1,4-naphthoquinone derivatives and preparation methods thereof

Abstract

The present invention relates to novel 1,4-naphthoquinone derivatives, preparation methods thereof, and uses thereof. When a compound of the present invention is used, the following effects can be achieved: enhanced NQO1 activity, increased NAD+, increased ATP, and improved mitochondrial function, and accordingly it is possible to prevent or treat related diseases.

Description

1,4-naphthoquinone derivative and method for producing the same

[0001] The present invention relates to a novel 1,4-naphthoquinone derivative, a method for producing the same, and uses thereof.

[0002] NAD (Nicotinamide adenine dinucleotide) is a coenzyme involved in various biochemical reactions in the body, and its oxidized form (NAD + ) and reduced form (NADH). NAD + It is necessary for glycolysis, which is the process by which cells break down sugars to create energy, and fatty acid oxidation, which creates energy from fat. NADH is essential for cellular metabolism, such as serving as a substrate used in the electron transport chain when mitochondria synthesize ATP. As aging or certain diseases progress, intracellular NAD + It is well known that the amount of NAD is rapidly reduced. + Increased activity of poly(ADP-ribose) polymerase (PARP), which repairs DNA damage using NAD as a substrate + It is closely related to the decrease in the activity of enzymes involved in the production of NAD in cells. + Research continues to find treatments for various diseases by increasing or at least maintaining the amount of NAD + How to regulate the salvage pathway, a biosynthetic process, NAD + How to supply synthetic precursors, activating enzymes that use NADH to produce intracellular NAD + NAD is being studied in various ways, including how to increase its concentration. + The synthetic precursor supply method has been reported to have limitations, such as low bioavailability and the salvage pathway modulation method has limited effect duration.

[0003]

[0004] NAD(P)H:quinone oxidoreductase 1 (NQO1) is a protein that maintains cellular homeostasis by removing external substances or oxidative stress. It is expressed in all tissues of the human body and exists at relatively low levels under normal conditions. However, it is known that the activity and expression of NQO1 are significantly increased in various diseases such as obesity, steatohepatitis related to metabolic disorders, muscle diseases, degenerative neurodegenerative diseases, cancer, and diseases caused by mitochondrial dysfunction. Meanwhile, NQO1 converts NADH to NAD through its enzymatic activity. + can be converted to and increased NAD + can induce effects such as improvement of cellular energy metabolism and mitochondrial function through sirtuins and AMP-activated protein kinase (AMPK). As a specific example, substrate compounds of NQO1, including β-Lapachone, can induce effects such as improvement of cellular energy metabolism and mitochondrial function through sirtuins and AMP-activated protein kinase (AMPK). + It shows therapeutic effects on various diseases such as metabolic diseases, neurodegenerative diseases, age-related diseases, mitochondrial diseases, inflammatory diseases and fibrotic diseases such as obesity, muscular dystrophy, Parkinson's disease, Huntington's disease, cancer, kidney disease, hypertension, hearing loss, heart disease, pulmonary fibrosis, MELAS syndrome and primary sclerosing cholangitis through increase. By utilizing the phenomenon of increased activity and expression of NQO1 in disease states, intracellular NAD + Although some attempts have been reported to treat diseases through effective increases in , their therapeutic effects are limited, and there is a growing need for new, more effective and safer substrate compounds.

[0005] Mitochondria are double-membrane organelles found in most eukaryotic cells, including animals, plants, and fungi. They generate cellular energy (adenosine triphosphate, ATP) through aerobic respiration. Mitochondria also play a crucial role in maintaining cellular homeostasis, including cell signaling, cell differentiation, apoptosis, the cell cycle, and growth control. Furthermore, mitochondrial dysfunction is well-known to be closely associated with various diseases, including metabolic diseases, muscle diseases, cancer, neurodegenerative diseases, and mitochondrial diseases. Among these, over 300 mitochondrial diseases are caused by mutations in nuclear DNA (nDNA) or mitochondrial DNA (mtDNA), which directly disrupt the expression and function of mitochondrial complex proteins. ATP synthesis disorders are the most common cause. Except for Leber hereditary optic neuropathy (LHON), all mitochondrial diseases have no approved treatments yet, and patients receive symptomatic treatment with antioxidants and vitamin cocktails. LHON is caused by a deficiency of mitochondrial complex I. Idebenone, a known NQO1 substrate, is approved in Europe under the brand name Raxone for treatment. Idebenone is known to treat the disease by inducing ATP synthesis by bypassing the dysfunction of mitochondrial complex I by transferring electrons obtained through reduction by NQO1 to mitochondrial complex III. However, existing compounds still have limitations in terms of bioavailability, target selectivity, and safety, and thus the development of more effective and improved novel drugs is necessary. Therefore, based on the characteristics of increased NQO1 activity and expression associated with various diseases mentioned above, intracellular NAD + There has been a need to develop novel drugs that optimize the ability of electron transport to the mitochondrial electron transport chain.

[0006] [Prior Art Literature]

[0007] [Patent Document]

[0008] (Patent Document 1) KR 10-2008-0039361 A

[0009] To meet the above-mentioned needs, the present inventors have developed NAD that acts as a substrate for NQO1. + We have conducted extensive research to develop novel compounds capable of preventing or treating diseases associated with decreased or impaired mitochondrial function and their associated symptoms. As a result, we have synthesized novel compounds exhibiting the aforementioned effects, thereby completing the present invention.

[0010] Accordingly, the object of the present invention is to provide a novel compound capable of acting as a substrate of NQO1, a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer or diastereomer thereof.

[0011] Another object of the present invention is to provide a pharmaceutical composition, cosmetic composition or food composition comprising the novel compound described above, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer or diastereomer thereof.

[0012] Another object of the present invention is to provide a method for producing the novel compound described above.

[0013]

[0014] According to one aspect of the present invention, the present invention provides a compound represented by the following chemical formula 1, a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer or diastereomer thereof:

[0015] [Chemical Formula 1]

[0016]

[0017] In the above formula,

[0018] The above R1 and R2 are each independently hydrogen, a halogen element, hydroxy, a substituted or unsubstituted alkoxy, a substituted or unsubstituted alkyl, or a substituted or unsubstituted cycloalkyl,

[0019] The above R3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl,

[0020] The above R4 is a substituted or unsubstituted aryl,

[0021] The above R5 is substituted or unsubstituted alkoxy.

[0022]

[0023] The features and advantages of the present invention are summarized as follows:

[0024] (a) The present invention provides novel compounds for preventing, improving or treating related symptoms and diseases due to enhancement of NQO1 activity.

[0025] (b) When using a composition containing the compound of the present invention as an active ingredient, intracellular NAD + It can achieve the effect of preventing, improving or treating diseases accompanied by a decrease or mitochondrial dysfunction.

[0026]

[0027] The present invention is described in more detail below.

[0028]

[0029] When the “substituted or unsubstituted” functional group in the present specification is substituted, the functional group may be substituted with any one or more selected from the group consisting of a halogen element, hydroxy, straight-chain or branched C1-C10 alkyl, straight-chain or branched C2-C10 alkenyl, straight-chain or branched C2-C10 alkynyl, straight-chain or branched C1-C10 alkoxy, straight-chain or branched C1-C10 alkoxycarbonyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C4-C10 aryl, and C2-C10 heteroaryl.

[0030] In another specific embodiment of the present invention, the “substituted” functional group in the present specification may be substituted with at least one selected from the group consisting of a halogen atom, hydroxy, straight or branched C1-C6 alkyl, straight or branched C1-C6 alkoxy, C6-C10 aryl, and C6-C10 heteroaryl.

[0031] Additionally, the above-described “substituting” functional group may be substituted as many times as possible within the range of, for example, 1 to 4.

[0032] The term "pharmaceutically acceptable salt" as used herein means a formulation of a compound that does not cause serious irritation to an organism to which the compound is administered and does not impair the biological activity and physical properties of the compound.

[0033] The terms “hydrate”, “solvate”, “prodrug”, “tautomer”, “enantiomer” or “diastereoisomer” in this specification also have the same meanings as above.

[0034] The above "pharmaceutically acceptable salt" includes acid addition salts formed by acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, etc., organic carboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid, etc., sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. For example, pharmaceutically acceptable carboxylic acid salts include metal salts or alkaline earth metal salts formed by lithium, sodium, potassium, calcium, magnesium, etc.; amino acid salts such as lysine, arginine, guanidine, etc.; organic salts such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline, and triethylamine, etc. The compound of formula 1 according to the present invention may also be converted into its salt by a conventional method.

[0035] The term "hydrate" means a compound of the present invention or a salt thereof containing a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[0036] The term "solvate" refers to a compound of the present invention or a salt thereof that contains a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents include those that are volatile, non-toxic, and / or suitable for human administration.

[0037] The term "prodrug" refers to a substance that is transformed into the parent drug in vivo. Prodrugs are often used because, in some cases, they are easier to administer than the parent drug. For example, they may be bioactive when administered orally, whereas the parent drug may not. Prodrugs may also have improved solubility in pharmaceutical compositions compared to the parent drug. For example, a prodrug might be a compound administered as an ester ("prodrug"), which facilitates membrane passage, although water solubility would impede mobility. Once in cells where water solubility is beneficial, the prodrug is metabolized to the active carboxylic acid, which facilitates membrane passage.

[0038] The term "tautomer" refers to a type of structural isomer that has the same chemical or molecular formula but different ways in which its constituents are connected, such as the keto-enol structure, which continuously changes its structure by shuttling between the two isomers.

[0039] The term "enantiomers or pharmaceutically acceptable diastereomers" refers to isomers that have the same chemical formula or molecular formula but are formed due to different spatial arrangements of atoms within the molecule. The term "enantiomer" refers to an isomer that is not superimposable with its mirror image, like the relationship between right and left hands, and further, "diastereomer" refers to a stereoisomer that is not a mirror image relationship, such as trans or cis. All of these isomers and mixtures thereof are also included in the scope of the present invention.

[0040] The term "alkyl" refers to an aliphatic hydrocarbon group. In the present invention, alkyl is used as a concept including both "saturated alkyl" meaning that it does not contain any alkene or alkyne moiety, and "unsaturated alkyl" meaning that it contains at least one alkene or alkyne moiety, and specifically, it may be a "saturated alkyl" meaning that it does not contain any alkene or alkyne moiety. The alkyl may include a branched, straight-chain, or cyclic type, and also includes structural isomers, so for example, in the case of C3 alkyl, it may mean propyl, isopropyl, or cyclopropyl.

[0041] The term "heteroalkyl" refers to an alkyl group that contains at least one heteroatom (e.g., oxygen, nitrogen, sulfur, etc.) in addition to carbon and hydrogen. Like alkyl, heteroalkyl groups can be branched, straight-chain, or cyclic, and include structural isomers.

[0042] The term "alkene" refers to a group of at least two carbon atoms with at least one carbon-carbon double bond, and "alkyne" refers to a group of at least two carbon atoms with at least one carbon-carbon triple bond.

[0043] The term "alkoxy" refers to a substituent having a structure in which an alkyl group is connected through an oxygen atom. Specific examples include methoxy (-OCH3) and ethoxy (-OCH2CH3).

[0044] The term “cycloalkyl” refers to a saturated hydrocarbon group in which three or more carbon atoms form a ring structure.

[0045] The term "heterocycloalkyl" refers to a cycloalkyl in which a ring carbon is replaced by oxygen, nitrogen, sulfur, etc.

[0046] The term "aryl" refers to an aromatic substituent having at least one ring with a shared pi electron system. The term includes monocyclic or fused ring polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) groups. When substituted, the substituent may be attached at the ortho (o), meta (m), or para (p) positions, as appropriate.

[0047] The term "heteroaryl" refers to an aromatic group in which at least one of the ring carbon atoms constituting the aryl is replaced with oxygen, nitrogen, sulfur, etc.

[0048] Examples of the above aryl or heteroaryl include, but are not limited to, phenyl, furan, pyran, pyridyl, pyrimidyl, triazyl, etc.

[0049] The term "thioalkyl" refers to a substituent having a structure in which an alkyl group is connected via a sulfur atom. Specific examples include methylthio (-SCH3), ethylthio (-SCH2CH3), etc. The alkyl included in thioalkyl may have a straight-chain, branched-chain, or cyclic structure, and is not particularly limited.

[0050] The term "halogen" refers to elements in group 17 of the periodic table, specifically fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0051] The term "aryloxy" refers to a group in which one of the carbons forming the aromatic substituent is bonded to oxygen, for example, when oxygen is bonded to a phenyl group, it can be expressed as -O-C6H5, -C6H4-O-.

[0052] Other terms may be interpreted as having the meaning commonly understood in the field to which the present invention belongs.

[0053] In one embodiment of the present invention, R1 and R2 of formula 1 may each independently be hydrogen, a halogen element, hydroxy, a substituted or unsubstituted C1 to C10 alkoxy, a substituted or unsubstituted C1 to C10 alkyl, or a substituted or unsubstituted C3 to C8 cycloalkyl.

[0054] In another embodiment of the present invention, R1 and R2 of formula 1 can each independently be hydrogen, a substituted or unsubstituted C1 to C10 alkyl, or a substituted or unsubstituted C3 to C8 cycloalkyl.

[0055] In another embodiment of the present invention, R1 and R2 of formula 1 can each independently be hydrogen, a substituted or unsubstituted C1 to C6 alkyl, or a substituted or unsubstituted C5 to C8 cycloalkyl.

[0056] In another embodiment of the present invention, R1 and R2 of formula 1 may each independently be hydrogen, or substituted or unsubstituted C1 to C4 alkyl.

[0057] For example, R1 and R2 in the formula 1 can each independently be hydrogen or an unsubstituted C1 to C4 alkyl, and the unsubstituted C1 to C4 alkyl can have a straight or branched chain structure. The unsubstituted C1 to C4 alkyl as described above can be specifically, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl.

[0058] In another specific embodiment, R1 and R2 of formula 1 can each independently be hydrogen or methyl.

[0059] In embodiments of the present invention, R1 and R2 of chemical formula 1 may be bonded as substituents on carbon or nitrogen constituting the pyrazine ring, and in one specific example, may be bonded by replacing hydrogen bonded to carbon constituting the pyrazine ring.

[0060] In another embodiment of the present invention, R3 of formula 1 may be hydrogen, substituted or unsubstituted C1 to C6 alkyl, or substituted or unsubstituted C3 to C8 cycloalkyl.

[0061] More specifically, for example, R3 in chemical formula 1 can be hydrogen or unsubstituted C1 to C4 alkyl, and the unsubstituted C1 to C4 alkyl can have a straight or branched chain structure. The unsubstituted C1 to C4 alkyl as described above can be specifically, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl.

[0062] In another embodiment, R3 of formula 1 can be hydrogen or methyl.

[0063] In one embodiment of the present invention, R4 in chemical formula 1 is substituted or unsubstituted phenyl.

[0064] In one embodiment of the present invention, the above-described substituted phenyl that can be selected as R4 of Chemical Formula 1 may be substituted with any one, or two or more substituents that are the same or different, selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, and halogen elements. The halogen element may be fluorine, chlorine, bromine, or iodine, and more specifically, for example, fluorine or chlorine. The substituted or unsubstituted alkyl that can be bonded to the phenyl may be specifically, for example, C1 to C4 alkyl, and may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl, and more specifically, may be, for example, methyl or ethyl.

[0065] In one embodiment of the present invention, the above-described substituted alkyl that may be substituted for the substituted phenyl selected as R4 of Chemical Formula 1 may be substituted with one to three halogen elements. The halogen elements may be fluorine, chlorine, bromine, or iodine.

[0066] In one embodiment of the present invention, the above-described substituted phenyl that can be selected as R4 of Chemical Formula 1 may be substituted with one or more substituents selected from the group consisting of unsubstituted C1 to C4 alkyl, unsubstituted C1 to C4 alkoxy, C1 to C4 alkyl substituted with 1 to 3 halogen elements, and halogen elements. The unsubstituted C1 to C4 alkyl may be specifically, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl. The above unsubstituted C1 to C4 alkoxy includes a C1 to C4 alkyl group bonded to oxygen, and specifically, for example, may be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl, and more specifically, may be methyl or ethyl, and thus, the alkoxy may be methoxy or ethoxy, but is not necessarily limited thereto.

[0067] In one embodiment of the present invention, the halogen element in the 'C1 to C4 alkyl substituted with 1 to 3 halogen elements' that may be substituted for the phenyl of the substitution that may be selected as R4 of the chemical formula 1 may be fluorine.

[0068] In one embodiment of the present invention, R5 is a substituted or unsubstituted alkoxy. In addition, the substituted or unsubstituted alkoxy that may be selected as R5 may be more specifically selected as, for example, methoxy or ethoxy.

[0069]

[0070] In one embodiment of the present invention, the compound of formula 1 may be any one or more compounds selected from the group consisting of compounds 1 to 43 below. However, the compounds below are only some of the embodiments of compounds that can be assumed from the detailed description of the invention described above and are not necessarily limited thereto. The embodiments of the compounds below demonstrate that the compound of formula 1 of the present invention exhibits certain usefulness even when including various substituent changes:

[0071]

[0072]

[0073] According to another aspect of the present invention, the present invention provides a composition for enhancing NQO1 activity comprising the compound described above.

[0074] The composition of the present invention specifically comprises NAD(P)H:quinone oxidoreductase (NQO1) as a redox enzyme, which is an in vivo NAD + / It can increase the AMP / ATP ratio by inducing an increase in the ratio of NADH. This increase in AMP in the cell activates AMPK, which acts as an energy gauge, and promotes fat metabolism by activating the expression of PGC1a, which activates energy metabolism in mitochondria, thereby replenishing the insufficient ATP energy. In addition, the composition reduced by NQO1 plays a role in inducing ATP synthesis by transferring electrons to mitochondrial complex III. Meanwhile, the NAD increased by the composition + It is used as a cofactor for enzymes related to glucose and fat metabolism in the body, promoting metabolism and NAD + cADPR, which is generated by the breakdown of Ca, is released into the endoplasmic reticulum (ER). 2+It can have an in vivo exercise-mimetic effect by synergistically activating mitochondrial metabolism by releasing mitochondrial peptides. Through this, it can exhibit preventive or therapeutic activities for various metabolic diseases and diseases related to mitochondrial activity.

[0075] In one embodiment of the present invention, the composition of the present invention may be provided in the form of a pharmaceutical composition, a cosmetic composition, or a food composition.

[0076]

[0077] According to another aspect of the present invention, the present invention provides a pharmaceutical composition for preventing or treating a disease related to NQO1, comprising the compound described above.

[0078] In one embodiment of the present invention, the NQO1-related disease of the present invention may be any one selected from the group consisting of metabolic diseases such as obesity, diabetes, and metabolic disorder-related steatohepatitis, primary and secondary mitochondrial diseases, muscle diseases, degenerative neurodegenerative diseases, inflammatory diseases, fibrotic diseases, autoimmune diseases, and cancer, but is not limited thereto.

[0079] When the present invention is provided in the form of a pharmaceutical composition, the composition of the present invention comprises a pharmaceutically acceptable carrier in addition to the active ingredient. The pharmaceutically acceptable carrier contained in the pharmaceutical composition of the present invention is one commonly used in formulation, and includes, but is not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. In addition to the above components, the pharmaceutical composition of the present invention may further comprise a lubricant, a wetting agent, a sweetener, a flavoring agent, an emulsifier, a suspending agent, a preservative, and the like. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington's Pharmaceutical Sciences (19th ed., 1995).

[0080] The appropriate dosage of the pharmaceutical composition of the present invention may vary depending on factors such as the formulation method, administration method, patient age, body weight, sex, pathological condition, food, administration time, administration route, excretion rate, and response sensitivity. Meanwhile, the dosage of the pharmaceutical composition of the present invention is preferably 0.001-1000 mg / kg (body weight) per day.

[0081] The pharmaceutical composition of the present invention can be administered orally or parenterally. When administered parenterally, it can be administered by topical application to the skin, intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal administration, etc. Considering that the pharmaceutical composition of the present invention is applied to enhance NQO1 activity, oral administration or parenteral administration in the form of an injection is preferable.

[0082] The pharmaceutical composition of the present invention can be manufactured in a unit dose form or can be manufactured by placing it in a multi-dose container by formulating it using a pharmaceutically acceptable carrier and / or excipient according to a method that can be easily performed by a person having ordinary skill in the art to which the present invention pertains.

[0083] Conventional dosage forms include, for example, oral (tablets, capsules, powders), buccal, sublingual, rectal, vaginal, intranasal, topical or parenteral (including intravenous, intracavernosal, intramuscular, subcutaneous and intraductal) administration dosage forms. For example, the compounds according to the present invention may be administered orally, buccally or sublingually in the form of tablets containing starch or lactose, or in the form of capsules alone or with excipients, or in the form of elixirs or suspensions containing chemicals for flavoring or coloring. Liquid preparations are prepared with pharmaceutically acceptable excipients such as suspending agents (e.g., methylcellulose, semi-synthetic glycerides such as witepsol, or glyceride mixtures such as mixtures of apricot kernel oil and PEG-6 esters or mixtures of PEG-8 and caprylic / capric glycerides). In addition, when injected parenterally, for example, intravenously, intracavernosally, intramuscularly, subcutaneously, and intraductally, it is most preferable to use it in the form of a sterile aqueous solution, and in this case, the solution may contain other substances (for example, salt or monosaccharides such as mannitol or glucose) to have isotonicity with blood.

[0084] When the pharmaceutical composition of the present invention is administered orally, solid preparations for oral administration include tablets, pills, powders, granules, capsules, troches, etc., and these solid preparations are prepared by mixing one or more compounds of the present invention with at least one excipient, such as starch, calcium carbonate, sucrose, lactose, or gelatin. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, oral solutions, emulsions, or syrups, and in addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included.

[0085] Formulations for oral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solutions and suspensions can include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases include witepsol, macrogol, Tween 61, cocoa butter, laurin, glycerol, and gelatin.

[0086] The compound of the present invention can be used in the form of a pharmaceutically acceptable salt, and as a salt, an acid addition salt formed by a pharmaceutically acceptable free acid can be used. The acid addition salt is obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, non-toxic organic acids such as aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates and alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids, organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid and fumaric acid. These pharmaceutically non-toxic salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphate chlorides, bromides, iodides, fluorides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caprates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyn-1,4-dioate, hexane-1,6-dioate, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, Including, but not limited to, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate or mandelate.

[0087] The acid addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the compound of the present invention in an organic solvent, for example, methanol, ethanol, acetone, methylene chloride, acetonitrile, etc., adding an organic acid or inorganic acid, filtering and drying the resulting precipitate, or by distilling the solvent and an excess of acid under reduced pressure and then drying or crystallizing the same in an organic solvent.

[0088] Additionally, pharmaceutically acceptable metal salts can be prepared using bases. Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering out the undissolved compound salt, and evaporating and drying the filtrate. Among the metal salts, sodium, potassium, or calcium salts are pharmaceutically suitable. Furthermore, the corresponding silver salts are obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

[0089] The composition of the present invention can also be manufactured in the form of a cosmetic composition. The cosmetic composition of the present invention can be manufactured in any formulation commonly manufactured in the art, and for example, can be formulated as a solution, suspension, emulsion, paste, gel, cream, lotion, powder, soap, surfactant-containing cleansing, oil, powder foundation, emulsion foundation, wax foundation, and spray, etc., but is not limited thereto. More specifically, it can be manufactured in the form of a flexible toner, a nourishing toner, a lotion, a nourishing cream, a massage cream, an essence, an eye cream, a cleansing cream, a cleansing foam, a cleansing water, a pack, a spray, or a powder.

[0090] When the formulation of the present invention is a paste, cream, lotion, or gel, animal oil, vegetable oil, wax, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silica, talc, or zinc oxide may be used as a carrier component.

[0091] When the formulation of the present invention is a powder or spray, lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used as a carrier component, and particularly in the case of a spray, a propellant such as chlorofluorohydrocarbon, propane / butane or dimethyl ether may be additionally included.

[0092] When the formulation of the present invention is a solution or emulsion, a solvent, solubilizer or emulsifier is used as a carrier component, and examples thereof include water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylglycol oil, glycerol aliphatic ester, polyethylene glycol or fatty acid ester of sorbitan.

[0093] When the formulation of the present invention is a suspension, a liquid diluent such as water, ethanol or propylene glycol, a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar or tragacanth may be used as a carrier component.

[0094] When the formulation of the present invention is a surfactant-containing cleansing agent, aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyl taurate, sarcosinate, fatty acid amide ether sulfate, alkylamidobetaine, fatty alcohol, fatty acid glyceride, fatty acid diethanolamide, vegetable oil, lanolin derivative, or ethoxylated glycerol fatty acid ester may be used as a carrier component.

[0095] The components included in the cosmetic composition of the present invention include, in addition to the active ingredient and the carrier component, components commonly used in cosmetic compositions, and may include conventional excipients such as antioxidants, stabilizers, solubilizers, vitamins, pigments, and fragrances. The cosmetic composition of the present invention may be prepared in a form with enhanced percutaneous permeability, depending on the purpose, and can realize percutaneous permeation of the active ingredient through topical application on the skin, thereby achieving the desired effect.

[0096] The cosmetic composition of the present invention may be more suitable for achieving the NQO1 activation effect on a local area. For example, NAD + It can achieve the effect of preventing or improving symptoms or diseases caused by decreased or impaired mitochondrial function.

[0097] The composition of the present invention can be manufactured in the form of a food composition. The food composition of the present invention includes ingredients commonly added during food manufacturing, such as proteins, carbohydrates, fats, nutrients, and seasonings. For example, when manufactured as a drink, flavoring agents or natural carbohydrates may be included as additional ingredients in addition to the active ingredient. For example, natural carbohydrates include monosaccharides (e.g., glucose, fructose, etc.); disaccharides (e.g., maltose, sucrose, etc.); oligosaccharides; polysaccharides (e.g., dextrin, cyclodextrin, etc.); and sugar alcohols (e.g., xylitol, sorbitol, erythritol, etc.). Natural flavoring agents (e.g., thaumatin, stevia extract, etc.) and synthetic flavoring agents (e.g., saccharin, aspartame, etc.) can be used.

[0098] The food composition of the present invention comprises NAD + It can achieve the effect of preventing or improving symptoms or diseases caused by decreased or impaired mitochondrial function.

[0099]

[0100] The present invention provides a method for preparing a compound of formula 1, comprising the following steps:

[0101] (S1) A step of reacting a compound of chemical formula 2 and HNO3 to obtain a compound of chemical formula 3;

[0102] (S2) A step of reducing the compound of the above chemical formula 3 to obtain a compound of the chemical formula 4;

[0103] (S3) A step of reacting the compound of the above chemical formula 4 with glyoxal sodium bisulfite or a substituted or unsubstituted C1 to C10 alkane dione or a substituted or unsubstituted C1 to C10 oxalate to obtain a compound of the chemical formula 5;

[0104] (S4) A step of dissolving the compound of the above chemical formula 5 in acetonitrile and then reacting it with an oxidizing agent to obtain quinoxaline-5,8-dione of the chemical formula 6;

[0105] (S5) A step of performing a halogenation reaction of quinazoline-5,8-dione of the above chemical formula 6 to obtain a compound of the chemical formula 7;

[0106] (S6) A step of dissolving the compound of chemical formula 7 in THF, adding NaR5, and reacting to obtain the target compound of chemical formula 8;

[0107] (S7) A step of additionally reacting the compound of chemical formula 8 with NaR5 to obtain the target compound of chemical formula 9; and

[0108] (S8) A step of reacting a compound of chemical formula 9 with a compound containing an amino group of chemical formula 10 to obtain a compound of chemical formula 1, which is the final target compound:

[0109] [Chemical Formula 1]

[0110]

[0111] [Chemical Formula 2]

[0112]

[0113] [Chemical Formula 3]

[0114]

[0115] [Chemical Formula 4]

[0116]

[0117] [Chemical Formula 5]

[0118]

[0119] [Chemical Formula 6]

[0120]

[0121] [Chemical Formula 7]

[0122]

[0123] [Chemical Formula 8]

[0124]

[0125] [Chemical Formula 9]

[0126]

[0127] [Chemical Formula 10]

[0128] NHR3R4

[0129] In the above formula,

[0130] R a and R b are each independently H or substituted or unsubstituted C1 to C10 alkyl, X1 and X2 are the same or different halogen elements,

[0131] R1 to R5 are each as defined in chemical formula 1.

[0132]

[0133] In a specific example, when the substituted or unsubstituted C1 to C10 alkane dione or the substituted or unsubstituted C1 to C10 oxalate of the step (S3) is substituted, it may be substituted by R1 and / or R2.

[0134]

[0135] In one embodiment of the present invention, compounds 1 to 43 can be prepared by performing steps (S1) to (S8).

[0136]

[0137] Hereinafter, the present invention will be described in more detail through examples. These examples are intended solely to illustrate the present invention more specifically, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples, in accordance with the gist of the present invention.

[0138]

[0139] Example

[0140]

[0141] Reference Example 1: Synthesis of Compound F

[0142]

[0143] A 60% nitric acid aqueous solution (50 mL) was cooled at 0°C for 20 minutes, 1,4-dimethoxybenzene (5.00 g, 36.2 mmol) was added, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was stirred at room temperature for 1 hour and then stirred for another hour at 80°C. The reaction solution was poured onto ice to quench, and the resulting yellow solid was filtered and washed thoroughly with water. The obtained solid was dissolved cleanly in DCM, dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (1,4-dimethoxy-2,3-dinitrobenzene, B).

[0144] Yellow solid, 6.84 g (82.8%)

[0145] 1 H NMR (400 MHz, CHLOROFORM-D) δ 7.20 (s, 2H), 3.93 (s, 6H).

[0146]

[0147] B (3.42 g, 15.0 mmol) was dissolved in EtOAc (50 mL), 10% Pd / C (wetted with 55% water, 1.06 g, 450 μmol) was added, and the mixture was stirred under a hydrogen atmosphere. The reaction solution was further stirred at room temperature for 24 h. The Pd / C was removed by filtration through a celite pad, and the filtrate was concentrated under reduced pressure to obtain the target compound (3,6-dimethoxy-benzene-1,2-diamine, crude C).

[0148] Purple solid, 2.28 g (90.3%)

[0149] 1 H NMR (400 MHz, CHLOROFORM-D) δ 6.31 (s, 2H), 3.81 (s, 6H).

[0150]

[0151] Add distilled water (27 mL) to crude C (2.28 g, 13.6 mmol) and heat to 50°C. In another flask, add glyoxal sodiumbisulfite (4.69 g, 17.6 mmol), add distilled water (39 mL), and heat to 50°C to dissolve. Add the aqueous glyoxal sodiumbisulfite solution to the reaction solution and stir under a nitrogen atmosphere. The reaction solution is stirred at 100°C for another 2.5 hours and then cooled to room temperature. Adjust the pH to 8–9 with saturated NaHCO3 aqueous solution, add DCM, and extract several times. The separated organic layer is dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography (EtOAc / Hex) and then recrystallized (EtOAc / Hex) to obtain the target compound (5,8-dimethoxyquinoxaline, D).

[0152] Yellow solid, 2.07 g (80.0%)

[0153] 1H NMR (400 MHz, CHLOROFORM-D) δ 8.90 (s, 2H), 7.04 (s, 2H), 4.08 (s, 6H).

[0154]

[0155] D (1.94 g, 10.2 mmol) was dissolved in acetonitrile (MeCN, 29 mL), and then ceric ammonium nitrate (CAN, 14.0 g, 25.5 mmol) aqueous solution (water, 29 mL) was slowly added over 10 minutes. The reaction solution was stirred at room temperature for an additional 12 minutes. Saturated NaCl aqueous solution and DCM were added and extracted several times. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / Hex) and recrystallized (EtOAc / Hex) to obtain the target compound (quinoxaline-5,8-dione, E).

[0156] Yellow solid, 1.20 g (73.5%)

[0157] 1 H NMR (400 MHz, CHLOROFORM-D) δ 9.08 (s, 2H), 7.27 (s, 2H).

[0158]

[0159] Add AcOH (22 mL) to E (1.74 g, 10.8 mmol) and stir at room temperature. Dilute bromine (1.11 mL, 21.7 mmol) in AcOH (11 mL) and slowly add it at the same temperature. After stirring for 1.5 hours at room temperature, add sodium acetate (NaOAc) (1.78 g, 21.7 mmol) and heat at 120-130℃ for 10 minutes. Cool the reaction solution to 90℃ and quench it by adding water (88 mL). After cooling the reaction solution to 0℃, filter the formed solid and wash it several times with water. Dry the obtained solid under reduced pressure under P2O5 to obtain the target compound (6,7-dibromoquinoxaline-5,8-dione, F).

[0160] Yellow solid, 1.93 g (56.3%)

[0161] 1 H NMR (400 MHz, DMSO-D6) δ 9.09 (s, 2H).

[0162]

[0163] Example 1: Synthesis of Compound 1

[0164]

[0165] F (5.00 g, 15.7 mmol) was dissolved in THF (50.0 mL), and NaOMe (2.83 g, 15.7 mmol) was added. The mixture was stirred at room temperature for 1 h, and then distilled water was added at 0 °C. After several extractions with EtOAc, the separated organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the target compound (6-bromo-7-methoxyquinoxaline-5,8-dione, G).

[0166] Yellow solid, 3.60 g (80.8%)

[0167] 1H NMR (400 MHz, DMSO-D6) δ 9.07 (dd,J= 2.3, 12.0 Hz, 2H), 4.26 (s, 3H).

[0168]

[0169] G (4.00 g, 14.9 mmol) was dissolved in MeOH (40.0 mL), and then NaOMe (2.70 g, 15.0 mmol) was added. The mixture was stirred at room temperature for 1 h, and then distilled water was added at 0 °C. After extracting several times with EtOAc, the organic layer was washed with a saturated aqueous NaCl solution. The separated organic layer was dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (EtOAc / Hex) to obtain the target compound (6,7-dimethoxyquinoxaline-5,8-dione, H).

[0170] Yellow solid, 1.00 g (27.4%)

[0171] 1 H NMR (400 MHz, CHLOROFORM-D) δ 8.99 (s, 2H), 4.21 (s, 6H).

[0172]

[0173] H (100 mg, 454 μmol) was dissolved in MeOH (3.00 mL), and p-anisidine (55.9 mg, 454 μmol) was added. The black mixture was stirred at 60 °C for 6 h and then filtered. The filtered solid was triturated in petroleum ether for 10 min to obtain the target compound (6-methoxy-7-((4-methoxyphenyl)amino)quinoxaline-5,8-dione, compound 1).

[0174] Black solid, 82.0 mg (57.2%)

[0175] 1H NMR (400 MHz, DMSO-D6) δ 8.99 (d,J= 2.25 Hz, 1H), 8.93 (d,J= 2.25 Hz, 1H), 8.70 (s, 1H), 7.06 (d,J= 8.88 Hz, 2H), 6.87 (d,J= 8.88 Hz, 2H), 3.75 (s, 3H), 3.44 (s, 3H).

[0176]

[0177] Example 2: Synthesis of Compound 2

[0178]

[0179] H (300 mg, 1.36 mmol) was added to 4-fluoro-3-(trifluoromethyl)aniline (2.44 g, 13.6 mmol). The black mixture was stirred at 80 °C for 24 h and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / petroleum ether) and purified by Prep-HPLC (H2O / ACN) to obtain the target compound (6-((4-fluoro-3-(trifluoromethyl)phenyl)amino)-7-methoxyquinoxaline-5,8-dione, compound 2).

[0180] Deep purple solid, 68.2 mg (13.8%)

[0181] 1 H NMR (400 MHz, DMSO-D6) δ 9.02 (d,J= 2.38 Hz, 1H), 8.97 (d,J= 2.25 Hz, 1H), 8.94 (s, 1H), 7.42 (br s, 3H), 3.60 (s, 3H).

[0182]

[0183] Example 3: Synthesis of Compound 3

[0184]

[0185] H (150 mg, 681 μmol) was added to 2,4-Dimethoxyaniline (1.04 g, 6.81 mmol). The black mixture was stirred at 80 °C for 2 h and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / petroleum ether) and purified by Prep-HPLC (H2O / ACN) to obtain the target compound (6-((2,4-dimethoxyphenyl)amino)-7-methoxyquinoxaline-5,8-dione, compound 3).

[0186] Black solid, 127 mg (54.6%)

[0187] 1 H NMR (400 MHz, DMSO-D6) δ 8.98 (d,J= 2.38 Hz, 1H), 8.92 (d,J= 2.38 Hz, 1H), 8.16 (s, 1H), 7.02 (d,J= 8.63 Hz, 1H), 6.59 (d,J= 2.63 Hz, 1H), 6.50 (dd,J= 8.63, 2.63 Hz, 1H), 3.78 (s, 3H), 3.74 (s, 3H), 3.42 (s, 3H).

[0188]

[0189] Example 4: Synthesis of compound 4

[0190]

[0191] H (50.0 mg, 227 μmol) was added to 2,4-Dimethoxyaniline (104 g, 681 μmol), degassed, and filled with nitrogen. The mixture was stirred at 80 °C for 2 h and extracted several times with EtOAc. The organic layer was washed with a saturated aqueous solution of NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrate was purified by Prep-TLC (EtOAc / petroleum ether) to obtain the target compound (6-((3,4-dimethoxyphenyl)amino)-7-methoxyquinoxaline-5,8-dione, compound 4).

[0192] brown to black solid, 52.0 mg (66.7%)

[0193] 1 H NMR (400 MHz, DMSO-D6) δ 8.98 (d,J= 2.0 Hz, 1H), 8.90 (d,J= 2.0 Hz, 1H), 7.32 (br s, 1H), 7.27 (s, 1H), 6.83 (d,J= 8.4 Hz, 1H), 6.75 - 6.68 (m, 2H), 3.90 (d,J= 7.2 Hz, 6H), 3.60 (s, 3H).

[0194]

[0195] Example 5: Synthesis of Compound 5

[0196]

[0197] H (250 mg, 1.14 mmol) was dissolved in N,N-diisopropylethylamine (DIEA) (5.0 mL), and 3,5-Dimethoxyaniline (5.22 g, 34.1 mmol) was added dropwise. The mixture was stirred at 80 °C for 14 h, distilled water was added, and the mixture was extracted several times with EtOAc. The organic layer was washed with a saturated aqueous solution of NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrate was purified by Prep-HPLC (H2O / ACN) to obtain the target compound (6-((3,5-dimethoxyphenyl)amino)-7-methoxyquinoxaline-5,8-dione, compound 5).

[0198] Purple solid, 64.6 mg (15.8%)

[0199] 1 H NMR (400 MHz, CHLOROFORM-D) δ 8.98 (d,J= 2.3 Hz, 1H), 8.91 (d,J= 2.3 Hz, 1H), 7.27 (s, 1H), 6.31 - 6.30 (m, 1H), 6.27 (d,J= 2.1 Hz, 2H), 3.80 (s, 6H), 3.74 (s, 3H).

[0200]

[0201] Example 6: Synthesis of compound 6

[0202]

[0203] H (1.10 g, 5.00 mmol) was added to 3-(trifluoromethyl)aniline (8.05 g, 49.9 mmol). The mixture was stirred at 80 °C for 12 h and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / petroleum ether) and purified by Prep-HPLC (H2O / ACN) to obtain the target compound (6-methoxy-7-((3-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione, compound 6).

[0204] Black solid, 307 mg (17.4%)

[0205] 1 H NMR (400 MHz, DMSO-D6) δ 9.00 (dd,J= 18, 2.4 Hz, 2H), 8.94 (br s, 1 H), 7.45 - 7.52 (m, 1H), 7.39 (s, 1H), 7.33 (br d,J= 8.0 Hz, 2H), 3.63 (s, 3H).

[0206]

[0207] Example 7: Synthesis of Compound 7

[0208]

[0209] H (700 mg, 3.18 mmol) was added to 4-fluoroaniline (3.53 g, 31.8 mmol). The mixture was stirred at 80 °C for 6 h and then concentrated under reduced pressure. The concentrate was triturated with MeOH for 10 min to obtain the target compound (6-((4-fluorophenyl)amino)-7-methoxyquinoxaline-5,8-dione, compound 7).

[0210] Black solid, 224 mg (22.8%)

[0211] 1H NMR (400 MHz, DMSO-D6) δ 9.00 (d,J= 2.4 Hz, 1H), 8.95 (d,J= 2.4 Hz, 1H), 8.77 (s, 1H), 7.12 (d,J= 6.8 Hz, 4H), 3.50 (s, 3H).

[0212]

[0213] Example 8: Synthesis of Compound 8

[0214]

[0215] H (500 mg, 2.27 mmol) was dissolved in MeOH (5.0 mL), and 4-chloroaniline (348 mg, 2.73 mmol) was added. The mixture was stirred at 60 °C for 12 h and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / petroleum ether) and purified by Prep-HPLC (H2O / ACN) to obtain the target compound (6-((4-chlorophenyl)amino)-7-methoxyquinoxaline-5,8-dione, compound 8).

[0216] Dark purple solid, 260 mg (36.1%)

[0217] 1 H NMR (400 MHz, DMSO-D6) δ 9.01 (d,J= 2.4 Hz, 1H), 8.96 (d,J= 2.4 Hz, 1H), 8.84 (s, 1H), 7.34 - 7.29 (m, 2H), 7.10 - 7.04 (m, 2H), 3.57 (s, 3H).

[0218]

[0219] Example 9: Synthesis of compound 9

[0220]

[0221] H (500 mg, 2.27 mmol) was dissolved in MeOH (5.0 mL), and 4-chloroaniline (336 mg, 2.73 mmol) was added. The mixture was stirred at 60 °C for 2 h and concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / petroleum ether) and purified by Prep-HPLC (H2O / ACN) to obtain the target compound (6-methoxy-7-((2-methoxyphenyl)amino)quinoxaline-5,8-dione, compound 9).

[0222] Purple solid, 330 mg (46.2%)

[0223] 1 H NMR (400 MHz, CHLOROFORM-D) δ 8.97 (d,J= 2.4 Hz, 1H), 8.90 (d,J= 2.4 Hz, 1H), 7.44 (br s, 1H), 7.18 - 7.12 (m, 1H), 7.05 - 6.99 (m, 1H), 6.95 (dd,J= 8.0, 12.9 Hz, 2H), 3.92 (s, 3H), 3.62 (s, 3H).

[0224]

[0225] Example 10: Synthesis of compound 10

[0226]

[0227] H (600 mg, 2.73 mmol) was dissolved in MeOH (6.0 mL), and 4-chloroaniline (403 mg, 3.27 mmol) was added. The mixture was stirred at 60 °C for 12 h and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / petroleum ether) and purified by Prep-HPLC (H2O / ACN) to obtain the target compound (6-methoxy-7-((3-methoxyphenyl)amino)quinoxaline-5,8-dione, compound 10).

[0228] Dark purple solid, 240 mg (28.2%)

[0229] 1 H NMR (400 MHz, DMSO-D6) δ 9.00 (d,J= 2.4 Hz, 1H), 8.95 (d,J= 2.4 Hz, 1H), 8.67 (s, 1H), 7.17 (t,J= 8.0 Hz, 1H), 6.71 - 6.58 (m, 3H), 3.72 (s, 3H), 3.58 (s, 3H).

[0230]

[0231] Example 11: Synthesis of compound 11

[0232]

[0233] H (300 mg, 1.36 mmol) was added to 4-methyl-3-(trifluoromethyl)aniline (2.39 g, 13.6 mmol), and the reaction vessel was filled with nitrogen. The reaction solution was stirred at 78°C for 4 hours and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / petroleum ether) and purified by Prep-HPLC [Water(NH4HCO3) / CAN] to obtain the target compound (6-methoxy-7-((4-methyl-3-(trifluoromethyl) phenyl)amino)quinoxaline-5,8-dione, compound 11).

[0234] Purple solid, 180 mg (35.5%)

[0235] 1 H NMR (400 MHz, DMSO-D6) δ 9.01 (d,J= 2.4 Hz, 1H), 8.96 (d,J= 2.4 Hz, 1H), 8.90 (s, 1H), 7.40 (s, 1H), 7.32 (d,J= 8.4 Hz, 1H), 7.21 (d,J= 8.4 Hz, 1H), 3.58 (s, 3H), 2.40 (s, 3H).

[0236]

[0237] Example 12: Synthesis of Compound 12

[0238]

[0239] Place H (100 mg, 454 μmol) and MeOH (4.5 mL) in a sealed tube and stir at room temperature. At the same temperature, add 4-(Trifluoromethyl)aniline (88.0 mg, 545 μmol) and stir at 80℃ for 4.5 hours. Add CeCl3·7H2O (17.0 mg, 45.4 μmol) to the reaction solution and stir at room temperature for another 19 hours. Add saturated NaCl aqueous solution and extract several times with DCM. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / Ether) and recrystallized (DCM / Hex) to obtain the target compound (6-methoxy-7-((4-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione, compound 12).

[0240] Dark brown solid, 83.9 mg (52.9%)

[0241] 1 H NMR (500 MHz, DMSO-D6) δ 9.08 - 8.94 (m, 3H), 7.59 (d,J= 8.7 Hz, 2H), 7.17 (d,J= 8.7 Hz, 2H), 3.68 (s, 3H).

[0242]

[0243] Example 13: Synthesis of Compound 13

[0244]

[0245] Add MeOH (4.5 mL) to H (100 mg, 454 μmol) and stir at room temperature. At the same temperature, add CeCl3·7H2O (17.0 mg, 45.4 μmol) and 2-Fluoroaniline (52.0 μL, 545 μmol) and stir at room temperature for another 3 hours. Add saturated aqueous NaCl solution and extract several times with DCM. The separated organic layer is dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) and recrystallized (DCM / Hex) to obtain the target compound (6-((2-fluorophenyl)amino)-7-methoxyquinoxaline-5,8-dione, compound 13).

[0246] Red brown solid, 89.4 mg (65.8%)

[0247] 1 H NMR (500 MHz, DMSO-D6) δ 9.00 (d,J= 2.4 Hz, 1H), 8.95 (d,J= 2.4 Hz, 1H), 8.70 (s, 1H), 7.28 (t,J= 8.0 Hz, 1H), 7.24 - 7.18 (m, 2H), 7.15 (ddd,J= 7.6, 5.4, 3.2 Hz, 1H), 3.47 (s, 3H).

[0248]

[0249] Example 14: Synthesis of compound 14

[0250]

[0251] Add MeOH (4.5 mL) to H (100 mg, 454 μmol) and stir at room temperature. At the same temperature, add CeCl3·7H2O (17.0 mg, 45.4 μmol) and 3-Fluoroaniline (52.0 μL, 545 μmol) and stir at room temperature for another 16.5 h. Add saturated NaCl aqueous solution and extract several times with DCM. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) and recrystallized (DCM / Hex) to obtain the target compound (6-((3-fluorophenyl)amino)-7-methoxyquinoxaline-5,8-dione, compound 14).

[0252] Red brown solid, 92.4 mg (68.0%)

[0253] 1 H NMR (500 MHz, DMSO-D6) δ 9.02 (d,J= 2.3 Hz, 1H), 8.97 (d,J= 2.4 Hz, 1H), 8.84 (s, 1H), 7.33- 7.23 (m, 1H), 6.95 - 6.77 (m, 3H), 3.63 (s, 3H).

[0254]

[0255] Example 15: Synthesis of Compound 15

[0256]

[0257] Add MeOH (4.5 mL) to H (100 mg, 454 μmol) and stir at room temperature. At the same temperature, add CeCl3·7H2O (17.0 mg, 45.4 μmol) and p-Toluidine (58.4 mg, 545 μmol) and stir at room temperature for another 19 hours. Add saturated aqueous NaCl solution and extract several times with DCM. The separated organic layer is dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) and recrystallized (DCM / Hex) to obtain the target compound (6-methoxy-7-(p-tolylamino)quinoxaline-5,8-dione, compound 15).

[0258] Dark brown to black solid, 87.0 mg (64.9%)

[0259] 1 H NMR (500 MHz, DMSO-D6) δ 8.99 (d,J= 2.4 Hz, 1H), 8.94 (d,J= 2.3 Hz, 1H), 8.71 (s, 1H), 7.09 (d,J= 8.4 Hz, 2H), 6.99 (d,J= 8.4 Hz, 2H), 3.48 (s, 3H), 3.33 (s, 3H).

[0260]

[0261] Example 16: Synthesis of Compound 16

[0262]

[0263] H (100 mg, 454 μmol) was dissolved in MeOH (4.5 mL), and 4-methoxy-3-(trifluoromethyl)aniline (130 mg, 680 μmol) was added. The reaction solution was stirred at 60–80°C for 3 days, distilled water was added, and extracted several times with DCM. The separated organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (ACN / H2O) and recrystallization (EtOAc / Hex) to obtain the target compound (6-methoxy-7-((4-methoxy-3-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione, compound 16).

[0264] Dark violet solid, 58.5 mg (34.0%)

[0265] 1 H NMR (400 MHz, DMSO-D6) δ 9.00 (d,J= 2.4 Hz, 1H), 8.95 (d,J= 2.3 Hz, 1H), 8.82 (s, 1H), 7.40 - 7.31 (m, 2H), 7.20 (d,J= 8.9 Hz, 1H), 3.88 (s, 3H), 3.52 (s, 3H).

[0266]

[0267] Example 17: Synthesis of compound 17

[0268]

[0269] H (50 mg, 227 μmol) was dissolved in MeOH (2.3 mL), 4-fluoro-3-methoxyaniline (38.5 mg, 273 μmol) and CeCl3·7H2O (8.5 mg, 22.7 μmol) were added, and the mixture was stirred at room temperature for 1 h. Distilled water was added, and the mixture was extracted several times with DCM. The separated organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) and recrystallized (EtOAc / Hex) to obtain the target compound (6-((4-fluoro-3-methoxyphenyl)amino)-7-methoxyquinoxaline-5,8-dione, compound 17).

[0270] Dark violet solid, 57.3 mg (76.7%)

[0271] 1 H NMR (500 MHz, DMSO-D6) δ 9.01 (d,J= 2.3 Hz, 1H), 8.96 (d,J= 2.3 Hz, 1H), 8.70 (s, 1H), 7.11 (dd,J= 11.4, 8.7 Hz, 1H), 6.95 (dd,J= 7.8, 2.5 Hz, 1H), 6.64 (ddd,J= 8.7, 3.9, 2.3 Hz, 1H), 3.78 (s, 3H), 3.56 (s, 3H).

[0272]

[0273] Example 18: Synthesis of compound 18

[0274]

[0275] H (100 mg, 454 μmol) was dissolved in MeOH (4.5 mL), 4-amino-2-fluorobenzotrifluoride (122 mg, 681 μmol) and CeCl3·7H2O (67.7 mg, 182 μmol) were added, and the mixture was stirred at room temperature for 46 h. Distilled water was added, and the mixture was extracted several times with DCM. The separated organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (ACN / H2O) and recrystallized (EtOAc / Hex) to obtain the target compound (6-((3-fluoro-4-(trifluoromethyl)phenyl)amino)-7-methoxy quino-xaline-5,8-dione, compound 18).

[0276] Red brown solid, 24.7 mg (14.8%)

[0277] 1 H NMR (400 MHz, DMSO-D6) δ 9.11 (s, 1H), 9.04 (d,J= 2.4 Hz, 1H), 9.01 (d,J= 2.3 Hz, 1H), 7.59 (t,J= 8.7 Hz, 1H), 7.02 - 6.92 (m, 2H), 3.80 (s, 3H).

[0278]

[0279] Example 19: Synthesis of Compound 19

[0280]

[0281] H (100 mg, 454 μmol) was dissolved in MeOH (4.5 mL), 3-methoxy-4-(trifluoromethyl)aniline (104 mg, 545 μmol) and CeCl3·7H2O (8.5 mg, 22.7 μmol) were added, and the mixture was stirred at room temperature for 27 h. Distilled water was added, and the mixture was extracted several times with DCM. The separated organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (ACN / H2O) and recrystallized (EtOAc / Hex) to obtain the target compound (6-methoxy-7-((3-methoxy-4-(trifluoromethyl) phenyl) amino)quinoxaline-5,8-dione, compound 19).

[0282] Dark violet solid, 53.8 mg (31.2%)

[0283] 1 H NMR (400 MHz, DMSO-D6) δ 9.03 (d,J= 2.4 Hz, 1H), 8.99 (d,J= 2.4 Hz, 1H), 8.89 (s, 1H), 7.44 (d,J= 9.0 Hz, 1H), 6.90 (d,J= 1.6 Hz, 1H), 6.66 (dd,J= 8.2, 1.8 Hz, 1H), 3.81 (s, 3H), 3.75 (s, 3H).

[0284]

[0285] Example 20: Synthesis of Compound 20

[0286]

[0287] Add MeOH (4.5 mL) to H (100 mg, 454 μmol) and stir at room temperature. At the same temperature, add CeCl3·7H2O (17.0 mg, 45.4 μmol) and 3,4-Dimethylaniline (66.0 mg, 545 μmol) and stir at room temperature for another 3.5 hours. Add saturated NaCl aqueous solution and extract several times with DCM. The separated organic layer is dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) and recrystallized (DCM / Hex) to obtain the target compound (6-((3,4-dimethylphenyl)amino)-7-methoxy quinoxaline-5,8-dione, compound 20).

[0288] Dark violet to black solid, 86.4 mg (61.5%)

[0289] 1 H NMR (400 MHz, DMSO-D6) δ 8.99 (d,J= 2.3 Hz, 1H), 8.94 (d,J= 2.3 Hz, 1H), 8.62 (s, 1H), 7.03 (d,J= 7.7 Hz, 1H), 6.90 (d,J= 2.6 Hz, 1H), 6.82 (dd,J= 7.9, 2.5 Hz, 1H), 3.51 (s, 3H), 2.19 (s, 6H).

[0290]

[0291] Example 21: Synthesis of Compound 21

[0292]

[0293] Add MeOH (4.5 mL) to H (100 mg, 454 μmol) and stir at room temperature. At the same temperature, add CeCl3·7H2O (17.0 mg, 45.4 μmol) and 3,4-Difluoroaniline (54.0 μL, 545 μmol) and stir at room temperature for another 24 h. Add saturated NaCl aqueous solution and extract several times with DCM. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) and recrystallized (DCM / Hex) to obtain the target compound (6-((3,4-difluorophenyl)amino)-7-methoxy quinoxaline-5,8-dione, compound 21).

[0294] Indigo solid, 104 mg (72.2%)

[0295] 1 H NMR (400 MHz, DMSO-D6) δ 9.02 (d,J= 2.4 Hz, 1H), 8.97 (d,J= 2.3 Hz, 1H), 8.82 (s, 1H), 7.33 (dt,J= 10.7, 9.0 Hz, 1H), 7.14 - 7.05 (m, 1H), 6.91 (dddd,J= 8.9, 4.1, 2.7, 1.5 Hz, 1H), 3.61 (s, 3H).

[0296]

[0297] Example 22: Synthesis of Compound 22

[0298]

[0299] H (100 mg, 454 μmol) was stirred at room temperature with MeOH (4.5 mL). At the same temperature, CeCl3·7H2O (17.0 mg, 45.4 μmol) and 3-Fluoro-4-Methylaniline (68.0 mg, 545 μmol) were added and stirred at room temperature for another 2.5 hours. After adding saturated aqueous NaCl solution and extracting several times with DCM, the separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) and recrystallized (DCM / Hex) to obtain the target compound (6-((3-fluoro-4-methylphenyl)amino)-7-methoxyquinoxaline-5,8-dione, compound 22).

[0300] Dark brown solid, 126 mg (88.6%)

[0301] 1 H NMR (400 MHz, DMSO-D6) δ 9.01 (d,J= 2.3 Hz, 1H), 8.96 (d,J= 2.4 Hz, 1H), 8.77 (s, 1H), 7.15 (t,J= 9.0 Hz, 1H), 6.88 - 6.80 (m, 2H), 3.58 (s, 3H), 2.19 (d,J= 2.1 Hz, 3H).

[0302]

[0303] Example 23: Synthesis of Compound 23

[0304]

[0305] Dissolve H (100 mg, 454 μmol) in MeOH (3.0 mL), then add 3-methyl-4-(trifluoromethyl)aniline (95.5 mg, 545 μmol) dissolved in MeOH (1.5 mL). CeCl3·7H2O (16.9 mg, 45.4 μmol) and stir at room temperature for 23.5 hours. Add distilled water, extract several times with DCM, and then separate the organic layer, dry over Na2SO4, filter, and concentrate under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) and recrystallization (EtOAc / Hex) to obtain the target compound (6-methoxy-7-((3-methyl-4-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione, compound 23).

[0306] Dark violet solid, 47.7 mg (28.9%)

[0307] 1 H NMR (400 MHz, DMSO-D6) δ 9.03 (d,J= 2.3 Hz, 1H), 8.99 (d,J= 2.4 Hz, 1H), 8.89 (s, 1H), 7.52 (d,J= 8.7 Hz, 1H), 7.04 (d,J= 2.2 Hz, 1H), 6.97 (dd,J= 8.6, 2.2 Hz, 1H), 3.72 (s, 3H), 2.38 (d,J= 1.8 Hz, 3H).

[0308]

[0309] Example 24: Synthesis of Compound 24

[0310]

[0311] H (100 mg, 454 μmol) was dissolved in MeOH (4.5 mL), 3-fluoro-4-methoxyaniline (76.9 mg, 545 μmol) and CeCl3·7H2O (8.5 mg, 22.7 μmol) were added, and the mixture was stirred at room temperature for 1 h. Distilled water was added, and the mixture was extracted several times with DCM. The separated organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) and recrystallized (EtOAc / Hex) to obtain the target compound (6-((3-fluoro-4-methoxyphenyl)amino)-7-methoxyquinoxaline-5,8-dione, compound 24).

[0312] Dark violet solid, 126 mg (84.5%)

[0313] 1 H NMR (400 MHz, DMSO-D6) δ 9.00 (d,J= 2.4 Hz, 1H), 8.95 (d,J= 2.4 Hz, 1H), 8.73 (s, 1H), 7.12 - 7.04 (m, 1H), 6.99 (dd,J= 13.0, 2.6 Hz, 1H), 6.89 (ddd,J= 8.8, 2.6, 1.4 Hz, 1H), 3.83 (s, 3H), 3.53 (s, 3H).

[0314]

[0315] Example 25: Synthesis of Compound 25

[0316]

[0317] H (100 mg, 454 μmol) was dissolved in MeOH (4.5 mL), 5-amino-2-chlorobenzotrifluoride (107 mg, 545 μmol) and CeCl3·7H2O (8.5 mg, 22.7 μmol) were added, and the mixture was stirred at room temperature for 19.5 h. Distilled water was added, and the mixture was extracted several times with DCM. The separated organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrate was purified by C18 silica gel column chromatography (ACN / H2O) and recrystallized (EtOAc / Hex) to obtain the target compound (6-((4-chloro-3-(trifluoromethyl)phenyl)amino)-7-methoxy quinoxaline-5,8-dione, compound 25).

[0318] Dark violet solid, 113 mg (64.7%)

[0319] 1 H NMR (400 MHz, DMSO-D6) δ 9.03 (d,J= 2.4 Hz, 2H), 8.98 (d,J= 2.3 Hz, 1H), 7.59 (d,J= 8.7 Hz, 1H), 7.51 (d,J= 2.7 Hz, 1H), 7.28 (dd,J= 8.1, 2.7 Hz, 1H), 3.68 (s, 3H).

[0320]

[0321] Example 26: Synthesis of compound 26

[0322]

[0323] H (100 mg, 454 μmol) was dissolved in MeOH (4.5 mL), 3,5-difluoro-4-methoxyaniline (86.7 mg, 545 μmol) and CeCl3·7H2O (8.5 mg, 22.7 μmol) were added, and the mixture was stirred at room temperature for 24 h. Distilled water was added, and the mixture was extracted several times with DCM. The separated organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrate was purified by C18 silica gel column chromatography (ACN / H2O) and recrystallized (EtOAc / Hex) to obtain the target compound (6-((3,5-difluoro-4-methoxyphenyl)amino)-7-methoxyquinoxaline-5,8-dione, compound 26).

[0324] Black solid, 135 mg (85.4%)

[0325] 1 H NMR (400 MHz, DMSO-D6) δ 9.02 (d,J= 2.3 Hz, 1H), 8.98 (d,J= 2.3 Hz, 1H), 8.80 (s, 1H), 6.87 - 6.77 (m, 2H), 3.86 (s, 3H), 3.69 (s, 3H).

[0326]

[0327] Example 27: Synthesis of compound 27

[0328]

[0329] H (100 mg, 454 μmol) was dissolved in MeOH (4.5 mL), 3-Methoxy-5-(trofluoromethyl)aniline (104 mg, 545 μmol) and CeCl3·7H2O (17.0 mg, 45.4 μmol) were added, and the mixture was stirred at room temperature for 5 hours. Distilled water was added, and the mixture was extracted several times with DCM. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by C18 silica gel column chromatography (ACN / H2O) and recrystallized (EtOAc / Hex) to obtain the target compound (6-methoxy-7-((3-methoxy-5-(trifluoromethyl)phenyl)ami no)quinoxaline-5,8-dione, compound 27).

[0330] Dark violet solid, 103 mg (59.7%)

[0331] 1 H NMR (500 MHz, DMSO-D6) δ 9.02 (d,J= 2.3 Hz, 1H), 8.98 (d,J= 2.4 Hz, 1H), 8.86 (s, 1H), 6.99 (s, 1H), 6.90 (s, 1H), 6.84 (s, 1H), 3.79 (s, 3H), 3.69 (s, 3H).

[0332]

[0333] Example 28: Synthesis of compound 28

[0334]

[0335] H (100 mg, 454 μmol) was dissolved in MeOH (4.5 mL), 3,5-Dimethylaniline (68 μL, 545 μmol) and CeCl3·7H2O (17.0 mg, 45.4 μmol) were added, and the mixture was stirred at room temperature for 2 h. Distilled water was added, and the mixture was extracted several times with DCM. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by recrystallization (DCM / Hex) after being purified by C18 silica gel column chromatography (ACN / H2O) to obtain the target compound (6-((3,5-dimethylphenyl)amino)-7-methoxyquinoxaline-5,8-dione, compound 28).

[0336] Dark violet solid, 109 mg (77.9%)

[0337] 1 H NMR (500 MHz, DMSO-D6) δ 9.00 (d,J= 2.3 Hz, 1H), 8.94 (d,J= 2.3 Hz, 1H), 8.59 (s, 1H), 6.72 (s, 2H), 6.69 (s, 1H), 3.56 (s, 3H), 2.23 (s, 6H).

[0338]

[0339] Example 29: Synthesis of Compound 29

[0340]

[0341] H (100 mg, 454 μmol) was dissolved in MeOH (4.5 mL), 2-Methyl-5-(trifluoromethyl)aniline (95.5 mg, 545 μmol) and CeCl3·7H2O (17.0 mg, 45.4 μmol) were added, and the mixture was stirred at room temperature for 18 h. Distilled water was added, and the mixture was extracted several times with DCM. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by recrystallization (DCM / Hex) and purified by C18 silica gel column chromatography (ACN / H2O) to obtain the target compound (6-methoxy-7-((2-methyl-5-(trifluoromethyl)phenyl)amino) quinoxaline-5,8-dione, compound 29).

[0342] Red brown solid, 74.2 mg (45.0%)

[0343] 1 H NMR (500 MHz, DMSO-D6) δ 9.00 (d, J= 2.3 Hz, 1H), 8.96 (d, J= 2.3 Hz, 1H), 8.43 (s, 1H), 7.44 (s, 3H), 3.35 (s, 3H), 2.34 (s, 3H).

[0344]

[0345] Example 30: Synthesis of compound 30

[0346]

[0347] H (100 mg, 454 μmol) was dissolved in MeOH (4.5 mL), 2,4-Dimethylaniline (67 μL, 545 μmol) and CeCl3·7H2O (17.0 mg, 45.4 μmol) were added, and the mixture was stirred at room temperature for 4.5 h. Distilled water was added, and the mixture was extracted several times with DCM. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by recrystallization (DCM / Hex) and purified by C18 silica gel column chromatography (ACN / H2O) to obtain the target compound (6-((2,4-dimethylphenyl)amino)-7-methoxyquinoxaline-5,8-dione, compound 30).

[0348] Dark violet solid, 90.3 mg (64.3%)

[0349] 1 H NMR (500 MHz, DMSO-D6) δ 8.98 (d,J= 2.3 Hz, 1H), 8.93 (d,J= 2.3 Hz, 1H), 8.37 (s, 1H), 7.03 (s, 1H), 6.98 (t,J= 6.9 Hz, 2H), 3.27 (s, 3H), 2.28 (s, 3H), 2.19 (s, 3H).

[0350]

[0351] Example 31: Synthesis of compound 31

[0352]

[0353] H (100 mg, 454 μmol) was dissolved in MeOH (4.5 mL), 2,4-Dimethylaniline (67 μL, 545 μmol) and CeCl3·7H2O (17.0 mg, 45.4 μmol) were added, and the mixture was stirred at room temperature for 4.5 h. Distilled water was added, and the mixture was extracted several times with DCM. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by recrystallization (DCM / Hex) and purified by C18 silica gel column chromatography (ACN / H2O) to obtain the target compound (6-((2,5-dimethylphenyl)amino)-7-methoxyquinoxaline-5,8-dione, compound 31).

[0354] Dark brown solid, 77.3 mg (55.0%)

[0355] 1 H NMR (500 MHz, DMSO-D6) δ 8.99 (d,J= 2.3 Hz, 1H), 8.93 (d,J= 2.4 Hz, 1H), 8.35 (s, 1H), 7.09 (d,J= 7.6 Hz, 1H), 6.94-6.92 (m, 2H), 3.31 (s, 3H), 2.25 (s, 3H), 2.18 (s, 3H).

[0356]

[0357] Example 32: Synthesis of compound 32

[0358]

[0359] H (100 mg, 454 μmol) was dissolved in MeOH (4.5 mL), 5-Fluoro-2-methylaniline (68.2 mg, 545 μmol) and CeCl3·7H2O (17.0 mg, 45.4 μmol) were added, and the mixture was stirred at room temperature for 16 h. Distilled water was added, and the mixture was extracted several times with DCM. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by recrystallization (DCM / Hex) and purified by C18 silica gel column chromatography (ACN / H2O) to obtain the target compound (6-((5-fluoro-2-methylphenyl)amino)-7-methoxyquinoxaline-5,8-dione, compound 32).

[0360] Red brown solid, 89.2 mg (62.7%)

[0361] 1 H NMR (500 MHz, DMSO-D6) δ 9.00 (d,J= 2.4 Hz, 1H), 8.95 (d,J= 2.3 Hz, 1H), 8.34 (s, 1H), 7.22 (t,J= 7.3 Hz, 1H), 6.94 (t,J= 8.4 Hz, 2H), 3.40 (s, 3H), 2.22 (s, 3H).

[0362]

[0363] Example 33: Synthesis of compound 33

[0364]

[0365] H (100 mg, 454 μmol) was dissolved in MeOH (4.5 mL), 2,3-Dimethylaniline (66 μL, 545 μmol) and CeCl3·7H2O (17.0 mg, 45.4 μmol) were added, and the mixture was stirred at room temperature for 4 h. Distilled water was added, and the mixture was extracted several times with DCM. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by C18 silica gel column chromatography (ACN / H2O) and recrystallized (DCM / Hex) to obtain the target compound (6-((2,3-dimethylphenyl)amino)-7-methoxyquinoxaline-5,8-dione, compound 33).

[0366] Red brown solid, 74.1 mg (52.8%)

[0367] 1 H NMR (400 MHz, DMSO-D6) δ 8.98 (d,J= 2.3 Hz, 1H), 8.93 (d,J= 2.4 Hz, 1H), 8.46 (s, 1H), 7.07 - 7.01 (m, 2H), 6.96 (dd,J= 5.3, 4.0 Hz, 1H), 3.26 (s, 3H), 2.27 (s, 3H), 2.13 (s, 3H).

[0368]

[0369] Example 34: Synthesis of compound 34

[0370]

[0371] H (100 mg, 454 μmol) was dissolved in MeOH (4.5 mL), 3-chloro-4-methoxyaniline (85.9 mg, 545 μmol) and CeCl3·7H2O (8.5 mg, 22.7 μmol) were added, and the mixture was stirred at room temperature for 4.5 h. Distilled water was added, and the mixture was extracted several times with DCM. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by C18 silica gel column chromatography (ACN / H2O) and recrystallized (EtOAc / Hex) to obtain the target compound (6-((3-chloro-4-methoxyphenyl)amino)-7-methoxyquinoxaline-5,8-dione, compound 34).

[0372] Dark violet solid, 108 mg (69.1%)

[0373] 1 H NMR (500 MHz, DMSO-D6) δ 9.00 (d,J= 2.4 Hz, 1H), 8.95 (d,J= 2.3 Hz, 1H), 8.75 (s, 1H), 7.19 (d,J= 2.3 Hz, 1H), 7.11 - 7.03 (m, 2H), 3.84 (s, 3H), 3.53 (s, 3H).

[0374]

[0375] Example 35: Synthesis of compound 35

[0376]

[0377] H (100 mg, 454 μmol) was dissolved in MeOH (4.5 mL), 4-fluoro-2-methylaniline (61 μL, 545 μmol) and CeCl3·7H2O (8.5 mg, 22.7 μmol) were added, and the mixture was stirred at room temperature for 16 h. Distilled water was added, and the mixture was extracted several times with DCM. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by C18 silica gel column chromatography (ACN / H2O) and recrystallized (EtOAc / Hex) to obtain the target compound (6-((4-fluoro-2-methylphenyl)amino)-7-methoxyquinoxaline-5,8-dione, compound 35).

[0378] Red brown solid, 106 mg (74.8%)

[0379] 1 H NMR (500 MHz, DMSO-D6) δ 8.99 (d,J= 2.4 Hz, 1H), 8.94 (d,J= 2.4 Hz, 1H), 8.44 (s, 1H), 7.14 (dd,J= 8.7, 5.6 Hz, 1H), 7.09 (dd,J= 9.7, 3.1 Hz, 1H), 6.99 (td,J= 8.5, 3.1 Hz, 1H), 3.28 (s, 3H), 2.23 (s, 3H).

[0380]

[0381] Example 36: Synthesis of compound 36

[0382]

[0383] H (100 mg, 454 μmol) was dissolved in MeOH (4.5 mL), 2-methyl-4-(trifluoromethyl)aniline (95.5 mg, 545 μmol) and CeCl3·7H2O (16.9 mg, 45.4 μmol) were added, and the mixture was stirred at room temperature for 24 h. Distilled water was added, and the mixture was extracted several times with DCM. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by C18 silica gel column chromatography (ACN / H2O) and recrystallized (EtOAc / Hex) to obtain the target compound (6-methoxy-7-((2-methyl-4-(trifluoromethyl)phenyl)amino)quino-xaline-5,8-dione, compound 36).

[0384] Dark brown solid, 60.4 mg (36.6%)

[0385] 1 H NMR (500 MHz, DMSO-D6) δ 9.01 (d,J= 2.4 Hz, 1H), 8.97 (d,J= 2.4 Hz, 1H), 8.40 (s, 1H), 7.59 (s, 1H), 7.50 (d,J= 8.4 Hz, 1H), 7.22 (d,J= 8.4 Hz, 1H), 3.42 (s, 3H), 2.34 (s, 3H).

[0386]

[0387] Example 37: Synthesis of compound 37

[0388]

[0389] H (100 mg, 454 μmol) was dissolved in MeOH (4.5 mL), 4-chloro-2-methylaniline (77.2 mg, 545 μmol) and CeCl3·7H2O (8.5 mg, 22.7 μmol) were added, and the mixture was stirred at room temperature for 18.5 h. Distilled water was added, and the mixture was extracted several times with DCM. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by C18 silica gel column chromatography (ACN / H2O) and recrystallized (EtOAc / Hex) to obtain the target compound (6-((4-chloro-2-methylphenyl)amino)-7-methoxyquinoxaline-5,8-dione, compound 37).

[0390] Dark brown solid, 84.6 mg (56.5%)

[0391] 1 H NMR (500 MHz, DMSO-D6) δ 8.99 (d,J= 2.4 Hz, 1H), 8.94 (d,J= 2.4 Hz, 1H), 8.41 (s, 1H), 7.31 (d,J= 2.6 Hz, 1H), 7.21 (dd,J= 8.4, 2.6 Hz, 1H), 7.10 (d,J= 8.4 Hz, 1H), 3.34 (s, 3H), 2.24 (s, 3H).

[0392]

[0393] Example 38: Synthesis of compound 38

[0394]

[0395] H (100 mg, 454 μmol) was dissolved in MeOH (4.5 mL), then o-toluidine (58 μL, 545 μmol) and CeCl3·7H2O (16.9 mg, 45.4 μmol) were added and stirred at room temperature for 18.5 h. Distilled water was added, and the mixture was extracted several times with DCM. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) and purified by C18 silica gel column chromatography (ACN / H2O) to obtain the target compound (6-methoxy-7-(o-tolylamino)quinoxaline-5,8-dione, compound 38).

[0396] Dark brown solid, 83.9 mg (62.6%)

[0397] 1 H NMR (500 MHz, DMSO-D6) δ 8.99 (d,J= 2.4 Hz, 1H), 8.94 (d,J= 2.4 Hz, 1H), 8.42 (s, 1H), 7.22 (d,J= 7.3 Hz, 1H), 7.13 (dddd,J= 23.9, 9.2, 7.4, 1.8 Hz, 3H), 3.28 (s, 3H), 2.24 (s, 3H).

[0398]

[0399] Example 39: Synthesis of Compound 39

[0400]

[0401] H (100 mg, 454 μmol) was dissolved in MeOH (4.5 mL), 3-fluoro-2-methylaniline (60 μL, 545 μmol) and CeCl3·7H2O (16.9 mg, 45.4 μmol) were added, and the mixture was stirred at room temperature for 5 h. Distilled water was added, and the mixture was extracted several times with DCM. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by C18 silica gel column chromatography (ACN / H2O) and recrystallized (EtOAc / Hex) to obtain the target compound (6-((3-fluoro-2-methylphenyl)amino)-7-methoxyquinoxaline-5,8-dione, compound 39).

[0402] Dark brown solid, 86.4 mg (60.7%)

[0403] 1 H NMR (500 MHz, DMSO-D6) δ 9.00 (d,J= 2.3 Hz, 1H), 8.95 (d,J= 2.5 Hz, 1H), 8.50 (s, 1H), 7.17 (q,J= 7.7 Hz, 1H), 7.02 (t,J= 8.9 Hz, 1H), 6.97 (d,J= 8.1 Hz, 1H), 3.34 (s, 3H), 2.14 (s, 3H).

[0404]

[0405] Example 40: Synthesis of compound 40

[0406]

[0407] H (100 mg, 454 μmol) was dissolved in MeOH (4.5 mL), 3-amino-4-fluorobenzotrifluoride (70 μL, 545 μmol) and CeCl3·7H2O (16.9 mg, 45.4 μmol) were added, and the mixture was stirred at room temperature for 16.5 h. Distilled water was added, and the mixture was extracted several times with DCM. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by C18 silica gel column chromatography (ACN / H2O) and recrystallized (Ether / Hex) to obtain the target compound (6-((2-fluoro-5-(trifluoromethyl)phenyl)amino)-7-methoxy quinoxaline-5,8-dione, compound 40).

[0408] Red brown solid, 33.7 mg (20.2%)

[0409] 1 H NMR (500 MHz, DMSO-D6) δ 9.02 (d,J= 2.4 Hz, 1H), 8.98 (d,J= 2.4 Hz, 1H), 8.78 (s, 1H), 7.64 (d,J= 7.5 Hz, 1H), 7.55 (ddd,J= 8.5, 4.1, 2.2 Hz, 1H), 7.46 (t,J= 9.5 Hz, 1H), 3.57 (s, 3H).

[0410]

[0411] Example 41: Synthesis of compound 41

[0412]

[0413] H (100 mg, 454 μmol) was dissolved in MeOH (4.5 mL), 2,3-difluoro-4-methoxyaniline (86.7 mg, 545 μmol) and CeCl3·7H2O (16.9 mg, 45.4 μmol) were added, and the mixture was stirred at room temperature for 4.5 h. Distilled water was added, and the mixture was extracted several times with DCM. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by C18 silica gel column chromatography (ACN / H2O) and recrystallized (EtOAc / Hex) to obtain the target compound (6-((2,3-difluoro-4-methoxyphenyl)amino)-7-methoxyquinoxaline-5,8-dione, compound 41).

[0414] Dark brown solid, 121 mg (77.0%)

[0415] 1 H NMR (500 MHz, DMSO-D6) δ 9.00 (d,J= 2.3 Hz, 1H), 8.95 (d,J= 2.3 Hz, 1H), 8.73 (s, 1H), 7.07 (t,J= 8.8 Hz, 1H), 6.98 (t,J= 8.9 Hz, 1H), 3.89 (s, 3H), 3.45 (s, 3H).

[0416]

[0417] Example 42: Synthesis of compound 42

[0418]

[0419] H (100 mg, 454 μmol) was dissolved in MeOH (4.5 mL), 2-Methyl-3-trifluoromethylaniline (95.5 mg, 545 μmol) and CeCl3·7H2O (17.0 mg, 45.4 μmol) were added, and the mixture was stirred at room temperature for 24 h. Distilled water was added, and the mixture was extracted several times with DCM. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by recrystallization (DCM / Hex) and purified by C18 silica gel column chromatography (ACN / H2O) to obtain the target compound (6-methoxy-7-((2-methyl-3-(trifluoromethyl)phenyl)amino) quinoxaline-5,8-dione, compound 42).

[0420] Dark violet solid, 104 mg (62.9%)

[0421] 1 H NMR (500 MHz, DMSO-D6) δ 9.00 (d,J= 2.3 Hz, 1H), 8.95 (d,J= 2.3 Hz, 1H), 8.58 (s, 1H), 7.56 (d,J= 7.8 Hz, 1H), 7.43 (d,J= 8.1 Hz, 1H), 7.36 (t,J= 7.9 Hz, 1H), 3.30 (s, 3H), 2.35 (s, 3H).

[0422]

[0423] Example 43: Synthesis of compound 43

[0424]

[0425] H (100 mg, 454 μmol) was dissolved in MeOH (4.5 mL), 5-chloro-2-methylaniline (77.2 mg, 545 μmol) and CeCl3·7H2O (16.9 mg, 45.4 μmol) were added, and the mixture was stirred at room temperature for 4 hours. Distilled water was added, and the mixture was extracted several times with DCM. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by C18 silica gel column chromatography (ACN / H2O) and recrystallized (EtOAc / Hex) to obtain the target compound (6-((5-chloro-2-methylphenyl)amino)-7-methoxyquinoxaline-5,8-dione, compound 43).

[0426] Red brown solid, 67.6 mg (45.2%)

[0427] 1 H NMR (400 MHz, DMSO-D6) δ 9.00 (d,J= 2.4 Hz, 1H), 8.95 (d,J= 2.3 Hz, 1H), 8.36 (s, 1H), 7.24 (d,J= 8.1 Hz, 1H), 7.19 - 7.12 (m, 2H), 3.40 (s, 3H), 2.23 (s, 3H).

[0428]

[0429] Example 44: NQO1 activity assay (cytochrome c reduction)

[0430] In order to analyze the efficacy of the evaluation substances on NQO1 activity, a previously known method (Kang-Sik Seo, Jin-Hwan Kim, Ki-Nam Min, Jeong-A Moon et al. KL1333, a novel NAD +This study was performed with some improvements on the previous method (a modulator, improves energy metabolism and mitochondrial dysfunction in MELAS fibroblasts. Front. Neurol. 9:552 (2018)). More specifically, human NQO1 recombinant protein was used after diluting 1 / 100 of the reagent at 1 mg / ml, NADH was used after dissolving in 0.01 N NaOH at 20 mM, and cytochrome C was used after dissolving in distilled water at 7.5 mM. To verify the specificity of the enzymatic reaction, the results were corrected using ES936, an NQO1 selective inhibitor. The reaction buffer used in the experiment was 50 mM Tris-HCl containing 0.14% BSA. The reagents were prepared in advance, and 200 μl of the reaction buffer was dispensed into a 5 ml round tube without touching the wall, equal to the number of drugs to be evaluated for activity. NQO1, NADH, and cytochrome c were added to the wall of a tube containing 200 μl of reaction buffer without mixing them. The final concentrations of each reagent added to the 200 μl of reaction buffer were 10 ng NQO1, 0.4 mM NADH, and 75 nM cytochrome c. Care was taken to ensure that the test substances did not mix with the buffer, and the final concentrations were 0.2, 1, and 5 μM. Since the enzyme reaction was initiated simultaneously with the mixing of each reagent, the tube was gently vortexed immediately after the addition of all reagents, and 180 μl per sample was dispensed into a 96-well plate without delay. The absorbance was measured at 550 nm, and the effect of the test substances on NQO1 enzyme activity was quantitatively analyzed based on the rate of change in absorbance according to the reduction of cytochrome c. The related results are presented in Table 1.

[0431] Cytochrome C Reduction (nmole / min / mg) Compound Name 0.2 μM 1 μM 5 μM 111,21045,149112,78128,79434,26291,68837,45428,57872,71749,00438,40086,098510,11636,21960,52068,62235,34672,749712,28745,61396,435810, 20737,70690,98499,50729,51563,5741012,94044,23598,851114,86627,57167,70812--130,23013--122,64714--127,58815--107,43516--87,65017--120,280 18--66,24419--77,50920--82,16721--169,26522--125,33923--144,02424--169,04025--109,92926--119,60527--42,56328--60,06829--49,36130--43,151 31--49,69832--101,96333--79,23434--109,87735--78,79636--88,51437--101,44738--76,61439--107,33640--115,21641--119,58842--95,55743--110,024

Claims

1. A compound represented by the following chemical formula 1, a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer or diastereomer thereof: [Chemical Formula 1] In the above formula, The above R1 and R2 are each independently hydrogen, a halogen element, hydroxy, a substituted or unsubstituted alkoxy, a substituted or unsubstituted alkyl, or a substituted or unsubstituted cycloalkyl, The above R3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, The above R4 is a substituted or unsubstituted aryl, The above R5 is substituted or unsubstituted alkoxy.

2. In paragraph 1, A compound wherein R1 and R2 are each independently hydrogen, a halogen element, hydroxy, a substituted or unsubstituted C1 to C10 alkoxy, a substituted or unsubstituted C1 to C10 alkyl, or a substituted or unsubstituted C3 to C8 cycloalkyl, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer thereof.

3. In paragraph 1, A compound wherein R1 and R2 are each independently hydrogen, a substituted or unsubstituted C1 to C10 alkyl, or a substituted or unsubstituted C3 to C8 cycloalkyl, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer or diastereomer thereof.

4. In paragraph 1, A compound wherein R1 and R2 are each independently hydrogen, a substituted or unsubstituted C1 to C6 alkyl, or a substituted or unsubstituted C5 to C8 cycloalkyl, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer or diastereomer thereof.

5. In paragraph 1, A compound wherein R1 and R2 are each independently hydrogen, or a substituted or unsubstituted C1 to C4 alkyl, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer or diastereomer thereof.

6. In paragraph 1, A compound wherein R3 is hydrogen, substituted or unsubstituted C1 to C6 alkyl, substituted or unsubstituted C3 to C8 cycloalkyl, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer or diastereomer thereof.

7. In paragraph 1, The above R4 is a substituted or unsubstituted phenyl compound, a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer or diastereomer thereof.

8. In paragraph 7, A compound, a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer or diastereoisomer thereof, wherein the phenyl of the above substitution is substituted with one or two or more substituents selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, and halogen elements, which are the same or different.

9. In paragraph 8, A compound, a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer or diastereomer thereof, wherein the alkyl of the above substitution is substituted with one to three halogen elements.

10. In paragraph 8, A compound, a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer or diastereoisomer thereof, wherein the phenyl of the above substitution is substituted with one or more substituents selected from the group consisting of unsubstituted C1 to C4 alkyl, unsubstituted C1 to C4 alkoxy, C1 to C4 alkyl substituted with one to three halogen elements, and halogen elements.

11. In paragraph 10, A compound, a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer or diastereomer thereof, wherein the halogen element is fluorine.

12. In the first paragraph, the compound is at least one compound selected from the group consisting of the following compounds, a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer or diastereomer thereof: .

13. A composition for enhancing NQO1 activity, comprising a compound according to any one of claims 1 to 12.

14. A composition according to claim 13, characterized in that the composition is a pharmaceutical composition, a cosmetic composition, or a food composition.

15. NAD comprising a compound according to any one of claims 1 to 12 + A pharmaceutical composition for preventing or treating diseases associated with decreased or impaired mitochondrial function.

16. In the 15th paragraph, the NAD + A pharmaceutical composition, wherein the disease associated with a decrease or mitochondrial dysfunction is any one selected from the group consisting of metabolic diseases, primary and secondary mitochondrial diseases, muscle diseases, neurodegenerative diseases, inflammatory diseases, fibrotic diseases, autoimmune diseases, or cancer.

17. A pharmaceutical composition according to claim 16, wherein the metabolic disease is any one selected from the group consisting of obesity, diabetes, and metabolic disorder-related steatohepatitis.

18. A method for preparing a compound according to any one of claims 1 to 12, comprising the following steps: (S1) A step of reacting a compound of chemical formula 2 and HNO3 to obtain a compound of chemical formula 3; (S2) A step of reducing the compound of the above chemical formula 3 to obtain a compound of the chemical formula 4; (S3) A step of reacting the compound of the above chemical formula 4 with glyoxal sodium bisulfite or a substituted or unsubstituted C1 to C10 alkane dione or a substituted or unsubstituted C1 to C10 oxalate to obtain a compound of the chemical formula 5; (S4) A step of dissolving the compound of the above chemical formula 5 in acetonitrile and then reacting it with an oxidizing agent to obtain quinoxaline-5,8-dione of the chemical formula 6; (S5) A step of performing a halogenation reaction of quinazoline-5,8-dione of the above chemical formula 6 to obtain a compound of the chemical formula 7; (S6) A step of dissolving the compound of chemical formula 7 in THF, adding NaR5, and reacting to obtain the target compound of chemical formula 8; (S7) A step of additionally reacting the compound of chemical formula 8 with NaR5 to obtain the target compound of chemical formula 9; and (S8) A step of reacting a compound of chemical formula 9 with a compound containing an amino group of chemical formula 10 to obtain a compound of chemical formula 1, which is the final target compound. [Chemical Formula 1] [Chemical Formula 2] [Chemical Formula 3] [Chemical Formula 4] [Chemical Formula 5] [Chemical Formula 6] [Chemical Formula 7] [Chemical Formula 8] [Chemical Formula 9] [Chemical Formula 10] NHR3R4 In the above formula, R a and R b are each independently H or substituted or unsubstituted C1 to C10 alkyl, X1 and X2 are the same or different halogen elements, R1 to R5 are each as defined in chemical formula 1.

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