Compounds and methods for treatment of viral infections

Abstract

The invention discloses compounds, methods of using such compounds alone or in combination with additional agents, and salts or pharmaceutical compositions of such compounds for treating viral infections.

Description

Prior Art

[0001] There is a need for compounds and methods for treating viral infections, such as paramyxoviridae, pneumoviridae, picornaviridae, flaviviridae, filoviridae, arenaviridae, orthomyxovirus, and coronaviridae infections. The present disclosure addresses these and other needs.

[0002] The oral route is a preferred route for daily drug administration due to its advantages such as non-invasiveness, patient compliance, and convenience. However, oral administration can be limited by the unfavorable physicochemical properties of drug molecules, including low aqueous solubility between pH 2 and pH 7, instability, low permeability, and rapid metabolism, all of which can result in low and irregular oral bioavailability. Oral bioavailability (F%) is the fraction of an orally administered drug that reaches the systemic circulation relative to the same dose delivered via intravenous administration. Following intravenous administration, the drug is directly available in the bloodstream and can be distributed via the systemic circulation to sites of pharmacological effect. If a drug is administered orally, it must survive in the intestinal fluids and cross further barriers, such as the gastrointestinal (GI) cell layer and then the liver, to reach the systemic circulation, which can significantly reduce the amount of drug reaching the bloodstream. Therefore, oral bioavailability is a crucial property in drug design and development. High oral bioavailability reduces the dosage required to achieve the desired pharmacological effect and, therefore, reduces the risk of side effects and toxicity during the absorption process. The present disclosure also provides compounds with combined solubility, stability, and permeability properties, thereby improving oral bioavailability. Summary of the Invention

[0003] The present disclosure provides a compound of formula I: Formula I or a pharmaceutically acceptable salt thereof, wherein R 1, R 2, R 3, and the base are defined herein.

[0004] Also provided herein is a pharmaceutical composition comprising a compound disclosed herein (eg, a compound of Formula I) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0005] Also disclosed herein is a method of treating or preventing a viral infection in a human in need thereof, wherein the method comprises 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.

[0006] Also provided herein is the use of a compound disclosed herein (eg, a compound of Formula I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing a viral infection in a human in need thereof.

[0007] Also provided herein is a composition comprising a compound described herein (eg, 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. Simple diagram description

[0008] [ [picture] [1]] shows the GI stability of compound 4, compound 128, ester reference compound, and the third ester reference compound. [ [picture] [2]] shows the stability of compound 128, compound 129, ester reference compound, second ester reference compound, and third ester reference compound. Implementation Method

[0009] [Cross-reference to related applications]

[0010] This application claims priority to U.S. Provisional Patent Application No. 63 / 315,769, filed on March 2, 2022, U.S. Provisional Patent Application No. 63 / 390,421, filed on July 19, 2022, U.S. Provisional Patent Application No. 63 / 424,083, filed on November 9, 2022, and U.S. Provisional Patent Application No. 63 / 434,993, filed on December 23, 2022. The entire contents of each of these applications are incorporated herein by reference. [] I. Overview

[0011] The present invention generally relates to methods and compounds for treating or preventing viral infections, such as Paramyxoviridae, Pneumoviridae, Picornaviridae, Flaviviridae, Filoviridae, Arenaviridae, Orthomyxoviridae, and Coronaviridae infections. II. Definitions

[0012] Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings: "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-C20 alkyl), 1 to 8 carbon atoms (i.e., C1-C8 alkyl), 1 to 6 carbon atoms (i.e., C1-C6 alkyl), or 1 to 3 carbon atoms (i.e., C1-C3 alkyl). Examples of suitable alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, isopropyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, isobutyl, -CH2CH(CH3)2), 2-butyl (s-Bu, secondary butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, tertiary butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH 3), 3-pentyl (-CH(CH 2CH 3) 2), 2-methyl-2-butyl (-C(CH 3) 2CH 2CH 3), 3-methyl-2-butyl (-CH(CH 3)CH(CH 3) 2), 3-methyl-1-butyl (-CH 2CH 2CH(CH 3) 2), 2-methyl-1-butyl (-CH 2CH(CH 3)CH 2CH 3), 1-hexyl (-CH 2CH 2CH 2CH 2CH 2CH 3), 2-hexyl (-CH(CH 3)CH 2CH 2CH 2CH 3), 3-hexyl (-CH(CH 2CH 3)(CH 2CH 2CH 3)), 2-methyl-2-pentyl (-C(CH 3) 2CH 2CH 2CH 3), 3-methyl-2-pentyl (-CH(CH 3)CH(CH 3)CH 2CH 3), 4-methyl-2-pentyl (-CH(CH 3)CH 2CH(CH 3) 2), 3-methyl-3-pentyl (-C(CH 3)(CH 2CH 3) 2), 2-methyl-3-pentyl (-CH(CH 2CH 3)CH(CH 3) 2), 2,3-dimethyl-2-butyl (-C(CH 3) 2CH(CH 3) 2), and 3,3-dimethyl-2-butyl (-CH(CH 3)C(CH 3) 3).

[0013] "Alkenyl" refers to an aliphatic group containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C2-20 alkenyl), 2 to 8 carbon atoms (i.e., C2-8 alkenyl), 2 to 6 carbon atoms (i.e., C2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C2-4 alkenyl). Examples of alkenyl groups include ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0014] "Alkynyl" refers to an aliphatic group containing at least one carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C2-20 alkynyl), 2 to 8 carbon atoms (i.e., C2-8 alkynyl), 2 to 6 carbon atoms (i.e., C2-6 alkynyl), or 2 to 4 carbon atoms (i.e., C2-4 alkynyl). The term "alkynyl" also includes groups having one triple bond and one double bond.

[0015] "Haloalkyl" is an alkyl group (as defined above) in which one or more hydrogen atoms of the alkyl group are replaced by a halogen atom. The alkyl portion of the haloalkyl group can have 1 to 20 carbon atoms (i.e., C1-C20 haloalkyl), 1 to 12 carbon atoms (i.e., C1-C12 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, but are not limited to, -CF3, -CHF2, -CFH2, -CH2CF3, and the like.

[0016] "Aryl" means an aromatic hydrocarbon radical derived by removing a single hydrogen atom from a single carbon atom of a parent aromatic ring system. For example, an aryl group may have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 10 carbon atoms. Typical aryl groups include, but are not limited to, radicals derived from benzene (e.g., phenyl), substituted benzenes, naphthalene, anthracene, biphenyl, and the like.

[0017] "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 groups include 1 to 20 ring atoms (i.e., 1-20 membered heteroaryl), 3 to 12 ring atoms (i.e., 3-12 membered heteroaryl), 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, pyridinyl, pyridinyl, benzothiazolyl, and pyrazolyl. Heteroaryl does not encompass or overlap with the above-defined aryl groups.

[0018] "Carbocyclyl" or "carbocyclic ring" refers to a non-aromatic hydrocarbon ring composed of carbon and hydrogen atoms having three to twenty carbon atoms, in certain embodiments, three to fifteen carbon atoms, in certain embodiments, three to ten carbon atoms, three to eight carbon atoms, three to seven carbon atoms, or three to six carbon atoms, which is saturated or partially unsaturated and attached to the rest of the molecule by a single bond. Carbocyclic rings include, for example, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, cycloheptane, cycloheptene, and cyclooctane. Carbocyclic rings include cycloalkyl groups.

[0019] "Cycloalkyl" refers to a saturated cyclic alkyl group having a single ring or multiple rings, including fused, bridged, and spiro ring systems. As used herein, a cycloalkyl group has 3 to 20 ring carbon atoms (i.e., C3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C3-6 cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0020] As used herein, "heterocycle" or "heterocyclyl" includes, by way of example and not limitation, those heterocycles described in Paquette, Leo A.; Principles of Modern Heterocyclic Chemistry (WA Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; "The Chemistry of Heterocyclic Compounds, A Series of Monographs" (John Wiley & Sons, New York, 1950 to present), particularly Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566. For example, "heterocycle" includes a "carbocycle" as defined herein in which one or more (e.g., 1, 2, 3, or 4) carbon atoms have been replaced with a heteroatom (e.g., O, N, or S). As used herein, a heterocycle or heterocyclyl group 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 carbon atoms and heteroatoms of the heterocycle group may optionally be oxidized to form pendant oxygen groups or sulfide groups or other oxidized bonds (e.g., C(O), S(O), C(S), or S(O)2, N-oxide, etc.), or the nitrogen atom may be quaternized. The term "heterocycle" or "heterocyclyl" includes saturated and partially unsaturated rings. Substituted heterocyclyl groups include, for example, heterocyclic rings substituted with any of the substituents disclosed herein, including carbonyl. Non-limiting examples of carbonyl-substituted heterocyclyl groups are: .

[0021] Example heterocycles include, but are not limited to, tetrahydrofuranylazacycloalkyl and 2-oxo-1,3-dioxol-4-yl.

[0022] The term "optionally substituted" when referring to a particular moiety of a compound described herein (such as a compound of Formula I) (e.g., an optionally substituted aryl) refers to a moiety in which all substituents are hydrogen or in which one or more hydrogens of the moiety can be replaced with the listed substituents.

[0023] Unless otherwise indicated, the carbon atoms of the compounds of Formula I are intended to have a valence of four. If, in some chemical structure representations, a carbon atom does not have a sufficient number of variables attached to produce a valence of four, the remaining carbon substituents required to provide the four valences should be assumed to be hydrogen.

[0024] As used herein, unless otherwise indicated, the term "treating" means reversing, alleviating, or inhibiting the progress of the disorder or condition to which the term applies, or one or more symptoms of the disorder or condition. As used herein, the term "treatment" refers to the act of treating, and "treating" is defined above.

[0025] "Prevention" or "preventing" refers to any treatment of a disease or condition that results in the clinical symptoms of the disease or condition not developing. In some embodiments, the compounds and compositions disclosed herein can be administered to a subject (including humans) at risk for the disease or condition. As used herein, the term "prevention" encompasses administering a compound, composition, or pharmaceutically acceptable salt according to the embodiments disclosed herein before or after exposure to a virus, but before symptoms of viral infection develop and / or before the virus is detected in the blood. The term also refers to preventing the onset of disease symptoms and / or preventing the virus from reaching detectable levels in the blood. The term encompasses pre-exposure prophylaxis (PrEP), post-exposure prophylaxis (PEP), and event-driven or "on-demand" prophylaxis. The term also refers to preventing perinatal viral transmission from mother to infant by administering the drug to the mother before birth and to the child within the first few days of life. The term also refers to preventing viral transmission through blood transfusion.

[0026] 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 that is required to provide the desired level of drug in the secretions and tissues of the respiratory tract and lungs of the subject to be treated, or alternatively, in the bloodstream, to confer the desired physiological response or desired biological effect when the composition is administered by the chosen route of administration. The exact amount will depend on several factors, such as the specific compound described herein (e.g., a compound of Formula I), the specific activity of the composition, the delivery device employed, the physical properties of the composition, its intended use, and patient considerations, such as the severity of the disease state, patient compliance, etc., and can be readily determined by one of ordinary skill in the art based on the information provided herein. III. Compounds

[0027] Any reference to the compounds of the present invention described herein also includes a reference to their pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts of the compounds of the present invention include salts derived from appropriate bases, such as alkali metals or alkaline earths (e.g., Na+, Li+, K+, Ca+2, and Mg+2), ammonium, and NR4+ (wherein R is defined herein). Pharmaceutically acceptable salts of nitrogen atoms or amine groups 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) salts formed with organic acids, such as, for example, acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, 2-hydroxyethanesulfonic acid, lactobionic acid, and the like. (c) salts formed with elemental anions such as chloride, bromide, and iodide. Pharmaceutically acceptable salts of compounds of a hydroxy group include combinations of an anion of the compound with a suitable cation such as Na+ and NR4+.

[0028] In some embodiments, R is H, (C 1-C 8)alkyl, (C 2-C 8)alkenyl, (C 2-C 8)alkynyl, C 6-C 20 aryl, or C 2-C 20 heterocyclyl.

[0029] For therapeutic use, salts of the active ingredients of the compounds of this invention will be pharmaceutically acceptable, that is, they will be salts derived from pharmaceutically acceptable acids or bases. However, salts of non-pharmaceutically acceptable acids or bases also find use, for example, in the preparation or purification of pharmaceutically acceptable compounds. All salts, whether or not derived from pharmaceutically acceptable acids or bases, are within the scope of this invention.

[0030] It is also understood that the compositions herein include compounds of the present invention in unionized form as well as in zwitterionic form, and in combination with stoichiometric amounts of water as hydrates.

[0031] It is important to note that the present invention encompasses all enantiomers, diastereomers, racemic mixtures, tautomers, polymorphs, pseudopolymorphs, and pharmaceutically acceptable salts thereof of the compounds described herein (e.g., compounds within the scope of Formula I). All mixtures of such enantiomers and diastereomers are within the scope of the present invention.

[0032] The compounds of the present invention (exemplified by Formula I) may possess chiral centers, such as chiral carbon or phosphorus atoms. The compounds of the present invention thus include racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and atropisomers. Furthermore, the compounds of the present invention include enriched or resolved optical isomers at any or all asymmetric, chiral atoms. In other words, chiral centers apparent from the depiction are presented as chiral isomers or racemic mixtures. Both racemic and diastereomer mixtures, as well as the isolation or synthesis of individual optical isomers substantially free of their enantiomer or diastereomer counterparts, are within the scope of the present invention. Racemic mixtures are separated into their individual, substantially optically pure isomers by appropriate techniques, such as separation of diastereomers formed with an optically active adjuvant (acid or base), followed by conversion back to the optically active species. In most cases, the desired optical isomers are synthesized by means of stereospecific reactions, starting from the appropriate stereoisomer of the desired starting material.

[0033] Stereochemical definitions and conventions used herein generally follow those in 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, that is, they have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l, D and L, or (+) and (-) are used to designate the sign of the compound's rotation of plane-polarized light, where S, (-), or l means the compound is levorotatory, and compounds with the prefixes R, (+), or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. Specific stereoisomers may also be referred to as mirror-enantiomers, and mixtures of such isomers are often called mirror-enantiomer mixtures. A 50:50 mixture of mirror-enantiomers is called a racemic mixture or racemate, which can occur when stereoselectivity or stereospecificity is not achieved in a chemical reaction or procedure. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two mirror-enantiomer species that is optically inactive.

[0034] The compounds of the present invention may also exist as tautomers in certain circumstances. Although only one delocalized resonance structure may be depicted, all such forms are contemplated as being 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 such possible tautomeric forms are contemplated as being within the scope of the present invention.

[0035] Any formula or structure given herein (including compounds of Formula I) is also intended to represent unlabeled forms of the compounds as well as isotopically labeled forms. Isotopically labeled compounds have the structure depicted by the formula given herein except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, but not limited to, 2H (deuterium, D), 3H (tritium), 11C, 13C, 14C, 15N, 18F, 31P, 32P, 35S, 36Cl, and 125I. Various isotopically labeled compounds of the present disclosure, for example, have radioactive isotopes (such as 3H, 13C, and 14C) incorporated therein. Such isotopically labeled compounds can be used in metabolic studies, reaction kinetics studies, detection or imaging techniques (such as positron emission tomography (PET) or single photon emission computed tomography (SPECT)), including drug or substrate tissue distribution assays, or in radiotherapy of patients.

[0036] The present disclosure also includes compounds (e.g., compounds of Formula I) in which 1 to x hydrogen atoms attached to carbon atoms are replaced by deuterium, where x is the number of hydrogen atoms 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 mammals, particularly humans. See, e.g., Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism”, Trends Pharmacol. Sci. 5(12):524-527 (1984). In view of the present disclosure, such compounds are synthesized by means known in the art, for example, by employing starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0037] Deuterium-labeled or substituted therapeutic compounds disclosed herein may have improved DMPK (drug metabolism and pharmacokinetic) properties regarding distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes, such as deuterium, may provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life, reduced dosage requirements, and / or an improved therapeutic index. 18F-labeled compounds may be used in PET or SPECT studies. Isotopically labeled compounds disclosed herein and their prodrugs can generally be prepared by carrying out the procedures disclosed in the following schemes or examples and preparations, substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. It should be understood that, in this context, deuterium is considered a substituent in the compound of Formula I.

[0038] In some embodiments, the carbon at the 5 position bonded to the tetrahydrofuranyl ring of Formula I is substituted with one or two deuterium atoms. In some embodiments, the compound of Formula I is In some embodiments, the compound of formula I is In some embodiments, the carbon atoms of the bases of Formula I are substituted with one or more deuterium atoms. In some embodiments, the bases are 、 ,or In some embodiments, the carbon atom at R 12 of the base of Formula I is substituted with one or more deuterium atoms. In some embodiments, the carbon atom at R 11 of the base of Formula I is substituted with one or more deuterium atoms. In some embodiments, the carbon atom at R 1 of the base of Formula I is substituted with one or more deuterium atoms. In some embodiments, the carbon atom at R 2 of the base of Formula I is substituted with one or more deuterium atoms. In some embodiments, the carbon atom at R 3 of the base of Formula I is substituted with one or more deuterium atoms.

[0039] In some embodiments, the compound of formula I is 、 、 、 、 、 、 、 、 ,or .

[0040] In some embodiments, the base pair 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ,or .

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

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

[0043] Wavy lines Indicates the site of covalent attachment to an adjacent substructure, group, moiety, or atom. IV. Compounds

[0044] In certain embodiments, provided herein is a compound of Formula I: Formula I or a pharmaceutically acceptable salt thereof, wherein: R 1 is -OH, -OC(=O)R 4, -OC(=O)OR 4, or -OP(=O)(OH)(OR 4); R 2 is -OH, -OC(=O)R 5, -OC(=O)OR 5, or -OP(=O)(OH)(OR 5); or R 1 and R 2 together form -OC(=O)O-, -OP(=O)(OH)O-, or -OCHR 6O-; R 3 series -C(=O)OR 7; R 4, R 5, and R 7 are each independently C 1-C 20 alkyl, C 2-C 8 alkenyl, C 2-C 8 alkynyl, C 3-C 10 carbocyclyl, C 6-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; wherein the C1-C20 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C10 carbocyclyl, C6-C10 aryl, 4- to 8-membered heterocyclyl, or 5- to 6-membered heteroaryl represented by R4, R5, and R7 is each independently optionally substituted with one, two, or three substituents independently selected from the group consisting of C1-C8 alkyl, halogen, cyano, carbonyl, -N3, -OR8, -NR9R10, -OP(=O)(OH)2, -OP(=O)(OR8)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 substituents C3-C8 carbocyclyl of R4, R5, and R7 are optionally substituted by one, two, or three substituents independently selected from C1-C8 alkyl, halogen, -CF3, cyano, -CH2CN, and phenyl, wherein the substituents of R4, R5, and R7 are 4 to 6 membered heterocyclic groups which are optionally substituted by one, two, or three substituents independently selected from carbonyl and C1-C6 alkyl, and Wherein the phenyl substituents of R 4, R 5, and R 7 are optionally substituted by one, two, or three substituents independently selected from halo, cyano, C 1-C 6 alkyl, and -OR 8; R 6 is H, C 1-C 6 alkyl, C 1-C 6 alkoxy, 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or C 6-C 10 aryl; wherein R 6 of the 5- to 6-membered heteroaryl and C 6-C 10 aryl are each independently optionally substituted by one, two, or three substituents independently selected from halo, cyano, C 1-C 6 alkoxy, and C 1-C 6 alkyl; Each R 8 is independently H, C 1-C 6 alkyl, C 1-C 6 haloalkyl, C 3-C 6 cycloalkyl, and 4 to 6 membered heterocyclic group; Wherein R 8 of C 1-C 6 alkyl is optionally substituted by C 3-C 6 cycloalkyl or 4 to 6 membered heterocyclic group; Each R 9 is independently H, C 1-C 6 alkyl, C 1-C 6 haloalkyl, and C 3-C 6 cycloalkyl; Each R 10 is independently H, C 1-C 6 alkyl, C 1-C 6 haloalkyl, and C 3-C 6 cycloalkyl; base series 、 ,or ; R 11 is C 1-C 6 alkyl optionally substituted by -OP(=O)(OH)(OR 14); R 12 is H, C 1-C 6 alkyl, -C(=O)R 13, or -C(=O)OR 13; each R 13 is independently H or C 1-C 8 alkyl; wherein the C 1-C 8 alkyl of R 13 is optionally substituted with one, two, or three substituents independently selected from halogen, cyano, -OP(=O)(OH)(OR 14), and phenyl, wherein the phenyl substituent of R 13 is optionally substituted with -OP(=O)(OH)(OR 14); and Each R 14 is independently H, C 1-C 8 alkyl, C 3-C 8 carbocyclyl, C 6-C 10 aryl, or a 5- to 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein the C 1-C 8 alkyl group of R 14 is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, and phenyl.

[0045] In certain embodiments, provided herein is a compound of Formula I: Formula I or a pharmaceutically acceptable salt thereof, wherein: R 1 is -OH, -OC(=O)R 4, or -OC(=O)OR 4; R2 is -OH, -OC(=O)R5, or -OC(=O)OR5; or R 1 and R 2 together form -OC(=O)O-, -OP(=O)(OH)O-, or -OCHR 6O-; R 3 series -C(=O)OR 7; R 4, R 5, and R 7 are each independently C 1-C 20 alkyl, C 2-C 8 alkenyl, C 2-C 8 alkynyl, C 3-C 8 carbocyclyl, C 6-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 the C1-C20 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclyl, C6-C10 aryl, 4- to 6-membered heterocyclyl, or 5- to 6-membered heteroaryl represented by R4, R5, and R7 is each independently optionally substituted with one, two, or three substituents independently selected from the group consisting of C1-C8 alkyl, halogen, cyano, carbonyl, -N3, -OR8, -NR9R10, OP(=O)(OH)2, -OP(=O)(OR8)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 substituents C3-C8 carbocyclyl of R4, R5, and R7 are optionally substituted by one, two, or three substituents independently selected from C1-C8 alkyl, halogen, -CF3, cyano, -CH2CN, and phenyl, wherein the substituents of R4, R5, and R7 are 4 to 6 membered heterocyclic groups which are optionally substituted by one, two, or three substituents independently selected from carbonyl and C1-C6 alkyl, and Wherein the phenyl substituents of R4, R5, and R7 are optionally substituted by one, two, or three substituents independently selected from halo, cyano, C 1-C 6 alkyl, and -OR 8; R 6 is H, C 1-C 6 alkyl, C 1-C 6 alkoxy, 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or C 6-C 10 aryl; Wherein R 6 of 5 to 6 membered heteroaryl and C 6-C 10 aryl are each independently optionally substituted by one, two, or three substituents independently selected from halogen, cyano, C1-C6 alkoxy, and C 1-C 6 alkyl; Each R 8 is independently H, C 1-C 6 alkyl, C 1-C 6 haloalkyl, and C 3-C 6 cycloalkyl; Each R 9 is independently H, C 1-C 6 alkyl, C 1-C 6 haloalkyl, and C 3-C 6 cycloalkyl; Each R 10 is independently H, C 1-C 6 alkyl, C 1-C 6 haloalkyl, and C 3-C 6 cycloalkyl; base series 、 ,or ; R 11 is C 1-C 6 alkyl optionally substituted by -OP(=O)(OH)(OR 14); R 12 is H, C 1-C 6 alkyl, -C(=O)R 13, or -C(=O)OR 13; each R 13 is independently H or C 1-C 8 alkyl; wherein the C 1-C 8 alkyl of R 13 is optionally substituted with one, two, or three substituents independently selected from halogen, cyano, -OP(=O)(OH)(OR 14), and phenyl, wherein the phenyl substituent of R 13 is optionally substituted with -OP(=O)(OH)(OR 14); and Each R 14 is independently H, C 1-C 8 alkyl, C 3-C 8 carbocyclyl, C 6-C 10 aryl, or a 5- to 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein the C 1-C 8 alkyl group of R 14 is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, and phenyl.

[0046] In certain embodiments, provided herein is a compound of Formula I: Formula I or a pharmaceutically acceptable salt thereof, wherein: R 1 is -OH, -OC(=O)R 4, or -OC(=O)OR 4; R2 is -OH, -OC(=O)R5, or -OC(=O)OR5; or R 1 and R 2 together form -OC(=O)O-, -OP(=O)(OH)O-, or -OCHR 6O-; R 3 series -C(=O)OR 7; R 4, R 5, and R 7 are each independently C 1-C 8 alkyl, C 2-C 8 alkenyl, C 2-C 8 alkynyl, C 3-C 8 carbocyclyl, C 6-C 10 aryl, 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 the C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclyl, C6-C10 aryl, 4- to 6-membered heterocyclyl, or 5- to 6-membered heteroaryl represented by R4, R5, and R7 are each independently optionally substituted with one, two, or three substituents independently selected from the group consisting of C1-C8 alkyl, halogen, cyano, carbonyl, -N3, -OR8, -NR9R10, -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 heterocyclic group substituents of R 4, R 5, and R 7 are optionally substituted with one, two, or three substituents independently selected from carbonyl and C 1-C 6 alkyl, and wherein the phenyl substituents of R 4, R 5, and R 7 are optionally substituted with one, two, or three substituents independently selected from halo, cyano, and C 1-C 6 alkyl; R6 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-C10 aryl; Wherein R 6 of 5 to 6 membered heteroaryl and C 6-C 10 aryl are each independently optionally substituted by one, two, or three substituents independently selected from halogen, cyano, C1-C6 alkoxy, and C 1-C 6 alkyl; Each R 8 is independently H, C 1-C 6 alkyl, C 1-C 6 haloalkyl, and C 3-C 6 cycloalkyl; Each R 9 is independently H, C 1-C 6 alkyl, C 1-C 6 haloalkyl, and C 3-C 6 cycloalkyl; Each R 10 is independently H, C 1-C 6 alkyl, C 1-C 6 haloalkyl, and C 3-C 6 cycloalkyl; base series 、 ,or ; R 11 is C 1-C 6 alkyl optionally substituted by -OP(=O)(OH)(OR 14); R 12 is H, C 1-C 6 alkyl, -C(=O)R 13, or -C(=O)OR 13; each R 13 is independently H or C 1-C 8 alkyl; wherein the C 1-C 8 alkyl of R 13 is optionally substituted with one, two, or three substituents independently selected from halogen, cyano, -OP(=O)(OH)(OR 14), and phenyl, wherein the phenyl substituent of R 13 is optionally substituted with -OP(=O)(OH)(OR 14); and Each R 14 is independently H, C 1-C 8 alkyl, C 3-C 8 carbocyclyl, C 6-C 10 aryl, or a 5- to 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein the C 1-C 8 alkyl group of R 14 is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, and phenyl.

[0047] In certain embodiments, provided herein is a compound of Formula I: Formula I or a pharmaceutically acceptable salt thereof, wherein: R 1 is -OH, -OC(=O)R 4, or -OC(=O)OR 4; R2 is -OH, -OC(=O)R5, or -OC(=O)OR5; or R 1 and R 2 together form -OC(=O)O-, -OP(=O)(OH)O-, or -OCHR 6O-; R 3 series -C(=O)OR 7; R 4, R 5, and R 7 are each independently C 1-C 8 alkyl, C 2-C 8 alkenyl, C 2-C 8 alkynyl, C 3-C 8 carbocyclyl, C 6-C 10 aryl, 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 the C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclyl, C6-C10 aryl, 4- to 6-membered heterocyclyl, or 5- to 6-membered heteroaryl represented by R4, R5, and R7 is each independently optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, carbonyl, -N3, -OR8, -NR9R10, -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 heterocyclic group is optionally substituted with one, two, or three substituents independently selected from carbonyl and C 1-C 6 groups, and wherein the phenyl group is optionally substituted with one, two, or three substituents independently selected from halo, cyano, and C 1-C 6 alkyl groups; R 6 is H, C 1-C 6 alkyl, C 1-C 6 alkoxy, 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or C 6-C 10 aryl; wherein the 5- to 6-membered heteroaryl and C 6-C 10 aryl are each independently optionally substituted by one, two, or three substituents independently selected from halo, cyano, C 1-C 6 alkoxy, and C 1-C 6 alkyl; Each R 8 is independently H, C 1-C 6 alkyl, C 1-C 6 haloalkyl, and C 3-C 6 cycloalkyl; Each R 9 is independently H, C 1-C 6 alkyl, C 1-C 6 haloalkyl, and C 3-C 6 cycloalkyl; Each R 10 is independently H, C 1-C 6 alkyl, C 1-C 6 haloalkyl, and C 3-C 6 cycloalkyl; base series 、 ,or ; R 11 is C 1-C 6 alkyl optionally substituted by -OP(=O)(OH)(OR 14); R 12 is H, C 1-C 6 alkyl, -C(=O)R 13, or -C(=O)OR 13; and each R 13 is independently H or C 1-C 8 alkyl; wherein the C 1-C 8 alkyl of R 13 is optionally substituted with one, two, or three substituents independently selected from halogen, cyano, -OP(=O)(OH)(OR 14), and phenyl, wherein phenyl is optionally substituted with -OP(=O)(OH)(OR 14); and Each R 14 is independently H, C 1-C 8 alkyl, C 3-C 8 carbocyclyl, C 6-C 10 aryl, or a 5- to 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein the C 1-C 8 alkyl group of R 14 is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, and phenyl.

[0048] 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.

[0049] In some embodiments, R 1 is -OP(═O)(OH)(OR 4 ).

[0050] In some embodiments, R 2 is -OH. In some embodiments, R 2 is -OC(=O)R 5. In some embodiments, R 2 is -OC(=O)OR 5.

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

[0052] 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 form -OCHR 6O-.

[0053] 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)R 4, 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)OR 5.

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

[0055] In some embodiments, R 1 is -OC(=O)CH 3. In some embodiments, R 2 is -OC(=O)CH 3. In some embodiments, R 1 and R 2 are both -OC(=O)CH 3.

[0056] In some embodiments, R 1 is OH, OC(O)CH(CH 3) 2, or OC(O)CH 3, R2 is OH, OC(O)CH(CH3)2, or OC(O)CH3, or R1 and R2 together form -OC(=O)O-.

[0057] In some embodiments, R 4 is C 1-C 8 alkyl, C 2-C 8 alkenyl, or C 2-C 8 alkynyl; wherein the C 1-C 8 alkyl, C 2-C 8 alkenyl, and C 2-C 8 alkynyl of R 4 are each independently optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, -N 3, -OR 8, -NR 9R 10, -OP(=O)(OH) 2, C 3-C 8 carbocyclyl, and phenyl; wherein the phenyl substituent of R 4 is optionally substituted with one, two, or three substituents independently selected from halo, cyano, and C 1-C 6 alkyl.

[0058] In some embodiments, R 4 is C 1-C 8 alkyl, C 2-C 8 alkenyl, or C 2-C 8 alkynyl; wherein the C 1-C 8 alkyl, C 2-C 8 alkenyl, and C 2-C 8 alkynyl of R 4 are each independently optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, -N 3, -OR 8, -NR 9R 10, -OP(═O)(OH) 2, C 3-C 8 carbocyclyl, and phenyl; wherein the phenyl group is optionally substituted with one, two, or three substituents independently selected from halo, cyano, and C 1-C 6 alkyl.

[0059] In some embodiments, R 4 is C 1-C 8 alkyl, optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, -N 3 , -OR 8 , -NR 9R 10 , -OP(═O)(OH) 2 , C 3 -C 8 carbocyclyl, and phenyl. In some embodiments, R 4 is C 1-C 8 alkyl. In some embodiments, R 4 is C 1-C 6 alkyl. In some embodiments, R 4 is C 1-C 3 alkyl. In some embodiments, R 4 is -CH 3 , -CH 2CH 3 , -(CH 2) 2CH 3 , -CH(CH 3) 2 , -(CH 2) 3CH 3 , or -C(CH 3) 3 . In some embodiments, R 4 is -CH 3 or -CH(CH 3) 2 .

[0060] In some embodiments, R 4 is -CH 3, -CH 2CH 3, -(CH 2) 2CH 3, -CH(CH 3) 2, -(CH 2) 3CH 3, -C(CH 3) 3, or -C(CH 3) 2CH 2CH 3.

[0061] In some embodiments, R 4 is C 1-C 20 alkyl substituted with one, two, or three substituents independently selected from the group consisting of carbonyl, -OR 8, -NR 9R 10, and -OP(=O)(OH) 2. In some embodiments, R 4 is C 2-C 8 alkyl substituted with carbonyl and -OR 8. In some embodiments, R 4 is .

[0062] In some embodiments, R 4 is C 2 -C 8 alkenyl. In some embodiments, R 4 is C 4 alkenyl. In some embodiments, R 4 is .

[0063] In some embodiments, R 5 is C 1-C 8 alkyl, C 2-C 8 alkenyl, or C 2-C 8 alkynyl; wherein the C 1-C 8 alkyl, C 2-C 8 alkenyl, and C 2-C 8 alkynyl of R 4 are each independently optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, -N 3, -OR 8, -NR 9R 10, -OP(=O)(OH) 2, C 3-C 8 carbocyclyl, and phenyl; wherein the phenyl substituent of R 5 is optionally substituted with one, two, or three substituents independently selected from halo, cyano, and C 1-C 6 alkyl.

[0064] In some embodiments, R 5 is C 1-C 8 alkyl, C 2-C 8 alkenyl, or C 2-C 8 alkynyl; wherein the C 1-C 8 alkyl, C 2-C 8 alkenyl, and C 2-C 8 alkynyl of R 4 are each independently optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, -N 3, -OR 8, -NR 9R 10, -OP(═O)(OH) 2, C 3-C 8 carbocyclyl, and phenyl; wherein phenyl is optionally substituted with one, two, or three substituents independently selected from halo, cyano, and C 1-C 6 alkyl.

[0065] In some embodiments, R 5 is C 1-C 8 alkyl, optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, -N 3 , -OR 8 , -NR 9R 10 , -OP(═O)(OH) 2 , C 3 -C 8 carbocyclyl, and phenyl. In some embodiments, R 5 is C 1-C 8 alkyl. In some embodiments, R 5 is C 1-C 6 alkyl. In some embodiments, R 5 is C 1-C 3 alkyl. In some embodiments, R 5 is -CH 3 , -CH 2CH 3 , -(CH 2) 2CH 3 , -CH(CH 3) 2 , -(CH 2) 3CH 3 , or -C(CH 3) 3 . In some embodiments, R 5 is -CH 3 or -CH(CH 3) 2 .

[0066] In some embodiments, R 5 is -CH 3, -CH 2CH 3, -(CH 2) 2CH 3, -CH(CH 3) 2, -(CH 2) 3CH 3, -C(CH 3) 3, or -C(CH 3) 2CH 2CH 3.

[0067] In some embodiments, R 5 is C 1-C 20 alkyl substituted with one, two, or three substituents independently selected from the group consisting of carbonyl, -OR 8, -NR 9R 10, and -OP(=O)(OH) 2. In some embodiments, R 5 is C 2-C 8 alkyl substituted with carbonyl and -OR 8. In some embodiments, R 5 is .

[0068] In some embodiments, R 5 is C 2-C 8 alkenyl. In some embodiments, R 5 is C 4 alkenyl. In some embodiments, R 5 is .

[0069] In some embodiments, R4 and R5 are the same. In some embodiments, R4 and R5 are different. In some embodiments, R4 is C1-C8 alkyl, and R5 is C1-C8 alkyl. In some embodiments, R4 is -CH3 or -CH(CH3)2, and R5 is -CH3 or -CH(CH3)2. In some embodiments, R4 is -CH3, and R5 is -CH3. In some embodiments, R4 is -CH(CH3)2, and R5 is -CH(CH3)2.

[0070] In some embodiments, R 6 is H. In some embodiments, R 6 is C 1-C 6 alkyl. In some embodiments, R 6 is -CH 3, -CH 2CH 3, -(CH 2) 2CH 3, -CH(CH 3) 2, -(CH 2) 3CH 3, or -C(CH 3) 3. In some embodiments, R 6 is C 1-C 6 alkoxy. In some embodiments, R 6 is -OCH 3.

[0071] In some embodiments, R 6 is a 5- to 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S, which is optionally substituted with one, two, or three substituents independently selected from halo, cyano, C 1-C 6 alkoxy, and C 1-C 6 alkyl. In some embodiments, R 6 is a 5- to 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S, which is optionally substituted with one, two, or three substituents independently selected from halo, cyano, C 1-C 6 alkoxy, and C 1-C 6 alkyl. In some embodiments, R 6 is a 5- to 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S.

[0072] In some embodiments, R is C6-C10 aryl, optionally substituted with one, two, or three substituents independently selected from halo, cyano, C1-C6 alkoxy, and C1-C6 alkyl. In some embodiments, R is C6-C10 aryl, optionally substituted with one, two, or three substituents independently selected from halo, cyano, C1-C6 alkoxy, and C1-C6 alkyl. In some embodiments, R is C6-C10 aryl. In some embodiments, R is phenyl.

[0073] In some embodiments, R 7 is C 1-C 20 alkyl, C 2-C 8 alkenyl, C 3-C 10 carbocyclyl, C 6-C 10 aryl, 4-8 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 each of the C 1-C 20 alkyl, C 3-C 8 carbocyclyl, C 6-C 10 aryl, 4-6 membered heterocyclyl, or 5-6 membered heteroaryl of R 7 is optionally substituted with one, two, or three substituents independently selected from the group consisting of C 1-C 8 alkyl, halogen, cyano, carbonyl, -N 3, -OR 8, -NR 9R 10, OP(═O)(OH) 2, -OP(═O)(OR 8) 2, C 3-C 8-membered carbocyclyl, a 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl; wherein the C 3 -C 8 carbocyclyl substituent of R 7 is optionally substituted with one, two, or three substituents independently selected from C 1 -C 8 alkyl, halogen, -CF 3, cyano, -CH 2CN, and phenyl, wherein the 4- to 6-membered heterocyclyl substituent of R 7 is optionally substituted with one, two, or three substituents independently selected from carbonyl and C 1 -C 6 alkyl, and wherein the phenyl substituent of R 7 is optionally substituted with one, two, or three substituents independently selected from halogen, cyano, C 1 -C 6 alkyl, and OR 8.

[0074] In some embodiments, R 7 is C 1-C 20 alkyl, C 2-C 8 alkenyl, C 3-C 8 carbocyclyl, C 6-C 10 aryl, 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 each of the C 1-C 20 alkyl, C 3-C 8 carbocyclyl, C 6-C 10 aryl, 4-6 membered heterocyclyl, or 5-6 membered heteroaryl of R 7 is optionally substituted with one, two, or three substituents independently selected from the group consisting of C 1-C 8 alkyl, halogen, cyano, carbonyl, -N 3, -OR 8, -NR 9R 10, OP(═O)(OH) 2, -OP(═O)(OR 8) 2, C 3-C 8-membered carbocyclyl, a 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl; wherein the C3-C8 carbocyclyl substituent of R7 is optionally substituted with one, two, or three substituents independently selected from C1-C8 alkyl, halogen, -CF3, cyano, -CH2CN, and phenyl, wherein the 4- to 6-membered heterocyclyl substituent of R7 is optionally substituted with one, two, or three substituents independently selected from carbonyl and C1-C6 alkyl, and wherein the phenyl substituent of R7 is optionally substituted with one, two, or three substituents independently selected from halogen, cyano, C1-C6 alkyl, and OR8.

[0075] In some embodiments, R 7 is C 1-C 20 alkyl, C 3-C 8 carbocyclyl, C 6-C 10 aryl, 4-6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein each of R 7 's C 1-C 20 alkyl, C 3-C 8 carbocyclyl, C 6-C 10 aryl, 4-6 membered heterocyclyl, or 5-6 membered heteroaryl is optionally substituted with one, two, or three substituents independently selected from the group consisting of C 1-C 8 alkyl, halogen, cyano, carbonyl, -N 3 , -OR 8 , -NR 9R 10 , OP(═O)(OH) 2 , -OP(═O)(OR 8) 2 , C 3-C 8-membered carbocyclyl, a 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl; wherein the C3-C8 carbocyclyl substituent of R7 is optionally substituted with one, two, or three substituents independently selected from C1-C8 alkyl, halogen, -CF3, cyano, -CH2CN, and phenyl, wherein the 4- to 6-membered heterocyclyl substituent of R7 is optionally substituted with one, two, or three substituents independently selected from carbonyl and C1-C6 alkyl, and wherein the phenyl substituent of R7 is optionally substituted with one, two, or three substituents independently selected from halogen, cyano, C1-C6 alkyl, and OR8.

[0076] In some embodiments, R 7 is C 1-C 20 alkyl, C 3-C 8 carbocyclyl, C 6-C 10 aryl, 4-6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein each of the C 1-C 20 alkyl, C 3-C 8 carbocyclyl, C 6-C 10 aryl, 4-6 membered heterocyclyl, or 5-6 membered heteroaryl of R 7 is optionally substituted with one, two, or three substituents independently selected from the group consisting of C 1-C 8 alkyl, -OR 8, -NR 9R 10, -OP(═O)(OH) 2, -OP(═O)(OR 8) 2, C 3-C 8-membered carbocyclyl, a 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl; wherein the C3-C8 carbocyclyl substituent of R7 is optionally substituted with one, two, or three substituents independently selected from C1-C8 alkyl, halogen, -CF3, cyano, -CH2CN, and phenyl, wherein the 4- to 6-membered heterocyclyl substituent of R7 is optionally substituted with one, two, or three substituents independently selected from carbonyl and C1-C6 alkyl, and wherein the phenyl substituent of R7 is optionally substituted with one, two, or three substituents independently selected from halogen, cyano, C1-C6 alkyl, and OR8.

[0077] In some embodiments, R7 is C1-C8 alkyl, C3-C8 carbocyclyl, C6-C10 aryl, 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 the C1-C8 alkyl, C3-C8 carbocyclyl, C6-C10 aryl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl of R7 are each optionally substituted with one, two, or three substituents independently selected from the group consisting of C1-C8 alkyl, -OR8, -OP(=O)(OH)2, C3-C 8-membered 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 substituent of R 7 is optionally substituted with one, two, or three substituents independently selected from carbonyl and C 1-C 6 groups, and wherein the phenyl substituent of R 7 is optionally substituted with one, two, or three substituents independently selected from halo, cyano, and C 1-C 6 alkyl.

[0078] In some embodiments, R 7 is C 1-C 8 alkyl, C 3-C 8 carbocyclyl, C 6-C 10 aryl, 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 the C 1-C 8 alkyl, C 3-C 8 carbocyclyl, C 6-C 10 aryl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl of R 7 are each optionally substituted with one, two, or three substituents independently selected from the group consisting of: -OR 8, -OP(═O)(OH) 2, C 3-C 8-membered carbocyclyl, a 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl; wherein the C3-C8 carbocyclyl substituent of R7 is optionally substituted with one, two, or three substituents independently selected from C1-C8 alkyl, halogen, -CF3, cyano, -CH2CN, and phenyl, wherein the 4- to 6-membered heterocyclyl substituent of R7 is optionally substituted with one, two, or three substituents independently selected from carbonyl and C1-C6 alkyl, and wherein the phenyl substituent of R7 is optionally substituted with one, two, or three substituents independently selected from halogen, cyano, C1-C6 alkyl, and OR8.

[0079] In some embodiments, R 7 is C 1-C 8 alkyl, C 3-C 8 carbocyclyl, C 6-C 10 aryl, 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 the C 1-C 8 alkyl, C 3-C 8 carbocyclyl, C 6-C 10 aryl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl of R 7 are each optionally substituted with one, two, or three substituents independently selected from the group consisting of: -OR 8, -OP(═O)(OH) 2, C 3-C 8-membered 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 substituent of R 7 is optionally substituted with one, two, or three substituents independently selected from carbonyl and C 1-C 6 groups, and wherein the phenyl substituent of R 7 is optionally substituted with one, two, or three substituents independently selected from halo, cyano, and C 1-C 6 alkyl.

[0080] In some embodiments, R 7 is C 1-C 8 alkyl, C 3-C 8 carbocyclyl, C 6-C 10 aryl, 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 the C 1-C 8 alkyl, C 3-C 8 carbocyclyl, C 6-C 10 aryl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl of R 7 are each optionally substituted with one, two, or three substituents independently selected from the group consisting of: -OR 8, -OP(═O)(OH) 2, C 3-C 8-membered 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 one, two, or three substituents independently selected from carbonyl and C1-C6 groups, and wherein the phenyl is optionally substituted with one, two, or three substituents independently selected from halo, cyano, and C1-C6 alkyl.

[0081] In some embodiments, R7 is C1-C8 alkyl, C3-C8 carbocyclyl, C6-C10 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 the C1-C8 alkyl, C3-C8 carbocyclyl, C6-C10 aryl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl of R7 are each optionally substituted with one, two, or three substituents independently selected from the group consisting of C1-C8 alkyl, OR8, -OP(=O)(OH)2, C3-C8 carbocyclyl, and phenyl; wherein the phenyl substituent of R7 is optionally substituted with one, two, or three substituents independently selected from halo, cyano, and C1-C6 alkyl.

[0082] In some embodiments, R7 is C1-C8 alkyl, C3-C8 carbocyclyl, C6-C10 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 the C1-C8 alkyl, C3-C8 carbocyclyl, C6-C10 aryl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl of R7 are each optionally substituted with one, two, or three substituents independently selected from the group consisting of -OR8, -OP(=O)(OH)2, C3-C8 carbocyclyl, and phenyl; wherein the phenyl substituent of R7 is optionally substituted with one, two, or three substituents independently selected from halo, cyano, and C1-C6 alkyl.

[0083] In some embodiments, R7 is C1-C8 alkyl, C3-C8 carbocyclyl, C6-C10 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 the C1-C8 alkyl, C3-C8 carbocyclyl, C6-C10 aryl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl of R7 are each optionally substituted with one, two, or three substituents independently selected from the group consisting of -OR8, -OP(=O)(OH)2, C3-C8 carbocyclyl, and phenyl; wherein the phenyl group is optionally substituted with one, two, or three substituents independently selected from halo, cyano, and C1-C6 alkyl.

[0084] In some embodiments, R7 is C1-C8 alkyl, C3-C8 carbocyclyl, C6-C10 aryl, 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 the C1-C8 alkyl, C3-C8 carbocyclyl, C6-C10 aryl, 4-6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S of R7 are each optionally substituted with one, two, or three substituents independently selected from the group consisting of C1-C8 alkyl, -OR8, -OP(=O)(OH)2, C3-C 8-membered 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 of R7 is optionally substituted with one, two, or three substituents independently selected from carbonyl and C1-C6 alkyl.

[0085] In some embodiments, R 7 is C 1-C 8 alkyl, C 3-C 8 carbocyclyl, C 6-C 10 aryl, 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 the C 1-C 8 alkyl, C 3-C 8 carbocyclyl, C 6-C 10 aryl, 4-6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S of R 7 are each optionally substituted with one, two, or three substituents independently selected from the group consisting of: -OR 8, -OP(═O)(OH) 2, C 3-C 8-membered 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 of R7 is optionally substituted with one, two, or three substituents independently selected from carbonyl and C1-C6 alkyl.

[0086] In some embodiments, R7 is C1-C8 alkyl, C3-C8 carbocyclyl, C6-C10 aryl, 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-C10 aryl, 4-6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S are optionally substituted with one, two, or three substituents independently selected from the group consisting of: -OR8, -OP(=O)(OH)2, C3-C 8-membered 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 one, two, or three substituents independently selected from carbonyl and C 1 -C 6 alkyl.

[0087] In some embodiments, R7 is C1-C8 alkyl, C3-C8 carbocyclyl, C6-C10 aryl, 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 the C1-C8 alkyl, C3-C8 carbocyclyl, C6-C10 aryl, 4-6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S of R7 are each optionally substituted with one, two, or three substituents independently selected from the group consisting of C1-C8 alkyl, -OR8, -OP(=O)(OH)2, C3-C 8-membered 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.

[0088] In some embodiments, R 7 is C 1-C 8 alkyl, C 3-C 8 carbocyclyl, C 6-C 10 aryl, 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 the C 1-C 8 alkyl, C 3-C 8 carbocyclyl, C 6-C 10 aryl, 4-6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S of R 7 are each optionally substituted with one, two, or three substituents independently selected from the group consisting of: -OR 8, -OP(═O)(OH) 2, C 3-C 8-membered 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.

[0089] In some embodiments, R7 is C1-C8 alkyl, C3-C8 carbocyclyl, C6-C10 aryl, 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-C10 aryl, 4-6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S are optionally substituted with one, two, or three substituents independently selected from the group consisting of: -OR8, -OP(=O)(OH)2, C3-C 8-membered 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.

[0090] In some embodiments, R7 is C1-C8 alkyl, C3-C8 carbocyclyl, C6-C10 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 the C1-C8 alkyl, C3-C8 carbocyclyl, C6-C10 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 of R7 are each optionally substituted with one, two, or three substituents independently selected from the group consisting of C1-C8 alkyl, -OR8, -OP(=O)(OH)2, C3-C8 carbocyclyl, and phenyl.

[0091] In some embodiments, R7 is C1-C8 alkyl, C3-C8 carbocyclyl, C6-C10 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 the C1-C8 alkyl, C3-C8 carbocyclyl, C6-C10 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 of R7 are each optionally substituted with one, two, or three substituents independently selected from the group consisting of: -OR8, -OP(=O)(OH)2, C3-C8 carbocyclyl, and phenyl.

[0092] In some embodiments, R7 is C1-C8 alkyl, C3-C8 carbocyclyl, C6-C10 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-C10 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 optionally substituted with one, two, or three substituents independently selected from the group consisting of: -OR8, -OP(=O)(OH)2, C3-C8 carbocyclyl, and phenyl.

[0093] In some embodiments, R 7 is C 1-C 8 alkyl, C 3-C 8 carbocyclyl, C 6-C 10 aryl, 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 the C 1-C 8 alkyl of R 7 is optionally substituted with one, two, or three substituents independently selected from the group consisting of C 1-C 8 alkyl, -OR 8, -OP(═O)(OH) 2, C 3-C 8 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 R The substituents of 7: the 4- to 6-membered heterocyclic group may be optionally substituted with one, two, or three substituents independently selected from carbonyl and C 1 -C 6 alkyl.

[0094] In some embodiments, R 7 is C 1-C 8 alkyl, C 3-C 8 carbocyclyl, C 6-C 10 aryl, 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 the C 1-C 8 alkyl of R 7 is optionally substituted with one, two, or three substituents independently selected from the group consisting of: -OR 8, -OP(═O)(OH) 2, C 3-C 8 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 substituent of R 7 is optionally substituted with one, two, or three substituents independently selected from carbonyl and C 1-C 6 alkyl substituents are substituted.

[0095] In some embodiments, R7 is C1-C8 alkyl, C3-C8 carbocyclyl, C6-C10 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 the C1-C8 alkyl group is optionally substituted with one, two, or three substituents independently selected from the group consisting of: -OR8, -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 group is optionally substituted with one, two, or three substituents independently selected from carbonyl and C1-C6 alkyl.

[0096] In some embodiments, R7 is C1-C8 alkyl, C3-C8 carbocyclyl, C6-C10 aryl, 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 the C1-C8 alkyl group of R7 is optionally substituted with one, two, or three substituents independently selected from the group consisting of -OR8, -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.

[0097] In some embodiments, R7 is C1-C8 alkyl, C3-C8 carbocyclyl, C6-C10 aryl, 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 the C1-C8 alkyl group is optionally substituted with one, two, or three substituents independently selected from the group consisting of -OR8, -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, R7 is C1-C8 alkyl, C3-C8 carbocyclyl, C6-C10 aryl, 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 the C1-C8 alkyl group of R7 is optionally substituted with one, two, or three substituents independently selected from the group consisting of: -OR8, -OP(=O)(OH)2, C3-C8 carbocyclyl, and phenyl.

[0099] In some embodiments, R7 is C1-C8 alkyl, C3-C8 carbocyclyl, C6-C10 aryl, 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 the C1-C8 alkyl group is optionally substituted with one, two, or three substituents independently selected from the group consisting of: -OR8, -OP(=O)(OH)2, C3-C8 carbocyclyl, and phenyl.

[0100] In some embodiments, R 7 is C 1-C 8 alkyl, C 2-C 8 alkenyl, or C 2-C 8 alkynyl; wherein the C 1-C 8 alkyl, C 2-C 8 alkenyl, or C 2-C 8 alkynyl of R 7 is each independently optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, -N 3, -OR 8, -NR 9R 10, -OP(═O)(OH) 2, C 3-C 8 carbocyclyl, and phenyl; wherein phenyl is optionally substituted with one, two, or three substituents independently selected from halo, cyano, and C 1-C 6 alkyl.

[0101] In some embodiments, R7 is C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl; wherein the C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl is each independently optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, -N3, -OR8, -NR9R10, -OP(=O)(OH)2, C3-C8 carbocyclyl, and phenyl; wherein the phenyl is optionally substituted with one, two, or three substituents independently selected from halo, cyano, and C1-C6 alkyl.

[0102] In some embodiments, R 7 is C 1-C 20 alkyl, which is optionally substituted with one, two, or three substituents independently selected from the group consisting of C 1-C 8 alkyl, halogen, cyano, carbonyl, -N 3, -OR 8, -NR 9R 10, -OP(=O)(OH) 2, -OP(=O)(OR 8) 2, C 3-C 8 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 C 3-C 8 carbocyclyl substituent of R 7 is optionally substituted with one, two, or three substituents independently selected from C 1-C 8 alkyl, halogen, -CF 3, cyano, -CH 2CN, and phenyl, wherein R The 4- to 6-membered heterocyclic group of R 7 is optionally substituted by one, two, or three substituents independently selected from carbonyl and C 1-C 6 alkyl, and the phenyl substituent of R 7 is optionally substituted by one, two, or three substituents independently selected from halogen, cyano, C 1-C 6 alkyl, and OR 8.

[0103] In some embodiments, R 7 is C 1-C 20 alkyl, which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, -N 3, -OR 8, -NR 9R 10, -OP(═O)(OH) 2, C 3-C 8 carbocyclyl, a 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl; wherein the 4- to 6-membered heterocyclyl substituent of R 7 is optionally substituted with one, two, or three substituents independently selected from carbonyl and C 1-C 6 groups, and wherein the phenyl substituent of R 7 is optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and C 1-C 6 alkyl.

[0104] In some embodiments, R 7 is C 1-C 8 alkyl, which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, -N 3, -OR 8, -NR 9R 10, -OP(═O)(OH) 2, C 3-C 8 carbocyclyl, a 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl; wherein the 4- to 6-membered heterocyclyl substituent of R 7 is optionally substituted with one, two, or three substituents independently selected from carbonyl and C 1-C 6 group, and wherein the phenyl substituent of R 7 is optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and C 1-C 6 alkyl.

[0105] In some embodiments, R7 is C1-C8 alkyl, which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, -N3, -OR8, -NR9R10, -OP(=O)(OH)2, C3-C8 carbocyclyl, a 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl; wherein the 4- to 6-membered heterocyclyl is optionally substituted with one, two, or three substituents independently selected from carbonyl and C1-C6, and wherein the phenyl is optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and C1-C6 alkyl.

[0106] In some embodiments, R 7 is C 1-C 8 alkyl, which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, carbonyl, -N 3, -OR 8, -NR 9R 10, -OP(═O)(OH) 2, C 3-C 8 carbocyclyl, and phenyl; wherein the C 3-C 8 carbocyclyl substituent of R 7 is optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and C 1-C 6 alkyl, and wherein the phenyl substituent of R 7 is optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and C 1-C 6 alkyl.

[0107] In some embodiments, R 7 is C 1-C 8 alkyl, which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, -N 3, -OR 8, -NR 9R 10, -OP(═O)(OH) 2, C 3-C 8 carbocyclyl, and phenyl; wherein the phenyl substituent of R 7 is optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and C 1-C 6 alkyl.

[0108] In some embodiments, R 7 is C 1-C 8 alkyl, which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, -N 3, -OR 8, -NR 9R 10, -OP(═O)(OH) 2, C 3-C 8 carbocyclyl, and phenyl; wherein the phenyl group is optionally substituted with one, two, or three substituents independently selected from halo, cyano, and C 1-C 6 alkyl.

[0109] In some embodiments, R 7 is C 1-C 6 alkyl, which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, -N 3, -OR 8, -NR 9R 10, -OP(═O)(OH) 2, C 3-C 8 carbocyclyl, and phenyl; wherein the phenyl substituent of R 7 is optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and C 1-C 6 alkyl.

[0110] In some embodiments, R 7 is C 1-C 6 alkyl, which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, -N 3, -OR 8, -NR 9R 10, -OP(═O)(OH) 2, C 3-C 8 carbocyclyl, and phenyl; wherein the phenyl group is optionally substituted with one, two, or three substituents independently selected from halo, cyano, and C 1-C 6 alkyl.

[0111] In some embodiments, R 7 is C 1 -C 8 alkyl, which is optionally substituted with a substituent independently selected from the group consisting of: -OR 8, -OP(=O)(OH) 2, -OP(=O)(OR 8) 2, C 3 -C 8 carbocyclyl, and phenyl.

[0112] In some embodiments, R 7 is C 1-C 8 alkyl, which is optionally substituted with a substituent independently selected from the group consisting of: -OR 8, -OP(=O)(OH) 2, C 3-C 8 carbocyclyl, and phenyl. In some embodiments, R 7 is C 1-C 6 alkyl, which is optionally substituted with a substituent independently selected from the group consisting of: -OR 8, -OP(=O)(OH) 2, C 3-C 8 carbocyclyl, and phenyl.

[0113] In some embodiments, R 7 is C 1-C 8 alkyl substituted with halogen. In some embodiments, R 7 is C 1-C 8 alkyl substituted with -F or -Cl. In some embodiments, R 7 is 、 ,or In some embodiments, R 7 is

[0114] In some embodiments, R 7 is C 1 -C 8 alkyl substituted with -OR 8. In some embodiments, R 7 is C 2 -C 4 alkyl substituted with -OR 8. In some embodiments, R 7 is C 2 -C 4 alkyl substituted with -OCH 3. In some embodiments, R 7 is .

[0115] In some embodiments, R 7 is 、 、 ,or In some embodiments, R 7 is 、 、 、 .

[0116] In some embodiments, R 7 is C 1 -C 8 alkyl substituted with —NR 9R 10. In some embodiments, R 7 is C 1 -C 8 alkyl substituted with —N(CH 3) 2.

[0117] In some embodiments, R 7 is C 1 -C 8 alkyl substituted with carbonyl.

[0118] In some embodiments, R 7 is C 1-C 8 alkyl substituted with a carbonyl group and -OR 8. In some embodiments, R 7 is C 1-C 8 alkyl substituted with a carbonyl group and -OCH 2CH 3. In some embodiments, R 7 is or In some embodiments, R 7 is In some embodiments, R 7 is a C 1-C 8 alkyl group substituted with a carbonyl group and -NR 9R 10. In some embodiments, R 7 is a C 1-C 8 alkyl group substituted with a carbonyl group and -N(CH 3) 2. In some embodiments, R 7 is In some embodiments, R 7 is 、 ,or .

[0119] In some embodiments, R 7 is C 1 -C 8 alkyl substituted with carbonyl and -OC(CH 3) 3. In some embodiments, R 7 is In some embodiments, R 7 is a C 1 -C 8 alkyl group substituted with a carbonyl group and an -OH group. In some embodiments, R 7 is 、 、 ,or .

[0120] In some embodiments, R 7 is C 1-C 8 alkyl substituted with carbonyl, -NR 9R 10, and -OR 8. In some embodiments, R 7 is C 1-C 8 alkyl substituted with carbonyl, -N(CH 3) 2, and -OCH 3. In some embodiments, R 7 is C 1-C 8 alkyl substituted with carbonyl, -N(CH 3) 2, and -OCH(CH 3) 2. In some embodiments, R 7 is C 1-C 8 alkyl substituted with carbonyl, -N(CH 3) 2, and -OCH 2C(CH 3) 3. In some embodiments, R 7 is C 1-C 8 alkyl substituted with carbonyl, -N(CH 3) 2, and -OCH 2C(CH 3) 3. In some embodiments, R 7 is a carbonyl, -N(CH 3) 2, and In some embodiments, R 7 is substituted by carbonyl, -N(CH 3) 2, and In some embodiments, R 7 is 、 、 、 、 、 、 、 ,or In some embodiments, R 7 is 、 、 、 、 、 、 、 ,or .

[0121] In some embodiments, R 7 is a C 1-C 8 alkyl group substituted with a 5- to 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, R 7 is an alkyl group substituted with a pyridyl group, a pyrimidyl group, or an imidazolyl group. In some embodiments, R 7 is 、 、 、 、 ,or .

[0122] In some embodiments, R 7 is C 1-C 8 alkyl substituted with phenyl, wherein the phenyl substituent of R 7 is optionally substituted with one, two, or three substituents independently selected from halo, cyano, C 1-C 6 alkyl, and OR 8. In some embodiments, R 7 is C 1-C 8 alkyl substituted with phenyl, wherein the phenyl substituent of R 7 is substituted with OR 8. In some embodiments, R 7 is .

[0123] In some embodiments, R 7 is C 1-C 8 alkyl substituted with phenyl. In some embodiments, R 7 is C 1-C 4 alkyl substituted with phenyl. In some embodiments, R 7 is .

[0124] In some embodiments, R 7 is In some embodiments, R 7 is or .

[0125] In some embodiments, R 7 is C 1-C 8 alkyl substituted with C 3-C 8 carbocyclyl, wherein the C 3-C 8 carbocyclyl of R 7 is optionally substituted with one, two, or three substituents independently selected from C 1-C 8 alkyl, halogen, -CF 3, cyano, -CH 2CN, and phenyl. In some embodiments, R 7 is 、 、 、 、 、 、 、 、 ,or .

[0126] In some embodiments, R 7 is C 1-C 8 alkyl substituted by C 3-C 8 carbocyclyl. In some embodiments, R 7 is C 2-C 4 alkyl substituted by C 4-C 7 carbocyclyl. In some embodiments, R 7 is C 2-C 4 alkyl substituted by C 4-C 7 carbocyclyl. In some embodiments, R 7 is .

[0127] In some embodiments, R 7 is 、 、 、 、 ,or .

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

[0129] In some embodiments, R 7 is C 1 -C 8 alkyl substituted with a 4- to 6-membered heterocyclic group containing 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, R 7 is In some embodiments, R 7 is a C 1 -C 8 alkyl group substituted with a 4- to 6-membered heterocyclic group containing 1, 2, or 3 heteroatoms selected from N, O, and S, wherein the 4- to 6-membered heterocyclic group of R 7 is substituted with one, two, or three substituents independently selected from the group consisting of a C 1 -C 8 alkyl group and a carbonyl group. In some embodiments, R 7 is .

[0130] In some embodiments, R 7 is C 1-C 8 alkyl substituted with -OP(=O)(OH) 2. In some embodiments, R 7 is C 1-C 4 alkyl substituted with -OP(=O)(OH) 2. In some embodiments, R 7 is .

[0131] In some embodiments, R 7 is C 1 -C 8 alkyl substituted with -OP(=O)(OR 8) 2. In some embodiments, R 7 is .

[0132] In some embodiments, R 7 is C 1-C 20 alkyl. In some embodiments, R 7 is 、 、 、 、 、 、 、 、 ,or In some embodiments, R 7 is 、 、 ,or .

[0133] In some embodiments, R 7 is C 1-C 8 alkyl. In some embodiments, R 7 is C 1-C 6 alkyl. In some embodiments, R 7 is 、 、 、 、 、 ,or In some embodiments, R 7 is 、 、 、 、 、 、 、 、 、 ,or .

[0134] In some embodiments, R 7 is C 1-C 3 alkyl. In some embodiments, R 7 is In some embodiments, R 7 is .

[0135] In some embodiments, R 7 is C 1-C 3 alkyl, and R 1 and R 2 are both -OC(=O)CH 3. In some embodiments, R 7 is , and R 1 and R 2 are both -OC(=O)CH 3. In some embodiments, R 7 is , and R 1 and R 2 are both -OC(=O)CH 3.

[0136] In some embodiments, R 7 is 、 , 、 、 、 、 、 、 、 、 、 , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , 、 、 . 、 、 、 、 、 、 、 、 、 、 、 、 , . 、 、 、 、 、 ,or .

[0137] In some embodiments, R 7 is 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ,or .

[0138] In some embodiments, R 7 is 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ,or .

[0139] In some embodiments, R 7 is C 2 -C 8 alkenyl. In some embodiments, R 7 is .

[0140] In some embodiments, R 7 is C 3 -C 10 carbocyclyl, which is optionally substituted with one, two, or three substituents independently selected from the group consisting of C 1 -C 8 alkyl, halogen, cyano, -N 3 , -OR 8 , -NR 9R 10 , -OP(═O)(OH) 2 , C 3 -C 8 carbocyclyl, and phenyl; wherein the phenyl substituent of R 7 is optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and C 1 -C 6 alkyl.

[0141] In some embodiments, R 7 is C 3 -C 8 carbocyclyl, which is optionally substituted with one, two, or three substituents independently selected from the group consisting of C 1 -C 8 alkyl, halogen, cyano, -N 3 , -OR 8 , -NR 9R 10 , -OP(═O)(OH) 2 , C 3 -C 8 carbocyclyl, and phenyl; wherein the phenyl substituent of R 7 is optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and C 1 -C 6 alkyl.

[0142] In some embodiments, R 7 is C 3 -C 8 carbocyclyl, which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, -N 3 , -OR 8 , -NR 9R 10 , -OP(═O)(OH) 2 , C 3 -C 8 carbocyclyl, and phenyl; wherein the phenyl substituent of R 7 is optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and C 1 -C 6 alkyl.

[0143] In some embodiments, R 7 is C 3 -C 8 carbocyclyl, which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, -N 3 , -OR 8 , -NR 9R 10 , -OP(═O)(OH) 2 , C 3 -C 8 carbocyclyl, and phenyl; wherein the phenyl group is optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and C 1 -C 6 alkyl.

[0144] In some embodiments, R 7 is C 3 -C 8 carbocyclyl, which is optionally substituted with one, two, or three substituents independently selected from the group consisting of C 1 -C 8 alkyl, halogen, cyano, -N 3 , -OR 8 , -NR 9R 10 , -OP(═O)(OH) 2 , C 3 -C 8 carbocyclyl, and phenyl.

[0145] In some embodiments, R 7 is C 3 -C 8 carbocyclyl, which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, -N 3 , -OR 8 , -NR 9R 10 , -OP(=O)(OH) 2 , C 3 -C 8 carbocyclyl, and phenyl.

[0146] In some embodiments, R 7 is C 3 -C 8 carbocyclyl, which is optionally substituted with one, two, or three substituents independently selected from the group consisting of C 1 -C 8 alkyl, -OR 8, -NR 9R 10, C 3 -C 8 carbocyclyl, and phenyl.

[0147] In some embodiments, R 7 is C 3 -C 8 carbocyclyl, which is optionally substituted with one, two, or three substituents independently selected from the group consisting of: -OR 8 , -NR 9R 10 , C 3 -C 8 carbocyclyl, and phenyl.

[0148] In some embodiments, R 7 is C 3 -C 8 carbocyclic group, which is substituted by one, two, or three substituents independently selected from the group consisting of C 1 -C 8 alkyl and halogen. In some embodiments, R 7 is 、 、 、 、 、 、 、 、 、 、 ,or In some embodiments, R 7 is 、 、 、 ,or .

[0149] In some embodiments, R 7 is .

[0150] In some embodiments, R 7 is C 3 -C 10 carbocyclic group. In some embodiments, R 7 is .

[0151] In some embodiments, R 7 is C 3 -C 8 carbocyclic group. In some embodiments, R 7 is 、 ,or .

[0152] In some embodiments, R 7 is 、 ,or .

[0153] In some embodiments, R 7 is 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ,or .

[0154] In some embodiments, R 7 is 、 、 、 、 、 、 、 、 ,or .

[0155] In some embodiments, R 7 is C 6 -C 10 aryl, which is optionally substituted with one, two, or three substituents independently selected from the group consisting of C 1 -C 8 alkyl, halogen, cyano, -N 3, -OR 8, -NR 9R 10, -OP(=O)(OH) 2, C 3 -C 8 carbocyclyl, and phenyl; wherein the phenyl substituent of R 7 is optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and C 1 -C 6 alkyl.

[0156] In some embodiments, R 7 is C 6 -C 10 aryl, which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, -N 3, -OR 8, -NR 9R 10, -OP(═O)(OH) 2, C 3 -C 8 carbocyclyl, and phenyl; wherein the phenyl substituent of R 7 is optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and C 1 -C 6 alkyl.

[0157] In some embodiments, R 7 is C 6 -C 10 aryl, which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, -N 3, -OR 8, -NR 9R 10, -OP(═O)(OH) 2, C 3 -C 8 carbocyclyl, and phenyl; wherein the phenyl group is optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and C 1 -C 6 alkyl.

[0158] In some embodiments, R 7 is C 6 -C 10 aryl, which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, -N 3 , -OR 8 , -NR 9R 10 , -OP(=O)(OH) 2 , C 3 -C 8 carbocyclyl, and phenyl.

[0159] In some embodiments, R 7 is phenyl or naphthyl, which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, -N 3 , -OR 8 , -NR 9R 10 , -OP(=O)(OH) 2 , C 3 -C 8 carbocyclyl, and phenyl.

[0160] In some embodiments, R 7 is phenyl, which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, -N 3 , -OR 8 , -NR 9R 10 , -OP(=O)(OH) 2 , C 3 -C 8 carbocyclyl, and phenyl.

[0161] In some embodiments, R 7 is phenyl, which is substituted with three substituents independently selected from the group consisting of C 1-8 alkyl and -OR 8. In some embodiments, or .

[0162] In some embodiments, R 7is .

[0163] In some embodiments, R 7 is 、 ,or .

[0164] In some embodiments, R 7 is a 4- to 8-membered heterocyclic group containing 1, 2, or 3 heteroatoms selected from N, O, and S, which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, -N 3, -OR 8, -NR 9R 10, -OP(═O)(OH) 2, C 3 -C 8 carbocyclyl, and phenyl; wherein the phenyl substituent of R 7 is optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and C 1 -C 6 alkyl.

[0165] In some embodiments, R 7 is a 4- to 6-membered heterocyclic group containing 1, 2, or 3 heteroatoms selected from N, O, and S, which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, -N 3, -OR 8, -NR 9R 10, -OP(═O)(OH) 2, C 3 -C 8 carbocyclyl, and phenyl; wherein the phenyl substituent of R 7 is optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and C 1 -C 6 alkyl.

[0166] In some embodiments, R 7 is a 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, -N 3, -OR 8, -NR 9R 10, -OP(═O)(OH) 2, C 3 -C 8 carbocyclyl, and phenyl; wherein the phenyl group is optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and C 1 -C 6 alkyl.

[0167] In some embodiments, R 7 is a 4- to 6-membered heterocyclic group containing 1, 2, or 3 heteroatoms selected from N, O, and S, which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, -N 3 , -OR 8 , -NR 9R 10 , -OP(═O)(OH) 2 , C 3 -C 8 carbocyclyl, and phenyl.

[0168] In some embodiments, R 7 is a 6-membered heterocyclic group containing 1, 2, or 3 heteroatoms selected from N, O, and S, which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, -N 3, -OR 8, -NR 9R 10, -OP(═O)(OH) 2, C 3 -C 8 carbocyclyl, and phenyl.

[0169] In some embodiments, R 7 is .

[0170] In some embodiments, R 7 is a 5-membered heterocyclic group containing 1, 2, or 3 heteroatoms selected from N, O, and S, which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, -N 3 , -OR 8 , -NR 9R 10 , -OP(═O)(OH) 2 , C 3 -C 8 carbocyclyl, and phenyl.

[0171] In some embodiments, R 7 is a 5-membered heterocyclic group containing 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, R 7 is .

[0172] In some embodiments, R 7 is a 4-membered heterocyclic group containing 1, 2, or 3 heteroatoms selected from N, O, and S, which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, -N 3 , -OR 8 , -NR 9R 10 , -OP(═O)(OH) 2 , C 3 -C 8 carbocyclyl, and phenyl.

[0173] In some embodiments, R 7 is a 4-membered heterocyclic group containing 1, 2, or 3 heteroatoms selected from N, O, and S.

[0174] In some embodiments, R 7 is .

[0175] In some embodiments, R 7 is 、 ,or .

[0176] In some embodiments, R 7 is In some embodiments, R 7 is .

[0177] In some embodiments, R 7 is a 5- to 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S, which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, -N 3, -OR 8, -NR 9R 10, -OP(═O)(OH) 2, C 3 -C 8 carbocyclyl, and phenyl; wherein the phenyl substituent of R 7 is optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and C 1 -C 6 alkyl.

[0178] In some embodiments, R 7 is a 5- to 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S, which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, -N 3, -OR 8, -NR 9R 10, -OP(═O)(OH) 2, C 3 -C 8 carbocyclyl, and phenyl; wherein the phenyl group is optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and C 1 -C 6 alkyl.

[0179] In some embodiments, R 7 is a 5- to 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S, which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, -N 3 , -OR 8 , -NR 9R 10 , -OP(═O)(OH) 2 , C 3 -C 8 carbocyclyl, and phenyl.

[0180] In some embodiments, R 7 is a 5-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S, which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, -N 3 , -OR 8 , -NR 9R 10 , -OP(═O)(OH) 2 , C 3 -C 8 carbocyclyl, and phenyl.

[0181] In some embodiments, R 7 is a 5-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S.

[0182] In some embodiments, R 7 is a 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S, which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, -N 3, -OR 8, -NR 9R 10, -OP(═O)(OH) 2, C 3 -C 8 carbocyclyl, and phenyl.

[0183] In some embodiments, R 7 is a 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S, which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, and -NR 9R 10.

[0184] In some embodiments, R 7 is a 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, R 7 is 、 ,or .

[0185] In some embodiments, R 7 is 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ,or .

[0186] In some embodiments, R 7 is 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ,or .

[0187] In some embodiments, R 7 is 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ,or .

[0188] In some embodiments, R 7 is 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ,or .

[0189] In some embodiments, R 7 is 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ,or .

[0190] In some embodiments, R 7 is 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ,or .

[0191] In some embodiments, R 8 is H. In some embodiments, R 8 is C 1-C 6 alkyl. In some embodiments, R 8 is -CH 3. In some embodiments, R 8 is C 1-C 6 haloalkyl. In some embodiments, R 8 is C 3-C 6 cycloalkyl.

[0192] In some embodiments, R8 is In some embodiments, R 8 is -C(CH 3) 3, -CH(CH 3) 2, or -CH 2C(CH 3) 3. In some embodiments, R 8 is C 1-C 6 alkyl substituted with C 3-C 6 cycloalkyl. In some embodiments, R 8 is In some embodiments, R 8 is a 4- to 6-membered heterocyclic group. In some embodiments, R 8 is .

[0193] In some embodiments, R 9 is H. In some embodiments, R 9 is C 1-C 6 alkyl. In some embodiments, R 9 is -CH 3. In some embodiments, R 9 is C 1-C 6 haloalkyl. In some embodiments, R 9 is C 3-C 6 cycloalkyl.

[0194] In some embodiments, R 10 is H. In some embodiments, R 10 is C 1-C 6 alkyl. In some embodiments, R 10 is -CH 3. In some embodiments, R 10 is C 1-C 6 haloalkyl. In some embodiments, R 10 is C 3-C 6 cycloalkyl.

[0195] In some embodiments, the base pair In some embodiments, the base sequence In some embodiments, the base sequence .

[0196] In some embodiments, the base pair or .

[0197] In some embodiments, R 11 is C 1 -C 3 alkyl substituted with -OP(=O)(OH)(OR 14). In some embodiments, R 11 is -(CH 2)OP(=O)(OH)(OR 14).

[0198] In some embodiments, R 14 is H. In some embodiments, R 14 is H or C 1-C 8 alkyl; wherein the C 1-C 8 alkyl of R 14 is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, and phenyl.

[0199] In some embodiments, R 14 is C 1-C 8 alkyl, which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, and phenyl. In some embodiments, R 14 is C 1-C 3 alkyl, which is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, and phenyl. In some embodiments, R 14 is C 1-C 3 alkyl substituted with one phenyl. In some embodiments, R 14 is .

[0200] In some embodiments, R 11 is -(CH 2)OP(=O)(OH) 2. In some embodiments, R 11 is .

[0201] In some embodiments, R 12 is H. In some embodiments, R 12 is C 1-C 6 alkyl. In some embodiments, R 12 is -C(=O)R 13. In some embodiments, R 12 is -C(=O)(CH 2) 2CH 3. In some embodiments, R 12 is -C(=O)OR 13. In some embodiments, R 12 is -C(=O)OCH 2CH(CH 3) 2. In some embodiments, R 12 is -C(=O)OCH 2CH(CH 3) 2 or -C(=O)(CH 2) 2CH 3. In some embodiments, R 12 is In some embodiments, R12 is 、 、 、 、 ,or .

[0202] In some embodiments, R12 is .

[0203] In some embodiments, R 13 is C 1-C 8 alkyl; wherein the C 1-C 8 alkyl group of R 13 is optionally substituted with one, two, or three substituents independently selected from halogen, cyano, -OP(=O)(OH)(OR 14), and phenyl, wherein the phenyl substituent of R 13 is optionally substituted with -OP(=O)(OH)(OR 14). In some embodiments, R 13 is C 1-C 8 alkyl, which is optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and phenyl; wherein the phenyl substituent of R 13 is optionally substituted with -OP(=O)(OH)(OR 14).

[0204] In some embodiments, R 13 is H. In some embodiments, R 13 is C 1-C 8 alkyl; wherein the C 1-C 8 alkyl of R 13 is optionally substituted with one, two, or three substituents independently selected from halogen, cyano, -OP(=O)(OH)(OR 14), and phenyl, wherein phenyl is optionally substituted with -OP(=O)(OH)(OR 14). In some embodiments, R 13 is C 1-C 8 alkyl, which is optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and phenyl; wherein phenyl is optionally substituted with -OP(=O)(OH)(OR 14). In some embodiments, R 13 is C 1-C 8 alkyl, which is optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and phenyl. In some embodiments, R 13 is C 1-C 8 alkyl. In some embodiments, R 13 is -CH 3, -CH 2CH 3, -(CH 2) 2CH 3, -CH(CH 3) 2, -(CH 2) 3CH 3, or -C(CH 3) 3. In some embodiments, R 13 is -CH 2CH(CH 3) 2, or -(CH 2) 2CH 3. In some embodiments, R 13 is -(CH 2)OP(=O)(OH) 2.

[0205] In some embodiments, R 13 is -(CH 2)CH(CH 3) 2.

[0206] In some embodiments, R 13 is C 1-C 8 alkyl substituted with phenyl. In some embodiments, R 13 is .

[0207] In some embodiments, the base pair 、 、 、 、 、 、 、 、 ,or .

[0208] In some embodiments, the base pair .

[0209] In some embodiments, the base pair .

[0210] In some embodiments, R 1 is -OH or -OC(=O)R 4; R 2 is -OH or -OC(=O)R 5; R 3 series -C(=O)OR 7; R 4 is C 1-C 3 alkyl; R 5 is C 1-C 3 alkyl; R 7 is C 1-C 6 alkyl or C 6-C 8 carbocyclic group; base series .

[0211] In some embodiments, R 1 series-OC(=O)R 4; R 2 series-OC(=O)R 5; R 3 series -C(=O)OR 7; R 4 is C 1-C 3 alkyl; R 5 is C 1-C 3 alkyl; R 7 is C 1-C 6 alkyl; base series .

[0212] In some embodiments, R 1 is -OH, -OC(=O)R 4, -OC(=O)OR 4, or -OP(=O)(OH)(OR 4); R2 is -OH, -OC(=O)R5, or -OC(=O)OR5; or R 1 and R 2 together form -OC(=O)O-, -OP(=O)(OH)O-, or -OCHR 6O-; R 3 series -C(=O)OR 7; R 4 is C 1-C 8 alkyl or C 2-C 8 alkenyl, wherein the C 1-C 8 alkyl of R 4 is optionally substituted by one or two substituents independently selected from carbonyl and -OR 8; R 5 is C 1-C 8 alkyl or C 2-C 8 alkenyl; R 7 is C 1-C 20 alkyl, C 2-C 8 alkenyl, C 3-C 10 carbocyclyl, C 6-C 10 aryl, 4- to 8-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 the C1-C20 alkyl, C3-C10 carbocyclyl, C6-C10 aryl, or 4- to 8-membered heterocyclyl of R7 is each independently optionally substituted with one, two, or three substituents independently selected from the group consisting of C1-C8 alkyl, halogen, carbonyl, -OR8, -NR9R10, -OP(=O)(OH)2, -OP(=O)(OR8)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 substituent C 3 -C 8 carbocyclyl of R 7 is optionally substituted by one or two substituents independently selected from C 1 -C 8 alkyl, halogen, -CF 3 , cyano, -CH 2CN, and phenyl, wherein the substituent of R7 is a 4- to 6-membered heterocyclic group which is optionally substituted by two substituents independently selected from carbonyl and C1-C6 alkyl, and Wherein R 7 phenyl substituent is optionally substituted by -OR 8; R 6 is C 1-C 6 alkoxy or C 6-C 10 aryl; Each R 8 is independently H, C 1-C 6 alkyl, C 3-C 6 cycloalkyl, and 4 to 6 membered heterocyclic group; Wherein R 8 of C 1-C 6 alkyl is optionally substituted by C 3-C 6 cycloalkyl; Each R 9 and R 10 are independently C 1-C 6 alkyl; base series or ; R 11 is C 1-C 6 alkyl optionally substituted by -OP(=O)(OH)(OR 14); R 12 is H, -C(=O)R 13, or -C(=O)OR 13; each R 13 is independently C 1 -C 8 alkyl optionally substituted with phenyl or -OP(=O)(OH)(OR 14); and Each R 14 is independently H or C 1-C 8 alkyl; wherein the C 1-C 8 alkyl of R 14 is optionally substituted with phenyl.

[0213] In some embodiments, R 1 is -OH, -OC(=O)R 4, or -OC(=O)OR 4; R2 is -OH, -OC(=O)R5, or -OC(=O)OR5; or R 1 and R 2 together form -OC(=O)O-, -OP(=O)(OH)O-, or -OCHR 6O-; R 3 series -C(=O)OR 7; R 4 is C 1-C 8 alkyl or C 2-C 8 alkenyl, wherein the C 1-C 8 alkyl of R 4 is optionally substituted by one or two substituents independently selected from carbonyl and -OR 8; R 5 is C 1-C 8 alkyl or C 2-C 8 alkenyl; R 7 is C 1-C 20 alkyl, C 2-C 8 alkenyl, C 3-C 8 carbocyclyl, C 6-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 the C1-C20 alkyl, C3-C8 carbocyclyl, or C6-C10 aryl of R7 is each independently optionally substituted with one, two, or three substituents independently selected from the group consisting of C1-C8 alkyl, halogen, carbonyl, -OR8, -NR9R10, -OP(=O)(OH)2, -OP(=O)(OR8)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 substituent C 3 -C 8 carbocyclyl of R 7 is optionally substituted by one or two substituents independently selected from C 1 -C 8 alkyl, halogen, -CF 3 , cyano, -CH 2CN, and phenyl, wherein the substituent of R7 is a 4- to 6-membered heterocyclic group which is optionally substituted by two substituents independently selected from carbonyl and C1-C6 alkyl, and Wherein R 7 phenyl substituent is optionally substituted by -OR 8; R 6 is C 1-C 6 alkoxy or C 6-C 10 aryl; Each R 8 is independently H or C 1-C 6 alkyl; Each R 9 and R 10 are independently C 1-C 6 alkyl; base series or ; R 11 is C 1-C 6 alkyl optionally substituted by -OP(=O)(OH)(OR 14); R 12 is H, -C(=O)R 13, or -C(=O)OR 13; each R 13 is independently C 1 -C 8 alkyl optionally substituted with phenyl or -OP(=O)(OH)(OR 14); and Each R 14 is independently H or C 1-C 8 alkyl; wherein the C 1-C 8 alkyl of R 14 is optionally substituted with phenyl.

[0214] In some embodiments, R 1 is -OH, -OC(=O)R 4, or -OC(=O)OR 4; R2 is -OH, -OC(=O)R5, or -OC(=O)OR5; or R 1 and R 2 together form -OC(=O)O-, -OP(=O)(OH)O-, or -OCHR 6O-; R 3 series -C(=O)OR 7; R 4 and R 5 are C 1-C 8 alkyl; R 7 is C 1-C 20 alkyl, C 2-C 8 alkenyl, C 3-C 8 carbocyclyl, C 6-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 the C1-C20 alkyl, C3-C8 carbocyclyl, or C6-C10 aryl of R7 is each independently optionally substituted with one, two, or three substituents independently selected from the group consisting of C1-C8 alkyl, halogen, carbonyl, -OR8, -NR9R10, -OP(=O)(OH)2, -OP(=O)(OR8)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 substituent C 3 -C 8 carbocyclyl of R 7 is optionally substituted by one or two substituents independently selected from C 1 -C 8 alkyl, halogen, -CF 3 , cyano, -CH 2CN, and phenyl, wherein the substituent of R7 is a 4- to 6-membered heterocyclic group which is optionally substituted by two substituents independently selected from carbonyl and C1-C6 alkyl, and Wherein R 7 phenyl substituent is optionally substituted by -OR 8; R 6 is C 1-C 6 alkoxy or C 6-C 10 aryl; Each R 8, R 9, and R 10 is independently C 1-C 6 alkyl; base series or ; R 11 is C 1-C 6 alkyl optionally substituted by -OP(=O)(OH)(OR 14); R 12 is H, -C(=O)R 13, or -C(=O)OR 13; each R 13 is independently C 1 -C 8 alkyl optionally substituted with -OP(=O)(OH)(OR 14); and Each R 14 is independently H or C 1-C 8 alkyl; wherein the C 1-C 8 alkyl of R 14 is optionally substituted with phenyl.

[0215] In some embodiments, R 1 is –OH or –OC(=O)R 4; R2 is -OH or -OC(=O)R5; or R 1 and R 2 together form -OC(=O)O- or -OP(=O)(OH)O-; R 3 series -C(=O)OR 7; R 4, R 5 and R 7 are each independently C 1-C 8 alkyl, C 3-C 8 carbocyclyl, C 6-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 the C 1-C 8 alkyl groups of R 7 are each independently optionally substituted with a substituent selected from the group consisting of: C 1-C 8 alkyl, -OR 8, -OP(═O)(OH) 2, C 3-C 8 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 heterocyclic group is optionally substituted by one, two, or three substituents independently selected from carbonyl and C 1-C 6 alkyl; Each R 8 is independently C 1-C 6 alkyl; base series or ; R 11 is a C 1-C 6 alkyl group substituted with -OP(=O)(OH)(OR 14); R 12 is H, -C(=O)R 13, or -C(=O)OR 13; R 13 is C 1 -C 8 alkyl optionally substituted with -OP(=O)(OH)(OR 14); and Each R 14 is independently H or C 1-C 8 alkyl; wherein the C 1-C 8 alkyl of R 14 is optionally substituted with phenyl.

[0216] In some embodiments, R 1 is –OH or –OC(=O)R 4; R2 is -OH or -OC(=O)R5; or R 1 and R 2 together form -OC(=O)O- or -OP(=O)(OH)O-; R 3 series -C(=O)OR 7; R 4, R 5 and R 7 are each independently C 1-C 8 alkyl, C 3-C 8 carbocyclyl, C 6-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 the C 1-C 8 alkyl group of R 7 is each independently optionally substituted with a substituent selected from the group consisting of: -OR 8, -OP(=O)(OH) 2, a C 3-C 8 carbocyclyl, a 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and a phenyl group; wherein the 4- to 6-membered heterocyclic group is optionally substituted by one, two, or three substituents independently selected from carbonyl and C 1-C 6 alkyl; Each R 8 is independently C 1-C 6 alkyl; base series or ; R 11 is a C 1-C 6 alkyl group substituted with -OP(=O)(OH)(OR 14); R 12 is H, -C(=O)R 13, or -C(=O)OR 13; R 13 is C 1 -C 8 alkyl optionally substituted with -OP(=O)(OH)(OR 14); and Each R 14 is independently H or C 1-C 8 alkyl; wherein the C 1-C 8 alkyl of R 14 is optionally substituted with phenyl.

[0217] In some embodiments, R 1 is –OH or –OC(=O)R 4; R2 is -OH or -OC(=O)R5; or R 1 and R 2 together form -OC(=O)O; R 3 series -C(=O)OR 7; R 4, R 5 and R 7 are each independently C 1-C 8 alkyl, C 3-C 8 carbocyclyl, C 6-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 the C 1-C 8 alkyl of R 7 is each independently optionally substituted by a substituent selected from the group consisting of: -OR 8, -OP(=O)(OH) 2, C 3-C 8 carbocyclyl, and phenyl; Each R 8 is independently C 1-C 6 alkyl; base series or ; R 11 is a C 1-C 6 alkyl group substituted with -OP(=O)(OH)(OR 14); R 12 is H, -C(=O)R 13, or -C(=O)OR 13; R 13 is C 1-C 8 alkyl; and Each R 14 is independently H or C 1-C 8 alkyl; wherein the C 1-C 8 alkyl of R 14 is optionally substituted with phenyl.

[0218] In some embodiments, R 1 is –OH or –OC(=O)R 4; R2 is -OH or -OC(=O)R5; or R 1 and R 2 together form -OC(=O)O-; R 3 series -C(=O)OR 7; R 4, R 5, and R 7 are each independently C 1-C 8 alkyl, C 3-C 8 carbocyclyl, C 6-C 10 aryl, or a 4- to 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and S; Wherein R 7 C 1-C 8 alkyl are each independently optionally substituted by a substituent selected from the group consisting of -OR 8 and phenyl; Each R 8 is independently C 1-C 6 alkyl; base series or ; R 11 is a C 1-C 6 alkyl group substituted with -OP(=O)(OH)(OR 14); R 12 is H, -C(=O)R 13, or -C(=O)OR 13; R 13 is C 1-C 8 alkyl; and Each R 14 is independently H or C 1-C 8 alkyl; wherein the C 1-C 8 alkyl of R 14 is optionally substituted with phenyl.

[0219] In some embodiments, the compound of formula I is , or a pharmaceutically acceptable salt thereof.

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

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

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

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

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

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

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

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

[0228] In some embodiments, the compound of formula I is Instance number Compound number structure Example 1 1 Example 2 2 Example 3 3 Example 4 4 Example 5 5 Example 6 6 Example 7 7 Example 8 8 Example 9 9 Example 10 10 Example 11 11 Example 12 12 Example 13 13 Example 14 14 Example 15 15 Example 16 16 Example 17 17 Example 18 18 Example 19 19 Example 20 20 Example 21 twenty one or a pharmaceutically acceptable salt thereof.

[0229] In some embodiments, the compound of formula I is Instance number Compound number structure twenty two twenty three twenty four 25 Example 80 26 Example 74 27 28 Example 30 29 30 Example 72 31 32 33 34 Example 38 35 36 Example 81 37 38 39 Example 95 40 41 42 43 44 45 or a pharmaceutically acceptable salt thereof.

[0230] In some embodiments, the compound of formula I is Instance number Compound number structure Example 22 46 Example 23 47 Example 24 48 Example 25 49 Example 26 50 Example 27 51 Example 28 52 Example 29 53 Example 31 54 Example 32 55 Example 33 56 Example 34 57 Example 35 58 Example 36 59 Example 37 60 Example 39 62 Example 40 63 Example 42 64 Example 43 65 Example 44 66 Example 45 67 Example 46 68 Example 47 69 Example 48 70 Example 49 71 Example 50 72 Example 51 73 Example 52 74 Example 53 75 Example 54 76 Example 55 77 Example 56 78 Example 57 79 Example 58 80 Example 59 81 Example 60 82 Example 61 83 Example 62 84 Example 63 85 Example 64 86 Example 65 87 Example 66 88 Example 67 89 Example 68 90 Example 69 91 Example 70 92 Example 71 93 Example 73 94 Example 75 96 Example 76 97 Example 77 98 Example 78 99 Example 79 100 or a pharmaceutically acceptable salt thereof.

[0231] In some embodiments, the compound of formula I is Instance number Compound number structure Example 93 101 102 Example 96 103 104 105 Example 92 106 Example 97 107 108 109 Example 94 110 Example 109 111 Example 101 112 Example 102 114 Example 103 115 Example 104 116 Example 105 117 Example 106 118 Example 107 119 Example 99 120 Example 100 121 Example 108 122 Example 109 123 Example 113 124 Example 98 125 Example 114 126 or a pharmaceutically acceptable salt thereof.

[0232] In some embodiments, the compound of formula I is Instance number Compound number structure Example 82 127 Example 83 128 Example 84 129 Example 85 130 Example 86 131 Example 87 132 Example 88 133 Example 89 134 Example 90 135 Example 91 136 or a pharmaceutically acceptable salt thereof.

[0233] In some embodiments, the compound of formula I is Instance number Compound number structure Example 110 137 Example 111 138 Example 112 139 Example 115 140 Example 116 141 Example 117 142 Example 118 143 Example 119 144 Example 120 145 Example 121 146 Example 122 147 Example 123 148 Example 124 149 Example 125 150 Example 126 151 Example 127 152 Example 128 153 Example 131 154 Example 132 155 Example 133 156 or a pharmaceutically acceptable salt thereof. V. Pharmaceutical Formulas

[0234] The compounds disclosed herein can be formulated with conventional carriers and excipients. For example, tablets will contain excipients, glidants, fillers, binders, and the like. Aqueous formulations are prepared sterile and are typically isotonic when intended for oral administration. 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 formulations contain one or more pharmaceutically acceptable excipients. The pH of the formulations ranges from about 3 to about 11, but is typically about 7 to 10. In some embodiments, the pH of the formulations ranges from about 2 to about 5, but is typically about 3 to 4.

[0235] While the compounds of the present disclosure ("active ingredients") can be administered alone, they are preferably presented as pharmaceutical formulations. The formulations of the present invention (for both animal medicine and human use) comprise at least one active ingredient (as defined above), together with one or more carriers acceptable therefor, and optionally other therapeutic ingredients, especially additional therapeutic ingredients as discussed herein. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0236] Formulations include those suitable for the aforementioned routes of administration. The formulations are conveniently presented in unit dosage form and may be prepared by any suitable method known in the art of pharmaceutical technology. Techniques and formulations generally are found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing the active ingredient into association with a carrier, which may comprise one or more accessory ingredients. Generally, formulations are prepared by uniformly and intimately admixing the active ingredient with a liquid carrier or a finely divided solid carrier, or both, and then, if necessary, shaping the product.

[0237] In some embodiments, the pharmaceutical formulation is for subcutaneous, intramuscular, intravenous, oral, or inhalation administration.

[0238] In some embodiments, the compounds described herein (e.g., compounds of Formula I) or pharmaceutically acceptable salts thereof described herein have optimized / improved pharmacokinetic properties and are suitable for oral administration. For example, compounds of Formula I have improved bioavailability and, therefore, can be administered by oral administration.

[0239] In some embodiments, the formulations of the present invention are suitable for oral administration and 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 liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be administered as a bolus, electuary, or paste.

[0240] In some embodiments, tablets are made by compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form (such as a powder or granules) in a suitable machine, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant, or dispersant. Molded tablets can be made by molding a mixture of the powdered active ingredient moistened with an inert liquid diluent in a suitable machine. The tablets may optionally be coated or scored and are optionally formulated so as to provide slow or controlled release of the active ingredient therefrom.

[0241] For infections of the eye or other external tissues (e.g., mouth and skin), the formulation is applied as a topical ointment or cream containing the active ingredient(s) in an amount, for example, from 0.075 to about 20% w / w (including active ingredient(s) in a range between 0.1% and 20% in increments of 0.1% w / w, such as 0.6% w / w, 0.7% w / w, etc.), preferably 0.2 to 15% w / w, and most preferably 0.5 to 10% w / w. When formulated as an ointment, the active ingredient may be employed with a paraffinic or water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream with an oil-in-water cream base.

[0242] If desired, the aqueous phase of the cream base may include, for example, at least 30% w / w of a polyol, i.e., an alcohol having two or more hydroxyl groups, such as propylene glycol, 1,3-butylene glycol, mannitol, sorbitol, glycerol, and polyethylene glycol (including PEG 400), and mixtures thereof. Topical formulations may desirably include compounds that enhance the absorption or penetration of the active ingredient through the skin or other affected area. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogs.

[0243] The oil phase of the emulsions of the present invention can be composed of known ingredients in a known manner. While this phase may comprise only an emulsifier (also known as an emulsifier), it desirably comprises a mixture of at least one emulsifier with a fat or oil, or both. 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. The emulsifier(s) (with or without stabilizer(s)) together constitute the so-called emulsified wax, and the wax together with the oil and fat constitute the so-called emulsified ointment base, which forms the oily dispersed phase of the cream formulation.

[0244] Suitable emulsions and emulsion stabilizers for use in the formulations of the present invention include Tween® 60, Span® 80, cetearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate. Additional emulsions and emulsion stabilizers for use in the formulations of the present invention include Tween® 80.

[0245] The choice of oil or fat suitable for the formulation is based on achieving the desired cosmetic properties. Creams should preferably be non-greasy, non-staining, and washable, with suitable consistency to prevent leakage from tubes or other containers. Linear or branched, mono- or dibasic alkyl esters can be used, such as diisoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate, or the branched ester blend known as Crodamol CAP, the last three being the preferred esters. These can 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 can be used.

[0246] Pharmaceutical formulations according to the present invention comprise a compound according to the present invention together with one or more pharmaceutically acceptable carriers or excipients and, optionally, other therapeutic agents. Pharmaceutical formulations containing the active ingredient may be in any form suitable for the intended method of administration. For example, for oral use, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known in the art of pharmaceutical composition manufacture, and such compositions may contain one or more agents, including sweeteners, flavorings, coloring agents, and preservatives, to provide a palatable preparation. Tablets containing the active ingredient admixed with non-toxic, pharmaceutically acceptable excipients suitable for tablet manufacture are acceptable. Such excipients may include, for example, inert diluents such as calcium or sodium carbonate, lactose, or 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 absorption 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, alone or with a wax, may be employed.

[0247] Formulations for oral use may also be presented in hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, such as calcium phosphate or kaolin, or in soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil.

[0248] Aqueous suspensions of the present invention contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents (such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum arabic) and dispersing or wetting agents (such as naturally occurring phospholipids (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), 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-hydroxybenzoate), one or more coloring agents, 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®.

[0249] Oily suspensions can be prepared by suspending the active ingredient in a vegetable oil (such as peanut oil, olive oil, sesame oil, or coconut oil) or in a mineral oil (such as liquid paraffin). Oral suspensions may contain a thickening agent such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners (such as those mentioned above) and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant (such as ascorbic acid).

[0250] The dispersible powders and granules of the present invention, suitable for preparing an aqueous suspension by adding water, provide the active ingredient in admixture with a dispersant or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersants or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients (e.g., sweeteners, flavorings, and coloring agents) may also be present.

[0251] The pharmaceutical compositions of the present invention may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil (such as olive oil or peanut oil), a mineral oil (such as liquid paraffin), or a mixture thereof. Suitable emulsifiers include naturally occurring gums (such as gum arabic and gum tragacanth), naturally occurring phospholipids (such as soy lecithin), esters or partial esters derived from fatty acids and hexitol anhydrides (such as sorbitan monooleate), and condensation products of these partial esters with ethylene oxide (such as polyoxyethylene sorbitan monooleate). Emulsions may also contain sweeteners and flavorings. Syrups and elixirs may be formulated with sweeteners (such as glycerol, sorbitol, or sucrose). Such formulations may also contain a palliative, preservatives, flavorings, or coloring agents.

[0252] The pharmaceutical compositions of the present invention may be in the form of sterile injectable preparations, such as sterile injectable aqueous or oleaginous suspensions. Such suspensions can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents as mentioned above. Sterile injectable preparations may also be sterile injectable solutions or suspensions in a nontoxic parenterally acceptable diluent or solvent (such as a solution in 1,3-butanediol) or prepared as lyophilized powders. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, conventional sterile fixed oils may be used as solvents or suspending media. For this purpose, any bland fixed oil may be used, including synthetic monoglycerides or diglycerides. Furthermore, fatty acids (such as oleic acid) may similarly be used in the preparation of injectable preparations. Acceptable vehicles and solvents that may be used include water, Ringer's solution, isotonic sodium chloride solution, and hypertonic sodium chloride solution.

[0253] The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the specific mode of administration. For example, a time-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active material mixed 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 approximately 3 to 500 mg of active ingredient per mL of solution, allowing for infusion of a suitable volume at a rate of about 30 mL / hr.

[0254] Formulations suitable for topical administration to the eye also include eye drops in which the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations at a concentration of 0.5 to 20%, advantageously 0.5 to 10%, and particularly about 1.5% w / w.

[0255] Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

[0256] Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.

[0257] In some embodiments, the compounds disclosed herein are administered by inhalation. In some embodiments, formulations suitable for intrapulmonary or intranasal administration have a particle size, for example, in the range of 0.1 to 500 microns, such as 0.5, 1, 30, 35, etc., and are administered by rapid inhalation through the nasal passages or by inhalation through the mouth to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration can be prepared according to conventional methods and can be delivered with other therapeutic agents. In some embodiments, the compounds used herein are formulated and administered as dry powders. In some embodiments, the compounds used herein are formulated and administered as a nebulized formulation. 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.

[0258] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

[0259] Suitable formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions, which may contain antioxidants, buffers, bacteriostatics, and solutes that 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.

[0260] The formulations are presented in unit-dose or multi-dose containers (e.g., sealed ampoules and vials) and can be stored in a freeze-dried (lyophilized) condition, requiring only the addition of a sterile liquid carrier (e.g., water for injection) immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules, and tablets of the kind previously described. Preferred unit-dose formulations are those containing a daily dose or unit daily subdose (as described herein above), or an appropriate fraction thereof, of the active ingredient.

[0261] It should be understood that in addition to the ingredients particularly mentioned above, the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example, those suitable for oral administration may include flavoring agents.

[0262] The present invention further provides an animal pharmaceutical composition comprising at least one active ingredient as defined above together with an animal pharmaceutical carrier therefor.

[0263] Veterinary pharmaceutical carriers are materials useful for administering the composition and can be solid, liquid, or gaseous materials that are either inert or acceptable in the field of veterinary medicine and compatible with the active ingredient. These veterinary pharmaceutical compositions can be administered orally, parenterally, or by any other desired route.

[0264] The compounds of the present invention are useful in providing controlled-release pharmaceutical formulations containing one or more compounds of the present invention as active ingredients ("controlled-release formulations"), wherein the release of the active ingredient is controlled and regulated to allow less frequent dosing or to improve the pharmacokinetic or toxicity profile of a given active ingredient. [] [VI.] [Set]

[0265] Also provided herein are kits comprising a compound disclosed herein, a pharmaceutically acceptable salt thereof, a stereoisomer, a mixture of stereoisomers, or a tautomer thereof. In some embodiments, the kits described herein may include labeling and / or instructions for using the compound to treat 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.

[0266] In some embodiments, the kit may also comprise instructions for use of one or more additional therapeutic agents and / or additional therapeutic agents in combination with a compound of Formula I in treating a disease or condition in a subject (e.g., a human) in need thereof.

[0267] In some embodiments, the kits provided herein contain individual dosage units of a compound as described herein, or a pharmaceutically acceptable salt, racemate, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, amorphous form, hydrate, or solvate thereof. Examples of individual dosage units may include pills, tablets, capsules, prefilled syringes or syringe cartridges, IV bags, inhalers, nebulizers, etc., each containing a therapeutically effective amount of the compound in question, or a pharmaceutically acceptable salt, racemate, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, amorphous form, hydrate, or solvate thereof. In some embodiments, a kit may contain a single dosage unit, while in other cases, there may be multiple dosage units, such as the number of dosage units required for a given regimen or period.

[0268] Also provided are articles 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 container of the article of manufacture is a vial, a jar, an ampoule, a pre-filled syringe, a blister pack, a tin, a can, a bottle, a box, an intravenous bag, an inhaler, or a nebulizer. [] [VII.] [Injection]

[0269] 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), and the like. In some embodiments, the compounds disclosed herein are administered by inhalation or intravenously. In some embodiments, the compounds disclosed herein are administered orally. It will be appreciated that the preferred route may vary depending, for example, on the condition of the recipient.

[0270] In the methods of the present invention for treating viral infections, the compounds of the present invention can be administered at any time to a human who may have come into contact with a virus or who has already contracted a viral infection. In some embodiments, the compounds of the present invention can be administered prophylactically to a human who has come into contact with a human who has contracted a viral infection or who is at risk of coming into contact with a human who has contracted a viral infection (e.g., a healthcare provider). In some embodiments, the compounds of the present invention can be administered to a human who has tested positive for a viral infection but has not yet developed symptoms of the viral infection. In some embodiments, the compounds of the present invention can be administered to a human who has begun to develop symptoms of a viral infection.

[0271] In some embodiments, the methods disclosed herein comprise event-driven administration to a subject of a compound described herein, eg, a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0272] As used herein, the term "event driven" or "event driven administration" refers to the administration of a compound described herein (e.g., a compound of Formula I) or a pharmaceutically acceptable salt thereof (1) before (e.g., 2 hours, 1 day, 2 days, 5 days, or 7 or more days before) an event that would expose a subject to a virus (or would otherwise increase the subject's risk of acquiring a viral infection); and / or (2) during an event (or more than one recurring event) that would expose a subject to a virus (or would otherwise increase the subject's risk of acquiring a viral infection); and / or (3) after (or after the final event in a series of recurring events) an event that would expose a subject to a virus (or would otherwise increase the subject's risk of acquiring a viral infection). In some embodiments, event-driven administration is performed before the subject is exposed to the virus. In some embodiments, event-driven administration is performed after the subject is exposed to the virus. In some embodiments, event-driven administration is performed both before and after the subject is exposed to the virus.

[0273] In certain embodiments, the methods disclosed herein involve administration before and / or after an event that would expose a subject to a virus or otherwise increase the subject's risk of acquiring a viral infection, for example, as pre-exposure prophylaxis (PrEP) and / or as post-exposure prophylaxis (PEP). In some embodiments, the methods disclosed herein comprise pre-exposure prophylaxis (PrEP). In some embodiments, the methods disclosed herein comprise post-exposure prophylaxis (PEP).

[0274] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered to the subject prior to exposure to the virus.

[0275] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered to a subject before and after exposure to the virus.

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

[0277] An example of an event-driven dosing regimen includes administering a compound of Formula I, or a pharmaceutically acceptable salt thereof, within 24 to 2 hours before the viral exposure, followed by administration of a compound of Formula I, or a pharmaceutically acceptable salt thereof, every 24 hours during the exposure period, followed by further administration of a compound of Formula I, or a pharmaceutically acceptable salt thereof, after the last exposure, and a final administration of a compound of Formula I, or a pharmaceutically acceptable salt thereof, 24 hours later.

[0278] 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 prior to viral exposure, followed by daily administration during the exposure period, followed by a final administration (which may be an increasing dose, such as a double dose) approximately 24 hours after the last exposure.

[0279] The specific dosage level of a compound of the present disclosure for any particular subject will depend on various factors, including the activity of the specific compound employed, age, weight, overall health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination, and the severity of the particular disease in the subject being treated. For example, a dosage may be expressed as milligrams of a compound described herein per kilogram of subject body weight (mg / kg). Doses between approximately 0.1 and 150 mg / kg may be appropriate. In some embodiments, doses between approximately 0.1 and 100 mg / kg may be appropriate. In other embodiments, doses between 0.5 and 60 mg / kg may be appropriate. Normalizing by subject weight is particularly useful when adjusting dosages between subjects of widely varying sizes, such as occurs when administering a drug to both pediatric and adult humans, or when converting an effective dose in a non-human subject (such as a dog) to a dose suitable for use in a human subject.

[0280] A daily dose can also be described as the total amount of a compound described herein administered per dose or per day. A daily dose of a compound of Formula I, or a pharmaceutically acceptable salt thereof, can be between about 1 mg and 4,000 mg, between about 2,000 and 4,000 mg / day, between about 1 and 2,000 mg / day, between about 1 and 1,000 mg / day, between about 10 and 500 mg / day, between about 20 and 500 mg / day, between about 50 and 300 mg / day, between about 75 and 200 mg / day, or between about 15 and 150 mg / day.

[0281] The dosage or administration frequency of the compounds of the present disclosure may be adjusted during the course of treatment based on the judgment of the administering physician.

[0282] The compounds disclosed herein can be administered to a subject (e.g., a human) in a therapeutically effective amount. In some embodiments, the compounds are administered once daily.

[0283] The compounds provided herein can be administered by any available route and means, such as by oral or parenteral (e.g., intravenous) administration. A therapeutically effective amount of the compound may include about 0.00001 mg / kg body weight to about 10 mg / kg body weight per day, such as about 0.0001 mg / kg body weight to about 10 mg / kg body weight per day, or such as about 0.001 mg / kg body weight to about 1 mg / kg body weight per day, or such as about 0.01 mg / kg body weight to about 1 mg / kg body weight per day, or such as about 0.05 mg / kg body weight to about 0.5 mg / kg body weight per day. In some embodiments, a therapeutically effective amount of the compound provided herein includes about 0.3 mg to about 30 mg per day, or about 30 mg to about 300 mg per day, or about 0.3 mg to about 30 mg per day, or about 30 mg to about 300 mg per day.

[0284] The compounds of the present disclosure may be combined with one or more additional therapeutic agents at any dose of the compounds of the present disclosure (e.g., 1 mg to 1000 mg of the compounds). A therapeutically effective amount may include about 0.1 mg to about 1000 mg per dose, such as about 50 mg to about 500 mg per dose, or such as about 100 mg to about 400 mg per dose, or such as about 150 mg to about 350 mg per dose, or such as about 200 mg to about 300 mg per dose, or such as about 0.01 mg to about 1000 mg per dose, or such as about 0.01 mg to about 100 mg per dose, or such as about 0.1 mg to about 100 mg per dose, or such as about 1 mg to about 100 mg per dose, or such as about 1 mg to about 10 mg per dose, or such as about 1 mg 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 the compounds of the 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.

[0285] In some embodiments, the methods described herein comprise administering to a subject an initial daily dose of about 1 to 500 mg of a compound provided herein and increasing the dose by increments until a clinical therapeutic effect is achieved. The dose may be increased by increments of about 5, 10, 25, 50, or 100 mg. The dose may be increased daily, every other day, twice a week, weekly, every two weeks, every three weeks, or monthly.

[0286] When administered orally, the total daily dosage for human subjects can be between about 1 to 4,000 mg / day, between about 1 to 3,000 mg / day, between about 1 to 2,000 mg / day, between about 1 to 1,000 mg / day, between about 10 to 500 mg / day, between about 50 to 300 mg / day, between about 75 to 200 mg / day, or between about 100 to 150 mg / day. In some embodiments, the total daily dose for a human subject may be about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, or 3000 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 200, 300, 400, 500, 600, 700, or 800 mg / day administered as a single dose. In some embodiments, the total daily dosage for human subjects may be about 300, 400, 500, or 600 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject may be about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800, 3900, or 4000 mg / day.In some embodiments, the total daily dose for a human subject may be about 100-200, 100-300, 100-400, 100-500, 100-600, 100-700, 100-800, 100-900, 100-1000, 500-1100, 500-1200, 500-1300, 500-1400, 500-1500, 500-1600, 500-1700, 500-1800, 500-1900, 500-2000, 1500-2100, 1500-2200, 1500-2100, 1500-2200, 1500-2100, 1500-2100, 1500-2100, 1500-2100, 1500-2100, 1500-2100, 1500-2100, 1500-2100, 1500-2100 00, 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.

[0287] In some embodiments, the total daily dose for a human subject may be about 100 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 150 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 200 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 250 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 300 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 350 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 400 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 450 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 500 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 550 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 600 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 650 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 700 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 750 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 800 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 850 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 900 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 950 mg / day administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 1000 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject may be about 1500 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject may be about 2000 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject may be about 2500 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject may be about 3000 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject may be about 4000 mg / day administered in a single dose.

[0288] Single doses can be administered hourly, daily, weekly, or monthly. For example, a single dose can be administered every 1 hour, 2, 3, 4, 6, 8, 12, 16 hours, or every 24 hours. A single dose can also be administered every 1 day, 2, 3, 4, 5, 6 days, or every 7 days. A single dose can also be administered every 1 week, 2, 3 weeks, or every 4 weeks. In certain embodiments, a single dose can be administered weekly. A single dose can also be administered monthly. In some embodiments, a compound disclosed herein is administered once daily using the methods disclosed herein. In some embodiments, a compound disclosed herein is administered twice daily using the methods disclosed herein. In some embodiments, a compound disclosed herein is administered three times daily using the methods disclosed herein.

[0289] In some embodiments, the compounds disclosed herein are administered once daily at a total daily dose of 100 to 4000 mg / day. In some embodiments, the compounds disclosed herein are administered twice daily at a total daily dose of 100 to 4000 mg / day. In some embodiments, the compounds disclosed herein are administered three times daily at a total daily dose of 100 to 4000 mg / day.

[0290] The frequency of dosing of the disclosed compounds will be determined by the needs of the individual patient and may be, for example, once a day, or twice a day or more. The compounds are administered continuously for as long as necessary to treat the viral infection. For example, the compounds may 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.

[0291] Administration can be intermittent, wherein the patient receives a daily dose of a compound of the present disclosure for a period of several or more days, followed by a period of several or more days in which the patient does not receive the daily dose of the compound. For example, the patient may receive a dose of the compound every other day, or three times a week. By way of further example, the patient may receive a daily dose of the compound for a period of 1 to 14 days, followed by a period of 7 to 21 days in which the patient does not receive the dose of the compound, and then, for a subsequent period (e.g., 1 to 14 days), the patient again receives the daily dose of the compound. Alternating periods of administration of the compound followed by no administration of the compound may be repeated as clinically necessary to treat the patient.

[0292] The compounds or pharmaceutical compositions disclosed herein can be administered one, two, three, or four times daily using any suitable regimen described above. Furthermore, administration of the compounds or treatment with the compounds can continue for several days; for example, treatment will typically last at least 7, 14, or 28 days for a treatment cycle. Treatment cycles are well known in cancer chemotherapy and are often alternating between cycles with rest periods of about 1 to 28 days, typically about 7 or about 14 days. In other embodiments, treatment cycles can be continuous. [] [VIII.] [How to use]

[0293] The present disclosure also provides a method of treating or preventing a viral infection in a subject (eg, a human) in need thereof, comprising administering to the subject a compound described herein.

[0294] In some embodiments, the present disclosure provides a method of treating a viral infection in a subject (eg, a human) in need thereof, comprising administering to the subject in need thereof a compound described herein.

[0295] In some embodiments, the compounds described herein are administered to humans via oral, intramuscular, intravenous, subcutaneous, or inhalation administration.

[0296] In some embodiments, the present disclosure provides methods of treating or preventing a viral infection in a subject (e.g., a human) in need thereof, comprising administering to the subject a compound disclosed herein and at least one additional active therapeutic or disease preventive agent.

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

[0298] In one embodiment, the present disclosure provides a method for inhibiting viral polymerase in a cell, the method comprising contacting a cell infected with a virus with a compound disclosed herein, thereby inhibiting the viral polymerase.

[0299] In some embodiments, the present disclosure provides a method of inhibiting viral polymerase in a cell, the method comprising contacting a cell infected with a virus with a compound disclosed herein and at least one additional active therapeutic agent, thereby inhibiting the viral polymerase.

[0300] Also provided herein are uses of the compounds disclosed herein for treating or preventing a viral infection in a subject in need thereof. For example, provided herein are uses of the compounds disclosed herein for treating a viral infection in a subject in need thereof.

[0301] In some embodiments, the viral infection is a Paramyxoviridae virus infection. Thus, in some embodiments, the present disclosure provides methods for treating a Paramyxoviridae infection in a subject (e.g., a human) in need thereof, comprising administering to the subject a compound disclosed herein. Paramyxoviridae viruses include, but are not limited to, Nipah virus, Hendra virus, measles, mumps, and parainfluenza viruses.

[0302] In some embodiments, the viral infection is human parainfluenza virus, Nipah virus, Hendra virus, measles, or mumps infection.

[0303] In some embodiments, the viral infection is a Pneumoviridae virus infection. Thus, in some embodiments, the present disclosure provides a method of treating a Pneumoviridae virus infection in a human in need thereof, comprising administering to the human a compound provided herein. Pneumoviridae viruses include, but are not limited to, respiratory syncytial virus and human metapneumovirus. In some embodiments, the Pneumoviridae virus infection is a respiratory syncytial virus infection. In some embodiments, the Pneumoviridae virus infection is a human metapneumovirus infection.

[0304] In some embodiments, the present disclosure provides a compound disclosed herein for use in treating a Pneumoviridae infection in a human in need thereof. In some embodiments, the Pneumoviridae infection is a respiratory syncytial virus infection. In some embodiments, the Pneumoviridae infection is a human metapneumovirus infection.

[0305] In some embodiments, the present disclosure provides methods for treating RSV infection in a human in need thereof, comprising administering to the human a compound provided herein. In some embodiments, the human suffers from a chronic RSV infection. In some embodiments, the human suffers from an acute RSV infection.

[0306] In some embodiments, methods of inhibiting RSV replication are provided, wherein the method comprises administering a compound disclosed herein to a human in need thereof, wherein the administration is by inhalation.

[0307] In some embodiments, the present disclosure provides a method for reducing viral load associated with RSV infection, wherein the method comprises administering a compound disclosed herein to a human infected with RSV.

[0308] In some embodiments, the viral infection is a Picornaviridae infection. Thus, in some embodiments, the present disclosure provides a method for treating a Picornaviridae infection in a human in need thereof, comprising administering a compound of the present 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 poliomyelitis-like syndrome, epidemic costomyalgia (an acute, febrile, infectious illness typically occurring in epidemics), hand, foot and mouth syndrome, pancreatitis in children and adults, and severe myocarditis. In some embodiments, the Picornaviridae infection is a human rhinovirus infection (HRV). In some embodiments, the Picornaviridae infection is an HRV-A, HRV-B, or HRV-C infection.

[0309] In some embodiments, the viral infection is selected from the group consisting of: coxsackie virus infection, coxsackie virus infection, enterovirus D68 infection, enterovirus B69 infection, enterovirus D70 infection, enterovirus A71 infection, and poliovirus infection.

[0310] In some embodiments, the present disclosure provides a compound for use in treating a Picornaviridae viral infection in a human in need thereof. In some embodiments, the Picornaviridae viral infection is a human rhinovirus infection.

[0311] In some embodiments, the viral infection is a Flaviviridae virus infection. Thus, in some embodiments, the present disclosure provides a method of treating a Flaviviridae virus infection in a human in need thereof, comprising administering to the human a compound described herein. Representative Flaviviridae viruses include, but are not limited to, dengue, yellow fever, West Nile, Zika, Japanese encephalitis virus, and hepatitis C (HCV). In some embodiments, the Flaviviridae virus infection is a dengue virus infection. In some embodiments, the Flaviviridae virus infection is a yellow fever virus infection. In some embodiments, the Flaviviridae virus infection is a West Nile virus infection. In some embodiments, the Flaviviridae virus infection is a Zika virus infection. In some embodiments, the Flaviviridae virus infection is a Japanese encephalitis virus infection. In some embodiments, the Flaviviridae virus infection is a hepatitis C virus infection.

[0312] 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.

[0313] In some embodiments, the present disclosure provides uses of the compounds disclosed herein for treating a Flaviviridae infection in a human in need thereof. In some embodiments, the Flaviviridae infection is a dengue virus infection. In some embodiments, the Flaviviridae infection is a yellow fever virus infection. In some embodiments, the Flaviviridae infection is a West Nile virus infection. In some embodiments, the Flaviviridae infection is a Zika virus infection. In some embodiments, the Flaviviridae infection is a hepatitis C virus infection.

[0314] In some embodiments, the viral infection is a Filoviridae virus infection. Thus, in some embodiments, provided herein is a method of treating a Filoviridae virus infection in a human in need thereof, comprising administering to the human a compound disclosed herein. Representative Filoviridae viruses include, but are not limited to, Ebola (Zaire, Bundibugio, Sudan, Tai forest, or Reston variants) and Marburg. In some embodiments, the Filoviridae virus infection is an Ebola virus infection. In some embodiments, the Filoviridae virus infection is a Marburg virus infection.

[0315] In some embodiments, the present disclosure provides a compound for use in treating a Filoviridae infection in a human in need thereof. In some embodiments, the Filoviridae infection is an Ebola virus infection. In some embodiments, the Filoviridae infection is a Marburg virus infection.

[0316] In some embodiments, the viral infection is a coronavirus infection. Thus, in some embodiments, provided herein is a method of treating a coronavirus infection in a human in need thereof, wherein the method comprises administering a compound provided herein to the human. In some embodiments, the coronavirus infection is severe acute respiratory syndrome (SARS-CoV) infection, Middle East respiratory syndrome (MERS) infection, SARS-CoV-2 infection, infection with other human coronaviruses (229E, NL63, OC43, HKU1, or WIV1), or infection with a zoonotic coronavirus (PEDV or HKU CoV isolates, such as HKU3, HKU5, or HKU9). In some embodiments, the viral infection is severe acute respiratory syndrome (SARS). In some embodiments, the viral infection is Middle East respiratory syndrome (MERS). In some embodiments, the viral infection is SARS-CoV-2 infection. In some embodiments, the viral infection is a zoonotic coronavirus infection, and in some embodiments, the viral infection is caused by a virus that shares at least 70% sequence homology with 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 that has 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 that has 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 that has 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.

[0317] In some embodiments, the viral infection is caused by a variant of SARS-CoV-2, 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 and E484K variants, 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.

[0318] In some embodiments, the present disclosure provides a compound for use in treating a coronavirus infection in a human in need thereof. In some embodiments, the coronavirus infection is severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), SARS-CoV-2, other human coronaviruses (229E, NL63, OC43, HKU1, or WIV1), and zoonotic coronaviruses (PEDV or HKU CoV isolates, such as HKU3, HKU5, or HKU9). In some embodiments, the viral infection is severe acute respiratory syndrome (SARS). In some embodiments, the viral infection is Middle East respiratory syndrome (MERS). In some embodiments, the viral infection is SARS-CoV-2 (COVID-19).

[0319] In some embodiments, the viral infection is an Arenaviridae infection. Thus, in some embodiments, the present disclosure provides a method of treating an Arenaviridae infection in a human in need thereof, comprising administering to the human a compound disclosed herein. In some embodiments, the Arenaviridae infection is a Lassa infection or a Junin infection.

[0320] In some embodiments, the present disclosure provides a compound for use in treating an Arenaviridae infection in a human in need thereof. In some embodiments, the Arenaviridae infection is Lassa infection or Junin infection.

[0321] 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 type A, influenza virus type B, or influenza virus type C infection.

[0322] As described more fully herein, the compounds described herein can be administered to a subject (e.g., a human) infected with a viral infection along with one or more additional therapeutic agents. The additional therapeutic agent(s) can be administered to the infected subject simultaneously with, before, or after administration of the compounds of the disclosure. [] [IX.] [Combination therapy]

[0323] The compounds described herein may also be used in combination with one or more additional therapeutic agents. Thus, also provided herein are methods of treating a viral infection in a subject in need thereof, wherein the method comprises administering to the subject a compound disclosed herein and a therapeutically effective amount of one or more additional therapeutic or disease prevention agents.

[0324] In some embodiments, the additional therapeutic agent is an antiviral agent. Any suitable antiviral agent can be used in the methods described herein. In some embodiments, the antiviral agent is selected from the group consisting of 5-substituted 2'-deoxyuridine analogs, nucleoside analogs, pyrophosphate analogs, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, entry inhibitors, acyclic guanosine analogs, acyclic nucleoside phosphonate analogs, HCV NS5A / NS5B inhibitors, influenza virus inhibitors, interferons, immunostimulants, oligonucleotides, antimitotic inhibitors, and combinations thereof.

[0325] In some embodiments, the additional therapeutic agent is a 5-substituted 2'-deoxyuridine analog. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of idoxuridine, trifluridine, brivudine (BVDU), and combinations thereof.

[0326] In some embodiments, the additional therapeutic agent is a nucleoside analog. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of vidarabine, entecavir (ETV), telbivudine, lamivudine, adefovir dipivoxil, tenofovir disoproxil fumarate (TDF), and combinations thereof. In some embodiments, the additional therapeutic agent is favipiravir, ribavirin, galidesivir, β-D-N4-hydroxycytidine, or combinations thereof.

[0327] 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.

[0328] In some embodiments, the additional therapeutic agent is a nucleoside reverse transcriptase inhibitor. In some embodiments, the antiviral agent is zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine, or combinations thereof.

[0329] 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.

[0330] In some embodiments, the additional therapeutic agent is a protease inhibitor. In some embodiments, the protease inhibitor is an HIV protease inhibitor. For example, in some embodiments, the antiviral agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, cobicistat, and combinations thereof. In some embodiments, the antiviral agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, and combinations thereof. In some embodiments, the protease inhibitor is an HCV NS3 / 4A protease inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of voxilaprevir, asunaprevir, boceprevir, paritaprevir, simeprevir, telaprevir, vaniprevir, grazoprevir, ribavirin, danoprevir, faldaprevir, vedroprevir, sovaprevir, deldeprevir, narlaprevir, 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, ribavirin, danoprevir, faldaprevir, vedroprevir, sovaprevir, deldeprevir, narlaprevir, and combinations thereof.

[0331] 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.

[0332] 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 immune globulin [VariZIG], varicella zoster immune globulin [VZIG], and combinations thereof.

[0333] 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.

[0334] 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.

[0335] In some embodiments, the additional therapeutic agent is an HCV NS5A / NS5B inhibitor. In some embodiments, the additional therapeutic agent is an NS3 / 4A protease inhibitor. In some embodiments, the additional therapeutic agent is an NS5A protein inhibitor. In some embodiments, the additional therapeutic agent is a nucleoside / nucleotide NS5B polymerase inhibitor. In some embodiments, the additional therapeutic agent is a non-nucleoside NS5B polymerase inhibitor. In some embodiments, the additional therapeutic agent is selected from the group consisting of daclatasvir, ledipasvir, velpatasvir, ombitasvir, elbasvir, sofosbuvir, dasabuvir, ribavirin, asuprevir, simeprevir, paritaprevir, ritonavir, elbasvir, gezoprevir, AT-527, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of daclatasvir, ledipasvir, velpatasvir, ombitasvir, elbavir, sofosbuvir, dasabuvir, and combinations thereof.

[0336] 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.

[0337] In some embodiments, the additional therapeutic agent is interferon. In some embodiments, the additional therapeutic agent is selected from the group consisting of interferon alfacon 1, interferon α 1b, interferon α 2a, interferon α 2b, pegylated interferon alfacon 1, pegylated interferon α 1b, pegylated interferon α 2a (PegIFNα-2a), and PegIFNα-2b. In another embodiment, the additional therapeutic agent is selected from the group consisting of interferon alfacon 1, interferon α 1b, interferon α 2a, interferon α 2b, pegylated interferon α 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 α 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.

[0338] In some embodiments, the additional therapeutic agent is an immunostimulatory agent. In some embodiments, the additional therapeutic agent is an oligonucleotide. In some embodiments, the additional therapeutic agent is an anti-mitotic inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of fomivirsen, podofilox, imiquimod, sinecatechins, and combinations thereof.

[0339] In some embodiments, the additional therapeutic agent is selected from the group consisting of besifovir, nitazoxanide, REGN2222, doravirine, sofosbuvir, velpatasvir, daclatasvir, asuprevir, beclabuvir, FV100, and letermovir, and combinations thereof.

[0340] In some embodiments, the additional therapeutic agent is an agent used to treat RSV. For example, in some embodiments, the antiviral agent is ribavirin, ALS-8112, or presatovir. For example, in some embodiments, the antiviral agent is ALS-8112 or presatovir.

[0341] In some embodiments, the additional therapeutic agent is an agent used to treat picornaviruses. 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.

[0342] In some embodiments, the additional therapeutic agent is an agent used to treat malaria. In some embodiments, the additional therapeutic agent is chloroquine.

[0343] 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, amodiaquin, pyronaridine, artesunate, halofantrine, quinine sulfate, mefloquine, solithromycin, pyrimethamine, MMV-390048, ferroquine, artefenomel mesylate, mesylate), ganaplacide, DSM-265, cipargamin, artemisinin, and combinations thereof.

[0344] In some embodiments, the additional therapeutic agent is an agent used to treat coronavirus. In 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, anti-viroporin, and combinations thereof.

[0345] In some embodiments, the additional therapeutic agent is an agent used to treat Ebola virus. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of ribavirin, palivizumab, motavizumab, RSV-IGIV (RespiGam®), MEDI-557, A-60444, MDT-637, BMS-433771, amiodarone, dronedarone, verapamil, Ebola Convalescent Plasma, ECP), TKM-100201, BCX4430 ((2S,3S,4R,5R)-2-(4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-5-(hydroxymethyl)pyrrolidine-3,4-diol), Favipiravir (also known as T-705 or Avigan), T-705 monophosphate, T-705 diphosphate, T-705 triphosphate, FGI-106 (1-N,7-N-bis[3-(dimethylamino)propyl]-3,9-dimethylquinolino[8,7-h]quinolinone-1,7-diamine), JK-05, TKM-Ebola, ZMapp, rNAPc2, VRC-EBOADC076-00-VP, OS-2966, MVA-BN

[0014] In some embodiments, the additional therapeutic agent is ZMapp, mAb114, REGEN-EB3, or a combination thereof.

[0346] In some embodiments, the additional therapeutic agent is an agent used to treat 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, radalbuvir, 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, viroprevir, woxitegravir, and combinations thereof.

[0347] In some embodiments, the additional therapeutic agent is an NS5A inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of ledipasvir, velpatasvir, and combinations thereof.

[0348] In some embodiments, the additional therapeutic agent is an anti-HBV agent. For example, in some embodiments, the additional therapeutic agent is tenofovir disoproxil fumarate and emtricitabine, or a combination thereof. Examples of additional anti-HBV agents include, but are not limited to, alpha-hydroxyheptazone, amdoxovir, antroquinonol, beta-hydroxycytidine, ARB-199, CCC-0975, ccc-R08, elvucitabine, ezetimibe, cyclosporine A, gentiopicrin / gentiopicroside, HH-003, hepalatide, JNJ-56136379, nitazoxanide, birinapant, NJK14047, NOV-205 (molixan, BAM-205), oligotide, mivotilate, feron, GST-HG-131, levamisole, Kashunin, 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, IBP-006IA, and Hepuyinfen, DasKloster 0014-01, ISA-204, Jiangantai (Ganxikang), MIV-210, OB-AI-004, PF-06, picroside, DasKloster-0039, hepulantai, IMB-2613, TCM-800B, reduced glutathione, RO-6864018, RG-7834, QL-007 sofosbuvir, ledipasvir, UB-551, and ZH-2N, and compounds disclosed in: US20150210682,(Roche), US 2016 / 0122344 (Roche), WO2015173164, WO2016023877, US2015252057A (Roche), WO16128335A1 (Roche), WO16120186A1 (Roche), US2016237090A (Roche), WO16107833A1 (Roche), WO16107832A1 (Roche), US2016176899A (Roche), WO16102438A1 (Roche), WO16012470A1 (Roche), US2016220586A (Roche), and US2015031687A (Roche). In some embodiments, the additional therapeutic agent is an HBV polymerase inhibitor. Examples of HBV DNA polymerase inhibitors include, but are not limited to, adefovir (HEPSERA®), emtricitabine (EMTRIVA®), tenofovir disoproxil fumarate (VIREAD®), tenofovir alafenamide, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir dipivoxil, tenofovir dipivoxil fumarate, tenofovir octadecyloxyethyl, CMX-157, tenofovir exalidex, besifovir, entecavir (BARACLUDE®), entecavir maleate, telbivudine (TYZEKA®), and telocycline. ®), filocilovir, pradefovir, clevudine, ribavirin, lamivudine (EPIVIR-HBV®), phosphine azide, famciclovir, fusolin, metacavir, SNC-019754, FMCA, AGX-1009, AR-II-04-26, HIP-1302, tenofovir disoproxil aspartate, tenofovir disoproxil orotate, and HS-10234. In some embodiments, the additional therapeutic agent is an HBV capsid inhibitor.

[0349] In some embodiments, the additional therapeutic agent is an agent used to treat HIV. In some embodiments, the additional therapeutic agent is selected from the group consisting of HIV protease inhibitors, HIV integrase inhibitors, entry inhibitors, HIV nucleoside reverse transcriptase inhibitors, HIV non-nucleoside reverse transcriptase inhibitors, acyclic nucleoside phosphonate analogs, and combinations thereof.

[0350] In some embodiments, the additional therapeutic agent is selected from the group consisting of: HIV protease inhibitors, HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitors, HIV nucleoside or nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or ectopic) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, immunomodulatory agents, immunotherapeutic agents, antibody drug conjugates, gene modifying agents, gene editors (such as CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs), and cell therapies (such as chimeric antigen receptor T cells (CAR-T), and engineered T cell receptors (TCR-T), autologous T cell therapy).

[0351] In some embodiments, the additional therapeutic agent is selected from the group consisting of: combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or ectopic) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversing agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and "antibody-like" therapeutic proteins, and combinations thereof.

[0352] In some embodiments, the additional therapeutic agent is an HIV combination drug. Examples of HIV combination drugs include, but are not limited to, ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); BIKTARVY® (bittegravir, emtricitabine, and tenofovir alafenamide); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® ® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); SYMTUZA ® (darunavir, tenofovir alafenamide hemifumarate, emtricitabine, and cobicistat); SYMFI ™ (efavirenz, lamivudine, and tenofovir disoproxil fumarate); CIMDU ™ (lamivudine and tenofovir disoproxil fumarate); tenofovir and lamivudine; tenofovir alafenamide and emtricitabine; tenofovir alafenamide hemifumarate and emtricitabine; tenofovir alafenamide hemifumarate, emtricitabine, and rilpivirine; tenofovir alafenamide hemifumarate, emtricitabine, cobicistat, and elvitegravir; COMBIVIR ® (zidovudine and lamivudine; AZT+3TC); EPZICOM ® (LIVEXA ®; abacavir sulfate and lamivudine; ABC+3TC); KALETRA ® (ALUVIA ®; lopinavir and ritonavir); TRIUMEQ ® (dolutegravir, abacavir, and lamivudine); TRIZIVIR ® (abacavir sulfate sulfate), zidovudine, and lamivudine; ABC+AZT+3TC); atazanavir and cobicistat; atazanavir sulfate and cobicistat; atazanavir sulfate and ritonavir; darunavir and cobicistat; dolutegravir and rilpivirine; dolutegravir and rilpivirine hydrochloride; dolutegravir, abacavir sulfate, and lamivudine; lamivudine, nevirapine, and zidovudine; raltegravir and lamivudine; doravirine, lamivudine, and tenofovir disoproxil fumarate; doravirine, lamivudine, and tenofovir disoproxil fumarate;Dapivirine + levonorgestrel, dolutegravir + lamivudine, dolutegravir + emtricitabine + tenofovir alafenamide, elsulfavirine + emtricitabine + tenofovir disoproxil fumarate, 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.

[0353] 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.

[0354] 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, bitegravir, and combinations thereof. In some embodiments, the additional therapeutic agent is bitegravir. In some embodiments, the additional therapeutic agent is selected from the group consisting of: bitegravir, elvitegravir, curcumin, a derivative of curcumin, chicoric acid, a derivative of chicoric acid, 3,5-dicaffeoylquinic acid, a derivative of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, 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, bittegravir, AVX-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.

[0355] 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 attachment inhibitors, DS-003 (BMS-599793), gp120 inhibitors, and CXCR4 inhibitors. Examples of CCR5 inhibitors include apraviroc, 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 (vMIP).

[0356] 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.

[0357] In some embodiments, the additional therapeutic agent is an HIV nucleoside or nucleotide reverse transcriptase inhibitor. For example, the additional therapeutic agent is selected from the group consisting of adefovir, adefovir dipivoxil, azvudine, 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, efavirenz, festinavir, fosalvudine, foslavudine, fenavir ... tidoxil), CMX-157, dapivirine, doravirine, etravirine, OCR-5753, tenofovir disoproxil orotate, fozivudine tidoxil, islatravir, lamivudine, phosphazid, stavudine, zalcitabine, zidovudine, rovafovir etalafenamide (GS-9131), GS-9148, MK-8504, MK-8591, MK-858, VM-2500, KP-1461, and combinations thereof.

[0358] 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, efavirenz rilp (VM-1500), and combinations thereof.

[0359] In some embodiments, the additional therapeutic agent is selected from ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF + FTC); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); ® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); adefovir; adefovir dipivoxil; cobicistat; emtricitabine; tenofovir; tenofovir disoproxil fumarate; tenofovir alafenamide; tenofovir hemifumarate; TRIUMEQ ® (dolutegravir, abacavir, and lamivudine); dolutegravir, abacavir sulfate, and lamivudine; raltegravir; raltegravir and lamivudine; maraviroc; enfuvirtide; ALUVIA ® (KALETRA ®; lopinavir and ritonavir); COMBIVIR ® (zidovudine and lamivudine; AZT + 3TC); EPZICOM ® (LIVEXA ®; abacavir sulfate and lamivudine; ABC + 3TC); TRIZIVIR ® (abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); rilpivirine; rilpivirine hydrochloride; atazanavir sulfate and cobicistat; atazanavir and cobicistat; darunavir and cobicistat; atazanavir; atazanavir sulfate; dolutegravir; elvitegravir; ritonavir; atazanavir sulfate and ritonavir; darunavir; lamivudine; prolastin; fosanavir fosamprenavir calcium with efavirenz; etravirine; nelfinavir; nelfinavir mesylate; interferon; didanosine; stavudine; indinavir; indinavir sulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir; delavirdine; delavirdine mesylate; Radha-108 (Receptol); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovir disoproxil fumarate; phosphorus azide; lamivudine, nevirapine, and zidovudine; abacavir; and abacavir sulfate.

[0360] In some embodiments, the additional therapeutic agent is selected from the group consisting of colistin, valrubicin, icatibant, bepotastine, epirubicin, epoprosetnol, vapreotide, aprepitant, caspofungin, perphenazine, atazanavir, efavirenz, ritonavir, acyclovir, ganciclovir, penciclovir, prulifloxacin, bittegravir, nelfinavir, talvibuvir, nelfinavir, praziquantel, pitavastatin, perampanel, eszopiclone, and zopiclone.

[0361] In some embodiments, the additional therapeutic agent is an inhibitor of Bruton's tyrosine kinase (BTK, AGMX1, AT, ATK, BPK, IGHD3, IMD1, PSCTK1, XLA; NCBI Gene ID: 695). For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of: (S)-6-amino-9-(1-(but-2-ynyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one, acalabrutinib (ACP-196), BGB-3111, CB988, HM71224, ibrutinib (Imbruvica), M-2951 (evobrutinib), M7583, tirabrutinib (ONO-4059), PRN-1008, spebrutinib, (CC-292), TAK-020, vecabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, TAS-5315, AZD6738, calquence, danvatirsen, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of telatinib, ibrutinib, acalabrutinib, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of telatinib, ibrutinib, and combinations thereof. In some embodiments, the additional therapeutic agent is telatinib A9 (A9).

[0362] 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 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, MRTX-849 (G12C), and K-Ras (G12D)-selective inhibitory peptides (including KRpep-2 (Ac-RRCPLYISYDPVCRR-NH2), KRpep-2d (Ac-RRRRCPLYISYDPVCRRRR-NH2), and combinations thereof.

[0363] 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.

[0364] 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 the live-attenuated RSV vaccine MEDI-559, the human monoclonal antibody REGN2222 against RSV, palivizumab, respiratory syncytial virus immune globulin (intravenous) [RSV-IGIV], and combinations thereof. In some embodiments, the additional therapeutic agent is an HBV vaccine, such as Pediarix, Engerix-B, and Recombivax HB. In some embodiments, the additional therapeutic agent is a VZV vaccine, such as Zostavax and Varivax. In some embodiments, the additional therapeutic agent is an HPV vaccine, such as Cervarix, Gardasil 9, and Gardasil. In some embodiments, the additional therapeutic agent is an influenza virus vaccine, such as (i) a monovalent influenza A vaccine (e.g., Influenza A [H5N1] virus monovalent vaccine and Influenza A [H1N1] 2009 virus monovalent vaccine), (ii) a trivalent influenza A and B vaccine (e.g., Afluria, Agriflu, Fluad, Fluarix, Flublok, Flucelvax, FluLaval, Fluvirin, and Fluzone), and (iii) a quadrivalent influenza A and B vaccine (FluMist, Fluarix, Fluzone, and FluLaval). In some embodiments, the additional therapeutic agent is a human adenovirus vaccine (e.g., adenovirus types 4 and 7 oral live vaccine). In some embodiments, the additional therapeutic agent is a rotavirus vaccine (e.g., Rotarix for rotavirus serotypes G1, G3, G4, or G9 and RotaTeq for rotavirus serotypes G1, G2, G3, or G4). In some embodiments, the additional therapeutic agent is a hepatitis A virus vaccine (e.g., Havrix and Vaqta). In some embodiments, the additional therapeutic agent is a polio virus vaccine (e.g., Kinrix, Quadracel, and Ipol). In some embodiments, the additional therapeutic agent is a yellow fever virus vaccine (e.g., YF-Vax). In some embodiments, the additional therapeutic agent is a Japanese encephalitis virus vaccine (e.g., Ixiaro and JE-Vax). In some embodiments, the additional therapeutic agent is a measles vaccine (e.g., MMR II and ProQuad).In some embodiments, the additional therapeutic agent is a mumps vaccine (e.g., MMR II and ProQuad). In some embodiments, the additional therapeutic agent is a German measles vaccine (e.g., MMR II and ProQuad). In some embodiments, the additional therapeutic agent is a varicella vaccine (e.g., ProQuad). In some embodiments, the additional therapeutic agent is a rabies vaccine (e.g., Imovax and RabAvert). In some embodiments, the additional therapeutic agent is a smallpox virus (Variola) vaccine (ACAM2000). In some embodiments, the additional therapeutic agent is a hepatitis E virus (HEV) vaccine (e.g., HEV239). In some embodiments, the additional therapeutic agent is a 2019-nCov vaccine.

[0365] In some embodiments, the additional therapeutic agent is an antibody, such as a monoclonal antibody. For example, the additional therapeutic agent is an antibody against 2019-nCoV selected from the group consisting of: Regeneron antibodies, Wuxi antibodies, Vir Biotechnology antibodies, antibodies targeting the SARS-CoV-2 spike protein, antibodies that neutralize SARS-CoV-2 (SARS-CoV-2 neutralizing antibodies), and combinations thereof. In some embodiments, the additional therapeutic agent is the anti-SARS-CoV antibody CR-3022. In some embodiments, the additional therapeutic agent is a PD-1 antibody.

[0366] In some embodiments, the additional therapeutic agent is an injection of a protein derived from a recombinant cytokine gene.

[0367] 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.

[0368] In some embodiments, the additional therapeutic agent is selected from the group consisting of lopinavir, ritonavir, interferon-α-2b, ritonavir, arbidol, hydroxychloroquine, darunavir and cobicistat, abidol hydrochloride, oseltamivir, litonavir, emtricitabine, tenofovir alafenamide fumarate, baloxavir mapositol, ruxolitinib, and combinations thereof.

[0369] In some embodiments, the additional therapeutic agent is selected from the group consisting of 6'-fluorinated aristeromycin analogs, acyclovir fleximer analogs, disulfiram, thiopurine analogs, ASCO9F, GC376, GC813, phenylisoserine derivatives, neuroimindase inhibitor analogs, pyrithiobac derivatives, bananins and 5-hydroxychrome derivatives, SSYA10-001, griffithsin, HR2P-M1, HR2P-M2, P21S10, dihydrotanshinone, E-64-C and E-64-D, OC43-HR2P, MERS-5HB, 229E-HR1P, 229E-HR2P, resveratrol, 1-thia-4-azaspiro[4.5]decan-3-one derivatives, gemcitabine hydrochloride, loperamide, recombinant interferon, cyclosporine A, aliporivir, imatinib mesylate mesylate, dasatinib, selumetinib, trametinib, rapamycin, saracatinib, chlorpromazine, triflupromazine, fluphenazine, thiethylperazine, promethazine, cyclophilin inhibitors, K11777, camostat, k22, teicoplanin derivatives, benzo-heterocyclic amine derivative N30, mycophenolic acid, silvestrol, and combinations thereof.

[0370] In some embodiments, the additional therapeutic agent is an antibody. In some embodiments, the additional therapeutic agent is an antibody that binds to a coronavirus, such as an antibody that binds to SARS-CoV or MERS-CoV. In some embodiments, the additional therapeutic agent is an antibody against the 2019-nCoV virus.

[0371] The compositions of the present invention are also used in combination with other active ingredients. For the treatment of 2019-nCoV virus infection, it is preferred that the other active therapeutic agent is active against coronavirus infection (e.g., 2019-nCoV virus infection). The compounds and compositions of the present invention are also intended to be used with general care provided to patients infected with 2019-nCoV virus, including parenteral fluids (including dextrose saline and Ringer's lactate) and nutrients, antibiotics (including metronidazole and cephalosporin antibiotics, such as ceftriaxone and cefuroxime), and / or antifungal drugs. prophylaxis), antipyretics and analgesics, antiemetics (such as metoclopramide) and / or antidiarrheals, vitamin and mineral supplements (including vitamin K and zinc sulfate), anti-inflammatory agents (such as ibuprofen or steroids), corticosteroids (such as methylprednisolone), immunomodulatory drugs (e.g., interferon), other small molecule or biologic antiviral agents targeting 2019-nCoV (such as but not limited to lopinavir / ritonavir, EIDD-1931, favipiravir, ribavirin, neutralizing antibodies, etc.), vaccines, analgesics, and other common diseases in the patient population, such as antimalarial agents ( In some embodiments, the additional therapeutic agent is dihydroartemisinin / piperaquine. In some embodiments, the additional therapeutic agent is EIDD-2801 (MH-4482, Molnupiravir).

[0372] In some embodiments, the additional therapeutic agent is an immunomodulator. Examples of immune-based therapies include: toll-like receptor modulators, such as tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12, and tlr13; programmed cell death protein 1 (PD-1) modulators; programmed death ligand 1 (PD-L1) modulators; IL-15 modulators; DermaVir; interleukin-7; plaquenil (hydroxychloroquine); proleukin (aldesleukin, IL-2); interferon alpha; interferon alpha-2b; interferon alpha-n3; pegylated interferon alpha; interferon gamma; hydroxyurea; mycophenolate mofetil (mycophenolate mofetil, MPA) and its ester derivative mycophenolate mofetil (MMF); ribavirin; the polymer polyethyleneimine (PEI); Gepon; IL-12; WF-10; VGV-1; MOR-22; BMS-936559; CYT-107, interleukin-15 / Fc fusion protein, AM-0015, ALT-803, NIZ-985, NKTR-255, NKTR-262, NKTR-214, normferon, pegylated interferon alpha-2a, pegylated interferon alpha-2b, recombinant interleukin-15, Xmab-24306, RPI-MN, STING modulators, RIG-1 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.

[0373] In some embodiments, the additional therapeutic agent is an IL-6 inhibitor, such as tocilizumab, sarilumab, or a combination thereof.

[0374] In some embodiments, the additional therapeutic agent is an anti-TNF inhibitor, for example, adalimumab, etanercept, golimumab, infliximab, or a combination thereof.

[0375] 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.

[0376] In some embodiments, the additional therapeutic agent is an inflammation suppressant, such as pirfenidone.

[0377] 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.

[0378] In some embodiments, the compounds disclosed herein are used in combination with standard pneumonia care (see, for example, Pediatric Community Pneumonia Guidelines, CID 2011: 53 (1 October)). Treatment for pneumonia generally involves curing the infection and preventing complications. The specific treatment will depend on several factors, including the type and severity of the pneumonia, age, and the individual's overall health. Options include: (i) antibiotics, (ii) cough medicine, and (iii) fever reducers / analgesics (e.g., aspirin, ibuprofen (Advil, Motrin IB, etc.), and acetaminophen (Tylenol, etc.)). In some embodiments, the additional therapeutic agent is bromhexine, a cough suppressant.

[0379] In some embodiments, the compounds disclosed herein are used in combination with immunoglobulin from recovered COVID-19 patients. In some embodiments, the compounds disclosed herein are used in combination with plasma transfusion. In some embodiments, the compounds disclosed herein are used in combination with stem cells.

[0380] 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, rintatolimod, DSP-0509, AL-034, G-100, cobitolimod, AST-008, motolimod, GSK-1795091, GSK-2245035, VTX-1463, GS-9688, LHC-165, BDB-001, RG-7854, telratolimod, and RO-7020531.

[0381] In some embodiments, the additional therapeutic agent is selected from the group consisting of bortezomib, flurazepam, ponatinib, sorafenib, paramethasone, clocortolone, flucloxacillin, sertindole, clevidipine, atorvastatin, cinolazepam, clofazimine, fosaprepitant, and combinations thereof.

[0382] In some embodiments, the additional therapeutic agent is carrimycin, suramin, triazavirin, dipyridamole, bevacizumab, meplazumab, GD31 (Rhizobium), an NLRP inflammasome inhibitor, or α-ketoamine. In some embodiments, the additional therapeutic agent is recombinant human angiotensin-converting enzyme 2 (rhACE2). In some embodiments, the additional therapeutic agent is viral macrophage inflammatory protein (vMIP).

[0383] In some embodiments, the additional therapeutic agent is an antiviral porin therapeutic agent. For example, the additional therapeutic agent is BIT-314 or BIT-225. In some embodiments, the additional therapeutic agent is a coronavirus E protein inhibitor. For example, the additional agent is BIT-009. Further examples of additional therapeutic agents include those described in WO-2004112687, WO-2006135978, WO-2018145148, and WO-2009018609.

[0384] In some embodiments, the additional therapeutic agent or disease prevention agent is molnupiravir, oseltamivir, nirmatrelvir, or ritonavir. In some embodiments, the additional therapeutic agent or disease prevention agent is ritonavir or cobicistat.

[0385] Any compound of the present invention can be combined with one or more additional active therapeutic agents. For example, the compounds described herein can be combined with one, two, three, four, five, or more additional active therapeutic agents.

[0386] It is also possible to combine any of the compounds of the present invention with one or more additional active therapeutic agents in a unit dosage form for simultaneous or sequential administration to a patient. Combination therapy can be administered as a simultaneous or sequential regimen. When administered sequentially, the combination can be administered in two or more administrations.

[0387] Co-administration of a compound of the invention and one or more other active therapeutic agents generally refers to administering the compound of the invention and the one or more other active therapeutic agents simultaneously or sequentially such that therapeutically effective amounts of both the compound of the invention and the one or more other active therapeutic agents are present in the patient's body.

[0388] Co-administration includes administering a unit dose of a compound of the invention before or after administering a unit dose of one or more other active therapeutic agents, for example, administering the compound of the invention within seconds, minutes, or hours of administering the one or more other active therapeutic agents. For example, a unit dose of a compound of the invention may be administered first, followed by administration of a unit dose of the one or more other active therapeutic agents within seconds or minutes. Alternatively, a unit dose of the one or more other therapeutic agents may be administered first, followed by administration of a unit dose of the compound of the invention within seconds or minutes. In some cases, it may be desirable to administer a unit dose of the compound of the invention first, followed by administration of a unit dose of the one or more other active therapeutic agents after a period of several hours (e.g., 1 to 12 hours). In other cases, it may be desirable to administer a unit dose of the one or more other active therapeutic agents first, followed by administration of a unit dose of the compound of the invention after a period of several hours (e.g., 1 to 12 hours).

[0389] Combination therapy can provide "synergy" and "synergism," meaning that the effect achieved when the active ingredients are used together is greater than the sum of the effects of the compounds when used separately. A synergistic effect can be achieved when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combination formulation; (2) delivered as separate formulations, either alternating or concurrently; or (3) by some other regimen. When delivered in alternation therapy, a synergistic effect can be achieved when the compounds are administered or delivered sequentially, for example, as separate tablets, pills, or capsules, or by different injections in separate syringes. Generally, during alternation therapy, an effective dosage of each active ingredient is administered sequentially (i.e., serially), whereas in combination therapy, effective dosages of two or more active ingredients are administered together. A synergistic antiviral effect means an antiviral effect that is greater than the predicted simply additive effect of the individual compounds of the combination. [] [1.] [Combination therapy for the treatment of pneumoviral diseases]

[0390] The compounds provided herein can also be used in combination with other active therapeutic agents. For the treatment of Pneumoviridae infections, it is preferred that the other active therapeutic agent is active against Pneumoviridae infections (particularly respiratory syncytial virus infections and / or metapneumovirus infections). Non-limiting examples of such other active therapeutic agents active against RSV are ribavirin, palivizumab, motavizumab, RSV-IGIV (RespiGam®), MEDI-557, A-60444 (also known as RSV604), MDT-637, BMS-433771, ALN-RSVO, ALX-0171, and mixtures thereof. Other non-limiting examples of other active therapeutic agents that are active against RSV infections include RSV protein F inhibitors such as AK-0529; RV-521, ALX-0171, JNJ-53718678, BTA-585, and prosatovir; RNA polymerase inhibitors such as lumicitabine and ALS-8112; anti-RSV G protein antibodies such as anti-G protein mAb; viral replication inhibitors such as nitazoxanide.

[0391] In some embodiments, the other active therapeutic agent may be a vaccine for the treatment or prevention of RSV, including but not limited to MVA-BN RSV, RSV-F, MEDI-8897, JNJ-64400141, DPX-RSV, SynGEM, GSK-3389245A, GSK-300389-1A, RSV-MEDI deltaM2-2 vaccine, VRC-RSVRGP084-00VP, Ad35-RSV-FA2, Ad26-RSV-FA2, and RSV fusion glycoprotein subunit vaccine.

[0392] Non-limiting examples of other active therapeutic agents that are active against metapneumovirus infection include sialidase modulators, such as DAS-181; RNA polymerase inhibitors, such as ALS-8112; and antibodies for treating metapneumovirus infection, such as EV-046113.

[0393] In some embodiments, the other active therapeutic agent may be a vaccine for treating or preventing metapneumovirus infection, including but not limited to mRNA-1653 and rHMPV-Pa vaccines. [] [2.] [Combination therapy for the treatment of picornaviruses]

[0394] The compounds provided herein can also be used in combination with other active therapeutic agents. For the treatment of picornavirus infections, it is preferred that the other active therapeutic agent be active against picornavirus infections, particularly enterovirus infections. Non-limiting examples of such other active therapeutic agents include capsid binding inhibitors such as pleconaril, BTA-798 (vapendavir), and other compounds disclosed by Wu et al. (US 7,078,403) and Watson (US 7,166,604); fusion sialidase proteins such as DAS-181; capsid protein VP1 inhibitors such as VVX-003 and AZN-001; viral protease inhibitors such as CW-33; phosphatidylinositol 4-kinase beta inhibitors such as GSK-480 and GSK-533; and anti-EV71 antibodies.

[0395] In some embodiments, the other active therapeutic agent may be a vaccine for treating or preventing Picornaviridae infection, including but not limited to EV71 vaccine, TAK-021, and EV-D68 adeno-based vaccine. [] [3.] [Combination therapy for respiratory tract infections]

[0396] Many Pneumoviridae, Picornaviridae, and Coronaviridae viruses cause respiratory infections. Therefore, additional active therapeutic agents for treating respiratory symptoms and sequelae of infection can be used in combination with the compounds provided herein. These additional agents are preferably administered orally or by direct inhalation. For example, other preferred additional therapeutic agents for treating viral respiratory infections in combination with the compounds provided herein include, but are not limited to, bronchodilators and corticosteroids. Glucocorticoids

[0397] Glucocorticoids, first introduced as an asthma treatment in 1950 (Carryer, Journal of Allergy, 21, 282-287, 1950), remain the most potent and consistently effective treatment for this disease, although their mechanism of action is not fully understood (Morris, J. Allergy Clin. Immunol., 75 (1 Pt) 1-13, 1985). Unfortunately, oral glucocorticoid therapy is associated with severe undesirable side effects, such as truncal obesity, hypertension, glaucoma, glucose intolerance, accelerated cataract formation, bone mineral loss, and psychological effects, all of which limit the use of oral glucocorticoid therapy as a long-term treatment (Goodman and Gilman, 10th edition, 2001). One solution to systemic side effects is to deliver steroids directly to the site of inflammation. [. ] Inhaled corticosteroids (ICS) have been developed to alleviate the serious adverse effects of oral steroids. Non-limiting examples of corticosteroids that can 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, and the like. acetonide, flunisolide, fluocortin-21-butylate, flumethasone, flumetasone pivalate, budesonide, halobetasol propionate, mometasone furoate, fluticasone, AZD-7594, ciclesonide; or pharmaceutically acceptable salts thereof. anti-inflammatory agents

[0398] Other anti-inflammatory agents that act through anti-inflammatory cascade mechanisms can also be used as additional therapeutic agents in combination with the compounds provided herein to treat viral respiratory infections. The use of "anti-inflammatory signaling modulators" (referred to herein as AIS™) is a rational approach to interrupting inflammation, such as phosphodiesterase inhibitors (e.g., specific for PDE-4, PDE-5, or PDE-7), transcription factor inhibitors (e.g., blocking NFκB through IKK inhibition), or kinase inhibitors (e.g., blocking P38 MAP, JNK, PI3K, EGFR, or Syk), because these small molecules target a limited number of common intracellular pathways—signaling pathways that are key points for anti-inflammatory therapeutic intervention (see PJ Barnes, 2006). Such 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-methylsulfinyl-phenyl)-1H-imidazol-4-yl]-pyridine (P38 inhibitor SB-203850); 4-[4-(4-Fluorophenyl)-1-(3-phenyl-propyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-but-3-yn-1-ol (P38 inhibitor RWJ-67657); 4-Cyano-4-(3-cyclopentyloxy-4-methoxy-phenyl)-cyclohexanecarboxylic acid 2-diethylamino-ethyl ester (2-diethyl-ethyl ester prodrug of Cilomilast (PDE-4 inhibitor)); (3-Chloro-4-fluorophenyl)-[7-methoxy-6-(3- [4-(4-Methyl-piperidin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide (imatinib, EGFR inhibitor). β2-adrenergic receptor agonist bronchodilator

[0399] Combinations comprising an inhaled β2-adrenergic receptor agonist bronchodilator (such as formoterol, albuterol, or salmeterol) and a compound provided herein are also suitable, but non-limiting, combinations useful in treating respiratory viral infections.

[0400] Combinations of inhaled β2-adrenergic receptor agonist bronchodilators (such as formoterol or salmeterol) and ICS are also used to treat bronchoconstriction and inflammation (Symbicort® and Advair®, respectively). Combinations comprising these ICS and β2-adrenergic receptor agonist combinations along with the compounds provided herein are also suitable, but not limited to, combinations that can be used to treat respiratory viral infections.

[0401] Other examples of β2 adrenergic receptor agonists are bedoradrine, vilanterol, indacaterol, olodaterol, tulobuterol, formoterol, abediterol, salbutamol, arformoterol, levalbuterol, fenoterol, and TD-5471. Anticholinergics

[0402] Anticholinergics have potential use in the treatment or prevention of pulmonary bronchoconstriction and can be used as additional therapeutic agents in combination with the compounds provided herein to treat viral respiratory infections. Such anticholinergics include, but are not limited to, antagonists of muscarinic receptors (particularly the M3 subtype), which have shown therapeutic efficacy in controlling cholinergic tone in COPD in humans (Witek et al., 2001). 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-acetyloxy)-2-phenyl-propionyloxy]-8-isopropyl-8-methyl-8-azonia-bicyclo[3.2.1]octane (Ipratropium-N,N-diethylglycinate);1-Cyclohexyl-3,4-dihydro-1H -Isoquinoline-2-carboxylic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester (Solifenacin); 2-hydroxymethyl-4-methanesulfinyl-2-phenyl-butyric acid 1-aza-bicyclo[2.2.2]oct-3-yl ester (Revatropate); 2-{1-[2-(2,3-dihydro-benzofuran-5-yl)-ethyl]-pyrrolidin-3-yl}-2,2-diphenyl-acetamide (Darifenacin); 4-nitrobenzofuran-5-yl-2-phenyl-1-nitrobenzofuran-1-yl-2 ... -1-yl-2,2-diphenyl-butyramide (Buzepide); 7-[3-(2-diethylamino-acetyloxy)-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-acetyloxy)-2,2-di-thiophen-2-yl]- [3-(4-Diisopropylamino)-1-phenyl-propyl]-4-methyl-phenyl ester (tolterodine-N,N-dimethylglycinate); 3-[4,4-bis-(4-fluoro-phenyl)-2-oxo- 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]octan-3-yl)-1-phenyl-prop-2-yn-1-ol;3-[2-(2-diethylamino-acetyloxy)-2,2-dimethoxy-1-azabicyclo[2.2.2]octan-3-yl]-1-phenyl-prop-2-yn-1-ol;1-[1-(3-Fluoro-benzyl)-piperidin-4-yl]-4,4-bis-(4-fluoro-phenyl)-imidazolidin-2-one;1-cyclooctyl-3-(3-methoxy-1-aza ...1-[1-(3-Fluoro-benzyl)piperidin-4-yl]piperidin-2-one;1-cyclooctyl-3-(3-methoxy-1-azabicyclo[2.2.2]octan-3-yl)-1-phenyl-prop-2-yn-1-ol;1- [2-(2-phenoxy-ethyl)-piperidin-4-yl)-1-(2-thiophen-2-yl)acetyloxy]-1-(3-phenoxy-propyl)-1-azonia-bicyclo[2.2.2]octane (Aclidinium-N,N-diethylglycinate); or (2-diethylamino-acetyloxy)-di-thiophen-2-yl-acetic acid 1-methyl-1-(2-phenoxy-ethyl)-piperidin-4-yl ester; revefenacin, glycopyrronium bromide, umeclidinium bromide, tiotropium bromide, aclidinium bromide, bencycloquidium bromide. expectorant

[0403] The compounds provided herein can also be combined with expectorants to treat both infections and respiratory tract infection symptoms. A non-limiting example of an expectorant is ambroxol. Similarly, the compounds can be combined with expectorants to treat both infections and respiratory tract infection symptoms. A non-limiting example of an expectorant is guaifenesin.

[0404] Nebulized hypertonic saline is used to improve immediate and long-term clearance of the small airways in patients with lung disease (Kuzik, J. Pediatrics 2007, 266). Therefore, the compounds provided herein may also be combined with nebulized hypertonic saline, particularly when bronchiolitis is complicated by viral infection. Combinations of the compounds provided herein with hypertonic saline may also include any of the additional agents discussed above. In one embodiment, nebulized approximately 3% hypertonic saline is used. [] [4.] [Combination therapy for the treatment of Flaviviridae virus infections]

[0405] The compounds and compositions provided herein can also be used in combination with other active therapeutic agents. For the treatment of Flaviviridae infections, it is preferred that the other active therapeutic agent be active against Flaviviridae infections.

[0406] For the treatment of dengue virus infection, non-limiting examples of other active therapeutic agents are host cell factor modulators such as GBV-006; fenretinide ABX-220, BRM-211; α-glucosidase 1 inhibitors such as celgosivir; platelet-activating factor receptor (PAFR) antagonists such as modipafant; cadherin-5 / factor Ia modulators such as FX-06; NS4B inhibitors such as JNJ-8359; viral RNA splicing modulators such as ABX-202; NS5 polymerase inhibitors; NS3 protease inhibitors; and TLR modulators.

[0407] 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, quadrivalent dengue vaccine, quadrivalent DNA vaccine, rDEN2Δ30-7169; and DENV-1 PIV. [] [5.] [Combination therapy for the treatment of Filoviridae infections]

[0408] The compounds provided herein can also be used in combination with other active therapeutic agents. For the treatment of Filoviridae infections, it is preferred that the other active therapeutic agent is active against Filoviridae infections (particularly Marburg virus, Ebola virus, and Cueva virus infections). Non-limiting examples of such other active therapeutic agents are: ribavirin, amiodarone, dronedarone, verapamil, Ebola convalescent plasma (ECP), TKM-100201, BCX4430 ((2S,3S,4R,5R)-2-(4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-5-(hydroxymethyl)pyrrolidine-3,4-diol), TKM-Ebola, T-705 monophosphate, T-705 diphosphate, T-705 triphosphate, FGI-106 (1-N,7-N-bis[3-(dimethylamino) [propyl]-3,9-dimethylquinolino[8,7-h]quinolinone-1,7-diamine), rNAPc2, OS-2966, brincidofovir, remdesivir; RNA polymerase inhibitors such as galidesivir, favipiravir (also known as T-705 or Avigan), and JK-05; host cytokine 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.

[0409] Other non-limiting active therapeutic agents active against Ebola include α-glucosidase 1 inhibitors, cathepsin B inhibitors, CD29 antagonists, dendritic ICAM-3 sequestration non-integrin 1 inhibitors, estrogen receptor antagonists, factor VII antagonists, HLA class II antigen modulators, host cell factor modulators, interferon α ligands, neutral α-glucosidase AB inhibitors, Niemann-Pick C1 protein inhibitors, nucleoprotein inhibitors, polymerase cofactor VP35 inhibitors, serine protease inhibitors, tissue factor inhibitors, TLR-3 agonists, viral envelope glycoprotein inhibitors, and Ebola virus entry inhibitors (NPC1 inhibitors).

[0410] 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 vaccines, 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.

[0411] The compounds provided herein can also be combined with phosphoramidate N- Phosphoramidate morpholino oligomer (PMO) is used in combination with phosphoramidate N- Phenoyl oligomers 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.

[0412] The compounds provided herein are also intended for use with the general care provided to patients infected with a Filoviridae virus, including parenteral fluids (including dextrose saline and Ringer's lactate) and nutrients, antibiotics (including metronidazole and cephalosporin antibiotics such as ceftriaxone and cefuroxime) and / or antifungals, antipyretics and analgesics, antiemetics (such as metoclopramide) and / or antidiarrheals, vitamin and mineral supplements (including vitamin K and zinc sulfate), anti-inflammatory agents (such as ibuprofen), analgesics, and agents for other common ailments in the patient population, such as antimalarials (including artemether and artesunate-lumefantrine combination therapy), antityphoid agents (including quinolinone antibiotics (such as ciprofloxacin), macrolide antibiotics (such as azithromycin), cephalosporin antibiotics (such as ceftriaxone), or aminopenicillins (such as ampicillin), or anti-Shigella agents.

[0413] The present invention will be described in more detail by way of specific examples. The following examples are provided for illustrative purposes and are not intended to limit the present invention in any way. One of ordinary skill in the art will readily recognize various non-critical parameters that can be changed or modified to produce substantially the same results. [6.] [Combination therapy for the treatment of coronavirus infection]

[0414] In some embodiments, the additional therapeutic agent is a 2,5-oligoadenylate synthetase stimulator, a 5-HT2a receptor antagonist, a 5-lipoxygenase inhibitor, an ABL family tyrosine kinase inhibitor, an Abl tyrosine kinase inhibitor, an aldehyde dehydrogenase inhibitor, an acetyl CoA carboxylase inhibitor, an actin antagonist, an actin modulator, an activity-dependent neuroprotection modulator, an adenosine A3 receptor agonist, an adrenaline receptor antagonist, an adrenomedullin ligand, an adrenomedullin ligand inhibitor, an advanced glycosylation product receptor antagonist, an advanced glycosylation product receptor modulator, an AKT protein kinase inhibitor, a stimulator of alanine-proline-rich secretory protein, an aldose reductase inhibitor, an alkaline phosphatase stimulator, an α2 adrenergic receptor antagonist, an α2B adrenergic receptor agonist, an AMP-activated protein kinase stimulator, an AMPA receptor modulator, an amyloid deposition inhibitor, an androgen receptor antagonist, an angiotensin II AT-1 receptor antagonist, angiotensin II AT-2 receptor agonist, angiotensin II receptor modulator, angiotensin-converting enzyme 2 inhibitor, angiotensin-converting enzyme 2 modulator, angiotensin-converting enzyme 2 stimulator, angiotensin receptor modulator, annexin A5 stimulator, anoctamin 1 inhibitor, anticoagulant, antihistamine, antihypoxic agent, antithrombotic agent, AP1 transcription factor regulator, apelin receptor agonist, APOA1 gene stimulator, apolipoprotein A1 agonist, apolipoprotein B antagonist, apolipoprotein B modulator, apolipoprotein C3 antagonist, aryl hydrocarbon receptor agonist, aryl hydrocarbon receptor antagonist, ATP-binding cassette transporter B5 modulator, Axl tyrosine kinase receptor inhibitor, bactericidal permeabilin inhibitor, basic immunoglobulin (Basigin) inhibitor , basic immunoglobulin (Basigin) regulators, BCL2 gene inhibitors, BCL2L11 gene stimulators, Bcr protein inhibitors, β1 adrenergic receptor regulators, β2 adrenergic receptor agonists, β-adrenergic receptor agonists, β-arrestin stimulators, coagulation regulators, BMP10 gene inhibitors, BMP15 gene inhibitors, bone morphogenetic protein 10 ligand inhibitors, bone morphogenetic protein 15 ligand inhibitors, bradykininB2 antagonists, brain-derived neurotrophic factor ligands, bromodomain-containing protein 2 inhibitors, bromodomain-containing protein 4 inhibitors, Btk tyrosine kinase inhibitors, C-reactive protein modulators, Ca2+ release-activated Ca2+ channel 1 inhibitors, cadherin-5 modulators, calcium-activated chloride channel inhibitors, calcium channel modulators, calpain I inhibitors, calpain II inhibitors, calpain IX inhibitors, cannabinoid CB2 receptor agonists, cannabinoid receptor modulators, casein kinase II inhibitors, CASP8-FADD-like modulator inhibitors, apoptotic protease inhibitors, catalase stimulators, CC L26 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 agonists, CD95 antagonists, CFTR inhibitors, CGRP receptor antagonists, chemokine receptor-like 1 agonists, chloride channel inhibitors, chloride channel modulators, cholera toxin Bsubunit) inhibitors, cholesterol ester transfer protein inhibitors, collagen modulators, complement C1s subcomponent inhibitors, complement C3 inhibitors, complement factor C5 inhibitors, complement factor C5a inhibitors, complement factor H stimulators, complement cascade inhibitors, complement factor C2 inhibitors, complement factor D inhibitors, connective tissue growth factor ligand inhibitors, coronavirus nucleoprotein modulators, coronavirus small envelope protein modulators, coronavirus spike glycoprotein inhibitors, coronavirus spike glycoprotein modulators, COVID19 envelope small membrane protein modulators, COVID19 nonstructural protein 8 modulators, COVID19 nucleoprotein modulators, COVID19 protein 3a inhibitors, COVID19 replicase polyprotein 1a inhibitors, COVID19 replicase polyprotein 1a modulators, COVID19 replicase polyprotein 1ab inhibitors, COVID19 replicase polyprotein 1ab modulators, COVID19 spike glycoprotein inhibitors , COVID19 spike glycoprotein modulators, COVID19 structural glycoprotein modulators, CRF-2 receptor agonists, CSF-1 agonists, CSF-1 antagonists, CX3CR1 chemokine antagonists, CXC10 chemokine ligand inhibitors, CXC5 chemokine ligand inhibitors, CXCL1 gene regulators, CXCL2 gene regulators, CXCL3 gene regulators, 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 lymphoglobulin gene regulators, cytotoxic T lymphoglobulin-4 inhibitors, cytotoxic T lymphoglobulin-4 stimulators, DDX3 inhibitors, dehydrogenase inhibitors, dehydropeptidase-1 regulators, 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, EctoNOX disulfide thiol exchanger 2 inhibitors, EGFR gene inhibitors, elongation factor 1α2 modulators, endoplasmic reticulum regulators, endoribonuclease DICER regulators, 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-α sialidase regulators, exoportin 1 inhibitors, factor Ia regulators, factor IIa regulators, factor VII antagonists, factor Xa antagonists, factor XI Factor a antagonist, FGF receptor antagonist, FGF-1 ligand, FGF-1 ligand inhibitor, FGF-2 ligand inhibitor, FGF1 receptor antagonist, FGF2 receptor antagonist, FGF3 receptor antagonist, Flt3 tyrosine kinase inhibitor, Fractalkine ligand inhibitor, free fatty acid receptor 2 agonist, free fatty acid receptor 3 agonist, furin inhibitor, Fyn tyrosine kinase inhibitor, FYVE finger phosphatidyl inositol kinase inhibitor, G-protein coupled bile acid receptor 1 agonist, GABA A receptor modulators, Galectin-3 inhibitors, γ-secretase inhibitors, GDF agonists, Gelsolin stimulators, Glial cell neurotrophic factor ligands, Glucocorticoid receptor agonists, Glutathione peroxidase stimulators, GM-CSF ligand inhibitors, GM-CSF receptor agonists, GM-CSF receptor modulators, Griffithsin modulators, Somatomedin α ligand inhibitors, Grp78 calcium binding protein inhibitors, Heat shock protein HSP90 α inhibitors, Heat shock protein HSP90 β inhibitors, heat shock protein inhibitors, heat shock protein stimulators, hemagglutinin regulators, hemoglobin regulators, hemolysin α inhibitors, heparanase inhibitors, heparin agonists, hepatitis B structural protein inhibitors, hepatitis C virus NS5B polymerase inhibitors, HIF prolyl hydroxylase inhibitors, HIF prolyl hydroxylase-2 inhibitors, high-mobility group 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, Hsp90 inhibitors, human papillomavirus E6 protein modulators, human papillomavirus E7 protein modulators, hypoxia-inducible factor suppressor gene inhibitors, hypoxia-inducible factor-2 α modulators, I-kappa B kinase inhibitors, I-kappaB kinase modulators, ICAM-1 stimulators, IgG receptor FcRn large subunit p51 modulators, 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 agonists, IL-8 receptor antagonists, IL12 gene stimulators, IL8 gene modulators, immunoglobulin G modulators, immunoglobulin G1 agonists, immunoglobulin G1 modulators, immunoglobulin agonists, immunoglobulin gamma Fc receptor I modulators, immunoglobulin kappa modulators, inosine monophosphate dehydrogenase inhibitors, insulin sensitizers, integrin agonists, integrin α-4 / β-7 antagonists, integrin α-V / β-1 antagonists, integrin α-V / β-6 antagonists, interferon agonists, interferon α14 ligands, interferon α2 ligands, interferon α2 ligand modulators, interferon α ligands, interferon α ligand inhibitors, interferon α ligand modulators, interferon β ligands, interferon γ ligand inhibitors, interferon γ receptor agonists, interferon γ receptor antagonists, interferon receptor modulators, type I stem cells Interferon receptor agonists, interleukin 17A ligand inhibitors, interleukin 17F ligand inhibitors, interleukin 18 ligand inhibitors, interleukin 22 ligands, interleukin 1β ligand inhibitors, interleukin 1β ligand modulators, interleukin-1 ligand inhibitors, interleukin-2 ligands, interleukin-29 ligands, interleukin-6 ligand inhibitors, interleukin-7 ligands, interleukin-8 ligand inhibitors, IRAK-4 protein kinase inhibitors, JAK tyrosine kinase inhibitors, Jak1 tyrosine kinase inhibitors, Jak2 tyrosine kinase inhibitors, Jak3 tyrosine kinase inhibitors, Jun N-terminal kinase inhibitors, Jun N-terminal kinase regulators, kallikrein regulators, Kelch-like ECH-related 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 regulators, leukocyte elastase inhibitors, leukotriene BLT receptor antagonists, leukotriene D4 antagonists, leukotriene receptor antagonists, listeriolysin stimulators, liver X receptor antagonists, low molecular weight heparin, pulmonary surfactant-associated protein B stimulators, pulmonary surfactant-associated protein D regulators, Lyn tyrosine kinase inhibitors, Lyn tyrosine kinase stimulators, lysine-specific tissue protein demethylase 1 inhibitors, macrophage migration inhibitory factor inhibitors, polymannose-binding lectin serine protease inhibitors, polymannose-binding lectin serine protease-2 inhibitors, MAOB 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 modulators, muscarinic 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, erythroid 2-related factor 2 stimulators, nuclear factor κB inhibitors, nuclear factor κB modulators, nuclease stimulators, nucleolar protein inhibitors, nucleolar protein inhibitors, nucleoprotein regulators, nucleoside reverse transcriptase inhibitors, opioid receptor agonists, opioid receptor antagonists, opioid receptor mu modulators, opioid receptor sigma antagonist 1, ornithine decarboxylase inhibitors, outer membrane protein inhibitors, OX40 ligands, p38 MAP 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, peptidylproline cis-trans isomerase A inhibitors, peroxiredoxin 6 modulators, PGD2 antagonists, PGI2 agonists, P-glycoprotein inhibitors, phosphatidylinositol 3-kinase inhibitors, phosphatidylinositol-3-kinase delta inhibitors, phosphatidylinositol-3-kinase gamma inhibitors, phospholipase A2 inhibitors, plasma kallikrein inhibitors, plasminogen activator 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, PPARα agonists, progesterone receptor agonists, programmed cell death protein 1 regulators, proline hydroxylase inhibitors, prostaglandin E synthase-1 inhibitors, protease inhibitors, proteasome inhibitors, protein arginine deiminase IV inhibitors, protein tyrosine kinase inhibitors, protein tyrosine phosphatase β inhibitors, protein tyrosine phosphatase-2C inhibitors, proto-oncogene Mas agonists, purine receptor antagonists, Raf protein kinase inhibitors, RANTES ligands, Ras gene inhibitors, retinoic acid receptor response protein 2 stimulators, Rev protein regulators, ribonuclease stimulators, RIP-1 kinase inhibitors, RNA helicase inhibitors, RNA polymerase inhibitors, RNA polymerase regulators, S phase kinase-associated protein 2 inhibitors, SARS coronavirus 3C protease-like inhibitors, serine protease inhibitors, serine-threonine protein kinase ATR inhibitors, serine-threonine protein kinase TB K1 inhibitors, serum amyloid A protein modulators, signal transduction CD24 stimulators, sodium channel stimulators, sodium glucose transporter-2 inhibitors, neuramin kinase 1 inhibitors, neuramin kinase 2 inhibitors, neuramin kinase inhibitors, neuramin-1-phosphate receptor-1 agonists, neuramin-1-phosphate receptor-1 antagonists, neuramin-1-phosphate receptor-1 modulators, neuramin-1-phosphate receptor-5 agonists, neuramin-1-phosphate receptor-5 modulators, spike protein inhibitors, Src tyrosine kinase inhibitors, STAT-1 modulators, STAT-3 inhibitors, STAT-5 inhibitors, STAT3 gene inhibitors, stem cell antigen-1 inhibitors, interferon gene stimulator protein stimulators, sulfatase inhibitors, superoxide dismutase modulators, superoxide dismutase stimulators, Syk tyrosine kinase inhibitors, T cell immunoreceptor Ig ITIM protein inhibitors, T cell receptor agonists, T cell surface glycoprotein CD28 inhibitors, T cell differentiation antigen CD6 inhibitors, T cell surface glycoprotein CD8 stimulators, T cell transcription factor NFAT regulators, tankyrase-1 inhibitors, tankyrase-2 inhibitors, Tek tyrosine kinase receptor stimulators, telomerase regulators, tetanus toxin regulators, TGFβ receptor antagonists, TGFB2 gene inhibitors, thymosin β4 ligand, thyroid hormone receptor β agonist, tissue factor inhibitor, tissue plasminogen activator regulator, tissue plasminogen activator stimulator, TLR agonist, TLR modulator, TLR-2 agonist, TLR-2 antagonist, TLR-3 agonist, TLR-4 agonist, TLR-4 antagonist, TLR-6 agonist, TLR-7 agonist, TLR-7 antagonist, TLR-8 antagonist, TLR-9 agonist, TMPRSS2 gene inhibitor, TNF α ligand inhibitor, TNFα ligand modulators, TNF binders, TNF gene inhibitors, topoisomerase inhibitors, transcription factor EB stimulators, transferrin modulators, transketolase inhibitors, translocase-related protein inhibitors, transmembrane serine protease 2 inhibitors, transthyretin modulators, TREM receptor 1 antagonists, TRP cation channel C1 modulators, TRP cation channel C6 inhibitors, TRP cation channel V6 inhibitors, trypsin 1 inhibitors, trypsin 2 inhibitors, trypsin 3 inhibitors, trypsin inhibitors, tubulin α inhibitors, tubulin β inhibitors, tumor necrosis factor 14 ligand inhibitors, TYK2 gene inhibitors, type I IL-1 receptor antagonists, tyrosine kinase ABL1 inhibitors, ubiquinol cytochrome C reductase 14 kDa inhibitor, ubiquitin ligase modulator, unspecified GPCR agonist, unspecified cytokine receptor modulator, unspecified enzyme stimulator, unspecified gene inhibitor, unspecified receptor modulator, urokinase plasminogen activator inhibitor, vascular cell adhesion protein 1 agonist, vasodilator, VEGF ligand inhibitor, VEGF receptor antagonist, VEGF-1 receptor antagonist, VEGF-1 receptor modulator, VEGF-2 receptor antagonist, VEGF-3 receptor antagonist, vimentin inhibitor, vimentin modulator, VIP receptor agonist, viral envelope protein inhibitor, viral protease inhibitor, viral protease modulator, viral protein target modulator, viral ribonuclease inhibitor, viral structural protein modulator, vitamin D3 receptor agonist, X-linked inhibitor of apoptosis protein inhibitor, xanthine oxidase inhibitor, or disintegrin inhibitor.

[0415] In some embodiments, the compounds and compositions of the present disclosure may be administered in combination with SARS-CoV-2 treatments, such as parenteral fluids (including dextrose saline and Ringer's lactate), nutrients, antibiotics (including azithromycin, metronidazole, amphotericin B, amoxicillin / clavulanic acid, trimethoprim / sulfamethoxazole, R-327, and cephalosporin antibiotics such as ceftriaxone and cefuroxime), antifungals, antipyretics and analgesics, antiemetics (such as metoclopramide) and / or antidiarrheals, vitamin and mineral supplements (including vitamin K, vitamin D, cholecalciferol, vitamin C, and zinc sulfate), anti-inflammatory drugs (such as ibuprofen or steroids), corticosteroids such as methylprednisolone, prednisone, mometasone, immunomodulatory drugs (e.g., interferon), vaccines, and analgesics.

[0416] In some embodiments, the additional therapeutic agent is an Abl tyrosine kinase inhibitor, such as radotinib or imatinib.

[0417] In some embodiments, the additional therapeutic agent is an aldehyde dehydrogenase inhibitor, such as ADX-629.

[0418] In some embodiments, the additional therapeutic agent is an adenosine A3 receptor agonist, such as piclidenoson.

[0419] In some embodiments, the additional therapeutic agent is an adrenomedullin ligand, such as adrenomedullin.

[0420] In some embodiments, the additional therapeutic agent is a p38 MAPK + PPAR gamma agonist / insulin sensitizer, such as KIN-001.

[0421] In some embodiments, the additional therapeutic agent is a PPARα-agonist, such as DWTC-5101 (fenofibrate choline).

[0422] In some embodiments, the additional therapeutic agent is a cyclophilin inhibitor, such as rencofilstat.

[0423] In some embodiments, the additional therapeutic agent is a p38 MAP kinase inhibitor, such as PRX-201 or Gen-1124.

[0424] In some embodiments, the additional therapeutic agent is an aldose reductase inhibitor, such as caficrestat.

[0425] In some embodiments, the additional therapeutic agent is an AMPA receptor modulator, such as traneurocin.

[0426] In some embodiments, the additional therapeutic agent is an Annexin A5 stimulator, such as AP-01 and SY-005.

[0427] In some embodiments, the additional therapeutic agent is an apelin receptor agonist, such as CB-5064MM.

[0428] 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.

[0429] In some embodiments, the additional therapeutic agent is an androgen receptor antagonist, such as bicalutamide, enzalutamide, or pruxelutamide.

[0430] In some embodiments, the additional therapeutic agent is anti-hypoxic, such as trans sodium crocetinate.

[0431] In some embodiments, the additional therapeutic agent is an antithrombotic agent such as defibrotide, rivaroxaban, alteplase, tirofiban, clopidogrel, prasugrel, bemiparin, bivalirudin, sulodexide, or tenecteplase.

[0432] In some embodiments, the additional therapeutic agent is an antihistamine, such as cloroperastine, cloperastine, or clemastine.

[0433] In some embodiments, the additional therapeutic agent is an apolipoprotein A1 agonist, such as CER-001.

[0434] In some embodiments, the additional therapeutic agent is a phospholipase A2 inhibitor, such as eicosapent ethyl.

[0435] In some embodiments, the additional therapeutic agent is an ax1 tyrosine kinase receptor inhibitor, such as becitinib.

[0436] In some embodiments, the additional therapeutic agent is a corticosteroid / β2 adrenergic receptor agonist, such as budesonide + formoterol fumarate.

[0437] In some embodiments, the additional therapeutic agent is a BET bromodomain inhibitor / APOA1 gene stimulator, such as apabetalone.

[0438] In some embodiments, the additional therapeutic agent is a blood clot modulator, such as lanadelumab.

[0439] In some embodiments, the additional therapeutic agent is a bradykinin B2 receptor antagonist, such as icatibant.

[0440] In some embodiments, the additional therapeutic agent is an EGFR gene inhibitor / Btk tyrosine kinase inhibitor, such as bifatinib.

[0441] In some embodiments, the additional therapeutic agent is a Btk tyrosine kinase inhibitor, such as ibrutinib or zanubrutinib.

[0442] In some embodiments, the additional therapeutic agent is a calpain-I / II / IX inhibitor, such as BLD-2660.

[0443] In some embodiments, the additional therapeutic agent is a cannabinoid CB2 receptor agonist, such as onternabez or PPP-003.

[0444] In some embodiments, the additional therapeutic agent is a Ca2+ release-activated Ca2+ channel 1 inhibitor, such as zegocractin (CM-4620).

[0445] In some embodiments, the additional therapeutic agent is an ATR inhibitor, such as berzotinib.

[0446] In some embodiments, the additional therapeutic agent is a Cadherin-5 modulator, such as FX-06.

[0447] In some embodiments, the additional therapeutic agent is a casein kinase II inhibitor, such as silmitasertib.

[0448] In some embodiments, the additional therapeutic agent is an apoptosis protease inhibitor, such as emricasan.

[0449] In some embodiments, the additional therapeutic agent is a catalase stimulator / superoxide dismutase stimulator, such as MP-1032.

[0450] In some embodiments, the additional therapeutic agent is a CCR2 chemokine antagonist / CCR5 chemokine antagonist, such as cenikvir.

[0451] In some embodiments, the additional therapeutic agent is a CCR5 chemokine antagonist, such as maraviroc or leronalizumab.

[0452] In some embodiments, the additional therapeutic agent is a CD122 agonist / IL-2 receptor agonist, such as begadlucin.

[0453] In some embodiments, the additional therapeutic agent is a CD73 agonist / interferon beta ligand, such as FP-1201.

[0454] In some embodiments, the additional therapeutic agent is a cholesteryl ester transfer protein inhibitor, such as dalcetrapib.

[0455] In some embodiments, the additional therapeutic agent is a polymannose-binding lectin serine protease / complement C1s subcomponent inhibitor / myeloperoxidase inhibitor, such as RLS-0071.

[0456] In some embodiments, the additional therapeutic agent is a complement factor C5 inhibitor / leukotriene BLT receptor antagonist, such as nomacopan.

[0457] In some embodiments, the additional therapeutic agent is a complement factor C5 inhibitor, such as eculizumab, STSA-1002, or zilucoplan.

[0458] In some embodiments, the additional therapeutic agent is a CXCR4 chemokine antagonist, such as plerixafor or motixaforte.

[0459] In some embodiments, the additional therapeutic agent is a cytochrome P450 3A4 inhibitor / peptidyl-prolinyl cis-trans isomerase A inhibitor, such as alisporivir.

[0460] In some embodiments, the additional therapeutic agent is a cysteine protease inhibitor, such as SLV-213.

[0461] In some embodiments, the additional therapeutic agent is a dihydroorotate dehydrogenase inhibitor, such as Meds-433, brequinar, RP-7214, or emvododstat.

[0462] In some embodiments, the additional therapeutic agent is a dehydropeptidase-1 modulator, such as Metablok.

[0463] In some embodiments, the additional therapeutic agent is a dihydroorotate dehydrogenase inhibitor / IL-17 antagonist, such as vedoflulimus.

[0464] In some embodiments, the additional therapeutic agent is a diuretic, such as an aldosterone antagonist, such as spironolactone.

[0465] In some embodiments, the additional therapeutic agent is a DNase I stimulator, such as GNR-039 or dornase alfa.

[0466] In some embodiments, the additional therapeutic agent is a NET inhibitor, such as NTR-441.

[0467] In some embodiments, the additional therapeutic agent is a dihydroceramide delta 4 desaturase inhibitor / neuraminidase kinase 2 inhibitor, such as opanib.

[0468] In some embodiments, the additional therapeutic agent is a DNA methyltransferase inhibitor, such as azacitidine.

[0469] In some embodiments, the additional therapeutic agent is an LXR antagonist, such as larsucosterol.

[0470] In some embodiments, the additional therapeutic agent is a dipeptidyl peptidase I inhibitor, such as brensocatib.

[0471] In some embodiments, the additional therapeutic agent is a protein arginine deiminase IV inhibitor, such as JBI-1044.

[0472] In some embodiments, the additional therapeutic agent is an elongation factor 1α2 modulator, such as plitidecin.

[0473] In some embodiments, the additional therapeutic agent is a eukaryotic initiation factor 4A-I inhibitor, such as zotatifin.

[0474] In some embodiments, the additional therapeutic agent is an exo-α sialidase modulator, such as DAS-181.

[0475] In some embodiments, the additional therapeutic agent is an exportin 1 inhibitor, such as selinexor.

[0476] In some embodiments, the additional therapeutic agent is a fractalkine ligand inhibitor, such as KAND-567.

[0477] In some embodiments, the additional therapeutic agent is a phosphatidylinositol kinase inhibitor / IL-12 receptor antagonist / IL-23 antagonist, such as apilimod dimesylate.

[0478] In some embodiments, the additional therapeutic agent is a GABA A receptor modulator, such as brexanolone.

[0479] In some embodiments, the additional therapeutic agent is a glucocorticoid receptor agonist, such as ciclesonide, hydrocortisone, dexamethasone, dexamethasone phosphate, or 101-PGC-005.

[0480] In some embodiments, the additional therapeutic agent is a GM-CSF receptor antagonist, such as sargramostim.

[0481] In some embodiments, the additional therapeutic agent is a GPCR agonist, such as esuberaprost sodium.

[0482] In some embodiments, the additional therapeutic agent is a griffithsine modulator, such as Q-griffithsine.

[0483] In some embodiments, the additional therapeutic agent is a leukotriene D4 antagonist, such as montelukast.

[0484] In some embodiments, the additional therapeutic agent is a histamine H1 receptor antagonist, such as ebastine, tranilast, or levocetirizine dihydrochloride.

[0485] In some embodiments, the additional therapeutic agent is a histamine H2 receptor antagonist, such as phentermine.

[0486] In some embodiments, the additional therapeutic agent is a heat shock protein stimulator / insulin sensitizer / PARP inhibitor, such as BGP-15.

[0487] In some embodiments, the additional therapeutic agent is a histone inhibitor, such as STC-3141.

[0488] In some embodiments, the additional therapeutic agent is a histone deacetylase-6 inhibitor, such as CKD-506.

[0489] In some embodiments, the additional therapeutic agent is a HIF prolyl hydroxylase-2 inhibitor, such as desidustat.

[0490] In some embodiments, the additional therapeutic agent is a HIF prolyl hydroxylase inhibitor, such as vadadustat.

[0491] In some embodiments, the additional therapeutic agent is an IL-8 receptor antagonist, such as reparixin.

[0492] In some embodiments, the additional therapeutic agent is an IL-7 receptor agonist, such as CYT-107.

[0493] In some embodiments, the additional therapeutic agent is an IL-7 receptor agonist / interleukin-7 ligand, such as efineptakin alfa.

[0494] In some embodiments, the additional therapeutic agent is an IL-22 agonist, such as efmarodocokin alfa.

[0495] In some embodiments, the additional therapeutic agent is an IL-22 agonist / interleukin 22 ligand, such as F-652.

[0496] In some embodiments, the additional therapeutic agent targets IL-33, such as tozorakimab.

[0497] In some embodiments, the additional therapeutic agent is an IL-15 agonist, such as nogapendekin alfa.

[0498] In some embodiments, the additional therapeutic agent is an integrin α-V / β-1 antagonist / integrin α-V / β-6 antagonist, such as bexotegrast.

[0499] In some embodiments, the additional therapeutic agent is an interferon α2 ligand, such as interferon α-2b or Virafin.

[0500] In some embodiments, the additional therapeutic agent is an interferon beta ligand, such as an interferon beta-1a biosimilar, interferon beta-1b, or SNG-001.

[0501] In some embodiments, the additional therapeutic agent is an interferon receptor modulator, such as pegylated interferon lambda-1a.

[0502] In some embodiments, the additional therapeutic agent is an interleukin-2 ligand, such as aldesleukin.

[0503] In some embodiments, the additional therapeutic agent is an IRAK-4 protein kinase inhibitor, such as zimlovisertib.

[0504] In some embodiments, the additional therapeutic agent is a JAK inhibitor, for example, the additional therapeutic agent is baricitinib, filgotinib, jaktinib, tofacitinib, or nezulcitinib (TD-0903).

[0505] In some embodiments, the additional therapeutic agent is a neutrophil elastase inhibitor, such as alvelestat.

[0506] In some embodiments, the additional therapeutic agent is a pulmonary surfactant-associated protein D modulator, such as AT-100.

[0507] In some embodiments, the additional therapeutic agent is a plasma kallikrein inhibitor, such as donidalorsen.

[0508] In some embodiments, the additional therapeutic agent is a lysine-specific histone demethylase 1 / MAO B inhibitor, such as vafidemstat.

[0509] In some embodiments, the additional therapeutic agent is a polymannose-binding lectin serine protease inhibitor, such as conestat alfa.

[0510] In some embodiments, the additional therapeutic agent is a maxi K potassium channel inhibitor, such as ENA-001.

[0511] In some embodiments, the additional therapeutic agent is a MEK protein kinase inhibitor, such as zapnometinib.

[0512] In some embodiments, the additional therapeutic agent is a MEK-1 protein kinase inhibitor / Ras gene inhibitor, such as Anquinol.

[0513] In some embodiments, the additional therapeutic agent is a melanocortin MCl receptor agonist, such as PL-8177.

[0514] In some embodiments, the additional therapeutic agent is a melanocortin MC1 / MC3 receptor agonist, such as resomelagon acetate.

[0515] In some embodiments, the additional therapeutic agent is a matrix metalloproteinase-12 inhibitor, such as FP-025.

[0516] In some embodiments, the additional therapeutic agent is a NACHT LRR PYD domain protein 3 inhibitor, such as dapansutrile, DFV-890, or ZYIL-1.

[0517] In some embodiments, the additional therapeutic agent is an NADPH oxidase inhibitor, such as isuzinaxib.

[0518] In some embodiments, the additional therapeutic agent is a neuropilin 2 modulator, such as efzofitimod.

[0519] In some embodiments, the additional therapeutic agent is an NK1 receptor antagonist, such as aprepitant or tradipitant.

[0520] In some embodiments, the additional therapeutic agent is an NMDA receptor antagonist, such as transcrocetin or Ifenprodil.

[0521] In some embodiments, the additional therapeutic agent is a nuclear factor κB inhibitor / p38 MAP kinase inhibitor, such as zenuzolac.

[0522] In some embodiments, the additional therapeutic agent is an ornithine decarboxylase inhibitor, such as eflornithine.

[0523] In some embodiments, the additional therapeutic agent is an opioid receptor sigma antagonist 1, such as MR-309.

[0524] In some embodiments, the additional therapeutic agent is a PGD2 antagonist, such as asapiprant.

[0525] In some embodiments, the additional therapeutic agent is a PDGF receptor antagonist / TGFβ receptor antagonist / p38 MAP kinase inhibitor, such as deupirfenidone.

[0526] In some embodiments, the additional therapeutic agent is a phospholipase A2 inhibitor, such as varespladib methyl.

[0527] In some embodiments, the additional therapeutic agent is a phosphatidyl inositol 3-kinase inhibitor / mTOR complex inhibitor, such as dalutoxib.

[0528] In some embodiments, the additional therapeutic agent is an mTOR inhibitor, such as sirolimus.

[0529] In some embodiments, the additional therapeutic agent is a phosphatidylinositol 3-kinase delta / gamma inhibitor, such as durvicoxib.

[0530] In some embodiments, the additional therapeutic agent is a plasminogen activator inhibitor 1 inhibitor, such as TM-5614.

[0531] In some embodiments, the additional therapeutic agent is a protein tyrosine phosphatase beta inhibitor, such as razuprotafib.

[0532] In some embodiments, the additional therapeutic agent is a RIP-1 kinase inhibitor, such as DNL-758 or SIR-0365.

[0533] In some embodiments, the additional therapeutic agent is a Rev protein modulator, such as obefazimod.

[0534] In some embodiments, the additional therapeutic agent is an S phase kinase-associated protein 2 inhibitor, such as niclosamide, SCAI-502, or DWRX-2003.

[0535] In some embodiments, the additional therapeutic agent is a signal transducer CD24 stimulator, such as EXO-CD24.

[0536] In some embodiments, the additional therapeutic agent is a sodium glucose transporter-2 inhibitor, such as dapagliflozin propylene glycol.

[0537] In some embodiments, the additional therapeutic agent is a sodium channel stimulator, such as solnatide.

[0538] In some embodiments, the additional therapeutic agent is a neuramin-1-phosphate receptor-1 agonist / neuramin-1-phosphate receptor-5 agonist, such as ozanimod.

[0539] In some embodiments, the additional therapeutic agent is a nonsteroidal anti-inflammatory drug, such as Ampion.

[0540] In some embodiments, the additional therapeutic agent is a superoxide dismutase stimulator, such as avasopasem manganese.

[0541] In some embodiments, the additional therapeutic agent is a Syk tyrosine kinase inhibitor, such as fostamatinib disodium.

[0542] In some embodiments, the additional therapeutic agent is a Tie2 tyrosine kinase receptor agonist, such as AV-001.

[0543] In some embodiments, the additional therapeutic agent is a TGFB2 gene inhibitor, such as trabedersen.

[0544] In some embodiments, the additional therapeutic agent is a tissue factor inhibitor, such as AB-201.

[0545] In some embodiments, the additional therapeutic agent is a TLR-3 agonist, such as lintamatimod.

[0546] In some embodiments, the additional therapeutic agent is a TLR-4 antagonist, such as ApTLR-4FT, EB-05, or eritoran.

[0547] In some embodiments, the additional therapeutic agent is a TLR-7 / 8 antagonist, such as enpatoran.

[0548] In some embodiments, the additional therapeutic agent is a TLR-2 / 6 agonist, such as INNA-051.

[0549] In some embodiments, the additional therapeutic agent is a TLR-7 agonist, such as PRTX-007 or APR-002.

[0550] In some embodiments, the additional therapeutic agent is a TLR agonist, such as PUL-042.

[0551] In some embodiments, the additional therapeutic agent is a TLR-4 agonist, such as REVTx-99.

[0552] In some embodiments, the additional therapeutic agent is a TLR-2 / 4 antagonist, such as VB-201.

[0553] In some embodiments, the additional therapeutic agent is a TNFα ligand inhibitor, such as pegipanermin.

[0554] In some embodiments, the additional therapeutic agent is a type I IL-1 receptor antagonist, such as anakinra.

[0555] In some embodiments, the additional therapeutic agent is a TREM receptor 1 antagonist, such as nangibotide.

[0556] In some embodiments, the additional therapeutic agent is a trypsin inhibitor, such as ulinastatin.

[0557] In some embodiments, the additional therapeutic agent is a tubulin inhibitor, such as sabisulfar, CCI-001, PCNT-13, CR-42-24, albendazole, entasobulin, SAR-132885, or ON-24160.

[0558] In some embodiments, the additional therapeutic agent is a VIP receptor antagonist, such as aviptadil.

[0559] In some embodiments, the additional therapeutic agent is a xanthine oxidase inhibitor, such as oxypurinol.

[0560] In some embodiments, the additional therapeutic agent is a vasodilator, such as iloprost, VentaProst, zavegepant, TXA-127, USB-002, ambrisentan, nitric oxide nasal spray (NORS), pentoxifylline, propranolol, RESP301, sodium nitrite, or dipyridamol.

[0561] In some embodiments, the additional therapeutic agent is a vitamin D3 receptor agonist, such as cholecalciferol.

[0562] In some embodiments, the additional therapeutic agent is a disintegrin inhibitor, such as larazotide acetate.

[0563] In some embodiments, the additional therapeutic agent is a synthetic retinoid derivative, such as fenretinide.

[0564] In some embodiments, the additional therapeutic agent is a glucose metabolism inhibitor, such as WP-1122 or WP-1096.

[0565] In some embodiments, the additional therapeutic agent is adalimumab, AT-H201, 2-deoxy-D-glucose, AD-17002, AIC-649, AMTX-100, astodrimer, AZD-1656, berapetin, bitespiramycin, bucillamine, budesonide, CNM-AgZn-17, Codivir, CT-38, danicopan, didodecyl methotrexate, DW-2008S (DW-2008), EDP-1815, EG-009A, Fabencov, Gamunex, genistein, GLS-1200, hzVSF-v13, imidazolylacetamide glutaric acid, IMM-101, MAS-825, MRG-001, Nasitrol, Nylexa, orebactinib, OP-101, OPN-019, orynotide rhesus theta defensin-1, pyronaridine + artesunate, dapsone, RPH-104, sodium pyruvate pyruvate), Sulforadex, tafenoquine, TB-006, Telacebec, Tempol, TL-895, thimerosal, trimodulin, XC-221, XC-7, zunsemetinib, metformin glycinate, lucinactant, EOM-613, mosedipimod, ivermectin, leflunomide, ibudilast, RBT-9, raloxifene, prothione, gemcabene, or idronoxil.

[0566] In some embodiments, the additional therapeutic agent is a CD73 antagonist, such as AK-119.

[0567] In some embodiments, the additional therapeutic agent is a CD95 protein fusion, such as asunercept.

[0568] In some embodiments, the additional therapeutic agent is a complement factor C2 modulator, such as ARGX-117.

[0569] In some embodiments, the additional therapeutic agent is a complement C3 inhibitor, such as AMY-101 or NGM-621.

[0570] In some embodiments, the additional therapeutic agent is a CXC10 chemokine ligand inhibitor, such as EB-06.

[0571] In some embodiments, the additional therapeutic agent is a cytotoxic T-lymphoglobulin-4 fusion protein, such as abatacept.

[0572] In some embodiments, the additional therapeutic agent is an anti-S. aureus antibody, such as tosatoxumab.

[0573] In some embodiments, the additional therapeutic agent is an anti-LPS antibody, such as IMM-124-E.

[0574] In some embodiments, the additional therapeutic agent is an adrenomedullin ligand inhibitor, such as enibarcimab.

[0575] In some embodiments, the additional therapeutic agent is a basigin inhibitor, such as meplazumab.

[0576] In some embodiments, the additional therapeutic agent is a CD3 antagonist, such as foralumab.

[0577] In some embodiments, the additional therapeutic agent is a connective tissue growth factor ligand inhibitor, such as PRS-220, pamrevlumab.

[0578] In some embodiments, the additional therapeutic agent is a complement factor C5a inhibitor, such as BDB-1 or vilobelimab.

[0579] In some embodiments, the additional therapeutic agent is a complement factor C5 inhibitor, such as lavulizumab.

[0580] In some embodiments, the additional therapeutic agent is a polymannose-binding lectin serine protease-2 inhibitor, such as narsoplimab.

[0581] In some embodiments, the additional therapeutic agent is a GM-CSF modulator, such as STSA-1005, gimsilumab, namilumab, plonmarlimab, otilimab, or lenzilumab.

[0582] In some embodiments, the additional therapeutic agent is a heat shock protein inhibitor / IL-6 receptor antagonist, such as siltuximab.

[0583] In some embodiments, the additional therapeutic agent is an IL-6 receptor antagonist, such as clazakizumab, levilimab, olokizumab, tocilizumab, or sirukumab.

[0584] In some embodiments, the additional therapeutic agent is an IL-8 receptor antagonist, such as BMS-986253.

[0585] In some embodiments, the additional therapeutic agent is an interleukin-1 beta ligand inhibitor, such as canakinumab.

[0586] In some embodiments, the additional therapeutic agent is an interferon gamma ligand inhibitor, such as emapalumab.

[0587] In some embodiments, the additional therapeutic agent is an anti-ILT7 antibody, such as daxdilimab.

[0588] In some embodiments, the additional therapeutic agent is a monocyte differentiation antigen CD14 inhibitor, such as atibuclimab.

[0589] In some embodiments, the additional therapeutic agent is a plasma kallikrein inhibitor, such as lanadelumab.

[0590] In some embodiments, the additional therapeutic agent is a platelet glycoprotein VI inhibitor, such as glenzocimab.

[0591] In some embodiments, the additional therapeutic agent is an inhibitor of the T cell differentiation antigen CD6, such as itolizumab.

[0592] In some embodiments, the additional therapeutic agent is a TNFα ligand inhibitor / TNF binder, such as infliximab.

[0593] In some embodiments, the additional therapeutic agent is an anti-LIGHT antibody, such as AVTX-002.

[0594] In some embodiments, the additional therapeutic agent is IMC-2 (valacyclovir + celecoxib) or AXA-1125.

[0595] In some embodiments, the additional therapeutic agent is COVID-HIG.

[0596] In some embodiments, the compounds of the present disclosure or pharmaceutically acceptable salts thereof are co-administered with one or more agents useful for treating and / or preventing COVID-19.

[0597] 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 salimumab; Janus kinase (JAK) inhibitors such as baricitinib, ruxolitinib, or tofacitinib; and antiviral agents such as monapitravir, sotrovimab, or remdesivir.

[0598] In some embodiments, the compounds of the present disclosure or their pharmaceutically acceptable salts are co-administered with two or more agents useful for treating COVID-19. Agents useful for treating and / or preventing COVID-19 include, but are not limited to, the compounds of the present disclosure and two additional therapeutic agents, such as nematevir and ritonavir, casirizumab and imdevimab, or ruxolitinib and tofacitinib.

[0599] In some embodiments, the additional therapeutic agent is an antiviral agent. In some embodiments, the antiviral agent is an entry inhibitor. In some embodiments, the antiviral agent is a protease inhibitor. In some embodiments, the antiviral agent is an RNA polymerase inhibitor. In some embodiments, the additional therapeutic agent is an RNA-dependent RNA polymerase (RdRp) inhibitor.

[0600] In some embodiments, the antiviral agent is selected from angiotensin converting enzyme 2 inhibitors, angiotensin converting enzyme 2 modulators, angiotensin converting enzyme 2 stimulators, angiotensin II AT-2 receptor agonists, angiotensin II AT-2 receptor antagonists, angiotensin II receptor modulators, coronavirus nucleoprotein modulators, coronavirus small envelope protein modulators, coronavirus spike glycoprotein inhibitors, coronavirus spike glycoprotein modulators, SARS-CoV-2 small envelope protein inhibitors, SARS-CoV-2 small envelope protein modulators, SARS-CoV-2 MPro inhibitors, SARS-CoV-2 nonstructural protein 8 modulators, SARS-CoV-2 nucleoprotein inhibitors, SARS-CoV-2 nucleoprotein modulators, SARS-CoV-2 protein 3a inhibitors, SARS-CoV-2 replicase polyprotein 1a inhibitors, SARS-CoV-2 replicase polyprotein 1a modulators, SARS-CoV-2 replicase polyprotein 1ab inhibitors, SARS-CoV-2 replicase polyprotein 1ab modulators, SARS-CoV-2 spike glycoprotein inhibitors, SARS -CoV-2 spike glycoprotein modulators, SARS-CoV-2 structural glycoprotein modulators, papain inhibitors, protease inhibitors, protease modulators, RNA polymerase inhibitors, RNA polymerase modulators, RNA-dependent RNA polymerase (RdRp) inhibitors, SARS coronavirus 3C protease-like inhibitors, SARS-CoV-2 nsp14 methyltransferase inhibitors, 3CLpro / Mpro inhibitors, serine protease inhibitors, transmembrane serine protease 2 inhibitors, transmembrane serine protease 2 modulators, viral envelope protein inhibitors, viral protease inhibitors, viral protease modulators, viral protein target modulators, viral ribonuclease inhibitors, and viral structural protein modulators.

[0601] In some embodiments, the additional therapeutic agent is an entry inhibitor. For example, in some embodiments, the additional therapeutic agent is an ACE2 inhibitor, a fusion inhibitor, or a protease inhibitor.

[0602] In some embodiments, the additional therapeutic agent is an ACE2 inhibitor, such as SBK-001.

[0603] In some embodiments, the additional therapeutic agent is an ACE2 modulator, such as JN-2019.

[0604] In some embodiments, the additional therapeutic agent is an entry inhibitor, such as MU-UNMC-1.

[0605] In some embodiments, the additional therapeutic agent is an ACE-2 stimulator, such as alunacedase alfa.

[0606] In some embodiments, the additional therapeutic agent is an angiotensin II AT-2 receptor agonist, such as VP-01.

[0607] In some embodiments, the additional therapeutic agent is an ACE II receptor antagonist, such as DX-600.

[0608] In some embodiments, the additional therapeutic agent is an angiotensin II receptor modulator, such as TXA-127.

[0609] In some embodiments, the additional therapeutic agent is a transmembrane serine protease 2 modulator, such as BC-201.

[0610] In some embodiments, the additional therapeutic agent is a viral envelope protein inhibitor, such as MXB-9 or MXB-004.

[0611] In some embodiments, the additional therapeutic agent is a RNAi agent, such as ARO-COV or SNS-812.

[0612] 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 disease prevention vaccine, a protein-based vaccine, a viral vector vaccine, a cellular vaccine, or a dendritic cell vaccine.

[0613] In some embodiments, the additional therapeutic agent is a vaccine, such as tozinameran, NVX-CoV2373, elasomeran, KD-414, Ad26.COV2-S, Vaxzevria, SCB-2019, AKS-452, VLA-2001, HDT-301, S-268019, MVC-COV1901, mRNA-1273.214, mRNA-1273.213, mRNA-1273.222, NVX-CoV2515, Covaxin, BBIBP-CorV, GBP-510, mRNA-1273.351+ mRNA-1273.617 (SARS-CoV-2 multivalent mRNA vaccine, COVID-19), Ad5-nCoV, Omicron-based COVID-19 vaccine (mRNA vaccine, COVID-19), mRNA-1073, mRNA-1273.214, mRNA-1230, mRNA-1283, Omicron-based COVID-19 vaccine, SARS-CoV-2 protein subunit recombinant vaccine, Sputnik M, ZyCoV-D, COVID-19 XWG-03, mRNA-1273.529, mRNA-1010, CoronaVac, AZD-2816, Sputnik V, inactivated SARS-CoV-2 vaccine (Vero cells, COVID-19), DS-5670, PHH-1V, INO-4800, UB-612, coronavirus vaccine (whole virus, inactivated / purified), ReCOV, MT-2766, ARCT-154, SP-0253, CORBEVAX, mRNA-1273.211, ZF-2001, Sputnik Light, Recombinant Protein Vaccine (COVID-19 / SARS-CoV-2 Infection), VSV Vector-Based Vaccine Targeting Spike Glycoprotein (COVID-19), VLA-2101, GRT-R912, GRAd-COV2, VPM-1002, COViran Barekat, Ad5-nCoV-IH, ARCoV, Covax-19, Recombinant SARS-CoV-2 Vaccine (Protein Subunit / CHO Cells, COVID-19), BBV-154, 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 intranasal vaccine, VTP-500, or BNT162b5.

[0614] In some embodiments, the additional therapeutic agent is a protease inhibitor. For example, in some embodiments, the additional therapeutic agent is a 3C cysteine protease inhibitor (3CLPro, also known as main protease, Mpro), a papain inhibitor (PLpro), a serine protease inhibitor, or a transmembrane serine protease 2 inhibitor (TMPRSS2).

[0615] In some embodiments, the additional therapeutic agent is a 3CLpro / Mpro inhibitor, such as CDI-873, GC-373, GC-376, PBI-0451, UCI-1, bofutrelvir (FB-2001, DC-402234), DC-402267, GDI-4405, RAY-1216, MPI-8, SH-879, SH-580, EDP-235, VV-993, CDI-988, MI-30, nematevir, ensitrelvir, ASC-11, EDDC-2214, SIM-0417, CDI-45205, COR-803, ALG-097111, TJC-642, CVD-0013943, eravacycline, cynarine, or prexasertib.

[0616] In some embodiments, the additional therapeutic agent is a papain-like protease inhibitor (PLpro), such as SBFM-PL4 or GRL-0617.

[0617] In some embodiments, the additional therapeutic agent is an inhibitor of the SARS-CoV-2 helicase Nsp13, such as EIS-4363.

[0618] In some embodiments, the additional therapeutic agent is an inhibitor of the SARS-CoV-2 helicase Nsp14, such as PD-507.

[0619] In some embodiments, the additional therapeutic agent is a SARS-CoV-2 spike (S) and protease modulator, such as ENU-200.

[0620] In some embodiments, the additional therapeutic agent is a protease inhibitor, such as ALG-097558 or MRX-18.

[0621] In some embodiments, the additional therapeutic agent is a serine protease inhibitor, such as upamostat, nafamostat, camostat mesylate, nafamostat mesylate, or camostat.

[0622] In some embodiments, the additional therapeutic agent is a 3CLpro / transmembrane serine protease 2 inhibitor, such as SNB-01 (pentarlandir) or SNB-02.

[0623] In some embodiments, the additional therapeutic agent is a viral protease inhibitor, such as Pan-Corona, Cov-X, or bepridil.

[0624] In some embodiments, the additional therapeutic agent is an RNA polymerase inhibitor. For example, in some embodiments, the additional therapeutic agent is an RNA polymerase inhibitor, or an RNA-dependent RNA polymerase (RdRp) inhibitor.

[0625] 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.

[0626] In some embodiments, the additional therapeutic agent is an RNA polymerase inhibitor, such as monapiravir (EIDD-2801), favipiravir, bemnifosbuvir, sofosbuvir, ASC-10, or galidesivir.

[0627] In some embodiments, the additional therapeutic agent is a viral entry inhibitor, such as brilacidin.

[0628] In some embodiments, the additional therapeutic agent is an antibody that binds to a coronavirus, such as an antibody that binds to SARS or MERS.

[0629] In some embodiments, the additional therapeutic agent is an antibody, such as a monoclonal antibody. For example, the additional therapeutic agent is an antibody against SARS-CoV-2, a neutralizing antibody, an antibody targeting the SARS-CoV-2 spike protein, a fusion protein, a multispecific antibody, or an antibody that can neutralize SARS-CoV-2 (SARS-CoV-2 neutralizing antibody).

[0630] 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).

[0631] In some embodiments, the additional therapeutic agent is an antibody against the SARS-CoV-2 virus.

[0632] In some embodiments, the antibody is ABBV-47D11, COVI-GUARD (STI-1499), C144-LS + C135-LS, DXP-604, JMB-2002, LY-CovMab, bamanitumab (LY-CoV555), GIGA-2050, IBI-314, S309, SAB-185, etesevimab (CB6), COR-101, JS016, VNAR, VIR-7832 and / or sotrovimab (VIR-7831), casirizumab + edematumab (REGN-COV2 or REGN10933 + RGN10987), BAT2020, BAT2019, 47D11, YBSW-015, or PA-001.

[0633] In some embodiments, the additional therapeutic agent is STI-9199 (COVI-SHIELD), STI-9167, or AR-701 (AR-703 and AR-720).

[0634] In some embodiments, the additional therapeutic agent is BRII-196, BRII-198, ADG-10, adintrevimab (ADG-20), ABP-300, BA-7208, BI-767551, BHV-1200, CT-P63, JS-026, sotovetumab (GSK-4182136), tixagevimab + cilgavimab (AZD-7442), regdanvimab, SAB-301, AOD-01, plutavirimab (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), enuzovimab (HFB-30132A), INM-005, SCTA01, TY-027, XAV-19, amubarvimab + romlusevimab, SCTA-01, bebtelovimab, beludavir, IBI-O123, IGM-6268, FYB-207, FS-2101, RBT-0813, REGN-14256, REGN-14284, SPKM-001, XVR-011, TB202-3, TB181-36, TB339-031, LMN-301, LQ-050, COVAB-36, MAD-0004J08, STI-2099, TATX-03, TZLS-501, ZCB-11, or ACV-200-17.

[0635] In some embodiments, the additional therapeutic agent is an engineered ACE-2-IgG1-Fc-fusion protein targeting the SARS-Cov-2 RBD, such as EU-129, a bivalent ACE2-IgG Fc null fusion protein (SI-F019).

[0636] In some embodiments, the additional therapeutic agent is an ACE2-Fc receptor fusion protein, such as HLX-71.

[0637] In some embodiments, the additional therapeutic agent is ensovibep.

[0638] In some embodiments, the additional therapeutic agent is SYZJ-001.

[0639] In some embodiments, the additional therapeutic agent is an HIV-1 protease inhibitor, such as ASC-09F (ASC-09 + ritonavir) or lopinavir + ritonavir.

[0640] In some embodiments, the additional therapeutic agent is a non-nucleoside reverse transcriptase inhibitor, such as elfavirine.

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

[0642] 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, β-521, SIM-0417, namatevir, pan-Corona, Tollovir, namatevir + ritonavir (Paxlovid ®), favipiravir, GC-376, upasta, LeSoleil-01, LeSoleil-02+, benfovir, VV-116, VV-993, SNB-01, EDP-235, Cov-X, ensitrelvir, MPI-8, masitinib, 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, DEP remdesivir, GS-621763, GS-5245, GLS-5310, bemnifosbuvir, QLS-1128, ASC-10, SBFM-PL4, camostat mesylate, UCI-1, FB-2001(DC-402234), ebselen, SH-580, LeSoleil-01, LeSoleil-02+, MRX-18, MXB-9, MI-09, MI-30, SNB-02, SJP-002C, TJC-642, ENU-200, CVD-0013943, GS-441524, bepridil, MXB-004, ervacycline, GRL-0617, camostat, GC-373, nitazoxanide, cynarin, prexasertib, RAY-1216, SACT-COVID-19, MP-18, EIDD-1931, EDDC-2214, monoxide Nitrogen, apatalone, AnQlar, SBK-001, LQ-050, CG-SpikeDown, bamanitumab, HLX-71, HT-002, HY-209, HY-3000, FYB-207, ensovibep, SYZJ-001, EU-129, neumifil, JN-2019, AR-701, vostesyl, PLM-402, PJS-539, CTB-ACE2, TB181-36, TB202-3, ABP-300, XVR-011, MSP-008-22, MU-UNMC-1, MU-UNMC-2, alunacedase alfa, VP-01, TRV-027, DX-600, TXA-127, NVX-CoV2515, riamilovir, Pfizer vaccine, Moderna vaccine, Ad5-nCoV, BBIBP-CorV, CoronaVac, MVC-COV1901, NVX-CoV2373, sotovizumab, Sputnik V, TEE-001, Tyme-19, Vaxzevria, ZF-2001, or ZyCoV-D. [] [X.] [Example] [General synthesis:] [Scheme 1]

[0643] Scheme 1 shows the general synthesis of the compounds of the present invention, from [S1a] and nucleosides [S1b] The reaction is initiated under alkaline conditions (e.g., 4-dimethylaminopyridine (DMAP)) to obtain [S1c] LG represents a leaving group. Examples of leaving groups include, but are not limited to, chloride, bromide, methanesulfonate, toluenesulfonate, trifluoromethanesulfonate, 4-nitrobenzenesulfonate, 4-chlorobenzenesulfonate, 4-nitrophenoxy, and pentafluorophenoxy. After this reaction, the acetonide compound is cleaved under acidic conditions (e.g., HCl) to obtain the final compound of the present invention. [S1d]. [] [Scheme 2]

[0644] Scheme 2 shows the general synthesis of the compounds of the present invention, starting from nucleoside [S1b] starts with the reaction with 1,1'-carbonyldiimidazole (CDI) to produce the intermediate [S2a] Under basic conditions (e.g., 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)) [S2b] Displacement of imidazole to produce the penultimate intermediate [S1c] The acetonide compound is then cleaved under acidic conditions (e.g., HCl) to obtain the final compound of the present invention. [S1d]. [] [Scheme 3]

[0645] Scheme 3 shows the general synthesis of the compounds of the present invention, free nucleoside [S1b] starts with adding a protecting group (e.g., dimethylformamidine) to N6 to obtain [S3a]. [S3a] and [S1a] Reaction under basic conditions (e.g. pyridine) produces intermediate [S3b], which is then subjected to acidic conditions (such as HCl) to give the final compound of the present invention type [S1d]. [] [Scheme 4]

[0646] Scheme 4 shows the general synthesis of the compounds of the present invention, from [S1d] starts with the reaction with CDI or diphenyl carbonate to obtain the final compound type of the present invention [S4a]. [] [Scheme 5]

[0647] Scheme 5 shows the general synthesis of the compounds of the present invention, from [S1b] starts with the deprotection of the acetonide compound to produce the nucleoside [S5a]. [S5a] and anhydride [S5b] The reaction under basic conditions (e.g., DBU) yields the final compound of the present invention [S1d]. [] [Scheme 6a]

[0648] Scheme 6a shows that [S1d] General synthesis of the compounds of the present invention. In tetrahydrofuran (THF), in the presence of DMAP [S1d] reacts with dicarbonate to obtain the final compound type of the present invention [S6a-1] and [S6a-2]. [] [Scheme 7]

[0649] Scheme 7 describes the [S1d] The general synthesis of the compound of the present invention is as follows. In a solvent (such as acetone), the compound [S1d] reacts with chloromethyl disubstituted phosphate to provide an intermediate [S7a] PG is a protecting group. Examples of protecting groups include, but are not limited to, trimethylsilyl, dimethylhexylsilyl, tertiary butyldimethylsilyl, tertiary butyldiphenylsilyl, trityl, alkyl, and acyl groups such as acetyl and propionyl, methanesulfonyl, and p-toluenesulfonyl. Removal of the protecting group is achieved by hydrogenation or treatment with an acid, providing compounds of the present invention. [S7b] [.] [] [Scheme 8]

[0650] Scheme 8 describes [S1c] The N6-carbamate of the present invention is similar to General synthesis of [S8b]. [S1c] reacts with acyl chloride under alkaline conditions (such as pyridine) to produce an intermediate [S8a], which is then subjected to acidic conditions (e.g., HCl) to yield compounds of the present invention of the type [S8b]. [] [Scheme 9]

[0651] Scheme 9 describes [S1c] The N6-amide analogs of the present invention are similar to General synthesis of [S9b]. [S1c] and acyl chloride ( ) produces an intermediate under basic conditions (such as pyridine) [S9a], which is then subjected to acidic conditions (e.g., HCl) to yield compounds of the present invention of the type [S9b].

[0652] The compounds of the present invention are [S9b] can also be achieved through [S1c] is obtained by reacting with the corresponding acid. [S1c] and acid ( ) in the presence of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) to produce an intermediate [S9a], which is then subjected to acidic conditions (e.g., HCl) to yield compounds of the present invention of the type [S9b]. [] [Scheme 10]

[0653] Scheme 10 shows the general synthesis of the compounds of the present invention, starting from the diacid [S10a] reacts with 1,1'-carbonyldiimidazole to obtain the reagent [S10b]. [S10b] and nucleoside The reaction between [S1d] can further give the final compound type of the present invention [S10c]. [] [Scheme 11]

[0654] Scheme 11 shows the general synthesis of the compounds of the present invention, starting from alcohol [S11a] starts with acylation with 1,1'-carbonyldiimidazole (CDI) to obtain the reagent [S11b] Using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in [S11b] and [S1b] reacts to produce an intermediate [S1c]. [S1c] and [S11c] The reaction is carried out using pyridine as a base, followed by acid treatment (such as HCl), and then the final compound type of the present invention is obtained. [S11d]. [] [Scheme 12]

[0655] Scheme 12 shows alcohol [S1d] General synthesis of acetalization with propionaldehyde under acidic conditions (such as PTSA) to obtain the final compound type of the present invention [S12a]. [] [Scheme 13]

[0656] [Scheme 13] shows the use of carbodiimide reagents (such as N, N'-diisopropylcarbodiimide (DIC)) and 4-dimethylaminopyridine (DMAP) to [S1d] and acid [S13a] Perform the general synthesis of esterification to obtain the final compound type of the present invention [S13b]. [] [Scheme 14]

[0657] Scheme 14 shows the general synthesis of the compounds of the present invention, starting from the nucleoside [S1d] free amine protection group manipulation to obtain [S14a]. [S14a] with chloroformate [S14b] Reaction under basic conditions (such as pyridine) followed by acidic treatment (such as HCl) to obtain the final compound of the present invention [S14c]. [] [Intermediate Ia] [and Ib] [Synthesis of:]

[0658] To (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]trioxan-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxane-4-carbonitrile ( [intermediate] To a solution of [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). Isobutyl chloroformate (495 mg, 3.6 mmol) was added to the above solution at room temperature and stirred for 1 h. LC-MS showed the formation of two products, the 5'-carbonate and the 5'-carbonate along with the N6-carbamate. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water and brine, dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography using dichloromethane and methanol as eluents to separate the two products. [intermediate] [Ia] Isobutyl ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]trioxan-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl 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]trioxan-4-yl)carbamate. LCMS: MS m / z: 532.2 (M+1) [] [Intermediate II] [Synthesis of:]

[0659] To (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]trioxan-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxane-4-carbonitrile ( [intermediate] To a solution of [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 heated at 50°C for 1 h. After the reaction was complete, the solvent was evaporated under 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 obtain the 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]trioxan-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]] [three] [𠯤-7-] [Base)-5-] [Cyano-3,4-] [Dihydroxytetrahydrofuran-2-] [base)] [Methyl isobutyl carbonate (Compound 1)] [)]

[0660] ((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]trioxan-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl isobutyl carbonate ( [Intermediate] To a solution of [Ia]) (1300 mg, 3 mmol) in acetonitrile (10 mL) was added concentrated HCl (1.3 mL, 15 mmol) and stirred at room temperature for 1 h. After the reaction was complete, the reaction mixture was diluted with ethyl acetate (50 mL) and neutralized with saturated sodium bicarbonate. The organic layer was separated, washed with ...

Claims

1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: , , or.

2. The compound of claim 1 or its pharmaceutically acceptable salt, wherein the compound is a compound having the following formula: .

3. The compound of claim 1 or its pharmaceutically acceptable salt, wherein the compound is a compound having the following formula: .

4. The compound of claim 1 or its pharmaceutically acceptable salt, wherein the compound is a compound having the following formula: .

5. The compound of claim 1 or its pharmaceutically acceptable salt, wherein the compound is a compound having the following formula: .

6. A pharmaceutical composition comprising a compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

7. The pharmaceutical composition as described in claim 6 is a pharmaceutical preparation intended for subcutaneous, intramuscular, intravenous, oral, or inhalation administration.

8. The pharmaceutical composition described in claim 6 is a pharmaceutical preparation intended for oral administration.

9. Use of a compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of any one of claims 6 to 8, for the preparation of a medicine for the treatment or prevention of viral infections.

10. The use as claimed in claim 9, wherein the pharmaceutical product is intended for oral, intramuscular, intravenous, subcutaneous, or inhalation administration.

11. As claimed in claim 9, wherein the pharmaceutical product further comprises at least one additional therapeutic agent or disease prevention agent or is intended for use in combination with at least one additional therapeutic agent or disease prevention agent.

12. As requested in claim 11, wherein the additional therapeutic or preventive agent is molnupiravir, oseltamivir, nirmatrelvir, or ritonavir.

13. For any of the uses in claims 9 to 12, wherein the viral infection is a coronavirus infection.

14. For any of the uses in claims 9 to 12, wherein the viral infection is a zoonotic coronavirus infection.

15. For any of the uses in claims 9 to 12, wherein the virus infection is selected from the group consisting of: 229E virus infection, NL63 virus infection, OC43 virus infection and HKU1 virus infection.

16. For any of the uses in claims 9 to 12, wherein the viral infection is SARS-CoV-2 infection (COVID-19).

17. For any of the uses in claims 9 to 12, wherein the viral infection is SARS-CoV or MERS-CoV.

18. The use of any of claims 9 to 12, wherein the viral infection is a pneumoviridae virus infection.

19. As claimed in claim 18, wherein the pulmonary virus infection is a respiratory syncytial virus infection or a human interstitial pneumonia virus infection.

20. For any of the uses in claims 9 to 12, wherein the viral infection is caused by a virus of the Picornaviridae family, a virus of the Flaviviridae family, a virus of the Filoviridae family, an orthomyxovirus infection, or a virus of the Paramyxovirusidae family.

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