Derivatives and prodrugs of 2,4-dinitrophenol, as well as compositions and methods thereof.

Abstract

The present invention provides novel 2,4-dinitrophenol (DNP) derivatives and their prodrugs as modulators of mitochondrial function. The invention also provides pharmaceutical compositions comprising the compounds of the present invention, and methods thereof, for the treatment of various diseases and disorders related to or associated with mitochondrial dysfunction (e.g., obesity, diabetes, insulin resistance, liver disease, heart failure or renal failure, neurodegenerative diseases, or age-related diseases).

Description

[Technical Field]

[0001] Priority claims and related patent applications This application claims priority to China Application No. 202311013356.4 filed on 10 August 2023, U.S. Provisional Application No. 63 / 532,665 filed on 14 August 2023, and U.S. Provisional Application No. 63 / 536,051 filed on 31 August 2023, the entire contents of each application incorporated herein by reference. [Background technology]

[0002] The present invention generally relates to novel compounds and their therapeutic applications. More specifically, the present invention provides novel 2,4-dinitrophenol (DNP) derivatives and their prodrugs as modulators of mitochondrial activity. The present invention also provides pharmaceutical compositions comprising the compounds of the present invention, as well as methods for treating various diseases and disorders associated with or related to mitochondrial or mitochondrial dysfunction (e.g., obesity, diabetes, insulin resistance, liver disease, heart failure or renal failure, neurodegenerative diseases or age-related diseases).

[0003] Metabolic syndrome, exemplified by type 2 diabetes, obesity, dyslipidemia, hypertension, metabolic-associated fatty liver disease (MAFLD), and metabolic-associated steatohepatitis (MASH), is a group of diseases and disorders characterized by insulin resistance in the liver and periphery. (Fabbrini et al. 2009 PNAS 106,15430; Petersen et al. 2018 Physiology Reviews 98,2133.) The main causes of these conditions are excessive lipid accumulation in various organs and chronic inflammation due to excessive reactive oxygen species (ROS) production. Over the past decade, drug discovery efforts aimed at reducing energy intake (e.g., Glp-1R agonists, SGLT2 inhibitors) have made remarkable progress, but progress in exploring energy consumption has not been satisfactory.

[0004] Mitochondrial uncoupling is an endogenous energy dissipation process in which ATP synthesis is dissociated by "proton leak" at the end of the electron transport chain. It occurs in all eukaryotic cells and accounts for 20-30% of the basal metabolic rate depending on the tissue type (Geisler 2019 Cells 8,280). Over the years, many chemical uncoupling agents have been discovered and studied in addition to endogenous uncoupling proteins such as UCP-1, UCP-2, and UCP-3, with DNP being the best known among them. (Chen et al. 2021 Metabolism Clinical and Experimental 117,154724; Goedeke et al. 2021 Molecular Metabolism 46,101178.) DNP was used in the 1930s for weight loss purposes in over 100,000 people, but its use was restricted due to dose-dependent toxicity such as rash, cataracts, or hyperthermia-related death, and it was ultimately banned by the FDA in 1938. Since then, efforts have been made to explore various approaches to expand the therapeutic range of DNP. Examples of such efforts include liver-targeted approaches, sustained-release formulations of DNP, and C compared to DNP itself. max Examples include prodrugs that significantly reduce the AUC ratio. (Perry et al. 2013 Cell Metabolism 18,740; Perry et al. 2015 Science 347,1253); International Publication No. 2018 / 129258).

[0005] In addition to its usefulness in anti-obesity through increased energy expenditure via lipid and / or glucose metabolism, DNP-mediated mitochondrial uncoupling has also been shown to reduce excessive ROS production and brain-derived neurotrophic factor (BDNF) induction, which may be beneficial for many neurodegenerative or age-related diseases. (Kishimoto et al. 2020 Neurobiology of Aging 85,123.)

[0006] There is an urgent need for novel mitochondrial uncouplers that regulate mitochondrial function, particularly those useful in treating metabolic syndrome, neurodegenerative diseases, or age-related diseases and disorders.

Summary of the Invention

[0007] The present invention is based in part on novel DNP derivatives and prodrugs, pharmaceutical compositions thereof, and methods of preparation and use thereof as mitochondrial uncoupling agents in the treatment or alleviation of various diseases or disorders. More specifically, the present invention provides novel compounds that act as prodrugs of DNP and pharmaceutically acceptable salts thereof. Upon oral administration, these compounds release DNP with a significantly reduced C max / AUC ratio compared to DNP itself, resulting in an expanded safety margin. The compounds of the present invention are useful for regulating mitochondrial function and activity, including promoting the metabolism of glucose and lipids. Accordingly, the compounds of the present invention can be used in the treatment of metabolic diseases such as type 2 diabetes, hypertriglyceridemia, NAFLD, NASH, obesity, and other neurodegenerative diseases.

[0008] In one aspect, the present invention generally relates to a compound having the structural formula (I)

[0009]

Chemical formula

[0010] In another embodiment, the present invention generally relates to pharmaceutical compositions comprising compounds disclosed herein.

[0011] In yet another embodiment, the present invention generally relates to unit dosage forms comprising pharmaceutical compositions of the compounds disclosed herein.

[0012] In yet another embodiment, the present invention relates to a method for treating or alleviating a disease or disorder, comprising administering a therapeutically effective amount of one of the compounds disclosed herein to a subject in need thereof.

[0013] In yet another embodiment, the present invention relates to a method for reducing toxicity or side effects in the treatment of mitochondrial disorders or conditions, which generally involves administering a therapeutically effective amount of the compounds disclosed herein to a subject in need thereof.

[0014] In yet another embodiment, the present invention relates to the use of the compounds disclosed herein and pharmaceutically acceptable excipients, carriers, or diluents in the preparation of pharmaceuticals for the treatment of diseases or disorders.

[0015] In yet another embodiment, the present invention relates to the use of the compounds disclosed herein for the treatment of a disease or disorder. [Brief explanation of the drawing]

[0016] [Figure 1] Exemplary data of mean plasma concentrations of 2,4-DNP after intravenous administration of 1 mg / kg and oral administration of 5 mg / kg in male C57BL / 6 mice (N=3 in each group). [Figure 2] Exemplary data of mean plasma concentrations of compound 1 and its metabolite 2,4-DNP after intravenous administration (1 mg / kg) and oral administration (5 mg / kg) in male C57BL / 6 mice (N=3 in each group). [Figure 3] Exemplary data of mean plasma concentrations of compound 7 and its metabolite 2,4-DNP after intravenous administration (1 mg / kg) and oral administration (5 mg / kg) in male C57BL / 6 mice (N=3 in each group). [Figure 4] Exemplary data of mean plasma concentrations of 2,4-DNP after intravenous administration (1 mg / kg) or oral administration (5 mg / kg) in male SD rats (N=3 in each group). [Figure 5] Exemplary data of mean plasma concentrations of 1 and its metabolite 2,4-DNP after intravenous administration (1 mg / kg) or oral administration (5 mg / kg) in male SD rats (N=3 in each group). [Figure 6] Exemplary data of mean plasma concentrations of 7 and its metabolite 2,4-DNP after intravenous administration (1 mg / kg) or oral administration (5 mg / kg) in male SD rats (N=3 in each group). [Figure 7] Exemplary data of mean plasma concentrations of 7 and its metabolite 2,4-DNP after intravenous administration (1 mg / kg) or oral administration (5 mg / kg) in male beagle dogs (N=3 in each group). [Figure 8] Exemplary data of rectal temperature in SD rats after a single oral administration of 2,4-DNP. [Figure 9] Exemplary data of the acute survival curve in SD rats after a single oral administration of 2,4-DNP. [Figure 10] Exemplary data of rectal temperature in SD rats after a single oral administration of 2,4-DNP or compound 1, respectively. [Figure 11] Exemplary data of seconds to fall from a rotor rod in C57BL / 6J mice before treatment with 6-OHDA injection and compound 7. Data are shown mean ± SEM and analyzed by one-way ANOVA (n=10). [Figure 12]Exemplary data of seconds to fall from the rotarrod at 5 weeks after treatment with 6-OHDA injection and compound 7. Data are shown mean ± SEM and analyzed by one-way ANOVA (n=10). *p<0.05, ***p<0.001, ****p<0.0001 (comparison with model) [Figure 13] Exemplary data of maximum gripping force at 5 weeks after treatment with 6-OHDA injection and compound 7. Data are shown mean ± SEM and analyzed by one-way ANOVA (n=10). *p<0.05, ***p<0.001, ****p<0.0001 (compared to model). [Figure 14] Exemplary data of TH+ cell counts in SNs at 5 weeks after treatment with 6-OHDA injection and compound 7. Data are shown mean ± SEM and analyzed by one-way ANOVA (n=4). *p<0.05, ***p<0.001, ****p<0.0001 (compared to model). [Figure 15] Exemplary data of TH+ fiber density in Str at 5 weeks after treatment with 6-OHDA injection and compound 7. Data are shown mean ± SEM and analyzed by one-way ANOVA (n=4). *p<0.05, ***p<0.001, ****p<0.0001 (compared to model). [Modes for carrying out the invention]

[0017] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this invention pertains. The general principles of organic chemistry, as well as specific functional groups and reactivity, are described in "Organic Chemistry" (by Thomas Sorrell, University Science Books, Sausalito: 2006).

[0018] The following terms shall be interpreted as having the following meanings unless otherwise indicated in the context.

[0019] The ranges provided herein are understood to be a simplified representation of all values ​​within that range. For example, the range from 1 to 16 is understood to include any number, combination of numbers, or subrange from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

[0020] Any composition or method disclosed herein may be combined with one or more other compositions and methods provided herein.

[0021] Any description of a variable in this specification that lists chemical groups includes defining the variable as any single group or as a combination of the listed groups. Any description of an embodiment of a variable or aspect in this specification includes defining the embodiment as any single embodiment or in combination with other embodiments or parts thereof.

[0022] Definitions of specific functional groups and chemical terms are explained in more detail below. Where a range of values ​​is given, it is intended to include each value and subrange within that range. For example, "C 1-6 "Alkyl" refers to 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 It is intended to include alkyl groups.

[0023] When substituents are specified in a conventional chemical formula written from left to right, they similarly encompass chemically identical substituents that would result if the structure were written from right to left. For example, -C(=O)-O- is equivalent to -OC(=O)-.

[0024] 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, where a group may be substituted with one or more substituents, such substitutions are selected such that the compound conforms to the principles of chemical bonding, is not inherently unstable, and / or is known to those skilled in the art to be likely unstable under ambient conditions (e.g., aqueous, neutral, and some known physiological conditions).

[0025] In this specification and the appended claims, the singular forms "a," "an," and "the" are used with the plural form unless the context clearly indicates otherwise.

[0026] In this specification, "at least" a specific value means that value and all values ​​greater than it.

[0027] In this specification, the terms “comprise,” “comprising,” or “having” used to define compositions and methods mean that those compositions and methods include the elements described but do not exclude other elements. The term “consisting essentially of” used to define compositions and methods means that those compositions and methods include the elements described but exclude other elements that are essentially important to those compositions and methods. For example, “consisting essentially of” means the administration of an explicitly described pharmaceutically active agent and excludes pharmaceutically active agents that are not explicitly described. The term “consisting essentially of” does not exclude pharmaceutically inactive or inert agents, such as pharmaceutically acceptable excipients, carriers, or diluents. The term “consisting of” used to define compositions and methods means the exclusion of trace elements of other components and substantial method steps. Embodiments defined by each of these transition terms are within the scope of the present invention.

[0028] In this specification, the terms “disease” and “disorder” are used interchangeably and refer to any condition that impairs or disrupts the normal function of a cell, tissue, or organ.

[0029] In this specification, the term "hydrate" means a compound further containing a stoichiometric or nonstoichiometric amount of water, bound together by non-covalent intermolecular forces.

[0030] In this specification, the term “pharmaceutically acceptable” means that a compound is suitable for use in contact with human and other mammalian tissues without causing excessive toxicity, irritation, allergic reactions, etc., and that it is commensurate with a reasonable benefit / risk ratio. “pharmaceutically acceptable forms” of the disclosed compounds include, but are not limited to, pharmaceutically acceptable salts, esters, hydrates, solvates, polymorphs, isomers, and their isotopically labeled derivatives.

[0031] In certain embodiments, “pharmaceutically acceptable forms” include, but are not limited to, pharmaceutically acceptable salts, esters, and their isotopically labeled derivatives.

[0032] In certain embodiments, “pharmaceutically acceptable forms” include, but are not limited to, pharmaceutically acceptable isomers, stereoisomers, and their isotope-labeled derivatives.

[0033] In this specification, the term “pharmaceutically acceptable salt” refers to a salt that, within the bounds of sound medical judgment, is suitable for use in contact with the target tissue without causing excessive toxicity, irritation, or allergic reactions, and that is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds provided herein include salts arising from appropriate inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts include salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, and malonic acid, or by methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipine, alginate, ascorbate, aspartate, benzenesulfonate, besilate, benzoate, bisulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, Examples include glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.In some embodiments, 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, and salicylic acid.

[0034] Salts can be prepared in situ during the separation and purification of the disclosed compounds, or they can be prepared separately by reacting the free base or free acid of the parent compound with a suitable base or acid, respectively. Pharmacochemically acceptable salts obtained from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N + (C 1-4 Alkyl) 4 salts are included. Typical alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Furthermore, pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfons, and aryl sulfons, as needed. Organic bases from which salts can be obtained include primary amines such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine, as well as secondary, tertiary, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins. In some embodiments, pharmaceutically acceptable base addition salts can be selected from ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

[0035] In certain embodiments, a pharmaceutically acceptable form is a “solvate” (e.g., a hydrate). As used herein, the term “solvate” refers to a compound further comprising a stoichiometric or non-stoichiometric amount of solvent, bound by non-covalent intermolecular forces. A solvate may be a disclosed compound or a pharmaceutically acceptable salt thereof. If the solvent is water, the solvate is a “hydrate.” Pharmaceutically acceptable solvates and hydrates are complexes that may contain, for example, 1 to about 100, or 1 to about 10, or 1 to about 2, about 3, or about 4 solvent or water molecules. As used herein, the term “compound” will be understood to include a compound and its solvates, as well as mixtures thereof.

[0036] As used herein, the term “prodrug” (or “pro-drug”) refers to a compound that is converted in vivo to produce the disclosed compound or a pharmaceutically acceptable form thereof. A prodrug is inactive at the time of administration to a subject but is converted in vivo to an active compound by, for example, hydrolysis (such as hydrolysis in the blood). In some cases, a prodrug has improved physical and / or delivery properties compared to the parent compound. A prodrug can improve the bioavailability of a compound at the time of administration to a subject (e.g., enabling enhanced absorption into the blood after oral administration) or can accelerate delivery to a target biological site (e.g., the brain or lymphatic system) compared to the parent compound. Examples of prodrugs include derivatives of the disclosed compound that exhibit improved water solubility or active transport through the intestinal membrane compared to the parent compound.

[0037] 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, that is involved in transporting or delivering the pharmaceutical product in question from one organ or part of the body to another. Each carrier must be “acceptable” in the sense that it is compatible with the other components of the formulation and is not harmful to the patient. Examples of materials that can function 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 carboxymethylcellulose, ethylcellulose, and cellulose acetate); tragacanth powder; malt; gelatin; talc; excipients (such as cocoa butter and suppository wax); oils and fats (such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil); glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; buffers such as agar, magnesium hydroxide, and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer; and other non-toxic suitable substances used in pharmaceutical formulations. The composition may also include wetting agents, emulsifiers, lubricants (such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polypropylene oxide copolymer), as well as colorants, release agents, coating agents, sweeteners, flavorings, preservatives, and antioxidants.

[0038] As used herein, the term “polymorph” refers to the solid crystalline form of a compound or a complex of compounds, characterized by physical means such as X-ray powder diffraction patterns or infrared spectroscopy. Different polymorphs of the same compound may 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 may affect bioavailability). Differences in stability may result from changes in chemical reactivity (e.g., different oxidation may cause a dosage form composed of one polymorph to discolor more rapidly than one composed of another), changes in mechanical properties (e.g., a kinetically dominant polymorph transforms into a thermodynamically more stable polymorph, causing the tablet to disintegrate during storage), or both (e.g., a tablet of a certain polymorph may disintegrate under high humidity). Differences in the physical properties of polymorphs may affect their processing. For example, one polymorph may be more likely to form solvates or more difficult to filter or wash away impurities from than another polymorph, depending on its particle shape and size distribution.

[0039] As used herein, the term “solvate” means a compound further comprising stoichiometric or nonstoichiometric amounts of a solvent, such as water, acetone, ethanol, methanol, dichloromethane, or 2-propanol, and bonded by non-covalent intermolecular forces.

[0040] As used herein, the term “stable compound” means a compound that possesses sufficient stability to enable manufacturing and maintains its integrity for a sufficient period of time to be useful for the purposes described herein (e.g., formulation into therapeutic products, intermediates used in the manufacture of therapeutic compounds, isolateable or storable intermediate compounds, treatment of diseases or disorders that respond to therapeutic agents).

[0041] As used herein, the term “stereoisomer” refers to both enantiomers and diastereomers. As used herein, the term “substantially free of other stereoisomers” means that other stereoisomers are present in less than 25%, preferably less than 10%, more preferably less than 5%, most preferably less than 2%, or less than “X”% (where X is a number from 0 to 100) of other stereoisomers. Methods for obtaining or synthesizing diastereomers are well known in the art and are applicable so as to be rung for the final compound, starting material, or intermediate. Other embodiments include those in which the compound is an isolated compound. As used herein, the term “enantiomer-rich by at least X%” means that at least X% of the compound is in a single enantiomer form, where X is a number from 0 to 100 (inclusive).

[0042] As used herein, the terms “treat” or “alleviate” a disease or disorder refer to a method of reducing, delaying, or improving such a condition before or after the onset of the disease or disorder. Treatment may target one or more effects or symptoms of the disease and / or the underlying pathological condition. Treatment is any alleviation, including, but not limited to, the complete elimination of the disease or its symptoms. Thus, treating or curing means any sign of success in treating or improving an injury, disease, pathological condition or state, which includes objective or subjective parameters such as reduction, remission, reduction of symptoms, or making the injury, pathological condition or state more tolerable to the patient, slowing the rate of degeneration or decline, reducing debilitation in the final stages of degeneration, 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 a physical examination, neuropsychiatric examination, and / or psychiatric evaluation. Compared to an equivalent untreated control group, the degree of reduction or improvement, when measured by standard methods, may be at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, or 100%.

[0043] As used herein, the term “subject” refers to an animal (e.g., a mammal) that is a recipient of a particular treatment, and includes, but is not limited to, humans, non-human primates, rodents, etc. Generally, when referring to a human subject, the terms “subject” and “patient” are used interchangeably herein.

[0044] As used herein, the terms “alkyl (alk)” or “alkyl (alkyl)” refer to a linear, branched, or cyclic hydrocarbon group having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, and that is not unsaturated. The expression “lower alkyl” refers to an alkyl group having 1 to 4 carbon atoms (including both ends). Where a numerical range such as “1 to 10” is mentioned herein, it refers to each integer within the given range. For example, “1 to 10 carbon atoms” means that the alkyl group may have up to 10 carbon atoms, such as 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., but the term “alkyl” is also included in this definition when no numerical range is specified. In some embodiments, “alkyl” means C 1-6 It may be an alkyl group. In some embodiments, "alkyl" is C 1-3 It may be an alkyl group.

[0045] As used herein, the term "alkoxy" refers to an -O-alkyl group.

[0046] As used herein, the terms “carbocycle,” “carbocyclic,” and “carbocyclyl” refer to monocyclic or polycyclic groups containing only carbon as the cyclic atom, which may be saturated or partially unsaturated. Fully saturated carbocycles are called cycloalkyls. Partially unsaturated cycloalkyl groups are called “cycloalkenyls” if the carbocycle contains at least one double bond, and “cycloalkynyls” if the carbocycle contains at least one triple bond. Unless otherwise specified in the specification, these terms are intended to include both substituted and unsubstituted carbocycle groups. The term “carbocycle” also includes bridging structures and spirofusion cyclic structures that do not contain heterocyclic atoms. These terms also include monocyclic or fusion polycyclic (i.e., rings that share pairs of adjacent ring atoms) groups. Polycyclic groups include dicyclic, tricyclic, tetracyclic, and so on. Unless otherwise specified in the specification, carbocycle groups may be optionally substituted with one or more substituents.

[0047] As used herein, the term "cycloalkyl" refers to a cyclic alkyl group, including saturated and partially unsaturated cyclic hydrocarbon groups, each having 3 to 12 carbon atoms, preferably 3 to 8 carbon atoms.

[0048] As used herein, the terms “aromatic” or “aryl” refer to a group of 6 to 14 cyclic atoms (e.g., C) having at least one ring (e.g., phenyl, fluorenyl, naphthyl, and anthracene) having a conjugated π-electron system that is carbocyclic. 6-14 Aromatic or C 6-14 This refers to a group containing an aryl group. The aryl group may be, for example, a 6-membered monocyclic ring, a 10-membered dicyclic ring, or a 14-membered tricyclic ring, each ring having 6 to 14 carbon atoms.

[0049] As used herein, the terms "halo" or "halogen" refer to any of the following groups: fluorine, chlorine, bromine, or iodine.

[0050] As used herein, the terms “heteroaryl” or “heteroaromatic” refer to a monocyclic or polycyclic (e.g., dicyclic, tricyclic, tetracyclic, etc.) aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic arrangement) having a cyclic carbon atom and 1 to 6 cyclic heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur (“5-18 membered heteroaryl”). A heteroaryl polycyclic ring system may contain one or more heteroatoms in one or both rings. Where a numerical range such as “5-18” is mentioned herein, it refers to each integer within that range. For example, “5-18 cyclic atoms” means that the heteroaryl group contains up to 18 cyclic atoms, such as 5 cyclic atoms, 6 cyclic atoms, etc. In some cases, a heteroaryl may have 5 to 14 cyclic atoms. In some embodiments, heteroaryl groups have a divalent group derived from a monovalent heteroaryl group whose name ends in "-yl" by, for example, removing one hydrogen atom from an atom with free valence, and are named by adding "-ene" to the name of the corresponding monovalent group, for example. A pyridyl group having two bonding sites is pyridylene. The term "heteroaryl" refers to a monocyclic or fused ring (i.e., a ring sharing adjacent pairs of atoms) group consisting of 5 to 12 cyclic atoms, including, for example, 1, 2, 3, or 4 cyclic heteroatoms selected from N, O, or S, the remaining cyclic atoms being carbon and further having a fully conjugated π-electron system, and 0, 1, 2, 3, or 4 atoms in each ring may be substituted with substituents. Examples of heteroaryl groups include, but are not limited to, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, quinazoline, isoquinoline, purine, and carbazole.

[0051] As used herein, the terms "heterocycle", "heterocyclic", or "heterocyclyl" refer to a cyclic group that is fully saturated or partially unsaturated, for example, a monocyclic ring system of 3 to 7 members, a bicyclic ring system of 7 to 12 members, or a tricyclic ring system of 10 to 15 members having at least one heteroatom in at least one ring, where 0, 1, 2, or 3 atoms of each ring may be substituted with substituents. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3, or 4 heteroatoms selected from nitrogen atoms, oxygen atoms, and / or sulfur atoms, and the nitrogen heteroatoms and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatoms may optionally be quaternized. The heterocyclic group may be bonded to any heteroatom or carbon atom of the ring or ring system.

[0052] As used herein, the term "substituent" refers to a group "substituted" on any atom of any functional group described herein, for example, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, an aryl group, a heterocyclic group, or a heteroaryl group. Suitable substituents include halogen, CN, NO2, OR 15 , SR 15 , S(O)2OR 15 , NR 15 R 16 , C1-C2 perfluoroalkyl, C1-C2 perfluoroalkoxy, 1,2-methylenedioxy, C(O)OR 15 , C(O)NR 15 [[ID=十八]]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<000008%>)NR 15 R 16 , S(O)2NR 15 [[ID=四十六]]R 16 , R 17 , C(O)R17 and NR 15 C(O)R 17 and S(O)R 17 and S(O)₂R 17 and R 16 and oxo, C(O)R 16 and C(O)(CH₂)ₙOH, (CH₂)ₙOR 15 and (CH₂)ₙC(O)NR 15 R 16 and NR 15 and S(O)₂R 17 are included, but are not limited thereto, where n is independently any of 0 to 6 (including both ends). Each R 15 is independently hydrogen, C₁-C₄ alkyl, or C₃-C₆ cycloalkyl. Each R 16 is independently hydrogen, alkenyl, alkynyl, C₃-C₆ cycloalkyl, aryl, heterocyclyl, heteroaryl, C₁-C₄ alkyl, or C₁-C₄ alkyl, aryl, heterocyclyl, or heteroaryl substituted with C₃-C₆ cycloalkyl. Each R 17 is independently C₃-C₆ cycloalkyl, aryl, heterocyclyl, heteroaryl, C₁-C₄ alkyl, or C₁-C₄ alkyl, aryl, heterocyclyl, or heteroaryl substituted with C₃-C₆ cycloalkyl. Each R 15 and R 16 and R 17 in C₃-C₆ cycloalkyl, aryl, heterocyclyl, heteroaryl, and C₁-C₄ alkyl can each be substituted with 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.

[0053] In the definition of variables herein, the listing of chemical groups includes defining the variable as a single group or as a combination of the listed groups. In the description of embodiments of variables herein, the embodiment includes describing the embodiment as a single embodiment or in combination with other embodiments or parts thereof.

[0054] The compounds of the present invention may contain one or more chiral centers and therefore exist as racemates and racemic mixtures, single enantiomers, individual diastereomers, and diastereomer mixtures. All such isomeric forms of these compounds are explicitly included in the present invention. The compounds of the present invention may also be represented in multiple tautomer forms, in which case the present invention explicitly includes all tautomer forms of the compounds described herein. All isomeric forms of these compounds are explicitly included in the present invention. All crystalline forms of the compounds described herein are explicitly included in the present invention.

[0055] Detailed description of the invention The present invention provides novel DNP derivatives and their prodrugs as regulators of mitochondrial activity. The present invention also provides pharmaceutical compositions comprising the compounds of the present invention and methods thereof for treating various diseases and disorders related to or associated with mitochondrial dysfunction (e.g., obesity, diabetes, insulin resistance, liver disease, heart failure or renal failure, neurodegenerative diseases, or age-related diseases).

[0056] In one embodiment, the present invention generally relates to structural formula (I)

[0057] [ka] This relates to compounds having or pharmaceutically acceptable forms or isotopic derivatives thereof, R 1 and R 2 Each of them is independently C 1-6 Alkyl or R 1 and R2 Together with the carbon atoms to which they are bonded, they form a 3- to 8-membered ring (e.g., a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring) carbon ring or heteroring, C 1-6 Alkyl groups and 3- to 8-membered carbocyclic or heterocyclic rings optionally contain 1 to 6 R A Replaced by, R X , LR X1 , LR X2 or LR X3 And, L is a single bond or (CH2)n, and n is 1, 2, or 3. R X1 C(=O)OR 3 , C(=O)NR 4 R 5 , OR 6 , NR 7 R 8 , NR 9 C(=O)R 10 ,OC(=O)R 11 A group selected from halo and CN, R X2 This involves selecting 1 to 4 R's arbitrarily. B A monocyclic carbon ring, heterocycle, aryl group, or heteroaryl group of a 5-membered or 6-membered ring that is substituted with, R X3 This is an optional selection of 1 to 6 R B A bicyclic carbon ring, heterocycle, aryl group, or heteroaryl group of 8 to 10 members that is substituted with, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 Each of them is, H, C 1-6 Alkyl, optionally 1 to 6 R A Independently selected from 3- to 8-membered carbon rings or heterocycles that are substituted by, R 4 and R 5 , or R 7and R 8 Each of them, along with the N atom to which they are bonded, optionally contains 1 to 6 R atoms. A It forms a 3- to 8-membered heterocycle by substitution, Each R A Each is independently selected from the group consisting of D, Halo, R, and OR. R B Each is independently selected from the group consisting of D, Halo, CN, R, OR, NRR', C(=O)OR, C(=O)NRR', NRC(=O)R', OC(=O)R, SO4R, and OC(=O)CHCHC(=O)OR', Each R and R' is independently H or C 1-3 It is an alkyl group.

[0058] In a specific embodiment of (I), the compound exhibits the following chirality:

[0059] [ka]

[0060] In a specific embodiment of (I), the compound exhibits the following chirality:

[0061] [ka]

[0062] In a particular embodiment, R 1 and R 2 Each of them is independent of C 1-3 Alkyl groups (e.g., methyl group, ethyl group, propyl group, isopropyl group) that are either unsubstituted or substituted (e.g., substituted with D, F, Cl, or CH3).

[0063] In a particular embodiment, R 1 and R 2 These are each methyl groups.

[0064] In a particular embodiment, R 1 and R 2 These, together with the carbon atoms to which they are bonded, form a 3- to 6-membered ring (e.g., a 3-membered ring, a 4-membered ring, a 5-membered ring, or a 6-membered ring) of carbon rings. In certain embodiments, R 1 and R 2 These, along with the carbon atoms to which they are bonded, form a cyclopropyl group.

[0065] In a particular embodiment, R 1 and R 2 These, together with the carbon atoms to which they are bonded, form heterocycles of 3 to 6 members (e.g., 3-membered, 4-membered, 5-membered, and 6-membered rings), and these heterocycles have 1, 2, or 3 heteroatoms selected from N, O, and S.

[0066] In a particular embodiment of (I), R X , LR X1 That is the case.

[0067] In a particular embodiment, R X1 C(=O)OR 3 That is the case.

[0068] In a particular embodiment, R 3 H, C 1-3 Alkyl groups (e.g., methyl group, ethyl group, propyl group, isopropyl group) that are either unsubstituted or substituted (e.g., substituted with D, F, Cl, CH3, OH, or OCH3).

[0069] In a particular embodiment, R X1 C(=O)NR 4 R 5 That is the case.

[0070] In a particular embodiment, R 4 , R 5 H, C 1-3Alkyl groups (e.g., methyl group, ethyl group, propyl group, isopropyl group) are independently selected from those that are unsubstituted or substituted (e.g., substituted with D, F, Cl, CH3, OH, or OCH3).

[0071] In a particular embodiment, R 4 and R 5 These, together with the N atoms to which they are bonded, form heterocycles of 3 to 6 members (e.g., 3-membered, 4-membered, 5-membered, and 6-membered rings). In certain embodiments, R 4 and R 5 These, together with the N atom to which they are bonded, form an azetidine group or a morpholinyl group.

[0072] In a particular embodiment of (I), R X , LR X2 That is the case.

[0073] In a particular embodiment, R X2 It is a 5-membered ring heteroaryl group, with 1 to 4 R B It may be replaced with. In certain embodiments, R X2 This is an oxadiazolyl group.

[0074] In a particular embodiment, R X2 This is a 6-membered ring aryl group or heteroaryl group, with 1 to 4 R B It may be replaced with .

[0075] In a particular embodiment of (I), R X , LR X3 That is the case.

[0076] In a particular embodiment, R X3 This is a 9-membered ring bicyclic aryl group or heteroaryl group, with 1 to 6 R B It may be replaced with. In certain embodiments, R X3 This is a benzimidazolyl group.

[0077] In a particular embodiment, R X3 This is a 10-membered ring bicyclic aryl group or heteroaryl group, with 1 to 6 R B It may be replaced with .

[0078] In a particular embodiment of (I), L is a single bond.

[0079] In a particular embodiment of (I), L is (CH2)n, where n is 1, 2, or 3. In a particular embodiment of (I), n is 1 and L is CH2.

[0080] In a particular embodiment, the compound is selected from Table 1.

[0081] The compounds of the present invention include compounds having one or more deuterium atoms instead of one or more hydrogen atoms.

[0082] In another embodiment, the present invention generally relates to pharmaceutical compositions comprising the compounds disclosed herein.

[0083] In yet another embodiment, the present invention generally relates to unit dosage forms comprising pharmaceutical compositions of the compounds disclosed herein.

[0084] In certain embodiments, the unit dosage form is a tablet.

[0085] In certain embodiments, the unit dosage form is a capsule.

[0086] In yet another embodiment, the present invention generally relates to a method for treating or alleviating a disease or disorder, which includes administering a therapeutically effective amount of one of the compounds disclosed herein to a subject in need of treatment or alleviation.

[0087] In certain embodiments, the disease or disorder is related to the mitochondrial function of the subject.

[0088] In certain embodiments, the disease or disorder is associated with one or more defects in the mitochondrial function of the subject.

[0089] In certain embodiments, the disease or disorder is selected from metabolic diseases, liver diseases, cardiovascular diseases, or related diseases or disorders.

[0090] In certain embodiments, the disease or disorder is obesity, excess body fat, diabetes mellitus, 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 disorders associated with increased reactive oxygen species (ROS), Friedreich's ataxia, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), or related diseases or disorders.

[0091] In yet another embodiment, the present invention generally relates to a method for reducing toxicity or side effects in the treatment of mitochondrial-related diseases or conditions, comprising administering a therapeutically effective amount of one of the compounds disclosed herein to a subject in need of reduction.

[0092] In certain embodiments, administration is carried out by oral administration.

[0093] In yet another embodiment, the present invention generally relates to the compounds disclosed herein and the use of pharmaceutically acceptable excipients, carriers, or diluents in the preparation of pharmaceuticals for the treatment of diseases or disorders.

[0094] In yet another embodiment, the present invention generally relates to the use of the compounds disclosed herein for the treatment of diseases or disorders.

[0095] In certain embodiments, the compounds disclosed herein are used to treat diseases or disorders related to mitochondrial function.

[0096] In certain embodiments, the compounds disclosed herein are used to treat diseases or disorders associated with one or more defects in mitochondrial function.

[0097] In certain embodiments, the compounds disclosed herein are used to treat obesity, excess 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 disorders associated with increased reactive oxygen species (ROS), Friedreich's ataxia, Parkinson's disease, ALS, NAFLD or NASH, or diseases or disorders selected from a group selected from related diseases or disorders.

[0098] The specific methods and compounds disclosed herein are not intended to be limiting. The chemical structures in the figures herein represent variables defined proportionally to the definitions (parts, atoms, etc.) of the chemical groups at the corresponding positions in the compound formulas herein, and the same variable names (e.g., R) are used elsewhere. 1 , R 2Whether or not they are identified by R, R', X, etc. is irrelevant. Whether a chemical group in a compound structure is suitable for use in the synthesis of another compound structure is within the knowledge of those skilled in the art. Other methods for synthesizing the compounds of the chemical formulas herein and their synthetic precursors, including routes not expressly shown in the figures herein, are within the scope of the technical means of those skilled in the art. Methods for optimizing reaction conditions and, if necessary, minimizing competing by-products are well known in the art. The methods described herein may further include steps of adding or removing appropriate protecting groups either before or after the steps specifically described herein in order to ultimately enable the synthesis of the compounds herein. Furthermore, various synthetic steps may be carried out in alternative orders to obtain the desired compound. Synthetic chemical transformations and protecting group methods (protection and deprotection) useful for the synthesis of applicable compounds are well known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); TW. Greene and PGMWuts, Protective Groups in Organic Synthesis, 3rd Ed., 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 (ed.), Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions.

[0099] The methods described herein are intended for converting a compound of one chemical formula to a compound of another chemical formula. The conversion process refers to one or more chemical conversions and may be performed in situ or by isolating an intermediate compound. The conversion involves reacting a starting compound or intermediate with additional reagents using techniques and protocols well known in the art, including those described in the literature cited herein. The intermediate may be used with or without purification (e.g., filtration, distillation, sublimation, crystallization, grinding, solid-phase extraction, chromatography).

[0100] The combinations of substituents and variables envisioned in this invention are limited to those that result in the formation of stable compounds.

[0101] Certain compounds of the present invention may exist in the form of specific geometric or stereoisomers. The present invention considers all such compounds, including cis isomers, trans isomers, atrop isomers, R enantiomers, S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures thereof, and other mixtures, to be within the scope of the present invention. Substituents such as alkyl groups may have additional chiral carbon atoms. All such isomers, and mixtures thereof, are intended to be included in the present invention.

[0102] Isomer mixtures containing various isomer ratios can be utilized according to the present invention. For example, when combining only two isomers, the present invention envisions 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 can be envisioned for more complex isomer mixtures.

[0103] For example, if a specific enantiomer of the compound of the present invention is desired, it can be prepared by asymmetric synthesis or by derivatization using a chiral auxiliary group. The resulting diastereomer mixture is then separated, the auxiliary group is cleaved, and the pure enantiomer of the desired type is obtained. Alternatively, if the molecule contains a basic functional group such as an amino group or an acidic functional group such as a carboxyl group, a diastereomer salt is formed using a suitable optically active acid or base. The diastereomer formed is then separated by fractionation crystallography or chromatography, which are well known in the art, and the pure enantiomer is subsequently recovered.

[0104] Solvates and polymorphs of the compounds of the present invention are also assumed herein. Solvates of the compounds of the present invention include, for example, hydrates.

[0105] The present invention also provides compositions comprising an effective amount of any of the formulas described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph (if applicable) of said compound, and an acceptable carrier. Preferably, the compositions of the present invention are formulated for pharmaceutical use ("pharmaceutical composition"), and the carrier is a pharmaceutically acceptable carrier. The carrier must be compatible with the other components in the formulation and, in the case of a pharmaceutically acceptable carrier, must be "acceptable" in the sense that it is not harmful to the recipient at amounts typically used in pharmaceuticals.

[0106] Pharmaceutically acceptable carriers, adjuvants, and media that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, serum proteins such as lecithin and human serum albumin, phosphates, buffering substances such as glycine, sorbic acid and potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride and zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and lanolin.

[0107] The pharmaceutical compositions of the present invention include those suitable for oral, rectal, nasal, topical (including cheek and sublingual), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, and intradermal) administration. In certain embodiments, compounds of the chemical formulas described herein are administered transdermally (e.g., using transdermal patches). Other formulations are conveniently provided in unit dosage forms such as tablets and sustained-release capsules, and in liposomes, and can 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).

[0108] Such preparation methods involve a step of binding the administered molecule to components such as carriers that constitute one or more auxiliary components. Generally, compositions are prepared by uniformly and closely binding the active ingredient to a liquid carrier, liposomes, or finely dispersed solid carrier, or both, and then molding the product as needed.

[0109] In certain preferred embodiments, the compounds are administered orally. Compositions of the present invention suitable for oral administration may be provided as individual units such as capsules, pouches, or tablets, each containing a predetermined amount of the active ingredient; as powders or granules; as solutions or suspensions in aqueous or non-aqueous liquids; as oil-in-water or water-in-oil liquid emulsions; encapsulated in liposomes; and as boluses, etc. Soft gelatin capsules are useful for encapsulating such suspensions, thereby beneficially increasing the absorption rate of the compounds.

[0110] Tablets can be manufactured by compression or molding, and one or more auxiliary components may be added as needed. Compressed tablets can be prepared by mixing an active ingredient in a fluid form, such as powder or granules, with a binder, lubricant, inert diluent, preservative, surfactant, or dispersant as needed, and compressing it in a suitable machine. Molded tablets can be manufactured by molding a mixture of powder compounds moistened with an inert liquid diluent in a suitable machine. Tablets can be coated or scored as needed and can be formulated to release the active ingredient therein in a sustained or controlled manner. Methods for formulating sustained-release or controlled-release compositions of pharmaceutically effective ingredients, such as the compounds described herein and other compounds known in the art, are well known in the art and are described in several U.S. patents, including, but not limited to, U.S. Patents 4,369,172 and 4,842,866, and the references therein. The coating can be used to deliver the compound to the intestines (see, for example, U.S. Patents 6,638,534, 5,217,720, 6,569,457, 6,461,631, 6,528,080, 6,800,663, and the literature cited herein). A useful formulation form for the compound of the present invention is in the form of enteric-coated pellets, the enteric layer comprising hydroxypropyl methylcellulose acetate succinate.

[0111] For oral tablets, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also usually added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When administering aqueous suspensions orally, the active ingredient is mixed with emulsifiers and suspending agents. Specific sweeteners and / or flavorings and / or colorings may be added as needed.

[0112] Compositions suitable for topical administration include lozenges containing the active ingredient in a fragrance base, typically sucrose and acacia or tragacanth, and pastilles containing the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia.

[0113] Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions that can contain antioxidants, buffers, bacteriostatic agents, and solutes to make the formulation isotonic with the recipient's blood, as well as aqueous and non-aqueous sterile suspensions that can contain suspending agents and thickeners. These formulations can be filled into single-dose or multi-dose containers, such as sealed ampoules or vials, and stored in a freeze-dried (lyophilized) state, requiring only the addition of a sterile liquid carrier, such as sterile water for injection, immediately before use. It is also possible to prepare injection solutions and suspensions in situ from sterile powders, granules, and tablets.

[0114] Such injectable solutions may, for example, be in the form of sterilized, injectable aqueous or oily suspensions. These suspensions can be formulated according to techniques well known in the art, using suitable dispersants or wetting agents (e.g., Tween 80) and suspending agents. Sterilized injectable solutions may be sterilized injectable solutions or suspensions in non-toxic, parenterally administered diluents or solvents (e.g., 1,3-butanediol solution). Acceptable media and solvents include mannitol, water, Ringer's solution, and isotonic sodium chloride solutions. Furthermore, sterilized fixative oils have conventionally been used as solvents or suspension media. For this purpose, any non-irritating fixative oil, including synthetic monoglycerides or diglycerides, can be used. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectable solutions, as are naturally pharmaceutically acceptable oils such as olive oil and castor oil, particularly their polyoxyethylene versions. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants.

[0115] The pharmaceutical compositions of the present invention can be administered in the form of suppositories 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, and dissolves in the rectum to release the active ingredient. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

[0116] The pharmaceutical compositions of the present invention can be administered by nasal aerosol or inhalation. Such compositions can be prepared according to techniques well known in the field of pharmaceutical formulations, and may be prepared as a solution in physiological saline using benzyl alcohol or other suitable preservatives, absorption enhancers to increase bioavailability, fluorocarbons, and / or other solubilizers or dispersants well known in the art.

[0117] Topical administration of the pharmaceutical compositions of the present invention is particularly useful when the desired treatment concerns an area or organ that can be easily reached by topical application. For topical application to the skin, the pharmaceutical compositions should be formulated as a suitable ointment in which the active ingredient is suspended or dissolved in a carrier. Suitable carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquefied petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compounds, emulsifying waxes, and water. Alternatively, the pharmaceutical compositions may be formulated using a suitable lotion or cream in which the active compound is suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester waxes, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. The pharmaceutical compositions of the present invention can also be applied topically to the lower intestinal tract as a rectal suppository formulation or a suitable enema formulation. Topical transdermal patches and iontophoresis administration are also included in the present invention.

[0118] In another embodiment, the composition of the present invention further comprises a second therapeutic agent. The second therapeutic agent comprises any compound or therapeutic agent that is known or exhibits beneficial properties when used in combination with a compound of any of the chemical formulas described herein.

[0119] Such agents have been described in detail in the art. Preferably, the second therapeutic agent is an agent useful for the treatment or prevention of metabolic diseases or metabolic disorders.

[0120] In another embodiment, the present invention provides separate dosage forms in which the compound of the present invention and a second therapeutic agent are associated with each other. As used herein, the term “associated with each other” means that it is readily apparent that the separate dosage forms are intended to be sold and administered together (sequentially or simultaneously, within 24 hours of each other), such as by being packaged together or conjugated together.

[0121] In the pharmaceutical composition of the present invention, the compound of the present invention is present in an effective amount. As used herein, the term “effective amount” means an amount sufficient to reduce or improve the severity, duration, or progression of the disorder under treatment, prevent the progression of the disorder under treatment, reverse the disorder under treatment, or enhance or improve the prophylactic or therapeutic effect of other treatments, when administered according to an appropriate dosing regimen.

[0122] The correlation between animal and human dosages (based on milligrams per square meter of body surface area) is described in Freireich et al., 1966, Cancer Chemother Rep 50:219. Body surface area can be roughly determined from the patient's height and weight (see, for example, Scientific Tables, Geigy Pharmaceuticals, Ardley, NY, 1970, 537). The effective dose of the compound of the present invention may range from about 0.001 mg / kg to about 500 mg / kg, more preferably from 0.01 mg / kg to about 50 mg / kg, and even more preferably from 0.1 mg / kg to about 2.5 mg / kg. The effective dose also varies, as is recognized by those skilled in the art, depending on the disease being treated, the severity of the disease, the route of administration, the patient's sex, age, general condition, use of excipients, the possibility of concomitant use with other treatments such as other drugs, and the judgment of the treating physician.

[0123] In a pharmaceutical composition containing a second therapeutic agent, the effective dose of the second therapeutic agent is approximately 20% to 100% of the dose typically used in monotherapy with that therapeutic agent alone. Preferably, the effective dose is approximately 70% to 100% of the usual monotherapy dose. The usual monotherapy doses of these second therapeutic agents are well known in the art (see, for example, Wells et al., 2000, Pharmacotherapy Handbook, 2nd Edition; Appleton and Lange, Stamford, Conn.; PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition; Tarascon Publishing, Loma Linda, Calif. 2000). These documents are incorporated herein by reference in their entirety.

[0124] The present invention also provides a method for treating a subject suffering from or susceptible to a disease, disorder, 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. Several diseases are well known in the art and are disclosed herein.

[0125] In certain embodiments, the methods disclosed herein are suitable for treating age-related diseases or disorders, including common neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD).

[0126] As used herein, the term “combined administration” means that a second therapeutic agent may be administered together with the compound of the present invention as part of a single dosage form (for example, as a composition of the present invention comprising the compound of the present invention and the second therapeutic agent, as described above) or as separate dosage forms. Alternatively, the additional agent may be administered before, sequentially, 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(s) are administered by conventional methods. Administration of a composition of the present invention comprising the compound of the present invention and the second therapeutic agent to a subject does not preclude the administration of the same therapeutic agent, other second therapeutic agents, or the compound of the present invention to the subject separately at another point in the course of treatment.

[0127] The effective doses of these second therapeutic agents are well known to those skilled in the art, and guidelines for administration are described in the patents and published patent applications referenced herein, as well as in Wells et al., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000), PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000), and other medical textbooks. However, determining the optimal effective dose range of the second therapeutic agent is well within the technical scope of those skilled in the art.

[0128] In one embodiment of the present invention, in which a second therapeutic agent is administered, the effective dose of the compound of the present invention is less than the effective dose when the second therapeutic agent is not administered. In another embodiment, the effective dose of the second therapeutic agent is less than the effective dose when the compound of the present invention is not administered. This method minimizes the undesirable side effects associated with high doses of either drug. Other potential advantages, including but not limited to improvements in the administration plan and / or reductions in drug costs, will be apparent to those skilled in the art.

[0129] In yet another embodiment, the present invention provides the use of any compound of any of the chemical formulas described herein, either alone or in combination with one or more of the second therapeutic agents described above, in the manufacture of a pharmaceutical product as a single composition or separate dosage form for the treatment or prevention of a target of the disease, disorder, or symptom described herein. Another aspect of the present invention is a compound of any of the chemical formulas described herein, used for the treatment or prevention of a target of the disease, disorder, or symptom described herein.

[0130] In other embodiments, the methods described herein include methods further comprising monitoring the subject's response to therapeutic administration. Such monitoring may include periodic sampling of the subject's tissues, body fluids, specimens, cells, proteins, chemical markers, genetic material, etc., as markers or indicators of the therapeutic regimen. In other methods, the subject is pre-screened or identified as requiring such treatment by evaluation of relevant markers or indicators indicating suitability for such treatment.

[0131] In one embodiment, the present invention provides a method for monitoring the progress of treatment. This method includes the step of determining the level of a diagnostic marker (marker) (e.g., any target or cell type as described herein, modulated by a compound as described herein) or a diagnostic measurement (e.g., screening, assay) in a subject who has or is susceptible to the disorder or symptoms described herein, wherein the subject is administered a therapeutic dose of a compound as described herein sufficient to treat the disease or symptoms. The level of the marker measured by this method can be compared to known marker levels in a healthy normal control group or other affected patients to establish the disease state of the subject. In a preferred embodiment, a second level of the marker in the subject is measured at a later point in time than the measurement of the first level, and the two levels are compared to monitor the course of the disease or the effectiveness of the treatment. In a particular preferred embodiment, the level of the marker in the subject is measured before the initiation of treatment according to the present invention. The effectiveness of the treatment can be determined by comparing this pre-treatment marker level with the marker level of the subject after the initiation of treatment.

[0132] In certain embodiments of the method, the marker level or marker activity within the subject is measured at least once. Comparing the marker level to, for example, another marker level measurement obtained previously or later from the same patient, another patient, or a normal subject is useful in determining whether the treatment according to the present invention is producing the desired effect, thereby allowing for appropriate adjustment of the dosage. The measurement of marker levels can be carried out using any suitable sampling / expression assay method known in the art or described herein. Preferably, a tissue or body fluid sample is first taken from the subject. Examples of suitable samples include blood, urine, tissue, oral or buccal cells, and hair samples including hair follicles. Other suitable samples are known to those skilled in the art. The measurement of protein levels and / or mRNA levels (e.g., marker levels) in the sample can be carried out using any suitable technique known in the art, including but not limited to enzyme immunoassay, ELISA, radiolabeling / assay, blotting / chemiluminescence, and real-time PCR.

[0133] The present invention also provides kits for use in treating diseases, disorders, or symptoms thereof, including those described herein. These kits include a) a pharmaceutical composition comprising a compound of any of the formulas described herein, or a salt thereof, or a prodrug, or a salt thereof, or a hydrate, solvate, or polymorph thereof, wherein the pharmaceutical composition is contained in a container, and b) instructions describing a method of treating a disease, disorder, or symptom thereof using the pharmaceutical composition, including those described herein.

[0134] The container may be any container or other sealed or sealable device capable of containing the pharmaceutical composition. Examples include bottles, partitioned or multi-chambered holders or bottles in which each compartment or chamber contains a single dose of the composition, partitioned aluminum foil packets in which each compartment contains a single dose of the composition, or dispensers that supply single doses of the composition. The container may be any conventional shape or form known in the art, made of pharmaceutically acceptable material, such as a paper or corrugated box, a glass or plastic bottle or jar, a resealable bag (e.g., to hold "refills" of tablets for another container), or a blister pack with individual doses to be squeezed out of the pack according to a treatment schedule. The container used may vary depending on the exact dosage form; for example, conventional corrugated boxes are not generally used to contain liquid suspensions. It is also possible to use multiple containers in a single package for selling a single dosage form. For example, tablets may be contained in a bottle, and that bottle may be further contained in a box. Preferably, the container is a blister pack.

[0135] The kit may also include further information and / or instructions for a physician, pharmacist, or patient. Such memory aids may include numbers printed on each chamber or compartment with the dosage corresponding to the number of days in a treatment plan for which a specified tablet or capsule should be taken, days of the week printed on each chamber or compartment, or cards containing similar information.

[0136] The following examples are intended to illustrate the implementation of the present invention and are not intended to limit it in any way.

[0137] Examples Abbreviation

[0138] [Table 1-1]

[0139] [Table 1-2]

[0140] [Table 1-3]

[0141] chemical method All chemicals were purchased from commercial suppliers and used without further purification. Unless otherwise specified, reactions were carried out under an argon inert atmosphere and monitored by thin-layer chromatography (TLC) and / or LC-MS. All reagents were purchased from commercial suppliers and used as is. Synthetic intermediates and final compounds were purified using a Biotage Isolera Prime 3.2 chromatography system with 230-400 mesh silica gel or a GILSON GX-281 prep-HPLC. 1 H and 13 ¹³C NMR spectra were acquired using a Bruker Ascend 400 spectrometer at 400 MHz and 100 MHz, respectively. NMR chemical shifts were described in δ (ppm), with the residual solvent peak as the standard (chloroform-d, 7.26 ppm). 1 H), 77.16 ppm ( 13 C); methanol-d4, 3.31 ppm ( 1 H), 49.00 ppm ( 13 C); DMSO-d6, 2.50 ppm ( 1 H), 39.52 ppm ( 13C)). Data were reported in the form of chemical shift, multiplicity (s=singlet, d=doublet, dd=doublet of doublet, t=triplet, q=quadruplet, br=broad, m=multilet, abq=abquadruplet), proton number, and coupling constant. Mass spectral data were measured using Agilent 1260 and 6120MSD LC-MS. All compounds submitted for biological testing were confirmed to have a purity of 95% or higher by Shimadzu LC-2030C 3D analytical HPLC. The synthesis methods, spectral data, and MS results of the novel compounds are described in detail below.

[0142] Synthesis Scheme 1

[0143] [ka]

[0144] Step 1: 2-amino-1-methyl-1H-imidazole-5-carboxylate ethyl. NaH (60% in mineral oil, 10.94 g, 0.46 mol) was added to a solution of ethyl methylglycinate hydrochloride (20 g, 0.13 mol) in ethyl formate (200 mL). The mixture was stirred at 25°C for 2 hours. After evaporating the mixture under reduced pressure, the residue was dissolved in EtOH (60 mL). Then, concentrated HCl (120 mL) was added. The mixture was stirred at 80°C for 2 hours. After evaporating the mixture under reduced pressure, 6N NaOH (70 mL) and cyanamide (10.95 g, 0.26 mol) were added to the reaction mixture, and the mixture was stirred at 80°C for 4 hours. The residue was ground with MTBE and filtered to obtain 2-amino-1-methyl-1H-imidazole-5-carboxylate ethyl (22 g, 20% yield in 3 steps) as a yellow solid. MS(ESI), m / z:C7H 11 Calculated value of N3O2: Precise mass: 169.09 Measured value: t R =1.475 minutes [M+H] + =170.1; 1 H NMR (400MHz, CDCl3) δ7.44(s,1H), 4.56(s,2H), 4.26(q,J=7.1Hz,2H), 3.67(s,3H), 1.34(t,J=7.1Hz,3H).

[0145] Step 2: Ethyl 1-methyl-2-nitro-1H-imidazole-5-carboxylate. Ethyl 2-amino-1-methyl-1H-imidazole-5-carboxylate (22 g, 0.13 mol) was added to a solution of NaNO2 (53.82 g, 0.78 mol) in AcOH / H2O = 1 / 1 (600 mL) at 0 °C. The mixture was stirred at 25 °C for 2 hours, then the pH was adjusted to 8 with saturated aqueous potassium carbonate solution (600 mL), and extracted with DCM (3 × 400 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The concentrate was purified by silica gel column and eluted with PE / EA = 50 / 1 to 20 / 1, and ethyl 1-methyl-2-nitro-1H-imidazole-5-carboxylate (8 g, yield 41%) was obtained as an off-white solid. MS(ESI), m / z: Calculated for C7H9N3O4 Exact mass: 199.06 Measured value t R = 1.446 min [M+H] + = 200.1; 1 1H NMR (400 MHz, DMSO-d6) δ 7.79 (s, 1H), 4.34 (q, J = 7.1 Hz, 2H), 4.18 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H).

[0146] Step 3: (1-Methyl-2-nitro-1H-imidazol-5-yl)methanol. NaBH4 (3.8 g, 0.1 mol) was added to a solution of ethyl 1-methyl-2-nitro-1H-imidazole-5-carboxylate (10 g, 0.05 mol) in THF / MeOH = 8 / 1 (100 mL) stirred at 0 °C. The reaction mixture was stirred at 25 °C for 2 hours. The mixture was poured into water (100 mL) and extracted with EA (6 × 50 mL). The mixture was concentrated under reduced pressure. The residue was triturated with DCM and filtered to obtain (1-methyl-2-nitro-1H-imidazol-5-yl)methanol (5 g, yield 63%) as a yellow solid. MS(ESI), m / z: Calculated for C5H7N3O3 Exact mass: 157.05 Measured value t R = 1.254 min [M+H] + = 158.0; 11H NMR (400 MHz, DMSO-d6) δ 7.11 (s, 1H), 5.49 (t, J = 5.4 Hz, 1H), 4.54 (d, J = 5.3 Hz, 2H), 3.92 (s, 3H).

[0147] Step 4: 1-Methyl-2-nitro-1H-imidazole-5-carbaldehyde. DMP (29.7 g, 70.0 mmol) was added to a solution of (1-methyl-2-nitro-1H-imidazol-5-yl)methanol (10 g, 63.6 mmol) in DCM (100 mL). The mixture was stirred at 25 °C for 1 h. The mixture was poured into a saturated aqueous solution of Na2S2O3 (100 mL) and extracted with DCM (2 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, and the concentrate was purified by silica gel column eluting with PE / EA = 10 / 1 to 8 / 1, and 1-methyl-2-nitro-1H-imidazole-5-carbaldehyde (8.5 g, yield 86%) was obtained as a yellow solid. MS (ESI), m / z: calculated for C5H5N3O3 exact mass: 155.0 found RT = 1.341 min [M+H] + = 155.7; 1 1H NMR (400 MHz, CDCl3) δ 9.93 (s, 1H), 7.82 (s, 1H), 4.36 (s, 1H).

[0148] Step 5: Methyl 3-hydroxy-2,2-dimethyl-3-(1-methyl-2-nitro-1H-imidazole-5-yl)propionate. To a solution of methyl 2-bromo-2-methylpropionate (19.0 g, 104.8 mmol) in THF (200 mL) stirred at -78°C under a nitrogen atmosphere, n-BuLi (41.9 mL, 104.8 mmol, 2.5 mol / L) was added. The mixture was stirred at -78°C for 30 minutes. Next, 1-methyl-2-nitro-1H-imidazole-5-carbaldehyde (12.5 g, 80.6 mmol) was added and stirred for a further 5 hours. The mixture was poured into a saturated aqueous solution of ammonium chloride (200 mL) and extracted with EA (2 × 200 mL). The mixed organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by silica gel column chromatography. Elution at PE / EA = 8 / 1 to 5 / 1 yielded methyl 3-hydroxy-2,2-dimethyl-3-(1-methyl-2-nitro-1H-imidazole-5-yl)propionate (8.0 g, yield 35%) as a yellow solid. MS(ESI), m / z:C 10 H 15 Calculated value of N3O5: Precise mass: 257.1 Measured value: RT = 1.809 mins [M+H] + =257.8; 1 H NMR (400MHz, DCl3) δ7.27(s,1H), 4.70(d,J=8.0Hz,1H), 4.07(s,3H),3.78(s,3H), 3.70(d,J=8.4Hz,1H), 1.38(s,3H), 1.32(s,3H).

[0149] Step 6: 3-(2,4-dinitrophenoxy)-2,2-dimethyl-3-(1-methyl-2-nitro-1H-imidazole-5-yl)propionate methyl (1). To a solution of 3-hydroxy-2,2-dimethyl-3-(1-methyl-2-nitro-1H-imidazole-5-yl)propionate methyl (8.0 g, 31.1 mmol) in THF (100 mL), NaH (60%, 1.6 g, 40.4 mmol) was added at 0°C. The mixture was stirred at 0°C for 30 minutes. Next, 1-chloro-2,4-dinitrobenzene (7.4 g, 40.4 mmol) was added and the mixture was stirred at 25°C for 4 hours. The mixture was adjusted to pH 5-6 with aqueous HCl and extracted with EA (2 × 100 mL). The mixed organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified using a silica gel column. Elution at PE / EA = 2 / 1 to 1 / 1 yielded compound 1 (5.0 g, yield 38%) as a yellow solid.

[0150] MS(ESI), m / z:C 16 H 17 Calculated value of N5O9: Precise mass: 423.1 Measured value RT=3.080 min [M+H] + =424.1; 1 H NMR (400MHz, CDCl3) δ8.75(d,J=2.8Hz,1H), 8.36(dd,J=9.2,2.4Hz,1H), 7.26(d,J=5.2Hz,1 H), 6.98(d,J=9.2Hz,1H), 5.96(s,1H), 4.16(s,3H), 3.73(s,3H), 1.50(s,3H), 1.28(s,3H).

[0151] Step 7: 3-(2,4-dinitrophenoxy)-2,2-dimethyl-3-(1-methyl-2-nitro-1H-imidazole-5-yl)propanoic acid (2). To a THF / H2O=1 / 1 (10 mL) solution of compound 1 (500 mg, 1.18 mmol) stirred at 0°C, lithium hydroxide (33.94 mg, 1.42 mmol) was added. The reaction mixture was stirred at 25°C for 20 hours. The mixture was adjusted to pH 3 with 1N HCl (40 mL) and extracted with  (40 mL × 3). The mixed organic layer was dried over anhydrous Na2SO4. The residue was purified by Prep-HPLC (column: Sunfire 5 μm 19-150 mm; mobile phase: ACN / H2O (0.1% NH3H2O); gradient: 10-60% ACN, 7 min; flow rate: 20 mL / min) to obtain compound 2. One of the seven batches was deesterified in the same manner as described above, and then mixed to obtain compound 2 (1.9 g, 48% yield) as a yellow solid. MS(ESI), m / z:C 15 H 15 Calculated value of N5O9: Precise mass: 409.09 Measured value: t R =3.316 minutes [M+H] + =410.0; 1 H NMR(400MHz,CD3OD)δ8.74(d,J=2.8Hz,1H), 8.39(dd,J=9.3,2.8Hz,1H), 7.30(d ,J=9.3Hz,1H), 7.20(s,1H), 6.21(s,1H), 4.18(s,3H), 1.45(s,3H), 1.29(s,3H).

[0152] Step 8: 3-(2,4-dinitrophenoxy)-2,2-dimethyl-3-(1-methyl-2-nitro-1H-imidazole-5-yl)-1-morpholinopropan-1-one (3). Compound 2 (200 mg, 0.489 mmol), HOBt (79.2 mg, 0.586 mmol), and EDCI (112 mg, 0.586 mmol) were stirred in DCM (3 mL) under a nitrogen atmosphere at 25°C. DIPEA (189 mg, 1.47 mmol) and morpholine (63.9 mg, 0.733 mmol) were added to the mixture. The reaction mixture was stirred at 25°C for 3 hours. The mixture was washed with water (5 mL) and brine (5 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by Prep-TLC (DCM / MeOH = 15 / 1) to obtain compound 3 (111 mg, 99% yield) as an off-white solid. MS(ESI), m / z:C 19 H 22 Calculated value of N6O9: Precise mass: 478.14 Measured value: t R =2.062 minutes [M+H] + =479.3; 1 H NMR(400MHz,DMSO-d6)δ8.74(d,J=2.8Hz,1H), 8.37(dd,J=9.3,2.9Hz,1H), 7.38(d,J=9.4Hz, 1H), 7.18(s,1H), 6.30(s,1H), 4.11(s,3H), 3.54(d,J=4.0Hz,8H), 1.51(s,3H), 1.31(s,3H).

[0153] Synthesis Scheme 2

[0154] [ka]

[0155] Step 1: 2-(3-(2,4-dinitrophenoxy)-2,2-dimethyl-3-(1-methyl-2-nitro-1H-imidazole-5-yl)propanoyl)hydrazine-1-carboxylate tert-butyl. To a solution of compound 2 (150 mg, 0.36 mmol) in DMF (5 mL), HATU (167.2 mg, 0.44 mmol) and DIPEA (94.7 mg, 0.73 mmol) were added. The mixture was stirred at 25°C for 30 minutes. Next, tert-butylcarbazate (58.57 mg, 0.44 mmol) was added. After stirring the mixture at 25°C for 4 hours, it was poured into water (20 mL) and extracted with  (30 mL x 3). The mixed organic layers were washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by silica gel column chromatography. Elution at DCM / MeOH = 50 / 1 to 20 / 1 yielded the target compound (140 mg, 73% yield) as a yellow solid. MS(ESI), m / z:C 20 H 25 N7O 10 Calculated value: Precise mass: 523.17 Measured value: t R =1.733 minutes [M+H] + = 524.3.

[0156] Step 2: 3-(2,4-dinitrophenoxy)-2,2-dimethyl-3-(1-methyl-2-nitro-1H-imidazole-5-yl)propanehydrazide. 2-(3-(2,4-dinitrophenoxy)-2,2-dimethyl-3-(1-methyl-2-nitro-1H-imidazole-5-yl)propanoyl)hydrazine-1-carboxylate tert-butyl (140 mg, 0.27 mmol) was dissolved in DCM (5 mL) and TFA (2.5 mL) was added at 0°C. The mixture was stirred at 30°C for 2 hours. The mixture was concentrated under reduced pressure to obtain the target compound (110 mg, yield 97%) as a yellow solid. MS (ESI), m / z:C 15 H 17 Calculated value of N7O8: Precise mass: 423.11 Measured value: t R =1.437 minutes [M+H] + =424.2; 1H NMR(400MHz,DMSO_d6)δ9.18(s,1H), 8.75(d,J=2.8Hz,1H), 8.36(dd,J=9.3,2.8Hz,1H), 7.35(d,J=9.4Hz,1H), 7.10(s,1H), 6.25(s,1H), 4.07(s,3H), 1.33(s,3H), 1.16(s,3H).

[0157] Step 3: 2-(1-(2,4-dinitrophenoxy)-2-methyl-1-(1-methyl-2-nitro-1H-imidazole-5-yl)propan-2-yl)-1,3,4-oxadiazole (4). To a solution of 3-(2,4-dinitrophenoxy)-2,2-dimethyl-3-(1-methyl-2-nitro-1H-imidazole-5-yl)propanehydrazide (100 mg, 0.26 mmol) in ACN (5 mL), triethoxymethane (116 g, 0.78 mmol) was added at 30 °C. The mixture was stirred at 50 °C for 6 hours under an N2 atmosphere. The mixture was poured into water (5 mL) and extracted with siRNA (3 × 20 mL). The organic layer was washed with water (10 mL) and brine (5 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by Prep-TLC (DCM / MeOH=20 / 1) to obtain compound 4 (73 mg, yield 64%) as a yellow solid. MS(ESI), m / z:C 16 H 15 Calculated value of N7O8: Precise mass: 433.1 Measured value: t R =1.355 minutes [M+H] + =434.1; 1 H NMR(400MHz,DMSO_d6)δ9.26(s,1H), 8.75(d,J=2.8Hz,1H), 8.36(dd,J=9.3,2.8Hz ,1H), 7.30(d,J=9.4Hz,1H), 6.89(s,1H), 6.41(s,1H), 3.99(s,3H), 1.54(d,J=9.5 Hz,6H).

[0158] Synthesis scheme 3

[0159] [ka]

[0160] Step 1: 4-(hydroxy(1-methyl-2-nitro-1H-imidazole-5-yl)methyl)tetrahydro-2H-pyran-4-carboxylate ethyl. To a solution of oxan-4-carboxylate ethyl (1.27 g, 8.06 mmol) in THF (5 mL), LDA (4 mL, 8.06 mmol, 2 mmol / L) was added at -78°C under an N2 atmosphere. The mixture was stirred at -78°C under an N2 atmosphere for 0.5 hours. The reaction mixture was added to a solution of 1-methyl-2-nitro-1H-imidazole-5-carbaldehyde (500 mg, 3.22 mmol) in THF (1 mL) at -78°C under an N2 atmosphere. The mixture was stirred at 25°C under an N2 atmosphere for 2 hours. The mixture was quenched with a saturated NH4Cl solution (10 mL) and extracted with EA (3 × 5 mL). The mixed organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by prep-TLC with PE / EA = 1 / 1 to obtain 4-(hydroxy(1-methyl-2-nitro-1H-imidazole-5-yl)methyl)tetrahydro-2H-pyran-4-carboxylate ethyl (200 mg, yield 20%) as a yellow solid. MS(ESI), m / z:C 13 H 19 Calculated value of N3O6: Precise mass: 313.1 Measured value: t R =1.514 minutes. [M+H] + =314.1; 1 H NMR(400MHz,DMSO_d6)δ7.08(s,1H), 6.18(d,J=5.5Hz,1H), 4.81(d,J=5.5Hz ,1H), 4.11(td,J=7.1,5.9Hz,2H), 3.80(dd,J=11.7,3.7Hz,3H), 3.29-3.18(m ,2H), 3.30-3.20(m,2H), 1.99(d,J=13.2Hz,1H), 1.88(d,J=13.4Hz,1H), 1.73 (td,J=12.8,4.7Hz,1H), 1.61(td,J=13.0,4.8Hz,1H), 1.14(t,J=7.1Hz,3H).

[0161] Step 2: 4-((2,4-dinitrophenoxy)(1-methyl-2-nitro-1H-imidazole-5-yl)methyl)tetrahydro-2H-pyran-4-carboxylate ethyl (5). To a solution of 4-(hydroxy(1-methyl-2-nitro-1H-imidazole-5-yl)methyl)tetrahydro-2H-pyran-4-carboxylate ethyl (75 mg, 0.23 mmol) in THF (1 mL), NaH (10 mg, 0.250 mmol, 60% in oil) was added at 0°C under an N2 atmosphere. After 0.5 hours, 1-chloro-2,4-dinitrobenzene (70 mg, 0.34 mmol) was added to the reaction mixture at 0°C under an N2 atmosphere. The mixture was stirred for 2 hours at 0°C under an N2 atmosphere. The mixture was quenched with a saturated NH4Cl solution (20 mL) and extracted with EA (3 × 10 mL). The mixed organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by prep-TLC with PE / EA = 1 / 1 to obtain 5 (90 mg, yield 27%) as an off-white solid. MS(ESI), m / z:C 19 H 21 N5O 10 Calculated value: Precise mass: 479.13 Measured value: RT = 2.386 mins. [M+H] + =480.1; 1 H NMR (400MHz, CDCl3) δ8.75(d,J=2.7Hz,1H), 8.35(dd,J=9.2,2.8Hz,1H), 7.23(s,1H), 6.9 2(d,J=9.3Hz,1H), 5.67(s,1H), 4.24(qd,J=7.1,2.3Hz,2H), 4.10(s,3H), 4.01-3.91(m,2H ), 3.60(td,J=11.9,1.6Hz,1H), 3.45-3.36(m,1H), 2.27(d,J=13.4Hz,1H)2.11(d,J=11.2 Hz,1H), 1.86(td,J=12.7,5.2Hz,1H), 1.70(td,J=12.5,4.7Hz,1H), 1.26(t,J=7.1Hz,3H).

[0162] Synthesis scheme 4

[0163] [ka]

[0164] Step 1: Methyl 1-(hydroxy(1-methyl-2-nitro-1H-imidazol-5-yl)methyl)cyclopropane-1-carboxylate. A solution of methyl 1-bromocyclopropane-1-carboxylate (807 mg, 4.51 mmol) in THF (10 mL) was cooled to -78 °C in a dry ice-acetone bath under a nitrogen atmosphere. n-BuLi (3.61 mL, 9.02 mmol, 2.5 mol / L in THF) was added to the stirred solution. After 1 hour, a solution of 1-methyl-2-nitro-1H-imidazole-5-carbaldehyde (700 mg, 4.51 mmol) in THF (2 mL) was added at -78 °C. The mixture was stirred for 1 hour and then warmed to 25 °C. The reaction was quenched with saturated aqueous ammonium chloride solution (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to give the crude product. The crude product was purified by prep-TLC (EA / PE = 1 / 1) to give the product (110 mg, yield 10%) as a yellow oil. MS (ESI), m / z: C 10 H 13 Calculated for C R H + N3O5 exact mass: 255.09, found t 1 = 1.181 min. [M+H] + = 256.2; 1 1H NMR (400 MHz, DMSO-d6) δ 7.03 (s, 1H), 5.81 (d, J = 6.7 Hz, 1H), 5.21 (d, J = 6.7 Hz, 1H), 3.96 (s, 3H), 1.25 - 1.10 (m, 2H), 1.12 - 0.93 (m, 2H).

[0165] Step 2: 1-((2,4-dinitrophenoxy)(1-methyl-2-nitro-1H-imidazole-5-yl)methyl)cyclopropane-1-carboxylate methyl (6). To a solution of 1-(hydroxy(1-methyl-2-nitro-1H-imidazole-5-yl)methyl)cyclopropane-1-carboxylate (20 mg, 0.0784 mmol) in THF (2 mL) stirred at 0°C, sodium hydroxide (3.45 mg, 0.862 mmol, 60% in oil) and 1-chloro-2,4-dinitrobenzene (17.1 mg, 0.0784 mmol) were added. The reaction mixture was stirred at 25°C for 1 hour. The reaction was quenched with saturated aqueous solution of ammonium chloride (5 mL), followed by extraction with  (3 × 5 mL). The mixed organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to obtain the crude product. The crude product was purified by prep-HPLC (column: XBridge-1, 5 μm, 19-150 mm; detector: 254 nm; mobile phase: ACN / H2O (H2O, 0.1% NH3, H2O); gradient: 20-53 / 9 min, 95-95 / 2 min, ACN in H2O; retention time: 8.7 min) to obtain compound 6 (14.2 mg, yield 7%) as a yellow solid. MS(ESI), m / z:C 16 H 15 Calculated mass of N5O9: Precise mass: 421.09 Measured value: tR = 2.343 mins. [M+H] + =422.1; 1 H NMR(400MHz,DMSO_d6)δ8.78(d,J=2.6Hz,1H), 8.41(dd,J=9.3,2.6Hz,1H), 7.62(d,J=9.4Hz,1H) , 7.11(s,1H), 6.73(s,1H), 4.00(s,3H), 3.62(s,4H), 1.29-1.07(m,2.5H), 0.93-0.91(m,1.5H).

[0166] Synthesis scheme 5

[0167] [ka]

[0168] 2-hydroxyethyl 3-(2,4-dinitrophenoxy)-2,2-dimethyl-3-(1-methyl-2-nitro-1H-imidazole-5-yl)propionate (7). A mixture of compound 2 (120 mg, 0.29 mmol), TCFH (164 mg, 0.58 mmol), and NMI (120 mg, 1.46 mmol) in ethylene glycol (1819 mg, 29.32 mmol) was stirred at room temperature for 1 hour. LC-MS indicated that SM was consumed and DP was detected. The reaction mixture was diluted with DCM (120 mL) and washed with 1N HCl (50 mL). The mixed organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified over FCC (12 g, silica gel, MeOH=5% in DCM) to obtain product 7 (81 mg, yield 62%) as a yellow solid. MS (ESI), m / z:C 17 H 19 N5O 10 Calculated value: Precise mass: 453.11 Measured value: t R =1.155 minutes. [M+H] + =454.10; 1 H NMR(400MHz,CDCl3)δ8.76(d,J=2.8Hz,1H), 8.36(dd,J=9.2,2.8Hz,1H),7.27(s,1H),6.98 (d,J=9.2Hz,1H), 5.97(s,1H), 4.31-4.21(m,2H), 4.16(s,3H), 3.85-3.76(m,2H), 1.68(br s,1H), 1.52(s,3H), 1.30(s,3H).

[0169] Synthesis scheme 6

[0170] [ka]

[0171] 3-(2,4-dinitrophenoxy)-2,2-dimethyl-3-(1-methyl-2-nitro-1H-imidazole-5-yl)propionic acid 2-methoxyethyl (8). A mixture of 2 (110 mg, 0.27 mmol), TCFH (151 mg, 0.54 mmol), and NMI (66 mg, 0.81 mmol) in 2-methoxyethane-1-ol (2044 mg, 26.89 mmol) was stirred at room temperature for 1 hour. LC-MS indicated that SM was consumed and DP was detected. The reaction mixture was diluted with DCM (120 mL) and washed with 1N HCl (50 mL). The mixed organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified over FCC (12 g, silica gel, MeOH=5% in DCM) to obtain product 8 (39 mg, yield 31%) as a yellow solid. MS (ESI), m / z:C 18 H 21 N5O 10 Calculated value: Precise mass: 467.13 Measured value: t R =1.283 minutes. [M+H] + =468.00; 1 H NMR(400MHz,MeOD)δ8.75(d,J=2.8Hz,1H), 8.39(dd,J=9.2,2.8Hz,1H), 7.27(d,J=9.2Hz,1H), 7.21(s,1H), 6 .23(s,1H), 4.31-4.26(m,1H), 4.21-4.15(m,4H), 3.55-3.45(m,2H), 3.20(s,3H), 1.45(s,3H), 1.31(s,3H).

[0172] Synthesis scheme 7

[0173] [ka]

[0174] 3-(2,4-dinitrophenoxy)-N-(2-hydroxyethyl)-2,2-dimethyl-3-(1-methyl-2-nitro-1H-imidazole-5-yl)propanamide (9). A mixture of compound 2 (65 mg, 0.16 mmol), 2-aminoethane-1-ol (11.6 mg, 0.19 mmol), TCFH (89 mg, 0.32 mmol), and NMI (52 mg, 0.64 mmol) in ACN (2 mL) was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was diluted with 1N HCl (20 mL) and extracted with siRNA (20 mL x 2). The mixed organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain the residue. The residue was purified by prep-HPLC (C18, MeCN / H2O (0.1% FA)) to obtain product 9 (39 mg, yield 54%) as a white solid. MS(ESI), m / z:C 17 H 20 Calculated mass of N6O9: Precise mass: 452.13 Measured value: tR = 1.051 min. [M+H] + =453.0; 1 H NMR (400MHz, DMSO-d6): δ8.75(d,J=2.8Hz,1H), 8.36(dd,J=9.2,2.8Hz,1H), 7.73(t,J=5.6Hz,1H), 7.32(d,J=9. 2Hz,1H), 7.12(s,1H), 6.23(s,1H), 4.07(s,3H), 3.35-3.24(m,2H), 3.17-3.04(m,2H), 1.32(s,3H), 1.17(s,3H).

[0175] Synthesis scheme 8

[0176] [ka]

[0177] 3-(2,4-dinitrophenoxy)-2,2-dimethyl-3-(1-methyl-2-nitro-1H-imidazole-5-yl)propionic acid azetidine-3-yl (13). Compound 2 (110 mg, 0.27 mmol), TCFH (151 mg, 0.54 mmol), and NMI (47 mg, 0.54 mmol) were dissolved in DCM (3 mL), to which 3-hydroxyazetidine-1-carboxylate tert-butyl (56 mg, 0.32 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction was quenched with H2O (50 mL) and extracted with DCM (10 mL x 3). The mixed 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, DCM / CH3OH = 5%) to obtain the intermediate.

[0178] The intermediate TFA / DCM (1 mL / 3 mL) solution produced in the previous step was stirred at room temperature for 2 hours. After the reaction was complete, the solvent was removed under reduced pressure to obtain the residue. The residue was freeze-dried to obtain product 13 (84 mg, 67% yield in 2 steps) as a yellow solid. MS(ESI), m / z:C 18 H 20 Calculated value of N6O9: Precise mass: 464.13 Measured value: t R =0.844 minutes. [M+H] + =465.00; 1 H NMR(400MHz,MeOD)δ8.76(d,J=2.8Hz,1H), 8.40(dd,J=9.2,2.4Hz,1H), 7.24-7.19(m,2H), 6.18( s,1H), 5.35(m,1H), 4.46-4.38(m,2H), 4.18(s,3H), 4.16-4.09(m,2H), 1.49(s,3H), 1.36(s,3H).

[0179] Synthesis scheme 9

[0180] [ka]

[0181] 2-(1-(2,4-dinitrophenoxy)-2-methyl-1-(1-methyl-2-nitro-1H-imidazole-5-yl)propan-2-yl)-1H-benzo[d]imidazole (15). A mixture of compound 2 (120 mg, 0.293 mmol), benzene-1,2-diamine (35 mg, 0.322 mmol), N,N,N',N'-tetramethylchloroformamidinium-hexafluorophosphate (TCFH, 206 mg, 0.733 mmol), and 1-methylimidazole (NMI, 96 mg, 1.173 mmol) in ACN (5 mL) was stirred at room temperature for 30 minutes. After the reaction was complete, the solvent was removed under reduced pressure to obtain the residue. The residue was purified in FCC (25 g silica gel, 5% MeOH in DCM) to obtain the intermediate as a brown oil.

[0182] To a 3 mL solution of the intermediate pyridine, phosphoryl trichloride (80 mg, 0.52 mmol) was added at room temperature under an N2 atmosphere. The reaction mixture was stirred and heated at 80°C for 1 hour under an N2 atmosphere. After the reaction was complete, the mixture was diluted with  (30 mL) and washed with 0.5 N HCl (30 mL x 2). The recovered 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 in DCM = 0-5%) to obtain product 15 (30 mg, 21% yield in 2 steps) as a yellow solid. MS (ESI), m / z:C 21 H 19 Calculated value of N7O7: Precise mass: 481.13 Measured value: t R =1.066 minutes. [M+H] + =482.0; 1 H NMR(400MHz,d6-DMSO)δ12.20(br s,1H), 8.71(d,J=2.8Hz,1H), 8.34(dd,J=9.2,2.8Hz,1H), 7.63-7.42(m,2H), 7.39(d,J=9.2 Hz,1H), 7.20-7.12(m,2H), 7.06(s,1H), 6.44(s,1H), 3.76(s,3H), 1.67(s,3H), 1.51(s,3H).

[0183] Synthesis scheme 10

[0184] [ka]

[0185] Step 1: tert-butyl 3-hydroxy-2,2-dimethyl-3-(3-methyl-2-nitroimidazole-4-yl)propionate. To a solution of tert-butyl 2-bromo-2-methylpropionate (11.21 g, 0.05 mol) in THF (100 mL) stirred under a nitrogen atmosphere at -78°C, n-BuLi (3.22 g, 0.05 mmol) was added dropwise. The reaction mixture was stirred at -78°C for 30 minutes. Next, a solution of 3-methyl-2-nitroimidazole-4-carbaldehyde (6.0 g, 0.04 mol) in THF (20 mL) was added dropwise. The reaction mixture was stirred at 0°C for a further 2 hours. The reaction was quenched with NH4Cl (30 mL) and diluted with  (30 mL). The mixed organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain the residue. The residue was purified using FCC (80g, silica gel, PE / EA=60%) to obtain compound 3 (5.0g, 43% yield) as a yellow solid.

[0186] Step 2: tert-butyl 3-(2,4-dinitrophenoxy)-2,2-dimethyl-3-(3-methyl-2-nitroimidazole-4-yl)propionate (16). A solution of tert-butyl 3-hydroxy-2,2-dimethyl-3-(3-methyl-2-nitroimidazole-4-yl)propionate (5 g, 0.017 mol), 1-fluoro-2,4-dinitrobenzene (3.7 g, 0.020 mol), and Cs2CO3 (9.15 g, 0.028 mol) in DMF (20 mL) was stirred and heated at 50°C for 1 hour. The reaction mixture was diluted with H2O (100 mL) and extracted with ELISA (100 mL x 3). The mixed organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain the residue. The residue was purified by FCC (80g, silica gel, PE / EA=60%) to obtain product 16 (6.2g, 80% yield) as a yellow solid. MS(ESI), m / z:C 19 H 23 Calculated value of N5O9, precise mass: 465.15 Measured value [M+H] += 466.1.

[0187] Synthesis scheme 11

[0188] [ka]

[0189] Step 1: (Cyclobutylidene (methoxy)methoxy)trimethylsilane. Lithium diisopropylamide (LDA, 22 mL, 44 mmol, 2M in THF) was added to a solution of methyl cyclobutanecarboxylate (4.0 g, 35 mmol) in THF (12 mL) under an N2 atmosphere at -78°C. The reaction mixture was stirred at -78°C for 1 hour. Subsequently, a solution of chlorotrimethylsilane (TMSCl, 4.75 g, 43.7 mmol) in THF (4 mL) was added. The reaction mixture was stirred at -78°C for 1 hour, and then stirred at room temperature for a further 10 hours. After the reaction was complete, the reaction mixture was diluted with PE (100 mL) and washed with water (100 mL). The organic layer was collected, dried over Na2SO4, and concentrated under reduced pressure to obtain the product (5.5 g, yield 84%) as a brown oil. 1 H NMR (400MHz, CDCl3): δ3.36(s,3H), 2.58-2.50(m,2H), 2.41-2.36(m,2H), 1.76-1.68(m,2H), 0.11(s,9H).

[0190] Step 2: 1-(hydroxy(1-methyl-2-nitro-1H-imidazole-5-yl)methyl)cyclobutan-1-carboxylate methyl. To a solution of a mixture of 1-methyl-2-nitro-1H-imidazole-5-carbaldehyde (110 mg, 0.71 mmol) and AcOLi (14 mg, 0.213 mmol) in DMF (2 mL), (cyclobutylidene(methoxy)methoxy)trimethylsilane (528 mg, 2.84 mmol) was added under an N2 atmosphere at 0°C. The reaction mixture was stirred at 0°C for 1 hour and at room temperature for 1 hour. After the reaction was complete, the reaction mixture was diluted with water (100 mL) and extracted with  (30 mL x 2). The mixed organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain the residue. The residue was purified over FCC (4 g silica gel,  in PE = 0-50%) to obtain the product (18 mg, yield 9%) as a brown oil. MS(ESI), m / z:C 11 H 15 Calculated value of N3O5: Precise mass: 269.10 Measured value: t R =0.932 minutes. [M+H] + =270.10; 1 H NMR (400MHz, CDCl3): δ6.68(s,1H), 4.87(d,J=10.4Hz,1H), 4.12(s,3H), 3.95(d,J=10.4Hz,1 H), 3.81(s,3H), 2.77-2.68(m,1H), 2.58-2.47(m,2H), 2.18-2.12(m,1H), 2.05-1.96(m,2H).

[0191] Step 3: 1-((2,4-dinitrophenoxy)(1-methyl-2-nitro-1H-imidazole-5-yl)methyl)cyclobutan-1-carboxylate methyl (17). Cs2CO3 (33 mg, 0.1 mmol) was added to a DMF (1 mL) container of a mixture of 1-(hydroxy(1-methyl-2-nitro-1H-imidazole-5-yl)methyl)cyclobutan-1-carboxylate methyl (18 mg, 0.07 mmol) and 1-fluoro-2,4-dinitrobenzene (16.2 mg, 0.087 mmol). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was diluted with saturated NaCl (50 mL) and extracted with ELISA (20 mL x 2). The mixed organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain the residue. The residue was purified by FCC (4g silica gel, MeOH in DCM = 0-5%), followed by prep-HPLC (C18 column, MeCN / H2O (0.1% FA)) to obtain product 17 (6mg, yield 20%) as a white solid. MS (ESI), m / z:C 17 H 17 Calculated value of N5O9: Precise mass: 435.10 Measured value: t R =1.333 minutes. [M+H] + =436; 1 H NMR (400MHz, CDCl3): δ8.77(d,J=2.4Hz,1H), 8.39(dd,J=9.2,2.4Hz,1H), 7.26(s,1H), 7.04(d,J=9.2H) z,1H), 5.87(s,1H), 4.10(s,3H), 3.77(s,3H), 2.60-2.41(m,4H), 2.23-2.11(m,1H), 1.94-1.84(m,1H).

[0192] Synthesis scheme 11

[0193] [ka]

[0194] Step 1: 3-(2,4-dinitrophenoxy)-2,2-dimethyl-3-(1-methyl-2-nitro-1H-imidazole-5-yl)-N-(2-oxopropyl)propanamide. A solution of compound 2 (250 mg, 0.61 mmol), 1-aminopropan-2-one hydrochloride (53 mg, 0.73 mmol), HATU (278 mg, 0.73 mmol), and DIPEA (275 mg, 2.14 mmol) in DMF (5 mL) was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was diluted with  (40 mL) and washed with water (50 mL x 2). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain the residue. The residue was purified in FCC (12 g silica gel, 5% MeOH in DCM) to obtain the product (220 mg, yield 78%) as a brown oil. MS (ESI), m / z:C 18 H 20 Calculated value of N6O9: Precise mass: 464.13 Measured value: t R =1.150 minutes. [M+H] + = 465.

[0195] Step 2: 2-(1-(2,4-dinitrophenoxy)-2-methyl-1-(1-methyl-2-nitro-1H-imidazole-5-yl)propan-2-yl)-5-methyloxazole (18). To a stirred solution of 3-(2,4-dinitrophenoxy)-2,2-dimethyl-3-(1-methyl-2-nitro-1H-imidazole-5-yl)-N-(2-oxopropyl)propanamide (140 mg, 0.61 mmol) in DCM (2 mL), concentrated H2SO4 (2 mL) was added at room temperature. The reaction mixture was then stirred and heated at 65°C for 2 hours. After the reaction was complete, the reaction mixture was poured into water (50 mL) and extracted with DCM (30 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain the residue. The residue was purified by prep-HPLC (C18, MeCN / H2O (0.1% FA)) to obtain compound 18 (35 mg, yield 26%) as a white solid. MS (ESI), m / z:C 18 H 18 Calculated value of N6O8: Precise mass: 446.12 Measured value: t R =1.346 minutes, [M+H] + =447; 1H NMR (400MHz, CDCl3): δ8.74(d,J=2.8Hz,1H), 8.34(dd,J=9.2,2.8Hz,1H), 7.19(s,1H), 6.97(d ,J=9.2Hz,1H), 6.64(s,1H), 5.89(s,1H), 3.94(s,3H), 2.28(s,3H), 1.65(s,3H), 1.51(s,3H).

[0196] Synthesis scheme 12

[0197] [ka]

[0198] 3-(2,4-dinitrophenoxy)-2,2-dimethyl-3-(1-methyl-2-nitro-1H-imidazole-5-yl)propionic acid 2-(sulfoxy)ethyl (19). To a solution of compound 7 (90 mg, 0.20 mmol) in DCM (2 ml), solutions of DIPEA (256 mg, 1.98 mmol) and pyridine (156 mg, 1.98 mmol) in DCM (1 ml) were added at 0°C. Subsequently, a solution of chlorosulfuric acid (231 mg, 1.98 mmol) in DCM (1 mL) was added 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 water (20 mL) and extracted with DCM (20 mL x 2). The mixed organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain the residue. The residue was purified by prep-HPLC (C18, MeCN / H2O (0.1% NH3·H2O)) to obtain product 19 (52 mg, yield 49%) as a yellow solid. MS(ESI), m / z:C 17 H 19 N5O 13 Calculated value of S: Precise mass: 533.07 Measured value of t R =1.092 minutes. [MH] - =532; 1H NMR (400MHz, DMSO-d6): δ8.74(d,J=2.8Hz,1H), 8.36(dd,J=9.2,2.8Hz,1H), 7.48(d,J=9.2Hz,1H), 7.23 -6.94(m,5H), 6.36(s,1H), 4.21-4.11(m,2H), 4.09(s,3H), 3.93-3.81(m,2H), 1.34(s,3H), 1.22(s,3H).

[0199] Synthesis scheme 13

[0200] [ka]

[0201] Step 1: 2-((tert-butoxycarbonyl)amino)ethylmethylfumarate. Oxalyl chloride (1.47 g, 11.6 mmol) was added to a solution of (E)-4-methoxy-4-oxobuto-2-enoic acid (1 g, 7.7 mmol) in DCM (10 mL) at 0°C. The reaction mixture was stirred at 25°C for 3 hours under an N2 atmosphere. The reaction mixture was evaporated under reduced pressure to obtain the crude product, methyl(E)-4-chloro-4-oxobuto-2-enoic acid (1 g, yield 88%), as a brown solid.

[0202] To a 10 mL solution of N-Boc-ethanolamine (1.31 g, 8.08 mmol) and TEA (1.63 g, 16.2 mmol) in DCM, a 5 mL solution of (E)-4-chloro-4-oxobuto-2-enoate methyl (800 mg, 5.39 mmol) in DCM was added at 0°C. The reaction mixture was stirred at 0°C for 1 hour under an N2 atmosphere. The reaction was quenched with water (50 mL) and extracted with DCM (3 × 10 mL). The mixed organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was purified by silica gel column chromatography (PE / EA = 30 / 1 to 10 / 1) to obtain 2-((tert-butoxycarbonyl)amino)ethyl fumarate methyl (400 mg, yield 27%) as a white solid. MS (ESI), m / z:C 12 H 19Calculated value of NO6: Precise mass: 273.121 Measured value: t R =1.815 minutes. [M+H-100] + =174.1; 1 H NMR (400MHz, CDCl3) δ6.88(s,2H), 4.77(br.s,1H), 4.27(t,J=5.3Hz,2H), 3.82(s,3H), 3.45(d,J=5.1Hz,2H), 1.45(s,9H).

[0203] Step 2: 2-Methyl 2-aminoethyl fumarate hydrochloride. 2-((tert-butoxycarbonyl)amino)ethyl fumarate methyl (450 mg, 1.64 mmol) in dioxane / HCl (9 mL). The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was evaporated under reduced pressure to obtain 2-methyl 2-aminoethyl fumarate hydrochloride (270 mg, 64% yield) as an off-white solid. MS(ESI), m / z:C7H 11 Calculated value of NO4: Precise mass: 173.069 Measured value: t R =0.353 minutes. [M+H] + =174.1; 1 H NMR(400MHz,DMSO_d6)δ8.16(br.s,3H), 6.99(d,J=15.9Hz,1H), 6.77(d,J=15.9Hz,1H), 4.34(t,J=5.2Hz,2H), 3.77(s,3H), 3.15(t,J=5.2Hz,2H).

[0204] Step 3: 2-(3-(2,4-dinitrophenoxy)-2,2-dimethyl-3-(1-methyl-2-nitro-1H-imidazole-5-yl)propanamide)methyl ethyl fumarate (20). To a solution of 2-aminoethyl methyl fumarate hydrochloride (156 mg, 0.64 mmol) and compound 2 (130 mg, 0.32 mmol) in DMF (3 mL), HOBT (51.5 mg, 0.38 mmol), EDCI (73.1 mg, 0.38 mmol), and TEA (128 mg, 1.27 mmol) were added. The reaction mixture was stirred at room temperature under an N2 atmosphere for 16 hours. The reaction was quenched with water (10 mL) and extracted with EA (3 × 3 mL). The mixed organic layer was washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was purified by prep-TLC (DCM / MeOH=20 / 1) to obtain product 20 (90 mg, yield 48%) as a pale yellow solid. MS(ESI), m / z:C 22 H 24 N6O 12 Calculated value: Precise mass: 564.145 Measured value: t R = 1.639 minutes and 1.699 minutes. [M+H] + =565.2; 1 H NMR(400MHz, CDCl3) δ8.76(t,J=2.8Hz,1H), 8.38-8.32(m,1H), 7.23(d,J=14.9Hz,1H), 7.03(d,J=9.2Hz,0.4H), 6.89(t,J=8.1Hz,0.6H), 6.87-6.75(m,2H), 6.41(br.s,0.55H) ), 6.19(br.s,0.45H), 6.04(d,J=3.2Hz,1H), 4.38-4.26(m,1.6H), 4.24-4.14(m,3.4H) , 3.82(d,J=2.2Hz,3H), 3.72-3.48(m,2H), 1.48(d,J=3.3Hz,3H), 1.23(d,J=9.4Hz,3H).

[0205] [Table 2-1]

[0206] [Table 2-2]

[0207] [Table 2-3]

[0208] [Table 2-4]

[0209] Study I. Pharmacokinetic studies in mice General Protocol Male C57BL / 6 mice (body weight 20-40g, bred by Zhejiang Vital River or SLAC) were randomly assigned to groups (n=3) and administered the test substance intravenously (1 mg / kg, 5 mL / kg) or orally (5 mg / kg, 10 mL / kg). The formulations were prepared by adding an appropriate amount of solvent to the test substance to achieve the desired concentration. Mice in the intravenous administration group received a single intravenous bolus injection of the test substance via the tail vein. Mice in the oral administration group received the test substance orally. At each time point (2 minutes after administration (intravenous administration only), 5 minutes (oral administration only), 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours), at least 30 μL of blood was collected from the saphenous vein or mandibular vein. Whole blood was immediately collected on wet ice into an EP tube containing EDTA-K2, centrifuged at 3500 g, 4°C for 5 minutes, and plasma was obtained within 30 minutes. Plasma samples were placed in sealed tubes on dry ice and stored in a -80°C freezer until analysis. The concentrations of analytes in mouse plasma were quantified by LC-MS / MS based on multiple reaction monitoring (MRM) of fragment ions. This method consisted of two independent standard curves encompassing all other samples. Three levels of QC (low, medium, high) were used to ensure assay reliability. Pharmacokinetic parameters were calculated using non-compartmental analysis with Phoenix WinNonlin software (version 8.3, Certara, Princeton, New Jersey).

[0210] Table 2 shows the pharmacokinetics of 2,4-DNP after intravenous administration (1 mg / kg) and oral administration (5 mg / kg) in male C57BL / 6 mice, respectively, and Figure 1 shows the mean plasma concentration.

[0211] [Table 3]

[0212] a Mouse PK parameters (mean, n=3). b Intravenous administration (1 mg / kg). c Oral administration (5 mg / kg)

[0213] Table 3 shows the results of pharmacokinetic studies of compound 1 and its metabolite 2,4-DNP after intravenous administration (1 mg / kg) and oral administration (5 mg / kg) of compound 1 to male C57BL / 6 mice. Figure 2 shows the mean plasma concentrations of compound 1 and its metabolite 2,4-DNP.

[0214] [Table 4]

[0215] a Mouse PK parameters (mean, n=3). b Intravenous administration (1 mg / kg). c Oral administration (5 mg / kg). d 2,4-dinitrophenol released from the parent compound

[0216] These data showed that compound 1 resulted in a significantly lower Cmax / AUC ratio in mice compared to 2,4-DNP.

[0217] Table 4 shows the results of pharmacokinetic studies of compound 7 and its metabolite 2,4-DNP after intravenous administration (1 mg / kg) or oral administration (5 mg / kg) of compound 7 to male C57BL / 6 mice. Figure 3 shows the mean plasma concentrations of compound 7 and its metabolite 2,4-DNP.

[0218] [Table 5]

[0219] a Mouse PK parameters (mean, n=3). b Intravenous administration (1 mg / kg). c Oral administration (5 mg / kg). d 2,4-dinitrophenol released from the parent compound

[0220] These data showed that compound 7 significantly reduced the Cmax / AUC ratio in mice compared to 2,4-DNP.

[0221] Study II. Pharmacokinetic studies in rats

[0222] General Protocol

[0223] Male SD rats (170-300g, Zhejiang Vital River) were randomly assigned to groups (n=3) and administered the test substance intravenously (1 mg / kg, 5 mL / kg) or orally (5 mg / kg, 10 mL / kg). The formulations were prepared by adding an appropriate amount of solvent to the test substance to achieve the desired concentration. In the intravenous administration group, the test substance was administered to the rats as a single intravenous bolus injection via the tail vein. In the oral administration group, the test substance was administered orally to the animals. At each time point (2 minutes after administration (intravenous administration only), 5 minutes (oral administration only), 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours), at least 65 μL of blood was collected from the jugular vein. Whole blood was immediately collected in an EP tube containing EDTA-K2, stored on moist ice, and centrifuged at 3500 g at 4°C for 5 minutes to obtain plasma within 30 minutes. Plasma samples were placed in sealed tubes on dry ice and then stored in a -80°C freezer until analysis. The concentrations of analytes in rat plasma were quantified by LC-MS / MS based on multiple reaction monitoring (MRM) of fragment ions. This method consisted of two independent standard curves that combined all other samples. Three levels of QC (low, medium, and high) were used to ensure assay reliability. Pharmacokinetic parameters were calculated using non-compartmental analysis with Phoenix WinNonlin software (version 8.3, Certara, Princeton, New Jersey).

[0224] Table 5 shows the results of pharmacokinetic studies of 2,4-DNP after intravenous administration (1 mg / kg) and oral administration (5 mg / kg) to male SD rats, and Figure 4 shows the mean plasma concentrations.

[0225] [Table 6]

[0226] a Rat PK parameters (mean, n=3). b Intravenous administration (1 mg / kg). c Oral administration (5 mg / kg).

[0227] Table 6 shows the results of pharmacokinetic studies of compound 1 and its metabolite 2,4-DNP after intravenous administration (1 mg / kg) or oral administration (5 mg / kg) to male SD rats. Figure 5 shows the mean plasma concentrations of compound 1 and its metabolite 2,4-DNP.

[0228] [Table 7]

[0229] a Rat PK parameters (mean, n=3). b Intravenous administration (1 mg / kg). c Oral administration (5 mg / kg). d 2,4-dinitrophenol released from parent compound 1

[0230] The results showed that compound 1 exhibited a significant decrease in the Cmax / AUC ratio compared to 2,4-DNP in rats.

[0231] Table 7 shows the results of pharmacokinetic studies of compound 7 and its metabolite 2,4-DNP after intravenous administration (1 mg / kg) or oral administration (5 mg / kg) to male SD rats. Figure 6 shows the mean plasma concentrations of compound 7 and its metabolite 2,4-DNP.

[0232] [Table 8]

[0233] a Rat PK parameters (mean, n=3). b Intravenous administration (1 mg / kg). c Oral administration (5 mg / kg). d 2,4-dinitrophenol released from parent compound 7

[0234] The results showed that compound 7 exhibited a significant decrease in the Cmax / AUC ratio compared to 2,4-DNP in rats.

[0235] Study III. Pharmacokinetic studies in dogs

[0236] General Protocol

[0237] Male Beagle dogs (7-10 kg, Beijing Marshall Biotechnology) were randomly assigned to groups (n=3) and administered the test substance intravenously (1 mg / kg, 5 mL / kg) or orally (5 mg / kg, 10 mL / kg). The formulations were prepared by adding an appropriate amount of solvent to the test substance to achieve the desired concentration. In the intravenous administration group, the dogs received a single intravenous bolus injection of the test substance. In the oral administration group, the dogs received oral administration of the test substance. At least 150 μL of blood was collected at each time point (5 minutes after administration (intravenous administration only), 10 minutes (oral administration only), 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours, 48 ​​hours (oral administration only)). Whole blood was immediately collected on wet ice into an EP tube containing EDTA-K2, centrifuged at 3500 g at 4°C for 5 minutes, and plasma was collected within 30 minutes. Plasma samples were placed in sealed tubes on dry ice and then stored in a -80°C freezer until analysis. The concentrations of analytes in rat plasma were quantified by LC-MS / MS based on multiple reaction monitoring (MRM) of fragment ions. This method consisted of two independent standard curves that combined all other samples. Three levels of QC (low, medium, and high) were used to ensure assay reliability. Pharmacokinetic parameters were calculated using non-compartmental analysis with Phoenix WinNonlin software (version 8.3, Certara, Princeton, New Jersey).

[0238] Table 8 shows the results of pharmacokinetic studies of compound 7 and its metabolite 2,4-DNP after intravenous administration (1 mg / kg) or oral administration (5 mg / kg) to male beagle dogs. Figure 7 shows the mean plasma concentrations of compound 7 and its metabolite 2,4-DNP.

[0239] [Table 9]

[0240] a PK parameters in dogs (mean values, n=3). b Intravenous administration (1 mg / kg). c Oral administration (5 mg / kg). d 2,4-dinitrophenol released from parent compound 7

[0241] The results showed that compound 7 exhibited a low Cmax / AUC ratio.

[0242] Experiment IV. Rectal temperature measurement in rats

[0243] General Protocol

[0244] Male SD rats (200-250g, Zhejiang Vital River) were randomly assigned to groups (n=8) and administered orally with the desired compound at various doses. The formulations were prepared before the experiment by adding an appropriate amount of solvent to the test substance to achieve the desired concentration. Rectal temperature was measured at 0, 15, 30, 45, 60, 90, and 120 minutes after administration using a microprobe thermometer (Physitemp Instruments).

[0245] Figure 8 shows the rectal temperature results after single oral administration of 2,4-DNP at doses of 5 mg / kg, 25 mg / kg, and 125 mg / kg to SD rats. Figure 9 shows the survival curves.

[0246] Figure 10 shows the rectal temperature results after single oral administration of 2,4-DNP at 25 mg / kg and compound 1 at 50 mg / kg and 500 mg / kg to SD rats. No significant difference in temperature was observed between the solvent group and the compound 1 treatment group. No dose-dependent deaths were observed.

[0247] The results disclosed herein support the conclusion that compound 1 did not cause an increase in body temperature compared to the solvent group, even at a dose of 500 mg / kg, whereas 2,4-DNP significantly increased body temperature at a dose of 25 mg / kg. This result is consistent with the lower Cmax / AUC ratio of compound 1 compared to 2,4-DNP, leading to an improved safety profile.

[0248] Test V. The compound protects dopaminergic neurons and improves behavioral disorders in a mouse model of Parkinson's disease.

[0249] General Protocol

[0250] The benefits of compound 7 for treating Parkinson's disease were evaluated using wild-type mice injected with 6-hydroxydopamine hydrobromide (6-OHDA). The neuroprotective effects of different doses of compound 7 (2.5 mg / kg, 8 mg / kg, or 16 mg / kg) on ​​dopaminergic degeneration of substantia nigra and striatal neurons induced by a single stereotactic injection of 6-OHDA into the medial forebrain bundle (MFB) region were investigated in 8-week-old male C57BL / 6 mice. Compound 7 was administered orally daily starting 3 days before the 6-OHDA stereotactic injection and continued for 5 weeks. The dose was 10 mL / kg. Mice were randomly assigned to five treatment groups (10 mice per group). Five weeks after 6-OHDA injection, animals were injected with apomorphine and behavioral changes were evaluated. The animals exhibited a consistent number of counterclockwise whole-body rotations within 30 minutes, indicating a successful PD model. Subsequently, motor skills were evaluated using rotorod tests and gripping force measurements. Finally, the animals were slaughtered, and brain samples were collected for further analysis.

[0251] We quantified tyrosine hydroxylase (TH) immunoreactive neurons. Figures 11-15 show the protective effects of treatment with compound 7 against dopaminergic neuron loss and behavioral disorders.

[0252] Treatment with compound 7 improved motor impairment in a 6-OHDA mouse PD model. As shown in Figure 11, the mice's ability to stay on the rotorod was stable, and the mice were assigned to different treatment groups based on baseline values ​​of time on the rotorod before 6-OHDA injection and before treatment with the compound. The duration on the rotorod after 5 weeks of treatment with compound 7 showed a dose-dependent trend (Figure 12), indicating an improvement in the mice's ability to avoid falling off the rotorod. In addition, maximal gripping force was significantly improved after treatment with compound 7 (2.5 mpk, 8 mpk, 16 mpk) (Figure 13).

[0253] Furthermore, to investigate whether compound therapy could improve dopaminergic neuron loss in the 6-OHDA PD model, tyrosine hydroxylase (TH)-positive neurons were evaluated. As shown in Figures 14 and 15, 16mpk compound 7 was effective in protecting against dopaminergic neuron loss in the substantia nigra and striatum after 6-OHDA injection. Mice treated with 16mpk compound 7 showed significantly more TH-immunoreactive neurons in the substantia nigra compared to control mice. In addition, TH levels in the striatum were better maintained in the 16mpk compound 7 group compared to the control group, suggesting a neuroprotective effect of compound 7.

[0254] The applicant's disclosures are described herein in preferred embodiments with reference to the drawings, and similar numbers represent identical or similar components. Throughout this specification, any reference to “one embodiment,” “embodiment,” or similar expressions means that a particular function, structure, or feature described in relation to that embodiment is included in at least one embodiment of the present invention. Thus, throughout this specification, every occurrence of “one embodiment,” “embodiment,” and similar expressions does not necessarily refer to the same embodiment, but may.

[0255] The functions, structures, or features described in the applicant's disclosure can be combined in any suitable manner in one or more embodiments. This specification provides numerous specific details to fully understand embodiments of the invention. However, those skilled in the art will recognize that the applicant's compositions and / or methods can be implemented without using one or more specific details, or using other methods, components, materials, etc. In other instances, well-known structures, materials, or operations are not shown or described in detail, so as not to obscure the nature of the disclosure.

[0256] Similar or equivalent methods and materials to those described herein may also be used in carrying out or testing the disclosure; however, preferred methods and materials are described here. The methods described herein may be carried out in any logically possible order, in addition to the specific order disclosed.

[0257] Reference

[0258] This disclosure includes references and citations to other documents, such as patents, patent applications, patent publications, journals, books, articles, and web content. All of these documents are incorporated herein by reference in their entirety for any purpose. If any material or any part thereof that is incorporated herein by reference conflicts with any existing definitions, descriptions, or other disclosures expressly set forth herein, such material shall be incorporated only to the extent that it does not create a conflict between the incorporated material and the disclosures herein. In the event of any conflict, this disclosure shall prevail.

[0259] Equivalents

[0260] The representative examples are intended to aid in illustrating the present invention and are not intended to limit the scope of the invention, nor should they be construed as such. In fact, various variations of the invention and many further embodiments, in addition to those shown and described herein, will be apparent to those skilled in the art from the entirety of this specification, including the examples and references to the scientific and patent literature contained herein. The examples contain important additional information, examples, and guidance applicable to the implementation of various embodiments of the invention and their equivalents.

Claims

1. Structural formula (I) 【Chemistry 1】 A compound having or a pharmaceutically acceptable form thereof or an isotopic derivative thereof, R １ and R ２ Each of them is independently C １－６ Alkyl or R １ and R ２ Together with the carbon atoms to which they are bonded, they form a 3- to 8-membered carbon ring or heterocycle, C １－６ Alkyl groups and 3- to 8-membered carbon rings or heterocycles optionally contain 1 to 6 R Ａ Replaced by, R Ｘ is L - R Ｘ１ or L - R Ｘ２ or L - R Ｘ３ and L is a single bond or (CH ２ ) ｎ And n is 1, 2, or 3. R Ｘ１ is C(=O)OR ３ , C(=O)NR ４ R ５ , OR ６ , NR ７ R ８ , NR ９ C(=O)R １０ OC(=O)R １１ A group selected from , halo, and CN, R Ｘ２ This involves selecting 1 to 4 R's arbitrarily. Ｂ A monocyclic carbon ring, heterocyclic ring, aryl group, or heteroaryl group of a five-membered or six-membered ring that is substituted with, R Ｘ３ This involves selecting 1 to 6 R's arbitrarily. Ｂ A bicyclic carbon ring, heterocycle, aryl group, or heteroaryl group of 8 to 10 members that is substituted with, R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , R １０ , and R １１ Each of them is, Selectively choose 1 to 6 R Ａ H and C are replaced by １－６ A alkyl group, a 3- to 8-membered carbocyclic ring, or a heterocyclic ring can be independently selected, or R ４ and R ５ or R ７ and R ８ Each of these atoms, along with the N atom to which they are bonded, optionally contains 1 to 6 R atoms. Ａ It forms a 3- to 8-membered heterocycle by substitution, R Ａ Each is independently selected from the groups consisting of D, Halo, R, and OR. R Ｂ These are D, Halo, CN, R, OR, NRR', C(=O)OR, C(=O)NRR', NRC(=O)R', OC(=O)R, SO ４ R and the group consisting of OC(=O)CHCHC(=O)OR' are independently selected, R and R' are each independently H or C １－３ A compound that is an alkyl group, or a pharmaceutically acceptable form thereof, or an isotopic derivative thereof.

2. The following shows the chirality. 【Chemistry 2】 A compound according to claim 1 or a pharmaceutically acceptable form thereof, or an isotopic derivative thereof, having the above.

3. The following shows the chirality. 【Transformation 3】 A compound according to claim 1 or a pharmaceutically acceptable form thereof, or an isotopic derivative thereof, having the above.

4. R １ and R ２ Each of them is independently C １－３ A compound according to any one of claims 1 to 3, which is alkyl, or a pharmaceutically acceptable form thereof, or an isotopic derivative thereof.

5. R １ and R ２ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable form thereof, or an isotopic derivative thereof, wherein each of the isotopes is methyl.

6. R １ and R ２ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable form thereof, or an isotopic derivative thereof, wherein the carbon atoms to which they are bonded form a 3- to 6-membered carbon ring.

7. The compound according to claim 6, or a pharmaceutically acceptable form thereof, or an isotopic derivative thereof, wherein the 3- to 6-membered carbon ring is cyclopropyl.

8. R １ and R ２ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable form thereof, or an isotopic derivative thereof, wherein the carbon atoms to which they are bonded form a 3- to 6-membered heterocycle.

9. R Ｘ L-R Ｘ１ The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable form thereof, or an isotopic derivative thereof.

10. R Ｘ L-R Ｘ２ The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable form thereof, or an isotopic derivative thereof.

11. R Ｘ L-R Ｘ３ The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable form thereof, or an isotopic derivative thereof.

12. R Ｘ１ is C(=O)OR ３ The compound according to claim 9, or a pharmaceutically acceptable form thereof, or an isotopic derivative thereof.

13. R Ｘ１ C(=O)NR ４ R ５ The compound according to claim 9, or a pharmaceutically acceptable form thereof, or an isotopic derivative thereof.

14. R Ｘ２ It is a five-membered ring heteroaryl group, with 1 to 4 R Ｂ The compound according to claim 10, or a pharmaceutically acceptable form thereof, or an isotopic derivative thereof, which may be substituted with.

15. R Ｘ２ This is a six-membered ring aryl group or heteroaryl group, with 1 to 4 R Ｂ The compound according to claim 10, or a pharmaceutically acceptable form thereof, or an isotopic derivative thereof, which may be substituted with.

16. R Ｘ３ This is a nine-membered ring bicyclic aryl group or heteroaryl group, with 1 to 6 R Ｂ The compound according to claim 11, or a pharmaceutically acceptable form thereof, or an isotopic derivative thereof, which may be substituted with.

17. R Ｘ３ This is a 10-membered ring bicyclic aryl group or heteroaryl group, with 1 to 6 R Ｂ The compound according to claim 11, or a pharmaceutically acceptable form thereof, or an isotopic derivative thereof, which may be substituted with.

18. L is a single bond, the compound according to any one of claims 1 to 17, or a pharmaceutically acceptable form thereof, or an isotopic derivative thereof.

19. L is (CH ２ ) ｎ The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable form thereof, or an isotopic derivative thereof, wherein n is 1, 2, or 3.

20. The compound according to claim 19 or a pharmaceutically acceptable form thereof or an isotopic derivative thereof, wherein n is 1.

21. A compound selected from Table 1.

22. A compound according to any one of claims 1 to 21, having one or more deuterium atoms instead of one or more hydrogen atoms, or a pharmaceutically acceptable form thereof, or an isotopic derivative thereof.

23. The compound according to claim 22, or a pharmaceutically acceptable form thereof, or an isotopic derivative thereof, having one deuterium atom instead of one hydrogen atom.

24. A pharmaceutical composition comprising the compound described in any one of claims 1 to 23.

25. A unit dosage form comprising the pharmaceutical composition described in claim 24.

26. The unit dosage form according to claim 25 is a tablet.

27. The unit dosage form according to claim 25, which is a capsule.

28. A method for treating or alleviating a disease or disorder, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 23 to a subject in need thereof.

29. The method according to claim 28, wherein the disease or disorder is related to one or more defects in mitochondrial function.

30. The method according to claim 28, wherein the disease or disorder is obesity, diabetes mellitus, insulin resistance, liver disease, heart failure or renal failure, or a related disease or disorder.

31. The method according to claim 28, wherein the disease or disorder is obesity, excess body fat, diabetes mellitus, insulin resistance or intolerance, hypertension, dyslipidemia, cardiovascular disease, 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's ataxia, neurodegenerative diseases or liver diseases, or related diseases or disorders.

32. A method for reducing toxicity or side effects in the treatment of mitochondrial-related diseases or conditions, comprising administering a therapeutically effective amount of the compound described in any one of claims 1 to 23 to a subject in need thereof.

33. The method according to any one of claims 28 to 32, wherein the administration is by oral administration.

34. Use of a compound according to any one of claims 1 to 23 and a pharmaceutically acceptable excipient, carrier, or diluent in the preparation of a drug for treating a disease or disorder.

35. Use of the compound according to any one of claims 1 to 23 for the treatment of a disease or disorder.

36. The use according to claim 34 or 35, wherein the disease or disorder is related to one or more defects in mitochondrial function.

37. The use according to claim 35, wherein the disease or disorder is selected from the group consisting of obesity, excess body fat, diabetes mellitus, insulin resistance or intolerance, hypertension, dyslipidemia, cardiovascular disease, 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's ataxia, and liver disease, or related diseases or disorders.

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