Methods of treating viral infections with hexose-type monosaccharides and analogs thereof

Abstract

The present invention relates to methods of treating and preventing viral diseases and infections comprising administering hexoses and their analogs and prodrugs that inhibit glycolysis and / or glycosylation.

Description

[0001] Citation of relevant applications

[0002] This application claims priority to U.S. Provisional Application No. 62 / 990,337, filed March 16, 2020, the entire contents of which are incorporated herein by reference. background Technical Field

[0004] This article discloses novel methods and pharmaceutical compositions for the treatment and prevention of viral infections. Hexosaccharides and their analogues have been found to act as glucose and mannose imitators, thereby inhibiting glycolysis, altering or inhibiting glycosylation, and reducing viral replication and infection. Background of the Invention

[0006] Hexose monosaccharides such as D-mannose and D-glucose play important biological roles. In particular, monosaccharides are used to generate energy for cells, enabling them to replicate, and are also used to produce glycans, which are key structural components of cells and viruses.

[0007] Glucose plays a crucial role in how virus-infected cells produce the energy needed for replication. Cells can produce energy under aerobic or anaerobic conditions. Cells typically rely on a relatively efficient glycolysis process to efficiently generate ATP (adenosine 5'-triphosphate).

[0008] A recent study showed that rhinovirus (RV; causing the common cold) forces host cells to operate in an anabolic state, making rapid viral replication highly dependent on glycolysis, which in turn depends heavily on an adequate supply of glucose. Similarly, a previous study on human foreskin fibroblasts infected with dengue virus (DENV) showed increased glucose consumption during viral infection, and that depriving infected cells of exogenous glucose reduced viral replication. Inhibition of the glycolytic pathway also reduces viral RNA synthesis. These studies suggest that inhibition of glycolysis is an important mechanism of antiviral activity and that other viruses may also force infected cells to rely on glycolysis.

[0009] Glycosylation is the process by which sugars (such as mannose) form complex oligosaccharides and bind to proteins to form glycoproteins, which are important components of cell membranes. Viruses utilize host cell mechanisms to glycosylate their own proteins, including viral envelope proteins. The exposed sugars, called glycans, essentially coat the cell to form a "glycan coat" and play a crucial role in the viral life cycle, including evading the immune system through glycan barriers and enhancing infection by immune cells.

[0010] Many human pathogenic viruses have extensively glycosylated envelope proteins. These viruses include HIV-1, influenza virus, Lassa virus, coronavirus, SARS, Zika virus, dengue virus, and Ebola virus. By inhibiting glycosylation and the formation of the glycan barrier, people can make virus-infected cells more vulnerable to attack by the immune system.

[0011] 2-Deoxy-D-arabinose-pyranoylhexose, also known as 2-deoxy-D-glucose, 2-deoxy-D-mannose, and 2-deoxy-D-glucose (hereinafter referred to as "2-DG"), is a so-called glucose decoy that resembles glucose but does not perform the final functions of glucose. As a glucose decoy, 2-DG has been shown to inhibit glycolysis and energy production. 2-DG has also been shown to severely inhibit rotavirus ("RV") and dengue virus ("DENV") because it prevents glucose from being successfully converted into energy, thus causing host cell death, and also reduces the chance of RV replication. Although 2-DG has been shown to have in vitro antiviral activity, it is not suitable as an effective in vivo treatment because it lacks drug-like properties, including poor pharmacokinetics, rapid metabolism, and unsatisfactory tissue and organ distribution.

[0012] The current global COVID-19 pandemic demonstrates that the need to develop new treatments for viral infections remains unmet. Invention Overview

[0013] In some aspects, this disclosure provides methods for treating and preventing viral infections, comprising administering a therapeutically effective amount of a compound of formula I, including esters of pyranose monosaccharides (such as WP1122), which possess surprisingly superior properties, including increased plasma 2-DG levels and excellent distribution in critical organs such as the lungs and brain, important given the fact that many human pathogenic viruses damage lung function and can localize in the brain, leading to debilitating and often fatal consequences. The surprisingly superior plasma levels and tissue distribution can effectively enhance the observed in vivo antiviral properties of 2-DG. In some embodiments, the invention provides novel methods for treating and preventing viral infections by administering hexose monosaccharides and analogues to patients in need. Without being limited to specific mechanisms of action, these compounds are considered to act as mimics of D-mannose and D-glucose, producing a two-pronged attack to reduce viral replication: inhibiting energy production and altering glycosylation patterns in infected cells, and inhibiting the formation of desired N-glycans.

[0014] In another aspect of the invention, a method for treating and preventing viral infection is provided, comprising administering a therapeutically effective amount of a compound of formula I:

[0015] (I)

[0016] Or its pharmaceutically acceptable salt, wherein:

[0017] X is chosen from the groups composed of O and S;

[0018] R1, R2, R3 and R6 are independently selected from the group consisting of hydrogen, hydroxyl, thiol, halogen, alkoxy, haloalkoxy, perhaloalkoxy, alkoxyalkoxy, -OC(O)alkyl, OCO2alkyl, alkylthio, amino, alkylamino, N-sulfonamide, N-amide and carbamate, any one of which may be optionally substituted.

[0019] R4 and R5 are independently selected from hydrogen, hydroxyl, thiol, halogen, alkoxy, haloalkoxy, perhaloalkoxy, alkoxyalkoxy, -OC(O)alkyl, OCO2alkyl, alkylthio, amino, alkylamino, N-sulfonamide, N-amide, carbamate, alkyl, haloalkyl, perhaloalkyl, -N(R7)OR8, -ON(R9)2, -N(R 10 )N(R 11 A group consisting of 2 elements, any one of which can be arbitrarily replaced, or R4 and R5 can be chosen together = N - OR 12 and =NN(R) 13 A group consisting of 2; and

[0020] R7, R8, R9, R 10 R 11 R 12 and R 13 Each is independently selected from the group consisting of hydrogen and alkyl groups, wherein the alkyl groups may optionally be substituted.

[0021] In another aspect of the invention, a pharmaceutical composition for use in treating viral infections is provided, comprising an application of a therapeutically effective amount of a compound of formula I:

[0022] (I)

[0023] Or its pharmaceutically acceptable salt, wherein:

[0024] X is chosen from the groups composed of O and S;

[0025] R1, R2, R3 and R6 are independently selected from the group consisting of hydrogen, hydroxyl, thiol, halogen, alkoxy, haloalkoxy, perhaloalkoxy, alkoxyalkoxy, -OC(O)alkyl, OCO2alkyl, alkylthio, amino, alkylamino, N-sulfonamide, N-amide and carbamate, any one of which may be optionally substituted.

[0026] R4 and R5 are independently selected from hydrogen, hydroxyl, thiol, halogen, alkoxy, haloalkoxy, perhaloalkoxy, alkoxyalkoxy, -OC(O)alkyl, OCO2alkyl, alkylthio, amino, alkylamino, N-sulfonamide, N-amide, carbamate, alkyl, haloalkyl, perhaloalkyl, -N(R7)OR8, -ON(R9)2, -N(R 10 )N(R 11 A group consisting of 2 elements, any one of which can be arbitrarily replaced, or R4 and R5 can be chosen together = N - OR 12 and =NN(R) 13 A group consisting of 2; and

[0027] R7, R8, R9, R 10 R 11 R 12 and R 13 Each is independently selected from the group consisting of hydrogen and alkyl groups, wherein the alkyl groups may optionally be substituted.

[0028] On the other hand, a pharmaceutical composition is provided for use in the manufacture of a medicament for treating and preventing viral infections in patients, comprising compounds of formula I:

[0029] (I)

[0030] Or its pharmaceutically acceptable salt, wherein:

[0031] X is chosen from the groups composed of O and S;

[0032] R1, R2, R3 and R6 are independently selected from the group consisting of hydrogen, hydroxyl, thiol, halogen, alkoxy, haloalkoxy, perhaloalkoxy, alkoxyalkoxy, -OC(O)alkyl, OCO2alkyl, alkylthio, amino, alkylamino, N-sulfonamide, N-amide and carbamate, any one of which may be optionally substituted.

[0033] R4 and R5 are independently selected from hydrogen, hydroxyl, thiol, halogen, alkoxy, haloalkoxy, perhaloalkoxy, alkoxyalkoxy, -OC(O)alkyl, OCO2alkyl, alkylthio, amino, alkylamino, N-sulfonamide, N-amide, carbamate, alkyl, haloalkyl, perhaloalkyl, -N(R7)OR8, -ON(R9)2, -N(R 10 )N(R 11 A group consisting of 2 elements, any one of which can be arbitrarily replaced, or R4 and R5 can be chosen together = N - OR 12 and =NN(R) 13 A group consisting of 2; and

[0034] R7, R8, R9, R 10 R 11 R 12 and R 13 Each is independently selected from the group consisting of hydrogen and alkyl groups, wherein the alkyl groups may optionally be substituted. Brief description of the attached figures

[0035] The following figures form part of this specification and are included to further illustrate certain aspects of this disclosure. A better understanding of the invention can be achieved by referring to one of these figures in conjunction with the detailed description of specific embodiments given herein.

[0036] Figure 1 The pharmacokinetic (PK) analysis of 2-DG in plasma following oral administration of WP1122 and 2-DG is presented.

[0037] Figure 2 A graphical comparison of 2-DG and metabolites from both WP1122 and 2-DG found in rat lungs at different time points following intravenous administration of radiolabeled drugs is shown. Detailed description of the invention

[0038] This invention provides a method for treating and preventing viral infections in patients in need of treatment, comprising administering a therapeutically effective amount of a compound having structural formula I:

[0039] (I)

[0040] Or its pharmaceutically acceptable salt, wherein:

[0041] X is chosen from the groups composed of O and S;

[0042] R1, R2, R3 and R6 are independently selected from the group consisting of hydrogen, hydroxyl, thiol, halogen, alkoxy, haloalkoxy, perhaloalkoxy, alkoxyalkoxy, -OC(O)alkyl, OCO2alkyl, alkylthio, amino, alkylamino, N-sulfonamide, N-amide and carbamate, any one of which may be optionally substituted.

[0043] R4 and R5 are independently selected from hydrogen, hydroxyl, thiol, halogen, alkoxy, haloalkoxy, perhaloalkoxy, alkoxyalkoxy, -OC(O)alkyl, OCO2alkyl, alkylthio, amino, alkylamino, N-sulfonamide, N-amide, carbamate, alkyl, haloalkyl, perhaloalkyl, -N(R7)OR8, -ON(R9)2, -N(R 10 )N(R 11 A group consisting of 2 elements, any one of which can be arbitrarily replaced, or R4 and R5 can be chosen together = N - OR 12 and =NN(R)13 A group consisting of 2; and

[0044] R7, R8, R9, R 10 R 11 R 12 and R 13 Each is independently selected from the group consisting of hydrogen and alkyl groups, wherein the alkyl groups may optionally be substituted.

[0045] In some embodiments, the compound has structural formula II:

[0046] (II)

[0047] Or its pharmaceutically acceptable salt, wherein:

[0048] R 14 R 15 R 16 and R 17 Independently selected from the group consisting of hydrogen, COCH3, COCH2CH3, and COCH2CH2CH3; and

[0049] R4 and R5 are independently chosen from hydrogen, Cl, Br, I, 18 F and 19 Group F consists of...

[0050] In other implementations, R4 and R5 are independently selected from hydrogen, 18 F and 19 Group F consists of...

[0051] In other implementations, R 14 R 15 R 16 and R 17 The group consisting of hydrogen and COCH3 is selected independently.

[0052] In some embodiments, the compound has structural formula III or structural formula IV:

[0053]

[0054] (Ⅲ) (Ⅳ)

[0055] Or its pharmaceutically acceptable salt, wherein:

[0056] R 14 R 15 R 16 and R 17 The group consisting of hydrogen, COCH3, COCH2CH3, and COCH2CH2CH3 can be selected independently.

[0057] R4 and R5 are independently selected from alkyl, lower alkyl, substituted alkyl, cycloalkyl, hydroxyl, alkoxy, acyl, alkenyl, alkylamino, alkylthio, alkylene, alkynyl, amino, carbamoyl, acylamino, carbamate, O-carbamoyl, N-carbamoyl, carbonyl, carboxyl, carboxylic acid ester, ester, ether, halogen, haloalkoxy, haloalkyl, heteroalkyl, hydrazine, hydroxyalkyl, isocyanoxy, isothiocyanate, alkylsulfide, nitro, oxygen, NH2, NR 18 R 19 and NHCOR 20 The group formed;

[0058] R 18 and R 19 The group is selected from hydrogen, alkyl, lower alkyl, substituted alkyl, cycloalkyl, acyl, alkenyl, alkylene, alkylamino, alkylthio, alkylene, alkynyl, amino, haloalkyl, heteroalkyl, hydrazyl, and hydroxyalkyl; and

[0059] R 20 It is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, alkenyl, alkylene, alkylamino, alkylthio, alkylene, alkynyl, amino, carbamoyl, haloalkyl and heteroalkyl.

[0060] In other implementations, R 14 R 15 R 16 and R 17 It is hydrogen.

[0061] In some embodiments, the compound has structural formula V:

[0062]

[0063] (V)

[0064] Or its pharmaceutically acceptable salt, wherein:

[0065] R 14 R 15 R 16 and R 17 The group consisting of hydrogen, COCH3, COCH2CH3 and COCH2CH2CH3 is selected independently.

[0066] In some embodiments, the compound is selected from the group consisting of Examples 1 to 84.

[0067] In some embodiments, the compound has the following structural formula:

[0068]

[0069] And its pharmaceutically acceptable salts.

[0070] In some embodiments, the viral infection is selected from the group consisting of viruses caused by HIV-1, influenza virus, Lassa virus, coronaviruses including SARS-CoV-1 and SARs-CoV-2, Zika virus, dengue virus, and Ebola virus. In some embodiments, the viral infection is a respiratory viral infection. In some embodiments, the patient has viral pneumonia. In some embodiments, the viral infection is caused by SARs-CoV-2.

[0071] In some implementations, the patient has COVID-19.

[0072] definition

[0073] As used herein, the following terms have the meanings indicated.

[0074] When a numerical range is published and the notation "from n1... to n2" or "between n1... and n2" is used, where n1 and n2 are numbers, then unless otherwise specified, the notation is intended to include the numbers themselves and the range between them. This range can be an integer or a consecutive value between the endpoints (including the endpoint). As an example, the range "from 2 carbons to 6 carbons" is intended to include 2, 3, 4, 5, and 6 carbons, since carbon is taken as an integer unit. Similarly, as an example, the range "from 1 µM to 3 µM (micromolar)," is intended to include 1 µM, 3 µM, and any significant digits of numbers in between (e.g., 1.255 µM, 2.1 µM, 2.9999 µM, etc.).

[0075] As used herein, the term “about” is intended to quantify the numerical value it modifies, representing such a value as a variable within an error range. When no specific error range is stated, such as the standard deviation of the mean given in a data graph or data table, the term “about” should be understood to include the range of the stated numerical value and the range included by rounding up or down to that number (while taking into account significant figures).

[0076] As used alone or in combination herein, the term "acyl" refers to a carbonyl group attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocyclic, or any other moiety, wherein the atom attached to the carbonyl group is carbon. An "acetyl" group refers to a –C(O)CH3 group. An "alkylcarbonyl" or "alkanoyl" group refers to an alkyl group attached to a parent molecule moiety via a carbonyl group. Examples of such groups include methylcarbonyl and ethylcarbonyl. Examples of acyl groups include formyl, alkanoyl, and aromatic acyl groups. Preferably, "acyl" is a lower acyl group, meaning that the carbonyl group is attached to a lower alkyl group.

[0077] As used alone or in combination herein, the term "alkenyl" refers to a straight-chain or branched hydrocarbon group having one or more double bonds and containing 2 to 20 carbon atoms. In some embodiments, the alkenyl group will contain 2 to 6 carbon atoms. The term "alkenylene" refers to a carbon-carbon double bond system connected at two or more positions, such as vinylene [(–CH=CH-), (–C::C-)]. Examples of suitable alkenyl groups include vinyl, propenyl, 2-methylpropenyl, 1,4-butadienyl, etc. Unless otherwise stated, the term "alkenyl" may include an "alkenylene" group.

[0078] The term "alkoxy" as used alone or in combination herein refers to an alkyl ether group, wherein the term alkyl is defined as follows. Examples of suitable alkyl ether groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.

[0079] As used herein, the term "alkyl" alone or in combination means a straight-chain or branched alkyl group containing 1 to 20 carbon atoms. In some embodiments, the alkyl group will contain 1 to 10 carbon atoms. In other embodiments, the alkyl group will contain 1 to 6 carbon atoms. In still other embodiments, the alkyl group will contain 1 to 3 carbon atoms. As defined herein, the alkyl group may optionally be substituted. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, octyl, nonyl, etc. As used herein, the term "alkylene group" alone or in combination means a saturated aliphatic group derived from a straight-chain or branched saturated hydrocarbon and attached to two or more positions, such as methylene (–CH2-). Unless otherwise stated, the term "alkyl" may include an "alkylene group".

[0080] The term "alkylamino" as used alone or in combination herein refers to an alkyl group that is attached to a parent molecule moiety via an amino group. Suitable alkylamino groups can be monoalkylated or dialkylated, forming groups such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-ethylmethylamino, etc.

[0081] The term “alkylene” as used alone or in combination in this article refers to an alkenyl group, in which one carbon atom of the carbon-carbon double bond belongs to the part to which the alkenyl group is attached.

[0082] The term "alkylthio" as used alone or in combination herein refers to an alkyl thioether (R–S–) group, wherein the term alkyl is as defined above, and wherein the sulfur may be mono-oxidized or di-oxidized. Examples of suitable alkyl thioether groups include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, methanesulfonyl, ethylsulfinyl, etc.

[0083] As used alone or in combination herein, the term "alkynyl" refers to a straight-chain or branched hydrocarbon group having one or more triple bonds and containing 2 to 20 carbon atoms. In some embodiments, the alkynyl group contains 2 to 6 carbon atoms. In other embodiments, the alkynyl group contains 2 to 4 carbon atoms. The term "ynynyl" refers to a carbon-carbon triple bond connected in two positions, such as ethynylene (–C:::C–, –C≡C–). Examples of alkynyl groups include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyyn-1-yl, 3-methylbutyn-1-yl, hexyn-2-yl, etc. Unless otherwise stated, the term "alkynyl" may include an "ynynyl" group.

[0084] The terms “amido” and “carbamoyl” as used alone or in combination herein refer to an amino group that is moietyly linked to a parent molecule via a carbonyl group, as described below, and vice versa. The term “C-amido” as used alone or in combination herein refers to a C(O)N(RR') group having R and R' as defined herein or by a specifically listed designated “R” group. The term “N-amido” as used alone or in combination herein refers to an RC(O)N(R') group having R and R' as defined herein or by a specifically listed designated “R” group. The term “acylamino” as used alone or in combination herein includes an acyl group that is moietyly linked to a parent molecule via an amino group. An example of “acylamino” is acetamido (CH3C(O)NH–).

[0085] The term "amino" as used alone or in combination herein refers to —NRR', wherein R and R' are independently selected from the group consisting of hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any of which may be optionally substituted. Furthermore, R and R' may combine to form heterocycloalkyl, any of which may be optionally substituted.

[0086] The term "aryl" as used alone or in combination herein refers to a carbocyclic aromatic system containing one, two, or three rings, wherein these polycyclic systems are fused together. The term "aryl" includes aromatic groups such as phenyl, naphthyl, anthracene, and phenanthrene.

[0087] The term "arylalkenyl" as used alone or in combination in this article refers to an aryl group that is attached to a parent molecule via an alkenyl group.

[0088] The term “arylalkoxy” or “arylalkoxy” as used alone or in combination in this article refers to an aryl group that is attached to the parent molecule via an alkoxy group.

[0089] The terms “arylalkyl” or “aralkyl” as used alone or in combination herein refer to an aryl group that is attached to the parent molecule via an alkyl group.

[0090] The terms “arylalkynyl” or “aralkynyl” as used alone or in combination in this article refer to an aryl group that is attached to the parent molecule via an alkynyl group.

[0091] The terms “arylalkylacyl” or “aryl acyl” as used alone or in combination herein refer to the acyl group derived from an aryl-substituted alkane carboxylic acid, such as benzoyl, naphthoyl, phenylacetyl, 3-phenylpropionyl (hydrogenated cinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl chloride, etc.

[0092] The term aryloxy, used alone or in combination in this article, refers to an aryl group that is attached to the parent molecule via oxygen.

[0093] The term "benzo(benzo and benz)" as used alone or in combination herein refers to the divalent group C6H4= derived from benzene. Examples include benzothiophene and benzimazole.

[0094] The term “carbamate” as used alone or in combination herein refers to an ester of carbamic acid (–NHCOO–) that may be attached from the nitrogen end or the acid end to a parent molecule moiety and may be optionally substituted as defined herein.

[0095] The term “O-carbamoyl” as used alone or in combination herein refers to an OC(O)NRR’ group having R and R’ as defined herein.

[0096] The term “N-carbamoyl” as used alone or in combination herein refers to a ROC(O)NR’ group having R and R’ as defined herein.

[0097] The term “carbonyl” as used in this article includes, when alone, a formyl group [–C(O)H], and when combined, a –C(O)- group.

[0098] As used herein, the term "carboxyl" refers to –C(O)OH or the corresponding "carboxylate" anion, for example, in a carboxylate salt. The "O-carboxyl" group refers to the RC(O)O- group, where R is as defined herein. The "C-carboxyl" group refers to the –C(O)OR group, where R is as defined herein.

[0099] The term "cyano" as used alone or in combination in this article refers to –CN.

[0100] The term “cycloalkyl” or optionally “carbocyclic” as used alone or in combination herein refers to a saturated or partially saturated monocyclic, bicyclic, or tricyclic alkyl group, wherein each ring moiety contains 3 to 12 carbon atom ring members, and which may optionally be a benzo[a]-fused-ring system as defined herein. In some embodiments, the cycloalkyl group will contain 5 to 7 carbon atoms. Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, indanyl, octahydronaphthyl, 2,3-dihydro-1H-indanyl, adamantyl, etc. The terms “bicyclic” and “tricyclic” as used herein are intended to include two types of fused-ring systems, such as decahydronaphthalene, octahydronaphthalene, and polycyclic (multi-center) saturated or partially unsaturated types. The latter type of isomers are typically exemplified by bicyclic [1,1,1]pentane, camphor, adamantane, and bicyclic [3,2,1]octane.

[0101] The term "ester" as used alone or in combination in this article refers to a carboxyl group that bridges two parts of a carbon atom.

[0102] The term "ether" as used alone or in combination in this article refers to an oxygen group that bridges two parts of a carbon atom.

[0103] The term “halo” or “halogen” as used alone or in combination in this article refers to fluorine, chlorine, bromine, or iodine.

[0104] The term “haloalkoxy” as used alone or in combination in this article refers to a haloalkyl group that is attached to a portion of the parent molecule by an oxygen atom.

[0105] The term "haloalkyl" as used alone or in combination herein refers to an alkyl group having the meaning as defined above, wherein one or more hydrogen atoms are substituted with halogens. Specifically, this includes monohaloalkyl, dihaloalkyl, and polyhaloalkyl. For example, a monohaloalkyl group may have an iodine, bromine, chlorine, or fluorine atom within the group. Dihaloalkyl and polyhaloalkyl groups may have two or more identical halogen atoms or combinations of different halogen groups. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. "Haloalkylene" refers to a haloalkyl group attached to two or more positions. Examples include fluoromethylene (–CFH-), difluoromethylene (–CF2-), chloromethylene (–CHCl-), etc.

[0106] As used alone or in combination herein, the term "heteroalkyl" refers to a stable straight-chain or branched or cyclic hydrocarbon group or a combination thereof, fully saturated or containing a degree of unsaturation of 1 to 3, consisting of the stated number of carbon atoms and 1 to 3 heteroatoms selected from the group consisting of O, N, and S, wherein the nitrogen and sulfur atoms may optionally be oxidized, and wherein the nitrogen heteroatom may optionally be quaternized. The heteroatoms O, N, and S may be placed in any internal position of the heteroalkyl group. At most two heteroatoms may be consecutive, for example, -CH2-NH-OCH3.

[0107] As used alone or in combination herein, the term "heteroaryl" refers to a 3- to 15-membered unsaturated heterocyclic or fused monocyclic, bicyclic, or tricyclic system, wherein at least one of the fused rings is aromatic and contains at least one atom selected from the group consisting of O, S, and N. In some embodiments, the heteroaryl group will contain 5 to 7 carbon atoms. The term also includes fused polycyclic groups, wherein the heterocycle is fused with an aromatic ring, wherein the heteroaryl ring is fused with another heteroaryl ring, wherein the heteroaryl ring is fused with a heterocyclic alkyl ring, or wherein the heteroaryl ring is fused with a cycloalkyl ring. Examples of heteroaryl groups include pyrroloyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, pyranyl, furanyl, thiophene, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiazolyl, isothodolyl, indoleyl, isoindoleyl, indolazidoleyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinoxolinyl, quinazolinyl, inzolyl, benzotriazolyl, benzodioxazolyl, benzopyranyl, benzooxazolyl, benzooxadiazolyl, benzothiazolyl, benzothiazolyl, benzofuranyl, benzothiophene, chromonyl, coumarinyl, benzopyranyl, tetrahydroquinolinyl, tetrazopyridyl, tetrahydroisoquinolinyl, thiophene-pyridyl, furan-pyridyl, pyrrolopyridyl, etc. Exemplary tricyclic heterocyclic groups include carbazole, benzoindolyl, phenanthrolinyl, dibenzofuranyl, acridineyl, phenanthridinyl, xanthenyl, etc.

[0108] As used individually or in combination herein, the terms "heterocyclic alkyl" and the interchangeable term "heterocycle" refer to a saturated, partially unsaturated, or fully unsaturated monocyclic, bicyclic, or tricyclic heterocyclic group containing at least one heteroatom as a ring member, wherein each heteroatom may be independently selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclic alkyl group will contain 1 to 4 heteroatoms as ring members. In other embodiments, the heterocyclic alkyl group will contain 1 to 2 heteroatoms as ring members. In some embodiments, the heterocyclic alkyl group will contain 3 to 8 ring members in each ring. In other embodiments, the heterocyclic alkyl group will contain 3 to 7 ring members in each ring. In still other embodiments, the heterocyclic alkyl group will contain 5 to 6 ring members in each ring. "Heterocyclic alkyl" and "heterocycle" are intended to include sulfones, sulfoxides, and oxynitrides among tertiary nitrogen ring members, as well as carbocyclic fused ring systems and benzo[a]fused ring systems; furthermore, both terms also include systems in which a heterocycle is fused with an aryl or other heterocyclic group as defined herein. Examples of heterocyclic groups include acridinel, aziridine, benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocenolinyl, dihydrobenzodioxinyl, dihydro[1,3]oxazolo[4,5-b]pyridyl, benzothiazolyl, dihydroindolyl, dihydropyridyl, 1,3-dioxalkyl, 1,4-dioxalkyl, 1,3-dioxopentyl, isoindololinyl, morpholinyl, piperazine, pyrrolidinyl, tetrahydropyridyl, piperidinyl, thiomorpholinyl, etc. Unless specifically prohibited, heterocyclic groups may be optionally substituted.

[0109] The term "hydrazine" as used alone or in combination in this article refers to two amino groups linked by a single bond, namely –N–N–.

[0110] The term "hydroxyl" as used alone or in combination in this article refers to –OH.

[0111] The term “hydroxyalkyl” as used alone or in combination in this article refers to a hydroxyl group that is attached to a parent molecule moiety via an alkyl group.

[0112] The term "imino" as used alone or in combination in this article refers to =N–.

[0113] The term “iminohydroxy” as used alone or in combination in this article refers to =N(OH) and =N–O–.

[0114] The phrase “in the main chain” refers to the longest continuous or adjacent chain of carbon atoms starting from the point where the group connects to any of the compounds in the formulas disclosed herein.

[0115] The term "isocyanoxy" refers to the –NCO group.

[0116] The term "isothiocyanate" refers to the –NCS group.

[0117] The phrase “linear atomic chain” refers to the longest straight chain of atoms independently selected from carbon, nitrogen, oxygen, and sulfur.

[0118] The term "lower" as used alone or in combination herein, unless otherwise specifically defined, refers to a moiety containing one to six carbon atoms. Preferably, when describing an alkyl moiety, the term "lower" refers to one to three carbon atoms.

[0119] The term “lower aryl” as used alone or in combination herein refers to phenyl or naphthyl, either of which may be optionally substituted as needed.

[0120] The term “lower heteroaryl” as used alone or in combination herein refers to 1) a monocyclic heteroaryl containing 5 or 6 ring members, wherein 1 to 4 of the members may be heteroatoms selected from the group consisting of O, S and N, or 2) a bicyclic heteroaryl, wherein each of the fused rings contains 5 or 6 ring members, wherein therein are 1 to 4 heteroatoms selected from the group consisting of O, S and N.

[0121] The term "lower cycloalkyl" as used alone or in combination herein refers to a monocyclic cycloalkyl group having three to six ring members. Lower cycloalkyl groups may be unsaturated. Examples of lower cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0122] As used alone or in combination herein, the term "lower heterocyclic alkyl" refers to a monocyclic heterocyclic alkyl group having 3 to 6 ring members, of which 1 to 4 may be heteroatoms selected from the group consisting of O, S, and N. Examples of lower heterocyclic alkyl groups include pyrrolidinyl, imidazoalkyl, pyrazolyl, piperidinyl, piperazinyl, and morpholinyl. Lower heterocyclic alkyl groups may be unsaturated.

[0123] The term "lower amino" as used alone or in combination herein refers to —NRR', where R and R' are independently selected from the group consisting of hydrogen, lower alkyl, and lower heteroalkyl, any of which may be optionally substituted. Furthermore, the R and R' of the lower amino group may combine to form a five- or six-membered heterocyclic alkyl group, any of which may be optionally substituted.

[0124] The term “alkyl sulfide (mercaptyl)” as used alone or in combination herein refers to an RS- group, where R is as defined herein.

[0125] The term “nitro” as used alone or in combination in this article refers to –NO2.

[0126] The term "oxy (or oxa)" as used alone or in combination in this article refers to –O–.

[0127] The term "oxo" as used alone or in combination in this article refers to =O.

[0128] The term "perhaloalkoxy" refers to an alkoxy group in which all hydrogen atoms are replaced by halogen atoms.

[0129] The term “fully halogenated alkyl” as used alone or in combination in this article refers to an alkyl group in which all hydrogen atoms are replaced by halogen atoms.

[0130] The terms “sulfonate,” “sulfonic acid,” and “sulfonic” used alone or in combination in this article refer to the –SO3H group and its anion, because sulfonic acid is used for salt formation.

[0131] The term "sulfanyl" as used alone or in combination in this article refers to –S–.

[0132] The term "sulfinyl" as used alone or in combination in this article refers to –S(O)–.

[0133] The term "sulfonyl" as used alone or in combination in this article refers to –S(O)2–.

[0134] The term “N-sulfonamide group” refers to an RS(=O)2NR’ group having the R and R' described herein.

[0135] The term "S-sulfonamide group" refers to a -S(=O)2NRR' group having the R and R' described herein.

[0136] The term "thia and thio" as used alone or in combination herein refers to an –S– group or an ether in which oxygen is replaced by sulfur. Oxidized derivatives of the thio group, namely sulfinyl and sulfonyl groups, are included in the definition of thio.

[0137] The term "thiol" as used alone or in combination in this article refers to the –SH group.

[0138] The term “thiocarbonyl” as used in this article includes thioformyl–C(S)H when used alone, and –C(S)– when used in combination.

[0139] The term "N-thiocarbamoyl" refers to a ROC(S)NR'– group having the R and R' groups described herein.

[0140] The term "O-thiocarbamoyl" refers to the –OC(S)NRR' group having the R and R' described herein.

[0141] The term "thiocyanato" refers to the –CNS group.

[0142] The term “trihalomethanesulfonamide” refers to the X3CS(O)2NR- group, where X is a halogen and R is as described herein.

[0143] The term "trihalomethanesulfonyl" refers to the X3CS(O)2- group, where X is a halogen.

[0144] The term "trihalomyco-" refers to the X3CO– group, where X is a halogen.

[0145] The term “trisubstituted silyl” as used alone or in combination herein refers to a siloxane in which all three of its free valences are replaced by groups listed herein in the definition of substituted amino groups. Examples include trimethylsilyl, tert-butyldimethylsilyl, triphenylsilyl, etc.

[0146] Any definition in this document may be used in conjunction with any other definition to describe complex structural groups. By convention, the trailing element in any such definition is the element attached to the parent part. For example, the complex group alkylamino will represent an alkyl group attached to the parent molecule via an amide group, and the term alkoxyalkyl will represent an alkoxy group attached to the parent molecule via an alkyl group.

[0147] When a group is defined as "null", it means that the group does not exist.

[0148] The term "optionally substituted" means that the preceding group can be substituted or unsubstituted. When substituted, the substituents of the "optionally substituted" group can include, but are not limited to, one or more substituents independently selected from the following groups or a specifically designated group of groups, either alone or in combination: lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl, phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxy(oxo) The following groups are permitted to be substituents: lower acyloxy groups, carbonyl groups, carboxyl groups, lower alkyl carbonyl groups, lower carboxyl esters, lower formamido groups, cyano groups, hydrogen, halogens, hydroxyl groups, amino groups, lower alkylamino groups, arylamino groups, amide groups, nitro groups, thiols, lower alkylthio groups, lower haloalkylthio groups, lower perhaloalkylthio groups, arylthio groups, sulfonates, sulfonic acids, trisubstituted silyl groups, N3, SH, SCH3, C(O)CH3, CO2CH3, CO2H, pyridyl, thiophene, furanyl, lower carbamates, and lower ureas. Two substituents can be linked together to form a fused five-, six-, or seven-membered carbon ring or heterocycle consisting of 0 to 3 heteroatoms, for example, forming methylenedioxy or ethylenedioxy. Optionally substituted groups can be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted at any level between full and monosubstituted (e.g., -CH2CF3). When a substituent is described without specifying substitution, both substituted and unsubstituted forms are included. When a substituent is specified as "substituted," the substituted form is specifically designated. Furthermore, different groups of optional substituents may be defined for specific parts as needed; in these cases, optional substitution will be as defined, usually immediately following the phrase "optionally substituted."

[0149] Unless otherwise defined, the term R or R', appearing alone and without a number designation, refers to a part selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, and heterocycloalkyl, any of which may be optionally substituted. Such R and R' groups should be understood as optionally substituted as described herein. Regardless of whether an R group is designated by a number, each R group, including R, R', and R... n(where n = (1, 2, 3, ..., n)), each substituent and each term should be understood as independent of each other in terms of the choice of groups. If any variable, substituent, or term (e.g., aryl, heterocyclic, R, etc.) appears more than once in the formula or general structure, its definition each time it appears is independent of its definition for each subsequent appearance. Those skilled in the art will further recognize that certain groups can be attached to the parent molecule or can occupy a position at either end of the elemental chain as written. Thus, by way of example only, an asymmetric group such as –C(O)N(R) – can be attached to the parent moiety on either carbon or nitrogen.

[0150] Asymmetric centers are present in the compounds disclosed herein. These centers are indicated by the symbols “R” or “S” depending on the configuration of the substituents surrounding the chiral carbon atom. It should be understood that this invention includes all stereochemical isomer forms, including diastereomers, enantiomers, and epimers, as well as d-isomers and 1-isomers and mixtures thereof. Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials containing chiral centers, or by preparing a mixture of enantiomers followed by separation, for example, by converting to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, on a chiral column, or by any other suitable method known in the art. The starting compounds of a particular stereochemistry are either commercially available or can be prepared and resolved by techniques known in the art. Furthermore, the compounds disclosed herein can exist as geometric isomers. This invention includes all cis, trans, syn, anti, E-type, and Z-type isomers and suitable mixtures thereof. Furthermore, the compounds can exist as tautomers; this invention provides all tautomer isomers. Additionally, the compounds disclosed herein can exist in both unsolvated and solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc. Generally, the solvated form is considered equivalent to the unsolvated form.

[0151] The term "bond" refers to a covalent bond between two atoms, or between two parts when the atoms connected by a bond are considered part of a larger molecular structure. Unless otherwise specified, a bond can be a single, double, or triple bond. The dashed line between two atoms in a molecular diagram indicates whether an additional bond may or may not be present at that location.

[0152] The term “disease” as used in this article is generally synonymous with and interchangeable with the terms “symptom,” “syndrome,” and “condition” (as in a medical condition) because they all reflect an abnormal condition of the human or animal body or a part thereof that impairs normal function, usually manifested as various signs and symptoms, and leading to a shortened lifespan or reduced quality of life in humans or animals.

[0153] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat the therapeutic condition or symptom described in this disclosure. Such administration includes the combined administration of these therapeutic agents in a substantially simultaneous manner, for example, in a single capsule containing multiple active ingredients in a fixed proportion or in multiple separate capsules for each active ingredient. Furthermore, such administration also includes the sequential use of each type of therapeutic agent. In either case, the treatment regimen will provide the beneficial effect of the combination of drugs in treating the condition or symptom described herein.

[0154] The term "glycolysis inhibitor" as used in this article refers to compounds that exhibit glycolytic activity and inhibit energy production.

[0155] The phrase “therapeuticly effective” aims to quantify the amount of active ingredient used in the treatment of a disease or condition or that affects clinical endpoints.

[0156] The term “therapeuticly acceptable” refers to compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) that are suitable for contact with patient tissues without undue toxicity, irritation, or allergic reactions, are commensurate with a reasonable benefit / risk ratio, and are effective for their intended use.

[0157] As used in this article, the term "treatment" for a patient is intended to include prevention. Treatment can also be proactive in nature, meaning it can include disease prevention. Disease prevention may involve complete protection against the disease, such as in the case of preventing viral infection, or it may involve stopping the progression of the disease. For example, disease prevention may not mean completely eliminating any disease-related effects at any level, but may mean preventing the symptoms of the disease at a clinically significant or detectable level. Disease prevention can also mean preventing the disease from progressing to a late stage.

[0158] The term "patient" is generally synonymous with the term "subject" and includes all mammals, including humans. Examples of patients include humans, livestock such as cattle, goats, sheep, pigs, and rabbits, as well as companion animals such as dogs, cats, rabbits, and horses. Preferably, the patient is a human.

[0159] The term "prodrug" refers to a compound that is more active in the body. For example... Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and EnzymologyAs described in (Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003), some of the compounds disclosed herein can also exist as prodrugs. A prodrug of a compound described herein is a structurally modified form of the compound that readily undergoes chemical change under physiological conditions to provide the compound. Furthermore, prodrugs can be converted into compounds in an in vitro environment by chemical or biochemical methods. For example, a prodrug can be slowly converted into a compound when placed in a transdermal patch reservoir along with a suitable enzyme or chemical reagent. Prodrugs are often useful because, in certain situations, they may be easier to administer than the compound or the parent drug. For example, they can be bioavailable by oral administration, whereas the parent drug cannot. The solubility of prodrugs in pharmaceutical compositions may also be higher than that of the parent drug. Various prodrug derivatives are known in the art, such as those that depend on the hydrolytic cleavage or oxidative activation of the prodrug. A non-limiting example of a prodrug is a compound administered as an ester (“prodrug”) but subsequently metabolized and hydrolyzed into a carboxylic acid and the active entity. Other examples include peptide derivatives of the compound.

[0160] The compounds disclosed herein can exist as therapeutically acceptable salts. This invention includes salt forms of the compounds listed above, including acid addition salts. Suitable salts include those formed with organic and inorganic acids. Such acid addition salts are generally pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable salts can be used to prepare and purify the compounds discussed. Basic addition salts can also be formed and are pharmaceutically acceptable. For a more complete discussion of the preparation and selection of salts, refer to [reference needed]. Pharmaceutical Salts: Properties, Selection, and Use (Stahl, P. Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002).

[0161] As used herein, the term "therapeuticly acceptable salt" refers to a salt or zwitterionic form of a compound disclosed herein that is water-soluble or oil-soluble or dispersible and is therapeutically acceptable as described herein. Salts may be prepared during the final separation and purification of the compound, or by reacting a suitable compound in its free base form with a suitable acid. Representative acid addition salts include acetates, adipates, alginates, L-ascorbic acid salts, aspartate salts, benzoates, benzenesulfonates, hydrogen sulfates, butyrates, camphorates, camphorsulfonates, citrates, digluconates, formates, fumarates, gentianates, glutarate, glycerophosphates, glycolates, hemisulfates, heptahydrates, hexanoates, hippurates, hydrochlorides, hydrobromide salts, hydroiodates, 2-hydroxyethanesulfonate (hydroxyethylsulfonate), lactates, and maleate salts. Salts, malonates, DL-mandelates, mesitylenesulfonates, methanesulfonates, naphthalenesulfonates, nicotinates, 2-naphthalenesulfonates, oxalates, dihydroxynaphthalates, pectates, persulfates, 3-phenylpropionates, phosphates, picrates, neopentanoates, propionates, pyroglutamates, succinates, sulfonates, tartrates, L-tartrates, trichloroacetic acid salts, trifluoroacetic acid salts, phosphates, glutamates, bicarbonates, para-toluenesulfonate (p-tosylate), and undecanoates. Furthermore, the basic groups in the compounds disclosed herein can be quaternized with: methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and dipentyl sulfates; decyl, lauryl, myristyl, and steroid chlorides, bromides, and iodides; and benzyl and phenethyl bromides. Examples of acids that can be used to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, as well as organic acids such as oxalic acid, maleic acid, succinic acid, and citric acid. Salts can also be formed by coordination of the compound with alkali metal or alkaline earth metal ions. Therefore, the present invention contemplates sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein.

[0162] Base addition salts can be prepared during the final separation and purification of compounds by reacting the carboxyl group with a suitable base, such as a hydroxide, carbonate, or bicarbonate of a metal cation, or with ammonia or an organic primary, secondary, or tertiary amine. Therapeutically acceptable cations include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as non-toxic quaternary ammonium cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, and N,N'-dibenzylethylenediamine. Other representative organic amines used to form base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.

[0163] Salts of compounds can be prepared by reacting a suitable compound in its free base form with a suitable acid.

[0164] While the compounds of the present invention can be administered as chemical raw materials, they can also be presented as pharmaceutical formulations. Therefore, pharmaceutical formulations are provided herein comprising one or more of certain compounds disclosed herein, or one or more pharmaceutically acceptable salts, esters, prodrugs, amides, or solvates thereof, and one or more pharmaceutically acceptable carriers and optionally one or more other therapeutic ingredients. The carrier must be “acceptable,” meaning compatible with the other components in the formulation and harmless to the recipient. A suitable formulation depends on the chosen route of administration. Any known techniques, carriers, and excipients may be suitably used, as understood in the art; for example, techniques, carriers, and excipients found in the Remington Pharmacopoeia. The pharmaceutical compositions disclosed herein can be manufactured in any manner known in the art, such as by conventional methods of mixing, dissolving, granulating, forming sugar-coated pellets, grinding, emulsifying, encapsulating, coating, or pressing.

[0165] Formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intra-articular, and intramedullary), intraperitoneal, transmucosal, transdermal, rectal, and topical (including skin, oral, sublingual, and intraocular) administration, but the most suitable route may depend, for example, on the recipient's condition and illness. Formulations can conveniently exist in unit dosage forms and can be prepared by any method known in the pharmaceutical field. Typically, these methods involve the step of binding the compound of the present invention or its pharmaceutically acceptable salt, ester, amide, prodrug, or solvation thereof (“active ingredient”) to a carrier constituting one or more excipients. Generally, formulations are prepared by uniformly and tightly binding the active ingredient to a liquid carrier or a finely fragmented solid carrier, or both, and then, if necessary, shaping the product into the desired formulation.

[0166] The formulations of the compounds disclosed herein for oral administration can exist as dispersion units, such as capsules, granules, or tablets, each containing a predetermined amount of the active ingredient; as powders or granules; as solutions or suspensions in aqueous or non-aqueous liquids; or as oil-in-water or water-in-oil emulsions. The active ingredient can also exist as pills, granules, or pastes.

[0167] Orally administered pharmaceutical formulations include tablets, push-in capsules made of gelatin, and sealed soft capsules made of gelatin and plasticizers (such as glycerin or sorbitol). Tablets can be made by compression or molding, optionally using one or more excipients. Compressed tablets are prepared by compressing the active ingredient in a free-flowing form (e.g., powder or granules, optionally mixed with a binder, inert diluent, or lubricant, surfactant, or dispersant) in a suitable machine. Molded tablets can be made by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. Tablets can optionally be coated or scored and can be formulated to provide a slow or controlled release of the active ingredient therein. All formulations for oral administration should be at a dose suitable for such administration. Push-in capsules may contain the active ingredient mixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compound can be dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin, or liquid polyethylene glycol. Additionally, a stabilizer may be added. The sugar-coated core is fitted with a suitable coating. For this purpose, a concentrated sugar solution may be used, optionally containing gum arabic, talc, polyvinylpyrrolidone, carbomer gel, polyethylene glycol and / or titanium dioxide, lacquer, and a suitable organic solvent or solvent mixture. Dyes or pigments may be added to the coating of the tablet or sugar-coated core for the identification or characterization of different combinations of active compound dosages.

[0168] The compound can be formulated for parenteral administration by injection, such as by bolus or continuous infusion. Injectable formulations can be in single-dose units, such as ampoules or multi-dose containers, with added preservatives. The composition can be in the form of suspensions, solutions, or emulsions in oily or aqueous solvents and may contain formulation agents such as suspending agents, stabilizers, and / or dispersants. Formulations can be in single-dose or multi-dose containers, such as in sealed ampoules and vials, and can be stored in powder form or under freeze-dried (lyophilized) conditions, requiring only immediate addition of a sterile liquid carrier, such as saline or sterile pyrogen-free water, before use. Temporary injectable solutions and suspensions can be prepared from the aforementioned types of sterile powders, granules, and tablets.

[0169] Parenteral formulations include aqueous and non-aqueous (oil-based) sterile injectable solutions of the active compound, which may contain antioxidants, buffers, antibacterial agents, and solutes that make the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickeners. Suitable lipophilic solvents or media include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injectable suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound to allow for the preparation of highly concentrated solutions.

[0170] In addition to the formulations described above, compounds can also be formulated into reservoir formulations. Such long-acting formulations can be administered via implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Thus, for example, compounds can be formulated with suitable polymeric or hydrophobic materials (e.g., as emulsions in acceptable oils) or ion exchange resins, or as slightly soluble derivatives, such as slightly soluble salts.

[0171] For oral or sublingual administration, the composition can be formulated in the form of tablets, lozenges, pastures, or gels using conventional methods. This composition may contain the active ingredient within a flavoring matrix such as sucrose and gum arabic or tragacanth.

[0172] The compound can also be formulated into rectal compositions such as suppositories or retention enemas, for example, containing conventional suppository bases such as cocoa butter, polyethylene glycol or other glycerides.

[0173] Some of the compounds disclosed herein can be administered topically, i.e., without systemic administration. This includes external application of the compounds disclosed herein to the epidermis or oral cavity, and instillation of such compounds into the ear, eye, and nose, such that the compounds do not significantly enter the bloodstream. Conversely, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

[0174] Formulations suitable for topical application include liquid or semi-liquid formulations, such as gels, liniments, lotions, creams, ointments, or pastes, suitable for penetration through the skin to sites of inflammation or hyperplasia, and drops suitable for application to the eyes, ears, or nose. The active ingredient for topical application may, for example, comprise 0.001% w / w to 10% w / w (by weight) of the formulation. In some embodiments, the active ingredient may comprise up to 10% w / w. In other embodiments, it may comprise less than 5% w / w. In some embodiments, the active ingredient may comprise from 2% w / w to 5% w / w. In other embodiments, it may comprise 0.1% w / w to 1% w / w of the formulation.

[0175] Gels for topical or transdermal application typically comprise a mixture of volatile solvents, non-volatile solvents, and water. In some embodiments, the volatile solvent component of the buffer solvent system may include lower (C1-C6) alkyl alcohols, lower alkyl glycols, and lower glycol polymers. In other embodiments, the volatile solvent is ethanol. The volatile solvent component is considered to act as a penetration enhancer and also provides a cooling effect on the skin upon evaporation. The non-volatile solvent portion of the buffer solvent system is selected from lower alkylene glycols and lower glycol polymers. In some embodiments, propylene glycol is used. The non-volatile solvent slows the evaporation of the volatile solvent and lowers the vapor pressure of the buffer solvent system. As with the volatile solvent, the amount of this non-volatile solvent component is determined by the pharmaceutical compound or drug used. When there is too little non-volatile solvent in the system, the pharmaceutical compound may crystallize due to the evaporation of the volatile solvent, while an excess may result in insufficient bioavailability due to poor drug release from the solvent mixture. The buffer component of the buffer solvent system may be selected from any buffer commonly used in the art; in some embodiments, water is used. The common proportions of the ingredients are approximately 20% non-volatile solvents, approximately 40% volatile solvents, and approximately 40% water. Several optional ingredients can be added to the topical composition. These include, but are not limited to, chelating agents and gelling agents. Suitable gelling agents may include, but are not limited to, semi-synthetic cellulose derivatives (such as hydroxypropyl methylcellulose) and synthetic polymers, as well as cosmetic agents.

[0176] Lotions include those intended for use on the skin or eyes. Eye lotions may include sterile aqueous solutions optionally containing a bactericide and may be prepared by methods similar to those used for eye drops. Lotions or liniments applied to the skin may also include agents that accelerate drying and cool the skin, such as ethanol or acetone, and / or moisturizers, such as glycerin or oils, such as castor oil or peanut oil.

[0177] Creams, ointments, or pastes are semi-solid formulations of topical active ingredients. They can be prepared by mixing the finely pulverized or powdered active ingredient alone with an oily or non-oily matrix, or by mixing a solution or suspension in aqueous or non-aqueous solution with an oily or non-oily matrix using suitable machinery. The matrix may include hydrocarbons such as hard, soft, or liquid paraffin, glycerin, beeswax, or metallic soaps; mucus; naturally derived oils such as almond oil, corn oil, peanut oil, castor oil, or olive oil; lanolin or its derivatives; fatty acids such as stearic acid or oleic acid; alcohols such as propylene glycol; or macromolecular gels. The formulation may incorporate any suitable surfactant, such as anionic, cationic, or nonionic surfactants, such as sorbitol esters or their polyoxyethylene derivatives. It may also include suspensions such as natural gums, cellulose derivatives, or inorganic materials such as silica, and other ingredients such as lanolin.

[0178] Drops may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in an aqueous solution of a suitable bactericide and / or fungicide and / or any other suitable preservative, and in some embodiments, a surfactant may be included. The resulting solution can then be clarified by filtration, transferred to a suitable container, and subsequently sealed and sterilized by autoclaving or by holding at 98-100°C for half an hour. Alternatively, the solution may be sterilized by filtration and transferred to a container using aseptic techniques. Examples of bactericides and fungicides suitable for inclusion in drops are phenylmercuric nitrate or phenylmercuric acetate (0.002%), benzalkonium chloride (0.01%), and chlorhexidine acetate (0.01%). Suitable solvents for preparing oily solutions include glycerol, diluted ethanol, and propylene glycol.

[0179] Formulations intended for topical oral application (e.g., orally or sublingually) include lozenges containing the active ingredient in a flavoring matrix such as sucrose and gum arabic or tragacanth, and lozenges containing the active ingredient in a matrix such as gelatin and glycerin or sucrose and gum arabic.

[0180] For inhalation administration, the compound can be conveniently delivered via a blowpipe, a nebulizer pressurized pack, or other convenient aerosol spray delivery method. The pressurized pack may include a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of pressurized aerosols, the dosage unit can be determined by providing a valve to deliver the measured amount. Alternatively, for administration by inhalation or blowing, the compounds of the present invention can be in the form of a dry powder composition, such as a powder mixture of the compound and a suitable powder matrix such as lactose or starch. The powder composition can be present in unit dosage forms, such as capsules, cartons, gelatin, or blister packs, from which the powder can be administered using an inhaler or blowpipe.

[0181] Preferred unit-dose formulations are those containing an effective dose (or appropriate proportion thereof) of the active ingredient as described below.

[0182] It should be understood that, in addition to the ingredients specifically mentioned above, the formulations discussed may include other agents conventional in the art, such as flavoring agents, depending on the type of formulation being discussed.

[0183] The compound can be administered orally or by injection at doses ranging from 0.1 mg / kg / day to 500 mg / kg / day. The typical adult dose range is 5 mg / day to 2 g / day. Tablets or other forms of presentation, provided in dispersible units, conveniently contain an amount of one or more compounds that are effective at that dose or multiples thereof, for example, units containing 5 mg to 500 mg, typically about 10 mg to 200 mg.

[0184] The amount of active ingredient that can be combined with carrier materials to produce a single dosage form will vary depending on the host being treated and the specific method of administration.

[0185] These compounds can be administered in various ways (e.g., orally, topically, or by injection). The precise amount of compound administered to a patient will be the responsibility of the attending physician. The specific dosage level for any particular patient will depend on a number of factors, including the activity of the specific compound used, age, weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combinations, the exact condition being treated, and the severity of the indication or condition being treated. Furthermore, the route of administration may vary depending on the condition and its severity.

[0186] In some cases, it may be appropriate to administer at least one of the compounds described herein (or a pharmaceutically acceptable salt, ester, or prodrug thereof) in combination with another therapeutic agent. For example only, if one of the side effects a patient experiences while receiving one of the compounds described herein is high blood pressure, then administering an antihypertensive agent in combination with that initial therapeutic agent may be appropriate. Alternatively, for example only, the therapeutic effect of one of the compounds described herein may be enhanced by the administration of an adjuvant (i.e., the adjuvant itself may have only minimal therapeutic benefit, but when combined with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Alternatively, for example only, the benefit experienced by the patient may be increased by administering one of the compounds described herein together with another therapeutic agent (which also includes treatment regimens) that also has a therapeutic benefit. For example only, in the treatment of COVID-19 involving the administration of one of the compounds described herein, an increased therapeutic benefit may also be generated by providing the patient with another therapeutic agent, for example, for viral or bacterial infection or anti-inflammatory purposes. In any case, regardless of the disease, condition, or status treated, the overall benefit experienced by the patient may simply be the sum of the two therapeutic agents, or the patient may experience a synergistic benefit.

[0187] In some embodiments, topical steroids include, but are not limited to, clobetasol propionate, betamethasone, betamethasone dipropionate, halobetasol propionate, fluocinolone acetonide, difluralasone diacetate, mometasone furoate, halcinonide, deshydroxymethasone, fluticasone propionate, fludroxil, triamcinolone acetonide, fluocinolone acetonide, hydrocortisone, hydrocortisone valerate, prednisolone, desonide, and aclomethasone dipropionate.

[0188] In some implementations, nonsteroidal anti-inflammatory agents include, but are not limited to, aceclofenac, amoxicillin, aspirin, azaacetone, benorilate, bromofenac, carbofenac, celecoxib, choline magnesium salicylate, diclofenac, diflunisal, etodoxacin, etoricoxib, faislamine, fenbufen, fenprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, lornoxicam, loxoprofen, lumiracoxib, meloxicam, meclofenac, mefenamic acid, meloxicam, aminopyrine, methyl salicylate, magnesium salicylate, nabumetone, naproxen, nimesulide, hydroxyphenylbutazone, parecoxib, phenylbutazone, piroxicam, and salicylates. salicylate, sulindac, sulfinpyrazone, sulofen, tenoscillamine, tiprofen, and tometetin.

[0189] In some embodiments, the antimicrobial agents include, but are not limited to, amikacin, amoxicillin, ampicillin, arsphenamine, azithromycin, aztreonam, allocillin, bacitracin, carbenicillin, cefaclor, cefamandole, cefazolin, cefalexin, cefdinir, ceftoran, cefepime, cefixime, cefoperazone, cefotaxime, cefoxitin, cefpodoxime, cefprozil, ceftazidime, and cefbufen. Cefazolin, ceftriaxone, cefuroxime, chloramphenicol, cilastin, ciprofloxacin, clarithromycin, clindamycin, cloxacillin, colistin, dalfopristin, demeclocycline, dicloxacillin, erythromycin, doxycycline, erythromycin, enrofloxacin, ertapenem, ethambutol, flucloxacillin, fosfomycin, furazolidone, gatifloxacin, geldromycin, gentamicin, herbimycin, imipenem, isoniazid, kanamycin, levofloxacin, linezolid, lomefloxacin, chloramphenicol, sulfamethoxazole, moxifloxacin, meropenem, metronidazole, meropenem, minocycline, mupirocin, nafcillin, neomycin, netilmicin, nitrofurantoin, norfloxacin Flufloxacin, ofloxacin, oxytetracycline, penicillin, piperacillin, acanthomil, polymyxin B, prontosil, pyrazinamide, quinupristin, rifampin, retamoline, roxithromycin, spectinomycin, streptomycin, sulfacetamide, sulfamethoxazole, teicoplanin, telithromycin, tetracycline, ticarcillin, tobramycin, trimethoprim, travafloxacin, and vancomycin.

[0190] In any case, multiple therapeutic agents (at least one of which is a compound disclosed herein) may be administered in any order or even simultaneously. If administered simultaneously, the multiple therapeutic agents may be provided in a single, uniform form, or in multiple forms (by way of example only, as a single pill or as two separate pills). One of the therapeutic agents may be administered in multiple doses, or both therapeutic agents may be administered in multiple doses. If not administered simultaneously, the time between multiple doses may be any duration from several minutes to four weeks.

[0191] Therefore, in another aspect, some embodiments provide a method for treating a viral infection in a human or animal subject requiring such treatment, comprising administering to the subject an amount of the disclosed compound that effectively reduces or prevents the infection in the subject, in combination with at least one additional agent known in the art for treating the disease. In a related aspect, some embodiments provide a therapeutic composition comprising at least one compound disclosed herein in combination with one or more additional agents for treating viral infections and conditions caused by such infections, such as pneumonia.

[0192] The compounds, compositions, and methods disclosed herein treat specific viral diseases, including but not limited to infections of HIV, influenza virus, Lassa virus, coronaviruses including SARS virus, Zika virus, dengue virus, and Ebola virus. In some embodiments, the viral disease is a viral respiratory infection including viral pneumonia. In some embodiments, the viral infection is COVID 19 caused by SARS-CoV-2.

[0193] In addition to their use in human treatment, some of the compounds and formulations disclosed herein may also be used for veterinary treatment of companion animals, exotic animals, and farm animals (including mammals, rodents, etc.). More preferred animals include horses, dogs, and cats.

[0194] General synthetic methods for preparing compounds

[0195] The compounds disclosed herein can be synthesized according to the methods described in US 8927506 B2 (columns 14-26); WO 2010005799 (paragraphs

[0086] -

[0145] ); WO 2009108926 (paragraphs

[0173] -

[0185] ); WO 2008131024 (paragraphs

[0067] -

[0072] ); US 20100152121 (paragraphs

[0067] -

[0083] ); US 7160865 (columns 11-13); and US6979675 (columns 28-29), the disclosures of which are incorporated herein by reference as if their entire contents were written into this document.

[0196] The present invention is further illustrated by the following embodiments.

[0197] Example 1

[0198] (4R,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-acetate

[0199]

[0200] Example 2

[0201] (4R,5S,6R)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2,4-diacetic acid diester

[0202]

[0203] Example 3

[0204] Methyl ((2R,3S,4R)-6-acetoxy-3,4-dihydroxytetrahydro-2H-pyran-2-yl)acetate

[0205]

[0206] Example 4

[0207] Methyl ((2R,3S,4R)-3-acetoxy-4,6-dihydroxytetrahydro-2H-pyran-2-yl)acetate

[0208]

[0209] Example 5

[0210] ((2R,3S,4R)-4-acetoxy-3,6-dihydroxytetrahydro-2H-pyran-2-yl)methyl acetate (WP1122)

[0211]

[0212] Example 6

[0213] Methyl ((2R,3S,4R)-3,4,6-trihydroxytetrahydro-2H-pyran-2-yl)acetate

[0214]

[0215] Example 7

[0216] (2R,3S,4R)-4,6-dihydroxy-2-(hydroxymethyl)tetrahydro-2H-pyran-3-acetate

[0217]

[0218] Example 8

[0219] (4R,5S,6R)-4-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2,5-diacetic acid diester

[0220]

[0221] Example 9

[0222] (2R,3S,4R)-6-hydroxy-2-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diacetic acid diester

[0223]

[0224] Example 10

[0225] (4R,5S,6R)-6-(acetoxymethyl)-5-hydroxytetrahydro-2H-pyran-2,4-diacetate diester

[0226]

[0227] Example 11

[0228] (4R,5S,6R)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,4,5-triacetate

[0229]

[0230] Example 12

[0231] (4R,5S,6R)-6-(acetoxymethyl)tetrahydro-2H-pyran-2,4,5-triacetate

[0232]

[0233] Example 13

[0234] (4S,5S,6R)-3,3-difluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-2,4,5-triol

[0235] (2-Deoxy-2,2-Difluoro-D-arabinose-hexanopyranose (DFG))

[0236]

[0237] Example 14

[0238] (3R,4S,5S,6R)-6-(hydroxymethyl)-3-iodotetrahydro-2H-pyran-2,4,5-triol

[0239] (2-Deoxy-2-iodine-D-glucose)

[0240]

[0241] Example 15

[0242] (3S,4S,5S,6R)-6-(hydroxymethyl)-3-iodotetrahydro-2H-pyran-2,4,5-triol

[0243] (2-Deoxy-2-iodo-D-mannose)

[0244]

[0245] Example 16

[0246] (3R,4S,5R,6R)-6-(hydroxymethyl)-3-iodotetrahydro-2H-pyran-2,4,5-triol

[0247] (2-Deoxy-2-iodo-D-galactose)

[0248]

[0249] Example 17

[0250] (3S,4S,5R,6R)-6-(hydroxymethyl)-3-iodotetrahydro-2H-pyran-2,4,5-triol

[0251] (2-Deoxy-2-iod-D-tarose)

[0252]

[0253] Example 18

[0254] (4R,5S,6R)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,4,5-triol

[0255] (2-Deoxy-D-glucose)

[0256]

[0257] Example 19

[0258] (3S,4S,5S,6R)-3-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-2,4,5-triol

[0259] (2-Deoxy-2-Fluoro-D-mannose)

[0260]

[0261] Example 20

[0262] (3R,4S,5S,6R)-3-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-2,4,5-triol

[0263] (2-Deoxy-2-Fluoro-D-glucose)

[0264]

[0265] Example 21

[0266] (3R,4S,5S,6R)-3-chloro-6-(hydroxymethyl)tetrahydro-2H-pyran-2,4,5-triol

[0267] (2-Deoxy-2-chloro-D-glucose)

[0268]

[0269] Example 22

[0270] (3S,4S,5S,6R)-3-chloro-6-(hydroxymethyl)tetrahydro-2H-pyran-2,4,5-triol

[0271] (2-Deoxy-2-chloro-D-mannose)

[0272]

[0273] Example 23

[0274] (3R,4S,5S,6R)-3-bromo-6-(hydroxymethyl)tetrahydro-2H-pyran-2,4,5-triol

[0275] (2-Deoxy-2-bromo-D-glucose)

[0276]

[0277] Example 24

[0278] (3S,4S,5S,6R)-3-bromo-6-(hydroxymethyl)tetrahydro-2H-pyran-2,4,5-triol

[0279] (2-Deoxy-2-bromo-D-mannose)

[0280]

[0281] Example 25

[0282] (3R,4S,5S,6R)-6-methyltetrahydro-2H-pyran-2,3,4,5-tetraol

[0283] (6-Deoxy-D-glucose)

[0284]

[0285] Example 26

[0286] (3R,4S,5S,6S)-6-(fluoromethyl)tetrahydro-2H-pyran-2,3,4,5-tetraol

[0287] (6-Deoxy-6-Fluoro-D-glucose)

[0288]

[0289] Example 27

[0290] (3R,4S,5S,6R)-6-(methoxymethyl)tetrahydro-2H-pyran-2,3,4,5-tetraol

[0291] (6- O -Methyl-D-glucose)

[0292]

[0293] Example 28

[0294] (3R,4S,5S,6R)-2-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

[0295] (D-fluorinated glucose)

[0296]

[0297] Example 29

[0298] (2R,3S,4R,5S)-2-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

[0299] (1-Deoxy-D-glucose)

[0300]

[0301] Example 30

[0302] (3R,4R,5S,6R)-5-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-2,3,4-triol

[0303] (4-Fluoro-D-glucose)

[0304]

[0305] Example 31

[0306] (3R,4S,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,3,4-triol

[0307] (4-Deoxy-D-glucose)

[0308]

[0309] Example 32

[0310] (3S,4S,5R,6R)-4-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-2,3,5-triol

[0311] (3-Fluoro-D-glucose)

[0312]

[0313] Example 33

[0314] (3R,5S,6R)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,3,5-triol

[0315] (3-Deoxy-D-glucose)

[0316]

[0317] Example 34

[0318] (3R,4S,5S,6S)-6-(mercaptomethyl)tetrahydro-2H-pyran-2,3,4,5-tetraol

[0319] (6-Thio-D-glucose)

[0320]

[0321] Example 35

[0322] (3R,4S,5S,6R)-6-(hydroxymethyl)tetrahydro-2H-thiopyran-2,3,4,5-tetraol

[0323] (5-Thio-D-glucose)

[0324]

[0325] Example 36

[0326] Methyl ((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)valerate

[0327]

[0328] Example 37

[0329] Methyl ((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)tetradecanoate

[0330]

[0331] Example 38

[0332] Methyl palmitate ((2R,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl)palmitate

[0333]

[0334] Example 39

[0335] (2R,3S,4R,5R)-4,5,6-trihydroxy-2-(hydroxymethyl)tetrahydro-2H-pyran-3-pentanoate

[0336]

[0337] Example 40

[0338] (2S,3S,4S,5R)-Tetrazyl-4,5,6-trihydroxy-2-(hydroxymethyl)tetrahydro-2H-pyran-3-carboxylic acid ester

[0339]

[0340] Example 41

[0341] (2R,3S,4R,5R)-4,5,6-trihydroxy-2-(hydroxymethyl)tetrahydro-2H-pyran-3-palmitate

[0342]

[0343] Example 42

[0344] (3R,4S,5R,6R)-2,3,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-4-pentanoate

[0345]

[0346] Example 43

[0347] (3R,4S,5R,6R)-2,3,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-4-tetradecanoate

[0348]

[0349] Example 44

[0350] (3R,4S,5R,6R)-2,3,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-4-palmitate

[0351]

[0352] Example 45

[0353] (3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-pentanoate

[0354]

[0355] Example 46

[0356] (3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-tetradecanoate

[0357]

[0358] Example 47

[0359] (3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-palmitate

[0360]

[0361] Example 48

[0362] (3R,4R,5S,6R)-3-amino-6-(hydroxymethyl)tetrahydro-2H-pyran-2,4,5-triol

[0363] (2-Glucosamine)

[0364]

[0365] Example 49

[0366] (3R,4R,5R,6R)-3-amino-6-(hydroxymethyl)tetrahydro-2H-pyran-2,4,5-triol

[0367] (2-Galactosamine)

[0368]

[0369] Example 50

[0370] (3S,4R,5S,6R)-3-amino-6-(hydroxymethyl)tetrahydro-2H-pyran-2,4,5-triol

[0371] (2-Mannosamine)

[0372]

[0373] Example 51

[0374] (3S,4S,5S,6R)-3-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-2,4,5-triol

[0375] (2-Deoxy-2-Fluoro-D-mannose)

[0376]

[0377] Example 52

[0378] (4R,5R,6R)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,4,5-triol

[0379] (2-Deoxy-D-galactose)

[0380]

[0381] Example 53

[0382] (3R,4S,5R,6R)-3-fluoro-6-(hydroxymethyl)tetrahydro-2H-pyran-2,4,5-triol

[0383] (2-Deoxy-2-Fluoro-D-galactose)

[0384]

[0385] Example 54

[0386] N-((3R,4R,5S,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)methanesulfonamide

[0387]

[0388] Example 55

[0389] N-((3S,4R,5S,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)methanesulfonamide

[0390]

[0391] Example 56

[0392] (3R,4R,5S,6R)-6-(hydroxymethyl)-3-methyltetrahydro-2H-pyran-2,4,5-triol

[0393]

[0394] Example 57

[0395] (3R,4R,5S,6R)-3-(fluoromethyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,4,5-triol

[0396]

[0397] Example 58

[0398] (3R,4R,5S,6R)-3-(difluoromethyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,4,5-triol

[0399]

[0400] Example 59

[0401] (3R,4R,5S,6R)-6-(hydroxymethyl)-3-(trifluoromethyl)tetrahydro-2H-pyran-2,4,5-triol

[0402]

[0403] Example 60

[0404] (3S,4R,5S,6R)-6-(hydroxymethyl)-3-methyltetrahydro-2H-pyran-2,4,5-triol

[0405]

[0406] Example 61

[0407] (3S,4R,5S,6R)-3-(fluoromethyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,4,5-triol

[0408]

[0409] Example 62

[0410] (3S,4R,5S,6R)-3-(difluoromethyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,4,5-triol

[0411]

[0412] Example 63

[0413] (3S,4R,5S,6R)-6-(hydroxymethyl)-3-(trifluoromethyl)tetrahydro-2H-pyran-2,4,5-triol

[0414]

[0415] Example 64

[0416] (3S,4S,5S,6R)-6-(hydroxymethyl)-3-methyltetrahydro-2H-pyran-2,3,4,5-tetraol

[0417]

[0418] Example 65

[0419] (3S,4S,5S,6R)-3-(fluoromethyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,3,4,5-tetraol

[0420]

[0421] Example 66

[0422] (3S,4S,5S,6R)-3-(difluoromethyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,3,4,5-tetraol

[0423]

[0424] Example 67

[0425] (3S,4S,5S,6R)-6-(hydroxymethyl)-3-(trifluoromethyl)tetrahydro-2H-pyran-2,3,4,5-tetraol

[0426]

[0427] Example 68

[0428] (3R,4S,5S,6R)-6-(hydroxymethyl)-3-methyltetrahydro-2H-pyran-2,3,4,5-tetraol

[0429]

[0430] Example 69

[0431] (3R,4S,5S,6R)-3-(fluoromethyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,3,4,5-tetraol

[0432]

[0433] Example 70

[0434] (3R,4S,5S,6R)-3-(difluoromethyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,3,4,5-tetraol

[0435]

[0436] Example 71

[0437] (3R,4S,5S,6R)-6-(hydroxymethyl)-3-(trifluoromethyl)tetrahydro-2H-pyran-2,3,4,5-tetraol

[0438]

[0439] Example 72

[0440] N-((3R,4R,5S,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)acetamide

[0441]

[0442] Example 73

[0443] (3R,4S,5S,6R)-3-(aminooxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,4,5-triol

[0444]

[0445] Example 74

[0446] (3S,4S,5S,6R)-3-(aminooxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,4,5-triol

[0447]

[0448] Example 75

[0449] (3R,4R,5S,6R)-3-(hydroxyamino)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,4,5-triol

[0450]

[0451] Example 76

[0452] (3S,4R,5S,6R)-3-(hydroxyamino)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,4,5-triol

[0453]

[0454] Example 77

[0455] (3R,4R,5S,6R)-3-hydrazino-6-(hydroxymethyl)tetrahydro-2H-pyran-2,4,5-triol

[0456]

[0457] Example 78

[0458] (3S,4R,5S,6R)-3-hydrazino-6-(hydroxymethyl)tetrahydro-2H-pyran-2,4,5-triol

[0459]

[0460] Example 79

[0461] (3R,4S,5S,6R)-6-(hydroxymethyl)-3-mercaptotetrahydro-2H-pyran-2,4,5-triol

[0462]

[0463] Example 80

[0464] (3S,4S,5S,6R)-6-(hydroxymethyl)-3-mercaptotetrahydro-2H-pyran-2,4,5-triol

[0465]

[0466] Example 81

[0467] (4R,5S,6R)-3-hydrazino-6-(hydroxymethyl)tetrahydro-2H-pyran-2,4,5-triol

[0468]

[0469] Example 82

[0470] (4R,5S,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3(4H)-ketooxime

[0471]

[0472] Example 83

[0473] (2 R ,3 S 4 R )-2-(acetoxymethyl)-6-hydroxytetrahydro-2 H -Pyran-3,4-diacetate diester

[0474]

[0475] Example 84

[0476]

[0477] Biological Examples

[0478] Example A

[0479] Pharmacokinetic studies of WP1122 and in vivo conversion of 2-DG

[0480] An analytical method (LC / MS) has been developed that can quantify the concentration of the compounds of the present invention and / or the release of 2-DG in plasma.

[0481] The absorption and pharmacokinetics of WP1122 and 2-DG were investigated in female CD1 mice. Mice were orally administered equimolar doses of 0.5 g / kg and 0.33 g / kg of WP1122 and 2-DG, respectively. Animals in each group were sacrificed at designated time points (n=5 / time point) after dose administration. Plasma, skin, and other tissues were collected from each animal, and the concentration of 2-DG was measured by LC / MS.

[0482] Results. Peak plasma concentrations of 2-DG were reached 15 minutes after administration of either WP1122 or 2-DG, with maximum concentrations of 230 µg / mL and 89.5 µg / mL, respectively. The plasma half-lives of 2-DG were 252 and 137.7, respectively. Similarly, the recorded AUC value for WP1122 was almost twice that of the corresponding measured levels of 2-DG. Figure 1 This table shows the pharmacokinetic (PK) analysis of 2-DG in plasma after oral administration of WP1122 and 2-DG. Table 1 summarizes the PK parameters of the two compounds.

[0483] Table 1. PK parameters for 2-DG production in plasma after oral administration of WP1122 or 2-DG.

[0484]

[0485] Example B

[0486] Comparison of WP1122 and 2-DG levels in the lungs after intravenous administration

[0487] Experimental Procedure. The pharmacokinetics and tissue / organ distribution of tritium-labeled WP1122 and 2-DG were analyzed in male SD rats. Animals (n=3 at each time point) were administered 2-DG or WP1122 intravenously at equimolar doses of 0.2 g / kg and 0.13 g / kg, respectively. Animals were euthanized at 15 min, 30 min, 60 min, 6 h, and 24 h post-administration. Organs were harvested, washed with PBS, and radioactivity was measured using liquid scintillation counting (LCS).

[0488] Results. 2-DG and its metabolites from WP1122 and 2-DG were detected in the lungs at all detection time points. The highest concentration of the radiolabeled compound from WP1122 was observed within 15 minutes post-injection, and was nearly three times the radioactivity obtained from 2-DG administration. Increased presence of metabolites from WP1122 was observed at all time points (including 24 hours post-administration). (See...) Figure 2 ).

[0489] This experiment demonstrates a surprisingly good distribution of esters of pyranose monosaccharides (such as WP1122) in the lungs, making them superior for use in treating viral infections targeting the lungs, such as COVID-19.

[0490] All references cited in this article, including patents, patent applications and publications, whether or not they were previously specifically incorporated, are incorporated herein by reference in their entirety.

[0491] The various features and embodiments of the invention mentioned in the foregoing sections, with appropriate modifications, may be applied to other sections as appropriate. Therefore, a feature specified in one section may be combined with features specified in other sections as appropriate.

[0492] The specific embodiments described above provide sufficient information to enable others to readily modify or adapt these specific embodiments for various applications by applying current knowledge without departing from the general concept. Therefore, such modifications and adaptations should and are intended to be understood as equivalents to the embodiments disclosed herein. It should be understood that the wording or terminology used herein is for descriptive purposes and not for limitation. While exemplary embodiments have been disclosed in the drawings and description, and although specific terminology may be used, it is used only in a general and descriptive sense and not for limiting purposes unless otherwise stated, and therefore the scope of the claims is not limited thereto. Furthermore, those skilled in the art will understand that certain steps of the methods discussed herein may be ordered in an alternative order or may be combined. Therefore, the appended claims are intended to be limited to the specific embodiments disclosed herein. Those skilled in the art will recognize or be able to determine many equivalent embodiments of the invention described herein using only conventional experimentation. Such equivalents are included in the following claims.

Claims

1. Use of a compound of formula II or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of viral infection caused by SARS-CoV-2 in patients in need of it. Ⅱ in: R 14 and R 16 It is COCH3; and R 15 R 17 R4 and R5 are hydrogen.

2. Use of a compound of formula II or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment in patients in need of it of viral infections caused by HIV-1, SARS-CoV-2, Lassa virus, Zika virus, dengue virus, or Ebola virus. Ⅱ in: R 14 R 15 R 16 and R 17 It is hydrogen; and One of R4 and R5 is hydrogen, and the other of R4 and R5 is I.

3. The use according to claim 2, wherein the viral infection is caused by SARs-CoV-2.

4. The use according to claim 2, wherein the viral infection is caused by Ebola virus.

5. The use according to claim 2, wherein the viral infection is caused by Lassa virus.

6. Use of compounds selected from ((2R,3S,4R)-4-acetoxy-3,6-dihydroxytetrahydro-2H-pyran-2-yl)acetate and pharmaceutically acceptable salts thereof in the preparation of a medicament for the treatment of viral infection caused by SARs-CoV-2 in patients in need of it.

7. Use of compounds selected from 2-deoxy-2-iodide-D-glucose and 2-deoxy-2-iodide-D-mannose and their pharmaceutically acceptable salts in the preparation of a medicament for the treatment in patients in need of the treatment of viral infections caused by HIV-1 virus, SARs-CoV-2, Lassa virus, Zika virus, dengue virus or Ebola virus.

8. The use according to claim 7, wherein the viral infection is caused by SARs-CoV-2.

9. The use according to claim 7, wherein the compound is selected from 2-deoxy-2-iodo-D-glucose and pharmaceutically acceptable salts thereof.

10. The use according to claim 7, wherein the compound is selected from 2-deoxy-2-iodo-D-mannose and pharmaceutically acceptable salts thereof.

11. The use according to claim 7, wherein the viral infection is caused by Ebola virus.

12. The use according to claim 7, wherein the viral infection is caused by Lassa virus.

13. The use according to any one of claims 1-12, wherein the viral infection is caused by a virus characterized by glycosylation of envelope proteins on the infected cell.

14. The use according to any one of claims 1-12, wherein the patient has COVID-19.

15. The use according to any one of claims 1-12, wherein the patient is asymptomatic.

16. The use according to any one of claims 1-12, wherein the drug is administered by inhalation or blowing.

17. Compounds with structural formula II Ⅱ Use of its pharmaceutically acceptable salt or in the preparation of a pharmaceutical composition for treating viral infection caused by SARs-CoV-2, wherein: R 14 and R 16 It is COCH3; and R 15 R 17 R4 and R5 are hydrogen. The pharmaceutical composition comprises a pharmaceutically acceptable carrier and a compound of structural formula II or a pharmaceutically acceptable salt thereof.

18. Compounds with structural formula II Ⅱ Use of a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition for treating viral infections caused by HIV-1, SARs-CoV-2, Lassa virus, Zika virus, dengue virus, or Ebola virus, wherein: R 14 R 15 R 16 and R 17 It is hydrogen; and One of R4 and R5 is hydrogen, and the other of R4 and R5 is I. The pharmaceutical composition comprises a pharmaceutically acceptable carrier and a compound of structural formula II or a pharmaceutically acceptable salt thereof.

19. The use according to claim 18, wherein the compound is selected from 2-deoxy-2-iodo-D-glucose and pharmaceutically acceptable salts thereof.

20. The use according to claim 18, wherein the compound is selected from 2-deoxy-2-iodo-D-mannose and pharmaceutically acceptable salts thereof.

21. The use according to claim 18, wherein the viral infection is caused by Ebola virus.

22. The use according to claim 18, wherein the viral infection is caused by Lassa virus.

23. The use according to any one of claims 17-22, wherein the pharmaceutical composition is administered by inhalation or blowing.

24. Use of the compound in the manufacture of a medicament for the prevention or treatment of viral infection caused by SARS-CoV-2, said compound having structural formula II. Ⅱ Or its pharmaceutically acceptable salt, wherein: R 14 and R 16 It is COCH3; and R 15 R 17 R4 and R5 are hydrogen.

25. Use of the compound in the manufacture of a medicament for the prevention or treatment of viral infections caused by HIV-1, SARs-CoV-2, Lassa virus, Zika virus, dengue virus, or Ebola virus, said compound having structural formula II. Ⅱ Or its pharmaceutically acceptable salt, wherein: R 14 R 15 R 16 and R 17 It is hydrogen; and One of R4 and R5 is hydrogen, and the other of R4 and R5 is I.

26. The use according to claim 25, wherein the viral infection is caused by Ebola virus.

27. The use according to claim 25, wherein the viral infection is caused by Lassa virus.

28. Use of a compound in the manufacture of a medicament for the prevention or treatment of viral infection caused by SARs-CoV-2, wherein the compound is selected from methyl ((2R,3S,4R)-4-acetoxy-3,6-dihydroxytetrahydro-2H-pyran-2-yl)acetate and pharmaceutically acceptable salts thereof.

29. Use of a compound in the manufacture of a medicament for the prevention or treatment of viral infections caused by HIV-1, SARs-CoV-2, Lassa virus, Zika virus, dengue virus, or Ebola virus, wherein said compound is selected from 2-deoxy-2-iodo-D-glucose and 2-deoxy-2-iodo-D-mannose and pharmaceutically acceptable salts thereof.

30. The use according to claim 29, wherein the compound is selected from 2-deoxy-2-iodo-D-glucose and pharmaceutically acceptable salts thereof.

31. The use according to claim 29, wherein the compound is selected from 2-deoxy-2-iodo-D-mannose and pharmaceutically acceptable salts thereof.

32. The use according to claim 29, wherein the viral infection is caused by Ebola virus.

33. The use according to claim 29, wherein the viral infection is caused by Lassa virus.

34. The use according to any one of claims 24-33, wherein the drug is administered by inhalation or blowing.

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