Compositions and methods for treating and preventing viral infections

Abstract

Probenecid prodrug compounds and formulations are provided, including one or more of probenecid, its metabolites and analogs, and its prodrugs, and its pharma- ceutically acceptable salts. Delivery vehicles and pharmaceutical compositions including any of the foregoing are also provided. Methods of treating viral infections using the compounds and compositions are also provided. In some embodiments, the viral infection is caused by an RNA virus. Specific viruses include, but are not limited to, influenza A, B, or C, respiratory syncytial virus (RSV), coronavirus, measles virus, mumps virus, Zika virus, and dengue virus. Dosage regimens are also provided.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to USSN 63 / 203,026, filed July 6, 2021, and USSN 63 / 349,364, filed June 6, 2022, each of which is incorporated by reference in its entirety.

[0002] Reference to sequence listing The sequence listing submitted as an xml file entitled "UGA2022-128-03PCT.xml", created on July 6, 2022 and 146,686 bytes in size, is incorporated herein by reference pursuant to 37 CFR § 1.834(c)(1).

[0003] FIELD OF THEINVENTION The field of the invention relates generally to small molecule compounds and their formulations and methods of use for treating viral infections. [Background technology]

[0004] 2. Background of the Invention Viral replication and transmissibility are the main causes of endemic and pandemic threats. Broad-spectrum antiviral agents remain needed. Examples of the most common respiratory viruses are certain endemic pathogens, such as coronaviruses, respiratory syncytial viruses, and influenza viruses. Although vaccines are available against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and some influenza viruses, effective antiviral drugs are lacking, whereas for RSV there is no available vaccine and therapeutic treatments are very limited.

[0005] For example, there are currently only two FDA-approved drugs against RSV: palivizumab, a monoclonal antibody for preventing RSV in high-risk children, and ribavirin, approved for the treatment of severe RSV disease. Both of these drugs are of questionable efficacy (Bergeron, et al., Expert Opin Investig Drugs, 29, 285-294, doi: 10.1080 / 13543784.2020.1735349(2020)). Despite the availability of these approved drugs, RSV remains a global health concern due to the lack of a safe and effective vaccine and substantial morbidity and some mortality across a range of ages, i.e., from young to elderly. Several promising antiviral candidates with different mechanisms of action (Bergeron, et al., Expert Opin Investig Drugs, 29, 285-294, doi: 10.1080 / 13543784.2020.1735349(2020); Boyoglu-Barnum, et al., Expert Opin Biol Ther, 20, 1073-1082, doi: 10.1080 / 14712598.2020.1753696(2020)) are helping to advance development (Soto, et al., Front Immunol 11, 1507, doi: 10.3389 / fimmu.2020.01507(2020); Drydale, et al., Sci Transl Med 12, doi: 10.1126 / scitranslmed.aax 2466 (2020)), new options for treating and preventing RSV disease and other viral infections are needed.

[0006] Probenecid has been identified as therapeutically effective for other purposes in the treatment of influenza and SARS-CoV-2. See, for example, U.S. Patent Publication No. 2014 / 0121237 and U.S. Patent No. 11,116,737. Probenecid is a highly lipid-soluble benzoic acid derivative with an excellent safety profile that was developed in the 1950s to reduce serum levels of uric acid in gout patients and to reduce renal tubular excretion of penicillin. Probenecid, USP, is a white or nearly white, fine, crystalline powder. Probenecid is soluble in dilute alkali, alcohol, chloroform, and acetone, but is practically insoluble in water and dilute acids. Probenecid is completely absorbed after oral administration, reaching peak plasma concentrations in 2-4 hours. The plasma half-life of the drug is dose-dependent and varies from less than 5 hours to more than 8 hours. Probenecid is often administered in the form of high dose tablets, which results in poor patient compliance, particularly with pediatric patients. Thus, there remains a need for improved, more soluble and patient compliant probenecid prodrugs and formulations.

[0007] It is therefore an object of the present invention to provide compounds, compositions and methods of use thereof for treating viruses. It is also an object of the present invention to provide probenecid analogs and prodrugs, and compositions and methods of use thereof, preferably with improved solubility. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Bergeron, et al., Expert Opin Investig Drugs, 29, 285-294, doi: 10.1080 / 13543784.2020.1735349(2020) [Non-Patent Document 2] Boyoglu-Barnum, et al., Expert Opin Biol Ther, 20, 1073-1082, doi: 10.1080 / 14712598.2020.1753696(2020) [Non-Patent Document 3] Soto, et al., Front Immunol 11, 1507, doi: 10.3389 / fimmu.2020.01507(2020) [Non-Patent Document 4] Drydale, et al., Sci Transl Med 12, doi: 10.1126 / scitranslmed.aax 2466(2020) Summary of the Invention [Means for solving the problem]

[0009] Summary of the Invention Synthetic compounds have been developed that can be used as the prodrug of probenecid or probenecid analogue.These compounds (also referred to herein as "prodrug") are inactive forms prepared from active probenecid or probenecid analogue, and can release probenecid or probenecid analogue in active form after being administered to a subject in need of it.The released probenecid or probenecid analogue has antiviral properties and should be suitable for use in the prevention and / or treatment of multiple classes of viruses.

[0010] In some forms, the compounds are formed by modifying the carboxyl group of probenecid with water-soluble moieties such as carbonate, carbamate, imine, ether, ester, amide, or phosphate.By adding such water-soluble moieties, the ability of these compounds to cross certain biological membranes, such as those associated with the blood-brain barrier or the blood-placental barrier, can be effectively attenuated.In some forms, these compounds show a reduced biological membrane crossing rate compared to the biological membrane crossing rate of probenecid that is not attached to a water-soluble moiety.Furthermore, compared to probenecid administered in free form, the prodrugs disclosed herein can change the pharmacokinetics of probenecid, improve the stability and solubility of probenecid, reduce the toxicity of probenecid, increase the specificity of probenecid, and / or extend the duration of the pharmacological effect of probenecid.

[0011] The prodrug has formula I: [ka] (In the formula, (a) Z' is O, NR 5 or S; (b) X' may be absent and is O, NR 5 or S; (c) R 1 may be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, azo, alkoxy, polyether, thiol, sulfanimine, amino, carbonate, ester, amide, carbamate, imine, substituted or unsubstituted carbonyl, hydroxyl, polyol, phosphonyl, sulfinyl, sulfonamide, nitro, cyano, lipid, peptide, cholesterol, phytosterol, glycoside, or glucuronide; (d) n may be an integer from 0 to 4; (e) each R 2may be independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteropolyaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, alkoxy, amido, amino, phosphonium, phosphanyl, phosphonyl, silyl, sulfinyl, sulfonyl, sulfate, thiol, hydroxyl, or halogen; (f) R 3 ~R 5 may be independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, alkoxy, amido, amino, imine, or thiol; (g) the substituents may be independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, alkoxy, halogen, hydroxyl, phenoxy, thiol, alkylthio, phenylthio, arylthio, cyano, isocyano, nitro, carboxyl, amino, amido, oxo, silyl, sulfinyl, sulfonyl, sulfonic acid, phosphonium, phosphanyl, phosphoryl, or phosphonyl). The structure may be as follows:

[0012] In some embodiments of Formula I, R 1 is hydrogen, substituted or unsubstituted C 1 ~C 20 Straight-chain or branched alkyl (e.g., haloalkyl), substituted or unsubstituted C 3 ~C 20 Cycloalkyl, substituted or unsubstituted C 1 ~C 20 Linear or branched heteroalkyl, substituted or unsubstituted C 3 ~C20 Heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteropolyaryl, polyol, polyalkylene glycol, lipid, peptide, cholesterol, phytosterol, glucuronide, [ka] where G' is hydrogen, a lipid, a peptide, cholesterol, a plant sterol, a glycoside, a glucuronide, [ka] R may be 9 ~R 12 are independently hydrogen, substituted or unsubstituted C 1 ~C 20 Straight-chain or branched alkyl (e.g., haloalkyl), substituted or unsubstituted C 3 ~C 20 Cycloalkyl, substituted or unsubstituted C 1 ~C 20 Linear or branched heteroalkyl, substituted or unsubstituted C 3 ~C 20 R' may be heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, alkoxy, dialkylamino, or halogen; 5 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, alkoxy, amido, amino, imine, or thiol, e.g., hydrogen or substituted or unsubstituted C 1 ~C 6 Alkyl (e.g., unsubstituted C 1 ~C 6 Straight or branched alkyl, unsubstituted C 1 ~C 6 Cycloalkyl, unsubstituted C 1 ~C 4 Straight or branched alkyl, unsubstituted C 1 ~C 4 Cycloalkyl, unsubstituted C 1 ~C 3Straight or branched alkyl, unsubstituted C 1 ~C 3 m, k, p, and q may independently be an integer from 0 to 20, 0 to 18, 0 to 16, 0 to 14, 0 to 12, 0 to 10, 0 to 8, 0 to 6, 0 to 4, 0 to 3, or 0 to 2, e.g., 0 or 1; each Y' may independently be O or S; R 7 , R 8 , and R 15 ~R 20 is, for each occurrence, independently, hydrogen, substituted or unsubstituted C 1 ~C 20 or R may be alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteropolyaryl, substituted or unsubstituted carbonyl, alkoxy, amido, amino, phosphonium, phosphanyl, phosphonyl, silyl, sulfinyl, sulfonyl, sulfate, thiol, hydroxyl, or halogen; 7 and R 8 together with the carbon atom to which they are attached, R 15 and R 16 together with the carbon atom to which they are attached, and / or R 17 and R 18 together with the carbon atom to which they are attached, C 1 ~C 20 cycloalkyl or X' is NR 5 If m is not 0 and at least one of p and q is not 0, then (i) R 7 is hydrogen, and R 8 is R 5 Substituted or unsubstituted C, which together with the adjacent N and C atoms form a ring 1 ~C 20 (ii) R is alkyl; 15 is hydrogen, and R 16 is R5 Substituted or unsubstituted C, which together with the adjacent N and C atoms form a ring 1 ~C 20 and / or (iii) R is alkyl; 17 is hydrogen, and R 18 is R 5 Substituted or unsubstituted C, which together with the adjacent N and C atoms form a ring 1 ~C 20 R is alkyl; 13 and R 14 are independently hydrogen, substituted or unsubstituted C 1 ~C 20 It may be alkyl, or alkoxy.

[0013] In some embodiments of Formula I, R 1 is unsubstituted C 1 ~C 20 Straight or branched alkyl, unsubstituted C 3 ~C 20 Cycloalkyl, C 1 ~C 20 Haloalkyl, unsubstituted aryl, unsubstituted polyaryl, unsubstituted heteroaryl, unsubstituted heteropolyaryl, polyalkylene glycol, lipid, peptide, cholesterol, phytosterol, glucuronide, [ka] [ka] where m, m', p', and n' may independently be integers from 0 to 10, 0 to 8, 0 to 6, 0 to 4, 0 to 3, 0 to 2, or 0 or 1; p is an integer from 1 to 6, 1 to 4, 1 to 3, or 1 or 2; and k is an integer from 1 to 6, 1 to 4.

[0014] In some forms of Formula I, Z' can be O, X' can be absent or can be O, and R 1 is a substituted or unsubstituted C 1 ~C 20Straight-chain or branched alkyl (e.g., haloalkyl), substituted or unsubstituted C 3 ~C 20 Cycloalkyl, substituted or unsubstituted C 1 ~C 20 Linear or branched heteroalkyl, substituted or unsubstituted C 3 ~C 20 It may be a heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteropolyaryl, polyalkylene glycol, lipid, peptide, cholesterol, plant sterol, glycoside, or glucuronide.

[0015] In some embodiments of Formula I, Z′ is O or NR 5 and [ka] teeth, [ka] It may be.

[0016] In some forms of Formula I, Z' can be O, X' can be O, and R 1 teeth, [ka] It may be.

[0017] In some forms of Formula I, Z' can be O, X' can be O, and R 1 teeth, [ka] where m' and n' are independently an integer from 0 to 6, 0 to 5, 0 to 4, 0 to 3, 1 to 3, e.g., 1 or 2; p' is an integer from 1 to 10, 1 to 8, 1 to 6, 1 to 4, or 1 to 3; R 17 and R 18is, for each occurrence, independently, hydrogen, hydroxyl, -SH, -(CH 2 ) 1~6 NR 22 R 23 , -(CH 2 ) 1~6 OH, -(CH 2 ) 1~6 SH or unsubstituted C 1 ~C 10 In some forms of Formula I, Z' can be O, X' can be O, and R 1 teeth, [ka] where q is an integer from 1 to 10, 1 to 8, 1 to 6, 1 to 4, or 1 to 3; R 17 ~R 20 is, for each occurrence, independently, hydrogen, hydroxyl, -SH, -(CH 2 ) 1~6 NR 22 R 23 , -(CH 2 ) 1~6 OH, -(CH 2 ) 1~6 SH or unsubstituted C 1 ~C 10 In these forms of formula I, R 2 is hydrogen, hydroxyl, -SH, -(CH 2 ) 1~6 NR 22 R 23 , -(CH 2 ) 1~6 OH, -(CH 2 ) 1~6 SH or unsubstituted C 1 ~C 10 alkyl, e.g. hydrogen; R 3 and R 4 are independently unsubstituted C 1 ~C 10 Alkyl may be, for example, unsubstituted methyl, ethyl, propyl, butyl, pentyl, or hexyl, for example, unsubstituted propyl.

[0018] In some forms of Formula I, Z' can be O, X' can be S, and R 1 teeth, [ka] It may be.

[0019] In any one of the forms of formula I above, R 7 , R 8 , and R 15 ~R 20 is, for each occurrence, independently, hydrogen, substituted or unsubstituted C 1 ~C 20 Alkyl, -(CH 2 ) 1~6 NR 22 R 23 , -(CH 2 ) 1~6 OH, substituted or unsubstituted aralkyl, -(CH 2 ) 1~6 SH, -(CH 2 ) 1~6 S(O) 0~2 CH 3 , -(CH 2 ) 1~6 NHC(=NH)NH 2 , -(1H-indol-3-yl)methyl, -(1H-imidazol-4-yl)methyl, -(CH 2 ) 0~6 COOR 21 , -(CH 2 ) 0~6 CONR 22 R 23 , substituted or unsubstituted aryl, aryl-C 1~3 Alkyl, CH 2 -Indol-3-yl, -(CH 2 ) 1~6 SCH 3 , -CH2-imidazol-4-yl, CH(OH)(CH 2 ) 0~5 CH 3 , -CH 2 ((4'-OH)-Ph), where R 21 ~R 23 are independently hydrogen or unsubstituted C 1~6It may be alkyl.

[0020] In any one of the forms of formula I above, R 3 and R 4 may independently be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, alkoxy, amino, or imine; R 3 and R 4 are independently hydrogen or substituted or unsubstituted C 1 ~C 20 It is preferably alkyl.

[0021] In any one of the forms of formula I above, R 5 and / or R' 5 is hydrogen or substituted or unsubstituted C 1 ~C 20 It may be alkyl.

[0022] In any one of the above forms of formula I, when substituents are present, the substituents are independently unsubstituted C 1 ~C 6 Alkyl, unsubstituted C 1~6 Alkyl-substituted C 1 ~C 6 Alkyl, unsubstituted C 1 ~C 6 Heteroalkyl, unsubstituted C 1~6 Alkyl-substituted C 1 ~C 6 Heteroalkyl, unsubstituted C 2 ~C 6 Alkenyl, unsubstituted C 2 ~C 6 Alkynyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted C 1 ~C 6 Alkoxy, -(CH 2 ) 1~6 CO 2 R 21 , halogen, C 1 ~C 6 Haloalkyl, -NR 22 R 23 , C 1~6Acylamino, -NHSO 2 C 1~6 Alkyl, -SO 2 NR 22 R 23 , -SO 2 C 1~6 Alkyl, -COOR 21 , -CONR 22 R 23 , nitro, cyano, hydroxide, thiol, or unsubstituted C 1~5 Aryl or heteroaryl substituted with alkyl, alkoxy, di(C 1~6 Alkyl)-amino, fluoro, or unsubstituted C 3 ~C 6 It may be a cycloalkyl.

[0023] In some forms of Formula I, when a peptide is present, the peptide can be any one of the peptides listed in Table 1.

[0024] In some forms, the prodrug is not one of the compounds listed in Table 2.

[0025] In some forms, the prodrug has the following structure: [ka] [ka] has.

[0026] Any of the compounds disclosed herein, including probenecid, metabolites or analogs, prodrugs thereof, including those described herein, may be present in a delivery vehicle. In some embodiments, the delivery vehicle is a nanoparticle or a liposome.

[0027] Any of the compounds disclosed herein, alone or present in a delivery vehicle, may be present in a composition, such as a pharmaceutical composition or a feed composition. A pharmaceutical composition generally includes a pharmaceutically acceptable carrier and / or excipient. Also disclosed are pharmaceutical formulations containing one or more compounds selected from, for example, probenecid, metabolites or analogs, prodrugs thereof, including those described herein, and pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients and / or carriers. For example, feed compositions, including commercial agricultural feeds, may include proteins, fats, sugars, amino acids, minerals, starches, vitamins, and the like. The one or more compounds may be present in an effective amount to prevent, treat, or ameliorate one or more symptoms associated with a viral infection in a subject in need thereof. The formulation may further contain one or more additional active agents. The one or more additional active agents may be one or more antiviral agents and / or anti-inflammatory agents.

[0028] In some forms, the pharma- ceutically acceptable carrier may be a nanoparticle, a liposome, a cyclodextrin, or a hydrogel, and optionally, one or more prodrugs are encapsulated in, conjugated to, and / or complexed with the nanoparticle, liposome, cyclodextrin, or hydrogel. In some forms, the pharmaceutical formulation may be in the form of a tablet, syrup, capsule, powder, or microneedle.

[0029] Methods of treatment are also provided. For example, a method of treating a subject for gout may include administering to a subject in need thereof an effective amount of any of the prodrugs disclosed herein. Methods of treating a subject for hyperuricemia are also provided, and may include administering to a subject in need thereof an effective amount of any of the prodrugs disclosed herein.

[0030] Also provided are methods of treating or preventing a viral infection in a subject. The methods may include administering to the subject an effective amount of one or more compounds selected from probenecid, metabolites or analogs, prodrugs thereof, including prodrugs described herein, and pharma- ceutically acceptable salts thereof, or pharmaceutical compositions thereof. Subjects include, but are not limited to, humans, non-human mammals, and birds. The subject may be an adult or child of any age. In some embodiments, the subject is a human child under the age of 18, for example, between 2 and 10 years of age, inclusive. The viral infection may be due to a DNA virus or an RNA virus. Exemplary DNA viruses include those belonging to the following families: adenoviridae, papoviridae, herpesviridae, poxviridae, anelloviridae, and pleolipoviridae. Exemplary RNA viruses include those belonging to the following families: Reoviridae, Picornaviridae, Caliciviridae, Togaviridae, Arenaviridae, Flaviviridae, Orthomyxoviridae, Paramyxoviridae, Bunyaviridae, Rhabdoviridae, Filoviridae, Coronaviridae, Astroviridae, Bornaviridae, Arteriviridae, and Hepeviridae. For example, in some embodiments, the virus is from a negative strand RNA virus family, such as Arenaviridae, Bunyaviridae, Filoviridae, Nymaviridae, Orthomyxoviridae, Paramyxoviridae, Pneumoviridae, or Rhabdoviridae; or a positive strand family, such as Arteriviridae, Astroviridae, Caliciviridae, Coronaviridae, Flaviviridae, Hepeviridae / Nodaviridae, Picornaviridae, or Togaviridae.

[0031] In some embodiments, the virus is a respiratory virus.

[0032] In some embodiments, the virus is selected from influenza virus, optionally influenza A virus, influenza B virus, or influenza C virus, respiratory syncytial virus (RSV), human metapneumovirus, coronavirus, measles virus, parainfluenza virus, mumps virus, Zika virus, dengue virus, yellow fever virus, Japanese encephalitis virus, West Nile virus, hepatitis A virus, hepatitis B virus, or hepatitis C virus.

[0033] In some embodiments, the virus is a coronavirus, optionally including Severe Acute Respiratory Syndrome-associated coronavirus, Bat Hp-betacoronavirus Zhejiang2013, Rousettus bat coronavirus GCCDC1, Rousettus bat coronavirus HKU9, Eidolon bat coronavirus C704, Pipistrellus bat coronavirus HKU5, Tylonycteris bar coronovirus HKU4, Middle East Respiratory Syndrome-associated coronavirus, hedgehog coronavirus, murine coronavirus, human coronavirus HKU1, China Rattus coronavirus HKU24 HKU24, betacoronavirus 1, Myodes coronavirus 2JL14, human coronavirus NL63, human coronavirus 229E, or human coronavirus OC43.

[0034] In certain embodiments, the coronavirus is a severe acute respiratory syndrome-associated coronavirus, e.g., SARS-CoV-2, SARS-CoV, SARSr-CoV RaTG13, SARS-CoV PC4-227, or SARSr-CoV BtKY72.

[0035] In some embodiments, the subject has COVID-19.

[0036] In some embodiments, the virus has an RNA genome that optionally encodes an RNA-dependent RNA polymerase (RdRp).

[0037] The virus may be a member of the kingdom Orthornavirae. In some embodiments, the virus optionally utilizes a host organic anion transporter selected from OAT1, OAT2, OAT3, OAT4, OAT5, OAT6, OAT7, rOAT8, OAT9, OAT10, and / or URAT1.

[0038] In some embodiments, the subject has one or more symptoms selected from fever, sinus and / or lung congestion, runny or stuffy nose, cough, sneezing, sore throat, body aches, fatigue, shortness of breath, chest tightness, wheezing when breathing out, chills, muscle aches, headache, diarrhea, fatigue, nausea, anosmia, skin rash, and combinations thereof. In some embodiments, the subject is asymptomatic.

[0039] In some embodiments, the compound is administered systemically, topically, or locally. In some embodiments, the compound is administered orally, parenterally, topically, or through a mucous membrane. In certain embodiments, the compound is administered through a mucous membrane to the lungs, nasal mucosa, or a combination thereof. In some embodiments, the compound is administered prophylactically and / or therapeutically to animals, particularly agricultural animals, such as chickens, cows, and / or pigs, or domestic animals, such as dogs or cats.

[0040] Dosages and dosage regimens are also provided. For example, in some embodiments, the compound is administered in an effective amount to reduce viral replication. Exemplary dosages include, but are not limited to, 10 mg to 2,000 mg, or 600 mg, 900 mg, or 1,800 mg, twice daily as needed, for 14 days or longer as needed. In more detailed embodiments, the dose is 250 mg to 2,000 mg once daily or twice daily, for example, 600 mg or 900 mg twice daily, or 1,800 mg once daily. In some embodiments, the subject is treated by pulse dosing. The subject may be a mammal, such as a human. [Brief description of the drawings]

[0041] [Figure 1] Figure 1 is a graph of probenecid prophylaxis against RSV A2. Cell lines were prophylactically treated with probenecid 24 hours prior to RSV A2 infection. Probenecid prophylaxis significantly (****p<0.0001) inhibited viral replication in Vero E6, HEp-2, and NHBE cells compared to control (DMSO only). Viral titers were determined by plaque assay. IC50 and IC90 values ​​are shown in Table 3.

[0042] [Diagram 2] Figure 2 is a graph of probenecid treatment for RSV A2. Cell lines were treated with probenecid 24 hours after RSV A2 infection. Treatment significantly (****p<0.0001) inhibited viral replication in Vero E6, HEp-2, and NHBE cells compared to control (DMSO only). Viral titers were determined by plaque assay. IC50 and IC90 values ​​are shown in Table 3.

[0043] [Diagram 3]Figure 3 is a graph of probenecid prophylaxis against RSV B1. Cell lines were prophylactically treated with probenecid 24 hours prior to RSV B1 infection. Probenecid prophylaxis significantly (****p<0.0001) inhibited viral replication in Vero E6, HEp-2, and NHBE cells compared to control (DMSO only). Viral titers were determined by plaque assay. IC50 values ​​are shown in Table 3; IC90 values ​​are not available because the virus was not reduced by 90%.

[0044] [Figure 4] Figure 4 is a graph of probenecid treatment for RSV B1. Cell lines were treated with probenecid 24 hours after RSV B1 infection. Treatment significantly (****p<0.0001) inhibited viral replication in Vero E6, HEp-2, and NHBE cells compared to control (DMSO only). Viral titers were determined by plaque assay. IC50 values ​​are shown in Table 1; IC90 values ​​are not available because the virus was not reduced by 90%.

[0045] [Diagram 5] Figure 5 is a graph of probenecid prophylaxis against Memphis-37. Cell lines were prophylactically treated with probenecid 24 hours prior to RSV Memphis-37 infection. Probenecid prophylaxis significantly (****p<0.0001) inhibited viral replication in Vero E6, HEp-2, and NHBE cells compared to control (DMSO only). Viral titers were determined by plaque assay. IC50 and IC90 values ​​are shown in Table 3.

[0046] [Figure 6]Figure 6 is a graph of probenecid treatment of Memphis-37. Cell lines were treated with probenecid 24 hours after RSV Memphis-37 infection. Treatment significantly (****p<0.0001) inhibited viral replication in Vero E6, HEp-2, and NHBE cells compared to control (DMSO only). Viral titers were determined by plaque assay. IC50 and IC90 values ​​are shown in Table 3.

[0047] [Figure 7] Figure 7 is a bar graph of viral titers in the lungs of female BALB / c mice. Mice were given 2 mg / kg or 200 mg / kg of probenecid 24 hours before infection (prophylaxis) or 24 hours after infection (treatment). Mice were infected intranasally with 106 PFU of RSV A2. Lungs were harvested and viral titers were determined by plaque assay on days 3, 5, and 7 post-infection. All probenecid treatments significantly (****p<0.0001) reduced viral titers in the lungs compared to control (PBS).

[0048] [Figure 8] Figure 8 is a bar graph of viral titers in the lungs of male BALB / c mice. Mice were given 2 mg / kg or 200 mg / kg of probenecid 24 hours before infection (prophylaxis) or 24 hours after infection (treatment). Mice were infected intranasally with 106 PFU of RSV A2. Lungs were harvested and viral titers were determined by plaque assay on days 3, 5, and 7 post-infection. All probenecid treatments significantly (****p<0.0001) reduced viral titers in the lungs compared to control (PBS).

[0049] [Figure 9]Figure 9 is a bar graph showing the results of the RSV A2 ELISA. Sera from female BALB / c mice (n=4 / group) 7 days post-infection were assayed for antibodies to RSV A2. Graphs show total IgG, IgG1, or IgG2a as determined by specific secondary antibodies. Included as controls are 131-2A (anti-F protein; IgG2a) or 131-2G (anti-G protein; IgG1), or a mixture of these monoclonal antibodies (total IgG). As expected, IgG levels were very low, since the serum was from a primary RSV A2 infection. Bars show the mean OD450 value + SEM of three independent experiments.

[0050] [Figure 10] Figure 10 is a graph of probenecid treatment against Mumps (Jones) virus. Cell lines were treated with probenecid 24 hours after virus infection. LOD = limit of detection.

[0051] [Figure 11] Figure 11 is a graph of probenecid treatment against Zika (MR766) virus. Cell lines were treated with probenecid 24 hours after virus infection. LOD = limit of detection.

[0052] [Figure 12] Figure 12 is a graph of probenecid treatment against Dengue 1 virus. Cell lines were treated with probenecid 24 hours after virus infection. LOD = limit of detection.

[0053] [Figure 13A]13A-13F are graphs of probenecid treatment against influenza viruses: influenza A Swine / Missouri / 2006 (13A, 13B), influenza A Vietnam / 2004 PR8 (13C, 13D), and influenza B / Malaysia / 2506 / 2004 (13E, 13F). Cell lines were treated with probenecid 24 hours after virus infection. LOD = limit of detection. [Figure 13BC] 13A-13F are graphs of probenecid treatment against influenza viruses: influenza A Swine / Missouri / 2006 (13A, 13B), influenza A Vietnam / 2004 PR8 (13C, 13D), and influenza B / Malaysia / 2506 / 2004 (13E, 13F). Cell lines were treated with probenecid 24 hours after virus infection. LOD = limit of detection. [Figure 13DE] 13A-13F are graphs of probenecid treatment against influenza viruses: influenza A Swine / Missouri / 2006 (13A, 13B), influenza A Vietnam / 2004 PR8 (13C, 13D), and influenza B / Malaysia / 2506 / 2004 (13E, 13F). Cell lines were treated with probenecid 24 hours after virus infection. LOD = limit of detection. [Figure 13F] 13A-13F are graphs of probenecid treatment against influenza viruses: influenza A Swine / Missouri / 2006 (13A, 13B), influenza A Vietnam / 2004 PR8 (13C, 13D), and influenza B / Malaysia / 2506 / 2004 (13E, 13F). Cell lines were treated with probenecid 24 hours after virus infection. LOD = limit of detection.

[0054] [Figure 14A]Figure 14A is a graph of probenecid protection against measles virus, scaling the mean number of syncytia per well (log10) against the concentration of probenecid (μM). Figures 14B and 14C are graphs of probenecid treatment prior to infection of Hep2 cells (14B) and Vero cells (14C) with measles virus (MOI=0.01). [Figure 14BC] Figure 14A is a graph of probenecid protection against measles virus, scaling the mean number of syncytia per well (log10) against the concentration of probenecid (μM). Figures 14B and 14C are graphs of probenecid treatment prior to infection of Hep2 cells (14B) and Vero cells (14C) with measles virus (MOI=0.01).

[0055] [Figure 15] Figure 15A is a flow chart showing the simulation plan for steady state concentration to reach IC90. Figure 15B is a flow chart showing the simulation plan for time to reach IC90.

[0056] [Figure 16] FIG. 16 is a graph showing the concentration-time profiles of probenecid stratified based on administered dose.

[0057] [Figure 17A] 17A-17D are goodness-of-fit plots showing actual vs. population (17A), actual vs. individual predicted (17B), conditional weighted residuals (CWRES) vs. population predicted (17C), and conditional weighted residuals (CWRES) vs. time (time after dosing (TAD)) (17D). [Figure 17BCD] 17A-17D are goodness-of-fit plots showing actual vs. population (17A), actual vs. individual predicted (17B), conditional weighted residuals (CWRES) vs. population predicted (17C), and conditional weighted residuals (CWRES) vs. time (time after dosing (TAD)) (17D).

[0058] [Fig. 18AB] 18A-18C are plots showing observed plasma value (DV)-time profiles and predicted plasma value (PRED)-time profiles. [Figure 18C] 18A-18C are plots showing observed plasma value (DV)-time profiles and predicted plasma value (PRED)-time profiles.

[0059] [Figure 19] FIG. 19 is a plot of simulated pharmacokinetic (PK) profiles following repeated dosing of probenecid at 600 mg and 900 mg.

[0060] [Figure 20] FIG. 20 is a plot of simulated pharmacokinetics of probenecid after repeated dosing at 1800 mg.

[0061] [Figure 21AB] Figures 21A-21D are plots of simulated pharmacokinetic (PK) profiles following repeated dosing of probenecid at 100 mg (21A), 500 mg (21B), 600 mg (21C), and 1800 mg (21D) once daily (qd). The IC90 level corrected for 95% protein binding is 2.08 μg / ml (shown by the dashed line). [Figure 21CD] Figures 21A-21D are plots of simulated pharmacokinetic (PK) profiles following repeated dosing of probenecid at 100 mg (21A), 500 mg (21B), 600 mg (21C), and 1800 mg (21D) once daily (qd). The IC90 level corrected for 95% protein binding is 2.08 μg / ml (shown by the dashed line).

[0062] [Diagram 22AB]Figures 22A-22D are plots of simulated pharmacokinetic (PK) profiles following repeated dosing of probenecid at 500 mg (22A), 600 mg (22B), 900 mg (22C), and 1000 mg (22D) twice daily (bid). The IC90 level corrected for 95% protein binding is 2.08 μg / ml (shown by the dashed line). [Fig. 22CD] Figures 22A-22D are plots of simulated pharmacokinetic (PK) profiles following repeated dosing of probenecid at 500 mg (22A), 600 mg (22B), 900 mg (22C), and 1000 mg (22D) twice daily (bid). The IC90 level corrected for 95% protein binding is 2.08 μg / ml (shown by the dashed line).

[0063] [Diagram 23] Figures 23A-23D are plots comparing probenecid at 10 mg / kg administered once daily (qd) (23C, 23D) or twice daily (bid) (23A, 23B) to female (23A, 23C) and male (23B, 23D) subjects (ages 2-10).

[0064] [Figure 24] 24A-24D are plots comparing probenecid at 20 mg / kg administered once daily (qd) (24C, 24D) or twice daily (bid) (24A, 24B) to female (24A, 24C) and male (24B, 24D) subjects (ages 2-10).

[0065] [Diagram 25] 25A-25F are plots showing a comparison of probenecid administered once daily (qd) at 10 mg / kg (25A, 25B), 20 mg / kg (25C, 25D), and 25 mg / kg (25E, 25F) to female (25A, 25C, 25E) and male (25B, 25D, 25F) subjects (ages 2-13).

[0066] [Fig. 26AB] 26A-26B are plots showing the results of plaque assays following prophylactic (24 hours pre-) or post-infection (24 hours post-) treatment with probenecid ("Treatment") in BALB / c male (26A) and female (26B) mice challenged intranasally with 1×106 PFU of hMPV CAN83 (A2 strain) mice (n=5 / sex / group). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0067] Detailed Description of the Invention I. Definition It should be understood that the compounds, compositions, and methods disclosed herein are not limited to specific synthetic methods, specific analytical techniques, or to specific reagents, unless otherwise specified, and thus may vary. It should also be understood that the terminology used herein is merely for the purpose of describing particular forms and embodiments, and is not intended to be limiting.

[0068] "Substituted," as used herein, refers to any permissible substituent of a compound or functional group described herein. In the broadest sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Exemplary substituents include, but are not limited to, halogens, hydroxyl groups, or any other organic radical containing any number of carbon atoms, preferably 1-14 carbon atoms, and optionally including one or more heteroatoms, e.g., oxygen, sulfur, or nitrogen groups, in a linear, branched, or cyclic structural format. Representative substituents include substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, halogen, hydroxyl, alkoxy, phenoxy, aroxy, silyl, thiol, alkylthio, substituted alkylthio, phenylthio, arylthio, cyano, isocyano, nitro, substituted or unsubstituted carbonyl, carboxyl, amino, amido, oxo, sulfinyl, sulfonyl, sulfonic acid, phosphonium, phosphanyl, phosphoryl, phosphonyl, amino acid. Such substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, halogen, hydroxyl, alkoxy, phenoxy, aroxy, silyl, thiol, alkylthio, substituted alkylthio, phenylthio, arylthio, cyano, isocyano, nitro, substituted or unsubstituted carbonyl, carboxyl, amino, amido, oxo, sulfinyl, sulfonyl, sulfonic acid, phosphonium, phosphanyl, phosphoryl, phosphonyl, and amino acids may be further substituted.

[0069] Heteroatoms such as nitrogen may have hydrogen substituents which satisfy the valences of the heteroatoms and / or any permissible substituents of organic compounds described herein. It is understood that "substituted" or "substituted" includes the implicit proviso that such substitution is subject to the allowed valences of the substituted atom and substituents, as well as that the substitution results in a stable compound, i.e., a compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, and the like.

[0070] "Alkyl," as used herein, refers to the radical of a saturated aliphatic group, including straight-chain alkyl groups, branched-chain alkyl groups, and cycloalkyl (alicyclic). In some forms, a straight-chain or branched-chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C for straight chain). 1 ~C 30 , C for branched chains 3 ~C 30 ), 20 or less, 15 or less, or 10 or less. Alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. Similarly, cycloalkyls are carbon-based non-aromatic rings made up of at least three carbon atoms, e.g., non-aromatic monocyclic or non-aromatic polycyclic rings containing 3-30 carbon atoms, 3-20 carbon atoms, or 3-10 carbon atoms in their ring structure, having 5, 6, or 7 carbons in the ring structure. Cycloalkyls containing polycyclic ring systems can have two or more non-aromatic rings in which two or more carbons are shared between two adjacent rings (i.e., "fused cycloalkyl rings"). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctanyl, and the like.

[0071] "Substituted alkyl" refers to an alkyl moiety in which a hydrogen on one or more carbons of the hydrocarbon backbone has been replaced by one or more substituents. Such substituents include any of the substituents described above, such as halogen (e.g., fluorine, chlorine, bromine, or iodine), hydroxyl, substituted or unsubstituted carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (e.g., thioester, thioacetic acid, or thioformic acid), aryl, alkoxyl, aralkyl, phosphonium, phosphanyl, phosphonyl, phosphoryl, phosphate, phosphonic acid, phosphinic acid, amino, amide, amidine, isopropyl, ethyl ... amine, cyano, nitro, azido, oxo, sulfhydryl, thiol, alkylthio, silyl, sulfinyl, sulfate, sulfonic acid, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, aromatic or heteroaromatic moieties, -NRR', where R and R' are independently hydrogen, alkyl, or aryl, and the nitrogen atom is optionally quaternized; -SR, where R is phosphonyl, sulfinyl, silyl, hydrogen, alkyl, or aryl; -CN; -NO 2 ;-COOH; carboxylic acid;-COR, -COOR, or -CON(R) 2 where R is hydrogen, alkyl, or aryl; imino, silyl, ether, haloalkyl (e.g., -CF, -CH 2 CF 3 , -CCl 3 etc.);-CN;-NCOCOCH 2 CH 2 -NCOCOCHCH; and -NCS; and combinations thereof.

[0072] It will be understood by those skilled in the art that, where appropriate, the substituted moieties on the hydrocarbon chain can themselves be substituted. For example, the substituents of substituted alkyl can include halogen, hydroxy, nitro, thiol, amino, aralkyl, azido, imino, amide, phosphonium, phosphanyl, phosphoryl (including phosphonic acid and phosphinic acid), oxo, sulfonyl (including sulfate, sulfonamide, sulfamoyl and sulfonic acid), and silyl groups, as well as ether, alkylthio, substituted or unsubstituted carbonyl (including ketone, aldehyde, carboxylic acid, and ester), haloalkyl, -CN, and the like. Cycloalkyl can also be substituted in the same manner.

[0073] Unless the number of carbons is specifically indicated, "lower alkyl," as used herein, means an alkyl group as defined above, but having from 1 to 10 carbons, more preferably 1 to 6 carbon atoms, in its backbone structure. Similarly, "lower alkenyl" and "lower alkynyl" have similar chain lengths.

[0074] "Heteroalkyl" as used herein refers to a straight or branched chain or cyclic carbon-containing alkyl radical, or combination thereof, containing at least one heteroatom in the carbon backbone. Suitable heteroatoms include, but are not limited to, O, N, Si, P and S, where the nitrogen, phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. For example, the term "heterocycloalkyl group" refers to a cycloalkyl group as defined above, where at least one of the carbon atoms of the ring is replaced by a heteroatom, such as, but not limited to, nitrogen, oxygen, sulfur or phosphorus.

[0075] The term "alkenyl" as used herein is a hydrocarbon group of structural formula containing at least one carbon-carbon double bond, from 2 to 24 carbon atoms. Alkenyl groups include straight chain alkenyl groups, branched chain alkenyl, and cycloalkenyl. Cycloalkenyl is a carbon-based non-aromatic ring composed of at least three carbon atoms and at least one carbon-carbon double bond, for example, a non-aromatic monocyclic or polycyclic ring containing 3-30 carbon atoms and at least one carbon-carbon double bond, 3-20 carbon atoms and at least one carbon-carbon double bond, or 3-10 carbon atoms and at least one carbon-carbon double bond in the ring structure, having 5, 6, or 7 carbons and at least one carbon-carbon double bond in the ring structure. Cycloalkenyls containing polycyclic ring systems may have two or more non-aromatic rings in which two or more carbons are shared between two adjacent rings (i.e., "fused cycloalkenyl rings") and contain at least one carbon-carbon double bond. Asymmetric structures such as (AB)C=C(C'D) are intended to include both E and Z isomers. This may be inferred for structural formulas herein in which an asymmetric alkene is present, or may be explicitly indicated by the bond symbol C. The term "alkenyl" as used throughout the specification, examples, and claims is intended to include both "unsubstituted alkenyl" and "substituted alkenyl", the latter referring to one in which a hydrogen on one or more carbons of the hydrocarbon backbone of the alkenyl moiety is replaced by one or more substituents. The term "alkenyl" also encompasses "heteroalkenyl".

[0076] The term "substituted alkenyl" refers to one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone of the alkenyl moiety replaced by one or more substituents. Such substituents may be any of the substituents described above, such as halogen, azido, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, substituted or unsubstituted carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thiocarbonyl (e.g., thioester, thioacetic acid, or thioformic acid), alkoxyl, phosphonium, phosphanyl, phosphoryl, phosphate, phosphonic acid, phosphinic acid, amino (e.g., quaternized amino), amide, amidine, imine, cyano, nitro, azido, oxo, sulfhydryl, alkylthio, sulfate, sulfonic acid, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof.

[0077] "Heteroalkenyl" as used herein refers to a straight or branched chain or cyclic carbon-containing alkenyl radical, or combination thereof, containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P, and S, where the nitrogen, phosphorus, and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. For example, the term "heterocycloalkenyl group" refers to a cycloalkenyl group in which at least one of the ring carbon atoms is replaced by a heteroatom, such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.

[0078] The term "alkynyl group" as used herein is a hydrocarbon group of structural formula containing 2-24 carbon atoms and at least one carbon-carbon triple bond. Alkynyl groups include straight chain alkynyl groups, branched chain alkynyl, and cycloalkynyl. Cycloalkynyl is a carbon-based non-aromatic ring composed of at least three carbon atoms and at least one carbon-carbon triple bond, for example, a non-aromatic monocyclic or polycyclic ring containing 3-30 carbon atoms and at least one carbon-carbon triple bond, 3-20 carbon atoms and at least one carbon-carbon triple bond, or 3-10 carbon atoms and at least one carbon-carbon triple bond in the ring structure, and having 5, 6, or 7 carbons and at least one carbon-carbon triple bond in the ring structure. Cycloalkynyl containing polycyclic ring systems may have two or more non-aromatic rings in which two or more carbons are shared between two adjacent rings (i.e., "fused cycloalkynyl rings") and contain at least one carbon-carbon triple bond. Asymmetric structures such as (AB)C≡C(C"D) are intended to include both E and Z isomers. This may be inferred for structural formulas herein in which an asymmetric alkyne is present, or may be explicitly indicated by the bond symbol C. The term "alkynyl" as used throughout the specification, examples, and claims is intended to include both "unsubstituted alkynyl" and "substituted alkynyl", the latter of which refers to one in which a hydrogen on one or more carbons of the hydrocarbon backbone of the alkynyl moiety is replaced by one or more substituents. The term "alkynyl" also encompasses "heteroalkynyl".

[0079] The term "substituted alkynyl" refers to one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone of the alkynyl moiety replaced by one or more substituents. Such substituents may be any of the substituents described above, such as halogen, azido, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, substituted or unsubstituted carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thiocarbonyl (e.g., thioester, thioacetic acid, or thioformic acid), alkoxyl, phosphonium, phosphanyl, phosphoryl, phosphate, phosphonic acid, phosphinic acid, amino (e.g., quaternized amino), amide, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonic acid, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof.

[0080] "Heteroalkynyl" as used herein refers to a straight or branched chain or cyclic carbon-containing alkynyl radical, or combination thereof, containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P and S, where the nitrogen, phosphorus and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. For example, the term "heterocycloalkynyl group" refers to a cycloalkynyl group in which at least one of the carbon atoms of the ring is replaced by a heteroatom, such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.

[0081] "Aryl" as used herein means C 5 ~C 26 It refers to a fused aromatic ring system. Examples of aromatic groups are benzene, naphthalene, anthracene, phenanthrene, chrysene, pyrene, corannulene, coronene, and the like.

[0082] The term "substituted aryl" refers to an aryl group in which one or more hydrogen atoms on one or more aromatic rings are substituted with, but not limited to, halogen, azido, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxy, substituted or unsubstituted carbonyl (such as, for example, ketone, aldehyde, carboxyl, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thiocarbonyl (such as, for example, thioester, thioacetic acid, or thioformic acid), alkoxyl, phosphoryl, phosphate, phosphonic acid, phosphinic acid, amino (or quaternized amino), amide, amidine, imine, cyano, nitro, azido, sulfhydryl, imino, alkylthio, sulfate, sulfonic acid, sulfamoyl, sulfoxide, sulfonamide, sulfonyl, heterocyclyl, alkylaryl, haloalkyl (such as, for example, CF 3 , -CH 2 -CF 3 , -CCl 3 and the like), -CN, aryl, heteroaryl, and combinations thereof.

[0083] "Heterocycle" and "heterocyclyl" are used interchangeably and refer to a non-aromatic monocyclic or polycyclic ring containing 3 to 30 ring atoms, 3 to 20 ring atoms, 3 to 10 ring atoms, or 5 to 6 ring atoms to which a cyclic radical is attached via a ring carbon or nitrogen atom, where each ring is composed of carbon and each of the non-peroxide oxygen, sulfur, and N(Y), where Y is absent or is selected from the group consisting of H, O, C, H ... 1 ~C 10Heterocyclic groups may be optionally substituted with one or more substituents, such as heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, etc., such as piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, dihydrofuro[2,3-b]tetrahydrofuran, morpholinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pyranyl, 2H-pyrrolyl, 4H-quinolizinyl, quinuclidinyl, tetrahydrofuranyl, 6H-1,2,5-thiadiazinyl. Heterocyclic groups may be optionally substituted with one or more substituents, as defined above for alkyl and aryl.

[0084] The term "heteroaryl" refers to 5 ~C 26It refers to a fused aromatic ring system in which one or more carbon atoms on one or more aromatic ring structures are replaced by heteroatoms. Suitable heteroatoms include, but are not limited to, oxygen, sulfur, and nitrogen. Examples of heteroaryl groups include pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine.Examples of heteroaryl rings include, but are not limited to, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5, 2-Dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolinyl, 1,2,3-oxadiazolyl , 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridox ... Examples of heteroaryl include lysinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thiophenyl, and xanthenyl. As defined below for "substituted heteroaryl," one or more of the rings may be substituted.

[0085] The term "substituted heteroaryl" refers to an alkyl group in which one or more hydrogen atoms on one or more heteroaromatic rings of a heteroaryl group are substituted with, but not limited to, a halogen, azido, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxy, substituted or unsubstituted carbonyl (e.g., ketone, aldehyde, carboxyl, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thiocarbonyl (e.g., thioester, thioacetic acid, or thioformic acid), alkoxyl, phosphoryl, phosphate, phosphonic acid, phosphinic acid, amino (or quaternized amino), amide, amidine, imine, cyano, nitro, azido, sulfhydryl, imino, alkylthio, sulfate, sulfonic acid, sulfamoyl, sulfoxide, sulfonamide, sulfonyl, heterocyclyl, alkylaryl, haloalkyl (e.g., CF 3 , -CH 2 -CF 3 , -CCl 3 and the like), -CN, aryl, heteroaryl, and combinations thereof.

[0086] The term "polyaryl" refers to a chemical moiety that contains two or more fused aryl groups. When two or more fused heteroaryl groups are involved, the chemical moiety can be referred to as a "polyheteroaryl."

[0087] The term "substituted polyaryl" refers to a polyaryl in which one or more of the aryls are substituted with one or more substituents, including, but not limited to, halogen, azido, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, substituted or unsubstituted carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thiocarbonyl (e.g., thioester, thioacetic acid, or thioformic acid), alkoxyl, phosphoryl, phosphate, phosphonic acid, phosphinic acid, amino (or quaternized amino), amide, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonic acid, sulfamoyl, sulfoxide, sulfonamide, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, and combinations thereof. When polyheteroaryl is involved, the chemical moiety may be referred to as a "substituted polyheteroaryl."

[0088] The term "cyclic ring" or "cyclic group" refers to a substituted or unsubstituted monocyclic ring or a substituted or unsubstituted polycyclic ring (such as, for example, those formed from a single ring or a fused ring system), such as a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, or substituted or unsubstituted heterocyclyl, having from 3 to 30 carbon atoms, permitted with respect to geometric constraints. Substituted cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl are substituted as defined above for alkyl, alkenyl, alkynyl, and heterocyclyl, respectively.

[0089] The term "aralkyl," as used herein, refers to an aryl or heteroaryl group to which an alkyl, alkynyl, or alkenyl group, as defined above, is attached to an aromatic group, such as the aryl, heteroaryl, polyaryl, or polyheteroaryl of the aryl or heteroaryl group. An example of an aralkyl group is the benzyl group.

[0090] The term "alkoxyl" or "alkoxy" generally refers to a group of the formula -OR v wherein R v Examples include, but are not limited to, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted alkylheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, phosphonium, phosphanyl, phosphonyl, sulfinyl, silyl, thiol, amido, and amino. Exemplary alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy, and the like. A "lower alkoxy" group is an alkoxy group containing 1 to 6 carbon atoms. An "ether" is a difunctional group covalently linked by an oxygen as defined below. Thus, the substituent of an alkyl that renders it an ether is or resembles an alkoxyl and can be represented, for example, by one of -O-alkyl, -O-alkenyl, -O-alkynyl, -O-arakyl, -O-aryl, -O-heteroaryl, -O-polyaryl, -O-polyheteroaryl, -O-heterocyclyl, and the like. R v When R is a substituted group, vwherein one or more hydrogen atoms on one or more carbons are replaced by one or more substituents. Such substituents may be any of the above-mentioned substituents, for example, halogen, azido, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, substituted or unsubstituted carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thiocarbonyl (e.g., thioester, thioacetic acid, or thioformic acid), alkoxyl, phosphonium, phosphanyl, phosphoryl, phosphate, phosphonic acid, phosphinic acid, amino (e.g., quaternized amino), amide, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, oxo, sulfate, sulfonic acid, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, and combinations thereof.

[0091] The term "ether" as used herein refers to a compound of formula A 2 Office Automation 1 In the formula, A 2 and A 1 may independently be substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, phosphonium, phosphanyl, phosphonyl, sulfinyl, silyl, thiol, substituted or unsubstituted carbonyl, alkoxy, amido, or amino as described above.

[0092] The term "polyether" as used herein refers to a polyether having the formula: [ka] In the formula, A 3may independently be substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, phosphonium, phosphanyl, substituted or unsubstituted carbonyl, alkoxy, amido, or amino as described above, and g may be a positive integer from 1 to 30.

[0093] The term "phenoxy" is art recognized and refers to a group of the formula -OR v In the formula, R v is C 6 H 5 (i.e., -OC 6 H 5 It is understood by those of skill in the art that phenoxy is a member of the alkoxyl and aroxy genus.

[0094] The term "substituted phenoxy" refers to a phenoxy group, as defined above, in which one or more hydrogen atoms on one or more carbons of the phenyl ring are replaced by one or more substituents, including, but not limited to, halogen, azido, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, substituted or unsubstituted carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thiocarbonyl (e.g., thioester, thioacetic acid, or thioformic acid), alkoxyl, phosphonium, phosphanyl, phosphanyl, phosphoryl, phosphate, phosphonic acid, phosphinic acid, amino (e.g., quaternized amino), amide, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonic acid, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, and combinations thereof.

[0095] The terms "aroxy" and "aryloxy" are used interchangeably herein and are represented by -O-aryl or -O-heteroaryl, where aryl and heteroaryl are defined herein. It will be understood by one of ordinary skill in the art that aroxy or aryloxy are species of the alkoxyl genus.

[0096] The terms "substituted aroxy" and "substituted aryloxy" are used interchangeably herein and refer to -O-aryl or -O-heteroaryl in which one or more hydrogen atoms on one or more ring atoms of the aryl and heteroaryl are replaced by one or more substituents, as defined herein. Such substituents may be any of the substituents described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, substituted or unsubstituted carbonyl (such as, for example, carboxyl, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thiocarbonyl (such as, for example, thioester, thioacetic acid, or thioformic acid), alkoxyl, phosphonium, phosphanyl, phosphanyl, phosphoryl, phosphate, phosphonic acid, phosphinic acid, amino (e.g., quaternized amino), amide, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonic acid, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof.

[0097] The term "amino" as used herein refers to the following group: [ka] wherein E is absent or E is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl, and independently of E is R x , R xi , and R xii are each independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl, hydroxyl, alkoxy, phosphonium, phosphanyl, phosphonyl, sulfinyl, silyl, thiol, amido, amino, or -(CH 2 ) m -R''', where R''' represents a hydroxyl group, a substituted or unsubstituted carbonyl group, a substituted or unsubstituted aryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, an alkoxy, a phosphonium, a phosphanyl, an amido, or an amino; and m is zero or an integer ranging from 1 to 8. The term "quaternary amino" refers to any group selected from the group consisting of nitrogen, R x , R xi , and R xii However, the N +as well as groups completing heterocyclyl or heteroaryl having from 3 to 14 atoms in the ring structure. It will be understood by those of ordinary skill in the art that the E groups listed above are divalent (e.g., methylene, ethane-1,2-diyl, ethene-1,2-diyl, 1,4-phenylene, cyclohexane-1,2-diyl).

[0098] The terms "amide" or "amido" are used interchangeably and refer to both "unsubstituted amides" and "substituted amides" and have the general formula: [ka] wherein E is absent or E is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, or substituted or unsubstituted heterocyclyl; and independently of E, R and R' are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl, hydroxyl, alkoxy, phosphonium, phosphanyl, phosphonyl, sulfinyl, silyl, thiol, amido, amino, or -(CH 2 ) mrepresents -R''', or R and R' together with the N atom to which they are attached complete a heterocycle having from 3 to 14 atoms in the ring structure; R''' represents a hydroxyl group, a substituted or unsubstituted carbonyl group, a substituted or unsubstituted aryl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted polyheteroaryl, an alkoxy, a phosphonium, a phosphanyl, an amido, or an amino; m is zero or an integer ranging from 1 to 8. In some forms, when E is oxygen, a carbamate is formed. It will be understood by those skilled in the art that the E groups listed above are divalent (e.g., methylene, ethane-1,2-diyl, ethene-1,2-diyl, 1,4-phenylene, cyclohexane-1,2-diyl).

[0099] "Carbonyl" as used herein is art-recognized and refers to a radical having the general formula: [ka] where X is a bond or represents oxygen or sulfur, and R is hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted heterocyclyl, unsubstituted aralkyl (e.g., unsubstituted alkylaryl, unsubstituted arylalkyl), unsubstituted aryl, unsubstituted heteroaryl, unsubstituted polyaryl, unsubstituted polyheteroaryl, unsubstituted heterocyclyl, hydroxyl, alkoxy, phosphonium, phosphanyl, amido, amino, or -(CH 2 ) mE" is absent or E" is unsubstituted alkylene, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted aralkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted polyaryl, unsubstituted polyheteroaryl, unsubstituted heterocyclyl; R' is hydrogen, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted heterocyclyl, unsubstituted aralkyl (e.g., unsubstituted alkylaryl, unsubstituted arylalkyl), unsubstituted aryl, unsubstituted heteroaryl, unsubstituted polyaryl, unsubstituted polyheteroaryl, unsubstituted heterocyclyl, hydroxyl, alkoxy, phosphonium, phosphanyl, amido, amino, or -(CH 2 ) m -R"; R" represents hydroxyl, unsubstituted aryl, unsubstituted cycloalkyl, unsubstituted cycloalkenyl, unsubstituted heterocyclyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted polyaryl, unsubstituted polyheteroaryl, alkoxy, phosphonium, phosphanyl, amido, or amino; m is zero or an integer ranging from 1 to 8. It will be understood by those of skill in the art that the E" groups listed above are divalent (e.g., methylene, ethane-1,2-diyl, ethene-1,2-diyl, 1,4-phenylene, cyclohexane-1,2-diyl). When X is oxygen and R is defined as above, the moiety is also referred to as a carboxyl group. When X is oxygen and R is hydrogen, the formula represents a "carboxylic acid". When X is oxygen and R' is hydrogen, the formula represents a "formic acid". When X is oxygen and R or R' is not hydrogen, the formula represents an "ester". In general, when the oxygen atom of the above formula is replaced by a sulfur atom, the formula represents a "thiocarbonyl" group. When X is a sulfur and R or R' is not hydrogen, the formula represents a "thioester". When X is a sulfur and R is hydrogen, the formula represents a "thiocarboxylic acid". When X is a sulfur and R' is hydrogen, the formula represents a "thioformic acid". When X is a bond and R is not hydrogen, the above formula represents a "ketone". When X is a bond and R is hydrogen, the above formula represents an "aldehyde".

[0100] The term "substituted carbonyl" refers to a carbonyl as defined above in which one or more hydrogen atoms of R, R', and / or E" are independently replaced. Such substituents include any of the substituents described above, for example, halogen, azido, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thiocarbonyl (e.g., thioester, thioacetic acid, or thioformic acid), alkoxyl, phosphonium, phosphanyl, phosphoryl, etc. , phosphate, phosphonate, phosphinate, amino (e.g., quaternized amino), amide, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, and combinations thereof. It will be understood by those of skill in the art that the E and E" groups listed above are divalent (e.g., methylene, ethane-1,2-diyl, ethene-1,2-diyl, 1,4-phenylene, cyclohexane-1,2-diyl).

[0101] The term "phosphanyl" means a phosphatase having the formula [ka] wherein E is absent or E is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl, and independently of E is R vi and R viiare each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, etc.), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl, hydroxyl, alkoxy, phosphonium, phosphanyl, phosphonyl, sulfinyl, silyl, thiol, amido, amino, or -(CH 2 ) m -R''' or R vi and R viitogether with the P atom to which they are attached complete a heterocycle having from 3 to 14 atoms in the ring structure; R''' represents a hydroxyl group, a substituted or unsubstituted carbonyl group, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, alkoxy, phosphonium, phosphanyl, amido, or amino; m is zero or an integer ranging from 1 to 8. The substituents may be any of the above-mentioned substituents, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, substituted or unsubstituted carbonyl (such as, for example, carboxyl, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thiocarbonyl (such as, for example, thioester, thioacetic acid, or thioformic acid), alkoxyl, phosphoryl, phosphate, phosphonic acid, phosphinic acid, amino (e.g., quaternized amino), amide, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonic acid, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof. It will be understood by those of ordinary skill in the art that the E groups listed above are divalent (eg, methylene, ethane-1,2-diyl, ethene-1,2-diyl, 1,4-phenylene, cyclohexane-1,2-diyl).

[0102] The term "phosphonium" refers to a compound of the formula [ka] wherein E is absent or E is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl, and independently of E is R vi , R vii , and R viii are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, etc.), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl, hydroxyl, alkoxy, phosphonium, phosphanyl, phosphonyl, sulfinyl, silyl, thiol, amido, amino, or -(CH 2 ) m -R''' or R vi , R vii , and R viii The P to which they are attached +together with the atoms complete a heterocycle having from 3 to 14 atoms in the ring structure; R''' represents a hydroxyl group, a substituted or unsubstituted carbonyl group, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, alkoxy, phosphonium, phosphanyl, amido, or amino; and m is zero or an integer ranging from 1 to 8. The substituents may be any of the above-mentioned substituents, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, substituted or unsubstituted carbonyl (such as, for example, carboxyl, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thiocarbonyl (such as, for example, thioester, thioacetic acid, or thioformic acid), alkoxyl, phosphoryl, phosphate, phosphonic acid, phosphinic acid, amino (e.g., quaternized amino), amide, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonic acid, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof. It will be understood by those of ordinary skill in the art that the E groups listed above are divalent (eg, methylene, ethane-1,2-diyl, ethene-1,2-diyl, 1,4-phenylene, cyclohexane-1,2-diyl).

[0103] The term "phosphonyl" refers to a group of the formula [ka] wherein E is absent or E is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, etc.), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl, oxygen, alkoxy, aroxy, or substituted alkoxy or substituted aroxy, and independently of E, R vi and R vii are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, etc.), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl, hydroxyl, alkoxy, phosphonium, phosphanyl, phosphonyl, sulfinyl, silyl, thiol, amido, amino, or -(CH 2 ) m -R''' or R vi and R viitogether with the P atom to which they are attached complete a heterocycle having from 3 to 14 atoms in the ring structure; R''' represents a hydroxyl group, a substituted or unsubstituted carbonyl group, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, alkoxy, phosphonium, phosphanyl, amido, or amino; m is zero or an integer ranging from 1 to 8. The substituents may be any of the above-mentioned substituents, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, substituted or unsubstituted carbonyl (such as, for example, carboxyl, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thiocarbonyl (such as, for example, thioester, thioacetic acid, or thioformic acid), alkoxyl, phosphoryl, phosphate, phosphonic acid, phosphinic acid, amino (e.g., quaternized amino), amide, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonic acid, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof. It will be understood by those of ordinary skill in the art that the E groups listed above are divalent (eg, methylene, ethane-1,2-diyl, ethene-1,2-diyl, 1,4-phenylene, cyclohexane-1,2-diyl).

[0104] The term "phosphoryl" refers to the formula of phosphonyl where E is absent, oxygen, alkoxy, aroxy, substituted alkoxy, or substituted aroxy, as defined above, and independently of E, R vi and R viiis defined as being independently hydroxyl, alkoxy, aroxy, substituted alkoxy or substituted aroxy as defined above. As will be appreciated by those of skill in the art, when E is oxygen, the phosphoryl cannot be attached to another chemical species to form, for example, an oxygen-oxygen bond or other labile bond. E, R vi and R vii When is substituted, the substituents include, but are not limited to, halogen, azido, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, substituted or unsubstituted carbonyl (such as, for example, carboxyl, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thiocarbonyl (such as, for example, thioester, thioacetic acid, or thioformic acid), alkoxyl, phosphoryl, phosphate, phosphonic acid, phosphinic acid, amino (e.g., quaternized amino), amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonic acid, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof. It will be understood by those of ordinary skill in the art that the E groups listed above are divalent (eg, methylene, ethane-1,2-diyl, ethene-1,2-diyl, 1,4-phenylene, cyclohexane-1,2-diyl).

[0105] The term "sulfinyl" means a group of the formula: [ka] wherein E is absent or E is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, etc.), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl; and independently of E, R is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl, hydroxyl, alkoxy, phosphonium, phosphanyl, phosphonyl, silyl, thiol, amido, amino, or -(CH 2 ) m-R''', or E and R together with the S atom to which they are attached complete a heterocycle having from 3 to 14 atoms in the ring structure; R''' represents a hydroxyl group, a substituted or unsubstituted carbonyl group, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, alkoxy, phosphonium, phosphanyl, amido, or amino; m is zero or an integer ranging from 1 to 8. The substituents may be any of the above-mentioned substituents, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, substituted or unsubstituted carbonyl (such as, for example, carboxyl, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thiocarbonyl (such as, for example, thioester, thioacetic acid, or thioformic acid), alkoxyl, phosphoryl, phosphate, phosphonic acid, phosphinic acid, amino (e.g., quaternized amino), amide, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonic acid, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof. It will be understood by those of ordinary skill in the art that the E groups listed above are divalent (eg, methylene, ethane-1,2-diyl, ethene-1,2-diyl, 1,4-phenylene, cyclohexane-1,2-diyl).

[0106] The term "sulfonyl" refers to a group of the formula: [ka] wherein E is absent or E is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, etc.), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl; and independently of E, R is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl, hydroxyl, alkoxy, phosphonium, phosphanyl, amido, amino, or -(CH 2 ) m-R''', or E and R together with the S atom to which they are attached complete a heterocycle having from 3 to 14 atoms in the ring structure; R''' represents a hydroxyl group, a substituted or unsubstituted carbonyl group, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, alkoxy, phosphonium, phosphanyl, amido, or amino; m is zero or an integer ranging from 1 to 8. The substituents may be any of the above-mentioned substituents, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, substituted or unsubstituted carbonyl (such as, for example, carboxyl, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thiocarbonyl (such as, for example, thioester, thioacetic acid, or thioformic acid), alkoxyl, phosphoryl, phosphate, phosphonic acid, phosphinic acid, amino (e.g., quaternized amino), amide, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonic acid, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof. It will be understood by those of ordinary skill in the art that the E groups listed above are divalent (eg, methylene, ethane-1,2-diyl, ethene-1,2-diyl, 1,4-phenylene, cyclohexane-1,2-diyl).

[0107] The term "sulfonic acid" refers to the sulfonyl formula defined above, where R is hydroxyl and E is absent or E is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, or substituted or unsubstituted heteroaryl. The substituents may be any of the above-mentioned substituents, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, substituted or unsubstituted carbonyl (such as, for example, carboxyl, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thiocarbonyl (such as, for example, thioester, thioacetic acid, or thioformic acid), alkoxyl, phosphoryl, phosphate, phosphonic acid, phosphinic acid, amino (e.g., quaternized amino), amide, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonic acid, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof. It will be understood by those of ordinary skill in the art that the E groups listed above are divalent (eg, methylene, ethane-1,2-diyl, ethene-1,2-diyl, 1,4-phenylene, cyclohexane-1,2-diyl).

[0108] The term "sulfate" refers to the sulfonyl formula defined above where E is absent, oxygen, alkoxy, aroxy, substituted alkoxy, or substituted aroxy, as defined above, and R is independently hydroxyl, alkoxy, aroxy, substituted alkoxy, or substituted aroxy, as defined above. As will be understood by one of skill in the art, when E is oxygen, the sulfate cannot be attached to another chemical species to form, for example, an oxygen-oxygen bond, or other labile bond. The substituents may be any of the above-mentioned substituents, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, substituted or unsubstituted carbonyl (such as, for example, carboxyl, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thiocarbonyl (such as, for example, thioester, thioacetic acid, or thioformic acid), alkoxyl, phosphoryl, phosphate, phosphonic acid, phosphinic acid, amino (e.g., quaternized amino), amide, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonic acid, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof. It will be understood by those of ordinary skill in the art that the E groups listed above are divalent (eg, methylene, ethane-1,2-diyl, ethene-1,2-diyl, 1,4-phenylene, cyclohexane-1,2-diyl).

[0109] The term "sulfonic acid" refers to a group consisting of the sulfonyl formula defined above, where E is oxygen, alkoxy, aroxy, substituted alkoxy, or substituted aroxy as defined above, and R is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, -(CH 2 ) m -R''', where R''' represents a hydroxy group, a substituted or unsubstituted carbonyl group, an aryl, a cycloalkyl ring, a cycloalkenyl ring, a heterocycle, an amide, an amino, or a polycycle; and m is zero or an integer ranging from 1 to 8. As will be understood by one of ordinary skill in the art, when E is oxygen, the sulfonic acid cannot be attached to another chemical species to form, for example, an oxygen-oxygen bond, or other labile bond. The substituents may be any of the above-mentioned substituents, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, substituted or unsubstituted carbonyl (such as, for example, carboxyl, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thiocarbonyl (such as, for example, thioester, thioacetic acid, or thioformic acid), alkoxyl, phosphoryl, phosphate, phosphonic acid, phosphinic acid, amino (e.g., quaternized amino), amide, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonic acid, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof. It will be understood by those of ordinary skill in the art that the E groups listed above are divalent (eg, methylene, ethane-1,2-diyl, ethene-1,2-diyl, 1,4-phenylene, cyclohexane-1,2-diyl).

[0110] The term "sulfamoyl" refers to a group of the formula: [ka] wherein E is absent or E is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted cycloalkyl, etc.), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl, and independently of E, R and R' are each independently hydrogen, Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, etc.), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl, hydroxyl, alkoxy, phosphonium, phosphanyl, amido, amino, or -(CH 2 ) mrepresents -R''', or R and R' together with the N atom to which they are attached complete a heterocycle having from 3 to 14 atoms in the ring structure; R''' represents a hydroxyl group, a substituted or unsubstituted carbonyl group, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, alkoxy, phosphonium, phosphanyl, amido, or amino; m is zero or an integer ranging from 1 to 8. The substituents may be any of the above-mentioned substituents, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, substituted or unsubstituted carbonyl (such as, for example, carboxyl, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thiocarbonyl (such as, for example, thioester, thioacetic acid, or thioformic acid), alkoxyl, phosphoryl, phosphate, phosphonic acid, phosphinic acid, amino (e.g., quaternized amino), amide, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonic acid, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof. It will be understood by those of ordinary skill in the art that the E groups listed above are divalent (eg, methylene, ethane-1,2-diyl, ethene-1,2-diyl, 1,4-phenylene, cyclohexane-1,2-diyl).

[0111] The term "silyl group," as used herein, is represented by the formula -SiRR'R", where R, R', and R" can independently be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, etc.), substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted carbonyl, phosphonium, phosphanyl, phosphonyl, sulfinyl, thiol, amido, amino, alkoxy, or oxo, as described above. The substituents may be any of the above-mentioned substituents, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, substituted or unsubstituted carbonyl (such as, for example, carboxyl, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thiocarbonyl (such as, for example, thioester, thioacetic acid, or thioformic acid), alkoxyl, phosphoryl, phosphate, phosphonic acid, phosphinic acid, amino (e.g., quaternized amino), amide, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonic acid, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof.

[0112] The term "thiol" is used interchangeably with and is represented by -SR, where R can be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted arylalkyl, etc.), substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted carbonyl, phosphonium, phosphanyl, amido, amino, alkoxy, oxo, phosphonyl, sulfinyl, or silyl as described above. The substituents may be any of the above-mentioned substituents, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, substituted or unsubstituted carbonyl (such as, for example, carboxyl, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thiocarbonyl (such as, for example, thioester, thioacetic acid, or thioformic acid), alkoxyl, phosphoryl, phosphate, phosphonic acid, phosphinic acid, amino (e.g., quaternized amino), amide, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonic acid, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof.

[0113] The term "phenylthio" is art-recognized and includes the term -SC 6 H 5 i.e., a phenyl group attached to a sulfur atom. Those skilled in the art will appreciate that phenylthio is a member of the thiol genus.

[0114] The term "substituted phenylthio" refers to a phenylthio group defined above in which a hydrogen on one or more carbons of the phenyl ring is replaced with one or more substituents, including, but not limited to, halogen, azido, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, substituted or unsubstituted carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thiocarbonyl (e.g., thioester, thioacetic acid, or thioformic acid), alkoxyl, phosphonium, phosphanyl, phosphoryl, phosphate, phosphonic acid, phosphinic acid, amino (e.g., quaternized amino), amide, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonic acid, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, and combinations thereof.

[0115] The compounds and substituents disclosed herein may independently have two or more of the groups listed above. For example, if the compound or substituent is a straight chain alkyl group, one of the hydrogen atoms of the alkyl group may be replaced by a hydroxyl group, an alkoxy group, etc. Depending on the group selected, the first group may be incorporated into the second group, or the first group may be attached (i.e., attached) to the second group. For example, in the phrase "an alkyl group containing an ester group," the ester group may be incorporated into the backbone of the alkyl group. Alternatively, the ester may be attached to the backbone of the alkyl group. The nature of the group selected will determine whether the first group is embedded or attached to the second group.

[0116] Compounds and substituents may be independently substituted with substituents described above in the definition of "substituted."

[0117] "Analog" in the context of a given compound refers to another compound that is structurally similar, functionally similar, or both to the named compound. Structural similarity can be determined using any criteria known in the art, such as the Tanimoto coefficient, which provides a quantitative measure of similarity between two compounds based on their molecular identifiers. The molecular identifiers are preferably 2D properties such as fingerprints, topology indices, and maximum common substructures, or 3D properties such as overall shape and molecular field. The Tanimoto coefficient ranges between zero and one, inclusive, with zero being dissimilar pairs of molecules and one being identical pairs of molecules. A compound can be considered an analog of a named compound if its Tanimoto coefficient for the named compound is between 0.5 and 1.0, inclusive, preferably between 0.7 and 1.0, inclusive, and most preferably between 0.85 and 1.0, inclusive. A compound is functionally similar to a named compound if it induces the same pharmacological effect, physiological action, or both as the named compound. "Analog" can also refer to modifications, including but not limited to, hydrolysis, reduction, or oxidation products of the compounds disclosed herein. Hydrolysis, reduction, and oxidation reactions are known in the art.

[0118] As used herein, the terms "individual," "host," "subject," and "patient" are used interchangeably herein and refer to animals, particularly birds and mammals, including, but not limited to, primates such as humans, bats, rodents such as mice and rats, and other laboratory animals, or farm or domesticated animals.

[0119] As used herein, the term "effective amount" or "therapeutically effective amount" refers to a dosage sufficient to treat, inhibit or alleviate one or more symptoms of the condition being treated, or otherwise produce a desired pharmacological and / or physiological effect. The exact dosage will vary depending on a variety of factors, including those that vary depending on the subject (e.g., age, immune system health, etc.), the disease, and the treatment being administered.

[0120] As used herein, the term "carrier" or "excipient" refers to an organic or inorganic ingredient, natural or synthetic, inert ingredient in a formulation with which one or more active ingredients are combined.

[0121] As used herein, the term "pharmacologically acceptable" means a non-toxic material that does not interfere with the effectiveness of the biological activity of the active ingredients.

[0122] As used herein, the term "treatment" refers to the medical management of a patient with the intention of curing, ameliorating, stabilizing, or preventing a disease, pathological condition, or disorder. This term includes active treatment, i.e., treatment that is specifically aimed at improving the disease, pathological condition, or disorder, and also includes causal therapy (treatment), i.e., treatment that is aimed at eliminating the cause of the associated disease, pathological condition, or disorder. In addition, this term includes palliative treatment, i.e., treatment designed to relieve symptoms rather than cure the disease, pathological condition, or disorder; preventive treatment, i.e., treatment that is aimed at minimizing or partially or completely inhibiting the occurrence of the associated disease, pathological condition, or disorder; and supportive treatment, i.e., treatment used to supplement another specific treatment that is aimed at improving the associated disease, pathological condition, or disorder.

[0123] Recitation of ranges of values ​​herein, unless otherwise stated herein, is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, and each separate value is incorporated herein the same as if each separate value was individually set forth herein.

[0124] Use of the term "about" is intended to describe values ​​that are approximately + / - 10% above or below the stated value. In other forms, values ​​may fall within a range of values ​​that are approximately + / - 5% above or below the stated value. In other forms, values ​​may fall within a range of values ​​that are approximately + / - 2% above or below the stated value. In other forms, values ​​may fall within a range of values ​​that are approximately + / - 1% above or below the stated value. The foregoing ranges are intended to be clear from the context and do not imply further limitation.

[0125] Numerical ranges individually disclose each possible number that may reasonably be included within such range, as well as any subranges and combinations of subranges included within such ranges. For example, in a given range, C 1 ~C 6 Regarding the carbon range of this range, 1 , C 2 , C 3 , C 4 , C 5 , and C 6 , as well as any subrange between these numbers (e.g., C 3 ~C 6 ), and any possible combination of possible ranges between these values. In yet another example, a given temperature range may be from about 25° C. to 30° C., where this range also discloses temperatures that can be independently selected from about 25° C., 26° C., 27° C., 28° C., 29° C., and 30° C., as well as any range between these numbers (e.g., 26-28° C.), and any possible combination of ranges between these values.

[0126] Disclosed are materials, compositions, and components that can be used for, can be used in conjunction with, can be used in preparation for, or are the product of the methods and compositions disclosed herein. These and other materials are disclosed herein, and combinations, subsets, interactions, groups, etc. of these materials are disclosed, but it is understood that each is specifically contemplated and described herein, even if specific reference to each of the various individual and collective combinations and permutations of these compounds may not be expressly disclosed. For example, if a ligand is disclosed and discussed, and several modifications that can be made to several molecules that include the ligand are discussed, any and all combinations and permutations of the ligand and possible modifications are specifically contemplated, unless specifically indicated otherwise. Thus, if a class of molecules A, B, and C and a class of molecules D, E, and F are disclosed, and an example combination of molecules AD is disclosed, each is individually contemplated and collectively contemplated, even if each is not individually described. Thus, in this example, each of the combinations AE, AF, BD, BE, BF, CD, CE, and CF is specifically contemplated and should be considered disclosed by the disclosure of A, B, and C; D, E, and F; and combination example AD. Likewise, any subset or combination of these is specifically contemplated and disclosed. Thus, for example, the subgroups AE, BF, and CE are specifically contemplated and should be considered disclosed by the disclosure of A, B, and C; D, E, and F; and combination example AD. Furthermore, each of the materials, compositions, components, etc. contemplated and disclosed above can be specifically and independently included in or excluded from any group, subgroup, list, set, etc. of such materials.

[0127] These concepts apply to all aspects of this application, including, but not limited to, steps in methods of making and using the compositions disclosed herein. Thus, where there are various additional steps that can be performed, it is understood that each of these additional steps can be performed with any particular embodiment or combination of method embodiments disclosed herein, and that each such combination is specifically contemplated and should be considered as disclosed.

[0128] All methods described herein can be performed in any suitable order unless otherwise specified or otherwise clearly contradicted by context. Any and all examples presented herein, or the use of exemplary language (e.g., "such as"), are intended merely to better illuminate the embodiments, and do not pose a limitation on the scope of the embodiments unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention. II. Composition

[0129] Provided herein are probenecid, metabolites, analogs, prodrugs, and pharma- ceutically acceptable salts thereof, including but not limited to the sodium salt of any of the foregoing; compositions and formulations thereof; and methods of use thereof, including but not limited to the prevention and treatment of viral infections. The methods disclosed herein generally include administering to a subject in need thereof an effective amount of probenecid, metabolites, analogs, or prodrugs thereof, or pharma-ceutically acceptable salts thereof, including but not limited to the sodium salt thereof. A. Probenecid and its metabolites, analogs, and prodrugs

[0130] Probenecid (4-[(dipropylamino)sulfonyl]benzoic acid (CAS number 57-66-9)) has the following structure: [ka] and is sold under the trade names BENEMID® and PROBALAN®.

[0131] Probenecid is a highly lipid-soluble benzoic acid derivative with an excellent safety profile that was developed in the 1950s to reduce the renal tubular excretion of penicillin. Probenecid, USP, is a white or nearly white, fine, crystalline powder. Probenecid is soluble in dilute alkali, alcohol, chloroform, and acetone; it is practically insoluble in water and dilute acids. The half-life of probenecid is 6-12 hours. See also Drugbank Accession No. DB01032 (APRD00167), and PubChem CID 4911.

[0132] Metabolites and analogues of probenecid are known. See, e.g., Guarino, et al., "Mass spectral identification of probenecid metabolites in rat bile," Eur. J. Pharmacol., 8, 244-252 (1969); Perel, et al., "Identification and renal excretion of probenecid metabolites in man," Life Sciences, 9, 23, 1337-1343 (1970); Perel, et al., "Studies of the renal excretion of probenecid acyl glucuronide in man," Eur. J. Clin. Pharmacol, 3, 106-112 (1971); Dayton and Perel, "The metabolism of probenecid in man,". NY Acad. Sci., 179, 399-402 (1971); Dayton, et al., "The effect of See, probenecid, phenylbutazone and their analogues on the excretion of L-ascorbic acid in rats," J. Med. Chem. 9, 941-944 (1966), and Israeli, et al., "Metabolites of probenecid. Chemical, physical, and pharmacological studies," J. Med. Chem., 15, 7, 709-713 (1972).

[0133] In some embodiments, the metabolite is a glucuronide derivative of probenecid, such as an acyl glucuronide or a β-ether glucuronide.

[0134] Exemplary probenecid metabolites and analogs include, but are not limited to, dl-p-(N-propyl-N-2-hydroxypropylsulfamoyl)benzoic acid, p-(N-propyl-N-3-hydroxypropylsulfamoyl)benzoic acid, p-(N-propyl-N-3-propionitrilesulfamoyl)benzoic acid, p-(N-propyl-N-2-carboxyethylsulfamoyl)benzoic acid, p-(N-propylsulfamoyl)benzoic acid, p-(N,N-pentamethylenesulfamoyl)benzoic acid (piperidyl analogue), p-(N-propyl-N-2-propenylsulfamoyl)benzoic acid, p-(N-propyl-N-2-oxopropylsulfamoyl)benzoic acid, p-sulfamoylbenzoic acid, p-(N-methylsulfamoyl)benzoic acid, p-(N-ethylsulfamoyl)benzoic acid, p-(N-hexylsulfamoyl)benzoic acid, p-(N-cyclohexylsulfamoyl)benzoic acid, p-(N-dimethylsulfamoyl)benzoic acid, p-(N-methyl,N-ethylsulfamoyl)benzoic acid, p-(N,N-diethylsulfamoyl)benzoic acid, p-(N-ethyl, N-propylsulfamoyl)benzoic acid, p-(N,N-diisopropylsulfamoyl)benzoic acid, p-(N,N-dibutylsulfamoyl)benzoic acid, o-Hydroxy-p-(N-dipropylsulfamoyl)benzoic acid, o-Methoxy-p-(N-dipropylsulfamoyl)benzoic acid, o-Nitro-p-(N,N-dipropylsulfamoyl)benzoic acid, m-Nitro-p-(N,N-dipropylsulfamoyl)benzoic acid, and m-Methyl-p-(N,N-dipropylsulfamoyl)benzoic acid Examples include:

[0135] Other exemplary probenecid-related compounds are listed in Table 1. Thus, in some embodiments, the compound is selected from those listed in Table 1. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12]

[0136] Probenecid is soluble in dilute alkali, alcohol, chloroform, and acetone; it is practically insoluble in water and dilute acids. Probenecid is completely absorbed after oral administration, reaching peak plasma concentrations in 2-4 hours. The plasma half-life of the drug is dose-dependent and varies from less than 5 hours to more than 8 hours. Probenecid is often administered in high-dose tablet form, which results in poor compliance with patients, especially pediatric patients.

[0137] Synthetic compounds have been developed that can be used as the prodrug of probenecid or probenecid analogue.These compounds (also referred to herein as "prodrug") are inactive forms prepared from active probenecid or probenecid analogue, and can release probenecid or probenecid analogue in active form after being administered to a subject in need of it.For example, prodrug is an inactive form of probenecid, which can be converted to probenecid by chemical or enzymatic cleavage in the body of a subject.The released probenecid or probenecid analogue should have antiviral properties and be suitable for use in the prevention and / or treatment of many families of viruses.

[0138] The compounds disclosed herein can be formed by modifying active probenecid or probenecid analogues to include one or more water-soluble moieties.For example, the compounds can be prepared by (a) forming esters, hemiesters, carbonates, nitrates, amides, hydroxamic acids, carbamates, imines, Mannich bases, and enamines of active probenecid or probenecid analogues; (b) functionalizing active probenecid or probenecid analogues with azo groups, glycoside groups, peptide groups, and ether groups; and / or (c) using polymers, salts, complexes, phosphoramides, acetals, hemiacetals, and ketal forms of active probenecid or probenecid analogues. Additional functional groups that can be used to modify active probenecid or probenecid analogs can be found in Andrejus Korolkovas', "Essentials of Medicinal Chemistry", pp. 97-118, and U.S. Patent No. 8,357,723, which are incorporated by reference in their entireties.

[0139] In some forms, the compounds are formed by modifying the carboxyl group of probenecid with water-soluble moieties such as carbonate, carbamate, imine, ether, ester, amide, or phosphate.The addition of such water-soluble moieties can effectively attenuate the ability of these compounds to cross certain biological membranes, such as those associated with the blood-brain barrier or blood-placental barrier.In some forms, these compounds show a reduced biological membrane crossing rate compared to that of probenecid without the water-soluble oligomer attached.Furthermore, compared to probenecid administered in free form, the prodrugs disclosed herein can modify the pharmacokinetics of probenecid, improve the stability and solubility of probenecid, reduce the toxicity of probenecid, increase the specificity of probenecid, and / or extend the duration of the pharmacological effect of probenecid.

[0140] Pharmaceutical compositions and formulations containing the prodrugs are also disclosed.

[0141] 1. Prodrug compounds The compound has formula I: [ka] (In the formula, (a) Z' is O, NR 5 or S; (b) X' may be absent and may be O, NR 5 or S; (c) R 1 may be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, azo, alkoxy, polyether, thiol, sulfanimine, amino, carbonate, ester, amide, carbamate, imine, substituted or unsubstituted carbonyl, hydroxyl, polyol, phosphonyl, sulfinyl, sulfonamide, nitro, cyano, lipid, peptide, cholesterol, phytosterol, glycoside, or glucuronide; (d) n may be an integer from 0 to 4; (e) each R 2 may be independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteropolyaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, alkoxy, amido, amino, phosphonium, phosphanyl, phosphonyl, silyl, sulfinyl, sulfonyl, sulfate, thiol, hydroxyl, or halogen; (f) R 3 ~R 5may be independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, alkoxy, amido, amino, imine, or thiol; (g) the substituents may be independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, alkoxy, halogen, hydroxyl, phenoxy, thiol, alkylthio, phenylthio, arylthio, cyano, isocyano, nitro, carboxyl, amino, amido, oxo, silyl, sulfinyl, sulfonyl, sulfonic acid, phosphonium, phosphanyl, phosphoryl, or phosphonyl).

[0142] In some embodiments of Formula I, R 1 is hydrogen, substituted or unsubstituted C 1 ~C 20 Straight-chain or branched alkyl (e.g., haloalkyl), substituted or unsubstituted C 3 ~C 20 Cycloalkyl, substituted or unsubstituted C 1 ~C 20 Linear or branched heteroalkyl, substituted or unsubstituted C 3 ~C 20 Heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteropolyaryl, polyol, polyalkylene glycol, lipid, peptide, cholesterol, phytosterol, glucuronide, [ka] [ka] where (a) G' is hydrogen, a lipid, a peptide, cholesterol, a plant sterol, a glycoside, a glucuronide, [ka] R may be 9 ~R 12 are independently hydrogen, substituted or unsubstituted C 1 ~C 20 Straight-chain or branched alkyl (e.g., haloalkyl), substituted or unsubstituted C 3 ~C 20 Cycloalkyl, substituted or unsubstituted C 1 ~C 20 Linear or branched heteroalkyl, substituted or unsubstituted C 3 ~C 20 R' may be heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, alkoxy, dialkylamino, or halogen; 5 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, alkoxy, amido, amino, imine, or thiol, e.g., hydrogen or substituted or unsubstituted C 1 ~C 6 Alkyl (e.g., unsubstituted C 1 ~C 6 Straight or branched alkyl, unsubstituted C 1 ~C 6 Cycloalkyl, unsubstituted C 1 ~C 4 Straight or branched alkyl, unsubstituted C 1 ~C 4 Cycloalkyl, unsubstituted C 1 ~C 3 Straight or branched alkyl, unsubstituted C 1 ~C 3 (b) m, k, p, and q may independently be an integer from 0 to 20, 0 to 18, 0 to 16, 0 to 14, 0 to 12, 0 to 10, 0 to 8, 0 to 6, 0 to 4, 0 to 3, or 0 to 2, e.g., 0 or 1; (c) each Y' may independently be O or S; (d) R 7 , R 8, and R 15 ~R 20 is, for each occurrence, independently, hydrogen, substituted or unsubstituted C 1 ~C 20 R may be alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteropolyaryl, substituted or unsubstituted carbonyl, alkoxy, amido, amino, phosphonium, phosphanyl, phosphonyl, silyl, sulfinyl, sulfonyl, sulfate, thiol, hydroxyl or halogen, or 7 and R 8 together with the carbon atom to which they are attached, R 15 and R 16 together with the carbon atom to which they are attached, and / or R 17 and R 18 together with the carbon atom to which they are attached, C 1 ~C 20 cycloalkyl or X' is NR 5 and m is not 0 and at least one of p and q is not 0, then (i) R 7 is hydrogen and R 8 is R 5 Substituted or unsubstituted C, which together with the adjacent N and C atoms form a ring 1 ~C 20 (ii) R is alkyl; 15 is hydrogen and R 16 is R 5 Substituted or unsubstituted C, which together with the adjacent N and C atoms form a ring 1 ~C 20 and / or (iii) R is alkyl; 17 is hydrogen and R 18 is R 5 Substituted or unsubstituted C, which together with the adjacent N and C atoms form a ring 1 ~C 20 (e) R 13 and R14 are independently hydrogen, substituted or unsubstituted C 1 ~C 20 It may be alkyl, or alkoxy.

[0143] In some embodiments of Formula I, R 1 is unsubstituted C 1 ~C 20 Straight or branched alkyl, unsubstituted C 3 ~C 20 Cycloalkyl, C 1 ~C 20 Haloalkyl, unsubstituted aryl, unsubstituted polyaryl, unsubstituted heteroaryl, unsubstituted heteropolyaryl, polyalkylene glycol, lipid, peptide, cholesterol, phytosterol, glucuronide, [ka] [ka] where m, m', p', and n' may independently be an integer from 0 to 10, 0 to 8, 0 to 6, 0 to 4, 0 to 3, 0 to 2, or 0 or 1; p may be an integer from 1 to 6, 1 to 4, 1 to 3, or 1 or 2; and k may be an integer from 1 to 6, 1 to 4, or 1 to 3.

[0144] In some forms of Formula I, Z' can be O. In some forms of Formula I, Z' can be S. In some forms of Formula I, Z' can be NR 5In some forms of formula I, X' may be absent or may be O or S. In some forms of formula I, X' may be absent. In some forms of formula I, X' may be O. In some forms of formula I, X' may be S. In some forms of formula I, Z' may be O and X' may be O. In some forms of formula I, Z' may be O and X' may be S. In some forms of formula I, Z' may be O and X' may be absent. In some forms of formula I, Z' may be S and X' may be O. In some forms of formula I, Z' may be S and X' may be S. In some forms of formula I, Z' may be S and X' may be absent. In some forms of formula I, Z' is NR 5 and X' may be absent.

[0145] In some forms of Formula I, Z' can be O, X' can be absent or can be O, and R 1 is a substituted or unsubstituted C 1 ~C 20 Straight-chain or branched alkyl (e.g., haloalkyl), substituted or unsubstituted C 3 ~C 20 Cycloalkyl, substituted or unsubstituted C 1 ~C 20 Linear or branched heteroalkyl, substituted or unsubstituted C 3 ~C 20 It may be a heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteropolyaryl, polyalkylene glycol, lipid, peptide, cholesterol, plant sterol, glycoside, or glucuronide.

[0146] In some embodiments of Formula I, Z′ is O or NR 5 and [ka] teeth, [ka] In some forms of Formula I, Z' can be O, X' can be O, and R 1 teeth, [ka] In some forms of Formula I, Z' can be O, X' can be S, and R 1 teeth, [ka] It may be.

[0147] In some forms of Formula I, Z' can be O, X' can be O, and R 1 teeth, [ka] where m' and n' are independently an integer from 0 to 6, 0 to 5, 0 to 4, 0 to 3, 1 to 3, e.g., 1 or 2; p' is an integer from 1 to 10, 1 to 8, 1 to 6, 1 to 4, or 1 to 3; R 17 and R 18 is, for each occurrence, independently, hydrogen, hydroxyl, -SH, -(CH 2 ) 1~6 NR 22 R 23 , -(CH 2 ) 1~6 OH, -(CH 2 ) 1~6 SH or unsubstituted C 1 ~C 10 In some forms of Formula I, Z' can be O, X' can be O, and R 1 teeth, [ka] where q is an integer from 1 to 10, 1 to 8, 1 to 6, 1 to 4, or 1 to 3; R 17 ~R 20 is, for each occurrence, independently, hydrogen, hydroxyl, -SH, -(CH2 ) 1~6 NR 22 R 23 , -(CH 2 ) 1~6 OH, -(CH 2 ) 1~6 SH or unsubstituted C 1 ~C 10 In these forms of formula I, R 2 is hydrogen, hydroxyl, -SH, -(CH 2 ) 1~6 NR 22 R 23 , -(CH 2 ) 1~6 OH, -(CH 2 ) 1~6 SH or unsubstituted C 1 ~C 10 alkyl, e.g. hydrogen; R 3 and R 4 are independently unsubstituted C 1 ~C 10 Alkyl may be, for example, unsubstituted methyl, ethyl, propyl, butyl, pentyl, or hexyl, for example, unsubstituted propyl.

[0148] In any one of the forms of formula I above, R 7 , R 8 , and R 15 ~R 20 is, for each occurrence, independently, hydrogen, substituted or unsubstituted C 1 ~C 20 Alkyl, -(CH 2 ) 1~6 NR 22 R 23 , -(CH 2 ) 1~6 OH, substituted or unsubstituted aralkyl, -(CH 2 ) 1~6 SH, -(CH 2 ) 1~6 S(O) 0~2 CH 3 , -(CH 2 ) 1~6 NHC(=NH)NH 2, -(1H-indol-3-yl)methyl, -(1H-imidazol-4-yl)methyl, -(CH 2 ) 0~6 COOR 21 , -(CH 2 ) 0~6 CONR 22 R 23 , substituted or unsubstituted aryl, aryl-C 1~3 Alkyl, CH 2 -Indol-3-yl, -(CH 2 ) 1~6 SCH 3 , -CH2-imidazol-4-yl, CH(OH)(CH 2 ) 0~5 CH 3 , -CH 2 ((4'-OH)-Ph), where R 21 ~R 23 are independently hydrogen or unsubstituted C 1~6 In some embodiments of Formula I, R 7 , R 8 , and R 15 ~R 20 is, for each occurrence, independently, hydrogen, unsubstituted C 1 ~C 20 Alkyl, -(CH 2 ) 1~6 NR 22 R 23 , -(CH 2 ) 1~6 OH, unsubstituted aralkyl, -(CH 2 ) 1~6 SH, -(CH 2 ) 1~6 S(O) 0~2 CH 3 , -(CH 2 ) 1~6 NHC(=NH)NH 2 , -(1H-indol-3-yl)methyl, -(1H-imidazol-4-yl)methyl, -(CH 2 ) 0~6 COOR 21 , -(CH 2 ) 0~6 CONR 22 R 23 , unsubstituted aryl, aryl-C1~3 Alkyl, CH 2 -Indol-3-yl, -(CH 2 ) 1~6 SCH 3 , -CH2-imidazol-4-yl, CH(OH)(CH 2 ) 0~5 CH 3 , -CH 2 ((4'-OH)-Ph), where R 21 ~R 23 are independently hydrogen or unsubstituted C 1~6 It may be alkyl.

[0149] In any one of the forms of formula I above, R 3 and R 4 may independently be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, alkoxy, amino, or imine; R 3 and R 4 are independently hydrogen or substituted or unsubstituted C 1 ~C 20 It is preferably alkyl.

[0150] In any one of the forms of formula I above, R 5 and / or R' 5 is hydrogen or substituted or unsubstituted C 1 ~C 20 Alkyl, e.g., unsubstituted C 1 ~C 20 Linear or branched alkyl or unsubstituted C 1 ~C 20 It may be a cycloalkyl.

[0151] In any one of the above forms of formula I, when substituents are present, the substituents are independently unsubstituted C 1 ~C 6 Alkyl, unsubstituted C 1~6 Alkyl-substituted C 1 ~C 6 Alkyl, unsubstituted C 1 ~C 6Heteroalkyl, unsubstituted C 1~6 Alkyl-substituted C 1 ~C 6 Heteroalkyl, unsubstituted C 2 ~C 6 Alkenyl, unsubstituted C 2 ~C 6 Alkynyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted C 1 ~C 6 Alkoxy, -(CH 2 ) 1~6 CO 2 R 21 , halogen, C 1 ~C 6 Haloalkyl, -NR 22 R 23 , C 1~6 Acylamino, -NHSO 2 C 1~6 Alkyl, -SO 2 NR 22 R 23 , -SO 2 C 1~6 Alkyl, -COOR 21 , -CONR 22 R 23 , nitro, cyano, hydroxide, thiol, or unsubstituted C 1~5 Aryl or heteroaryl substituted with alkyl, alkoxy, di(C 1~6 Alkyl)-amino, fluoro, or unsubstituted C 3 ~C 6 It may be a cycloalkyl.

[0152] In some embodiments of Formula I, R 1 When is a peptide, the peptide may be any one of the peptides shown in Table 2. [Table 2-1] [Table 2-2]

[0153] In some forms of Formula I, the compound is not one of the compounds in Table 1 above.

[0154] Examples of probenecid prodrugs are shown below: [ka]

[0155] Prodrugs may contain one or more chiral centers or may otherwise be capable of existing as multiple stereoisomers. They may be pure (single) stereoisomers or mixtures of stereoisomers, such as enantiomers, diastereomers, and mixtures enriched in enantiomers or diastereomers. Prodrugs may be capable of existing as geometric isomers. Therefore, it should be understood that the prodrugs disclosed herein encompass pure geometric isomers or mixtures of geometric isomers. 2. Pharmaceutically acceptable salts

[0156] A compound containing a prodrug may be neutral or may be one or more pharma- ceutically acceptable salts, crystalline forms, amorphous forms, hydrates, or solvates, or combinations thereof. Reference to a compound containing a prodrug may refer to the neutral molecule and / or additional forms thereof collectively or individually, depending on the context. Pharmaceutically acceptable salts of a prodrug include its acid addition salts and base salts.

[0157] Suitable acid addition salts of prodrugs are formed from acids which form non-toxic salts, examples of which include acetate, aspartate, benzoate, besylate, bicarbonate / carbonate, hydrogensulfate / sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, sugarate, stearate, succinate, tartrate, tosylate and trifluoroacetate.

[0158] Suitable base salts of the compounds, including prodrugs, are formed from bases which form non-toxic salts, examples of which include the aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

[0159] Hemi-salts of prodrug acids and bases may also be formed, such as hemisulfate and hemicalcium salts.

[0160] Generally, metabolites, analogs, and prodrugs are those that, when administered in an effective amount as discussed herein, can prevent and / or treat viruses when metabolized by a subject. For example, in some embodiments, prodrugs are those that, when metabolized by a subject, can reduce viral replication. B. Preparation

[0161] Probenecid, its metabolites, analogs, and prodrugs, and its pharmaceutically acceptable salts can be formulated into compositions, such as pharmaceutical compositions or animal feed or water.The pharmaceutical compositions can be for administration by parenteral route (intramuscular, intraperitoneal, intravenous (IV) or subcutaneous injection), enteral route, topical route, transdermal route (passively or using iontophoresis or electroporation), transmucosal route (nasal, pulmonary, vaginal, rectal or sublingual) or by using bioerodible inserts, and can be formulated into dosage forms suitable for each administration route.The formulations can also be administered by ocular route, such as topical, local ocular delivery (i.e. subconjunctival, retrobulbar, intracameral, intravitreal), and systemic ocular delivery. See, e.g., Whelan, Merck Manual, Veterinary Manual, "Systemic Pharmacotherapeutics Of The Eye," (2022). For example, in some embodiments, the compound is administered as an eye drop.

[0162] The compositions may be administered systemically.

[0163] The composition can be formulated for immediate release, sustained release, or modified release. A delayed release dosage form is one that releases drug(s) at a time other than immediately after administration. A sustained release dosage form is one that allows for at least a half-fold reduction in dosing frequency compared to drugs provided in conventional dosage forms (e.g., liquids or conventional solid dosage forms that release drug immediately). A modified release dosage form is one in which the drug release characteristics over time and / or location are selected to achieve therapeutic or convenience goals that cannot be achieved by conventional dosage forms such as liquids, ointments, or quickly dissolving dosage forms. Delayed release and sustained release dosage forms and their combinations are types of modified release dosage forms.

[0164] The formulation is prepared using a pharma- ceutically acceptable "carrier" that is composed of a material that is deemed safe and effective and can be administered to an individual without causing undesirable biological side effects or undesirable interactions. A "carrier" is any component present in a pharmaceutical formulation other than the active ingredient(s). The term "carrier" includes, but is not limited to, diluents, binders, lubricants, disintegrants, fillers, and coating compositions.

[0165] "Carrier" also includes all components of the coating composition, which may include plasticizers, pigments, colorants, stabilizers, and lubricants. Delayed release dosage formulations may be prepared by using a carrier, a material, a tablet, and a capsule, and may be prepared by using a material, material, or a material that is suitable for use in the preparation of delayed release dosage forms of tablets, capsules, and granules, as described in references such as "Pharmaceutical dosage forms: tablets", eds. Liberman et. al. (New York, Marcel Dekker, Inc., 1989), "Remington - The science and practice of pharmacy", 21st ed., Lippincott Williams & Wilkins, Baltimore, MD, 2006, and "Ansel's Pharmaceutical dosage forms and drug delivery systems", 11th ed., ... th Edition, Loyd Allen., (Media, PA: Williams and Wilkins, 2017).

[0166] Simulation test shows that it is preferable to administer probenecid at a relatively high dose to maintain steady-state concentration in plasma and to achieve therapeutic concentration while being safe.In order to reduce dosage and achieve a steady release of drug over several days, delivery vehicles can be used to deliver probenecid and probenecid metabolites, analogs and prodrugs, achieving the same or improved effect with lower doses and / or less frequent administration.Lower doses and / or less frequent administration can also increase patient compliance.

[0167] Thus, the compound can be administered to a subject with or without a delivery vehicle. Suitable delivery vehicles for compounds are known in the art and can be selected for a particular active agent. For example, in some embodiments, the active agent is incorporated, encapsulated, or associated with nanoparticles, microparticles, micelles, synthetic lipoprotein particles, or carbon nanotubes. For example, the composition can be incorporated into a vehicle such as a polymeric microparticle that provides controlled release of the active agent. In some embodiments, the release of the drug is controlled by the diffusion of the active agent from the microparticle and / or the degradation of the polymeric particle by hydrolysis and / or enzymatic degradation.

[0168] Suitable polymers include ethylcellulose and other natural or synthetic cellulose derivatives. Polymers that dissolve slowly in an aqueous environment and form gels, such as hydroxypropylmethylcellulose or polyethylene oxide, may also be suitable as materials for the drug containing microparticles or particles. Other polymers include, but are not limited to, polyanhydrides, poly(ester anhydrides), polyhydroxy acids, such as polylactic acid (PLA), polyglycolide (PGA), poly(lactide-co-glycolide) (PLGA), poly-3-hydroxybutyric acid (PHB) and its copolymers, poly-4-hydroxybutyric acid (P4HB) and its copolymers, polycaprolactone and its copolymers, and combinations thereof. In some embodiments, both agents are incorporated into the same particle and formulated to be released at different times and / or over different periods of time. For example, in some embodiments, one of the agents is completely released from the particle before the release of the second agent begins. In other embodiments, the second agent is released after the release of the first agent begins, but before all of the first agent is released. In yet other embodiments, both agents are released simultaneously, either over the same or different time periods.

[0169] Cyclodextrins can be used to prepare aqueous-based formulations of drugs such as probenecid that are poorly or completely soluble in water. The formulations include cyclodextrin and probenecid with a sufficient amount of water to solubilize the cyclodextrin, where the probenecid is placed in the cyclodextrin. For example, the aqueous composition can be heated to a temperature below the decomposition point of the compound but above its melting point, where the compound and cyclodextrin are mixed in a ratio of about 1:100 to about 1:10, respectively, on a percent weight basis. In certain embodiments, the cyclodextrin is hydroxypropyl beta-cyclodextrin.

[0170] Liposomes are water-in-oil-in-water (w / o / w) emulsions with a closed bilayer membrane that entraps an aqueous volume. Liposomes can encapsulate both hydrophilic and hydrophobic molecules. There are two types of liposomes: multilamellar vesicles (MLVs) and large unilamellar vesicles (LUVs). Unilamellar and multilamellar liposomes can be prepared by standard methods from commercially available phospholipids such as phosphatidylcholine and phosphatidylethanolamine. Drug-loaded liposomes can be used as liquid suspensions (for intravenous injection) or can be attached to the surface of an implant. Attachment can be achieved by covalent tethering using click chemistry or by embedding in a biocompatible hydrogel. In an exemplary embodiment, liposomes are formed using a molar ratio of 65:10:25 DMPC:DSPG:cholesterol, although other components and / or ratios are contemplated. Exosome formulations can be prepared by mixing compounds with EL-4 exosomes in PBS. 1. Oral immediate release formulations

[0171] Suitable oral dosage forms include tablets, capsules, liquids, suspensions, syrups and lozenges.Therefore, the composition can be formulated as solid or liquid.Tablets can be made by using compression or molding techniques well known in the art.For gelatin or non-gelatin capsules, they can be prepared as hard capsules or soft capsule shells by using techniques well known in the art, and liquid, solid and semi-solid fill materials can be enclosed in the capsule shell.

[0172] Examples of suitable coating materials include, but are not limited to, cellulose polymers such as cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and hydroxypropyl methylcellulose acetate succinate; polyvinyl acetate phthalate, acrylic acid polymers and copolymers, and methacrylic resins commercially available under the trade name Eudragit® (Roth Pharma, Westerstadt, Germany), Zein, shellac, and polysaccharides.

[0173] Additionally, the coating material may contain conventional carriers such as plasticizers, pigments, colorants, lubricants, stabilizers, pore formers and surfactants.

[0174] Optional pharma- ceutically acceptable excipients present in drug-containing tablets, beads, granules, or particles include, but are not limited to, diluents, binders, lubricants, disintegrants, colorants, stabilizers, and surfactants. Diluents, also called "fillers," are generally necessary to increase the bulk of solid dosage forms and thus provide a practical size for tablet compression or bead and granule formation. Suitable diluents include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starch, pregelatinized starch, silicon dioxide, titanium dioxide, magnesium aluminum silicate, and powdered sugar.

[0175] Binders are used to provide cohesiveness to solid dosage formulations, thus ensuring that tablets or beads or granules remain intact after formation of the dosage form. Suitable binder materials include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (including sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, waxes, natural and synthetic gums, such as gum arabic, tragacanth, sodium alginate, celluloses including hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, and veegum, as well as synthetic polymers, such as acrylic and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid / polymethacrylic acid, and polyvinylpyrrolidone.

[0176] Lubricants are used to facilitate tablet manufacture. Examples of suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, glycerol behenate, polyethylene glycol, talc, and mineral oil.

[0177] Disintegrants are used to facilitate the disintegration or "breaking apart" of the dosage form after administration and typically include, but are not limited to, starch, sodium starch glycolate, sodium carboxymethyl starch, sodium carboxymethylcellulose, hydroxypropylcellulose, pregelatinized starch, clay, cellulose, arginine, gums or crosslinked polymers such as crosslinked PVP (Polyplasdone XL from GAF Chemical Corp).

[0178] Stabilizers are used to inhibit or retard drug decomposition reactions which include, by way of example, oxidative reactions.

[0179] The surfactant may be an anionic, cationic, amphoteric or nonionic surfactant. Suitable anionic surfactants include, but are not limited to, those containing carboxylate, sulfonate and sulfate ions. Examples of anionic surfactants include sodium, potassium, ammonium salts of long chain alkyl and alkylaryl sulfonates, such as sodium dodecylbenzenesulfonate; dialkyl sodium sulfosuccinates, such as sodium dodecylbenzenesulfonate; dialkyl sodium sulfosuccinates, such as sodium bis-(2-ethylthioxyl)-sulfosuccinate; and alkyl sulfates, such as sodium lauryl sulfate. Cationic surfactants include, but are not limited to, quaternary ammonium compounds, such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyldimethylbenzylammonium chloride, polyoxyethylene and coconut amine. Examples of nonionic surfactants include ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4 oleate, acylated sorbitan, acylated sucrose, PEG-150 laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbate, polyoxyethylene octylphenyl ether, PEG-1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, POLOXAMER® 401, stearoyl monoisopropanolamide, and polyoxyethylene hydrogenated tallow amide. Examples of amphoteric surfactants include sodium N-dodecyl-β-alanine, sodium N-lauryl-β-iminodipropionate, myristamphoacetate, lauryl betaine, and lauryl sulfobetaine.

[0180] If desired, the tablets, beads, granules, or particles may contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, dyes, pH buffering agents, and preservatives. 2. Sustained release dosage forms

[0181] Sustained release formulations are generally prepared as diffusion or osmotic systems, as described, for example, in "Remington - The science and practice of pharmacy" (21st ed., Lippincott Williams & Wilkins, Baltimore, MD. 2006). Diffusion systems generally consist of two types of devices, reservoirs and matrices, and are well known and described in the art. Matrix devices are generally prepared by compressing the drug with a slowly dissolving polymeric carrier into a tablet form. The three main types of materials used in the preparation of matrix devices are insoluble plastics, hydrophilic polymers, and fatty compounds. Plastic matrices include, but are not limited to, methyl acrylate-methyl methacrylate, polyvinyl chloride, and polyethylene. Hydrophilic polymers include, but are not limited to, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, and carbopol 934, polyethylene oxide. Fatty compounds include, but are not limited to, various waxes, such as carnauba wax and glyceryl tristearate.

[0182] Alternatively, sustained release formulations can be prepared using osmotic systems or by applying semipermeable coatings to the dosage form. In the latter case, the desired drug release profile can be achieved by combining low and high permeability coating materials in appropriate ratios.

[0183] The above devices with different drug release mechanisms can be combined to form a final dosage form containing a single or multiple units. Examples of multiple units include capsules containing multi-layer tablets, tablets, beads, granules, etc.

[0184] An immediate release portion can be added to the sustained release system, either by applying an immediate release layer on top of the sustained release core using a coating or compression process, or as a multiple unit system, such as a capsule containing sustained release beads and immediate release beads.

[0185] The sustained release tablets containing hydrophilic polymers are prepared by techniques generally known in the art, such as direct compression, wet granulation, or dry granulation processes. Their formulations usually incorporate polymers, diluents, binders, and lubricants, and active pharmaceutical ingredients. Conventional diluents include inert powdered substances, such as many different types of starch, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol, and sucrose, flours, and similar edible powders. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride, and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders include substances such as starch, gelatin, and sugars, such as lactose, fructose, and glucose. Natural and synthetic gums, including gum arabic, alginates, methylcellulose, and polyvinylpyrrolidine, can also be used. Polyethylene glycol, hydrophilic polymers, ethylcellulose, and waxes can also function as binders. Lubricants are necessary in tablet formulations to prevent the tablet and punch from sticking to the die. Lubricants are selected from slippery solids such as talc, magnesium and calcium stearates, stearic acid and hydrogenated vegetable oils.

[0186] Extended release tablets containing wax materials are generally prepared using methods known in the art, such as direct blending, congealing, and aqueous dispersion methods, in which the drug is mixed with a wax material, spray congealed or congealed, and screened and processed. 3. Delayed release dosage forms

[0187] Delayed release formulations are created by coating a solid dosage form with a film of a polymer that is insoluble in the acidic environment of the stomach and soluble in the neutral environment of the small intestine.

[0188] The delayed release dosage unit can be prepared, for example, by coating the drug or drug-containing composition with a selected coating material. The drug-containing composition can be, for example, a tablet for incorporation into a capsule, a tablet for use as an inner core of a "core-coated" dosage form, or a plurality of drug-containing beads, particles, or granules for incorporation into a tablet or capsule. Preferred coating materials include biodegradable, slowly hydrolyzable, slowly water-soluble, and / or enzymatically degradable polymers, which may be conventional "enteric" polymers. Enteric polymers, as understood by those skilled in the art, are soluble in the high pH environment of the lower gastrointestinal tract or are slowly degraded as the dosage form passes through the gastrointestinal tract, while enzymatically degradable polymers are degraded by bacterial enzymes present in the lower gastrointestinal tract, particularly the colon.Suitable coating materials for effecting delayed release include, but are not limited to, cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, methyl cellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate, and sodium carboxymethyl cellulose; acrylic acid polymers and copolymers, preferably those formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate, and / or ethyl methacrylate, and polysaccharides sold under the trade names EUDRAGIT® (Rohm), including EUDRAGIT® L30D-55 and L100-55 (soluble at pH 5.5 and above), EUDRAGIT® L-100 (soluble at pH 6.0 and above), EUDRAGIT® S (soluble at pH 7.0 and above, due to a higher degree of esterification). Other methacrylic resins available commercially under the trademarks of Pharma; Westerstadt, Germany, and under EUDRAGITS®. NE, RL and RS (water-insoluble polymers with different degrees of permeability and swelling); vinyl polymers and copolymers such as polyvinylpyrrolidone, vinyl acetate, vinyl acetate phthalate, vinyl acetate crotonic acid copolymers, and ethylene-vinyl acetate copolymers; enzymatically degradable polymers such as azopolymers, pectin, chitosan, amylose and guar gum; zein and shellac. Combinations of different coating materials can also be used. Multi-layer coatings using different polymers can also be applied.

[0189] The preferred coating weight for a particular coating material can be readily determined by one skilled in the art by evaluating the individual release profiles for tablets, beads and granules prepared with different amounts of various coating materials. The combination of materials, methods and application forms that results in the desired release characteristics can only be determined by clinical trials.

[0190] The coating composition may contain conventional additives such as, for example, plasticizers, pigments, colorants, stabilizers, lubricants, etc. Plasticizers are usually present to reduce the brittleness of the coating and generally comprise about 10 wt.% to 50 wt.% based on the dry weight of the polymer. Examples of typical plasticizers include polyethylene glycol, propylene glycol, triacetin, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, acetyl triethyl citrate, castor oil, and acetylated monoglycerides. Stabilizers are preferably used to stabilize the particles in dispersion. Typical stabilizers are non-ionic emulsifiers such as sorbitan esters, polysorbates, and polyvinylpyrrolidone. Lubricants are recommended to reduce the sticking effect during film formation and drying and generally comprise approximately 25 wt.% to 100 wt.% of the polymer weight in the coating solution. One effective lubricant is talc. Other lubricants such as magnesium stearate and glycerol monostearate can also be used. Pigments such as titanium dioxide can also be used. A small number of antifoaming agents, such as silicones (e.g., simethicone), can also be added to the coating composition. Manufacturing method

[0191] As will be appreciated by those skilled in the art and described in the pertinent texts and literature, several methods are available for preparing drug-containing tablets, beads, granules or particles that result in various drug release profiles, including, but not limited to, coating the drug or drug-containing composition with a suitable coating material, which typically but not necessarily incorporates a polymeric material, increasing the drug particle size, placing the drug inside a matrix, and forming a complex of the drug with a suitable complexing agent.

[0192] The delayed release dosage unit can be coated with a delayed release polymer coating using conventional techniques, for example, using conventional coating pans, airless spray techniques, fluidized bed coating equipment (with or without Wurster inserts).For detailed information on materials, equipment and processes for preparing tablets and delayed release dosage forms, please refer to Pharmaceutical Dosage Forms: Tablets, eds. Lieberman et al. (New York: Marcel Dekker, Inc., 1989), and Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, 11th Ed. (Media, PA: Williams & Wilkins, 2017).

[0193] The preferred method for preparing sustained release tablets is by compressing a drug-containing blend, e.g., a blend of granules, prepared using a direct blend, wet granulation, or dry granulation process. Sustained release tablets can also be formed, rather than compressed, starting from a hydrous material containing a suitable water-soluble lubricant. However, tablets are preferably manufactured using compression rather than molding. The preferred method for forming sustained release drug-containing blends is to directly mix drug particles with one or more excipients, such as diluents (or fillers), binders, disintegrants, glidants, glidants, and colorants. As an alternative to direct blending, a wet granulation or dry granulation process can be used to prepare the drug-containing blend. Beads containing active agents can also be prepared by any one of several conventional techniques, generally starting with a fluid dispersion. For example, a typical method for preparing drug-containing beads involves dispersing or dissolving the active agent in a coating suspension or solution containing pharmaceutical excipients, e.g., polyvinylpyrrolidone, methylcellulose, talc, metal stearates, silicon dioxide, plasticizers, etc. The admixture is used to coat bead cores, such as sugar spheres (or so-called "nonpareils") approximately 60-20 mesh in size.

[0194] An alternative procedure for preparing drug beads is by blending the drug with one or more pharma- ceutically acceptable excipients, such as microcrystalline cellulose, lactose, cellulose, polyvinylpyrrolidone, talc, magnesium stearate, disintegrants, etc., extruding the blend, spheronizing the extrudate, drying, and optionally coating to form immediate release beads. 4. Formulations for mucosal and pulmonary administration

[0195] Probenecid, its metabolites, analogs, and prodrugs, and pharmaceutical compositions thereof can be formulated for pulmonary or mucosal administration. Such administration can include delivery of the composition to the pulmonary mucosa, nasal mucosa, oral mucosa (sublingual, buccal), vaginal mucosa, or rectal mucosa. In certain embodiments, the composition is formulated for sublingual delivery to a subject and is delivered sublingually to a subject.

[0196] In some embodiments, the compound is formulated for delivery to the lungs, such as by intranasal administration or oral inhalation. The airways are structures involved in gas exchange between air and the bloodstream. The lungs are branching structures that end up in the alveoli, where gas exchange occurs. The alveolar surface area is the largest in the respiratory system and is where drug absorption occurs. The alveoli are covered with a thin epithelium or mucus layer without villi, and secrete surfactant phospholipids. The airways include the upper airways, including the oropharynx and larynx, followed by the trachea, which then branches into the bronchi, and the lower airways, including the bronchioles. The upper and lower airways are referred to as conducting airways. The terminal bronchioles then divide into respiratory bronchioles, which then lead to the final respiratory area, the alveoli, or deep lung. The deep lung, or alveoli, are the primary target of inhaled therapeutic aerosols for systemic drug delivery.

[0197] Therapeutic compositions composed of low molecular weight drugs have been observed to be administered to the lungs, for example, beta-androgenic antagonists to treat asthma. Other therapeutic agents are active in the lungs and are administered systemically and targeted by pulmonary absorption.

[0198] Nasal delivery is considered a promising technique for administering therapeutic agents for the following reasons: the nose has a large surface area available for drug absorption due to an epithelial surface covered by numerous microvilli, the subepithelial layer is highly vascularized, venous blood from the nose passes directly into the systemic circulation, thus avoiding drug loss due to first-pass metabolism in the liver, allowing lower doses to be administered, therapeutic blood levels are achieved more rapidly, pharmacological activity occurs more rapidly, side effects are fewer, and the nasal delivery is less than 1 cm. 3high total blood flow per unit area, porous endothelial basement membrane, and easy accessibility.

[0199] In some embodiments, composition is formulated as aerosol.The term aerosol as used herein refers to any preparation of fine mist, which can be in solution or suspension, whether or not it uses propellant to generate.Aerosol can be produced by standard techniques such as ultrasonication or high pressure processing.

[0200] Probenecid has been used to reduce the nephrotoxicity of cidofovir when administered intravenously. Direct delivery of cidofovir to the airways has also been shown to be an effective prophylactic strategy to maximize tissue concentrations at the site of initial viral replication while minimizing accumulation in the kidney (Roy, et al., Antimicrob Agents Chemother., 47 (9): 2933-2937 (2003)).

[0201] Carriers for pulmonary formulations can be divided into those for dry powder formulations and those for administration as liquids. Aerosols for delivering therapeutic agents to the respiratory tract are known in the art. For administration via the upper respiratory tract, the formulation can be formulated as a solution or suspension, for example in buffered or unbuffered water or isotonic saline, and for intranasal administration, as drops or sprays. Such solutions or suspensions are preferably isotonic to nasal secretions and have approximately the same pH, for example, ranging from about pH 4.0 to about pH 7.4, or from pH 6.0 to pH 7.0. Buffers should be physiologically compatible, and include, by way of example only, phosphate buffers. For example, a representative nasal decongestant is described as being buffered to a pH of about 6.2. Those skilled in the art can easily determine the appropriate saline content and pH for a harmless aqueous solution for administration to the nose and / or upper respiratory tract.

[0202] The aqueous solution is preferably water containing salts and / or buffers such as phosphate buffered saline (PBS), a physiologically acceptable aqueous solution, or any other aqueous solution acceptable for administration to animals or humans. Such solutions are well known to those skilled in the art and include, but are not limited to, distilled water, deionized water, pure or ultrapure water, physiological saline, phosphate buffered saline (PBS). Other suitable aqueous vehicles include, but are not limited to, Ringer's solution and isotonic sodium chloride. Aqueous suspensions may contain suspending agents such as cellulose derivatives, sodium alginate, polyvinyl-pyrrolidone and gum tragacanth, and wetting agents such as lecithin. Suitable preservatives for aqueous suspensions include ethyl and n-propyl p-hydroxybenzoates.

[0203] In another embodiment, solvents that are low toxicity organic (i.e., non-aqueous) Class 3 residual solvents, such as ethanol, acetone, ethyl acetate, tetrahydrofuran, ethyl ether, and propanol, can be used in the formulation. The solvent is selected based on its ability to easily aerosolize the formulation. The solvent should not adversely react with the compound. A suitable solvent should be used in which the compound dissolves or in which a suspension of the compound is formed. The solvent should be sufficiently volatile to allow the formation of an aerosol of the solution or suspension. Additional solvents or aerosolizing agents, such as Freons, can be added as desired to increase the volatility of the solution or suspension.

[0204] In one embodiment, the composition may contain trace amounts of polymers, surfactants, or other excipients known in the art, in this context, "trace amount" means the absence of excipients that may affect or mediate pulmonary uptake of the compound, and that any excipients present are present in amounts that do not adversely affect pulmonary uptake of the compound.

[0205] Dry lipid powders can be dispersed directly in ethanol because they are hydrophobic. For lipids stored in organic solvents such as chloroform, the desired quantity of solution is placed in a vial and the chloroform is evaporated under a stream of nitrogen to form a thin dry film on the surface of the glass vial. This film swells easily upon reconstitution with ethanol. To thoroughly disperse the lipid molecules in the organic solvent, the suspension is sonicated. Non-aqueous suspensions of lipids can also be prepared in absolute ethanol using a reusable PARI LC Jet+ nebulizer (PARI Respiratory Equipment, Monterey, CA).

[0206] Dry powder formulations ("DPF") with larger particle size have improved flow characteristics, e.g., less aggregation, easier aerosolization, and potentially less phagocytosis. Dry powder aerosols for inhalation therapy are generally produced with mean diameters that fall primarily in the range of less than 5 microns, with aerodynamic diameters between 1 micron and 10 microns being the preferred range. To help achieve efficient aerosolization, among other potential benefits, large "carrier" particles (not containing drug) have been co-delivered with therapeutic aerosols.

[0207] Polymer particles can be prepared using single and double emulsion solvent evaporation, spray drying, solvent extraction, solvent evaporation, phase separation, simple and complex coacervation, interfacial polymerization, and other methods known to those skilled in the art.The particles can be made using the methods known in the art for making microspheres or microcapsules.The preferred method of manufacture is by spray drying and freeze drying, which requires using a solution containing a surfactant, spraying to form droplets of desired size, and removing the solvent.

[0208] Particles can be fabricated with suitable materials, surface roughness, diameter, and tap density for localized delivery to selected regions of the airway, such as deep lung or upper airway.For example, denser or larger particles can be used for delivery to the upper airway.Similarly, mixtures of particles of different sizes provided with the same or different active agents can be administered to target different regions of the lung with one administration.

[0209] Compositions and methods for preparing inhaled pharmaceutical compositions containing probenecid are described in US Patent Application Publication No. 2015 / 0272870.

[0210] Thus, the compositions disclosed herein are provided in the form of formulations and methods of administering them to the nasal mucosa and / or lungs by intranasal delivery, and to the lungs by oral inhalation.For intranasal delivery, the formulation and delivery device can be selected and prepared to drive absorption through the nasal mucosa or lungs. The nasal mucosa is easily accessible compared to other mucosae, providing a practical portal of entry for small and large molecules (Bitter, et al., "Nasal Drug Delivery in Humans," in Surber, et al., (eds): Topical Applications and the Mucosa. Curr Probl Dermatol. Basel, Karger, 2011, vol 40, pp 20-35, Pires, et al., J Pharm Pharmaceut Sci., 12 (3) 288 - 311, 2009, and Djupesland, Drug Deliv. and Transl. Res., 3: 42-62 (2013)DOI 10.1007 / s13346-012-0108-9). Intranasal administration provides rapid onset of therapeutic effect, reduced first-pass effect, reduced gastrointestinal degradation and pulmonary toxicity, non-invasive, essentially painless application, and easy and rapid use by patients, particularly suitable for children, or by physicians in emergency situations. For example, Flu Mist® is an exemplary effective nasal influenza vaccine spray.

[0211] A number of delivery devices are available for intranasal administration. The devices vary in delivery accuracy, dose reproducibility, cost and ease of use. Metered dose systems provide dose accuracy and reproducibility. There are also differences in delivery force, spray pattern and droplet size emitted. Droplet size is important for drug deposition in the nasal cavity. Parameters can be modulated to enhance deposition while limiting the fraction of small particles that can bypass the nose and enter the lungs, or to reduce deposition while increasing the fraction of small particles that can bypass the nose and enter the lungs.

[0212] The following aspects of the nasal anatomy can affect drug delivery: During exhalation, the soft palate automatically closes, separating the nose and the oral cavity. Thus, it is possible to use smaller particles during nasal sprays, and still avoid lung deposition. Furthermore, while the soft palate is closed, there is a communication channel between the two nostrils, located behind the wall separating the two passages. Under these circumstances, it is possible for airflow to enter one nostril and exit the other. This bidirectional delivery concept combines two anatomical facts into one complete functional device. The device is inserted into one nostril by a sealing nozzle, and the patient exhales into the mouthpiece. The combination of the closed soft palate and the sealed nozzle creates an airflow that enters one nostril, turns 180 degrees through the communication channel, and exits the other nostril (bidirectional flow). Since delivery occurs during exhalation, small particles cannot enter the lungs.

[0213] Particle size, flow rate and direction can be tailored for efficient delivery to the nasal mucosa. Adding an exit resistance to provide additional control of input pressure can improve distribution to the sinuses and middle ear. Manipulation of the flow pattern allows delivery to the olfactory region, potentially achieving direct "nose-to-brain" delivery. A 180 degree turn behind the septum captures particles still suspended, allowing targeted delivery of cargo to the pharyngeal tonsils.

[0214] Strategies for enhancing drug absorption via nasal and pulmonary routes are also known in the art and can be utilized in the formulations and delivery methods disclosed herein.Such strategies include, for example, the use of absorption enhancers such as surfactants, cyclodextrins, protease inhibitors, and tight junction regulators, and the application of carriers such as liposomes and nanoparticles.See, for example, Ghadiri, et al., Pharmaceutics, 11 (3): 113 (2019).

[0215] For example, in certain embodiments, the compounds disclosed herein are formulated as aerosol compositions comprising a suspension of drug particles in a propellant for treating respiratory diseases or disorders, the process comprising forming a slurry of a bulking agent, such as lactose, with a less volatile solvent, such as ethanol, subjecting the slurry to high pressure homogenization to reduce the mass median particle size of the bulking agent to less than 1 micron, and then mixing the resulting slurry with other components of the aerosol formulation, including the drug and a propellant, and the mass median particle size of the drug being equal to or greater than 1 micron. The aerosol formulation can be administered either nasally or orally. 5. Formulations for parenteral administration

[0216] Probenecid, its metabolites, analogs, and prodrugs, and its pharmaceutical compositions can be administered by parenteral injection or infusion as an aqueous solution. Formulations may be in the form of suspensions or emulsions. In general, pharmaceutical compositions are provided containing an effective amount of active agent, and optionally contain pharma- ceutically acceptable diluents, preservatives, solubilizers, emulsifiers, adjuvants, and / or carriers. Such compositions include diluents such as sterile water, buffered saline of various buffer contents (e.g., Tris-HCl, acetate, phosphate), pH and ionic strength; and, optionally, additives such as surfactants and solubilizers (e.g., TWEEN® 20, TWEEN® 80, POLYSORBATE® 20 or 80), antioxidants (e.g., ascorbic acid, sodium metabisulfite), and preservatives (e.g., Thimersol, benzyl alcohol) and bulking substances (e.g., lactose, mannitol). Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. The formulation can be lyophilized and redissolved / resuspended immediately before use. The formulation can be sterilized, for example, by filtering through a bacteria-retaining filter, by incorporating a sterilizing agent into the composition, by irradiating the composition, or by heating the composition. In some embodiments, the formulation is a long-acting parenteral formulation with or without the use of an implantable device and / or delivery vehicle. These formulations include, but are not limited to, microencapsulation, oil-based formulations, nanoparticle or nanocrystal formulations, and hydrogel formulations. 6. Topical and transdermal preparations

[0217] Transdermal formulations can also be prepared. Transdermal formulations are generally gels, ointments, lotions, sprays, or patches, all of which can be prepared using standard techniques. Transdermal formulations can include permeation enhancers.

[0218] A "gel" is a colloid in which a dispersed phase and a continuous phase are combined to produce a semi-solid material, such as a jelly.

[0219] An "oil solution" is a composition that contains at least 95 wt% lipophilic substances. Examples of lipophilic substances include, but are not limited to, naturally occurring and synthetic oils, fats, fatty acids, lecithins, triglycerides, and combinations thereof.

[0220] "Continuous phase" refers to the liquid in which solids are suspended or droplets of another liquid are dispersed, sometimes referred to as the external phase. Continuous phase also refers to the fluid phase of a colloid in which solid or fluid particles are distributed. When the continuous phase is water (or another hydrophilic solvent), water-soluble or hydrophilic drugs are dissolved (rather than dispersed) in the continuous phase. In multiphasic formulations (e.g., emulsions), separate phases are suspended or dispersed in the continuous phase.

[0221] An "emulsion" is a composition that contains a homogeneously blended mixture of immiscible components. In certain embodiments, the immiscible components include a lipophilic component and an aqueous component. An emulsion is a preparation in which one liquid is distributed as small globules throughout a second liquid. The dispersed liquid is the discontinuous phase, and the dispersion medium is the continuous phase. If the dispersed liquid is an oil and the continuous phase is an aqueous solution, it is known as an oil-in-water emulsion, while if the dispersed phase is water or an aqueous solution and the continuous phase is an oil or an oily material, it is known as a water-in-oil emulsion. Either or both of the oil and aqueous phases may contain one or more surface active substances, emulsifiers, emulsion stabilizers, buffers, and other excipients. Preferred excipients include surface active substances, especially nonionic surface active substances; emulsifying agents, especially emulsifying waxes; and liquid non-volatile non-aqueous materials, especially glycols such as propylene glycol. The oil phase may contain other pharma- ceutically accepted oil excipients, for example, materials such as hydroxylated castor oil or sesame oil can be used as surfactants or emulsifiers in the oil phase.

[0222] "Emollients" are externally applied agents that soften or smooth the skin and are generally known in the art and are described in "Handbook of Pharmaceutical Excipients", 4 th Ed., Pharmaceutical Press, 2003. These emollients include, but are not limited to, almond oil, castor oil, carob extract, cetostearyl alcohol, cetyl alcohol, cetyl esters wax, cholesterol, cottonseed oil, cyclomethicone, ethylene glycol palmitostearate, glycerin, glycerin monostearate, glyceryl monooleate, isopropyl myristate, isopropyl palmitate, lanolin, lecithin, light mineral oil, medium chain triglycerides, mineral oil and lanolin alcohol, petrolatum, petrolatum and lanolin alcohol, soybean oil, starch, stearyl alcohol, sunflower oil, xylitol, and combinations thereof. In one embodiment, the emollient is ethylhexyl stearate and ethylhexyl palmitate.

[0223] A "surfactant" is a surface active agent that reduces surface tension, thereby increasing the emulsifying, foaming, dispersing, spreading and wetting properties of the product. Suitable non-ionic surfactants include emulsifying wax, glyceryl monooleate, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polysorbates, sorbitan esters, benzyl alcohol, benzyl benzoate, cyclodextrins, glycerol monostearate, poloxamer, povidone and combinations thereof. In one embodiment, the non-ionic surfactant is stearyl alcohol.

[0224] An "emulsifier" is a surface-active substance that promotes the suspension of one liquid in another and promotes the formation of stable mixtures or emulsions of oil and water. Common emulsifiers are metal soaps, certain animal and vegetable oils, and various polar compounds. Suitable emulsifiers include gum arabic, anionic emulsifying wax, calcium stearate, carbomer, cetostearyl alcohol, cetyl alcohol, cholesterol, diethanolamine, ethylene glycol palmitostearate, glycerin monostearate, glyceryl monooleate, hydroxypropyl cellulose, hypromellose, hydrolyzed lanolin, lanolin alcohol, lecithin, medium chain triglycerides, methylcellulose, mineral oil and lanolin alcohol, sodium dihydrogen phosphate, monoethanolamine, nonionic emulsifying wax, oleic acid, poloxamers, poloxamers, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearate, propylene glycol alginate, self-emulsifying glyceryl monostearate, anhydrous sodium citrate, sodium lauryl sulfate, sorbitan esters, stearic acid, sunflower oil, tragacanth, triethanolamine, xanthan gum and combinations thereof. In one embodiment, the emulsifier is glycerol stearate.

[0225] A "lotion" is a liquid formulation with low to medium viscosity. A lotion may contain finely divided substances that are soluble in the dispersion medium by using suspending and dispersing agents. Alternatively, a lotion may have as a dispersed phase a liquid substance that is immiscible with the vehicle and is usually dispersed by an emulsifying agent or other suitable stabilizer. In one embodiment, the lotion is in the form of an emulsion with a viscosity between 100 centistokes and 1000 centistokes. The flowability of lotions allows them to be applied quickly and evenly over a large surface area. Lotions are generally intended to dry on the skin leaving a thin coating of pharmaceutical components on the surface of the skin.

[0226] A "cream" is a liquid or semi-solid emulsion of either "oil-in-water" or "water-in-oil" viscosity. Creams may contain emulsifying agents and / or other stabilizing agents. In one embodiment, the formulation is in the form of a cream having a viscosity greater than 1000 centistokes, generally in the range of 20,000 to 50,000 centistokes. Creams are often preferred over ointments because they are generally easier to spread and remove.

[0227] An emulsion is a preparation in which one liquid is distributed as small globules throughout a second liquid. The dispersed liquid is the discontinuous phase and the dispersion medium is the continuous phase. If the dispersed liquid is an oil and the continuous phase is an aqueous solution, it is known as an oil-in-water emulsion, whereas if the dispersed phase is water or an aqueous solution and the continuous phase is an oil or an oily material, it is known as a water-in-oil emulsion. The oil phase may be at least partially composed of a propellant, such as an HFA propellant. Either or both of the oil and aqueous phases may contain one or more surfactants, emulsifiers, emulsion stabilizers, buffers, and other excipients. Preferred excipients include surfactants, especially nonionic surfactants; emulsifying agents, especially emulsifying waxes; and liquid non-volatile non-aqueous materials, especially glycols such as propylene glycol. The oil phase may contain other pharma-ceutically accepted oil excipients. For example, materials such as hydroxylated castor oil or sesame oil can be used as surfactants or emulsifiers in the oil phase.

[0228] Self-emulsifying systems are a subset of emulsions. These drug delivery systems are generally capsules (hard or soft shell) consisting of a drug dispersed or dissolved in a mixture of surfactant and a lipophilic liquid such as oil or other water-immiscible liquid. When the capsule is exposed to an aqueous environment and the outer gelatin shell dissolves, very small emulsion droplets are immediately generated by contact between the aqueous medium and the capsule contents. The size of these droplets is generally in the micellar or nanoparticle range. No mixing forces are required to produce an emulsion, as is typical for emulsion formulation processes.

[0229] The basic difference between creams and lotions is the viscosity, which depends on the amount / use of various oils and the percentage of water used to prepare the formulation. Creams are generally more viscous than lotions, can have a variety of applications, and often use a wide variation of oils / butter depending on the desired effect on the skin. In cream formulations, the percentage of water base is about 60-75% of the total, oil base is about 20-30%, and the remaining percentages are emulsifiers, preservatives, and additives, totaling 100%.

[0230] "Ointment" is a semi-solid preparation that contains an ointment base and optionally one or more active agents.Examples of suitable ointment bases include hydrocarbon bases (e.g., petrolatum, white petrolatum, yellow ointment, and mineral oil); absorbent bases (e.g., hydrophilic petrolatum, dehydrated lanolin, lanolin, and cold cream); water-removable bases (e.g., hydrophilic ointments), and water-soluble bases (e.g., polyethylene glycol ointments).Pastes are generally different from ointments in that they contain a higher percentage of solids.Pastes are generally more absorbent and less sticky than ointments prepared with the same components.

[0231] A "gel" is a semi-solid system containing a dispersion of small or large molecules in a liquid vehicle that is rendered semi-solid by the action of a thickening agent or polymeric material dissolved or suspended in the liquid vehicle. The liquid may contain a lipophilic component, an aqueous component, or both. Some emulsions may be gels or may not contain a gel component. However, some gels are not emulsions because they do not contain a homogenized blend of immiscible components.

[0232] Suitable gelling agents include, but are not limited to, modified celluloses such as hydroxypropyl cellulose and hydroxyethyl cellulose; Carbopol homopolymers and copolymers; and combinations thereof. Suitable solvents in the liquid vehicle include, but are not limited to, diglycol monoethyl ether; alkylene glycols such as propylene glycol; dimethyl isosorbide; alcohols such as isopropyl alcohol and ethanol. Solvents are generally selected for their ability to dissolve the drug. Other additives that improve the skin feel and / or emollient properties of the formulation can also be incorporated. Examples of such additives include, but are not limited to, isopropyl myristate, ethyl acetate, C12-C15 alkyl benzoates, mineral oil, squalane, cyclomethicone, capric / caprylic triglyceride, and combinations thereof.

[0233] The foam consists of a combination of an emulsion and a gas propellant. The gas propellant is mainly composed of hydrofluoroalkanes (HFAs). Suitable propellants include HFAs such as 1,1,1,2-tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA 227), but also mixtures and admixtures of these and other HFAs that are currently approved or may be approved for medical use. The propellant is preferably not a hydrocarbon propellant gas that may produce flammable or explosive vapors during spraying. In addition, the composition preferably does not contain volatile alcohols that may produce flammable or explosive vapors during use.

[0234] A buffering agent is used to control the pH of the composition. Preferably, the buffering agent buffers the composition to a pH of from about 4 to about pH 7.5, more preferably from about pH 4 to about pH 7, and most preferably from about pH 5 to about pH 7. In a preferred embodiment, the buffering agent is triethanolamine.

[0235] Preservatives can be used to prevent fungal and microbial growth. Suitable antifungal and antimicrobial agents include, but are not limited to, benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, and thimerosal.

[0236] Additional agents that can be added to the formulation include permeation enhancers. In some embodiments, the permeation enhancer increases the solubility of the drug, improves the transdermal delivery of the drug across the skin, especially across the stratum corneum, or a combination thereof. Some permeation enhancers cause skin irritation, skin toxicity, and skin allergies. However, the more commonly used ones include urea, (carbonyldiamide), imidourea, N,N-diethylformamide, N-methyl-2-pyrrolidone, 1-dodecyl-azacycloheptan-2-one, calcium thioglycolate, 2-pyrrolidone, N,N-diethyl-m-toluamide, oleic acid and its ester derivatives, such as methyl, ethyl, propyl, isopropyl, butyl, vinyl, and glyceryl monooleate, sorbitan esters, such as sorbitan monolaurate and sorbitan monooleate, other fatty acid esters, such as lauric acid, sorbitan monolaurate, sorbitan monooleate ... isopropyl phosphate, isopropyl myristate, isopropyl palmitate, disoisopropyl adipate, propylene glycol monolaurate, propylene glycol monooleate, and non-ionic surfactants such as BRIJ® 76 (stearyl poly(10) oxyethylene ether), BRIJ® 78 (stearyl poly(20) oxyethylene ether), BRIJ® 96 (oleyl poly(10) oxyethylene ether), and BRIJ® 721 (stearyl poly(21) oxyethylene ether) (ICI and other permeation enhancers, such as glycerol, glycerol, terpenes, and glycerols. Chemical permeation and methods of increasing transdermal drug delivery are described in Inayat, et al., Tropical Journal of Pharmaceutical Research, 8 (2): 173-179 (2009) and Fox, et al., Molecules, 16: 10507-10540 (2011). In some embodiments, the permeation enhancer is or includes an alcohol, such as ethanol, or others disclosed herein or known in the art.

[0237] The delivery of drugs by transdermal route has been known for many years.The advantages of transdermal drug delivery compared to other types of drug delivery, such as oral, intravenous, intramuscular, etc., include: avoiding first-pass metabolism in liver, being able to discontinue administration by removing delivery system, being able to control drug delivery over a longer period than the normal gastrointestinal transit of oral dosage forms, and being able to modify the properties of biological barriers for absorption.

[0238] The effectiveness of controlled release transdermal devices is due to the fact that the drug is delivered to the skin at a known rate over an extended period of time, typically a day, several days, or a week. Two mechanisms are used to regulate the drug rate: the drug is contained in a drug reservoir separated from the wearer's skin by a synthetic membrane through which the drug diffuses; or the drug is held dissolved or suspended in a polymer matrix through which the drug diffuses to the skin. In devices incorporating a reservoir, a constant rate of drug is delivered across the membrane as long as there is not too much undissolved drug remaining in the reservoir; matrix or integrated devices are generally characterized by a decrease in drug rate over time as the layer of the matrix closer to the skin is depleted of drug. Reservoir-type patches typically include a porous membrane covering a reservoir of drug, which allows for controlled release, while the release of drug from matrix or integrated devices can be controlled by a thin thermofusible layer (e.g., an adhesive layer) of drug embedded in a polymer matrix. Thus, the patch can release the active agent in a controlled manner, without necessarily being a controlled release formulation.

[0239] The patch may include a liner that protects the patch during storage and is removed before use; a drug or drug solution in direct contact with a release liner; an adhesive that serves to adhere the patch components together and to adhere the patch to the skin; one or more membranes that separate other layers and may control the release of drug from reservoirs, multi-layer patches, and the like; and a backing that protects the patch from the outside environment.

[0240] Common types of transdermal patches include, but are not limited to, single-layer drug-containing adhesive patches, in which the adhesive layer contains the drug and serves to adhere the various layers of the patch together, as well as adhere the entire system to the skin and is also responsible for drug release; multi-layer drug-containing adhesive patches, which are similar to single-layer drug-containing adhesive patches, but contain multiple layers, for example, a layer for immediate release of drug and another layer for controlled release of drug from a reservoir; reservoir-type patches, in which the drug layer is a liquid compartment containing a drug solution or suspension and is separated from the adhesive layer; matrix-type patches, in which the drug layer is a semi-solid matrix containing a drug solution or suspension, surrounded and partially covered by an adhesive layer; and vapor patches, in which the adhesive layer not only serves to adhere the various layers together, but also releases vapor. Methods for making transdermal patches are described in US Pat. Nos. 6,461,644, 6,676,961, 5,985,311, and 5,948,433. 7. Animal feed, water, and milk

[0241] Probenecid, its metabolites, analogs, and prodrugs, and pharma- ceutically acceptable salts thereof, can be formulated into animal feed, nutritional supplements, drinking water, and / or milk. Animal feed can include commercial livestock feeds, and the like.

[0242] Exemplary animal feeds include chicken feeds, including (i) special starter, grower and / or finisher diets for meat chickens, such as broilers, or (ii) feeds for layer chickens, such as pullets or hens, or (iii) feeds for breeders. It will be understood by those skilled in the art that the feeds for other poultry, such as turkeys, geese, quails, pheasants, or ducks, or livestock, such as cattle, sheep, goats or pigs, alpacas, bantengs, bison, camels, cats, deer, dogs, donkeys, gayal, guinea pigs, horses, llamas, mules, rabbits, reindeer, water buffaloes, and yaks, are also included, but also include feeds for other animals, including zoo animals, captive animals, game animals, and farm animals, such as cats and dogs, rodents (e.g., mice, rats, guinea pigs, hamsters), and horses, and any other farmed, wild, and livestock animals, including mammals and birds. For example, in some embodiments, probenecid, a metabolite, analog, or prodrug thereof, or a pharmaceutically acceptable salt thereof, is formulated as part of chicken feed. Chicken diet feed generally contains crude protein, fat, sugar, amino acids, minerals, starch, and vitamins. There are many ingredients available. See, for example, Commercial Poultry Nutrition, 3rd Edition, University books, Steven Leeson, John D. Summers, PO Box 1326 Guelph, Ontario, Canada N1H 6N8 (2005), the entire contents of which are expressly incorporated herein by reference in their entirety. Chapter 2 details the advantages and disadvantages of common ingredients in such diets. The main energy-providing ingredients in the diet are corn, wheat, soybeans, soybean oil, and amino acids. Corn may be the main contributor to metabolic energy.Thus, in some embodiments, probenecid, metabolites, analogs, or prodrugs thereof, or pharma- ceutically acceptable salts thereof are formulated with one or more of corn, soybean, sorghum, vegetable fat, molasses, vitamins, minerals, amino acids, salts, phosphate, calcium, or combinations thereof, alone or in further combination with other materials. Chickens used in optimized commercial broiler production are generally fed different diets depending on their age. For example, chickens for broiler production may be raised using three types of diets. These diets are generally referred to as "starter", "grower" and "finisher". A "pre-starter" diet is also possible. The compounds disclosed herein may be added to any of the aforementioned diets.

[0243] Similarly, in some embodiments, probenecid, a metabolite, analog, or prodrug thereof, or a pharma- ceutically acceptable salt thereof, is formulated as part of the swine feed. The swine feed may be formed from one or more of grains (i.e., corn, wheat, barley, oats), oilseed meals (i.e., soybean meal, cottonseed meal, linseed meal, rapeseed meal, sunflower meal), by-products (i.e., wheat bran, rice bran, corn distillers grains, brewers grains, corn gluten meal, corn gluten feed, molasses, rice milling by-products), oils (i.e., corn oil, flax oil, soy oil, palm oil, animal fats, restaurant used greases, and blends thereof), vitamins and minerals, amino acids, antioxidants, tocochromanols, tocopherols, salts, coccidiostats and / or antibiotics, enzymes (i.e., phytase, xylanase), and other feed additives.

[0244] Feed additives and nutritional supplements can include, for example, macrominerals including those selected from the group consisting of calcium, phosphorus, magnesium, sodium, potassium and chlorine; trace minerals including zinc and / or selenium; and / or supplemental vitamins including those selected from the group consisting of vitamin A, nicotinic acid, pantothenic acid, pyridoxine (B6) and biotin in maize and wheat based feeds. In addition, broilers have a basic requirement of 10-15 mg / kg vitamin E. The need for additional supplementation of vitamin E depends on the level and type of fat, the level of selenium, and the presence of pro-oxidants and antioxidants in the diet. By heat processing the feed, up to 20% of vitamin E can be destroyed. Choline can also be added to the complete feed.

[0245] Non-nutrient feed additives can also be included. Enzymes are routinely used in poultry feed to improve the digestibility of feed ingredients. Feed enzymes are generally available that act on carbohydrates, plant-bound minerals and proteins. Non-starch polysaccharide (NSP) enzymes are economically beneficial for wheat-based feeds. These enzymes also allow for increased flexibility in the level of barley included in the ration. Phytase enzymes can be used to enhance phytate phosphorus utilization. Protease enzymes can be included to act on plant products. Carbohydrase enzymes can be added, which can provide beneficial responses when using maize-soybean diets. If enzymes are added before heat treatment of broiler feed, there is a potential for loss of enzyme activity. This can be avoided by spraying the enzymes on the feed at the end of treatment.

[0246] Additional pharmaceuticals and / or prophylactics can be added. A wide range of pharmaceuticals can be administered through the feed, such as anticoccidials and antibiotics. Antibiotic growth promoters / digestion enhancers can be included, which can have a mode of action involving, for example, modification of the intestinal flora, resulting in benefits to nutrient utilization.

[0247] Prebiotics can be added, which refers to a group of substances that counteract harmful microorganisms and stimulate the growth of beneficial ones. Currently, oligosaccharides form the largest group of these products.

[0248] Probiotics can be added to introduce live microorganisms into the digestive tract to help establish a stable and beneficial flora, with the goal of providing the digestive tract with active non-pathogenic microorganisms, thus preventing colonization by pathogenic microorganisms through competitive exclusion.

[0249] Organic acids can be added. Organic acid products can be used to reduce bacterial contamination of the feed (e.g. after heat treatment) and can also promote the development of beneficial flora in the avian digestive tract.

[0250] Sorbents are used specifically to adsorb mycotoxins and may also have beneficial effects on general avian health and nutrient absorption. A variety of products are available for use as adsorbents, including various clays and charcoal.

[0251] Antioxidants can provide important protection from nutrient losses in broiler diets. Some feed ingredients, e.g., fish meal and fat, can be protected. Vitamin premixes should be protected by antioxidants unless optimal storage times and conditions are provided. When stored for long periods or when poor storage conditions are unavoidable, additional antioxidants can be added to the final feed.

[0252] Mold inhibitors can be added, for example to contaminated feed ingredients or finished food products, to reduce fungal growth and mycotoxin production.

[0253] Pelletizing agents can be added, which are used to improve the hardness of the pellets. Some examples of pellet binders are hemicellulose, bentonite and guar gum.

[0254] Other products that may be used in the production of feed and nutritional supplements include essential oils, nucleotides, glucans and specialized plant extracts. In parts of the world where formaldehyde use is permitted, it can be used to treat / preserve feed. III. Treatment Methods

[0255] Methods of use are also provided, generally comprising administering to a subject in need thereof an effective amount of probenecid, or a metabolite, analog, or prodrug thereof, or a pharma- ceutically acceptable salt thereof, or a composition or formulation formed therefrom. A. Methods of Treating and / or Preventing Viral Infections

[0256] Methods of treating a viral infection in a subject in need thereof are provided. Accordingly, methods of treating and / or preventing a viral infection and / or symptoms associated therewith are provided.

[0257] In some embodiments, the virus can be one that causes a respiratory disease or illness or a non-respiratory disease or illness. Thus, methods of treating a respiratory disease or illness, particularly in a subject infected with a virus, are also provided.

[0258] The method may be a prophylactic method. Thus, methods of preventing viral infection and / or respiratory or non-respiratory diseases and illnesses, particularly due to viral infection, are also provided.

[0259] The method may include administering to the subject an effective amount of probenecid, a metabolite, analog, or prodrug thereof, or a pharma- ceutically acceptable salt thereof, to reduce viral replication, infection, or a combination thereof, which in some embodiments is effective to reduce viral titer in the subject, reduce viral collection in host cells, reduce and / or limit severe inflammation and / or one or more severe respiratory symptoms associated with the infection.

[0260] In some embodiments, the subject has been exposed to a virus or will be exposed to a virus. In some embodiments, the subject has been exposed to a virus or has an active viral infection.

[0261] In some embodiments, viral infection is detected by a PCR test designed to detect viral DNA or RNA in a sample from a subject, such as a nasal swab, throat swab, saliva, or other bodily fluid, or by a serological or immunodiagnostic test designed to detect antibodies produced by the body's immune system in response to infection, typically in a blood sample from a subject.

[0262] The composition can also be administered prophylactically, for example, to reduce or prevent future exposure to virus and the effects of infection that may accompany it.Thus, in some embodiments, the subject has not been exposed to virus and / or has not yet developed active virus infection.In some embodiments, the subject is a healthy subject.

[0263] In some embodiments, the subject is a subject who has been in close contact with a subject who has tested positive for the virus.Such a subject may or may not show one or more symptoms of infection.Close contact can be or include, for example, being within 6 feet (or 2 meters) of an infected person for a total of 15 minutes or longer, caring for an infected person at home, having direct physical contact (hug or kiss) with an infected person, sharing eating utensils with an infected person, or being contacted by an infected person's sneeze, cough, or other respiratory droplets.

[0264] In some embodiments, the subject is one who has been identified through contact tracing as having been exposed to the virus or one or more subjects infected with the virus.

[0265] In some embodiments, the subject is one who will be exposed to the virus. An exemplary subject is a healthcare worker who will be treating an infected individual.

[0266] In some embodiments, treatment is initiated 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, or more, days, or weeks before exposure to the virus, or 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, or more, days, or weeks after exposure to the virus.

[0267] In some embodiments, probenecid, its metabolites or analogs or prodrugs, or pharma- ceutically acceptable salts thereof are administered in an effective amount to reduce or prevent one or more symptoms of viral infection. Symptoms include acute respiratory illness symptoms, such as fever, sinus and / or lung congestion, runny or stuffy nose, coughing, sneezing, sore throat, body aches, fatigue, shortness of breath, chest tightness, and wheezing when breathing out. Exemplary viruses and the specific symptoms associated with their infection are discussed in more detail below.

[0268] In some embodiments, the subject does not have gout, a need for sustained serum levels of penicillin (or other antibiotics), pelvic inflammatory disease, or gonorrhea. 1. Exemplary Viruses

[0269] The compounds, compositions, and methods of use disclosed herein can be used to prevent and therapeutically treat infection with one or more viruses.

[0270] In some embodiments, the virus is an RNA virus. In some embodiments, the virus is a negative strand RNA virus. In some embodiments, the virus is a DNA virus. In some embodiments, the virus is not a DNA virus.

[0271] In a preferred embodiment, the virus has an RNA genome, for example, a negative or positive sense genome composed of ribonucleic acid. In some embodiments, the virus encodes an RNA-dependent RNA polymerase (RdRp). In some embodiments, the virus is a member of the kingdom Orthornavirae.

[0272] The virus may, for example, belong to the following families: Adenoviridae, Papoviridae, Herpesviridae, Poxviridae, Anelloviridae, Pleolipoviridae, Reoviridae, Picornaviridae, Caliciviridae, Togaviridae, Arenaviridae, Flaviviridae, Orthomyxoviridae, Paramyxoviridae, Bunyaviridae, Rhabdoviridae, Filoviridae, Coronaviridae, Astroviridae, Bornaviridae, Arteriviridae or Hepeviridae.

[0273] For example, in some embodiments, the virus is from a negative strand RNA virus family, e.g., Arenaviridae, Bunyaviridae, Filoviridae, Nymaviridae, Orthomyxoviridae, Paramyxoviridae, Pneumoviridae, or Rhabdoviridae; or a positive strand family, e.g., Arteriviridae, Astroviridae, Caliciviridae, Coronaviridae, Flaviviridae, Hepeviridae / Nodaviridae, Picornaviridae, or Togaviridae.

[0274] Host gene pathway analysis indicates that the replication of some viruses may intersect with OAT activity, and that OAT may be required to transport viral components required for viral replication using a process similar to OAT-mediated vectorial transport of sodium and chloride ions across the airway lumen (Zhang, et al., J Virol 76, 5654-5666, doi: 10.1128 / jvi.76.11.5654-5666.2002 (2002), Chen, et al., Am J Respir Cell Mol Biol 40, 588-600, doi: 10.1165 / rcmb.2008-0034OC (2009)). In some embodiments, the virus utilizes an organic anion transporter. In some embodiments, the transporter is a SLC22 family member. See, e.g., Engelhart, et al., Int. J. Mol. Sci., 21 (5), 1791 (2020); doi.org / 10.3390 / ijms21051791, which is expressly incorporated herein by reference in its entirety. In some embodiments, the transporter is an OAT selected from OAT1, OAT2, OAT3, OAT4, OAT5, OAT6, OAT7, rOAT8, OAT9, OAT10, and / or URAT1. In some embodiments, probenecid, a metabolite, analog, or prodrug, or a pharma- ceutically acceptable salt thereof, is effective to reduce or inhibit the activity of a transporter, such as one or more of the foregoing.

[0275] In some embodiments, the compositions are used as prophylactic or therapeutic pan-antiviral agents to prevent or treat infections with two or more viruses.

[0276] Examples of viruses that can prevent and / or treat infection include, but are not limited to, influenza viruses, such as influenza A virus, influenza B virus, influenza C virus, respiratory syncytial virus (RSV), human metapneumovirus, coronavirus, measles virus, parainfluenza virus, mumps virus, Zika virus, dengue virus, yellow fever virus, Japanese encephalitis virus, Ebola virus, Hantavirus, Lassa virus, and West Nile virus. Viral infections include viral infections of the liver. Examples of viruses that cause infections of the liver include, but are not limited to, hepatitis A virus, hepatitis B virus, and hepatitis C virus. Some of these viruses are discussed in more detail below.

[0277] In some embodiments, the virus is a respiratory virus, and thus, viral infections include viral infections of the respiratory tract.

[0278] In some embodiments, the subject is infected with a second virus that may or may not be treatable with the virus that is the target of the compounds, compositions, and methods disclosed herein, the compounds, compositions, and methods disclosed herein. In some embodiments, the second virus is human immunodeficiency virus (HIV). A. Respiratory syncytial virus (RSV)

[0279] In some embodiments, the virus is respiratory syncytial virus (RSV), also called human respiratory syncytial virus (hRSV) and human orthopneumovirus.RSV is a common infectious virus that causes infections of the respiratory tract.RSV is a negative-sense, single-stranded RNA virus, and its name comes from the large cells known as syncytia that form when infected cells fuse.

[0280] RSV is divided into two antigenic subtypes, A and B, based on the reactivity of the F and G surface proteins with monoclonal antibodies. These subtypes tend to circulate together within local epidemics, although subtype A tends to be more common. RSV subtype A (RSVA) is generally considered to be more virulent than RSV subtype B (RSVB), with higher viral loads and shorter transmission times.

[0281] The model of RSV transmission is that annual RSV outbreaks are due to variants arising from locally evolved clades and not necessarily due to viruses introduced from distant regions. Griffiths, et al., Clinical microbiology reviews, 30 (1): 277-319 (2017)doi: 10.1128 / CMR.00010-16. Initially, five RSVA clades and four RSVB clades were identified, designated GA1-GA5 and GB1-GB4, respectively. This list of clades has since expanded to 16 RSVA clades and 22 RSVB clades. A recent global survey identified GA1, GA2, GA5, and GA7 as the predominantly circulating RSVA clades worldwide. GA7 is the only predominantly circulating RSVA clade found in the United States. Globally, the BA clade of RSVB dominates. The compounds, compositions, and methods disclosed herein can be used to treat or prevent RSVA, RSVB, or a combination thereof. The compounds, compositions, and methods disclosed herein can be used to treat or prevent any one or more of GA1-GA16, and any one or more of GB1-GB22, or any combination thereof. B mumps virus

[0282] Mumps orthorubulavirus, also known as Mumps orthorubulavirus, is assigned to the genus Orthorubulavirus in the family Paramyxoviridae, subfamily Rubulavirinae. There is one serotype and 12 genotypes of mumps virus. The genotypes can be differentiated based on the F, SH, and HN genes. The SH gene varies between genotypes by 5% to 21%, and this variability is the highest among the MuV genes. The genotypes are designated genotypes A to N, i.e., genotypes A, B, C, D, F, G, H, I, J, K, L, and N, except for E and M. Genotypes E and M were previously recognized, but phylogenetic analysis revealed that the MuVs assigned to them belonged instead to genotypes C and K, respectively, and they were eliminated.

[0283] The frequency of occurrence of the various genotypes varies from region to region. For example, genotypes C, D, H, and J are more common in the Western Hemisphere, while genotypes F, G, and I are more common in Asia, although genotype G is considered to be the global genotype. Genotypes A and B have not been observed in the wild since the 1990s. This diversity of MuV is not reflected in the antibody response, because there is only one serotype and antibodies against one genotype are functional against all other genotypes.

[0284] The compounds, compositions, and methods disclosed herein can be used to treat any one or more of mumps virus genotypes A, B, C, D, F, G, H, I, J, K, L, and N. C measles virus

[0285] Measles morbillivirus (MeV), also known as measles virus (MV), is a single-stranded, negative-sense, enveloped, non-segmented RNA virus in the genus Morbillivirus and family Paramyxoviridae. The virus is the cause of measles. The measles virus genome is generally 15,894 nucleotides long and encodes eight proteins. The WHO currently recognizes eight clades of measles (A-H). Subtypes are designated numerically, such as A1, D2, etc. Twenty-four subtypes are recognized (Bianchi, et al., Epidemiol Infect., 147: e80 (2019)). Despite the diversity of measles genotypes, there is only one measles serotype. Since 1990, 19 genotypes have been detected: A*, B2, B3, C1, C2, D2, D3, D4, D5, D6, D7, D8, D9, D10, D11, G2, G3, H1, H2 (Centers for Disease Control Website, "Measles (Rubeola)"). Four major measles genotypes currently circulate worldwide: D8, B3, H1, and D4. Antibodies to measles bind to the hemagglutinin protein. Thus, antibodies to one genotype (e.g., vaccine strain) protect against all other genotypes.

[0286] The compounds, compositions, and methods disclosed herein can be used to treat any one or more of the eight clades and / or 24 subtypes of measles virus. D. Zika virus

[0287] Zika virus is a mosquito-borne virus belonging to the Flaviviridae family, Flavivirus genus, and is therefore related to dengue virus, yellow fever virus, Japanese encephalitis virus, and West Nile virus. Like other flaviviruses, Zika virus is enveloped, icosahedral, non-segmented, single-stranded, 10 kilobase, and has a positive-sense RNA genome. Zika virus is most closely related to Spondwenivirus, which is one of two viruses known in the Spondwenivirus clade. There are two Zika lineages: African and Asian lineages. Phylogenetic studies have shown that the virus circulating in the Americas is 89% identical to the African genotype, but most closely related to the Asian strain circulating in French Polynesia during the 2013-2014 pandemic. The compounds, compositions, and methods disclosed herein can be used to treat any one or more Zika viruses, including those of African and / or Asian lineages. e. Dengue virus

[0288] Dengue virus is the cause of dengue fever. Dengue virus is a mosquito-borne, single positive strand RNA virus of the Flaviviridae family and Flavivirus genus. The virus has been found in four serotypes, with a fifth serotype reported but not yet confirmed, all of which may cause a full range of disease. The compounds, compositions, and methods disclosed herein can be used to treat any one or more dengue viruses, including their serotypes. f. Influenza virus

[0289] In some embodiments, the virus is a member of the family Orthomyxoviridae, e.g., a member of the genus Influenzavirus A, a member of the genus Influenzavirus B, a member of the genus Influenzavirus C, or a member of the genus Thogotovirus. Type species for members of the genus Influenzavirus A include, but are not limited to, influenza A viruses.

[0290] There are 18 different hemagglutinin subtypes and 11 different neuraminidase subtypes (H1-H18 and N1-N11, respectively). There are potentially 198 different influenza A subtype combinations, but only 131 subtypes have been detected in nature. Exemplary serotypes of reference species influenza A viruses include, but are not limited to, H1N1, H1N2, H2N2, H3N1, H3N2, H3N8, H5N1, H5N2, H5N3, H5N8, H5N9, H7N1, H7N2, H7N3, H7N4, H7N7, H9N2, and H10N7. Those skilled in the art will appreciate that other serotypes are possible given antigenic drift and co-infection of an animal with different influenza viruses.

[0291] Subtypes of influenza A viruses currently circulating routinely among humans include A(H1N1) and A(H3N2). Currently circulating influenza A(H1N1) viruses are related to the pandemic 2009 H1N1 virus that emerged in the spring of 2009 and caused an influenza pandemic (CDC 2009 H1N1 Flu website). This virus, scientifically named "A(H1N1)pdm09 virus" or more commonly referred to as "2009 H1N1", has been circulating seasonally ever since. These H1N1 viruses have undergone relatively little genetic change over time and have undergone relatively little change in their antigenic characteristics (i.e., the characteristics of the virus that affect immunity).

[0292] Type species for members of the Influenzavirus B genus include, but are not limited to, Influenza virus type B. Type species for members of the Influenzavirus C genus include, but are not limited to, Influenza virus type C. Type species for members of the Thogotovirus genus include, but are not limited to, Thogotovirus and Dori virus. Serotypes of the type species Dori virus include, but are not limited to, Batken virus and Dori virus.

[0293] In some embodiments, the subject has an influenza infection. See, for example, Perwitasari, et al., Antimicrob Agents Chemother, 57 (1): 475-83 (2013). doi: 10.1128 / AAC.01532-12. For example, in some embodiments, the subject has an influenza (e.g., influenza A, influenza B, influenza C, and / or influenza D) infection, and an infection with another virus, such as a coronavirus. In some embodiments, the subject does not have an influenza virus infection. G. Coronavirus

[0294] In some embodiments, the virus is a coronavirus. The latest classification of coronaviruses recognizes 39 species, 5 genera, 27 subgenera, and 39 species in the Riboviria region, Nidovirales order, Cornidovirineae suborder, and Coronaviridae family (Coronaviridae Study Group of the International Committee on Taxonomy of Viruses, Nat Microbiol 2020.DOI:10.1038 / s41564-020-0695-z). Coronaviruses are enveloped viruses with a positive-sense single-stranded RNA genome and a nucleocapsid with helical symmetry. The genome size of coronaviruses ranges from approximately 26 kilobases to 32 kilobases, making them one of the largest RNA viruses.

[0295] Coronaviruses cause disease in mammals and birds. Most typically, alphacoronaviruses and betacoronaviruses infect mammals, while gammacoronaviruses and deltacoronaviruses primarily infect birds. At least seven of these viruses can infect humans: 229E (alpha), NL63 (alpha), OC43 (beta), HKU1 (beta), MERS-CoV (beta), SARS-CoV (beta), and SARS-CoV-2 (beta).

[0296] Coronavirus species and their representative viruses include [Representative viruses (among species)]: SARSr-CoV BtKY72 (Severe Acute Respiratory Syndrome-associated coronavirus), SARS-CoV-2 (Severe Acute Respiratory Syndrome-associated coronavirus), SARSr-CoV RaTG13 (Severe Acute Respiratory Syndrome-associated coronavirus), SARS-CoV PC4-227 (Severe Acute Respiratory Syndrome-associated coronavirus), SARS-CoV (Severe Acute Respiratory Syndrome-associated coronavirus), Bat-Hp-BetaCovC (Bat Hp-betacoronavirus Zhejiang2013), Ro-BatCoV GCCDC1 (Rousettus bat coronavirus GCCDC1), Ro-BatCoV HKU9 (Rousettus bat coronavirus HKU9), Ei-BatCoV C704 (Eidolon bat coronavirus C704), Pi-BatCoV HKU5 (Pipistrellus bat coronavirus HKU5), Ty-BatCoV HKU4 (Tylonycteris bar coronavirus HKU4), MERS-CoV (Middle East respiratory syndrome-related coronavirus), EriCoV (hedgehog coronavirus), MHV (mouse coronavirus), HCoV HKU1 (human coronavirus HKU1), ChRCoV HKU24 (China Rattus coronavirus HKU24), ChRCovC HKU24 (beta coronavirus 1), MrufCoV 2JL14 (Myodes coronavirus 2JL14), HCoV NL63 (human coronavirus NL63), HCoV 229E (human coronavirus 229E), and HCoVOC43 (human coronavirus OC43). For example, see Coronaviridae Study Group of the International Committee on Taxonomy of Viruses, Nat Microbiol 2020. DOI: 10.1038 / s41564-020-0695-z, the entire contents of which are expressly incorporated by reference. In some embodiments, the coronavirus is a common cold coronavirus, such as 229E, NL63, OC43, and HKU1.

[0297] In particularly preferred embodiments, the virus is a severe acute respiratory syndrome-associated virus, such as SARSr-CoV BtKY72, SARS-CoV-2, SARSr-CoV RaTG13, SARS-CoV PC4-227, or SARS-CoV, preferably one that infects humans, such as SARS-CoV or SARS-CoV-2.

[0298] In some embodiments, the virus is a Middle East Respiratory Syndrome-related virus, such as MERS-CoV.

[0299] In some embodiments, the virus is SARS-CoV-2. The sequence WIV04 / 2019, which belongs to the GISAID S clade / PANGO A lineage / Nextstrain 19B clade, is believed to most closely reflect the sequence of the prototype SARS-CoV-2 that infects humans. This is known as "sequence zero" and is widely used as the reference sequence. Since its initial isolation in Wuhan, China, numerous WIV04 / 2019 SARS-CoV-2 viral sequence variants have been identified, some of which may be of particular interest due to their potential for increased transmissibility, increased virulence, and reduced efficacy of vaccines against the virus. SARS-CoV-2 with WIV04 / 2019 sequence variations include, but are not limited to, the following:

[0300] B.1.1.7 lineage (also known as 20I / 501Y.V1, Variant of Concern (VOC) 202012 / 01). This variant has a mutation in the receptor binding domain (RBD) of the spike protein in which the amino acid at position 501, asparagine (N), is replaced by tyrosine (Y). The shorthand for this mutation is N501Y. This variant also has several other mutations, including:

[0301] 69 / 70 deletion: This occurs spontaneously multiple times and likely results in a conformational change in the spike protein.

[0302] P681H: Near the S1 / S2 furin cleavage site, a highly variable site in coronaviruses. This mutation also occurs naturally many times.

[0303] B.1.351 lineage (also known as 20H / 501Y.V2). This variant has multiple mutations in the spike protein, including K417N, E484K, and N501Y. Unlike the B.1.1.7 lineage detected in the UK, this variant does not have the 69 / 70 deletion.

[0304] P.1 lineage (also known as 20J / 501Y.V3). The P.1 variant is an offshoot of the B.1.1.28 lineage and was first reported by Japan's National Institute of Infectious Diseases (NIID) in four travelers arriving from Brazil who were sampled during routine screening at Haneda Airport outside Tokyo. The P.1 lineage has three mutations in the spike protein receptor-binding domain: K417T, E484K, and N501Y.

[0305] Omicron lineage. B.1.1.529, BA.1, BA.1.1, BA.2, BA.3, BA.4 and BA.5 lineages. Substitutions in the spike protein include A67V, del69-70, T95I, del142-144, Y145D, del211, L212I, ins214EPE, G339D, S371L, S373P, S375F, K417N, N440K, G446S, S477N, T478K, E484A, Q493R, G496S, Q498R, N501Y, Y505H, T547K, D614G, H655Y, N679K, P681H, N764K, D796Y, N856K, Q954H, N969K, and L981F. The Omicron variant has been described as having the potential for increased transmissibility, the potential for reduced neutralization by some EUA monoclonal antibody treatments, and the potential for reduced neutralization by post-vaccination sera. CDC website, "SARS-CoV-2 Variant Classifications and Definitions," updated April 26, 2022.

[0306] Other strains and mutations of interest include, but are not limited to, B.1.1.207, B.1.429, B.1.427, B.1.525, and other spike protein 2-mutation (e.g., N501T-G142D) or 3-mutation (e.g., N501T-G142D-F486L) variants. All of these strains and sequence alternatives to the WIV04 / 2019 strain are similarly considered SARS-CoV-2 viruses. In some embodiments, the SARS-CoV-2 is a strain or isolate that is at high or potentially high risk of causing human disease compared to WIV04 / 2019.For example, see Science Brief, Emerging SARS-CoV-2 variants (CDC website, updated January 28, 2021), Horby, et al., "NERVTAG note on B.1.1.7 severity." SAGE meeting report. January 21, 2021; Wu, et al. "mRNA-1273 vaccine induces neutralizing antibodies against spike mutants from global SARS-CoV-2 variants." bioRxiv. Posted January 25, 2021; Xie, et al., "Neutralization of N501Y mutant SARS-CoV-2 by BNT162b2 vaccine-elicited sera." bioRxiv. Posted January 7, 2021; Greaney, et al. "Comprehensive mapping of mutations to the SARS-CoV-2 receptor-binding domain that affect recognition by polyclonal human serum antibodies." bioRxiv. [Preprint posted online January 4, 2021]; Weisblum, et al., "Escape from neutralizing antibodies by SARS-CoV-2 spike protein variants." eLife 2020; 9: e61312; Resende, at al. "Spike E484K mutation in the first SARS-CoV-2 reinfection case confirmed in Brazil," 2020. [Posted on virological.org on January 10, 2021].

[0307] Various strains and isolates of the aforementioned viruses are known, including, for example, representative genome sequences provided under GenBank Accession Nos. MN908947.3 (SEQ ID NO: 1), MN985325.1 (SEQ ID NO: 2), AY274119.3 (SEQ ID NO: 3), or JX869059.2 (SEQ ID NO: 4), other accession numbers presented herein, as well as sequences and accession numbers provided by, for example, Coronaviridae Study Group of the International Committee on Taxonomy of Viruses, Nat Microbiol 2020. DOI: 10.1038 / s41564-020-0695-z), as well as NCBI and GISAID, which provide hundreds of SARS-CoV-2 sequences, all of which are expressly incorporated herein by reference in their entireties.

[0308] In some embodiments, the SARS-CoV-2 has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or more mutations in the spike protein compared to another reference sequence, such as, for example, WIV04 / 2019, SEQ ID NO:1, and / or SEQ ID NO:2 or those set out therein. The spike protein sequence of SEQ ID NO:1 is

[0309] [ka] and

[0310] It is encoded by 21563..25384 in GenBank: MN908947.3 (SEQ ID NO:1), / gene="S", / note="structural protein", / codon_start=1 / product="surface glycoprotein", / protein_id="QHD43416.1".

[0311] In some embodiments, the spike protein of SARS-CoV-2 has at least 70%, 75%, or 80%, preferably at least 85%, and more preferably at least 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the spike protein of one or more of SEQ ID NOs: 1 or 2, or another viral accession number presented herein.

[0312] In some embodiments, the spike protein of SARS-CoV-2 has at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO:5.

[0313] The mutations can be substitutions, insertions, deletions, or combinations thereof. Exemplary mutations include those discussed herein, such as one or more of the following mutations in the spike protein sequence: H69, its deletion as necessary; V70, deletion thereof as necessary; G142, G142D as appropriate; K417, K417N or K417T as appropriate; E484, E484K if necessary; F486, F486L as appropriate; and / or

[0314] N501 mutation, N501Y or N501T as appropriate.

[0315] These mutations are provided individually and in all combinations. These residues are illustrated in SEQ ID NO:5 above in bold / italics / shading.

[0316] In some embodiments, the SARS-CoV-2 is of the B.1.1.7 lineage, B.1.351 lineage, P.1 lineage, B.1.1.207 lineage, B.1.429 lineage, B.1.427 lineage, or B.1.525 lineage.

[0317] In an exemplary embodiment, the SARS-CoV-2 is isolate USA / CA_CDC_5574 / 2020 or another isolate that shares one or more mutations with isolate USA / CA_CDC_5574 / 2020 compared to the prototype Wuhan isolate. Under the naming scheme introduced by GISAID (Global Initiative on Sharing All Influenza Data), SARS-CoV-2, isolate USA / CA_CDC_5574 / 2020, is assigned to lineage B.1.1.7 and GISAID clade GR using the Phylogenetic Assignment of Named Global Outbreak LINeages (PANGOLIN) tool (GISAID website, 3. Rambaut, et al., Nat. Microbiol. 5 (2020): 1403-1407. PubMed: 32669681; Mercatelli, et al., Front. Microbiol. (2020): doi.org / 10.3389 / fmicb.2020.01800. PubMed: 32793182). The complete genome of SARS-CoV-2, isolate USA / CA_CDC_5574 / 2020, has been sequenced (GISAID: EPI_ISL_751801). The following mutations are present in the clinical isolate:

[0318] Spike A570D, Spike D614G, Spike D1118H, Spike H69del, Spike N501Y, Spike P681H, Spike S982A, Spike T716I, Spike V70del, Spike Y145del, M (membrane protein) V70L, N (nucleocapsid protein) D3L, N G204R, N R203K, N S235F, NS3 T223I, NS8 (nonstructural protein 8) Q27stop, NS8 R52I, NS8 Y73C, NSP3 (nonstructural protein 3) A890D, NSP3 I1412T, NSP3 T183I, NSP6 (nonstructural protein 6) F108del, NSP6 G107del, NSP6 S106del, NSP12 (nonstructural protein 12) P323L, NSP13 (nonstructural protein 13) A454V, NSP13 K460R. One additional SNP, L3826F, was reported in ORF1ab for the deposited second passage virus compared to clinical material. See also BEI Resources, Catalog No. NR-54011 and the description therein, which are expressly incorporated herein by reference in their entirety.

[0319] However, these are non-limiting examples, and the compositions and methods disclosed herein can also be used to treat other strains of coronavirus, particularly SARS coronavirus and MERS coronavirus. In some embodiments, the (DNA sequence) of the viral genome has a sequence having at least 70%, 75%, or 80%, preferably at least 85%, more preferably at least 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to one or more of SEQ ID NOs: 1, 2, 3, or 4, or another viral accession number presented herein, or the sequences or accession numbers presented in Coronaviridae Study Group of the International Committee on Taxonomy of Viruses, Nat Microbiol 2020. DOI: 10.1038 / s41564-020-0695-z, all of which are expressly incorporated herein by reference in their entirety. Although the sequences are presented as DNA sequences, it will be understood that the viral genome itself will generally have a corresponding RNA sequence. Accordingly, the corresponding RNA sequences are also expressly presented herein.

[0320] GenBank Accession No. MN908947.3, NCBI Accession No. NC_045512.2, both of which are expressly incorporated by reference in their entireties, provide the (DNA) genome sequence of SARS-CoV-2 (Severe Acute Respiratory Syndrome coronavirus 2 isolate Wuhan-Hu-1, complete genome): (SEQ ID NO:1).

[0321] GenBank Accession No. MN985325.1, expressly incorporated herein by reference in its entirety, provides the (DNA) genome sequence of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2 isolate 2019-nCoV / USA-WA1 / 2020, complete genome): (SEQ ID NO:2).

[0322] GenBank Accession No. GenBank:AY274119.3, expressly incorporated herein by reference in its entirety, provides the (DNA) genome sequence of SARS-CoV (Severe Acute Respiratory Syndrome-associated coronavirus isolate Tor2, complete genome): (SEQ ID NO:3).

[0323] GenBank Accession No. GenBank:JX869059.2, expressly incorporated herein by reference in its entirety, provides the (DNA) genome sequence of MERS-CoV (human betacoronavirus 2c EMC / 2012, complete genome): (SEQ ID NO:4).

[0324] In some embodiments, the subject has tested positive for the SARS-CoV-2 virus prior to the first administration of probenecid, its metabolite or analog or prodrug, or a pharma- ceutically acceptable salt thereof, and has had at least one mild or moderate symptom of COVID-19 (i.e., fever or chills, cough, shortness of breath or difficulty breathing, fatigue, muscle or body aches, headache, new loss of taste or smell, sore throat, congestion or runny nose, nausea, vomiting, or diarrhea) for six days or less.

[0325] In some embodiments, the subject does not have a viral infection caused by a coronavirus. B. Exemplary Objects

[0326] The subject may be male and / or female. The subject may be an adult (e.g., 18 years of age or older) and / or a child under 18 years of age.

[0327] The age of the subject may range from infants to geriatrics, including pediatric subjects. Thus, the formulation may be administered to adult patients or pediatric patients. In some embodiments, the pediatric patient may be 0-18 years old or any integer or fractional subrange or specific number therebetween. For example, in some embodiments, the subject is 2-10 years old, or 8-17 years old, or 12-17 years old, or 8-11 years old, or 1 month to 7 years old, or 0.5 years old to 8 years old, or 6 years old or younger, or 4 years old or younger, or 2 years old or younger. In some embodiments, the child is under 2 years old. In some embodiments, the subject is at least 2 years old and optionally has one or more symptoms, such as cough, fever, and / or other symptoms discussed herein. Treatment may be indicated, particularly if the subject is male and / or is over 40 years old, over 50 years old, over 60 years old, over 70 years old, or over 80 years old. In some embodiments, the subject is obese (BMI greater than 30, where BMI is the body mass index, calculated as a person's weight in kilograms divided by the square of their height in meters).

[0328] In some embodiments, the subject has an underlying condition, such as asthma, heart disease, diabetes, cancer, chronic lung disease, chronic heart disease, chronic kidney disease, vitamin A deficiency, an immune deficiency, or a combination thereof.

[0329] In some embodiments, the subject is a human. In some embodiments, a group of humans is treated en masse. Certain viruses can be highly contagious, including but not limited to influenza, SARS-CoV-2, and measles. For example, measles is highly contagious and spreads through the air when an infected person coughs or sneezes. Measles is so contagious that one infected person can infect 9 out of 10 people of any age around them if they are not protected (CDC.gov "Measles is Highly Contagious Infographic"). Although vaccines are highly effective in controlling the measles virus, measles has recently re-emerged in the United States (Dimala, et al., Scientific Reports volume 11, Article number: 51 (2021)). As a result, there is growing concern about the potential re-establishment of measles transmission and the loss of "measles elimination" status by the United States in the coming years. It has been suggested that this re-emergence may be due to declining vaccination rates as a result of vaccine hesitancy. Furthermore, given the high infectiousness of measles, several factors such as population density; inter / intragenerational contact; timing of vaccination and escalation of conferred immunity may potentially favor measles transmission and eventual resurgence. Because measles is highly contagious, beginning about 4 days before the rash appears, a subject with the measles virus may spread it to other subjects before he or she knows that he or she is infected. This problem is particularly prominent in institutional settings such as schools, hospitals, prisons, churches, and other places where large numbers of people congregate. Thus, in some embodiments, the methods disclosed herein include treating a group of people. The group of people may be infected, uninfected, or a combination of the virus. Thus, treatment may be preventive for some subjects in the group and / or therapeutic for some subjects. Because the compounds disclosed herein can be used for preventive and therapeutic treatment of the virus, all subjects in the group can be advantageously treated together, regardless of their status.In some embodiments, the group is or has been in an institution together, such as a school, hospital, prison, church, etc., and / or is unable or unwilling to social distance, such as, for example, children ages 2-10, 2-18, etc., as described above, military, etc. Thus, as a non-limiting example, some embodiments treat a class of students, optionally children, after exposure to a classmate diagnosed with a viral infection. Exemplary viruses include all of the viruses disclosed herein. In some embodiments, the virus is a highly infectious and / or highly virulent virus. In certain embodiments, the virus is measles or SARS-CoV-2.

[0330] In other embodiments, the subject is a non-human mammal or bird. For example, the non-human mammal may be a member of the Muridae family (a murine such as a rat or mouse), a primate, (e.g., monkey, human), a gerbil, a guinea pig, a ferret, or a porcine species. The subject may be an avian species, including, but not limited to, seagulls, terns, and shore birds, waterfowl, such as swans, ducks, and geese, chickens, turkeys, backyard birds, and pigeons. The subject may be a dog or cat, an agricultural animal, such as a cow, a poultry (e.g., chicken), a sheep, a pig, a goat, a horse, etc.

[0331] For example, birds can get influenza just like humans. Avian influenza viruses infect birds, including chickens, other poultry, and wild birds, such as ducks. Usually, avian influenza viruses only infect other birds. Humans can rarely be infected with avian influenza viruses, but it can happen. Two types, H5N1 and H7N9, have infected some humans during pandemics in parts of Asia, Africa, the Pacific, the Middle East, and Europe. Thus, disclosed herein is a method of administering an effective amount of probenecid, metabolites, analogs, or prodrugs thereof, or pharmaceutically acceptable salts thereof, to treat influenza, including but not limited to H5N1 and H7N9, in birds, including but not limited to agricultural poultry such as chickens and turkeys.

[0332] Poultry are domesticated birds raised by farmers for meat and eggs. Poultry include, but are not limited to, chickens, ducks, geese, turkeys, guinea fowl, and pheasants. An example of a commercially raised duck is the White Pekin duck.

[0333] Examples of commercially raised geese are the Embden, Toulouse, Chinese goose, African goose, Sebastopol, Pilgrim, and American Buff breeds. Examples of commercially raised turkeys include the White, Holland, Bronze, Narragansett, Bourbon Red, Black, Slate, Royal Palm, Beltsville, and Small White breeds.

[0334] Examples of commercially raised chickens include the American Class, Asiatic Class, English Class, and Mediterranean Class. The American Class includes the Buckeye, Chantecler, Delaware, Dominique, Holland, Java, Jersey Giant, Lamona, New Hampshire, Plymouth Rock, Rhode Island Red, Rhode Island White, and Wyandotte breeds. The Asian Class includes the Brahma, Cochin, and Langshan breeds. The British class includes Australorp, Cornish, Dorking, Orpington, Redcap, and Sussex breeds. The Mediterranean class includes Ancona, Blue Andalusian, Catalana, Leghorn, Minorca, Spanish, and Buttercup breeds. As will be appreciated by those skilled in the art, there are other classes and breeds of poultry than those listed above. The compositions disclosed herein can be used for all classes and breeds of poultry.

[0335] Similarly, swine flu is a respiratory disease of pigs caused by influenza A virus, which periodically causes influenza pandemics in pigs. Influenza viruses that commonly circulate in pigs are referred to as "swine flu viruses" or "swine flu viruses". As with human influenza viruses, there are different subtypes and strains of swine flu viruses. The major swine flu viruses that have been circulating in pigs in the United States in recent years are swine triple reassortant (tr) H1N1 influenza virus, trH3N2 virus, and trH1N2 virus. Thus, disclosed herein is a method of administering an effective amount of probenecid, a metabolite, an analog, or a prodrug thereof, or a pharma- ceutically acceptable salt thereof, to treat influenza, including but not limited to H5N1 and H7N9, in swine (i.e., pigs).

[0336] A preferred method of administration to non-human mammals and birds is orally, for example in the animal's water or feed.

[0337] The method includes both preventing and / or therapeutically treating viral infections in non-human animals, particularly non-human mammals and birds. The method can be performed on a single animal or on multiple animals, which can be optionally housed together, and further optionally, all animals housed together can be matched in age to within one month, one week or less of each other, for example, within 6 days, 5 days, 4 days, 3 days, 2 days or 1 day.

[0338] For example, the method may involve up to, about, or at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 70, 80, 90, 100, 150, 200, 250, 300, 400, 500, 600, 700, 800, 900, 1×10 3 , 2×10 3 , 3×10 3 , 4×10 3, 5×10 3 , 6×10 3 , 7×10 3 , 8×10 3 , 9×10 3 , 1×10 4 , 2×10 4 , 3×10 4 , 4×10 4 , 5×10 4 , 6×10 4 , 7×10 4 , 8×10 4 , 9×10 4 , 1×10 5 , 2×10 5 , 3×10 5 , 4×10 5 , 5×10 5 , 6×10 5 , 7×10 5 , 8×10 5 , 9×10 5 , 1×10 6 The present invention can be performed on a group of animals, or more, where all animals in the group can be age-matched as necessary as set forth above. In this context, the term "about" can mean within ±50%, ±40%, ±30%, ±20%, ±10%, ±5%, ±4%, ±3%, ±2%, ±1% or less of the specified value.

[0339] The animals to be treated may be healthy animals, e.g., animals not infected with a virus. In another embodiment, the animals are unhealthy animals, e.g., animals infected with a virus. In some embodiments, the animals are or include animals that have been exposed to unhealthy (e.g., infected with a virus) animals. In some embodiments, a mix of healthy and unhealthy animals are treated together as a group.

[0340] Additionally or alternatively, probenecid can be provided to improve weight gain in animals (important for pigs and chickens) because it can improve the effectiveness of antibiotics in animals (e.g., chickens and pigs) and can reduce inflammation in addition to treating or preventing influenza and other viral infections. C. Illustrative Symptoms and Infections

[0341] In some embodiments, the subject is exhibiting one or more symptoms associated with the one or more viruses for which treatment is desired, and / or the compounds, compositions, and methods disclosed herein are effective for treating one or more symptoms associated with the one or more viruses for which treatment is desired.

[0342] For example, RSV infections can present with a wide variety of signs and symptoms ranging from mild upper respiratory tract infections (URTIs) to severe, potentially life-threatening lower respiratory tract infections (LRTIs) that require hospitalization and mechanical ventilation. The majority of childhood RSV infections may include one or more of nasal congestion, runny nose, cough, and low-grade fever. Inflammation of the nasal mucosa (rhinitis) and throat (pharyngitis), as well as eye congestion (conjunctival infection), may be present, and bronchiolitis may occur. Reinfection in adulthood often results in only mild to moderate symptoms similar to a cold or sinus infection. Infections may be asymptomatic. Symptoms, if present, are generally limited to the upper respiratory tract: runny nose, pharyngitis, fever, and fatigue.

[0343] Mumps virus infection results in fever, myalgia, and painful swelling of the parotid glands, two salivary glands located on the sides of the mouth in front of the ears. Many other tissues and organs may also be involved in the infection, resulting in a variety of inflammatory responses, including encephalitis, aseptic meningitis, orchitis, myocarditis, pancreatitis, nephritis, oophoritis, and mastitis. Mumps is not usually life-threatening and typically resolves within a few weeks after the onset of symptoms, although long-term complications, such as paralysis, seizures, hydrocephalus, and hearing loss, may occur.

[0344] Measles is a highly contagious infectious disease caused by the measles virus. Symptoms usually appear 10-12 days after exposure to an infected person and last for 7-10 days. Initial symptoms generally include fever, often above 40°C (104°F), cough, runny nose, and eye irritation. Small white spots known as Koplik spots may form inside the mouth 2 or 3 days after symptoms appear, followed by a red, flat rash, usually on the face, which then spreads to other parts of the body 3-5 days after symptoms appear. Common complications include diarrhea, middle ear infections, and pneumonia, which occur in part due to measles-induced immune suppression, and, less commonly, seizures, blindness, or brain inflammation.

[0345] Zika fever (also known as Zika virus disease) is a disease caused by the Zika virus. The majority of cases are asymptomatic, but when symptoms are present, they are usually mild and may resemble dengue fever. Symptoms may include fever, red eyes, joint pain, headache, and a maculopapular rash. Symptoms generally last less than seven days, and no deaths have been reported associated with initial infection. Infection during pregnancy can cause microcephaly and other brain abnormalities in some fetuses, infection in adulthood is associated with Guillain-Barré syndrome (GBS), and Zika virus has been shown to infect human Schwann cells.

[0346] Dengue virus causes dengue fever disease, also called breakbone fever, vomiting and dandy fever; and severe forms, called dengue hemorrhagic fever and dengue shock syndrome. Signs and symptoms can include severe headache; retro-orbital pain; muscle, joint, and bone pain; macular or maculopapular rash; and minor bleeding symptoms, including petechiae, ecchymoses, purpura, epistaxis, bleeding gums, hematuria, or positive tourniquet test. Allergic symptoms are one of the core symptoms that are largely related to the severity of dengue.

[0347] Influenza, commonly known as "the flu," is an infectious disease caused by the influenza virus. Symptoms range from mild to severe and often include fever, runny nose, sore throat, muscle aches, headache, cough, and fatigue. These symptoms begin 1-4 days (usually 2 days) after exposure to the virus and last for about 2-8 days. Diarrhea and vomiting may occur, especially in children. Influenza can progress to pneumonia, which may be caused by the virus or by a subsequent bacterial infection. Other complications of infection include acute respiratory distress syndrome, meningitis, encephalitis, and worsening of existing health problems such as asthma and cardiovascular disease.

[0348] In humans, coronaviruses can cause respiratory tract infections that can range from mild to fatal, including some cases of the common cold, while fatal ones include SARS, MERS, and COVID-19 (i.e., caused by SARS-CoV-2).

[0349] The subject may be one who has one or more symptoms characteristic of SARS, MERS, or COVID-19.

[0350] SARS (i.e., SARS-CoV) usually begins with flu-like signs and symptoms, such as fever, chills, muscle aches, headache, and sometimes diarrhea. After about a week, signs and symptoms include fever of 100.5°F (38°C) or higher, a dry cough, and shortness of breath.

[0351] Reported illness from COVID-19 (i.e., caused by SARS-CoV-2) ranges from mild symptoms to severe illness and death in confirmed cases. The most common symptoms are fever, fatigue, dry cough, anosmia (loss of taste and / or smell), and shortness of breath. Runny nose, vomiting, diarrhea, skin rash (especially on the toes and fingers), sore throat, fatigue, muscle or body aches, headache, and sore throat have also been reported. These symptoms may appear 2 to 14 days after exposure.

[0352] The majority of people confirmed to have MERS-CoV infection had severe respiratory illness with symptoms of fever, cough, and / or shortness of breath. Some also had diarrhea and nausea / vomiting. Many with MERS went on to have more severe complications, such as pneumonia and kidney failure. Some infected people had mild symptoms (e.g., cold-like symptoms) or no symptoms at all.

[0353] In some embodiments, the subject has at least one mild or moderate COVID-19 symptom, e.g., fever or chills, cough, shortness of breath or difficulty breathing, fatigue, muscle or body aches, headache, new loss of taste or smell, sore throat, congestion or runny nose, nausea, vomiting or diarrhea for 6, 5, 4, 3, 2, or 1 day or less prior to treatment.

[0354] The symptoms caused by coronavirus infections in non-human species are not uniform: in chickens they cause upper respiratory tract disease, whereas in cattle and pigs they cause diarrhea.

[0355] In some embodiments, the subject has post-COVID sequelae (PCC) or long-haul COVID (also referred to as long-haul COVID, post-acute COVID-19, post-acute sequelae of SARS CoV-2 infection (PASC), long-term effects of COVID, and chronic COVID). COVID sequelae are a wide range of new, recurrent, or persistent health problems experienced by a person after they are first infected with SARS-CoV-2. Most people with COVID-19 get better within days to weeks of infection, and therefore COVID sequelae can first only be identified at least four weeks after infection. Anyone who is infected can experience COVID sequelae. Most people with COVID sequelae experience symptoms several days after SARS CoV-2 infection and knew they had COVID-19 at the time, but some people with COVID sequelae were unaware when they were first infected. D. Other indications

[0356] The compounds, compositions, and methods disclosed herein can also be used to treat a variety of other diseases, disorders, and indications.For example, in some embodiments, probenecid, or a probenecid metabolite, analog, prodrug, or a pharma- ceutically acceptable salt thereof, or a formulation thereof, is used to treat a subject having a condition previously identified as treatable with probenecid.

[0357] For example, probenecid is a drug used to treat gouty arthritis, tophaceous gout, and hyperuricemia. Probenecid inhibits renal excretion of organic anions and also reduces tubular reabsorption of uric acid. Probenecid is also used to treat patients with impaired renal function and is used as an adjunct to antibacterial therapy because it reduces renal tubular excretion of other drugs. Probenecid is a uricosuric and renal tubular blocking agent, and is used in combination with colchicine to treat chronic gouty arthritis complicated by frequent recurrent acute attacks of gout. Probenecid inhibits reabsorption of uric acid in the proximal convoluted tubule, thus increasing urinary excretion of uric acid and reducing serum uric acid levels. Effective uricosuria reduces the miscible uric acid pool, retards uric acid deposition, and promotes reabsorption of uric acid deposits. In the proximal and distal renal tubules, probenecid competitively inhibits the secretion of many weak organic acids, including penicillin, most cephalosporins, and some other β-lactam antibiotics. This results in an increase in the plasma concentration of acidic drugs excreted primarily by renal secretion, but only slightly if the drug is excreted primarily by filtration. Thus, probenecid can be used for therapeutic benefit to increase the concentration of certain β-lactam antibiotics in the treatment of gonorrhea, neurosyphilis, or pelvic inflammatory disease (PID). For the treatment of uncomplicated gonorrhea in men or women, a single dose of 1000 mg probenecid (2 tablets) can be given with a sufficient dose of oral ampicillin, aqueous procaine penicillin G injected intramuscularly, or cefoxitin. When oral ampicillin is used, probenecid can be administered simultaneously. When administering parenteral antibiotics, probenecid can be administered preferably at least 30 minutes before injection.In some embodiments, subject has bacterial infection.Therefore, in some embodiments, subject is administered probenecid metabolite, analog or prodrug in an effective amount in addition to probenecid or instead of probenecid to treat one or more of the above-mentioned diseases, disorders or conditions. E. Exemplary Dosages and Regimens

[0358] Probenecid, its metabolites, analogs and prodrugs and its pharmaceutically acceptable salts can be administered to a subject as pharmaceutical compositions such as those described above, and can be administered by parenteral route (intramuscular injection, intraperitoneal injection, intravenous (IV) injection or subcutaneous injection), enteral route, transdermal route (passively or using iontophoresis or electroporation), or transmucosal route (nasal, pulmonary, vaginal, rectal, or sublingual) as discussed in more detail above.The intended routes and strategies of administration include, but are not limited to, oral, buccal, nasal, transdermal, injection, slow release, controlled release, iontophoresis, sonophoresis, and other delivery devices and methods.Injection methods include, but are not limited to, parenteral administration routes, intravenous, intramuscular, subcutaneous, intraperitoneal, intraspinal, intrathecal, intraventricular, intraarterial and other injection routes.

[0359] Compounds can also be delivered transdermally as a continuous release drug delivery system through microneedles.In the microneedle system for transdermal delivery of compounds, a transdermal patch with microneedles facilitates the delivery of drugs through the skin of a subject, the device can generate at least one microchannel in an area of ​​the skin of a subject, and the patch comprises a pharmaceutical composition comprising probenecid and a cyclodextrin molecule that enhances the solubility of probenecid in aqueous solution.

[0360] The exact dosage varies depending on various factors, including those that vary with the subject (e.g., age, immune health, clinical symptoms, delivery route, etc.). Controlled, slow, or sustained release of therapeutic compounds over a period of time is also contemplated. Administering compositions using these formulations allows the desired concentration of drug in the patient's bloodstream to be maintained for a longer period than with conventional formulations. Slow, controlled, or sustained release formulations are known to those skilled in the art, and include formulations such as coated tablets, pellets, capsules, active agents dispersed in media that are insoluble in biological fluids, or active agents released after the formulation is degraded due to mechanical, chemical, or enzymatic activity.

[0361] For pediatric doses, syrups are generally preferred, being visually appealing to increase patient compliance. However, probenecid is water-insoluble, and formulation as syrup is less stable. Therefore, a method for producing a sustained release syrup formulation is provided. The syrup formulation comprises a water-insoluble polymer and probenecid in water, where the water-insoluble polymer can be ethyl cellulose, polyvinyl acetate, hydroxymethyl cellulose, etc. After dissolving in an organic solvent, the solution containing the water-insoluble polymer and probenecid is spray-dried to form microparticles, and the microparticles are dispersed in sugar syrup to form a uniformly mixed dispersion.

[0362] For the treatment of gout, probenecid has been given at 250 mg per os / po twice daily for one week, with dosage increased in 500 mg increments to 500 mg PO twice daily up to a maximum of 2 g / day.

[0363] Probenecid, 500 mg PO 4 times daily, has been given to prolong penicillin serum levels.

[0364] For pelvic inflammatory disease, probenecid 1 g PO has been given as a single dose along with cefoxitin 2 g intramuscularly (IM).

[0365] For gonorrhea, probenecid 1 g PO and cefoxitin 2 g IM have been given as a single dose.

[0366] In general, the dosage as an adjuvant to antibiotic therapy for children (e.g., ages 2-14 years, weight less than 50 kg) is: Initial: 25 mg / kg (or 0.7 g / m2) orally in one dose; Maintenance: 40 mg / kg (or 1.2 g / m2) per day orally in four equally divided doses four times daily.

[0367] Thus, in general, and by way of example only, dosage forms useful in the methods disclosed herein may include doses in the ranges of 0.1 mg to 3,000 mg; 25 mg to 2,000 mg; 25 mg to 1,000 mg; 50 mg to 1,000 mg; 100 mg to 1,000 mg; or 250 mg to 1,000 mg, with doses of 10 mg, 25 mg, 45 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 750 mg, and 1,000 mg being exemplary doses.

[0368] Treatment can be administered, for example, once, twice, three, four, or five times a day, once a week, twice a week, etc., for one, two, three, four, or longer, for example, until symptoms improve or disappear, or other biochemical or physiological endpoints are reached. In some embodiments, a single treatment can be repeated 1, 2, 3, 4, 5, 6, 7 days, or longer, weeks, or months apart. In some embodiments, the treatment period is several days, weeks, or months. For example, in some embodiments, the treatment period is 1 to 62 days, inclusive, or any subrange or specific integer number therebetween. In non-limiting examples, the treatment period is 5 days, 7 days, 10 days, 14 days, 15 days, 20 days, 21 days, 28 days, 30 days, 31 days, 40 days, 50 days, 56 days, 58 days, 60 days, 61 days, or 62 days long.

[0369] In some embodiments, treatment regimens are similar to those described above for, for example, gout, prolonging penicillin serum levels, pelvic inflammatory disease, gonorrhea, and the like.

[0370] In a particular embodiment, probenecid or a metabolite or analog or prodrug or a pharma- ceutically acceptable salt thereof is administered at 250 mg twice per day.

[0371] Results show that both 2 mg / kg and 200 mg / kg dosages were effective for treating SARS-CoV-2 in vivo in hamsters. Thus, in some embodiments, the dosage is between 2 mg / kg and 200 mg / kg, inclusive.

[0372] The results below also show that the probenecid exposure profiles generated by the pop-PK model indicate that steady-state 500 mg bid, 600 mg bid, 900 mg bid, 1000 mg bid and 1800 mg qd dosing regimens appear to result in the achievement of drug concentrations several-fold higher than those required for 90% inhibition of viral replication. All of these doses are below the maximum tolerated dose approved by the FDA and are generally safe and without significant side effects.

[0373] Thus, in some embodiments, the dosage is between 500 mg and 2,000 mg, or between 600 mg and 1,800 mg, once or twice daily. The results of the examples below show that the dosage for many viruses other than influenza can fall within the range of 500-1000 mg once or twice daily. For influenza, lower doses are likely, since the IC50 is in the picomolar range. Specific dosages are, for example, 500 mg or 1000 mg twice daily. Dosage can also be determined based on body weight, especially for pediatric patients.

[0374] As derived above, the recitation of ranges of values ​​herein, including the dosage ranges set forth above and elsewhere in the specification, is intended merely to serve as a shorthand method of referring individually to each separate value falling within the range, each separate value being incorporated herein the same as if each separate value were individually set forth herein.

[0375] The dosing regimen may be, for example, intermittent dosing or continuous dosing (e.g., constant infusion). The dosing regimen may include administering the same dose or different doses. Thus, the dosing regimen may include dose escalation, dose reduction, or a combination thereof.

[0376] In some embodiments, the composition is administered in a pulse dosage regimen.Pulse dosage refers to a dosage technique that causes a gradual increase in drug level at the beginning of the dosage interval, followed by a long drug-free period.For example, in some embodiments, drug administration is initially loaded with, for example, one, two, three, four or five successive bolus doses, and then the drug level is reduced until the next dose.In some embodiments, serum drug level is reduced to about 0.

[0377] This type of drug delivery technology can provide therapeutic benefits such as reduced dosing frequency and increased patient compliance. Compared to intermittent dosing, pulse dosing allows for an early loading of drug, which allows for extended drug-free periods during which drug concentrations can fall to near zero. However, unlike a single bolus high dose (e.g., given once a day), short bursts of drug are separated by short drug-free periods, which allows serum concentrations to increase and decrease (Ibrahim, et al., Antimicrobial Agents and Chemotherapy, 48 (11): 4195-4199 (2004)). In certain embodiments, pulse dosing is administered orally or intravenously. For example, in some embodiments, treatment includes discontinuous / intermittent intravenous infusion of very high doses of probenecid, its metabolites or analogs or prodrugs, or pharma- ceutically acceptable salts thereof, over a short period of time.

[0378] In some embodiments, the bolus high dose of probenecid, its metabolites or analogs or prodrugs, or a pharma- ceutically acceptable salt thereof is between about 1,000 mg and 5,000 mg, inclusive, or any subrange or specific dosage therebetween.

[0379] In some embodiments, a single dose, including (e.g., one or two injections), provides sufficient plasma concentrations as either therapeutic or prophylactic concentrations throughout the treatment period. In some embodiments, the treatment period is 1-31 days, or any integer number of days therebetween. Such long-acting formulations may be sustained-release or slow-release formulations, such as sustained-release or slow-release parenteral formulations.

[0380] In some embodiments, probenecid, metabolites, analogs, or prodrugs are administered in dosages known in the art. The maximum recommended dosage of probenecid is 2 grams / day PO for adults, adolescents and children over 50 kg, and 40 mg / kg / day (1.2 grams / m2 / day) PO (not to exceed 2 grams / day PO) for adolescents and children under 50 kg. Thus, in some embodiments, administration is not to exceed 5 g, not to exceed 4 g, not to exceed 3 g, or not to exceed 2 g per day. In some embodiments, administration is not to exceed 40 mg / kg / day. See also "probenecid - Drug Summary", the Prescribers' Digital Reference.

[0381] In some embodiments, tablets for oral administration contain, for example, 500 mg of probenecid, and optionally one or more of the following inactive ingredients: microcrystalline cellulose, sodium lauryl sulfate, sodium starch glycolate, starch (corn), povidone, colloidal silicon dioxide, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, D&C Yellow #10 Aluminum Lake, FD&C Yellow #6 Aluminum Lake, and FD&C Blue #2 Aluminum Lake.

[0382] In some embodiments, subjects are administered 500 mg of probenecid, or a metabolite or analog or prodrug, or a pharma- ceutically acceptable salt thereof, twice daily (BID) orally (PO) for 14 days.

[0383] In some embodiments, treatment is terminated 0, 1, 2, 3, 4, or 5 days after the subject's symptoms have resolved, after the subject has tested negative for viral infection one, two or more times (e.g., a negative SARS-CoV-2 / COVID-19 test), or a combination thereof.

[0384] In some embodiments, the dose and / or dosage regimen is effective to achieve a plasma concentration in the subject that is at or above the IC90 over a period of 5-10 days, as needed, but preferably, this is considered sufficient for both treatment and prevention. See also Example 4 below.

[0385] The results presented in the following examples illustrate that there are strain-specific differences in efficacy, and this difference may be related to the viral replication rate and / or the cell tropism that the virus prefers to replicate in a certain cell type.For example, influenza A appears to be more sensitive to probenecid than influenza B, and the same is true for RSV A vs. RSV B.These results indicate that lower dosages and / or less frequent dosage regimes may be effective for treating highly sensitive viruses, while relatively higher dosages and / or more frequent dosage regimes may be required for treating less sensitive viruses.

[0386] Dosages for non-human animals may be the same or similar to those used in humans, and may be adjusted or empirically determined as for other drugs. For example, pigs have a similar metabolism to humans, so dosage and bioavailability in pigs may be similar to humans. See, e.g., Nielson, et al., The American Journal of Clinical Nutrition, Volume 99, Issue 4, April 2014, Pages 941-949, doi.org / 10.3945 / ajcn.113.074724; Tang and Mayersohn, Drug Metabolism and Disposition, 46 (11) 1712-1724; doi.org / 10.1124 / dmd.118.083311; and Hutchinson, et al., Phil. Trans. R. Soc. B369: 20130583.20130583, doi.org / 10.1098 / rstb.2013.0583. F. Combination Therapy

[0387] In some embodiments, probenecid, its metabolite or analog or prodrug, or its pharmaceutically acceptable salt, is administered in combination with one or more additional active agents.Combination therapy may include administering active agents together in the same mixture, or in separate mixtures.Thus, in some embodiments, pharmaceutical compositions include two, three or more active agents.Such formulations generally include probenecid, its metabolite or analog or prodrug, or its pharmaceutically acceptable salt, in an effective amount.

[0388] In some embodiments, the combination of probenecid, its metabolites or analogs or prodrugs, or a pharma- ceutically acceptable salt thereof with a second or more active agents results in an additive or greater than additive response in a subject in need thereof.

[0389] In some embodiments, the second active agent is an antiviral agent (ie, a second antiviral agent), an antipyretic agent, an anti-inflammatory agent, an analgesic agent, or a combination thereof.

[0390] Some of the drugs that can be used as the second drug to treat an infection include, but are not limited to, oxaprozin, ketorolac tromethamine, irbesartan, balsalazide, meclofenamic acid, nateglinide, diflunisal, valsartan, ethacrynic acid, pioglitazone, amlexanox, nitazoxanide, telmisartan, ivosidenib, lenvatinib, teriflunomide, taurocholic acid, salicylic acid, quinidine, benzylpenicillin, ouabain, indomethacin, benzoylpenicill ... Synth, ibuprofen, guanidine, glutaric acid, furosemide, diclofenac, cholic acid, bumetanide, cilastatin, piroxicam, aminohippuric acid, caprylic acid, cimetidine, aspartame, tetracycline, oxytetracycline, minocycline, ganciclovir, acyclovir, dinoprostone, cephalothin, cefoperazone, cefazolin, cefamandole, cefadroxil, ceftriaxone, cefotaxime, phenylbutazone, ketoprofen, famotidine , liothyronine, methotrexate, conjugated estrogens, tenoxicam, enalapril, trans-2-hydroxycinnamic acid, cephalexin, valproic acid, melatonin, benzoic acid, mercaptopurine, novobiocin, liotrix, cefacetrile, zidovudine, dabrafenib, topiroxostat, ataluren, enasidenib, letermovir, dolutegravir, rucaparib, baricitinib, apalutamide, avatrombopag, cefaclor, cefotiam, ceftibuten, ceftizo These include cephaloridine, leucovorin, rosuvastatin, ivermectin, rifampicin, cabotegravir, prazigastat, lansoprazole, acetylsalicylic acid, pantoprazole, esomeprazole, pravastatin, tazobactam, pretomanid, latanoprost, gemfibrozil, dronedarone, tafamidis, rimegepant, favipiravir, osilodrostat, hydroflumethiazide, artesunate, ritonavir, lopinavir, and losartan.

[0391] Exemplary anti-inflammatory agents that can be included in the pharmaceutical composition or formulation include, but are not limited to, ibuprofen, naproxen sodium, aspirin, naproxen sodium, diclofenac potassium, celecoxib, sulindac, oxaprozin, piroxicam, indomethacin, meloxicam, fenoprofen, naproxen, esomeprazole, diclofenac, diflunisal, etodolac, ketorolac tromethamine, ketoprofen, meclofenamic acid, nabumetone, salsalate, tolmetin, and steroids, such as corticosteroids (e.g., hydrocortisone, cortisone, ethamethasoneb, prednisone, prednisolone, triamcinolone, methylprednisolone, and dexamethasone) and mineralocorticoids (e.g., fludrocortisone), and combinations thereof.

[0392] Exemplary antiviral agents that can be included in the pharmaceutical composition or formulation include, but are not limited to, anti-SARS-CoV-2 monoclonal or polyclonal antibodies, convalescent plasma (e.g., from a subject previously diagnosed with COVID-19), itaconic acid, acyclovir, adefovir, amantadine, ampligen, umifenovir, baloxavir marboxil, bictarvy, boceprivir, brevirtide, combivir, daclusteravir, darunavir, delavirdine, descovy, didanosine, docosanol, dolutegravir, doravirine, edoxudine, ensitrevir, famciclovir, foscarnet, ganciclovir, ibasitabine, idoxuridine, imiquimod, immunovir, indinavir, serovar 1, serovar 2, serovar 3, serovar 4, serovar 5, serovar 6, serovar 7, serovar 8, serovar 9, serovar 10, serovar 11, serovar 12, serovar 13, serovar 14, serovar 15, serovar 16, serovar 17, serovar 18, serovar 19 ... vir, letermovir, methisazone, moroxydine, Nexavir, nitazoxanide, oseltamivir, penciclovir, peramavir, pleconaril, podophyllotoxin, remdesivir, ribavirin, rilpivirine, rimantadine, simeprevir, sovosbuvir, taribavirin, telaprivir, telbivudine, tenofovir alafenamide, tipranavir, tromantadine, umifenovir, valacyclovir, valganciclovir, vidarabine, zalcitabine, zanamivir, zidovudine, nilmatrerovir, remdesivir, molnupiravir, interferon alpha, interferon beta, interferon lambda, ivermectin, hydroxychloroquine, chloroquine, and fluvoxamine.

[0393] In certain embodiments, the antiviral agent is oseltamivir phosphate (TAMIFLU®). Tamiflu is a prescription drug used to treat influenza in people 2 weeks of age and older who have influenza symptoms. Probenecid or a metabolite or analog or prodrug or pharmaceutical salt thereof can enhance the effectiveness of antiviral agents such as oseltamivir phosphate by helping to retain the drug during treatment.

[0394] Some products that may interact with the compounds disclosed herein include cancer chemotherapy, baricitinib, dyphylline, ketorolac, methotrexate, pyrazinamide, salicylates (e.g., high-dose aspirin), zidovudine, and certain drugs that are removed from the body by the kidney (e.g., ceftazidime / avibactam, dapsone, heparin, fosfomycin, etc.).Thus, in some embodiments, one or more of these drugs are not administered to the subject during treatment with probenecid or its metabolites or analogs or prodrugs or pharmaceutical salts.

[0395] In some embodiments, the one or more additional active agents is remdesivir.

[0396] The invention disclosed herein can be further understood by the following numbered items: 1. The following structure: [ka] (In the formula, (a) Z' is O, NR 5 , or S; (b) X' is absent, O, or NR 5 , or S; (c)R 1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, azo, alkoxy, polyether, thiol, sulfanimine, amino, carbonate, ester, amide, carbamate, imine, substituted or unsubstituted carbonyl, hydroxyl, polyol, phosphonyl, sulfinyl, sulfonamide, nitro, cyano, lipid, peptide, cholesterol, phytosterol, glycoside, or glucuronide; (d) n is an integer from 0 to 4; (e) Each R 2are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteropolyaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, alkoxy, amido, amino, phosphonium, phosphanyl, phosphonyl, silyl, sulfinyl, sulfonyl, sulfate, thiol, hydroxyl, or halogen; (f)R 3 ~R 5 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, alkoxy, amido, amino, imine, or thiol; (g) the substituents are independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, alkoxy, halogen, hydroxyl, phenoxy, thiol, alkylthio, phenylthio, arylthio, cyano, isocyano, nitro, carboxyl, amino, amido, oxo, silyl, sulfinyl, sulfonyl, sulfonic acid, phosphonium, phosphanyl, phosphoryl, or phosphonyl. A compound having the formula:

[0397] 2.R 1 is hydrogen, substituted or unsubstituted C 1 ~C 20 Straight-chain or branched alkyl (e.g., haloalkyl), substituted or unsubstituted C 3 ~C 20 Cycloalkyl, substituted or unsubstituted C 1 ~C 20 Linear or branched heteroalkyl, substituted or unsubstituted C 3 ~C20 Heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteropolyaryl, polyol, polyalkylene glycol, lipid, peptide, cholesterol, phytosterol, glucuronide, [ka] where G' is hydrogen, lipid, peptide, cholesterol, phytosterol, glycoside, glucuronide, [ka] and R 9 ~R 12 are independently hydrogen, substituted or unsubstituted C 1 ~C 20 Straight-chain or branched alkyl (e.g., haloalkyl), substituted or unsubstituted C 3 ~C 20 Cycloalkyl, substituted or unsubstituted C 1 ~C 20 Linear or branched heteroalkyl, substituted or unsubstituted C 3 ~C 20 heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, alkoxy, dialkylamino, or halogen; R' 5 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, alkoxy, amido, amino, imine, or thiol, e.g., hydrogen or substituted or unsubstituted C 1 ~C 6 Alkyl (e.g., unsubstituted C 1 ~C 6 Straight or branched alkyl, unsubstituted C 1 ~C 6 Cycloalkyl, unsubstituted C 1 ~C 4 Straight or branched alkyl, unsubstituted C 1 ~C 4 Cycloalkyl, unsubstituted C 1~C 3 Straight or branched alkyl, unsubstituted C 1 ~C 3 cycloalkyl, etc.); m, k, p, and q are independently integers from 0 to 20, 0 to 18, 0 to 16, 0 to 14, 0 to 12, 0 to 10, 0 to 8, 0 to 6, 0 to 4, 0 to 3, or 0 to 2, e.g., 0 or 1; each Y' is independently O or S; R 7 , R 8 , and R 15 ~R 20 is, for each occurrence, independently, hydrogen, substituted or unsubstituted C 1 ~C 20 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteropolyaryl, substituted or unsubstituted carbonyl, alkoxy, amido, amino, phosphonium, phosphanyl, phosphonyl, silyl, sulfinyl, sulfonyl, sulfate, thiol, hydroxyl or halogen, or R 7 and R 8 together with the carbon atom to which they are attached, R 15 and R 16 together with the carbon atom to which they are attached, and / or R 17 and R 18 together with the carbon atom to which they are attached, C 1 ~C 20 forming a cycloalkyl; or X' is NR 5 and m is not 0 and at least one of p and q is not 0, then (i) R 7 is hydrogen and R 8 But R 5 and form a ring containing adjacent N and C atoms, 1 ~C 20(ii) R is alkyl; 15 is hydrogen and R 16 But R 5 and form a ring containing adjacent N and C atoms, 1 ~C 20 and / or (iii) R is alkyl. 17 is hydrogen and R 18 But R 5 and form a ring containing adjacent N and C atoms, 1 ~C 20 is alkyl; R 13 and R 14 are independently hydrogen, substituted or unsubstituted C 1 ~C 20 alkyl, or alkoxy; Compound of item 1.

[0398] 3.R 1 But non-substituted C 1 ~C 20 Straight or branched alkyl, unsubstituted C 3 ~C 20 Cycloalkyl, C 1 ~C 20 Haloalkyl, unsubstituted aryl, unsubstituted polyaryl, unsubstituted heteroaryl, unsubstituted heteropolyaryl, polyalkylene glycol, lipid, peptide, cholesterol, phytosterol, glucuronide, [ka] and wherein m, m', p', and n' are independently integers from 0 to 10, 0 to 8, 0 to 6, 0 to 4, 0 to 3, 0 to 2, or 0 or 1; p is an integer from 1 to 6, 1 to 4, 1 to 3, or 1 or 2; and k is an integer from 1 to 6, 1 to 4. Compound of item 2.

[0399] 4. Z' is O, X' is absent or O, and R 1is substituted or unsubstituted C 1 ~C 20 Straight-chain or branched alkyl (e.g., haloalkyl), substituted or unsubstituted C 3 ~C 20 Cycloalkyl, substituted or unsubstituted C 1 ~C 20 Linear or branched heteroalkyl, substituted or unsubstituted C 3 ~C 20 The compound of any one of items 1 to 3, which is a heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted polyaryl, a substituted or unsubstituted heteropolyaryl, a polyalkylene glycol, a lipid, a peptide, cholesterol, a phytosterol, a glycoside, or a glucuronide.

[0400] 5. Z' is O or NR 5 and [ka] but, [ka] The compound according to any one of items 1 to 3,

[0401] 6. Z' is O, X' is O, and R 1 but, [ka] and Optionally, Z' can be O and X' can be O, R 1 but, [ka] and m' and n' are independently an integer from 0 to 6, 0 to 5, 0 to 4, 0 to 3, 1 to 3, e.g., 1 or 2; p' is an integer from 1 to 10, 1 to 8, 1 to 6, 1 to 4, or 1 to 3; q is an integer from 1 to 10, 1 to 8, 1 to 6, 1 to 4, or 1 to 3; R 17 ~R 20 is, for each occurrence, independently, hydrogen, hydroxyl, -SH, -(CH 2 ) 1~6 NR 22 R 23 , -(CH 2 ) 1~6 OH, -(CH 2 ) 1~6 SH or unsubstituted C 1 ~C 10 is alkyl, Any one of the compounds from items 1 to 3.

[0402] 7. Z' is O, X' is S, and R 1 but, [ka] The compound according to any one of items 1 to 3,

[0403] 8.R 7 , R 8 , and R 15 ~R 20 is, for each occurrence, independently, hydrogen, substituted or unsubstituted C 1 ~C 20 Alkyl, -(CH 2 ) 1~6 NR 22 R 23 , -(CH 2 ) 1~6 OH, substituted or unsubstituted aralkyl, -(CH 2 ) 1~6 SH, -(CH 2 ) 1~6 S(O) 0~2 CH 3 , -(CH 2 ) 1~6 NHC(=NH)NH2 , -(1H-indol-3-yl)methyl, -(1H-imidazol-4-yl)methyl, -(CH 2 ) 0~6 COOR 21 , -(CH 2 ) 0~6 CONR 22 R 23 , substituted or unsubstituted aryl, aryl-C 1~3 Alkyl, CH 2 -Indol-3-yl, -(CH 2 ) 1~6 SCH 3 , -CH2-imidazol-4-yl, CH(OH)(CH 2 ) 0~5 CH 3 , -CH 2 ((4'-OH)-Ph), R 21 ~R 23 are independently hydrogen or unsubstituted C 1~6 is alkyl, Any one of the compounds from items 2 to 7.

[0404] 9.R 3 and R 4 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, alkoxy, amino, or imine, preferably R 3 and R 4 are independently hydrogen or substituted or unsubstituted C 1 ~C 20 alkyl, e.g., unsubstituted methyl, ethyl, propyl, butyl, pentyl, or hexyl, e.g., unsubstituted propyl; and / or R 2 is, for each occurrence, independently, hydrogen, hydroxyl, -SH, -(CH 2 ) 1~6 NR 22 R 23 , -(CH 2 ) 1~6 OH, -(CH 2 ) 1~6SH or unsubstituted C 1 ~C 10 alkyl, for example hydrogen; Any one of the compounds from items 1 to 8.

[0405] 10.R 5 and / or R' 5 are independently hydrogen or substituted or unsubstituted C 1 ~C 20 The compound of any one of items 1 to 9, wherein the compound is alkyl.

[0406] 11. If substituents are present, the substituents are independently unsubstituted C 1 ~C 6 Alkyl, unsubstituted C 1~6 Alkyl-substituted C 1 ~C 6 Alkyl, unsubstituted C 1 ~C 6 Heteroalkyl, unsubstituted C 1~6 Alkyl-substituted C 1 ~C 6 Heteroalkyl, unsubstituted C 2 ~C 6 Alkenyl, unsubstituted C 2 ~C 6 Alkynyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted C 1 ~C 6 Alkoxy, -(CH 2 ) 1~6 CO 2 R 21 , halogen, C 1 ~C 6 Haloalkyl, -NR 22 R 23 , C 1~6 Acylamino, -NHSO 2 C 1~6 Alkyl, -SO 2 NR 22 R 23 , -SO 2 C 1~6 Alkyl, -COOR 21 , -CONR 22 R 23 , nitro, cyano, hydroxide, thiol, or unsubstituted C1~5 Aryl or heteroaryl substituted with alkyl, alkoxy, di(C 1~6 Alkyl)-amino, fluoro, or unsubstituted C 3 ~C 6 The compound of any one of items 1 to 10, wherein the compound is cycloalkyl.

[0407] 12. The peptide is selected from the group consisting of RKKRRQRRR (SEQ ID NO: 6), RRRRRRRR (SEQ ID NO: 7), RKKRRRESRKKRRRES (SEQ ID NO: 8), GRPRESGKKRKRKRLKP (SEQ ID NO: 9), RQIKIWFQNRRMKWKK (SEQ ID NO: 10), GRRRRRRRRRPPQ (SEQ ID NO: 11), LLIILRRRIRKQAHAHSK (SEQ ID NO: 12), RVRVFVVHIPRLT (SEQ ID NO: 13), GALFLGFLGAAGSTMGAWSQPKKKRVK (SEQ ID NO: 14), 12. The compound of any one of items 2 to 11, comprising or being a peptide selected from the group consisting of: KLALKLALKALKAALKLA (SEQ ID NO: 15), GWTLNSAGYLLGKINLKALAALAKKIL (SEQ ID NO: 16), VSALK (SEQ ID NO: 17), CSIPPEVKFNPFVYLI (SEQ ID NO: 18), GIGAVLKVLTTGLPALISWIKRKRQQ (SEQ ID NO: 19), HGLASTLTRWAHYNALIRAF (SEQ ID NO: 20).

[0408] 13. The compound is not any of the compounds in Table 2, and optionally the compound is [ka] 13. The compound according to any one of items 1 to 12,

[0409] 14. A pharmaceutical formulation comprising one or more compounds of any one of items 1 to 13; and a pharma- ceutically acceptable excipient and / or carrier, wherein the one or more compounds are present in an amount effective to prevent, treat, or ameliorate one or more symptoms associated with a viral infection in a subject in need thereof.

[0410] 15. The pharmaceutical formulation of item 14, wherein the pharma- ceutically acceptable carrier is a nanoparticle, a liposome, a cyclodextrin, or a hydrogel, and, optionally, one or more prodrugs are encapsulated in, conjugated to, and / or complexed with the nanoparticle, liposome, cyclodextrin, or hydrogel.

[0411] 16. The pharmaceutical formulation of item 14 or 15, in the form of a tablet, syrup, capsule, powder, or microneedle.

[0412] 17. The pharmaceutical formulation of any one of items 14 to 16, further comprising one or more additional active agents, optionally wherein the one or more additional active agents are one or more antiviral agents and / or anti-inflammatory agents.

[0413] 18. A method for treating or preventing a viral infection in a subject, comprising administering to the subject an effective amount of a compound according to any one of items 1 to 13.

[0414] 19. A method of treating or preventing a viral infection, comprising administering to each of a group of subjects an effective amount of a compound selected from probenecid, or a metabolite or analogue thereof, or a prodrug thereof, or a pharma- ceutically acceptable salt thereof, wherein optionally the prodrug is a compound of any one of items 1 to 13, and optionally wherein the group includes at least one subject that has been in contact with a subject having a viral infection.

[0415] 20. The method of item 19, wherein the subject is a virally infected subject, a virally uninfected subject, or a combination thereof.

[0416] 21. The method of any one of items 18 to 20, wherein the viral infection is caused by a DNA virus or an RNA virus.

[0417] 22. The method of item 21, wherein the viral infection is caused by a DNA virus belonging to the following families: adenoviridae, papoviridae, herpesviridae, poxviridae, anelloviridae or pleolipoviridae.

[0418] 23. The method of item 21, wherein the viral infection is caused by an RNA virus belonging to the following families: reoviridae, picornaviridae, caliciviridae, togaviridae, arenaviridae, Flaviviridae, Orthomyxoviridae, paramyxoviridae, bunyaviridae, rhabdoviridae, filoviridae, coronaviridae, astroviridae, bornaviridae, arteriviridae, Nymaviridae, Pneumoviridae, Flaviviridae, Hepeviridae / Nodaviridae, Picornaviridae, or Togaviridae.

[0419] 24. The method of any one of items 21 to 23, wherein the virus is a respiratory virus.

[0420] 25. The method of any one of items 21 to 23, wherein the virus is selected from influenza virus, optionally influenza A virus, influenza B virus, or influenza C virus, respiratory syncytial virus (RSV), human metapneumovirus, coronavirus, measles virus, parainfluenza virus, mumps virus, Zika virus, dengue virus, yellow fever virus, Japanese encephalitis virus, West Nile virus, hepatitis A virus, hepatitis B virus, or hepatitis C virus.

[0421] 26. The viruses include Severe Acute Respiratory Syndrome-associated coronavirus, Bat Hp-betacoronavirus Zhejiang 2013, Rousettus bat coronavirus GCCDC1, Rousettus bat coronavirus HKU9, Eidolon bat coronavirus C704, Pipistrellus bat coronavirus HKU5, Tylonycteris bar coronovirus HKU4, Middle East Respiratory Syndrome-associated coronavirus, Hedgehog coronavirus, Mouse coronavirus, Human coronavirus HKU1, China Rattus coronavirus HKU24 21. The method of item 20, wherein the coronavirus is selected from the group consisting of betacoronavirus 1, Myodes coronavirus 2JL14, human coronavirus NL63, human coronavirus 229E, and human coronavirus OC43.

[0422] 27. The method of item 26, wherein the coronavirus is severe acute respiratory syndrome-associated coronavirus.

[0423] 28. The method of item 27, wherein the severe acute respiratory syndrome-associated coronavirus is SARS-CoV-2, SARS-CoV, SARSr-CoV RaTG13, SARS-CoV PC4-227, or SARSr-CoV BtKY72.

[0424] 29. The method of item 28, wherein the severe acute respiratory syndrome-associated coronavirus is SARS-CoV-2 and, optionally, the subject has COVID 19.

[0425] 30. A method for treating or preventing a viral infection in a subject, comprising administering to the subject an effective amount of a compound selected from probenecid, or a metabolite or analog thereof, or a prodrug thereof, or a pharma- ceutically acceptable salt thereof, optionally wherein the prodrug is a compound of any one of items 1 to 13, and wherein the causative virus of the infection is selected from Zika virus, Dengue virus, RSV subtype A, and RSV subtype B.

[0426] 31. The method of any one of items 18 to 30, wherein the virus optionally has an RNA genome encoding an RNA-dependent RNA polymerase (RdRp), optionally is a member of the kingdom Orthornavirae, and optionally utilizes a host organic anion transporter optionally selected from OAT1, OAT2, OAT3, OAT4, OAT5, OAT6, OAT7, rOAT8, OAT9, OAT10, and / or URAT1.

[0427] 32. Any one of the methods of items 18 to 31, wherein the subject has one or more symptoms selected from fever, sinus and / or pulmonary congestion, runny or stuffy nose, cough, sneezing, sore throat, body aches, fatigue, shortness of breath, chest tightness, wheezing when breathing out, chills, muscle aches, headache, diarrhea, fatigue, nausea, anosmia, skin rash, and combinations thereof.

[0428] 33. Any one of the methods of items 18 to 31, wherein the subject is asymptomatic.

[0429] 34. The method of any one of items 18 to 33, wherein the compound is optionally present in a delivery vehicle selected from a nanoparticle and a liposome.

[0430] 35. The method of any one of items 18 to 34, wherein the compound is present in a pharmaceutical composition further comprising a pharma- ceutically acceptable carrier and / or excipient.

[0431] 36. The method of any one of items 18 to 35, wherein the compound is administered systemically.

[0432] 37. The method of any one of items 18 to 36, wherein the compound is administered orally, parenterally, topically, or through a mucous membrane.

[0433] 38. The method of any one of items 18 to 37, wherein the compound is administered mucosally to the lungs, nasal mucosa, or a combination thereof.

[0434] 39. The method of any one of items 18 to 38, wherein the compound is administered in an effective amount to reduce viral replication.

[0435] 40. The method of any one of items 18 to 39, wherein the dosage of the compound is 10 mg to 2,000 mg, or 600 mg, 900 mg, or 1,800 mg, twice daily as needed, for 14 days as needed.

[0436] 41. The method of any one of items 18 to 40, wherein the subject is treated by pulse dosing.

[0437] 42. The method of any one of items 18 to 41, wherein the subject is a human.

[0438] 43. The method of any one of items 18 to 42, wherein the compound is administered in a dose of 250 mg to 2,000 mg once a day or twice a day, optionally with a dose of 600 mg or 900 mg twice a day, or 1,800 mg once a day.

[0439] 44. The method of any one of items 18 to 42, wherein the compound is administered to the subject for 2 weeks or longer.

[0440] 45. The method of any one of items 18 to 44, wherein the subject is a human, a non-human mammal, or an avian.

[0441] 46. ​​The method of any one of items 18 to 45, wherein the subject is a non-human mammal or bird, and the compound is formulated in the subject's drinking water, milk, or feed and administered when the subject drinks the water or eats the feed.

[0442] 47. The method of item 46, wherein the subject is a chicken and, optionally, the virus is influenza A H5N1.

[0443] 48. The method of item 46, wherein the subject is a pig and, optionally, the virus is influenza A H1N1.

[0444] 49. Any one of the methods of items 18 to 45, wherein the subject is a human and the virus is measles.

[0445] 50. A method according to item 49, in which the subjects are pediatric subjects between 2 and 10 years of age, inclusive, as appropriate.

[0446] 51. An animal feed comprising an effective amount of a compound selected from probenecid, or a metabolite or analogue thereof, or a prodrug thereof, or a pharma- ceutically acceptable salt thereof, wherein, optionally, the prodrug is a compound according to any one of items 1 to 13.

[0447] 52. The animal feed of item 51, further comprising one or more of crude protein, fat, sugar, amino acids, minerals, starch, and vitamins.

[0448] 53. A method of treating a subject for gout, comprising administering to a subject in need thereof an effective amount of a compound of any one of items 1 to 13.

[0449] 54. A method for treating a subject for hyperuricemia, comprising administering to a subject in need thereof an effective amount of a compound of any one of items 1 to 13. EXAMPLES

[0450] Example 1 Probenecid reduces RSV replication prophylactically and therapeutically Respiratory syncytial virus (RSV) is the leading viral pathogen associated with lower respiratory tract disease in infants and young children worldwide, as well as afflicting the elderly and immunocompromised (Welliver, et al., Curr Med Res Opin 26, 2175-2181, doi: 10.1185 / 03007995.2010.505126 (2010), Falsey, et al., The New England Journal of Medicine 352, 1749-1759, doi: 10.1056 / NEJMoa043951 (2005)). For decades, research and vaccine development efforts have attempted to reduce RSV morbidity and mortality. RSV is responsible for over 150,000 pediatric hospitalizations per year, costing young children over $300 million (Han, et al., J Infect Dis 179, 25-30, doi: 10.1086 / 314567 (1999)). Therapeutic interventions are limited to inhaled ribavirin and palivizumab (Synagis), a humanized monoclonal antibody that targets the F protein. Ribavirin has shown mixed to unfavorable results, and treatment with palivizumab has shown limited efficacy (Turner, et al., Clinicoecon Outcomes Res 6, 217-225, doi: 10.2147 / CEOR.S60710 (2014), Foolad, et al., Clin Infect Dis 68, 1641-1649, doi: 10.1093 / cid / ciy760 (2019)).Additionally, palivizumab is administered monthly throughout the RSV season to help protect at-risk infants from severe RSV disease, and treatment reduces hospitalization in treated infants by approximately 50%, but efficacy is reduced as treatment induces mutations in the F protein (Olchanski, et al., Open Forum Infect Dis 5, ofy031, doi: 10.1093 / ofid / ofy031 (2018), Moore, et al., J Pediatr 214, 121-127 e121, doi: 10.1016 / j.jpeds.2019.06.058 (2019). Unfortunately, despite years of efforts, there is no safe and effective RSV vaccine available, and therefore, there is a need for effective RSV therapeutics. material and method

[0451] Murray, et al., "Probenecid Inhibits Respiratory Syncytial Virus (RSV) Replication," Viruses, 14 (5): 912 (2022). doi: 10.3390 / v14050912; and Murray, et al., "Probenecid Inhibits Respiratory Syncytial Virus (RSV) Replication," Research Square, posted February 1, 2022, doi.org / 10.21203 / rs.3.rs-1280404 / v1 are expressly incorporated by reference herein in their entireties. Cells and cell culture

[0452] Vero E6 cells (ATCC; CRL-1586) and human epithelial (HEp-2) cells (ATCC; CCL-23) were cultured in Dulbecco's modified Eagle's medium (DMEM; Gibco) supplemented with 5% heat-inactivated fetal bovine serum (FBS; Hyclone) at 37°C and 5% CO 2 Vero E6 and HEp-2 cells were grown in T75cm 2HEp-2 were used for virus propagation, maintained in log phase in culture flasks (ThermoFisher). In HEp-2 and Vero E6 cells, binding of the RSV G protein is highly dependent on cell surface glycosaminoglycans (GAGs). GAG-dependent infection is reduced by a single passaging of RSV in Vero E6 cells (Kwilas, et al., J Virol 83, 10710-10718, doi: 10.1128 / JVI.00986-09 (2009)). Normal human bronchial epithelial (NHBE) cells (Lonza) from a healthy male donor were expanded, cryopreserved, and maintained in bronchial epithelial cell growth medium (BEGM; Lonza) for 15 population doublings and used undifferentiated. virus

[0453] RSV A2 (ATCC VR-1540), RSV B1 (ATCC VR-1580), or Memphis-37 (clinical strain of human RSV A obtained from Meridian Life Science) were propagated in HEp-2 and Vero E6 cells, quantified, and then stored at -80°C as previously described (Haynes, et al., J Virol 76, 6873-6881 (2002)). HEp-2 and Vero E6 cells were maintained in Dulbecco's modified essential medium (DMEM) supplemented with glutamine and 5% fetal bovine serum (5% DMEM; Gibco). Viral titers were determined using a methylcellulose plaque assay as described (Matrosovich, et al., Virol J 3, 63, doi: 10.1186 / 1743-422X-3-63 (2006)). In vitro probenecid inhibition assay

[0454] A working stock of probenecid (Sigma) was dissolved in DMSO (Sigma) and dilutions of the working stock were resuspended in PBS (Gibco). Cytotoxicity was determined using the ToxiLight Bioassay (Lonza). Vero E6 cells, HEp-2 cells, or undifferentiated NHBE cells were plated in 96-well flat-bottom plates (Costar) at 10 cells per well. 4 Cells were plated overnight at 100 μM, 50 μM, 25 μM, 12 μM, 6 μM, 3 μM, 1 μM, 0.5 μM, 0.2 μM, 0.1 μM, 0.05 μM, 0.01 μM, or 0 μM. Cells were pretreated 24 hours prior to infection (prophylactically) or 24 hours post-infection (therapeutic) with probenecid at different concentrations: 100 μM, 50 μM, 25 μM, 12 μM, 6 μM, 3 μM, 1 μM, 0.5 μM, 0.2 μM, 0.1 μM, 0.05 μM, 0.01 μM, or 0 μM. The medium and probenecid were then removed and the cells were infected with RSV A2, RSV B1, or Memphis-37 at an MOI of 0.1. At 72 hours post-infection, the plates containing the cells were frozen at -80°C and freeze-thawed three times, and cell-free supernatants were used for log10 dilution in the RSV plaque assay. In vivo inhibition test

[0455] BALB / c male and female mice (6–8 weeks old) were obtained from Charles River and were left for 1 week before use. All experiments and procedures were approved by the Institutional Animal Care and Use Committee (IACUC) of the University of Georgia. All experiments were performed with five mice per group and were repeated twice independently. To assess viral titers in the lungs, probenecid was administered intraperitoneally (i.p.) at the doses and time points indicated in the results before or after RSV infection. Briefly, 2 mg / kg or 200 mg / kg probenecid in PBS was delivered i.p. to mice. On days 3, 5, and 7, bronchoalveolar lavage (BAL) samples were collected from individual mice and analyzed. BAL cell yield was determined by counting total cell numbers, and cell viability was determined by trypan blue (Sigma) exclusion. Smears for cell differentiation were prepared by cytocentrifugation (Shandon) and cytospin-processed slides were stained with hematoxylin-eosin stain, followed by cell differentiation by microscopy, and at least 100 cells were counted for macrophages, polymorphonuclear (PMN) cells, lymphocytes, and eosinophils (Haynes, et al., J Virol 77, 9831-9844, doi: 10.1128 / jvi.77.18.9831-9844.2003 (2003)). At each time point, serum was collected and lungs were isolated to determine virus titers by PFU / ml analysis (Perwitasari, et al., Antimicrob Agents Chemother 57, 475-483, doi: 10.1128 / AAC.01532-12 (2013)). For viral titration analysis, lung homogenates were serially diluted and titers were determined in Vero E6 cells (Caidi, et al., Antiviral Res 154, 149-157, doi: 10.1016 / j.antiviral.2018.04.014 (2018)).

[0456] BAL cellular patterns reflect the inflammatory cell profile in the lungs (Haynes, et al., J Virol 77, 9831-9844, doi: 10.1128 / jvi.77.18.9831-9844.2003 (2003)). Neither prophylactic nor therapeutic probenecid treatment with 2 mg / kg or 200 mg / kg probenecid had a substantial effect on either the white blood cell percentages or the BAL white blood cell subpopulations at days 3, 5, or 7 post-infection (Table 5). Furthermore, despite reduced RSV titers in the lungs in probenecid-treated mice, no substantial differences in BAL cells were evident by smear, highlighting the anti-RSV effect of the drug. Viral titers in the lungs

[0457] Viral titers in lungs from RSV-infected mice were determined as previously described (Haynes, et al., J Virol 76, 6873-6881 (2002)). Briefly, lungs were homogenized in 1 ml of sterile Dulbecco's PBS per lung, and 10-fold serial dilutions in serum-free DMEM (Gibco) were added to confluent Vero cell monolayers in 24-well plates. After adsorption for 2 hours at 37°C, the cell monolayers were overlaid with 2% methylcellulose and incubated at 37°C for 6 days, then enumerated by immunostaining with anti-F protein monoclonal antibody, 131-2A.

[0458] RSV-specific ELISA antibodies against RSV prevent disease by a variety of mechanisms, including virus neutralization, antibody-dependent cellular cytotoxicity (ADCC), and complement-mediated neutralization. To determine whether treatment with probenecid affects anti-RSV antibody responses, serum collected 7 days post-infection from 4 female mice per group was diluted (1:40) and assayed by ELISA using a modified protocol as described (Bergeron, et al., Viruses 13, doi: 10.3390 / v13020352 (2021)). The ELISA detects both neutralizing and non-neutralizing antibodies, and the use of RSV A2 lysate antigen provides a means to detect antibodies against multiple RSV proteins. As expected, these mice received a primary infection and serum was collected 7 days after challenge, so IgG, IgG1, and IgG2a levels were very low (Figure 9). OAT3 expression

[0459] SLC22A8 (OAT3) transcripts were assessed by qPCR as previously described (Perwitasari, et al., Pharmaceuticals (Basel) 6, 124-160, doi: 10.3390 / ph6020124 (2013); Tripp, et al., Methods Mol Biol 555, 43-61, doi: 10.1007 / 978-1-60327-295-7_4 (2009); Wu, et al., Sci Data 4, 170021, doi: 10.1038 / sdata.2017.21 (2017)). For in vitro studies, HEp-2 cells were plated in 96-well tissue culture plates (Corning) and treated with IC90 of probenecid [7.2uM] or DMSO only control for 24 hours. RNA was isolated by RNAzol RT (Molecular Research Center), digested with DNAse1, and total RNA was quantified by Nanodrop (ThermoFisher). First strand cDNA synthesis was performed using LunaScript (New England Biolabs) as described by the manufacturer. cDNA was used as a template for qPCR with Luna Universal qPCR Master Mix (New England Biolabs). For in vivo studies, BALB / c lung RNA was extracted by RNAdvance Tissue (Beckman Coulter) at the indicated time points and processed as described above.

[0460] [Table 3]

[0461] Gene expression was determined and presented as raw Ct values ​​or fold changes (reciprocal of 2ΔΔCt) normalized to housekeeping genes. Data represent the mean Ct value ± 95% confidence interval or SEM, respectively, of three independent replicates.

[0462] statistical analysis

[0463] Statistical analysis was performed using Student's t-test or one-way analysis of variance (ANOVA) as indicated. Results were calculated as mean ± SEM. A value of p<0.05 was considered significant. result

[0464] Experiments were designed to determine whether RSV replication in Vero E6, HEp-2, or NHBE cells infected with RSV A2, RSV B1, or Memphis-37 was affected by treatment with probenecid. Different epithelial cell types were pretreated (prophylaxis) with different probenecid concentrations (i.e., 100 μM, 50 μM, 25 μM, 12 μM, 6 μM, 3 μM, 1 μM, 0.5 μM, 0.2 μM, 0.1 μM, 0.05 μM, 0.01 μM, or 0 μM) and 72 hours after infection, the effect of treatment on replication was determined by plaque assay. Probenecid prophylaxis resulted in a dose-dependent reduction in RSV A2 replication in all infected cell types with IC50 / IC90 values ​​of 0.07 / 0.63 uM in Vero E6 cells, 0.8 / 7.2 uM in HEp-2 cells, and 0.4 / 3.6 uM in NHBE cells (Figure 1).

[0465] Cell viability was examined and, similar to previous studies, no cytotoxicity was evident (Perwitasari, et al., Antimicrob Agents Chemother 57, 475-483, doi:10.1128 / AAC.01532-12 (2013), Murray, et al., Sci Rep 11, 18085, doi:10.1038 / s41598-021-97658-w (2021)). Furthermore, treatment of HEp-2 cells with IC90 of probenecid resulted in undetectable levels of OAT3 transcripts (Table 4).

[0466] [Table 4]

[0467] HEp-2 cells were treated with IC 90 Mice were treated with a concentration of probenecid [7.2uM] or mock treated (DMSO only) for 24 hours. OAT3 transcripts were determined as described in the methods. Treatment with probenecid resulted in undetectable levels of OAT3 transcripts, so fold change calculations were not performed. Lung RNA was extracted in mice treated with 200mg / kg probenecid or PBS (i.e., 24 hours after treatment) on day 2 post-infection. OAT3 gene expression in mice treated with 200mg / kg probenecid was normalized to housekeeping genes and compared to mice treated with PBS. Data are presented as a 2-fold average. ΔΔCt (fold change reduction). Data represent the mean Ct values ​​or fold changes and 95% confidence intervals (CI) of three separate experiments.

[0468] Treatment with probenecid was highly effective in inhibiting RSV A2 replication in all cell types (Figure 2). The IC50 / IC90 was 0.1 / 2.7uM in Vero E6 cells, 1.2 / 10.8uM in HEp-2 cells, and 0.3 / 2.7uM in NHBE cells. Probenecid prevention results showed the highest IC50 / IC90 activity in Vero E6 and NHBE cells.

[0469] Because RSV groups A and B co-spread and both groups can cause infections at one time (Sullender, et al., Clin Microbiol Rev 13, 1-15, table of contents, doi: 10.1128 / CMR.13.1.1 (2000)), it was important to determine the susceptibility of RSV A and RSV B to probenecid, especially since the two groups have been shown to have evolved separately over a significant period of time (Mufson, et al., J Gen Virol 66 (Pt 10), 2111-2124, doi: 10.1099 / 0022-1317-66-10-2111 (1985)). As with RSV A2, probenecid prophylaxis resulted in a dose-dependent reduction in RSV B1 replication in all infected cell types (Figure 3). RSV No IC90 was obtained for RSV B1, as B1 was not reduced by 90% in the treated cell types using the concentrations tested. Probenecid prophylaxis resulted in IC50s of 0.85uM in Vero E6 cells, 0.8uM in HEp-2 cells, and 0.8uM in NHBE cells (Figure 3, Table 5). Probenecid-treated RSV B1-infected Vero E6 cells had IC50=2.0uM, probenecid-treated RSV B1-infected HEp-2 cells had IC50=0.9uM, and probenecid-treated RSV B1-infected NHBE cells had IC50=1.2uM (Figure 4, Table 5). As with RSV A2-infected cells, no cytotoxicity was detected. The results showed that prophylaxis or treatment with probenecid was more effective against RSV A2-infected cell types compared to RSV B1.

[0470] Memphis-37 is an RSV A strain isolated from a pediatric case and used in studies in human adult subjects (Kim, et al., PLoS One 9, e113100, doi: 10.1371 / journal.pone.0113100 (2014)). Memphis-37 grown in Vero E6 cells has been shown to generate a truncated G protein (Kwilas, et al. J Virol 83, 10710-10718, doi: 10.1128 / JVI.00986-09 (2009)), therefore the Memphis-37 strain used in these studies was grown in HEp-2 cells. Probenecid prophylaxis was effective in inhibiting Memphis-37 replication in all infected cell types (Figure 5). The IC50 / IC90 were 0.03 / 0.27uM in Vero E6 cells, 0.04 / 0.36uM in HEp-2 cells, and 0.16 / 1.44uM in NHBE cells (Table 5), with no detectable effect on cell viability for any of the probenecid concentrations. Treatment with probenecid inhibited Memphis-37 replication in all infected cell types as expected, similar to the RSV A2 and B1 studies (Figure 6). The IC50 / IC90 were 0.4 / 3.6uM in Vero E6 cells, 0.5 / 4.5uM in HEp-2 cells, and 0.2 / 1.8uM in NHBE cells (Table 5).

[0471] [Table 5]

[0472] Table legend: IC50 and IC90 values ​​in NHBE, Vero E6, and HEp-2 cells after treatment with different probenecid concentrations and infection with RSV A2, RSV B1, or Memphis-37. *= IC90 values ​​were not obtained for RSV B1 virus because the probenecid concentration used did not reduce virus titers by 90%.

[0473] Having shown that probenecid has potent activity against the cell types treated prophylactically or therapeutically (Figures 1-6), we tested the effect of prophylactic or therapeutic treatment in a BALB / c mouse model of RSV infection. Male or female 6-8 week old BALB / c mice were infected intranasally (in) with the RSV A2 strain. Mice were treated 24 hours prior to infection (prophylaxis) or 24 hours after infection (treatment) with a dose of 2 mg / kg or 200 mg / kg probenecid, or once with PBS. There were no substantial clinical signs of disease as determined by BAL cell infiltration (Tables 6 and 7), and there was no effect of treatment on antibody levels (Figure 9) (Altamirano-Lagos, et al., Front Microbiol 10, 873, doi: 10.3389 / fmicb.2019.00873 (2019)).

[0474] [Table 6]

[0475] [Table 7]

[0476] BAL cells were harvested from BALB / c mice on days 3, 5, or 7 postinfection. Total cell numbers and cell viability were determined by trypan blue exclusion. Neither prophylactic nor therapeutic treatment with probenecid at 2 mg / kg or 200 mg / kg on days 3, 5, or 7 postinfection had any significant effect on cell counts or BAL leukocyte subpopulations.

[0477] In female and male mice, all probenecid regimens significantly (p<0.0001) reduced lung viral titers at days 3, 5, and 7 post-infection (Figures 7 and 8, respectively). As predicted from the in vitro results (Figures 1 and 2), a substantial reduction in lung viral load was observed in mice challenged with RSV A2 and treated with 2 mg / kg and 200 mg / kg probenecid. The greatest reduction in lung viral load occurred in mice pretreated with 200 mg / kg probenecid 24 hours prior to infection, whereas a substantial reduction in lung viral titers occurred after prophylaxis with 2 mg / kg probenecid (Figures 7 and 8). Mice treated once with 2 mg / kg or 200 mg / kg probenecid 24 hours after RSV infection also showed a significant reduction in RSV A2 lung titers at days 3, 5, and 7 post-infection (Figures 7 and 8). The greatest reduction in lung viral load occurred in mice treated with 200 mg / kg probenecid, while a significant (p<0.0001) and substantial reduction in lung viral titers was observed in mice treated with 2 mg / kg probenecid. Furthermore, RNA extracted from lungs of mice treated with 200 mg / kg probenecid showed a significant reduction in OAT3 transcripts compared to PBS controls at day 2 postinfection (Table 4).

[0478] A population pharmacokinetic (pop-PK) model was created to characterize probenecid PK using a one-compartment structure with saturable elimination and first-order absorption as previously reported (Murray, et al., Sci Rep 11, 18085, doi: 10.1038 / s41598-021-97658-w (2021), expressly incorporated by reference in its entirety). Simulations using the final pop-PK model were completed to generate probenecid exposure profiles comparing dosing of 600 mg twice daily, 900 mg twice daily, or 1800 mg once daily, and free drug concentrations were calculated (Table 8).

[0479] [Table 8]

[0480] The doses investigated were predicted to produce plasma concentrations that exceeded protein binding-adjusted IC50 / IC90 values ​​for all RSV strains under all test conditions, were below the FDA-approved maximum tolerated doses, and were generally safe and well tolerated with no significant side effects.

[0481] Overall, pretreatment of Vero E6, HEp-2, or NHBE cells with probenecid was highly effective in preventing RSV replication. The IC50 and IC90 of probenecid prophylaxis against RSV A2 were 0.07 / 0.63uM in Vero E6 cells, 0.8 / 7.2uM in HEp-2 cells, and 0.4 / 3.6uM in NHBE cells. Similarly, the IC50 of probenecid treatment against RSV B1-infected Vero E6 cells was 0.85uM, the IC50 of probenecid treatment against RSV B1-infected HEp-2 cells was 0.8uM, and the IC50 of probenecid treatment against RSV B1-infected NHBE cells was 0.8uM. Importantly, comparable results were evident for IC50 / IC90 after prophylaxis or treatment with probenecid against Memphis-37-infected cells. These results ...

Claims

1. The following structure: 【Chemical 48】 wherein (a) Z' is O, NR ５ , or S; (b) X' does not exist, or is O, NR ５ , or S; (c) R １ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, azo, alkoxy, polyether, thiol, sulfanimine, amino, carbonate, ester, amide, carbamate, imine, substituted or unsubstituted carbonyl, hydroxyl, polyol, phosphonyl, sulfinyl, sulfonamide, nitro, cyano, lipid, peptide, cholesterol, phytosterol, glycoside, or glucuronide; (d) n is an integer from 0 to 4; (e) Each R ２ is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteropolyaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, alkoxy, amide, amino, phosphonium, phosphanyl, phosphonyl, silyl, sulfinyl, sulfonyl, sulfate, thiol, hydroxyl, or halogen; (f) R ３ ~ R ５ is, independently, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, alkoxy, amide, amino, imine, or thiol; (g) the substituents are, independently, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, alkoxy, halogen, hydroxyl, phenoxy, thiol, alkylthio, phenylthio, arylthio, cyano, isocyano, nitro, carboxyl, amino, amide, oxo, silyl, sulfinyl, sulfonyl, sulfonic acid, phosphonium, phosphanyl, phosphoryl, or phosphonyl) A compound having provided that the compound 【Chemical 60】 is not probenecid having the structure of

2. R １ is hydrogen, substituted or unsubstituted C １ to C ２０ linear or branched alkyl (e.g., haloalkyl), substituted or unsubstituted C ３ to C ２０ cycloalkyl, substituted or unsubstituted C １ to C ２０ linear or branched heteroalkyl, substituted or unsubstituted C ３ to C ２０ heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, polyol, polyalkylene glycol, lipid, peptide, cholesterol, phytosterol, glucuronide, 【Chemical Formula 49】 【Chemical 50】 and where G' is hydrogen, lipid, peptide, cholesterol, phytosterol, glycoside, glucuronide, 【Chemical 51】 and R ９ ~R １２ is, independently, hydrogen, substituted or unsubstituted C １ ~C ２０ linear or branched alkyl (e.g., haloalkyl), substituted or unsubstituted C ３ ~C ２０ cycloalkyl, substituted or unsubstituted C １ ~C ２０ linear or branched heteroalkyl, substituted or unsubstituted C ３ ~C ２０ heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, alkoxy, dialkylamino, or halogen; R' ５ is, independently, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, alkoxy, amide, amino, imine, or thiol, for example, hydrogen or substituted or unsubstituted C １ -C ６ alkyl (for example, unsubstituted C １ -C ６ linear or branched alkyl, unsubstituted C １ -C ６ cycloalkyl, unsubstituted C １ -C ４ linear or branched alkyl, unsubstituted C １ -C ４ cycloalkyl, unsubstituted C １ -C ３ linear or branched alkyl, unsubstituted C １ -C ３ cycloalkyl, etc.); m, k, p, and q are independently integers from 0 to 20, 0 to 18, 0 to 16, 0 to 14, 0 to 12, 0 to 10, 0 to 8, 0 to 6, 0 to 4, 0 to 3, or 0 to 2, for example, 0 or 1; each Y' is independently O or S; R ７ 、 R ８ 、 and R １５ ~R ２０ is, for each entity, independently, hydrogen, substituted or unsubstituted C １ ~C ２０ alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteropolyaryl, substituted or unsubstituted carbonyl, alkoxy, amide, amino, phosphonium, phosphanyl, phosphonyl, silyl, sulfinyl, sulfonyl, sulfate, thiol, hydroxyl or halogen, or, R ７ and R ８ together with the carbon atom to which they are attached form R １５ and R １６ together with the carbon atom to which they are attached, and / or R １７ and R １８ together with the carbon atom to which they are attached form C １ -C ２０ to form cycloalkyl, or, X' is NR ５ and when m is not 0 and at least one of p and q is not 0, (i) R ７ is hydrogen and R ８ together with R ５ forms a ring containing adjacent N and C atoms, which is a substituted or unsubstituted C １ to C ２０ alkyl, (ii) R １５ is hydrogen and R １６ together with R ５ forms a ring containing adjacent N and C atoms, which is a substituted or unsubstituted C １ to C ２０ alkyl, and / or (iii) R １７ is hydrogen and R １８ together with R ５ forms a ring containing adjacent N and C atoms, which is a substituted or unsubstituted C １ to C ２０ alkyl; R １３ and R １４ are, independently, hydrogen, substituted or unsubstituted C １ -C ２０ alkyl, or alkoxy, the compound according to claim 1.

3. R １ is unsubstituted C １ -C ２０ linear or branched alkyl, unsubstituted C ３ -C ２０ cycloalkyl, C １ -C ２０ haloalkyl, unsubstituted aryl, unsubstituted polyaryl, unsubstituted heteroaryl, unsubstituted heteropolyaryl, polyalkylene glycol, lipid, peptide, cholesterol, phytosterol, glucuronide, 【Chemical 52】 【Chemical 53】 and where m, m', p', and n' are independently integers from 0 to 10, 0 to 8, 0 to 6, 0 to 4, 0 to 3, 0 to 2, or 0 or 1, p is an integer from 1 to 6, 1 to 4, 1 to 3, or 1 or 2, and k is an integer from 1 to 6, 1 to 4, the compound according to Claim 2.

4. Z' is O, X' does not exist or is O, and R １ is substituted or unsubstituted C １ -C ２０ linear or branched alkyl (e.g., haloalkyl), substituted or unsubstituted C ３ -C ２０ cycloalkyl, substituted or unsubstituted C １ -C ２０ linear or branched heteroalkyl, substituted or unsubstituted C ３ -C ２０ heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, polyalkylene glycol, lipid, peptide, cholesterol, phytosterol, glycoside, or glucuronide, the compound according to claim 1.

5. Z' is O or NR ５ and 【Chemical Formula 54】 is 【Chemical Formula 55】 and wherein R7 and R8 are each independently, for each occurrence, hydrogen, substituted or unsubstituted C1-C20 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteropolyaryl, substituted or unsubstituted carbonyl, alkoxy, amide, amino, phosphonium, phosphanyl, phosphonyl, silyl, sulfinyl, sulfonyl, sulfate, thiol, hydroxyl or halogen, or R7 and R8 together with the carbon atom to which they are attached form C1-C20 cycloalkyl; R9 to R12 are independently hydrogen, substituted or unsubstituted C1-C20 straight or branched alkyl (e.g., haloalkyl), substituted or unsubstituted C3-C20 cycloalkyl, substituted or unsubstituted C1-C20 straight or branched heteroalkyl, substituted or unsubstituted C3-C20 heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, alkoxy, dialkylamino, or halogen; R'5 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, alkoxy, amide, amino, imine, or thiol, for example, hydrogen or substituted or unsubstituted C1-C6 alkyl (for example, unsubstituted C1-C6 straight-chain or branched alkyl, unsubstituted C1-C6 cycloalkyl, unsubstituted C1-C4 straight-chain or branched alkyl, unsubstituted C1-C4 cycloalkyl, unsubstituted C1-C3 straight-chain or branched alkyl, unsubstituted C1-C3 cycloalkyl, etc.), the compound according to claim 1.

6. Z' is O, X' is O, and R １ is 【Chemical 56】 and, if necessary, Z' is O, X' is O, and R １ is 【Chemical 57】 where m’ and n’ are, independently, integers from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, or from 1 to 3, such as 1 or 2; p’ is an integer from 1 to 10, from 1 to 8, from 1 to 6, from 1 to 4, or from 1 to 3; q is an integer from 1 to 10, from 1 to 8, from 1 to 6, from 1 to 4, or from 1 to 3; and R １７ ~R ２０ is, for each occurrence, independently, hydrogen, hydroxyl, -SH, -(CH ２ ) １～６ NR ２２ R ２３ , -(CH ２ ) １～６ OH, -(CH ２ ) １～６ SH, or unsubstituted C １ ~C １０ alkyl, the compound according to claim 1.

7. Z' is O, X' is S, and R １ is 【Chemical 58】 which is, the compound according to claim 2.

8. R ７ 、R ８ 、and R １５ ~R ２０ is, for each entity, independently, hydrogen, substituted or unsubstituted C １ ~C ２０ alkyl, -(CH ２ １～６ NR ２２ R ２３ 、-(CH ２ １～６ OH, substituted or unsubstituted aralkyl, -(CH ２ １～６ SH, -(CH ２ １～６ S(O) ０～２ CH ３ 、-(CH ２ １～６ NH C(=NH)NH ２ 、-(1H-indol-3-yl)methyl, -(1H-imidazol-4-yl)methyl, -(CH ２ ０～６ COOR ２１ 、-(CH ２ ０～６ CONR ２２ R ２３ 、substituted or unsubstituted aryl, aryl-C １～３ alkyl, CH ２ -indol-3-yl, -(CH ２ １～６ SCH ３ 、-CH2-imidazol-4-yl, CH(OH)(CH ２ ０～５ CH ３ 、-CH ２ ((4'-OH)-Ph), and​​​​​​​​​ R ２１ ~R ２３ is, independently, hydrogen or unsubstituted C １～６ alkyl; or R3 and R4 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, alkoxy, amino, or imine, preferably, R3 and R4 are independently hydrogen or substituted or unsubstituted C1-C20 alkyl, for example, unsubstituted methyl, ethyl, propyl, butyl, pentyl, or hexyl, for example, unsubstituted propyl; or R2, for each occurrence, is independently hydrogen, hydroxyl, -SH, -(CH2)1-6NR22R23, -(CH2)1-6OH, -(CH2)1-6SH, or unsubstituted C1-C10 alkyl, for example, hydrogen; or R5 and / or R'5 are independently hydrogen or substituted or unsubstituted C1-C20 alkyl; or a combination thereof, the compound according to claim 2.

9. The compound according to claim 1, wherein the peptide is a peptide selected from RKKRRQRRR (SEQ ID NO: 6), RRRRRRRR (SEQ ID NO: 7), RKKRRRESRKRRRRRES (SEQ ID NO: 8), GRPRESGKKRKRKRLKP (SEQ ID NO: 9), RQIKIWFQNRRMKWKK (SEQ ID NO: 10), GRRRRRRRRRPPQ (SEQ ID NO: 11), LLIILRRRI RKQAHAHSK (SEQ ID NO: 12), RVRVFVVHIPRLT (SEQ ID NO: 13), GALFLGFLGAAGSTMGAWSQPKKKRVK (SEQ ID NO: 14), KLALKALKALKALKAAALKLA (SEQ ID NO: 15), GWTLNSAGYLLGKINLKALAALAKKIL (SEQ ID NO: 16), VSALK (SEQ ID NO: 17), CSIPPEVKFN PFVYLII (SEQ ID NO: 18), GIGAVLKVLTTGLPALISWIKRKRQQ (SEQ ID NO: 19), HGLASTLTRWAHYNALIRAF (SEQ ID NO: 20), or is such a peptide.

10. Not any of the compounds in Table 1, and optionally, 【Chemical Formula 59】 The compound according to claim 1, which is

11. A pharmaceutical preparation comprising a compound according to any one of claims 1 to 10; and a pharmaceutically acceptable excipient and / or carrier, wherein the one or more compounds are present in an effective amount to prevent, treat, or ameliorate one or more symptoms associated with a viral infection in a subject in need thereof.

12. The pharmaceutical preparation according to claim 11, wherein the pharmaceutically acceptable carrier is a nanoparticle, liposome, cyclodextrin, or hydrogel, and optionally, one or more prodrugs are encapsulated in, conjugated with, and / or complexed with the nanoparticle, liposome, cyclodextrin, or hydrogel.

13. The pharmaceutical preparation according to claim 11, which is in the form of a tablet, syrup, capsule, powder, or microneedle.

14. The pharmaceutical preparation according to claim 11, further comprising one or more additional active agents, and optionally, the one or more additional active agents are one or more antiviral agents and / or anti-inflammatory agents.

15. A composition for treating or preventing a viral infection in a subject, wherein the composition has the structure of Formula I 【Chemical 48】 (wherein (a) Z' is O, NR5, or S; (b) X' is absent, O, NR5, or S; (c) R1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, azo, alkoxy, polyether, thiol, sulfanimine, amino, carbonate, ester, amide, carbamate, imine, substituted or unsubstituted carbonyl, hydroxyl, polyol, phosphonyl, sulfinyl, sulfonamide, nitro, cyano, lipid, peptide, cholesterol, phytosterol, glycoside, or glucuronide; (d) n is an integer from 0 to 4; (e) each R2 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteropolyaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, alkoxy, amide, amino, phosphonium, phosphanyl, phosphonyl, silyl, sulfinyl, sulfonyl, sulfate, thiol, hydroxyl, or halogen; (f) R3 to R5 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, alkoxy, amide, amino, imine, or thiol; (g)The substituents are independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, alkoxy, halogen, hydroxyl, phenoxy, thiol, alkylthio, phenylthio, arylthio, cyano, isocyano, nitro, carboxyl, amino, amide, oxo, silyl, sulfinyl, sulfonyl, sulfonic acid, phosphonium, phosphanyl, phosphoryl, or phosphonyl). A composition comprising a compound having the same or a pharmaceutically acceptable salt thereof, and optionally, the subject contacts an infected subject having the viral infection. **Claim 16**: A composition for treating or preventing a viral infection in a subject, the composition comprising probenecid or a pharmaceutically acceptable salt thereof, and optionally, the subject contacts an infected subject having the viral infection. **Claim 17** The subject is an infected subject infected with the virus, an uninfected subject not infected with the virus, or a combination thereof, and optionally The viral infection is caused by a DNA virus or an RNA virus, and optionally The viral infection is caused by a DNA virus belonging to the following families: Adenoviridae, Papoviridae, Herpesviridae, Poxviridae, Anelloviridae or Pleolipoviridae; or The composition according to claim 15 or 16, wherein the viral infectious disease is caused by an RNA virus belonging to the following families: Reoviridae, Picornaviridae, Caliciviridae, Togaviridae, Arenaviridae, Flaviviridae, Orthomyxoviridae, Paramyxoviridae, Bunyaviridae, Rhabdoviridae, Filoviridae, Coronaviridae, Astroviridae, Bornaviridae, Arteriviridae, Nymaviridae, Pneumoviridae, Flaviviridae, Hepaviridae / Nodaviridae, Picornaviridae, or Togaviridae.

18. The virus is a respiratory virus, and optionally, the virus is selected from influenza virus, optionally influenza A virus, influenza B virus, or influenza C virus, respiratory syncytial virus (RSV), human metapneumovirus, coronavirus, measles virus, parainfluenza virus, mumps virus, Zika virus, dengue virus, yellow fever virus, Japanese encephalitis virus, West Nile virus, hepatitis A virus, hepatitis B virus, or hepatitis C virus; or The composition according to claim 17, wherein the virus is selected from severe acute respiratory syndrome-related coronavirus, bat Hp-beta coronavirus Zhejiang2013 (Bat Hp-beta coronavirus Zhejiang2013), Rousettus bat coronavirus GCCDC1 (Rousettus bat coronavirus GCCDC1), Rousettus bat coronavirus HKU9 (Rousettus bat coronavirus HKU9), Eidolon bat coronavirus C704 (Eidolon bat coronavirus C704), Pipistrellus bat coronavirus HKU5 (Pipistrellus bat coronavirus HKU5), Tylonycteris bat coronavirus HKU4 (Tylonycteris bar coronavirus HKU4), Middle East respiratory syndrome-related coronavirus, hamster coronavirus, mouse coronavirus, human coronavirus HKU1, China Rattus coronavirus HKU24 (China Rattus coronavirus HKU24), beta coronavirus 1, Myodes coronavirus 2JL14 (Myodes coronavirus 2JL14), human coronavirus NL63, human coronavirus 229E, and human coronavirus OC43.

19. The composition according to claim 17, wherein the virus has an RNA genome encoding an RNA-dependent RNA polymerase (RdRp) as needed, and is a member of the order Orthornavirae as needed, and optionally utilizes a host organic anion transporter selected from OAT1, OAT2, OAT3, OAT4, OAT5, OAT6, OAT7, rOAT8, OAT9, OAT10, and / or URAT1 as needed.

20. The subject has one or more symptoms selected from fever, congestion of the sinuses and / or lungs, runny nose or nasal congestion, cough, sneeze, pharyngitis, body aches, fatigue, shortness of breath, chest constriction, wheezing when exhaling, chills, myalgia, headache, diarrhea, malaise, nausea, anosmia, rash, and combinations thereof; or The composition according to claim 15 or 16, wherein the subject is asymptomatic. **Claim 21** The compound is present in a delivery vehicle selected from nanoparticles and liposomes as required; and / or The composition further comprises a pharmaceutically acceptable carrier and / or excipient. The composition according to claim 15 or 16. **Claim 22** The composition is characterized by being administered systemically, orally, parenterally, topically, or through the mucosa, and optionally, The composition is characterized by being administered through the mucosa to the lung, nasal mucosa, or a combination thereof. The composition according to claim 15 or 16. **Claim 23** The composition is characterized by being administered in an effective amount to reduce viral replication, and optionally, The dosage of the compound is from 10 mg to 2,000 mg, or 600 mg, 900 mg, or 1,800 mg, optionally twice a day, optionally over 14 days, and optionally over 2 weeks or longer; or the compound is administered at a dose of 250 mg to 2,000 mg once or twice a day, and optionally, the dose is 600 mg or 900 mg twice a day, or 1,800 mg once a day. The composition according to claim 15 or 16. **Claim 24** The composition according to claim 15 or 16, wherein the subject is treated by pulse dosing. **Claim 25** The subject is a human, non-human mammal, or bird, and optionally, The composition is formulated as the subject's drinking water, milk, or feed, and is administered when the subject drinks the water or eats the feed. The composition according to claim 15 or 16. **Claim 26** The subject is a chicken, and optionally, the virus is influenza A H5N1; or The subject is a pig, and optionally, the virus is influenza A H1N1; or The subject is a human, and the virus is measles; or The composition according to claim 25, wherein the subject is a pediatric subject, optionally between 2 and 10 years old including both ends. **Claim 27** An effective amount of the structure of Formula I 【Chemical Formula 48】 (wherein, (a) Z' is O, NR5, or S; (b) X' is absent, O, NR5, or S; (c) R1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, azo, alkoxy, polyether, thiol, sulfanimine, amino, carbonate, ester, amide, carbamate, imine, substituted or unsubstituted carbonyl, hydroxyl, polyol, phosphonyl, sulfinyl, sulfonamide, nitro, cyano, lipid, peptide, cholesterol, phytosterol, glycoside, or glucuronide; (d) n is an integer from 0 to 4; (e) Each R2 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteropolyaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, alkoxy, amide, amino, phosphonium, phosphanyl, phosphonyl, silyl, sulfinyl, sulfonyl, sulfate, thiol, hydroxyl, or halogen; (f) R3 to R5 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, alkoxy, amide, amino, imine, or thiol; (g) The substituents are independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, alkoxy, halogen, hydroxyl, phenoxy, thiol, alkylthio, phenylthio, arylthio, cyano, isocyano, nitro, carboxyl, amino, amide, oxo, silyl, sulfinyl, sulfonyl, sulfonic acid, phosphonium, phosphanyl, phosphoryl, or phosphonyl) An animal feed comprising a compound having the same, or a pharmaceutically acceptable salt thereof.

28. A composition for treating a subject with respect to gout or hyperuricemia, having the structure of Formula I, 【Chemical 48】 wherein, (a) Z' is O, NR5, or S; (b) X' is absent, O, NR5, or S; (c) R1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, azo, alkoxy, polyether, thiol, sulfanilimine, amino, carbonate, ester, amide, carbamate, imine, substituted or unsubstituted carbonyl, hydroxyl, polyol, phosphonyl, sulfinyl, sulfonamide, nitro, cyano, lipid, peptide, cholesterol, phytosterol, glycoside, or glucuronide; (d) n is an integer from 0 to 4; (e) each R2 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteropolyaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, alkoxy, amide, amino, phosphonium, phosphanyl, phosphonyl, silyl, sulfinyl, sulfonyl, sulfate, thiol, hydroxyl, or halogen; (f) R3 to R5 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, alkoxy, amide, amino, imine, or thiol. (g)The substituents are independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, alkoxy, halogen, hydroxyl, phenoxy, thiol, alkylthio, phenylthio, arylthio, cyano, isocyano, nitro, carboxyl, amino, amide, oxo, silyl, sulfinyl, sulfonyl, sulfonic acid, phosphonium, phosphanyl, phosphoryl, or phosphonyl) A composition comprising a compound having the same, or a pharmaceutically acceptable salt thereof.

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