucleoside-based NS5B polymerase inhibitor. In some embodiments, the additional therapeutic agent is selected from the group consisting of daclatasvir, ledipasvir, velpatasvir, ombitasvir, elbasvir, sofosbuvir, dasabuvir, ribavirin, asunaprevir, simeprevir, paritaprevir, ritonavir, elbasvir, grazoprevir, AT-527, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of daclatasvir, ledipasvir, velpatasvir, ombitasvir, elbasvir, sofosbuvir, dasabuvir, and combinations thereof.

[0337] In some embodiments, the additional therapeutic agent is an influenza virus inhibitor. In some embodiments, the additional therapeutic agent is a matrix 2 inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of amantadine, rimantadine, and combinations thereof. In some embodiments, the additional therapeutic agent is a neuraminidase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of zanamivir, oseltamivir, peramivir, laninamivir octanoate, and combinations thereof. In some embodiments, the additional therapeutic agent is a polymerase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of ribavirin, favipiravir, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of amantadine, rimantadine, arbidol (umifenovir), baloxavir marboxil, oseltamivir, peramivir, ingavirin, laninamivir octanoate, zanamivir, favipiravir, ribavirin, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of amantadine, rimantadine, zanamivir, oseltamivir, peramivir, laninamivir octanoate, ribavirin, favipiravir, and combinations thereof.

[0338] In some embodiments, the additional therapeutic agent is an interferon. In some embodiments, the additional therapeutic agent is selected from the group consisting of interferon alfacon 1, interferon alfa 1b, interferon alfa 2a, interferon alfa 2b, pegylated interferon alfacon 1, pegylated interferon alfa 1b, pegylated interferon alfa 2a (PegIFNα-2a), and PegIFNα-2b. In some embodiments, the additional therapeutic agent is selected from the group consisting of interferon alfacon 1, interferon alfa 1b, interferon alfa 2a, interferon alfa 2b, pegylated interferon alfa 2a (PegIFNα-2a), and PegIFNα-2b. In some embodiments, the additional therapeutic agent is selected from the group consisting of interferon alfacon 1, pegylated interferon alfa 2a (PegIFNα-2a), PegIFNα-2b, and ribavirin. In some embodiments, the additional therapeutic agent is pegylated interferon alpha-2a, pegylated interferon alpha-2b, or a combination thereof.

[0339] In some embodiments, the additional therapeutic agent is an immunostimulant. In some embodiments, the additional therapeutic agent is an oligonucleotide. In some embodiments, the additional therapeutic agent is a mitotic inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of fomivirsen, podofilox, imiquimod, sinecatechin, and combinations thereof.

[0340] In some embodiments, the additional therapeutic agent is selected from the group consisting of besifovir, nitazoxanide, REGN2222, doravirine, sofosbuvir, velpatasvir, daclatasvir, asunaprevir, beclabuvir, FV100, and letermovir, and combinations thereof.

[0341] In some embodiments, the additional therapeutic agent is an agent for the treatment of RSV. For example, in some embodiments, the antiviral agent is ribavirin, ALS-8112, or presatovir. For example, in some embodiments, the antiviral agent is ALS-8112 or presatovir.

[0342] In some embodiments, the additional therapeutic agent is an agent for the treatment of picornavirus. In some embodiments, the additional therapeutic agent is selected from the group consisting of hydantoin, guanidine hydrochloride, l-buthionine sulfoximine, Py-11, and combinations thereof. In some embodiments, the additional therapeutic agent is a picornavirus polymerase inhibitor. In some embodiments, the additional therapeutic agent is rupintrivir.

[0343] In some embodiments, the additional therapeutic agent is an agent for the treatment of malaria, hi some embodiments, the additional therapeutic agent is chloroquine.

[0344] In some embodiments, the additional therapeutic agent is selected from the group consisting of hydroxychloroquine, chloroquine, artemether, lumefantrine, atovaquone, proguanil, tafenoquine, pyronaridine, artesunate, artenimol, piperaquine, artesunate, amodiaquine, pyronaridine, artesunate, halofantrine, quinine sulfate, mefloquine, solithromycin, pyrimethamine, MMV-390048, ferroquine, artefenomer mesylate, ganaplacid, DSM-265, cypargamine, artemisone, and combinations thereof.

[0345] In some embodiments, the additional therapeutic agent is an agent for the treatment of coronavirus, hi some embodiments, the additional therapeutic agent is selected from the group consisting of IFX-1, FM-201, CYNK-001, DPP4-Fc, ranpirnase, nafamostat, LB-2, AM-1, antiviroporin, and combinations thereof.

[0346] In some embodiments, the additional therapeutic agent is an agent for the treatment of Ebola virus. For example, in some embodiments, the additional therapeutic agent is ribavirin, palivizumab, motavizumab, RSV-IGIV (RespiGam®), MEDI-557, A-60444, MDT-637, BMS-433771, amiodarone, dronedarone, verapamil, Ebola Convalescent Plasma, or the like. Plasma, ECP), TKM-100201, BCX4430 ((2S,3S,4R,5R)-2-(4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-5-(hydroxymethyl)pyrrolidine-3,4-diol), favipiravir (also known as T-705 or Avigan), T-705 monophosphate, T-705 diphosphate, T-705 triphosphate, FGI-106 (1-N,7-N-bis[3-(dimethylamino)propyl]-3,9-dimethylquinolin[8,7 [-h]quinolone-1,7-diamine), JK-05, TKM-Ebola, ZMapp, rNAPc2, VRC-EBOADC076-00-VP, OS-2966, MVA-BN Filo, brincidofovir, Vaxart adenoviral vector 5-based Ebola vaccine, Ad26-ZEBOV, FiloVax vaccine, GOVX-E301, GOVX-E302, Ebola virus entry inhibitor (NPC1 inhibitor), rVSV-EBOV, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of ZMapp, mAB114, REGEN-EB3, and combinations thereof.

[0347] In some embodiments, the additional therapeutic agent is an agent for the treatment of HCV. In some embodiments, the additional therapeutic agent is an HCV polymerase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of sofosbuvir, GS-6620, PSI-938, ribavirin, tegobuvir, ladarbuvir, MK-0608, and combinations thereof. In some embodiments, the additional therapeutic agent is an HCV protease inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of GS-9256, vedroprevir, voxilaprevir, and combinations thereof.

[0348] In some embodiments, the additional therapeutic agent is an NS5A inhibitor, e.g., in some embodiments, the additional therapeutic agent is selected from the group consisting of ledipasvir, velpatasvir, and combinations thereof.

[0349] In some embodiments, the additional therapeutic agent is an anti-HBV agent, for example, in some embodiments, the additional therapeutic agent is tenofovir disoproxil fumarate and emtricitabine, or a combination thereof. Examples of additional anti-HBV agents include α-hydroxytropolone, amdoxovir, antroquinonol, β-hydroxycytosine nucleosides, ARB-199, CCC-0975, ccc-R08, elvucitabine, ezetimibe, cyclosporine A, gentiopicrin (gentiopicroside), HH-003, heparatide, JNJ-56136379, nitazoxanide, birinapant, NJK14047, NOV-205 (Mollixan, BAM-205), oligotide, mibotylate, Feron, GST-HG-131, levamisole, Ka Shu Ning, alloferon, WS-007, Y-101 (Ti Fen Tai), rSIFN-co, PEG-IIFNm, KW-3, BP-Inter-014, oleanolic acid, HepB-nRNA, cTP-5 (rTP-5), HSK-II-2, HEISCO-106-1, HEISCO-106, Hepbarna, IBPB-006IA, Hepuyinfen, DasKloster0014-01, ISA-204, Jiangantai (Ganxikang), MIV-210, OB-AI-004, PF-06, picroside, DasKloster-0039, Heplantai, IMB-2613, TCM-800B, reduced glutathione, RO-6864018, RG-7834, QL-007 sofosbuvir, ledipasvir, UB-551, and ZH-2N, as well as U.S. Patent Application Publication Nos. 20150210682 (Roche), 2016 / 0122344 (Roche), WO 2015173164, WO 2016023877, U.S. Patent Application Publication No. 2015252057(A) (Roche), WO 2015252057(B) (Roche), WO 2015252057(C) (Roche), WO 2015252057(D) (Roche), WO 2015252057(E) (Roche), WO 2015252057(F) (Roche), WO 2015252057(G) (Roche), WO 2015252057(H) (Roche), WO 2015252057(I ... Examples of therapeutic agents include, but are not limited to, compounds disclosed in Publication Nos. 16128335(A1) (Roche), 16120186(A1) (Roche), U.S. Patent Application Publication Nos. 2016237090(A) (Roche), WO 16107833(A1) (Roche), WO 16107832(A1) (Roche), U.S. Patent Application Publication Nos. 2016176899(A) (Roche), WO 16102438(A1) (Roche), WO 16012470(A1) (Roche), U.S. Patent Application Publication Nos. 2016220586(A) (Roche), and 2015031687(A) (Roche). In some embodiments, the additional therapeutic agent is an HBV polymerase inhibitor. HBVExamples of DNA polymerase inhibitors include adefovir (HEPSERA®), emtricitabine (EMTRIVA®), tenofovir disoproxil fumarate (VIREAD®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir dipivoxil, tenofovir dipivoxil fumarate, tenofovir octadecyloxyethyl ester, CMX-157, tenofovir exalidex, bicifovir, and entecavir. In some embodiments, the additional therapeutic agent includes, but is not limited to, HBV capsid inhibitors, including, but not limited to, HBV capsid inhibitors ...

[0350] In some embodiments, the additional therapeutic agent is an agent for the treatment of HIV, hi some embodiments, the additional therapeutic agent is selected from the group consisting of an HIV protease inhibitor, an HIV integrase inhibitor, an entry inhibitor, an HIV nucleoside reverse transcriptase inhibitor, an HIV non-nucleoside reverse transcriptase inhibitor, an acyclic nucleoside phosphonate analog, and combinations thereof.

[0351] In some embodiments, the additional therapeutic agent is selected from the group consisting of HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, immune modulators, immunotherapeutics, antibody-drug conjugates, gene modulating agents, gene editing agents (CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs, etc.), and cell therapy (e.g., chimeric antigen receptor T cells, CAR-T, and engineered T cell receptors, TCR-T, autologous T cell therapy).

[0352] In some embodiments, the additional therapeutic agent is selected from the group consisting of HIV combination medications, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reactivators, capsid inhibitors, immune system therapeutics, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and "antibody-like" therapeutic proteins, and combinations thereof.

[0353] In some embodiments, the additional therapeutic agent is an HIV combination medication. Examples of HIV combination medications include ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); BIKTARVY® (bictegravir, emtricitabine, and tenofovir alafenamide); COMPLERA® (EVIPLERA®, rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine). TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); SYMTUZA® (darunavir, tenofovir alafenamide hemifumarate, emtricitabine) , and cobicistat; SYMFI™ (efavirenz, lamivudine, and tenofovir disoproxil fumarate); CIMDU™ (lamivudine and tenofovir disoproxil fumarate); tenofovir and lamivudine; tenofovir alafenamide and emtricitabine; tenofovir alafenamide hemifumarate and emtricitabine; tenofovir alafenamide hemifumarate, emtricitabine, and rilpivirine; tenofovir alafenamide hemifumarate, emtricitabine, cobicistat, and ervivir Tegravir; COMBIVIR® (zidovudine and lamivudine, AZT+3TC); EPZICOM® (LIVEXA®, abacavir sulfate and lamivudine, ABC+3TC); KALETRA® (ALUVIA®, lopinavir and ritonavir); TRIUMEQ® (dolutegravir, abacavir, and lamivudine); TRIZIVIR® (abacavir sulfate, zidovudine, and lamivudine, ABC+AZT+3TC); atazanavir and cobicistat;Atazanavir sulfate and cobicistat; atazanavir sulfate and ritonavir; darunavir and cobicistat; dolutegravir and rilpivirine; dolutegravir and rilpivirine hydrochloride; dolutegravir, abacavir sulfate, and lamivudine; lamivudine, nevirapine, and zidovudine; raltegravir and lamivudine; doravirine, lamivudine, and tenofovir disoproxil fumarate; doravirine, lamivudine, and tenofovir disoproxil; dapivirine and levonorgestrel, dolutegravir and lamivudine, dolutegravir and emtricitabine and tenofovir alafena These include, but are not limited to, elsulfavirine + 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;

[0354] In some embodiments, the additional therapeutic agent is an HIV protease inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, cobicistat, ASC-09, AEBL-2, MK-8718, GS-9500, GS-1156, and combinations thereof. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, and 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.

[0355] In some embodiments, the additional therapeutic agent is an HIV integrase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of raltegravir, elvitegravir, dolutegravir, abacavir, lamivudine, bictegravir, and combinations thereof. In some embodiments, the additional therapeutic agent is bictegravir. In some embodiments, the additional therapeutic agent is bictegravir, elvitegravir, curcumin, curcumin derivatives, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, raltegravir, dolutegravir, JTK-351, bictegravir, A Selected from the group consisting of VX-15567, BMS-986197, cabotegravir (long-acting injectable), diketoquinoline 4-1 derivatives, integrase-LEDGF inhibitors, ledgin, M-522, M-532, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbene disulfonic acid, T-169, VM-3500, cabotegravir, and combinations thereof.

[0356] In some embodiments, the additional therapeutic agent is an HIV entry inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of enfuvirtide, maraviroc, and combinations thereof. Further examples of HIV entry inhibitors include, but are not limited to, cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 adhesion inhibitors, DS-003 (BMS-599793), gp120 inhibitors, and CXCR4 inhibitors. Examples of CCR5 inhibitors include aplaviroc, vicriviroc, maraviroc, cenicriviroc, leronlimab (PRO-140), adaptavir (RAP-101), nifeviroc (TD-0232), anti-GP120 / CD4 or CCR5 bispecific antibodies, B-07, MB-66, polypeptide C25P, TD-0680, and vMIP (Haimipu). Examples of CXCR4 inhibitors include plerixafor, ALT-1188, N15 peptide, and vMIP (Haimipu).

[0357] 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.

[0358] In some embodiments, the additional therapeutic agent is a nucleoside or nucleotide inhibitor of HIV reverse transcriptase, for example, adefovir, adefovir dipivoxil, azuvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, VIDEX®, and VIDEX EC® (didanosine, ddl), abacavir, abacavir sulfate, alovudine, apricitabine, censavudine, didanosine, elvucitabine, festinavir, fosalvudine tidoxil, CMX-157, dapivirine, doravirine, etravirine, OCR-5753, tenofovir disoproxil orotate, fozivudine tidoxil, islatravir, lamivudine, phosphazide, stavudine, zalcitabine, zidovudine, lobafovir etalafenamid (GS-9131), GS-9148, MK-8504, MK-8591, MK-858, VM-2500, KP-1461, and combinations thereof.

[0359] In some embodiments, the additional therapeutic agent is a non-nucleoside or non-nucleotide inhibitor of HIV reverse transcriptase, for example, the additional agent is selected from the group consisting of dapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz, etravirine, lentinan, MK-8583, nevirapine, rilpivirine, TMC-278LA, ACC-007, AIC-292, KM-023, PC-1005, elsulfavirin rilp (VM-1500), and combinations thereof.

[0360] In some embodiments, the additional therapeutic agent is ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®, rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine); TDF+FT C); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); adefovir, adefovir dipivoxil; cobicistat; emtricitabine; tenofovir; tenofovir disoproxil; tenofovir disoproxil fumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate; T RIUMEQ® (dolutegravir, abacavir, and lamivudine); dolutegravir, abacavir sulfate, and lamivudine; raltegravir; raltegravir and lamivudine; maraviroc; enfuvirtide; ALUVIA® (KALETRA®, lopinavir and ritonavir); COMBIVIR® (zidovudine and lamivudine, AZT+3TC); EPZICOM® (LIVEXA®, abacavir sulfate and lamivudine, ABC+3TC); TRIZIVIR® (abacavir sulfate) salts, zidovudine, and lamivudine, ABC+AZT+3TC); rilpivirine; rilpivirine hydrochloride; atazanavir sulfate and cobicistat; atazanavir and cobicistat; darunavir and cobicistat; atazanavir; atazanavir sulfate; dolutegravir; elvitegravir; ritonavir; atazanavir sulfate and ritonavir; darunavir; lamivudine; prolastin; fosamprenavir; fosamprenavir calcium efavirenz; etravirine; nelfinavir; nelfinavir mesylate; interferon; didanosine;Selected from stavudine; indinavir; indinavir sulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir; delavirdine; delavirdine mesylate; Radha-108 (Receptor); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovir disoproxil fumarate; phosphazide; lamivudine, nevirapine, and zidovudine; abacavir; and abacavir sulfate.

[0361] In some embodiments, the additional therapeutic agent is selected from the group consisting of colistin, barbicin, icatibant, bepotastine, epirubicin, epoprocetonol, vapreotide, aprepitant, caspofungin, perphenazine, atazanavir, efavirenz, ritonavir, acyclovir, ganciclovir, penciclovir, prulifloxacin, bictegravir, nelfinavir, tegovyne, nelfinavir, praziquantel, pitavastatin, perampanel, eszopiclone, and zopiclone.

[0362] In some embodiments, the additional therapeutic agent is combined with an inhibitor of Bruton's tyrosine kinase (BTK, AGMX1, AT, ATK, BPK, IGHD3, IMD1, PSCTK1, XLA, NCBI gene ID: 695). For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of (S)-6-amino-9-(1-(but-2-ynoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one, acalabrutinib (ACP-196), BGB-3111, CB988, HM71224, ibrutinib (Imbruvica), M-2951 (evobrutinib), M7583, tirabrutinib (ONO-4059), PRN-1008, spebrutinib (CC-292), TAK-020, becabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, TAS-5315, AZD6738, calquence, dambatrisen, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of tirabrutinib, ibrutinib, acalabrutinib, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of tirabrutinib, ibrutinib, and combinations thereof. In some embodiments, the additional therapeutic agent is tyrphostin A9 (A9).

[0363] In some embodiments, the additional therapeutic agent is a KRAS inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of MRTX-849(G12C) and K-Ras(G12D) selective inhibitory peptides, including AMG-510, COTI-219, MRTX-1257, ARS-3248, ARS-853, WDB-178, BI-3406, BI-1701963, ARS-1620(G12C), SML-8-73-1(G12C), compound 3144(G12D), Kobe0065 / 2602 (Ras GTP), RT11, KRpep-2(Ac-RRCPLYISYDPVCRR-NH2), KRpep-2d(Ac-RRRRCPLYISYDPVCRRRR-NH2), and combinations thereof.

[0364] 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.

[0365] In some embodiments, the additional therapeutic agent is a vaccine. For example, in some embodiments, the additional therapeutic agent is a DNA vaccine, an RNA vaccine, a live attenuated vaccine, a therapeutic vaccine, a prophylactic vaccine, a protein-based vaccine, or a combination thereof. In some embodiments, the additional therapeutic agent is mRNA-1273. In some embodiments, the additional therapeutic agent is INO-4800 or INO-4700. In some embodiments, the additional therapeutic agent is a live attenuated RSV vaccine MEDI-559, a human monoclonal antibody against RSV REGN2222, palivizumab, respiratory syncytial virus immune globulin, intravenous (RSV-IGIV), and combinations thereof. In some embodiments, the additional therapeutic agent is an HBV vaccine, e.g., Pedialix, Engelix-B, and RecombiVax HB. In some embodiments, the additional therapeutic agent is a VZV vaccine, e.g., Zostavix and Varivax. In some embodiments, the additional therapeutic agent is an HPV vaccine, e.g., cervical, Gardasil 9, and Gardasil. In some embodiments, the additional therapeutic agent is an influenza virus vaccine, such as (i) a monovalent influenza A vaccine (e.g., an influenza A [H5N1] virus monovalent vaccine and an influenza A [H1N1] 2009 virus monovalent vaccine), (ii) a trivalent vaccine for influenza A and B viruses (e.g., Afluria, Agriflu, Fluud, Fluarix, Flublox, Flucervax, Flulaval, Fluvirin, and Fluzone), and (iii) a quadrivalent vaccine for influenza A and B viruses (Flumist, Fluarix, Fluzone, and Flulaval). In some embodiments, the additional therapeutic agent is a human adenovirus vaccine (e.g., adenovirus types 4 and 7 vaccine, live, oral). In some embodiments, the additional therapeutic agent is a rotavirus vaccine (e.g., Rotarix for rotavirus serotypes G1, G3, G4, or G9, and RotaTeq for rotavirus serotypes G1, G2, G3, or G4).In some embodiments, the additional therapeutic agent is a hepatitis A virus vaccine (e.g., Havrix and Vaqta). In some embodiments, the additional therapeutic agent is a poliovirus vaccine (e.g., Kinrix, Quadracel, and Ipol). In some embodiments, the additional therapeutic agent is a yellow fever virus vaccine (e.g., YF-Vax). In some embodiments, the additional therapeutic agent is a Japanese encephalitis virus vaccine (e.g., Ixiaro and JE-Vax). In some embodiments, the additional therapeutic agent is a measles vaccine (e.g., MM-RII and ProQuad). In some embodiments, the additional therapeutic agent is a mumps vaccine (e.g., MM-RII and ProQuad). In some embodiments, the additional therapeutic agent is a rubella vaccine (e.g., MM-RII 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 variola virus (smallpox) vaccine (ACAM2000). In some embodiments, the additional therapeutic agent is a hepatitis E virus (HEV) vaccine (e.g., HEV239). In some embodiments, the additional therapeutic agent is a 2019-nCov vaccine.

[0366] In some embodiments, the additional therapeutic agent is an antibody, e.g., a monoclonal antibody. For example, the additional therapeutic agent is an antibody against 2019-nCov selected from the group consisting of a Regeneron antibody, a Wuxi antibody, a Vir Biotechnology antibody, an antibody targeting the SARS-CoV-2 spike protein, an antibody capable of neutralizing SARS-CoV-2 (a 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.

[0367] In some embodiments, the additional therapeutic agent is a recombinant cytokine gene-derived protein injection.

[0368] In some embodiments, the additional therapeutic agent is a polymerase inhibitor. In some embodiments, the additional therapeutic agent is a DNA polymerase inhibitor. For example, in some embodiments, the additional therapeutic agent is cidofovir. In some embodiments, the additional therapeutic agent is an RNA polymerase inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of ribavirin, favipiravir, lamivudine, pimodivir, and combinations thereof.

[0369] In some embodiments, the additional therapeutic agent is selected from the group consisting of lopinavir, ritonavir, interferon-alpha-2b, ritonavir, arbidol, hydroxychloroquine, darunavir and cobicistat, abidol hydrochloride, oseltamivir, ritonavir, emtricitabine, tenofovir alafenamide fumarate, baloxavir marboxil, ruxolitinib, and combinations thereof.

[0370] In some embodiments, the additional therapeutic agent is a 6'-fluorinated aristemicin analog, an acyclovir fleximer analog, disulfiram, a thiopurine analog, ASC09F, GC376, GC813, a phenylisoserine derivative, a neuroimidase inhibitor analog, a pyrithiobac derivative, a vananin and a 5-hydroxychromone derivative, SSYA10-001, a griffithsin, a HR2P-M1, a HR2P-M2, a P21S10, dihydrotanshinone E-64-C and E-64-D, an OC43-HR2P, a MERS-5HB, a 229E-HR1P, a 229E-HR2P, a resveratrol, rol, 1-thia-4-azaspiro[4.5]decan-3-one derivatives, gemcitabine hydrochloride, loperamide, recombinant interferon, cyclosporin A, alisporivir, imatinib mesylate, dasatinib, selumetinib, trametinib, rapamycin, saracatinib, chlorpromazine, triflupromazine, fluphenazine, thiethylperazine, promethazine, cyclophilin inhibitors, K11777, camostat, k22, teicoplanin derivatives, benzoheterocyclic amine derivative N30, mycophenolic acid, silvestrol, and combinations thereof.

[0371] In some embodiments, the additional therapeutic agent is an antibody. In some embodiments, the additional therapeutic agent is an antibody that binds to a coronavirus, e.g., an antibody that binds to SARS-CoV or MERS-CoV. In some embodiments, the additional therapeutic agent is a viral antibody of 2019-nCoV.

[0372] The compositions of the present invention may also be used in combination with other active ingredients. For the treatment of 2019-nCoV viral infection, preferably, the other active therapeutic agent is active against coronavirus infection, e.g., 2019-nCoV viral infection. The compounds and compositions of the present invention may also be used in combination with parenteral fluids (including dextrose saline and lactated Ringer's solution) and nutrients, antibiotics (including metronidazole and cephalosporin antibiotics, such as ceftriaxone and cefuroxime) and / or antifungal prophylactics, fever and analgesics, antiemetics (such as metoclopramide) and / or antidiarrheal medications, vitamin and mineral supplements (including vitamin K and zinc sulfate), anti-inflammatory agents (such as ibuprofen or steroids), corticosteroids such as methylprednisolone, immunomodulatory agents (e.g., interferons), and other small molecule or biological antivirals targeting 2019-nCoV. The additional therapeutic agent is intended for use in conjunction with general care provided to patients with 2019-nCoV virus infection, including other common illnesses in the patient population, such as antivirals (including, but not limited to, lopinavir / ritonavir, EIDD-1931, favipiravir, ribavirin, neutralizing antibodies, etc.), vaccines, analgesics, and drugs for other common illnesses in the patient population, such as antimalarials (including artemether and artemether-lumefantrine combination therapy), typhoid fever (quinolone antibiotics such as ciprofloxacin, macrolide antibiotics such as azithromycin, cephalosporin antibiotics such as ceftriaxone, or aminopenicillins such as ampicillin), or shigellosis. In some embodiments, the additional therapeutic agent is dihydroartemisinin / piperaquine. In some embodiments, the additional therapeutic agent is EIDD-2801 (MH-4482, molnupiravir).

[0373] In some embodiments, the additional therapeutic agent is an immune modulator. Examples of immune system therapies include toll-like receptor modulators, such as tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12, and tlr13, programmed cell death protein 1 (Pd-1) modulators, programmed death-ligand 1 (Pd-L1) modulators, IL-15 modulators, DermaVir, interleukin-7, Plaquenil (hydroxychloroquine), Proleukin (aldesleukin, IL-2), interferon alpha, interferon alpha-2b, interferon alpha-n3, pegylated interferon alpha, interferon gamma, hydroxyurea; mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MPA). mofetil, MMF), ribavirin, polymer polyethyleneimine (PEI), gepon, IL-12; WF-10; VGV-1; MOR-22; BMS-936559; CYT-107, interleukin-15 / Fc fusion protein, AM-0015, ALT-803, NIZ-985, NKTR-255, NKTR-262, NKTR-214, normferon, pegylated interferon alfa-2a, pegylated interferon alfa-2b, recombinant interleukin-15, Xmab-24306, RPI-MN, STING modulators, RIG-I modulators, NOD2 modulators, SB-9200, and IR-103. In some embodiments, the additional therapeutic agent is fingolimod, leflunomide, or a combination thereof. In some embodiments, the additional therapeutic agent is thalidomide.

[0374] In some embodiments, the additional therapeutic agent is an IL-6 inhibitor, e.g., tocilizumab, sarilumab, or a combination thereof.

[0375] In some embodiments, the additional therapeutic agent is an anti-TNF inhibitor, e.g., the additional therapeutic agent is adalimumab, etanercept, golimumab, infliximab, or a combination thereof.

[0376] In some embodiments, the additional therapeutic agent is a JAK inhibitor, for example, the additional therapeutic agent is baricitinib, filgotinib, Olumiant, or a combination thereof.

[0377] In some embodiments, the additional therapeutic agent is an inflammation inhibitor, eg, pirfenidone.

[0378] 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.

[0379] In some embodiments, the compounds disclosed herein are used in combination with standard treatments for pneumonia (see, e.g., Pediatric Community Pneumonia Guidelines, CID 2011:53 (1 October)). Treatment of pneumonia generally involves curing the infection and preventing complications. The specific treatment depends on several factors, including the type and severity of the pneumonia, the age, and the overall health of the individual. Options include: (i) antibiotics; (ii) cough suppressants; and (iii) antipyretics / pain relievers (e.g., aspirin, ibuprofen (Advil, Motrin IB, etc.), and acetaminophen (Tylenol, etc.)). In some embodiments, the additional therapeutic agent is a bromhexine cough suppressant.

[0380] In some embodiments, the compounds disclosed herein are used in combination with immunoglobulin from cured COVID-19 patients. In some embodiments, the compounds disclosed herein are used in combination with plasma transfusions. In some embodiments, the compounds disclosed herein are used in combination with stem cells.

[0381] In some embodiments, the additional therapeutic agent is a TLR agonist. Examples of TLR agonists include, but are not limited to, vesatolimod (GS-9620), GS-986, IR-103, lefitolimod, tilsotolimod, lintatolimod, DSP-0509, AL-034, G-100, cobitolimod, AST-008, motolimod, GSK-1795091, GSK-2245035, VTX-1463, GS-9688, LHC-165, BDB-001, RG-7854, tellulatorimod, and RO-7020531.

[0382] In some embodiments, the additional therapeutic agent is selected from the group consisting of bortezomib, flurazepam, ponatinib, sorafenib, paramethasone, clocortolone, flucloxacillin, sertindole, crividipine, atorvastatin, cinolazepam, clofazimine, fosaprepitant, and combinations thereof.

[0383] In some embodiments, the additional therapeutic agent is kalimycin, suramin, triazavirine, dipyridamole, bevacizumab, meplasmab, GD31 (Rhizobium), an NLRP inflammasome inhibitor, or an alpha-ketoamine. In some embodiments, the additional therapeutic agent is recombinant human angiotensin-converting enzyme 2 (rhACE2). In some embodiments, the additional therapeutic agent is viral macrophage inflammatory protein (vMIP).

[0384] In some embodiments, the additional therapeutic agent is an anti-viroporin therapeutic agent. For example, the additional therapeutic agent is BIT-314 or BIT-225. In some embodiments, the additional therapeutic agent is a coronavirus E protein inhibitor. For example, the additional therapeutic agent is BIT-009. Further examples of additional therapeutic agents include those described in WO 2004112687, WO 2006135978, WO 2018145148, and WO 2009018609.

[0385] In some embodiments, the additional therapeutic or prophylactic agent is molnupiravir, oseltamivir, nilmatrervir, or ritonavir. In some embodiments, the additional therapeutic or prophylactic agent is ritonavir or cobicistat.

[0386] Any compound of the present invention can be combined with one additional active therapeutic agent, for example, the compounds described herein can be combined with one, two, three, four, five, or more additional active therapeutic agents.

[0387] Any compound of the present invention can also be combined with one or more additional active therapeutic agents in a single dosage form for simultaneous or sequential administration to a patient. The combination therapy can be administered as a simultaneous or sequential regimen. When administered sequentially, the combination can be administered in two or more doses.

[0388] Co-administration of a compound of the invention with one or more other active therapeutic agents generally refers to the simultaneous or sequential administration of a compound of the invention with one or more other active therapeutic agents such that therapeutically effective amounts of both the compound of the invention and the one or more other active therapeutic agents are present in the patient's body.

[0389] Co-administration includes administration of a unit dose of a compound of the invention before or after administration of a unit dose of one or more other active therapeutic agents, e.g., within seconds, minutes, or hours of administration of a compound of the invention. For example, a unit dose of a compound of the invention can be administered first, followed within seconds or minutes by administration of a unit dose of one or more other active therapeutic agents. Alternatively, a unit dose of one or more other therapeutic agents can be administered first, followed within seconds or minutes by administration of a unit dose of a compound of the invention. In some cases, it may be desirable to administer a unit dose of a compound of the invention first, followed several hours (e.g., 1-12 hours) later by administration of a unit dose of one or more other active therapeutic agents. In other embodiments, it may be desirable to administer a unit dose of one or more other active therapeutic agents first, followed several hours (e.g., 1-12 hours) later by administration of a unit dose of a compound of the invention.

[0390] Combination therapy can provide "synergistic" and "synergistic" effects, i.e., effects achieved when the active ingredients used together are greater than the sum of the effects resulting from using the compounds separately. Synergistic effects can be achieved when the active ingredients are (1) co-formulated and administered or delivered simultaneously in a combined formulation, (2) delivered alternately or in parallel as separate formulations, or (3) by some other regimen. When delivered in alternation therapy, synergistic effects can be achieved when the compounds are administered or delivered sequentially, for example, by separate tablets, pills, capsules, or different injections in separate syringes. Generally, during alternation therapy, effective dosages of each active ingredient are administered sequentially, i.e., consecutively, whereas in combination therapy, effective dosages of two or more active ingredients are administered together. A synergistic antiviral effect indicates an antiviral effect that is greater than the expected purely additive effect of the individual compounds of the combination.

[0391] 1. Combination therapy for the treatment of Pneumoviridae The compounds provided herein may also be used in combination with other active therapeutic agents. In the case of treating Pneumoviridae virus infections, preferably, the other active therapeutic agent is active against Pneumoviridae virus infections, particularly respiratory syncytial virus infections and / or metapneumovirus infections. Non-limiting examples of these other active therapeutic agents against RSV include ribavirin, palivizumab, motavizumab, RSV-IGIV (RespiGam®), MEDI-557, A-60444 (also known as RSV604), MDT-637, BMS-433771, ALN-RSV0, ALX-0171, and mixtures thereof. Other non-limiting examples of other active therapeutic agents active against respiratory syncytial virus infection include respiratory syncytial virus protein F inhibitors such as AK-0529; RV-521, ALX-0171, JNJ-53718678, BTA-585, and presatovir; RNA polymerase inhibitors such as lumicitabine and ALS-8112; anti-RSV G protein antibodies such as anti-G protein mAb; and viral replication inhibitors such as nitazoxanide.

[0392] In some embodiments, the other active therapeutic agent may be a vaccine for the treatment or prevention of RSV, including, but not limited to, MVA-BN RSV, RSV-F, MEDI-8897, JNJ-64400141, DPX-RSV, SynGEM, GSK-3389245A, GSK-300389-1A, RSV-MEDI δM2-2 vaccine, VRC-RSVRGP084-00VP, Ad35-RSV-FA2, Ad26-RSV-FA2, and RSV fusion glycoprotein subunit vaccine.

[0393] Non-limiting examples of other active therapeutic agents active against metapneumovirus infection include sialidase modulators such as DAS-181, RNA polymerase inhibitors such as ALS-8112; and antibodies for the treatment of metapneumovirus infection such as EV-046113.

[0394] In some embodiments, the other active therapeutic agent may be a vaccine for the treatment or prevention of metapneumovirus infection, including but not limited to mRNA-1653 and rHMPV-Pa vaccines.

[0395] 2. Combination therapy for the treatment of Picornaviridae The compounds provided herein can also be used in combination with other active therapeutic agents.When treating Picornaviridae virus infections, preferably, the other active therapeutic agents are active against Picornaviridae virus infections, particularly enterovirus infections.Non-limiting examples of these other active therapeutic agents include capsid binding inhibitors, such as pleconaril, BTA-798 (vapendavir), and other compounds disclosed by Wu et al. (U.S. Patent No. 7,078,403) and Watson (U.S. Patent No. 7,166,604), fusion sialidase proteins such as DAS-181, capsid protein VP1 inhibitors such as VVX-003 and AZN-001, viral protease inhibitors such as CW-33, phosphatidylinositol 4 kinase beta inhibitors such as GSK-480 and GSK-533, and anti-EV71 antibodies.

[0396] In some embodiments, the other active therapeutic agent may be a vaccine for the treatment or prevention of Picornaviridae virus infection, including but not limited to, EV71 vaccine, TAK-021, and EV-D68 adenovector-based vaccine.

[0397] 3. Combination therapy for respiratory infections Many infections caused by Pneumoviridae, Picornaviridae, and Coronaviridae viruses are respiratory infections. Therefore, additional active therapeutic agents used to treat respiratory symptoms and sequelae of infections can be used in combination with the compounds provided herein. The additional agents are preferably administered orally or by direct inhalation. For example, other preferred additional therapeutic agents combined with the compounds provided herein for the treatment of viral respiratory infections include, but are not limited to, bronchodilators and corticosteroids.

[0398] Glucocorticoids Glucocorticoids, first introduced as an asthma treatment in 1950 (Carryer, Journal of Allergy, 21, 282–287, 1950), remain the most potent and consistently effective therapy for this disease, although 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 significant undesirable side effects, including truncal obesity, hypertension, glaucoma, glucose intolerance, accelerated cataract formation, bone mineral loss, and psychological effects, all of which limit their use as long-term treatments (Goodman and Gilman, 10th edition, 2001). A solution to systemic side effects is to deliver steroid drugs directly to the site of inflammation. To mitigate the severe adverse effects of oral steroids, inhaled corticosteroids (ICS) have been developed. Non-limiting examples of corticosteroids that may be used in combination with the compounds provided herein are dexamethasone, dexamethasone sodium phosphate, fluorometholone, fluorometholone acetate, loteprednol, loteprednol etabonate, hydrocortisone, prednisolone, fludrocortisone, triamcinolone, triamcinolone acetonide, betamethasone, beclomethasone diproprionate, methylprednisolone, fluocinolone, fluocinolone acetonide, flunisolide, fluocortin-21-butyrate, flumethasone, flumethasone pivalate, budesonide, halobetasol propionate, mometasone furoate, fluticasone, AZD-7594, ciclesonide, or a pharmaceutically acceptable salt thereof.

[0399] anti-inflammatory agents Other anti-inflammatory agents that act through anti-inflammatory cascade mechanisms are also useful as additional therapeutic agents combined with the compounds provided herein for the treatment of viral respiratory infections.The application of "anti-inflammatory signaling modulators" (referred to herein as AISTMs), such as phosphodiesterase inhibitors (e.g., PDE-4, PDE-5, or PDE-7 specific), transcription factor inhibitors (e.g., blocking NFκB through IKK inhibition), or kinase inhibitors (e.g., P38 MAP, JNK, PI3K, EGFR, or Syk), is a logical approach to stop inflammation because these small molecules target a limited number of common intracellular pathways, i.e., signaling pathways that are key points for anti-inflammatory therapeutic intervention (see review by PJBarnes, 2006).These non-limiting additional therapeutic agents include 5-(2,4-difluoro-phenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (2-dimethylamino-ethyl)-amide (P38 MAP kinase inhibitor ARRY-797), 3-cyclopropylmethoxy-N-(3,5-dichloro-pyridin-4-yl)-4-difluoromethoxy-benzamide (PDE-4 inhibitor roflumilast), 4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenyl-ethyl]-pyridine (PDE-4 inhibitor CDP-840), N-(3,5-dichloro-4-pyridinyl)-4-(difluoromethoxy)-8-[(methylsulfonyl)amino]-1-dibenzofurancarboxamide (PDE-4 inhibitor oglemilast), N-(3,5-dichloro-pyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxo-acetamide (PDE-4 inhibitor AWD 12-281), 8-methoxy-2-trifluoromethyl-quinoline-5-carboxylic acid (3,5-dichloro-1-oxy-pyridin-4-yl)-amide (PDE-4 inhibitor Sch 351591), 4-[5-(4-fluorophenyl)-2-(4-methanesulfinyl-phenyl)-1H-imidazol-4-yl]-pyridine (P38 inhibitor SB-203850), 4-[4-(4-fluoro-phenyl)-1-(3-phenyl-propyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-but-3-yn-1-ol (P38 inhibitor RWJ-67657), 4-cyano-4-(3-cyclopentyloxy-4-methoxy-phenyl)-2-diethylcyclohexanecarboxylate 2-diethyl-ethyl ester prodrug of cilomilast, a PDE-4 inhibitor), (3-chloro-4-fluorophenyl)-[7-methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-yl]-amine (gefinib, an EGFR inhibitor), and 4-(4-methyl-piperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide (imatinib, an EGFR inhibitor).

[0400] Beta-2 adrenergic receptor agonist bronchodilators Combinations including an inhaled β2-adrenergic receptor agonist bronchodilator, such as formoterol, albuterol, or salmeterol, together with a compound provided herein are also suitable, but non-limiting, combinations useful for treating respiratory viral infections.

[0401] Combinations of inhaled β2-adrenergic receptor agonist bronchodilators, such as formoterol or salmeterol, with ICS are also used to treat both bronchial constriction and inflammation (Symbicort® and Advair®, respectively). Combinations including these ICS and β2-adrenergic receptor agonists with the compounds provided herein are also suitable, but not limited to, combinations useful for treating respiratory viral infections.

[0402] Other examples of β2 adrenergic receptor agonists are bedoradrine, vilanterol, indacaterol, olodaterol, tulobuterol, formoterol, abesiterol, salbutamol, arformoterol, levalbuterol, fenoterol, and TD-5471.

[0403] Anticholinergic drugs Anticholinergic agents may be useful for the treatment or prevention of pulmonary bronchoconstriction and are therefore useful as additional therapeutic agents in combination with the compounds provided herein for the treatment of viral respiratory infections. These anticholinergic agents include muscarinic receptor antagonists (especially of the M3 subtype) that have shown therapeutic efficacy in humans for controlling cholinergic tone in COPD (Witek, 1999); 1-{4-hydroxy-1-[3,3,3-tris-(4-fluoro-phenyl)-propionyl]-pyrrolidine-2-carbonyl}-pyrrolidine-2-carboxylic acid (1-methyl-piperidin-4-ylmethyl)-amide, 3-[3-(2-diethylamino-acetoxy)-2-phenyl-propionyloxy]-8-isopropyl-8-methyl-8-azonia-bicyclo[3.2.1]octane (ipratropium-N,N-diethylglycinate), 1-cyclohexyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester (solifenacin), ), 2-hydroxymethyl-4-methanesulfinyl-2-phenyl-butyric acid 1-aza-bicyclo[2.2.2]oct-3-yl ester (levatropate), 2-{1-[2-(2,3-dihydro-benzofuran-5-yl)-ethyl]-pyrrolidin-3-yl}-2,2-diphenyl-acetamide (darifenacin), 4-azepan-1-yl-2,2-diphenyl-butyramide (buzepide), 7-[3-( 2-Diethylamino-acetoxy)-2-phenyl-propionyloxy]-9-ethyl-9-methyl-3-oxa-9-azonia-tricyclo[3.3.1.02,4]nonane (oxitropium-N,N-diethylglycinate), 7-[2-(2-diethylamino-acetoxy)-2,2-di-thiophen-2-yl-acetoxy]-9,9-dimethyl-3-oxa-9-azonia-tricyclo[3.3.1.02,4]nonane (tiotropium-N,N-diethylglycinate), dimethylaminoacetic acid 2-(3-diisopropylamino-1-phenyl-propyl)-4-methyl-phenyl ester (tolterodine-N,N-dimethylglycinate), 3-[4,4-bis-(4-fluoro-phenyl)-2-oxo-imidazolidin-1-yl]-1-methyl-1-(2-oxo-2-pyridin-2-yl-ethyl)-pyrrolidinium, 1-[1-(3-fluoro-benzyl)-piperidin-4-yl]-4,4-bis-(4-fluoro-phenyl)-imidazolidin-2-one, 1-cyclooctyl-3-(3-methoxy-1-aza-bicyclo[2.2.2] These include, but are not limited to, oct-3-yl)-1-phenyl-prop-2-yn-1-ol, 3-[2-(2-diethylamino-acetoxy)-2,2-di-thiophen-2-yl-acetoxy]-1-(3-phenoxy-propyl)-1-azonia-bicyclo[2.2.2]octane (acridinium-N,N-diethylglycinate), or (2-diethylamino-acetoxy)-di-thiophen-2-yl-acetic acid 1-methyl-1-(2-phenoxy-ethyl)-piperidin-4-yl ester, rebefenacin, glycopyrronium bromide, umeclidinium bromide, tiotropium bromide, acridinium bromide, and bencycloquidium bromide.

[0404] mucolytics The compounds provided herein can also be combined with mucolytic agents to treat both the infection and symptoms of respiratory infections. A non-limiting example of a mucolytic agent is ambroxol. Similarly, the compounds can be combined with expectorants to treat both the infection and symptoms of respiratory infections. A non-limiting example of an expectorant is guaifenesin.

[0405] Nebulized hypertonic saline is used to improve the immediate and long-term clearance of small airways in patients with lung disease (Kuzik, J. Pediatrics 2007, 266). Therefore, the compounds provided herein can also be combined with nebulized hypertonic saline, especially when viral infections are coexisting with bronchiolitis. The combination of the compounds provided herein and hypertonic saline can also include any of the additional agents discussed above. In one embodiment, about 3% nebulized hypertonic saline is used.

[0406] 4. Combination therapy for the treatment of Flaviviridae infections The compounds and compositions provided herein are also used in combination with other active therapeutic agents. In the case of treating Flaviviridae infections, preferably the other active therapeutic agent is active against Flaviviridae infections.

[0407] For the treatment of dengue virus infection, non-limiting examples of other active therapeutic agents are host cell factor modulators such as GBV-006; alpha-glucosidase 1 inhibitors such as fenretinide ABX-220, BRM-211, celgosivir, platelet activating factor receptor (PAFR) antagonists such as modipafant, cadherin-5 / factor Ia modulators such as FX-06, NS4B inhibitors, e.g., JNJ-8359, viral RNA splicing modulators such as ABX-202, NS5 polymerase inhibitors, NS3 protease inhibitors, and TLR modulators.

[0408] In some embodiments, the other active therapeutic agent may be a vaccine for the treatment or prevention of dengue fever, including, but not limited to, TetraVax-DV, Dengvaxia®, DPIV-001, TAK-003, live attenuated dengue vaccine, tetravalent dengue vaccine, tetravalent DNA vaccine, rDEN2δ30-7169; and DENV-1 PIV.

[0409] 5. Combination therapy for the treatment of Filoviridae infections The compounds provided herein may also be used in combination with other active therapeutic agents. In the case of treatment of Filoviridae infections, preferably the other active therapeutic agent is active against Filoviridae infections, particularly Marburg virus infection, Ebola virus infection, and Cueva virus infection. Non-limiting examples of these other active therapeutic agents include ribavirin, amiodarone, dronedarone, verapamil, Ebola convalescent plasma, and the like. Plasma, ECP), TKM-100201, BCX4430 ((2S,3S,4R,5R)-2-(4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-5-(hydroxymethyl)pyrrolidine-3,4-diol), TKM-Ebola, T-705 monophosphate, T-705 diphosphate, T-705 triphosphate, FGI-106 (1-N,7-N-bis[3-(dimethylamino)propyl]-3,9-dimethylquinolin[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 cell factor modulators such as GMV-006, cadherin-5 / factor Ia modulators such as FX-06; and antibodies for the treatment of Ebola such as REGN-3470-3471-3479 and ZMapp.

[0410] Other non-limiting active therapeutic agents active against Ebola include alpha-glucosidase 1 inhibitors, cathepsin B inhibitors, CD29 antagonists, dendritic ICAM-3 binding nonintegrin 1 inhibitors, estrogen receptor antagonists, factor VII antagonists HLA class II antigen modulators, host cell factor modulators, interferon alpha ligands, neutral alpha-glucosidase AB inhibitors, Niemann-Pick C1 protein inhibitors, nucleoprotein inhibitors, polymerase cofactor VP35 inhibitors, serine protease inhibitors, tissue factor inhibitors, TLR-3 agonists, viral envelope glycoprotein inhibitors, and Ebola virus entry inhibitors (NPC1 inhibitors).

[0411] In some embodiments, the other active therapeutic agent may be a vaccine for the treatment or prevention of Ebola, including, but not limited to, VRC-EBOADC076-00-VP, adenovirus-based Ebola vaccine, rVSV-EBOV, rVSVN4CT1-EBOVGP, MVA-BN Filo+Ad26-ZEBOV regimen, INO-4212, VRC-EBODNA023-00-VP, VRC-EBOADC069-00-VP, GamEvac-combi vaccine, SRC VB vector, HPIV3 / EboGP vaccine, MVA-EBOZ, Ebola recombinant glycoprotein vaccine, Vaxart adenovirus vector 5-based Ebola vaccine, FiloVax vaccine, GOVX-E301, and GOVX-E302.

[0412] The compounds provided 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.

[0413] The compounds provided herein are also intended for use in combination with the general care provided to patients with Filoviridae virus infections, including parenteral fluids (including dextrose saline and lactated Ringer's solution) and nutrients, antibiotics (including metronidazole and cephalosporin antibiotics such as ceftriaxone and cefuroxime) and / or antifungal prophylaxis, antipyretics and analgesics, antiemetics (such as metoclopramide) and / or antidiarrheal medications, vitamin and mineral supplements (including vitamin K and zinc sulfate), anti-inflammatory agents (such as ibuprofen), analgesics, and antimalarials (including artemether and artesunate-lumefantrine combination therapy), typhoid (including quinolone antibiotics such as ciprofloxacin, macrolide antibiotics such as azithromycin, cephalosporin antibiotics such as ceftriaxone, or aminopenicillins such as ampicillin), or medications for other common illnesses in the patient population, such as shigellosis.

[0414] The present invention will be described in more detail with reference to 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 a variety of non-critical parameters that can be changed or modified to produce essentially the same results.

[0415] 6. Combination therapy for the treatment of coronavirus family virus infections In some embodiments, the additional therapeutic agent is a 2,5-oligoadenylate synthetase stimulator, 5-HT 2a receptor antagonists, 5-lipoxygenase inhibitors, ABL family tyrosine kinase inhibitors, Abl tyrosine kinase inhibitors, acetaldehyde dehydrogenase inhibitors, acetyl-CoA carboxylase inhibitors, actin antagonists, actin modulators, activity-dependent neuroprotective modulators, adenosine A3 receptor agonists, adrenergic receptor antagonists, adrenomedullin ligands, adrenomedullin ligand inhibitors, advanced glycosylation product receptor antagonists, advanced glycosylation product receptor modulators, AKT protein kinase inhibitors, alanine-proline-rich secretory protein stimulators, aldose reductase inhibitors, alkaline phosphatase stimulators, α2 adrenergic receptor antagonists, α2B adrenergic receptor agonists, AMP-activated protein kinase stimulators, AMPA receptor modulators, amyloid protein deposition inhibitors, androgen receptor antagonists, angiotensin II AT-1 receptor antagonist, 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 agents, antithrombotic agents, AP1 transcription factor modulators, apelin receptor agonists, APOA1 gene stimulators, apolipoprotein A1 agonists, apolipoprotein B antagonists, apolipoprotein B modulators, apolipoprotein C3 antagonists, aryl hydrocarbon receptor agonists, aryl hydrocarbon receptor antagonists, ATP-binding cassette transporter B5 modulators, Axl tyrosine kinase receptor inhibitors, bactericidal permeability protein inhibitors, basigin inhibitors, basigin modulators, BCL2 gene inhibitors, BCL2L11 gene stimulators, Bcr protein inhibitors, Beta 1-adrenergic receptor modulators, β2-adrenergic receptor agonists, β-adrenergic receptor agonists, β-arrestin stimulators, blood coagulation regulators, BMP10 gene inhibitors, BMP15 gene inhibitors, bone morphogenetic protein-10 ligand inhibitors,Bone morphogenetic protein-15 ligand inhibitor, bradykinin B2 receptor antagonist, brain-derived neurotrophic factor ligand, bromodomain-containing protein 2 inhibitor, bromodomain-containing protein 4 inhibitor, Btk tyrosine kinase inhibitor, C-reactive protein modulator, Ca2+ release-activated Ca2+ channel 1 inhibitor, cadherin-5 modulator, calcium-activated chloride channel inhibitor, calcium channel modulator, calpain-I inhibitor, calpain-II inhibitor, calpain-IX inhibitor, cannabinoid CB2 receptor agonist, cannabinoid receptor Regulators of thyroid cancer, casein kinase II inhibitors, CASP8-FADD-like regulator inhibitors, caspase inhibitors, catalase stimulators, CCL26 gene inhibitors, CCR2 chemokine antagonists, CCR5 chemokine antagonists, CD11a agonists, CD122 agonists, CD3 antagonists, CD4 agonists, CD40 ligands, CD40 ligand modulators, CD40 ligand receptor agonists, CD40 ligand receptor modulators, CD49d agonists, CD70 antigen modulators, CD73 agonists, CD73 antagonists, CD95 agonists antagonists, CFTR inhibitors, CGRP receptor antagonists, chemokine receptor-like 1 agonists, chloride channel inhibitors, chloride channel modulators, cholera enterotoxin subunit B inhibitors, cholesterol ester transfer protein inhibitors, collagen modulators, complement C1s minor component inhibitors, complement C3 inhibitors, complement factor C5 inhibitors, complement factor C5a inhibitors, complement 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 inhibitors COVID-19 protein modulators, coronavirus spike glycoprotein inhibitors, coronavirus spike glycoprotein modulators, COVID-19 envelope small membrane protein modulators, COVID-19 nonstructural protein 8 modulators, COVID-19 nucleoprotein modulators, COVID-19 protein 3a inhibitors, COVID-19 replicase polyprotein 1a inhibitors, COVID-19 replicase polyprotein 1a modulators, COVID-19 replicase polyprotein 1ab inhibitors, COVID-19 replicase polyprotein 1ab modulators,COVID-19 spike glycoprotein inhibitors, COVID-19 spike glycoprotein modulators, COVID-19 structural glycoprotein modulators, CRF-2 receptor agonists, CSF-1 agonists, CSF-1 antagonists, CX3CR1 chemokine antagonists, CXC10 chemokine ligand inhibitors, CXC5 chemokine ligand inhibitors, 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 modulators, cytotoxic T lymphocyte protein 4 inhibitors, cytotoxic T lymphocyte protein 4 stimulators, DDX3 inhibitors, dehydrogenase inhibitors, dehydropeptidase-1 modulators, deoxyribonuclease I stimulators, deoxyribonuclease gamma stimulators, deoxyribonuclease stimulators, dihydroceramide 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, endoplasmin 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 XIa antagonist, FGF receptor antagonist, FGF-1 ligand, FGF-1 ligand inhibitor, FGF-2 ligand inhibitor, FGF1 receptor antagonist, FGF2 receptor antagonist, FGF3 receptor antagonist, Flt3 tyrosine kinase inhibitor, fractalkine ligand inhibitor, free fatty acid receptor 2 agonist, free fatty acid receptor 3 agonist, furin inhibitor, Fyn tyrosine kinase inhibitor, FYVE finger phosphoinositide kinase inhibitor, G protein-coupled bile acid receptor 1 agonist, GABA A receptor modulators, galectin 3 inhibitors, gamma-secretase inhibitors, GDF agonists, gelsolin stimulators, glial neurotrophic factor ligands, glucocorticoid receptor agonists, glutathione peroxidase stimulators, GM-CSF ligand inhibitors, GM-CSF receptor agonists, GM-CSF receptor modulators, Griffithin modulators, growth regulatory protein alpha ligand inhibitors, Grp78 calcium binding protein inhibitors, heat shock protein HSP90 alpha inhibitors, heat shock protein HSP90 beta inhibitors, heat shock protein inhibitors, heat shock protein stimulators, hemagglutinin modulators, hemoglobin modulators , hemolysin alpha inhibitors, heparanase inhibitors, heparin agonists, type B structural protein inhibitors, hepatitis C virus NS5B polymerase inhibitors, HIF prolyl hydroxylase inhibitors, HIF prolyl hydroxylase-2 inhibitors, high mobility group protein B1 inhibitors, histamine H1 receptor antagonists, histamine H2 receptor antagonists, histone deacetylase 6 inhibitors, histone inhibitors, HIV protease inhibitors, HIV-1 gp120 protein inhibitors, HIV-1 protease inhibitors, HIV-1 reverse transcriptase inhibitors, HLA class I antigen modulators, HLA class II antigen modulators, host cell factor modulators, Hsp 90 inhibitors, human papillomavirus E6 protein regulators, human papillomavirus E7 protein regulators, hypoxia-inducible factor inhibitor gene inhibitors, hypoxia-inducible factor-2α regulators, I-kappa B kinase inhibitors, I-kappa B kinase regulators, ICAM-1 stimulators, IgG receptor FcRn large subunit p51 regulators, IL-12 receptor antagonists, IL-15 receptor agonists,IL-15 receptor modulators, IL-17 antagonists, IL-18 receptor accessory protein antagonists, IL-2 receptor agonists, IL-22 agonists, IL-23 antagonists, IL-6 receptor agonists, IL-6 receptor antagonists, IL-6 receptor modulators, IL-7 receptor antagonists, IL-8 receptor antagonists, IL-12 gene modulators, IL-8 gene modulators, immunoglobulin G modulators, immunoglobulin G1 agonists, immunoglobulin G1 modulators, immunoglobulins Agonists, Immunoglobulin gamma Fc receptor I modulators, Immunoglobulin kappa modulators, Inosine monophosphate dehydrogenase inhibitors, Insulin sensitizers, Integrin agonists, Integrin alpha-4 / beta-7 antagonists, Integrin alpha-V / beta-1 antagonists, Integrin alpha-V / beta-6 antagonists, Interferon agonists, Interferon alpha 14 ligands, Interferon alpha 2 ligands, Interferon alpha 2 ligand modulators agents, 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-1 beta ligand inhibitors, interleukin-1 beta 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 regulators, callicrein regulators, Kelch-like ECH-associated protein 1 regulators, 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, lycerin stimulators, liver X receptor antagonists, low molecular weight hepatocellular carcinoma (HEPA), Lysine, 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 agonists, metalloproteinase-12 inhibitors, METTL3 gene inhibitors, moesin inhibitors, moesin modulators, monocyte chemoattractant protein 1 ligand inhibitors, monocyte differentiation antigen CD14 inhibitors, mRNA cap guanine N7 methyltransferase modulators, mTOR complex 1 inhibitors, mTOR complex 2 inhibitors, mTOR inhibitors, mucolipin modulator inhibitors, mucarin receptor antagonists, myeloperoxidase inhibitors, NACHT LRR PYD domain protein 3 inhibitors, NAD synthase modulators, NADPH oxidase inhibitors, neuropilin 2 modulators, neuroplastin inhibitors, NFE2L2 gene stimulators, NK cell receptor agonists, NK1 receptor antagonists, NMDA receptor antagonists, NMDA receptor epsilon 2 subunit inhibitors, non-receptor tyrosine kinase TYK2 antagonists, non-nucleoside reverse transcriptase inhibitors, nuclear erythroid 2-related factor 2 stimulators, nuclear factor kappa B inhibitors, nuclear factor kappa B modulators, nuclease stimulators, nucleolin inhibitors, nucleoprotein inhibitors, nucleoside protein modulators, nucleoside reverse transcriptase inhibitors, opioid receptor agonists, opioid receptor antagonists, opioid receptor μ modulators, opioid receptor sigma antagonist 1, ornithine decarboxylase inhibitors, outer membrane protein inhibitors, OX40 ligand, p38 MAP 38 kinase alpha 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, plasma kallikrein inhibitors, plasminogen activator inhibitor-1 inhibitors , platelet inhibitors, platelet glycoprotein VI inhibitors, Polo-like kinase 1 inhibitors, poly ADP-ribose polymerase 1 inhibitors, poly ADP-ribose polymerase 2 inhibitors, polymerase cofactor VP35 inhibitors, PPAR alpha agonists, progesterone receptor agonists, programmed cell death protein 1 regulators, prolyl hydroxylase inhibitors, prostaglandin E synthase-1 inhibitors, protease inhibitors, proteasome inhibitors, protein arginine deiminase IV inhibitors, protein tyrosine kinase inhibitors , protein tyrosine phosphatase beta inhibitors, protein tyrosine phosphatase-2C inhibitors, proto-oncogene Mas agonists, purinergic receptor antagonists, Raf protein kinase inhibitors, RANTES ligands, Ras gene inhibitors, retinoate receptor response protein 2 stimulators, Rev protein modulators, ribonuclease stimulators, RIP-1 kinase inhibitors, RNA helicase inhibitors, RNA polymerase inhibitors, RNA polymerase modulators, S-phase kinase-associated protein 2 inhibitors, SARS coronavirus RUS3C protease-like inhibitors, serine protease inhibitors, serine-threonine protein kinase ATR inhibitors, serine-threonine protein TBK1 inhibitors, serum amyloid A protein modulators, signal transduction CD24 stimulators, sodium channel stimulators, sodium glucose transporter-2 inhibitors, sphingosine kinase 1 inhibitors, 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 protein stimulators, sulfatase inhibitors, superoxide dismutase modulators, superoxide dismutase stimulators, Syk tyrosine kinase inhibitors, T cell immune receptor 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 modulators, tankyrase-1 inhibitors, tankyrase-2 inhibitors, Tek tyrosine kinase receptor stimulators, telomerase modulators, tetanus toxin modulators, TGFβ receptor antagonists, TGFB2 gene inhibitors, thymosin beta 4 ligands, thyroid hormone receptor beta agonists, tissue factor inhibitors, tissue plasminogen activator modulators, tissue plasminogen activator stimulators, TLR agonists, TLR modulators, 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 antagonist, TLR-9 agonist, TMPRSS2 gene inhibitor, TNFα ligand inhibitor, TNFα ligand modulator, TNF binder, TNF gene inhibitor, topoisomerase inhibitor, transcription factor EB stimulator, transferrin modulator, transketolase inhibitor, translocation-related protein inhibitor, transmembrane serine protease 2 inhibitor, transthyretin modulator, TREM receptor 1 antagonist, TRP cation channel C1 modulator, TRP cation channel C6 inhibitor, TRP cation channel V6 inhibitor, trypsin 1 inhibitor, trypsin 2 inhibitor, trypsin 3 inhibitor, trypsin inhibitor, tubulin α inhibitor, tubulin β inhibitor, tumor necrosis factor 14 ligand inhibitor, TYK2 gene inhibitor, type I IL-1 receptor antagonist, tyrosine kinase ABL1 inhibitor,Ubiquinol cytochrome C reductase 14 kDa inhibitors, ubiquitin ligase modulators, non-specific GPCR agonists, non-specific cytokine receptor modulators, non-specific enzyme stimulators, non-specific gene inhibitors, non-specific receptor modulators, urokinase plasminogen activator inhibitors, vascular cell adhesion protein 1 agonists, vasodilators, VEGF ligand inhibitors, VEGF receptor antagonists, VEGF-1 receptor antagonists, VEGF-1 receptor modulators, VEGF-2 receptor antagonists, VEGF-3 receptor antagonists, vimentin inhibitors, vimentin modulators, VIP receptor agonists, viral envelope protein inhibitors, viral protease inhibitors, viral protease modulators, viral protein target modulators, viral ribonuclease inhibitors, viral structural protein modulators, vitamin D3 receptor agonists, X-linked inhibitors of inhibitor of apoptosis proteins, xanthine oxidase inhibitors, or zonulin inhibitors.

[0416] In some embodiments, compounds and compositions of the disclosure may be administered in combination with SARS-Cov-2 treatments such as parenteral fluids (including dextrose saline and lactated Ringer's solution), nutrition, antibiotics (including azithromycin, metronidazole, amphotericin B, amoxicillin / clavulanate, trimethoprim / sulfamethoxazole, R-327, and cephalosporin antibiotics such as ceftriaxone and cefuroxime), antifungal prophylaxis, fever and pain medications, antiemetics (such as metoclopramide) and / or antidiarrheal medications, vitamin and mineral supplements (including vitamin K, vitamin D, cholecalciferol, vitamin C, and zinc sulfate), anti-inflammatory medications (such as ibuprofen or steroids), corticosteroids such as dexamethasone, methylprednisolone, prednisone, mometasone, immunomodulatory agents (e.g., interferons), vaccines, and analgesics.

[0417] In some embodiments, the additional therapeutic agent is an Abl tyrosine kinase inhibitor (such as, for example, radotinib or imatinib).

[0418] In some embodiments, the additional therapeutic agent is an acetaldehyde dehydrogenase inhibitor, such as ADX-629.

[0419] In some embodiments, the additional therapeutic agent is an adenosine A3 receptor agonist, such as piclidenoson.

[0420] In some embodiments, the additional therapeutic agent is an adrenomedullin ligand, such as adrenomedullin.

[0421] In some embodiments, the additional therapeutic agent is a p38 MAPK+PPAR gamma agonist / insulin sensitizer, such as KIN-001.

[0422] In some embodiments, the additional therapeutic agent is a PPAR alpha agonist, such as DWTC-5101 (fenofibrate choline).

[0423] In some embodiments, the additional therapeutic agent is a cyclophilin inhibitor, such as lencofilstat.

[0424] In some embodiments, the additional therapeutic agent is a p38 MAP kinase inhibitor, such as PRX-201 or Gen-1124.

[0425] In some embodiments, the additional therapeutic agent is an aldose reductase inhibitor, such as cafficlestat.

[0426] In some embodiments, the additional therapeutic agent is an AMPA receptor modulator, such as traneurosin.

[0427] In some embodiments, the additional therapeutic agent is an annexin A5 stimulator, such as AP-01 or SY-005.

[0428] In some embodiments, the additional therapeutic agent is an apelin receptor agonist, such as CB-5064MM.

[0429] In some embodiments, the additional therapeutic agent is an anticoagulant such as heparin (heparin and low molecular weight heparin), aspirin, apixaban, dabigatran, edoxaban, argatroban, enoxaparin, or fondaparinux.

[0430] In some embodiments, the additional therapeutic agent is an androgen receptor antagonist, such as bicalutamide, enzalutamide, or purselutamide (procultamide).

[0431] In some embodiments, the additional therapeutic agent is an antihypoxic agent, such as trans-sodium crocetinate.

[0432] In some embodiments, the additional therapeutic agent is an antithrombotic agent such as defibrotide, rivaroxaban, alteplase, tirofiban, clopidogrel, prasugrel, bemiparin, bivalirudin, sulodexide, or tenecteplase.

[0433] In some embodiments, the additional therapeutic agent is an antihistamine such as chloroperastine or clemastine.

[0434] In some embodiments, the additional therapeutic agent is an apolipoprotein A1 agonist, eg, CER-001.

[0435] In some embodiments, the additional therapeutic agent is a phospholipase A2 inhibitor, such as ethyl icosapentate.

[0436] In some embodiments, the additional therapeutic agent is an axl tyrosine kinase receptor inhibitor, such as bemcentinib.

[0437] In some embodiments, the additional therapeutic agent is a corticosteroid / beta 2 adrenergic receptor agonist such as budesonide plus formoterol fumarate.

[0438] In some embodiments, the additional therapeutic agent is a BET bromodomain inhibitor / APOA1 gene stimulator, e.g., apabetalone.

[0439] In some embodiments, the additional therapeutic agent is a blood clotting modulator, such as lanadelumab.

[0440] In some embodiments, the additional therapeutic agent is a bradykinin B2 receptor antagonist, eg, icatiban.

[0441] In some embodiments, the additional therapeutic agent is an EGFR gene inhibitor / Btk tyrosine kinase inhibitor, e.g., abivertinib.

[0442] In some embodiments, the additional therapeutic agent is a Btk tyrosine kinase inhibitor (such as, for example, ibrutinib or zanubrutinib).

[0443] In some embodiments, the additional therapeutic agent is a calpain-I / II / IX inhibitor, eg, BLD-2660.

[0444] In some embodiments, the additional therapeutic agent is a cannabinoid CB2 receptor agonist, such as Onternaviz or PPP-003.

[0445] In some embodiments, the additional therapeutic agent is a Ca2+ release-activated Ca2+ channel 1 inhibitor, for example, zegoculactin (CM-4620).

[0446] In some embodiments, the additional therapeutic agent is an ATR inhibitor, such as berzosertib.

[0447] In some embodiments, the additional therapeutic agent is a cadherin-5 modulating agent, such as FX-06.

[0448] In some embodiments, the additional therapeutic agent is a casein kinase II inhibitor, such as silmitasertib.

[0449] In some embodiments, the additional therapeutic agent is a caspase inhibitor, such as emricasan.

[0450] In some embodiments, the additional therapeutic agent is a catalase / superoxide dismutase stimulator, such as MP-1032.

[0451] In some embodiments, the additional therapeutic agent is a CCR2 / CCR5 chemokine antagonist (such as, for example, cenicriviroc).

[0452] In some embodiments, the additional therapeutic agent is a CCR5 chemokine antagonist (such as, for example, maraviroc or leronlimab).

[0453] In some embodiments, the additional therapeutic agent is a CD122 agonist / IL-2 receptor agonist, eg, bempegaldeleukin.

[0454] In some embodiments, the additional therapeutic agent is a CD73 agonist / interferon beta ligand (eg, FP-1201).

[0455] In some embodiments, the additional therapeutic agent is a cholesterol ester transfer protein inhibitor, such as dalcetrapib.

[0456] In some embodiments, the additional therapeutic agent is a mannan-binding lectin serine protease / complement C1s subcomponent inhibitor / myeloperoxidase inhibitor, such as RLS-0071.

[0457] In some embodiments, the additional therapeutic agent is a complement factor C5 inhibitor / leukotriene BLT receptor antagonist, e.g., nomacopan.

[0458] In some embodiments, the additional therapeutic agent is a complement factor C5 inhibitor, eg, eculizumab, STSA-1002, zilucoplan.

[0459] In some embodiments, the additional therapeutic agent is a CXCR4 chemokine antagonist, such as plerixafor or motixafortide.

[0460] In some embodiments, the additional therapeutic agent is a cytochrome P450 3A4 inhibitor / peptidyl-prolyl cis-trans isomerase A inhibitor, such as alisporivir.

[0461] In some embodiments, the additional therapeutic agent is a cysteine ​​protease inhibitor, such as SLV-213.

[0462] In some embodiments, the additional therapeutic agent is a dihydroorotate dehydrogenase inhibitor, such as Meds-433, brequinar, RP-7214, or emvodostat.

[0463] In some embodiments, the additional therapeutic agent is a dehydropeptidase-1 modulator, eg, Metablok.

[0464] In some embodiments, the additional therapeutic agent is a dihydroorotate dehydrogenase inhibitor / IL-17 antagonist, such as bidofurzimus.

[0465] In some embodiments, the additional therapeutic agent is a diuretic, such as an aldosterone antagonist, such as spironolactone.

[0466] In some embodiments, the additional therapeutic agent is a desoxyribonuclease I stimulator, such as GNR-039 or dornase alfa.

[0467] In some embodiments, the additional therapeutic agent is a NET inhibitor, such as NTR-441.

[0468] In some embodiments, the additional therapeutic agent is a dihydroceramide delta 4 desaturase inhibitor / sphingosine kinase 2 inhibitor, e.g., opaganib.

[0469] In some embodiments, the additional therapeutic agent is a DNA methyltransferase inhibitor, for example, azacytidine.

[0470] In some embodiments, the additional therapeutic agent is an LXR antagonist (such as, for example, larscosterol).

[0471] In some embodiments, the additional therapeutic agent is a dipeptidyl peptidase I inhibitor, such as brenosertib.

[0472] In some embodiments, the additional therapeutic agent is a protein arginine deiminase IV inhibitor, such as JBI-1044.

[0473] In some embodiments, the additional therapeutic agent is an elongation factor 1 alpha 2 modulator, eg, plitidepsin.

[0474] In some embodiments, the additional therapeutic agent is a eukaryotic initiation factor 4A-I inhibitor, such as zotatifine.

[0475] In some embodiments, the additional therapeutic agent is an exo-alpha sialidase modulator, such as DAS-181.

[0476] In some embodiments, the additional therapeutic agent is an expotin 1 inhibitor, such as selinexor.

[0477] In some embodiments, the additional therapeutic agent is a fractalkine ligand inhibitor, such as KAND-567.

[0478] In some embodiments, the additional therapeutic agent is a FYVE finger phosphoinositide kinase inhibitor / IL-12 receptor antagonist / IL-23 antagonist, e.g., apilimod dimesylate.

[0479] In some embodiments, the additional therapeutic agent is a GABA A receptor modulator, such as brexanolone.

[0480] In some embodiments, the additional therapeutic agent is a glucocorticoid receptor agonist, eg, ciclesonide, hydrocortisone, dexamethasone, dexamethasone phosphate, or 101-PGC-005.

[0481] In some embodiments, the additional therapeutic agent is a GM-CSF receptor agonist, such as sargramostim.

[0482] In some embodiments, the additional therapeutic agent is a GPCR agonist, such as esveraprost sodium.

[0483] In some embodiments, the additional therapeutic agent is a Griffithin modulator, eg, Q-Griffithin.

[0484] In some embodiments, the additional therapeutic agent is a leukotriene D4 antagonist, such as montelukast.

[0485] In some embodiments, the additional therapeutic agent is a histamine H1 receptor antagonist, such as ebastine, tranilast, or levocetirizine dihydrochloride.

[0486] In some embodiments, the additional therapeutic agent is a histamine H2 receptor antagonist, such as famotidine.

[0487] In some embodiments, the additional therapeutic agent is a heat shock protein stimulator such as BGP-15 / insulin sensitizer / PARP inhibitor.

[0488] In some embodiments, the additional therapeutic agent is a histone inhibitor, such as STC-3141.

[0489] In some embodiments, the additional therapeutic agent is a histone deacetylase-6 inhibitor, eg, CKD-506.

[0490] In some embodiments, the additional therapeutic agent is a HIF prolyl hydroxylase-2 inhibitor, eg, desidustat.

[0491] In some embodiments, the additional therapeutic agent is a HIF prolyl hydroxylase inhibitor (such as, for example, vadadustat).

[0492] In some embodiments, the additional therapeutic agent is an IL-8 receptor antagonist (such as, for example, reparixin).

[0493] In some embodiments, the additional therapeutic agent is an IL-7 receptor agonist, such as CYT-107.

[0494] In some embodiments, the additional therapeutic agent is an IL-7 receptor agonist / interleukin-7 ligand, eg, efyneptakine alfa.

[0495] In some embodiments, the additional therapeutic agent is an IL-22 agonist, such as efmarodocoquin alfa.

[0496] In some embodiments, the additional therapeutic agent is an IL-22 agonist / interleukin 22 ligand, such as F-652.

[0497] In some embodiments, the additional therapeutic agent targets IL-33 (such as, for example, tozorakimab).

[0498] In some embodiments, the additional therapeutic agent is an IL-15 agonist, such as nogapenkin alfa.

[0499] In some embodiments, the additional therapeutic agent is an integrin alpha-V / beta-1 antagonist / integrin alpha-V / beta-6 antagonist, such as bexotegrast.

[0500] In some embodiments, the additional therapeutic agent is an interferon alpha-2 ligand, eg, interferon alpha-2b or virafm.

[0501] 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.

[0502] In some embodiments, the additional therapeutic agent is an interferon receptor modulator, such as pegylated interferon lambda-1a.

[0503] In some embodiments, the additional therapeutic agent is an interleukin-2 ligand, eg, aldesleukin.

[0504] In some embodiments, the additional therapeutic agent is an IRAK-4 protein kinase inhibitor, eg, dimlobicertib.

[0505] In some embodiments, the additional therapeutic agent is a JAK inhibitor, for example, the additional therapeutic agent is baricitinib, filgotinib, jactinib, tofacitinib, or nedulcitinib (TD-0903).

[0506] In some embodiments, the additional therapeutic agent is a neutrophil elastase inhibitor, eg, alberestat.

[0507] In some embodiments, the additional therapeutic agent is a pulmonary surfactant-associated protein D modulator, eg, AT-100.

[0508] In some embodiments, the additional therapeutic agent is a plasma kallikrein inhibitor, e.g., donidalorsen.

[0509] In some embodiments, the additional therapeutic agent is a lysine-specific histone demethylase 1 / MAO B inhibitor, such as bafidemstat.

[0510] In some embodiments, the additional therapeutic agent is a mannan-binding lectin serine protease inhibitor, e.g., conestat alfa.

[0511] In some embodiments, the additional therapeutic agent is a maximum K potassium channel inhibitor, such as ENA-001.

[0512] In some embodiments, the additional therapeutic agent is a MEK protein kinase inhibitor (such as, for example, zapnometinib).

[0513] In some embodiments, the additional therapeutic agent is a MEK-1 protein kinase inhibitor / Ras gene inhibitor, eg, antroquinonol.

[0514] In some embodiments, the additional therapeutic agent is a melanocortin MC1 receptor agonist, eg, PL-8177.

[0515] In some embodiments, the additional therapeutic agent is a melanocortin MC1 / MC3 receptor agonist, such as resomeragon acetate.

[0516] In some embodiments, the additional therapeutic agent is a matrix metalloproteinase-12 inhibitor, eg, FP-025.

[0517] In some embodiments, the additional therapeutic agent is a NACHT LRR PYD domain protein 3 inhibitor, such as dapanstril, DFV-890, or ZYIL-1.

[0518] In some embodiments, the additional therapeutic agent is an NADPH oxidase inhibitor, for example, isquinaxib.

[0519] In some embodiments, the additional therapeutic agent is a neuropilin 2 modulator, such as efzofitimod.

[0520] In some embodiments, the additional therapeutic agent is an NK1 receptor antagonist, such as aprepitant or tradipitant.

[0521] In some embodiments, the additional therapeutic agent is an NMDA receptor antagonist, such as translocetin or ifenprodil.

[0522] In some embodiments, the additional therapeutic agent is a nuclear factor kappa B inhibitor / p38 MAP kinase inhibitor (such as, for example, Zenuzolac).

[0523] In some embodiments, the additional therapeutic agent is an ornithine decarboxylase inhibitor, such as eflornithine.

[0524] In some embodiments, the additional therapeutic agent is an opioid receptor sigma antagonist 1, such as MR-309.

[0525] In some embodiments, the additional therapeutic agent is a PGD2 antagonist, e.g., asapiprant.

[0526] In some embodiments, the additional therapeutic agent is a PDGF receptor antagonist / TGFβ receptor antagonist / p38 MAP kinase inhibitor (such as, for example, deupirfenidone).

[0527] In some embodiments, the additional therapeutic agent is a phospholipase A2 inhibitor, such as varespladib methyl.

[0528] In some embodiments, the additional therapeutic agent is a phosphoinositide 3-kinase inhibitor / mTOR complex inhibitor, such as ductolisib.

[0529] In some embodiments, the additional therapeutic agent is an mTOR inhibitor, such as sirolimus.

[0530] In some embodiments, the additional therapeutic agent is a phosphoinositide-3 kinase delta / gamma inhibitor (such as, for example, duvelisib).

[0531] In some embodiments, the additional therapeutic agent is a plasminogen activator inhibitor-1 inhibitor, such as TM-5614.

[0532] In some embodiments, the additional therapeutic agent is a protein tyrosine phosphatase beta inhibitor, e.g., razuprotafib.

[0533] In some embodiments, the additional therapeutic agent is a RIP-1 kinase inhibitor (such as, for example, DNL-758 or SIR-0365).

[0534] In some embodiments, the additional therapeutic agent is a Rev protein modulator, such as obefagimod.

[0535] In some embodiments, the additional therapeutic agent is an S-phase kinase-associated protein 2 inhibitor (such as, for example, niclosamide, SCAI-502, or DWRX-2003).

[0536] In some embodiments, the additional therapeutic agent is a signal transducer CD24 stimulator, such as EXO-CD24.

[0537] In some embodiments, the additional therapeutic agent is a sodium glucose transporter-2 inhibitor, such as dapagliflozin propanediol.

[0538] In some embodiments, the additional therapeutic agent is a calcium channel stimulator, such as solnatide.

[0539] In some embodiments, the additional therapeutic agent is a sphingosine-1-phosphate receptor-1 agonist / sphingosine-1-phosphate receptor-5 agonist, such as ozanimod.

[0540] In some embodiments, the additional therapeutic agent is a nonsteroidal anti-inflammatory drug, such as Ampion.

[0541] In some embodiments, the additional therapeutic agent is a superoxide dismutase stimulator, such as avasopasem manganese.

[0542] In some embodiments, the additional therapeutic agent is a Syk tyrosine kinase inhibitor, such as fostamacitinib sodium hydrate.

[0543] In some embodiments, the additional therapeutic agent is a Tie2 tyrosine kinase receptor agonist, such as AV-001.

[0544] In some embodiments, the additional therapeutic agent is a TGFB2 gene inhibitor, e.g., travedersen.

[0545] In some embodiments, the additional therapeutic agent is a tissue factor inhibitor, such as AB-201.

[0546] In some embodiments, the additional therapeutic agent is a TLR-3 agonist, such as lintatolimod.

[0547] In some embodiments, the additional therapeutic agent is a TLR-4 antagonist, such as ApTLR-4FT, EB-05, or erythrolan.

[0548] In some embodiments, the additional therapeutic agent is a TLR-7 / 8 antagonist (such as, for example, empatran).

[0549] In some embodiments, the additional therapeutic agent is a TLR-2 / 6 agonist, such as INNA-051.

[0550] In some embodiments, the additional therapeutic agent is a TLR-7 agonist, such as PRTX-007 or APR-002.

[0551] In some embodiments, the additional therapeutic agent is a TLR agonist such as, for example, PUL-042.

[0552] In some embodiments, the additional therapeutic agent is a TLR-4 agonist, such as REVTx-99.

[0553] In some embodiments, the additional therapeutic agent is a TLR-2 / 4 antagonist, such as VB-201.

[0554] In some embodiments, the additional therapeutic agent is a TNFα ligand inhibitor, such as pezipanelmin.

[0555] In some embodiments, the additional therapeutic agent is a type I IL-1 receptor antagonist, such as anakinra.

[0556] In some embodiments, the additional therapeutic agent is a TREM receptor 1 antagonist, eg, nangibotide.

[0557] In some embodiments, the additional therapeutic agent is a trypsin inhibitor, such as urinastatin.

[0558] In some embodiments, the additional therapeutic agent is a tubulin inhibitor such as sabizabrin, CCI-001, PCNT-13, CR-42-24, albendazole, entasobrin, SAR-132885, or ON-24160.

[0559] In some embodiments, the additional therapeutic agent is a VIP receptor agonist, such as aviptadil.

[0560] In some embodiments, the additional therapeutic agent is a xanthine oxidase inhibitor, such as oxypurinol.

[0561] In some embodiments, the additional therapeutic agent is a vasodilator, e.g., iloprost, epoprostenol (VentaProst), zavegepant, TXA-127, USB-002, ambrisentan, nitric oxide nasal spray (NORS), pentoxifylline, propranolol, RESP301, sodium nitrite, or dipyridamole.

[0562] In some embodiments, the additional therapeutic agent is a vitamin D3 receptor agonist, such as cholecalciferol.

[0563] In some embodiments, the additional therapeutic agent is a zonulin inhibitor, such as larazotide acetate.

[0564] In some embodiments, the additional therapeutic agent is a synthetic retinoid derivative, such as fenretinide.

[0565] In some embodiments, the additional therapeutic agent is a glucose metabolism inhibitor (such as, for example, WP-1122 or WP-1096).

[0566] 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, vitepiramicin, bucillamine, budesonide, CNM-AgZn-17, codevir, CT-38, danicopan, didodecylmethotrexate, DW -2008S (DW-2008), EDP-1815, EG-009A, Fabencov, Gamunex, Genistein, GLS-1200, hzVSF-v13, Imidazolyl ethanamidopentanedioic acid, IMM-101, MAS-825, MRG-001, Nasitrol, Nylexa, Orbelemtinib, OP-101, OPN-019, Orynotide rhesus theta defensin-1, pyronaridine plus artesunate, dapsone, RPH-104, sodium pyruvate, sulfoladex, tafenoquine, TB-006, telasevec, Tempol, TL-895, thimesol, trimodulin, XC-221, XC-7, duncemtinib, metformin glicinate, lucinactant, EOM-613, mosdipimode, ivermectin, leflunomide, ibudilast, RBT-9, raloxifene, prothion, gemcabene, or idronoxyl.

[0567] In some embodiments, the additional therapeutic agent is a CD73 antagonist, such as AK-119.

[0568] In some embodiments, the additional therapeutic agent is a CD95 protein fusion, such as asnercept.

[0569] In some embodiments, the additional therapeutic agent is a complement factor C2 modulator, eg, ARGX-117.

[0570] In some embodiments, the additional therapeutic agent is a complement C3 inhibitor, such as AMY-101 or NGM-621.

[0571] In some embodiments, the additional therapeutic agent is a CXC10 chemokine ligand inhibitor (such as, for example, EB-06).

[0572] In some embodiments, the additional therapeutic agent is a cytotoxic T-lymphocyte protein-4 fusion protein, such as abatacept.

[0573] In some embodiments, the additional therapeutic agent is an anti- S. aureus antibody (e.g., tosatocumab, etc.).

[0574] In some embodiments, the additional therapeutic agent is an anti-LPS antibody, such as IMM-124-E.

[0575] In some embodiments, the additional therapeutic agent is an adrenomedullin ligand inhibitor (such as, for example, enivalcimab).

[0576] In some embodiments, the additional therapeutic agent is a basigin inhibitor, such as meplasmab.

[0577] In some embodiments, the additional therapeutic agent is a CD3 antagonist, such as foralaumab.

[0578] In some embodiments, the additional therapeutic agent is a connective tissue growth factor ligand inhibitor (e.g., PRS-220, pamrevlumab, etc.).

[0579] In some embodiments, the additional therapeutic agent is a complement factor C5a inhibitor, such as BDB-1 or vilobelimab.

[0580] In some embodiments, the additional therapeutic agent is a complement factor C5 inhibitor, e.g., ravulizumab.

[0581] In some embodiments, the additional therapeutic agent is a mannan-binding lectin serine protease-2 inhibitor (such as, for example, narsoplimab).

[0582] In some embodiments, the additional therapeutic agent is a GM-CSF modulator such as STSA-1005, gimcilumab, namilumab, prommallimab, otilimab, or lenzilumab.

[0583] In some embodiments, the additional therapeutic agent is a heat shock protein inhibitor / IL-6 receptor antagonist (such as, for example, siltuximab).

[0584] In some embodiments, the additional therapeutic agent is an IL-6 receptor antagonist, such as clazakizumab, revilimab, olokizumab, tocilizumab, or sirukumab.

[0585] In some embodiments, the additional therapeutic agent is an IL-8 receptor antagonist (such as, for example, BMS-986253).

[0586] In some embodiments, the additional therapeutic agent is an interleukin-1 beta ligand inhibitor, such as canakinumab.

[0587] In some embodiments, the additional therapeutic agent is an interferon gamma ligand inhibitor, such as emapalumab.

[0588] In some embodiments, the additional therapeutic agent is an anti-ILT7 antibody, such as daxzilimab.

[0589] In some embodiments, the additional therapeutic agent is a monocyte differentiation antigen CD14 inhibitor, such as atibuclimab.

[0590] In some embodiments, the additional therapeutic agent is a plasma kallikrein inhibitor, such as lanadelumab.

[0591] In some embodiments, the additional therapeutic agent is a platelet glycoprotein VI inhibitor (such as, for example, glenzocimab).

[0592] In some embodiments, the additional therapeutic agent is a T-cell differentiation antigen CD6 inhibitor, such as itolizumab.

[0593] In some embodiments, the additional therapeutic agent is a TNFα ligand inhibitor / TNF binder (such as, for example, infliximab).

[0594] In some embodiments, the additional therapeutic agent is an anti-LIGHT antibody, such as AVTX-002.

[0595] In some embodiments, the additional therapeutic agent is IMC-2 (valacyclovir plus celecoxib) or AXA-1125.

[0596] In some embodiments, the additional therapeutic agent is COVID-HIG.

[0597] In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with one or more agents useful in the treatment and / or prevention of COVID-19.

[0598] Non-limiting examples of such agents include corticosteroids, such as dexamethasone, hydrocortisone, methylprednisolone, or prednisone; interleukin-6 (IL-6) receptor blockers, such as tocilizumab or sarilumab; Janus kinase (JAK) inhibitors, such as baricitinib, ruxolitinib, or tofacitinib; and antiviral agents, such as molnupiravir, sotrovimab, or remdesivir.

[0599] In further embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with two or more agents useful in the treatment of COVID-19, including, but not limited to, a compound of the present disclosure and two additional therapeutic agents, such as nilmatrervir and ritonavir, casirivimab and imdevimab, or ruxolitinib and tofacitinib.

[0600] In some embodiments, the additional therapeutic agent comprises an antiviral agent. In some embodiments, the antiviral agent is an entry inhibitor. In some embodiments, the antiviral agent is a protease inhibitor. In some embodiments, the antiviral agent is an RNA polymerase inhibitor. In some embodiments, the additional therapeutic agent is an RNA-dependent RNA polymerase (RdRp) inhibitor.

[0601] In some embodiments, the antiviral agent is an angiotensin converting enzyme 2 inhibitor, an angiotensin converting enzyme 2 modulator, an angiotensin converting enzyme 2 stimulator, an angiotensin II AT-2 receptor agonist, an angiotensin II AT-2 receptor antagonist, an angiotensin II receptor modulator, a coronavirus nucleoprotein modulator, a coronavirus small envelope protein modulator, a coronavirus spike glycoprotein inhibitor, a coronavirus spike glycoprotein modulator, a SARS-CoV-2 envelope small membrane protein inhibitor, a SARS-CoV-2 envelope small membrane protein modulator, a 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-2ase 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 glycoprotein spike inhibitors, SARS-CoV-2 spike glycoprotein modulators, SARS-CoV-2 structural glycoprotein modulators, papain inhibitors, protease inhibitors, protease inhibitors, RNA polymerase inhibitors, RNA polymerase modulators, RNA-dependent RNA polymerase (RdRp) inhibitors, SARS-CoV-2 coronavirus 3C protease-like inhibitors, SARS-CoV-2 The inhibitor is selected from an nsp14 methyltransferase enzyme inhibitor, a 3CLpro / Mpro inhibitor, a serine protease inhibitor, a transmembrane serine protease 2 inhibitor, a transmembrane serine protease 2 modulator, a viral envelope protein inhibitor, a viral protease inhibitor, a viral protease modulator, a viral protein target modulator, a viral ribonuclease inhibitor, and a viral structural protein modulator.

[0602] In some embodiments, the additional therapeutic agent is an entry inhibitor, e.g., in some embodiments, the additional therapeutic agent is an ACE2 inhibitor, a fusion inhibitor, or a protease inhibitor.

[0603] In some embodiments, the additional therapeutic agent is an angiotensin-converting enzyme 2 inhibitor, eg, SBK-001.

[0604] In some embodiments, the additional therapeutic agent is an angiotensin-converting enzyme 2 modulator, such as Numifil or JN-2019.

[0605] In some embodiments, the additional therapeutic agent is an entry inhibitor, such as MU-UNMC-1.

[0606] In some embodiments, the additional therapeutic agent is an angiotensin-converting enzyme 2 stimulator, such as alnasidase alfa.

[0607] In some embodiments, the additional therapeutic agent is an angiotensin II AT-2 receptor agonist, eg, VP-01.

[0608] In some embodiments, the additional therapeutic agent is an ACE II receptor antagonist, eg, DX-600.

[0609] In some embodiments, the additional therapeutic agent is an angiotensin II receptor modulator, such as TXA-127.

[0610] In some embodiments, the additional therapeutic agent is a transmembrane serine protease 2 modulator, eg, BC-201.

[0611] In some embodiments, the additional therapeutic agent is a viral envelope protein inhibitor, such as MXB-9 or MXB-004.

[0612] In some embodiments, the additional therapeutic agent is an RNAi agent, such as ARO-COV or SNS-812.

[0613] 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.

[0614] In some embodiments, the additional therapeutic agent is selected from the group consisting of Tojinameran, NVX-CoV2373, Elasomeran, KD-414, Ad26.COV2-S, Bakhiszebria, 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-127 3.351+mRNA-1273.617 (SARS-CoV-2 multivalent mRNA vaccine, COVID-19), Ad5-nCoV, Omicron-based COVID-19 vaccine (mRNA vaccine, COVID-19), mRNA-1073, mRNA-1273.214, mRNA-1230, mRNA-1283, Omicron-based COVID-19 vaccine, SARS-CoV-2 subunit recombinant, recombinant vaccine, etc., Sputnik M, ZyCoV-D, COVID-19 XWG-03, mRNA-1273.529, mRNA-1010, CoronaVac, AZD-2816, Sputnik V, Inactivated SARS-CoV-2 Vaccine (Verocell, COVID-19), DS-5670, PHH-1V, INO-4800, UB-612, Coronavirus Vaccine (Whole Virion, Inactivated / Purified), ReCOV, MT-2766, ARCT-154, SP-0253, CORBEVAX, mRNA-1273.211, ZF-2001, Sputnik Light, Recombinant Protein Vaccine (COVID-19 / SARS-CoV-2 Infection), VSV Vectored 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, RAZI Cov 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.

[0615] 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 (3CL (also called main protease, M)), a papain-like protease inhibitor (PL), a serine protease inhibitor, or a transmembrane serine protease 2 inhibitor (TMPRSS2).

[0616] In some embodiments, the additional therapeutic agent is a 3CLpro / Mpro inhibitor such as CDI-873, GC-373, GC-376, PBI-0451, UCI-1, voftrervir (FB-2001, DC-402234), DC-402267, GDI-4405, RAY-1216, MPI-8, SH-879, SH-580, EDP-235, VV-993, CDI-988, MI-30, nilmatrervir, ensitrervir, ASC-11, EDDC-2214, SIM-0417, CDI-45205, COR-803, ALG-097111, TJC-642, CVD-0013943, eravacycline, cynarin, or prexasertib.

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

[0618] In some embodiments, the additional therapeutic agent is a SARS-CoV-2 helicase Nsp13 inhibitor, such as EIS-4363.

[0619] In some embodiments, the additional therapeutic agent is a SARS-CoV-2 helicase Nsp14 inhibitor, such as TO-507.

[0620] In some embodiments, the additional therapeutic agent is a SARS-CoV-2 spike (S) and a protease modulator, e.g., ENU-200.

[0621] In some embodiments, the additional therapeutic agent is a protease inhibitor, such as ALG-097558 or MRX-18.

[0622] In some embodiments, the additional therapeutic agent is a serine protease inhibitor, for example, upamostat, nafamostat, camostat mesylate, nafamostat mesylate, or camstat.

[0623] In some embodiments, the additional therapeutic agent is a 3CLpro / transmembrane serine protease 2 inhibitor, e.g., SNB-01 (pentalandil) or SNB-02.

[0624] In some embodiments, the additional therapeutic agent is a Pan-Corona, Cov-X, or a viral protease inhibitor such as bepridil.

[0625] In some embodiments, the additional therapeutic agent is an RNA polymerase inhibitor, e.g., in some embodiments, the additional therapeutic agent is an RNA polymerase inhibitor or an RNA-dependent RNA polymerase (RdRp) inhibitor.

[0626] In some embodiments, the additional therapeutic agent is an RNA-dependent RNA polymerase (RdRp) inhibitor, such as remdesivir, NV-CoV-2-R, NV-CoV-1 encapsulated remdesivir, GS-621763, GS-5245, GS-441524, DEP remdesivir, ATV-006, VV-116, LGN-20, CMX-521, and compounds disclosed in WO2022142477, WO2021213288, and WO2022047065.

[0627] In some embodiments, the additional therapeutic agent is an RNA polymerase inhibitor, such as molnupiravir (EIDD-2801), favipiravir, bemnifosbuvir, sofosbuvir, ASC-10, or galdisivir.

[0628] In some embodiments, the additional therapeutic agent is a viral entry inhibitor, such as brilacidin.

[0629] In some embodiments, the additional therapeutic agent is an antibody that binds to a coronavirus, e.g., an antibody that binds to SARS or MERS.

[0630] In some embodiments, the additional therapeutic agent is an antibody, e.g., a monoclonal antibody. For example, the additional therapeutic agent is an antibody against 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).

[0631] 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).

[0632] In some embodiments, the additional therapeutic agent is a SARS-CoV-2 virus antibody.

[0633] In some embodiments, the antibody is ABBV-47D11, COVI-GUARD (STI-1499), C144-LS+C135-LS, DXP-604, JMB-2002, LY-CovMab, bamlanivimab (LY-CoV555), GIGA-2050, IBI-314, S309, SAB-185, etesevimab (CB6), COR-101, JS016, VNAR, VIR-7832 and / or sotrovimab (VIR-7831), casirivimab+imdevimab (REGN-COV2 or REGN 10933+RGN 10987), BAT2020, BAT2019, 47D11, YBSW-015, or PA-001.

[0634] In some embodiments, the additional therapeutic agent is STI-9199 (COVI-SHIELD), STI-9167, or AR-701 (AR-703 and AR-720).

[0635] In some embodiments, the additional therapeutic agent is BRII-196, BRII-198, ADG-10, azintrevimab (ADG-20), ABP-300, BA-7208, BI-767551, BHV-1200, CT-P63, JS-026, sotrovimab (GSK-4182136), tixagevimab + silgavimab (AZD-7442), regdanvimab, SAB-301, AOD-01, putavimab (COVI-AMG), 9MW-3311 (MW-33), DXP-593, BSVEQAb, anti-SARS-CoV-2 IgY, COVID-EIG, CSL-760, F-61, REGN-3048-3051, SARS-CoV-2 monoclonal antibody (COVID-19, ADM-03820), enobuzimab (HFB-30132A), INM-005, SCTA01, TY-027, XAV-19, amvalvimab + romursevimab, SCTA-01, bebuterovimab, veldavimab, IBI-O123, and IGM-6268. FYB-207, FS-2101, RBT-0813, REGN-14256, REGN-14284, SPKM-001, XVR-011, TB202-3, TB181-36, TB339 -031, LMN-301, LQ-050, COVAB-36, MAD-0004J08, STI-2099, TATX-03, TZLS-501, ZCB-11 or ACV-200-17.

[0636] 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).

[0637] In some embodiments, the additional therapeutic agent is an ACE2-Fc receptor fusion protein, such as HLX-71.

[0638] In some embodiments, the additional therapeutic agent is ensobibep.

[0639] In some embodiments, the additional therapeutic agent is SYZJ-001.

[0640] In some embodiments, the additional therapeutic agent is an HIV-1 protease inhibitor, such as ASC-09F (ASC-09 plus ritonavir) or lopinavir plus ritonavir.

[0641] In some embodiments, the additional therapeutic agent is a non-nucleoside reverse transcriptase inhibitor, such as elsulfavirine.

[0642] In some embodiments, the additional therapeutic agent is a nucleoside reverse transcriptase inhibitor, such as azuvudine.

[0643] In some embodiments, the additional therapeutic agent is Abbv-990, BAT-2022, NED-260, ALG-097431, bardoxolone, delcetravir, ESFAM-289, ENOB-CV-01, ENOB-CV-11, EIS-10700, Beta-521, SIM-0417, molnupiravir, Pan-Corona, Tolovir, nilmatorivir plus ritonavir (Paxlovid®), favipiravir, GC-376, upamostat, Lesolair-01, Lesolair-02 +, benfovir, VV-116, VV-993, SNB-01, EDP-235, CovX, ensitrevir, MPI-8, mastinib, ALG-097558, ASC-11, PBI-0451, nafamostat, nafamostat mesylate, CDI-45205, 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, DEPRemdesivir, GS-621763, GS-5245, GLS-5310, bemnifosbuvir, QLS-1128, ASC-10, SBFM-PL4, camstat 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, eravacycline, GRL-0617, camostat, GC-373, nitazoxanide, cynarin, prexasertib, RAY-1216, SACT-COVID-19, MP-18, EIDD-1931, EDDC-2214, nitric oxide, apabetalone, AnQlar, SB K-001, LQ-050, CG-SpikeDown, bamlanivimab, HLX-71, HT-002, HY-209, HY-3000, FYB-207, ensovibep, SYZJ-001, EU-129, Numifil, JN-2019, AR-701, Bostecil, PLM-402, PJS-539, CTB-ACE2, TB181-36, TB202-3, ABP-300, XVR-011, MSP-008-22, MU-UNMC-1, MU-UNMC-2, alnasidase alfa, VP-01, TRV-027, DX-600, TXA-127, NVX-CoV2515, riamirovir, tosinameran, elasomeran, Ad5-nCoV, BBIBP-CorV, CoronaVac, MVC-COV1901, NVX-CoV2373, sotrovimab, Sputnik V, TEE-001, Tyme-19, bakiszebria, ZF-2001, or ZyCoV-D. X. Working Example General synthesis: Scheme 1 [ka]

[0644] Scheme 1 shows a general synthesis of compounds of the invention starting from the reaction of S1a with nucleoside S1b under basic conditions (e.g., 4-dimethylaminopyridine (DMAP)) to give S1c. LG represents a leaving group. Examples of leaving groups include, but are not limited to, chloride, bromide, mesylate, tosylate, triflate, 4-nitrobenzenesulfonate, 4-chlorobenzenesulfonate, 4-nitrophenoxy, and pentafluorophenoxy. This reaction is followed by acetonide cleavage under acidic conditions (e.g., HCl) to give final compounds of the invention of type S1d. Scheme 2 [ka]

[0645] Scheme 2 shows a general synthesis of compounds of the present invention, starting from the reaction of nucleoside S1b with 1,1'-carbonyldiimidazole (CDI) to generate intermediate S2a. Displacement of the imidazole with alcohol S2b under basic conditions (e.g., 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)) generates penultimate intermediate S1c. The acetonide is then cleaved under acidic conditions (e.g., HCl) to give final compounds of the present invention of type S1d. Scheme 3 [ka]

[0646] Scheme 3 shows a general synthesis of compounds of the invention, starting with the addition of a protecting group (e.g., dimethylformamidine) on N6 of nucleoside S1b to give S3a. Reaction of S3a with S1a under basic conditions (e.g., pyridine) generates intermediate S3b, which is subsequently subjected to acidic conditions (e.g., HCl) to give final compounds of the invention of type S1d. Scheme 4 [ka]

[0647] Scheme 4 shows the general synthesis of compounds of the invention starting from the reaction of S1d with CDI or diphenyl carbonate to give final compounds of the invention of type S4a. Scheme 5 [ka]

[0648] Scheme 5 shows a general synthesis of compounds of the invention starting from acetonide deprotection of S1b to give nucleoside S5a. Reaction of S5a with anhydride S5b under basic conditions (e.g., DBU) gives final compounds of the invention of type S1d. Scheme 6a [ka]

[0649] Scheme 6a shows the general synthesis of compounds of the invention starting from S1d. Reaction of S1d with a dicarbonate in the presence of DMAP in tetrahydrofuran (THF) gives final compounds of the invention of type S6a-1 and S6a-2. Scheme 7 [ka]

[0650] Scheme 7 describes a general synthesis of compounds of the present invention starting from S1d. Reaction of compound S1d with a chloromethyl disubstituted phosphate in the presence of sodium iodide in a solvent (e.g., acetone) gives intermediate S7a. PG is a protecting group. Examples of protecting groups include, but are not limited to, trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, trityl, alkyl groups, and acyl groups such as acetyl and propionyl, methanesulfonyl, and p-toluenesulfonyl. Removal of the protecting group is achieved by either hydrogenation or treatment with acid, which provides compounds of the present invention of type S7b. Scheme 8 [ka]

[0651] Scheme 8 describes a general synthesis of N6-carbamates of the invention, such as S8b, starting from S1c. Reaction of S1c with an acid chloride (such as pyridine) under basic conditions generates intermediate S8a, which is subsequently subjected to acidic conditions (e.g., HCl) to afford compounds of the invention of type S8b. Scheme 9 [ka]

[0652] Scheme 9 describes the general synthesis of N6-amide analogs of the invention, such as S9b, starting from S1c. S1c and an acid chloride under basic conditions (e.g., pyridine) [ka] Reaction with affords intermediate S9a, which is subsequently subjected to acidic conditions (eg, HCl) to afford compounds of the invention of type S9b.

[0653] Compounds of the present invention, such as S9b, can also be obtained by the reaction of S1c with the corresponding acid. S1c and the acid in the presence of 1-[4,5-b]-1H-1,2,3-triazolopyridinium 3-oxide hexafluorophosphate (HATU) or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) can be obtained by the reaction of S1c with the corresponding acid. [ka] produces intermediate S9a, which is subsequently subjected to acidic conditions (eg, HCl) to give compounds of the invention of type S9b. Scheme 10 [ka]

[0654] Scheme 10 shows the general synthesis of compounds of the invention starting from the reaction of diacid S10a with 1,1'-carbonyldiimidazole to give reagent S10b. Final compounds of the invention of type S10c can further be obtained by reaction between S10b and nucleosides S1d. Scheme 11 [ka]

[0655] Scheme 11 shows a general synthesis of compounds of the invention starting from the acylation of alcohol S11a with 1,1'-carbonyldiimidazole (CDI) to give reagent S11b. Reaction between S11b and S1b with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) produces intermediate S1c. Reaction between S1c and S11c using pyridine as base followed by acidic treatment (e.g., HCl) gives final compounds of the invention of type S11d. Scheme 12 [ka]

[0656] Scheme 12 shows a general synthesis of the acetalization of alcohol S1d with propionaldehyde under acidic conditions (eg PTSA) to give final compounds of the invention of type S12a. Scheme 13 [ka]

[0657] Scheme 13 shows a general synthesis of the esterification of alcohol S1d with acid S13a using a carbodiimide reactant (e.g., N,N'-diisopropylcarbodiimide (DIC)) and 4-dimethylaminopyridine (DMAP) to give final compounds of the invention of type S13b. Scheme 14 [ka]

[0658] Scheme 14 shows the general synthesis of compounds of the invention starting from the protecting group manipulation on the free amine of nucleoside S1d to give S14a. Reaction of S14a with chloroformate S14b under basic conditions (e.g., pyridine) followed by acidic treatment (e.g., HCl) gives final compounds of the invention of type S14c. Synthesis of intermediates Ia and Ib: [ka]

[0659] To a solution of (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile, intermediate I (1000 mg, 3.0 mmol) (Siegel et al. J. Med. Chem. 2017, 60, 1648-1661) in DMF (5 mL) was added diisopropylethylamine (780 mg, 6 mmol) followed by 4-dimethylaminopyridine (369 mg, 3 mmol). To the above solution at room temperature, isobutyl chloroformate (495 mg, 3.6 mmol) was added and stirred for 1 h. LC-MS indicated the formation of two products, the 5'-carbonate and the 5'-carbonate, along with the N-carbamate. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water, brine, dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography using dichloromethane and methanol as eluents to separate two products. Intermediate Ia: ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl isobutyl carbonate. LCMS: MS m / z: 432.1 (M+1). Intermediate Ib: isobutyl (7-((3aR,4R,6R,6aR)-4-cyano-6-(((isobutoxycarbonyl)oxy)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)carbamate. LCMS: MS m / z: 532.2 (M+1) Synthesis of intermediate II: [ka]

[0660] To a solution of (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile, intermediate I (3000 mg, 9.0 mmol) (Siegel et al. J. Med. Chem. 2017, 60, 1648-1661) in toluene (20 mL) was added N,N-dimethylformamide dimethyl acetal (2158 mg, 18 mmol), and the resulting mixture was stirred for 50 minutes. ℃ The mixture was heated at rt for 1 hour. After completion of the reaction, the solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate (100 mL). The solvent was washed with water (10 mL) and brine (10 mL), dried over sodium sulfate, and concentrated to give intermediate N'-[7-[(3aR,4R,6R,6aR)-4-cyano-6-(hydroxymethyl)-2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,1-f][1,2,4]triazin-4-yl]-N,N-dimethyl-formamidine, intermediate II. LCMS: MS m / z: 387.2 Example 1: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl isobutyl carbonate (Compound 1) [ka]

[0661] ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl isobutyl carbonate: To a solution of intermediate Ia (1300 mg, 3 mmol) in acetonitrile (10 mL), concentrated HCl (1.3 mL, 15 mmol) was added and stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (50 mL) and neutralized with saturated sodium bicarbonate. The organic layer was separated, washed with water, brine, dried, and concentrated. The residue was purified by flash chromatography using dichloromethane and methanol as eluents to give the title compound 1. 1 H NMR(400MHz,DMSO-d6)δ7.92(s,2H),6.90(d,J=4.6Hz,1H),6.79(d,J=4.5Hz,1H),6.32(d,J=6.0Hz,1H),5.40(d,J=5.8Hz,1H),4.67(dd,J=6.1, 4.9Hz,1H),4.46-4.36(m,1H),4.28-4.17(m,2H),3.98-3.90(m,1H),3. 87(d,J=6.5Hz,2H),1.89(dt,J=13.3,6.7Hz,1H),0.89(d,J=6.7Hz,6H). LCMS:MS m / z:392.1(M+1) Example 2: Isobutyl (7-((2R,3R,4S,5R)-2-cyano-3,4-dihydroxy-5-(((isobutoxycarbonyl)oxy)methyl)tetrahydrofuran-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)carbamate (Compound 2) [ka]

[0662] To a solution of isobutyl (7-((3aR,4R,6R,6aR)-4-cyano-6-(((isobutoxycarbonyl)oxy)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)carbamate intermediate Ib (650 mg, 1.2 mmol) in acetonitrile (10 mL) was added concentrated HCl (0.6 mL, 6 mmol) and stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (50 mL) and neutralized with saturated sodium bicarbonate. The organic layer was separated, washed with water, brine, dried, and concentrated. The residue was purified by flash chromatography using dichloromethane and methanol as eluents to give compound 2. 1 H NMR(400MHz,DMSO-d6)δ10.88(s,1H),8.37(s,1H),7.31(d,J=4.7Hz,1H),7.02(d,J=4.7Hz, 1H),6.42(d,J=6.0Hz,1H),5.45(d,J=5.9Hz,1H),4.66(t,J=5.4Hz,1H),4.42(dd,J=11.6,2. 5Hz,1H),4.34-4.13(m,2H),3.96(dd,J=16.0,6.2Hz,3H),3.86(d,J=6.5Hz,2H),1.97(dq,J= 13.6,6.8Hz,1H),1.88(dt,J=13.3,6.7Hz,1H),0.96(d,J=6.7Hz,6H),0.88(d,J=6.7Hz,6H). LCMS:MS m / z:492.2(M+1) Example 3: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl neopentyl carbonate (compound 3) [ka]

[0663] To a solution of (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile, Intermediate I (2000 mg, 6.0 mmol) in DMF (5 mL) was added diisopropylethylamine (1560 mg, 12 mmol) followed by 4-dimethylaminopyridine (737 mg, 6 mmol). To the above solution at room temperature, neopentyl chloroformate (1091 mg, 7.2 mmol) was added and stirred for 1 hour. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (50 mL), washed with water, brine, dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography using dichloromethane and methanol to give Intermediate 3a.

[0664] Intermediate 3a (2400 mg, 5.4 mmol) in acetonitrile (5 mL) was treated with concentrated aqueous HCl (2.2 mL, 27 mmol) and stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (50 mL), neutralized with saturated sodium bicarbonate, and the organic layer was separated, washed with water, brine, dried, and concentrated. The residue was purified by flash chromatography using dichloromethane and methanol as eluents to give compound 3. 1 H NMR(400MHz,DMSO-d6)δ7.92(s,1H),6.90(d,J=4.5Hz,1H),6.80(d,J=4.5Hz,1H),6.33(d,J=6.0Hz,1H),5.40(d,J=5.8Hz,1H),4.66 (dd,J=6.0,4.9Hz,1H),4.49-4.36(m,1H),4.32-4.17(m,2H),3.93(ddd,J=8.8,6.6,4.4Hz,1H),3.80(d,J=1.7Hz,2H),0.90(s,9H). LCMS:MS m / z:406.2(M+1). Example 4: [(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methyl isopropyl carbonate (compound 4) [ka]

[0665] To a solution of Intermediate II (850 mg, 2.2 mmol) in dichloromethane (20 mL) was added pyridine (1 mL). ℃ The mixture was cooled to RT, and isopropyl chloroformate (270 mg, 2.2 mmol) in dichloromethane (5 mL) was slowly added. Upon completion of the addition, the cooling bath was removed and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was diluted with dichloromethane (50 mL), washed with water, brine, and concentrated. The residue was purified by flash chromatography using ethyl acetate and dichloromethane as eluents to give intermediate [(3aR,4R,6R,6aR)-4-cyano-4-[4-[2,1-f]pyrrolo[1,2,4]triazin-7-yl]-2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-6-yl]methyl isopropyl carbonate (and / or its (E)-isomer), intermediate 4a. LCMS: MS m / z: 473.2 (M+1). It should be noted that compounds such as intermediate 4a can be E or Z isomers. While the Z isomer is depicted throughout this disclosure, the E isomer can also be produced and isolated.

[0666] To a solution of intermediate 4a (1300 mg, 2.8 mmol) in tetrahydrofuran (10 mL) in an ice bath, concentrated HCl (1.3 mL, 43 mmol) was slowly added, and the reaction mixture was stirred for 6 to 18 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (50 mL) and neutralized with saturated sodium bicarbonate. The organic layer was separated, washed with water, brine, and concentrated. The residue was purified by flash chromatography using dichloromethane and methanol as eluents to give the title compound [(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methyl isopropyl carbonate, compound 4. 1H NMR (400 MHz, acetonitrile-d3) δ 7.94 (s, 1H), 6.84 (d, J = 4.6 Hz, 1H), 6.78 (d, J = 4.6 Hz, 1H), 6.33 (s, 3H), 4.83-4.69 (m, 3H), 4.45-4.31 (m, 2H), 4.26-4.14 (m, 2H), 3.67 (d, J = 5.1 Hz, 1H), 1.22 (t, J = 6.7 Hz, 6H). LCMS: MS m / z: 378.1 Example 5: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl methyl carbonate (compound 5) [ka]

[0667] Compound 5 was synthesized as described in Example 4, starting with methyl chloroformate instead of isopropyl chloroformate.

[0668] Intermediate 5a: [(3aR,4R,6R,6aR)-4-cyano-4-[4-[2,1-f]pyrrolo[1,2,4]triazin-7-yl]-2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-6-yl]methyl methyl carbonate (and / or its (E)-isomer); LCMS: MS m / z=445.1 (M+1).

[0669] Compound 5: 1 H NMR(400MHz,DMSO-d6)δ7.92(s,1H),6.91(d,J=4.5Hz,1H),6.79(d,J=4.5Hz,1H),6.30(d,J=6.1Hz,1H),5.75(s,0H),5.4 0(d,J=5.8Hz,1H),4.68(dd,J=6.1,4.9Hz,1H),4.47-4.32(m,1H),4.30-4.16(m,2H),3.94(q,J=5.6Hz,1H),3.70(s,3H). LCMS:MS m / z=350.1(M+1) Example 6: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl ethyl carbonate (compound 6) [ka]

[0670] Compound 6 was synthesized as described in Example 4, starting with ethyl chloroformate instead of isopropyl chloroformate.

[0671] Intermediate 6a: [(3aR,4R,6R,6aR)-4-cyano-4-[4-[2,1-f]pyrrolo[1,2,4]triazin-7-yl]-2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-6-yl]methyl ethyl carbonate (and / or its (E)-isomer). LCMS: MS m / z=459.2 (M+1)

[0672] Compound 6: 1 H NMR(400MHz,DMSO-d6)δ7.92(s,3H),6.91(d,J=4.5Hz,1H),6.79(d,J=4.5Hz,1H),6.30(d,J=6.1Hz,1H),5.40(d,J=5.8Hz,1H),4.69(dd ,J=6.1,5.0Hz,1H),4.39(dd,J=10.3,4.1Hz,1H),4.29-4.17(m,2H),4.11(q,J=7.1Hz,2H),3.94(q,J=5.8Hz,1H),1.20(t,J=7.1Hz,3H). LCMS:MS m / z=363.9(M+1) Example 7: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl phenyl carbonate (compound 7) [ka]

[0673] Compound 7 was synthesized as described in Example 4, starting with phenyl chloroformate instead of isopropyl chloroformate.

[0674] Intermediate 7a: [(3aR,4R,6R,6aR)-4-cyano-4-[4-[2,1-f]pyrrolo[1,2,4]triazin-7-yl]-2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-6-yl]methyl phenyl carbonate (and / or its (E)-isomer). LCMS: MS m / z=507.1 (M+1)

[0675] Compound 7: 1 H NMR(400MHz,DMSO-d6)δ7.93(s,1H),7.48-7.37(m,2H),7.35-7.25(m,1H),7.25-7.14(m,2H),6.92(d,J=4.5Hz,1H),6.82(d,J=4.5Hz,1H),6. 34(d,J=6.1Hz,1H),5.45(d,J=5.7Hz,1H),4.71(dd,J=6.1,4.9Hz,1H),4.53(dd,J=11.5,2.6Hz,1H),4.44-4.23(m,2H),4.01(q,J=5.7Hz,1H). LCMS:MS m / z=412.1(M+1) Example 8: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl propyl carbonate (compound 8) [ka]

[0676] Compound 8 was synthesized as described in Example 4, starting with propyl chloroformate instead of isopropyl chloroformate.

[0677] Intermediate 8a: [(3aR,4R,6R,6aR)-4-cyano-4-[4-[2,1-f]pyrrolo[1,2,4]triazin-7-yl]-2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-6-yl]methyl propyl carbonate (and / or its (E)-isomer). LCMS: MS m / z=473.1 (M+1)

[0678] Compound 8: 1 H NMR(400MHz,DMSO-d6)δ7.92(s,1H),6.90(d,J=4.5Hz,1H),6.79(d,J=4.5Hz,1H),6.31(d,J=6.1Hz,1H),5.40(d,J=5.8Hz,1H),4.68(dd,J=6.1 ,4.9Hz,1H),4.50-4.30(m,1H),4.30-4.14(m,2H),4.03(t,J=6.6Hz,2H ),3.98-3.85(m,2H),1.60(dt,J=7.5,6.6Hz,2H),0.88(t,J=7.4Hz,3H). LCMS:MS m / z=378.1(M+1) Example 9: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl cyclopropyl carbonate (compound 9) [ka]

[0679] Compound 9 was synthesized as described in Example 4, starting with cyclopropyl chloroformate instead of isopropyl chloroformate.

[0680] Intermediate 9a: [(3aR,4R,6R,6aR)-4-cyano-4-[4-[2,1-f]pyrrolo[1,2,4]triazin-7-yl]-2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-6-yl]methyl cyclopropyl carbonate (and / or its (E)-isomer). LCMS: MS m / z=471.1 (M+1)

[0681] Compound 9: 1 H NMR(400MHz,DMSO-d6)δ7.91(s,1H),6.91(d,J=4.5Hz,1H),6.78(d,J=4.5Hz,1H),6.30(d,J=6.1Hz,1H),5.40(d,J=5.7Hz,1 H),4.68(dd,J=6.1,5.0Hz,1H),4.50-4.31(m,1H),4.29-4.16(m,2H),4.13-3.99(m,1H),3.94(q,J=5.5Hz,1H),0.68(m,4H). LCMS:MS m / z=376.1(M+1) Example 10: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(2-methoxyethyl)carbonate (Compound 10) [ka]

[0682] Compound 10 was synthesized as described in Example 4, starting with methoxyethyl chloroformate instead of isopropyl chloroformate.

[0683] Intermediate 10a: [(3aR,4R,6R,6aR)-4-cyano-4-[4-[2,1-f]pyrrolo[1,2,4]triazin-7-yl]-2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-6-yl]methyl 2-methoxyethyl carbonate (and / or its (E)-isomer). LCMS: MS m / z=489.3 (M+1)

[0684] Compound 10: 1H NMR(400MHz,DMSO-d6)δ7.92(s,3H),6.91(d,J=4.5Hz,1H),6.79(d,J=4.5Hz,1H),6.30(d,J=6.1Hz,1H),5.41(d,J=5.7Hz,1 H),4.69(dd,J=6.1,5.0Hz,1H),4.47-4.35(m,1H),4.30-4.13(m,4H),3.94(q,J=5.5Hz,1H),3.58-3.47(m,2H),3.26(s,3H). LCMS:MS m / z=394.2(M+1) Example 11: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(tetrahydrofuran-3-yl)carbonate (Compound 11) [ka]

[0685] Compound 11 was synthesized as described in Example 4, starting with tetrahydrofuran-3-yl chloroformate instead of isopropyl chloroformate.

[0686] Intermediate 11a: [(3aR,4R,6R,6aR)-4-cyano-4-[4-[2,1-f]pyrrolo[1,2,4]triazin-7-yl]-2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-6-yl]methyl tetrahydrofuran-3-yl carbonate (and / or its (E)-isomer). LCMS: MS m / z=501.3 (M+1)

[0687] Compound 11: 1H NMR(400MHz,DMSO-d6)δ7.92(s,1H),6.92(d,J=4.5Hz,1H),6.80(dd,J=4.5,1. 3Hz,1H),6.32(d,J=6.1Hz,1H),5.41(d,J=5.7Hz,1H),5.15(ddt,J=5.9,3.7,1 .7Hz,1H),4.70(dd,J=6.1,4.9Hz,1H),4.49-4.35(m,1H),4.32-4.15(m,2H),3 .95(q,J=4.9Hz,1H),3.85-3.65(m,5H),2.25-2.03(m,1H),2.02-1.86(m,1H). LCMS: MS m / z=406.1 (M+1) Example 12: ((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl cyclopentyl carbonate (compound 12) [ka]

[0688] Compound 12 was synthesized as described in Example 4, starting with cyclopentyl chloroformate instead of isopropyl chloroformate.

[0689] Intermediate 12a: [(3aR,4R,6R,6aR)-4-cyano-4-[4-[2,1-f]pyrrolo[1,2,4]triazin-7-yl]-2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-6-yl]methyl cyclopentyl carbonate (and / or its (E)-isomer). LCMS: MS m / z=499.3 (M+1)

[0690] Compound 12: 1H NMR(400MHz,DMSO-d6)δ7.92(s,2H),6.91(d,J=4.5Hz,1H),6.78(d,J=4.6Hz,1H),6.31(d,J=6.0Hz,1H),5.39(d,J=5.8Hz,1H),4.98(tt,J=6. 0,2.4Hz,1H),4.67(dd,J=6.0,4.9Hz,1H),4.49-4.32(m,1H),4.29-4.11(m,2H),3.93(q,J=5.8Hz,1H),1.95-1.71(m,4H),1.74-1.45(m,4H). LCMS:MS m / z=404.2(M+1) E...

Claims

1. A compound of the following: 【Chemistry 353】 or a pharmaceutically acceptable salt thereof, selected from:

2. The compound of claim 1, wherein the compound is a compound of the formula: 【Transformation 347】 2. The compound of claim 1, wherein:

3. The compound of claim 2, wherein the compound is a compound of the formula: 【Transformation 348】 2. The compound of claim 1, wherein:

4. 10. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

5. 5. The pharmaceutical composition of claim 4, wherein the pharmaceutical composition is formulated for subcutaneous, intramuscular, intravenous, oral, or inhalation administration.

6. 5. The pharmaceutical composition of claim 4, wherein the pharmaceutical composition is formulated for oral administration.

7. 10. A composition comprising the compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 4 to 6, for use in a method for treating or preventing a viral infection in a human in need thereof.

8. 8. The composition or pharmaceutical composition for use according to claim 7, characterized in that the composition or pharmaceutical composition is for administration to the human via oral, intramuscular, intravenous, subcutaneous or inhalation administration.

9. A composition or pharmaceutical composition for use as described in claim 7, wherein the method comprises administering at least one additional therapeutic or prophylactic agent to the human.

10. 10. The composition or pharmaceutical composition for use according to claim 9, wherein the additional therapeutic or prophylactic agent is molnupiravir, oseltamivir, nilmatrervir or ritonavir.

11. 8. The composition or pharmaceutical composition for use according to claim 7, wherein the viral infection is a coronavirus infection.

12. The viral infection is a zoonotic coronavirus infection; a viral infection caused by a virus having at least 70% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2; a viral infection caused by a virus having at least 80% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2; SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2. a viral infection caused by a virus having at least 90% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2; or a viral infection selected from the group consisting of 229E viral infection, NL63 viral infection, OC43 viral infection, and HKU1 viral infection.

13. The composition or pharmaceutical composition for use according to claim 11, wherein the viral infection is SARS-CoV-2 infection (COVID-19).

14. The composition or pharmaceutical composition for use according to claim 11, wherein the viral infection is SARS-CoV viral infection.

15. The composition or pharmaceutical composition for use according to claim 11, wherein the viral infection is a MERS-CoV viral infection.

16. The composition or pharmaceutical composition for use according to claim 7, wherein the viral infection is a Pneumoviridae virus infection.

17. 17. The composition or pharmaceutical composition for use according to claim 16, wherein the Pneumoviridae virus infection is a respiratory syncytial virus infection or a human metapneumovirus infection.

18. A composition or pharmaceutical composition for use as described in claim 7, wherein the viral infection is a Picornaviridae virus infection.

19. 19. The composition or pharmaceutical composition for use according to claim 18, wherein the Picornaviridae virus infection is selected from the group consisting of enterovirus infection, Coxsackie A virus infection, Coxsackie A virus infection, enterovirus D68 infection, enterovirus B69 infection, enterovirus D70 infection, enterovirus A71 infection, poliovirus infection, rhinovirus infection (HRV), HRV-A infection, HRV-B infection, and HRV-C infection.

20. The composition or pharmaceutical composition for use according to claim 7, wherein the viral infection is a Flaviviridae virus infection.

21. 21. The composition or pharmaceutical composition for use according to claim 20, wherein the Flaviviridae virus infection is selected from the group consisting of dengue virus infection, yellow fever virus infection, West Nile virus infection, tick-borne encephalitis, Kunjin Japanese encephalitis, St. Louis encephalitis, Murray Valley encephalitis, Omsk hemorrhagic fever, bovine viral diarrhea, Zika virus infection, and HCV infection.

22. 8. The composition or pharmaceutical composition for use according to claim 7, wherein the viral infection is a Filoviridae virus infection.

23. 23. The composition or pharmaceutical composition for use according to claim 22, wherein the Filoviridae virus infection is Ebola virus infection or Marburg virus infection.

24. 8. The composition or pharmaceutical composition for use according to claim 7, wherein the viral infection is an orthomyxovirus infection.

25. 25. The composition or pharmaceutical composition for use according to claim 24, wherein the viral infection is selected from the group consisting of influenza virus infection, influenza A virus infection, and influenza B virus infection.

26. The composition or pharmaceutical composition for use according to claim 7, wherein the viral infection is a Paramyxoviridae virus infection.

27. 27. The composition or pharmaceutical composition for use according to claim 26, wherein the viral infection is selected from the group consisting of human parainfluenza virus, Nipah virus, Hendra virus, measles, and mumps infection.

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