Novel prodrugs derived from nicotinic acid and ribose.

Abstract

Novel prodrugs derived from nicotinic acid and pharmaceutical compositions thereof are disclosed that can be used to treat or prevent various medical disorders that can be characterized by mitochondrial dysfunction. The compounds and pharmaceutical compositions thereof can be used to treat or prevent metabolic disorders, cardiovascular disorders, cerebrovascular disorders, hepatic disorders, renal disorders, or muscular disorders.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 63 / 315,640, filed March 2, 2022, which is hereby incorporated by reference in its entirety.

[0002] Novel prodrugs derived from nicotinic acid and pharmaceutical compositions thereof are disclosed that can be used to treat or prevent various medical disorders that can be characterized by mitochondrial dysfunction. The compounds and pharmaceutical compositions thereof can be used to treat or prevent metabolic disorders, cardiovascular disorders, cerebrovascular disorders, hepatic disorders, renal disorders, or muscular disorders. [Background technology]

[0003] Mitochondrial dysfunction is a hallmark of chronic and acute inflammatory and metabolic pathologies, often associated with NAD depletion. + There are three synthetic pathways: the salvage pathway utilizes nicotinamide, the de novo synthesis utilizes tryptophan, and the price-handler pathway utilizes nicotinic acid. The price-handler pathway is particularly relevant in metabolically active organs, including the liver, kidney, brain, and skeletal muscle. In addition, nicotinic acid directly regulates key metabolic enzymes involved in lipid metabolism.

[0004] Nicotinic acid or niacin has been used to treat hypertriglyceridemia and, more recently, mitochondrial myopathy. These benefits are based on its unique mechanism of directly regulating several key metabolic enzymes and the broader benefit of enhancing NAD+ levels in key vital organs. However, nicotinic acid is associated with flushing, a dose-limiting adverse event, limiting its use. Flushing is mediated by nicotinic acid's interaction with the GPR109A receptor. Furthermore, nicotinic acid is cleared rapidly with poor penetration and / or retention in vital organs. This necessitates high doses to achieve efficacy, but increased doses of nicotinic acid are poorly tolerated by the majority of patients. Summary of the Invention [Problem to be solved by the invention]

[0005] There is a great unmet need for new approaches to maximize the pharmacological effects of nicotinic acid, such as increasing bioavailability and significantly enhancing intracellular nicotinic acid concentrations. Currently, this is not possible with nicotinic acid. Sustained levels of nicotinic acid in key vital organs, such as kidney, liver, and muscle, would provide greater efficacy in diseases associated with severe organ damage. [Means for solving the problem]

[0006] These and other needs are addressed herein in the present disclosure, which may uniquely improve mitochondrial and metabolic dysfunction in vital organs. In one aspect, a compound of structural formula (I): [ka] or a pharma- ceutically acceptable salt, hydrate or solvate thereof, wherein R1 is -H, R8C(O)-, [ka] or [ka] R2 is -H or R9C(O)-; R3 is -H or R 10 C(O)-; R4 is -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, R 11 C(O)- or [ka] R6 is -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; and R5, R7, R8, R9, R 10 and R 11 are independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl; with the proviso that at least one of R or R is [ka] The compounds of structural formula (I) are believed to be more effective in delivering and subsequently inhibiting NAD, with potentially greater efficacy and safety compared to nicotinic acid. + may provide a conversion to

[0007] Also provided are derivatives, including salts, esters, enol ethers, enol esters, solvates, hydrates, metabolites, and prodrugs, of the compounds described herein. Additionally, provided are pharmaceutical compositions comprising a compound provided herein and a pharma- ceutically acceptable vehicle.

[0008] In yet another aspect, a method for treating, preventing, or ameliorating the symptoms of a medical disorder, such as a metabolic disorder, a cardiovascular disorder, a cerebrovascular disorder, a hepatic disorder, a renal disorder, or a muscular disorder. [Brief description of the drawings]

[0009] [Figure 1] FIG. 1 illustrates the increase in NAD+ in Jurkat cells in RPMI medium supplemented with 30 μM of compounds 100, 101 and 102. [Diagram 2] FIG. 2 illustrates the increase in NAD+ in Huh7 cells supplemented with 125 μM of compounds 100, 101, 102 and nicotinic acid. [Diagram 3] Figure 3A illustrates the dose-dependent increase in NAD+ in Huh7 cells supplemented with various amounts of nicotinic acid. Figure 3B illustrates the dose-dependent increase in NAD+ in Huh7 cells supplemented with various amounts of nicotinamide. Figure 3C illustrates the dose-dependent increase in NAD+ in Huh7 cells supplemented with various amounts of compound 100. Figure 3D illustrates the dose-dependent increase in NAD+ in Huh7 cells supplemented with various amounts of compound 101. [Figure 4] Figure 4A shows the results of NAD cycling assay in HepG2 cells for 10 μM of compounds 100, 101, 103, 104 and nicotinic acid. Figure 4B shows the results of NAD cycling assay in HepG2 cells for 50 μM of compounds 100, 101, 103, 104 and nicotinic acid. Figure 4C shows the results of NAD cycling assay in HepG2 cells for 100 μM of compounds 100, 101, 103, 104 and nicotinic acid. Figure 4D shows the results of NAD cycling assay in HepG2 cells for 250 μM of compounds 100, 101, 103, 104 and nicotinic acid. [Diagram 5] FIG. 5 graphically illustrates the effect of 250 μM compounds 103 and 104 on NAD+ levels in primary human hepatocytes. [Figure 6]Figure 6A illustrates the in vitro cytotoxicity of compounds 103 and 104 at 10 μM in HepG2 cells. Figure 6B illustrates the in vitro cytotoxicity of compounds 103 and 104 at 100 μM in HepG2 cells. [Figure 7] FIG. 7 graphically illustrates the cytotoxicity of compounds 100, 101 and 102 at various concentrations on HepG72 cells. [Figure 8] Figure 8A illustrates the human plasma stability of compound 100. Figure 8B illustrates the human plasma stability of compound 101. Figure 8C illustrates the human plasma stability of compound 102. Figure 8D illustrates the human plasma stability of compound 103. Figure 8E illustrates the human plasma stability of nicotinic acid. [Figure 9] Figure 9A illustrates the human hepatocyte stability of compound 103. Figure 9B illustrates the human hepatocyte stability of compound 104. Figure 9C illustrates the human hepatocyte stability of compound 101. Figure 9D illustrates the human hepatocyte stability of testosterone. Figure 9E illustrates the human hepatocyte stability of warfarin. [Figure 10] Figure 10A graphically illustrates the pharmacokinetic results for the Group 2 dosage of Compound 100 (83 mg / kg). Figure 10B graphically illustrates the pharmacokinetic results for the Group 1 dosage of Compound 100 (415 mg / kg). [Figure 11] Figure 11A graphically illustrates the pharmacokinetic results for the Group 4 dose (40 mg / kg) of nicotinic acid. Figure 11B graphically illustrates the nicotinic acid pharmacokinetic results for the Group 3 dose (200 mg / kg). [Figure 12] Figure 12A illustrates the distribution of Group 1 dose of Compound 100 (415 mg / kg) in kidney and liver tissues after 24 hours. Figure 12B illustrates the distribution of Group 2 dose of Compound 100 (83 mg / kg) in kidney and liver tissues after 24 hours. Figure 12C illustrates the distribution of Group 3 dose of nicotinic acid (200 mg / kg) and Group 4 dose of nicotinic acid (40 mg / kg) in kidney and liver tissues after 24 hours. [Figure 13]FIG. 13 graphically illustrates plasma creatine levels in mice treated with control, cisplatin (25 mg / kg), Compound 100 (50 mg / kg) and cisplatin (25 mg / kg), Compound 100 (250 mg / kg) and cisplatin (25 mg / kg), and Compound 100 (500 mg / kg) and cisplatin (25 mg / kg). [Figure 14] FIG. 14 graphically illustrates blood urea nitrogen (BUN) in mice treated with control, cisplatin (25 mg / kg), Compound 100 (50 mg / kg) and cisplatin (25 mg / kg), Compound 100 (250 mg / kg) and cisplatin (25 mg / kg), and Compound 100 (500 mg / kg) and cisplatin (25 mg / kg). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] definition Unless otherwise defined, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the event that there are multiple definitions for a term in this specification, the definition in this section shall prevail unless otherwise stated. Unless otherwise defined, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the event that there are multiple definitions for a term in this specification, the definition in this section shall prevail unless otherwise stated. Unless otherwise defined, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the event that there are multiple definitions for a term in this specification, the definition in this section shall prevail unless otherwise stated.

[0011] As used herein, and unless otherwise specified, the terms "about" and "approximately" when used in connection with properties associated with a numerical value or range of values ​​indicate that the value or range of values ​​may have some degree of deviation that would be considered reasonable by one of ordinary skill in the art, while still describing the specific properties. Specifically, the terms "about" and "approximately" when used in this context indicate that the numerical value or range of values ​​may vary by 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% from the stated value or range of values. Also, the singular forms "a" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "the compound" includes a plurality of such compounds, and reference to "the assay" includes reference to one or more assays and equivalents thereof known to those of ordinary skill in the art.

[0012] A dash symbol ("-") other than between two letters or symbols is used to indicate the point at which a substituent is attached. For example, -C(O)NH2 is attached at the carbon atom. A dash symbol at the beginning or end of a chemical group is for convenience; a chemical group may be illustrated with or without one or more dash symbols without losing its ordinary meaning. A wavy line drawn on a line in a structure indicates the point at which a group is attached. Unless chemically or structurally necessary, no directionality is indicated or implied by the order in which chemical groups are written or named.

[0013] Prefix “C” u~v indicates that the group that follows has u through v carbon atoms. It should be understood that u through v carbons includes u+1 through v, u+2 through v, u+3+v, etc. carbons, u+1 through u+3 through v, u+1 through u+4 through v, u+2 through u+4 through v, etc., covering all possible permutations of u and v.

[0014] "Alkyl," alone or as part of another substituent, refers to a saturated or unsaturated, branched, straight-chain, or cyclic monovalent hydrocarbon group derived by removal of one hydrogen atom from a single carbon atom of a parent alkane. Typical alkyl groups include, but are not limited to, methyl; ethyl; propyls, such as propan-1-yl, propan-2-yl, and the like; butyls, such as butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, and the like. In some embodiments, an alkyl group contains 1 to 20 carbon atoms (C1-C 20 In other embodiments, the alkyl group contains 1 to 10 carbon atoms (C1 to C 10 In yet other embodiments, the alkyl group comprises 1 to 6 carbon atoms (C1-C6 alkyl).

[0015] "Alkenyl," alone or as part of another substituent, refers to an unsaturated branched, straight chain, or cyclic alkyl group having at least one carbon-carbon double bond derived by the removal of a hydrogen atom from a single carbon atom of a parent alkene. The group may be in either the cis or trans conformation about the double bond(s). Typical alkenyl groups include, but are not limited to, ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, and the like. In some embodiments, the alkenyl group contains 1 to 20 carbon atoms (C 20 In other embodiments, the alkenyl group contains 1 to 10 carbon atoms (C1-C 10In yet other embodiments, the alkenyl group contains 1 to 6 carbon atoms (C1-C6 alkenyl).

[0016] "Alkynyl," alone or as part of another substituent, refers to an unsaturated branched, straight chain, or cyclic alkyl group having at least one carbon-carbon triple bond derived by removal of one hydrogen atom from a single carbon atom of a parent alkyne. Typical alkynyl groups include, but are not limited to, ethynyl; propynyls, such as prop-1-yn-1-yl, prop-2-yn-1-yl, and the like; butynyls, such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, and the like. In some embodiments, an alkynyl group contains 1 to 20 carbon atoms (C1-C 20 In other embodiments, the alkynyl group contains 1 to 10 carbon atoms (C 10 In still other embodiments, the alkynyl group contains 1 to 6 carbon atoms (C1-C6 alkynyl).

[0017] "Aryl," alone or as part of another substituent, refers to a monovalent aromatic hydrocarbon radical derived by removing one hydrogen atom from a single carbon atom of a parent aromatic ring system, as defined herein. Typical aryl groups include, but are not limited to, radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, and the like. In some embodiments, an aryl group contains 6 to 20 carbon atoms (C6-C8). 20 In other embodiments, the aryl group contains 6 to 15 carbon atoms (C 15In yet other embodiments, the aryl group contains 6 to 10 carbon atoms (C 10 aryl).

[0018] "Arylalkyl," alone or as part of another substituent, refers to an alkyl group consisting of a carbon atom, typically a terminal or sp 3 It refers to a non-cyclic alkyl group in which one of the hydrogen atoms bonded to the carbon atom is replaced with an aryl group as defined herein. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethene-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl, and the like. In some embodiments, the arylalkyl group is (C6-C 30 ) arylalkyl, for example, the alkyl portion of this arylalkyl group is (C1-C 10 ) alkyl, and the aryl portion is (C6-C 20 In another embodiment, the arylalkyl group is (C6-C 20 ) arylalkyl, for example, the alkyl portion of the arylalkyl group is (C1-C8) alkyl and the aryl portion is (C6-C 12 In yet another embodiment, the arylalkyl group is (C6-C 15 ) arylalkyl, for example, the alkyl portion of the arylalkyl group is (C1-C5) alkyl and the aryl portion is (C6-C 10 ) aryl.

[0019] "Arylalkenyl," alone or as part of another substituent, refers to a non-cyclic alkenyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced with an aryl group, as defined herein. In some embodiments, an arylalkenyl group is a (C6-C 30 ) arylalkenyl, for example, the alkenyl portion of this arylalkenyl group is (C1-C 10 ) alkenyl, and the aryl portion is (C6-C 20In another embodiment, the arylalkenyl group is (C6-C 20 )arylalkenyl, for example, the alkenyl portion of the arylalkenyl group is (C1-C8)alkenyl and the aryl portion is (C6-C 12 In yet other embodiments, the arylalkenyl group is (C6-C 15 )arylalkenyl, for example, the alkenyl portion of the arylalkenyl group is (C1-C5)alkenyl and the aryl portion is (C6-C 10 ) aryl.

[0020] "Arylalkynyl," alone or as part of another substituent, refers to a non-cyclic alkynyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced with an aryl group, as defined herein. In some embodiments, an arylalkynyl group is a (C6-C 30 ) arylalkynyl, for example, the alkynyl portion of this arylalkynyl group is (C1-C 10 ) alkynyl, and the aryl portion is (C6-C 20 In another embodiment, the arylalkynyl group is (C6-C 20 )arylalkynyl, for example, the alkynyl portion of the arylalkenyl group is (C1-C8)alkynyl and the aryl portion is (C6-C 12 In yet other embodiments, the arylalkynyl group is (C6-C 15 )arylalkynyl, for example, the alkynyl portion of the arylalkynyl group is (C1-C5)alkynyl and the aryl portion is (C6-C 10 ) aryl.

[0021] "Cycloalkyl," alone or as part of another substituent, refers to a saturated cyclic monovalent hydrocarbon group derived by removal of one hydrogen atom from a single carbon atom of a parent cycloalkane. Typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, and the like. In some embodiments, cycloalkyl groups contain 3 to 20 carbon atoms (C1-C 15 In other embodiments, the cycloalkyl group contains 3 to 10 carbon atoms (C1 to C 10 In yet other embodiments, the cycloalkyl group contains 3 to 8 carbon atoms (C1-C8 cycloalkyl). The term "cyclic monovalent hydrocarbon group" also includes polycyclic hydrocarbon ring systems having a single radical and 3 to 12 carbon atoms. Exemplary polycyclic cycloalkyl rings include, for example, norbornyl, pinyl, and adamantyl.

[0022] "Cycloalkenyl," alone or as part of another substituent, refers to an unsaturated cyclic monovalent hydrocarbon group derived by removal of one hydrogen atom from a single carbon atom of a parent cycloalkene. Typical cycloalkenyl groups include, but are not limited to, cyclopropene, cyclobutene, cyclopentene, and the like. In some embodiments, cycloalkenyl groups contain 3 to 20 carbon atoms (C1-C 20 In other embodiments, the cycloalkenyl group contains 3 to 10 carbon atoms (C1-C 10 In yet other embodiments, the cycloalkenyl group contains 3 to 8 carbon atoms (C1-C8 cycloalkenyl). The term "cyclic monovalent hydrocarbon group" also includes single radicals and polycyclic hydrocarbon ring systems having 3 to 12 carbon atoms.

[0023] "Cycloheteroalkyl," alone or as part of another substituent, refers to a cycloalkyl group, as defined herein, in which one or more of the carbon atoms (and optionally any associated hydrogen atoms) are each, independently of the other, replaced by the same or different heteroatoms or heteroatom groups, as defined under "heteroalkyl" below. In some embodiments, a cycloheteroalkyl group contains from 3 to 20 carbon atoms and heteroatoms ( 1~20 In other embodiments, the cycloheteroalkyl group contains 3 to 10 carbon atoms and heteroatoms ( 1~10 In yet other embodiments, the cycloheteroalkyl group contains 3 to 8 carbon atoms and heteroatoms (cycloheteroalkyl). 1~8 The term "cyclic monovalent heteroalkyl group" also includes single radical and polycyclic heteroalkyl ring systems having 3 to 12 carbons and at least one heteroatom.

[0024] "Cycloheteroalkenyl," alone or as part of another substituent, refers to a cycloalkenyl group, as defined herein, in which one or more of the carbon atoms (and optionally any associated hydrogen atoms) are each, independently of the other, replaced by the same or different heteroatoms or heteroatom groups, as defined under "heteroalkenyl" below. In some embodiments, a cycloheteroalkenyl group contains from 3 to 20 carbon atoms and heteroatoms ( 1~20 In other embodiments, the cycloheteroalkenyl group contains 3 to 10 carbon atoms and heteroatoms ( 1~10) In yet other embodiments, the cycloheteroalkenyl group contains 3 to 8 carbon atoms and heteroatoms ( 1~8 The term "cyclic monovalent heteroalkenyl group" also includes monocyclic and polycyclic heteroalkenyl ring systems having 3 to 12 carbon atoms and at least one heteroatom.

[0025] "Compound" refers to a compound encompassed by the structural formulas disclosed herein, including any specific compound whose structure falls within the scope of these formulas disclosed herein. A compound may be identified by either its chemical structure and / or chemical name. The chemical structure is determinative of the identity of the compound. The compounds described herein may contain one or more chiral centers and / or double bonds, and therefore may exist as stereoisomers, such as double bond isomers (i.e., geometric isomers), enantiomers or diastereomers. Thus, the chemical structures depicted herein encompass the stereoisomerically pure (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) forms depicted in the structures. The chemical structures depicted herein also encompass the enantiomeric and stereoisomeric derivatives of the depicted compounds. Enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomers or stereoisomers using separation or chiral synthesis techniques well known to those skilled in the art. Compounds may also exist in several tautomeric forms, including the enol form, the keto form, and mixtures thereof. Thus, the chemical structures depicted herein encompass all possible tautomeric forms of the compounds depicted in the drawings. The compounds described also include isotopically labeled compounds, where one or more atoms have an atomic mass different from the atomic mass conventionally found in nature. Examples of isotopes that may be incorporated into compounds disclosed herein include, but are not limited to, 2 H, 3 H, 11 C. 13 C. 14 C. 15 N, 18 O. 17 O and the like. Compounds may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, compounds may be hydrated or solvated. Certain compounds may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated herein and are intended to be within the scope of this disclosure. Furthermore, when a substructure of a compound is shown in a diagram, it should be understood that a bracket indicates the point at which the substructure is attached to the remainder of the molecule.

[0026] "Halo," by itself or as part of another substituent, refers to the groups -F, -Cl, -Br, or -I.

[0027] "Heteroalkyl" refers to an alkyl group in which one or more of the carbon atoms (and optionally any associated hydrogen atoms) are each, independently of the other, replaced with the same or different heteroatoms or heteroatomic groups. Exemplary heteroatoms or heteroatomic groups that can replace carbon atoms include, but are not limited to, -O-, -S-, -N-, -Si-, -NH-, -S(O)-, -S(O)2-, -S(O)NH-, -S(O)2NH-, and the like, and combinations thereof. The heteroatoms or heteroatomic groups may be located at any interior position of the alkyl, alkenyl, or alkynyl group. Exemplary heteroatomic groups that can be included in these groups include, but are not limited to, -O-, -S-, -OO-, -SS-, -OS-, -NR 501 R 502 , =NN=, -N=N-, -N=N-NR 503 R 404 , -PR 505 -, -P(O)2-, -POR 506 -, -OP(O)2-, -SO-, -SO2-, -SnR 507 R 508 In the formula, R 501 , R 502 , R 503 , R 504 , R 505 , R 506 , R 507 and R 508 is independently hydrogen, alkyl, aryl, substituted aryl, heteroalkyl, heteroaryl, or substituted heteroaryl. In some embodiments, the heteroalkyl group contains 1 to 20 carbon atoms and heteroatoms ( 1~20 In other embodiments, the heteroalkyl group contains 1 to 10 carbon atoms and heteroatoms ( 1~10 In yet other embodiments, the heteroalkyl group contains 1 to 6 carbon atoms and heteroatoms (heteroalkyl). 1~6 Heteroalkyl).

[0028] "Heteroalkenyl" refers to an alkenyl group in which one or more of the carbon atoms (and optionally any associated hydrogen atoms) are each, independently of the other, replaced with the same or different heteroatoms or heteroatomic groups. Exemplary heteroatoms or heteroatomic groups that can replace the carbon atoms include, but are not limited to, -O-, -S-, -N-, -Si-, -NH-, -S(O)-, -S(O)2-, -S(O)NH-, -S(O)2NH-, and the like, and combinations thereof. The heteroatoms or heteroatomic groups may be located at any interior position of the alkyl, alkenyl, or alkynyl group. Exemplary heteroatomic groups that can be included in these groups include, but are not limited to, -O-, -S-, -OO-, -SS-, -OS-, -NR 501 R 502 , =NN=, -N=N-, -N=N-NR 503 R 404 , -PR 505 -, -P(O)2-, -POR 506 -, -OP(O)2-, -SO-, -SO2-, -SnR 507 R 508 In the formula, R 501 , R 502 , R 503 , R 504 , R 505 , R 506 , R 507 and R 508 is independently hydrogen, alkyl, aryl, substituted aryl, heteroalkyl, heteroaryl, or substituted heteroaryl. In some embodiments, heteroalkenyl groups contain 1 to 20 carbon atoms and heteroatoms (e.g., 1~20 In other embodiments, the heteroalkenyl group contains 1 to 10 carbon atoms and heteroatoms ( 1~10 In yet other embodiments, the heteroalkenyl group contains 1 to 6 carbon atoms and heteroatoms ( 1~6 heteroalkenyl).

[0029] "Heteroaryl," alone or as part of another substituent, refers to a monovalent heteroaromatic group derived by removing one hydrogen atom from a single atom of a parent heteroaromatic ring system, as defined herein. Typical heteroaryl groups include, but are not limited to, groups derived from acridine, β-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and the like. In some embodiments, heteroaryl groups contain from 5 to 20 ring atoms (5-20 membered heteroaryls). In other embodiments, heteroaryl groups contain from 5 to 10 ring atoms (5-10 membered heteroaryls). Exemplary heteroaryl groups include those derived from furan, thiophene, pyrrole, benzothiophene, benzofuran, benzimidazole, indole, pyridine, pyrazole, quinoline, imidazole, oxazole, isoxazole, and pyrazine.

[0030] "Heteroarylalkyl," alone or as part of another substituent, refers to a heteroaryl group consisting of a carbon atom, typically a terminal or sp 3 It refers to a non-cyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced by a heteroaryl group. In some embodiments, the heteroarylalkyl group is a 6-21 membered heteroarylalkyl, e.g., the alkyl portion of the heteroarylalkyl is a (C1-C6)alkyl and the heteroaryl portion is a 5-15 membered heteroaryl. In other embodiments, the heteroarylalkyl group is a 6-13 membered heteroarylalkyl, e.g., the alkyl portion is a (C1-C3)alkyl and the heteroaryl portion is a 5-10 membered heteroaryl.

[0031] "Heteroarylalkenyl," alone or as part of another substituent, refers to an acyclic alkenyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced with a heteroaryl group. In some embodiments, a heteroarylalkenyl group is a 6-21 membered heteroarylalkyl, e.g., the alkenyl moiety of the heteroarylalkenyl is a (C1-C6)alkenyl and the heteroaryl moiety is a 5-15 membered heteroaryl. In other embodiments, a heteroarylalkenyl is a 6-13 membered heteroarylalkenyl, e.g., the alkenyl moiety is a (C1-C3)alkyl and the heteroaryl moiety is a 5-10 membered heteroaryl.

[0032] "Heteroarylalkynyl," alone or as part of another substituent, refers to an acyclic alkenyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced with a heteroaryl group. In some embodiments, a heteroarylalkynyl group is a 6-21 membered heteroarylalkyl, e.g., the alkynyl moiety of the heteroarylalkynyl is a (C1-C6)alkynyl and the heteroaryl moiety is a 5-15 membered heteroaryl. In other embodiments, a heteroarylalkynyl is a 6-13 membered heteroarylalkynyl, e.g., the alkynyl moiety is a (C1-C3)alkyl and the heteroaryl moiety is a 5-10 membered heteroaryl.

[0033] "Hydrate" refers to the incorporation of water in a stoichiometric ratio into the crystal lattice of a compound described herein, resulting in the formation of an adduct. Methods for making hydrates include, but are not limited to, storage in an atmosphere containing water vapor, a dosage form containing water, or a routine pharmaceutical processing step, such as, for example, crystallization (i.e., from water or mixed aqueous solvents), lyophilization, wet granulation, aqueous film coating, or spray drying. Hydrates may also form under certain circumstances from crystalline solvates upon exposure to water vapor or upon suspension of anhydrous materials in water. Hydrates may also crystallize in more than one form, resulting in hydrate polymorphs. See, for example, (Guillory, K., Chapter 5, pp. 202-205 in Polymorphism in Pharmaceutical Solids, (Brittain, H. ed.), Marcel Dekker, Inc., New York, NY, 1999). The above-mentioned methods of preparing hydrates are well within the scope of the art, completely conventional, and do not require any experimentation beyond that typical in the art. Hydrates can be characterized and / or analyzed by methods well known to those skilled in the art, such as, for example, single crystal X-ray diffraction, powder X-ray diffraction, polarized light microscopy, thermal microscopy, thermogravimetry, differential thermal analysis, differential scanning calorimetry, TR spectroscopy, Raman spectroscopy, and NMR spectroscopy (Brittain, H., Chapter 6, pp.205-208 in Polymorphism in Pharmaceutical Solids, (Brittain, H. ed.), Marcel Dekker, Inc. New York, 1999). In addition, many commercial companies routinely provide services that include the preparation and / or characterization of hydrates, such as, for example, HOLODIAG, Pharmaparc II, Voie de l'Innovation, 27 100 Val de Reuil, France (http: / / www.holodiag.com).

[0034] "Parent Aromatic Ring System" refers to an unsaturated cyclic or polycyclic ring system having a conjugated p-electron system. Specifically included within the definition of "parent aromatic ring system" are fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, such as, for example, fluorene, indane, indene, phenalene, etc. Exemplary parent aromatic ring systems include, but are not limited to, aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, and the like.

[0035] "Parent Heteroaromatic Ring System" refers to a parent aromatic ring system in which one or more carbon atoms (and optionally any associated hydrogen atoms) are each independently replaced with the same or different heteroatoms. Typical heteroatoms replacing carbon atoms include, but are not limited to, N, P, O, S, Si, etc. Specifically included within the definition of "parent heteroaromatic ring system" are fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, such as, for example, benzodioxane, benzofuran, chromane, chromene, indole, indoline, xanthene, etc. Exemplary parent heteroaromatic ring systems include, but are not limited to, arsindole, carbazole, b-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and the like.

[0036] "Pharmaceutically acceptable salt" refers to a salt of a compound that possesses the desired pharmacological activity of the parent compound. Such salts include: (1) salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or salts formed with acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methyl ... or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or when an organic base, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc., is coordinated.

[0037] "Preventing" or "prevention" refers to reducing the risk of acquiring a disease or disorder (i.e., not developing at least one clinical symptom of the disease in a patient who may be exposed to or predisposed to the disease, but who has not yet observed or manifested symptoms of the disease). The application of a therapeutic agent to prevent or prevent a disease or disorder is known as "prophylaxis." In some embodiments, the compounds provided herein provide superior prevention due to their low long-term side effects over time.

[0038] "Prodrug," as used herein, refers to a derivative of a drug molecule that must be transformed within the body to release the active drug. Prodrugs are frequently, but not necessarily, pharmacologically inactive until converted to the parent drug.

[0039] "Promoiety," as used herein, refers to a form of protecting group that, when used to mask a functional group present in a drug molecule, converts the drug into a prodrug. Typically, a promoiety will be attached to the drug via one or more bonds that are cleaved in vivo by enzymatic or non-enzymatic means.

[0040] "Protective group" refers to a class of atoms that, when attached to a reactive functional group in a molecule, masks, reduces, or prevents the reactivity of the functional group during chemical synthesis. Examples of protecting groups are described in Green et al., "Protective Groups in Organic Chemistry", (Wiley, 2003). nd ed. 1991) and Harrison et al., "Compendium of Synthetic Organic Methods", Vols. 1-8 (John Wiley and Sons, 1971-1996). Representative amino-protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilyl-ethanesulfonyl ("SES"), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl ("FMOC"), nitroveratryloxycarbonyl ("NVOC"), and the like. Representative hydroxy protecting groups include, but are not limited to, those in which the hydroxy group is either acylated or alkylated, such as benzyl, and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers, and allyl ethers.

[0041] "Spirocycloheteroalkyl," alone or as part of another substituent, refers to a double-ring alkyl structure that shares one atom and contains at least one heteroatom in the ring independently selected from the group consisting of N, O, and S.

[0042] "Solvate" refers to the incorporation of a solvent into the crystal lattice of a compound described herein in a stoichiometric ratio, resulting in the formation of an adduct. Methods for making solvates include, but are not limited to, storage in an atmosphere containing the solvent, a dosage form containing the solvent, or a routine pharmaceutical processing step, such as, for example, crystallization (i.e., from a solvent or mixture of solvents), vapor diffusion, etc. Solvates may also form from other crystalline solvates or hydrates under certain circumstances upon exposure to a solvent or upon suspension of a material in a solvent. Solvates may also crystallize in more than one form, resulting in solvate polymorphs. See, for example, (Guillory, K., Chapter 5, pp. 202-205 in Polymorphism in Pharmaceutical Solids, (Brittain, H. ed.), Marcel Dekker, Inc., New York, NY, 1999). The above-mentioned methods of preparing solvates are well within the scope of those skilled in the art, are completely conventional, and do not require any experimentation beyond the typical experimentation in the art.Solvates can be characterized and / or analyzed by methods well known to those skilled in the art, such as, for example, single crystal X-ray diffraction, powder X-ray diffraction, polarized light microscopy, thermal microscopy, thermogravimetry, differential thermal analysis, differential scanning calorimetry, IR spectroscopy, Raman spectroscopy and NMR spectroscopy (Brittain, H., Chapter 6, pp.205-208 in Polymorphism in Pharmaceutical Solids, (Brittain, H. ed), Marcel Dekker, Inc. New York, 1999).In addition, many commercial companies routinely provide services that include the preparation and / or characterization of solvates, such as, for example, HOLODIAG, Pharmaparc II, Voie de l'Innovation, 27 100 Val de Reuil, France (http: / / www.hoiodiag.com).

[0043] "Substituted," when used to modify a specified group or radical, means that one or more hydrogen atoms of the specified group or radical are each replaced, independently of the other, with one or more substituents which may be the same or different. Substituents useful for replacing saturated carbon atoms in a specified group or radical include R a , halo, -O-, =O, -OR b , -SR b , -S-, =S, -NR c R c , =NR b , =N-OR b , trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO2, -N-OR b , -N-NR c R c , -NR b S(O)2R b , =N2, -N3, -S(O)2R b , -S(O)NR b R b , -S(O)2O-, -S(O)2OR b , -OS(O)2R b , -OS(O)2O-, -OS(O)2OR b , -OS(O)2NR c NR c , -P(O)(O - )2, -P(O)(OR b )(O - ), -P(O)(OR b )(OR b ), -C(O)R b , -C(O)NR b -OR b -C(S)R b , -C(NR b )R b , -C(O)O-, -C(O)OR b , -C(S)OR b , -C(O)NR c R c , -C(NR b )NR c R c , -OC(O)R b , -OC(S)Rb , -OC(O)O-, -OC(O)OR b , -OC(O)NR c R c , -OC(NCN)NR c R c -OC(S)OR b , -NR b C(O)R b , -NR b C(S)R b , -NR b C(O)O-, -NR b C(O)OR b , -NR b C(NCN)OR b , -NR b S(O)2NR c R c , -NR b C(S)OR b , -NR b C(O)NR c R c , -NR b C(S)NR c R c , -NR b C(S)NR b C(O)R a , -NR b S(O)2OR b , -NR b S(O)2R b , -NR b C(NCN)NR c R c , -NR b C(NR b )R b and -NR b C(NR b )NR c R c In the formula, each R a is independently aryl, substituted aryl, heteroalkyl, substituted heteroalkyl, heteroaryl, or substituted heteroaryl; each R b is independently hydrogen, alkyl, heteroalkyl, substituted heteroalkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, or substituted heteroarylalkyl; and each R c are independently bor alternatively, two R c together with the nitrogen atom to which they are attached form a 4-, 5-, 6- or 7-membered cycloheteroalkyl, substituted cycloheteroalkyl or cycloheteroalkyl fused to an aryl group, which optionally contain 1 to 4 of the same or different additional heteroatoms selected from the group consisting of O, N and S. Specific examples include -NR c R c is meant to include -NH, -NH-alkyl, N-pyrrolidinyl, and N-morpholinyl. In other embodiments, substituents useful for replacing saturated carbon atoms in the specified group or radical include R a , Halo, -OR b , -NR c R c , trihalomethyl, -CN, -NR b S(O)2R b , -C(O)R b , -C(O)NR b -OR b , -C(O)OR b , -C(O)NR c R c , -OC(O)R b , -OC(O)OR b , -OS(O)2NR c NR c , -OC(O)NR c R c , and -NR b C(O)OR b In the formula, each R a is independently alkyl, aryl, or heteroaryl; each R b are independently hydrogen, R a , heteroalkyl, arylalkyl, heteroarylalkyl; and each R c are independently b or alternatively, two R ctogether with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered cycloheteroalkyl ring. In still other embodiments, substituents useful for replacing saturated carbon atoms in the specified groups or radicals include R a , Halo, -OR b , -NR c R c , trihalomethyl, -CN, -C(O)R b , -C(O)OR b , -C(O)NR c R c , -OC(O)R b , -OC(O)NR c R c , and -NR b C(O)OR b In the formula, each R a is independently alkyl, aryl, or heteroaryl; each R b are independently hydrogen, R a , heteroalkyl, arylalkyl, heteroarylalkyl; and each R c are independently b or alternatively, two R c together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered cycloheteroalkyl ring.

[0044] Useful substituents for replacing unsaturated carbon atoms in the specified group or radical include -R a , halo, -O-, -OR b , -SR b , -S-, -NR c R c , trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO2, -N3, -S(O)2O-, -S(O)2OR b , -OS(O)2R b , -OS(O)2OR b , -OS(O)2O-, -P(O)(O - )2, -P(O)(OR b )(O - ), -P(O)(OR b )(ORb ), -C(O)R b , -C(S)R b , -C(NR b )R b , -C(O)O-, -C(O)OR b , -C(S)OR b , -C(O)NR c R c , -C(NR b )NR c R c , -OC(O)R b , -OC(S)R b , -OC(O)O-, -OC(O)OR b , -OC(S)OR b , -OC(O)NR c R c , -OS(O)2NR c NR c , -NR b C(O)R b , -NR b C(S)R b , -NR b C(O)O-, -NR b C(O)OR b , -NR b S(O)2OR a , -NR b S(O)2R a , -NR b C(S)OR b , -NR b C(O)NR c R c , -NR b C(NR b )R b , -NR b C(NR b )NR c R c and -C(NR b )NR b C(NR b )NR c R c In the formula, R a , R b and R cis as defined above. In other embodiments, substituents useful for replacing the unsaturated carbon atom in the specified group or radical include -R a , Halo, -OR b , -SR b , -NR c R c , trihalomethyl, -CN, -S(O)2OR b , -C(O)R b , -C(O)OR b , -C(O)NR c R c , -OC(O)R b , -OC(O)OR b , -OS(O)2NR c NR c , -NR b C(O)R b and -NR b C(O)OR b In the formula, R a , R b and R c is as defined above. In still other embodiments, substituents useful for replacing an unsaturated carbon atom in a specified group or radical include -R a , Halo, -OR b , -NR c R c , trihalomethyl, -S(O)2OR b , -C(O)R b , -C(O)OR b , -C(O)NR c R c , -OC(O)R b , -NR b C(O)R b and -NR b C(O)OR b In the formula, R a , R b and R c is as defined above.

[0045] Useful substituents for replacing nitrogen atoms in heteroalkyl and cycloheteroalkyl groups include, but are not limited to, -R a , -O-, -ORb 、 -SR b 、 -S-, -NR c R c 、 trihalomethyl, -CF3, -CN, -NO, -NO2, -S(O)2R b 、 -S(O)2O-, -S(O)2OR b 、 -OS(O)2R b 、 -OS(O)2O-, -OS(O)2OR b 、 -P(O)(O - )2, -P(O)(OR b )(O - )、 -P(O)(OR b )(OR b )、 -C(O)R b 、 -C(S)R b 、 -C(NR b )R b 、 -C(O)OR b 、 -C(S)OR b 、 -C(O)NR c R c 、 -C(NR b )NR c R c 、 -OC(O)R b 、 -OC(S)R b 、 -OC(O)OR b 、 -OC(S)OR b 、 -NR b C(O)R b 、 -NR b C(S)R b 、 -NR b C(O)OR b 、 -NR b C(S)OR b 、 -NR b C(O)NR c R c 、 -NR b C(NR b )R b 、 -NR b C(NR b )NR c R c 及び -C(NR b )NR b C(NR b )NR c R c が挙げられ、式中、R a 、Rb and R c is as defined above. In some embodiments, useful substituents for substituting the nitrogen atom in heteroalkyl and cycloheteroalkyl groups include R a , Halo, -OR b , -NR c R c , trihalomethyl, -CN, -S(O)2OR b , -OS(O)2R b , -C(O)R b , -C(NR b )R b , -C(O)OR b , -C(O)NR c R c , -OC(O)R b , -OC(O)OR b , -OS(O)2NR c NR c , -NR b C(O)R b and -NR b C(O)OR b In the formula, R a , R b and R c is as defined above. In yet another embodiment, useful substituents for substituting a nitrogen atom in heteroalkyl and cycloheteroalkyl groups include R a , Halo, -OR b , -NR c R c , trihalomethyl, -CN, -S(O)2OR b , -C(O)R b , -C(NR b )R b , -C(O)OR b , -C(O)NR c R c , -OC(O)R b , -NR b C(O)R b and -NR b C(O)OR b In the formula, R a , R b and R c is as defined above.

[0046] Substituents from the above list that are useful for replacing other specified groups or atoms will be apparent to those of skill in the art.

[0047] The substituents used to substitute the designated groups may typically be further substituted with one or more of the same or different groups selected from the various groups specified above.

[0048] "Subject", "individual", or "patient" are used interchangeably herein and refer to vertebrates, preferably mammals. Mammals include, but are not limited to, murines, rodents, primates, humans, farm animals, sport animals, and pets. In some embodiments, a subject, individual, or patient is a member of the Homo sapiens species. In other embodiments, a subject, individual, or patient includes any mammal except Homo sapiens.

[0049] "Treating" any disease or disorder, or its "treatment", in some embodiments, refers to improving the disease or disorder (i.e., arresting or reducing the onset of the disease or at least one of its clinical symptoms). Treatment may also be considered to include ameliorating, arresting, or preventing the onset of at least one of the disease or clinical symptoms by preemptive or prophylactic administration. In a further feature, when treatment is given, the likelihood of long-term side effects over many years is reduced. In other embodiments, "treating" or "treatment" refers to improving at least one physical parameter, which may be imperceptible to the patient. In still other embodiments, "treating" or "treatment" refers to inhibiting the disease or disorder in either or both physical (e.g., stabilization of discernible symptoms), physiological (e.g., stabilization of physical parameters) or both. In still other embodiments, "treating" or "treatment" refers to delaying the onset of the disease or disorder.

[0050] "Therapeutically effective amount" means the amount of a compound that, when administered to a patient for treating a disease, is sufficient to treat the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, absorption, distribution, metabolism, excretion, etc., of the patient to be treated.

[0051] "Vehicle" refers to a diluent, excipient, or carrier with which a compound is administered to a subject. In some embodiments, the vehicle is pharma- ceutically acceptable.

[0052] compound Provided herein is a compound of formula (I): [ka] or a pharma- ceutically acceptable salt, hydrate or solvate thereof (wherein R1 is -H, R8C(O)-, [ka] or [ka] R2 is -H or R9C(O)-; R3 is -H or R 10 C(O)-; R4 is -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, R 11 C(O)- or [ka] R6 is -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; and R5, R7, R8, R9, R 10 and R 11are independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl; with the proviso that at least one of R or R is [ka] (which shall be the same as above) is provided.

[0053] In some embodiments, R4 is -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, R 11 C(O)-, or [ka] In other embodiments, R4 is -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, R 11 C(O)- or [ka] In still other embodiments, R4 is alkyl, alkenyl, R 11 C(O)- or [ka] It is.

[0054] In some embodiments, R, R, R 10 and R 11 is independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl. In other embodiments, R and R 11 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, or heteroaryl; R and R 10 is independently alkyl, substituted alkyl, alkenyl, or substituted alkenyl. In yet other embodiments, R and R 11is alkyl, substituted alkyl, alkenyl, substituted alkenyl, or heteroaryl; R and R 10 are independently -CH, -C2H, -C3H, -CH(CH3), -CH2CH(CH3), -CH(C2H5)(CH2)2CH3, or -CH(NH2)CH(CH3). In still other embodiments, R8 and R 11 are independently -CH3, -C2H5, -C3H7, -CH(CH3)2, -CH2CH(CH3)2, -CH(C2H5)(CH2)2CH3, or -CH(NH2)CH(CH3)2 or heteroaryl; R9 and R 10 are independently -CH, -C2H, -C3H, -CH(CH3), -CH2CH(CH3), -CH(C2H5)(CH2)2CH3, or -CH(NH2)CH(CH3). In yet other embodiments, R and R 10 is independently -CH3, -C2H5, -C3H7, -CH(CH3)2, -CH2CH(CH3)2, -CH(C2H5)(CH2)2CH3, or -CH(NH2)CH(CH3)2.

[0055] In some embodiments, R1 is [ka] It is.

[0056] In some embodiments, R5 is alkyl, alkenyl, aryl, substituted aryl, arylalkyl, heteroaryl, or heteroarylalkyl. In other embodiments, R5 is alkyl, alkenyl, aryl, or substituted aryl. In yet other embodiments, R5 is aryl.

[0057] In some embodiments, R6 is -H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl. In other embodiments, R6 is -H, alkyl, substituted alkyl, arylalkyl, or heteroarylalkyl.

[0058] In some embodiments, R7 is alkyl, alkenyl, aryl, substituted aryl, arylalkyl, heteroaryl, or heteroarylalkyl. In other embodiments, R7 is alkyl, alkenyl, or arylalkyl.

[0059] In some embodiments, R5 is alkyl, alkenyl, aryl or substituted aryl, R6 is alkyl, substituted alkyl, arylalkyl or heteroarylalkyl, and R7 is alkyl, alkenyl or arylalkyl. In other embodiments, R5 is aryl or arylalkyl, R6 is alkyl, substituted alkyl, arylalkyl or heteroarylalkyl, and R7 is alkyl, alkenyl or arylalkyl.

[0060] In some embodiments, a compound of structural formula (II): [ka] In another embodiment, R, R 10 and R 11 is independently alkyl or substituted alkyl. In still other embodiments, R, R 10 and R 11 is independently -CH3, -C2H5, -C3H7, -CH(CH3)2, -CH2CH(CH3)2, -CH(C2H5)(CH2)2CH3, or -CH(NH2)CH(CH3)2.

[0061] In some embodiments, R2 is R9C(O)-; R3 is R 10 In another embodiment, R and R are -C(O)-, and R is -H. 10 is independently alkyl or substituted alkyl. In yet other embodiments, R and R 10 is independently -CH3, -C2H5, -C3H7, -CH(CH3)2, -CH2CH(CH3)2, -CH(C2H5)(CH2)2CH3, or -CH(NH2)CH(CH3)2.

[0062] In some embodiments, R2 is R9C(O)-; R3 is R 10 C(O)- and R4 is alkyl. In other embodiments, R9 and R 10 is independently alkyl or substituted alkyl. In yet other embodiments, R and R 10 is independently -CH3, -C2H5, -C3H7, -CH(CH3)2, -CH2CH(CH3)2, -CH(C2H5)(CH2)2CH3, or -CH(NH2)CH(CH3)2.

[0063] In some embodiments, R2 is R9C(O)-; R3 is R 10 C(O)-, and R4 is R 11 In another embodiment, R, R 10 and R 11 is independently alkyl or substituted alkyl. In still other embodiments, R, R 10 and R 11 is independently -CH3, -C2H5, -C3H7, -CH(CH3)2, -CH2CH(CH3)2, -CH(C2H5)(CH2)2CH3, or -CH(NH2)CH(CH3)2.

[0064] In some embodiments, R2 is -H and R3 is R 10 C(O)-, and R4 is R 11 In another embodiment, R 10 and R 11 is independently alkyl or substituted alkyl. In still other embodiments, R 10 and R 11 is independently -CH3, -C2H5, -C3H7, -CH(CH3)2, -CH2CH(CH3)2, -CH(C2H5)(CH2)2CH3, or -CH(NH2)CH(CH3)2.

[0065] In some embodiments, R2 is R9C(O)-; R3 is -H, and R4 is R 11In another embodiment, R and R 11 is independently alkyl or substituted alkyl. In still other embodiments, R and R 11 is independently -CH3, -C2H5, -C3H7, -CH(CH3)2, -CH2CH(CH3)2, -CH(C2H5)(CH2)2CH3, or -CH(NH2)CH(CH3)2.

[0066] In some embodiments, a compound of structural formula (III): [ka] In some embodiments, R, R and R 10 is independently alkyl or substituted alkyl. In other embodiments, R, R and R 10 is independently -CH3, -C2H5, -C3H7, -CH(CH3)2, -CH2CH(CH3)2, -CH(C2H5)(CH2)2CH3, or -CH(NH2)CH(CH3)2.

[0067] In some embodiments, R1 is R8C(O)-; R2 is R9C(O)-; and R3 is R 10 In another embodiment, R, R and R 10 is independently alkyl or substituted alkyl. In yet other embodiments, R, R and R 10 is independently -CH3, -C2H5, -C3H7, -CH(CH3)2, -CH2CH(CH3)2, -CH(C2H5)(CH2)2CH3, or -CH(NH2)CH(CH3)2.

[0068] In some embodiments, R1 is -H, R2 is R9C(O)-, and R3 is R 10 In another embodiment, R and R 10 is independently alkyl or substituted alkyl. In still other embodiments, R and R 10is independently -CH3, -C2H5, -C3H7, -CH(CH3)2, -CH2CH(CH3)2, -CH(C2H5)(CH2)2CH3, or -CH(NH2)CH(CH3)2.

[0069] In some embodiments, R1 is R8C(O)-; R2 is -H, and R3 is R 10 In another embodiment, R and R 10 is independently alkyl or substituted alkyl. In still other embodiments, R and R 10 is independently -CH3, -C2H5, -C3H7, -CH(CH3)2, -CH2CH(CH3)2, -CH(C2H5)(CH2)2CH3, or -CH(NH2)CH(CH3)2.

[0070] In some embodiments, R1 is RC(O)-; R2 is RC(O)-, and R3 is -H. In other embodiments, R8 and R9 are independently alkyl or substituted alkyl. In yet other embodiments, R8 and R9 are independently -CH3, -C2H5, -C3H7, -CH(CH3)2, -CH2CH(CH3)2, -CH(C2H5)(CH2)2CH3, or -CH(NH2)CH(CH3)2.

[0071] In some embodiments, the compound of formula (IV [ka] In another embodiment, R and R 10 is independently alkyl or substituted alkyl. In yet other embodiments, R and R 10 is independently -CH3, -C2H5, -C3H7, -CH(CH3)2, -CH2CH(CH3)2, -CH(C2H5)(CH2)2CH3, or -CH(NH2)CH(CH3)2.

[0072] In some embodiments, R2 is R9C(O)- and R3 is R 10 C(O)-, and R and R10 is independently alkyl or substituted alkyl. In other embodiments, R5 is aryl or arylalkyl, R6 is alkyl, substituted alkyl, arylalkyl or heteroarylalkyl, and R7 is alkyl, alkenyl or arylalkyl. In yet other embodiments, R9 and R 10 is independently -CH3, -C2H5, -C3H7, -CH(CH3)2, -CH2CH(CH3)2, -CH(C2H5)(CH2)2CH3, or -CH(NH2)CH(CH3)2. In still other embodiments, R5 is phenyl, napthyl, or benzyl, R6 is CH3, -C2H5, and R7 is -CH3, -C2H5, -C3H7, -CH(CH3)2, -CH2CH(CH3)2, -CH(C2H5)(CH2)2CH3, or cyclopropyl.

[0073] In some embodiments, R2 is -H and R3 is R 10 C(O)-, and R 10 is alkyl or substituted alkyl. In other embodiments, R5 is aryl or arylalkyl, R6 is alkyl, substituted alkyl, arylalkyl or heteroarylalkyl, and R7 is alkyl, alkenyl or arylalkyl. In yet other embodiments, R 10 is -CH3, -C2H5, -C3H7, -CH(CH3)2, -CH2CH(CH3)2, -CH(C2H5)(CH2)2CH3, or -CH(NH2)CH(CH3)2. In yet other embodiments, R5 is aryl or arylalkyl, R6 is alkyl, substituted alkyl, arylalkyl, or heteroarylalkyl, and R7 is alkyl, alkenyl, or arylalkyl. In yet other embodiments, R5 is phenyl, naphthyl, or benzyl, R6 is CH3, -C2H5, and R7 is -CH3, -C2H5, -C3H7, -CH(CH3)2, -CH2CH(CH3)2, -CH(C2H5)(CH2)2CH3, or cyclopropyl.

[0074] In some embodiments, R2 is RC(O)-, R3 is -H, and R9 is alkyl or substituted alkyl. In other embodiments, R5 is aryl or arylalkyl, R6 is alkyl, substituted alkyl, arylalkyl, or heteroarylalkyl, and R7 is alkyl, alkenyl, or arylalkyl. In yet other embodiments, R9 is -CH3, -C2H5, -C3H7, -CH(CH3)2, -CH2CH(CH3)2, -CH(C2H5)(CH2)2CH3, or -CH(NH2)CH(CH3)2. In still other embodiments, R5 is phenyl, naphthyl or benzyl, R6 is CH3, -C2H5, and R7 is -CH3, -C2H5, -C3H7, -CH(CH3)2, -CH2CH(CH3)2, -CH(C2HS)(CH2)2CH3 or cyclopropyl.

[0075] Exemplary compounds are provided in Table 1 below.

[0076] [Table 1]

[0077] The above compounds can be made by well known procedures, some of which are exemplified in the experimental section.

[0078] Compositions and Methods of Administration The compositions provided herein contain one or more therapeutically effective amounts of compounds provided herein that are useful in preventing, treating, or improving one or more symptoms of diseases or disorders described herein, and a vehicle.Vehicles suitable for administering the compounds provided herein include any carrier known to those skilled in the art to be suitable for the specific mode of administration.In addition, these compounds may be formulated as the only active ingredient in the composition, or may be combined with other active ingredients.

[0079] Compositions contain one or more compounds provided herein.Compounds are in some embodiments formulated into suitable preparations for oral administration, such as solution, suspension, tablet, dispersible tablet, pill, capsule, powder, sustained release formulation or elixir, or are formulated into sterile solution or suspension for parenteral administration, and for topical administration, transdermal administration, intrathecal administration, and oral inhalation by nebulizer, pressurized metered dose inhaler and dry powder inhaler.In some embodiments, the compounds described above are formulated into compositions using techniques and procedures well known in the art (see, for example, Ansel, Introduction to Pharmaceutical Dosage Forms, Seventh Edition (1999)).

[0080] In the composition, one or more compounds or derivatives thereof at effective concentrations are mixed with a suitable vehicle. The compounds may be derivatized as corresponding salts, esters, enol ethers or esters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, solvates, ion pairs, hydrates, or prodrugs prior to formulation, as described above. The concentration of the compound in the composition is effective to deliver an amount that, upon administration, treats, prevents, or improves one or more symptoms of the disease or disorder described herein. In some embodiments, the composition is formulated for single dosage administration. To formulate the composition, a weight fraction of the compound is dissolved, suspended, dispersed, or otherwise mixed in a selected vehicle at an effective concentration to alleviate, prevent, or improve one or more symptoms of the pathology being treated.

[0081] The active compound is contained in the medium in an amount sufficient to exert a therapeutically useful effect without undesirable side effects on the treated patient.The therapeutically effective concentration can be predicted experimentally by testing the compound in in vitro and in vivo systems well known to those skilled in the art, and then the dosage for humans can be extrapolated therefrom.The human dosage is then typically fine-tuned in clinical trials and titrated until a response is observed.

[0082] The concentration of the active compound in the composition will depend on the absorption, inactivation and excretion rates of the active compound, the physicochemical properties of the compound, the dosing schedule, and the amount administered and other factors known to those skilled in the art. For example, the amount delivered is sufficient to ameliorate one or more symptoms of a disease or disorder as described herein.

[0083] In instances where a compound exhibits poor solubility, methods of solubilizing the compound may be used, such as the use of liposomes, prodrugs, complexation / chelation, nanoparticles, or emulsions, or tertiary templating. Such methods are known to those skilled in the art and include, but are not limited to, the use of cosolvents such as dimethylsulfoxide (DMSO), the use of surfactants or surface modifiers such as TWEEN®, complexing agents such as cyclodextrins, or dissolution by enhancing ionization (i.e., dissolving in aqueous sodium bicarbonate). Derivatives of the compound, such as prodrugs of the compound, may also be used in formulating effective compositions.

[0084] The resulting mixture upon mixing or adding one or more compounds may be a solution, suspension, emulsion, etc. The form of the resulting mixture depends on several factors, including the intended mode of administration and the solubility of the compound in the selected vehicle. The effective concentration is sufficient to ameliorate the symptoms of the disease, disorder, or condition being treated, and can be empirically determined.

[0085] The compositions are provided for administration to humans and animals in dosage forms appropriate for the indication, such as dry powder inhalers (DPIs), pressurized metered dose inhalers (pMDIs), nebulizers, tablets, capsules, pills, sublingual tapes / bioerodible strips, tablets or capsules, powders, granules, lozenges, lotions, salves, suppositories, fast melts, transdermal patches or other transdermal application devices / preparations, sterile parenteral solutions or suspensions, and oral solutions or suspensions, and oil-water emulsions, containing a suitable amount of the compound or its derivatives. The therapeutically active compounds and their derivatives are in some embodiments formulated and administered in unit dosage forms or multiple dosage forms. Unit dosage forms, as used herein, refer to physically discrete units suitable for human and animal subjects, packaged individually as known in the art. Each unit dosage contains a predetermined quantity of the therapeutically active compound sufficient to produce the desired therapeutic effect, in association with the required vehicle. Examples of unit dosage forms include ampoules and syringes, and individually packaged tablets or capsules. A unit dose form may be administered in a fraction or multiple thereof. A multiple dose form is a plurality of identical unit dosage forms packaged in a single container to be administered in separate unit dose forms. Examples of multiple dose forms include vials of tablets or capsules, bottles, or bottles of pints or gallons. Thus, a multiple dose form is a plurality of unit doses without separation of packaging.

[0086] Liquid compositions can be prepared, for example, by dissolving, dispersing, or otherwise mixing the active compound as defined above and optional auxiliary agents in a vehicle such as, for example, water, saline, aqueous dextrose, glycerol, glycols, ethanol, etc., thereby forming a solution or suspension, a colloidal dispersion, an emulsion, or a liposomal preparation. If necessary, the composition to be administered can also contain small amounts of non-toxic auxiliary substances such as wetting agents, emulsifiers, solubilizers, pH buffers, for example, acetates, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine, sodium acetate, triethanolamine oleate, and other such agents.

[0087] Actual methods for preparing such dosage forms are known, or will be apparent, to those skilled in the art; see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15th Edition, 1975, or subsequent editions.

[0088] Dosage forms or compositions may be prepared containing active ingredient in the range of 0.005%-100%, with the remainder being comprised of vehicles or carriers. Methods for preparing such compositions are known to those skilled in the art. Contemplated compositions may contain 0.001%-100% active ingredient, 0.1-95% in one embodiment, and 0.4-10% in another embodiment.

[0089] In certain embodiments, the composition is a lactose-free composition containing excipients well known in the art, for example, those listed in the United States Pharmacopoeia (USP) 25-NF20 (2002).In general, lactose-free compositions contain active ingredients, binders / fillers, and lubricants in compatible amounts.A specific lactose-free dosage form contains active ingredients, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.

[0090] In addition, anhydrous compositions and dosage forms containing active ingredients are provided because water can facilitate the decomposition of some compounds.Adding water (e.g., 5%) is widely accepted as a means of simulating long-term storage, for example, to determine characteristics such as shelf life or stability of a formulation over time.See, for example, Jens T. Carstensen, Drug Stability: Principles and Practice, 2d.Ed., Marcel Dekker, NY, NY, 1995, pp.379-80.In effect, water and heat accelerate the decomposition of some compounds.Therefore, the effect of water on formulations can be very important, since moisture and / or humidity are commonly encountered during the manufacture, handling, packaging, storage, shipping, and use of formulations.

[0091] Anhydrous compositions and dosage forms provided herein can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.

[0092] Anhydrous compositions must be prepared and stored in such a way that their anhydrous nature is maintained.Thus, anhydrous compositions are generally packaged using materials known to prevent exposure to water so that they can be included in suitable formulary kits.Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packaging.

[0093] Oral dosage forms are either solid, gel or liquid. Solid dosage forms are tablets, capsules, granules, and bulk powders. Types of oral tablets include compressed, chewable lozenges and tablets that may be enteric coated, sugar coated or film coated. Capsules may be hard or soft gelatin capsules, while granules and powders may be provided in non-effervescent or effervescent form, including combinations of other ingredients known to those skilled in the art.

[0094] In certain embodiments, the formulation is a solid dosage form, such as a capsule or tablet. Tablets, pills, capsules, lozenges, etc. may contain one or more of the following ingredients, or compounds of similar nature: binders; lubricants; diluents; flow agents; disintegrants; colorants; sweeteners; flavoring agents; wetting agents; enteric coatings; film coatings, and release modifiers. Examples of binders include microcrystalline cellulose, methylparaben, polyalkylene oxides, tragacanth, glucose solution, acacia mucilage, gelatin solution, molasses, polyvinylpyrrolidine, povidone, crospovidones, sucrose, and starch and starch derivatives. Lubricants include talc, starch, magnesium / calcium stearate, lycopodium, and stearic acid. Diluents include, for example, lactose, sucrose, trehalose, lysine, leucine, lecithin, starch, kaolin, salt, mannitol, and dicalcium phosphate. Flow agents include, but are not limited to, colloidal silicon dioxide. Disintegrants include, but are not limited to, croscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar and carboxymethylcellulose. Coloring agents include, for example, any of the approved water-soluble FD&C dyes, mixtures thereof; and water-insoluble FD&C dyes suspended on alumina hydrate and high-performance colorants or anti-counterfeit color / opalescence additives known to those skilled in the art. Sweetening agents include sucrose, lactose, mannitol and artificial sweeteners such as saccharin and a number of spray-dried flavors. Flavoring agents include natural flavors extracted from plants such as fruit and synthetic blends of compounds that produce a pleasant sensation or mask unpleasant tastes, such as, but are not limited to, peppermint and methyl salicylate. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether.Enteric coatings include fatty acids, fats, waxes, shellac, ammoniated shellac and cellulose acetate phthalates.Film coatings include hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellulose acetate phthalate. Release modifying agents include polymers and cellulose esters such as the Eudragit® series.

[0095] The compound, or a derivative thereof, can be provided in a composition that protects it from the acidic environment of the stomach. For example, the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine. The composition may also be formulated in combination with an antacid or other such ingredient.

[0096] When the dosage unit form is a capsule, it may contain liquid carriers such as fatty oils in addition to the above-mentioned materials.In addition, the dosage unit form may contain various other materials that improve the physical form of the dosage unit, such as sugar and other enteric coatings.The compound may also be administered as a component of elixirs, suspensions, syrups, wafers, sprinkles, chewing gums, etc.Syrups may contain sucrose as a sweetener and certain preservatives, dyes and colorings and flavors in addition to the active compound.

[0097] The active material can also be mixed with other active materials that do not impair the desired action, such as antacids, H2 blockers, and diuretics, or with materials that supplement the desired action. The active ingredient is a compound or derivative thereof as described herein. High concentrations, up to about 98% by weight of the active ingredient, can be included.

[0098] In all embodiments, tablet and capsule formulations may be coated as known to those skilled in the art to improve or sustain dissolution of the active ingredient. Thus, for example, such formulations may be coated with conventional enterically digestible coatings such as phenylsalicylate, waxes and cellulose acetate phthalate.

[0099] Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules. Aqueous solutions include, for example, elixirs and syrups. Emulsions are either oil-in-water or water-in-oil.

[0100] Elixirs are clear, sweetened, hydroalcoholic preparations. Vehicles used in elixirs include solvents. Syrups are concentrated aqueous solutions of a sugar, such as sucrose, and may contain preservatives. Emulsions are two-phase systems in which one liquid is dispersed throughout another in the form of small globules. Carriers used in emulsions are non-aqueous liquids, emulsifying agents, and preservatives. Suspensions use suspending agents and preservatives. Acceptable substances used in non-effervescent granules, to be reconstituted into a liquid oral dosage form, include diluents, sweeteners, and wetting agents. Acceptable substances used in effervescent granules, to be reconstituted into a liquid oral dosage form, include organic acids and a source of carbon dioxide. Coloring and flavoring agents are used in any of the above dosage forms.

[0101] Solvents include glycerin, sorbitol, ethyl alcohol and syrup. Examples of preservatives include glycerin, methyl and propyl parabens, benzoic acid, sodium benzoate and alcohol. Examples of non-aqueous liquids utilized in emulsions include mineral oil and cottonseed oil. Examples of emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate. Suspending agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum and acacia. Sweetening agents include sucrose, syrup, glycerin and artificial sweeteners such as saccharin. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether. Organic acids include citric acid and tartaric acid. Carbon dioxide sources include sodium bicarbonate and sodium carbonate. Coloring agents include any of the approved certified water-soluble FD&C dyes and mixtures thereof.Flavoring agents include natural flavors extracted from fruits and other plants, and synthetic blends of compounds which produce a pleasant taste sensation.

[0102] For solid dosage forms, the solution or suspension, for example in propylene carbonate, vegetable oils, or triglycerides, is encapsulated in some embodiments in a gelatin capsule. Such solutions, and their preparation and encapsulation, are disclosed in U.S. Patent Nos. 4,328,245; 4,409,239; and 4,410,545. For liquid dosage forms, the solution, for example in, for example, a polyethylene glycol, may be diluted with a sufficient quantity of a liquid medium, for example water, to be easily measured for administration.

[0103] Alternatively, liquid or semisolid oral formulations may be prepared by dissolving or dispersing the active compound or salt in vegetable oils, glycols, triglycerides, propylene glycol esters (e.g., propylene carbonate) and other such carriers and encapsulating the solution or suspension in a hard or soft gelatin capsule shell. Other useful formulations include those shown in U.S. Patents RE28,819 and 4,358,603. Briefly, such formulations include, but are not limited to, those containing a compound provided herein and a dialkylated mono- or polyalkylene glycol, including, but not limited to, 1,2-dimethoxyethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether (where 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol), and one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, thiodipropionic acid and its esters, and dithiocarbamates.

[0104] Other formulations include aqueous alcohol solutions, including, but not limited to, acetals. The alcohols used in these formulations are any water-miscible solvents with one or more hydroxyl groups, including, but not limited to, propylene glycol and ethanol. Acetals include, but are not limited to, di(lower alkyl) acetals of lower alkyl aldehydes, such as acetaldehyde diethyl acetal.

[0105] Also contemplated herein is parenteral administration, characterized in some embodiments by injection, either subcutaneously, intramuscularly, intrathecally or intravenously. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for dissolving or suspending in liquid before injection, or as emulsions. Injectables, solutions and emulsions also contain one or more excipients. Suitable excipients are, for example, water, saline, dextrose, glycerol or ethanol. In addition, if necessary, the composition to be administered can also contain small amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents, for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, and cyclodextrins.

[0106] Implantation of a slow-release or sustained-release system (see, e.g., U.S. Pat. No. 3,710,795) which maintains a constant level of dosage is also contemplated herein. Briefly, an outer polymeric membrane insoluble in body fluids, such as polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, silicone rubber, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomeric polyethylene terephthalate, butyl rubber epichlorohydrin rubber, ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol terpolymers, and ethylene / vinyloxyethanol. The compounds provided herein are dispersed in an inner solid matrix surrounded by a terpenoid copolymer, such as hydrophilic polymers, such as polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubber, polydimethylsiloxanes, silicone carbonate copolymers, hydrogels of acrylic and methacrylic acid esters, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate. The compound diffuses through the outer polymeric membrane in a release rate-limiting step. The percentage of active compound contained in such parenteral compositions depends largely on the specific nature thereof, as well as the activity of the compound and the needs of the subject.

[0107] Parenteral administration of the composition includes intravenous, subcutaneous, intrathecal and intramuscular administration.Preparations for parenteral administration include sterile dry soluble products, such as freeze-dried powders, which can be combined with solvent immediately before use, including sterile solutions ready for injection, tablets for subcutaneous injection, sterile suspensions ready for injection, sterile dry insoluble products, and sterile emulsions, which can be combined with vehicle immediately before use.Solutions can be either aqueous or non-aqueous.

[0108] If administered intravenously, suitable carriers include saline or phosphate buffered saline (PBS), as well as solutions containing viscosity enhancing and solubilizing agents, such as glucose, polyethylene glycol, and polypropylene glycol, and mixtures thereof.

[0109] Vehicles used for parenteral preparations include aqueous vehicles, non-aqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other substances.

[0110] Examples of aqueous vehicles include sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringer's injection. Non-aqueous parenteral vehicles include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil, and peanut oil. Parenteral preparations packaged in multi-dose containers should be supplemented with bacteriostatic or fungistatic concentrations of antimicrobial agents, including phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, p-hydroxybenzoic acid methyl and propyl esters, thimerosal, benzalkonium chloride, and benzethonium chloride. Isotonic agents include sodium chloride and dextrose. Buffers include phosphates and citrates. Antioxidants include sodium bisulfate. Local anesthetics include procaine hydrochloride. Suspending and dispersing agents include sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Emulsifying agents include polysorbate 80 (Tween® 80). Sequestering or chelating agents for metal ions include EDTA. Carriers also include ethyl alcohol, polyethylene glycol, and propylene glycol for water-miscible vehicles; and sodium hydroxide, hydrochloric acid, citric acid, or lactic acid for pH adjustment.

[0111] The concentration of the compound is adjusted so that an effective amount to produce the desired pharmacological effect is provided by injection. The exact dose depends on the age, weight, body surface area and condition of the patient or animal as is known in the art.

[0112] Unit dose parenteral preparations are packaged in ampoules, vials or syringes with needles. All preparations for parenteral administration must be sterile, as known and practiced in the art.

[0113] Illustratively, intravenous or intraarterial infusion of a sterile aqueous solution containing an active compound is an effective mode of administration. Another embodiment is a sterile aqueous or oily solution or suspension containing the active material injected as necessary to produce the desired pharmacological effect.

[0114] Injectables are designed for local and systemic administration. In some embodiments, a therapeutically effective dosage is formulated to contain a concentration of at least about 0.01% w / w and up to about 90% w / w or more of the active compound in the treated tissue or tissues, and in certain embodiments, greater than 0.1% w / w.

[0115] The compound may be suspended in micronized or other suitable form, or may be derivatized to produce a more soluble active product or to produce a prodrug. The form of the resulting mixture depends on a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient to ameliorate the symptoms of the pathology and may be empirically determined.

[0116] The active ingredients provided herein can be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474; 5,92 Examples of suitable compositions include those described in the following patents: 2,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461; 6,419,961; 6,589,548; 6,613,358; 6,699,500 and 6,740,634. Such dosage forms can be used to provide sustained or controlled release of one or more active ingredients, such as by using, for example, hydroxypropylmethylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multi-layer coatings, microparticles, liposomes, microspheres, or combinations thereof to provide a desired release profile in various ratios. Suitable controlled release formulations known to those skilled in the art can be readily selected for use with the active ingredients provided herein, including those described herein.

[0117] All controlled release products have a common goal of improving drug therapy compared to that achieved by their non-controlled counterparts. Ideally, the use of an optimally designed controlled release preparation in medical treatment is characterized by the use of a minimum amount of drug substance for a minimum amount of time to cure or manage a pathology. Advantages of controlled release formulations include extended drug activity, reduced dosing frequency, and increased patient compliance. In addition, the use of controlled release formulations can affect the time of onset of action or other characteristics, such as blood levels of the drug, which can in turn affect the occurrence of side effects (e.g., adverse effects).

[0118] Many controlled release formulations are designed to initially release an amount of drug (active ingredient) that immediately produces the desired therapeutic effect, and then slowly and continuously release another amount of drug that maintains that level of therapeutic or prophylactic effect over an extended period of time. To maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug metabolized and excreted from the body. Controlled release of the active ingredient can be stimulated by various conditions, including but not limited to pH, temperature, enzymes, water, or other physiological conditions or compounds.

[0119] In certain embodiments, the agent may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of administration. In some embodiments, a pump may be used (see Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989)). In other embodiments, polymeric materials may be used. In other embodiments, the controlled release system may be placed in close proximity to the therapeutic target, i.e., so that only a fraction of the systemic dose is required (see, e.g., Goodson, Medical Applications of Controlled Release, vol. 2, pp. 115-138 (1984)). In some embodiments, the controlled release device is introduced in close proximity to a site of inappropriate immune activation or a tumor in a subject. Other controlled release systems are discussed in the review by Langer (Science 249:1527-1533 (1990)).The active ingredient is coated with an outer polymeric membrane that is insoluble in body fluids, such as polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubbers, chlorinated polyethylene, polyvinyl chloride, vinyl chloride copolymers with vinyl acetate, with vinylidene chloride, with ethylene and with propylene, ionomeric polyethylene terephthalate, butyl rubber epichlorohydrin rubber, ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol terpolymers, and ethylene / vinyl oxysilanes. The active ingredient may be dispersed in an inner solid matrix surrounded by a polyethanol copolymer, for example, hydrophilic polymers such as polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubber, polydimethylsiloxanes, silicone carbonate copolymers, hydrogels of acrylic and methacrylic acid esters, collagen, cross-linked polyvinyl alcohol and cross-linked partially hydrolyzed polyvinyl acetate. The active ingredient then diffuses through the outer polymeric membrane in a release rate-limiting step. The percentage of active ingredient contained in such parenteral compositions is highly dependent on their specific nature and the needs of the subject.

[0120] Also advantageous herein are lyophilized powders that can be reconstituted for administration as solutions, emulsions and other mixtures. These powders may also be reconstituted and formulated as solids or gels.

[0121] The sterile lyophilized powder is prepared by dissolving a compound provided herein, or a derivative thereof, in a suitable solvent. The solvent may contain excipients that improve the stability or other pharmacological components of the powder or a solution prepared from the powder after reconstitution. Excipients that may be used include, but are not limited to, antioxidants, buffers, and bulking agents. In some embodiments, the excipients are selected from dextrose, sorbitol, fructose, corn syrup, xylitol, glycerin, glucose, sucrose, and other suitable agents. The solvent may contain a buffer such as citrate, sodium, or potassium phosphate at approximately neutral pH, or other such buffers known to those of skill in the art. Subsequent sterile filtration of the solution followed by lyophilization under standard conditions known to those of skill in the art provides the desired formulation. In some embodiments, the resulting solution will be apportioned into vials for lyophilization. Each vial will contain a single or multiple doses of the compound. The lyophilized powder can be stored under appropriate conditions, such as at about 4°C to room temperature.

[0122] This lyophilized powder is reconstituted with water for injection to provide a formulation for use in parenteral administration. For reconstitution, the lyophilized powder is added to sterile water or other suitable carrier. The exact amount depends on the compound selected. Such amounts can be determined empirically.

[0123] Topical mixtures are prepared as described for local and systemic administration. The resulting mixture may be a solution, suspension, emulsion, etc., and is formulated as a cream, gel, ointment, emulsion, solution, elixir, lotion, suspension, tincture, paste, foam, aerosol, douche, spray, suppository, bandage, skin patch, or any other formulation suitable for topical administration.

[0124] The compound or its derivatives may be formulated as an aerosol for topical application, such as by inhalation (see, for example, U.S. Pat. Nos. 4,044,126, 4,414,209, and 4,364,923, which describe aerosols for delivery of steroids useful for treating inflammatory diseases, particularly asthma). These formulations for administration to the respiratory tract may be in the form of an aerosol or solution for nebulizers, or as ultrafine particles for insufflation, alone or in combination with an inert carrier such as lactose. In such cases, the particles of the formulation have a geometric mass median diameter of less than 5 microns in some embodiments, and less than 10 microns in other embodiments.

[0125] Oral inhalation formulations of the compound or derivative suitable for inhalation include metered dose inhalers, dry powder inhalers and liquid formulations for administration from a nebulizer or metered dose liquid dispensing system. For both metered dose inhalers and dry powder inhalers, a crystalline form of the compound or derivative is the preferred physical form of the drug to provide longer term product stability.

[0126] In addition to micronization methods known to those skilled in the art, supercritical fluid processing can be used to generate crystalline particles of the compound or derivative, which offers the distinct advantage of producing respirable particles of the desired size in a single step, such particles for inhalation delivery (e.g., WO 2005 / 025506). A controlled particle size for the crystallites can be selected to ensure that the majority of the compound or derivative is deposited in the lungs. In some embodiments, such particles have a mass median aerodynamic diameter of about 0.1 to about 10 microns, in other embodiments about 1 to about 5 microns, and yet other embodiments, about 1.2 to about 3 microns.

[0127] The inert and non-flammable HFA propellants are selected from HFA 134a (1,1,1,2-tetrafluoroethane) and HFA 227e (1,1,1,2,3,3,3-heptafluoropropane), either provided alone or in a ratio that is compatible with the density of the crystalline particles of the compound or derivative. The ratio is also selected to ensure that the product suspension avoids deleterious settling or creaming (which can precipitate irreversible clumps) and instead promotes a loose flocculating system that disperses easily upon shaking. A loose flocculating system is deemed sufficient to provide optimal stability for pMDI canisters. As a result of the formulation properties, the formulation contained no ethanol and no surfactants / stabilizers.

[0128] The compounds may be formulated for local or topical application, such as in the eye, in the form of gels, creams, and lotions, for topical application to the skin and mucous membranes, and for application to the eye, or for intracisternal or intrathecal application. Topical administration is contemplated for transdermal delivery, and also for administration to the eye or mucous membranes, or for inhalation therapy. Nasal solutions of the active compounds, alone or in combination with other excipients, can also be administered.

[0129] For nasal administration, the preparation may contain the esterified phosphonate compound dissolved or suspended in a liquid carrier, particularly an aqueous carrier, for aerosol application. The carrier may contain solubilizing or suspending agents, such as propylene glycol, surfactants, absorption enhancers, such as lecithin or cyclodextrin, or preservatives.

[0130] Solutions, particularly those intended for ophthalmic use, may be formulated as 0.01% to 10% isotonic solutions, pH about 5 to 7.4, containing appropriate salts.

[0131] Other routes of administration, such as transdermal patches, including iontophoretic and electrophoretic devices, and rectal administration are also contemplated herein.

[0132] Transdermal patches, including iontophoretic and electrophoretic devices, are well known to those skilled in the art. For example, such patches are disclosed in U.S. Patent Nos. 6,267,983, 6,261,595, 6,256,533, 6,167,301, 6,024,975, 6,010715, 5,985,317, 5,983,134, 5,948,433 and 5,860,957.

[0133] For example, dosage forms for rectal administration are rectal suppositories, capsules and tablets for systemic action. Rectal suppositories are used herein to mean solid bodies for insertion into the rectum that melt or soften at body temperature to release one or more pharmacologically or therapeutically active ingredients. The substances utilized in rectal suppositories are bases or vehicles and agents that increase the melting temperature. Examples of bases include cocoa butter (theobroma oil), glycerin-gelatin, carbowax (polyoxyethylene glycol) and appropriate mixtures of mono-, di- and triglycerides of fatty acids. Combinations of various bases may be used. Agents that increase the melting temperature of the suppository include spermaceti and wax. Rectal suppositories may be prepared either by compression or by molding. The weight of a rectal suppository is, in one embodiment, about 2 to 3 g. Tablets and capsules for rectal administration are manufactured using the same substances and by the same methods as formulations for oral administration.

[0134] The compounds provided herein, or derivatives thereof, may also be formulated to target to a particular tissue, receptor, or other area of ​​the subject's body to be treated. Many such targeting methods are known to those skilled in the art. All such targeting methods are contemplated for use in the compositions herein. Non-limiting examples of targeting methods are described, for example, in U.S. Pat. Nos. 6,316,652, 6,274,552, 6,271,359, 6,253,872, 6,139,865, 6,131,570, 6,120,751, 6,071,495, 6,060, 6,121, 6,122, 6,123, 6,124, 6,125, 6,136, 6,137, 6,138, 6,139 ... See US Pat. Nos. 5,985,307, 5,972,366, 5,900,252, 5,840,674, 5,759,542 and 5,709,874.

[0135] In some embodiments, liposome suspensions, including tissue-targeted liposomes, such as tumor-targeted liposomes, may also be suitable as carriers. They may be prepared by methods known to those skilled in the art. For example, liposome formulations may be prepared as described in U.S. Pat. No. 4,522,811. Briefly, liposomes, such as multilamellar vesicles (MLVs), may be formed by thoroughly drying phosphatidylcholine and phosphatidylserine (7:3 molar ratio) in a flask. A solution of a compound provided herein in phosphate buffered saline (PBS) without divalent cations is added, and the flask is shaken until the lipid film is dispersed. The resulting vesicles are washed to remove unencapsulated compound, pelleted by centrifugation, and then resuspended in PBS.

[0136] The compound or derivative may be packaged as an article of manufacture comprising packaging material and, within the packaging material, a compound provided herein or a derivative thereof that is effective for the treatment, prevention, or amelioration of one or more symptoms of the disease or disorder described above, and labeling indicating that the compound or composition or derivative thereof is used for the treatment, prevention, or amelioration of one or more symptoms of the disease or disorder described above.

[0137] The products provided herein include packaging materials. Packaging materials used in packaging products are well known to those skilled in the art. For example, see U.S. Patent Nos. 5,323,907, 5,052,558 and 5,033,252. Examples of packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for the selected formulation and intended mode of administration and treatment. Various formulations of the compounds and compositions provided herein are contemplated, as well as various treatments for any disease or disorder described herein.

[0138] Dosage For use in treating or preventing infectious diseases, the compounds described herein, or pharmaceutical compositions thereof, are administered or applied in a therapeutically effective amount. For human therapeutics, the physician will determine the optimal dosage regimen for preventive or curative treatment, as well as for the age, weight, stage of disease, and other factors specific to the subject to be treated. The amount of active ingredient in the formulations provided herein that will be effective in preventing or treating infectious diseases will vary with the nature and severity of the disease or condition, and the route by which the active ingredient is administered. The frequency and dosage will also vary according to factors specific to each subject, depending on the specific therapy (e.g., therapeutic or prophylactic agent) administered, the severity of the infection, the route of administration, and the age, physical condition, weight, response, and past medical history of the subject.

[0139] Exemplary dosages of the formulations include milligram or microgram amounts of active compound per kilogram of subject (e.g., from about 1 microgram per kilogram to about 50 milligrams per kilogram, from about 10 micrograms per kilogram to about 30 milligrams per kilogram, from about 100 micrograms per kilogram to about 10 milligrams per kilogram, or from about 100 micrograms per kilogram to about 5 milligrams per kilogram).

[0140] In some embodiments, a therapeutically effective dosage should produce a serum concentration of the active ingredient of about 0.001 ng / ml to about 50-200 μg / ml. The compositions, in other embodiments, should provide a dosage of about 0.0001 mg to about 70 mg of compound per kilogram of body weight per day. Dosage unit forms are prepared to provide from about 0.01 mg, 0.1 mg, or 1 mg to about 500 mg, 1000 mg, or 5000 mg, and in some embodiments, from about 10 mg to about 500 mg of the active ingredient or combination of essential ingredients per dosage unit form.

[0141] The active ingredient may be administered at once or divided into several small doses that will be administered at intervals.It is understood that the exact dosage and duration of treatment depend on the disease under treatment and may be empirically determined by using known test protocols or by extrapolating from in vivo or in vitro test data or subsequent clinical trials.It should be noted that concentration and dosage values ​​may also vary according to the severity of the condition to be alleviated.Furthermore, it should be understood that for any particular subject, specific dosage regimens must be adjusted over time according to the individual's needs and the professional judgment of the person administering or supervising the administration of the composition, and that the concentration ranges set forth herein are merely exemplary and are not intended to limit the scope or practice of the claimed compositions.

[0142] As will be apparent to those skilled in the art, in some cases it may be necessary to use dosages of the active ingredients outside the ranges disclosed herein.Furthermore, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with the subject's response.

[0143] For systemic administration, the therapeutically effective dose can be estimated initially from in vitro assays, e.g., in animal models, IC 50 (i.e., the concentration of test compound at which 50% of the cell cultures are lethal), or IC 100 A dose can be formulated to achieve a circulating concentration range that includes the compound (i.e., the concentration of the compound that is lethal to 100% of the cell cultures). Such information can be used to more accurately determine useful doses in humans.

[0144] Initial dosages can also be estimated from in vivo data (e.g., animal models) using techniques well known in the art. Those skilled in the art can readily optimize administration to humans based on the animal data.

[0145] Alternatively, the initial dosage may be determined by varying the dose of the known agent from the IC 50 , MIC and / or I 100 can be determined by comparing the initial dosages to known agents and adjusting the initial dosages accordingly. Optimal dosages can be obtained from these initial values ​​by routine optimization.

[0146] In cases of local administration or selective uptake, the effective local concentration of compound used may be independent of plasma concentration. One of skill in the art will be able to optimize therapeutically effective local dosages without undue experimentation.

[0147] Ideally, a therapeutically effective dose of the compounds described herein will provide therapeutic benefit without causing substantial toxicity. Compound toxicity can be assessed using standard pharmaceutical procedures in cell cultures or experimental animals, e.g., LD 50 (the dose lethal to 50% of the population) or LD 100 The dose ratio between toxic and therapeutic effects is the therapeutic index. Compounds that exhibit high therapeutic indices are preferred. Data obtained from these cell culture assays and animal studies can be used to formulate a dosage range that can be used in subjects without toxicity. The dosage of the compounds described herein is preferably within a range of circulating concentrations that include the effective dose but with little or no toxicity. Dosage can vary within this range depending on the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be selected by the individual physician in consideration of the patient's condition (see, for example, Fingl et al., 1975, In: The Pharmacological Basis of Therapeutics, Ch.1, p.1).

[0148] In some embodiments, the compounds of structural formula (I) are used to treat a disease / disorder or condition disclosed herein or to produce a biological effect (e.g., NAD +A therapeutically effective amount of a compound of formula (I) (e.g., for increasing levels, enhancing mitochondrial or cellular function, improving metabolic health or cell viability, or providing cytoprotection) is about 1-1000 mg, 1-100 mg, 100-500 mg, or 500-1000 mg (e.g., per day or per dose), or as deemed appropriate by the treating physician, which can be administered in a single dose or in divided doses. In further embodiments, a therapeutically effective amount of a compound of formula (I) is about 1-50 mg, 50-100 mg, 100-200 mg, 200-300 mg, 300-400 mg, 400-500 mg, 500-600 mg, 600-700 mg, 700-800 mg, 800-900 mg, or 900-1000 mg (e.g., per day or per dose). In further embodiments, the therapeutically effective amount of a compound of structural formula (I) is about 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1000 mg (e.g., per day or per dose).

[0149] In some embodiments, the therapeutically effective amount of the compound of structural formula (I) is about 100-500 mg, 100-200 mg, 200-300 mg, 300-400 mg, or 400-500 mg per day, which can be administered in a single dose (e.g., N mg once per day) or in divided doses (e.g., N / 2 mg twice per day). In further embodiments, the therapeutically effective amount of the compound of structural formula (I) is about 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, or 500 mg per day. In certain embodiments, the therapeutically effective amount of the compound of structural formula (I) is about 200-300 mg per day, or about 200 mg, 250 mg, or 300 mg per day.

[0150] The therapy may be repeated intermittently. In certain embodiments, administration of the same formulation provided herein may be repeated, and these administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.

[0151] Methods of Use of the Compounds and Compositions Disclosed herein are methods for treating, preventing, or ameliorating symptoms of medical disorders, such as metabolic disorders, cardiovascular disorders, cerebrovascular disorders, hepatic disorders, renal disorders, or muscular disorders, with compounds of structural formula (I) and pharmaceutical compositions thereof. In some embodiments, the metabolic disorder is type 1 or type 2 diabetes, impaired glucose tolerance, insulin resistance, obesity, hyperlipidemia, dyslipidemia, hypercholesterolemia, or hypertriglyceridemia; the cardiovascular disorder is cardiomyopathy, heart failure, or myocardial ischemia, infarction, or ischemia-reperfusion injury (IRI); the cerebrovascular disorder is stroke or cerebral ischemia, neuroinflammation, multiple sclerosis, hepatic encephalopathy, neurodegeneration, Parkinson's disease, or Alzheimer's disease; the hepatic disorder is nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), The renal disorder is acute renal injury or chronic renal injury, including renal ischemia or IRI, renal failure, glomerulonephritis, diabetic renal disease; and the muscular disorder is muscle atrophy, cachexia, sarcopenia, muscular dystrophy, Duchenne muscular dystrophy (DMD), myositis, neuromuscular degeneration, ataxia, spinocerebellar ataxia, adult-onset mitochondrial myopathy, Friedreich's ataxia, or ataxia-telangiectasia. In carrying out the method, a therapeutically effective amount of the compound or pharmaceutical composition described herein above is administered to a patient with these disorders or conditions.

[0152] The compounds described herein are capable of inhibiting NAD in cells, tissues and organs, and potentially in the blood. + Targeted NAD including levels + It can increase NAD levels. +By increasing the levels, the compounds of structural formula (I) can improve mitochondrial and cellular functions (e.g., DNA repair) and cell viability of target cells, tissues and organs. Benefits of improving mitochondrial function include, without limitation, improved mitochondrial oxidative metabolism, mitochondrial respiration, ATP production, mitochondrial membrane potential, mitophagy (autophagy of defective mitochondria) and mitochondrial biogenesis, and reduced reactive oxygen species (ROS) levels. For example, NAD + Higher levels increase the activity of mitochondrial NAD-dependent deacetylases sirtuin-1 (SIRT1) and sirtuin-3 (SIRT3). SIRT1 promotes autophagy of defective mitochondria, stimulates mitochondrial biogenesis, inhibits the proinflammatory transcription factor NF-κB, increases insulin sensitivity, and mimics the effects of calorie restriction. Stimulation of SIRT3 activity increases mitochondrial biogenesis, increases cellular respiration and energy production, reduces ROS levels (e.g., by stimulating mitochondrial superoxide dismutase 2 [SOD2]), promotes cell survival under genotoxic stress, functions as a mitochondrial tumor suppressor, increases insulin sensitivity and sensitizes cells to glucose uptake, and mimics calorie restriction and exercise. Improved DNA repair reduces cell damage and promotes cell function, health, and lifespan. In addition, NAD + Prevention of depletion protects neurons under excitotoxic or ischemic conditions.

[0153] Thus, the compounds of structural formula (I) are useful in the treatment of pellagra, mitochondrial diseases, mitochondrial-related diseases and conditions, acute NAD caused by DNA damage, + In some embodiments, the compounds are useful for treating diseases and conditions associated with NAD depletion, age-related disorders and conditions, skin disorders and conditions, and other types of disorders and conditions. In some embodiments, the compounds are useful for treating a disease / disorder or condition disclosed herein or for producing a biological effect disclosed herein (e.g., NAD +In some embodiments, a single compound of structural formula (I) is used to treat a disease / disorder or condition disclosed herein or to produce a biological effect disclosed herein (e.g., to increase levels of mitochondrial or cellular function, improve metabolic health or cell viability, or provide cytoprotection). In other embodiments, multiple compounds of structural formula (I) are used to treat a disease / disorder or condition disclosed herein or to produce a biological effect disclosed herein. The use of multiple compounds of structural formula (I) may have additive or potentially synergistic effects.

[0154] Compounds of structural formula (I) have other beneficial effects. For example, they can enhance the immune function of peripheral blood mononuclear cells (e.g., T cells, B cells, macrophages, and natural killer [NK] cells) based on improved antigen recognition and proliferation as a function of immune surveillance. For such applications, one or more compounds of structural formula (I) can be used alone, as a component of a vaccine, as a component of an ex vivo therapy (e.g., CAR-T cell therapy), or as a component of any other therapy.

[0155] Mitochondrial diseases include, without limitation, mitochondrial myopathy; limb-girdle distribution weakness; Kearns-Sayre syndrome (KSS); Pearson syndrome; Leigh syndrome; Barth syndrome; Friedreich's ataxia; neuropathy, ataxia, retinitis pigmentosa, and ptosis (NARP); mitochondrial DNA depletion syndrome (Alpers disease); mitochondrial neurogastrointestinal encephalopathy (MNGIE) syndrome; mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome; myoclonic epilepsy with ragged-red fibers (MERRF or Fukuhara syndrome); chronic progressive external ophthalmoplegia (CPEO); Leber's hereditary optic neuropathy (LHON); inherited forms of blindness and deafness (e.g., glycosuria). diabetic and hearing loss); and acquired, reversible or permanent hearing loss {e.g., type 2 diabetes mellitus-related hearing loss and hearing loss induced by ototoxic chemicals (e.g., heavy metals [e.g., lead], solvents [e.g., styrene and toluene] and asphyxiants [e.g., carbon monoxide]) and medications (e.g., loop diuretics [e.g., bumetanide and furosemide], NSAIDs [e.g., aspirin, celecoxib, diclofenac, ibuprofen and naproxen], PDE5 inhibitors, macrolide antibiotics, aminoglycosides [e.g., gentamicin], platinum-based chemotherapy drugs [e.g., carboplatin and cisplatin], paracetamol and quinine).

[0156] Mitochondrial-related diseases and conditions include, but are not limited to, neurodegenerative disorders, neuronal activation disorders, muscle disorders (including ocular muscle disorders), fatty acid / beta-oxidation disorders, metabolic disorders, inflammatory disorders, vascular disorders (including ocular vascular disorders), renal disorders, hepatic disorders, tumors, cancer, male and female infertility, and age-related disorders.

[0157] Neurodegenerative disorders include, without limitation, dementia (e.g., Alzheimer's disease [AD], vascular dementia, dementia with Lewy bodies, and frontotemporal dementia [Pick's disease]), motor neuron disorders (e.g., Parkinson's disease, amyotrophic lateral sclerosis [ALS or Lou Gehrig's disease], primary lateral sclerosis [PLS], and spinal muscular atrophy [SMA]), ataxia (e.g., spinocerebellar ataxia / degeneration, Friedreich's ataxia, ataxia-telangiectasia [Louis-Baumeister's disease], and cerebrovascular disease [Cavity syndrome]), and neurodegenerative disorders (e.g., myelopathy, myelopathy, and cerebrovascular disease [Cavity syndrome]). These conditions include: dyskinesia (e.g., cerebral palsy, chorea, dystonia, and essential tremor), cognitive-motor disorders (e.g., corticobasal degeneration, Huntington's disease [HD], and Parkinson-plus syndromes), chorea-acanthocytosis, retinal neurodegeneration, Batten disease, DNA repair disorders (e.g., Cockayne syndrome), and prion diseases (e.g., Creutzfeldt-Jakob disease).

[0158] Neuronal activation disorders include, without limitation, neurodegenerative disorders (e.g., ALS), neuronal injury (including traumatic and mechanical injury to the brain, spinal cord, and peripheral nervous system [PNS], and excitotoxic neuronal injury, such as that associated with stroke and ischemia), neuropathies, neuropathies (e.g., peripheral neuropathies [e.g., Charcot-Marie-Tooth disease], mononeuropathies [caused by, e.g., compression, trauma, cumulative trauma, ischemia, inflammation, connective tissue disorders, and neoplasms], polyneuropathies [e.g., These include chronic inflammatory demyelinating polyneuropathy, brachial plexus neuropathy, diabetic neuropathies (e.g., cranial third nerve palsy, mononeuropathy, multiple mononeuropathy, autonomic neuropathy, thoracic-abdominal neuropathy, and diabetic amyotrophy), and chemotherapy-induced neuropathies), autoimmune neuropathies (e.g., multiple sclerosis, Guillain-Barré syndrome, Lambert-Eaton myasthenic syndrome, and myasthenia gravis), neuroinflammation, tardive ulnar nerve palsy, and toxic neuromuscular disorders.

[0159] Muscle disorders include, but are not limited to, muscle structure disorders, muscle mass disorders, and muscle fatigue disorders. Muscle structure disorders include, but are not limited to, myopathy (e.g., cardiomyopathy), neuromuscular degeneration, muscular dystrophies (MD), congenital MD, distal MD, Duchenne MD, Becker MD, Emery-Dreyfus MD, limb-girdle MD, myotonic MD, facioscapulohumeral MD, oculopharyngeal MD, Bethlem myopathy, central core disease, congenital muscle fiber type inequality, hyaline body myopathy, muscle sodium channelopathy, myotonic dystrophy, myotonic chondrodystrophy, myotubular myopathy, nemaline body disease, myositis, sarcopenia, rhabdomyolysis, and stress urinary incontinence. Muscle mass disorders include, without limitation, muscle atrophy, cachexia, cartilage degeneration, cerebral palsy, compartment syndrome, critical illness myopathy, inclusion body myositis, sarcopenia, steroid myopathy, and systemic lupus erythematosus (SLE). Muscle fatigue disorders include, without limitation, chronic fatigue syndrome, fibromyalgia, thyrotoxic myopathy, lipid storage myopathy, Friedreich's ataxia, glycogen storage disease (e.g., Pompe disease), intermittent claudication, adult-onset mitochondrial myopathy, MELAS, and mucopolysaccharidoses.

[0160] Eye muscle disorders include, but are not limited to, refractive errors, accommodative disorders, refractive dysregulation, strabismus, progressive external ophthalmoplegia, internal ophthalmoplegia, esotropia, exotropia, hyperopia, myopia, astigmatism, anisometropia, and presbyopia.

[0161] Fatty acid / beta-oxidation disorders include, without limitation, systemic carnitine transporter deficiency, carnitine palmitoyltransferase (CPT) II deficiency, very long-chain acyl-CoA dehydrogenase (LCHAD or VLCAD) deficiency, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, short-chain acyl-CoA dehydrogenase (SCAD) deficiency, triglyceride deficiency, and riboflavin-responsive disorder of beta-oxidation (RR-MADD).

[0162] Metabolic disorders include, without limitation, lipodystrophy (hereditary and acquired), metabolic syndrome, hyperglycemia, impaired glucose tolerance (including prediabetes and diabetes), insulin resistance, hyperinsulinism, diabetes mellitus (including type 1 and type 2), diabetic complications (e.g., diabetic neuropathy and diabetic retinopathy), obesity, dyslipidemia, familial hyperlipidemia, hypercholesterolemia, non-high density lipoprotein (HDL) hypercholesterolemia, low density lipoprotein (LDL) hypercholesterolemia, HDL hypocholesterolemia, hypertriglyceridemia, dyslipoproteinemia, very low density lipoprotein (VLDL) hyperproteinemia, apolipoprotein AI hypoproteinemia. , hypertension, cardiovascular disease (e.g., cardiomyopathy [e.g., metabolic cardiomyopathy], heart failure, myocardial infarction, atherosclerosis, thrombotic disorders, and peripheral vascular disease), inflammatory disorders (e.g., arthritis, asthma, and pancreatitis), liver disorders (e.g., nonalcoholic fatty liver disease [NAFLD] and nonalcoholic steatohepatitis [NASH]), renal disorders (e.g., chronic kidney disease), gastrointestinal (GI) disorders (e.g., Crohn's disease, irritable bowel syndrome, ulcerative colitis, and dyspepsia), neurodegenerative disorders (e.g., Alzheimer's disease, Parkinson's disease), demyelinating disorders (e.g., multiple sclerosis), skin disorders (e.g., acne, dermatitis, psoriasis, and skin aging), ectopic hair growth, adrenoleukodystrophy, edema, ketoacidosis, sexual (e.g., erectile) dysfunction, tumors, and cancer.

[0163] In some embodiments, the compounds of structural formula (I) are used to treat hyperglycemia, impaired glucose tolerance and insulin resistance and disorders and conditions related thereto, including prediabetes, type 1 and type 2 diabetes, and disorders and conditions related to obesity. Compounds of structural formula (I) can stimulate STRT1 and STRT3 activity, both of which increase insulin sensitivity, sensitize cells to glucose uptake, and mimic calorie restriction. Increasing insulin sensitivity can decrease insulin production. Hyperinsulinemia promotes differentiation of preadipocytes into adipocytes. Thus, reducing blood insulin levels can inhibit adipocyte differentiation and adipogenesis, which in turn can have therapeutic effects on disorders and conditions related to obesity, including, but not limited to, dyslipidemia, hyperlipidemia, atherosclerosis, metabolic syndrome, lipodystrophy, and hypertension.

[0164] ROS induce inflammation, in part, by activating transcription factors such as NF-κB, which increase the expression of proinflammatory cytokines. Compounds of structural formula (I) disclosed herein can reduce ROS levels, for example, by stimulating SIRT3 activity. Moreover, compounds of structural formula (I) can increase the activity of NAD-dependent deacetylase sirtuin-1 (SIRT1), which inhibits NF-κB. NF-κB is the primary promoter of transcription of genes encoding proinflammatory cytokines. Thus, compounds of structural formula (I) are useful for treating inflammatory disorders. Inflammatory disorders include, without limitation, neuroinflammation (e.g., neuritis [e.g., ophthalmic neuritis and peripheral neuritis], Alzheimer's disease and multiple sclerosis), GI disorders (e.g., gastritis, necrotizing enterocolitis, mucous colitis, ulcerative colitis, inflammatory bowel disease, irritable bowel syndrome, Crohn's disease and celiac disease), peritonitis, pancreatitis (acute and chronic), glomerulonephritis, liver disorders (e.g., hepatitis, nonalcoholic and alcoholic steatohepatitis, cirrhosis and chronic liver disease), multiple organ dysfunction syndrome (e.g., secondary to sepsis or trauma), metabolic disorders (e.g., diabetes [e.g., type 1 and type 2 diabetes and juvenile onset diabetes] and metabolic syndrome), cardiac disorders (e.g., myocarditis and myocardial infarction, congestive heart failure with preserved or reduced ejection fraction), vascular disorders (e.g., vasculitis, atherosclerosis, stroke, peripheral arterial disease and shock), reperfusion injury (e.g. due to myocardial ischemia, cerebral ischemia, cardiopulmonary bypass or renal dialysis), airway disorders (e.g. rhinitis [e.g. allergic rhinitis], esophagitis, asthma, acute respiratory distress syndrome, bronchitis [e.g. chronic bronchitis], pneumonitis and chronic obstructive pulmonary disease [COPD]), arthritis (e.g. osteoarthritis [degenerative joint disease], rheumatoid arthritis, psoriatic arthritis, gouty arthritis, axial spondyloarthritis, ankylosing spondylitis and juvenile arthritis), skin disorders (e.g. dermatitis / eczema, psoriasis, urticaria, skin diseases with an acute inflammatory component, and sunburn), Sjogren's syndrome, eye disorders (e.g. conjunctivitis, retinitis and AMD), SLE, hypertension and dysmenorrhea (menstrual pain).

[0165] Inflammation is a major stimulant of fibrosis. In part by reducing inflammation, the compounds of structural formula (I) disclosed herein are useful for treating fibrotic disorders, including, without limitation, cardiomyopathies (e.g., diabetic and uremic cardiomyopathy), cardiac fibrosis, myocardial fibrosis, collagen vascular diseases (e.g., arteriosclerosis and vascular fibrosis), atherosclerosis, chronic heart failure, diabetic nephropathy, renal fibrosis, chronic kidney disease (e.g., chronic renal failure), liver fibrosis, cirrhosis, NASH, chronic liver disease, liver failure (e.g., chronic liver failure), pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis and radiation pulmonary fibrosis), cystic fibrosis, and scleroderma (e.g., localized scleroderma and systemic sclerosis / systemic sclerosis).

[0166] Vascular disorders include, but are not limited to, cardiovascular disease (e.g., myocardial ischemia, ischemia-reperfusion injury [IRI], arteriosclerosis, and atherosclerosis), cerebrovascular disease (e.g., cerebral ischemia and IRI), peripheral vascular disease (e.g., peripheral vascular insufficiency, peripheral arterial disease, intermittent / vascular claudication, critical limb ischemia, peripheral arterial occlusive disease, and peripheral occlusive arteriopathy), thrombotic / blood coagulation / hemostatic disorders (e.g., disseminated intravascular coagulation, deep vein thrombosis, thrombophilia [e.g., antithrombin III deficiency, protein S deficiency, protein β ... C deficiency or activated protein C resistance], thrombotic thrombocytopenic purpura, heparin-induced thrombocytopenia, dysfibrinogenemia, atherosclerosis, arteriosclerosis, myocardial ischemia / infarction, angina (e.g., unstable angina), ischemic stroke, sickle cell disease, myeloproliferative neoplasms, cancer metastasis, homocystinuria, and miscarriage), and embolism (e.g., thromboembolism, fat embolism, arterial embolism (e.g., myocardial ischemia, ischemic stroke, and acute limb ischemia), and venous embolism (e.g., pulmonary embolism). As an illustrative example, one or more compounds of structural formula (I) can be used for the treatment or prevention of thrombosis or thrombotic disorders during and / or following a thrombus removal intervention (e.g., surgery such as angioplasty), including the reduction or prevention of thrombotic events or reocclusion.

[0167] Ocular vascular disorders include, without limitation, retinopathies (eg, hypertensive retinopathy and diabetic retinopathy), macular degeneration (eg, age-related macular degeneration [AMD]), Stargardt's disease, retinal hemorrhage, and glaucoma.

[0168] Renal disorders include, without limitation, acute nephritis, chronic nephritis, rapidly progressive nephritis, glomerulonephritis, glomerulosclerosis, hypertensive nephrosclerosis, renal ischemia, IRI, Bartter's syndrome, diabetic nephropathy, acute renal failure (acute kidney injury), chronic renal failure, nephrotic syndrome, recurrent hematuria, and persistent hematuria.

[0169] Liver disorders include, without limitation, NAFLD, NASH, alcoholic liver disease, hepatitis (e.g., autoimmune hepatitis, hepatitis B and hepatitis C), cholestatic disorders (e.g., cholestasis, primary biliary cholangitis / cirrhosis and primary sclerosing cholangitis), liver injury, chronic liver disease, liver failure (acute and chronic), cirrhosis, and liver cancer.

[0170] Tumors (benign and malignant) and cancers include, without limitation, brain tumors, spinal tumors, germ cell tumors, neuroendocrine tumors, carcinoid tumors, tumors and cancers associated with viral infections (e.g., HIV and HTLV-1), carcinomas, sarcomas, and cancers of the digestive / gastrointestinal system, gynecological organs (e.g., breast cancer), genitourinary system, musculoskeletal system, respiratory system, head and neck, eye, skin (e.g., melanoma), blood cancers (e.g., leukemia, multiple myeloma, Hodgkin's lymphoma and non-Hodgkin's lymphoma), endocrine system cancers (e.g., hormone-dependent cancers such as breast, ovarian, prostate and testicular cancer), neuroendocrine system, nervous system, and germ cell cancers. In some embodiments, one or more compounds of structural formula (I) are used to treat breast cancer, ovarian cancer, colon / colon cancer, rectal cancer, pancreatic cancer, liver cancer, kidney cancer, lung cancer, prostate cancer, brain cancer, or skin cancer. In further embodiments, one or more compounds of structural formula (I) are used in the treatment of hematological malignancies, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), non-Hodgkin's lymphoma, or multiple myeloma.

[0171] Disorders related to female infertility include, but are not limited to, polycystic ovarian syndrome (PCOS), diminished ovarian reserve, endometriosis, and infertility caused by radiation or chemotherapy. Disorders related to male infertility include, but are not limited to, oligospermia and spermatogenesis caused by drug therapy.

[0172] Somatic mutations in mitochondrial DNA increase significantly with age, which can result in defective mitochondria. Moreover, respiratory chain activity declines with age. Non-limiting examples of age-related disorders are described below.

[0173] In some embodiments, one or more compounds of structural formula (I) are used to treat a mitochondrial-related disease or condition selected from hereditary lipodystrophies, metabolic syndrome, obesity, type 1 and type 2 diabetes, NAFLD, NASH, alcoholic liver disease, autoimmune hepatitis, cholestatic liver disease, hemochromatosis, alpha 1-antitrypsin deficiency, other inherited inborn errors of metabolism, and renal ischemia and IRI.

[0174] Acute NAD due to DNA damage + Diseases and conditions characterized by depletion include, without limitation, exposure to radiation (e.g., ionizing radiation such as UV and X-rays), radiation or chemotherapy-induced injuries (e.g., dermatitis, myositis, myocarditis, colitis, prostatitis, hepatitis, pneumonitis, neuropathy, and bone marrow failure), burns (including first, second, and third degree burns), chemical exposures with exfoliative dermatitis manifestations, exposure to chemical warfare agents, Stevens-Johnson syndrome, acute respiratory distress syndrome, inhalation lung injury from smoking or chemical toxins, trauma-related crush injuries (including those with bone fractures), peripheral nerve injury, spinal cord injury, and visceral contusion (e.g., heart, lung, liver, and kidney). In such diseases and conditions, ROS, such as superoxide, peroxide, and hydroxyl radicals, are generated in large quantities, which can cause DNA damage and, ultimately, cell damage or cell death. In other words, DNA damage induced, for example, by radiation, chemotherapy, or oxidative stress, can result in acute NAD +Exhaustion can result in systemic toxicity and damage (e.g., dermatitis, pneumonitis, bone marrow failure, and neuropathy), as well as local toxicity and damage. Exemplary chemical warfare agents include blister agents (e.g., vesicants, nitrogen mustards, sulfur mustards, arsenicals, and gall blister agents [e.g., phosgene]), blood agents (e.g., cyanides), pulmonary agents (e.g., phosgene), and nerve agents (e.g., G agents [e.g., sarin and soman], GV agents, and V agents).

[0175] NAD + Decreased levels are associated with aging, leading to age-related metabolic dysfunction and disorders (e.g., inflammatory disorders). - The expression and activity of CD38, which rapidly degrades NMN and its precursor NMN, increases during the aging process. Thus, the compounds of structural formula (I) described herein are useful for treating age-related disorders and conditions. Furthermore, the compounds of structural formula (I) described herein can extend cell lifespan, for example, by slowing or delaying cellular aging / senescence, promoting cell survival, preventing cellular apoptosis, extending the proliferation potential of cells, increasing cellular stress resistance (e.g., oxidative stress resistance), mimicking the effects of caloric restriction, or promoting wound healing, or any combination thereof. In addition, NAD + Supplementation of improves stem cell function. Age-related disorders and conditions include, but are not limited to, aging / senescence, hypertension, eye disorders (e.g., AMD, cataracts, and keratoconjunctivitis sicca [dry eye syndrome]), hearing loss, osteoporosis, sarcopenia, dementia (e.g., Alzheimer's disease), metabolic disorders (e.g., metabolic decline, diabetes [including T1D and T2D], and obesity), cardiovascular disorders (e.g., arteriosclerosis), inflammatory disorders (e.g., arthritis and COPD), DNA repair syndromes (e.g., Cockayne syndrome), and tumors and cancers. Due to its cytoprotective and antioxidant properties, for example, the compound of structural formula (I) can be used to prevent or reduce hearing loss, including noise-induced hearing loss, traumatic hearing loss, and progressive hearing loss syndromes.

[0176] By enhancing cell viability, providing cytoprotection, and / or increasing cell life span, compounds of structural formula (I) can be used to treat disorders characterized by cell degeneration or cell death, including, but not limited to, retinal disorders characterized by cell degeneration or cell death, including AMD, retinitis pigmentosa, cone-rod dystrophy / degeneration, diabetic retinopathy, Leber's congenital amaurosis, and vision loss.

[0177] Cytoprotective compounds of structural formula (I) may be used to treat, without limitation, neuronal disorders (e.g., Alzheimer's disease, Creutzfeldt-Jakob disease, Parkinson's disease, ALS, and multiple sclerosis), brain degeneration (e.g., cerebellar degeneration and traumatic brain injury), muscle disorders (e.g., muscular dystrophies such as Duchenne MD, facioscapulohumeral MD, and myotonic dystrophy), ischemic disorders (e.g., myocardial ischemia / infarction and cerebral ischemia [stroke] / infarction), atherosclerosis, myelodysplastic syndromes (e.g., aplastic anemia), hepatitis (e.g., alcoholic hepatitis), and the like. The compounds of formula (I) can be used to treat hepatitis C, fulminant hepatitis, hepatitis A, hepatitis B, hepatitis C, hepatitis D, and hepatitis E), joint disorders (e.g., osteoarthritis), atrophy of the skin, lichen planus, skin damage caused by ultraviolet light, graft rejection, alopecia, AIDS, and other disorders and conditions characterized by cell degeneration and / or cell death, including cell damage and / or cell death caused by trauma (e.g., of the brain or spinal cord), surgery, drug therapy, chemicals, biological and chemical toxins, and radiation (e.g., ionizing radiation such as X-rays). For example, to prevent cell damage and / or cell death that may result from a medical intervention such as surgery or radiation therapy, one or more compounds of formula (I) can be administered to a subject prior to or / and immediately after the intervention.

[0178] Due in part to their ability to protect cells from the effects of DNA damage and to enhance cell viability and longevity, the compounds of structural formula (I) described herein are useful in treating skin disorders and conditions that may be associated with or caused by, for example, natural aging, inflammation, oxidative stress, or sun damage. Such skin disorders and conditions include, without limitation, skin wrinkles, dermatitis / eczema (e.g., atopic dermatitis, contact dermatitis [allergic and irritant], exfoliative dermatitis, and seborrheic dermatitis), psoriasis (e.g., plaque psoriasis), skin damage caused by sunlight or other light sources (e.g., sunburn, actinic keratosis, and xeroderma pigmentosum), keratinization disorders, erythema (e.g., erythema multiforme and erythema nodosum), dermatomyositis, discoid lupus erythematosus, pemphigoid (e.g., bullous pemphigoid), pemphigus (e.g., pemphigus vulgaris), epidermolysis bullosa, burns (e.g., first-, second-, and third-degree burns, and burns, radiation burns, chemical burns, and electrical burns), wounds, and skin cancer.

[0179] In part due to their cytoprotective properties, the compounds of structural formula (I) disclosed herein can promote donor graft protection in organ transplantation. Thus, the compounds of structural formula (I) can be applied to cells, tissues, or organs used in transplantation and cell therapy, such as solid tissue grafts, organ transplants, cell suspensions, stem cells, and bone marrow cells. Such cells, tissues, or organs can be autografts, allografts, syngeneic grafts, or xenografts. The cells, tissues, or organs can be treated with one or more compounds of structural formula (I) before, simultaneously with, or / and after administration / implantation of the cells, tissues, or organs to a recipient. The cells, tissues, or organs can be treated with one or more compounds of structural formula (I) before removing the cells, tissues, or organs from a donor, ex vivo after removing the cells, tissues, or organs from a donor, or after administration / implantation to a recipient. For example, the donor and / or recipient can be subjected to systemic treatment with one or more compounds of structural formula (I) or a portion of a cell, tissue or organ can be subjected to localized treatment with one or more compounds of structural formula (I). In certain embodiments, the cell, tissue or organ (or the donor and / or recipient) is treated with an additional therapeutic agent that extends the survival of the graft, such as an immunosuppressant, a cytokine or an angiogenic factor, or any combination thereof.

[0180] For example, NAD + The use of one or more compounds of structural formula (I) can improve bone marrow transplant engraftment rates by promoting differentiation of transplanted cells through increased levels, thereby minimizing cytopenias (including neutropenia, lymphopenia, anemia, and thrombocytopenia), the need for growth factors, and infectious complications. As another example, one or more compounds of structural formula (I) can be used to prevent graft-versus-host disease (GVHD) in allogeneic transplants.

[0181] In some embodiments, one or more compounds of structural formula (I) are used in culture medium as a component of ex vivo therapy, such as chimeric antigen receptor (CAR) T cell therapy. CAR-T cell therapy can be autologous or allogeneic. In certain embodiments, ex vivo therapy utilizes hematopoietic stem cells (HSCs), embryonic stem cells (ESCs) or pluripotent stem cells (PSCs). One or more compounds of structural formula (I) can be used to improve the production of pancreatic endocrine cells at the end stage of in vitro ESC and PSC differentiation into islet-like insulin-secreting cells.

[0182] In further embodiments, the compounds of structural formula (I) are used to enhance mitochondrial or cellular function or / and cellular energy production in oocytes, postnatal female germline stem cells, or / and preimplantation embryos prior to or / and after in vitro fertilization, or following exposure of the ovaries, oocytes, postnatal female germline cells, or / and preimplantation embryos in vivo. In some embodiments, one or more compounds of structural formula (I) are used in assisted reproduction techniques, such as in vitro fertilization, with a solution selected from cell culture media, oocyte retrieval solutions, oocyte washing solutions, oocyte in vitro maturation media, follicular in vitro maturation media, oocyte in vitro fertilization media, vitrification solutions, and cryopreservation solutions. The present disclosure encompasses compositions comprising isolated oocytes, oogonial stem cells (OSCs), or OSC progeny, and one or more compounds of structural formula (I).

[0183] In some embodiments, the compound of formula (I) may be used as a lipid-lowering agent. The compound of formula (I) may be more effective as a lipid-lowering agent than NA. The lipid-lowering effect of the compound of formula (I) may be mediated through effects on the liver (DGAT1 inhibition, VLDL and HDL metabolism) and on adipocytes / adipose tissue (inhibition of lipolysis). The sustained pharmacological action may provide superior effects in reducing liver fat for the treatment of NAFLD.

[0184] In some embodiments, the compounds of formula (I) may be used to improve muscle function. The compounds of formula (I) may have significant benefits over NA on muscle function. This is due to the fact that NAD + This may be mediated by increased oxidative phosphorylation associated with increased levels and improved mitochondrial function. In particular, the compounds of formula (I) may improve the treatment of myolipidosis-associated sarcopenia associated with immobilization, cancer cachexia, chronic malnutrition, liver cirrhosis, and age-related chronic diseases.

[0185] The therapeutically effective dose of the compound of structural formula (I) can be administered once a day, more than once a day, once every two days, once every three days, twice a week or once a week, or as deemed appropriate by the treating physician.In certain embodiments, the therapeutically effective dose of the compound of structural formula (I) is administered once or twice a day.As an illustrative example, if the therapeutically effective dose of the compound of structural formula (I) is about 300 mg per day, 300 mg of the compound may be administered once a day, or 150 mg of the compound may be administered twice a day.

[0186] When it is desired to establish therapeutic levels of the compound of structural formula (I) more quickly, such as in the treatment of ischemia-reperfusion injury, the compound may be administered according to a dosing schedule in which a loading dose is administered, followed by (i) one or more additional loading doses followed by one or more therapeutically effective maintenance doses, or (ii) one or more therapeutically effective maintenance doses without additional loading doses, as deemed appropriate by the treating physician. In such cases, the loading dose of the drug is higher (e.g., about 1.5, 2, 3, 4, or 5 times higher) than the subsequent maintenance doses, designed to establish therapeutic levels of the drug more quickly. The one or more therapeutically effective maintenance doses may be any therapeutically effective amount / dosage described herein. In certain embodiments, the loading dose is about 3 times higher than the maintenance dose. In some embodiments, a loading dose of the compound of structural formula (I) is administered on day 1, followed by a maintenance dose on day 2 and thereafter throughout the duration of therapy. In other embodiments, a first loading dose of a compound of structural formula (I) is administered on day 1, a second loading dose on day 2, and a maintenance dose on day 3 and thereafter throughout the course of therapy. In certain embodiments, the first loading dose is about 3 times as high as the maintenance dose and the second loading dose is about 2 times as high as the maintenance dose.

[0187] Combination therapy The compounds and compositions disclosed herein may also be used in combination with one or more other active ingredients. In certain embodiments, the compounds may be administered in combination with another therapeutic agent or sequentially. Such other therapeutic agents include those known to treat, prevent, or ameliorate one or more symptoms associated with the diseases and / or disorders disclosed herein. Other therapeutic agents include, without limitation, those known to treat, prevent, or ameliorate one or more symptoms of any disease and / or disorder disclosed herein.

[0188] It should be understood that any suitable combination of the compounds and compositions provided herein with one or more of the above therapeutic agents and optionally one or more additional pharmacologically active substances is considered to be within the scope of the present disclosure.In some embodiments, the compounds and compositions provided herein are administered prior to, simultaneously with, or after one or more additional active ingredients.In other embodiments, the compounds and compositions provided herein are administered in the same or different pharmaceutical composition of one or more additional active ingredients.

[0189] Other types of therapeutic agents that can be used in combination with compounds of structural formula (I) include, without limitation, sirtuin activators, AMPK activators, CD38 inhibitors, PARP inhibitors, SARM1 inhibitors, ACMSD inhibitors, stimulants of cellular oxygen consumption, NMDA receptor antagonists, acetylcholinesterase inhibitors, antidiabetic agents, antiobesity agents, antiplatelet agents, anticoagulants, antihypertensive agents, antioxidants, anti-inflammatory agents, analgesics, anesthetics, anticancer agents, antiviral agents, antibiotics, antifungal agents, natural compounds, vitamins, and vaccines. Additional therapeutic agents can also include, for example, farnesoid X receptor agonists, liver X receptor inverse agonists, and sunscreens.

[0190] Sirtuin activators are agents that increase the activity, level (e.g., expression) or signaling of sirtuins, such as SIRT1 or SIRT3. The beneficial properties of SIRT1 and SIRT3 are described above. Sirtuin activators mimic calorie restriction, enhance mitochondrial and cellular function, enhance cell viability, increase cell life span, increase mitochondrial biogenesis, protect against fatty liver and muscle wasting, and exert anti-inflammatory, anti-diabetic, cardioprotective and anti-aging effects, among other therapeutic effects. SIRT1 activators include, without limitation, lamin A, methylene blue, resveratrol, SRT-1460, SRT-1720, SRT-2104, SRT-2183, and analogs, derivatives, fragments and salts thereof. In addition to resveratrol, other polyphenols that activate sirtuins, such as SIRT1, include, but are not limited to, butein, fisetin, isoliquiritigenin, piceatannol, quercetin, and analogs, derivatives, and salts thereof. Metformin inhibits NAD + NAD via activation of the salvage pathway enzyme nicotinamide phosphoribosyltransferase (NAMPT) + By increasing levels of NAD + By increasing the / NADH ratio, it increases the activity of sirtuins such as SIRT1. Other sirtuin activators include, without limitation, amino acids with branched side chains, including leucine and its metabolites, such as hydroxymethylbutyrate and ketoisocaproic acid / isocaproate. Such amino acids increase the levels of sirtuins such as SIRT1 and SIRT3 and stimulate their signaling.

[0191] AMPK activators include agents that increase the activity, level (e.g., expression) or signaling of 5'-AMP-activated protein kinase (AMPK). AMPK plays a key role in cellular energy homeostasis, mostly through stimulation of glucose and fatty acid uptake and oxidation when cellular energy is low. Activation of AMPK stimulates lipolysis, liver and skeletal muscle fatty acid oxidation, ketogenesis and glucose uptake, inhibits cholesterol and triglyceride synthesis and lipogenesis (including adipocyte lipogenesis), and regulates insulin secretion by pancreatic β cells. Activation of AMPK also inhibits NAD + The levels are also increased. AMPK activators include, without limitation, sirtuin activators (e.g., resveratrol, quercetin, metformin, and amino acids with branched side chains and their metabolites), thiazolidinedione PPAR-γ agonists (such as pioglitazone and rosiglitazone, described below), cannabinoids, 5-aminoimidazole-4-carboxamide-1-β-D-riboside, berberine, curcumin, dinitrophenol (DNP), epigallocatechin-3-gallate, α-lipoic acid, N-769662, PT-1, adiponectin, ghrelin, leptin, interleukin-6 (IL-6), and analogs, derivatives, fragments, and salts thereof.

[0192] CD38 expression and activity increase during aging, thereby increasing NAD + Inhibition of CD38 reduces NAD levels, leading to age-related metabolic dysfunction and disorders (e.g., inflammatory disorders). +The levels are increased, which in turn improves mitochondrial and cellular function and increases the activity of sirtuins such as SIRT1 and SIRT3. CD38 inhibitors include, but are not limited to, flavonoids (e.g., apigenin and quercetin), thiazoloquinones (azo)olin(ones) (e.g., compounds 76a, 76c, 77a, 77c, 77d, 78a, 78c, 78d, 78e, 79a, 79c, and 79d) disclosed in C. Haffner et al., J. Med. Chem., 58:3 548-3 571 (2015), and analogs, derivatives, and salts thereof.

[0193] Cellular oxygen consumption is a reliable indicator of mitochondrial activity, since it is responsible for almost all of the oxygen use by cells. Mitochondria play a critical role in various cellular processes, including energy production and biosynthesis. Agents that increase mitochondrial activity can be used, for example, to treat mitochondrial diseases (e.g., Leigh syndrome and LHON), mitochondrial-related diseases and conditions (e.g., metabolic disorders and neurodegenerative disorders [e.g., Alzheimer's disease, Parkinson's disease, ALS, Friedreich's ataxia and FXTAS]), aid in recovery from injury (e.g., traumatic brain injury) or disease, and slow aging. Stimulators of cellular oxygen consumption increase mitochondrial activity through increasing mitochondrial function or / and number. Stimulators of cellular oxygen consumption include, without limitation, acarbose, chlormadinone (e.g., chlormadinone acetate), desoximetasone, dichlorophene, enilconazole, flumazenil, quinidine (e.g., quinidine gluconate), succinylsulfathiazole, toltrazuril, and analogues, derivatives and salts thereof.

[0194] In some embodiments, one or more compounds of structural formula (I) are used in combination with an N-methyl-D-aspartate receptor (NMDAR) antagonist for the treatment of disorders characterized by neurodegeneration or neurotoxicity, such as dementia (e.g., Alzheimer's disease) or motor neuron disorders (e.g., Parkinson's disease). In certain embodiments, the NMDAR antagonist inhibits Mg in the opened ion channels of activated NMDARs, allowing the antagonist to inhibit NMDAR-mediated excitotoxicity while maintaining physiological NMDAR activity. 2+ Moderate affinity for the dizocilpine (MK-801) / phencyclidine binding site at or near the binding site (e.g., K of about 200 nM to about 10 μM) i or IC 50 ) are non-competitive antagonists (or channel blockers) with the NMDAR receptor. Such NMDAR non-competitive antagonists include, without limitation, alaprolclate, amantadine, atomoxetine, budipine, delsemin, dextralorphan, dextromethorphan, dextrorphan, dexanabinol, eliprodil, ketamine, lanicemine, minocycline, memantine, nitromemantine, NEFA (a tricyclic small molecule), neramexane, orphenadrine, procyclidine, ARL / FPL 12495 / 12495AA (a desglycine metabolite of remacemide), and analogs, derivatives, and salts thereof. In some embodiments, the NMDAR antagonist is memantine, nitromemantine, amantadine, lanicemine, neramexane, dextralorphan, dextromethorphan, dextrorphan (a metabolite of dextromethorphan), or procyclidine. In certain embodiments, the NMDAR antagonist is memantine, nitromemantine, dextralorphan, dextromethorphan, or dextrorphan.

[0195] In further embodiments, one or more compounds of structural formula (I) are used in combination with an acetylcholinesterase inhibitor (AChEI) for the treatment of cognitive disorders (e.g., dementias such as Alzheimer's disease, dementia with Lewy bodies, or Parkinson's disease-related dementia) or neuromuscular disorders (e.g., myasthenia gravis). Reversible AChEIs include, but are not limited to, neostigmine, physostigmine, pyridostigmine, rivastigmine, ambenonium, demecarium, donepezil, edrophonium, ladostigil, and analogs, derivatives, and salts thereof.

[0196] Other therapeutic agents that can be used in conjunction with one or more compounds of structural formula (I) for the treatment of Parkinson's disease include, without limitation, levodopa, dopamine agonists (e.g., apomorphine, bromocriptine, cabergoline, lisuride, pergolide, piribedil, pramipexole, ropinirole, and rotigotine), catechol-O-methyltransferase (COMT) inhibitors (e.g., entacapone, opicapone, and tolcapone), monoamine oxidase B (MAO-B) inhibitors (e.g., ladostigil, safinamide, selegiline, and rasagiline), peripheral aromatic L-amino acid decarboxylase inhibitors (e.g., carbidopa), and analogs, derivatives, and salts thereof.

[0197] In further embodiments, one or more compounds of structural formula (I) are used in combination with one or more antidiabetic agents for the treatment of hyperglycemia, insulin resistance or diabetes (e.g., type 1 or type 2), or disorders related thereto (e.g., NAFLD or NASH). In certain embodiments, the one or more antidiabetic agents are or include a biguanide (e.g., metformin), a thiazolidinedione (e.g., pioglitazone or rosiglitazone), a GLP-1 agonist (e.g., dulaglutide or semaglutide), or an SGLT2 inhibitor (e.g., empagliflozin or tofogliflozin), or any combination thereof.

[0198] Antidiabetic agents include, without limitation, AMP-activated protein kinase (AMPK) agonists, including biguanides (e.g., buformin, metformin, and phenformin); peroxisome proliferator-activated receptor agonists, including thiazolidinediones (e.g., balaglitazone, ciglitazone, darglitazone, englitazone, lobeglitazone, netoglitazone, pioglitazone, rivoglitazone, rosiglitazone, and troglitazone) and saroglitazar (a dual PPAR-α / γ agonist). PPAR-γ agonists; glucagon-like peptide-1 (GLP-1) receptor agonists, including exendin-4, albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, semaglutide, taspoglutide, CNTO736, CNTO3649, HM11260C (LAPS-exendin), NN9926 (OG9S7GT), TT401, and ZY0G1; long-acting oxyntomodulin analogs {e.g., lipid-conjugated OXM analogs (e.g., A. Pocai DualAG disclosed in et al., Diabetes, 58:2258-2266

[2009] ), PEGylated OXM analogues, cross-linked OXM analogues disclosed in A. Muppidi et al., ACS Chern. Biol., 11:324-328 (2016), and R. Scott et al.OX-SR}, HM12525A, JNJ-54728518, LY2944876 (TT-401), MEDI0382, MK-8521, MOD-6031, NN9277, SAR425899, SP-1373 and ZP2929; dual GLP-1 receptor (GLP-1R) / glucagon receptor (GCGR) agonists, including Cpd86, LY3298176, NN9709 (MAR709), SAR438335, ZP-DI-70 and ZP - Dual GLP-1R / Gastric Inhibitory Peptide Receptor (GIPR) agonists, including I-98; Triple GLP-1R / GIPR / GCGR agonists, including HM15211 and MAR423; Alogliptin, Anagliptin, Dutogliptin, Evogliptin, Gemigliptin, Gosogliptin, Linagliptin, Omarigliptin, Saxagliptin, Septagliptin, Sitagliptin, Des-Fluoro-Sitagliptin, Teneligliptin, Trelagliptin and Vildagliptin dipeptidyl peptidase 4 (DPP-4) inhibitors, including alpha-glucosidase inhibitors, including acarbose, miglitol, and voglibose; ketohexokinase (KHK) inhibitors, including PF-06835919; sodium-glucose transport protein inhibitors, including canagliflozin (which also inhibits SGLT1), dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, remogliflozin etabonate, sotagliflozin (which also inhibits SGLT1), and tofogliflozin. ATP-dependent K+ capsulase 2 (SGLT2) inhibitors; meglitinides (e.g., mitiglinide, nateglinide, and repaglinide) and sulfonylureas {including first generation (e.g., acetohexamide, carbutamide, chlorpropamide, glycyrrhizamide [tolhexamide], metahexamide, tolazamide, and tolbutamide) and second generation (e.g., glibenclamide [glyburide], glibornuride, gliclazide, glimepiride, glipizide, gliquidone, glisoxepide, and glyclopyramide)} on pancreatic β cells; + (K ATP) channel blockers; insulin and its analogs, including fast-acting insulins (e.g., insulin aspart, insulin glulisine, and insulin lispro), intermediate-acting insulins (e.g., NPH insulin), and long-acting insulins (e.g., insulin degludec, insulin detemir, and insulin glargine); and analogs, derivatives, and salts thereof.

[0199] In further embodiments, one or more compounds of structural formula (I) are used in combination with one or more anti-obesity agents for the treatment of obesity or hyperlipidemia or disorders related thereto, such as metabolic disorders (e.g., T2D, metabolic syndrome, or NAFLD) or cardiovascular disorders (e.g., atherosclerosis or coronary artery disease). Obesity also promotes inflammatory processes. In certain embodiments, the one or more anti-obesity agents are or include lipase inhibitors (e.g., orlistat) or / and antihyperlipidemic agents (e.g., statins, such as atorvastatin, or / and fibrates, such as fenofibrate).

[0200] Antiobesity agents include, but are not limited to, appetite suppressants (appetite reducers), including amphetamine, dexamphetamine, amfepramone, clobenzorex, mazindol, phentermine (with or without topiramate), and lorcaserin; satiety promoters, including ciliary neurotrophic factor (e.g., axokine) and long-acting amylin analogs, calcitonin, cholecystokinin (CCK), glucagon (GCG), GLP-1, gastric inhibitory peptide (GIP, also known as glucose-dependent insulinotropic polypeptide), leptin, oxyntomodulin (OXM), pancreatic polypeptide (PP), peptide YY (PYY), and neuropeptide Y (NPY); caulerpenic, cetilistat, ebelactone A and B, estellastin, lipstatin, orlistat, percyquinin, panclicin A-E, valirac agents that increase energy expenditure or / and fat burning, including long-acting glucagon analogues, glucagon receptor agonists (e.g., NN9030) and dual GLP-1 receptor / glucagon receptor agonists (above), triiodothyronine (T3) and thyroid hormone receptor beta (THR-β) agonists (e.g., MB07344, MB07811, MGL-3196, MGL-3745, VK0214 and VK2809); and fibroblast growth factor 21 (FGF21) and its analogues and derivatives (e.g., BMS-986036 [PEGylated FGF21]); antihyperlipidemic agents; other agents that reduce body weight or / and body fat mass, including dual GLP-1R / GIPR agonists (above) and triple GLP-1R / GIPR / GCGR agonists (above); and analogues, derivatives and salts thereof.

[0201] Antihyperlipidemic agents include, without limitation, HMG-CoA reductase inhibitors, including statins {e.g., atorvastatin, cerivastatin, fluvastatin, mevastatin, monacolins (e.g., monacolin K [lovastatin]), pitavastatin, pravastatin, rosuvastatin, and simvastatin} and flavanones (e.g., naringenin); squalene synthase inhibitors, including lapaquistat, zaragozic acid, and RPR-107393; anthocyanins, avenaciolides, chloroacetylated biotin, cyclodim, diclofop, haloxyfop, soraphens (e.g., soraphen A 1α), 5-(tetradecyloxy)-2-furancarboxylic acid (TOFA), CP-640186, GS-0976, NDI-010976, acetyl-CoA carboxylase (ACC) inhibitors; 7-(4-propyloxy-phenylethynyl)-3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin; N-ethyl-N'-(3-{[4-(3,3-dimethyl-1-oxo-2-oxa-7-azaspiro[4.5]dec-7-yl)piperidin-1-yl]-carbo 1-(3-{[4-(3,3-dimethyl-1-oxo-2-oxa-7-azaspiro[4.5]dec-7-yl)piperidin-1-yl]-carbonyl}-5-(pyridin-2-yl)-2-thienyl)-3-ethylurea; bempedoic acid (ETC-1002), 2-furoic acid, (-)-hydroxycitric acid, BMS-303141, MEDICA-16 and ATP citrate lyase (ACL) inhibitors, including SB-204990; fibrates (e.g., bezafibrate, ciprofibrate, clinofibrate, clofibric acid, clofibrate, aluminum clofibrate [alfibrate], clofibride, etofibrate, fenofibric acid, fenofibrate, gemfibrozil, lonifibrate, and simfibrate), isoflavones (e.g., daidzein and genistein), and perfluoroalkanoic acids. PPAR-α agonists, including (e.g., perfluorooctanoic acid and perfluorononanoic acid); PPAR-δ agonists, including elafibranor (dual PPAR-α / δ agonist), lanifibranor (triple PPAR-α / δ / γ agonist), GFT5O5 (dual PPAR-α / δ agonist), GW0742, GW501516 (dual PPAR-β / δ agonist), soderglitazar (GW677954), MBX-8025, and isoflavones (e.g., daidzein and genistein);PPAR-γ agonists, including thiazolidinediones (supra), saroglitazar (a dual PPAR-α / γ agonist), 4-oxo-2-thioxothiazolinones (e.g., rhodanine), berberine, honokiol, perfluorononanoic acid, cyclopentenone prostaglandins (e.g., cyclopentenone 15-deoxy-Δ-prostaglandin J2 [15d-PGJ2]), and isoflavones (e.g., daidzein and genistein); endogenous ligands (e.g., 22(R liver X receptor (LXR) agonists, including oxysterols (e.g., 24(S)-hydroxycholesterol, 27-hydroxycholesterol, and cholestenoic acid) and synthetic agonists (e.g., acetyl-podocarboxamide dimer, hypocholamide, N,N-dimethyl-3β-hydroxy-cholesterol [DMHCA], GW3965, and T0901317); endogenous ligands (e.g., 9-cis-retinoic acid) and synthetic agonists (e.g., bexarotene, AGN 191659, AGN 191701, AGN 191702, AGN 191703, AGN 191704, AGN 191705, AGN 191706, AGN 191707, AGN 191709, AGN 191708, AGN 191709 ... retinoid X receptor (RXR) agonists, including 192849, BMS649, LG100268, LG100754, and LGD346; triiodothyronine and thyroid hormone receptor beta agonists (above); ketohexokinase inhibitors (above); acyl-CoA cholesterol acyltransferase (ACAT, also known as sterol O-acyltransferase [SOAT], including ACAT1 [SOAT1] and ACAT2 [SOAT2]), including avasimibe, pactimibe, pellitorin, terpendol C, and flavanones (e.g., naringenin); ); inhibitors of stearoyl-CoA desaturase-1 (SCD-1, also known as stearoyl-CoA delta-9 desaturase) activity or expression, including aramchol, CAY-10566, CVT-11127, SAR-224, SAR-707, XEN-103; 3-(2-hydroxyethoxy)-4-methoxy-N-[5-(3-trifluoromethylbenzyl)thiazol-2-yl]benzamide and 4-ethylamino-3-(2-hydroxyethoxy)-N-[5-(3-trifluoromethylbenzyl)thiazol-2-yl]benzamide;1-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-5-(trifluoromethyl)-3,4-dihydrospiro[chromene-2,4-piperidine];5-Fluoro-1-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-3,4-dihydrospiro[chromene-2,4-piperidine];6-[5-(cyclopropylmethyl)-4,5-dihydro-1H,3H-spiro[1,5-benzoxazepine-2, 4-Piperidin]-1-yl]-N-(2-hydroxy-2-pyridin-3-ylethyl)pyridazine-3-carboxamide;6-[4-(2-methylbenzoyl)piperidin-1-yl]pyridazine-3-carboxylic acid (2-hydroxy-2-pyridin-3-ylethyl)amide;4-(2-chlorophenoxy)-N-[3-(methylcarbamoyl)phenyl]piperidine-1-carboxamide;cis-9,trans-11 and trans-10,cis-12 isomers of conjugated linoleic acid, WO 2009 / 129625 Substituted heteroaromatic compounds disclosed in the A1 brochure, antisense polynucleotides and peptide nucleic acids (PNAs) targeting SCD-1 mRNA, and SCD-1-targeting siRNA; cholesteryl ester transfer protein (CETP) inhibitors, including anacetrapib, dalcetrapib, evacetrapib, torcetrapib, and AMG899 (TA-8995); implitapide, lomitapide, dirlotapide, mitratapide, CP-346086, JTT-130, SLx-4090, MTTP mRNA inhibitors of microsomal triglyceride transfer protein (MTTP) activity or expression, including antisense polynucleotides and PNAs targeting MTTP, MTTP-targeting microRNAs (e.g., miRNA-30c), and MTTP-targeting siRNAs; GLP-1 receptor agonists (above), glucagon receptor agonists (above), and dual GLP-1 receptor / glucagon receptor agonists (above); fibroblast growth factor 21 (FGF21) and analogs and derivatives thereof, including BMS-986036 (pegylated FGF21);Inhibitors of proprotein convertase subtilisin / kexin type 9 (PCSK9) activity or expression, including berberine (which reduces PCSK9 levels), annexin A2 (which inhibits PCSK9 activity), anti-PCSK9 antibodies (e.g., alirocumab, bococizumab, evolocumab, LGT-209, LY3015014, and RG7652), peptides that mimic the epidermal growth factor A (EGF-A) domain of the LDL receptor that binds PCSK9, PCSK9-binding adnectins (e.g., BMS-962476), antisense polynucleotides and PNAs that target PCSK9 mRNA, and PCSK9-targeting siRNA (e.g., inclisiran [ALN-PCS] and ALN-PCS02); FGF21 and its analogs and derivatives (supra). These also include anti-ANGPTL3, anti-ANGTPT4, anti-ANGPTL3 / 8 mAbs and siRNAs against ANGPTL3 in development for the treatment of dylipidemia.

[0202] ApoA-I mimics (e.g., 2F, 3F, 3F-1, 3F-2, 3F-14, 4F, 4F-P-4F, 4F-IHS-4F, 4F2, 5F, 6F, 7F, 18F, 5A, 5A-C1, 5A-CH1, 5A-CH2, 5A-H1, 18A, 37pA [18A-P-18A], ELK[name], ELK-1A, ELK-1F, ELK- 1K1A1E, ELK-1L1K, ELK-1W, ELK-2A, ELK-2A2K2E, ELK-2E2K, ELK-2F, ELK-3E3EK, ELK-3E3K 3A, ELK-3E3LK, ELK-PA, ELK-P2A, ELKA[name], ELKA-CH2, ATI-5261, CS-6253, ETC-642, FA apolipoprotein mimetic peptides, including Ac-hE18A-NH2[AEM-28], Ac-[R]hE18A-NH2, AEM-28-14, EpK, hEp, mR18L, COG-112, COG-133, and COG-1410; omega-3 fatty acids, including docosahexaenoic acid (DHA), docosapentaenoic acid (DPA), eicosapentaenoic acid (EPA), alpha-linolenic acid (ALA), fish oils (which contain, for example, DHA and EPA), and esters thereof (e.g., glyceryl and ethyl esters); and analogs, derivatives, and salts thereof.

[0203] In other embodiments, one or more compounds of structural formula (I) are used in combination with an antiplatelet agent and / or an anticoagulant for the treatment of a thrombotic or hemostatic disorder, such as a cardiovascular disorder (e.g., myocardial ischemia / infarction) or a cerebrovascular disorder (e.g., ischemic stroke). In certain embodiments, the antiplatelet agent is a COX-1 inhibitor (e.g., aspirin) or / and a P2Y 12 inhibitors (e.g., clopidogrel), and the anticoagulant is or includes a direct factor Xa inhibitor (e.g., apixaban or rivaroxaban) or / and a direct thrombin inhibitor (e.g., dabigatran).

[0204] Antiplatelet agents include, without limitation, cyclooxygenase (e.g., COX-1) inhibitors, including buspirin, naproxen, triflusal, and 2-hydroxy-4-trifluoromethylbenzoic acid (the major metabolite of triflusal); thromboxane (e.g., A2) synthase inhibitors, including isbogrel, ozagrel, picotamide, ridogrel, samixogrel, terbogrel, and EV-077; thromboxane (e.g., A2) receptor antagonists, including dipyridamole, ifetroban, isbogrel, picotamide, ramatroban, ridogrel, samixogrel, terbogrel, terutroban, EV-077, and TRA-418; adenosine diphosphate (ADP) receptor / P2Y antagonists, including cangrelor, clopidogrel, prasugrel, ticagrelor, and ticlopidine. 12 inhibitors; adenosine reuptake inhibitors, including cilostazol and dipyridamole; glycoprotein IIb / IIIa inhibitors, including abciximab, eptifibatide, tirofiban, TRA-418, and prostacyclin and its analogues; phosphodiesterase (e.g., PDE3 and / or PDE5) inhibitors, including cilostazol and dipyridamole; protease-activated receptor 1 (PAR1) antagonists, including vorapaxar; ataprost, beraprost (e.g., esveraprost), 5,6,7-trinor-4,8- Prostacyclin and its analogs, including inter-m-phenylene-9-fluoro-PGI2, carbacyclin, isocarbacyclin, clinprost (isocarbacyclin methyl ester), ciprostene, eptaloprost, cicaprost (a metabolite of eptaloprost), iloprost, pimilprost, SM-10906 (des-methylpimilprost), naxaprostene, taprostenyl, treprostinil, CS-570, OP-2507, and TY-11223; and analogs, derivatives, and salts thereof.

[0205] Anticoagulants include, but are not limited to, vitamin K antagonists, including 4-hydroxycoumarins (e.g., acenocoumarol, brodifacoum, coumatetralyl, dicoumarol, phenprocoumon, thiochromarol, and warfarin) and 1,3-indanediones (e.g., chlorindione, diphenadione, fluindione, and phenindione); heparin (unfractionated), low molecular weight (MW) heparin (e.g., Fraxiparine®), low molecular weight heparin derivatives (e.g., bemiparin, certoparin, dalteparin, enoxaparin, nadroparin, parnaparin, reviparin, and tinzaparin), heparin analogs (e.g., fondaparinux and idraparinux), and heparinoids (e.g., danaparoid, sulodexide, and dermatan sulfate); direct factor Xa inhibitors, including apixaban, betrixaban, darexaban, edoxaban, elivaxaban, retaxaban, otamixaban, razaxaban, rivaroxaban, LY-517717, and YM-466; direct thrombin (factor IIa) inhibitors (DTIs), including monovalent DTIs (e.g., argatroban, dabigatran, inogatran, melagatran, and ximelagatran) and bivalent DTIs (e.g., hirudin and hirudin analogs [e.g., bivalirudin, desirudin, and lepirudin]); and analogs, derivatives, and salts thereof.

[0206] In further embodiments, one or more compounds of structural formula (I) are used in combination with one or more antihypertensive agents. Hypertension is a clinical feature or a major risk factor for a wide range of disorders. Hypertension-related disorders include, without limitation, cardiovascular disorders (e.g., cardiomyopathy, heart failure, atherosclerosis, arteriosclerosis, coronary artery disease [e.g., myocardial ischemia / infarction], and peripheral vascular disease [e.g., peripheral arterial disease]), cerebrovascular disorders (e.g., stroke and cerebral infarction), metabolic disorders (e.g., metabolic syndrome and T2D), renal disorders (e.g., diabetic nephropathy, glomerulonephritis, renal ischemia, nephrotic syndrome, and renal failure [e.g., acute kidney injury and chronic kidney disease]), hepatic failure (e.g., cirrhosis), and ophthalmic disorders (e.g., retinopathy, ocular vascular damage, and vision loss).

[0207] Antihypertensive agents include, without limitation, renin inhibitors (e.g., aliskiren), angiotensin-converting enzyme (ACE) inhibitors (e.g., benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril), angiotensin II receptor type 1 (AT1) antagonists (e.g., azilsartan, candesartan, eprosartan, fimasartan, irbesartan, losartan, olmesartan medoxomil, olmesartan, telmisartan, and valsartan), and antagonists of the renin-angiotensin-aldosterone system (RAAS), including aldosterone receptor antagonists (e.g., eplerenone and spironolactone); loop diuretics (e.g., bumetanide, ethacrynic acid, furosemide and torsemide), thiazide diuretics (e.g., bendroflumethiazide, chlorothiazide, hydrochlorothiazide, epitizide, methyclothiazide and polythiazide), thiazide diuretics (e.g., chlorthalidone, indapamide and metolazone), cicletanine (an early distal tubular diuretic), potassium-sparing diuretics diuretics, including dihydropyridines (e.g., amiloride, eplerenone, spironolactone, and triamterene), and theobromine; calcium channel blockers, including dihydropyridines (e.g., amlodipine, lebuamlodipine, cilnidipine, clevidipine, felodipine, isradipine, lercanidipine, nicardipine, nifedipine, nimodipine, nisoldipine, and nitrendipine) and non-dihydropyridines (e.g., diltiazem and verapamil); alpha2-adrenergic receptor agonists; alpha1-adrenergic receptor antagonists (alpha blockers), including doxazosin, indoramin, nicergoline, phenoxybenzamine, phentolamine, prazosin, terazosin, and tolazoline; beta-adrenergic receptor (beta1 and / or beta2) antagonists (beta blockers), including atenolol, betaxolol, bisoprolol, carteolol, carvedilol, labetalol, metoprolol, nadolol, nebivolol, oxprenolol, penbutolol, pindolol, propranolol, and timolol;Mixed alpha / beta blockers, including bucindolol, carvedilol, and labetalol; selective ET; A Receptor antagonists (e.g., ambrisentan, atrasentan, edonentan, sitaxsentan, zibotentan, and BQ-123) and dual ET A / ET B endothelin receptor antagonists, including antagonists (e.g., bosentan, macitentan, and tezosentan); hydralazine, minoxidil, theobromine, sodium nitroprusside, organic nitrates (e.g., isosorbide mononitrate, isosorbide dinitrate, and nitroglycerin, which are converted to nitric oxide in the body), endothelial nitric oxide synthase (eNOS) stimulators (e.g., cicletanine), activators of soluble guanylate cyclase (e.g., cinaciguat and riociguat), phosphodiesterase type 5 (PDE5) inhibitors (e.g., avanafil, benzamidonafil, dasantafil, dynafil, lodenafil, mirodenafil, sildenafil, tadalafil, udenafil, vardenafil, dipyridamole, papaverine, propentofylline, zaprinast, and T- 1032), other vasodilators, including prostaglandin E1 (alprostadil) and its analogs (e.g., limaprost and misoprostol), prostacyclin and its analogs (above), non-prostanoid prostacyclin receptor agonists (e.g., 1-phthalazinol, lalinepag, selexipag, ACT-333679 [MRE-269, the active metabolite of selexipag], and TRA-418), phospholipase C (PLC) inhibitors, and protein kinase C (PKC) inhibitors (e.g., BIM-1, BIM-2, BIM-3, BIM-8, chelerythrine, cicletanine, gossypol, myabenol C, myricitrin, ruboxistaurin, and verbascoside); minerals, including magnesium and magnesium sulfate; and analogs, derivatives, and salts thereof.

[0208] In certain embodiments, the one or more antihypertensive agents are or include a thiazide or thiazide-type diuretic (e.g., hydrochlorothiazide or chlorthalidone), a calcium channel blocker (e.g., amlodipine or nifedipine), an ACE inhibitor (e.g., benazepril, captopril, or perindopril), or an angiotensin II receptor antagonist (e.g., olmesartan medoxomil, olmesartan, telmisartan, or valsartan), or any combination thereof.

[0209] In further embodiments, one or more compounds of structural formula (I) are used in combination with one or more antioxidants for the treatment of disorders whose etiology or pathophysiology involves oxidative stress or / and oxidative damage / injury. Such oxidative disorders include, without limitation, neurodegenerative disorders (e.g., Alzheimer's, Huntington's and Parkinson's diseases, ALS and multiple sclerosis), metabolic disorders (e.g., type 1 and type 2 diabetes and metabolic syndrome), cardiovascular disorders (e.g., atherosclerosis, heart failure, myocardial ischemia / infarction and IRI), cerebrovascular disorders (e.g., stroke and IRI), renal disorders (e.g., diabetic nephropathy), hepatic disorders (e.g., cirrhosis), and ocular disorders (e.g., AMD). Furthermore, oxidants (e.g., ROS) and oxidized molecules (e.g., oxidized lipids) can be highly inflammatory.

[0210] Antioxidants include, without limitation, vitamins and their analogs, including vitamin A, vitamin B3 (e.g., niacin [nicotinic acid] and nicotinamide), vitamin C (ascorbic acid), vitamin E (tocopherols [e.g., α-tocopherol] and tocotrienols), and vitamin E analogs (e.g., Trolox [water soluble]); carotenes (e.g., β-carotene), xanthophylls (e.g., lutein, zeaxanthin, and meso-zeaxanthin), and saffron carotenoids (e.g., crocin and crocetin). also carotenoids; sulfur-containing antioxidants, including glutathione (GSH), N-acetyl-L-cysteine ​​(NAC), bucillamine, S-nitroso-N-acetyl-L-cysteine ​​(SNAC), S-allyl-L-cysteine ​​(SAC), S-adenosyl-L-methionine (SAM), alpha-lipoic acid, and taurine; carnosine, N-acetyl-carnosine, curcuminoids (e.g., curcumin, demethoxycurcumin, and tetrahydrocurcumin), cysteamine, ebselen, glutathione, hydroxycinnamic acid and its derivatives (e.g., esters and amides) (e.g., caffeic acid, rosmarinic acid, and tranilast), melatonin and its metabolites, nitrones (e.g., disfenton sodium [NXY-059]), nitroxides (e.g., XJB-5-131), polyphenols (e.g., flavonoids [e.g., apigenin, genistein, luteolin, naringenin, and quercetin]), superoxide dismutase mimetics (see below), tirilazad, vitamin C, vitamin E and its analogs (e.g., α-tocopherol and trolox), and xanthine derivatives (e.g., pentoxycholic acid ... scavengers of ROS and radicals, including cyphylline; NADPH oxidase (NOX) inhibitors (e.g., apocynin, decursin, and decursinol angelate [both of which inhibit NOX-1, -2, and -4 activity and expression], diphenyleneiodonium, and GKT-831 [formerly GKT-137831, a dual NOX1 / 4 inhibitor]); NADH:ubiquinone oxidoreductase (complex I) inhibitors (e.g., metformin and rotenone), and myeloperoxidase inhibitors (e.g., azide and 4-aminobenzoic acid hydrazide,inhibitors of ROS-producing enzymes, including apoE mimetics such as AEM-28 and AEM-28-14; superoxide dismutase (SOD) {e.g., manganese(III)- and zinc(II)-porphyrin complexes (e.g., MnTBAP, MnTMPyP, and ZnTBAP), manganese(II) penta-azamacrocyclic complexes (e.g., M40401 and M40403), manganese(II)-salen complexes (e.g., those disclosed in U.S. Pat. No. 7,122,537), and OT-551 (cyclopropyl ester of tempol hydroxylamine); terprodrugs), and SOD mimetics such as resveratrol and apo AI mimetics such as 4F (both increase expression)}, catalase (e.g., catalase mimetics such as manganese(III)-salen complexes [e.g., those disclosed in U.S. Pat. No. 7,122,537], and zinc [increases activity]), glutathione peroxidase (GPx) (e.g., apomorphine and zinc [both increase activity], and β-catenin, etoposide, and resveratrol [all three increase expression]), glutathione reductase ( For example, redox cofactors such as 4-tert-butylcatechol and flavin adenine dinucleotide [FAD] and NADPH [all three enhance activity]), glutathione S-transferases (GSTs) (for example, phenylalkyl isothiocyanate-cysteine ​​conjugates {e.g., S-[N-benzyl(thiocarbamoyl)]-L-cysteine}, phenobarbital, rosemary extract, and carnosol [all enhance activity]), thioredoxins (Trxs) (for example, geranylgeranylacetone, prostaglandin E1, and and sulforaphane [all increase expression]), NADPH-quinone oxidoreductase 1 (NQO1) {e.g., flavones [e.g., β-naphthoflavone (5,6-benzoflavone)] and triterpenoids [e.g., TP-151 (CDDO), TP-155 (CDDO methyl ester), TP-190, TP-218, TP-222, TP-223 (CDDO carboxamide), TP-224 (CDDO monomethylamide), TP-225, TP-226 (CDDO dimethylamide), TP-230, TP-235 (CDDO imidazolide),agents that mimic or increase the activity or production of antioxidant enzymes, including oleanolic acid analogs such as TP-241, CDDO monoethylamide, CDDO mono(trifluoroethyl)amide, and (+)-TBE-B, all of which increase expression via activation of Nrf2}, heme oxygenase 1 (HO-1) {e.g., curcuminoids (e.g., curcumin), triterpenoids (e.g., oleanolic acid analogs [e.g., TP-225, above]), and apoA I mimetics (e.g., 4F, above), all of which increase expression}, and paraoxonase 1 (PON-1) (e.g., apoE mimetics [e.g., AEM-28 and AEM-28-14, above] and apoA I mimetics [e.g., 4F, above], both types increase activity); nuclear factor activator (erythroid-derived 2)-like 2 (NFE2L2 or Nrf2) {e.g., transcription factor activators that upregulate expression of antioxidant enzymes, including bardoxolone methyl, OT-551, fumarates (e.g., dimethyl and monomethyl fumarate), dithiolethiones (e.g., oltipraz), flavones (e.g., β-naphthoflavone), isoflavones (e.g., genistein), sulforaphane, trichostatin A, triterpenoids (e.g., oleanolic acid analogs [such as TP-225, supra]), and melatonin (which increase Nrf2 expression)}; mitochondrial targeted antioxidants, including MitoE and MitoQ; anthocyanins, benzenediol abietane diterpenes (e.g., carnosic acid), cyclopentenone prostaglandins (e.g., 15d-PGJ2), flavonoids {e.g., Ginkgo biloba ( biloba flavonoids (e.g., myricetin and quercetin [which increase levels of GSH, SOD, catalase, GPx, and GST]), prenylflavonoids (e.g., isoxanthohumol), flavones (e.g., apigenin), isoflavones (e.g., genistein), flavanones (e.g., naringenin), and flavanols (e.g., catechin and epigallocatechin-3-gallate)}, omega-3 fatty acids and their esters (mentioned above), phenylethanoids (e.g., tyrosol and hydroxytyrosol), retinoids (e.g., all-trans retinol [vitamin A]),Other types of antioxidants include stilbenoids (e.g., resveratrol), uric acid, apo AI mimetics (e.g., 4F), apo E mimetics (e.g., AEM-28 and AEM-28-14), and minerals (e.g., selenium and zinc [e.g., zinc monocysteine]); and analogs, derivatives, and salts thereof.

[0211] In certain embodiments, the one or more antioxidants are or include a vitamin or analog thereof (e.g., vitamin E or an analog thereof such as alpha-tocopherol or trolox) or / and a ROS or radical scavenger (e.g., melatonin or / and glutathione). In other embodiments, the antioxidant and / or natural compound is selected from resveratrol, pterostilbene, ellagic acid, urolithin A, quercetin, coenzyme Q, glutathione, N-acetyl-L-cysteine, alpha-lipoic acid, melatonin, creatine, S-adenosylmethionine, leucine, pyruvic acid / pyruvate, and combinations thereof.

[0212] In some embodiments, the one or more compounds of structural formula (I) are selected from the group consisting of thiamine (B1), riboflavin (B2), niacin (B3), pantothenic acid (B5), pyridoxine (B6), biotin (B7), folic acid (B9), and cobalamin (B 12 In certain embodiments, one or more compounds of structural formula (I) are used in combination with one or more B vitamins selected from the group consisting of vitamins B1, B2, B3, or B6, or any combination thereof.

[0213] In further embodiments, one or more compounds of structural formula (I) are used in combination with one or more anti-inflammatory agents for the treatment of inflammatory disorders. Inflammation contributes to the pathogenesis or pathophysiology of a wide variety of disorders. Moreover, inflammation is a major stimulant of fibrosis. In certain embodiments, the one or more anti-inflammatory agents are or include NSAIDs and / or inhibitors of proinflammatory cytokines or their receptors or their production (e.g., TNF-α, IL-4, IL-6, or IL-23, or any combination thereof).

[0214] Anti-inflammatory agents include, without limitation, nonsteroidal anti-inflammatory drugs (NSAIDs), including: immunomodulators, including imides (e.g., thalidomide, lenalidomide, pomalidomide, and apremilast) and xanthine derivatives (e.g., lisofylline, pentoxifylline, and propentofylline); interferon beta (IFN-β), glucocorticoids (see below), antimetabolites (e.g., hydroxyurea [hydroxycarbamide], antifolates [e.g., methotrexate], and purine analogs [e.g., azathioprine, mercaptopurine, and thioguanine]), pyrimidine synthesis inhibitors (e.g., leflunomide and teriflunomide), calcineurin inhibitors (e.g., cyclosporine [cyclosporine A], pimecrolimus, and tacrolimus), inosine-5-monophosphate dehydrogenase (IMPDH) inhibitors (e.g., mycophenolic acid and its derivatives [e.g., mycophenolate sodium and mycophenolate mofetil]), mechanistic / mammalian target of rapamycin (mTOR) inhibitors (e.g., rapamycin [sirolimus], defoaminase [defoaminase], foamyltransferase [defoamyltransfer ... immunosuppressants, including sphingosine-1-phosphate receptor (e.g., S1PR1) (e.g., fingolimod), and serine C-palmitoyltransferase inhibitors (e.g., myriocin); IL-10 and compounds that increase IL-10 production {e.g., S-adenosyl-L-methionine, melatonin, metformin, rotenone, curcuminoids (e.g., curcumin), prostacyclin, and anti-inflammatory cytokines and compounds that increase their production, including compounds and their analogs (above), triterpenoids (e.g., oleanolic acid analogs [above, such as TP-225]), and apo AI mimetics (above, such as 4F); tumor necrosis factor-α (TNF-α) (e.g., adalimumab, certolizumab pegol, golimumab, infliximab, etanercept, bupropion, curcumin, catechins, and ART-621) or inhibitors of its receptor (TNFR1) (e.g., antibodies or fragments thereof that target it), thymic stromal lymphopoietin (TNF-α) (e.g., thymic stromal lymphopoietin (THF) ...anti-TSLP antibodies and fragments thereof [e.g., tezepelumab and M702] and immunoconjugates comprising the extracellular domain of TSLPR) or inhibitors of its receptor (TSLPR), inhibitors of proinflammatory interferons (e.g., interferon-α [IFN-α]) or its receptor (e.g., antibodies or fragments thereof that target same), inhibitors of proinflammatory interleukins or their receptors {e.g., IL-1 (e.g., IL-1α and IL-1β [e.g., canakinumab and rilonacept]) or IL-1R (e.g., anakinra and isunakinra [EBI- 005]), IL-2 or IL-2R (e.g., basiliximab and daclizumab), IL-4 or IL-4R (e.g., dupilumab), IL-5 (e.g., mepolizumab and reslizumab) or IL-5R, IL-6 (e.g., clazakizumab, ercilimomab, olokizumab, siltuximab and sirukumab) or IL-6R (e.g., sarilumab and tocilizumab), IL-8 or IL-8R, IL-12 (e.g., briakinumab and ustekinumab) or IL-12R, IL-13 or IL-13R, IL-15 or IL-15R, IL- IL-17 (e.g., ixekizumab and secukinumab) or IL-17R (e.g., brodalumab), IL-18 (e.g., GSK1070806) or IL-18R, IL-20 (e.g., antibody 7E) or IL-20R, IL-22 (e.g., fezakinumab) or IL-22R, IL-23 (e.g., briakinumab, guselkumab, risankizumab, tildrakizumab [SCH-900222], ustekinumab, and BI-655066) or IL-23R, IL-31 (e.g., anti-IL-31 antibodies disclosed in U.S. Pat. No. 9,822,177) or IL-31R, and inhibitors of (e.g., antibodies or fragments thereof targeting) monocyte chemoattractant protein 1 (MCP-1) {e.g., bindarit, anti-MCP1 antibodies (e.g., 5D3-F7 and 10F7), MCP1-binding peptides (e.g., HSWRHFHTLGGG (SEQ ID NO: 2)), and MCP1-binding RNA aptamers (e.g., ADR22 and mNOX-E36 [Spiegelmer])} or its receptors (e.g.,inhibitors of proinflammatory cytokines or their receptors, including inhibitors of CCR2 antagonists such as spiropiperidines [e.g., RS-29634, RS-102895, and RS-504393]; inhibitors of TNF-α production {e.g., N-acetyl-L-cysteine, S-adenosyl-L-methionine, L-carnitine, hydroxychloroquine, melatonin, parthenolide, pirfenidone, sulfasalazine, mesalazine (5-aminosalicylic acid), taurine, flavonoids (e.g., epigallocatechin-3-gallate [EGCG], naringenin, and quercetin), omega-3 fatty acids and their esters, glucocorticoids, immunomodulatory imides and xanthine derivatives, PDE4 inhibitors, serine protease inhibitors (e.g., gabexate and nafamostat), prostacyclin and its analogs, SOCS1 mimetics (see below), myxoma virus M013 protein, Yersinia YopM protein, apo AI mimetics (e.g., 4F), and apo E mimetics (e.g., AEM-28 and hEp)}, IFN-α (e.g., alefacept), IL-1 (e.g., IL-1α and IL-1β) (e.g., chloroquine, hydroxychloroquine, nafamostat, pirfenidone, sulfasalazine, mesalazine, prostacyclin and its analogs, glucocorticoids, TNF-α inhibitors, PARI antagonists [e.g., vorapaxar], M013 proteins, YopM proteins, and apoAI mimetics [e.g., 4F]), IL-1β (e.g., melatonin, metformin, rotenone, flavonoids [e.g., EGCG and naringenin], annexin A1 mimetics, and caspase-1 inhibitors [e.g., vernacasan, prasugrel ... lunacasan and parthenolide]), IL-2 (e.g., glucocorticoids, calcineurin inhibitors and PDE4 inhibitors), IL-4 (e.g., glucocorticoids and serine protease inhibitors [e.g., gabexate and nafamostat]), IL-5 (e.g., glucocorticoids), IL-6 (e.g., nafamostat, parthenolide, prostacyclin and its analogs, tranilast, L-carnitine, taurine, flavonoids [e.g., EGCG, naringenin and quercetin], omega-3 fatty acids and their esters,glucocorticoids, immunomodulatory imides, TNF-α inhibitors, M013 protein and apoE mimetics [e.g., AEM-28 and hEp]), IL-8 (e.g., alefacept and glucocorticoids), IL-12 (e.g., apilimod, PDE4 inhibitors and YopM protein), IL-15 (e.g., YopM protein), IL-17 (e.g., protein kinase C inhibitors such as sotrastaurin), IL-18 (e.g., M013 protein, YopM protein and caspase-1 inhibitors), and IL-23 (e.g., apilimod, inhibitors of the production of proinflammatory cytokines or their receptors, including proinflammatory cytokines (e.g., alefacept and PDE4 inhibitors), and MCP-1 (e.g., EGCG, melatonin and tranilast); inhibitors of NF-κB or its activation or expression {e.g., aliskiren, melatonin, minocycline and parthenolide (both of which inhibit NF-κB nuclear translocation), nafamostat, niclosamide, (-)-DHMEQ, IT-603, IT-901, PBS-1086, flavonoids (e.g., EGCG and quercetin), hydroxycinnamic acids and their esters (e.g., These include, for example, ethyl caffeate), lipoxins (e.g., 15-epi-LXA4 and LXB4), omega-3 fatty acids and their esters, stilbenoids (e.g., resveratrol), statins (e.g., rosuvastatin), triterpenoids (e.g., oleanolic acid analogues such as TP-225), TNF-α inhibitors, apoE mimetics (e.g., AEM-28), M013 protein, penetratin, and activators of sirtuin 1 (SIRT1, which inhibits NF-κB) (e.g., flavones [e.g., luteolin], phenylethanoids [e.g., tyrosol, which induces SIRT1 expression], stilbenoids [e.g., resveratrol, which increases SIRT1 activity and expression] and lamin A}, and inhibitors of STAT (signal transducer and activator of transcription) proteins or their activation or expression {e.g., Janus kinase 1 (JAK1) inhibitors (e.g., itacitinib, upadacitinib, GLPG0634 and GSK2586184), JAK2 inhibitors (e.g., lestaurtinib, pacritinib, CYT387, TG101348, SOCS1 mimetics and SOCS3 mimetics),JAK3 inhibitors (e.g., ASP-015K, R348, and VX-509), dual JAK1 / JAK2 inhibitors (e.g., baricitinib and ruxolitinib), dual JAK1 / JAK3 inhibitors (e.g., tofacitinib), inhibitors of cytokine signaling (SOCS) mimetic peptides (e.g., SOCS1 mimetics [e.g., SOCS1-KIR, NewSOCS1-KIR, PS-5, and Tkip] and SOCS3 mimetics), niclosamide, hydroxycinnamic acids and their esters (e.g., rosmarinic acid), and lipoxins (e.g., cyclooxygenase inhibitors (e.g., NSAIDs [including non-selective COX-1 / COX-2 inhibitors such as aspirin and selective COX-2 inhibitors such as coxibs], glucocorticoids [which inhibit COX activity and expression], omega-3 fatty acids and their esters, curcuminoids [e.g., curcumin], stilbenoids [e.g., resveratrol, which inhibits COX-1 and -2 activity and expression], and bile acid inhibitors (e.g., cyclooxygenase inhibitors, proinflammatory prostaglandins (e.g., prostaglandin E2 [PGJ2], Δ12-PGJ2 and 15-deoxy-Δ12,14-PGJ2), hydroxycinnamic acids and their esters (e.g., ethyl caffeate, which inhibits COX-2 expression), and triterpenoids (e.g., oleanolic acid analogs such as TP-225, which inhibit COX-2 expression), including prostaglandins (e.g., prostaglandin E2 [PGJ2], Δ12-PGJ2 and 15-deoxy-Δ12,14-PGJ2), E2]) or its receptors (e.g., EP3) or inhibitors of its production; cysteinyl leukotriene receptor 1 (cysLTR1) antagonists (e.g., sinalukast, gemilukast [dual cysLTR1 / cysLTR2 antagonist], iralukast, montelukast, pranlukast, tomelukast, berlukast, zafirlukast, CP-195494, CP-199330, ICI-198615, MK-571 and lipoxins [e.g., LXA4 and 15-epi-LXA4]), cysLTR2 antagonists (e.g., HAMI-3379),5-lipoxygenase (5-LOX) inhibitors (e.g., baicalein, caffeic acid, curcumin, hyperforin, gamma-linolenic acid [GLA], meclofenamic acid, meclofenamic acid sodium, minocycline, zileuton, MK-886, and omega-3 fatty acids, inhibitors of leukotrienes or their receptors or their production, including leukotrienes (e.g., esters thereof), and immunomodulatory xanthine derivatives; inhibitors of phospholipase A2 (e.g., secreted and cytosolic PLA2), including glucocorticoids, arachidonyl trifluoromethyl ketone, bromoenol lactone, chloroquine, cytidine 5-diphosphoamines, darapladib, quinacrine, vitamin E, RO-061606, ZPL-521, lipocortins (annexins, such as annexin A1), and annexin mimetic peptides (e.g., annexin A1 mimetics [e.g., Ac2-26 and CGEN-855A]); statins (e.g., rosuvastatin), thiazolidinediones (e.g., inhibitors of C-reactive protein (CRP) activity or levels, including DPP-4 inhibitors (above), stilbenoids (e.g., resveratrol), epigallocatechin-3-gallate, and CRP-i2; mast cell stabilizers, including cromoglycate (cromolyn), ketotifen, methylxanthines, nedocromil, nicotinamide, olopatadine, omalizumab, pemirolast, quercetin, and zinc sulfate; phosphodiesterase inhibitors, including PDE4 inhibitors (e.g., apremilast, cilomilast, ibudilast, piclamilast, roflumilast, crisaborole, diazepam, luteolin, mesembrenone, rolipram, AN2728, and E6005);Metabolites of polyunsaturated fatty acids (PUFAs), such as lipoxins (e.g., LXA4, 15-epi-LXA4, LXB4, and 15-epi-LXB4), resolvins (e.g., 5Z,8Z,11Z,14Z,17Z-eicosapentaenoic acid [EPA]-derived resolvins, 4Z,7Z,10Z,13Z,16Z,19Z-docosahexaenoic acid [DHA]-derived resolvins, and 7Z,10Z,13Z,16Z,19Z-docosahexaenoic acid [n-3 DPA]-derived resolvins), protectins / neuroprotectins (e.g., DHA-derived protectins / neuroprotectins and n-3 DPA-derived protectins / neuroprotectins), maresins (e.g., DHA-derived maresins and n-3 DPA-derived maresins), n-3 DPA metabolites, n-6 Specialized pro-resolution mediators (SPMs), including DPA (4Z,7Z,10Z,13Z,16Z-docosapentaenoic acid) metabolites, oxo-DHA metabolites, oxo-DPA metabolites, docosahexaenoylethanolamide metabolites, cyclopentenone prostaglandins (e.g., Δ12-PGJ2 and 15-deoxy-Δ12,14-PGJ2), and cyclopentenone isoprostanes (e.g., 5,6-epoxyisoprostane A2 and 5,6-epoxyisoprostane E2); other classes of anti-inflammatory agents, including pirfenidone, nintedanib, vitamin A, omega-3 fatty acids and their esters, apo AI mimetics (e.g., 4F), apo E mimetics (e.g., AEM-28 and AEM-28-14), and antioxidants (e.g., sulfur-containing antioxidants); and analogs, derivatives, fragments, and salts thereof.

[0215] Nonsteroidal anti-inflammatory drugs (NSAIDs) include, without limitation, acetic acid derivatives such as aceclofenac, bromfenac, diclofenac, etodolac, indomethacin, ketorolac, nabumetone, sulindac, sulindac sulfide, sulindac sulfone, and tolmetin; anthranilic acid derivatives (fenamates), such as flufenamic acid, meclofenamic acid, mefenamic acid, and tolfenamic acid; enolic acid derivatives (oxicams), such as droxicam, isoxicam, lornoxicam, meloxicam, piroxicam, and tenoxicam; fenoprofen, flurbiprofen, ibuprofen, dexibuprofen, ketoprofen, dexketoprofen, loxoprofen, naproxen, and oxaprodi propionic acid derivatives such as diflunisal, salicylic acid, acetylsalicylic acid (aspirin), choline magnesium trisalicylate, salsalate, and mesalazine; salicylates such as apricoxib, celecoxib, etoricoxib, firocoxib, fluorocoxibs (e.g., fluorocoxib A-C), lumiracoxib, mavacoxib, parecoxib, rofecoxib, tilmacoxib (JTE-522), valdecoxib, 4-O-methylhonokiol, niflumic acid, DuP-697, CG100649, GW406381, NS-398, SC-236, SC-58125, benzothieno[3,2-d]pyrimidin-4-one sulfonamide thio derivatives, and Tribulus terrestris. COX-2 selective inhibitors, such as those derived from C. terrestris; other types of NSAIDs, such as monoterpenoids (e.g., eucalyptol and phenols (e.g., carvacrol)), anilinopyridine carboxylic acids (e.g., clonixin), sulfonanilides (e.g., nimesulide), and dual inhibitors of lipoxygenase (e.g., 5-LOX) and cyclooxygenase (e.g., COX-2) {e.g., chebulazic acid, licofelone, 2-(3,4,5-trimethoxyphenyl)-4-(N-methylindol-3-yl)thiophene, and di-tert-butylphenols (e.g., DTPBHZ, DTPINH, DTPNHZ, and DTPSAL)}; and analogs, derivatives, and salts thereof.

[0216] The glucocorticoid class of corticosteroids has anti-inflammatory and immunosuppressant properties. Glucocorticoids include, without limitation, hydrocortisone-type (e.g., cortisone and its derivatives [e.g., cortisone acetate], hydrocortisone and its derivatives [e.g., hydrocortisone acetate, hydrocortisone-17-aceponate, hydrocortisone-17-buteprate, hydrocortisone-17-butyrate, and hydrocortisone-17-valerate], prednisolone, methylprednisolone and its derivatives [e.g., methylprednisolone aceponate], prednisone, and tixocortol and its derivatives [e.g., tixocortol pivalate]), betamethasone-type (e.g., betamethasone and its derivatives [e.g., betamethasone dipropionate, betamethasone sodium phosphate, and betamethasone valerate], dexamethasone and its derivatives [e.g., dexamethasone sodium phosphate], and fluocortolone and its derivatives [e.g., capronate, fluocortolone acid and fluocortolone pivalate]), halogenated steroids (e.g., alclometasone and its derivatives [e.g., alclometasone dipropionate], beclomethasone and its derivatives [e.g., beclomethasone dipropionate], clobetasol and its derivatives [e.g., clobetasol-17-propionate], clobetasone and its derivatives [e.g., clobetasone-17-butyrate], desoxymetasone and its derivatives [e.g., desoxymetasone acetate], diflorasone and its derivatives [e.g., diflorasone diacetate], diflucortolone and its derivatives [e.g., diflucortolone valerate], fluprednidene and its derivatives [e.g., fluprednidene acetate], fluticasone and its derivatives [e.g., fluticasone propionate], halobetasol [urobetasol] and its derivatives [e.g., halobetasol propionate],proprionate), halometasone and its derivatives [e.g., halometasone acetate], and mometasone and its derivatives [e.g., mometasone furoate]), acetonides and related substances (e.g., amcinonide, budesonide, ciclesonide, desonide, fluocinonide, fluocinolone acetonide, flurandrenolide [flurandrenolide or fludroxycortide], halcinonide, triamcinolone acetonide, and triamcinolone alcohol), carbonates (e.g., prednicarbate), and their analogues, derivatives, and salts.

[0217] In additional embodiments, one or more compounds of structural formula (I) are used in combination with one or more antifibrotic agents for the treatment of fibrotic disorders. In some embodiments, the one or more antifibrotic agents are or include anti-inflammatory agents or / and antioxidants (e.g., vitamin E or its analogs [e.g., α-tocopherol or trolox], sulfur-containing antioxidants or ROS or radical scavengers [e.g., melatonin], or any combination thereof). In certain embodiments, the one or more antifibrotic agents are or include pirfenidone (which also reduces fibroblast proliferation, among other antifibrotic and anti-inflammatory properties described herein) or / and nintedanib (which blocks the signal transduction of fibroblast growth factor receptor [FGFR], platelet-derived growth factor receptor [PDGFR], and vascular endothelial growth factor receptor [VEGFR], which are involved in fibroblast proliferation, migration, and transformation).

[0218] In further embodiments, the one or more antifibrotic agents are or include one or more agents with antihyperglycemic activity or / and insulin sensitizing activity for the treatment of fibrotic disorders in which hyperglycemia, diabetes, or insulin resistance contribute to the development of fibrosis. Examples of such disorders include diabetic nephropathy, which is characterized by renal fibrosis, and NASH and cirrhosis, both of which are characterized by liver fibrosis. The use of one or more antihyperglycemic agents or / and insulin sensitizing agents can, for example, reduce or prevent renal inflammation and renal fibrosis or liver inflammation and liver fibrosis. In certain embodiments, the one or more antifibrotic agents are or include PPAR-gamma agonists (e.g., thiazolidinediones [above], such as pioglitazone or rosiglitazone). PPARgamma-activating thiazolidinediones have both antihyperglycemic and insulin sensitizing properties.

[0219] Antifibrotic agents include, without limitation, protein kinase C (PKC) inhibitors (as described above, inhibit collagen production), colchicine and its metabolite colchiceine (both of which inhibit collagen synthesis and deposition), dilinoleoylphosphatidylcholine (which inhibits collagen production induced by transforming growth factor beta 1 [TGF-β1]), and luteolin (which reduces fibrosis, in part, by increasing expression of matrix metalloproteinase 9 [MMP-9] and metallothionein, which degrade the extracellular matrix [ECM]). ), malotilate (which reduces procollagen Iα2 [Col1a2] expression), melatonin (which inhibits expression of procollagen I and III), S-nitroso-N-acetyl-L-cysteine ​​(which reduces the amount of collagen I, in part by activating MMP-13 and inhibiting tissue inhibitor of metalloproteinases 2 [TIMP-2]), oxymatrine {which reduces procollagen Iα1 (Col1a1) (and α-smooth muscle actin [α-SMA]) expression}, and pioglitazone (which reduces collagen I [and α-SMA] production ), pirfenidone (reduces production of procollagen I and II and inhibits TGF-β-stimulated collagen production), quercetin (reduces Col1a1 and procollagen IIIα1 [Col3a1] expression), resveratrol (reduces collagen I [and α-SMA] production), RGD mimetics and analogues (see below, in part, reduce collagen I accumulation by increasing collagenase secretion), safilonil (reduces collagen I [and α-SMA] production), statins (e.g., atorvastatin, lovastatin, and simvastatin [all three reduce collagen production]), tranilast (inhibits procollagen expression and fibroblast proliferation), valproic acid (reduces collagen deposition), inhibitors of collagen cross-linking {e.g., D-penicillamine and lysyl oxidase-like 2 (LOXL2, which promotes collagen cross-linking) inhibitors (e.g., β-aminopropionitrile and anti-LOXL2 antibodies [e.g., simtuzumab and AB-0023])}, procollagen-proline dioxygenase (or prolyl 4-hydroxylase, whichinhibitors of collagen accumulation, including procollagen glucosyltransferase (which forms more stable hydroxylated collagen) inhibitors (e.g., malotilate, HOE-077, S-0885, and S-4682), and procollagen glucosyltransferase (or galactosyl hydroxylysine glucosyltransferase, which is important in collagen fibril formation) inhibitors (e.g., malotilate); TGF-β inhibitors {e.g., anti-TGF-β antibodies (e.g., fresolimumab [GC1008] and CAT-192) and soluble TGF-β receptors (e.g., sTGFβR1 , sTGFβR2 and sTGFβR3)}, TGFβR antagonists {e.g., TGFβR1 (ALK5) antagonists (e.g., galunisertib [LY-2157299], EW-7197, GW-788388, LY-2109761, SB-431542, SB-525334, SKI-2162, SM-16, and inhibitory Smads [e.g., Smad6 and Smad7])}, anti-CTGF antibodies (e.g., FG-3019), PDGF inhibitors (e.g., squalamine, PP1, anti-PDGF aptamers [e.g., E10030], anti-PDGF antibodies [e.g., PDG F-B, PDGF-C, and PDGF-D], and soluble PDGF receptors [e.g., sPDGFRα and sPDGFRβ]), PDGFR (e.g., PDGFRα and / or PDGFRβ) antagonists (e.g., anti-PDGFR antibodies [e.g., REGN2176-3]), bone morphogenetic protein-7 (BMP-7) (directly antagonizing TGF-β1 signaling and Smad3 activation and promoting mesenchymal-epithelial transition), N-acetyl-L-cysteine ​​(inhibiting TGF-β expression and activation by monomerizing biologically active TGF-β dimers), S -nitroso-N-acetyl-L-cysteine ​​(inhibits TGF-β1), L-carnitine (reduces PDGF-B expression), epigallocatechin-3-gallate (inhibits activation of Smad2 and Smad3 [and Akt]), galectin-7 (binds to and inhibits phosphorylated Smad2 and Smad3), Leu-Ser-Lys-Leu (SEQ ID NO: 3) (inhibits TGF-β1 activation), α-lipoic acid (inhibits TGF-β signaling by inhibiting Smad3 and AP-1), luteolin (inhibits TGF-β and PDGF signaling),Melatonin (inhibits TGF-β and CTGF expression and Smad3 activation), naringenin (suppresses Smad3 expression and activation), niacin (reduces TGF-β expression), pirfenidone (reduces TGF-β production), quercetin (reduces expression of TGF-β1, CTGF, PDGF-B, and Smad3), resveratrol (inhibits TGF-β expression), simvastatin (reduces TGF-β1 [and α-SMA] expression), taurine (reduces TGF-β1 [and α-SMA] expression), tranilast (inhibits TGF-β1 expression), vitamin E and its analogs (e.g., α-tocopherol and trolox, which both inhibitors of pro-fibrosis growth factors (e.g., transforming growth factor beta [including TGF-β1], connective tissue growth factor [CTGF], and platelet-derived growth factor [including PDGF-B, PDGF-C, and PDGF-D]) or their production, activation, or signaling, including inhibitors of αvβ6 integrin (which activates TGF-β1) (e.g., anti-αvβ6 antibodies such as STX-100), both of which suppress TGF-β expression; epidermal growth factor receptor (EGFR) TK inhibitors (e.g., afatinib, brigatinib, erlotinib, gefitinib, icotinib, lapatinib, osimertinib, and isoflavones [e.g., genistein]), PDGFR TK inhibitors (e.g., crenolanib, imatinib, and AG-1295), dual FGFR / VEGFR TK inhibitors (e.g., brivanib and brivanib alaninate), dual PDGFR / VEGFR TK inhibitors (e.g., axitinib, sorafenib, sunitinib, vatalanib, and X-82), and triple FGFR / PDGFR / VEGFR receptor tyrosine kinase (TK) inhibitors, including TK inhibitors (e.g., nintedanib and pazopanib); anti-EGFR antibodies, such as cetuximab, matuzumab, nimotuzumab, panitumumab and zalutumumab; anti-inflammatory cytokines (e.g., IL-10), inhibitors of pro-inflammatory cytokines or their receptors or their production (e.g., TNF-α [e.g., anti-TNF-α antibodies such as infliximab or immunomodulators such as pentoxifylline], IL-1β, IL-6 and MCP-1), colchicine, curcuminoids (e.g., curcumin), malotilate,Anti-inflammatory agents, including those listed above, such as nintedanib, pirfenidone, and tranilast; vitamins and their analogs (e.g., vitamin E and its analogs such as α-tocopherol and trolox), sulfur-containing antioxidants (e.g., glutathione, NAC, SNAC, SAC [which also suppresses α-SMA expression], and SAM), ROS and radical scavengers (e.g., melatonin and glutathione), Nrf2 activators {e.g., fumarates (e.g., dimethyl and monomethyl fumarate), trichostatin A, and triterpenoids (e.g., oleanolic acid analogs [such as TP-225, as above]). )}, and antioxidants, including those listed above, such as omega-3 fatty acids and their esters (e.g., Lovaza fish oil); renin inhibitors (e.g., aliskiren [reduces hepatic steatosis, oxidative stress, inflammation and fibrosis]), ACE inhibitors (e.g., captopril [inhibits fibroblast proliferation and reduces fibrotic lung response] and perindopril [inhibits hepatic fibrosis]), and angiotensin II receptor type 1 (AT1) antagonists (e.g., candesartan [inhibits hepatic fibrosis], irbesartan and losartan) (activation of AT1 by angiotensin II activates PLC, which increases cytosolic Ca, 2+antagonists of the renin-angiotensin-aldosterone system (RAAS), including those listed above, such as AGE-1, AGE-2, AGE-3, AGE-4, AGE-5, AGE-6, AGE-7, AGE-8, AGE-9, AGE-10, AGE-11, AGE-12, AGE-13, AGE-14, AGE-15, AGE-16, AGE-17, AGE-18, AGE-19, AGE-20, AGE-21, AGE-22, AGE-23, AGE-24, AGE-25, AGE-26, AGE-27, AGE-28, AGE-29, AGE-29, AGE-29, AGE-29, AGE-30, AGE-31, AGE-32, AGE-33, AGE-34, AGE-35, AGE-36, AGE-37, AGE-38, AGE-39 ... inhibitors of the accumulation or effects of advanced glycation end products (AGEs, which, among other things, increase arteriosclerosis and stimulate the expansion of the mesangial matrix), including RGD mimetics and analogs (which inhibit adhesion of fibroblasts and immune cells to ECM glycoproteins) (e.g., NS-11, SF-6,5, and GRGDS), galectin-3 (which is critically important in liver fibrosis) inhibitors (e.g., GM-CT-01 and GR-MD-02), marinobufagenin inhibitors (e.g., resibufogenin, spironolactone, and canrenone), trichostatin A (which inhibits TGFβ1-induced epithelial-mesenchymal transition), and PPAR-γ agonists (e.g., thiazolidinediones [supra]), and analogs, derivatives, fragments, and salts thereof.

[0220] Nonalcoholic fatty liver disease (NAFLD), the most common liver disorder in developed countries, is characterized by fatty liver (hepatic steatosis) that occurs when fat, specifically free fatty acids and triglycerides, accumulate in liver cells due to causes other than excessive alcohol consumption, such as nutrient overload, high caloric intake, and metabolic dysfunction (e.g., hyperlipidemia and glucose dysregulation). The liver can remain fatty without impairing liver function, but fatty liver can progress to nonalcoholic steatohepatitis (NASH), a condition in which steatosis is accompanied by inflammation, hepatocyte ballooning, and cellular injury, with or without liver fibrosis. Fibrosis is the strongest predictor of death from NASH. NASH is the most extreme form of NAFLD. NASH is a progressive disease, with approximately 20% of patients developing cirrhosis and approximately 10% dying from liver disease, such as cirrhosis or liver cancer (e.g., hepatocellular carcinoma).

[0221] NAFLD, including NASH, is associated with obesity, metabolic syndrome and insulin resistance.For example, insulin resistance contributes to the progression of fatty liver to hepatitis and fibrosis, and then to NASH.Furthermore, obesity promotes and aggravates NASH, and weight loss can alleviate NASH.

[0222] In some embodiments, one or more compounds of structural formula (I) are used in combination with one or more additional therapeutic agents for the treatment of NAFLD, such as NASH, in some embodiments, the one or more additional therapeutic agents are selected from antidiabetic agents, antiobesity agents, anti-inflammatory agents, antifibrotic agents, antioxidants, and combinations thereof.

[0223] Therapeutic agents that can be used to treat NAFLD (e.g., NASH) include, without limitation, PPAR agonists-PPAR-δ, including PPAR-δ agonists (e.g., MBX-8025, elafibranor [dual PPAR-α / δ agonist], lanifibranor [triple PPAR-α / δ / y agonist], and GW501516 [dual PPAR-β / δ agonist]) and PPAR-γ agonists (e.g., thiazolidinediones such as pioglitazone and rosiglitazone, and saroglitazar [dual PPAR-α / γ agonist]). and -gamma agonists increase insulin sensitivity, PPAR-alpha agonists reduce hepatic steatosis, and PPAR-delta agonists inhibit macrophage and Kupffer cell activation;GLP-1R agonists (e.g., exenatide, liraglutide and semaglutide), dual GLP-1R / GCGR agonists (e.g., MEDI0382 and SP-1373) and dual GLP-1R / GIPR agonists - such agonists reduce hepatic steatosis, hepatitis and liver fibrosis;obeticholic acid, EDP-305, GS-9674, LJN4 Farnesoid X receptor (FXR) agonists, such as TERN-101 and TERN-52 - FXR agonists reduce hepatic gluconeogenesis, hepatic lipogenesis, hepatic steatosis and hepatic fibrosis; Thyroid hormone receptor beta agonists, such as MGL-3196 and VK2809 - THR-β agonists reduce hepatic steatosis; Fibroblast growth factor 19 (FGF19) and its analogs and derivatives, such as NGM-282 - FGF19 analogs reduce hepatic gluconeogenesis and steatosis; Fibroblast growth factor 21 (FGF21) and its analogs and derivatives, such as BMS-986036 and PF-05231023 - FGF19 analogs reduce hepatic gluconeogenesis and steatosis; and their analogs and derivatives - FGF21 analogs reduce hepatic steatosis, cellular injury and fibrosis; HMG-CoA reductase inhibitors, including statins (e.g., atorvastatin, pitavastatin and rosuvastatin) - statins reduce steatohepatitis and hepatic fibrosis; ACC inhibitors, such as NDI-010976 (liver-targeted) and GS-0976 - ACC inhibitors reduce de novo lipogenesis and hepatic steatosis; SCD-1 inhibitors, such as aramchol - SCD-1 inhibitors reduce hepatic steatosis and increase insulin sensitivity;ATP citrate lyase inhibitors - ACL inhibitors, such as bempedoic acid, reduce hepatic steatosis; Ketohexokinase inhibitors - KHK inhibitors, such as PF-06835919, reduce hepatic lipogenesis and hepatitis; SGLT2 inhibitors - SGLT2 inhibitors, such as canagliflozin, dapagliflozin, empagliflozin, ipragliflozin and luseogliflozin, reduce body weight, hepatic ALT levels and liver fibrosis; N-[4-(2-{4-[(2-amino-1H -imidazol-4-yl)methyl]phenyl}ethyl)thiazol-2-yl]acetamide hydrochloride, 2-bromoethylamine, semicarbazide, vascular adhesion protein-1 (VAP-1) inhibitors, such as ASP8232, BI-1467335 (PXS-4728A), PXS-4681A, PRX-167700, and TERN-201 - VAP-1 inhibitors increase insulin sensitivity and reduce hepatitis and liver fibrosis; antagonists CCR2, such as cenicriviroc or / and CCR5 antagonists - antagonists of CCR2 (which bind CCL2 [MCP1]) and CCR5 (which bind CCL5 [RANTES]) inhibit activation and migration of inflammatory cells (e.g., macrophages) to the liver and reduce liver fibrosis; apoptosis inhibitors - including apoptosis signal-regulating kinase 1 (ASK1) inhibitors (e.g., selonsertib) and caspase inhibitors (e.g., emricasan [pan-caspase inhibitor]). , which reduce hepatic steatosis and fibrosis; TGF-β inhibitors (e.g., fresolimumab) and TGF-βR antagonists (e.g., galunisertib), which reduce hepatic fibrosis; lysyl oxidase-like 2 (LOXL2) inhibitors, such as simtuzumab, which are key matrix enzymes in collagen formation and are highly expressed in the liver; galectin-3 inhibitors, such as GR-MD-02 and TD139, which are critical for the development of hepatic fibrosis;Inhibitors of lysophosphatidic acid (LPA) or its receptors (e.g., LPAR1) or its production, such as autotaxin inhibitors (e.g., GLPG1690, HA-130, ONO-8430506, PF-8380, S-32826) and anti-autotaxin DNA aptamers (e.g., RB011 and RB014) - such inhibitors inhibit myofibroblast proliferation and thus liver fibrosis; antioxidants, including vitamin E (e.g., α-tocopherol) and scavengers of ROS and free radicals (e.g., cysteamine, glutathione, melatonin and pentoxifylline [also anti-inflammatory through inhibition of TNF-α and phosphodiesterases]) - vitamin E reduces hepatic steatosis, hepatocyte ballooning and lobular inflammation; and analogs, derivatives and salts thereof. Other NASH compounds include LXR inverse agonists, ACMSD inhibitors, VAP1 inhibitors, IBAT inhibitors, DGAT inhibitors, ACC2 inhibitors, HSD17b13 inhibitors (roal and siRNA), PNPLA3 siRNA, THRb agonists (remetirom, TERN, Viking), FGF21 (Efruxfermin, pegosafermin), TLC-3595 (ACC2 inhibitor), mitochondrial protonophores (TLC-6740, Rivus HU6, TLC-1235, siRNAs for NASH- (e.g., PNPLA3, HSD17B13, GPAM, mARC1 and CIDEB) and mitochondrial uncouplers. Drugs for liver failure include terlipressin, octreotide and tolvaptan;

[0224] In some embodiments, the one or more additional therapeutic agents for the treatment of NAFLD (e.g., NASH) are or include a PPAR agonist (e.g., a PPAR-δ agonist such as elafibranor or / and a PPAR-γ agonist such as pioglitazone), an HMG-CoA reductase inhibitor (e.g., a statin such as rosuvastatin), an FXR agonist (e.g., obeticholic acid) or an antioxidant (e.g., vitamin E), or any combination thereof. In certain embodiments, the one or more additional therapeutic agents for the treatment of NAFLD (e.g., NASH) are or include vitamin E or / and pioglitazone.

[0225] In other embodiments, one or more compounds of structural formula (I) are used in combination with one or more anti-cancer agents for the treatment of tumors (benign or malignant) or cancer. For brevity, the term "anti-cancer agent" as used herein encompasses anti-tumor agents. In some embodiments, the one or more anti-cancer agents are or include radiation therapy, chemotherapy, or cancer immunotherapy, or any combination or all of these.

[0226] In some embodiments, the chemotherapeutic agent is or includes a PARP inhibitor, a TGF-β inhibitor, or a cytotoxic agent, or any combination or all of these. Examples of PARP inhibitors are described above. In certain embodiments, the PARP inhibitor is olaparib.

[0227] Transforming growth factor beta (TGF-β) is a cytokine that promotes the growth of precancerous and cancerous cells, angiogenesis, and invasion of cancer cells. TGF-β also converts effector T cells, which normally attack cancer cells with inflammatory (immune) responses, into regulatory T cells that suppress immune responses. Increased expression of TGF-β often correlates with malignancy in many cancers. Therefore, inhibitors of TGF-β or its production, activation, or signal transduction can be used to treat tumors and cancers. TGF-β (including TGF-β1) is also a major driver of collagen production and fibrosis, so inhibitors of TGF-β or its production, activation, or signal transduction are also included as antifibrotic agents.

[0228] Anti-cancer cytotoxic agents include, without limitation, aziridines (e.g., diazicon, mitomycin, and thiotepa), nitrogen mustards (e.g., mannomustine, mustine [mechlorethamine or chlormethine], aniline mustard, bendamustine, benzoic acid mustard, chlorambucil, C6-galactose mustard, melphalan, ossichlorin [nitromin], prednimustine, uramustine, nitrogen mustard carbamates [e.g., estramustine], and oxazaphosphorines [e.g., cyclophosphamide, ifosfamide, mafosfamide, and trofosfamide]), nitrosoureas (e.g., carmustine, fotemustine, lomustine, nimustine, N-nitroso-N-methylurea, ranimustine, semustine, and streptozotocin). alkylating agents, including cyclosulfonate (e.g., cyclosulfonate), platinum-containing compounds (e.g., cisplatin, carboplatin, and oxaliplatin), alkyl sulfonates (e.g., busulfan, mannosulfan, and treosulfan), hydrazines (e.g., dacarbazine and procarbazine), imidazotetrazines (e.g., mitozolomide and temozolomide), and triazines (e.g., hexamethylmelamine [altretamine]); cytotoxic antibiotics, including anthracyclines (e.g., aclarubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, pirarubicin, and valrubicin), actinomycins (e.g., actinomycin D), bleomycins (e.g., bleomycin A2 and B2), mitomycins (e.g., mitomycin C), and plicamycins;Antifolates (e.g., aminopterin, methotrexate, pemetrexed, and pralatrexate), deoxynucleoside analogues (e.g., 5-azacytidine [azacitidine], 5-aza-2-deoxycytidine [decitabine], cladribine, clofarabine, cytarabine, decitabine, fludarabine, gemcitabine, nelarabine, and pentostatin), fluoropyrimidines (e.g., 5-fluorouracil, antimetabolites, including pecitabine, 5-fluoro-5-deoxyuridine [doxifluridine], and trifluridine), and thiopurines (e.g., thioguanine, azathioprine, and mercaptopurine); antimicrotubule agents, including dolastatins (e.g., dolastatin 15), epothilones (e.g., epothilones A-F), halichondrins (e.g., halichondrin B) and their analogs (e.g., eribulin), maytansine, maytansinoids (e.g., ansamitocin, emtansine, mertansine, ravtansine, and soravtansine), taxanes (e.g., paclitaxel, docetaxel, and cabazitaxel), vinca alkaloids (e.g., vinblastine, vincristine, vindesine, vinflunine, and vinorelbine), colchicine, nocodazole, podophyllotoxin, and rhizoxin; histone deacetylase inhibitors, including, for example, trichostatin A), romidepsin, panobinostat, and vorinostat; bortezomib, erlotinib, gefitinib, imatinib, vemurafenib, vismodegib, curcumin, cyclocreatine, deguelin, fostriecin, hispidin, staurosporine and its derivatives (for example, midostaurin), and tyrphostins (for example, tyrphostin AG kinase inhibitors, including AG 34 and AG 879; topoisomerase I inhibitors, including camptothecin, irinotecan and topotecan; topoisomerase II targeting agents, including topoisomerase II poisons (e.g., etoposide, tafluposide, teniposide, doxorubicin and mitoxantrone) and topoisomerase II inhibitors (e.g., novobiocin, mervalone and aclarubicin);DNA or RNA synthesis inhibitors, including 3-amino-1,2,4-benzotriazine 1,4-dioxide, cytosine β-D-arabinofuranoside, 5,6-dichlorobenzimidazole 1-β-D-ribofuranoside, ganciclovir, and hydroxyurea; protein synthesis inhibitors, including homoharringtonine; retinoids (e.g., all-trans-retinol [vitamin A], 11-cis-retinol, all-trans-retinal [vitamin A aldehyde], 11-cis-retinal, all-trans-retinoic acid [tretinoin], 9-cis-retinoic acid [alitretinoin], 11-cis-retinoic acid, 13-cis-retinoic acid [isotretinoin], all-trans-retinyl esters, etretinate, acitretin ... cell growth and differentiation regulators, including dapalene, bexarotene, and tazarotene; cell proliferation inhibitors, including mTOR inhibitors (e.g., everolimus, novolimus, ridaforolimus, sirolimus [rapamycin], temsirolimus, umirolimus [biolimus A9], and zotarolimus), apigenin, cholecalciferol (vitamin D3), and sex hormone binding globulin; apoptosis inducers, including 17-allylamino-17-demethoxygeldanamycin, melatonin, mevinolin, psoralens, thapsigargin, troglitazone, histone deacetylase inhibitors (e.g., romidepsin), and RXR agonists (as above, retinoids [e.g., bexarotene], etc.); and analogs, derivatives, and salts thereof;

[0229] Cancer immunotherapeutics include agents that block immune checkpoints and agents that stimulate the immune system. In certain embodiments, the cancer immunotherapeutics are or include anti-PD-1 or anti-PD-L1 antibodies, or / and anti-CTLA-4 antibodies.

[0230] Anti-cancer drugs that block immune checkpoints include, without limitation, anti-PD-1 antibodies (e.g., cemiplimab, nivolumab, pembrolizumab, pidilizumab, and MEDI-0680 [AMP-514]), anti-PD-1 fusion proteins (e.g., AMP-224 [F cinhibitors of the programmed cell death 1 (PD-1) receptor or its ligands (e.g., PD-L1 and PD-L2), including anti-PD-L1 antibodies (e.g., avelumab, atezolizumab, durvalumab, and BMS-936559 [MDX-1105]), and small molecule inhibitors of PD-L1 (e.g., BMS-1001 and BMS-1166); inhibitors of the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) receptor or its ligands, including anti-CTLA-4 antibodies (e.g., ipilimumab and tremelimumab); inhibitors of the killer cell immunoglobulin-like receptors (KIR) or their ligands, including anti-KIR antibodies (e.g., lirilumab); inhibitors of the T-cell immunoglobulin and mucin domain containing 3 (TIM-3, also known as hepatitis A virus cellular receptor 2 [HAVCR2]), including anti-TIM3 antibodies (e.g., LY3321367, MBG453, and TSR-022); inhibitors of indoleamine 2,3-dioxygenase (IDO or IDO1), including indoximod (1-methyl-D-tryptophan), naboximide, α-methyl-tryptophan, β-carbolines (9H-pyrido[3,4-b]indole or norharman), epacadostat (INCB024360), BMS-986205, NLG-919, and COX-2 inhibitors (e.g., coxibs [supra], which downregulate the expression of IDO); and analogs, derivatives, fragments, and salts thereof.

[0231] Anti-cancer agents that stimulate the immune system include, but are not limited to, agonists of tumor necrosis factor receptor superfamily member 4 (TNFRSF4, OX40 or CD134), including OX40-targeting antibodies (e.g., MEDI-6469 and 9B12) and ligands for OX40 (e.g., OX40L); agonists of TNFRSF member 5 (TNFRSF5 or CD40), including CD40-targeting antibodies (e.g., dacetuzumab and CP-870,893) and ligands for CD40 (e.g., CD40L [CD154]); 4-1BB-targeting antibodies (e.g., Urelumab and agonists of TNFRSF member 9 (TNFRSF9, 4-1BB or CD137), including TNFRSF targeting antibodies (e.g., DTA-1 and TRX518) and ligands of 4-1BB (e.g., 4-1BBL); agonists of TNFRSF member 18 (TNFRSF18, glucocorticoid-inducible TNFR-related protein [GITR] or CD357), including GITR targeting antibodies (e.g., DTA-1 and TRX518) and ligands of GITR (e.g., GITRL); agonists of Toll-like receptors (TLRs), including ligands of TLR9 (e.g., unmethylated CpG oligodeoxynucleotides [CpG ODN], such as agatolimod); cytokines and hormones that stimulate immune cells, including IL-6 and epinephrine (e.g., stimulators of natural killer cells); and analogs, derivatives, fragments and salts thereof.

[0232] Angiogenesis is important for the transition from benign to malignant tumors (i.e., cancer) and for the metastasis of cancer. Thus, anti-cancer drugs include angiogenesis inhibitors. Angiogenesis inhibitors include, without limitation, inhibitors of vascular endothelial growth factor (VEGF) {e.g., squalamine, ACU-6151, LHA-510, PAN-90806, decorin, anti-VEGF antibodies and fragments thereof (e.g., bevacizumab, ranibizumab, brolucizumab, ENV1305, ESBA903, and ESBA1008), anti-VEGF immunoconjugates (e.g., KSI-301), anti-VEGF aptamers (e.g., pegaptanib), anti-VEGF artificial ankyrin repeat proteins (DARPins) (e.g., soluble VEGFR (e.g., sVEGFR1), and soluble fusion proteins containing one or more extracellular domains of one or more VEGFRs (e.g., VEGFR1, VEGFR2, and VEGFR3) (e.g., aflibercept, conbercept, and OPT-302)}; inhibitors of VEGF receptors (e.g., VEGFR1 and VEGFR2) (e.g., axitinib, fruquintinib, pazopanib, regorafenib, sorafenib, sunitinib, tivozanib, isoxanthohumol, progesterone-binding protein 1 (PO1), progesterone-binding protein 2 (PO2), progesterone-binding protein 3 (PO3), progesterone-binding protein 4 (PO4), progesterone-binding protein 5 (PO5), progesterone-binding protein 6 (PO6), progesterone-binding protein 7 (PO7), progesterone-binding protein 8 (PO8), progesterone-binding protein 9 (PO9), progesterone-binding protein 10 (PO10), progesterone-binding protein 11 (PO11), progesterone-binding protein 12 (PO12), progesterone-binding protein 13 (PO13), progesterone-binding protein 14 (PO14), progesterone-binding protein 15 (PO15), progesterone-binding protein 16 (PO15), progesterone-binding protein 17 (PO15), progesterone-binding protein 18 (PO15), progesterone-binding protein 19 ... ristimerin, KPI-285, PF-337210, PP1, TG100572, X-82, D-(LPR), decorin, and anti-VEGFR antibodies and fragments thereof [e.g., ramucirumab]), platelet-derived growth factor (PDGF) {e.g., squalamine, PP1, decorin, anti-PDGF aptamers (e.g., E10030 and pegprelanib), anti-PDGF antibodies and fragments thereof (e.g., linucumab), and soluble PDGFR} or its receptor (PDGFR) (e.g., axitinib, imatinib, nilotinib, pazopa, inhibitors of fibroblast growth factor (FGF) (e.g., squalamine, decorin, anti-FGF antibodies and fragments thereof, anti-FGF aptamers and soluble FGFR) or its receptor (FGFR) (e.g., erdafitinib, pazopanib and anti-FGFR antibodies and fragments thereof), angiopoietin (e.g., decorin, anti-angiopoietin antibodies and fragments thereof such as nesbacumab and REGN910-3,and soluble angiopoietin receptor) or its receptor (e.g., antibodies and fragments thereof against the angiopoietin receptor), bispecific anti-VEGF / anti-angiopoietin antibodies and fragments thereof (e.g., anti-VEGF / anti-angiopoietin-2 antibodies such as ABP-201 and RG7716), integrin inhibitors (e.g., ALG-1001, JSM-6427, SF0166, and anti-integrin antibodies and fragments thereof), tissue factor (TF) inhibitors (e.g., anti-TF antibodies and fragments thereof and fusion proteins thereof [e.g., ICON-1]), kallikrein inhibitors drugs (e.g., avoralstat, ecallantide, BCX7353, KVD001, and anti-kallikrein antibodies and fragments thereof [e.g., DX-2930]), serine / arginine-protein kinase 1 (SRPK1) inhibitors (e.g., SPHTNX31), Src kinase inhibitors (e.g., SKT-606 and TG100572), anecortave (anecortave acetate), angiostatins (e.g., angiostatin K1-3), αvβ3 inhibitors (e.g., etaracizumab), apoA mimetics (e.g., L-4F and L-5F), apoE mimetics (e.g., apoE poEdp), azurin (50-77) (p28), berberine, bleomycins, borrelidin, carboxyamidotriazole, cartilage-derived angiogenesis inhibitors (e.g., chondromodulin I and troponin I), castanospermine, CM101, corticosteroids (including glucocorticoids), cyclopropene fatty acids (e.g., sterculic acid), α-difluoromethylornithine, endostatin, everolimus, fumagillin, genistein, heparin, interferon-α, interleukin-12, interleukin-18, itraconazole, Nazole, KV11, linomide, 2-methoxyestradiol, pigment epithelium-derived factor (PEDF), platelet factor-4, PPAR-α agonists (e.g., fibrates), PPAR-γ agonists (e.g., thiazolidinediones), prolactin, rapamycin (sirolimus), sphingosine-1-phosphate inhibitors (e.g., sonepcizumab), squalene, staurosporine, angiogenesis-suppressing steroids (e.g., tetrahydrocortisol) + heparin, stilbenoids, suramin, SU5416, tasquinimod, tecogalan, tetrathiomolybdate,thalidomide and its derivatives (e.g., lenalidomide and pomalidomide), thiabendazole, thrombospondins (e.g., thrombospondin 1), TNP-470, tranilast, triterpenoids (e.g., oleanolic acid analogs such as TP-225 [above]), (+)-TBE-B, tumstatin and its fusion proteins (e.g., OCU200), vasostatin, vasostatin 48, withaferin A, and analogs, derivatives, fragments and salts thereof.

[0233] Other types of anti-cancer agents include, but are not limited to, drug efflux pump inhibitors, including P-glycoprotein inhibitors (e.g., mifepristone and verapamil); cell adhesion inhibitors, such as cimetidine; Golgi disruptors, such as the brefeldins (e.g., brefeldin A); ionizing radiation, such as X-rays; 131 I-iodide, 131 I-MIBG (m-iodobenzylguanidine), 223 Ra-dichloride, 153 Sm-EDTMP (ethylenediaminotetramethylene phosphate), and 89 These include radiopharmaceuticals, such as Sr-chloride; radiosensitizers for cancer cells, including PARP inhibitors (below), berberine and indomethacin; agents that promote cell survival after treatment with cytotoxic drugs or radiation, such as pifithrin-α; vaccines, including those that stimulate the immune system to recognize proteins produced by tumor / cancer cells and thereby attack the tumor / cancer cells; and analogues, derivatives and salts thereof.

[0234] The compounds of structural formula (I) can enhance immune responses to acute or chronic viral, bacterial or fungal infections when used in conjunction with antiviral, antibacterial or antifungal agents. In certain embodiments, the antibiotic is ethionamide and optionally SMARt-420, for example, for the treatment of tuberculosis. Ethionamide has antibiotic properties against mycobacteria, such as M. tuberculosis. SMARt-420, for example, reverses the ethionamide resistance of M. tuberculosis, increasing the susceptibility of the bacteria to ethionamide.

[0235] The compound of structural formula (I) can also enhance and direct the adaptive immune response to vaccine antigens, thereby improving the efficacy of vaccines. The compound of structural formula (I) can be used as a component of vaccine adjuvants. In certain embodiments, the compound of structural formula (I) is administered to a subject in combination with a vaccine to enhance the efficacy of the vaccine.

[0236] Upon activation by DNA damage, poly(ADP-ribose) polymerase (PARP) recruits other proteins that repair single-stranded DNA breaks ("nicks"). PARP activity is essential for the repair of DNA nicks. PARP expression and activity are upregulated under a variety of conditions, including hypoxia, that lead to DNA damage and ultimately cell injury or death. However, PARP does not regulate NAD in cells. + PARP is the major consumer of NAD + This can result in severe mitochondrial and cellular dysfunction, leading to NAD depletion. + levels (e.g., levels in mitochondria, cytosol, or / and nucleus, total intracellular NAD + levels) may be increased, which may enhance mitochondrial function (e.g., oxidative metabolism), mitochondrial biogenesis, and cellular function (e.g., activity of sirtuins such as SIRT1 and SIRT3 may be increased).

[0237] PARP inhibitors are currently approved as antitumor / anticancer drugs. DNA damage occurs countless times during every cell cycle, and failure to repair the damaged DNA leads to the death of tumor / cancer cells. Some PARP inhibitors mainly block PARP enzyme activity and do not trap PARP on DNA, while other PARP inhibitors both block PARP enzyme activity and act as PARP poisons. In the latter case, PARP bound to PARP inhibitors will be trapped at DNA nick sites, and since PARP activity blocks DNA replication, such trapped PARP-DNA complexes (PARP poisons) are more toxic to cells than unrepaired single-stranded DNA breaks that would otherwise accumulate. PARP inhibitors include, without limitation, niraparib, olaparib, pamiparib (BGB290), rucaparib, talazoparib, veliparib, 4-amino-1,8-naphthalimide, CEP9722, E7016, PJ34, and analogues, derivatives and salts thereof.

[0238] The combination of the compound of structural formula (I) and olaparib at a dose much lower than its chemotherapy dose inhibits NAD + levels (e.g., levels in mitochondria, cytosol, or / and nucleus, total intracellular NAD + levels) and provide cytoprotection (reducing cytotoxicity) under DNA damage-inducing conditions. Without intending to be bound by theory, low-level PARP inhibition with low doses of PARP inhibitors (e.g., olaparib) may reduce NAD synthesis by PARP. + Reduces the rate of consumption and NAD + Increasing levels of PARP may thus enhance mitochondrial and cellular function, providing cytoprotection. Moreover, low levels of PARP inhibition may prevent PARP from being trapped at DNA nick sites, thus allowing cellular DNA repair mechanisms to repair DNA damage.

[0239] In some embodiments, one or more compounds of structural formula (I) in combination with a PARP inhibitor may inhibit NADPH in vitro, ex vivo, or in vivo. + levels (e.g., levels in target cells, total intracellular NAD + In certain embodiments, one or more compounds of structural formula (I) in combination with a PARP inhibitor may increase NAD levels in vitro, ex vivo, or in vivo. + levels (e.g., levels in target cells, total intracellular NAD + The level) may be increased by at least about 50%, 100% (2-fold), 3-fold or 5-fold.

[0240] In further embodiments, one or more compounds of structural formula (I) in combination with a PARP inhibitor increases the number of viable cells (e.g., target cells) in vitro, ex vivo, or in vivo by at least about 10%, 20%, 30%, 50%, 100% (2-fold), 150%, 200% (3-fold), 4-fold, or 5-fold. In certain embodiments, a compound of structural formula (I) in combination with a PARP inhibitor increases the number of viable cells (e.g., target cells) in vitro, ex vivo, or in vivo by at least about 20%, 50%, 100%, or 200%.

[0241] In some embodiments, the compounds of structural formula (I) are used to treat a non-tumor / non-cancer disease / disorder or condition disclosed herein, or to produce a biological effect disclosed herein (e.g., NAD +In certain embodiments, the PARP inhibitor is a selective or non-selective PARP-1 inhibitor. The non-tumor / non-cancer disease or condition may be, for example, any mitochondrial disease, mitochondrial-associated disease or condition, or acute NADPH-induced DNA damage as described herein. + In certain embodiments, the disease or condition may be a disease or condition characterized by depletion of NAD. In certain embodiments, the disease or condition is a metabolic disorder (e.g., obesity or type 2 diabetes). Optionally, one or more other therapeutic agents described herein can be used in combination with the compound of structural formula (I) and the PARP inhibitor. The use of one or more compounds of structural formula (I) in combination with a PARP inhibitor (e.g., olaparib) at a dose significantly below the chemotherapeutic dose can reduce NAD + levels (e.g., levels in mitochondria, cytosol, or / and nucleus, total intracellular NAD + In some embodiments, the compounds may synergistically increase the levels of certain polypeptides (e.g., polypeptides that are involved in the synthesis of certain polypeptides) and / or provide cytoprotection (e.g., reducing cell injury, damage or death) or exert a synergistic therapeutic effect.

[0242] PARP inhibitors at doses significantly sub-chemotherapeutic doses can be used in combination with one or more compounds of structural formula (I) for the treatment of any non-tumor / non-cancer disease / disorder or condition associated with DNA damage. DNA damage can result from any cause, including radiation (e.g., ionizing radiation such as UV or X-rays), chemicals, chemotherapeutic agents, oxidative stress, or hypoxia. The disease / disorder or condition can be acute or chronic, and can include NAD + Such diseases / disorders and conditions may be associated with acute NAD depletion or / and cell injury, damage, degeneration or death. +These include diseases and conditions characterized by depletion and described above. In certain embodiments, the disease / disorder or condition is an acute, life-threatening cardiovascular (e.g., myocardial ischemia / infarction / IRI) or cerebrovascular (e.g., cerebral ischemia / infarction / IRI) disorder, or a neurodegenerative disorder.

[0243] In some embodiments, the dosage of the PARP inhibitor in combination with one or more nicotinyl riboside compounds for treating a non-tumor / non-cancer disease / disorder or condition disclosed herein or for producing a biological effect disclosed herein is about 10%, 5%, 1%, 0.5%, or 0.1% or less of the recommended dosage of the PARP inhibitor as an anti-tumor / anti-cancer agent. In certain embodiments, the dosage of the PARP inhibitor for such use is about 1% or less of the recommended dosage of the PARP inhibitor as an anti-tumor / anti-cancer agent. In some embodiments, the PARP inhibitor is olaparib, and the dose (e.g., per day or per dose) of olaparib in combination with one or more nicotinyl riboside compounds for treating a non-tumor / non-cancer disease / disorder or condition disclosed herein or for producing a biological effect disclosed herein is about 10 mg, 5 mg, 1 mg, 0.5 mg, or 0.1 mg or less; or about 0.01 or 0.1 mg to about 10 mg, about 0.01 or 0.1 mg to about 1 mg, or about 1 mg to about 10 mg; or about 0.01 to 0.1 mg, 0.1 to 0.5 mg, 0.5 to 1 mg, 1 to 5 mg, or 5 to 10 mg; or about 10 μg, 50 μg, 0.1 mg, 0.5 mg, 1 mg, 5 mg, or 10 mg. In certain embodiments, the dose (e.g., per day or per dose) of olaparib for such uses is about 1 mg or less.

[0244] The PARP inhibitor can be administered at any suitable frequency, hi certain embodiments, the PARP inhibitor is administered once or twice daily.

[0245] The dose or therapeutically effective amount, frequency of administration, and route of administration of the compound of formula (I) used in conjunction with a low dose of a PARP inhibitor may be, for example, any dose or therapeutically effective amount, any frequency of administration, and any route of administration described herein. In some embodiments, the dose of the compound of formula (I) is from about 1, 50, or 100 mg to about 500 or 1000 mg per day, which may be administered (e.g., orally) in a single dose (e.g., N mg once per day) or in divided doses (e.g., N / 2 mg twice per day). In certain embodiments, the dosage of the compound of formula (I) is about 1-100 mg, 100-500 mg, or 500-1000 mg per day, or about 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1000 mg per day. In further embodiments, the dosage of the compound of formula (I) is about 1-50 mg, 50-100 mg, 100-200 mg, 200-300 mg, 300-400 mg, or 400-500 mg per day. In certain embodiments, the dosage of the compound of formula (I) is about 10, 50, or 100 mg to about 200 or 300 mg per day. In some embodiments, lower doses of the compound of structural formula (I) are used to treat less severe non-neoplastic / non-cancer diseases / disorders or conditions, while higher doses of the compound of structural formula (I) are used to treat more severe non-neoplastic / non-cancer diseases / disorders or conditions.

[0246] NAD +The synergistic effect of combining one or more compounds of structural formula (I) with a low dose of a PARP inhibitor, such as by increasing the levels of erythrocyte proliferation and enhancing cytoprotection, can be prophylactically exploited to prevent non-tumor / non-cancer diseases / disorders or conditions, or potentially prevent tumors or cancer. As an example, one or more compounds of structural formula (I) and a low dose of a PARP inhibitor can be administered before surgery to reduce morbidity caused by general anesthesia or hypoxia- or hypotension-induced cytotoxicity. For example, one or more compounds of structural formula (I) and a low dose of a PARP inhibitor can be administered before a cardiac procedure (e.g., angioplasty or valvular surgery) to reduce morbidity and mortality due to hypotension or bleeding episodes. As another example, one or more compounds of structural formula (I) and a low dose of a PARP inhibitor can be applied to the skin to prevent sun-induced skin damage.

[0247] In some embodiments, one or more compounds of structural formula (I) or / and a PARP inhibitor are administered as a complex with a dendrimer (e.g., PAMAM) or in a dendrimer-containing composition. The dendrimer may optionally have one or more moieties that are targeted to a specific organ or organs, tissue or tissues, cell type or cell types, or sub-organelles, such as, for example, one or more N-acetylgalactosamine moieties that are targeted to the liver for the treatment of liver or metabolic disorders.

[0248] In other embodiments, one or more compounds of structural formula (I) or / and PARP inhibitors are utilized in ex vivo therapy, including any of the ex vivo therapies described herein.In yet other embodiments, one or more compounds of structural formula (I) and PARP inhibitors are utilized to enhance DNA editing, such as by using CRISPR, transcription activator-like effector nucleases (TALENs) or Arcus nucleases to promote non-homologous end joining (NHEJ) or homology directed repair (HDR).Low levels of PARP inhibition by low doses of PARP inhibitors allow repair of single-stranded DNA breaks.

[0249] Other synergistic approaches are with ACMSD inhibitors, NR, NMN, NRH, CD38 inhibitors, SARM1 inhibitors, uncouplers and other lipid / TG lowering approaches.

[0250] In other embodiments, one or more compounds of structural formula (I) can be used simultaneously with medications that may cause acute kidney injury (AKI) or prevent the worsening of chronic kidney injury. Common medications associated with AKI are antibiotics: aminoglycosides, cephalosporins, amphotericin B, bacitracin, and vancomycin. The entire class of ACE inhibitors, and angiotensin receptor blockers (candesartan and valsartan). Medications used in cancer chemotherapy: cisplatin, carboplatin, and methotrexate. Dyes (contrast agents) used in medical imaging exams - at risk, especially in patients with coronary artery disease or post-CABG patients with compromised kidney function. Another large class is the NSAIDS - ibuprofen, ketoprofen, and naproxen.

[0251] In other embodiments, one or more compounds of structural formula (I) can be used concomitantly with drug therapies such as mitochondrial stress response modulators, such as tetracyclines, including non-microbial compounds such as 9TB, to enhance host tolerance--prevention and treatment of acute and chronic severe viral infections, bacterial sepsis, and ischemia-reperfusion injury conditions.

[0252] In other embodiments, one or more compounds of structural formula (I) can be used concomitantly with medications such as SPT1 inhibitors for the treatment of myopathies, including inclusion body myositis, sarcopenia, DMD, and other myopathies with genetic etiologies.

[0253] Finally, it should be noted that there are alternative ways of implementing the invention, and thus the present embodiments should be considered as illustrative rather than restrictive, and the invention should not be limited to the details given herein, but may be modified within the scope of the appended claims and their equivalents.

[0254] All publications and patents cited herein are incorporated by reference in their entirety.

[0255] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the present invention. EXAMPLES

[0256] Abbreviations used in this experimental procedure. Aq.Aqueous solution RT room temperature MeOH Methanol THF Tetrahydrofuran DMF Dimethylformamide TLC Thin-layer chromatography using silica gel plates EtOAc Ethyl acetate HCl Hydrochloric acid TBDMS tert-Butyldimethylsilyl chloride TFA Trifluoroacetic acid Et3N 3HF Triethylamine trihydrofluoride DMAP N,N-Dimethylaminopyridine Py Pyridine

[0257] Scheme 1 illustrates the preparation of compounds 100 and 101. [ka]

[0258] (((3R,4R,5R)-5-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2,3,4-triyl)tris(oxy))tris(tert-butyldimethylsilane) (1) [ka] To a stirred solution of ribose (50 g, 0.33 mol) in DMF (120 mL) at 0° C. was added imidazole (90.6 g, 1.33 mol), followed by TBDMSCl (200 g, 1.33 mmol). The resulting mixture was stirred at room temperature for 24 h. TLC of the reaction mixture showed complete conversion of the starting material, and a new non-polar spot was observed. The reaction mixture was quenched with aqueous NaHCO3 and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide the crude compound. The crude material was purified by column chromatography to give compound 1 (125 g, 62%) as a pale yellow liquid. 1 H NMR(400MHz,DMSO):δ 5.09(d,J=1.6Hz,1H),4.04-4.05(m,1H),3.92-3.91(m,1H),3.73(d,J=3.2Hz,2H),3.58-3.59(m,1H),0.9(s,36H),0.6(s,24H). R f : 0.8. Mobile phase: 5% EA / Hexane.

[0259] (3R,4R,5R)-3,4-bis((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-ol (2) [ka] To a stirred solution of compound 1 (150 g, 0.24 mol) in DCM (2.5 L) at 0 °C was added TFA (452 ​​g, 3.4 mol). The resulting mixture was stirred at the same temperature for 2-3 min (Note: Need to quench immediately). After 3 min, the reaction mixture was poured into aqueous NaHCO3 solution. The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide the crude compound. The crude material was purified by using column chromatography to give compound 2 (40 g, 33%) as a pale yellow gum. 1H NMR(400MHz,CDCl3):δ 5.011-5.017(m,1H),4.206-4.234(m,1H),4.051-4.062(m,3H),3.65-3.658(m,1H),3.529-3.541(m,1H),0.9(s,27H),0.6(s,18H). R f : 0.4 (mobile phase: 5% EA / hexane).

[0260] (3R,4R,5R)-3,4-bis((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl nicotinate (3) [ka] To a stirred solution of compound 2 (80 g, 0.16 mol) in DMF (320 mL) at 0° C. was added dropwise a solution of nicotinyl chloride (34 g, 0.19 mol) in pyridine (80 mL). The resulting mixture was allowed to stir at room temperature for 12 h. TLC showed complete conversion of the starting material and a new polar spot was observed. The reaction mixture was quenched with aqueous NaHCO3 and extracted with ethyl acetate. The combined organic layers were washed with 1N HCl (500 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to provide the crude compound. The crude material was purified by using column chromatography to give compound 3 (80 g, 82%) as a pale yellow gummy liquid. 1 H NMR(400MHz,CDCl3):δ 9.2(m,1H),8.78(d,J=1.6Hz,1H),8.27(t,J=2Hz,1H),7.39(q,J=4.8Hz,1H),6.14(d,J=1.2Hz,1H),4.36(q,J=4.4Hz,1 H),4.16(dd,J=1.2Hz,1H),4.07-4.08(m,1H),3.89(d,J=2.4Hz,1H),3.69(d,J=3.2Hz,1H),0.93(s,27H),0.2(s,18H). R f : 0.4. Mobile phase: 10% EA / Hexane.

[0261] Example 1: (3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl nicotinate (100) [ka] To a stirred solution of compound 3 (40 g, 0.06 mol) in THF (160 mL) at -40°C was added Et3N.3HF (38 g, 0.2 mol; Spectrochem; 97% purity). The reaction mixture was allowed to stir at room temperature for 16 h. The reaction mixture was then cooled to -40°C, the THF layer was removed without any aqueous workup, and the gummy compound was washed with diethyl ether (3 x 100 mL) and purified by column chromatography using 100-200 mesh (neutralized with triethylamine) eluting with 2-5% methanol in DCM to give an off-white sticky solid (9 g, 53%). LCMS showed 80% of the desired mass, which was purified again by RP-C18 to give (4 g, 24%) of compound 100 in 98% purity. 1 H NMR(400MHz,CD3OD):δ 9.1l(s,1H),8.75(d,J=1.6Hz,1H),8.40(m,1H),7.58(d,1H),6.24(s,1H),4 .35(q,1H),4.18(d,1H),4.04-4.05(m,1H),3.82-3.79(d,1H),3.63(dd,1H). LCMS:m / z:256.11[M+H] + , 91.49% (0.89 min, 0.76 min). Column: Acquity BEH C18 (2.1 × 100 mm, 1.7 μm). Mobile phase: A-0.01% FA in water; B-0.01% FA in ACN, (T / %B: 0.01 / 10, 0.5 / 10, 4 / 90, 8 / 90). Flow rate: 0.4 mL / min. R f :0.4. Mobile phase: 10% MeOH in DCM.

[0262] Example 2: (3R,4S,5R)-3,4-dihydroxy-5-(((((1-methoxy-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydrofuran-2-yl nicotinate (101) [ka] To a stirred solution of compound 100 (8 g, 0.03 mol, 80% purity material) in THF (80 mL) at room temperature was added N-methylimidazole (12 g, 0.15 mol) dropwise over 5 min. The reaction mixture was stirred for 15 min, then a solution of compound 4 (26 g, 0.09 mol) in THF (20 mL) was added and stirring was continued for 12 h at room temperature. The reaction mixture was directly concentrated under reduced pressure to provide a brown liquid compound, which was washed with diethyl ether (3×100 mL) without any aqueous workup and purified by column chromatography eluting with 2-7% methanol in DCM to provide compound 101 (3.2 g) in 55% purity by LCMS (approximately 1:1 diastereomeric mixture). This material was purified again by C-18 RP preparative HPLC and the fractions were lyophilized to give compound 101 (800 mg, approximately 5%) as an off-white gummy solid. 1 H NMR[400MHz,CD3OD]:δ 9.11(dd,1H),8.75(d,J=1.6Hz,1H),8.38(m,1H),7.50(dd,Hz,1H),7.29(m,2H),7.15(t,2H) ,7.10(d,1H)6.24(s,1H),4.41(m,2H),4.20(m,3H),3.375(m,1H),3.56(d,3H),1.25(d,3H). LCMS purity: (44.46% and 48.09% diastereomeric mixture). Column: Acquity Halo C18 (2.1 x 100mm, 2.7μm). Mobile phase: A-0.1%NH3; B-ACN, (T / %B:0.01 / 10,0.5 / 10,5 / 40,10 / 90). Flow rate: 0.4mL / min. R f :0.5. Mobile phase: 10% MeOH / DCM.

[0263] 2-((chloro(phenoxy)phosphoryl)amino)propanoic acid (2S)-methyl ester (4) [ka] To a stirred solution of compound 5 (60 g, 0.43 mol) and compound 6 (90 g, 0.43 mol) in DCM (200 mL) at -78 °C was added a solution of EtN (87 g, 0.86 mol) in DCM (100 mL) dropwise. The reaction mixture was allowed to stir at room temperature for 4 h. TLC showed complete conversion of the starting material and a new non-polar spot was observed. The reaction was directly concentrated under reduced pressure to provide a white solid. Diethyl ether was added to the solid compound and the suspension was stirred for 30 min. The solid was filtered off and the filtrate was concentrated under reduced pressure to give the crude compound. The crude material was purified by column chromatography eluting with 10% to 30% ethyl acetate in hexane to give compound 4 (50 g, 28%) as a pale yellow gum. 1 H NMR (400 MHz, CDCl3): δ 7.2 (m, 5H), 4.0 (m, 1H), 3.8 (s, 3H), 1.37 (dd, 3H). LCMS: m / z: 260.05 (chloro replaced by hydroxy) [M+H] + , 90% (1.87 min.). Column: Acquity BEH C18 (2.1 × 100 mm, 1.7 μm). Mobile phase: A-0.01% FA in water; B-0.01% FA in ACN, (T / %B: 0.01 / 10, 0.5 / 10, 4 / 90, 8 / 90). Flow rate: 0.4 mL / min. R f : 0.5. Mobile phase: 40% EA / Hexane.

[0264] Scheme 2 illustrates the preparation of compound 102. [ka]

[0265] 6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-ol (2)(7) [ka] A solution of ribose (10.0 g, 66.6 mmol) in dry acetone (100 mL) was cooled to 0° C., then pTSA (80 mg, 2.1 mmol) was added followed by DMP (9 mL, 73.3 mmol). The resulting mixture was stirred at room temperature for 2 h. The clear reaction mass was neutralized with anhydrous sodium bicarbonate, filtered through a bed of Celite, and the filtrate was concentrated under reduced pressure to give a gum-like crude compound. The crude compound was purified by column chromatography using 100-200 silica gel (eluted with 30% EtOAc:Hexane) to afford compound 2 (7.4 g, 59%) as a colorless liquid, 1 The product was confirmed by 1 H NMR. 1 H NMR (400MHz, DMSO) δ 6.49(d,1H),5.18(m,1H),4.9(m,1H),4.7(t,1H),4.42(m,1H),4.0(m,1H),3.42(m,24=H),1.38(m,3H),1.28(s,3H). R f = 0.3 (mobile phase: 40% EtOAc:hexanes).

[0266] (3R,4R,5R)-3,4-bis((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl nicotinate (9) [ka] To a stirred solution of compound 7 (80 g, 0.16 mol) in DMF (320 mL) at 0° C. was added dropwise a solution of nicotinyl chloride (8) (34 g, 0.19 mol) in pyridine (80 mL). The resulting mixture was allowed to stir at room temperature for 12 h. TLC showed complete conversion of the starting material, and a new polar spot was observed. The reaction mixture was quenched with aqueous NaHCO3 and extracted with ethyl acetate. The combined organic layers were washed with 1N HCl (500 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to provide crude compound 9. The crude material was purified by using column chromatography to give compound 9 (80 g, 82%) as a pale yellow gummy liquid. 1H NMR[400MHz,CDCl3]:δ 9.2(m,1H),8.78(d,J=1.6Hz,1H),8.27(t,J=2Hz,1H),7.39(q,J=4.8Hz,1H),6.14(d,J=1.2Hz,1H),4.36(q,J=4.4Hz,1 H),4.16(dd,J=1.2Hz,1H),4.07-4.08(m,1H),3.89(d,J=2.4Hz,1H),3.69(d,J=3.2Hz,1H),0.93(s,27H),0.2(s,18H). R f : 0.4. Mobile phase: 10% EA / Hexane.

[0267] Example 3: (3,4,5-trihydroxytetrahydrofuran-2-yl)methyl picolinate (102) [ka] Compound 9 (9.0 g, 22.5 mmol) was dissolved in TFA:HO at 0° C. and then stirred at room temperature for 16 h. The solvent was evaporated to give the crude product, which was purified by column chromatography using 100-200 silica gel (eluting with 5% MeOH:DCM) to give compound 102 (800 mg, 14%) as a pale yellow liquid. 1 H NMR[400MHz, CDCl3]:δ 9.15(s,1H),8.75-8.74(d,J=1.6Hz,1H),8.49-8.46(d,1H),7.60-7.56(m,1H),5.20(s,1H) ),4.65(m,lH),4.4(m,1H),4.30(m,1H),4.28(m,1H),4.18-4.15(m,1H),3.85-3.80(d,1H). LCMS:m / z:256.19[M+H] + ,96.65%(8.28min.). Column: LUNA 5μ C18 (4.6 x 100mm). Mobile phase: A 0.1% TFA in water; B-0.1% TFA in ACN, (T / %B: 0.01 / 10, 5 / 10, 20 / 90, 25 / 90). Flow rate: 0.7mL / min. R f :0.3 (mobile phase: 10% MeOH:DCM).

[0268] Scheme 3 illustrates the preparation of compounds 103 and 104. [ka]

[0269] Example 4: (2S,3R,4S,5R)-3,4-dihydroxy-5-((((S)-(((S)-1-methoxy-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydrofuran-2-yl nicotinate (103) and (2S,3R,4S,5R)-3,4-dihydroxy-5-((((R)-(((S)-1-methoxy-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydrofuran-2-yl nicotinate (104) [ka] Compound 101 (2.5 g, 75% purity by LC-MS) was purified by chiral HPLC (CHIRALPAK IG, 250×4.6 mm, 5μ (mobile phase: n-hexane:IPA:MeOH (75:05:20)) to provide 450 mg of compound 103 and 450 ng of compound 104.

[0270] Compound 103: 1 H NMR[400MHz,CD3OD]:δ 9.09-9.08(m,1H),8.69-8.68(m,1H),8.38-8.35(m,1H),7.58-7.48(m,1H),7.28(m,J=8.0Hz,2H),7.14-7.09 (m,3H),6.24(s,1H),4.41-4.33(m,2H),4.24-4.15(m,3H),3.88-3.84(m,1H),3.61(s,3H),1.28-1.24(m,3H). LCMS:m / z:497.18[M+H] + , 98.51% (2.80min.); Column: Kinetex EVO C18 (2.1×50mm, 1.7μm), Mobile phase: A-0.1%NH3 in water; B-ACN, (T / %B:0.01 / 10,0.5 / 10,5 / 40,10 / 90);Flow rate: 0.4mL / min.

[0271] Compound 104: 1 H NMR[400MHz, CD3OD]:δ 9.107-9.104(m,1H),8.68(dd,J=1.2,4.8Hz,1H),8.38-8.35(m,1H),7.47-7.43(m,1H),7.27(t,J=7.6Hz,2H),7.12(t,J=7.6Hz, 1H),7.03(d,J=8.4Hz,2H),6.24(s,1H),4.47-4.39(m,2H),4.25-4.19(m,3H),3.83-3.79(m,1H),3.56(s,3H),1.28-1.23(m,3H). LCMS:m / z:497.18[M+H] + , 98.51% (2.80min.); Column: Kinetex EVO C18 (2.1 x 50mm, 1.7im); Mobile phase: A 0.1%NH3 in water; B-ACN, (T / %B:0.01 / 10,0.5 / 10,5 / 40,10 / 90);Flow rate: 0.4mL / min.

[0272] Scheme 4 illustrates the preparation of compound 105. [ka]

[0273] Example 5 Preparation of ((2S,3R,4S,5R)-3,4-dihydroxy-5-((((S)-(((S)-1-isopropoxy-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydrofuran-2-yl nicotinate (105) To a stirred solution of (2S,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-ylnicotinate (100) (100 mg, 1.33 mmol) in THF (1 mL) was added MgCl2 (20 mg, 0.204 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 15 min. Then (S)-isopropyl 2-(((S)-(perfluorophenoxy)(phenoxy)phosphoryl)amino)propanoate (10) (110 mg, 0.243 mmol) and DIPEA (0.1 mL, 0.608 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 16 h. The above procedure was carried out twice simultaneously to provide two batches. Both batches were combined and the volatiles were evaporated under reduced pressure to provide the crude compound. The crude compound was purified by column chromatography (100-200 mesh silica gel, 10% MeOH-DCM as eluent) to give 105 (35 mg, 12% LCMS). LCMS: m / z: 525.16 [M+H] + , (2.11 min.). Column: EVO C 18 (2.1×50mm, 1.7μM). Mobile phase: A-0.01% FA in water; B-0.01% FA in ACN, (T / %B:0.01 / 10,0.5 / 10,4 / 90,7 / 90). Flow rate: 0.4mL / min.

[0274] Example 6: Solid-state stability of compounds 100, 101 and 102 To determine the solid state stability at room temperature, refrigerated conditions and in a deep freezer, compounds 100, 101 and 102 were stored in glass vials at three different locations at temperatures of -25°C, 2-8°C and -20°C. The compounds in these vials were determined for purity by UPLC at three different time points, 0 hours, 24 hours and 48 hours. Table 2 illustrates the results obtained for solid state stability at 25°C, 2-8°C and -20°C, respectively. Purity measurements were performed at 0 hours, 24 hours and 48 hours.

[0275] [Table 2]

[0276] Example 7: Stability in solution (simulated gastric fluid, simulated intestinal fluid and pH stability) 1 mg / ml solutions of compounds 101 and 102 were prepared in each buffer and analyzed, respectively, as follows: Column: Acquity Halo C18 (2.1×100 mm, 2.7 μm), Mobile phase: A-0.1% NH3; B-ACN, (T / %B: 0.01 / 10, 0.5 / 10, 5 / 40, 10 / 90), Flow rate: 0.4 mL / min; and Column: Luna C18 (4.6×150 mm, 5 μm), Mobile phase: A-0.1% TFA in water; B-0.1% TFA in ACN, (T / %B: 0.01 / 0, 5 / 0, 20 / 90, 25 / 90), Flow rate: 0.7 mL / min.

[0277] A 1 mg / ml solution of Compound 100 was prepared in each buffer and diluted to 0.1 mg / ml in methanol at each time point and analyzed as follows: Gemini C-18, 250×4.6 mm, 5 μm, mobile phase: methanol isocratic flow rate: 0.4 mL / min.

[0278] Table 3 illustrates the pH and buffers used.

[0279] [Table 3]

[0280] Table 4 shows the stability of Compound 100 in solution over a range of pH, simulated gastric and intestinal fluids.

[0281] [Table 4]

[0282] Table 5 shows the stability of Compound 101 in solution over a range of pH, simulated gastric and intestinal fluids.

[0283] [Table 5]

[0284] Table 6 shows the stability of Compound 102 in solution over a range of pH, simulated gastric and intestinal fluids.

[0285] [Table 6]

[0286] Preparation of stock solutions for cell-based assays Compounds 100, 101 and 102 were weighed out to prepare 60 μM stock solutions in RPMI medium. A 200 ng / mL solution of Rac-tenofovir d6 (Vivan Life-Sciences) was prepared in methanol (MeOH) and kept at −20° C. until use.

[0287] Example 8: Compounds Increase Cellular NAD in Jurkat Cells + Effect on levels Jurkat cells procured from NCCS Pune were cultured in RPMI medium containing FBS and antibiotics. Cells (90% confluent) from different flasks were pooled in a 15 mL conical tube and centrifuged at 1200 rpm for 5 min. The supernatant solution was discarded and the pellet was resuspended in 5 mL sterile PBS (Ca 2+The cells were washed with PBS-free RPMI medium (free of Mg2+). The tubes were then centrifuged at 1200 rpm for 5 minutes and the supernatant was discarded. The cell pellet was resuspended in 7 mL of RPMI medium and a cell count was performed using 10 uL of the cell solution. 1.5 million cells from this cell solution were seeded into a 1.5 mL microcentrifuge tube. Compounds (100, 101, 102 and nicotinic acid) were added to make up a total volume of 1 mL with RPMI medium without PBS, with a final concentration of 30 μM. The tubes were placed in a rack and gently rocked to mix the compounds into the medium containing the cells. The tubes were then incubated for 4 hours in a 37° C. incubator with 5% CO2. After the 4 hour incubation, the cells were spun down at 1000 rpm for 10 minutes, the supernatant was carefully discarded and the cells were snap frozen in liquid nitrogen. When samples were run, cell extraction was done on ice and cells were lysed using 20uL deionized water followed by the addition of ice-cold 80% methanol containing the internal standard-Rac-tenofovir D. The tubes were then vortexed at 2500rpm for 8 minutes and then centrifuged at 125000rpm for 10 minutes. 150uL of the supernatant was carefully transferred into an HPLC vial and analyzed for NAD+ on an Abscised 4000 Q Trap LCMS / MS system. A C18, 3.5μm, 2.1x100mm, Bridge column was used for LC. The mobile phase consisted of 10mM ammonium acetate with 0.1% acetic acid and 0.1% hexylamine as solvent A and 10mM ammonium acetate with 0.1% acetic acid and 0.1% hexylamine in 95 / 5 MeOH / H2O as solvent B. The gradient used was 0 min-0.0% B, 0.5 min-100% B, 1.5 min-100% B, 3.0 min-100% B, 3.1 min-0.0% B, 7.0-end. The column flow rate was 0.5 mL / min. The sample injection volume was 3 μL.

[0288] All four compounds (100, 101, 102 and nicotinic acid) significantly increased NAD levels compared to untreated cells after 4 hours of incubation. + The increase in levels showed statistical significance, with the greatest increase seen in cells treated with compound 101, as depicted in FIG.

[0289] Example 9: Compounds inhibit cellular NAD in Huh-7 cells + Effect on levels Huh-7 cells procured from NCCS Pune were cultured in RPMI medium containing FBS and antibiotics. Cells (80-90% confluent) from different flasks were pooled in a 15 mL conical tube and centrifuged at 1200 rpm for 5 min. The supernatant solution was discarded and the pellet was resuspended in 5 mL sterile PBS (Ca 2+ and Mg 2+The cells were washed with PBS-free RPMI medium. The tubes were then centrifuged at 1200 rpm for 5 minutes and the supernatant was discarded. The cell pellet was resuspended in 7 mL of RPMI medium and a cell count was performed using 10 uL of the cell solution. 1.5 million cells from this cell solution were seeded into a 1.5 mL microcentrifuge tube. Compounds (100, 101, 102 and nicotinic acid) were added to make a total volume of 1 mL with RPMI medium without PBS, with a final concentration of 30 μM. The tubes were placed in a rack and gently rocked to mix the compounds into the medium containing the cells. The tubes were then incubated for 4 hours in a 37° C. incubator with 5% CO2. After the 4-hour incubation, the cells were spun down at 1000 rpm for 10 minutes, the supernatant was carefully discarded, and the cells were snap frozen in liquid nitrogen. When samples were run, cell extraction was done on ice and cells were lysed using 20uL deionized water followed by the addition of ice cold 80% methanol containing the internal standard-Rac-Tenofovir D. The tubes were then vortexed at 2500rpm for 8 minutes and then centrifuged at 125000rpm for 10 minutes. 150uL of the supernatant was carefully transferred into an HPLC vial and analyzed for NAD+ on an Abscised 4000 Q Trap LCMS / MS system. A C18, 3.5μm, 2.1x100mm, Bridge column was used for LC. The mobile phase consisted of 10mM ammonium acetate with 0.1% acetic acid and 0.1% hexylamine as solvent A and 10mM ammonium acetate with 0.1% acetic acid and 0.1% hexylamine in 95 / 5 MeOH / H2O as solvent B. The gradient used was 0 min-0.0% B, 0.5 min-100% B, 1.5 min-100% B, 3.0 min-100% B, 3.1 min-0.0% B, 7.0-end. The column flow rate was 0.5 mL / min. The sample injection volume was 3 μL.

[0290] Figure 2 illustrates the increase in NAD+ in HEPG2 cells. All four compounds (100, 101, 102 and nicotinic acid) at 125 μM showed an increase in terms of increased NAD+ levels compared to untreated cells after 4 hours of incubation.

[0291] Example 10: Effect of Compounds 103 and 104 in Primary Human Hepatocytes at 250 μM Cryopreserved primary human hepatocytes procured from Lonza were cultured and seeded in 6-well dishes with 500,000 cells per well. Compounds 103 and 104 were added in duplicate and incubated for 4 hours at 37°C in an incubator. Cells were then spun down and extracted. Supernatants were tested for NAD+ by LCMS / MS.

[0292] The results are shown in Figures 3A-3D. In primary human hepatocytes, compounds 103, 104 and nicotinic acid at 250 μM reduced statistically significant NAD after 4 hours of incubation compared to untreated cells. + The increase was due to increased levels.

[0293] Example 11: Compounds inhibit cellular NAD in HepG2 cells + Effects on levels - NAD cycling assay HepG2 cells were seeded in 6-well plates at a density of 1 million cells per well. The next day, cells were treated with test compounds for 4 hours and harvested using the following protocol. Each well was washed once with 2 mL ice-cold PBS to remove it, 400 μL 2M HClO4 (perchloric acid) was added to each well, scraped off, and the remainder was transferred to a 1.5 mL tube and spun down. 100 μL of the supernatant was transferred to a clean 1.5 mL vial, and 150 μL KOH / MOPS 2M / 0.6M (neutralization buffer) was added to each vial under vortexing, which was spun down. pH was measured according to the NAD cycling protocol.

[0294] NAD standards of 0-0.5 μM in water were prepared as per Table 7.

[0295] [Table 7]

[0296] Cycling reactions were prepared as follows: 10 μl sample was added, followed by water to bring the volume to 25 μl. 25 μl of each standard was used in duplicate in this reaction. 50 μl of Mix A (cycling mix) was then added to the samples and standards. Mix A contains:

[0297] [Table 8]

[0298] The reaction was started using 25 μL enzyme mix (15 U / ml alcohol dehydrogenase + 15 U / mL malate dehydrogenase). The sample was incubated at 37° C. for 30 min in a water bath and the reaction was terminated by heating at 80° C. for 5 min in a water bath. 25 μl of the sample was then used for the detection step. 100 μl of Mix B containing the following components was added to the sample:

[0299] [Table 9]

[0300] (Reactions were initiated using starting reagents prepared by mixing 10 μl of malate dehydrogenase and 10 μl of glutamic oxaloacetic transaminase in 1 ml of water. Readings were taken at 340 nm on an envision plate reader. Results are shown in Figures 4A-D.

[0301] All five compounds (100-105 and nicotinic acid) showed an increase with MP at 10 μM, 50 μM, 100 μM and 250 μM - with statistical significance for 101, 103 and 104 in terms of increased NAD+ levels compared to untreated cells after 4 hours of incubation. Compounds 103 and 104 showed a statistically significant increase even at the lowest concentration of 10 μM. Compound 104 also showed a statistically significant increase when compared to nicotinic acid at all concentrations.

[0302] Example 12: Effect of Compounds 103 and 104 in Primary Human Hepatocytes Cryopreserved primary human hepatocytes procured from Lonza were cultured and seeded in a 6-well dish with 500,000 cells per well. Compounds 103 and 104 were added in duplicate and incubated for 4 hours at 37°C in an incubator. Afterwards, the cells were spun down and extracted. The supernatant was analyzed by LCMS / MS for NAD. + was tested.

[0303] The results are shown in Figures 5 and 6. In primary human hepatocytes, compounds 103, 104 and nicotinic acid showed statistically significant reductions in NAD at 10 μM compared to untreated cells after 4 hours of incubation. + The increase was due to increased levels.

[0304] Example 13: In vitro cytotoxicity of compounds 100, 101 and 102 in HepG2 HepG2 cells were cultured and used to test the in vitro cytotoxicity of compounds 100, 101 and 102. The Cell Titer-Glo® Luminescent Cell Viability Assay Kit from Promega was used for this determination. Compounds 100, 101 and 102 were tested at concentrations of 0.3, 1, 3, 10, 30, 100, 300 and 1000 μM. 1000 cells were seeded per well and incubated with each of these concentrations for 72 hours. Cisplatin (6.5 μM) and nicotinamide riboside (NR) (100 μM) were used as controls. The production of a luminescent signal proportional to the amount of ATP present was measured as luminescence (RLU) in a plate reader. The amount of ATP is directly proportional to the number of cells present in culture. The results are shown in FIG. 7.

[0305] Example 14: CACO2 permeability of compounds 100, 101 and 102 A Caco-2 permeability assay was performed to measure the permeability of compounds 100, 101 and 102 through the human intestinal epithelial cell barrier. The endpoint measured is intestinal permeability expressed as apparent permeability-Papp values. All permeability values ​​are expressed as a function of x10 -6It is expressed as cm / sec. Table 8 shows the permeability ranked based on the following criteria:

[0306] [Table 10]

[0307] Example 15: Kinetic solubility of compounds 100, 101 and 102

[0308] [Table 11]

[0309] The kinetic solubility of test compounds was measured in aqueous buffer when added from a pre-existing stock solution in DMSO (50 μL 10 mM DMSO stock). The target compound concentration was 100 μM (kinetic), the assay buffer was 0.1 M phosphate buffered saline pH 7.4, and the mixing time was 1.5 hours (kinetic). Samples were prepared by centrifugation or filtration, and the detection methods used were HPLC and UV-Vis spectroscopy.

[0310] All compounds tested demonstrated greater than 95% solubility at 100 μM as shown above in Table 9. Albendazole and flurbiprofen (QC compounds) data are consistent with historical actual data.

[0311] Example 16: Human hepatocyte clearance of compounds 100-104

[0312] [Table 12]

[0313] The hepatocyte vials were removed from the liquid nitrogen tank and thawed in a water bath maintained at 37°C. The thawed cell suspension was transferred to a torsion tube containing 50 mL of thawing medium (Xenotech). The thawing medium containing the hepatocytes was centrifuged at 1000 rpm for 5 minutes, the supernatant was discarded, and the pellet was resuspended in 2 ml of Xenotech Optilncubate medium. An aliquot of the cell suspension was mixed with an equal volume of trypan blue, and then the cells were counted by using a hemocytometer. The cell suspension was diluted to a working density of 2 million cells in DMEM medium without FBS / incubation medium. A 10 mM stock solution of the test compound was prepared in DMSO and diluted to a concentration of 1 mM with DMSO. A working concentration of 2 μM was prepared by further dilution with PBS.

[0314] The assay was performed in duplicate (n=2). 150 μL of 2 million cell working stock of hepatocyte cell suspension was added to a 24-well plate and incubated for 10 minutes in a 37° C. incubator at a speed of 500 RPM. 150 μL of 2 μM working stock of test compound was incubated separately. At 0, 15, 30, 60 and 90 minutes, the reaction was stopped by precipitating 20 μL of the incubation mixture with 200 μL of acetonitrile containing the internal standard. The samples were vortexed at 1200 rpm for 5 minutes and centrifuged at 4000 rpm for 10 minutes. The supernatant was separated and diluted 1:1 with water before being loaded onto the LC-MS / MS analysis. Testosterone and warfarin were used as assay controls.

[0315] Compounds 100, 102 and 104 demonstrated moderate clearance in human hepatocytes, while compounds 101 and 109 demonstrated high clearance, as shown above in Table 10. Testosterone and warfarin (QC compounds) data are consistent with reference data.

[0316] [Table 13]

[0317] Example 17: Human hepatocyte stability of compounds 100, 101, 103 and 104

[0318] [Table 14]

[0319] A 10 mM stock solution of the test compound was prepared in DMSO and diluted to a concentration of 1 mM with DMSO. A working concentration of 2 μM was prepared by further dilution with PBS. A preincubation mixture of 150 μL of hepatocyte cell suspension (1,000,000 cells / mL, INVITROGRO HT medium buffer) was added to the vial and preincubated at 37° C. for 10 minutes.

[0320] 150 μL of 2 μM working stock of test compound was added to the cell suspension and incubated at 37° C. at 500 rpm. At 0, 15, 30, 60 and 90 min, the reaction was stopped by precipitating 50 μL of the incubation mixture with 150 μL of acetonitrile. The samples were vortexed at 1200 rpm for 5 min and centrifuged at 4000 rpm for 10 min. 150 μL of the supernatant was diluted with 150 μL of water and injected into an MS system (SCIEX, API 4500 Q Trap) for analysis.

[0321] Compounds 100, 102, and 104 demonstrated moderate clearance in human hepatocytes, while compounds 101 and 109 demonstrated high clearance, as shown in Table 11 above. Testosterone and warfarin (QC compounds) data are consistent with reference data. Figures 9A-9E show the results for compounds 101, 103, 104, testosterone, and warfarin in graphical format.

[0322] Example 18: Human plasma protein binding of compounds 100, 101 and 102 Test compounds were weighed and prepared as 10 mM stocks in 100% DMSO. 10 μM was the final test concentration for all compounds. The bottom plate of the RED chamber was rinsed with 20% ethanol for 10 minutes, rinsed twice with water, dried, and either used immediately or covered using the manufacturer's suggested protocol.

[0323] Samples were prepared by spiking one or more test compounds in plasma at a final concentration of 10 μM. 200 μL of plasma containing the test compound was added to the donor well (RED chamber) of the insert. At the same time, 350 μL of dialysis buffer (1×PBS) was added to the receiver well (white chamber). Duplicate measurements were performed for each test compound. Plates were covered with a sealer and incubated at 37° C. on an orbital shaker at 500 rpm for 5 hours.

[0324] After incubation, 25 μl of plasma (RED chamber) and 25 μl of buffer (white chamber) samples were collected separately in separate centrifuge tubes. Plasma and buffer samples were precipitated with 200 μL of acetonitrile containing 100% internal standard. 25 μl of T0 (T zero) plasma samples (samples before 5 hours incubation) were collected (T0 samples were processed immediately after preparation of plasma working stock solution. These samples served as a measure for calculating the percentage recovery of test compounds and were precipitated using acetonitrile containing 100% internal standard). Samples were vortexed at 1000 rpm for 5 minutes and centrifuged at 4000 rpm for 10 minutes. The supernatant was diluted 2-fold with water and loaded onto the LC-MS / MS. One or more reference compounds are atenolol and warfarin.

[0325] The % plasma bound / unbound ratio was calculated by the following formula: % unbound or % free = 100 x (Fc / Tc); % recovery = 100 (Fc + Tc) / Tc, where Tc = total compound concentration (concentration in the plasma chamber) as determined by calculated concentration on the plasma side of the membrane, Fc = free compound concentration (concentration in the buffer chamber) as determined by calculated concentration on the buffer side of the membrane, and T0 = total compound concentration as determined before dialysis.

[0326] [Table 15]

[0327] As shown above in Table 12, compounds 100 and 102 were not detected, indicating a lack of protein binding. Atenolol and warfarin data are consistent with reference data.

[0328] Example 19: Plasma stability of compounds 101, 102, 103 and 104 Fresh plasma was incubated at 37°C for 10 minutes, mixed and centrifuged to remove any aggregated protein. The clear supernatant was aliquoted into the assay plate. Plasma was equilibrated at 37°C and biotransformation was initiated by adding compound solution (1 μL of 200× compound was added to 200 μl plasma and mixed thoroughly (final concentration −1 μM)).

[0329] After compound mixing, TO samples were collected immediately. The assay plate was placed on a shaker at 37°C and samples were collected at 15, 30, 60 and 120 min. At each time point, 20 μl of sample was added to 300 μl of acetonitrile containing internal standard. Samples were vortexed at 1200 rpm for 5 min, centrifuged at 4000 rpm for 10 min, and the supernatant was diluted with water before being loaded onto the LC-MS / MS for analysis.

[0330] % remaining = 100 × (peak area ratio at time point / peak area ratio at TO). Peak area ratio = peak area of ​​analyte / peak area of ​​internal standard. Plasma half-life (T 1 / 2 )=0.693 / K, where K is the slope of the linear fit of the natural logarithm of the percent parent compound remaining versus incubation time.

[0331] [Table 16]

[0332] [Table 17]

[0333] The results are shown graphically in Figures 8A-8E and in tabular form in Tables 13 and 14. Compounds 100-104 and nicotinic acid (NA) were evaluated for human plasma stability from 0 to 2 hours at 5 μM. Compounds 101-104 showed slow degradation of the parent molecule, indicating stability over the 2 hour period. All four compounds were converted to nicotinic acid over the 2 hour time course. Compound 100 and nicotinic acid were measured to determine compound degradation. The LCMS assay was the same for the determination of both isomers of compound 101, so the measurements for compound 101 are representative of compounds 103 and 104.

[0334] Example 20: PK study of Compound 100 in rats

[0335] [Table 18]

[0336] Rats were divided into four groups, Group 1 to Group 4 (n=3 rats). Compound 100 was administered to Group 1 and Group 2 (Group 1: 415 mg / kg by oral route, Group 2: 83 mg / kg by intravenous route). Nicotinic acid was administered to Group 3 and Group 4 (Group 3: 200 mg / kg by oral route, Group 4: 40 mg / kg by intravenous route). 150-200 μL of blood was collected into 1.5 mL centrifuge tubes pre-added with K2-EDTA at pre-administration, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 12 h, and 24 h for oral doses, and at pre-administration, 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, and 24 h for intravenous doses. The K2EDTA blood samples were immediately (within less than 5 minutes) centrifuged at 14000 rpm for 10 minutes at 4°C to separate the plasma and the remainder was stored at -80°C for analysis for Compound 100 and nicotinic acid estimation. The study design is summarized in Table 15 above.

[0337] One aliquot (50 μL) of whole blood was collected at the same time, crushed with 1 ml crush solution immediately after collection, vortexed for 2 min, and stored at -80°C until analysis for NAD and NADH estimation. Kidneys and livers were collected by sacrificing animals without perfusion 24 h after dose administration. Immediately after collection, tissue samples were snap frozen in liquid nitrogen and stored at -80°C until homogenization and analysis (tissues were homogenized in methanol:water (1:1), this ratio was maintained at 19 mL of solvent per g prior to analysis).

[0338] Further details of this procedure are given in Table 16 below.

[0339] [Table 19]

[0340] Bioanalysis was performed on the analytes (NAD, NADH, Compound 100 and NA) in each sample by using an API 4500 Q trap system. All analyte quantifications were analyzed using Analyst software.

[0341] The results for Groups 2 and 1 are shown in Figures 10A and 10B, respectively. The results for Groups 4 and 3 are shown in Figures 11A and 11B, respectively.

[0342] The pharmacokinetic parameters for Group 2 are tabulated in Table 17.

[0343] [Table 20]

[0344] The pharmacokinetic parameters for Group 4 are tabulated in Table 18.

[0345] [Table 21]

[0346] The pharmacokinetic parameters for Group 3 are tabulated in Table 19.

[0347] [Table 22]

[0348] Compound 100 IV pharmacokinetics shows a biphasic rapid distribution followed by excretion. Compound 100 delivered IV has a T of 1 hour in rat plasma. 1 / 2 Compound 100 is expected to decompose at the T 1 / 2 is consistent with hepatocyte stability in vitro (5-6 h).

[0349] When nicotinic acid was administered, no distribution phase was observed after IV. Both compound 100 and nicotinic acid were detectable in liver and kidney tissues after 24 hours, both after oral and IV administration of compound 100, as shown in Figures 12A-12C. Insignificant levels of nicotinic acid were detected in the nicotinic acid treatment group. Compound 100 delivers nicotinic acid to these tissues more efficiently than nicotinic acid, as shown in Figures 12A-12C. In conclusion, compound 100 shows better in vivo pharmacology than nicotinic acid, with a longer half-life, a lower maximum concentration (C), better bioavailability, and a depot effect in the kidney and liver.

[0350] Example 21: Efficacy of Compound 100 in a cisplatin-induced renal injury model in mice This study was conducted using an Institutional Animal Ethics Committee (IAEC) approved protocol based on the CPCSEA guidelines for the care and use of animals. BALB / c female mice, aged 6–8 weeks, were divided into five groups with six members in each group. The animal room environment was monitored twice daily for temperature and relative humidity. The temperature range was 22°C ± 3°C, and the humidity range was 30–70%, although the upper humidity range may be exceeded during room cleaning. The animals were housed in an IVC system and provided with a 12-h light and 12-h dark cycle throughout the study. SDS diet (M / s. SDS Diet Services) and autoclaved drinking water were provided ad libitum.

[0351] The group parameters are provided in Table 20 below.

[0352] [Table 23]

[0353] The vehicle for cisplatin was 0.9% saline, while the vehicle for Compound 100 was PBS at pH 6. Compound 100 formulations were prepared immediately before each administration. The study was conducted in five groups.

[0354] Animals were acclimated prior to the study. Pretreatment with Compound 100 was administered for 3 days followed by cisplatin. Animals were weighed and on study day 3, Group 1 received vehicle and Groups 2, 3, 4, and 5 received a single dose of cisplatin at 25 mg / kg intraperitoneally. Oral dose groups (Groups 3-5) received Compound 100 twice daily for 6 days (after 3 days of pretreatment and 3 days of cisplatin).

[0355] Blood samples were collected at the end of the study into 2 ml Eppendorf tubes (terminal sampling 12 hours after the last dose administration, cardiac puncture) and serum was separated and stored at -20°C for clinical chemistry analysis.

[0356] All animals survived and were sacrificed with CO2 overdose at the end of the study (12 hours after the last test compound administration). Livers, kidneys and muscles (gastrocnemius and soleus / vastus lateralis) were harvested, weighed, snap frozen in liquid nitrogen and stored at -80°C for analysis. Serum creatinine and blood urea nitrogen (BUN) were determined using a clinical chemistry analyzer on the last day of blood collection. The results are shown graphically in Figures 13 and 14 for Groups 1-5, respectively.

[0357] Mice in group 2 became sluggish from day 5 until the time of sacrifice. Weight loss was observed in groups 2 and 5, with group 2 showing the greatest weight loss. Mild to moderate renal discoloration was observed in group 2. No observable abnormalities were detected in the kidneys in the other groups.

[0358] Mice in group 2 showed a significant increase in serum creatinine and BUN compared to group 1 [p<0.05]. Treatment with compound 100 showed a significant decrease in serum creatinine and BUN compared to group 2 at all three doses (i.e., groups 3-5) when administered orally twice daily for six days [p<0.05]. No obvious differences in serum creatinine and BUN were observed between groups 3, 4, and 5. In conclusion, all three oral doses of compound 100 were renal protective in a cisplatin-induced acute kidney injury (AKI) mouse model.

[0359] Example 22: Long-term solid state stability of Compound 100 To determine the solid state stability in a deep freezer, Compound 100 was stored in a tightly sealed glass vial at -15°C. Compound from this vial was assessed for purity by UPLC at two different time points: day 0 and day 93 (3 months). Table 21 shows the results obtained for solid state stability based on the purity measurement performed on day 0.

[0360] [Table 24]

[0361] Compound 100 is stable in its solid state for up to three months when stored at -15°C.

Claims

1. Compounds of structural formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein: R １ is -H, R ８ C(O)-, 【Chemistry 2】 or 【Transformation 3】 and R ２ is -H or R ９ C(O)—; R ３ is -H or R １０ C(O)—; R ４ is —H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, R １１ C(O)- or 【Chemistry 4】 and R ６ is —H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl; and R ５ , R ７ , R ８ , R ９ , R １０ and R １１ is independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl; However, R １ or R ４ At least one of 【Transformation 5】 (It shall be assumed that

2. R ４ is —H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, R １１ C(O)—, or 【Transformation 6】 2. The compound of claim 1, wherein:

3. R ４ is —H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, R １１ C(O)- or 【Transformation 7】 2. The compound of claim 1, wherein:

4. R ４ is alkyl, alkenyl, R １１ C(O)- or 【Transformation 8】 2. The compound of claim 1, wherein:

5. R ８ , R ９ , R １０ and R １１ 10. The compound of claim 1, wherein is independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl.

6. R ８ and R １１ is alkyl, substituted alkyl, alkenyl, substituted alkenyl, or heteroaryl, and R ９ and R １０ is independently alkyl, substituted alkyl, alkenyl, or substituted alkenyl.

7. R ８ and R １１ is alkyl, substituted alkyl, alkenyl, substituted alkenyl, or heteroaryl, and R ９ and R １０ are independently -CH ３ , -C ２ H ５ , -C ３ H ７ , -CH(CH ３ ) ２ , -CH ２ CH (CH ３ ) ２ , —CH(C ２ H ５ ) (CH ２ ) ２ CH ３ , or —CH(NH ２ ) CH(CH ３ ) ２ 2. The compound of claim 1, wherein:

8. R ８ and R １１ are independently -CH ３ , -C ２ H ５ , -C ３ H ７ , -CH(CH ３ ) ２ , -CH ２ CH (CH ３ ) ２ , —CH(C ２ H ５ ) (CH ２ ) ２ CH ３ , or —CH(NH ２ ) CH(CH ３ ) ２ or heteroaryl, R ９ and R １０ are independently -CH ３ , -C ２ H ５ , -C ３ H ７ , -CH(CH ３ ) ２ , -CH ２ CH (CH ３ ) ２ , —CH(C ２ H ５ ) (CH ２ ) ２ CH ３ , or —CH(NH ２ ) CH(CH ３ ) ２ 2. The compound of claim 1, wherein:

9. R ９ and R １０ are independently -CH ３ , -C ２ H ５ , -C ３ H ７ , -CH(CH ３ ) ２ , -CH ２ CH (CH ３ ) ２ , —CH(C ２ H ５ ) (CH ２ ) ２ CH ３ , or —CH(NH ２ ) CH(CH ３ ) ２ 2. The compound of claim 1, wherein:

10. R １ but, 【Chemistry 9】 2. The compound of claim 1, wherein:

11. R ５ 2. The compound of claim 1, wherein is alkyl, alkenyl, aryl, substituted aryl, arylalkyl, heteroaryl, or heteroarylalkyl.

12. R ５ The compound of claim 1 , wherein is alkyl, alkenyl, aryl, or substituted aryl.

13. R ５ The compound of claim 1 , wherein is aryl.

14. R ６ The compound of claim 1 , wherein is —H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl.

15. R ６ The compound of claim 1 , wherein is —H, alkyl, substituted alkyl, arylalkyl, or heteroarylalkyl.

16. R ７ 2. The compound of claim 1, wherein is alkyl, alkenyl, aryl, substituted aryl, arylalkyl, heteroaryl, or heteroarylalkyl.

17. R ７ The compound of claim 1 , wherein is alkyl, alkenyl, or arylalkyl.

18. R ５ is alkyl, alkenyl, aryl or substituted aryl, and R ６ is alkyl, substituted alkyl, arylalkyl, or heteroarylalkyl; R ７ The compound of claim 1 , wherein is alkyl, alkenyl, or arylalkyl.

19. R ５ is aryl or arylalkyl, and R ６ is alkyl, substituted alkyl, arylalkyl, or heteroarylalkyl; R ７ The compound of claim 1 , wherein is alkyl, alkenyl, or arylalkyl.

20. Formula (II): 【Chemistry 10】 The compound according to claim 1.

21. R ９ , R １０ and R １１ 21. The compound of claim 20, wherein is independently alkyl or substituted alkyl.

22. R ９ , R １０ and R １１ are independently -CH ３ , -C ２ H ５ , -C ３ H ７ , -CH(CH ３ ) ２ , -CH ２ CH (CH ３ ) ２ , —CH(C ２ H ５ ) (CH ２ ) ２ CH ３ , or —CH(NH ２ ) CH(CH ３ ) ２ 21. The compound of claim 20, wherein:

23. R ２ is R ９ C(O)—; R ３ is R １０ C(O)—, and R ４ The compound of claim 20, wherein is —H.

24. R ９ and R １０ 24. The compound of claim 23, wherein is independently alkyl or substituted alkyl.

25. R ９ and R １０ are independently -CH ３ , -C ２ H ５ , -C ３ H ７ , -CH(CH ３ ) ２ , -CH ２ CH (CH ３ ) ２ , —CH(C ２ H ５ ) (CH ２ ) ２ CH ３ , or —CH(NH ２ ) CH(CH ３ ) ２ 24. The compound of claim 23, wherein:

26. R ２ is R ９ C(O)—; R ３ is R １０ C(O)—, and R ４ 21. The compound of claim 20, wherein is alkyl.

27. R ９ and R １０ 27. The compound of claim 26, wherein is independently alkyl or substituted alkyl.

28. R ９ and R １０ are independently -CH ３ , -C ２ H ５ , -C ３ H ７ , -CH(CH ３ ) ２ , -CH ２ CH (CH ３ ) ２ , —CH(C ２ H ５ ) (CH ２ ) ２ CH ３ , or —CH(NH ２ ) CH(CH ３ ) ２ 27. The compound of claim 26, wherein:

29. R ２ is R ９ C(O)—; R ３ is R １０ C(O)—, and R ４ is R １１ The compound of claim 20, which is C(O)-.

30. R ９ , R １０ and R １１ 30. The compound of claim 29, wherein is independently alkyl or substituted alkyl.

31. R ９ , R １０ and R １１ are independently -CH ３ , -C ２ H ５ , -C ３ H ７ , -CH(CH ３ ) ２ , -CH ２ CH (CH ３ ) ２ , —CH(C ２ H ５ ) (CH ２ ) ２ CH ３ , or —CH(NH ２ ) CH(CH ３ ) ２ 30. The compound of claim 29, wherein:

32. R ２ is -H, and R ３ is R １０ C(O)—, and R ４ is R １１ The compound of claim 20, which is C(O)-.

33. R １０ and R １１ 33. The compound of claim 32, wherein is independently alkyl or substituted alkyl.

34. R １０ and R １１ are independently -CH ３ , -C ２ H ５ , -C ３ H ７ , -CH(CH ３ ) ２ , -CH ２ CH (CH ３ ) ２ , —CH(C ２ H ５ ) (CH ２ ) ２ CH ３ , or —CH(NH ２ ) CH(CH ３ ) ２ 33. The compound of claim 32, wherein:

35. R ２ is R ９ C(O)—; R ３ is —H, and R ４ is R １１ The compound of claim 20, which is C(O)-.

36. R ９ , and R １１ 36. The compound of claim 35, wherein is independently alkyl or substituted alkyl.

37. R ９ , and R １１ are independently -CH ３ , -C ２ H ５ , -C ３ H ７ , -CH(CH ３ ) ２ , -CH ２ CH (CH ３ ) ２ , —CH(C ２ H ５ ) (CH ２ ) ２ CH ３ , or —CH(NH ２ ) CH(CH ３ ) ２ 36. The compound of claim 35, wherein:

38. Formula (III): 【Chemistry 11】 The compound according to claim 1.

39. R ８ , R ９ and R １０ 39. The compound of claim 38, wherein is independently alkyl or substituted alkyl.

40. R ８ , R ９ and R １０ are independently -CH ３ , -C ２ H ５ , -C ３ H ７ , -CH(CH ３ ) ２ , -CH ２ CH (CH ３ ) ２ , —CH(C ２ H ５ ) (CH ２ ) ２ CH ３ , or —CH(NH ２ ) CH(CH ３ ) ２ 39. The compound of claim 38, wherein:

41. R １ is R ８ C(O)—; R ２ is R ９ C(O)—, and R ３ is R １０ 39. The compound of claim 38, which is C(O)-.

42. R ８ , R ９ and R １０ 42. The compound of claim 41, wherein is independently alkyl or substituted alkyl.

43. R ８ , R ９ and R １０ are independently -CH ３ , -C ２ H ５ , -C ３ H ７ , -CH(CH ３ ) ２ , -CH ２ CH (CH ３ ) ２ , —CH(C ２ H ５ ) (CH ２ ) ２ CH ３ , or —CH(NH ２ ) CH(CH ３ ) ２ 42. The compound of claim 41, wherein:

44. R １ is -H, and R ２ is R ９ C(O)—, and R ３ is R １０ 39. The compound of claim 38, which is C(O)-.

45. R ９ and R １０ 45. The compound of claim 44, wherein is independently alkyl or substituted alkyl.

46. R ９ and R １０ are independently -CH ３ , -C ２ H ５ , -C ３ H ７ , -CH(CH ３ ) ２ , -CH ２ CH (CH ３ ) ２ , —CH(C ２ H ５ ) (CH ２ ) ２ CH ３ , or —CH(NH ２ ) CH(CH ３ ) ２ 45. The compound of claim 44, wherein:

47. R １ is R ８ C(O)—; R ２ is —H, and R ３ is R １０ 39. The compound of claim 38, which is C(O)-.

48. R ８ , and R １０ 48. The compound of claim 47, wherein is independently alkyl or substituted alkyl.

49. R ８ and R １０ are independently -CH ３ , -C ２ H ５ , -C ３ H ７ , -CH(CH ３ ) ２ , -CH ２ CH (CH ３ ) ２ , —CH(C ２ H ５ ) (CH ２ ) ２ CH ３ , or —CH(NH ２ ) CH(CH ３ ) ２ 48. The compound of claim 47, wherein:

50. R １ is R ８ C(O)—; R ２ is R ９ 39. The compound of claim 38, wherein R is —C(O)— and R is —H.

51. R ８ and R ９ 51. The compound of claim 50, wherein is independently alkyl or substituted alkyl.

52. R ８ and R ９ are independently -CH ３ , -C ２ H ５ , -C ３ H ７ , -CH(CH ３ ) ２ , -CH ２ CH (CH ３ ) ２ , —CH(C ２ H ５ ) (CH ２ ) ２ CH ３ , or —CH(NH ２ ) CH(CH ３ ) ２ 51. The compound of claim 50, wherein:

53. Formula (IV): 【Chemistry 12】 The compound according to claim 1.

54. R ９ and R １０ 54. The compound of claim 53, wherein is independently alkyl or substituted alkyl.

55. R ９ and R １０ are independently -CH ３ , -C ２ H ５ , -C ３ H ７ , -CH(CH ３ ) ２ , -CH ２ CH (CH ３ ) ２ , —CH(C ２ H ５ ) (CH ２ ) ２ CH ３ , or —CH(NH ２ ) CH(CH ３ ) ２ 54. The compound of claim 53, wherein:

56. R ２ is R ９ C(O)—, and R ３ is R １０ C(O)—, and R ９ and R １０ 54. The compound of claim 53, wherein is independently alkyl or substituted alkyl.

57. R ５ is aryl or arylalkyl, and R ６ is alkyl, substituted alkyl, arylalkyl, or heteroarylalkyl; R ７ 57. The compound of claim 56, wherein is alkyl, alkenyl, or arylalkyl.

58. R ９ and R １０ are independently -CH ３ , -C ２ H ５ , -C ３ H ７ , -CH(CH ３ ) ２ , -CH ２ CH (CH ３ ) ２ , —CH(C ２ H ５ ) (CH ２ ) ２ CH ３ , or —CH(NH ２ ) CH(CH ３ ) ２ 58. The compound of claim 57, wherein:

59. R ５ is phenyl, naphthyl or benzyl, and R ６ But CH ３ , -C ２ H ５ and R ７ But -CH ３ , -C ２ H ５ , -C ３ H ７ , -CH(CH ３ ) ２ , -CH ２ CH (CH ３ ) ２ , —CH(C ２ H ５ ) (CH ２ ) ２ CH ３ or cyclopropyl.

60. R ２ is —H, and R ３ is R １０ C(O)—, and R １０ 54. The compound of claim 53, wherein is alkyl or substituted alkyl.

61. R ５ is aryl or arylalkyl, and R ６ is alkyl, substituted alkyl, arylalkyl, or heteroarylalkyl; R ７ 61. The compound of claim 60, wherein is alkyl, alkenyl, or arylalkyl.

62. R １０ But -CH ３ , -C ２ H ５ , -C ３ H ７ , -CH(CH ３ ) ２ , -CH ２ CH (CH ３ ) ２ , —CH(C ２ H ５ ) (CH ２ ) ２ CH ３ , or —CH(NH ２ ) CH(CH ３ ) ２ 62. The compound of claim 61, wherein:

63. R ５ is aryl or arylalkyl, and R ６ is alkyl, substituted alkyl, arylalkyl, or heteroarylalkyl; R ７ 63. The compound of claim 62, wherein is alkyl, alkenyl, or arylalkyl.

64. R ５ is phenyl, naphthyl or benzyl, and R ６ But CH ３ , -C ２ H ５ and R ７ But -CH ３ , -C ２ H ５ , -C ３ H ７ , -CH(CH ３ ) ２ , -CH ２ CH (CH ３ ) ２ , —CH(C ２ H ５ ) (CH ２ ) ２ CH ３ or cyclopropyl.

65. R ２ is R ９ C(O)—, and R ３ is —H, and R ９ 54. The compound of claim 53, wherein is alkyl or substituted alkyl.

66. R ５ is aryl or arylalkyl, and R ６ is alkyl, substituted alkyl, arylalkyl, or heteroarylalkyl; R ７ 66. The compound of claim 65, wherein is alkyl, alkenyl, or arylalkyl.

67. R ９ But -CH ３ , -C ２ H ５ , -C ３ H ７ , -CH(CH ３ ) ２ , -CH ２ CH (CH ３ ) ２ , —CH(C ２ H ５ ) (CH ２ ) ２ CH ３ , or —CH(NH ２ ) CH(CH ３ ) ２ 67. The compound of claim 66, wherein:

68. R ５ is phenyl, naphthyl or benzyl, and R ６ But CH ３ , -C ２ H ５ and R ７ But -CH ３ , -C ２ H ５ , -C ３ H ７ , -CH(CH ３ ) ２ , -CH ２ CH (CH ３ ) ２ , —CH(C ２ H ５ ) (CH ２ ) ２ CH ３ or cyclopropyl.

69. structure: 【Chemistry 13】 、 【Chemistry 14】 or 【Chemistry 15】 2. The compound of claim 1 having the formula:

70. structure: 【Chemistry 16】 、 【Chemistry 17】 or [Chemistry 18] 2. The compound of claim 1 having the formula:

71. 10. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

72. A method for preventing or treating a metabolic disorder, cardiovascular disorder, cerebrovascular disorder, liver disorder, renal disorder or muscular disorder in a mammal other than a human in need thereof, comprising administering to said mammal a therapeutically effective amount of a compound of claim 1.

73. The metabolic disorder is type 1 or type 2 diabetes, impaired glucose tolerance, insulin resistance, obesity, hyperlipidemia, dyslipidemia, hypercholesterolemia, or hypertriglyceridemia; the cardiovascular disorder is cardiomyopathy, heart failure, or myocardial ischemia, infarction, or ischemia-reperfusion injury (IRI); the cerebrovascular disorder is stroke or cerebral ischemia, neuroinflammation, multiple sclerosis, hepatic encephalopathy, neurodegeneration, Parkinson's disease, or Alzheimer's disease; the liver disorder is nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), alcoholic liver disease, or steroid hormone receptor agonist (SHR).

73. The method of claim 72, wherein the disorder is selected from the group consisting of: diabetic liver disease, alcoholic hepatitis, alcoholic steatohepatitis, liver fibrosis, cirrhosis, liver failure, acute liver failure, and chronic liver failure; the kidney disorder is acute kidney injury or chronic kidney disease, including renal ischemia or IRI and diabetic kidney disease; and the muscle disorder is muscle atrophy, cachexia, sarcopenia, muscular dystrophy, Duchenne muscular dystrophy (DMD), myositis, neuromuscular degeneration, ataxia, spinocerebellar ataxia, adult-onset mitochondrial myopathy, Friedreich's ataxia, and ataxia-telangiectasia.

74. A method for detecting nicotinamide adenine dinucleotide (NAD) in mammalian cell types or tissues other than humans. ＋ 10. A method for increasing IL-1 levels and / or providing cytoprotection, comprising administering to said mammal, other than a human, a therapeutically effective amount of a compound of claim 1.

75. Nicotinamide adenine dinucleotide (NAD) in cell types or tissues ＋ ) levels and / or providing cytoprotection to mammals other than humans in need thereof. ＋ A method for increasing the level of or / and providing cytoprotection, comprising administering to said mammal, other than a human, a therapeutically effective amount of the compound of claim 1 and a therapeutically effective amount of a poly(ADP-ribose) polymerase (PARP) inhibitor that is lower than the dose of said PARP inhibitor when used as an anticancer agent.

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