Compounds and methods for treating viral infections

Abstract

Compounds of Formula I, Formula A, or Formula B and methods of using such compounds, alone or in combination with additional agents, as well as salts or pharmaceutical compositions of such compounds, are disclosed for the treatment of viral infections.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 538,634, filed September 15, 2023, the entire contents of which are incorporated herein by reference. Background Technology

[0003] There is a need for compounds and methods for treating viral infections, such as those of the families Paramyxoviridae, Pneumoviridae, Picornaviridae, Flaviviridae, Fioviridae, Arenaviridae, Orthomyxovirus, and Coronaviridae. This disclosure addresses the above and other needs.

[0004] Oral administration is the preferred route for routine drug administration due to its advantages, such as non-invasiveness, patient compliance, and ease of administration. However, oral administration can be limited by the poor physicochemical properties of drug molecules, including low water solubility between pH 2 and pH 7, instability, low permeability, and rapid metabolism. All these factors combined result in low and irregular oral bioavailability. Oral bioavailability (F%) is the fraction of a drug delivered orally relative to the same dose delivered intravenously to the systemic circulation. After intravenous administration, the drug is directly and completely available in the bloodstream and distributed via the systemic circulation to the site of pharmacological action. If a drug is administered orally, it must survive in intestinal fluid, cross other barriers such as the gastrointestinal (GI) cell layer, and then cross the liver to reach the systemic circulation, which significantly reduces the amount of drug delivered to the bloodstream. Therefore, oral bioavailability is an important characteristic in drug design and development. High oral bioavailability reduces the amount of drug required to achieve the desired pharmacological action, thus reducing the risk of side effects and toxicity during absorption. This disclosure also provides compounds having combined solubility, stability and permeability properties, which result in improved oral bioavailability. Summary of the Invention

[0005] This disclosure provides compounds of formula I:

[0006]

[0007] Formula I

[0008] Or its pharmaceutically acceptable salt, wherein:

[0009] R 1It is -OH, -OC(=O)R 4 or -OC(=O)OR 4 ;

[0010] R 2 It is -OH, -OC(=O)R 5 or -OC(=O)OR 5 ;or

[0011] R 1 and R 2 Together they form -OC(=O)O- or -OCHR 6 O-;

[0012] R 3 R 4 and R 5 Each of these groups is independently a C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, or C6-C 10 Aryl or 5- to 6-membered heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, and S;

[0013] Where R 3 R 4 and R 5 C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, C6-C 10 The aryl or 5- to 6-membered heteroaryl groups are each independently and optionally selected by one, two, or three independently free from halogen, cyano, -N3, -OR. 7 -NR 8 R 9 The phenyl group is optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, cyano and C1-C6 alkyl groups;

[0014] R 6 It is H, C1-C6 alkyl or C6-C 10 Aryl;

[0015] Each R 7 Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl;

[0016] Each R 8 Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl;

[0017] Each R 9 Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl;

[0018] Alkali is , or ;and

[0019] R 10 It is a C1-C6 alkyl group substituted with -OP(O)(OH)2.

[0020] This disclosure also provides compounds of formula A:

[0021]

[0022] Formula A

[0023] Or its pharmaceutically acceptable salt, wherein:

[0024] R 1A and R 2A Linked to form a 3- to 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or a 5- to 10-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S;

[0025] Where R 1A and R 2A The 3- to 8-membered heterocyclic group or the 5- to 10-membered heteroaryl group is optionally selected independently from one, two, or three halogens, cyano groups, oxo groups, -N3, -OR groups. 3A -C(=O)R 3A -C(=O)OR 3A -NR 4A R 5A Substituents of the group consisting of C1-C6 alkyl and phenyl groups;

[0026] Where R 1A and R 2A The C1-C6 alkyl substituents are optionally substituted by one, two, or three independent substituents selected from halogens, cyano groups, and phenyl groups; and

[0027] R 1A and R 2A The substituted phenyl group is optionally substituted by one, two, or three independent substituents selected from halogen, cyano, and C1-C6 alkyl groups; or

[0028] R 1A It is H;

[0029] R 2A Is it -C(=O)OR 3A Substituted C1-C8 alkyl groups;

[0030] Where R 2A -C(=O)OR 3AThe substituted C1-C8 alkyl group is optionally replaced by one or two independently selected from halogen, cyano, and phenyl groups and -OR. 3A The substituents are further substituted;

[0031] Each R 3A Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, and 3 to 8-membered heterocyclic groups containing 1, 2, or 3 heteroatoms independently selected from N, O, and S;

[0032] Each R 4A Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl;

[0033] Each R 5A Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl;

[0034] Alkali is , or ;and

[0035] R 6A It is a C1-C6 alkyl group substituted with -OP(O)(OH)2.

[0036] This disclosure also provides compounds of formula B:

[0037]

[0038] Formula B

[0039] Or its pharmaceutically acceptable salt, wherein:

[0040] R 3B It is -OC(=O)R 5B or -OC(=O)OR 5B ;

[0041] R 4B It is -OC(=O)R 6B or -OC(=O)OR 6B ;or

[0042] R 3B and R 4B Together they form -OC(=O)O- or -OCHR 7B O-;

[0043] R 5B and R 6B Each of these groups is independently a C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, or C6-C 10Aryl or 5- to 6-membered heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, and S;

[0044] Where R 5B and R 6B C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, C6-C 10 The aryl or 5- to 6-membered heteroaryl groups are each independently and optionally selected by one, two, or three independently free from halogen, cyano, -N3, -OR. 8B -NR 9B R 10B The phenyl group is optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, cyano and C1-C6 alkyl groups;

[0045] Each R 8B Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl;

[0046] Each R 9B Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl;

[0047] Each R 10B Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl;

[0048] R 7B It is H, C1-C6 alkyl or C6-C 10 Aryl;

[0049] R 1B It is H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, C6-C 10 Aryl or 5- to 6-membered heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, and S;

[0050] Where R 1B C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, C6-C 10 The aryl or 5- to 6-membered heteroaryl group is optionally selected by one, two, or three independently free from halogen, cyano, -N3, -OR. 11B -C(=O)R 11B -C(=O)OR 11B -NR 12B R 13B The phenyl group is optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, cyano and C1-C6 alkyl groups;

[0051] R2B It is H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, C6-C 10 Aryl or 5- to 6-membered heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, and S;

[0052] Where R 2B C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, C6-C 10 The aryl or 5- to 6-membered heteroaryl group is optionally selected by one, two, or three independently free from halogen, cyano, -N3, -OR. 11B -C(=O)R 11B -C(=O)OR 11B -NR 12B R 13B And optionally substituted with one, two or three substituents selected independently from the group consisting of phenyl groups, which are substituted with halogens, cyano groups and C1-C6 alkyl groups; or

[0053] R 1B and R 2B Linked to form a 3- to 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or a 5- to 10-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S;

[0054] Where R 1B and R 2B The 3- to 8-membered heterocyclic group or the 5- to 10-membered heteroaryl group is optionally selected independently from one, two, or three halogens, cyano groups, oxo groups, -N3, -OR groups. 11B -C(=O)R 11B -C(=O)OR 11B -NR 12B R 13B Substituents of the group consisting of C1-C6 alkyl and phenyl groups;

[0055] Where R 1B and R 2B The C1-C6 alkyl substituents are optionally substituted by one, two, or three independent substituents selected from halogens, cyano groups, and phenyl groups; and

[0056] R 1B and R 2B The substituted phenyl group is optionally substituted by one, two or three independent substituents selected from halogen, cyano and C1-C6 alkyl groups;

[0057] Each R 11BIndependently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, and 3 to 8-membered heterocyclic groups containing 1, 2, or 3 heteroatoms independently selected from N, O, and S;

[0058] Each R 12B Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl;

[0059] Each R 13B Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl;

[0060] Alkali is , or ;and

[0061] R 14B It is a C1-C6 alkyl group substituted with -OP(O)(OH)2.

[0062] This document also provides a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0063] This article also provides a method for treating or preventing viral infections in a person in need, wherein the method comprises administering to a person a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0064] This article also provides a method for manufacturing a medicament for treating or preventing viral infections in people in need, characterized in that the compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0065] This article also provides for the use of the compounds disclosed herein or pharmaceutically acceptable salts thereof in the manufacture of medicaments for the treatment or prevention of viral infections in persons in need.

[0066] This article also provides a composition comprising the compounds disclosed herein or pharmaceutically acceptable salts thereof, for use in the treatment or prevention of viral infections in persons in need. Detailed Implementation

[0067] I. Overview

[0068] The present invention relates to methods and compounds for treating or preventing viral infections, such as those of the Paramyxoviridae, Pneumoviridae, Picornaviridae, Flaviviridae, Filoviridae, Arenaviridae, Orthomyxoviridae, and Coronaviridae families.

[0069] II. Definition

[0070] Unless otherwise indicated, the following terms and phrases as used herein are intended to have the following meanings:

[0071] "Alkyl" refers to a saturated hydrocarbon chain that is unbranched or branched. For example, an alkyl group can have 1 to 20 carbon atoms (i.e., C1-C2). 20 Alkyl groups, having 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, sec-butyl, -C H(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, tert-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1 -Butyl (-CH2CH2CH(CH3)2), 2-Methyl-1-Butyl (-CH2CH(CH3)CH2CH3), 1-Hexyl (-CH2CH2CH2CH2CH2CH3), 2-Hexyl (-CH(CH3)CH2CH2CH2CH3), 3-Hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-Methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-Methyl-2-pentyl (- CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2) and 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2) and 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3).

[0072] "Alkenyl" refers to a group containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C24-C24-C24). 2-20 alkenyl), 2 to 8 carbon atoms (i.e., C) 2-8 alkenyl), 2 to 6 carbon atoms (i.e., C) 2-6Alkenyl) or 2 to 4 carbon atoms (i.e., C) 2-4 Alkenyl groups are aliphatic groups. Examples of alkenyl groups include vinyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0073] "Alkyne" refers to a group containing at least one carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C24-C24-C24). 2-20 alkynyl group), 2 to 8 carbon atoms (i.e., C64) 2-8 alkynyl group), 2 to 6 carbon atoms (i.e., C64) 2-6 (alkynyl group) or 2 to 4 carbon atoms (i.e., C) 2-4 The term "alkynyl" also includes those groups having one triple bond and one double bond.

[0074] "Haloalkyl" is an alkyl group as defined above, wherein one or more hydrogen atoms of the alkyl group are replaced by halogen atoms. The alkyl portion of a haloalkyl group may have 1 to 20 carbon atoms (i.e., C1-C2). 20 Halogenated alkyl groups), 1 to 12 carbon atoms (i.e., C1-C1), 12 Halogenated alkyl groups, having 1 to 8 carbon atoms (i.e., C1-C8 alkyl groups), 1 to 6 carbon atoms (i.e., C1-C6 alkyl groups), or 1 to 3 carbon atoms (i.e., C1-C3 alkyl groups). Examples of suitable alkyl groups include, but are not limited to, -CF3, -CHF2, -CFH2, -CH2CF3, etc.

[0075] "Aryl" refers to an aromatic hydrocarbon group derived by removing a hydrogen atom from a single carbon atom in a parent aromatic ring system. For example, aryl groups can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 10 carbon atoms. Typical aryl groups include, but are not limited to, groups derived from benzene (e.g., phenyl), substituted benzenes, naphthalenes, anthracene, biphenyls, etc.

[0076] "Heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, wherein one or more heteroatoms are independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl includes 1 to 20 ring atoms (i.e., 1 to 20-membered heteroaryl rings), 3 to 12 ring atoms (i.e., 3 to 12-membered heteroaryl rings), or 3 to 8 carbon ring atoms (i.e., 3 to 8-membered heteroaryl rings), or 5 to 6 ring atoms (i.e., 5 to 6-membered heteroaryl rings). Examples of heteroaryl groups include pyrimidinyl, purine, pyridinyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Heteroaryl does not encompass aryl groups as defined above or overlaps with them.

[0077] A "carbocyclic group" or "carbocyclic ring" refers to a non-aromatic hydrocarbon ring composed of carbon and hydrogen atoms, having three to twenty carbon atoms, in some embodiments three to fifteen carbon atoms, and in some embodiments three to ten, three to eight, three to seven, or three to six carbon atoms, and is saturated or partially unsaturated and connected to the rest of the molecule by single bonds. 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.

[0078] "Cycloalkyl" refers to a saturated cyclic alkyl group having a single ring or comprising multiple rings in fused, bridged, and spirocyclic systems. As used herein, cycloalkyl groups have 3 to 20 cyclic carbon atoms (i.e., C46, ​​C56, C6 ... 3-20 cycloalkyl groups), 3 to 12 cyclic carbon atoms (i.e., C12+ ... 3-12 cycloalkyl groups), 3 to 10 cyclic carbon atoms (i.e., C146 ... 3-10 cycloalkyl groups), 3 to 8 cyclic carbon atoms (i.e., C1646-C ... 3-8 cycloalkyl groups or 3 to 6 cyclic carbon atoms (i.e., C16, C26, C36, C46, ​​C56, C6 ... 3-6 Cycloalkyl groups. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0079] As used herein, “heterocycle” or “heterocyclic group” includes, by way of example and not limitation, the heterocycles described in: Paquette, Leo A.; Principles of Modern Heterocyclic Chemistry (WA Benjamin, New York, 1968), 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 “carbon ring” as defined herein, in which one or more (e.g., 1, 2, 3, or 4) carbon atoms have been substituted with heteroatoms (e.g., O, N, or S). As used herein, heterocycles or heterocyclic groups have 3 to 20 ring atoms, 3 to 12 ring atoms, 3 to 10 ring atoms, 3 to 8 ring atoms, or 3 to 6 ring atoms. The cyclic carbon atoms and heteroatoms of the heterocyclic group may optionally be oxidized to form an oxo group or a sulfide ion group or other oxidized linker (e.g., C(O), S(O), C(S) or S(O)2, N-oxide, etc.), or the nitrogen atom may be quaternized. The terms "heterocycle" or "heterocyclic group" include saturated and partially unsaturated rings. Substituted heterocyclic groups include, for example, heterocycles substituted with any substituent disclosed herein, including a carbonyl group. Non-limiting examples of carbonyl-substituted heterocyclic groups include:

[0080] .

[0081] Examples of heterocycles include, but are not limited to, tetrahydrofuranyl, azahexacyclic butyl, and 2-oxo-1,3-dioxacyclopenten-4-yl.

[0082] The term “optionally substituted” (e.g., optionally substituted aryl group) for a particular portion of a compound described herein (such as a compound of formula I, a compound of formula A, or a compound of formula B) means a portion in which all substituents are hydrogen or in which one or more hydrogens of the portion may be replaced by the listed substituents.

[0083] Unless otherwise specified, the carbon atoms of compounds of Formula I, Formula A, or Formula B are intended to have a tetravalent oxidation state. If, in some chemical structural representation, the carbon atom is not connected to a sufficient number of variables to produce a tetravalent oxidation state, it should be assumed that the remaining carbon substituents required to provide the tetravalent oxidation state are hydrogen.

[0084] Unless otherwise specified, as used herein, the term "treatment" means reversing, alleviating, or suppressing the progression of a condition or symptom to which the term applies, or one or more symptoms of such condition or symptom. As used herein, the term "treatment" refers to the act of treatment, as "treatment" is as defined above.

[0085] "Prophylaxis" means any treatment that prevents the development of clinical symptoms of a disease or condition. In some embodiments, the compounds and compositions disclosed herein may be administered to subjects (including humans) at risk of developing a disease or condition. As used herein, the term "prophylaxis" encompasses the administration of a compound, composition, or pharmaceutically acceptable salt according to the embodiments disclosed herein before or after an individual's exposure to a virus, but before the onset of symptoms of viral infection and / or before the virus is detected in the blood. The term also refers to the prevention of the onset of disease symptoms and / or the prevention of the virus reaching detectable levels in the blood. The term includes pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP) and event-driven or "on-demand" prophylaxis. The term also refers to the prevention of perinatal transmission of the virus from mother to infant by administration to the mother before delivery and to the infant during the first few days of life. The term also refers to the prevention of viral transmission via blood transfusion.

[0086] As used herein, the term "therapeutic effective amount" refers to the amount of a compound described herein (e.g., a compound of formula I, a compound of formula A, or a compound of formula B) present in a composition described herein, which is necessary to deliver a desired level of the drug in the secretions and tissues of the airways and lungs, or alternatively, to produce a desired physiological response or desired biological effect in the bloodstream of a subject to be treated when such a composition is administered via a chosen route of administration. The precise amount will depend on many factors, such as the specific compound described herein (e.g., a compound of formula I, a compound of formula A, or a compound of formula B), the specific activity of the composition, the delivery device used, the physical properties of the composition, its intended use, and patient considerations such as the severity of the disease state, patient cooperation, etc., and this precise amount can be readily determined by someone skilled in the art based on the information provided herein.

[0087] Any reference to the compounds of the invention described herein also includes reference to their pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts of the compounds of the invention include those derived from suitable bases such as alkali metals or alkaline earth metals (e.g., Na₂O₃). + Li + K + Ca +2 and Mg +2 ), ammonium and NR4 +Salts of (where R is defined herein). Pharmaceutically acceptable salts of nitrogen atoms or amino groups include (a) acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, phosphoric acid, nitric acid, etc.); (b) salts formed with organic acids (e.g., acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, hydroxyethanesulfonic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, etc.). Salts formed from (acids such as p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, malonic acid, sulfosalicylic acid, glycolic acid, 2-hydroxy-3-naphthyl ester, dihydroxynaphthyl salt, salicylic acid, stearic acid, phthalic acid, mandelic acid, lactic acid, ethanesulfonic acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine, leucine, etc.); and (c) salts formed from elemental anions such as chlorine, bromine, and iodine. Pharmaceutically acceptable salts of hydroxyl compounds include salts formed from the anion of the compound and a suitable cation such as Na+. + and NR4 + The combination of .

[0088] In some embodiments, R is H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)ynyl, C6-C 20 Aryl or C2-C 20 Heterocyclic group.

[0089] For therapeutic purposes, the salts of the active ingredients of the compounds of the present invention will be pharmaceutically acceptable, i.e., they will be salts derived from pharmaceutically acceptable acids or bases. However, salts of pharmaceutically unacceptable acids or bases may also be used, for example, to prepare or purify pharmaceutically acceptable compounds. All salts, whether or not derived from pharmaceutically acceptable acids or bases, are within the scope of the present invention.

[0090] It should also be understood that the compositions herein include the non-ionic and zwitterionic forms of the compounds of the present invention and a combination with a stoichiometric amount of water in the hydrate.

[0091] It should be noted that this invention covers all enantiomers, diastereomers, racemic mixtures, tautomers, polymorphs, and pseudopolymorphs of the compounds described herein (e.g., compounds within the scope of Formula I) and their pharmaceutically acceptable salts. All mixtures of such enantiomers and diastereomers are within the scope of this invention.

[0092] The compounds of the present invention, exemplified by Formula I, may have a chiral center, such as a chiral carbon or phosphorus atom. Therefore, the compounds of the present invention comprise racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and transisomers. Furthermore, the compounds of the present invention comprise optical isomers enriched or resolved at any or all asymmetric, chiral atoms. In other words, the chiral center, as apparent from the description, is provided as a chiral isomer or a racemic mixture. Both racemic mixtures and diastereomer mixtures, as well as isolated or synthesized individual optical isomers (substantially free of their enantiomers or diastereomer conjugates), are within the scope of the present invention. Racemic mixtures are isolated into their individual, substantially optically pure isomers by suitable techniques, for example, by separating diastereomers formed with optically active auxiliaries (e.g., acids or bases), and then converting the diastereomers back into the optically active substance. In most cases, the desired optical isomers are synthesized via stereospecific reactions, starting from a suitable stereoisomer of the desired starting material.

[0093] The stereochemical definitions and conventions used in this article generally follow those of SP Parker, ed., “McGraw-Hill Dictionary of Chemical Terms” (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds” (1994), John Wiley & Sons, Inc., New York. Many organic compounds exist in an optically active form, meaning they possess the ability to rotate the plane of polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule around its chiral center. The prefixes d and l, D and L, or (+) and (-) are used to denote the plane-polarized rotation notation of a compound, where S, (-), or 1 indicates that the compound is levorotatory, while compounds prefixed with R, (+), or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be referred to as enantiomers, and mixtures of such isomers are often referred to as enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur in chemical reactions or processes where there is no stereoselectivity or stereospecificity. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers that lacks optical activity.

[0094] In some cases, the compounds of the present invention may also exist as tautomers. Although only one delocalized resonance structure can be described, all such forms are considered within the scope of the present invention. For example, for purine, pyrimidine, imidazole, guanidine, amidine, and tetrazolium systems, olefin-amine tautomers may exist, and all their possible tautomer forms are within the scope of the present invention.

[0095] Any formula or structure given herein, including compounds of formula I, is also intended to represent the unlabeled form and isotopically labeled form of the compounds. Isotopically labeled compounds have the structure described 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 may be incorporated into the compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, but not limited to, isotopes of these elements. 2 H (deuterium, D) 3 H (tritium) 11 C 13 C 14 C 15 N、 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I. Various isotope-labeled compounds disclosed herein, such as those in which radioactive isotopes such as 3 H, 13 C and 14 C is incorporated. These isotope-labeled compounds can be used in metabolic studies, reaction kinetic studies, detection or imaging techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including the determination of tissue distribution of drugs or substrates, or for the treatment of patients with radiation.

[0096] This disclosure also includes compounds (e.g., compounds of formula I, formula A, or formula B) wherein one to x hydrogen atoms bonded to a carbon atom 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 of the compounds described herein (e.g., compounds of formula I, formula A, or formula B) when administered to mammals, particularly humans. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci. 5(12):524-527 (1984). In view of this disclosure, such compounds are synthesized by methods known in the art, for example by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0097] The deuterium-labeled or substituted therapeutic compounds disclosed herein may have improved DMPK (drug metabolism and pharmacokinetics) properties, which involve distribution, metabolism, and excretion (ADME). Substitution with a heavier isotope (such as deuterium) can provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life, reduced dose requirement, and / or improved therapeutic index. 18 F-labeled compounds can be used in PET or SPECT studies. The isotopically labeled compounds and their prodrugs disclosed herein can generally be prepared by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents, or by following the procedures disclosed in the examples and formulations described below. It should be understood that, in this context, deuterium is considered a substituent in compounds of formula I, formula A, or formula B.

[0098] In some embodiments, the carbon atom bonded at the 5-position of the tetrahydrofuranyl ring of Formula I is replaced by 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 atom of the base of Formula I is replaced by one or more deuterium atoms. In some embodiments, the base is... , or In some implementations, the base of formula I, R 10 The carbon atom is replaced by one or more deuterium atoms. In some embodiments, R of formula I... 1 The carbon atom is replaced by one or more deuterium atoms. In some embodiments, R of formula I... 2 The carbon atom is replaced by one or more deuterium atoms. In some embodiments, R of formula I... 3 The carbon atoms are replaced by one or more deuterium atoms.

[0099] In some implementations, the compound of formula I is ,

[0100] .

[0101] In some implementation schemes, the alkali is , , , , , , , , , , , , , , , , or .

[0102] In some embodiments, the carbon at the 5-position of the tetrahydrofuranyl ring of formula A is replaced by one or two deuterium atoms. In some embodiments, the compound of formula A is In some embodiments, the compound of formula A is In some embodiments, the carbon atom of the base of formula A is replaced by one or more deuterium atoms. In some embodiments, the base is... , or In some implementations, the base of formula A has an R... 6A The carbon atom is replaced by one or more deuterium atoms. In some embodiments, the R of formula A... 1A The carbon atom is replaced by one or more deuterium atoms. In some embodiments, the R of formula A... 2A The carbon atoms are replaced by one or more deuterium atoms.

[0103] In some implementations, the compound of formula A is ,

[0104]

[0105]

[0106] In some implementation schemes, the alkali is , , , , , , , , , , , , , , , , or .

[0107] In some embodiments, the carbon at the 5-position of the tetrahydrofuranyl ring of formula B is replaced by one or two deuterium atoms. In some embodiments, the compound of formula B is... In some implementations, the compound of formula B is In some embodiments, the carbon atom of the base of formula B is replaced by one or more deuterium atoms. In some embodiments, the base is... , or In some implementations, the base of formula B has R 14B The carbon atom is replaced by one or more deuterium atoms. In some embodiments, the R in formula B... 3B The carbon atom is replaced by one or more deuterium atoms. In some embodiments, the R in formula B... 4B The carbon atom is replaced by one or more deuterium atoms. In some embodiments, the R in formula B... 1B The carbon atom is replaced by one or more deuterium atoms. In some embodiments, the R in formula B... 2B The carbon atoms are replaced by one or more deuterium atoms.

[0108] In some implementations, the compound of formula B is ,

[0109]

[0110] In some implementation schemes, the alkali is , , , , , , , , , , , , , , , , or .

[0111] The concentration of such heavier isotopes (particularly deuterium) can be defined by the isotope enrichment factor. In the compounds of this disclosure, any atom not specifically designated as a particular isotope means that atom represents any stable isotope. Unless otherwise stated, when a position is specifically designated as “H” or “hydrogen”, that position is understood to be hydrogen having its naturally occurring isotopic composition. Therefore, in the compounds of this disclosure, any atom specifically designated as deuterium (D) means that deuterium is represented.

[0112] Whenever a compound described herein is substituted with more than one of the same designated groups (e.g., “R” or “R”), it should be understood that these groups may be the same or different, i.e., each group is chosen independently.

[0113] Waveform, It indicates the position where a covalent bond is attached to an adjacent substructure, group, part, or atom.

[0114] III. Compounds

[0115] In some embodiments, compounds of formula I are provided herein:

[0116]

[0117] Formula I

[0118] Or its pharmaceutically acceptable salt, wherein:

[0119] R 1 It is -OH, -OC(=O)R 4 or -OC(=O)OR 4 ;

[0120] R 2 It is -OH, -OC(=O)R 5 or -OC(=O)OR 5 ;or

[0121] R 1 and R 2 Together they form -OC(=O)O- or -OCHR 6 O-;

[0122] R 3 R 4 and R 5 Each of these groups is independently a C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, or C6-C 10 Aryl or 5- to 6-membered heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, and S;

[0123] Where R 3 R 4 and R 5 C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, C6-C 10 The aryl or 5- to 6-membered heteroaryl groups are each independently and optionally selected by one, two, or three independently free from halogen, cyano, -N3, -OR. 7 -NR 8 R 9 The phenyl group is optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, cyano and C1-C6 alkyl groups;

[0124] R 6 It is H, C1-C6 alkyl or C6-C 10 Aryl;

[0125] Each R 7 Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl;

[0126] Each R 8 Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl;

[0127] Each R 9 Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl;

[0128] Alkali is , or ;and

[0129] R 10 It is a C1-C6 alkyl group substituted with -OP(O)(OH)2.

[0130] In some embodiments, the compound has formula Ia:

[0131]

[0132] Formula Ia.

[0133] In some implementation schemes, R 1 It is -OH. In some implementations, R 1 It is -OC(=O)R 4 In some implementations, R 1 It is -OC(=O)OR 4 .

[0134] In some implementation schemes, R 2 It is -OH. In some implementations, R 2 It is -OC(=O)R 5 In some implementations, R 2 It is -OC(=O)OR 5 .

[0135] In some implementation schemes, R 1 It is -OH and R 2 It is -OH. In some implementations, R 1 It is -OC(=O)R 4 And R 2 It is -OC(=O)R 5 In some implementations, R 1 It is -OC(=O)OR 4 And R 2 It is OC (=O) OR 5 In some implementations, R 1 It is -OH and R 2 It is -OC(=O)R 5 In some implementations, R1 It is -OH and R 2 It is -OC(=O)OR 5 In some implementations, R 1 It is -OC(=O)R 4 And R 2 It is -OH. In some implementations, R 1 It is -OC(=O)OR 4 And R 2 It is -OH.

[0136] In some implementation schemes, R 4 and R 5 Each of these groups is independently a C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, or C6-C 10 Aryl or 5- to 6-membered heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, and S.

[0137] In some implementation schemes, R 4 and R 5 Each is independently a C1-C8 alkyl or C3-C8 carbon cycloyl group.

[0138] In some implementation schemes, R 4 and R 5 Each is independently a C1-C8 alkyl group.

[0139] In some implementation schemes, R 4 and R 5 Each is independently a C1-C3 alkyl group.

[0140] In some implementation schemes, R 4 and R 5 Each is a methyl group.

[0141] In some implementation schemes, R 3 It is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, C6-C 10 Aryl or 5- to 6-membered heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, and S.

[0142] In some implementation schemes, R 3 It is a C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 carbocyclic group.

[0143] In some implementation schemes, R 3 It is a C1-C8 alkyl or C3-C8 carbocyclic group. In some embodiments, R 3 It is methyl, ethyl, propyl, butyl, or cyclopentyl.

[0144] In some implementation schemes, R 3 It is a C3-C8 carbon cyclic group. In some embodiments, R 3 It is cyclopentyl.

[0145] In some implementation schemes, R 3 It is a C1-C8 alkyl group. In some embodiments, R 3 It is methyl, ethyl, propyl, or butyl.

[0146] In some implementation schemes, R 3 yes , , or .

[0147] In some implementation schemes,

[0148] R 1 It is -OH or -OC(=O)R 4 ;

[0149] R 2 It is -OH or -OC(=O)R 5 ;and

[0150] R 3 R 4 and R 5 Each of these groups is independently a C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, or C6-C 10 Aryl or 5- to 6-membered heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, and S.

[0151] In some implementation schemes,

[0152] R 1 It is -OH or -OC(=O)R 4 ;

[0153] R 2 It is -OH or -OC(=O)R 5 ;and

[0154] R 3 R 4 and R 5 Each can be independently a C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 carbocyclic group.

[0155] In some implementation schemes,

[0156] R 1 It is -OH or -OC(=O)R 4 ;

[0157] R2 It is -OH or -OC(=O)R 5 ;and

[0158] R 3 R 4 and R 5 Each is independently a C1-C8 alkyl or C3-C8 carbon cycloyl group.

[0159] In some implementation schemes,

[0160] R 1 It is -OH or -OC(=O)R 4 ;

[0161] R 2 It is -OH or -OC(=O)R 5 ;

[0162] R 4 and R 5 Each is independently a C1-C6 alkyl group; and

[0163] R 3 It is a C1-C8 alkyl or C3-C8 carbon cycloyl group.

[0164] In some implementation schemes,

[0165] R 1 It is -OH or -OC(=O)R 4 ;

[0166] R 2 It is -OH or -OC(=O)R 5 ;

[0167] R 4 and R 5 Each is independently methyl or ethyl; and

[0168] R 3 It is a C1-C6 alkyl or C3-C8 carbon cyclic group.

[0169] In some implementation schemes, the alkali is .

[0170] In some implementation schemes,

[0171] R 1 It is -OH or -OC(=O)R 4 ;

[0172] R 2 It is -OH or -OC(=O)R 5 ;

[0173] R 3It is a C1-C8 alkyl or C3-C8 carbocyclic group;

[0174] R 4 and R 5 It is a C1-C8 alkyl group;

[0175] Alkali is .

[0176] In some implementation schemes, the compound is selected from:

[0177]

[0178] Or its pharmaceutically acceptable salt.

[0179] In some embodiments, compounds of formula A are provided herein:

[0180]

[0181] Formula A

[0182] Or its pharmaceutically acceptable salt, wherein:

[0183] R 1A and R 2A Linked to form a 3- to 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or a 5- to 10-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S;

[0184] Where R 1A and R 2A The 3- to 8-membered heterocyclic group or the 5- to 10-membered heteroaryl group is optionally selected independently from one, two, or three halogens, cyano groups, oxo groups, -N3, -OR groups. 3A -C(=O)R 3A -C(=O)OR 3A -NR 4A R 5A Substituents of the group consisting of C1-C6 alkyl and phenyl groups;

[0185] Where R 1A and R 2A The C1-C6 alkyl substituents are optionally substituted by one, two, or three independent substituents selected from halogens, cyano groups, and phenyl groups; and

[0186] R 1A and R 2A The substituted phenyl group is optionally substituted by one, two, or three independent substituents selected from halogen, cyano, and C1-C6 alkyl groups; or

[0187] R 1A It is H;

[0188] R 2A Is it -C(=O)OR 3A Substituted C1-C8 alkyl groups;

[0189] Where R 2A -C(=O)OR 3A The substituted C1-C8 alkyl group is optionally replaced by one or two independently selected from halogen, cyano, and phenyl groups and -OR. 3A The substituents are further substituted;

[0190] Each R 3A Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, and 3 to 8-membered heterocyclic groups containing 1, 2, or 3 heteroatoms independently selected from N, O, and S;

[0191] Each R 4A Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl;

[0192] Each R 5A Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl;

[0193] Alkali is , or ;and

[0194] R 6A It is a C1-C6 alkyl group substituted with -OP(O)(OH)2.

[0195] In some embodiments, the compound has the formula Aa:

[0196]

[0197] Formula Aa.

[0198] In some implementation schemes, R 1A and R 2A Linked to form a 3- to 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or a 5- to 10-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S;

[0199] Where R 1A and R 2A The 3- to 8-membered heterocyclic group or the 5- to 10-membered heteroaryl group is optionally selected independently from one, two, or three halogens, cyano groups, oxo groups, -N3, -OR groups. 3A -C(=O)R 3A -C(=O)OR 3A -NR4A R 5A Substituents of the group consisting of C1-C6 alkyl and phenyl groups;

[0200] Where R 1A and R 2A The C1-C6 alkyl substituents are optionally substituted by one, two, or three independent substituents selected from halogens, cyano groups, and phenyl groups; and

[0201] R 1A and R 2A The substituted phenyl group is optionally substituted by one, two or three substituents independently selected from halogen, cyano and C1-C6 alkyl groups.

[0202] In some implementation schemes, R 1A and R 2A Linked to form a 3- to 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or a 5- to 10-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S;

[0203] Where R 1A and R 2A The 3- to 8-membered heterocyclic group or the 5- to 10-membered heteroaryl group is optionally selected by one, two, or three independent oxy groups, -OR 3A -C(=O)R 3A -C(=O)OR 3A Substituents of the group consisting of C1-C6 alkyl and phenyl groups;

[0204] Where R 1A and R 2A The C1-C6 alkyl substituents are optionally replaced by one, two, or three independent substituents selected from halogens, cyano groups, and phenyl groups.

[0205] In some implementation schemes, R 1A and R 2A Linked to form a 3- to 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or a 5- to 10-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S;

[0206] Where R 1A and R 2A The 3- to 8-membered heterocyclic group or the 5- to 10-membered heteroaryl group is optionally selected by one, two, or three independent oxy groups, -OR 3A -C(=O)OR 3A Substitution with substituents in the group consisting of C1-C6 alkyl groups substituted with phenyl groups.

[0207] In some implementation schemes, R 1A and R2A Linked to form a 3- to 8-membered heterocyclic group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; a 3- to 8-membered heterocyclic group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S substituted with two oxo groups; a 3- to 8-membered heterocyclic group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S substituted with an oxo group and a C1-C6 alkyl group substituted with a phenyl group; or a 3- to 8-membered heterocyclic group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S substituted with -C(=O)OR 3A Substituted 3- to 8-membered heterocyclic groups containing 1, 2, or 3 heteroatoms independently selected from N, O, and S.

[0208] In some implementation schemes, R 1A and R 2A Connect to form , , , , or .

[0209] In some implementation schemes, R 1A and R 2A Connect to form -C(=O)OR 3A Substituted 5- to 10-membered heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, and S, and -C(=O)OR 3A and -OR 3A Substituted 5- to 10-membered heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, and S, or substituted with -C(=O)OR 3A Substituted 5- to 10-membered heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, and S.

[0210] In some implementation schemes, R 1A and R 2A Connect to form , , or .

[0211] In some implementation schemes, R 1A It is H and R 2A Is it -C(=O)OR 3A Substituted C1-C8 alkyl groups; wherein R 2A -C(=O)OR 3A The substituted C1-C8 alkyl group is optionally replaced by one or two independently selected from halogen, cyano, and phenyl groups and -OR. 3A The substituents further substitute.

[0212] In some implementation schemes, R 2A Is it -C(=O)OR 3ASubstituted C1-C8 alkyl groups. In some embodiments, R 2A It is a C1-C8 alkyl group substituted with -C(=O)OH or -C(=O)O(CH)(CH3)2.

[0213] In some implementation schemes, R 2A yes or In some implementations, R 2A yes or .

[0214] In some implementation schemes, R 3A It is an H, C1-C6 alkyl group, or a 3- to 8-membered heterocyclic group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S. In some embodiments, R 3A It is H. In some implementations, R 3A It is a C1-C6 alkyl group. In some embodiments, R 3A It is a 3- to 8-membered heterocyclic group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S. In some embodiments, R 3A yes , , or .

[0215] In some implementation schemes,

[0216] R 1A It is H;

[0217] R 2A It was COOR 3A Substituted C1-C8 alkyl groups;

[0218] Where R 2A -C(=O)OR 3A The substituted C1-C8 alkyl group is optionally replaced by one or two independently selected from halogen, cyano, phenyl, and -OR. 3A The substituents are further substituted; and

[0219] Each R 3A It is independently a H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or a 3- to 8-membered heterocyclic group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S.

[0220] In some implementation schemes,

[0221] R 1A It is H;

[0222] R 2A Is it -C(=O)OR3A Substituted C1-C8 alkyl groups; and

[0223] R 3A It is a 3- to 8-membered heterocyclic group consisting of H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or containing 1, 2, or 3 heteroatoms independently selected from N, O, and S.

[0224] In some implementation schemes,

[0225] R 1A It is H;

[0226] R 2A Is it -C(=O)OR 3A Substituted C1-C8 alkyl groups; and

[0227] R 3A It is H or C1-C6 alkyl.

[0228] In some implementation schemes,

[0229] R 1A It is H;

[0230] R 2A Is it -C(=O)OR 3A Substituted C1-C6 alkyl groups; and

[0231] R 3A It is an H or C1-C3 alkyl group.

[0232] In some implementations, the compound is:

[0233] (Compound 7) or

[0234] (Compound 6)

[0235] Or its pharmaceutically acceptable salt.

[0236] In some implementation schemes,

[0237] R 1A and R 2A Linked to form a 3- to 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or a 5- to 10-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S;

[0238] Where R 1A and R 2A The 3- to 8-membered heterocyclic group or the 5- to 10-membered heteroaryl group is optionally selected independently from one, two, or three halogens, cyano groups, oxo groups, -N3, -OR groups. 3A -COR 3A-COOR 3A -NR 4A R 5A Substituents of the group consisting of C1-C6 alkyl and phenyl groups;

[0239] Where R 1A and R 2A The C1-C6 alkyl substituents are optionally substituted by one, two, or three independent substituents selected from halogens, cyano groups, and phenyl groups; and

[0240] R 1A and R 2A The substituted phenyl group is optionally substituted by one, two or three independent substituents selected from halogen, cyano and C1-C6 alkyl groups;

[0241] Each R 3A Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, and 3 to 8-membered heterocyclic groups containing 1, 2, or 3 heteroatoms independently selected from N, O, and S;

[0242] Each R 4A Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; and

[0243] Each R 5A Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl.

[0244] In some implementation schemes,

[0245] R 1A and R 2A Linked to form a 3- to 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or a 5- to 10-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S;

[0246] Where R 1A and R 2A The 3- to 8-membered heterocyclic group or the 5- to 10-membered heteroaryl group is optionally selected independently from one, two, or three halogens, cyano groups, oxo groups, -OR groups, etc. 3A -C(=O)R 3A -C(=O)OR 3A Substituents of the group consisting of C1-C6 alkyl and phenyl groups;

[0247] Where R 1A and R 2A The C1-C6 alkyl substituents are optionally substituted by one, two, or three independent substituents selected from halogens, cyano groups, and phenyl groups; and

[0248] R 1A and R 2A The substituted phenyl group is optionally substituted by one, two, or three independent substituents selected from halogen, cyano, and C1-C6 alkyl groups; and

[0249] Each R 3A Independently, it is a H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or a 3- to 8-membered heterocyclic group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S.

[0250] In some implementation schemes, the alkali is .

[0251] In some implementation schemes,

[0252] R 1A and R 2A Linked to form a 3- to 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or a 5- to 10-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S;

[0253] Where R 1A and R 2A The 3- to 8-membered heterocyclic group or the 5- to 10-membered heteroaryl group is optionally selected by one or two independent oxy groups, -OR 3A -C(=O)OR 3A Substitution with the group consisting of C1-C6 alkyl groups;

[0254] Where R 1A and R 2A The substituents C1-C6 alkyl groups are optionally substituted phenyl groups;

[0255] R 1A It is H;

[0256] R 2A Is it -C(=O)OR 3A Substituted C1-C8 alkyl groups;

[0257] Each R 3A Independently, it is H or C1-C6 alkyl; and

[0258] Alkali is .

[0259] In some implementation schemes, the compound is selected from:

[0260]

[0261]

[0262] Or its pharmaceutically acceptable salt.

[0263] In some embodiments, compounds of formula B are provided herein:

[0264]

[0265] Formula B

[0266] Or its pharmaceutically acceptable salt, wherein:

[0267] R 3B It is -OC(=O)R 5B or -OC(=O)OR 5B ;

[0268] R 4B It is -OC(=O)R 6B or -OC(=O)OR 6B ;or

[0269] R 3B and R 4B Together they form -OC(=O)O- or -OCHR 7B O-;

[0270] R 5B and R 6B Each of these groups is independently a C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, or C6-C 10 Aryl or 5- to 6-membered heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, and S;

[0271] Where R 5B and R 6B C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, C6-C 10 The aryl or 5- to 6-membered heteroaryl groups are each independently and optionally selected by one, two, or three independently free from halogen, cyano, -N3, -OR. 8B -NR 9B R 10B The phenyl group is optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, cyano and C1-C6 alkyl groups;

[0272] Each R 8B Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl;

[0273] Each R 9B Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl;

[0274] Each R 10BIndependently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl;

[0275] R 7B It is H, C1-C6 alkyl or C6-C 10 Aryl;

[0276] R 1B It is H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, C6-C 10 Aryl or 5- to 6-membered heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, and S;

[0277] Where R 1B C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, C6-C 10 The aryl or 5- to 6-membered heteroaryl group is optionally selected by one, two, or three independently free from halogen, cyano, -N3, -OR. 11B -C(=O)R 11B -C(=O)OR 11B -NR 12B R 13B The phenyl group is optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, cyano and C1-C6 alkyl groups;

[0278] R 2B It is H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, C6-C 10 Aryl or 5- to 6-membered heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, and S;

[0279] Where R 2B C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, C6-C 10 The aryl or 5- to 6-membered heteroaryl group is optionally selected by one, two, or three independently free from halogen, cyano, -N3, -OR. 11B -C(=O)R 11B -C(=O)OR 11B -NR 12B R 13B And optionally substituted with one, two or three substituents selected independently from the group consisting of phenyl groups, which are substituted with halogens, cyano groups and C1-C6 alkyl groups; or

[0280] R 1B and R 2BLinked to form a 3- to 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or a 5- to 10-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S;

[0281] Where R 1B and R 2B The 3- to 8-membered heterocyclic group or the 5- to 10-membered heteroaryl group is optionally selected independently from one, two, or three halogens, cyano groups, oxo groups, -N3, -OR groups. 11B -C(=O)R 11B -C(=O)OR 11B -NR 12B R 13B Substituents of the group consisting of C1-C6 alkyl and phenyl groups;

[0282] Where R 1B and R 2B The C1-C6 alkyl substituents are optionally substituted by one, two, or three independent substituents selected from halogens, cyano groups, and phenyl groups; and

[0283] R 1B and R 2B The substituted phenyl group is optionally substituted by one, two or three independent substituents selected from halogen, cyano and C1-C6 alkyl groups;

[0284] Each R 11B Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, and 3 to 8-membered heterocyclic groups containing 1, 2, or 3 heteroatoms independently selected from N, O, and S;

[0285] Each R 12B Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl;

[0286] Each R 13B Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl;

[0287] Alkali is , or ;and

[0288] R 14B It is a C1-C6 alkyl group substituted with -OP(O)(OH)2.

[0289] In some implementation schemes, R 3B It is -OC(=O)R 5B or -OC(=O)OR 5B And R 4BIt is -OC(=O)R 6B or -OC(=O)OR 6B In some implementations, R 3B It is -OC(=O)R 5B In some implementations, R 3B It is -OC(=O)OR 5B In some implementations, R 4B It is -OC(=O)R 6B In some implementations, R 4B It is -OC(=O)OR 6B In some implementations, R 3B It is -OC(=O)R 5B And R 4B It is -OC(=O)R 6B In some implementations, R 3B It is -OC(=O)OR 5B And R 4B It is -OC(=O)OR 6B In some implementations, R 3B It is -OC(=O)R 5B And R 4B It is -OC(=O)OR 6B In some implementations, R 3B It is -OC(=O)OR 5B And R 4B It is -OC(=O)R 6B .

[0290] In some implementation schemes, R 3B and R 4B Together they form -OC(=O)O- or -OCHR 7B O-. In some implementations, R 3B and R 4B Together they form -OC(=O)O-. In some implementations, R 3B and R 4B Together they form -OCHR 7B O-.

[0291] In some embodiments, the compound has the formula Ba:

[0292]

[0293] Formula Ba

[0294] In some implementation schemes, R 5B and R 6BEach of these groups is independently a C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, or C6-C 10 The aryl group is a 5- to 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S. In some embodiments, R 5B and R 6B Each is independently a C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 carbocyclic group. In some embodiments, R 5B and R 6B Each is independently a C1-C8 alkyl group. In some embodiments, R 5B and R 6B Each is independently a C1-C6 alkyl group. In some embodiments, R 5B and R 6B Each is independently a C1-C3 alkyl group. In some embodiments, R 5B and R 6B Each is -CH3.

[0295] In some implementation schemes, R 1B and R 2B Linked to form a 3- to 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or a 5- to 10-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S;

[0296] Where R 1B and R 2B The 3- to 8-membered heterocyclic group or the 5- to 10-membered heteroaryl group is optionally selected independently from one, two, or three halogens, cyano groups, oxo groups, -N3, -OR groups. 11B -C(=O)R 11B -C(=O)OR 11B -NR 12B R 13B Substituents of the group consisting of C1-C6 alkyl and phenyl groups;

[0297] Where R 1B and R 2B The C1-C6 alkyl substituents are optionally substituted by one, two, or three independent substituents selected from halogens, cyano groups, and phenyl groups; and

[0298] R 1B and R 2B The substituted phenyl group is optionally substituted by one, two or three substituents independently selected from halogen, cyano and C1-C6 alkyl groups.

[0299] In some implementation schemes, R 1B and R 2BLinked to form a 3- to 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or a 5- to 10-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S;

[0300] Where R 1B and R 2B The 3- to 8-membered heterocyclic group or the 5- to 10-membered heteroaryl group is optionally selected by one, two, or three independent oxy groups, -OR 11B -C(=O)R 11B -C(=O)OR 11B Substituents of the group consisting of C1-C6 alkyl and phenyl groups;

[0301] Where R 1A and R 2A The C1-C6 alkyl substituents are optionally replaced by one, two, or three independent substituents selected from halogens, cyano groups, and phenyl groups.

[0302] In some implementation schemes, R 1B and R 2B Linked to form a 3- to 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or a 5- to 10-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S;

[0303] Where R 1B and R 2B The 3- to 8-membered heterocyclic group or the 5- to 10-membered heteroaryl group is optionally selected by one, two, or three independent oxy groups, -OR 11B -C(=O)OR 11B Substitution with substituents in the group consisting of C1-C6 alkyl groups substituted with phenyl groups.

[0304] In some implementation schemes, R 1B and R 2B Linked to form a 3- to 8-membered heterocyclic group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; a 3- to 8-membered heterocyclic group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S substituted with two oxo groups; a 3- to 8-membered heterocyclic group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S substituted with an oxo group and a C1-C6 alkyl group substituted with a phenyl group; or a 3- to 8-membered heterocyclic group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S substituted with -C(=O)OR 11B Substituted 3- to 8-membered heterocyclic groups containing 1, 2, or 3 heteroatoms independently selected from N, O, and S.

[0305] In some implementation schemes, R 1B and R 2B Connect to form , , , , or .

[0306] In some implementation schemes, R 1B and R 2B Connect to form -C(=O)OR 3A Substituted 5- to 10-membered heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, and S, and -C(=O)OR 3A and -OR 3A Substituted 5- to 10-membered heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, and S, or substituted with -C(=O)OR 3A Substituted 5- to 10-membered heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, and S.

[0307] In some implementation schemes, R 1B and R 2B Connect to form , , or .

[0308] In some implementation schemes, R 1B It is H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, C6-C 10 Aryl or 5- to 6-membered heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, and S;

[0309] Where R 1B C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, C6-C 10 The aryl or 5- to 6-membered heteroaryl group is optionally selected by one, two, or three independently free from halogen, cyano, -N3, -OR. 11B -C(=O)R 11B -C(=O)OR 11B -NR 12B R 13B And optionally substituted with one, two, or three substituents selected independently from the group consisting of phenyl groups, which are substituted with halogens, cyano groups, and C1-C6 alkyl groups; and

[0310] R 2B It is H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, C6-C 10 Aryl or 5- to 6-membered heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, and S;

[0311] Where R 2BC1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, C6-C 10 The aryl or 5- to 6-membered heteroaryl group is optionally selected by one, two, or three independently free from halogen, cyano, -N3, -OR. 11B -C(=O)R 11B -C(=O)OR 11B -NR 12B R 13B The phenyl group is optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, cyano and C1-C6 alkyl groups.

[0312] In some implementation schemes, R 1B It is H, C1-C8 alkyl, C3-C8 carbocyclic, C6-C 10 Aryl or 5- to 6-membered heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, and S;

[0313] Where R 1B C1-C8 alkyl, C2-C8 alkenyl, C6-C 10 Aryl or 5- to 6-membered heteroaryl groups are optionally -C(=O)OR 11B replace.

[0314] In some implementation schemes, R 1B It is a C1-C8 alkyl group. In some embodiments, R 1B yes In some implementations, R 1B Is it -C(=O)OR 11B Substituted C1-C8 alkyl groups. In some embodiments, R 1B yes or In some implementations, R 1B yes or In some implementations, R 1B yes , or .

[0315] In some implementation schemes, R 1B It is H.

[0316] In some implementation schemes, R 2B It is a C1-C8 alkyl group. In some embodiments, R 2B yes In some implementations, R 2B Is it -C(=O)OR 11B Substituted C1-C8 alkyl groups. In some embodiments, R1B yes or In some implementations, R 2B yes or In some implementations, R 2B yes , or .

[0317] In some implementation schemes, R 2B It is H.

[0318] In some implementation schemes, R 11B It is an H, C1-C6 alkyl group, or a 3- to 8-membered heterocyclic group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S. In some embodiments, R 11B It is H. In some implementations, R 11B It is a C1-C6 alkyl group. In some embodiments, R 11B It is a 3- to 8-membered heterocyclic group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S. In some embodiments, R 11B yes , , or .

[0319] In some implementation schemes,

[0320] R 1B It is H;

[0321] R 2B It is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, C6-C 10 Aryl or 5- to 6-membered heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, and S;

[0322] Where R 2B C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, C6-C 10 The aryl or 5- to 6-membered heteroaryl group is optionally selected by one, two, or three independently free from halogen, cyano, -N3, -OR. 11B -C(=O)R 11B -C(=O)OR 11B -NR 12B R 13B And optionally substituted with one, two or three substituents selected independently from the group consisting of phenyl groups, which are substituted with halogens, cyano groups and C1-C6 alkyl groups; or

[0323] R1B and R 2B Linked to form a 3- to 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or a 5- to 10-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S;

[0324] Where R 1B and R 2B The 3- to 8-membered heterocyclic group or the 5- to 10-membered heteroaryl group is optionally selected independently from one, two, or three halogens, cyano groups, oxo groups, -N3, -OR groups. 11B -C(=O)R 11B -C(=O)OR 11B -NR 12B R 13B Substituents of the group consisting of C1-C6 alkyl and phenyl groups;

[0325] Where R 1B and R 2B The C1-C6 alkyl substituents are optionally substituted by one, two, or three independent substituents selected from halogens, cyano groups, and phenyl groups; and

[0326] R 1B and R 2B The substituted phenyl group is optionally substituted by one, two, or three independent substituents selected from halogen, cyano, and C1-C6 alkyl groups; and

[0327] Each R 11B Independently, it is a H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or a 3- to 8-membered heterocyclic group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S.

[0328] In some implementation schemes,

[0329] R 1B It is H;

[0330] R 2B It is a C1-C8 alkyl, C3-C8 carbocyclic, C6-C 10 Aryl or 5- to 6-membered heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, and S;

[0331] Where R 2B C1-C8 alkyl, C3-C8 carbocyclic, C6-C 10 The aryl or 5- to 6-membered heteroaryl group is optionally free from one, two, or three halogens, -OR 11B and -C(=O)OR 11B Substituents of the group; or

[0332] R1B and R 2B Linked to form a 3- to 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or a 5- to 10-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S;

[0333] Where R 1B and R 2B The 3- to 8-membered heterocyclic group or the 5- to 10-membered heteroaryl group is optionally selected by one, two, or three independently free from oxy groups, -OR groups, etc. 11B -C(=O)OR 11B Substituents of the group consisting of C1-C6 alkyl and phenyl groups;

[0334] Where R 1B and R 2B The C1-C6 alkyl substituents are optionally substituted by one, two, or three independent substituents selected from halogens, cyano groups, and phenyl groups; and

[0335] Each R 11B Independently, it is a H, C1-C6 alkyl, C3-C6 cycloalkyl, or a 3- to 8-membered heterocyclic group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S.

[0336] In some implementation schemes,

[0337] R 1B It is H;

[0338] R 2B It is a C1-C8 alkyl, C3-C8 carbocyclic, C6-C 10 Aryl or 5- to 6-membered heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, and S;

[0339] Where R 2B C1-C8 alkyl, C3-C8 carbocyclic, C6-C 10 The aryl or 5- to 6-membered heteroaryl group is optionally free from one, two, or three halogens, -OR 11B and -C(=O)OR 11B The substituents of the group are substituted; and

[0340] Each R 11B Independently, it is a H, C1-C6 alkyl, C3-C6 cycloalkyl, or a 3- to 8-membered heterocyclic group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S.

[0341] In some implementation schemes,

[0342] R 1B and R 2BLinked to form a 3- to 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or a 5- to 10-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S;

[0343] Where R 1B and R 2B The 3- to 8-membered heterocyclic group or the 5- to 10-membered heteroaryl group is optionally selected by one, two, or three independently free from oxy groups, -OR groups, etc. 11B -C(=O)OR 11B Substituents of the group consisting of C1-C6 alkyl and phenyl groups;

[0344] Where R 1B and R 2B The C1-C6 alkyl substituents are optionally substituted by one, two, or three independent substituents selected from halogens, cyano groups, and phenyl groups; and

[0345] Each R 11B Independently, it is a H, C1-C6 alkyl, C3-C6 cycloalkyl, or a 3- to 8-membered heterocyclic group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S.

[0346] In some implementation schemes,

[0347] R 1B It is H;

[0348] R 2B It is a C1-C8 alkyl or C3-C8 carbocyclic group;

[0349] Where R 2B The C1-C8 alkyl or C3-C8 carbocyclic group is optionally selected by one, two or three independently free from halogen, -OR 11B and -C(=O)OR 11B Substituents of the group; or

[0350] R 1B and R 2B Linked to form a 3- to 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or a 5- to 10-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S;

[0351] Where R 1B and R 2B The 3- to 8-membered heterocyclic group or the 5- to 10-membered heteroaryl group is optionally selected by one, two, or three independently free from oxy groups, -OR groups, etc. 11B -C(=O)OR 11B Substitution with the group consisting of C1-C6 alkyl groups;

[0352] Where R1B and R 2B The C1-C6 alkyl substituents are optionally substituted by one, two, or three independent substituents selected from halogens, cyano groups, and phenyl groups; and

[0353] Each R 11B Independently, it is a H, C1-C6 alkyl, C3-C6 cycloalkyl, or a 3- to 8-membered heterocyclic group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S.

[0354] In some implementation schemes,

[0355] R 1B It is H;

[0356] R 2B It is optionally selected by one, two or three independent free halogens, -OR 11B and -C(=O)OR 11B The group consisting of substituents of C1-C8 alkyl groups; or

[0357] R 1B and R 2B Linked to form a 3- to 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or a 5- to 10-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S;

[0358] Where R 1B and R 2B The 3- to 8-membered heterocyclic group or the 5- to 10-membered heteroaryl group is optionally selected by one, two, or three independently free from oxy groups, -OR groups, etc. 11B -C(=O)OR 11B Substitution with the group consisting of C1-C6 alkyl groups;

[0359] Where R 1B and R 2B The C1-C6 alkyl substituents are optionally substituted by one, two, or three independent substituents selected from halogens, cyano groups, and phenyl groups; and

[0360] Each R 11B Independently, it is a H, C1-C6 alkyl, C3-C6 cycloalkyl, or a 3- to 8-membered heterocyclic group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S.

[0361] In some implementation schemes,

[0362] R 1B It is H;

[0363] R 2B It is a C1-C6 alkyl or C3-C8 carbocyclic group;

[0364] Where R 2B The C1-C6 alkyl or C3-C8 carbocyclic group is optionally selected by one, two or three independently free from halogen, -OR 11B and -C(=O)OR 11B Substituents of the group; or

[0365] R 1B and R 2B Linked to form a 3- to 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or a 5- to 10-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S;

[0366] Where R 1B and R 2B The 3- to 8-membered heterocyclic group or the 5- to 10-membered heteroaryl group is optionally selected by one, two, or three independently free from oxy groups, -OR groups, etc. 11B -C(=O)OR 11B Substitution of the group consisting of C1-C3 alkyl groups;

[0367] Where R 1B and R 2B The C1-C3 alkyl substituents are optionally substituted by one, two, or three independent substituents selected from halogens, cyano groups, and phenyl groups; and

[0368] Each R 11B Independently, it is a H, C1-C3 alkyl, C3-C6 cycloalkyl, or a 3- to 8-membered heterocyclic group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S.

[0369] In some implementation schemes,

[0370] R 1B It is H;

[0371] R 2B It is optionally selected by one, two or three independent free halogens, -OR 11B and -C(=O)OR 11B The group consisting of substituents of C1-C6 alkyl groups; or

[0372] R 1B and R 2B Linked to form a 3- to 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or a 5- to 10-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S;

[0373] Where R 1B and R 2BThe 3- to 8-membered heterocyclic group or the 5- to 10-membered heteroaryl group is optionally selected by one, two, or three independently free from oxy groups, -OR groups, etc. 11B -C(=O)OR 11B Substitution of the group consisting of C1-C3 alkyl groups;

[0374] Where R 1B and R 2B The C1-C3 alkyl substituents are optionally substituted by one, two, or three independent substituents selected from halogens, cyano groups, and phenyl groups; and

[0375] Each R 11B Independently, it is a H, C1-C3 alkyl, C3-C6 cycloalkyl, or a 3- to 8-membered heterocyclic group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S.

[0376] In some implementation schemes, the alkali is .

[0377] In some implementation schemes,

[0378] R 3B It is -OC(=O)R 5B ;

[0379] R 4B It is -OC(=O)R 6B ;

[0380] R 5B and R 6B Each is a C1-C8 alkyl group;

[0381] R 1B It is H;

[0382] R 2B It is -C(=O)R 11B Substituted C1-C8 alkyl groups; or

[0383] R 1B and R 2B Linked to form a 3- to 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or a 5- to 10-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S;

[0384] Where R 1B and R 2B The 3- to 8-membered heterocyclic group or the 5- to 10-membered heteroaryl group is optionally selected by one or two independent oxy groups, -OR 11B -C(=O)OR 11B Substitution with the group consisting of C1-C6 alkyl groups;

[0385] Where R1B and R 2B The substituents of the C1-C6 alkyl groups are optionally replaced by phenyl groups;

[0386] Each R 11B Independently, it is a 3- to 8-membered heterocyclic group consisting of H, C1-C6 alkyl groups and 1, 2 or 3 heteroatoms independently selected from N, O and S;

[0387] Alkali is .

[0388] In some implementation schemes, the compound is selected from:

[0389]

[0390] Or its pharmaceutically acceptable salt.

[0391] In some implementation schemes, the compound is selected from:

[0392]

[0393]

[0394] Or its pharmaceutically acceptable salt.

[0395] IV. Pharmaceutical Preparations

[0396] The compounds disclosed herein can be formulated with conventional carriers and excipients. For example, tablets will contain excipients, flow aids, fillers, binders, etc. Aqueous formulations are prepared aseptically and are typically isotonic when intended for delivery by non-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 dextrin, hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose, stearic acid, etc. In some embodiments, the formulation contains one or more pharmaceutically acceptable excipients. The pH range of the formulation is from about 3 to about 11, but is typically from about 7 to 10. In some embodiments, the pH range of the formulation is from about 2 to about 5, but is typically from about 3 to 4.

[0397] While the compounds of this disclosure (“active ingredients”) can be administered alone, they are preferably provided as pharmaceutical formulations. Both veterinary and human formulations of the present invention comprise at least one active ingredient as defined above, together with one or more of its acceptable carriers and optional other therapeutic ingredients, particularly those additional therapeutic ingredients discussed herein. The carrier must be “acceptable,” meaning compatible with the other components of the formulation and physiologically harmless to the recipient.

[0398] These formulations include those suitable for the aforementioned routes of administration. Formulations are readily available in unit dosage forms and can be prepared by any suitable method known in the pharmaceutical field. Techniques and formulations are commonly found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods involve the step of associating the active ingredient with a carrier constituting one or more auxiliary ingredients. Generally, formulations are prepared by uniformly and tightly associating the active ingredient with a liquid carrier or a finely divided solid carrier, or both, and then, if desired, shaping the product.

[0399] In some implementations, the pharmaceutical preparation is administered subcutaneously, intramuscularly, intravenously, or orally, or by inhalation.

[0400] In some embodiments, the compounds described herein (e.g., compounds of formula I, formula A, or formula B, or pharmaceutically acceptable salts thereof) have optimized / improved pharmacokinetic properties and are suitable for oral administration. For example, compounds of formula I, formula A, or formula B have improved bioavailability and are therefore administerable by oral administration.

[0401] In some embodiments, the formulations of the present invention suitable for oral administration may be provided as discrete units such as capsules, granules, or tablets each containing a predetermined amount of the active ingredient; as powders or granules; as solutions or suspensions in aqueous or non-aqueous liquids; or as oil-in-water or water-in-oil liquid emulsions. The active ingredient may also be administered as pills, granules, or pastes.

[0402] In some embodiments, tablets are prepared by compression or molding, optionally with one or more excipients. Compressed tablets are prepared by compressing an active ingredient in a free-flowing form (such as powder or granules) in a suitable machine, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant, or dispersant. Molded tablets are prepared by molding a mixture of powdered active ingredients moistened with an inert liquid diluent in a suitable machine. Tablets may optionally be coated or scored, and optionally formulated to provide a slow or controlled release of the active ingredient therefrom.

[0403] For infections of the eyes or other external tissues (e.g., the mouth and skin), the formulation is applied as a topical ointment or cream containing active ingredients in amounts, for example, from 0.075% w / w to 20% w / w (including active ingredients in increments of 0.1% w / w, such as 0.6% w / w, 0.7% w / w, etc.), preferably from 0.2% w / w to 15% w / w, and most preferably from 0.5% w / w to 10% w / w. When formulated as an ointment, the active ingredient may be used with a paraffin base or a water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream with an oil-in-water emulsion base.

[0404] If desired, the aqueous phase of the cream matrix may contain, for example, at least 30% w / w polyols, i.e., alcohols having two or more hydroxyl groups such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerin, and polyethylene glycol (including PEG 400), and mixtures thereof. Topical formulations may ideally include compounds that enhance the absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogues.

[0405] The oil phase of the emulsion of the present invention can be composed of known components in a known manner. While this phase may consist only of emulsifiers (or simply emulsifiers), it ideally includes at least one emulsifier with fats or oils, or a mixture of both. Preferably, hydrophilic emulsifiers are included together with lipophilic emulsifiers that act as stabilizers. It is also preferable to include both oils and fats. Emulsifiers, with or without stabilizers, together constitute a so-called emulsified wax, and the wax, together with the oils and fats, constitutes a so-called emulsified ointment matrix, which forms the oily dispersed phase of the ointment formulation.

[0406] Emulsifiers and emulsion stabilizers suitable for the formulations of this invention include Tween. ® 60. Span ® 80. Cetearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate. Other emulsifiers and emulsion stabilizers suitable for the formulations of this invention include Tween. ® 80.

[0407] The appropriate oil or fat is selected for the formulation based on achieving the desired cosmetic properties. The cream should preferably be a non-greasy, non-staining, and washable product with a suitable consistency to prevent leakage from tubes or other containers. Straight-chain or branched monoalkyl or dialkyl esters can be used, such as diisohexyl adipate, isohexadecanoyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate, or mixtures of branched esters known as Crodamol CAP, the last three being preferred esters. These esters 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.

[0408] Pharmaceutical formulations according to the invention comprise compounds according to the invention, as well as one or more pharmaceutically acceptable carriers or excipients and optional other therapeutic agents. Pharmaceutical formulations containing the active ingredient may be in any form suitable for the intended method of administration. For example, when intended for oral use, they may be prepared as tablets, lozenges, tablets, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for manufacturing pharmaceutical compositions, and such compositions may contain one or more pharmaceutical agents, including sweeteners, flavoring agents, coloring agents, and preservatives, to provide a palatable formulation. Tablets containing the active ingredient mixed with non-toxic, pharmaceutically acceptable excipients suitable for manufacturing tablets are acceptable. These excipients may be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrants such as corn starch or alginate; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or coated using known techniques, including microencapsulation, to delay disintegration and adsorption in the gastrointestinal tract, thereby providing sustained action over a longer period. For example, delaying materials, such as glyceryl monostearate or glyceryl distearate, may be used alone or in combination with waxes.

[0409] Formulations intended for oral use may also be provided as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (such as calcium phosphate or kaolin) or as soft gelatin capsules in which the active ingredient is mixed with an aqueous or oily medium (such as peanut oil, liquid paraffin, or olive oil).

[0410] The aqueous suspension of the present invention contains an active substance mixed with excipients suitable for manufacturing aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and gum arabic; and dispersants or wetting agents such as naturally occurring phospholipids (e.g., lecithin), condensation products of olefinic oxygen and fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide and long-chain fatty alcohols (e.g., heptadecanethoxycetyl alcohol), and condensation products of ethylene oxide and esters derived from fatty acids and hexyl anhydrides (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives, such as ethylparaben or n-propylparaben, one or more colorants, one or more flavoring agents, and one or more sweeteners such as sucrose or saccharin. Other non-limiting examples of suspending agents include cyclodextrin. In some examples, the suspending agent is sulfobutyl ether β-cyclodextrin (SEB-β-CD), such as Captisol. ® .

[0411] Oily suspensions can be prepared by suspending the active ingredients in vegetable oils (such as peanut oil, olive oil, sesame oil, or coconut oil) or mineral oils (such as liquid paraffin). Oral suspensions may contain thickeners such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners (such as those mentioned above) and flavoring agents may be added to provide palatable oral formulations. These compositions may be preserved by adding antioxidants (such as ascorbic acid).

[0412] The dispersible powders and granules of the present invention, suitable for preparing aqueous suspensions by adding water, provide an active ingredient that can be mixed with a dispersant or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersants or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, such as sweeteners, flavoring agents, and coloring agents, may also be present.

[0413] The pharmaceutical compositions of the present invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil (such as olive oil or peanut oil), a mineral oil (such as liquid paraffin), or a mixture thereof. Suitable emulsifiers include naturally occurring gums, such as gum arabic and tragacanth; naturally occurring phospholipids, such as soybean lecithin; esters or metaesters derived from fatty acids and hexitan anhydrides, such as sorbitan monooleate; and condensation products of these metaesters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavoring agents. Syrups and elixirs may be formulated with sweeteners such as glycerin, sorbitol, or sucrose. Such formulations may also contain modifiers, preservatives, flavoring agents, or coloring agents.

[0414] The pharmaceutical compositions of the present invention may be in the form of sterile injectable formulations, such as sterile injectable aqueous or oily suspensions. These suspensions may be formulated using suitable dispersants or wetting agents and suspending agents mentioned above, according to known techniques. The sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic, parenteral-acceptable diluents or solvents (such as solutions in 1,3-butanediol), or prepared as lyophilized powders. Acceptable solvents and media are water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile non-volatile oils are generally used as solvents or suspension media. For this purpose, any mild non-volatile oil may be used, including synthetic monoglycerides or diglycerides. Additionally, fatty acids such as oleic acid may also be used in the preparation of injectable formulations. Acceptable solvents and media are water, Ringer's solution, isotonic sodium chloride solution, and hypertonic sodium chloride solution.

[0415] 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 route of administration. For example, a sustained-release formulation intended for oral administration to humans may contain approximately 1 mg to 1000 mg of active material mixed with an appropriate and convenient amount of carrier material, which may vary between approximately 5% to approximately 95% (weight:weight) of the total composition. Pharmaceutical compositions can be prepared to provide easily measurable dosages. For example, an aqueous solution intended for intravenous infusion may contain approximately 3 mg to 500 mg of active ingredient per milliliter of solution to allow for the infusion of an appropriate volume at a rate of approximately 30 mL / hr.

[0416] Formulations suitable for topical application to the eyes also include eye drops, wherein the active ingredient is dissolved or suspended in a suitable carrier, particularly in an aqueous solution of 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.

[0417] Preparations suitable for topical application in the oral cavity include lozenges containing flavoring active ingredients, typically sucrose and gum arabic or tragacanth; tablets containing inert active ingredients, such as gelatin and glycerin, or sucrose and gum arabic; and mouthwashes containing the active ingredients in a suitable liquid carrier.

[0418] Formulations for rectal administration may be provided as suppositories with a suitable matrix, including, for example, cocoa butter or salicylates.

[0419] In some embodiments, the compounds disclosed herein are administered by inhalation. In some embodiments, formulations suitable for intrapulmonary or intranasal administration have particle sizes, such as 0.5 micrometers, 1 micrometer, 30 micrometers, 35 micrometers, etc., in the range of 0.1 micrometers to 500 micrometers, and are administered by rapid inhalation through the nasal passage 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 together 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 nebulized formulations. In some embodiments, the compounds used herein are formulated for delivery via a face mask. In some embodiments, the compounds used herein are formulated for delivery via a face mask inhaler.

[0420] Preparations suitable for vaginal application may be provided in the form of pessaries, tampons, creams, gels, pastes, foams or sprays, and contain, in addition to the active ingredient, a suitable carrier known in the art.

[0421] Preparations suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions that may contain antioxidants, buffers, antibacterial agents and solutes to make the preparation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions that may include suspending agents and thickeners.

[0422] The formulation is present in single-dose or multi-dose containers, such as sealed ampoules and vials, and can be stored under lyophilized (freeze-dried) conditions, requiring only the addition of a sterile liquid carrier, such as water for injection, immediately before use. Temporary injectable solutions and suspensions are prepared from sterile powders, granules, and tablets of the aforementioned types. Preferred single-dose formulations are those containing a daily dose or a sub-daily dose of the active ingredient as described above, or a suitable portion thereof.

[0423] It should be understood that, in addition to the ingredients specifically mentioned above, the formulations of the present invention may include other agents conventional in the art related to the type of formulation discussed, such as flavoring agents suitable for oral administration.

[0424] The present invention further provides a veterinary drug composition comprising at least one active ingredient as defined above and its veterinary drug carrier.

[0425] Veterinary drug carriers are materials that can be used to administer compositions and can be solid, liquid, or gaseous materials. They are otherwise inert or acceptable in the veterinary field and compatible with the active ingredient. These veterinary drug compositions can be administered orally, parenterally, or via any other desired route.

[0426] The compounds of the present invention are used to provide controlled-release pharmaceutical formulations (“controlled-release formulations”) containing one or more of the compounds of the present invention as active ingredients, wherein the release of the active ingredient is controlled and regulated to allow administration at a lower frequency or to improve the pharmacokinetic or toxicological characteristics of a given active ingredient.

[0427] V. Reagent Kit

[0428] This document also provides kits comprising the compounds disclosed herein, pharmaceutically acceptable salts thereof, stereoisomers, mixtures of stereoisomers, or tautomers. In some embodiments, the kits described herein may include a label and / or instructions for use to treat a disease or condition in a subject (e.g., a human) in need of the compound. In some embodiments, the disease or condition is a viral infection.

[0429] In some implementations, the kit may also include instructions for use of one or more additional therapeutic agents and / or instructions for using additional therapeutic agents in combination with compounds of Formula I, Formula A, or Formula B to treat a disease or condition of a subject in need (e.g., a human).

[0430] In some embodiments, the kits provided herein contain a single dose unit of the compound as described herein, or a pharmaceutically acceptable salt, racemate, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, amorphous form, hydrate, or solvation thereof. Examples of single dose units may include pills, tablets, capsules, pre-filled syringes or syringes, IV bags, inhalers, nebulizers, etc., each comprising a therapeutically effective amount of the compound in question, or a pharmaceutically acceptable salt, racemate, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, amorphous form, hydrate, or solvation thereof. In some embodiments, the kit may contain a single dose unit, and in other embodiments, multiple dose units are present, e.g., the number of dose units required for a specified regimen or cycle.

[0431] Articles of manufacture are also provided, comprising compounds of formula I, formula A, or formula B, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or tautomers thereof, and containers. In some embodiments, the containers for the articles of manufacture are vials, cans, ampoules, pre-filled syringes, blister packs, cans, tins, bottles, boxes, intravenous bags, inhalers, or nebulizers.

[0432] VI. Application

[0433] One or more compounds of the present invention may be administered via any route suitable for the condition to be treated. Suitable routes include oral, rectal, inhalation, pulmonary, local (including buccal and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). In some embodiments, the compounds disclosed herein are administered by inhalation or intravenous administration. In some embodiments, the compounds disclosed herein are administered orally. It should be understood that preferred routes may vary depending on, for example, the condition of the recipient.

[0434] In the method of treating viral infection of the present invention, the compounds of the present invention can be administered at any time to persons who may be exposed to the virus or who already have a viral infection. In some embodiments, the compounds of the present invention can be administered prophylactically to persons who have been in contact with or are at risk of contact with persons who have been in ...

[0435] In some implementations, the methods disclosed herein include event-driven administration to a subject of a compound described herein (e.g., a compound of formula I, a compound of formula A, or a compound of formula B) or a pharmaceutically acceptable salt thereof.

[0436] As used herein, the terms “event-driven” or “event-driven administration” mean that the compound described herein (e.g., a compound of formula I, a compound of formula A, or a compound of formula B) or a pharmaceutically acceptable salt thereof is administered (1) prior to an event that will expose an individual to a virus (or otherwise increase the individual’s risk of acquiring a viral infection) (e.g., 2 hours, 1 day, 2 days, 5 days, or 7 days or more prior to the event); and / or (2) during an event that will expose an individual to a virus (or otherwise increase the individual’s risk of acquiring a viral infection) (or more than one repeated event); and / or (3) after an event that will expose an individual to a virus (or otherwise increase the individual’s risk of acquiring a viral infection) (or after the final event in a series of repeated events). In some embodiments, event-driven administration is performed before the subject is exposed to a virus. In some embodiments, event-driven administration is performed after the subject is exposed to a virus. In some embodiments, event-driven administration is performed both before and after the subject is exposed to a virus.

[0437] In some embodiments, the methods disclosed herein involve administration, for example as pre-exposure prophylaxis (PrEP) and / or post-exposure prophylaxis (PEP), before and / or after an event that will expose an individual to a virus or otherwise increase the individual's risk of acquiring a viral infection. In some embodiments, the methods disclosed herein include pre-exposure prophylaxis (PrEP). In some embodiments, the methods disclosed herein include post-exposure prophylaxis (PEP).

[0438] In some implementations, a compound of formula I, a compound of formula A, or a compound of formula B, or a pharmaceutically acceptable salt thereof, is administered to the subject prior to exposure to the virus.

[0439] In some implementations, a compound of formula I, a compound of formula A, or a compound of formula B, or a pharmaceutically acceptable salt thereof, is administered to the subject before and after exposure to the virus.

[0440] In some implementations, a compound of formula I, a compound of formula A, or a compound of formula B, or a pharmaceutically acceptable salt thereof, is administered to the subject after exposure to the virus.

[0441] Examples of event-driven dosing regimens include administering a compound of Formula I, Formula A, or Formula B, or a pharmaceutically acceptable salt thereof, 24 hours to 2 hours prior to exposure, followed by administration of the same compound every 24 hours during the exposure period, then further administration of the same compound of Formula I, Formula A, or Formula B, or a pharmaceutically acceptable salt thereof after the last exposure, and a final administration of the same compound of Formula I, Formula A, or Formula B, or a pharmaceutically acceptable salt thereof, 24 hours later.

[0442] Another example of an event-driven dosing regimen involves administering a compound of Formula I, Formula A, or Formula B, or a pharmaceutically acceptable salt thereof, within 24 hours prior to viral exposure, followed by daily administration during the exposure period, and then a final administration approximately 24 hours after the last exposure (which may be an increased dose, such as a double dose).

[0443] The specific dose level of the compounds disclosed herein for any particular subject will depend on a variety of factors, including the activity of the specific compound used, the age, weight, general health condition, sex, diet, time of administration, route of administration and excretion rate, drug combination, and severity of the specific disease. For example, the dose may be expressed as milligrams (mg / kg) of the compound described herein per kilogram of subject body weight. A dose between about 0.1 mg / kg and 150 mg / kg may be appropriate. In some embodiments, a dose between about 0.1 mg / kg and 100 mg / kg may be appropriate. In other embodiments, a dose between 0.5 mg / kg and 60 mg / kg may be appropriate. Normalization based on the subject's weight is particularly useful when adjusting doses among subjects with large differences in size, such as when using the drug in children and adults, or when converting an effective dose for a non-human subject, such as a dog, to a dose suitable for a human subject.

[0444] The daily dose may also be described as the total amount of the compounds described herein administered per dose or per day. The daily dose of a compound of Formula I, a compound of Formula A, or a compound of Formula B, or a pharmaceutically acceptable salt thereof, may be between about 1 mg and 4,000 mg, between about 2,000 mg / day and 4,000 mg / day, between about 1 mg / day and 2,000 mg / day, between about 1 mg / day and 1,000 mg / day, between about 10 mg / day and 500 mg / day, between about 20 mg / day and 500 mg / day, between about 50 mg / day and 300 mg / day, between about 75 mg / day and 200 mg / day, or between about 15 mg / day and 150 mg / day.

[0445] The dosage or frequency of administration of the disclosed compounds may be adjusted during treatment based on the judgment of the physician administering the medication.

[0446] The compounds disclosed herein can be administered in therapeutically effective amounts to an individual (e.g., a human). In some embodiments, the compounds are administered once daily.

[0447] The compounds provided herein may be administered by any useful route and means, such as by oral or parenteral (e.g., intravenous) administration. Therapeutic amounts of the compounds may include from about 0.00001 mg / kg body weight / day to about 10 mg / kg body weight / day, such as from about 0.0001 mg / kg body weight / day to about 10 mg / kg body weight / day, or such as from about 0.001 mg / kg body weight / day to about 1 mg / kg body weight / day, or such as from about 0.01 mg / kg body weight / day to about 1 mg / kg body weight / day, or such as from about 0.05 mg / kg body weight / day to about 0.5 mg / kg body weight / day. In some embodiments, therapeutic amounts of the compounds provided herein include from about 0.3 mg / day to about 30 mg / day, or from about 30 mg / day to about 300 mg / day, or from about 0.3 mg / day to about 30 mg / day, or from about 30 mg / day to about 300 mg / day.

[0448] The compounds disclosed herein may be combined with one or more additional therapeutic agents at any dose of the disclosed compounds (e.g., 1 mg to 1000 mg of the compound). Therapeuticly effective doses may include about 0.1 mg / dose to about 1000 mg / dose, such as about 50 mg / dose to about 500 mg / dose, or such as about 100 mg / dose to about 400 mg / dose, or such as about 150 mg / dose to about 350 mg / dose, or such as about 200 mg / dose to about 300 mg / dose, or such as about 0.01 mg / dose to about 100 mg / dose, or such as about 0.01 mg / dose to about 100 mg / dose, or such as about 0.1 mg / dose to about 100 mg / dose, or such as about 1 mg / dose to about 100 mg / dose, or such as about 1 mg / dose to about 100 mg / dose, or such as about 1 mg / dose to about 1000 mg / dose. Other therapeutically effective doses of compounds of formula I, formula A, or formula B are about 1 mg / dose, or about 2 mg / dose, 3 mg / dose, 4 mg / dose, 5 mg / dose, 6 mg / dose, 7 mg / dose, 8 mg / dose, 9 mg / dose, 10 mg / dose, 15 mg / dose, 20 mg / dose, 25 mg / dose, 30 mg / dose, 35 mg / dose, 40 mg / dose, 45 mg / dose, 50 mg / dose, 55 mg / dose, 60 mg / dose, 65 mg / dose, 70 mg / dose, 75 mg / dose, 80 mg / dose, 85 mg / dose, 90 mg / dose, 95 mg / dose, or about 100 mg / dose. Other therapeutically effective doses of the compounds disclosed herein are approximately 100 mg / dose, 125 mg / dose, 150 mg / dose, 175 mg / dose, 200 mg / dose, 225 mg / dose, 250 mg / dose, 275 mg / dose, 300 mg / dose, 325 mg / dose, 350 mg / dose, 375 mg / dose, 400 mg / dose, 425 mg / dose, 450 mg / dose, 475 mg / dose, 500 mg / dose, and 525 mg / dose. g / dose, 550mg / dose, 575mg / dose, 600mg / dose, 625mg / dose, 650mg / dose, 675mg / dose, 700mg / dose, 725mg / dose, 750mg / dose, 775mg / dose, 800mg / dose, 825mg / dose, 850mg / dose, 875mg / dose, 900mg / dose, 925mg / dose, 950mg / dose, 975mg / dose or approximately 1000mg / dose.

[0449] In some embodiments, the method described herein involves administering an initial daily dose of about 1 mg to 500 mg of the compound provided herein to a subject, and gradually increasing the dose until clinical efficacy is achieved. Increments of about 5 mg, 10 mg, 25 mg, 50 mg, or 100 mg may be used to increase the dose. The dose may be increased daily, every other day, twice a week, once a week, once every two weeks, once every three weeks, or once a month.

[0450] When administered orally, the total daily dose for human subjects may range from about 1 mg / day to 4,000 mg / day, from about 1 mg / day to 3,000 mg / day, from 1 mg / day to 2,000 mg / day, from about 1 mg / day to 1,000 mg / day, from about 10 mg / day to 500 mg / day, from about 50 mg / day to 300 mg / day, from about 75 mg / day to 200 mg / day, or from about 100 mg / day to 150 mg / day. In some implementations, the total daily dose for human subjects may be approximately 100 mg / day, 200 mg / day, 300 mg / day, 400 mg / day, 500 mg / day, 600 mg / day, 700 mg / day, 800 mg / day, 900 mg / day, 1000 mg / day, 1100 mg / day, 1200 mg / day, 1300 mg / day, or 1400 mg / day, administered as a single dose. The daily dose for human subjects may be approximately 200 mg / day, 300 mg / day, 400 mg / day, 500 mg / day, 600 mg / day, 700 mg / day, or 800 mg / day, administered as a single dose. In some embodiments, the total daily dose for human subjects may be approximately 300 mg / day, 400 mg / day, 500 mg / day, 600 mg / day, or 600 mg / day, administered as a single dose. In some implementations, the total daily dose for human subjects may be approximately 100 mg / day, 200 mg / day, 300 mg / day, 400 mg / day, 500 mg / day, 600 mg / day, 700 mg / day, 800 mg / day, 900 mg / day, 1000 mg / day, 1100 mg / day, 1200 mg / day, 1300 mg / day, 1400 mg / day, 1500 mg / day, 1600 mg / day, 1700 mg / day, 1800 mg / day, 1900 mg / day, 20... 00mg / day, 2100mg / day, 2200mg / day, 2300mg / day, 2400mg / day, 2500mg / day, 2600mg / day, 2700mg / day, 2800mg / day, 2900mg / day, 3000mg / day, 3100mg / day, 3200mg / day, 3300mg / day, 3400mg / day, 3500mg / day, 3600mg / day, 3700mg / day, 3800mg / day, 3900mg / day, or 4000mg / day.In some implementations, the total daily dose for human subjects may be approximately 100 mg / day - 200 mg / day, 100 mg / day - 300 mg / day, 100 mg / day - 400 mg / day, 100 mg / day - 500 mg / day, 100 mg / day - 600 mg / day, 100 mg / day - 700 mg / day, 100 mg / day - 800 mg / day, 100 mg / day - 900 mg / day, 100 mg / day - 1000 mg / day, or 500 mg / day. -1100mg / day, 500mg / day-1200mg / day, 500mg / day-1300mg / day, 500mg / day-1400mg / day, 500mg / day-1500mg / day, 500mg / day-1600mg / day, 500mg / day-1700mg / day, 500mg / day-1800mg / day, 500mg / day-1900mg / day, 500mg / day-2000mg / day, 1500mg / day-21 00mg / day, 1500mg / day-2200mg / day, 1500mg / day-2300mg / day, 1500mg / day-2400mg / day, 1500mg / day-2500mg / day, 2000mg / day-2600mg / day, 2000mg / day-2700mg / day, 2000mg / day-2800mg / day, 2000mg / day-2900mg / day, 2000mg / day-3000mg / day, 2500mg / day 3100mg / day, 2500mg / day-3200mg / day, 2500mg / day-3300mg / day, 2500mg / day-3400mg / day, 2500mg / day-3500mg / day, 3000mg / day-3600mg / day, 3000mg / day-3700mg / day, 3000mg / day-3800mg / day, 3000mg / day-3900mg / day, or 3000mg / day-4000mg / day.

[0451] In some embodiments, the total daily dose for a human subject may be about 100 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 150 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 200 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 250 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 300 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 350 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 400 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 450 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 500 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 550 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 600 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 650 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 700 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 750 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 800 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 850 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 900 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 950 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 1000 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 1500 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 2000 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 2500 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 3000 mg / day, administered as a single dose. In some embodiments, the total daily dose for a human subject may be about 4000 mg / day, administered as a single dose.

[0452] A single dose may be administered hourly, daily, weekly, or monthly. For example, a single dose may be administered every 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 16 hours, or every 24 hours. A single dose may also be administered every 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or every 7 days. A single dose may also be administered every 1 week, 2 weeks, 3 weeks, or every 4 weeks. In some embodiments, a single dose may be administered weekly. A single dose may also be administered monthly. In some embodiments, the compounds disclosed herein are administered once daily using the methods disclosed herein. In some embodiments, the compounds disclosed herein are administered twice daily using the methods disclosed herein. In some embodiments, the compounds disclosed herein are administered three times daily using the methods disclosed herein.

[0453] In some embodiments, the compounds disclosed herein are administered once daily at a total daily dose of 100 mg / day to 4000 mg / day. In some embodiments, the compounds disclosed herein are administered twice daily at a total daily dose of 100 mg / day to 4000 mg / day. In some embodiments, the compounds disclosed herein are administered three times daily at a total daily dose of 100 mg / day to 4000 mg / day.

[0454] The frequency of dosage of the disclosed compound will be determined by the individual patient's needs and may be, for example, once daily or twice daily or more. Administration of the compound will continue as long as treatment of the viral infection is required. For example, the compound may be administered to a person infected with the virus for a period of 20 to 180 days, or for a period of, for example, 20 to 90 days, or for example, 30 to 60 days.

[0455] Administration may be intermittent, with the patient receiving a daily dose of the disclosed compound over periods of several days or more, followed by periods without receiving the same daily dose. For example, the patient may receive a dose of the compound every other day or three times a week. Again, by way of example, the patient may receive a daily dose of the compound over periods of 1 to 14 days, followed by periods without receiving the compound over periods of 7 to 21 days, and then receive a daily dose of the compound again over subsequent periods (e.g., 1 to 14 days). The alternating periods of compound administration followed by non-administration may be repeated as needed to treat the patient's clinical needs.

[0456] The compounds or pharmaceutical compositions thereof disclosed herein may be administered once, twice, three times, or four times daily in any of the suitable modes described above. Furthermore, administration of the compound or treatment may continue for multiple days; for example, for a treatment cycle, treatment typically continues for at least 7, 14, or 28 days. Treatment cycles are well known in cancer chemotherapy and typically alternate with rest periods of approximately 1 to 28 days, typically approximately 7 or 14 days, between cycles. In other embodiments, treatment cycles may also be continuous.

[0457] VII. Instructions for Use

[0458] This disclosure also provides a method for treating or preventing viral infection in a subject (e.g., a person) in need, the method comprising administering the compound described herein to the subject.

[0459] In some embodiments, this disclosure provides a method for treating a viral infection in a subject (e.g., a person) in need, the method comprising administering the compound described herein to the subject in need.

[0460] In some embodiments, the compounds described herein are administered to humans via oral, intramuscular, intravenous, subcutaneous, or inhalation administration.

[0461] In some embodiments, this disclosure provides a method for treating or preventing viral infection in a subject (e.g., a person) in need, the method comprising administering to the subject a compound disclosed herein and at least one additional active therapeutic or preventative agent.

[0462] In some embodiments, this disclosure provides a method for treating a viral infection in a subject (e.g., a person) in need, the method comprising administering to the subject a compound disclosed herein and at least one additional active therapeutic or preventative agent.

[0463] In one embodiment, this disclosure provides a method for inhibiting viral polymerase in cells, the method comprising contacting virus-infected cells with a compound disclosed herein, thereby inhibiting the viral polymerase.

[0464] In one embodiment, this disclosure provides a method for inhibiting viral polymerase in cells, the method comprising contacting virus-infected cells with the compounds disclosed herein and at least one additional active therapeutic agent, thereby inhibiting the viral polymerase.

[0465] This document also provides for the use of the disclosed compounds in treating or preventing viral infections in subjects in need. For example, this document provides for the use of the disclosed compounds in treating viral infections in subjects in need.

[0466] In some embodiments, the viral infection is a paramyxoviridae virus infection. Therefore, in some embodiments, this disclosure provides a method for treating a paramyxoviridae infection in a subject (e.g., a human) of need, comprising administering the disclosed compounds to the subject. Paramyxoviridae viruses include, but are not limited to, Nipah virus, Hendra virus, measles virus, mumps virus, and parainfluenza virus.

[0467] In some implementations, the viral infection is human parainfluenza virus, Nipah virus, Hendra virus, measles, or mumps infection.

[0468] In some embodiments, the viral infection is a pulmonaviridae virus infection. Therefore, in some embodiments, this disclosure provides a method for treating a person in need of a pulmonaviridae virus infection, the method comprising administering to the person a compound provided herein. Pulmonaviridae viruses include, but are not limited to, respiratory syncytial virus (RSV) and human metapneumovirus (HMV). In some embodiments, the pulmonaviridae virus infection is a respiratory syncytial virus (RSV) infection. In some embodiments, the pulmonaviridae virus infection is a human metapneumovirus (HMV) infection.

[0469] In some embodiments, this disclosure provides compounds disclosed herein for treating pulmonary viral infections in persons of need. In some embodiments, the pulmonary viral infection is respiratory syncytial virus infection. In some embodiments, the pulmonary viral infection is human metapneumovirus infection.

[0470] In some embodiments, this disclosure provides a method for treating RSV infection in a person of need, the method comprising administering to the person a compound provided herein. In some embodiments, the person has a chronic respiratory syncytial virus infection. In some embodiments, the person is acutely infected with RSV.

[0471] In some embodiments, a method for inhibiting RSV replication is provided, wherein the method includes administering the disclosed compound to a person in need, wherein the administration is by inhalation.

[0472] In some embodiments, this disclosure provides a method for reducing viral load associated with RSV infection, wherein the method includes administering the disclosed compounds to a person infected with RSV.

[0473] In some embodiments, the viral infection is a picoriviridae virus infection. Therefore, in some embodiments, this disclosure provides a method for treating a person in need of a picoriviridae virus infection, the method comprising administering the compound of this disclosure to the person. Picoriviridae viruses are heterogeneous enteroviruses that cause a wide range of infections, including herpetic pharyngitis, aseptic meningitis, common cold-like syndrome (human rhinovirus infection), nonparalytic poliomyelitis-like syndrome, epidemic pleuropneumonia (an acute, febrile, infectious disease that typically occurs during epidemics), hand-foot-mouth disease, pancreatitis in children and adults, and severe myocarditis. In some embodiments, the picoriviridae virus infection is a human rhinovirus infection (HRV). In some embodiments, the picoriviridae virus infection is an HRV-A, HRV-B, or HRV-C infection.

[0474] In some implementations, viral infection is selected from the group consisting of: Coxsackie A virus infection, Coxsackie A virus infection, enterovirus D68 infection, enterovirus B69 infection, enterovirus D70 infection, enterovirus A71 infection, and poliovirus infection.

[0475] In some embodiments, this disclosure provides compounds for treating microribonucleoviridae virus infections in people of need. In some embodiments, the microribonucleoviridae virus infection is a human rhinovirus infection.

[0476] In some embodiments, the viral infection is a flaviviridae virus infection. Therefore, in some embodiments, this disclosure provides a method of treating a person in need of a flaviviridae virus infection, the method comprising administering the compound described herein to that person. Representative flaviviridae viruses include, but are not limited to, dengue fever, yellow fever, West Nile virus, Zika virus, Japanese encephalitis virus, and hepatitis C virus (HCV). In some embodiments, the flaviviridae virus infection is dengue virus infection. In some embodiments, the flaviviridae virus infection is yellow fever virus infection. In some embodiments, the flaviviridae virus infection is West Nile virus infection. In some embodiments, the flaviviridae virus infection is Zika virus infection. In some embodiments, the flaviviridae virus infection is Japanese encephalitis virus infection. In some embodiments, the flaviviridae virus infection is hepatitis C virus infection.

[0477] In some implementation schemes, Flaviviridae virus infection includes dengue virus infection, yellow fever virus infection, West Nile virus infection, tick-borne encephalitis, Kunzin Japanese encephalitis, St. Louis encephalitis, Murray Valley encephalitis, Omsk hemorrhagic fever, bovine viral diarrhea, Zika virus infection, or HCV infection.

[0478] In some embodiments, this disclosure provides the use of the compounds disclosed herein for treating flaviviridae virus infections in persons of need. In some embodiments, the flaviviridae virus infection is dengue virus infection. In some embodiments, the flaviviridae virus infection is yellow fever virus infection. In some embodiments, the flaviviridae virus infection is West Nile virus infection. In some embodiments, the flaviviridae virus infection is Zika virus infection. In some embodiments, the flaviviridae virus infection is hepatitis C virus infection.

[0479] In some embodiments, the viral infection is a filoviridae virus infection. Therefore, in some embodiments, this document provides a method for treating a person in need of a filoviridae virus infection, the method comprising administering to that person a compound disclosed herein. Representative filoviridae viruses include, but are not limited to, Ebola virus (variants Zaire, Bundibugio, Sudan, Tai Forest, or Reston) and Marburg virus. In some embodiments, the filoviridae virus infection is an Ebola virus infection. In some embodiments, the filoviridae virus infection is a Marburg virus infection.

[0480] In some embodiments, this disclosure provides compounds for treating filoviridae virus infections in people of need. In some embodiments, the filoviridae virus infection is Ebola virus infection. In some embodiments, the filoviridae virus infection is Marburg virus infection.

[0481] In some embodiments, the viral infection is a coronavirus infection. Therefore, in some embodiments, this document provides a method for treating a person in need of a coronavirus infection, wherein the method comprises administering to the person a compound provided herein. In some embodiments, the coronavirus infection is severe acute respiratory syndrome (SARS-CoV) infection, Middle East respiratory syndrome (MERS) infection, SARS-CoV-2 infection, other human coronaviruses (229E, NL63, OC43, HKU1, or WIV1) infection, or zoonotic coronavirus infection (PEDV or HKU CoV isolates, such as HKU3, HKU5, or HKU9). In some embodiments, the viral infection is severe acute respiratory syndrome (SARS) infection. In some embodiments, the viral infection is Middle East respiratory syndrome (MERS) infection. In some embodiments, the viral infection is SARS-CoV-2 infection. In some embodiments, the viral infection is a zoonotic coronavirus infection, and in some embodiments, the viral infection is caused by a virus having at least 70% sequence homology with a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2. In some embodiments, viral infection is caused by a virus having at least 80% 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, viral infection is caused by a virus having at least 90% 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, viral infection is caused by a virus having at least 95% sequence homology with a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2.

[0482] In some embodiments, viral infection is caused by a variant of SARS-CoV-2, such as variant B.1.1.7 (UK variant), variant B.1.351 (South African variant), variant P.1 (Brazilian variant), variants B.1.1.7 and E484K, variant B.1.1.207, variant B.1.1.317, variant B.1.1.318, variant B.1.429, variant B.1.525, or variant P.3. In some embodiments, viral infection is caused by variant B.1.1.7 of SARS-CoV-2. In some embodiments, viral infection is caused by variant B.1.351 of SARS-CoV-2. In some embodiments, viral infection is caused by variant P.1 of SARS-CoV-2.

[0483] In some embodiments, this disclosure provides compounds for treating coronavirus infections in people in need. In some embodiments, the coronavirus infection is severe acute respiratory syndrome (SARS) infection, Middle East respiratory syndrome (MERS) infection, SARS-CoV-2 infection, other human coronaviruses (229E, NL63, OC43, HKU1, or WIV1), 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) infection. In some embodiments, the viral infection is Middle East respiratory syndrome (MERS) infection. In some embodiments, the viral infection is SARS-CoV-2 infection (COVID-19).

[0484] In some embodiments, the viral infection is an infection of a arenaviridae virus. Therefore, in some embodiments, this disclosure provides a method for treating an arenaviridae virus infection in a person of need, the method comprising administering to the person a compound disclosed herein. In some embodiments, the arenaviridae virus infection is a lassa virus infection or a juniper virus infection.

[0485] In some embodiments, this disclosure provides compounds for treating arenaviridae virus infections in persons in need. In some embodiments, the arenaviridae virus infection is lassa virus infection or Junin virus infection.

[0486] In some implementations, the viral infection is an orthomyxovirus infection, such as an influenza virus infection. In some implementations, the viral infection is an influenza A virus, influenza B virus, or influenza C virus infection.

[0487] As described more fully herein, the compounds described herein can be administered to an individual (e.g., a human) infected with a virus, together with one or more adjunctive therapeutic agents. The adjunctive therapeutic agents can be administered to the infected individual simultaneously with, before, or after the administration of the compounds of this disclosure.

[0488] VIII. Combination Therapy

[0489] The compounds described herein can also be used in combination with one or more additional therapeutic agents. Therefore, this document also provides methods for treating viral infections in subjects in need, wherein these methods include administering to the subject the disclosed compounds and a therapeutically effective amount of one or more additional therapeutic or prophylactic agents.

[0490] In some implementations, the additional treatment is an antiviral agent. Any suitable antiviral agent can be used in the methods described herein.

[0491] In some implementations, the adjunctive therapeutic agents are 2,5-oligoadenylate synthase stimulators, 5-HT 2a receptor antagonists, 5-lipoxygenase inhibitors, ABL family tyrosine kinase inhibitors, Abl tyrosine kinase inhibitors, aldehyde dehydrogenase inhibitors, acetyl-CoA carboxylase inhibitors, actin antagonists, actin modulators, activity-dependent neuroprotective modulators, adenosine A3 receptor agonists, adrenergic receptor antagonists, adrenal medullary ligands, adrenal medullary ligand inhibitors, higher glycosylation product receptor antagonists, higher glycosylation product receptor modulators, AKT protein kinase inhibitors, alanine-proline-rich secretory protein stimulators, aldose reductase inhibitors, alkaline phosphatase stimulators, α2-adrenergic receptor antagonists, α2β-adrenergic receptor agonists, AMP-activated protein kinase stimulators, AMPA receptor modulators, amyloid deposition inhibitors, androgen receptor antagonists, angiotensin II AT-1 receptor antagonists, and angiotensin II. AT-2 receptor agonists, angiotensin II receptor modulators, angiotensin-converting enzyme 2 inhibitors, angiotensin-converting enzyme 2 modulators, angiotensin-converting enzyme 2 stimulators, angiotensin receptor modulators, annexin A5 stimulators, anoctamin 1 inhibitors, anticoagulants, antihistamines, antihyperxia drugs, antithrombotic agents, AP1 transcription factor modulators, apralin peptide receptor agonists, APOA1 gene stimulators, apolipoprotein A1 agonists, apolipoprotein B antagonists, apolipoprotein B modulators, apolipoprotein C3 antagonists, aryl hydrocarbon receptor agonists, aryl hydrocarbon receptor antagonists, ATP-binding cassette transporter B5 modulators, Axl tyrosine kinase receptor inhibitors, bactericidal permeability protein inhibitors, basigin inhibitors, basigin modulators, BCL2 gene inhibitors, BCL2L11 gene stimulators, Bcr protein inhibitors, β1-adrenergic receptor modulators, β2-adrenergic receptor agonists, β-adrenergic... Receptor agonists, β-inhibitor stimulants, coagulation modulators, BMP10 gene inhibitors, BMP15 gene inhibitors, bone morphogenetic protein-10 ligand inhibitors, bone morphogenetic protein-15 ligand inhibitors, bradykinin B2 receptor antagonists, brain-derived neurotrophic factor ligands, brominated domain protein 2 inhibitors, brominated domain 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 regulatory factor inhibitors, caspase inhibitors, catalase stimulants, CCL26 gene inhibitors, CCR2 chemokine antagonists, CCR5 chemokine antagonists.CD11a agonist, CD122 agonist, CD3 antagonist, CD4 agonist, CD40 ligand, CD40 ligand modulator, CD40 ligand receptor agonist, CD40 ligand receptor modulator, CD49d agonist, CD70 antigen modulator, CD73 agonist, CD73 antagonist, CD95 antagonist, CFTR inhibitor, CGRP receptor antagonist, chemokine receptor-like 1 agonist, chloride channel inhibitor, chloride channel modulator, cholera enterotoxin subunit B inhibitor, cholesterol ester transfer protein inhibitor, collagen modulator, complement C1s subcomponent inhibitor. Complement C3 inhibitors, complement C5 inhibitors, complement C5a inhibitors, complement factor H stimulants, 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, COVID-19 envelope small membrane protein modulators, COVID-19 non-structural protein 8 modulators, COVID-19 nucleoprotein modulators, COVID-19 protein 3a inhibitors, COVID-19 replicase multi-components COVID-19 replicase polyprotein 1a inhibitors, COVID-19 replicase polyprotein 1ab inhibitors, COVID-19 replicase polyprotein 1ab regulators, COVID-19 spike glycoprotein inhibitors, COVID-19 spike glycoprotein regulators, COVID-19 structural glycoprotein regulators, 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. 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, cyclin inhibitors, cysteine ​​protease inhibitors, cytochrome P450 3A4 inhibitors, cytokine receptor antagonists, cytotoxic T lymphocyte protein gene modulators, cytotoxic T lymphocyte protein-4 inhibitors, cytotoxic T lymphocyte protein-4 stimulators, DDX3 inhibitors, dehydrogenase inhibitors, dehydropeptidase-1 modulators, deoxyribonuclease I stimulators, deoxyribonuclease gamma stimulators, deoxyribonuclease stimulators, dihydroceramide δ4 desaturase inhibitors, dihydroorotate dehydrogenase inhibitors, dipeptidyl peptidase I inhibitors, dipeptidyl peptidase III inhibitors,Diuretics, DNA-binding protein inhibitors, DNA methyltransferase inhibitors, dopamine transporter inhibitors, E-selectin antagonists, Ecto-NOX disulfide thiol exchanger 2 inhibitors, EGFR gene inhibitors, elongation factor 1 α2 regulators, endoplasmic reticulin regulators, DICER regulators, endothelin ET-A receptor antagonists, epidermal growth factor receptor antagonists, E-selectin antagonists, estrogen receptor β agonists, estrogen receptor regulators, eukaryotic initiation factor 4A-I inhibitors, exonuclease α-sialidase regulators, export protein 1 inhibitors, factor Ia regulators, factor IIa regulators, factor VII antagonists, factor Xa antagonists, factor XIa antagonists, FGF receptor antagonists, FGF-1 ligands, FGF-1 ligand inhibitors, FGF-2 ligand inhibitors, FGF1 receptor antagonists, FGF2 receptor antagonists, FGF3 receptor antagonists, Flt3 tyrosine kinase inhibitors, fractalkine ligand inhibitors, free fatty acid receptor 2 agonists, free fatty acid receptor 3 agonists, furin inhibitors, Fyn tyrosine kinase inhibitors, FYVE finger phosphatidylinositol kinase inhibitors, G protein-coupled bile acid receptor 1 agonists, GABA Alpha receptor modulators, galactoglobulin-3 inhibitors, gamma-secretase inhibitors, GDF agonists, colloid stimulants, glial cell neurotrophic factor ligands, glucocorticoid receptor agonists, glutathione peroxidase stimulants, GM-CSF ligand inhibitors, GM-CSF receptor agonists, GM-CSF receptor modulators, Griffithsin modulators, growth regulator protein α-ligand inhibitors, Grp78 calcium-binding protein inhibitors, heat shock protein HSP90α inhibitors, heat shock protein HSP90β inhibitors Inhibitors, heat shock protein inhibitors, heat shock protein stimulants, hemagglutinin modulators, hemoglobin modulators, hemolysin α inhibitors, heparin-like enzyme 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 box B1 inhibitors, histamine H1 receptor antagonists, histamine H2 receptor antagonists, histone deacetylase-6 inhibitors, histone inhibitors, HIV protease inhibitors, HIV-1 gp120 protein inhibitor, HIV-1 protease inhibitor, HIV-1 reverse transcriptase inhibitor, HLA class I antigen modulator, HLA class II antigen modulator, host cytokine modulator, Hsp90 inhibitor, human papillomavirus E6 protein modulator, human papillomavirus E7 protein modulator, hypoxia-inducible factor inhibitor gene inhibitor, hypoxia-inducible factor-2α modulator, I-κB kinase inhibitor, I-κB kinase modulator, ICAM-1 stimulator, IgG receptor FcRn large subunit p51 modulator, IL-12 receptor antagonist.IL-15 receptor agonists, IL-15 receptor modulators, IL-17 antagonists, IL-18 receptor cofactor 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, IL-12 gene stimulators, IL-8 gene modulators, immunoglobulin G modulators, immunoglobulin G1 agonists, immunoglobulin G1 modulators, immunoglobulin agonists, immunoglobulin γFc receptor I modulators, immunoglobulin κ 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, interferon type I receptor agonists, interleukin 17A ligand inhibitors, interleukin 17F ligand inhibitors, interleukin 18 ligand inhibitors, interleukin 22 ligands, interleukin-1β ligand inhibitors, interleukin-1β ligand modulators, interleukin-1 ligand inhibitors, interleukin-2 ligands, interleukin-29 ligands, interleukin-6 ligand inhibitors, interleukin-7 ligands, interleukin-8 ligand inhibitors, IRAK-4 protein kinase inhibitors, JAK tyrosine kinase inhibitors, Jak1 tyrosine kinase inhibitors, Jak2 tyrosine kinase inhibitors, Jak3 tyrosine kinase inhibitors, Jun N-terminal kinase inhibitors, Jun N-terminal kinase modulators, kallikrein modulators, Kelch-like ECH-associated protein 1 modulators, Kit tyrosine kinase inhibitors, KLKB1 gene inhibitors, lactoferrin stimulants, lanosterol-14 demethylase inhibitors, Lck tyrosine kinase inhibitors, leukocyte Ig-like receptor A4 modulators, leukocyte elastase inhibitors, leukotriene BLT receptor antagonists, leukotriene D4 antagonists, leukotriene receptor antagonists, listeriin stimulants, liver X receptor antagonists, low molecular weight heparin, lung surfactant-associated protein B stimulants, lung surfactant-associated protein D modulators, Lyn tyrosine kinase inhibitors, Lyn tyrosine kinase stimulants, lysine-specific histone demethylase 1 inhibitors, macrophage migration inhibitors, mannan-binding lectin serine protease inhibitors, mannan-binding lectin serine protease-2 inhibitors, MAO B inhibitors, MAP kinase inhibitors, MAPK gene modulators, matrix metalloproteinase modulators, Maxi Potassium K channel inhibitors, MCL1 gene inhibitors, MEK protein kinase inhibitors, MEK-1 protein kinase inhibitorsMelanocortin MC1 receptor agonists, melanocortin MC3 receptor agonists, metalloproteinase-12 inhibitors, METTL3 gene inhibitors, membrane spike protein inhibitors, membrane spike protein modulators, monocyte chemotactic protein 1 ligand inhibitors, monocyte differentiation antigen CD14 inhibitors, mRNA guanine N7 methyltransferase modulators, mTOR complex 1 inhibitors, mTOR complex 2 inhibitors, mTOR inhibitors, mucoprotein modulators, muscarinic receptor antagonists, myeloperoxidase inhibitors, NACHT LRRPYD domain protein 3 inhibitors, NAD synthase regulators, NADPH oxidase inhibitors, neurocilia protein 2 regulators, neuroplastin inhibitors, NFE2L2 gene stimulators, NK cell receptor agonists, NK1 receptor antagonists, NMDA receptor antagonists, NMDA receptor ε2 subunit inhibitors, non-receptor tyrosine kinase TYK2 antagonists, non-nucleoside reverse transcriptase inhibitors, nsp12 polymerase inhibitors, nuclear factor erythrocyte-associated factor 2 stimulators, nuclear factor κB inhibitors, nuclear factor κB regulators, nuclease stimulators, nucleolar protein inhibitors, nucleoprotein inhibitors, nucleoprotein regulators, nucleoside reverse transcriptase inhibitors, opioid receptor agonists, opioid receptor μ regulators, opioid receptor σ antagonists, ORF1ab polyprotein inhibitors, ornithine decarboxylase inhibitors, outer membrane protein inhibitors, OX40 ligands, p38 MAP kinase α inhibitors, p38 MAP kinase inhibitors, p38 MAP kinase modulators, p53 tumor suppressor protein stimulators, palmitoyl protein thioesterase 1 inhibitors, papain inhibitors, PARP inhibitors, PARP modulators, PDE 10 inhibitors, PDE 3 inhibitors, PDE 4 inhibitors, PDGF receptor α antagonists, PDGF receptor antagonists, PDGF receptor β antagonists, peptidyl prolyl cis-trans isomerase A inhibitors, peroxidase 6 modulators, PGD2 antagonists, PGI2 agonists, P-glycoprotein inhibitors, phosphoinositol 3-kinase inhibitors, phosphoinositol-3-kinase δ inhibitors, phosphoinositol-3-kinase γ inhibitors, phospholipase A2 inhibitors, PIKfyve inhibitors, plasma kallikrein inhibitors, plasminogen activator inhibitor 1 inhibitors, platelet inhibitors, platelet glycoprotein VI inhibitors, Polo Anti-phosphokinase 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 modulators, prolyl 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 responsive protein 2 stimulators, Rev protein modulators, ribonuclease stimulators, RIP-1 kinase inhibitors, RNA helicase inhibitors, RNA polymerase inhibitors, RNA polymerase modulators, S-phase kinase-associated protein 2 inhibitors, SARS coronavirus 3C protease-like inhibitors, serine protease inhibitors, serine threonine protein kinase ATR inhibitors, serine threonine protein kinase TBK1 inhibitors, serum amyloid A protein modulators, signal transduction protein CD24 stimulators, Sirtuin inhibitors, sodium channel stimulators, sodium glucose transporter-2 inhibitors, sphingosine kinase. 1. Inhibitors, Sphingosine kinase 2 inhibitors, Sphingosine kinase inhibitors, Sphingosine-1-phosphate receptor-1 agonists, Sphingosine-1-phosphate receptor-1 antagonists, Sphingosine-1-phosphate receptor-1 modulators, Sphingosine-1-phosphate receptor-5 agonists, Sphingosine-1-phosphate receptor-5 modulators, spike glycoprotein inhibitors, Src tyrosine kinase inhibitors, STAT-1 modulators, STAT-3 inhibitors, STAT-5 inhibitors, STAT3 gene inhibitors, stem cell antigen-1 inhibitors, interferon gene stimulator protein stimulators, sulfatase inhibitors, superoxide dismutase modulators, superoxide dismutase stimulators, Syk tyrosine kinase inhibitors, T cell immune receptor Ig ITIM protein inhibitors, T cell receptor agonists, T cell surface glycoprotein CD28 inhibitors, T cell differentiation antigen CD6 inhibitors, T cell surface glycoprotein CD8 stimulators, T cell transcription factor NFAT regulators, anchored polymerase-1 inhibitors, anchored polymerase-2 inhibitors, Tek tyrosine kinase receptor stimulators, telomerase regulators, tetanus toxin regulators, TGFβ receptor antagonists, TGFB2 gene inhibitors, thymosin β4 ligands, thyroid hormone receptor β agonists, tissue factor inhibitors, tissue plasminogen activator regulators, tissue plasminogen activator stimulators, TLR agonists, TLR regulators, TLR-2 agonists, TLR-2 antagonists, TLR-3 agonists, TLR-4 agonists. TLR-4 antagonists, TLR-6 agonists, TLR-7 agonists, TLR-7 antagonists, TLR-8 antagonists, TLR-9 agonists, TMPRSS2 gene inhibitors, TNFα ligand inhibitors, TNFα ligand modulators, TNF binding agents, TNF gene inhibitors, topoisomerase inhibitors, transcription factor EB stimulators, transferrin modulators, transketolase inhibitors, translocation-related protein inhibitors, transmembrane serine protease 2 inhibitors, thyroxine transporter 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 protein kinase ABL1 inhibitors, ubiquitin cytochrome C reductase 14kDa inhibitors, ubiquitin ligase modulators, unspecified GPCR agonists, unspecified cytokine receptor modulators, unspecified enzyme stimulants, unspecified gene inhibitors, unspecified receptor modulators, urokinase plasminogen activator inhibitors, vascular cell adhesion protein 1 agonists, vasodilators. VEGF ligand inhibitors, VEGF receptor antagonists, VEGF-1 receptor antagonists, VEGF-1 receptor modulators, VEGF-2 receptor antagonists, VEGF-3 receptor antagonists, vimentin inhibitors, vimentin modulators, VIP receptor agonists, viral envelope protein inhibitors, viral protease inhibitors, viral protease modulators, viral protein target modulators, viral ribonuclease inhibitors, viral structural protein modulators, vitamin D3 receptor agonists, X-linked apoptosis protein inhibitors, xanthine oxidase inhibitors, or ligand inhibitors.

[0492] In some embodiments, the compounds and compositions of this disclosure may be administered in combination with Sars-Cov-2 treatments such as parenteral fluids (including glucose saline and Ringer's lactate), nutrients, antibiotics (including azithromycin, metronidazole, amphotericin B, amoxicillin / clavulanic acid, trimethoprim / sulfamethoxazole, R-327 and cephalosporin antibiotics such as ceftriaxone and cefuroxime), antifungal prophylaxis, antipyretics and analgesics, antiemetics (such as metoclopramide) and / or antidiarrheals, vitamin and mineral supplements (including vitamin K, vitamin D, cholecalciferol, vitamin C and zinc sulfate), anti-inflammatory agents (such as ibuprofen or steroids), corticosteroids (such as dexamethasone, methylprednisolone, prednisone, mometasone), immunomodulatory agents (e.g., interferon), vaccines and analgesics.

[0493] In some implementations, the adjunctive treatment is an Abl tyrosine kinase inhibitor, such as ladotinib or imatinib.

[0494] In some implementations, the additional therapeutic agent is an acetaldehyde dehydrogenase inhibitor, such as ADX-629.

[0495] In some implementations, the additional therapeutic agent is an adenosine A3 receptor agonist, such as piclidenoson.

[0496] In some implementations, the additional therapeutic agent is an adrenomedullin ligand, such as adrenomedullin.

[0497] In some implementations, the additional therapeutic agent is a p38 MAPK + PPAR γ agonist / insulin sensitizer, such as KIN-001.

[0498] In some implementations, the additional therapeutic agent is a PPARα agonist, such as DWTC-5101 (fenofibratecholine).

[0499] In some implementations, the adjunctive treatment is a cyclin inhibitor, such as rencofilstat.

[0500] In some implementations, the additional therapeutic agent is a p38 MAP kinase inhibitor, such as PRX-201 or Gen-1124.

[0501] In some implementations, the additional therapeutic agent is an aldose reductase inhibitor, such as cabifrestat.

[0502] In some implementations, the additional therapeutic agent is an AMPA receptor modulator, such as traneurocin.

[0503] In some implementations, the additional therapeutic agent is an annexin A5 stimulant, such as AP-01 or SY-005.

[0504] In some implementations, the additional therapeutic agent is an apalynide receptor agonist, such as CB-5064MM.

[0505] In some implementations, the adjunctive therapeutic agent is an anticoagulant, such as heparin (heparin and low molecular weight heparin), aspirin, apixaban, dabigatran, edoxaban, argatroban, enoxaparin, or fondaparin.

[0506] In some implementations, the adjunctive therapeutic agent is an androgen receptor antagonist, such as bicalutamide, denlutamide, enzalutamide, or proxalutamide.

[0507] In some implementations, the additional treatment is an anti-hypoxia drug, such as disodium crocin.

[0508] In some implementations, the adjunctive therapeutic agent is an antithrombotic agent, such as defibrinoside, rivaroxaban, alteplase, tirofiban, clopidogrel, prasugrel, bemiparin, bivalirudin, sulodexide, or tenecteplase.

[0509] In some implementations, the additional treatment is an antihistamine, such as clopidogrel or clomaste.

[0510] In some implementations, the additional therapeutic agent is an apolipoprotein A1 agonist, such as CER-001.

[0511] In some implementations, the additional therapeutic agent is a phospholipase A2 inhibitor, such as icosapentaenoic acid ethyl.

[0512] In some implementations, the additional therapeutic agent is an axl tyrosine kinase receptor inhibitor, such as besentinib.

[0513] In some implementations, the adjunctive treatment is a corticosteroid / β2-adrenergic receptor agonist, such as budesonide plus formoterol fumarate.

[0514] In some implementations, the additional therapeutic agent is a BET bromide domain inhibitor / APOA1 gene stimulator, such as apabetalone.

[0515] In some implementations, the adjunctive therapeutic agent is a blood coagulation modifier, such as lanaruzumab.

[0516] In some implementations, the additional therapeutic agent is a bradykinin B2 receptor antagonist, such as ateband.

[0517] In some implementations, the adjunctive therapeutic agent is an EGFR gene inhibitor / Btk tyrosine kinase inhibitor, such as abivertinib.

[0518] In some implementations, the adjunctive treatment is a Btk tyrosine kinase inhibitor, such as ibrutinib or zanubrutinib.

[0519] In some implementations, the additional therapeutic agent is a calpain-I / II / IX inhibitor, such as BLD-2660.

[0520] In some implementations, the adjunctive therapeutic agent is a cannabinoid CB2 receptor agonist, such as onternabez or PPP-003.

[0521] In some implementations, the additional therapeutic agent is a Ca2+ release-activating Ca2+ channel 1 inhibitor, such as zegocractin (CM-4620).

[0522] In some implementations, the adjunctive treatment is an ATR inhibitor, such as bexostatinib (berzosertib).

[0523] In some implementations, the additional therapeutic agent is a cadherin-5 modulator, such as FX-06.

[0524] In some implementations, the additional therapeutic agent is a casein kinase II inhibitor, such as silmitasertib.

[0525] In some implementations, the additional therapeutic agent is a caspase inhibitor, such as emricasan.

[0526] In some implementations, the additional therapeutic agent is a catalase stimulator / superoxide dismutase stimulator, such as MP-1032.

[0527] In some implementations, the additional therapeutic agent is a CCR2 chemokine antagonist / CCR5 chemokine antagonist, such as cineviro.

[0528] In some implementations, the adjunctive treatment is a CCR5 chemokine antagonist, such as maraviro or lelimumab.

[0529] In some implementations, the additional therapeutic agent is a CD122 agonist / IL-2 receptor agonist, such as beempegaldesleukin.

[0530] In some implementations, the additional therapeutic agent is a CD73 agonist / interferon beta ligand, such as FP-1201.

[0531] In some implementations, the additional therapeutic agent is a cholesterol ester transporter inhibitor, such as dacetropeptide.

[0532] In some implementations, the additional therapeutic agent is a mannan-binding lectin serine protease / complement C1s subcomponent inhibitor / myeloperoxidase inhibitor, such as RLS-0071.

[0533] In some implementations, the additional therapeutic agent is a complement C5 factor inhibitor / leukotriene BLT receptor antagonist, such as nomacopan.

[0534] In some implementations, the adjunctive treatment is a complement factor C5 inhibitor, such as eculizumab, STSA-1002, or zilucoplan.

[0535] In some implementations, the additional therapeutic agent is a CXCR4 chemokine antagonist, such as praxafol or motixafortide.

[0536] In some implementations, the adjunctive therapeutic agent is a cytochrome P450 3A4 inhibitor / peptidyl prolyl cis-trans isomerase A inhibitor, such as arapovir.

[0537] In some implementations, the additional therapeutic agent is a cysteine ​​protease inhibitor, such as SLV-213.

[0538] In some implementations, the additional treatment agent is a dihydroorotate dehydrogenase inhibitor, such as Meds-433, buquina, RP-7214, faludosat, or emvododstat.

[0539] In some implementations, the additional therapeutic agent is a dehydropeptidase-1 modulator, such as Metablok.

[0540] In some implementations, the additional treatment is a dihydroorotate dehydrogenase inhibitor / IL-17 antagonist, such as vidofluradim.

[0541] In some implementations, the additional therapeutic agent is a diuretic, such as an aldosterone antagonist, such as spironolactone.

[0542] In some implementations, the additional therapeutic agent is a deoxyribonuclease I stimulator, such as GNR-039 or dornase alfa.

[0543] In some implementations, the additional treatment agent is a NET inhibitor, such as NTR-441.

[0544] In some implementations, the additional therapeutic agent is a dihydroceramide δ4 desaturase inhibitor / sphingosine kinase 2 inhibitor, such as opaganib.

[0545] In some implementations, the additional therapeutic agent is a DNA methyltransferase inhibitor, such as azoxymidine.

[0546] In some implementations, the additional treatment agent is an LXR antagonist, such as larsucosterol.

[0547] In some implementations, the additional therapeutic agent is a dipeptidyl peptidase I inhibitor, such as brensocatib.

[0548] In some implementations, the additional therapeutic agent is a protein arginine deiminase IV inhibitor, such as JBI-1044.

[0549] In some implementations, the additional therapeutic agent is an extension factor 1 α2 regulator, such as privitin.

[0550] In some implementations, the adjunctive therapeutic agent is a eukaryotic initiation factor 4A-I inhibitor, such as zotatifin.

[0551] In some implementations, the additional therapeutic agent is an exocrine α-sialidase modulator, such as DAS-181.

[0552] In some implementations, the additional therapeutic agent is an export protein 1 inhibitor, such as selinexor.

[0553] In some implementations, the additional therapeutic agent is a fractalkine ligand inhibitor, such as KAND-567.

[0554] In some implementations, the additional therapeutic agent is an FYVE finger phosphoinositol kinase inhibitor / IL-12 receptor antagonist / IL-23 antagonist, such as apimod dimethylsulfonate.

[0555] In some implementations, the additional therapeutic agent is a GABA A receptor modulator, such as brinolone.

[0556] In some implementations, the adjunctive therapeutic agent is a glucocorticoid receptor agonist, such as ccyclosone, hydrocortisone, dexamethasone, dexamethasone phosphate, or 101-PGC-005.

[0557] In some implementations, the additional therapeutic agent is a GM-CSF receptor agonist, such as saxaglastine.

[0558] In some implementations, the additional therapeutic agent is a GPCR agonist, such as esuberaprostsodium.

[0559] In some implementations, the additional therapeutic agent is a Griffithsin modulator, such as Q-Griffithsin.

[0560] In some implementations, the additional therapeutic agent is a leukotriene D4 antagonist, such as montelukast.

[0561] In some implementations, the additional therapeutic agent is a histamine H1 receptor antagonist, such as ebastine, tranilast, or levocetirizine hydrochloride.

[0562] In some implementations, the additional therapeutic agent is a histamine H2 receptor antagonist, such as famotidine.

[0563] In some implementations, the additional therapeutic agent is a heat shock protein stimulator / insulin sensitizer / PARP inhibitor, such as BGP-15.

[0564] In some implementations, the additional therapeutic agent is a histone inhibitor, such as STC-3141.

[0565] In some implementations, the additional therapeutic agent is a histone deacetylase-6 inhibitor, such as CKD-506.

[0566] In some implementations, the additional treatment agent is a HIF prolyl hydroxylase-2 inhibitor, such as dedustat.

[0567] In some implementations, the additional treatment agent is a HIF prolyl hydroxylase inhibitor, such as valdustat.

[0568] In some implementations, the additional treatment agent is an IL-8 receptor antagonist, such as reparixin.

[0569] In some implementations, the additional therapeutic agent is an IL-7 receptor agonist, such as CYT-107.

[0570] In some implementations, the additional therapeutic agent is an IL-7 receptor agonist / interleukin-7 ligand, such as efineptakin alfa.

[0571] In some implementations, the additional therapeutic agent is an IL-22 agonist, such as efmarodocokin alfa.

[0572] In some implementations, the additional therapeutic agent is an IL-22 agonist / interleukin-22 ligand, such as F-652.

[0573] In some implementations, additional therapeutic agents target IL-33, such as toretzimab.

[0574] In some implementations, the additional treatment is an IL-15 agonist, such as nogapendekinalfa.

[0575] In some implementations, the additional therapeutic agent is an integrin α-V / β-1 antagonist / integrin α-V / β-6 antagonist, such as bexotegrast.

[0576] In some implementations, the additional therapeutic agent is an interferon alpha2 ligand, such as interferon alpha-2b or Virafin.

[0577] In some implementations, the additional therapeutic agent is an interferon β ligand, such as a follow-up biologic to interferon β-1a, interferon β-1b, or SNG-001.

[0578] In some implementations, the additional therapeutic agent is an interferon receptor modulator, such as peginterferon lambda-1a.

[0579] In some implementations, the additional therapeutic agent is an interleukin-2 ligand, such as adeleukin.

[0580] In some implementations, the additional treatment is an IRAK-4 protein kinase inhibitor, such as zimlovisertib.

[0581] In some implementations, the adjunctive therapy is a JAK inhibitor, such as baricitinib, filgortinib, jaktinib, tofacitinib, or nezulcitinib (TD-0903).

[0582] In some implementations, the additional therapeutic agent is a neutral leukocyte elastase inhibitor, such as avelestat.

[0583] In some implementations, the additional therapeutic agent is a lung surfactant-associated protein D modulator, such as AT-100.

[0584] In some implementations, the additional therapeutic agent is a plasma kallikrein inhibitor, such as donidalorsen.

[0585] In some implementations, the adjunctive therapeutic agent is a lysine-specific histone demethylase 1 / MAO B inhibitor, such as varifidestat.

[0586] In some implementations, the additional therapeutic agent is a mannan-binding lectin serine protease inhibitor, such as conestat alfa.

[0587] In some implementations, the additional therapeutic agent is a maxi K potassium channel inhibitor, such as ENA-001.

[0588] In some implementations, the adjunctive therapeutic agent is a MEK protein kinase inhibitor, such as zapnometinib.

[0589] In some implementations, the adjunctive therapeutic agent is a MEK-1 protein kinase inhibitor / Ras gene inhibitor, such as androidquinolol.

[0590] In some implementations, the adjunctive therapeutic agent is a melanocortin MC1 receptor agonist, such as PL-8177.

[0591] In some implementations, the additional therapeutic agent is a melanocortin MC1 / MC3 receptor agonist, such as resomelega acetate.

[0592] In some implementations, the additional therapeutic agent is a matrix metalloproteinase-12 inhibitor, such as FP-025.

[0593] In some implementations, the additional therapeutic agent is a NACHT LRR PYD domain protein 3 inhibitor, such as dapansutrile, DFV-890, or ZYIL-1.

[0594] In some implementations, the additional therapeutic agent is an NADPH oxidase inhibitor, such as isuzinaxib.

[0595] In some implementations, the adjunctive therapeutic agent is a neuropilin 2 modulator, such as efzofitimod.

[0596] In some implementations, the additional therapeutic agent is an NK1 receptor antagonist, such as aprepitant or tripipitant.

[0597] In some implementations, the additional therapeutic agent is an NMDA receptor antagonist, such as crocin or fenfenidil.

[0598] In some implementations, the adjunctive therapeutic agent is a nuclear factor κB inhibitor / p38 MAP kinase inhibitor, such as zenuzolac.

[0599] In some implementations, the additional therapeutic agent is an ornithine decarboxylase inhibitor, such as efornithine.

[0600] In some implementations, the additional therapeutic agent is an opioid receptor σ antagonist, such as MR-309.

[0601] In some implementations, the additional treatment is a PGD2 antagonist, such as asapiprant.

[0602] In some implementations, the additional therapeutic agent is a PDGF receptor antagonist / TGFβ receptor antagonist / p38 MAP kinase inhibitor, such as deupirfenidone.

[0603] In some implementations, the additional therapeutic agent is a phospholipase A2 inhibitor, such as methylvarenaradil.

[0604] In some implementations, the adjunctive therapeutic agent is a phosphoinositol 3-kinase inhibitor / mTOR complex inhibitor, such as dactolisib.

[0605] In some implementations, the additional treatment is an mTOR inhibitor, such as sirolimus.

[0606] In some implementations, the additional therapeutic agent is a phosphoinositol-3 kinase δ / γ inhibitor, such as duveliximab.

[0607] In some implementations, the additional treatment agent is a PIKfyve inhibitor, such as VRG-101.

[0608] In some implementations, the additional therapeutic agent is a plasminogen activator inhibitor 1 inhibitor, such as TM-5614.

[0609] In some implementations, the additional therapeutic agent is a protein tyrosine phosphatase β inhibitor, such as ralotafine.

[0610] In some implementations, the adjunctive therapeutic agent is a RIP-1 kinase inhibitor, such as eclitasertib (DNL-758) or SIR-0365.

[0611] In some implementations, the additional therapeutic agent is a Rev protein modulator, such as obefazimod.

[0612] In some implementations, the adjunctive therapeutic agent is an S-phase kinase-associated protein 2 inhibitor, such as niclosamide, CP-COV3, SCAI-502, or DWRX-2003.

[0613] In some implementations, the additional therapeutic agent is a CD24 signal transduction protein stimulator, such as EXO-CD24.

[0614] In some implementations, the additional therapeutic agent is a sodium glucose transporter-2 inhibitor, such as dapagliflozin propylene glycol.

[0615] In some implementations, the additional therapeutic agent is a sodium channel inhibitor, such as solnatide.

[0616] In some implementations, the additional therapeutic agent is a sphingosine-1-phosphate-1 agonist / sphingosine-1-phosphate-5 agonist, such as ozamod.

[0617] In some implementations, the adjunctive therapeutic agent is a nonsteroidal anti-inflammatory drug, such as Ampion.

[0618] In some implementations, the additional therapeutic agent is a superoxide dismutase agonist, such as avasopasem manganese.

[0619] In some implementations, the additional therapeutic agent is a Syk tyrosine kinase inhibitor, such as futtatinib disodium salt.

[0620] In some implementations, the additional therapeutic agent is a Tie2 tyrosine kinase receptor agonist, such as AV-001.

[0621] In some implementations, the adjunctive therapeutic agent is a TGFB2 gene inhibitor, such as trabedsen.

[0622] In some implementations, the additional therapeutic agent is a tissue factor inhibitor, such as AB-201.

[0623] In some implementations, the additional treatment is a TLR-3 agonist, such as lentamod.

[0624] In some implementations, the additional treatment agent is a TLR-4 antagonist, such as ApTLR-4FT, EB-05, or iritolen.

[0625] In some implementations, the additional treatment is a TLR-7 / 8 antagonist, such as enpatoran.

[0626] In some implementations, the additional therapeutic agent is a TLR-2 / 6 agonist, such as INNA-051.

[0627] In some implementations, the additional treatment agent is a TLR-7 agonist, such as PRTX-007 or APR-002.

[0628] In some implementations, the additional therapeutic agent is a TLR agonist, such as PUL-042.

[0629] In some implementations, the additional therapeutic agent is a TLR-4 agonist, such as REVTx-99.

[0630] In some implementations, the additional therapeutic agent is a TLR-2 / 4 antagonist, such as VB-201.

[0631] In some implementations, the additional therapeutic agent is a TNF α ligand inhibitor, such as pegipanermin.

[0632] In some implementations, the additional therapeutic agent is a type I IL-1 receptor antagonist, such as anaspirin.

[0633] In some implementations, the additional therapeutic agent is a TREM receptor 1 antagonist, such as nangibotide.

[0634] In some implementations, the additional therapeutic agent is a trypsin inhibitor, such as ulinastatin.

[0635] In some implementations, the adjunctive therapeutic agent is a microtubule inhibitor, such as sabizabulin, CCI-001, PCNT-13, CR-42-24, albendazole, entabulin, SAR-132885, or ON-24160.

[0636] In some implementations, the additional therapeutic agent is a VIP receptor agonist, such as aviptadil.

[0637] In some implementations, the additional therapeutic agent is a xanthine oxidase inhibitor, such as hydroxypurine.

[0638] In some implementations, the adjunctive therapeutic agent is a vasodilator, such as iloprost, evoraprost (VentaProst), vazegepant, TXA-127, USB-002, ambesentan, nitric oxide nasal spray (NORS), pentoxifylline, propranolol, RESP301, sodium nitrite, or dipyridamole.

[0639] In some implementations, the additional therapeutic agent is a vitamin D3 receptor agonist, such as cholecalciferol.

[0640] In some implementations, the additional therapeutic agent is a zonulin inhibitor, such as larazotide acetate.

[0641] In some implementations, the additional therapeutic agent is a synthetic retinoic acid derivative, such as fenivel-Amin.

[0642] In some implementations, the additional therapeutic agent is a glucose metabolism inhibitor, such as WP-1122 or WP-1096.

[0643] In some implementations, the adjunctive treatment agents are adalimumab, AT-H201, 2-deoxy-D-glucose, AD-17002, AIC-649, AMTX-100, astodrimer, AZD-1656, belapectin, bitespiramycin, buximine, budesonide, CNM-AgZn-17, Codivir, CT-38, danicopan, dodecylmethopterin, DW-2008S (DW-2008), EDP-1815, EG-009A, Fabencov, Gamunex, genistein, GLS-1200, hzVSF-v13, imidazole acetamide glutaric acid, IMM-101, M AS-825, MRG-001, Nasitrol, Nylexa, Orabatinib, OP-101, OPN-019, Orynotide (rhesus monkey theta defense-1), phenazine + artemisinin, dapsone, RPH-104, sodium pyruvate, Sulforadex, tafenoxine, TB-006, telacebec, Tempol, TL-895, thimerosal, trimodulin, XC-221, XC-7, somotinib, metformin glycine, lucinactant, EOM-613, mosmod, ivermectin, leflunomide, isotetrast, RBT-9, raloxifene, prothione, zicarbene or dehydroestradiol (idronoxil).

[0644] In some implementations, the additional treatment agent is a CD73 antagonist, such as AK-119.

[0645] In some implementations, the additional therapeutic agent is a CD95 protein fusion, such as asunercept.

[0646] In some implementations, the additional therapeutic agent is a complement factor C2 modulator, such as ARGX-117.

[0647] In some implementations, the additional treatment agent is a complement C3 inhibitor, such as AMY-101 or NGM-621.

[0648] In some implementations, the additional therapeutic agent is a CXC10 chemokine ligand inhibitor, such as EB-06.

[0649] In some implementations, the adjunctive therapeutic agent is a cytotoxic T-lymphocyte protein-4 fusion protein, such as abatacept.

[0650] In some implementations, the adjunctive therapeutic agent is an anti-Staphylococcus aureus antibody, such as tosatoxumab.

[0651] In some implementations, the additional therapeutic agent is an anti-LPS antibody, such as IMM-124-E.

[0652] In some implementations, the adjunctive therapeutic agent is an adrenaline ligand inhibitor, such as embarreximab.

[0653] In some implementations, the additional treatment is a basigin inhibitor, such as meperizumab.

[0654] In some implementations, the adjunctive treatment is a CD3 antagonist, such as francirumab.

[0655] In some implementations, the adjunctive therapeutic agent is a connective tissue growth factor ligand inhibitor, such as PRS-220 or perrirumab.

[0656] In some implementations, the adjunctive therapeutic agent is a complement C5a factor inhibitor, such as BDB-1 or virolimab.

[0657] In some implementations, the adjunctive therapeutic agent is a complement factor C5 inhibitor, such as eculizumab.

[0658] In some implementations, the adjunctive therapeutic agent is a mannan-binding lectin serine protease-2 inhibitor, such as nasoribimab.

[0659] In some implementations, the adjunctive treatment is a GM-CSF modulator, such as STSA-1005, netlimumab, namexilumab, punelimumab, otelilimumab, or lenzrulimab.

[0660] In some implementations, the adjunctive therapeutic agent is a heat shock protein inhibitor / IL-6 receptor antagonist, such as sutuximab.

[0661] In some implementations, the adjunctive therapeutic agent is an IL-6 receptor antagonist, such as clazazumab, levilimab, olokizumab, tocilizumab, or sirukumab.

[0662] In some implementations, the additional therapeutic agent is an IL-8 receptor antagonist, such as BMS-986253.

[0663] In some implementations, the additional therapeutic agent is an interleukin-1β ligand inhibitor, such as canakinumab.

[0664] In some implementations, the additional therapeutic agent is an interferon-gamma ligand inhibitor, such as epavamab.

[0665] In some implementations, the additional therapeutic agent is an anti-ILT7 antibody, such as daxdilimab.

[0666] In some implementations, the adjunctive therapeutic agent is a CD14 inhibitor, such as atibuclimab.

[0667] In some implementations, the additional therapeutic agent is a plasma kallikrein inhibitor, such as lanarumab.

[0668] In some implementations, the adjunctive treatment is a platelet glycoprotein VI inhibitor, such as glenzocimab.

[0669] In some implementations, the adjunctive therapeutic agent is a T-cell differentiation antigen CD6 inhibitor, such as itolizumab.

[0670] In some implementations, the adjunctive therapeutic agent is a TNF α ligand inhibitor / TNF binder, such as infliximab.

[0671] In some implementations, the additional therapeutic agent is an anti-LIGHT antibody, such as AVTX-002.

[0672] In some implementations, the adjunctive treatment is IMC-2 (valacyclovir + celecoxib) or AXA-1125.

[0673] In some implementations, the additional treatment is COVID-HIG.

[0674] In some embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are co-administered with one or more agents that can be used to treat and / or prevent COVID-19.

[0675] 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 thalidomab; Janus kinase (JAK) inhibitors such as baricitinib, ruxotinib, or tofacitinib; and antiviral agents such as monopivir, sotromab, or remdesivir.

[0676] In another embodiment, the compounds of this disclosure or pharmaceutically acceptable salts thereof are co-administered with two or more agents that can be used to treat COVID-19. Agents that can be used to treat and / or prevent COVID-19 include, but are not limited to, the compounds of this disclosure and two additional therapeutic agents, such as nematvir and ritonavir, camrelizumab and edevimab, or ruxolitinib and tofacitinib.

[0677] In some embodiments, the adjunctive 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 adjunctive therapeutic agent is an RNA-dependent RNA polymerase (RdRp) inhibitor.

[0678] In some implementations, 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 envelope small membrane protein inhibitors, SARS-CoV-2 envelope small membrane protein modulators, and 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.

[0679] In some implementations, the adjunctive therapeutic agent is an entry inhibitor. For example, in some implementations, the adjunctive therapeutic agent is an ACE2 inhibitor, a fusion inhibitor, or a protease inhibitor.

[0680] In some implementations, the additional therapeutic agent is an angiotensin-converting enzyme 2 inhibitor, such as SBK-001.

[0681] In some implementations, the additional therapeutic agent is an angiotensin-converting enzyme 2 modulator, such as neumifil or JN-2019.

[0682] In some implementations, the additional therapeutic agent is an entry inhibitor, such as MU-UNMC-1 or SAI-4.

[0683] In some implementations, the additional therapeutic agent is an angiotensin-converting enzyme 2 stimulator, such as alunase alfa.

[0684] In some implementations, the additional therapeutic agent is an angiotensin II AT-2 receptor agonist, such as VP-01.

[0685] In some implementations, the additional therapeutic agent is an ACE II receptor antagonist, such as DX-600.

[0686] In some implementations, the additional therapeutic agent is an angiotensin II receptor modulator, such as TXA-127.

[0687] In some implementations, the additional therapeutic agent is a transmembrane serine protease 2 modulator, such as BC-201 or N-0385.

[0688] In some implementations, the additional therapeutic agent is a viral envelope protein inhibitor, such as MXB-9 or MXB-004.

[0689] In some implementations, the additional therapeutic agent is an RNAi agent, such as ARO-COV or SNS-812.

[0690] In some implementations, the adjunctive therapeutic agent is a vaccine. For example, in some implementations, the adjunctive therapeutic agent is a DNA vaccine, an RNA vaccine, a live attenuated vaccine, an inactivated vaccine (i.e., an inactivated SARS-CoV-2 vaccine), a therapeutic vaccine, a prophylactic vaccine, a protein-based vaccine, a viral vector vaccine, a cell vaccine, or a dendritic cell vaccine.

[0691] In some implementations, the adjunctive 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, and 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 particles, inactivated / purified), ReCOV, MT-2766, ARCT-154, SP-0253, CORBEVAX, mRNA-1273.211, ZF-2001, SputnikLight, recombinant protein vaccine (COVID-19 / SARS-CoV-2 infection), VSV vector-based vaccine targeting spike glycoprotein (COVID-19), VLA-2101, GRT-R912, GRAd-COV2, VPM-1002, COViran Barekat, Ad5-nCoV-IH, ARCoV, Covax-19, recombinant SARS-CoV-2 vaccine (protein subunit / CHO cells, COVID-19), BBV-154, RAZICov Pars, COVID-19 vaccine (inactivated / Vero cells / intramuscular, SARS-CoV-2 infection), COVID-19 vaccine (inactivated, Vero cells / intramuscular), BNT-162b2s01, BNT-162b4, BNT-162b5, BNT-162b2 Omi, BNT-162b2 bivalent, CIGB-66, mRNA-1273.617, Mycobacterium w, ERUCOV-VAC, AG-0301-COVID19, fakhravac, AV-COVID-19, peptide vaccine (COVID-19), Nanocovax, SARS-CoV-2 vaccine (inactivated / Vero cell / intramuscular, COVID-19), QAZCOVID-IN, S-875670 nasal vaccine, VTP-500 or BNT162b5.

[0692] In some embodiments, the adjunctive therapeutic agent is a protease inhibitor. For example, in some embodiments, the adjunctive therapeutic agent is a 3C-like cysteine ​​protease inhibitor (3CLpro, also known as the main protease, Mpro), a papain-like protease inhibitor (PLpro), a serine protease inhibitor, or a transmembrane serine protease 2 inhibitor (TMPRSS2).

[0693] In some implementations, the adjunctive treatment is a 3CLpro / Mpro inhibitor, such as ABBV-903, AB-343, CDI-873, GC-373, GC-376, pomotrelvir (PBI-0451), UCI-1, bofutrelvir (FB-2001, DC-402234), DC-402267, GDI-4405, HS-10517, RAY-1216, MPI-8, SH-879, SH-580, EDP-235, VV-993, CDI-988, MI-30, nelmatvir, etc. Enstavir, ASC-11, ASC-11 + ritonavir, EDDC-2214, SIM-0417, PF-07817883, Cenostatin, Cenostatin + ritonavir, SYH-2055, ISM-3312, CDI-45205, LHP-803 (COR-803), ALG-097111, TJC-642, CVD-0013943, olgotrelvir (STI-1558), epivacycline, cynarine, WPV-01, or prexasertib.

[0694] In some implementations, the additional therapeutic agent is a papain-like protease inhibitor (PLpro), such as SBFM-PL4 or GRL-0617.

[0695] In some implementations, the additional therapeutic agent is a SARS-CoV-2 helicase Nsp13 inhibitor, such as EIS-4363.

[0696] In some implementations, the additional therapeutic agent is a SARS-CoV-2 helicase Nsp14 inhibitor, such as TO-507.

[0697] In some implementations, the additional therapeutic agents are the SARS-CoV-2 spike protein (S) and protease modulators, such as ENU-200.

[0698] In some implementations, the additional therapeutic agent is a protease inhibitor, such as ALG-097558 or MRX-18.

[0699] In some implementations, the adjunctive therapeutic agent is a serine protease inhibitor, such as upparstat, naphthostat, carmostat mesylate, naphthostat mesylate, or carmostat.

[0700] In some implementations, the additional therapeutic agent is a 3CLpro / transmembrane serine protease 2 inhibitor, such as SNB-01 (pentarlandir) or SNB-02.

[0701] In some implementations, the additional therapeutic agent is a viral protease inhibitor such as Pan-Corona, Cov-X, or benprodil.

[0702] In some embodiments, the adjunctive therapeutic agent is an RNA polymerase inhibitor. For example, in some embodiments, the adjunctive therapeutic agent is an RNA polymerase inhibitor, or an RNA-dependent RNA polymerase (RdRp) inhibitor.

[0703] In some implementations, the adjunctive therapeutic agent is an RNA-dependent RNA polymerase (RdRp) inhibitor, such as remdesivir, NV-CoV-2, NV-CoV-2-R, NV-CoV-1-encapsulated remdesivir, CMX-8521, GS-621763, GS-5245, GS-441524, DEP remdesivir, ATV-006, deuterated remdesivir (VV-116), LGN-20, CMX-521, SHEN-26, MB-905, and compounds disclosed in WO2022142477, WO2021213288, and WO2022047065.

[0704] In some implementations, the adjunctive treatment is an RNA polymerase inhibitor, such as monoupivir (EIDD-2801), favipiravir, bemnifosbuvir, sofosbuvir, ASC-10, or galidivir.

[0705] In some implementations, the additional treatment is a viral entry inhibitor, such as brilacidin.

[0706] In some implementations, the additional therapeutic agent is an antibody that binds to the coronavirus, such as an antibody that binds to SARS or MERS.

[0707] In some implementations, the adjunctive therapeutic agent is an antibody, such as a monoclonal antibody. For example, adjunctive therapeutic agents are antibodies against SARS-CoV-2, neutralizing nanobodies, antibodies targeting the SARS-CoV-2 spike protein, fusion proteins, multispecific antibodies, and antibodies capable of neutralizing SARS-CoV-2 (SARS-CoV-2 neutralizing antibodies).

[0708] In some implementations, the adjunctive therapeutic agent is an antibody that targets a specific site on ACE2. In some implementations, the adjunctive therapeutic agent is a peptide that targets the SARS-CoV-2 spike protein (S-protein).

[0709] In some implementations, the additional treatment is a SARS-CoV-2 virus antibody.

[0710] In some implementations, the antibodies are ABBV-47D11, COVI-GUARD (STI-1499), C144-LS+C135-LS, DIOS-202, DIOS-203, DIOS-301, DXP-604, JMB-2002, LY-CovMab, bamlanivimab (LY-CoV555), GIGA-2050, and IBI-314. S309, SAB-185, etesevimab (CB6), COR-101, JS016, VNAR, VIR-7832 and / or sotramab (VIR-7831), camrevimab + edevimab (REGN-COV2 or REGN10933+RGN10987), BAT2020, BAT2019, 47D11, YBSW-015 or PA-001.

[0711] In some implementations, the additional treatment agent is STI-9199 (COVI-SHIELD), STI-9167, or AR-701 (AR-703 and AR-720).

[0712] In some implementations, adjunctive treatments include BRII-196, BRII-198, ADG-10, adintrevimab (ADG-20), ABP-300, BA-7208, BI-767551, BHV-1200, CT-P63, JS-026, sotraza (GSK-4182136), tesaxagvirimab + cigavir (AZD-7442), regdanvimab, SAB-301, AOD-01, plutavimab (COVI-AMG), 9MW-3311 (MW-33), DXP-593, BSVEQAb, and anti-SARS-CoV-2. IgY, COVID-EIG, CSL-760, F-61, REGN-3048-3051, SARS-CoV-2 monoclonal antibody (COVID-19, ADM-03820), enzovir (enuzovimab) (HFB-30132A), INM-005, SCTA01, TY-027, XAV-19, abavirin + romixisvir, SCTA-01, bebtelovimab, belugavir (beludavimab), IBI-O12 3. IGM-6268, FYB-207, FS-2101, RBT-0813, REGN-14256, REGN-14284, SPKM-001, XVR-011, TB202-3, TB181-36, TB339-031, L MN-301, LQ-050, COVAB-36, MAD-0004J08, STI-2099, TATX-03, TZLS-501, ZCB-11, AZD-3152, VYD-222, XVR-012 or ACV-200-17.

[0713] In some implementations, the adjunctive therapeutic agent is an engineered ACE-2-IgG1-Fc fusion protein that targets the SARS-CoV-2 RBD, such as EU-129 or a bivalent ACE2-IgG Fc zero fusion protein (SI-F019).

[0714] In some implementations, the additional therapeutic agent is an ACE2-Fc receptor fusion protein, such as HLX-71.

[0715] In some implementations, the additional treatment is ensovibep.

[0716] In some implementations, the additional therapeutic agent is SYZJ-001.

[0717] In some implementations, the adjunctive treatment is an HIV-1 protease inhibitor, such as ASC-09F (ASC-09 + ritonavir) or lopinavir + ritonavir.

[0718] In some implementations, the additional therapeutic agent is a non-nucleoside reverse transcriptase inhibitor, such as favirine.

[0719] In some implementations, the additional therapeutic agent is a nucleoside reverse transcriptase inhibitor, such as azvudine.

[0720] In some implementations, the adjunctive therapeutic agents are AbbV-990, ABBV-903, 2b-11, 5-aminolevulinic acid phosphate, AGP-600, AGM-380, AIP-502, ALG-150150, BAT-2022, NED-260, burfiralimab, ALG-097431, bardoxolone, BW-PS-119, and clofibrate. Cropsin, CR-405, delcetravir, D4-102-01, D4-102-02, ESFAM-289, ENOB-CV-01, ENOB-CV-11, E IS-10700, EV-300, β-521, GEA-001, SIM-0417, Monupivir, Pan-Corona, Tollovir, Nematvir + Ritonavir (Paxlovid ®JTBC-00201, Favipiravir, Favipiravir + cathepsin inhibitor (TNX-3900), GC-376, Upatalstat, LeSoleil-01, LeSoleil-02+, Benfovir, VV-116, VV-993, SNB-01, EDP-235, Cov-X, Enstevir, MPI-8, Macitinib, ALG-097558, ASC-11, PBI-0451, Naphamostat, Naphamostat Mesylate, CDI-45205, LHP-803 (COR-803), ALG-097111, BC-201, SH-879. CDI-873, CDI-988, Remdesivir, NV-CoV-2-R, NV-CoV-1-encapsulated Remdesivir, NA-831+ Remdesivir, DEP Remdesivir, GS-621763, GS-5245, GLS-5310, Benifosbuvir, QLS-1128, ASC-10, SBFM-PL4, Carmostat Mesylate, UCI-1, FB-2001 (DC-402234), Ebuselenium, 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, Bempidil, MXB-004, Iracycline, GRL-0617, GST-HG171, GST-HG171+ritonavir, Carmostat, GC-373, KD-1, Nizoralide, Cinnarizine, Precreser, PL-M, RAY-1216, SACT-COVID-19, MP-18, EIDD-1931, EDDC-2214, Nitric Oxide, Apabelon, AnQlar, SBK-001, LQ-050, CG-SpikeDown, Barnivir, JTBC-00101 HLX-71, HT-002, HY-209, HY-3000, HSC-1553, FYB-207, Ensovip, SYZJ-001, EU-129, Nymifine, JN-2019 (KG-2019), LCB-99, AR-701, Vostesyl, PLM-402, PJS-539, CTB-ACE2, TB181-36, TB202-3, ABP-300, XVR-011, MSP-008-22, MU-UNMC-1, MU-UNMC-2, MIC-1930, MLT-103, Mpro inhibitor (Anixa)Biosciences), PBF-4554, alunase α, VP-01, TRV-027, DX-600, TXA-127, NVX-CoV2515, raphamin, RCYM-002, RCYM-003, riamilovir, SARS-CoV-2 PL pro inhibitor (Enanta), SBP-502, SM-4, STB-R040, THY-01, toznamil, elassomil, Ad5-nCoV, BBIBP-CorV, CoronaVac, MVC-COV1901, NVX-CoV2373, sotrometaclopramide, Sputnik V, TEE-001, Tyme-19, Vaxzevria, XW-001, ZF-2001 or ZyCoV-D.

[0721] Any compound of the present invention can also be combined with one or more additional active therapeutic agents in a single dosage form for simultaneous or sequential administration to a patient. Combination therapy can be administered as a simultaneous or sequential regimen. When administered sequentially, the combination can be administered in two or more doses.

[0722] Co-administration of the compound of the present invention with one or more other active therapeutic agents generally refers to the simultaneous or sequential administration of the compound of the present invention and one or more other active therapeutic agents, such that therapeutically effective amounts of the compound of the present invention and one or more other active therapeutic agents are present in the patient.

[0723] Co-administration includes administering a unit dose of the compound of the present invention before or after administering a unit dose of one or more other active therapeutic agents, for example, administering the compound of the present invention within seconds, minutes, or hours of administering one or more other active therapeutic agents. For example, a unit dose of the compound of the present invention may be administered first, followed by a unit dose of one or more other active therapeutic agents within seconds or minutes. Alternatively, a unit dose of one or more other therapeutic agents may be administered first, followed by a unit dose of the compound of the present invention within seconds or minutes. In some cases, it may be necessary to administer a unit dose of the compound of the present invention first, followed by a unit dose of one or more other active therapeutic agents several hours (e.g., 1-12 hours). In other cases, it may be necessary to administer a unit dose of one or more other active therapeutic agents first, followed by a unit dose of the compound of the present invention several hours (e.g., 1-12 hours).

[0724] Combination therapy can provide “synergistic” or “synergistic” effects, meaning that the combined effect of active ingredients is greater than the sum of the effects of using the compounds alone. Synergistic effects are achieved when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combination formulation; (2) delivered alternately or in parallel as individual formulations; or (3) through some other protocol. Synergistic effects are achieved when delivered in alternating therapy, such as in separate tablets, pills, or capsules, or by different injection sequences in separate syringes. Generally, in alternating therapy, each active ingredient is administered in an effective dose sequentially (i.e., consecutively), while in combination therapy, two or more active ingredients are administered together in effective doses. A synergistic antiviral effect indicates that the antiviral effect is greater than the predicted additive effect of the individual compounds in the combination.

[0725] IX. Implementation Examples

[0726] Example 1: Indole-1,3-dicarboxylic acid O1-[[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2, [4] Triazine-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methyl ester] O3-methyl ester (Compound 1)

[0727]

[0728] A stirred suspension of N'-[7-[(4R,6R,6aR)-4-cyano-6-(hydroxymethyl)-2,2-dimethyl-6,6a-dihydro-3aH-furano[3,4-d][1,3]dioxacyclopenten-4-yl]pyrrolo[2,1-f][1,2,4]triazin-4-yl]-N,N-dimethylformamidinium (200 mg, 0.52 mmol) and bis(2,5-dioxopyrrolidine-1-yl) carbonate (265 mg, 1.04 mmol) in acetonitrile (2 mL) was treated with triethylamine (0.29 mL, 2.07 mmol) at room temperature and stirred for another 1 hour. The resulting homogeneous reaction mixture was treated with methyl 1H-indole-3-carboxylate (181 mg, 1.04 mmol), followed by treatment with 4-dimethylaminopyridine (63 mg, 0.52 mmol), and stirred for 16 hours. The reaction mixture was concentrated to give crude intermediate d, which was used directly in the next step without further purification.

[0729] The crude intermediate d was treated with concentrated HCl (0.43 mL, 5.18 mmol) in 3 mL of THF and stirred for 16 hours. The reaction mixture was alkalized with saturated sodium bicarbonate solution and then extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over MgSO4, concentrated, and the resulting crude residue was purified by rapid column chromatography using dichloromethane and methanol as eluents to give compound 1. ¹H NMR (400MHz, DMSO-d6) δ 8.20 (s, 1H), 8.17 – 8.05 (m, 2H), 7.81 (s, 3H), 7.48 – 7.34 (m, 2H), 6.87 – 6.80 (m, 2H), 6.37 (d, J = 6.0Hz, 1H), 5.51 (d, J = 5.6Hz, 1H), 4.87 – 4.74 (m, 2H), 4.62 (dd, J = 12.0, 5.0Hz, 1H), 4.45 (ddd, J = 7.9, 5.0, 3.0Hz, 1H), 4.19 (q, J = 5.7Hz, 1H), 3.88 (s, 3H). LCMS: MS m / z: 493.1 (M+1).

[0730] Example 2: Indole-1,3-dicarboxylic acid O1-[[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2, 4] Triazine-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methyl ester] O3-tetrahydropyran-4-yl ester (Compound 2)

[0731]

[0732] Compound 2 was synthesized in a similar manner to compound 1 in Example 1, by replacing methyl 1H-indole-3-carboxylate with tetrahydropyran-4-yl 1H-indole-3-carboxylate. ¹H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 8.19–8.03 (m, 2H), 7.98–7.73 (m, 3H), 7.48–7.34 (m, 2H), 6.92–6.80 (m, 2H), 6.37 (d, J = 6.1 Hz, 1H), 5.61–5.49 (m, 1H), 5.22–5.14 (m, 1H), 4.88–4.76 (m, 2H), 4.64 (dd, J = 12.0 Hz, 1H). 5.3Hz, 1H), 4.51 – 4.43 (m, 1H), 4.24 –4.14 (m, 1H), 3.92 – 3.81 (m, 2H), 3.61 – 3.49 (m, 2H), 2.04 – 1.95 (m, 2H),1.80 – 1.64 (m, 2H). LCMS: MS m / z: 563.1 (M+1).

[0733] Synthesis of 1H-indole-3-carboxylic acid tetrahydropyran-4-yl ester

[0734] A stirred suspension of 1H-indole-3-carboxylic acid (500 mg, 3.1 mmol) and KOH (174 mg, 3.1 mmol) in DMF (18 mL) was heated at 80 °C for 3 hours, cooled to 50 °C, and then treated with 4-bromotetrahydropyran (0.38 mL, 3.4 mmol) and stirred for 16 hours. The reaction mixture was cooled to room temperature and quenched by adding water (18 mL), and extracted with diethyl ether (3 × 40 mL). The combined organic layers were washed with water (3 × 40 mL), dried over MgSO4, concentrated, and the crude residue was purified by rapid column chromatography using ethyl acetate and hexane as eluents to give 1H-indole-3-carboxylic acid tetrahydropyran-4-yl ester.

[0735] Example 3: 6-Methoxyindole-1,3-dicarboxylic acid O1-[[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2, [1-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methyl ester]O3-methyl ester (compound 3)

[0736]

[0737] Compound 3 was synthesized in a similar manner to compound 1 in Example 1, using methyl 6-methoxy-1H-indole-3-carboxylate instead of methyl 1H-indole-3-carboxylate. ¹H NMR (400 MHz, DMSO-d6) δ 8.09 (s, 1H), 7.98–7.75 (m, 4H), 7.69 (d, J = 2.3 Hz, 1H), 7.04 (dd, J = 8.7, 2.4 Hz, 1H), 6.87–6.81 (m, 2H), 6.38 (d, J = 6.1 Hz, 1H), 5.51 (d, J = 5.6 Hz, 1H), 4.86–4.78 (m, 2H), 4.59 (dd, J = 11.9, 5.4 Hz, 1H), 4.50 – 4.43 (m, 1H), 4.19 (q, J =5.7Hz, 1H), 3.87 (s, 3H), 3.79 (s, 3H). LCMS: MS m / z: 523.1 (M+1).

[0738] Example 4: (4S)-4-benzyl-2-oxo-oxazolidine-3-carboxylic acid [(2R,3S,4R,5R)-5-(4-aminopyrrole)] [2,1-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methyl ester (compound 4)

[0739]

[0740] Compound 4 was synthesized in a similar manner to compound 1 in Example 1, by replacing methyl 1H-indole-3-carboxylate with (4S)-4-benzyloxazolidin-2-one. ¹H NMR (400 MHz, DMSO-d6) δ 8.23 ​​– 7.90 (m, 3H), 7.79 (s, 1H), 7.36 – 7.13 (m, 10H), 6.94 (d, J = 4.6 Hz, 1H), 6.84 (d, J = 4.6 Hz, 1H), 4.79 (d, J = 5.1 Hz, 1H), 4.57 – 4.22 (m, 6H), 4.14 (dd, J = 8.7, 2.9 Hz, 1H), 4.10 – 4.02 (m, 2H), 3.98 (dd, J = 8.7, 2.9 Hz, 1H), 3.98 (dd, J = 8.7, 2.9 Hz, 1H). 8.3, 5.4Hz, 1H), 3.05 – 2.88 (m, 2H), 2.87 – 2.71 (m, 2H). LCMS: MS m / z: 495.1.

[0741] Example 5: (4R)-2-oxooxazolidine-3,4-dicarboxylic acid O3-[[(2R,3S,4R,5R)-5-(4-aminopyrrole)] [2,1-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methyl ester]O4-methyl ester (compound) Object 5)

[0742]

[0743] Compound 5 was synthesized in a manner similar to that of compound 1 in Example 1, by replacing methyl 1H-indole-3-carboxylate with methyl (4R)-2-oxooxazolidine-4-carboxylate. ¹H NMR (400 MHz, DMSO-d6) δ 8.13 – 7.77 (m, 3H), 6.91 (d, J = 4.6 Hz, 1H), 6.79 (d, J = 4.5 Hz, 1H), 6.36 (d, J = 6.1 Hz, 1H), 5.45 (d, J = 5.6 Hz, 1H), 4.93 (dd, J = 9.4, 3.4 Hz, 1H), 4.73 (t, J = 5.6 Hz, 1H), 4.57 (t, J = 9.2 Hz, 1H), 4.53 – 4.41 (m, 2H). 4.41 – 4.30 (m,1H), 4.29 – 4.19 (m, 1H), 4.09 – 3.93 (m, 1H), 3.70 (s, 3H). LCMS: MS m / z: 463.1 (M+1).

[0744] Example 6: ((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methoxy)carbonyl)-L-valine (compound 6)

[0745]

[0746] Compound 6 was synthesized in a similar manner to compound 1 in Example 1, using L-valine instead of methyl 1H-indole-3-carboxylate. ¹H NMR (400MHz, DMSO-d6) δ 8.13 – 7.73 (m, 3H), 6.97 (d, J = 4.6Hz, 1H), 6.83 (d, J = 4.6Hz, 1H), 6.23 (d, J = 7.9Hz, 1H), 4.69 (d, J = 5.0Hz, 1H), 4.32 – 4.14 (m, 1H), 4.06 (dd, J = 11.1, 6.0Hz, 1H), 3.91 (s, 1H), 3.55 (dd, J = 7.5, 4.1Hz, 1H), 2.04 (s, 1H). 0.89 – 0.70 (m, 6H). LCMS: MS m / z: 435.1 (M+1).

[0747] Example 7: ((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano 3,4-Dihydroxytetrahydrofuran-2-yl)methoxy)carbonyl)-L-valine isopropyl ester (Compound 7)

[0748]

[0749] Compound 7 was synthesized in a similar manner to compound 1 in Example 1, using L-valine isopropyl ester instead of methyl 1H-indole-3-carboxylate. ¹H NMR (400MHz, DMSO-d6) δ 8.02 – 7.81 (m, 3H), 7.63 (d, J = 8.1Hz, 1H), 6.92 (d, J = 4.6Hz, 1H), 6.83 (d, J = 4.5Hz, 1H), 6.28 (d, J = 6.1Hz, 1H), 5.38 (d, J = 5.8Hz, 1H), 5.00 – 4.87 (m, 1H), 4.67 (t, J = 5.5Hz, 1H), 4.34 (dd, J = 12.0, 2.7Hz, 1H), 4.21 (td, J = 12.0, 2.7Hz, 1H). 6.9, 2.7Hz, 1H), 4.08 (dd,J = 12.0, 7.1Hz, 1H), 3.92 – 3.79 (m, 2H), 2.10 – 1.97 (m, 1H), 1.27 – 1.15(m, 6H), 1.14 – 1.08 (m, 1H), 0.95 – 0.81 (m, 6H). LCMS: MS m / z: 477.2 (M+1).

[0750] Example 8: N-Isopropylcarbamic acid [(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]] [Triazine-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methyl ester (Compound 8)

[0751]

[0752] Compound 8 was synthesized in a similar manner to compound 1 in Example 1, by replacing methyl 1H-indole-3-carboxylate with propan-2-amine. ¹H NMR (400MHz, DMSO-d6) δ 8.56 – 8.37 (m, 1H), 8.34 – 8.16 (m, 1H), 8.03 (s, 1H), 7.16 (d, J = 7.7Hz, 1H), 7.05 (d, J = 4.5Hz, 1H), 6.90 – 6.80 (m, 1H), 4.65 (d, J = 5.0Hz, 1H), 4.34 – 4.27 (m, 1H), 4.24 – 4.16 (m, 2H), 4.06 – 3.99 (m, 1H), 3.93 – 3.87 (m, 2H). 1H), 1.28 (d, J = 7.0Hz, 3H), 1.01 (d, J = 6.5Hz, 3H). LCMS: MS m / z: 377.1 (M+1).

[0753] Example 9: Azoalkyl-1-carboxylic acid [(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]tri] [Azine-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methyl ester (Compound 9)

[0754]

[0755] Compound 9 was synthesized by replacing methyl 1H-indole-3-carboxylate with azoane in a manner similar to that of compound 1 in Example 1. ¹H NMR (400MHz, DMSO-d6) δ 7.99 – 7.81 (m, 3H), 6.91 (d, J = 4.5Hz, 1H), 6.79 (d, J = 4.5Hz, 1H), 6.29 (d, J = 6.0Hz, 1H), 5.36 (d, J = 5.8Hz, 1H), 4.73 – 4.67 (m, 1H), 4.32 – 4.14 (m, 3H), 3.98 (q, J = 5.8Hz, 1H), 3.32– 3.26 (m, 1H), 3.26 – 3.18 (m, 2H), 1.63 – 1.38 (m, 10H). LCMS: MS m / z: 431.1(M+1).

[0756] Example 10: Pyrrole-1,2-dicarboxylic acid O1-[[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1, [2,4]triazine-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methyl ester]O2-ethyl ester (compound 10)

[0757]

[0758] Compound 10 was synthesized in a manner similar to that of compound 1 in Example 1, using ethyl 1H-pyrrole-2-carboxylate instead of methyl 1H-indole-3-carboxylate. ¹H NMR (400MHz, DMSO-d6) δ 8.01 – 7.80 (m, 3H), 7.38 (dd, J = 3.1, 1.6Hz, 1H), 6.92 (dd, J = 3.5, 1.7Hz, 1H), 6.87 (d, J = 4.5Hz, 1H), 6.78 (d, J = 4.5Hz, 1H), 6.35 (d, J = 6.1Hz, 1H), 6.31 (t, J = 3.3Hz, 1H), 5.47 (d, J = 5.8Hz, 1H), 4.81 – 4.73 (m, 1H). 4.64 (dd, J = 12.0, 2.9Hz,1H), 4.49 (dd, J = 12.0, 5.7Hz, 1H), 4.35 (td, J = 6.2, 2.8Hz, 1H), 4.19 (qd,J = 7.1, 1.0Hz, 2H), 4.10 – 4.01 (m, 1H), 1.22 (t, J = 7.1Hz, 3H). LCMS: MS m / z: 457.1 (M+1).

[0759] Example 11: 1,1-Dioxo-1,4-thiazinane-4-carboxylic acid [(2R,3S,4R,5R)-5-(4-aminopyrrolo)] [2,1-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methyl ester (compound 11)

[0760]

[0761] Compound 11 was synthesized in a similar manner to compound 1 in Example 1, by replacing methyl 1H-indole-3-carboxylate with 1,4-thiazine 1,1-dioxide. ¹H NMR (400 MHz, DMSO-d6) δ 8.03 – 7.75 (m, 3H), 6.95– 6.89 (m, 1H), 6.86 – 6.77 (m, 1H), 6.34 (d, J = 6.0 Hz, 1H), 5.39 (t, J = 5.9 Hz, 1H), 4.76 – 4.66 (m, 1H), 4.40 – 4.15 (m, 3H), 3.99 (qd, J = 6.1, 3.0 Hz, 1H), 3.85 – 3.65 (m, 2H), 3.15 (s, 4H), 3.06 (dd, J = 7.0, 3.5Hz, 1H), 3.00 – 2.92 (m, 1H). LCMS: MS m / z: 453.1 (M+1).

[0762] Example 12: Isoxazolidine-2-carboxylic acid [(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]] [Triazine-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methyl ester (Compound 12)

[0763]

[0764] Compound 12 was synthesized by replacing methyl 1H-indole-3-carboxylate with isoxazolidine hydrochloride in a manner similar to that of compound 1 in Example 1. ¹H NMR (400 MHz, DMSO-d6) δ 8.05 – 7.79 (m, 3H), 6.91 (d, J = 4.5 Hz, 1H), 6.84 (d, J = 4.6 Hz, 1H), 6.34 (dd, J = 6.0, 3.8 Hz, 1H), 5.39 (d, J = 5.8 Hz, 1H), 4.67 (dd, J = 6.0, 4.8 Hz, 1H), 4.40 – 4.32 (m, 1H), 4.29 – 4.20 (m, 2H), 4.00 – 3.92 (m, 1H), 3.83 – 3.76 (m, 2H), 3.57 – 3.48 (m, 2H), 2.21 – 2.11 (m, 2H). LCMS: MS m / z: 391.1 (M+1).

[0765] Example 13: Piperidine-1-carboxylic acid [(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine- [7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methyl ester (compound 13)

[0766]

[0767] Compound 13 was synthesized in a manner similar to that of compound 1 in Example 1, using piperidine instead of methyl 1H-indole-3-carboxylate. ¹H NMR (400 MHz, DMSO-d6) δ 7.94 (s, 2H), 6.93 (d, J = 4.5 Hz, 1H), 6.78 (d, J = 4.5 Hz, 1H), 4.67 (d, J = 4.8 Hz, 1H), 4.31 (dd, J = 12.1, 2.8 Hz, 1H), 4.26 – 4.18 (m, 1H), 4.12 (dd, J = 12.1, 4.6 Hz, 1H), 4.00 – 3.92 (m, 1H), 3.27 (d, J = 6.7 Hz, 3H), 1.65 – 1.33 (m, 6H). LCMS: MS m / z: 403.1 (M+1).

[0768] Example 14: Propylthiocarbamate [(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]tri] [Azine-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methyl ester (Compound 14)

[0769]

[0770] Compound 14 was synthesized by replacing methyl 1H-indole-3-carboxylate with propane-1-thiol, similar to compound 1 in Example 1. ¹H NMR (400 MHz, DMSO-d6) δ 8.03 – 7.80 (m, 3H), 6.92 (d, J = 4.5 Hz, 1H), 6.79 (d, J = 4.5 Hz, 1H), 6.36 (d, J = 6.0 Hz, 1H), 5.42 (d, J = 5.8 Hz, 1H), 4.68 (dd, J = 6.0, 4.9 Hz, 1H), 4.53 (dd, J = 12.0, 2.8 Hz, 1H), 4.34 (dd, J = 12.0, 5.5 Hz, 1H), 4.24 (ddd, J = 8.3, 5.5, 2.7Hz, 1H), 3.97 –3.88 (m, 1H), 2.83 (td, J = 7.0, 1.1Hz, 2H), 1.59 (q, J = 7.2Hz, 2H), 0.92(t, J = 7.3Hz, 3H). LCMS: MS m / z: 394.1 (M+1).

[0771] Example 15: Ethylthiocarbamic acid [(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]tri] [Azine-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methyl ester (Compound 15)

[0772]

[0773] Compound 15 was synthesized in a manner similar to that of compound 1 in Example 1, using ethyl mercaptan instead of methyl 1H-indole-3-carboxylate. ¹H NMR (400MHz, DMSO-d6) δ 8.02 – 7.80 (m, 3H), 6.91 (d, J = 4.5Hz, 1H), 6.79 (d, J = 4.6Hz, 1H), 6.35 (d, J = 6.0Hz, 1H), 5.42 (d, J = 5.9Hz, 1H), 4.74 – 4.62 (m, 1H), 4.53 (dd, J = 12.1, 2.8Hz, 1H), 4.34 (dd, J = 12.0, 5.7Hz, 1H), 4.29 – 4.19 (m, 1H), 4.19 – 4.10 (m, 0H), 4.02 – 3.92 (m, 1H), 2.85 (q, J = 7.3Hz, 2H), 1.28 – 1.20 (m, 3H). LCMS: MS m / z: 380.0 (M+1).

[0774] Example 16: Cyclopentylthiocarboxylic acid [(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]tri] [Azine-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methyl ester (Compound 16)

[0775]

[0776] Compound 16 was synthesized in a manner similar to that of compound 1 in Example 1, by replacing methyl 1H-indole-3-carboxylate with cyclopentanethiol. ¹H NMR (400MHz, DMSO-d6) δ 8.02 – 7.81 (m, 3H), 6.92 (d, J = 4.5Hz, 1H), 6.79 (d, J = 4.5Hz, 1H), 6.35 (d, J = 6.0Hz, 1H), 5.42 (d, J = 5.8Hz, 1H), 4.72 – 4.64 (m, 1H), 4.53 (dd, J = 12.1, 2.8Hz, 1H), 4.32 (dd, J = 12.0, 5.4Hz, 1H), 4.27 – 4.19 (m, 1H), 3.93 (q, J = 5.9Hz, 1H), 3.62 – 3.49 (m, 1H), 2.13 – 1.97 (m, 4H), 1.74 – 1.44 (m, 4H). LCMS: MS m / z: 420.1 (M+1).

[0777] Example 17: tert-butylthiocarboxylic acid [(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]tri] [Azine-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methyl ester (Compound 17)

[0778]

[0779] A solution of N'-[7-[(3aR,4R,6R,6aR)-4-cyano-6-(hydroxymethyl)-2,2-dimethyl-6,6a-dihydro-3aH-furano[3,4-d][1,3]dioxacyclopenten-4-yl]pyrrolo[2,1-f][1,2,4]triazin-4-yl]-N,N-dimethylformamidinium (150 mg, 0.39 mmol), 4-dimethylaminopyridine (47.4 mg, 0.39 mmol), and pyridine (0.09 mL, 1.16 mmol) in dichloromethane (4 mL) was treated at room temperature with S-tert-butyl chlorothiocarbamate (89 mg, 0.58 mmol) and stirred for 16 hours. The reaction mixture was quenched with water (4 mL) and extracted with dichloromethane (3 × 10 mL). The combined organic layers were dried with MgSO4 and then concentrated to obtain crude intermediate c, which was used directly in the next step without further purification.

[0780] The crude intermediate c was treated with concentrated HCl (0.48 mL, 5.82 mmol) at room temperature and stirred for 3.5 hours, then quenched and alkalized with saturated sodium bicarbonate solution. The biphase mixture was extracted with EtOAc (3 × 10 mL), and the combined organic layers were dried over MgSO4 and then concentrated. The crude residue was purified by rapid column chromatography using methanol and dichloromethane to give compound 17. ¹H NMR (400MHz, DMSO-d6) δ 8.07–7.74 (m, 3H), 6.92 (d, J = 4.5Hz, 1H), 6.79 (d, J = 4.6Hz, 1H), 6.35 (d, J = 6.0Hz, 1H), 5.41 (d, J = 5.8Hz, 1H), 4.74–4.61 (m, 1H), 4.52 (dd, J = 11.8, 2.6Hz, 1H), 4.32–4.15 (m, 2H), 3.92 (q, J = 5.9Hz, 1H), 1.44 (s, 9H). LCMS: MS m / z: 408.1 (M+1).

[0781] Example 18: Acetic acid [(2R,3R,4R,5R)-4-acetoxy-5-(4-aminopyrrolo[2,1-f][1,2,4]] [Triazine-7-yl)-5-cyano-2-(isopropylcarbamoyloxymethyl)tetrahydrofuran-3-yl ester] (Compound 18)

[0782]

[0783] A solution of N-isopropylcarbamate [(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methyl ester (150 mg, 0.31 mmol) and 4-dimethylaminopyridine (112 mg, 0.92 mmol) in THF (3 mL) was treated with acetic anhydride (62.5 mg, 0.61 mmol) at room temperature and stirred for 1 hour. The reaction mixture was quenched by adding saturated ammonium chloride aqueous solution (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over MgSO4, concentrated, and the resulting crude residue was purified by rapid column chromatography using a reversed-phase C18 column with acetonitrile and water as eluent and 0.1% TFA to give compound 18. ¹H NMR (400MHz, DMSO-d6) δ 8.61 – 8.19 (m, 2H), 8.04 (s, 1H), 7.19 (d, J = 7.8Hz, 1H), 7.05 (d, J = 4.6Hz, 1H), 6.86 (d, J = 4.6Hz, 1H), 6.01 (d, J = 6.0Hz, 1H), 5.76 (s, 1H), 5.33 (t, J = 5.6Hz, 1H), 4.52 (d, J = 4.3Hz, 1H), 4.43 –4.35 (m, 1H), 4.17 – 4.09 (m, 1H), 3.56 (h, J = 6.7Hz, 1H), 2.21 – 2.07 (m,6H), 1.09 – 0.97 (m, 6H). LCMS: MS m / z: 461.1 (M+1).

[0784] Example 19: Azoalkyl-1-carboxylic acid [(2R,3R,4R,5R)-3,4-diacetoxy-5-(4-aminopyrrolo)] [2,1-f][1,2,4]triazine-7-yl)-5-cyano-tetrahydrofuran-2-yl]methyl ester (compound 19)

[0785]

[0786] Compound 19 was synthesized in a manner similar to that of compound 18 in Example 18, by replacing N-isopropylcarbamate [(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methyl ester. ¹H NMR (400 MHz, DMSO-d6) δ 8.12 – 7.90 (m, 3H), 6.93 (d, J = 4.6 Hz, 1H), 6.77 (d, J = 4.6 Hz, 1H). 1H), 6.04(d, J = 5.9Hz, 1H), 5.43 (dd, J = 5.9, 4.3Hz, 1H), 4.60 (q, J = 3.9Hz, 1H), 4.28 (qd, J = 12.3, 3.7Hz, 2H), 3.31 – 3.19 (m, 4H), 2.15 – 2.09 (m, 6H), 1.66 – 1.34 (m, 10H). LCMS: MS m / z: 515.0 (M+1).

[0787] Example 20: Pyrrole-1,2-dicarboxylic acid O1-[[(2R,3R,4R,5R)-3,4-diacetoxy-5-(4-aminopyridine) [2,1-f][1,2,4]triazine-7-yl)-5-cyano-tetrahydrofuran-2-yl]methyl ester]O2-ethyl ester (compound 20)

[0788]

[0789] Compound 20 was synthesized in a manner similar to that of compound 18 in Example 18, using pyrrolo-1,2-dicarboxylic acid O1-[[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methyl ester]O2-ethyl ester instead of N-isopropylcarbamate [(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methyl ester. ¹H NMR (400MHz, DMSO-d6) δ 8.00 (d, J = 26.4Hz, 2H), 7.75 (s, 1H), 7.49 – 7.38 (m, 1H), 7.00– 6.87 (m, 2H), 6.82 (d, J = 4.6Hz, 1H), 6.34 (t, J = 3.4Hz, 1H), 6.22 (d, J= 6.1Hz, 1H), 5.53 (t, J = 5.3Hz, 1H), 4.82 – 4.65 (m, 2H), 4.65 – 4.50 (m,1H), 4.17 (tt, J = 7.8, 4.0Hz, 2H), 2.23 – 2.06 (m, 6H), 1.20 (t, J = 7.1Hz, 3H). LCMS: MS m / z: 540.9 (M+1).

[0790] Example 21: Piperidine-1-carboxylic acid [(2R,3R,4R,5R)-3,4-diacetoxy-5-(4-aminopyrrolo[2, 1-f][1,2,4]triazine-7-yl)-5-cyano-tetrahydrofuran-2-yl]methyl ester (compound 21)

[0791]

[0792] Compound 21 was synthesized in a manner similar to that of compound 18 in Example 18, using piperidine-1-carboxylic acid [(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methyl ester instead of N-isopropylcarbamate [(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methyl ester. ¹H NMR (400MHz, DMSO-d6) δ 8.10 –7.87 (m, 3H), 6.94 (d, J = 4.6Hz, 1H), 6.76 (d, J = 4.6Hz, 1H). 1H), 6.03 (d, J =5.7Hz, 1H), 5.41 (dd, J = 5.7, 4.5Hz, 1H), 4.61 (q, J = 3.8Hz, 1H), 4.40 –4.15 (m, 2H), 3.30 – 3.19 (m, 4H), 2.16 – 2.10 (m, 6H), 1.55 – 1.46 (m, 2H), 1.45 – 1.30 (m, 4H). LCMS: MS m / z: 487.1 (M+1).

[0793] Example 22: Acetic acid [(2R,3R,4R,5R)-4-acetoxy-5-(4-aminopyrrolo[2,1-f][1,2,4]] [Triazine-7-yl)-5-cyano-2-(propylthiocarbonyloxymethyl)tetrahydrofuran-3-yl ester] (Compound 22)

[0794]

[0795] Compound 22 was synthesized in a manner similar to that of compound 18 in Example 18, using methyl propylthiocarbamate [(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl] instead of N-isopropylcarbamate [(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl] methyl. ¹H NMR (400MHz, DMSO-d6) δ 8.45–8.14 (m, 2H), 8.01 (s, 1H), 7.02 (d, J = 4.6Hz, 1H), 6.82 (d, J = 4.6Hz, 1H), 6.05 (d, J = 5.9Hz, 1H), 5.39 (dd, J = 5.9, 4.7Hz, 1H), 4.71 – 4.53 (m, 2H), 4.43 (dd, J = 12.1, 4.6Hz, 1H), 2.81 (t, J = 7.1Hz, 2H), 2.15 – 2.09 (m, 6H), 1.56 (h, J = 7.3Hz, 2H), 0.90 (t, J = 7.4Hz, 3H). LCMS: MS m / z: 478.1 (M+1).

[0796] Example 23: Acetic acid [(2R,3R,4R,5R)-4-acetoxy-5-(4-aminopyrrolo[2,1-f][1,2,4]] [Triazine-7-yl)-5-cyano-2-(ethylthiocarbonyloxymethyl)tetrahydrofuran-3-yl ester] (Compound 23)

[0797]

[0798] Compound 23 was synthesized in a manner similar to that of compound 18 in Example 18, using methyl ethylthiocarbamate [(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl] instead of N-isopropylcarbamate [(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl] methyl ester. ¹H NMR (400MHz, DMSO-d6) δ 8.37–8.08 (m, 2H), 7.99 (s, 1H), 7.00 (d, J = 4.6Hz, 1H), 6.82 (d, J = 4.6Hz, 1H), 6.05 (d, J = 5.9Hz, 1H), 5.39 (dd, J = 5.9, 4.7Hz, 1H), 4.68 – 4.51 (m, 2H), 4.44 (dd, J = 12.1, 4.7Hz, 1H), 2.83 (q, J = 7.3Hz, 2H), 1.21 (t, J = 7.3Hz, 3H). LCMS: MS m / z: 464.0 (M+1).

[0799] Example 24: Acetic acid [(2R,3R,4R,5R)-4-acetoxy-5-(4-aminopyrrolo[2,1-f][1,2,4]] [Triazine-7-yl)-2-(tert-butylthiocarbonyloxymethyl)-5-cyano-tetrahydrofuran-3-yl ester] (Compound 24)

[0800]

[0801] Compound 24 was synthesized in a manner similar to that of compound 18 in Example 18, using tert-butylthiocarbamate [(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methyl ester instead of N-isopropylcarbamate [(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methyl ester. ¹H NMR (400MHz, DMSO-d6) δ 8.40 – 8.12 (m, 2H), 8.01 (s, 1H), 7.01 (d, J = 4.6Hz, 1H), 6.81 (d, J =4.6Hz, 1H), 6.02 (d, J = 5.9Hz, 1H), 5.37 (dd, J = 5.8, 4.7Hz, 1H), 4.67 –4.52 (m, 2H), 4.39 (dd, J = 12.2, 4.7Hz, 1H), 2.20 – 2.06 (m, 6H), 1.40 (s, 9H). LCMS: MS m / z: 492.0 (M+1).

[0802] Example 25: Acetic acid [(2R,3R,4R,5R)-4-acetoxy-5-(4-aminopyrrolo[2,1-f][1,2,4]] [Triazine-7-yl)-5-cyano-2-(cyclopentylthiocarbonyloxymethyl)tetrahydrofuran-3-yl ester] (Compound 25)

[0803]

[0804] Compound 25 was synthesized in a manner similar to that of compound 18 in Example 18, by replacing N-isopropylcarbamate [(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methyl cyclopentylthiocarbamate. ¹H NMR (400 MHz, chloroform-d) δ 8.04 (s, ¹H), 6.99 (d, J = 4.7 Hz, ¹H), 6.63 (d, J = 4.7 Hz, ¹H), 6.26 (d, J =5.9Hz, 1H), 5.75 – 5.56 (m, 2H), 5.53 – 5.45 (m, 1H), 4.66 – 4.53 (m, 2H), 4.46 (dd, J = 11.7,4.2Hz, 1H), 3.68 – 3.53 (m, 1H), 2.18 – 2.13 (m, 6H), 1.79 – 1.51 (m, 8H). LCMS: MS m / z: 504.1 (M+1).

[0805] Example A: A549-hACE2 SARS-CoV2-NLuc assay in 384 wells

[0806] The A549-hACE2 cell line was maintained in Dulbecco Limit Essential Medium (DMEM) (Corning, New York, NY, Catalogue No. 15-018CM) supplemented with 10% fetal bovine serum (FBS) (Hyclone, Logan, UT, Catalogue No. SH30071-03), 1X penicillin-streptomycin-L-glutamine (Corning, New York, NY, Catalogue No. 30-009-CI), and 10 µg / mL blastomycin (Life Technologies Corporation, Carlsbad, CA, Catalogue No. A11139-03). Cells were passaged twice weekly to maintain subconfluence density and used for experiments at passages 5–20. SARS-CoV-2 (SARS-CoV-2-NLuc), recombinant with NanoLuc, was obtained from the University of Texas Medical Branch (Galveston, TX). Viral replication in A549-hACE2 cells was measured as follows.

[0807] Compounds were prepared in 100% DMSO in 384-well polypropylene plates (Greiner, Monroe, NC, catalog 784201), with 8 compounds per plate, divided into 4 replicates at 10 serial dilutions (1:3). The serially diluted compounds were transferred to low dead volume Echo plates (Labcyte, Sunnyvale, CA, catalog LP-0200).

[0808] The test compound was spotted at 200 nL / well onto a 384-well assay plate (Greiner, Monroe, NC, catalog number 781091) using an Echo dispenser (Labcyte, Sunnyvale, CA). A549-hACE2 cells were harvested and suspended in DMEM (supplemented with 2% FBS and 1X penicillin-streptomycin-L-glutamine), and seeded at 10,000 cells / well in 30 µL of the pre-spotted assay plate. SARS-CoV2-NLuc virus was diluted in DMEM (supplemented with 2% FBS and 1X penicillin-streptomycin-L-glutamine) at 350,000 infectious units (IU) / mL and added at 10 µL / well to the assay plate containing cells and the compound, with an MOI of 0.35. The assay plate was incubated at 37°C and 5% CO2 for 2 days. At the end of incubation, Nano-Glo reagent (Promega, Madison, WI, catalog number N1150) was prepared. The assay plate and Nano-Glo reagent were equilibrated to room temperature for at least 15 minutes. 40 µL / well of Nano-Glo reagent was added, and the plate was incubated at room temperature for 15 minutes before reading the luminescence signal on an EnVision multimode plate reader (Perkin Elmer, Waltham, MA). Remdesivir was used as a positive control, and DMSO was used as a negative control. The values ​​were normalized to positive and negative controls (0% and 100% replication, respectively), and the data were fitted using nonlinear regression analysis using the Gilead dose-response tool. The EC50 values ​​for each compound were then calculated. 50 The value is defined as the concentration that reduces viral replication by 50%.

[0809] Remdesivir :

[0810]

[0811] Example B: NHBE RSV-Luc5 384-well assay

[0812] Normal human bronchial epithelial (NHBE) cells were purchased from Lonza (Walkersville, MD catalog number CC2540) and maintained in BEGM bronchial epithelial cell growth medium Bullet Kit (Lonza CC-3170).

[0813] Cells were thawed, expanded, and used in second-generation experiments. Recombinant respiratory syncytial virus (RSV-Luc5) containing luciferase (…) > 1×10 7 Infectious units / ml (IU / ml), via TCID 50 The assay (test results) was purchased from Microbiologics (SaintCloud, MN). Viral replication in NHBE cells was measured as follows.

[0814] Compounds were prepared in 100% DMSO in 384-well polypropylene plates (Greiner, Monroe, NC, catalog 784201), with 8 compounds per plate, divided into 4 replicates at 10 serial dilutions (1:3). The serially diluted compounds were transferred to low dead volume Echo plates (Labcyte, Sunnyvale, CA, catalog LP-0200).

[0815] The test compound was spotted at 200 nL / well onto a 384-well assay plate (Greiner, Monroe, NC, catalog number 781091). NHBE cells were harvested and suspended in BEGM bronchial epithelial cell growth medium Bullet Kit, and seeded at 30 µL for 5,000 cells / well in a pre-spotted assay plate. RSV-Luc5 was diluted at 500,000 infection units (IU) / mL in BEGM bronchial epithelial cell growth medium Bullet Kit, and 10 µL was added to each well of the assay plate containing cells and the compound, with an MOI of 1. The assay plate was incubated at 37 °C and 5% CO2 for 3 days. At the end of the incubation, the One-Glo reagent (Promega, Madison, WI, catalog number E6120) was prepared. The assay plate and One-Glo reagent were equilibrated to room temperature for at least 15 minutes. Add 40 µL / well of One-Glo reagent, incubate the plate at room temperature for 15 minutes, and then read the luminescence signal on an EnVision multimode plate reader (Perkin Elmer, Waltham, MA). Remdesivir was used as a positive control, and DMSO was used as a negative control. Values ​​were normalized to positive and negative controls (0% and 100% replication, respectively), and the data were fitted using nonlinear regression analysis via Gilead dose-response tool. The EC50 values ​​for each compound were then calculated. 50 The value is defined as the concentration that reduces viral replication by 50%.

[0816] Example C: CC50 MT4

[0817] The cytotoxicity of the compound was determined in uninfected cells using a cell viability reagent in a manner similar to that described previously for other cell types (Cihlar et al., Antimicrob Agents Chemother. 2008, 52(2):655-65). HEp-2 cells (1.5 × 10³ cells / well) and MT-4 cells (2 × 10³ cells / well) were seeded in 384-well plates and incubated with appropriate medium containing serially diluted 3-fold concentrations of the compound (ranging from 15 nM to 100,000 nM). Cells were cultured at 37°C for 4 to 5 days. After incubation, cells were equilibrated to 25°C, and cell viability was determined by adding Cell-TiterGlo viability reagent. The mixture was incubated for 10 minutes, and the luminescent signal was quantified using an Envision microplate reader. Untreated cells and cells treated with 2 μM puromycin (Sigma, St. Louis, MO) served as 100% and 0% cell viability controls, respectively. Relative to the 0% and 100% controls, the percentage of cell viability was calculated for each compound concentration tested, and the concentration of the compound that reduced cell viability by 50% was determined by nonlinear regression. 50 value.

[0818] Table C1

[0819]

[0820] Example D: GI S9 Stability - Phenylmethylsulfonyl fluoride (PMSF) Free :

[0821] Two aliquots of the test compound or positive control substrate (GS-7340) were added to a PMSF-free intestinal S9 fraction diluted with 100 mM phosphate-buffered saline (pH 7.4) to obtain a protein concentration of 1.0 mg / mL. The S9 metabolic reaction was initiated by adding the substrate to a final concentration of 2 µM in the S9 reaction mixture. At 0, 10, 20, 30, 60, and 120 minutes, 25 μL aliquots of the reaction mixture were transferred to a plate containing 225 μL of IS / Q solution. After quenching, the plate was centrifuged at 3000 × g for 30 min, and 150 µL aliquots of each supernatant were diluted with 150 µL of water. The diluted supernatant aliquots (10 μL) were analyzed on a Thermo Q-Exactive mass spectrometer as described below.

[0822] Example E: Plasma Stability

[0823] Two aliquots of plasma were heated to 37°C and a metabolic reaction was initiated by adding either the test compound (6 μL of 0.1 mM MDMSO stock solution) or a plasma stability standard (GS-7340) to obtain a final substrate concentration of 2 µM. At 0.05 h, 0.5 h, 1 h, 2 h, 3 h, and 4 h, 25 μL aliquots of the reaction mixture were transferred to a plate containing 225 μL of IS / Q quenching solution. After quenching, the plate was centrifuged at 3000 × g for 30 min, and 150 µL of the supernatant was diluted with 150 µL of water. Aliquots (10 μL) of the diluted supernatant were analyzed on a Thermo Q-Exactive mass spectrometer as described below.

[0824] Example F: Liver S9 Stability

[0825] Two aliquots of the test compound or positive control substrate (GS-7340) were added to the S9 stock solution diluted with 100 mM potassium phosphate buffer (pH 7.4) to obtain a protein concentration of 2.4 mg / mL. The S9 metabolic reaction was initiated by adding the substrate to a final concentration of 2 µM in the S9 reaction mixture. At 2 min, 12 min, 25 min, 45 min, 65 min, and 90 min, 25 μL aliquots of the reaction mixture were transferred to plates containing 225 μL of IS / Q solution. After quenching, the plates were centrifuged at 3000 × g for 30 min, and 150 µL aliquots of each supernatant were diluted with 150 µL of water. The diluted supernatant aliquots (10 μL) were analyzed on a Thermo Q-Exactive mass spectrometer as described below.

[0826] Example G: Liquid Chromatography / Mass Spectrometry Method for S9 and Plasma Stability

[0827] Quantification of test compounds and controls was performed using analyte / internal standard peak area ratio (PAR) values ​​measured on a Thermo Q-Exactive mass spectrometer coupled with a Dionex UltiMate 3000 HPLC system equipped with a Leap Technologies HTC PAL autosampler. The column used was a Thermo Hypersil GOLD (1.9 μm particle size, 2.1 × 50 mm). Mobile phase A consisted of an aqueous solution of 0.1% (v / v) formic acid. Mobile phase B consisted of an acetonitrile solution of 0.1% (v / v) formic acid. Elution of the analytes was achieved using a linear gradient of acetonitrile in water containing 0.1% (v / v) formic acid. The mass spectrometer was calibrated weekly using a mass tolerance of 5 ppm.

[0828] Table G1

[0829]

[0830] Example H: CACO-2 permeability

[0831] Pre-coated Caco-2 cells (clone C2BBe1) were obtained from Sigma-Aldrich, Inc. (Atlanta, GA). Cell monolayers were grown to confluence on collagen-coated microporous polycarbonate membranes in 24-well transwell plates for 21 days. Permeability assay buffer in donor wells was Hanks' balanced salt solution (HBSS) at pH 6.5 containing 10 mM HEPES and 15 mM glucose, supplemented with 200 µM BNPP. Receiver wells used HBSS buffer at pH 7.4 containing 10 mM HEPES and 15 mM glucose, supplemented with 1% BSA. TEER values ​​were read to test membrane integrity after initial equilibration with transport buffer. Experiments were initiated by adding 200 µL and 1000 µL of buffer containing the test compound to the top and outer basal compartments, respectively. At 0 and 2 hours post-dose, 10 µL samples were taken from the donor compartment and immediately diluted in 190 µL of 20% methanol. At 1 and 2 hours post-administration, 100 µl of solution was removed from the receiving chamber and immediately diluted in 100 µl of 20% methanol. The removed buffer was replaced with fresh buffer, and all calculations for the removed substances were corrected. For each condition, each compound was tested in two separate replicate wells. All samples were then extracted with 400 µl of 100% acetonitrile with an internal standard to precipitate proteins. Drug-administered cells were administered at the top or base side to determine forward (A to B) and reverse (B to A) permeability. To test for nonspecific binding and compound instability, the total amount of drug was quantified at the end of the experiment and compared with substances present in the original administered solution, expressed as recovery. The formation of the parent compound (GS-441524; reference compound A) was monitored in the assay wells of the pre-administered drug. Samples were analyzed by LC-MS / MS.

[0832] Table H1

[0833]

[0834] Example I: Thermodynamic solubility in pH 7 buffer solution

[0835] The water solubility of the compound was assessed over a 24-hour period. Solubility was determined at ambient temperature in a 50 mM phosphate buffer solution (pH 7) containing 150 mM NaCl (for isotonicity). The solid was added to the buffer solution in 1.5 mL Eppendorf tubes, vortexed for 1 min, and then stirred in an Eppendorf ThermoMixer C for 24 h. To determine the concentration in solution, the suspension was centrifuged at 15,000 rpm for 15 min. The supernatant was diluted to a volume of 1 mL with acetonitrile:water at a ratio of 30:70 v / v. All diluted supernatants were analyzed by UPLC using a Waters Acquity UPLC system with a PDA UV detector. The results are shown in Table I1.

[0836] Table I1

[0837]

[0838] All references, including publications, patents, and patent documents, are incorporated herein by reference as if separately cited. This disclosure provides reference to various embodiments and techniques. However, it should be understood that many changes and modifications can be made while maintaining the spirit and scope of this disclosure. In making this description, it should be understood that it is intended to be illustrative of the claimed subject matter and is not intended to limit the appended claims to the specific embodiments described.

Claims

1. A compound of Formula I: Formula I or a pharmaceutically acceptable salt thereof, wherein:

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula la: R 1 is -OH, -OC(=O)R 4 or -OC(=O)OR 4 ; R 2 is -OH, -OC(=O)R 5 or -OC(=O)OR 5 ; or R 1 and R 2 together form -OC(=O)O- or -OCHR 6 O-; R 3 , R 4 , and R 5 are each independently Ci-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C8carbocyclyl, C6-C 10 aryl, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; Where R 3 R 4 and R 5 C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, C6-C 10 The aryl or 5- to 6-membered heteroaryl groups are each independently and optionally selected by one, two, or three independently free from halogen, cyano, -N3, -OR. 7 -NR 8 R 9 The phenyl group is optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, cyano and C1-C6 alkyl groups; R 6 is H, Ci-C6alkyl or C6-C 10 aryl; Each R 7 Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; Each R 8 Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; Each R 9 Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; The base is , or ; and R 10 is C1-C6alkyl substituted with -OP(O)(OH)2. Formula la.

20. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein:

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 is -OH.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R 2 is -OH.

5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 1 is -OH and R 2 is -OH.

6. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 is -OC(=0)R 4 .

7. The compound of any one of claims 1, 2, and 6, or a pharmaceutically acceptable salt thereof, wherein R 2 is -OC(=0)R 5 .

8. The compound of any one of claims 1, 2, 6, and 7, or a pharmaceutically acceptable salt thereof, wherein R 1 is -OC(=0)R 4 and R 2 is -OC(=0)R 5 .

9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 each independently is C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C8carbocyclyl, C6-C 10 aryl, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S.

10. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 9, wherein R 4 and R 5 each independently is C1-C8alkyl or C3-C8carbocyclyl.

11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 each independently is C1-C8alkyl.

12. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 11, wherein R 4 and R 5 each independently is C1-C3alkyl.

13. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 12, wherein R 4 and R 5 are each methyl.

14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R 3 is Ci-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C8carbocyclyl, C6-C 10 aryl, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S.

15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R 3 is Ci-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, or C3-C8carbocyclyl.

16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R 3 is Ci-C8alkyl or C3-C8carbocyclyl.

17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R 3 is methyl, ethyl, propyl, butyl, or cyclopentyl.

18. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R 3 is Ci-C8alkyl.

19. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 18, wherein R 3 is methyl, ethyl, propyl, or butyl.

21. The compound of any one of claims 1, 2, and 20 or a pharmaceutically acceptable salt thereof, wherein: R 1 is -OH or -OC(=O)R 4 ; R 2 is -OH or -OC(=O)R 5 ; and R 3 , R 4 , and R 5 are each independently Ci-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C8carbocyclyl, C6-C 10 aryl, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S.

22. The compound of any one of claims 1, 2, 20, and 21 or a pharmaceutically acceptable salt thereof, wherein: R 1 is -OH or -OC(=O)R 4 ; R 2 is -OH or -OC(=O)R 5 ; and R 3 , R 4 , and R 5 are each independently Ci-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, or C3-C8carbocyclyl.

23. The compound of any one of claims 1, 2, and 20 to 22 or a pharmaceutically acceptable salt thereof, wherein: R 1 is -OH or -OC(=O)R 4 ; R 2 is -OH or -OC(=O)R 5 ; and R 3 , R 4 , and R 5 are each independently C1-C8alkyl or C3-C8carbocyclyl.

24. The compound of any one of claims 1, 2, and 20 to 22 or a pharmaceutically acceptable salt thereof, wherein: R 1 is -OH or -OC(=O)R 4 ; R 2 is -OH or -OC(=O)R 5 ; and R 4 and R 5 each independently is C1-C6alkyl; R 3 is C1-C8alkyl or C3-C8carbocyclyl.

25. The compound of any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: R 1 is -OH or -OC(=O)R 4 ; R 2 is -OH or -OC(=O)R 5 ; R 4 and R 5 each independently is methyl or ethyl; and R 3 is C1-C6alkyl or C3-C8carbocyclyl.

26. A compound of Formula A: 。 Formula A or a pharmaceutically acceptable salt thereof, wherein:

27. The compound of claim 26 or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula Aa: Formula Aa. R 1A and R 2A to form a 3- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S or a 5- to 10-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein R 1A and R 2A is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, oxo, -N3, -OR 3A , -C(=O)R 3A , -C(=O)OR 3A , -NR 4A R 5A , C1-C6 alkyl, and phenyl; wherein R 1A and R 2A substituents C1-C6alkyl is optionally substituted with one, two, or three substituents independently selected from halo, cyano, and phenyl; and R 1A and R 2A The substituted phenyl group is optionally substituted by one, two, or three independent substituents selected from halogen, cyano, and C1-C6 alkyl groups; or R 1A is H; R 2A is C1-C8alkyl substituted by -C(=O)OR 3A is C1-C8alkyl substituted by -C(=O)OR Where R 2A -C(=O)OR 3A The substituted C1-C8 alkyl group is optionally replaced by one or two independently selected from halogen, cyano, and phenyl groups and -OR. 3A The substituents are further substituted; Each R 3A Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, and 3 to 8-membered heterocyclic groups containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; Each R 4A Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; Each R 5A Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; The base is , or ; and R 6A is C1-C6alkyl substituted with -OP(O)(OH)2.

28. The compound of claim 26 or 27 or a pharmaceutically acceptable salt thereof, wherein 29. The compound of any one of claims 26 to 28 or a pharmaceutically acceptable salt thereof, wherein 30. The compound of any one of claims 26 to 29 or a pharmaceutically acceptable salt thereof, wherein R 1A is H; R 2A is C1-C8alkyl substituted by COOR 3A ; wherein R 2A C(=O)OR 3A substituted with one or two substituents independently selected from halo, cyano, phenyl, and -OR 3A ; and each R is independently H, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or 3- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S. 3A is independently H, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or 3- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S.

31. The compound of any one of claims 26 to 30 or a pharmaceutically acceptable salt thereof, wherein R 1A is H; R 2A is C1-C8alkyl substituted with -C(=O)OR 3A is C1-C8alkyl substituted with -C(=O)OR R 3A is H, Ci-C6alkyl, Ci-C6haloalkyl, C3-C6cycloalkyl, or a 3- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S.

32. The compound of any one of claims 26 to 30 or a pharmaceutically acceptable salt thereof, wherein the compound is R 1A is H; R 2A is C1-C8alkyl substituted with -C(=O)OR 3A is C1-C8alkyl substituted with -C(=O)OR R 3A is H or C1-C6alkyl.

33. The compound of claim 26 or 27, wherein R 1A is H; R 2A is C1-C6alkyl substituted with -C(=0)OR 3A C1-C6alkyl; and R 3A is H or C1-C3alkyl.

34. The compound of claims 26, 27, and 33, wherein or 。 35. The compound of claims 26, 27, 33, and 34, wherein the compound is selected from: R 1A and R 2A to form a 3- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S or a 5- to 10-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein R 1A and R 2A is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, oxo, -N3, -OR 3A , -COR 3A , -COOR 3A , -NR 4A R 5A , C1-C6 alkyl, and phenyl; wherein R 1A and R 2A the substituents of the group C1-C6alkyl are optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, cyano, and phenyl; and R 1A and R 2A The substituted phenyl group is optionally substituted by one, two or three independent substituents selected from halogen, cyano and C1-C6 alkyl groups; Each R 3A Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, and 3 to 8-membered heterocyclic groups containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; Each R 4A Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; and Each R 5A Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl.

36. A compound of Formula B: R 1A and R 2A are connected to form a 3- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S or a 5- to 10-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein R 1A and R 2A is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, oxo, -OR 3A , -C(=O)R 3A , -C(=O)OR 3A , C1-C6 alkyl, and phenyl; wherein R 1A and R 2A the substituents of the group C1-C6alkyl are optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, cyano, and phenyl; and R 1A and R 2A The substituted phenyl group is optionally substituted by one, two, or three independent substituents selected from halogen, cyano, and C1-C6 alkyl groups; and each R is independently H, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, and 3- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S. 3A is independently H, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, and 3- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S. Formula B or a pharmaceutically acceptable salt thereof, wherein: 。 40. The compound of any one of claims 33 to 36 or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula Ba: Formula Ba.

47. The compound of any one of claims 33 to 43 or a pharmaceutically acceptable salt thereof, wherein R 3B is -OC(=O)R 5B or -OC(=O)OR 5B ; R 4B is -OC(=O)R 6B or -OC(=O)OR 6B ; or R 3B and R 4B together form -OC(=0)0- or -OCHR 7B O-; R 5B and R 6B each independently is C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C8carbocyclyl, C6-C10aryl, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; and 10 C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C8carbocyclyl, C6-C wherein R 5B and R 6B C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C8carbocyclyl, C6-C 10 aryl, or 5- to 6-membered heteroaryl are each independently optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, cyano, -N3, -OR 8B , -NR 9B R 10B and phenyl optionally substituted with one, two, or three substituents independently selected from halo, cyano, and C1-C6alkyl. Each R 8B Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; Each R 9B Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; Each R 10B Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; R 7B is H, Ci-C6alkyl or C6-C 10 aryl; R 1B It is H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, C6-C 10 Aryl or 5- to 6-membered heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein R 1B C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C8carbocyclyl, C6-C 10 aryl, or 5- to 6-membered heteroaryl are optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, cyano, -N3, -OR 11B , -C(=O)R 11B , -C(=O)OR 11B , -NR 12B R 13B and phenyl optionally substituted with one, two, or three substituents independently selected from halo, cyano, and C1-C6alkyl. R 2B It is H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, C6-C 10 Aryl or 5- to 6-membered heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, and S; Where R 2B C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, C6-C 10 The aryl or 5- to 6-membered heteroaryl group is optionally selected by one, two, or three independently free from halogen, cyano, -N3, -OR. 11B -C(=O)R 11B -C(=O)OR 11B -NR 12B R 13B And optionally substituted with one, two or three substituents selected independently from the group consisting of phenyl groups, which are substituted with halogens, cyano groups and C1-C6 alkyl groups; or R 1B and R 2B to form a 3- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S or a 5- to 10-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein R 1B and R 2B is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, oxo, -N3, -OR 11B , -C(=O)R 11B , -C(=O)OR 11B , -NR 12B R 13B , C1-C6 alkyl, and phenyl; wherein R 1B and R 2B the substituents of the group C1-C6alkyl are optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, cyano, and phenyl; and R 1B and R 2B The substituted phenyl group is optionally substituted by one, two or three independent substituents selected from halogen, cyano and C1-C6 alkyl groups; Each R 11B Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, and 3 to 8-membered heterocyclic groups containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; Each R 12B Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; Each R 13B Independently, it is H, C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl; The base is , or ; and R 14B is C1-C6alkyl substituted with -OP(O)(OH)2.

37. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein R 3B is -OC(=0)R 5B .

38. The compound or pharmaceutically acceptable salt thereof of claim 33 or 34, wherein R 4B is -OC(=0)R 6B .

39. The compound or pharmaceutically acceptable salt thereof of any one of claims 33 to 35, wherein R 3B is -OC(=0)R 5B and R 4B is -OC(=0)R 6B .

48. The compound of any one of claims 33 to 44 or a pharmaceutically acceptable salt thereof, wherein 49. The compound of any one of claims 33 to 45 or a pharmaceutically acceptable salt thereof, wherein 41. The compound or pharmaceutically acceptable salt thereof of any one of claims 33 to 37, wherein R 5B and R 6B each independently is C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C8carbocyclyl, C6-C 10 aryl, or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S.

42. The compound or pharmaceutically acceptable salt thereof of any one of claims 33 to 38, wherein R 5B and R 6B each independently is C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, or C3-C8carbocyclyl.

43. The compound or pharmaceutically acceptable salt thereof of any one of claims 33-39, wherein R 5B and R 6B are each independently C1-C8alkyl.

44. The compound or pharmaceutically acceptable salt thereof of any one of claims 33-40, wherein R 5B and R 6B each independently is C1-C6alkyl.

45. The compound or pharmaceutically acceptable salt thereof of any one of claims 33-41, wherein R 5B and R 6B are each independently C1-C3alkyl.

46. The compound or pharmaceutically acceptable salt thereof of any one of claims 33-42, wherein R 1B is H.

50. The compound of any one of claims 33 to 42, 44, and 45 or a pharmaceutically acceptable salt thereof, wherein: R 1B is H R 2B It is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 carbocyclic, C6-C 10 Aryl or 5- to 6-membered heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein R 2B C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C8carbocyclyl, C6-C 10 aryl, or 5- to 6-membered heteroaryl are optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, cyano, -N3, -OR 11B , -C(=O)R 11B , -C(=O)OR 11B , -NR 12B R 13B and phenyl optionally substituted with one, two, or three substituents independently selected from halo, cyano, and C1-C6alkyl; or R 1B and R 2B are connected to form a 3- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S or a 5- to 10-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein R 1B and R 2B is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, cyano, oxo, -N3, -OR 11B , -C(=O)R 11B , -C(=O)OR 11B , -NR 12B R 13B , C1-C6 alkyl, and phenyl; wherein R 1B and R 2B the substituents of the group C1-C6alkyl are optionally substituted with one, two, or three substituents independently selected from the group consisting of halo, cyano, and phenyl; and R 1B and R 2B The substituted phenyl group is optionally substituted by one, two, or three independent substituents selected from halogen, cyano, and C1-C6 alkyl groups; and each R is independently H, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, and 3- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S. 11B is independently H, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, and 3- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S.

51. The compound of any one of claims 33 to 44 or a pharmaceutically acceptable salt thereof, wherein R 1B is H; R 2B is Ci-C8alkyl, C3-C8carbocyclyl, C6-C 10 aryl or 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein R 2B C1-C8alkyl, C3-C8carbocyclyl, C6-C 10 aryl, or 5- to 6-membered heteroaryl is optionally substituted with one, two, or three substituents selected independently from the group consisting of halogen, -OR 11B and -C(=O)OR 11B ; or R 1B and R 2B are connected to form a 3- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S or a 5- to 10-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein R 1B and R 2B the 3- to 8-membered heterocyclyl or the 5- to 10-membered heteroaryl is optionally substituted with one, two, or three substituents independently selected from the group consisting of oxo, -OR 11B , -C(=O)OR 11B , C1-C6alkyl, and phenyl; wherein R 1B and R 2B the substituents of the group C1-C6alkyl are optionally substituted with one, two, or three substituents independently selected from halo, cyano; and phenyl; and each R is independently H, C1-C6alkyl, C3-C6cycloalkyl, and 3- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S. 11B is independently H, C1-C6alkyl, C3-C6cycloalkyl, and 3- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S 52. The compound of any one of claims 33 to 48 or a pharmaceutically acceptable salt thereof, wherein R 1B is H; R 2B It is a C1-C8 alkyl, C3-C8 carbocyclic, C6-C 10 Aryl or 5- to 6-membered heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein R 2B C1-C8alkyl, C3-C8carbocyclyl, C6-C 10 aryl, or 5- to 6-membered heteroaryl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -OR 11B and -C(=O)OR 11B ; and each R is independently H, C1-C6alkyl, C3-C6cycloalkyl, and 3- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S. 11B is independently H, C1-C6alkyl, C3-C6cycloalkyl, and 3- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S ​ R 1B and R 2B to form a 3- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S or a 5- to 10-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein R 1B and R 2B is optionally substituted with one, two, or three substituents independently selected from the group consisting of oxo, -OR 11B , -C(=O)OR 11B , C1-C6alkyl, and phenyl; wherein R 1B and R 2B the substituents of the group C1-C6alkyl are optionally substituted with one, two, or three substituents independently selected from halo, cyano; and phenyl; and each R is independently H, C1-C6alkyl, C3-C6cycloalkyl, and 3- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S. 11B is independently H, C1-C6alkyl, C3-C6cycloalkyl, and 3- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S ​ R 1B is H; R 2B is C1-C8alkyl or C3-C8carbocyclyl; wherein R 2B -C8alkyl or C3-C8carbocyclyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -OR 11B and -C(=O)OR 11B ; or R 1B and R 2B are connected to form a 3- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S or a 5- to 10-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein R 1B and R 2B is optionally substituted with one, two, or three substituents independently selected from the group consisting of oxo, -OR 11B , -C(=O)OR 11B , and C1-C6 alkyl; wherein R 1B and R 2B the substituents of the group C1-C6alkyl are optionally substituted with one, two, or three substituents independently selected from halo, cyano; and phenyl; and each R is independently H, C1-C6alkyl, C3-C6cycloalkyl, and 3- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S. 11B is independently H, C1-C6alkyl, C3-C6cycloalkyl, and 3- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S ​ R 1B is H; R 2B is C1-C8alkyl optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -OR 11B and -C(=O)OR 11B ; or R 1B and R 2B are connected to form a 3- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S or a 5- to 10-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein R 1B and R 2B the 3- to 8-membered heterocyclyl or the 5- to 10-membered heteroaryl is optionally substituted with one, two, or three substituents independently selected from the group consisting of oxo, -OR 11B , -C(=O)OR 11B , and C1-C6 alkyl; wherein R 1B and R 2B the substituents of the group C1-C6alkyl are optionally substituted with one, two, or three substituents independently selected from halo, cyano; and phenyl; and each R is independently H, C1-C6alkyl, C3-C6cycloalkyl, and 3- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S. 11B is independently H, C1-C6alkyl, C3-C6cycloalkyl, and 3- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S 53. The compound or pharmaceutically acceptable salt thereof of any one of claims 33- 44, wherein R 1B is H; R 2B is C1-C6alkyl or C3-C8carbocyclyl; Where R 2B The C1-C6 alkyl or C3-C8 carbocyclic group is optionally selected by one, two or three independently free from halogen, -OR 11B and -C(=O)OR 11B Substituents of the group; or R 1B and R 2B to form a 3- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S or a 5- to 10-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein R 1B and R 2B the 3- to 8-membered heterocyclyl or the 5- to 10-membered heteroaryl is optionally substituted with one, two, or three substituents independently selected from the group consisting of oxo, -OR 11B , -C(=O)OR 11B , and C1-C3 alkyl; wherein R 1B and R 2B the substituents of the group C1-C3 alkyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halo, cyano; and phenyl; and each R is independently H, C1-C3alkyl, C3-C6cycloalkyl, and 3- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S. 11B is independently H, C1-C3alkyl, C3-C6cycloalkyl, and 3- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S 54. The compound or pharmaceutically acceptable salt thereof of any one of claims 33- 48, wherein R 1B is H; R 2B is C1-C6 alkyl optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, -OR 11B and -C(=0)OR 11B ; or R 1B and R 2B are connected to form a 3- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S or a 5- to 10-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; wherein R 1B and R 2B is optionally substituted with one, two, or three substituents independently selected from the group consisting of oxo, -OR 11B , -C(=O)OR 11B , and C1-C3 alkyl; wherein R 1B and R 2B the substituents C1-C3 alkyl are optionally substituted with one, two, or three substituents independently selected from halo, cyano; and phenyl; and each R is independently H, C1-C3alkyl, C3-C6cycloalkyl, and 3- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S. 11B is independently H, C1-C3alkyl, C3-C6cycloalkyl, and 3- to 8-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S 55. The compound or pharmaceutically acceptable salt thereof of any one of claims 33- 51, wherein the compound is selected from: 。 56. The compound or pharmaceutically acceptable salt thereof of any one of claims 33- 51, wherein the compound is selected from: 。 57. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof of any one of claims 1-56 and one or more pharmaceutically acceptable excipients.

58. The pharmaceutical composition of claim 57, wherein the pharmaceutical formulation is for subcutaneous, intramuscular, intravenous, oral, or inhalation administration.

59. The pharmaceutical composition of claim 57 or 58, wherein the pharmaceutical formulation is for oral administration.

60. 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 or pharmaceutically acceptable salt thereof of any one of claims 1-56, or a pharmaceutical composition of any one of claims 57-59.

61. The method of claim 60, wherein the compound or pharmaceutically acceptable salt thereof, or pharmaceutical composition is administered to the human via oral, intramuscular, intravenous, subcutaneous, or inhalation administration.

62. The method of claim 60 or 61, wherein the method comprises administering to the human at least one additional therapeutic or prophylactic agent.

63. The method of claim 62, wherein the additional therapeutic or prophylactic agent is molnupiravir, oseltamivir, nirmatrelvir, or ritonavir.

64. The method of any one of claims 60-63, wherein the viral infection is a coronavirus infection.

65. The method of any one of claims 60-63, wherein the viral infection is a zoonotic coronavirus infection.

66. The method of any one of claims 60-63, wherein the viral infection is caused by a virus having at least 70% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2.

67. The method of any one of claims 60-63, wherein the viral infection is caused by a virus having at least 80% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2.

68. The method of any one of claims 60-63, wherein the viral infection is caused by a virus having at least 90% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2.

69. The method of any one of claims 60-63, wherein the viral infection is caused by a virus having at least 95% sequence homology to a viral polymerase selected from the group consisting of SARS-CoV polymerase, MERS-CoV polymerase, and SARS-CoV-2.

70. The method of any one of claims 60-63, wherein the viral infection is selected from the group consisting of: 229E virus infection, NL63 virus infection, OC43 virus infection, and HKU1 virus infection.

71. The method of any one of claims 60-63, wherein the viral infection is a SARS-CoV-2 infection (COVID-19).

72. The method of any one of claims 60-63, wherein the viral infection is a SARS-CoV virus infection.

73. The method of any one of claims 60-63, wherein the viral infection is a MERS-CoV virus infection.

74. The method of any one of claims 60-63, wherein the viral infection is a Pneumoviridae virus infection.

75. The method of claim 74, wherein the Pneumoviridae virus infection is a respiratory syncytial virus infection.

76. The method of claim 75, wherein the Pneumoviridae virus infection is a human metapneumovirus infection.

77. The method of any one of claims 60-63, wherein the viral infection is a Picornaviridae virus infection.

78. The method of any one of claims 60-63, wherein the viral infection is an enterovirus infection.

79. The method of any one of claims 60-63, wherein the viral infection is selected from the group consisting of: Coxsackie A virus infection, Coxsackie A virus infection, enterovirus D68 infection, enterovirus B69 infection, enterovirus D70 infection, enterovirus A71 infection, and poliovirus infection.

80. The method of claim 77, wherein the Picornaviridae virus infection is a human rhinovirus infection (HRV).

81. The method of claim 77, wherein the Picornaviridae virus infection is a HRV-A, HRV-B, or HRV-C infection.

82. The method of any one of claims 60-63, wherein the viral infection is a Flaviviridae virus infection.

83. The method of any one of claim 82, wherein the Flaviviridae virus infection is a dengue virus infection, yellow fever virus infection, West Nile virus infection, tick-borne encephalitis, Kunjin Japanese encephalitis, St. Louis encephalitis, Murray Valley encephalitis, Omsk hemorrhagic fever, bovine viral diarrhea, Zika virus infection, or HCV infection.

84. The method of any one of claims 60-63, wherein the viral infection is a Filoviridae virus infection.

85. The method of any one of claim 84, wherein the Filoviridae virus infection is an Ebola virus infection or a Marburg virus infection.

86. The method of any one of claims 60-63, wherein the viral infection is an orthomyxovirus infection.

87. The method of any one of claims 60-63, wherein the viral infection is an influenza virus infection.

88. The method of any one of claims 60-63, wherein the viral infection is an influenza A virus infection or an influenza B virus infection.

89. The method of any one of claims 60-63, wherein the viral infection is a paramyxoviridae virus infection.

90. The method of any one of claims 60-63, wherein the viral infection is a human parainfluenza virus, a Nipah virus, a Hendra virus, a measles, or a mumps infection.

91. A method for manufacturing a medicament for treating or preventing a viral infection in a human in need thereof, characterized in that A compound or pharmaceutically acceptable salt thereof according to any one of claims 1-172.

92. Use of a compound or pharmaceutically acceptable salt thereof according to any one of claims 1-56 for the manufacture of a medicament for the treatment or prevention of a viral infection in a human in need thereof.

93. The use of claim 92, wherein the medicament is used with at least one additional therapeutic or prophylactic agent.

94. The use of claim 93, wherein the additional therapeutic or prophylactic agent is monupiravir, oseltamivir, nirmatrelvir, or ritonavir.

95. A composition comprising a compound or pharmaceutically acceptable salt thereof according to any one of claims 1-56 for use in the treatment or prevention of a viral infection in a human in need thereof.

96. The composition of claim 95, wherein the composition comprises at least one additional therapeutic or prophylactic agent.

97. The composition of claim 96, wherein the additional therapeutic or prophylactic agent is monupiravir, oseltamivir, nirmatrelvir, or ritonavir.

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