Prodrugs and conjugates of 2,4-dinitrophenol and compositions and methods thereof

Abstract

The present invention provides novel 2,4-dinitrophenol (DNP) derivatives and prodrugs thereof as modulators of mitochondrial function. The present invention also provides pharmaceutical compositions comprising the compounds of the present invention and methods for using the same to treat various diseases and conditions associated with or related to mitochondrial dysfunction (e.g., obesity, diabetes, insulin resistance, liver disease, heart or kidney failure, neurodegenerative diseases, and aging-related diseases, including but not limited to sarcopenia, osteoporosis, etc.).

Description

[0001] This application claims priority to Chinese application No. 202311324983.X, filed October 12, 2023, and U.S. Provisional Application Serial No. 63 / 544,113, filed October 13, 2023, the entire contents of which are incorporated herein by reference. Technical Field

[0002] This invention relates to novel compounds and their therapeutic uses. More specifically, the invention provides novel 2,4-dinitrophenol (DNP) derivatives, prodrugs, and conjugates thereof as regulators of mitochondrial activity. The invention also provides pharmaceutical compositions comprising the compounds of the invention and methods for treating various diseases and conditions related to or associated with mitochondria or mitochondrial dysfunction (e.g., obesity, diabetes, insulin resistance, dyslipidemia, liver disease, heart or kidney failure, neurodegenerative diseases, and age-related diseases, including sarcopenia, osteoporosis, etc.). Background Technology

[0003] Metabolic syndrome, represented by type 2 diabetes, obesity, dyslipidemia, hypertension, and metabolic dysfunction-associated fatty liver disease (MAFLD), is a group of diseases and symptoms characterized by insulin resistance in the liver and peripheral tissues. (Fabbrini) et al 2009 PNAS 106, 15430; Petersen, et al. 2018 Physiology Reviews (98, 2133.) The potential causes of these conditions include excessive lipid buildup in the relevant organs and chronic inflammation caused by excessive production of reactive oxygen species (ROS). While significant progress has been made in drug discovery efforts aimed at reducing energy intake over the past decade (e.g., Glp-1R agonists, SGLT2 inhibitors, etc.), progress in exploring energy expenditure has been less promising.

[0004] Mitochondrial uncoupling is an endogenous energy dissipation process caused by "proton leakage," where ATP synthesis is uncoupled at the ends of the electron transport chain. This process occurs in all eukaryotic cells and accounts for 20%–30% of basal metabolic rate, depending on tissue type. (Geisler 2019) Cells 8, 280.). Over the years, in addition to endogenous uncoupling proteins such as UCP-1, UCP-2, or UCP-3, many chemical uncoupling agents have been discovered and studied, among which DNP is the most well-known (Chen, et al 2021 Metabolism Clinical and Experimental 117, 154724; Goedeke, et al.2021 Molecular Metabolism 46, 101178.). In the 1930s, over 100,000 people used DNP for weight loss; however, its dose-related toxicities, such as rash, cataracts, or fever-related deaths, limited its clinical use and ultimately led to its ban by the FDA in 1938. Since then, numerous efforts have been made to explore different ways to increase the safety window of DNP therapy. Examples in this regard include liver-targeted approaches, sustained-release formulations of DNP, and methods that significantly reduce plasma C3 levels compared to DNP itself. max The prodrug with an AUC ratio. (Perry, et al. 2013 Cell Metabolism 18, 740; Perry, et al. 2015 Science 347, 1253; WO 2018 / 129258A1).

[0005] Besides its potential use in treating obesity due to increased energy metabolism, particularly lipid metabolism, mitochondrial uncoupling agents are generally considered indirect activators of adenosine monophosphate-activated protein kinase (AMPK), a key regulator of energy homeostasis and crucial for maintaining / building muscle mass and function (Narkar et al., 2008, Cell, Vol. 134, p. 405; Fan et al., 2017, Cell Metabolism, Vol. 25, p. 242). Furthermore, DNP has been shown to reduce the production of excess reactive oxygen species (ROS) and prevent calcium loss in mitochondria. 2+ Excessive levels can induce brain-derived neurotrophic factor (BDNF), which could potentially offer benefits for the treatment of many neurodegenerative diseases. (Kishimoto, et al. 2020 Neurobiology of Aging 85, 123.).

[0006] In summary, there is an urgent need for novel therapeutic agents, especially novel mitochondrial uncoupling agents, as regulators of mitochondrial function, to treat metabolic syndrome, neurodegenerative and age-related diseases and conditions, such as sarcopenia and osteoporosis. Summary of the Invention

[0007] This invention is based in part on novel DNP derivatives and prodrugs, pharmaceutical compositions thereof, methods of their preparation, and their use as mitochondrial uncoupling agents in the treatment or relief of various diseases or conditions. More specifically, this invention provides novel compounds for use as DNP prodrugs and pharmaceutically acceptable salts thereof. Upon oral administration, these compounds release DNP with a significantly reduced plasma Cmax / AUC ratio compared to DNP itself, thereby improving the safety window.

[0008] In addition, the present invention provides novel coupling compounds that affect or participate in two or more mechanisms of action, such as mitochondrial uncoupling binding mechanisms that reduce methylglyoxal (MGO) production (e.g., Nrf2 activators) and / or anti-inflammatory mechanisms.

[0009] Therefore, the compounds of the present invention can be used to treat various metabolic diseases, neurodegenerative diseases, age-related diseases, liver diseases and / or cardiovascular diseases.

[0010] In one respect, the present invention generally relates to compounds having structural formula (I) or (II):

[0011] Or its pharmaceutically acceptable form or isotopic derivative, wherein n is 1, 2, 3 or 4; and R X For R X1 R X2 Or R X3 , where R X1 The radical is selected from the following groups: CH2C(=O)OR 3 CH2C(=O)SR 3 C(=O)NR 4 R 5 OR 6 SR 6 NR 7 R 8 NR 9 C(=O)R 10 OC(=O)R 11 ,SC(=O)R 12 OC(=O)OR 13 ,SC(=O)OR 13 NR 9 C(=O)OR 13 OC(=O)NR 14 R 15 ,SC(=O)NR 14 R 15 NR 9 C(=O)NR 14 R 15 OC(=O)SR 3 ,SC(=O)SR 3 NR 9 C(=O)SR 3 Halogens, CN, H and C 1-6 Alkyl; and R X2 The groups are selected from the following: ;

[0012] And R X3The groups are selected from the following: ; And R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 and R 15 Each of them: Independently selected from H and C 1-6 Alkyl, 3- to 8-membered carbocyclic or heterocyclic, optionally surrounded by 1-6 R... A Replace, or R 4 and R 5 R 7 and R 8 、or R 14 and R 15 Together with the N atoms they are bonded to, they form 3- to 8-membered heterocycles, optionally bound by 1-6 R atoms. A replace; Each R A Independently selected from: D, halogen, R, OR, and NRR'; and each of R and R' is independently H or C. 1-6 Alkyl groups, optionally composed of 1-4 atoms selected from deuterium (D), halogens, C 1-6 The alkoxy and amino groups are substituted; or R and R' together with the N atom to which they are bonded form 3- to 6-membered heterocycles, optionally substituted with 1-4 groups selected from D, halogen, C. 1-6 Alkyl or alkoxy and amino groups are substituted.

[0013] On the other hand, the present invention generally relates to compounds having structural formula (III) or (IV):

[0014] Or a pharmaceutically acceptable form or isotopic derivative thereof, wherein n is 1, 2, 3 or 4; Y is selected from single bond, NR, S, CRR', and O; R Y The radical is selected from the following groups: H, halogen, CN, R, C(=O)OR, C(=O)NRR', C(=O)R, and C(=O)SR; and each of R and R' is independently H or C. 1-6Alkyl groups, or R and R', together with the N atoms they are bonded to form 3- to 6-membered heterocycles, wherein the alkyl group or heterocycle is optionally surrounded by 1-4 atoms selected from D, halogen, C. 1-6 Alkyl or alkoxy and amino groups are substituted.

[0015] In another aspect, the present invention generally relates to pharmaceutical compositions comprising the compounds disclosed herein.

[0016] In another aspect, the present invention generally relates to unit dosage forms of pharmaceutical compositions comprising the compounds disclosed herein.

[0017] In another aspect, the present invention generally relates to methods of treating or alleviating a disease or ailment, including administering a therapeutically effective amount of the compounds disclosed herein to a subject in need of such treatment.

[0018] In another aspect, the present invention generally relates to a method for reducing toxicity or side effects in the treatment of mitochondrial-related diseases or conditions, the method comprising administering a therapeutically effective amount of the compound disclosed herein to a subject in need of such treatment.

[0019] In another aspect, the present invention generally relates to the use of the compounds disclosed herein and pharmaceutically acceptable excipients, carriers or diluents in the preparation of medicaments for treating diseases or conditions.

[0020] In another aspect, the present invention generally relates to the use of the compounds disclosed herein for the treatment of diseases or conditions. Attached Figure Description

[0021] Figure 1 Exemplary data on mean plasma concentrations of 2,4-DNP in male C57BL / 6 mice (N=3 / group) after intravenous (1 mg / kg) and oral (5 mg / kg) administration.

[0022] Figure 2 Exemplary data on mean plasma concentrations of compound 1 and its metabolite 2,4-DNP in male C57BL / 6 mice (N=3 / group) after intravenous (1 mg / kg) or oral (5 mg / kg) administration.

[0023] Figure 3 Exemplary data on mean plasma concentrations of 2,4-DNP in male SD rats (N=3 / group) after intravenous (1 mg / kg) and oral (5 mg / kg) administration.

[0024] Figure 4 Exemplary data on mean plasma concentrations of compound 1 and its metabolite 2,4-DNP in male SD rats (N=3 / group) after intravenous (1 mg / kg) or oral (5 mg / kg) administration.

[0025] Figure 5 Exemplary data on mean plasma concentrations of compound 14 and its metabolite 2,4-DNP in male SD rats (N=3 / group) after intravenous (1 mg / kg) or oral (5 mg / kg) administration.

[0026] Figure 6 Exemplary data on mean plasma concentrations of compound 1 and its metabolite 2,4-DNP in male beagle dogs (N=3 / group) after intravenous (1 mg / kg) or oral (5 mg / kg) administration.

[0027] Figure 7 Exemplary data on rectal temperature in SD rats following a single oral tube feeding of 2,4-DNP.

[0028] Figure 8 Exemplary data on acute survival curves of SD rats following a single oral tube feeding of 2,4-DNP.

[0029] Figure 9 Exemplary data on rectal temperature in SD rats following a single oral tube feeding of 2,4-DNP or compound 1.

[0030] Figure 10 Exemplary data on weight changes after administration of compound 1.

[0031] Figure 11 Exemplary data on fasting blood glucose levels after administration of compound 1.

[0032] Figure 12 Exemplary data on fasting blood insulin levels after administration of compound 1.

[0033] Figure 13a Exemplary data on plasma TC levels after administration of compound 1.

[0034] Figure 13b Exemplary data on plasma TG levels after administration of compound 1.

[0035] Figure 13c Exemplary data on plasma HDL levels after administration of compound 1.

[0036] Figure 13d Exemplary data on plasma LDL levels after administration of compound 1.

[0037] Figure 13e Exemplary data on plasma MDA levels after administration of compound 1.

[0038] Figure 14a Exemplary data on liver TC levels after administration of compound 1.

[0039] Figure 14b Exemplary data on liver TG levels after administration of compound 1.

[0040] Figure 15a Exemplary data on plasma ALT levels after administration of compound 1.

[0041] Figure 15b Exemplary data on plasma AST levels after administration of compound 1.

[0042] Figure 16a Exemplary data on NAS scores after administration of compound 1.

[0043] Figure 16b Exemplary data on steatosis scores after administration of compound 1.

[0044] Figure 16c Exemplary data on inflammation scores after administration of compound 1.

[0045] Figure 16d Exemplary data on hepatocyte ballooning scores after administration of compound 1.

[0046] Figure 17a Exemplary data on running distance after administration of compound 1.

[0047] Figure 17b Exemplary data on running time after administration of compound 1.

[0048] Figure 18 Exemplary data on total muscle mass index after administration of compound 1.

[0049] Figure 19 Exemplary data on changes in type I muscle fibers after administration of compound 1.

[0050] Figure 20 Exemplary data on the p-AMPKα / AMPKα protein ratio in the left quadriceps femoris muscle after administration of compound 1.

[0051] Figure 21 Exemplary data on PDK4 gene expression in the left quadriceps femoris muscle after administration of compound 1. definition

[0052] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. General principles of organic chemistry, as well as specific functional groups and reactivity, are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 2006.

[0053] Unless otherwise specified in the context in which the terms appear, the following terms are intended to have the following meanings.

[0054] The ranges provided in this document should be understood as abbreviations of all values ​​within that range. For example, the range 1 to 16 should be understood as including any number, combination of numbers, or subrange of numbers that come from groups of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

[0055] Any composition or method disclosed herein may be combined with one or more of any other compositions and methods provided herein.

[0056] The description of a list of chemical groups in any definition of a variable herein includes the definition of that variable as any single group or combination of the listed groups. The description of embodiments of variables or aspects herein includes embodiments as any single embodiment or in combination with any other embodiment or part thereof.

[0057] The definitions of specific functional groups and chemical terms are described in more detail below. When listing ranges of values, the aim is to cover every value within that range and every subrange. For example, “C…” 1-6 "Alkyl" is intended to encompass C1, C2, C3, C4, C5, C6, C 1-6 C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-5 C 2-4 C 2-3 C 3-6 C 3-5 C 3-4 C 4-6 C 4-5 and C 5-6 alkyl.

[0058] When substituents are specified by their conventional chemical formula written from left to right, they also cover chemically identical substituents produced by structures written from right to left, for example, -C(=O)-O- is equivalent to -OC(=O)-.

[0059] The structure of the compounds of the present invention is limited by the principles of chemical bonding known to those skilled in the art. Therefore, when a group can be replaced by one or more of a plurality of substituents, such substituents are selected to conform to the principles of chemical bonding and to obtain compounds that are inherently unstable and / or known to those skilled in the art to be unstable under environmental conditions (e.g., aqueous, neutral, and several known physiological conditions).

[0060] As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural references, unless otherwise expressly provided.

[0061] As used in this article, "at least" a specific value should be understood as that value and all values ​​greater than that value.

[0062] As used herein, the terms “comprising,” “including,” or “having” when used to define compositions and methods are intended to mean that the compositions and methods include the listed elements, but do not exclude other elements. The term “consistently composed of” when used to define compositions and methods should mean that the compositions and methods include the listed elements and exclude other elements that are of any substantial significance to the composition and method. For example, “consistently composed of” means the application of a explicitly listed pharmacologically active agent and excludes pharmacologically active agents that are not explicitly listed. The term “consistently composed of” does not exclude pharmacologically inactive or inert agents, such as pharmaceutically acceptable excipients, carriers, or diluents. The term “composed of” when used to define compositions and methods should mean the exclusion of trace elements and substantial method steps that are other components. Examples defined by each of these transitional terms are within the scope of this invention.

[0063] As used herein, the terms “disease” and “symptom” are used interchangeably and refer to any condition that impairs or interferes with the normal function of cells, tissues or organs.

[0064] As used herein, the term "hydrate" refers to a compound that also includes stoichiometric or nonstoichiometric amounts of water bound together by noncovalent intermolecular forces.

[0065] As used herein, the term "pharmaceutically acceptable" means suitable for use in contact with human and other mammalian tissues without excessive toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. "Pharmaceutically acceptable forms" of the disclosed compounds include, but are not limited to, their pharmaceutically acceptable salts, esters, hydrates, solvates, polymorphs, isomers, and isotopically labeled derivatives.

[0066] In some embodiments, "pharmaceutically acceptable form" includes, but is not limited to, pharmaceutically acceptable salts, esters, and isotopically labeled derivatives thereof.

[0067] In some embodiments, "pharmaceutically acceptable form" includes, but is not limited to, its pharmaceutically acceptable isomers, stereoisomers, and isotopically labeled derivatives.

[0068] As used herein, the term "pharmaceutically acceptable salt" refers to those salts that, within reasonable medical judgment, are suitable for contact with the tissues of a subject without undue toxicity, irritation, allergic reactions, etc., and that are proportionate to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. in J. Pharmaceutical Sciences Pharmaceutically acceptable salts are described in detail in Volume 66 (1977), pages 1-19. Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed by amino groups with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts formed by other methods in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, disglucuronate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-heptahydrate, glyceryl phosphate, gluconate, hemisulfate, heptahydrate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. In some embodiments, the organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, lactic acid, trifluoroacetic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc.

[0069] These salts can be prepared in situ during the isolation and purification of the disclosed compounds, or prepared separately, such as by reacting the free base or free acid of the parent compound with a suitable base or acid, respectively. Pharmaceutically acceptable salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and nitrogen. + (C 1-4Alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc. Other pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations, which are formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, pharmaceutically acceptable base addition salts may be selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0070] In some embodiments, the pharmaceutically acceptable form is a “solvent” (e.g., a hydrate). As used herein, the term “solvent” refers to a compound that also includes stoichiometric or non-stoichiometric amounts of solvent bound by non-covalent intermolecular forces. A solvate can be a solvate of the disclosed compound or a pharmaceutically acceptable salt thereof. When the solvent is water, the solvate is a “hydrate.” Pharmaceutically acceptable solvates and hydrates are, for example, complexes comprising, for example, one to about 100, one to about 10, one to about 2, about 3, or about 4 solvent molecules or water molecules. It should be understood that the term “compound” as used herein encompasses the compound and its solvates, as well as mixtures thereof.

[0071] As used herein, the term "prodrug" refers to a compound that is converted in vivo to produce the disclosed compound or a pharmaceutically acceptable form of the compound. A prodrug may be inactive when administered to a subject, but may be converted in vivo to an active compound, for example, through hydrolysis (e.g., hydrolysis in the blood). In some cases, a prodrug has improved physical and / or delivery properties superior to the parent compound. Compared to the parent compound, a prodrug may increase the bioavailability of the compound when administered to a subject (e.g., by enhancing blood absorption after oral administration) or enhance delivery to the relevant biological compartment (e.g., the brain or lymphatic system). Exemplary prodrugs include derivatives of the disclosed compound that have enhanced water solubility relative to the parent compound or are actively transported via the intestinal membrane.

[0072] As used herein, the term "pharmaceutically acceptable excipient, carrier, or diluent" refers to a pharmaceutically acceptable material, composition, or medium, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, which relates to carrying or transporting a subject's medication from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable," meaning it is compatible with other components of the formulation and harmless to the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; tragacanth gum powder; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, such as propylene glycol; polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffer; and other non-toxic and compatible substances used in pharmaceutical formulations. Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate, magnesium stearate and polyethylene oxide-polypropylene oxide copolymers, as well as colorants, releasing agents, coating agents, sweeteners, flavorings and aromas, preservatives and antioxidants may also be present in the composition.

[0073] As used herein, the term "polymorph" refers to the solid crystalline form of a compound or its complexes, which can be characterized by physical means such as X-ray powder diffraction or infrared spectroscopy. Different polymorphs of the same compound can exhibit different physical, chemical, and / or spectroscopic properties. Different physical properties include, but are not limited to, stability (e.g., stability to heat, light, or moisture), compressibility and density (important in formulation and product manufacturing), hygroscopicity, solubility, and dissolution rate (which can affect bioavailability). Differences in stability may be due to variations in chemical reactivity (e.g., differential oxidation, causing dosage forms to change color more rapidly when composed of one polymorph than when composed of another) or mechanical properties (e.g., tablets break during storage when a kinetically favorable polymorph is converted to a thermodynamically more stable polymorph) or both (e.g., tablets of one polymorph are more prone to breakage at high humidity). The different physical properties of polymorphs can affect their processing. For example, due to the shape or size distribution of the particles, one polymorph may be more likely to form solvates or be more difficult to filter or wash away impurities than another polymorph.

[0074] As used herein, the term "solvent" refers to a compound that also includes stoichiometric or nonstoichiometric amounts of a solvent bound by noncovalent intermolecular forces, such as water, acetone, ethanol, methanol, dichloromethane, 2-propanol, etc.

[0075] As used herein, the term "stable compound" refers to a compound that has sufficient stability to allow preparation and maintains its integrity for a sufficiently long period of time to be used for the purposes detailed herein (e.g., formulation into therapeutic products, intermediates for the production of therapeutic compounds, separable or storable intermediate compounds, treatment of diseases or conditions that respond to therapeutic agents).

[0076] As used herein, the term "stereoisomer" refers to an enantiomer and a diastereomer. As used herein, the term "substantially free of other stereoisomers" means the presence of less than 25% of other stereoisomers, preferably less than 10% of other stereoisomers, more preferably less than 5% of other stereoisomers, most preferably less than 2% of other stereoisomers, or less than "X"% of other stereoisomers (where X is a number from 0 to 100, inclusive). Methods for obtaining or synthesizing diastereomers are well known in the art and can be applied, where feasible, to the final compound or starting material or intermediate. Other examples are those in which the compound is a separated compound. As used herein, the term "at least X% enantiomer enrichment" means at least X% of the compound is in a single enantiomer form, where X is a number from 0 to 100, inclusive.

[0077] As used herein, the terms “treatment” or “relief” of a disease or condition refer to methods of reducing, delaying, or improving such a condition before or after its occurrence. Treatment may involve one or more effects or symptoms of the disease and / or underlying pathology. Treatment can be any relief and may be, but is not limited to, complete elimination of the disease or disease symptoms. Thus, treatment or management refers to any sign of success in the treatment or improvement of an injury, disease, pathology, or condition, including any objective or subjective parameter such as relief; remission; reduction of symptoms or making the patient more tolerant of the injury, pathology, or condition; slowing of the rate of degeneration or decline; making the endpoint of degeneration less debilitating; or improving or stabilizing the patient’s physical or mental health. Treatment or improvement of symptoms may be based on objective or subjective parameters such as the results of physical examination, neuropsychiatric examination, and / or psychiatric evaluation. Such reduction or improvement, measured by any standard technique, may be at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, or 100% compared to an equivalent untreated control.

[0078] As used herein, the term "subject" refers to any animal (e.g., a mammal), including but not limited to humans, non-human primates, rodents, etc., that will become a recipient of a particular treatment. Generally, the terms "subject" and "patient" are used interchangeably herein and refer to human subjects.

[0079] As used herein, the term "alkane" or "alkyl" refers to a straight-chain, branched, or cyclic hydrocarbon group without unsaturated bonds having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms. The expression "lower alkyl" refers to an alkyl group with 1 to 4 carbon atoms (including the terminal number). Whenever it appears herein, numerical ranges such as "1 to 10" refer to each integer within a given range; for example, "1 to 10 carbon atoms" means that an alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, but this definition also covers instances where the term "alkyl" is not specified within a numerical range. In some embodiments, "alkyl" may be C 1-6 Alkyl group. In some embodiments, "alkyl group" may be C 1-3 alkyl.

[0080] As used herein, the term "alkoxy" refers to -O-alkyl.

[0081] As used herein, the term "cycloalkyl" refers to a cyclic alkyl group and includes saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons, preferably 3 to 8 carbons.

[0082] As used herein, the term "aromatic" or "aryl" refers to a group having 6 to 14 ring atoms (e.g., C14, C24 ... 6-14 Aroma or C 6-14 The aryl group has at least one ring having a conjugated π-electron system that is a carbon ring (e.g., phenyl, fluorenyl, naphthyl, and anthracene). The aryl group can be, for example, a 6-membered monocyclic, a 10-membered bicyclic, or a 14-membered tricyclic ring system, each ring system having 6 to 14 carbon atoms.

[0083] As used herein, the term “halogen” or “halogen” refers to any group consisting of fluorine, chlorine, bromine, or iodine.

[0084] As used herein, the term "heteroaryl" or "heteroaromatic" refers to a group comprising a 5- to 18-membered monocyclic or polycyclic (e.g., bicyclic, tricyclic, tetracyclic, etc.) aromatic ring system (e.g., sharing 6, 10, or 14 π electrons in a ring array) having a cyclic carbon atom and one to six cyclic heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5- to 18-membered heteroaryl"). A heteroaryl polycyclic ring system may contain one or more heteroatoms in one or two rings. Whenever appearing herein, numerical ranges such as "5 to 18" refer to each integer within a given range; for example, "5 to 18 ring atoms" means that a heteroalkyl group may consist of 5 ring atoms, 6 ring atoms, etc., up to and including 18 ring atoms. In some cases, a heteroaryl may have 5 to 14 ring atoms. In some embodiments, a heteroaryl group has, for example, a divalent group derived from a monovalent heteroaryl group, the name of which ends with "-aryl" by removing a hydrogen atom from an atom having a free valence, and is named by adding "-pyridyl" to the name of the corresponding monovalent group, for example, a pyridyl group having two connection points is a pyridylene group. The term "heteroaryl" may, for example, refer to a monocyclic or fused-ring (i.e., a ring sharing adjacent atom pairs) group containing five to twelve ring atoms selected from N, O, or S, with the remaining ring atoms being C, and additionally having a fully conjugated π-electron system, wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted with substituents. Examples of heteroaryl groups are not limited to pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, quinazoline, isoquinoline, purine, and carbazole.

[0085] As used herein, the terms "heterocyclic," "heterocyclic," or "heterocyclic group" refer to a fully saturated or partially unsaturated cyclic group, such as a 3- to 7-membered monocyclic, 7- to 12-membered bicyclic, or 10- to 15-membered tricyclic ring system, having at least one heteroatom in at least one ring, wherein 0, 1, 2, or 3 atoms in each ring may be substituted by substituents. Each ring of a heterocyclic group containing a heteroatom may have 1, 2, 3, or 4 heteroatoms selected from nitrogen, oxygen, and / or sulfur atoms, wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heterocyclic group may be attached to any heteroatom or carbon atom in the ring or ring system.

[0086] As used herein, the term "substituent" means a group that is "substituted" on any functional group described herein, such as alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclic, or heteroaryl groups at any atom of that group. Suitable substituents include, but are not limited to, halogens, CN, NO2, and OR. 15 SR 15 S(O)2OR 15 NR 15 R16 C1-C2 perfluoroalkyl, C1-C2 perfluoroalkoxy, 1,2-methylenedioxy, C(O)OR 15 C(O)NR 15 R 16 OC(O)NR 15 R 16 NR 15 C(O)NR 15 R 16 C(NR) 16 )NR 15 R 16 NR 15 C(NR 16 )NR 15 R 16 S(O)2NR 15 R 16 R 17 C(O)R 17 NR 15 C(O)R 17 S(O)R 17 S(O)2R 17 R 16 , Oxide group, C(O)R 16 C(O)(CH2)nOH, (CH2)nOR 15 (CH2)nC(O)NR 15 R 16 NR 15 S(O)2R 17 , where n is independently 0-6, including end values. Each R 15 Independently hydrogen, C1-C4 alkyl, or C3-C6 cycloalkyl. Each R 16 Independently, it is hydrogen, alkenyl, alkynyl, C3-C6 cycloalkyl, aryl, heterocyclic, heteroaryl, C1-C4 alkyl, or a C1-C4 alkyl substituted with C3-C6 cycloalkyl, aryl, heterocyclic, or heteroaryl. Each R 17 Independently, it is a C3-C6 cycloalkyl, aryl, heterocyclic, heteroaryl, C1-C4 alkyl, or a C1-C4 alkyl substituted with a C3-C6 cycloalkyl, aryl, heterocyclic, or heteroaryl. Each R 15 R 16 and R 17 Each of the C3-C6 cycloalkyl, aryl, heterocyclic, heteroaryl, and C1-C4 alkyl groups may optionally be substituted with a halogen, CN, C1-C4 alkyl, OH, C1-C4 alkoxy, NH2, C1-C4 alkylamino, C1-C4 dialkylamino, C1-C2 perfluoroalkyl, C1-C2 perfluoroalkoxy, or 1,2-methylenedioxy.

[0087] The description of a list of chemical groups in any definition of a variable herein includes the definition of that variable as any single group or combination of the listed groups. The description of embodiments of variables herein includes embodiments as any single embodiment or in combination with any other embodiment or part thereof.

[0088] The compounds of the present invention may contain one or more asymmetric centers, and therefore may exist as racemic mixtures and racemic mixtures, single enantiomers, single diastereomers, and mixtures of diastereomers. All such isomers of these compounds are explicitly included in this invention. The compounds of the present invention may also be represented in various tautomer forms, in which case this invention explicitly includes all tautomers of the compounds described herein. All such isomers of such compounds are explicitly included in this invention. All crystal forms of the compounds described herein are explicitly included in this invention. Detailed Implementation

[0089] This invention provides DNP derivatives, prodrugs, and conjugates thereof as regulators of mitochondrial activity. This invention also provides pharmaceutical compositions comprising the compounds of this invention and methods for treating various diseases and conditions (e.g., obesity, diabetes, insulin resistance, liver disease, neurodegenerative diseases, heart failure, or kidney failure) related to or associated with mitochondrial dysfunction.

[0090] Studies have shown that dicarbonyl stress, characterized by the accumulation of dicarbonyl metabolites such as methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucuronide due to increased production and / or decreased detoxification, is associated with metabolic diseases and age-related disorders, both of which are characterized by pro-inflammatory and pro-oxidative states. (Nigro et al., 2019) Cells (Volume 8, page 749.) For example, MGO is one of the most reactive, produced due to abnormal glucose / fructose metabolism. It not only significantly promotes the production of reactive oxygen species (ROS) and the depletion of glutathione in cells, but it also forms advanced glycation end products (AGEs), leading to loss of normal protein function, mitochondrial dysfunction, and cell senescence or death. (Seo et al., 2014, ...) Toxicology Res. Volume 30, page 193; Alejandra, 2017. Adv. Nutr. Volume 8, page 54; Nigro et al., 2019. Cells Volume 8, page 749.

[0091] Furthermore, some compounds of the present invention involve two or more mechanisms of action that combine mitochondrial uncoupling with mechanisms that reduce MGO production (e.g., Nrf2 activators) and / or anti-inflammatory mechanisms, which are of great significance in the treatment of metabolic diseases, neurodegenerative diseases and age-related diseases.

[0092] In one respect, the present invention generally relates to compounds having structural formula (I) or (II):

[0093] Or its pharmaceutically acceptable form or isotopic derivative, wherein n is 1, 2, 3 or 4; and R X For R X1 R X2 Or R X3 , where R X1 The radical is selected from the following groups: CH2C(=O)OR 3 CH2C(=O)SR 3 C(=O)NR 4 R 5 OR 6 SR 6 NR 7 R 8 NR 9 C(=O)R 10 OC(=O)R 11 ,SC(=O)R 12 OC(=O)OR 13 ,SC(=O)OR 13 NR 9 C(=O)OR 13 OC(=O)NR 14 R 15 ,SC(=O)NR 14 R 15 NR 9 C(=O)NR 14 R 15 OC(=O)SR 3 ,SC(=O)SR 3 NR 9 C(=O)SR 3 Halogens, CN, H and C 1-6 alkyl; And R X2 The groups are selected from the following: ;

[0094] And R X3 The groups are selected from the following: ; And R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 and R 15 Each of them: Independently selected from H and C 1-6 Alkyl, 3- to 8-membered carbocyclic or heterocyclic, optionally surrounded by 1-6 R... A Replace, or R 4 and R 5 R 7 and R 8 、or R 14 and R 15 Together with the N atoms they are bonded to, they form 3- to 8-membered heterocycles, optionally bound by 1-6 R atoms. A replace; Each R A Independently selected from: D, halogen, R, OR, and NRR'; And each of R and R' is independently H or C. 1-6 Alkyl group, optionally surrounded by 1-4 atoms selected from D, halogen, C 1-6 The alkoxy and amino groups are substituted; or R and R' together with the N atom to which they are bonded form 3- to 6-membered heterocycles, optionally substituted with 1-4 groups selected from D, halogen, C. 1-6 Alkyl or alkoxy and amino groups are substituted.

[0095] In some embodiments, the compounds of the present invention have formula (I).

[0096] In some embodiments, the compounds of the present invention have formula (II).

[0097] In some embodiments of formula (I) or (II), R X For R X1 .

[0098] In some embodiments, R X1 C(=O)OR 3 Or OC(=O)R 11 .

[0099] In some embodiments, R X1 For C(=O)NR 4 R 5 or NR 9C(=O)R 10 .

[0100] In some embodiments, R X1 For OC (=O) OR 13 Or OC(=O)NR 14 R 15 .

[0101] In some embodiments, R X1 OR 6 .

[0102] In some embodiments, R X1 For NR 7 R 8 .

[0103] In some embodiments, R X1 Halogen, CN or C 1-3 alkyl.

[0104] In some embodiments of formula (I) or (II), R X For R X2 .

[0105] In some embodiments, R X2 for: .

[0106] In some embodiments, R X2 for: .

[0107] In some embodiments, R X2 for: .

[0108] In some embodiments, R X2 for: .

[0109] In some embodiments, R X3 for: .

[0110] In some embodiments, R X3 for: .

[0111] In some embodiments of formula (I) or (II), n Not 1.

[0112] In some embodiments of formula (I) or (II), R X For RX3 .

[0113] In some embodiments of equation (I) or (II), each of R and R', if present, is independently H or C. 1-3 alkyl.

[0114] On the other hand, the present invention generally relates to compounds having structural formula (III) or (IV):

[0115] Or a pharmaceutically acceptable form or isotopic derivative thereof, wherein n is 1, 2, 3 or 4; Y is selected from single bond, NR, S, CRR', and O; R Y The radical is selected from the following groups: H, halogen, CN, R, C(=O)OR, C(=O)NRR', C(=O)R, and C(=O)SR; and each of R and R' is independently H or C. 1-6 Alkyl groups, or R and R', together with the N atoms they are bonded to form 3- to 6-membered heterocycles, wherein the alkyl group or heterocycle is optionally surrounded by 1-4 atoms selected from D, halogen, C. 1-6 Alkyl or alkoxy and amino groups are substituted.

[0116] In some embodiments, the compounds of the present invention have formula (III).

[0117] In some embodiments, the compounds of the present invention have formula (IV).

[0118] In some embodiments of formula (III) or (IV), Y is 0. In some embodiments, R Y Selected from R, C(=O)OR, C(=O)NRR', C(=O)R and C(=O)SR.

[0119] In some embodiments of formula (III) or (IV), Y is S. In some embodiments, R Y Selected from R, C(=O)OR, C(=O)NRR', C(=O)R and C(=O)SR.

[0120] In some embodiments of formula (III) or (IV), Y is NR. In some embodiments, R Y Selected from R, C(=O)OR, C(=O)NRR', C(=O)R and C(=O)SR.

[0121] In some embodiments of formula (III) or (IV), Y is CRR'. In some embodiments, R YSelected from halogens, CN, R, C(=O)OR, C(=O)NRR', C(=O)R and C(=O)SR.

[0122] In some embodiments of formula (III) or (IV), Y is a single bond.

[0123] In another aspect, the present invention generally relates to coupling compounds formed from the compounds disclosed herein and bioactive portions characterized by anti-ROS and / or anti-inflammatory activity.

[0124] In some embodiments of the coupling compound, the bioactive portion is selected from, but not limited to, the following:

[0125] Exemplary compounds of the present invention include those listed in Table 1A.

[0126] Exemplary compounds of the present invention include those listed in Table 1B.

[0127] In some embodiments, the compounds of the present invention are selected from the following:

[0128] The compounds of the present invention include compounds having one or more deuterium atoms in place of one or more hydrogen atoms.

[0129] In another aspect, the present invention generally relates to pharmaceutical compositions comprising the compounds disclosed herein.

[0130] In another aspect, the present invention generally relates to unit dosage forms of pharmaceutical compositions comprising the compounds disclosed herein.

[0131] In some embodiments, the unit dosage form is a tablet.

[0132] In some embodiments, the unit dosage form is a capsule.

[0133] In another aspect, the present invention generally relates to methods of treating or alleviating a disease or ailment, including administering a therapeutically effective amount of the compounds disclosed herein to a subject in need of such treatment.

[0134] In some embodiments, the disease or symptom is related to the subject's mitochondrial function.

[0135] In some embodiments, the disease or condition is associated with one or more mitochondrial functional defects in the subject.

[0136] In some embodiments, the disease or condition is a metabolic disease, a neurodegenerative disease, an age-related disease, a liver disease, a cardiovascular disease, or a related disease or condition.

[0137] In some embodiments, the disease or condition is obesity, excessive body fat, diabetes, insulin resistance or intolerance, hypertension, dyslipidemia, heart failure or kidney failure, atherosclerosis, hypertriglyceridemia, acquired lipodystrophy, hereditary lipodystrophy, partial lipodystrophy, metabolic syndrome, Rett syndrome, age-related metabolic syndrome, metabolic disease associated with increased reactive oxygen species (ROS), Friedreich ataxia, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) or related diseases or conditions.

[0138] In another aspect, the present invention generally relates to a method for reducing toxicity or side effects in the treatment of mitochondrial-related diseases or conditions, the method comprising administering a therapeutically effective amount of the compound disclosed herein to a subject in need of such treatment.

[0139] In some embodiments, administration is by oral administration.

[0140] In another aspect, the present invention generally relates to the use of the compounds disclosed herein and pharmaceutically acceptable excipients, carriers or diluents in the preparation of medicaments for treating diseases or conditions.

[0141] In another aspect, the present invention generally relates to the use of the compounds disclosed herein for the treatment of diseases or conditions.

[0142] In some embodiments of its use, the disease or symptom is associated with one or more mitochondrial functional defects.

[0143] In some embodiments of its use, the disease or condition is a metabolic disease, a neurodegenerative disease, an age-related disease, a liver disease, a cardiovascular disease, or a related disease or condition.

[0144] In some embodiments of its use, the disease or condition is selected from obesity, excessive body fat, diabetes, insulin resistance or intolerance, hypertension, dyslipidemia, heart failure or kidney failure, atherosclerosis, hypertriglyceridemia, acquired lipodystrophy, hereditary lipodystrophy, partial lipodystrophy, metabolic syndrome, Rett syndrome, age-related metabolic syndrome, metabolic diseases associated with increased reactive oxygen species (ROS), Friedreich ataxia, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), or related diseases or conditions.

[0145] The specific methods and compounds disclosed herein are not intended to be limiting. The variables used to describe the chemical structures in the schemes herein are consistent with the definitions of chemical groups (functional groups, atoms, etc.) at corresponding positions in the compound formulas herein, regardless of whether they are named with the same variable names (e.g., R...). 1 R 2The chemical groups in one compound structure are identified by (R, R', X, etc.). The applicability of a chemical group in one compound structure to the synthesis of another compound structure is within the knowledge of those skilled in the art. Other methods for synthesizing the compounds of this formula and their synthetic precursors, including those within routes not explicitly shown in this document, are within the chemical means of those skilled in the art. Methods for optimizing reaction conditions, and, if necessary, minimizing competing byproducts, are known in the art. The methods described herein may also include steps before or after the steps specifically described herein to add or remove suitable protecting groups in order to ultimately allow the synthesis of the compounds described herein. Furthermore, various synthetic steps may be performed in different orders or sequences to obtain the desired compounds. Synthetic chemical transformations and protecting group methods (protection and deprotection) for synthesizing applicable compounds are known in the art and include, for example, those described in the following literature: R. Larock, Comprehensive Organic Transformations VCH Publishers (1989); TW Greene and PGM Wuts, Protective Groups in Organic Synthesis 3rd edition, John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis John Wiley and Sons (1994); and L. Paquette (eds.), Encyclopedia of Reagents for Organic Synthesis John Wiley and Sons (1995) and subsequent editions.

[0146] The methods described herein contemplate the conversion of a compound of one formula into a compound of another formula. A conversion process refers to one or more chemical transformations, which may be carried out in situ or through the isolation of intermediate compounds. Conversion may include the use of techniques and methods known in the art, including those in the references cited herein, to react a starting compound or intermediate with another reagent. The intermediate may be used with or without purification (e.g., filtration, distillation, sublimation, crystallization, grinding, solid-phase extraction, and chromatography).

[0147] The combinations of substituents and variables envisioned in this invention are only those combinations that can form stable compounds.

[0148] Certain compounds of this invention may exist in specific geometric or stereoisomeric forms. This invention encompasses all such compounds, including cis and trans isomers, and trans-reactive isomers. R -enantiomers and S- Enantiomers, diastereomers, (d)-isomers, (l)-isomers, racemic mixtures thereof, and other mixtures thereof, all fall within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are intended to be included in this invention.

[0149] According to the present invention, mixtures of isomers containing any number of isomer ratios can be used. For example, in the case of only two isomer combinations, the present invention considers mixtures containing isomer ratios of 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0. Those skilled in the art will readily understand that similar ratios are considered for more complex isomer mixtures.

[0150] For example, if a specific enantiomer of the compound of the present invention is required, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliaries, wherein the resulting diastereomeric mixture is isolated and the auxiliary groups are cleaved to provide the desired enantiomer in pure form. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with a suitable optically active acid or base, and the resulting diastereomeric salt is then resolved by fractional crystallization or chromatographic methods well known in the art, followed by recovery of the pure enantiomer.

[0151] This document also considers solvates and polymorphs of the compounds of the present invention. Solvates of the compounds of the present invention include, for example, hydrates.

[0152] The present invention also provides compositions comprising an effective amount of a compound of any formula herein, or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph of said compound (if applicable); and an acceptable carrier. Preferably, the compositions of the present invention are formulated for pharmaceutical use (“pharmaceutical compositions”), wherein the carrier is a pharmaceutically acceptable carrier. The carrier must be “acceptable,” meaning compatible with other components of the formulation, and in the case of a pharmaceutically acceptable carrier, the amount typically used in a pharmaceutical medicament is harmless to the recipient.

[0153] Pharmaceutically acceptable carriers, adjuvants, and solvents that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering substances such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts, or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0154] The pharmaceutical compositions of the present invention include those suitable for oral, rectal, nasal, topical (including oral and sublingual), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, and intradermal) administration. In some embodiments, the compounds of this formulation are administered transdermally (e.g., using transdermal patches). Other formulations may be readily available in unit dosage forms, such as tablets and sustained-release capsules, and in liposomes, and may be prepared by any method well known in the pharmaceutical field. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA (17th edition, 1985).

[0155] Such preparation methods involve the step of combining the molecule to be applied with components such as a carrier constituting one or more auxiliary ingredients. Typically, the composition is prepared by uniformly and tightly binding the active ingredient with a liquid carrier, liposomes, or finely fragmented solid carrier, or both, and then shaping the product if necessary.

[0156] In some preferred embodiments, the compound is administered orally. The compositions of the invention suitable for oral administration can exist in discrete unit form, such as capsules, sachets, or tablets, each containing a predetermined amount of the active ingredient; as powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water emulsion or water-in-oil emulsion; or packaged in liposomes and as pills, etc. Soft gelatin capsules can be used to contain such suspensions, which can advantageously increase the rate of compound absorption.

[0157] Tablets can be prepared by compression or molding, optionally together with one or more excipients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form (such as powder or granules) optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant, or dispersant in a suitable machine. Molded tablets can be prepared by molding a mixture of powdered compounds wetted with an inert liquid diluent in a suitable machine. Tablets may optionally be coated or scored and can be formulated to provide a slow or controlled release of the active ingredient therein. Methods for formulating such sustained-release or controlled-release compositions of pharmaceutical active ingredients (such as those described herein and other compounds known in the art) are known in the art and described in several granted U.S. patents, some of which include, but are not limited to: U.S. Patent Nos. 4,369,172; and 4,842,866, and the references cited therein. Coating can be used to deliver compounds into the intestine (see, for example, U.S. Patent Nos. 6,638,534, 5,217,720 and 6,569,457, 6,461,631, 6,528,080, 6,800,663, and the references cited therein). A useful formulation of the compounds of the present invention is in the form of enteric-coated pellets, wherein the enteric layer comprises hydroxypropyl methylcellulose acetate succinate.

[0158] For tablets intended for oral administration, common carriers include lactose and corn starch. Lubricants, such as magnesium stearate, are also often added. For oral administration in capsule form, available diluents include lactose and dried corn starch. When administered orally in an aqueous suspension, the active ingredient is combined with an emulsifier and a suspending agent. If necessary, certain sweeteners and / or flavorings and / or colorings may be added.

[0159] Compositions suitable for topical application include: lozenges containing a flavoring matrix ingredient, typically sucrose and gum arabic or tragacanth; and ointments containing an active ingredient that is an inert matrix, such as gelatin and glycerin, or sucrose and gum arabic.

[0160] Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions that may contain antioxidants, buffers, antibacterial agents, and solutes that make the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickeners. The formulations may be available in single-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored under lyophilized (freeze-dried) conditions, requiring only the addition of a sterile liquid carrier, such as water for injection, immediately before use. Temporary injectable solutions and suspensions may be prepared from sterile powders, granules, and tablets.

[0161] Such injectable solutions can be, for example, in the form of sterile injectable aqueous or oily suspensions. These suspensions can be formulated using suitable dispersants or wetting agents (e.g., Tween 80) and suspending agents according to techniques known in the art. Sterile injectable formulations can also be sterile injectable solutions or suspensions in non-toxic, non-gut-acceptable diluents or solvents, such as solutions of 1,3-butanediol. Acceptable solvents and media that can be used include mannitol, water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile, non-volatile oils are typically used as solvents or suspension media. For this purpose, any mild, non-volatile oil can be used, including synthetic monoglycerides or diglycerides. Fatty acids, such as oleic acid and its glycerol derivatives, can be used in the preparation of the injectable formulation, as can pharmaceutically acceptable natural oils, such as olive oil or castor oil, particularly their polyoxyethylene forms. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants.

[0162] The pharmaceutical compositions of the present invention can be administered in suppository form for rectal administration. These compositions can be prepared by mixing the compounds of the present invention with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, thereby melting in the rectum to release the active ingredient. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

[0163] The pharmaceutical compositions of the present invention can be administered via nasal aerosol or inhaler. Such compositions are prepared according to techniques well known in the field of pharmaceutical formulation and can be prepared as salt solutions using benzyl alcohol or other suitable preservatives, absorption enhancers for improving bioavailability, fluorocarbons, and / or other solubilizers or dispersants known in the art.

[0164] Topical application of the pharmaceutical compositions of the present invention is particularly useful when the desired treatment involves an area or organ easily accessible by local application. For local application to the skin, the pharmaceutical compositions are formulated as suitable ointments containing an active ingredient suspended or dissolved in a carrier. Carriers for local application of the compounds of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsified waxes, and water. Alternatively, the pharmaceutical compositions may be formulated as suitable lotions or creams containing an active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, hexadecyl ester wax, cetearyl alcohol, 2-octyldodecyl alcohol, benzyl alcohol, and water. The pharmaceutical compositions of the present invention can also be applied topically to the lower intestine by rectal suppository formulations or by suitable enema formulations. Topical transdermal patches and iontophoresis are also included in the present invention.

[0165] In another embodiment, the composition of the present invention further comprises a second therapeutic agent. The second therapeutic agent includes any compound or therapeutic agent known to have or exhibiting advantageous properties when administered in combination with any compound of any form herein.

[0166] Such pharmaceutical agents are described in detail in the art. Preferably, the second therapeutic agent is a pharmaceutical agent that can be used to treat or prevent metabolic diseases or conditions.

[0167] In another embodiment, the present invention provides separate dosage forms of the compound of the invention and the second therapeutic agent that are related to each other. As used herein, the term “related to each other” means that the separate dosage forms are packaged together or otherwise linked to each other, so that it is clear that the separate dosage forms are intended to be sold and administered together (to be administered consecutively or simultaneously within 24 hours of each other).

[0168] In the pharmaceutical compositions of the present invention, the compounds of the present invention are present in an effective amount. As used herein, the term "effective amount" means an amount that, when administered in an appropriate dosing regimen, is sufficient to reduce or improve the severity, duration or progression of the treated condition, prevent the development of the treated condition, cause the remission of the treated condition, or enhance or improve the preventive or therapeutic effect of another therapy.

[0169] The dose-response relationships between animals and humans (based on mg / m² body surface area) were described by Freireich et al., 1966. Cancer Chemother Rep Volume 50: Page 219. Body surface area can be approximately determined by the patient's height and weight. (See, for example, Scientific Tables, Geigy Pharmaceuticals, Ardley, NY, 1970, 537.) The effective amount of the compounds of the present invention can be in the range of about 0.001 mg / kg to about 500 mg / kg, more preferably 0.01 mg / kg to about 50 mg / kg, more preferably 0.1 mg / kg to about 2.5 mg / kg. As will be appreciated by those skilled in the art, the effective dose will also vary depending on the disease being treated, the severity of the disease, the route of administration, the patient's sex, age and general health condition, the use of excipients, the possibility of co-use with other therapeutic treatments (such as the use of other pharmaceutical agents), and the judgment of the attending physician.

[0170] For pharmaceutical compositions comprising a second therapeutic agent, the effective amount of the second therapeutic agent is about 20% to 100% of the dose typically used in a monotherapy regimen employing only the drug. Preferably, the effective amount is about 70% to 100% of the normal monotherapy dose. The normal monotherapy doses of these second therapeutic agents are well known in the art. (See, for example, Wells et al., eds., *Handbook of Drug Therapy*, 2000) Pharmacotherapy Handbook(2nd edition, Appleton and Lange, Stamford, Conn.; PDR Pharmacopoeia, Tarascon Portable Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. 2000. Each reference is incorporated in full by way of citation.)

[0171] The present invention also provides a method for treating a subject who has or is susceptible to a disease or condition or its symptoms (e.g., those described herein), comprising the step of administering an effective amount of the compound or composition of the present invention to the subject. Some diseases are well known in the art and are also disclosed herein.

[0172] In some embodiments, the methods disclosed herein are suitable for treating age-related diseases or conditions, including common neurodegenerative diseases such as AD, PD, and HD.

[0173] As used herein, the term "co-administration" means that the second therapeutic agent may be administered together with the compound of the present invention as part of a single dosage form (such as an inventive composition comprising the compound of the present invention and the second therapeutic agent as described above) or as multiple separate dosage forms. Alternatively, additional agents may be administered before, simultaneously with, or after the administration of the compound of the present invention. In such combination therapy, both the compound of the present invention and the second therapeutic agent are administered by conventional methods. Administration of the inventive composition comprising both the compound of the present invention and the second therapeutic agent to a subject does not preclude the administration of the same therapeutic agent, any other second therapeutic agent, or any compound of the present invention alone to the subject at another time during treatment.

[0174] The effective doses of these secondary therapeutic agents are well known to those skilled in the art, and instructions for administration can be found in the patents and published patent applications cited herein, as well as in Wells et al., eds., *Handbook of Drug Therapy*, 2nd edition, Appleton and Lange, Stamford, Conn. (2000); *PDR Pharmacopoeia*, Tarascon Portable Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000), and other medical texts. However, determining the optimal effective dose range for a secondary therapeutic agent is entirely within the capabilities of those skilled in the art.

[0175] In one embodiment of the invention, the effective amount of the compound of the invention administered to the subject is lower than the effective amount when the second therapeutic agent is not administered. In another embodiment, the effective amount of the second therapeutic agent is lower than the effective amount when the compound of the invention is not administered. This minimizes undesirable side effects associated with high doses of either agent. Other potential advantages, including but not limited to improved dosing regimens and / or reduced drug costs, will be apparent to those skilled in the art.

[0176] In another aspect, the present invention provides the use of compounds of any form herein, alone or in combination with one or more of the aforementioned second therapeutic agents, in the preparation of a medicament, which is a single composition or a single dosage form, for treating or preventing the aforementioned disease, condition, or symptom in a subject. Another aspect of the invention is a compound of the form herein used for treating or preventing the disease, condition, or symptom described herein in a subject.

[0177] In other respects, the methods described herein include those that further include monitoring the subject's response to treatment administration. Such monitoring may include periodic sampling of the subject's tissues, fluids, samples, cells, proteins, chemical markers, genetic material, etc., as markers or indicators of the treatment regimen. In other methods, subjects are pre-screened or identified as requiring such treatment by assessing relevant markers or indicators of suitability for such treatment.

[0178] In one embodiment, the present invention provides a method for monitoring treatment progress. The method includes the step of determining the level of a diagnostic marker (marker) (e.g., any target or cell type regulated by the compounds described herein) or diagnostic measurement (e.g., screening, assay) in a subject who has or is susceptible to the disease or symptoms described herein, wherein the subject has been administered a therapeutic amount of the compounds described herein sufficient to treat the disease or symptoms. The marker level determined in this method can be compared with known marker levels in healthy controls or other diseased patients to determine the subject's disease status. In a preferred embodiment, a second level of the marker in the subject is determined at a time point later than the determination of the first level, and the two levels are compared to monitor disease progression or treatment efficacy. In some preferred embodiments, the pre-treatment level of the marker in the subject is determined before the start of treatment according to the invention; this pre-treatment level of the marker can then be compared with the marker level in the subject after the start of treatment to determine treatment efficacy.

[0179] In some method embodiments, the level of a marker or marker activity in the subject is measured at least once. For example, comparing the marker level with another measurement of the marker level obtained previously or subsequently from the same patient, another patient, or a normal subject can be used to determine whether the therapy according to the invention has the desired effect, thereby allowing for appropriate adjustment of the dose level. The determination of the marker level can be performed using any suitable sampling / expression assay method known in the art or described herein. Preferably, a tissue or fluid sample is first taken from the subject. Examples of suitable samples include blood, urine, tissue, oral or cheek cells, and hair samples containing the roots. Other suitable samples are known to those skilled in the art. The determination of protein and / or mRNA levels (e.g., marker levels) in the sample can be performed using any suitable technique known in the art, including but not limited to enzyme immunoassay, ELISA, radiolabeling / assay techniques, blotting / chemiluminescence methods, real-time PCR, etc.

[0180] The present invention also provides kits for treating diseases, conditions, or symptoms thereof, including those described herein. These kits comprise: a) a pharmaceutical composition comprising a compound of any formula herein or a salt thereof; a prodrug or a salt thereof; or a hydrate, solvate, or polymorph thereof, wherein the pharmaceutical composition is in a container; and b) a specification describing a method of treating a disease, condition, or symptom thereof using the pharmaceutical composition.

[0181] The container can be any vessel or other sealed or sealable device capable of containing the pharmaceutical composition. Examples include bottles, compartmentalized or multi-compartment holders or bottles, wherein each compartment or compartment contains a single dose of the composition, compartmentalized foil packaging, wherein each compartment contains a single dose of the composition, or dispensers for dispensing single doses of the composition. The container can be any conventional shape or form known in the art, made of pharmaceutically acceptable materials, such as paper or cardboard boxes, glass or plastic bottles or jars, resealable bags (e.g., “refill packs” for containing tablets to be placed into different containers), or blister packs having individual doses extruded from the package according to the treatment regimen. The container used may depend on the exact dosage form involved; for example, conventional cardboard boxes are generally not used to contain liquid suspensions. It is feasible to use more than one container in a single package to market a single dosage form. For example, tablets may be packaged in a bottle, which in turn is packaged in a box. Preferably, the container is a blister pack.

[0182] The kit may additionally include information and / or instructions for physicians, pharmacists, or subjects. Such memory aids include numbers printed on each compartment or section, which contain the dosage corresponding to the number of days of the prescribed regimen for which the tablets or capsules should be taken, or the number of days in a week printed on each compartment or section, or cards containing the same type of information.

[0183] The following examples are intended to illustrate the practice of the invention and not to limit it in any way.

[0184] The following examples are intended to illustrate the practice of the invention and not to limit it in any way. Example abbreviation

[0185]

[0186] Chemical methods

[0187] All chemicals were purchased from commercial suppliers and were ready for use without further purification. Unless otherwise specified, reactions were carried out under an inert argon atmosphere and monitored by thin-layer chromatography (TLC) and / or LCMS. All reagents were purchased from commercial suppliers and used as specified. Synthetic intermediates and the final compound were purified using a Biotage Isolera Prime 3.2 chromatographic system on 230–400 mesh silica gel or a GILSON GX-281 preparative HPLC. Nuclear magnetic resonance spectrometry (NMR) was obtained using a Bruker Ascend 400 at 400 MHz and 100 MHz, respectively. 1 H and 13 C10 NMR spectroscopy. NMR chemical shifts are described as δ (ppm), using the residual solvent peak as a standard (chloroform-). d 7.26 ppm ( 1 H), 77.16 ppm ( 13 C); Methanol d 4, 3.31 ppm ( 1 H), 49.00 ppm ( 13 C); DMSO- d 6 2.50 ppm ( 1 H), 39.52 ppm ( 13C). Data were reported in the following formats: chemical shift, multiplicity (s = singlet, d = doublet, dd = two doublets, t = triplet, q = quartet, br = broad peak, m = multiplet, abq = ab quartet), proton number, and coupling constant. Mass spectrometry data were measured using an Agilent 1260 and 6120MSD LC-MS. All compounds submitted for bioassay were confirmed to have a purity ≥95% by a Shimadzu LC-2030C 3D analytical HPLC. The synthetic methods, spectral data, and MS analysis of novel compounds are described in detail below. Synthesis Scheme 1

[0188]

[0189] Step 1: 2-((tert-butyldiphenylsilyl)oxy)ethyl-1-amine. Imidazole (89 g, 1.31 mol) and TBDPSCl (198 g, 0.72 mol) were added to a mixture of 2-aminoethyl-1-ol (40 g, 0.65 mol) in DCM (400 mL) at 25 °C. The mixture was stirred at 25 °C for 16 hours. The reaction mixture was poured into water (1000 mL) and extracted with DCM (500 mL × 3). The combined organic layers were washed with brine (500 mL), dried over Na₂SO₄, and concentrated under vacuum to give the desired product (150 g, 77% yield) as a yellow oil: MS (ESI), m / z: Calculated exact mass of C₅H₅N₃O₃: 299.2 t. R = 1.726 min. [M+H] + = 300.1; 1 1H NMR (400 MHz, CD3Cl) δ 7.68-7.66 (m, 4H), 7.45-7.36 (m, 6H), 3.67 (t, J = 5.2 Hz, 2H), 2.80 (t, J = 5.2 Hz, 2H), 1.06 (s, 9H).

[0190] Step 2: Ethyl glycine (2-((tert-butyldiphenylsilyl)oxy)ethyl)glycine. Ethyl 2-bromoethyl acetate (178.4 g, 1.07 mol) and TEA (324.4 g, 3.21 mol) were added to a solution of 2-((tert-butyldiphenylsilyl)oxy)ethyl-1-amine (320 g, 1.07 mol) in DCM (3200 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was concentrated under vacuum to obtain a crude product. The crude product was purified by rapid column chromatography (PE / EA = 10 / 1-3 / 1) to obtain a product (300 g, yield 73%) as a yellow oil: MS (ESI), m / z: Calculated exact mass of C5H5N3O3: 385.2 t. R =1.544 min. [M+H] + = 386.1.

[0191] Step 3: Ethyl 2-amino-1-(2-hydroxyethyl)-1H-imidazolium-5-carboxylate. NaH (36.3 g, 0.91 mol) was added to a solution of ethyl (2-((tert-butyldiphenylsilyl)oxy)ethyl)glycine (100 g, 0.26 mol) in ethyl formate (500 mL) at 25 °C. The mixture was stirred at 25 °C for 16 hours. The reaction mixture was concentrated under vacuum to obtain the desired product (100 g, crude product) as a yellow oil, which was used directly in the next step without further purification.

[0192] Add concentrated HCl (320 mL) to a 400 mL EtOH solution of the compound (100 g, crude) from the previous step at 25 °C. Stir the mixture at 75 °C for 2 hours. Cool the reaction solution to room temperature and concentrate. Adjust the pH of the residue to 3–4 with an aqueous NaOH solution (2N) and use the mixture directly in the next step.

[0193] Add water (1000 mL) to the solution prepared in the previous step, then add cyanamide (17.3 g, 0.41 mol) at 25 °C. Stir the mixture at 105 °C for 2 hours. Cool the reaction solution to room temperature, adjust the pH to 8-9 with solid Na₂CO₃, and extract with EA (500 mL × 3). Wash the combined organic layers with brine (500 mL), dry with Na₂SO₄, and concentrate under vacuum to obtain the crude product. Purify the crude product by rapid column chromatography (PE / EA = 20 / 1-1 / 1) to obtain the desired compound (15 g, 31% yield in 3 steps) as a yellow solid: MS (ESI), m / z: Calculated exact mass of C₅H₅N₃O₃: 199.1 t. R = 0.948min. [M+H] + = 200.1;1 H NMR (400 MHz, CD3Cl) δ 7.26 (s, 1H), 4.96 (s, 2H), 4.26-4.20 (m, 4H), 3.97 (t, J = 4.4Hz, 2H), 1.32 (t, J = 7.2 Hz, 2H).

[0194] Step 4: Ethyl 1-(2-hydroxyethyl)-2-nitro-1H-imidazolium-5-carboxylate. NaNO2 (38.1 g, 0.55 mol) was added to a solution of ethyl 2-amino-1-(2-hydroxyethyl)-1H-imidazolium-5-carboxylate (18.4 g, 0.092 mol) in CH3COOH (190 mL) and H2O (190 mL) at 10 °C. The mixture was stirred at 25 °C for 16 hours. The reaction mixture was poured into water (500 mL) and extracted with EA (500 mL × 3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, and concentrated under vacuum to give the crude product. The crude product was purified by rapid column chromatography (PE / EA = 10 / 1-3 / 1) to obtain the desired compound (10 g, yield 47%) as a yellow solid: MS (ESI), m / z: Calculated exact mass of C5H5N3O3: 229.1 t. R = 1.385 min. [M+H] + = 230.0; 1 1H NMR (400 MHz, CD3Cl) δ 7.76 (s, 1H), 5.09 (t, J = 5.2 Hz, 2H), 4.40 (q, J = 7.2 Hz, 2H), 4.01 (t, J = 5.2 Hz, 2H), 1.41 (t, J = 6.8 Hz, 2H).

[0195] Step 5: Ethyl 1-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-nitro-1H-imidazolium-5-carboxylate. At 25°C, TBDPSCl (15.8 g, 0.058 mol) and imidazole (7.1 g, 0.10 mol) were added to a mixture of ethyl 1-(2-hydroxyethyl)-2-nitro-1H-imidazolium-5-carboxylate (12 g, 0.052 mol) in DCM (120 mL). The mixture was stirred at 25°C for 16 hours. The reaction mixture was poured into water (200 mL) and extracted with DCM (100 mL × 3). The combined organic layers were washed with brine (200 mL), dried over Na₂SO₄, and concentrated under vacuum to give the crude product. The crude product was purified by a rapid column chromatography (PE / EA = 10 / 1-3 / 1) to give the product (20 g, 82% yield) as a yellow solid. 1 1H NMR (400 MHz, CD3Cl) δ 7.73(s, 1H), 7.44-7.40 (m, 6H), 7.38-7.32 (m, 4H), 5.20 (t, J = 4.8 Hz, 2H), 4.31(q, J = 7.2 Hz, 2H), 3.86 (t, J = 4.8 Hz, 2H), 1.36 t, J = 7.2 Hz, 2H), 0.93 (s, 9H).

[0196] Step 6: (1-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-nitro-1H-imidazol-5-yl)methanol. At 0°C, LiBHEt3 (0.13 L, 0.13 mol, 1 mmol / L THF solution) was added to a mixture of ethyl 1-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-nitro-1H-imidazol-5-carboxylate (20 g, 0.043 mol) in THF (200 mL). The mixture was stirred at 0°C for 2 hours. The reaction mixture was poured into an aqueous solution of ammonium chloride (200 mL) and extracted with EA (200 mL × 3). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, and concentrated under vacuum to obtain the crude product. The crude product was purified by rapid column chromatography (PE / EA = 10 / 1-3 / 1) to obtain a product (8.6 g, yield 47%) as a yellow solid: MS (ESI), m / z: Calculated exact mass of C5H5N3O3: 425.2 t. R = 2.304 min. [M+H] + = 426.1; 11H NMR (400 MHz, CD3Cl) δ 7.46-7.41 (m, 6H), 7.38-7.34 (m, 4H), 7.17 (s, 1H), 4.76 (s, 2H), 4.68 (t, J = 4.8 Hz, 2H), 3.97 (t, J = 4.8 Hz, 2H), 0.98 (s, 9H).

[0197] Step 7: 1-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-((2,4-dinitrophenoxy)methyl)-2-nitro-1H-imidazolium. NaH (1.2 g, 0.030 mol) was added to a THF (90 mL) solution of (8.6 g, 0.020 mol) of methanol (1-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-nitro-1H-imidazol-5-yl)methanol and stirred for 0.5 h. Then, 1-chloro-2,4-dinitrobenzene (6.1 g, 0.03 mol) was added. The mixture was stirred at 25 °C for 2 h. The reaction mixture was poured into water (200 mL) and extracted with DCM (100 mL × 3). The combined organic layers were washed with brine (200 mL), dried over Na₂SO₄, and concentrated under vacuum to obtain the crude product. The crude product was purified by a rapid column chromatography (PE / EA=10 / 1-3 / 1) to obtain a product (8 g, yield 67%), which was a yellow solid. 1 1H NMR (400 MHz, CD3Cl) δ 8.76 (d, J = 2.8 Hz, 1H), 8.40 (dd, J = 9.2, 2.8 Hz, 1H), 7.46-7.40 (m, 4H), 7.39-7.34 (m, 7H),7.08 (d, J = 9.2 Hz, 1H), 5.43 (s, 2H), 4.76-4.72 (m, 2H), 4.08 (t, J = 4.8Hz, 1H), 1.00 (s, 9H).

[0198] Step 8: 2-(5-((2,4-dinitrophenoxy)methyl)-2-nitro-1H-imidazol-1-yl)ethyl-1-ol (1). At -30°C, TBAF (10 mL, 0.010 mol, 1 mmol / L THF solution) was added to a THF solution of 1-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-5-((2,4-dinitrophenoxy)methyl)-2-nitro-1H-imidazolium (3 g, 0.0051 mol). The mixture was stirred at -30°C for 2 hours. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride (100 mL) and extracted with EA (100 mL × 3). The crude product was purified by rapid column chromatography (PE / EA = 10 / 1-3 / 1) to give compound 1 (16 g, yield 56%) as a yellow solid: MS (ESI), m / z: Calculated exact mass of C5H5N3O3: 353.1 t. R =1.757 min. [M+H] + = 354.1; 1 H NMR (400 MHz, DMSO) d 6 ) δ 8.80 (d, J = 2.8 Hz, 1H), 8.57 (dd, J = 9.2, 2.8 Hz, 1H), 7.82 (d, J = 9.2 Hz, 1H), 7.41 (s, 1H), 5.66 (s, 2H), 5.13 (t, J = 5.2 Hz, 1H), 4.51 (t, J = 5.2 Hz, 2H), 3.71 (q, J = 5.2 Hz, 2H).

[0199] Step 9: 2-(5-((2,4-dinitrophenoxy)methyl)-2-nitro-1H-imidazol-1-yl)ethyl isobutyrate (2). At 0 °C and N2, a solution of isobutyryl chloride (41 mg, 0.38 mmol) in DCM (0.5 mL) was added to a solution of compound 1 (90 mg, 0.25 mmol) and TEA (77 mg, 0.76 mmol) in DCM (3 mL). The reaction mixture was stirred at N2 and 0 °C for 1 hour. The reaction mixture was quenched by adding water (10 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was purified by preparative TLC (DCM / MeOH = 20 / 1) to give product 2 (54 mg, 49% yield) as a yellow solid: MS (ESI), m / z: C 16 H 17 Calculated exact mass of N5O9: 423.103 metric tons. R = 1.928 min. [M+H] + = 424.0; 1 H NMR (400 MHz, CDCl3) δ 8.79 (d, J = 2.7Hz, 1H), 8.56 – 8.49 (m, 1H), 7.38 (d, J = 9.2 Hz, 1H), 7.33 (s, 1H), 5.44(s, 2H), 4.86 (t, J = 5.7 Hz, 2H), 4.47 (t, J = 5.7 Hz, 2H), 2.53 – 2.40 (m,1H), 1.09 (d, J = 7.0 Hz, 6H). Synthesis Scheme 2

[0200]

[0201] Step 1: 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-nitro-1H-imidazolium. To 2-nitro-1 H2-(tert-butyldimethylsiloxy)-1-bromoethane (871.6 g, 3.65 mol) and K₂CO₃ (673 g, 4.86 mol) were added to a mixture of 275 g (2.43 mol) and 4 L (4 L) of DMF. The resulting mixture was stirred at 100 °C for 12 h. The reaction mixture was cooled to room temperature. DMF was removed under reduced pressure. The residue was partitioned between water and EtOAc. The combined organic layers were washed with water and brine, dried over Na₂SO₄ and concentrated. The crude product was ground and filtered in petroleum ether (1000 mL) to give the title compound (627 g, 95% yield) as a pale yellow solid: MS (ESI), m / z: C 11 H 21 Calculated exact mass of N3O3Si: 271.1, measured value [M+H] + = 272.0; 1 H NMR (400 MHz, CDCl3, 7.32ppm): δ 7.20 (d, J =0.8 Hz, 1H), 7.18 (d, J = 0.8 Hz, 1H), 4.60 (t, J = 5.0 Hz, 2H), 4.00 (t, J =5.0 Hz, 2H), 0.88 (s, 9H), 0.00 (s, 6H); According to the HNMR data, the total H count is: 21.

[0202] Step 2: (1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-nitro-1H-imidazol-5-yl)methanol. Under a nitrogen atmosphere, at -70°C to -65°C, LDA (69 mL, 138.2 mol, 2 M in THF) was added dropwise to a stirred solution of 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-nitro-1H-imidazolium (25 g, 92.1 mmol) and TMEDA (16 g, 138.2 mmol) in 400 mL of THF. The resulting dark solution was stirred at -70°C to -65°C for 30 minutes. DMF (10.1 g, 138.2 mmol) was added dropwise to the above mixture. The resulting mixture was stirred at -70°C to -65°C for 2 hours. The reaction mixture was poured into a saturated aqueous solution of NH4Cl. The organic layer was collected. THF was removed under reduced pressure. The residue was partitioned between water and EtOAc. The EtOAc layer was collected. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel rapid column chromatography (PE / EtOAc = 10 / 1 → 3 / 1) to give the crude compound as a pale yellow solid (8.5 g, a mixture of starting material and product).

[0203] At 15 °C, NaBH4 was added fractionally to a mixture of crude product (8.5 g, from the previous step) in methanol (100 mL). The reaction was monitored by TLC until the starting material disappeared. The reaction mixture was concentrated. The residue was partitioned between water and EtOAc. The EtOAc layer was collected. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel rapid column chromatography (PE / EtOAc = 8 / 1 → 1 / 1) to give the title compound as a pale yellow solid (3 g, 10.8% yield after two steps): MS (ESI), m / z: C 12 H 23 Calculated exact mass of N3O4Si: 301.2, measured value [M+H] + = 302.0; 1 H NMR (400 MHz, CDCl3, 7.28ppm): δ 7.17 (s, 1H), 4.73(d, J = 5.6 Hz, 2H), 4.67 (t, J = 4.8 Hz, 2H), 4.08 (t, J = 4.8 Hz, 2H), 3.26(t, J= 5.8 Hz, 1H), 0.83 (s, 9H), 0.00 (s, 6H); According to the HNMR data, the total H count is: 23.

[0204] Step 3: 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-((2,4-dinitrophenoxy)methyl)-2-nitro-1H-imidazolium. At 25 °C, Cs₂CO₃ (50.3 g, 154 mmol) was added to a mixture of (1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-nitro-1H-imidazol-5-yl)methanol (31 g, 103 mmol) and 1-chloro-2,4-dinitrobenzene (31.4 g, 154 mmol) in DMF (300 mL). The resulting mixture was stirred at 25 °C for 12 hours. The reaction mixture was partitioned between water and EtOAc. The EtOAc layer was collected. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na₂SO₄, and concentrated. The residue was purified by silica gel rapid column chromatography to give the crude product of the title compound. The crude product was recrystallized to obtain a pure product (22.4 g, yield 47%), which was a pale yellow solid. The mother liquor can be purified by column chromatography (PE / EtOAc = 8 / 1 → 1 / 1) to obtain the desired intermediate: MS (ESI), m / z: C 18 H 25 Calculated exact mass of N5O8Si: 467.2, measured value [M+H] + =468.1; 1 H NMR (400 MHz, CDCl3,7.26 ppm) δ 8.77 (d, J = 2.4 Hz, 1H), 8.50-8.47 (dd, J = 2.8 Hz, 5.2 Hz, 1H), 7.33 (d, J = 9.2 Hz,1H), 7.30 (s, 1H), 5.48 (s, 2H), 4.71 (t, J = 4.6 Hz, 2H), 4.01 (t, J = 4.6Hz, 2H), 0.79 (s, 9H), -0.06 (s, 6H); According to HNMR data, the total H count is: 25.

[0205] Step 4: 2-(5-{[(2,4-dinitrophenyl)oxy]methyl}-2-nitroimidazol-1-yl)ethyl-1-ol (1). Triethylamine trifluoride (45.7 g, 283.5 mmol) was added to a THF (250 mL) solution of 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-((2,4-dinitrophenoxy)methyl)-2-nitro-1H-imidazolium (26.5 g, 56.7 mmol) at 15 °C. The resulting mixture was stirred at room temperature for 4 hours. THF was removed under reduced pressure. The residue was ground with EtOAc. The precipitate was collected by filtration, washed with EtOAc, and dried to give the first batch of product (13 g). The filtrate was concentrated. The residue was suspended in water and adjusted to pH 8 with NaHCO3. The precipitate was collected by filtration, washed with water, and dried to give the product (4.0 g) as a pale yellow solid (overall yield 85%). (The reaction was carried out in a three-necked glass flask): MS (ESI), m / z: C 12 H 11 Calculated exact mass of N5O8: 353.1, measured value [M+H] + =353.8; 1 H NMR (400 MHz, DMSO-d6, 2.50ppm): δ8.08 (d, J = 2.8 Hz, 1H), 8.59-8.56 (dd, J = 2.8 Hz, 5.2 Hz, 1H), 7.84 (d, J = 9.2 Hz, 1H), 7.41 (s, 1H), 5.67 (s, 2H), 5.13 (t, J = 5.0 Hz, 1H), 4.52 (t, J = 5.2 Hz, 2H), 3.73-3.69 (m, 2H); According to the HNMR data, the total H count is: 11. Synthesis Scheme 3

[0207]

[0208] Step 1: 2-(5-((2,4-dinitrophenoxy)methyl)-2-nitro-1H-imidazol-1-yl)ethyl ethyl carbonate (3). A solution of ethyl chloroformate (335 mg, 3.1 mmol) in DCM (1 mL) was added dropwise to a solution of compound 1 (110 mg, 0.31 mmol) and DIEA (120 mg, 0.93 mmol) in DCM (3 mL) stirred at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. LCMS showed that SM was consumed and DP was detected. The reaction mixture was quenched with H2O (50 mL) and extracted with DCM (50 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by FCC (12 g, silica gel, MeOH / DCM = 5%) to give product 3 (68 mg, yield 56%) as a yellow solid: MS (ESI), m / z: C 15 H 15 N5O 10 Calculated accurate mass: 425.08 t (measured value) R = 1.256 min. [M+H] + = 426.00; 1 H NMR (400 MHz, CDCl3) δ 8.72 (d, J = 2.4 Hz, 1H), 8.44 (dd, J = 9.2, 2.8 Hz, 1H), 7.31 (d, J = 9.2Hz, 1H), 7.24 (s, 1H), 5.39 (s, 2H), 4.80 (t, J = 5.0 Hz, 2H), 4.49 (t, J =5.0 Hz, 2H), 4.07 (m, 2H), 1.19 (t, J = 7.2 Hz, 3H). Synthesis Scheme 4

[0209]

[0210] Step 1: ((4-Nitrophenoxy)carbonyl)glycine methyl ester. A solution of glycine methyl ester hydrochloride (1.0 g, 8.0 mmol) in DCM (10 mL) was added dropwise to a solution of 4-nitrophenyl chloroformate (1.93 g, 9.6 mmol) and DIEA (3.10 g, 24.0 mmol) in DCM (20 mL) stirred at 0 °C. The reaction mixture was stirred at room temperature for 12 hours. LCMS showed that SM was consumed and DP was detected. The reaction mixture was quenched with H₂O (50 mL) and extracted with DCM (50 mL × 3). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by FCC (12 g, silica gel, EA / PE = 30%) to give ((4-nitrophenoxy)carbonyl)glycine methyl ester (300 mg, 15% yield) as a white solid.

[0211] Step 2: Synthesis of ((2-(5-((2,4-dinitrophenoxy)methyl)-2-nitro-1H-imidazol-1-yl)ethoxy)carbonyl)glycine methyl ester (4). A solution of ((4-nitrophenoxy)carbonyl)glycine methyl ester (127 mg, 0.50 mmol) in DCM (3 mL) was added dropwise to a solution of compound 1 (150 mg, 0.42 mmol) and DIEA (163 mg, 1.26 mmol) in DCM (5 mL) stirred at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. LCMS showed that SM was consumed and DP was detected. The reaction mixture was diluted with H2O (50 mL) and extracted with DCM (50 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by FCC (12 g, silica gel, MeOH / DCM = 5%) to give product 4 (24 mg, yield 12%) as a yellow solid: MS (ESI), m / z: C 16 H 16 N6O 11 Calculated accurate mass: 468.09 t (measured value) R = 1.135 min. [M+H] + =469.00; 1 H NMR (400 MHz, MeOD) δ 8.79 (d, J = 2.8 Hz, 1H), 8.55 (dd, J = 9.6, 9.2 Hz, 1H), 7.74 (d, J = 9.2 Hz, 1H), 7.37 (s, 1H), 5.62 (s, 2H), 4.84 –4.81 (m, 2H), 4.54 (t, J= 5.0 Hz, 2H), 3.76 (s, 2H), 3.70 (s, 3H). Synthesis Scheme 5

[0212]

[0213] Step 1: Ethyl 2-nitro-1-(2-(toluenesulfonyloxy)ethyl)-1H-imidazolium-5-carboxylate. At 0 °C, TEA (1.32 g, 13.1 mmol) and TosCl (1.00 g, 5.25 mmol) were added to a DCM (20 mL) solution of ethyl 1-(2-hydroxyethyl)-2-nitro-1H-imidazolium-5-carboxylate (1.00 g, 4.37 mmol). The mixture was stirred at 25 °C for 16 hours. The reaction mixture was poured into water (50 mL) and extracted with DCM (10 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, and concentrated under vacuum to give a crude product (740 mg, 44% yield) as a yellow solid, which was used directly in the next step without further purification: MS (ESI), m / z: C 15 H 17 Calculated exact mass of N3O7S: 383.08 t (measured value) R = 2.314 min. [M+H] + = 384.1.

[0214] Step 2: Ethyl 1-(2-(bis(2,4-dimethoxybenzyl)amino)ethyl)-2-nitro-1H-imidazolium-5-carboxylate. Bis(2,4-dimethoxybenzyl)amine (795 mg, 2.51 mmol) and K₂CO₃ (865 mg, 6.27 mmol) were added to a solution of ethyl 2-nitro-1-(2-(toluenesulfonyloxy)ethyl)-1H-imidazolium-5-carboxylate (800 mg, 2.09 mmol) in 16 mL of ACN at 25 °C. The reaction mixture was then stirred at 60 °C for 16 hours. The reaction mixture was cooled to room temperature and filtered; the filtrate was concentrated under vacuum to give the crude product. The crude product was purified by rapid column chromatography (PE / EA = 10 / 1-1 / 1) to give the desired compound (650 mg, yield 59%) as a yellow solid: MS (ESI), m / z: C 26 H 32 Calculated exact mass of N4O8: 528.22 t (measured value) R = 1.560 min. [M+H] + = 529.3.

[0215] Step 3: (1-(2-(bis(2,4-dimethoxybenzyl)amino)ethyl)-2-nitro-1H-imidazol-5-yl)methanol. A 1M LiBHEt3 solution (3.41 mL, 3.41 mmol) of THF was added dropwise to a solution of ethyl 1-(2-(bis(2,4-dimethoxybenzyl)amino)ethyl)-2-nitro-1H-imidazol-5-carboxylic acid (600 mg, 1.14 mmol) in 12 mL of THF. The mixture was stirred at 0 °C for 2 hours. The reaction mixture was quenched with saturated NH4Cl solution (20 mL) and extracted with EA (10 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by rapid column chromatography (DCM / MeOH = 100 / 1-30 / 1) to obtain the product (330 mg, yield 60%) as a yellow solid: MS (ESI), m / z:C 24 H 30 Calculated exact mass of N4O7: 486.21 t (measured value). R = 1.408 min. [M+H] + = 487.2; 1 H NMR (400 MHz, CDCl3) δ 7.07-7.05 (m, 2H), 6.89 (s, 1H), 6.33-6.31 (m, 4H), 4.35-4.30 (m, 2H), 4.05-3.95 (m, 2H), 3.75-3.70 (m, 12H), 3.69-3.62 (m, 4H), 2.95-2.85 (m, 2H).

[0216] Step 4: N,N-bis(2,4-dimethoxybenzyl)-2-(5-(((2,4-dinitrophenoxy)methyl)-2-nitro-1H-imidazol-1-yl)ethyl-1-amine. Cs₂CO₃ (33.5 mg, 0.10 mmol) and 1-fluoro-2,4-dinitrobenzene (19.2 mg, 0.10 mmol) were added to a solution of (50 mg, 0.10 mmol) of methanol (1 mL) in ACN at 0 °C. The mixture was stirred at 0 °C for 2 hours. Six more batches were performed using the same procedure. The reaction mixtures were combined and filtered. The filtrate was concentrated under vacuum to give the crude product. The desired product (315 mg, yield 67%) was obtained by preparative TLC (PE / EA = 1 / 1) as a yellow solid: MS (ESI), m / z: C 30 H 32 N6O 11Calculated accurate mass: 652.21 measured value t R = 1.206, 1.365 min. [M+H] + = 653.2.

[0217] Step 5: 2-(5-((2,4-dinitrophenoxy)methyl)-2-nitro-1H-imidazol-1-yl)ethyl-1-amine (5). MsOH (0.1 mL) was added to a solution of N,N-bis(2,4-dimethoxybenzyl)-2-(5-((2,4-dinitrophenoxy)methyl)-2-nitro-1H-imidazol-1-yl)ethyl-1-amine (50 mg, 0.08 mmol) in CHCl3 (0.5 mL). The mixture was stirred at 80 °C for 16 hours. Five more batches were performed using the same procedure. The reaction mixtures were combined, diluted with water (6 mL), and extracted with DCM (5 mL × 3). The aqueous layer was purified by preparative HPLC (column: Sunfire 5µm 19-150mm; mobile phase: CH3CN / H2O (0.1% TFA); gradient: 10-60%, CH3CN, 7 min; flow rate: 500 μL / min) to give compound 5 (20 mg, yield 12%) as a brown solid: MS (ESI), m / z: C 12 H 12 Calculated exact mass of N6O7: 352.08 t (measured value). R = 1.187 min.[M+H] + = 353.0; 1 H NMR (400 MHz, DMSO) d 6 ) δ 8.84 (d, J = 2.8 Hz, 1H), 8.62(dd, J = 9.2, 2.8 Hz, 1H), 8.01 (brs, 3H), 7.82 (d, J = 9.2 Hz, 1H), 7.49 (s,1H), 5.62 (s, 2H), 4.65 (t, J = 6.8 Hz, 2H), 3.32-3.31 (m, 2H). Synthesis Scheme 6

[0218]

[0219] Step 1: 2-(2-(5-((2,4-dinitrophenoxy)methyl)-2-nitro-1H-imidazol-1-yl)ethyl)isoindoline-1,3-dione (6). Phthalimide (62 mg, 0.42 mmol), PPh3 (111 mg, 0.42 mmol), and DIAD (172 mg, 0.85 mmol) were added to a mixture of compound 1 (100 mg, 0.28 mmol) in THF (3 mL) at 0 °C. The mixture was stirred at 25 °C for 16 hours. The reaction mixture was poured into water (10 mL) and extracted with EA (20 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and concentrated under vacuum to give the crude product. The crude product was purified by preparative TLC (PE / EA = 1 / 1) to obtain product 6 (60 mg, yield 44%) as a yellow solid: MS (ESI), m / z: C 20 H 14 Calculated exact mass of N6O9: 482.1 Measured value RT = 1.985 min. [M+H] + = 483.1; 1 H NMR (400 MHz, DMSO) d 6 ) δ 8.77 (d, J = 2.8 Hz, 1H), 8.60 (dd, J = 9.2, 2.8 Hz, 1H), 7.88-7.79 (m, 5H), 7.45 (s, 1H), 5.62 (s, 2H), 4.71 (t, J = 6.4 Hz, 2H), 4.08 (t,J = 6.0 Hz, 2H). Synthesis Scheme 7

[0220]

[0221] Step 1: 2-(5-((2,4-dinitrophenoxy)methyl)-2-nitro-1H-imidazol-1-yl)ethyl dimethyl phosphate (7). Dimethyl chlorophosphonate (135 mg, 0.934 mmol) was added dropwise to a solution of compound 1 (110 mg, 0.311 mmol) in DCM / pyridine (4 mL / 2 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was diluted with DCM (10 mL) and washed with H2O (10 mL). The collected organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain the residue. The residue was purified by FCC (4 g, silica gel, MeOH / DCM = 5%) to give product 7 (34 mg, yield 23%) as a yellow solid: MS (ESI), m / z: C 14 H 16 N5O 11 The calculated precision of P is 461.06 times the measured value t. R = 1.105 min. [M+H] + =461.90; 1 H NMR (400 MHz, CDCl3) δ 8.79 (d, J = 2.8 Hz, 1H), 8.51 (dd, J = 9.2, 2.8 Hz, 1H), 7.41 (d, J = 9.2 Hz, 1H), 7.33 (s, 1H), 5.47 (s, 2H), 4.87 (t, J = 4.8 Hz, 2H), 4.46 (dt, J = 9.6, 5.2 Hz, 2H), 3.69 (s, 3H), 3.66 (s, 3H). Synthesis Scheme 8

[0222]

[0223] Step 1: 2-(5-((2,4-dinitrophenoxy)methyl)-2-nitro-1H-imidazol-1-yl)ethyl 3-hydroxyazacyclobutane-1-carboxylic acid ester (8). Di(trichloromethyl)dicarbonate (58 mg, 0.17 mmol) was added to a THF (5 mL) solution of compound 1 (100 mg, 0.28 mmol) and DIPEA (92 mg, 0.71 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. Then, a THF / H2O (5 mL / 5 mL) solution of azacyclobutane-3-ol hydrochloride (62 mg, 0.57 mmol) and K2CO3 (200 mg, 1.40 mmol) was added. The reaction mixture was stirred at 0 °C for 30 min and then at room temperature for 1 h. After the reaction was complete, the solvent was removed under reduced pressure to obtain the residue. The residue was purified by FCC (12g silica gel, MeOH / DCM=5%), followed by preparative HPLC (C18 column, MeCN / H2O (0.1% FA)) to give product 8 (78mg, yield 61%) as a white solid: MS (ESI), m / z: C 16 H 16 N6O 10 Calculated accurate mass: 452.09 t (measured value) R = 1.058 min. [M+H] + =453.0; 1 H NMR (400 MHz, d 6 -DMSO) δ 8.81 (d, J = 2.8 Hz, 1H), 8.60 (dd, J =9.2, 2.8 Hz, 1H), 7.82 (d, J = 9.2 Hz, 1H), 7.44 (s, 1H), 5.69 (d, J = 6.4Hz, 1H), 5.63 (s, 2H), 4.74 (t, J = 5.2 Hz, 2H), 4.42 – 4.34 (m, 1H), 4.29(t, J = 5.2 Hz, 2H), 4.01 – 3.90 (m, 2H), 3.62 – 3.49 (m, 2H). Synthesis Scheme 9

[0224]

[0225] Step 1: 2-(5-((2,4-dinitrophenoxy)methyl)-2-nitro-1H-imidazol-1-yl)ethyl hydrogen sulfate (9) was added to a solution of compound 1 (100 mg, 0.28 mmol) in DCM (2 mL) at 0 °C with chlorosulfonic acid (330 mg, 2.83 mmol). The reaction mixture was stirred at 0 °C for 30 min and then at 20 °C for 1.5 h. After the reaction was complete, the mixture was concentrated under reduced pressure to remove DCM. The residue was purified by preparative HPLC (C18 column, ACN-H2O (0.1% NH3·H2O)) to give product 9 (35 mg, 27% yield, ammonium salt) as a white solid: MS (ESI), m / z: C 12 H 11 N5O 11 The calculated precision mass of S is 433.02 times the measured value t. R = 1.002 min. [MH] - = 432. 1 H NMR (400 MHz, d 6 -DMSO) δ 8.79 (d, J = 2.8 Hz, 1H), 8.54 (dd, J = 9.6, 2.8 Hz, 1H), 7.79 (d, J = 9.6Hz, 1H), 7.35 (s, 1H), 7.04 (br s, 4H), 5.73 (s, 2H), 4.65 (t, J = 4.8 Hz, 2H), 4.13 (t, J = 4.8 Hz, 2H). Synthesis Scheme 10

[0226]

[0227] Step 1: 2-(5-((2,4-dinitrophenoxy)methyl)-2-nitro-1H-imidazol-1-yl)ethyl methyl fumarate (10). Oxaloyl chloride (28.7 mg, 0.23 mmol) was added to a DCM (2 mL) solution of monomethyl fumarate (22 mg, 0.17 mmol) at 0 °C. The reaction mixture was stirred at N2 and 25 °C for 3 hours. The reaction mixture was evaporated under vacuum to give the acyl chloride.

[0228] At 0 °C, a solution of acyl chloride in DCM (2 mL) was added to a solution of compound 1 (40 mg, 0.11 mmol) and TEA (45.7 mg, 0.45 mmol) in DCM (2 mL). The reaction mixture was stirred at N2 and 25 °C for 2 hours. The reaction mixture was quenched with additional water (10 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was purified by preparative TLC (DCM / MeOH = 15 / 1) to give product 10 (19 mg, 36% yield) as a grayish-white solid: MS (ESI), m / z: C 17 H 15 N5O 11 Calculated accurate mass: 465.077 metric tons. R = 1.806 min. [M+H] + = 466.0; 1 H NMR (400 MHz, CDCl3) δ 8.79 (d, J = 2.7 Hz, 1H), 8.55 – 8.50(m, 1H), 7.38 (d, J = 9.2 Hz, 1H), 7.34 (s, 1H), 6.84 – 6.67 (m, 2H), 5.41(s, 2H), 4.91 (t, J = 5.5 Hz, 2H), 4.64 (t, J = 5.5 Hz, 2H), 3.82 (s, 3H). Synthesis Scheme 11

[0229]

[0230] Step 1: 2-(5-((2,4-dinitrophenoxy)methyl)-2-nitro-1H-imidazol-1-yl)ethyl-2-acetoxybenzoate (11). Oxaloyl chloride (1.42 g, 11.2 mmol) was added to a solution of acetylsalicylic acid (1 g, 5.6 mmol) in DCM (20 mL) at 0 °C. The reaction mixture was stirred at N2 and 25 °C for 3 hours. The reaction mixture was evaporated under vacuum to give acyl chloride as a brown solid.

[0231] At 0 °C, a solution of acyl chloride (152 mg, 0.76 mmol) in DCM (1 mL) was added to a solution of compound 1 (90 mg, 0.25 mmol) and TEA (77.4 mg, 0.76 mmol) in DCM (4 mL). The reaction mixture was stirred at N2 and 0 °C for 1 hour. The reaction mixture was quenched by adding water (10 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was purified by preparative TLC (DCM / MeOH = 15 / 1) to give product 11 (90 mg, yield 64%) as a grayish-white solid: MS (ESI), m / z: C 21 H 17 N5O 11 Calculated accurate mass: 515.092 measured value t R = 2.415 min. [M+H] + = 516.0; 1 H NMR (400 MHz, DMSO) d 6) δ 8.78 (d, J =2.8 Hz, 1H), 8.58 – 8.53 (m, 1H), 7.78 – 7.73 (m, 2H), 7.69 – 7.62 (m, 1H), 7.45 (s, 1H), 7.38 – 7.33 (m, 1H), 7.22 – 7.18 (m, 1H), 5.66 (s, 2H), 4.86(t, J = 5.5 Hz, 2H), 4.63 (t, J = 5.5 Hz, 2H), 2.15 (s, 3H). Synthesis Scheme 12

[0232]

[0233] Step 1: Synthesis of 2-(5-((2,4-dinitrophenoxy)methyl)-2-nitro-1H-imidazol-1-yl)ethyl dihydrogen phosphate (12). TEA (6 mg, 0.057 mmol) was added dropwise to a solution of compound 1 (100 mg, 0.028 mmol) and POCl3 (22 mg, 0.141 mmol) in dioxane (4 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was diluted with H2O (10 mL) and extracted with EA (10 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC to give product 12 (60 mg, 47% yield) as a yellow solid: MS (ESI), m / z: C 12 H 12 N5O 11 The calculated precision of P is 433.03 t (measured value). R = 1.050 min. [M+H] + = 433.85; 1 HNMR (400 MHz, d 6 -DMSO) δ 8.76 (d, J = 2.8 Hz, 1H), 8.51 (dd, J = 9.2, 2.8 Hz, 1H), 7.96 (d, J = 9.2 Hz, 1H), 7.29 (s, 1H), 5.82 (s, 2H), 4.58 (t, J = 4.8Hz, 2H), 4.02 (m, 2H). Synthesis Scheme 13

[0234]

[0235] Step 1: 4-Methylbenzenesulfonic acid 2-(5-((2,4-dinitrophenoxy)methyl)-2-nitro-1 H2-Imidazol-1-yl)ethyl ester. TsCl (175 mg, 0.92 mmol) was added to a DCM (10 mL) solution of compound 1 (260 mg, 2.12 mmol) and DMAP (260 mg, 2.12 mmol) at 20 °C. The reaction mixture was then stirred at 20 °C for 1 hour. After the reaction was complete, the mixture was concentrated under vacuum to obtain a residue. The residue was purified by FCC (12 g, silica gel, MeOH / DCM = 0% to 5%) to give 2-(5-((2,4-dinitrophenoxy)methyl)-2-nitro-1H-imidazol-1-yl)ethyl ester of 4-methylbenzenesulfonic acid (260 mg, 0.51 mmol, yield 24%) as a brown solid: MS (ESI), m / z: C 19 H 17 N5O 10 Calculated exact mass of S: 507.07 Measured value tR = 1.365 min. [M+H] + = 508; 1 H NMR (400 MHz, CDCl3) δ 8.80 (d, J = 2.8Hz, 1H), 8.53 (dd, J = 9.2, 2.8 Hz, 1H), 7.62–7.57 (m, 2H), 7.43 (d, J = 9.2Hz, 1H), 7.34–7.30 (m, 3H), 5.50 (s, 2H), 4.87 (t, J = 4.6 Hz, 2H), 4.43 (t, J = 4.6 Hz, 2H).

[0236] Step 2: 1-(2-azidoethyl)-5-((2,4-dinitrophenoxy)methyl)-2-nitro-1 H -Imidazole. 4-Methylbenzenesulfonic acid 2-(5-((2,4-dinitrophenoxy)methyl)-2-nitro-1 H A mixture of imidazole-1-yl)ethyl ester (100 mg, 0.197 mmol) and NaN3 (26 mg, 0.394 mmol) in DMF (3 mL) was stirred at 30 °C for 3 hours. After the reaction was complete, the mixture was diluted with water (50 mL) and extracted with EtOAc (30 mL). The organic layer was dried over Na2SO4 and concentrated under vacuum to obtain the residue. The residue was purified by FCC (4 g, silica gel, MeOH / DCM = 0% to 10%) to give the product (22 mg, 0.058 mmol, yield 29%) as a yellow solid: MS (ESI), m / z: C 12H 10 Calculated exact mass of N8O7: 378.07 min. Measured value tR = 1.183 min. [M+H] + = 379; 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.81 (d, J = 2.8Hz, 1H), 8.59 (dd, J = 9.2, 2.8 Hz, 1H), 7.83 (d, J = 9.2 Hz, 1H), 7.46 (s,1H), 5.68 (s, 2H), 4.63 (t, J = 5.8 Hz, 2H), 3.85 (t, J = 5.8 Hz, 2H).

[0237] Step 3: 5-((2,4-dinitrophenoxy)methyl)-1-(2-isothiocyanate ethyl)-2-nitro-1 H -Imidazole (13). At 20 °C, to 1-(2-azidoethyl)-5-((2,4-dinitrophenoxy)methyl)-2-nitro-1 H -Imidazole (42 mg, 0.11 mmol) was added to a mixture in THF (3 mL) containing triphenylphosphine (43 mg, 0.166 mmol) and methanedithione (237 mg, 3.1 mmol). The reaction mixture was then stirred at 20 °C for 16 hours. After the reaction was complete, the reaction mixture was concentrated under vacuum to obtain a residue. The residue was purified by FCC (12 g, silica gel, MeOH / DCM = 5%) followed by preparative HPLC (C18, MeCN / H2O (containing 0.1% FA)) to give product 13 (11 mg, 0.028 mmol, yield 25%) as a yellow solid: MS (ESI), m / z: C 13 H 10 Calculated exact mass of N6O7S: 394.03. Measured value: tR = 1.326 min. [M+H] + =395; 1 H NMR (400 MHz, CDCl3): δ 8.80 (d, J = 2.8 Hz, 1H), 8.54 (dd, J = 9.2, 2.8 Hz, 1H), 7.42 (d, J= 9.2 Hz, 1H), 7.39 (s, 1H), 5.48 (s, 2H), 4.83 (t, J = 5.2 Hz, 2H), 4.17 (t, J = 5.2 Hz, 2H). Synthesis Scheme 14

[0238]

[0239] Step 1: 1-(2-(tert-butoxy)ethyl)-2-nitro-1 H -Imidazole. Under N2, at 0°C, to 2-nitro-1 H DIAD (5.34 g, 0.0264 mmol) was added to a mixture of 1.0 g (8.8 mmol), 2-(tert-butoxy)ethanol-1-ol (1.35 g, 11.4 mmol), and PPh3 (6.92 g, 0.0264 mol) in THF (40 mL). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the solvent was removed under reduced pressure to give the residue. The residue was purified by FCC (MeOH / DCM = 1%) to give the product (1.3 g, 6.10 mmol, yield 69%) as a brown oil: MS (ESI), m / z: C9H 15 Calculated exact mass of N3O3: 213.11 metric tons. R = 1.118 min. [M+H] + = 214.15.

[0240] Step 2: 4-Bromo-1-(2-(tert-butoxy)ethyl)-2-nitro-1 H -Imidazole. At room temperature, to 1-(2-(tert-butoxy)ethyl)-2-nitro-1 H NBS (1.3 g, 7.0 mmol) was added to a DMF (10 mL) solution of β-imidazole (1.0 g, 4.7 mmol). The reaction mixture was stirred at this temperature for 2 hours. After the reaction was complete, the reactants were quenched with water (50 mL) and extracted with EtOAc (30 mL × 2). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to obtain the residue. The residue was purified by FCC (25 g silica gel, EtOAc / PE = 10%) to give the product (350 mg, 1.2 mmol, yield 26%) as a colorless oil: MS (ESI), m / z: C9H 14 Calculated exact mass of BrN3O3: 291.02 t (measured value) R = 1.330 min. [M+H] +=292.05; 1 H NMR (400 MHz, CDCl3): δ 7.18 (s, 1H), 4.55 (t, J = 4.8 Hz, 2H), 3.68 (t, J = 4.8 Hz, 2H), 1.09 (s, 9H).

[0241] Step 3: 1-(2-(tert-butoxy)ethyl)-2-nitro-4-vinyl-1 H -Imidazole. A mixture of 4-bromo-1-(2-(tert-butoxy)ethyl)-2-nitro-1H-imidazole (320 mg, 1.10 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborhecyclopentane (253 mg, 1.64 mmol), K3PO4 (696 mg, 3.29 mmol), and Pd(dppf)Cl2 (80 mg, 0.11 mmol) in DMF (5 mL) was stirred and heated at 60 °C for 5 hours under N2. After the reaction was complete, the reactants were quenched with water (30 mL) and extracted with MTBE (20 mL × 2). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the residue. The residue was purified by FCC (25g silica gel, EtOAc / PE=20%) to give the product (150mg, 0.63mmol, 57% yield) as a yellow oil: MS (ESI), m / z: C 11 H 17 Calculated exact mass of N3O3: 239.13 t (measured value) R = 1.278 min. [M+H] + = 240.20; 1 H NMR (400 MHz, CDCl3): δ 7.14 (s, 1H), 6.57 (dd, J =17.6, 10.8 Hz, 1H), 5.96 (dd, J = 17.6, 1.2 Hz, 1H), 5.33 (dd, J = 10.8, 1.2Hz, 1H), 4.52 (t, J = 4.8 Hz, 2H), 3.68 (t, J = 4.8 Hz, 2H), 1.08 (s, 9H).

[0242] Step 4: 1-(2-(tert-butoxy)ethyl)-2-nitro-1H -Imidazole-4-carboxaldehyde. At room temperature, K2OsO4·2H2O (11.5 mg, 0.03 mmol) was added to a solution of 1-(2-(tert-butoxy)ethyl)-2-nitro-4-vinyl-1H-imidazolium (150 mg, 0.63 mmol) and NaIO4 (270 mg, 1.25 mmol) in 1,4-dioxane / H2O (3 mL / 3 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reactants were quenched with water (30 mL) and extracted with EtOAc (30 mL × 2). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the product (85 mg, crude) as a gray solid: MS (ESI), m / z: C 10 H 15 Calculated exact mass of N3O4: 241.11 metric tons. R = 1.121 min. [M+H] + = 242.15; 1 H NMR (400 MHz, CDCl3): δ 9.90 (s, 1H), 7.79 (s, 1H), 4.62 (t, J = 4.8 Hz, 2H), 3.70 (t, J = 4.8 Hz, 2H), 1.08 (s, 9H).

[0243] Step 5: (1-(2-(tert-butoxy)ethyl)-2-nitro-1 H 1-Imidazol-4-yl)methanol. NaBH4 (20 mg, 0.53 mmol) was added to a MeOH (2 mL) solution of 1-(2-(tert-butoxy)ethyl)-2-nitro-1H-imidazol-4-carboxaldehyde (85 mg, 0.35 mmol) at 0 °C. The reaction mixture was then stirred at 0 °C for 30 minutes. After the reaction was complete, the reactants were quenched with saturated NH4Cl (30 mL) and extracted with EtOAc (20 mL × 2). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the product (42 mg, crude) as a colorless oil: MS (ESI), m / z: C 10 H 17 Calculated exact mass of N3O4: 243.12 t (measured value) R = 0.973 min. [M+H] + = 244.15.

[0244] Step 6: 1-(2-(tert-butoxy)ethyl)-4-((2,4-dinitrophenoxy)methyl)-2-nitro-1 H-Imidazole (15). At room temperature, Cs₂CO₃ (140 mg, 0.43 mmol) was added to a solution of (1-(2-(tert-butoxy)ethyl)-2-nitro-1H-imidazol-4-yl)methanol (42 mg, 0.17 mmol) and 1-fluoro-2,4-dinitrobenzene (37 mg, 0.20 mmol) in DMF (1 mL). The reaction mixture was then stirred and heated at 50 °C for 1 hour. After the reaction was complete, the reactants were quenched with saturated NH₄Cl (20 mL) and extracted with EtOAc (20 mL × 2). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure to obtain the residue. The residue was purified by FCC (silica gel, MeOH / DCM = 0% to 5%) to give 15 (64 mg, 0.156 mmol) as a brown oil: MS (ESI), m / z: C 16 H 19 Calculated accurate mass of N5O8: 409.12 t (measured value) R = 1.455 min. [M+H] + = 410; 1 H NMR (400 MHz, CDCl3): δ 8.76 (d, J = 2.8 Hz, 1H), 8.45 (dd, J = 9.2, 2.8Hz, 1H), 7.44 (d, J = 9.2 Hz, 1H), 7.39 (s, 1H), 5.36 (s, 2H), 4.58 (t, J =5.2 Hz, 2H), 3.68 (t, J = 5.2 Hz, 2H), 1.04 (s, 9H).

[0245] Step 7: 2-(4-((2,4-dinitrophenoxy)methyl)-2-nitro-1 H -imidazol-1-yl)ethyl-1-ol (14). At room temperature, TFA (1 mL) was added dropwise to a solution of 15 (65 mg, 0.16 mmol) in DCM (2 mL). The reaction mixture was then stirred at this temperature for 30 minutes. After the reaction was complete, the reaction mixture was diluted with DCM (30 mL) and washed with water (25 mL × 2). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain the residue. The residue was purified by FCC (12 g silica gel, MeOH / DCM = 0% to 5%) and preparative HPLC (C18, MeCN / H2O (0.1% FA)) to give 14 (32.49 mg) as a yellow solid: MS (ESI), m / z: C12 H 11 Calculated exact mass of N5O8: 353.06, measured value t R = 1.239 min, [M+H] + =354.05; 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.78 (d, J = 2.8 Hz, 1H), 8.54 (dd, J =9.2, 2.8 Hz, 1H), 7.80 (d, J = 9.2 Hz, 1H), 7.76 (s, 1H), 5.41 (s, 2H), 5.03(br s, 1H), 4.46 (t, J = 5.2 Hz, 2H), 3.76–3.69 (m, 2H). Synthesis Scheme 15

[0246]

[0247] Step 1: 2-(4-((2,4-dinitrophenoxy)methyl)-2-nitro-1 H (16) Imidazol-1-yl)ethyl 3-hydroxyazacyclobutane-1-carboxylic acid ester. Triphosgene (50 mg, 0.17 mmol) was added to a mixture of 14 (100 mg, 0.28 mmol) and DIPEA (146 mg, 1.13 mmol) in THF (2 mL) under N2 and 0 °C. The reaction mixture was stirred at 0 °C for 30 min. Then, a mixture of azacyclobutane-3-ol hydrochloride (62 mg, 0.57 mmol) and K2CO3 (195 mg, 1.42 mmol) in THF / H2O (2 mL / 2 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 30 min and then stirred at room temperature for another 30 min. After the reaction was complete, the reactants were quenched with water (30 mL) and extracted with EtOAc (30 mL × 2). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the residue. The residue was purified by preparative HPLC (C18, MeCN / H2O (0.1% FA)) to give 16 (64 mg, yield 51%) as a pale yellow solid: MS (ESI), m / z: C 16 H 16 N6O 10 Calculated accurate mass: 452.09 t (measured value) R= 1.072 min. [M+H] + = 453; 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.78 (d, J = 2.8 Hz, 1H), 8.54 (dd, J = 9.6, 2.8 Hz, 1H), 7.84–7.72 (m, 2H), 5.66 (d, J = 6.0 Hz, 1H), 5.43 (s, 2H), 4.73–4.55 (m, 2H), 4.43–4.24 (m, 3H), 4.01–3.89 (m, 2H), 3.61–3.48 (m, 2H). Synthesis Scheme 16

[0248]

[0249] Step 1: 2-(4-((2,4-dinitrophenoxy)methyl)-2-nitro-1 H (17)-Imidazol-1-yl)ethyl hydrogen sulfate. Chlorosulfonic acid (660 mg, 5.66 mmol) was added to a solution of compound 14 (100 mg, 0.28 mmol) in DCM (1 mL) at 0 °C. The reaction mixture was then stirred at room temperature for 1 hour. After the reaction was complete, the solvent was removed under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (C18, MeCN / H2O (0.1% NH3·H2O)) to give 17 (16 mg, NH3 salt) as a pale yellow solid: MS (ESI), m / z: C 12 H 11 N5O 11 The calculated precision mass of S is 433.02 times the measured value t. R = 1.029 min. [MH] - = 432; 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.76 (d, J = 2.8 Hz, 1H), 8.53(dd, J = 9.6, 2.8 Hz, 1H), 7.79 (m, 2H), 7.07 (br s, 4H), 5.42 (s, 2H), 4.61(t,J = 5.2 Hz, 2H), 4.10 (t, J = 5.2 Hz, 2H). Synthesis Scheme 17

[0250]

[0251] Step 1: ((2-(4-((2,4-dinitrophenoxy)methyl)-2-nitro-1 H (18)-Imidazol-1-yl)ethoxy)carbonyl)glycine methyl ester. Triphosgene (50 mg, 0.17 mmol) was added to a mixture of compound 14 (100 mg, 0.28 mmol) and DIPEA (146 mg, 1.13 mmol) in THF (2 mL) under N2 and 0 °C. The reaction mixture was stirred at 0 °C for 30 min. Then, a mixture of glycine methyl ester hydrochloride (70 mg, 0.57 mmol) and K2CO3 (195 mg, 1.42 mmol) in THF / H2O (2 mL / 2 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 1 h and then at room temperature for another 1 h. After the reaction was complete, the mixture was diluted with water (50 mL) and extracted with EtOAc (30 mL × 2). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the residue. The residue was purified by preparative HPLC (C18, MeCN / H2O (0.1% FA)) to give 18 (71 mg, 0.15 mmol, yield 54%) as a pale yellow solid: MS (ESI), m / z: C 16 H 16 N6O 11 Calculated accurate mass: 468.09 t (measured value) R = min. [M+H] + = 469; 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.78 (d, J = 3.2 Hz, 1H), 8.54 (dd, J = 9.2, 3.2 Hz, 1H), 7.80–7.74 (m, 2H), 7.61 (t, J = 6.0 Hz, 1H), 5.40 (s, 2H), 4.65 (t, J = 4.8 Hz, 2H), 4.38 (t, J= 4.8 Hz, 2H), 3.69 (d, J = 6.0 Hz, 2H), 3.62 (s, 3H). Synthesis Scheme 18

[0252]

[0253] Step 1: 2-(4-((2,4-dinitrophenoxy)methyl)-2-nitro-1 H (19)-Imidazol-1-yl)ethyl dimethyl phosphate. At 0 °C, pyridine (1 mL) and dimethyl chlorophosphate (123 mg, 0.85 mmol) were added to a solution of compound 14 (100 mg, 0.28 mmol) in DCM (2 mL). The reaction mixture was then stirred at 0 °C for 0.5 h and then at room temperature for another 0.5 h. After the reaction was complete, the solvent was removed under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (C18, MeCN / H2O (0.1% FA)) to give 19 (78 mg, 60% yield) as a pale yellow solid: MS (ESI), m / z: C 14 H 16 N5O 11 The calculated precision of P is 461.06 times the measured value t. R = 1.125 min. [M+H] + = 462; 1 H NMR (400 MHz, CDCl3): δ 8.75 (d, J = 3.2 Hz, 1H), 8.47 (dd, J = 9.2, 3.2 Hz, 1H), 7.51–7.38(m, 2H), 5.36 (s, 2H), 4.77 (t, J = 4.8 Hz, 2H), 4.52–4.37 (m, 2H), 3.73 (d, J = 11.2 Hz, 6H).

[0254] Table 1A. Exemplary compounds and chemical characterization

[0255]

[0256]

[0257]

[0258]

[0259] Table 1B. Exemplary compounds and chemical characterization

[0260] Study I. Pharmacokinetic Study in Mice General Solution

[0261] Male C57BL / 6 mice (20-30 g, provided by Vital River or SLAC) were randomly assigned to several groups (n=3) to receive an intravenous (iv) dose (1 mg / kg, 5 mL / kg) or oral dose (5 mg / kg, 10 mL / kg) of the test product. The formulation was prepared by adding an appropriate volume of solvent to the test product to achieve the desired concentration. For the IV group, mice received a single IV bolus injection of the test product via the tail vein. For the PO group, mice received an oral tube feeding of the test product. At least 30 μL of blood was collected via the saphenous vein or mandibular vein at 2 minutes (IV only), 5 minutes (PO only), 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after administration. Whole blood was collected into EP tubes containing EDTA-K2, immediately placed on wet ice, and then centrifuged at 3500 g and 4°C for 5 minutes to obtain plasma within 30 minutes. Plasma samples were placed in sealed tubes on dry ice and then stored at -80°C until analysis. The concentration of the analyte in mouse plasma was quantified using LC-MS / MS based on fragment ion multiple reaction monitoring (MRM). This method consisted of two independent standard curves including all other samples. Three levels of QC (low, medium, and high) were used to ensure the reliability of the assay. Pharmacokinetic parameters were calculated using a non-compartmental model analysis with PhoenixWinNonlin software (version 8.3, Certara, Princeton, NJ).

[0262] The pharmacokinetic parameters of 2,4-DNP following intravenous injection of 1 mg / kg and oral administration of 5 mg / kg in male C57BL / 6 mice are shown in Table 2, and the mean plasma concentrations are shown in Table 2. Figure 1 middle.

[0263] Table 2. Pharmacokinetic studies of 2,4-DNP (intravenous and oral administration in male C57BL / 6 mice) a )

[0264] a Mouse PK parameters (mean, n=3). b IV administration of 1 mg / kg. c PO administration: 5 mg / kg.

[0265] Following intravenous (IV) (1 mg / kg) or PO (5 mg / kg) administration of compound 1 to male C57BL / 6 mice, the pharmacokinetic parameters of compound 1 and its metabolite 2,4-DNP are shown in Table 3. The mean plasma concentrations of compound 1 and its metabolite 2,4-DNP are shown in Table 3. Figure 2 middle.

[0266] Table 3. Pharmacokinetic studies of compound 1 (IV and PO administration in male C57BL / 6 mice) a )

[0267] a Mouse PK parameters (mean, n=3). b IV 1mg / kg. c PO 5mg / kg. d 2,4-Dinitrophenol released from the parent compound. Study II. Pharmacokinetic Study in Rats General Solution

[0268] Male SD rats (170g–300g, supplied by Vital River) were randomly assigned to several groups (n=3 or 4) to receive an intravenous (iv) dose (1 mg / kg, 5 mL / kg) or oral dose (5 mg / kg, 10 mL / kg) of the test product. The formulation was prepared by adding an appropriate volume of solvent to the test product to achieve the desired concentration. For the IV group, rats received a single intravenous (IV) bolus of the test product via the tail vein. For the PO group, rats received an oral tube feeding of the test product. At least 65 μL of blood was collected via the jugular vein at 2 minutes (IV only), 5 minutes (PO only), 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours post-administration. Whole blood was collected into EP tubes containing EDTA-K2, immediately placed on wet ice, and then centrifuged at 3500g and 4°C for 5 minutes to obtain plasma within 30 minutes. Plasma samples were placed in sealed tubes on dry ice and stored at -80°C until analysis. The concentration of the analyte in rat plasma was quantified using LC-MS / MS based on fragment ion multiple reaction monitoring (MRM). This method consisted of two independent standard curves including all other samples. Three levels of QC (low, medium, and high) were used to ensure the reliability of the assay. Pharmacokinetic parameters were calculated using a non-compartmental model analysis with Phoenix WinNonlin software (version 8.3, Certara, Princeton, NJ).

[0269] The pharmacokinetic parameters of 2,4-DNP after intravenous injection of 1 mg / kg and oral administration of 5 mg / kg in male SD rats are shown in Table 4, and the mean plasma concentrations are shown in Table 4. Figure 3 middle.

[0270] Table 4. Pharmacokinetic studies of 2,4-DNP in male SD rats after intravenous and oral administration a

[0271] a Rat PK parameters (mean, n=3). b Administer 1 mg / kg intravenously (iv). c Administer orally at 5 mg / kg (po).

[0272] The pharmacokinetic parameters of compound 1 and its metabolite 2,4-DNP after intravenous (IV) (1 mg / kg) or PO (5 mg / kg) administration in male SD rats are shown in Table 5. The mean plasma concentrations of compound 1 and its metabolite 2,4-DNP are shown in... Figure 4 middle.

[0273] Table 5. Pharmacokinetic studies of compound 1 (male SD rats IV (1 mg / kg) or PO (5 mg / kg) administration) a )

[0274] a Rat PK parameters (mean, n=3). b IV 1mg / kg. c PO 5mg / kg. d 2,4-Dinitrophenol released from the parent compound.

[0275] The pharmacokinetic parameters of compound 14 and its metabolite 2,4-DNP after intravenous (1 mg / kg) or PO (5 mg / kg) administration in male SD rats are shown in Table 6. The mean plasma concentrations of compound 14 and its metabolite 2,4-DNP are shown in... Figure 5 middle.

[0276] Table 6. Pharmacokinetic studies of compound 14 (male SD rats IV (1 mg / kg) or PO (5 mg / kg) administration) a )

[0277] a Rat PK parameters (mean, n=3 or 4). b IV 1mg / kg. c PO 5mg / kg. d 2,4-Dinitrophenol released from the parent compound. Study III. Pharmacokinetic Studies in Dogs General Solution

[0278] Male beagle dogs (7-10 kg, Beijing Marshall Biotechnology Co., Ltd.) were randomly assigned (n=3) to receive either an intravenous (IV) dose (1 mg / kg, 5 mL / kg) or an oral dose (5 mg / kg, 10 mL / kg) of the test product. The formulation was prepared by adding an appropriate volume of solvent to the test product to achieve the desired concentration. For the IV group, dogs received a single IV bolus of the test product. For the PO group, dogs received the test product via oral tube feeding. At least 150 μL of blood was collected at 5 minutes (IV only), 10 minutes (PO only), 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours, and 48 hours (PO only) after administration. Whole blood was collected into EP tubes containing EDTA-K2 and immediately placed on wet ice, then centrifuged at 3500 g and 4°C for 5 minutes to obtain plasma within 30 minutes. Plasma samples were placed in sealed tubes on dry ice and stored at -80°C until analysis. The concentration of analytes in plasma was quantified using LC-MS / MS based on fragment ion multiple reaction monitoring (MRM). This method consisted of two independent standard curves including all other samples. Three levels of QC (low, medium, and high) were used to ensure the reliability of the assay. Pharmacokinetic parameters were calculated using a non-compartmental model analysis with Phoenix WinNonlin software (version 8.3, Certara, Princeton, NJ).

[0279] The pharmacokinetic parameters of compound 1 and its metabolite 2,4-DNP following intravenous (1 mg / kg) or PO (5 mg / kg) administration in male beagle dogs are shown in Table 7. The mean plasma concentrations of compound 1 and its metabolite 2,4-DNP are shown in... Figure 6 middle.

[0280] Table 7. Pharmacokinetic studies of compound 1 (administered by male beagle IV (1 mg / kg) or PO (5 mg / kg)). a )

[0281] a Dog PK parameters (mean, n=3). b IV 1mg / kg. c PO 5mg / kg. d 2,4-Dinitrophenol released from the parent compound. Study IV. Rectal Temperature Measurement in Rats General Solution

[0282] Male SD rats (200g–250g, provided by Vital River) were randomly assigned to several groups (n=8) to receive oral tube feeding of various doses of the desired compound. Formulations were prepared prior to the experiment by adding an appropriate volume of solvent to the test sample to achieve the desired concentration. Rectal temperatures were measured using a Physitemp microprobe thermometer at 0, 15, 30, 45, 60, 90, and 120 minutes after chemical administration.

[0283] Results of rectal temperatures in SD rats following single oral administration of 5 mg / kg, 25 mg / kg, and 125 mg / kg 2,4-DNP were shown in... Figure 7 The survival curve is shown in the figure. Figure 8 middle.

[0284] Results of rectal temperatures in SD rats following single oral administration of 25 mg / kg, 50 mg / kg, and 500 mg / kg of compound 1 via tube feeding are shown below. Figure 9 There was no significant difference in temperature between the solvent group and the compound 1 treatment group. No dose-dependent mortality was observed.

[0285] The results presented in this paper support the following conclusion: compared with the solvent group, compound 1 did not cause an increase in body temperature even at a dose of 500 mg / kg, while 2,4-DNP significantly increased body temperature at a dose of 25 mg / kg. The lower Cmax / AUC ratio of compound 1 compared with 2,4-DNP, thus improving safety, is consistent with the above results. In vivo pharmacological study of compound 1 in V. DIO mice General Solution

[0286] For the development of a diet-induced obesity (DIO) mouse model, C57BL / 6j mice (provided by Jiangsu Jicui Pharmaceutical Biotechnology Co., Ltd.) were fed a high-fat diet (HFD) for 17 weeks starting at 6 weeks of age (D12492i, a rodent diet with 60 kcal% fat, Research Diets). Control mice were fed a standard control diet (SCD) during the study period. DIO mice were randomly assigned to three groups (model, compound 1 15 mg / kg, and 50 mg / kg) based on body weight and plasma lipid levels. Day 0 was defined as the first day of compound administration. Compound 1 was administered orally via tube feeding (po) once daily (qd) for six weeks. The dose volume was 10 ml / kg. Mice in the model and control groups were administered the solvent (5% DMSO + 10% Solutol HS-15 + 85% water). The test formulation was freshly prepared at each administration. It was thoroughly mixed before use. Body weight and food intake were measured daily.

[0287] On day 39, the animals were fasted overnight. On day 40, fasting glucose was measured 2 hours after compound administration. Blood samples were then collected via retro-orbital hemorrhage into pre-coated EDTA-K2 tubes for plasma preparation. Plasma samples were obtained by centrifugation at 4000 rpm for 10 minutes at 4°C and then stored at -80°C for fasting insulin measurement.

[0288] The study concluded on day 43, with animals fasted overnight (2 hours after compound administration). Animals were euthanized with CO2. Blood samples were collected via cardiac puncture and then deposited into pre-coated EDTA-K2 tubes for plasma preparation. Plasma was obtained by centrifugation at 4000 rpm for 10 minutes at 4°C and aliquoted. Plasma samples were stored at -80°C for further analysis (lipids, liver function tests, etc.). Shortly after blood sample collection, all animals were euthanized and perfused intracardiacly with ice-cold saline. Liver samples were collected and weighed. The right lobe of the liver sample was rapidly frozen and stored at -80°C for further analysis (liver lipids). The left lobe of the liver sample was preserved in tubes containing 10% neutral buffered formalin (NBF) and processed into formalin-fixed paraffin-embedded (FFPE) blocks for further pathological staining and analysis. Data are presented as mean ± SEM. Differences between groups were analyzed using one-way ANOVA and Graphpad Prism. p < 0.05 was considered statistically significant. For the G2 DIO model, *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001.

[0289] like Figure 10As shown, DIO mice exhibited a significant increase in body weight throughout the study period compared to the normal control group. In contrast, administration of compound 1 (50 mg / kg, qd*6w) significantly slowed the increase in body weight from day 8 to the end of the study compared to the DIO mouse model.

[0290] like Figure 11 and Figure 12 As shown, compared with the normal control group, HFD feeding (DIO model group) significantly increased fasting glucose and fasting insulin levels. Compared with the model group, administration of compound 1 (15 mg / kg and 50 mg / kg) for six weeks significantly reduced fasting plasma glucose and insulin levels in a dose-dependent manner.

[0291] For plasma lipids, such as Figure 13a and Figure 13b As shown, compared with the normal control group, HFD feeding significantly increased the levels of total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL), and low-density lipoprotein cholesterol (LDL) in mouse plasma. Compared with the model group, administration of compound 1 at 15 mg / kg significantly reduced the levels of TC and HDL in plasma, while administration of compound 1 at 50 mg / kg significantly reduced the levels of TC, TG, HDL, and LDL in plasma.

[0292] like Figure 13e As shown, compared with the normal control group, HFD feeding significantly increased plasma malondialdehyde (MDA) levels, while administration of compound 1 at 15 mg / kg and 50 mg / kg significantly reduced plasma MDA levels compared with the model group.

[0293] like Figure 14a and Figure 14b As shown, compared with the model group, HFD feeding significantly increased liver weight and lipid levels in mice. Administration of compound 1 at 50 mg / kg significantly reduced liver weight, liver TC, and TG levels.

[0294] like Figure 15a and Figure 15b As shown, HFD feeding significantly increased plasma ALT and AST levels in mice compared to the normal control group. In contrast, administration of compound 1 at 15 mg / kg and 50 mg / kg significantly reduced plasma ALT and AST levels compared to the model group.

[0295] Liver samples collected from the control group showed normal lobular structure with central veins and radial hepatic cords. HFD feeding induced severe pathological changes, including steatosis, hepatocyte ballooning, and liver inflammation in mice, and significantly increased steatosis, hepatocyte ballooning, inflammation, and NAS scores. Compared with the model group, administration of compound 1 at 15 mg / kg and 50 mg / kg (qd*6w) significantly reduced steatosis, inflammation, and NAS scores, respectively. Figures 16a to 16c Administration of compound 1 at 50 mg / kg significantly reduced hepatocellular ballooning scores. Figure 16d ).

[0296] In summary, compound 1 demonstrates significant improvements in liver health by reducing hepatic fat accumulation, reducing hepatocyte ballooning, exhibiting anti-inflammatory effects, and reversing hepatic steatosis. Compound 1 also shows systemic benefits by reducing circulating lipid levels and improving insulin sensitivity and glucose homeostasis. Study VI. In vivo pharmacological study of compound 1 in C57 BL / 6 wild-type mice. General Solution

[0297] Wild-type C57 BL / 6 mice were randomly assigned to two groups based on body weight (control and compound 1 administered at 30 mg / kg). Compound 1 was administered orally (po) once daily (qd) for six weeks at a dose volume of 10 ml / kg. Mice in the control group were administered the compound via a solvent (5% DMSO + 10% Solutol HS-15 + 85% water). The test formulation was freshly prepared at each administration and thoroughly mixed before use. Muscle endurance in mice was evaluated using a treadmill test. Each mouse was placed in an individual treadmill track. Each track was equipped with a shock grid for delivering foot shocks. Fatigue was defined as when a mouse could not avoid a continuous 5-second shock duration. Running distance (m), total time (s), and shock duration until fatigue were recorded. At the end of the study, animals were euthanized with CO2. All animals were sacrificed and perfused intracardiacly with ice-cold saline. Collect data from the quadriceps, gastrocnemius, tibialis anterior, soleus, and extensor digitorum longus muscles, and measure muscle weight.

[0298] The gastrocnemius muscle was placed directly in OCT compounds and rapidly frozen in isopentane cooled with liquid nitrogen, then stored at -80°C for pathological analysis. Frozen muscle sections were cut into 10 μm thick sections and stained with NADH-TR for analysis of type I (dark) and type II (light) muscle fibers. Type I and type II muscle fibers were measured using the Nuclei Seg (HALO AI) and Nuclei Phenotyper (HALO AI) modules. The type I muscle fiber ratio is expressed as the percentage of type I muscle fibers and all muscle fibers. Proteins and RNA were extracted from the quadriceps muscle for analysis of adenosine monophosphate (AMP)-activated protein kinase (AMPK) and pyruvate dehydrogenase kinase 4 (PDK4). Data are presented as mean ± SEM. Differences between groups were analyzed using Student's t-test and Graphpad Prism. p < 0.05 was considered statistically significant. *p < 0.05, **p < 0.01, ***p < 0.001 compared to the WT control group.

[0299] like Figure 17a and Figure 17b As shown, compared with the control group, administration of compound 1 (30 mg / kg, po, qd) significantly increased running distance and total time in the treadmill test, indicating that compound 1 significantly increased muscle endurance in mice.

[0300] like Figure 18 and Figure 19 As shown, compared with the control group, administration of compound 1 (30 mg / kg, po, qd) increased the total skeletal muscle index and the ratio of type I muscle, indicating that administration of compound 1 increased lean muscle mass and the ratio of type I muscle, thereby leading to improved endurance. Because type I muscle fibers utilize more oxidative metabolism to generate energy, they are generally more fatigue-resistant.

[0301] The results also showed that administration of compound 1 activated AMPK expression and upregulated PDK4 expression. Figure 20 and Figure 21 This is typically associated with increased fat oxidation during prolonged exercise.

[0302] The applicant's disclosure is described herein with reference to the accompanying drawings in preferred embodiments, wherein similar numerals denote the same or similar elements. References to "an embodiment" or "embodiment" or similar language throughout the specification mean that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment of the invention. Therefore, the phrases "in one embodiment," "in an embodiment," and similar language appearing throughout the specification may, but do not necessarily, refer to the same embodiment.

[0303] The features, structures, or characteristics described in the applicant's disclosure can be combined in any suitable manner in one or more embodiments. Numerous specific details are set forth in this description to provide a thorough understanding of embodiments of the invention. However, those skilled in the art will recognize that the applicant's compositions and / or methods can be practiced without one or more specific details, or in conjunction with other methods, components, materials, etc. In other instances, well-known structures, materials, or operations have not been shown or described in detail to avoid obscuring various aspects of this disclosure.

[0304] Although any methods and materials similar to or equivalent to those described and used herein may also be used in the practice or testing of this disclosure, preferred methods and materials are described herein. Except for the specific order disclosed, the methods described herein may be performed in any logically possible order. Reference merging

[0305] This disclosure references and cites other documents, such as patents, patent applications, patent publications, journals, books, papers, and online content. All of these documents are incorporated herein by reference in their entirety for all purposes. Any material or portion thereof that is considered to be incorporated herein by reference but conflicts with existing definitions, statements, or other disclosed material expressly set forth herein is incorporated only to the extent that there is no conflict between the incorporated material and the material of this disclosure. If a conflict exists, it will be resolved in a manner favorable to this disclosure as the preferred disclosure. Principle of Equivalence

[0306] The representative embodiments are intended to aid in illustrating the invention and are not intended to, nor should they be construed as, limiting the scope of the invention. In fact, various modifications to the invention and many further embodiments thereof, in addition to those shown and described herein, will be apparent to those skilled in the art from the entirety of this document, including the embodiments included herein and references in scientific and patent literature. The embodiments contain important additional information, illustrations, and guidance suitable for the practice of the invention in its various embodiments and equivalents.

Claims

1. A compound having structural formula (I) or (II): Or its pharmaceutically acceptable form or isotopic derivative, wherein n is 1, 2, 3 or 4; and R X For R X1 R X2 Or R X3 , where R X1 The radical is selected from the following groups: CH2C(=O)OR 3 CH2C(=O)SR 3 C(=O)NR 4 R 5 OR 6 SR 6 NR 7 R 8 NR 9 C(=O)R 10 OC(=O)R 11 ,SC(=O)R 12 OC(=O)OR 13 ,SC(=O)OR 13 NR 9 C(=O)OR 13 OC(=O)NR 14 R 15 ,SC(=O)NR 14 R 15 NR 9 C(=O)NR 14 R 15 OC(=O)SR 3 ,SC(=O)SR 3 NR 9 C(=O)SR 3 Halogens, CN, H and C 1-6 Alkyl; and R X2 The groups are selected from the following: ； And R X3 The groups are selected from the following: ； And R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 and R 15 Each of them: Independently selected from H and C 1-6 Alkyl, 3- to 8-membered carbocyclic or heterocyclic, optionally surrounded by 1-6 R... A Replace, or R 4 and R 5 R 7 and R 8 、or R 14 and R 15 Together with the N atoms they are bonded to, they form 3- to 8-membered heterocycles, optionally bound by 1-6 R atoms. A replace; Each R A Independently selected from: D, halogen, R, OR, and NRR'; and each of R and R' is independently H or C. 1-6 Alkyl group, optionally surrounded by 1-4 atoms selected from D, halogen, C 1-6 The alkoxy and amino groups are substituted; or R and R' together with the N atom to which they are bonded form 3- to 6-membered heterocycles, optionally substituted with 1-4 groups selected from D, halogen, C. 1-6 Alkyl or alkoxy and amino groups are substituted.

2. The compound according to claim 1, wherein the compound has structural formula (I).

3. The compound according to claim 1, wherein the compound has structural formula (II).

4. The compound according to any one of claims 1 to 3, wherein R X For R X1 .

5. The compound according to claim 4, wherein R X1 CH2C(=O)OR 3 Or OC(=O)R 11 .

6. The compound according to claim 4, wherein R X1 For C(=O)NR 4 R 5 or NR 9 C(=O)R 10 .

7. The compound according to claim 4, wherein R X1 CH2C(=O)SR 3 Or SC(=O)R 12 .

8. The compound according to claim 4, wherein R X1 For OC (=O) OR 13 ,SC(=O)OR 13 NR 9 C(=O)OR 13 OC(=O)NR 14 R 15 , SC(=O)NR 14 R 15 、NR 9 C(=O)NR 14 R 15 、OC(=O)SR 3 、SC(=O)SR 3 或NR 9 C(=O)SR 3 。 9. The compound according to claim 4, wherein R X1 OR 6 or SR 6 .

10. The compound according to claim 4, wherein R X1 For NR 7 R 8 .

11. The compound according to claim 4, wherein R X1 Halogen, CN or C 1-3 alkyl.

12. The compound according to any one of claims 1 to 3, wherein R X For R X2 .

13. The compound according to claim 12, wherein R X2 for: 。 14. The compound according to claim 12, wherein R X2 for: 。 15. The compound according to claim 12, wherein R X2 for: 。 16. The compound according to claim 12, wherein R X2 for: 。 17. The compound according to any one of claims 1 to 3, wherein R X For R X3 .

18. The compound according to any one of claims 1 to 17, wherein each of R and R', if present, is independently H or C. 1-3 alkyl.

19. A compound having structural formula (III) or (IV): ； Or a pharmaceutically acceptable form or isotopic derivative thereof, wherein n is 1, 2, 3 or 4; Y is selected from single bond, NR, S, CRR', and O; R Y It is selected from the following groups: H, halogen, CN, R, C(=O)OR, C(=O)NRR', C(=O)R and C(=O)SR; And each of R and R' is independently H or C. 1-6 Alkyl groups, or R and R', together with the N atoms to which they are bonded, form 3- to 6-membered heterocycles, wherein the alkyl group or heterocycle is optionally surrounded by 1-4 atoms selected from D, halogen, C. 1-6 Alkyl or alkoxy and amino groups are substituted.

20. The compound according to claim 19, wherein the compound has structural formula (III).

21. The compound according to claim 19, wherein the compound has structural formula (IV).

22. The compound according to any one of claims 19 to 21, wherein Y is O.

23. The compound according to claim 22, wherein R Y Selected from R, C(=O)OR, C(=O)NRR', C(=O)R and C(=O)SR.

24. The compound according to any one of claims 19 to 21, wherein Y is S.

25. The compound according to claim 24, wherein R Y Selected from R, C(=O)OR, C(=O)NRR', C(=O)R and C(=O)SR.

26. The compound according to any one of claims 19 to 21, wherein Y is NR.

27. The compound according to claim 26, wherein R Y Selected from R, C(=O)OR, C(=O)NRR', C(=O)R and C(=O)SR.

28. The compound according to any one of claims 19 to 21, wherein Y is CH2.

29. The compound according to claim 28, wherein R Y Selected from halogens, CN, R, C(=O)OR, C(=O)NRR', C(=O)R and C(=O)SR.

30. The compound according to any one of claims 19 to 21, wherein Y is a single bond.

31. A compound selected from Table 1A.

32. A compound selected from Table 1B.

33. A coupling compound formed from the compound according to any one of claims 1 to 31 and a bioactive portion characterized by anti-ROS and / or anti-inflammatory activity.

34. The coupling compound according to claim 33, wherein the bioactive moiety is selected from: 。 35. The compound according to any one of claims 1 to 34, wherein the compound has one or more deuterium atoms in place of one or more hydrogen atoms.

36. The compound according to claim 35, wherein the compound has a deuterium atom in place of a hydrogen atom.

37. A pharmaceutical composition comprising a compound according to any one of claims 1 to 36.

38. A unit dosage form comprising the pharmaceutical composition according to claim 37.

39. The unit dosage form according to claim 38, wherein the unit dosage form is a tablet.

40. The unit dosage form according to claim 38, wherein the unit dosage form is a capsule.

41. A method of treating or alleviating a disease or symptom, the method comprising administering to a subject in need a therapeutically effective amount of the compound according to any one of claims 1 to 36.

42. The method of claim 41, wherein the disease or condition is related to the mitochondrial function of the subject.

43. The method of claim 41, wherein the disease or condition is related to one or more mitochondrial functional defects.

44. The method of claim 41, wherein the disease or condition is a metabolic disease, a neurodegenerative disease, an age-related disease, a liver disease, a cardiovascular disease, or a related disease or condition.

45. The method of claim 41, wherein the disease or condition is obesity, excessive body fat, diabetes, insulin resistance or intolerance, hypertension, dyslipidemia, heart failure or renal failure, atherosclerosis, hypertriglyceridemia, acquired lipodystrophy, hereditary lipodystrophy, partial lipodystrophy, metabolic syndrome, Rett syndrome, age-related metabolic syndrome, metabolic disease associated with increased reactive oxygen species (ROS), Friedreich ataxia, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) or related diseases or conditions.

46. ​​A method for reducing toxicity or side effects in the treatment of mitochondrial-related diseases or conditions, the method comprising administering to a subject in need a therapeutically effective amount of the compound according to any one of claims 1 to 36.

47. The method according to any one of claims 41 to 46, wherein the administration is by oral administration.

48. Use of the compound according to any one of claims 1 to 36 and a pharmaceutically acceptable excipient, carrier or diluent in the preparation of a medicament for treating a disease or condition.

49. Use of the compound according to any one of claims 1 to 36 for treating diseases or conditions.

50. The use according to claim 48 or 49, wherein the disease or condition is related to one or more mitochondrial functional defects.

51. The use according to claim 48 or 49, wherein the disease or condition is a metabolic disease, a neurodegenerative disease, an age-related disease, a liver disease, a cardiovascular disease, or a related disease or condition.

52. The use according to claim 48 or 49, wherein the disease or condition is selected from obesity, excessive body fat, diabetes, insulin resistance or intolerance, hypertension, dyslipidemia, heart failure or renal failure, atherosclerosis, hypertriglyceridemia, acquired lipodystrophy, hereditary lipodystrophy, partial lipodystrophy, metabolic syndrome, Rett syndrome, age-related metabolic syndrome, metabolic diseases associated with increased reactive oxygen species (ROS), Friedreich ataxia, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), or related diseases or conditions.

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