Novel 1,4-naphthoquinone derivative and method for preparing same

Abstract

The present invention relates to a novel 1,4-naphthoquinone derivative, a preparation method therefor, and uses thereof, and the derivative acting as a substrate for NQO1 and effectively increasing enzyme activity has been confirmed. Therefore, a compound according to the present invention can prevent, alleviate, and / or treat various diseases associated with a decrease in NAD+ or mitochondrial dysfunction by increasing NQO1 activity and consequently increasing in NAD+.

Description

Novel 1,4-Naphthoquinone derivative and method for preparing the same

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

[0002] Cross-citation with related application(s)

[0003] This application claims the benefit of priority based on Korean Patent Application No. 10-2024-0187365 filed on December 16, 2024, and all contents disclosed in the document of said Korean patent application are incorporated herein as part of this specification.

[0004] This study was conducted with funding from the Ministry of Science and ICT, the Ministry of Trade, Industry and Energy, and the Ministry of Health and Welfare, and with support from the National Drug Development Project of the National Drug Development Agency (RS-2024-00259507).

[0005] Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to intracellular energy production, signal transduction, redox, and metabolic reactions, and its oxidized form (NAD + It exists in all cells in two forms: ) and the reduced form (NADH). NAD functions as a cofactor in redox reactions occurring in cellular metabolism, and NAD + As an oxidizing agent, it accepts electrons from other molecules to be reduced to NADH, and NADH acts as a reducing agent by donating electrons. NAD + And since NADH serves as substrates for various enzymes, NAD + The / NADH ratio is known to affect health status. For example, NAD + As the amount of NAD decreased + When the / NADH ratio decreases and NADH becomes excess, NADH is used as a major substrate for generating reactive oxygen species (ROS), which can be a cause of various diseases, including inflammatory conditions. In addition, NAD in various diseases such as cancer, diabetes, Alzheimer's disease, and neurodegenerative diseases +Because a sharp decrease in NAD is observed, + Research is being conducted on therapeutic methods that restore normal cell metabolism, etc., by increasing the / NADH ratio.

[0006] NAD + As a method to increase the concentration or ratio of, first, NAD + A method for regulating the biosynthetic de novo synthesis process and salvage pathway, and second, activating the gene or protein of an enzyme that uses NADH as a substrate or coenzyme to in vivo NAD + Methods to increase concentration, third, NAD + Or by supplying its analogs, derivatives, precursors, and prodrugs from an external source to NAD + Methods such as increasing the concentration of can be considered.

[0007] NAD(P)H:quinone dehydrogenase 1 (NQO1) is a flavoprotein that catalyzes the two-electron reduction and detoxification of quinones or quinone derivatives. NQO1 is part of the numerous cellular defense mechanisms induced by oxidative stress. The combined expression of genes involved in these defense mechanisms, including NQO1, plays a role in protecting cells against oxidative stress, free radicals, and neoplasmia. Therefore, while NQO1 exists at relatively low levels under normal conditions, its expression is induced by xenobiotics, antioxidants, oxidizers, heavy metals, ultraviolet rays, and radiation. It is known that the expression and activity of NQO1 are increased in various disease states, such as cancer, obesity, muscle diseases, degenerative diseases, and mitochondrial dysfunction.

[0008] NQO1 uses NADH as an electron donor. Therefore, activated NQO1 converts NADH to NAD + Convert to, and increased NAD +It can induce effects such as the improvement of cellular energy metabolism and mitochondrial function. Therefore, through the increased activity and expression of NQO1, intracellular NAD + An approach to treating various diseases by inducing an increase in [it] is gaining attention.

[0009] Mitochondria are essential organelles that serve as the cell's 'energy powerhouse.' Defects in mitochondrial function caused by genetic or environmental factors often lead to various serious diseases affecting organs with high energy demands, such as muscles and the brain. Diseases resulting from mitochondrial dysfunction may include dysfunction caused by oxidative stress due to swelling resulting from abnormal mitochondrial membrane potential, reactive oxygen species, or free radicals; dysfunction caused by genetic factors resulting from nuclear or mitochondrial DNA mutations; and diseases resulting from defects in the oxidative phosphorylation function for mitochondrial energy production. Diseases caused by the above factors include MELAS syndrome (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes), Leigh syndrome, Kearns-Sayre syndrome, MERRF (Myoclonus Epilepsy with Ragged-Red Fibers), MIDD (Maternally Inherited Diabetes and Deafness), CPEO (Chronic Progressive External Ophthalmoplegia), LHON (Leber Hereditary Optic Neuropathy), PMM (Primary mitochondrial myopathy), DMD (Duchenne Muscular Dystropy), and FRDA (Friedreich's Conditions such as ataxia and Charcot-Marie-Tooth disease (CMT) may occur. However, there is no fundamental cure for these mitochondrial dysfunction disorders, and only symptom relief through antioxidants and vitamins is possible.

[0010] [Prior Art Literature]

[0011] [Patent Literature]

[0012] (Patent Document 1) Republic of Korea Registered Patent No. 10-1677449

[0013] The present invention has been devised to solve the aforementioned requirements, and the inventors have developed NAD acting as a substrate for NQO1. + The present invention was completed by developing novel 1,4-naphthoquinone derivatives that can effectively increase the activity of and exert therapeutic effects on various diseases.

[0014] Accordingly, the main object of the present invention is to provide a novel 1,4-naphthoquinone derivative capable of serving as a substrate for NQO1, a compound of Formula 1 below, a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer thereof:

[0015] [Chemical Formula 1]

[0016]

[0017]

[0018] The present disclosure is summarized as follows:

[0019] 1. Compounds represented by the following chemical formula 1, pharmaceutically acceptable salts, hydrates, solvates, prodrugs, tautomers, enantiomers, or diastereomers thereof:

[0020] [Chemical Formula 1]

[0021]

[0022] In the above chemical formula 1,

[0023] The above R1 is hydrogen, a substituted or unsubstituted alkyl, or a substituted or unsubstituted cycloalkyl, and

[0024] R2 is a substituted or non-substituted aryl, or a substituted or non-substituted heteroaryl, and

[0025] R3 is -S(O)R'1, -S(O)2R'1 or -SO3H, and R'1 is a C1 to C4 alkyl.

[0026]

[0027] 2. In Paragraph 1,

[0028] The above R1 is a compound, pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer, wherein R1 is hydrogen, a substituted or unsubstituted C1 to C4 alkyl, or a substituted or unsubstituted C3 to C6 cycloalkyl.

[0029]

[0030] 3. In Paragraph 1,

[0031] The above-mentioned substituted alkyl or substituted cycloalkyl is substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, nitro, amino, C1 to C4 alkyl, C1 to C14 haloalkyl, C1 to C4 alkoxy, C2 to C4 alkenyl, C6 to C10 aryl, 4 to 12 heterocycloalkyl, and 4 to 12 heteroaryl.

[0032] At this time, the heterocycloalkyl or heteroaryl comprises one or more heteroatoms selected from the group consisting of N, O and S, a compound, a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer thereof.

[0033]

[0034] 4. In Paragraph 1,

[0035] The above R2 is a compound, pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer, wherein R2 is a substituted or unsubstituted C6 to C10 aryl, or a substituted or unsubstituted 4 to 12 heteroaryl.

[0036]

[0037] 5. In Paragraph 4,

[0038] A compound, pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer thereof, wherein the above-mentioned substituted C6 to C10 aryl or substituted 4-membered 12-membered heteroaryl is substituted with one or more substituents selected from the group consisting of substituted or unsubstituted C1 to C6 alkyl, substituted or unsubstituted C1 to C6 alkoxy, and halos.

[0039]

[0040] 6. In Paragraph 5,

[0041] A compound, pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer thereof, wherein the C1 to C6 alkyl group of the above substitution is substituted with one or more halogens, and the C1 to C6 alkoxy group of the above substitution is substituted with one or more selected from the group consisting of halogens, cyanos, C1 to C4 alkyls, C2 to C4 alkenyls, C6 to C10 aryls, 4 to 12 heterocycloalkyls, and 4 to 12 heteroaryls, wherein the heterocycloalkyl or heteroaryl comprises one or more heteroatoms selected from the group consisting of N, O, and S.

[0042]

[0043] 7. In Paragraph 1,

[0044] A compound, pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer thereof, wherein R'1 is CH3 or OH.

[0045]

[0046] 8. In Paragraph 1,

[0047] The above compound is a compound selected from the group consisting of the following compounds 1 to 42, a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer thereof.

[0048]

[0049] 9. NAD comprising, as an active ingredient, the compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer thereof. + A pharmaceutical composition for the prevention or treatment of diseases caused by a decrease in or mitochondrial dysfunction.

[0050]

[0051] 10. In Paragraph 9,

[0052] The above NAD + A pharmaceutical composition wherein the disease caused by a decrease in or mitochondrial dysfunction is one or more selected from the group consisting of metabolic diseases, primary and secondary mitochondrial diseases, muscle diseases, neurodegenerative diseases, inflammatory diseases, fibrotic diseases, autoimmune diseases, cancer, and cognitive impairment.

[0053]

[0054] 11. In Paragraph 10,

[0055] A pharmaceutical composition wherein the above metabolic disease is one or more selected from the group consisting of obesity, diabetes, and metabolic disorder-related fatty liver disease.

[0056]

[0057] 12. NAD comprising, as an active ingredient, a compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer thereof. + A food composition for the prevention or improvement of diseases caused by a decrease in or mitochondrial dysfunction.

[0058]

[0059] 13. A composition for enhancing the activity of NQO1, comprising as an active ingredient a compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer thereof.

[0060]

[0061] 14. A method for preparing a compound represented by Chemical Formula 1, comprising the following steps:

[0062] (S1) A step of reacting the compound of Chemical Formula 2 below with HNO3 to obtain the compound of Chemical Formula 3 below;

[0063] (S2) A step of reducing the compound of Formula 3 above to obtain the compound of Formula 4;

[0064] (S3) A step of reacting the compound of Formula 4 with Glyoxal sodium bisulfite to obtain the compound of Formula 5;

[0065] (S4) A step of dissolving the compound of Formula 5 in acetonitrile and then reacting it with an oxidizing agent to obtain quinoxalin-5,8-dione of Formula 6; and

[0066] (S5) A step of obtaining a compound of the following formula 7 by performing a halogenation reaction of the quinazoline-5,8-dione of formula 6 above;

[0067] (S6) A step of obtaining a compound of formula 9 by nucleophilically reacting the compound of formula 7 and the compound of formula 8;

[0068] (S7) A step of synthesizing a compound of the following formula 1 from a compound of the above formula 9, wherein the step is performed by a method comprising the following step (a) or (b),

[0069] (a) a step of obtaining a compound of formula 10 by reacting NaZ1 with the compound of formula 9; and a step of obtaining formula 1 by oxidizing the compound of formula 10 using an oxidizing agent,

[0070] (b) a step of obtaining a compound of Formula 11 by reacting NaR3 with the compound of Formula 9 above; and a step of obtaining Formula 1 by oxidizing the compound of Formula 11 using an oxidizing agent,

[0071]

[0072] [Chemical Formula 2]

[0073]

[0074] [Chemical Formula 3]

[0075]

[0076] [Chemical Formula 4]

[0077]

[0078] [Chemical Formula 5]

[0079]

[0080] [Chemical Formula 6]

[0081]

[0082] [Chemical Formula 7]

[0083]

[0084] [Chemical Formula 8]

[0085] NHR1R2

[0086] [Chemical Formula 9]

[0087]

[0088] [Chemical Formula 10]

[0089]

[0090] [Chemical Formula 11]

[0091]

[0092] [Chemical Formula 1]

[0093]

[0094] In the above chemical formulas,

[0095] R1 is hydrogen, a substituted or unsubstituted alkyl, or a substituted or unsubstituted cycloalkyl, and

[0096] R2 is a substituted or non-substituted aryl, or a substituted or non-substituted heteroaryl, and

[0097] R3 is -S(O)R'1, -S(O)2R'1 or -SO3H, and R'1 is a C1 to C4 alkyl, and

[0098] R a and R b Each is independently an H or a substituted or unsubstituted C1 to C10 alkyl, and

[0099] X1 and X2 are identical or different halogen elements, and

[0100] Z1 is -SR c , or -SOH and R c It is a C1 to C4 alkyl.

[0101] 15. A NAD comprising the step of administering to an individual a compound represented by Formula 1 according to claim 1, a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer thereof. + Method for preventing, improving, or treating diseases caused by a decrease in or mitochondrial dysfunction.

[0102] 16. NAD + Use of a compound represented by Formula 1 according to claim 1, or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, tautomers, enantiomers, or diastereomers, for the prevention, improvement, or treatment of diseases caused by a decrease in or mitochondrial dysfunction.

[0103] 17. NAD +Use of a compound represented by Formula 1 according to Claim 1, and its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, tautomers, enantiomers, or diastereomers, for preparing a pharmaceutical composition for the prevention, improvement, or treatment of diseases caused by a decrease in or mitochondrial dysfunction.

[0104]

[0105] However, the technical problems that the present invention aims to solve are not limited to those mentioned above, and other unmentioned problems will be clearly understood by those skilled in the art to which the present invention belongs from the description below.

[0106] The present invention provides a novel compound of Formula 1 that can serve as a substrate for NQO1, and a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer thereof.

[0107] In addition, the present invention comprises, as an active ingredient, the above compound, its pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer, NAD + A composition for the prevention, improvement, or treatment of diseases caused by a decrease in or mitochondrial dysfunction is provided.

[0108] In addition, the present invention provides a composition for enhancing the activity of NQO1, comprising the above compound, its pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer as an active ingredient.

[0109] In addition, the present invention comprises the step of administering the above compound, its pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer to an individual, NAD +A method for preventing, improving, or treating diseases caused by a decrease in or mitochondrial dysfunction is provided. Herein, the individual is NAD + It may be an individual requiring prevention, improvement, or treatment of a disease caused by a decrease in or mitochondrial dysfunction. Here, the method comprises administering NAD prior to the administering step. + It may additionally include a step of identifying individuals requiring prevention, improvement, or treatment of diseases caused by a decrease in or mitochondrial dysfunction.

[0110]

[0111] In addition, the present invention is NAD + The present invention provides the use of the above compound, its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, tautomers, enantiomers, or diastereomers for the prevention, improvement, or treatment of diseases caused by a decrease in or mitochondrial dysfunction.

[0112] In addition, the present invention is NAD + The present invention provides the use of the said compound, its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, tautomers, enantiomers, or diastereomers for the manufacture of pharmaceutical compositions or drugs for the prevention, improvement, or treatment of diseases caused by reduction or mitochondrial dysfunction.

[0113] In addition, the present invention provides a method for manufacturing the above compound.

[0114] The present invention relates to a novel 1,4-naphthoquinone derivative, which was completed by confirming that said derivative acts as a substrate for NQO1 and effectively increases enzyme activity. Accordingly, the compound according to the present invention increases NQO1 activity and consequently NAD + NAD through increase + It can achieve preventive, improved, and / or therapeutic effects for various diseases associated with a decrease in or mitochondrial dysfunction.

[0115] The present invention relates to a novel 1,4-naphthoquinone derivative, and was completed by confirming that the derivative acts as a substrate for NQO1 and effectively increases the activity of the enzyme.

[0116] The present invention will be described in detail below.

[0117] 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:

[0118] [Chemical Formula 1]

[0119]

[0120] In the above chemical formula 1,

[0121] The above R1 is hydrogen, a substituted or unsubstituted alkyl, or a substituted or unsubstituted cycloalkyl, and

[0122] R2 is a substituted or non-substituted aryl, or a substituted or non-substituted heteroaryl, and

[0123] R3 is -S(O)R'1, -S(O)2R'1 or -SO3H, and R'1 is a C1 to C4 alkyl.

[0124]

[0125] Unless otherwise stated below, the compound of Formula 1 of the present invention includes all of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, tautomers, enantiomers, or diastereomers, all of which should be interpreted as being included within the scope of the present invention. For convenience of explanation, the compound of Formula 1, 1,4-naphthoquinone derivatives, etc., may be simply abbreviated in this specification.

[0126] The term “pharmaceuticalally acceptable salt” refers to a formulation of a compound that does not cause severe irritation to the organism to which it is administered and does not impair the biological activity and physical properties of the compound.

[0127] The terms "hydrate," "solvent," "prodrug," "tautomer," "enantiomer," or "diastereomer" in this specification also have the same meaning as above.

[0128] The above "pharmaceutically acceptable salt" includes acid addition salts formed by acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as inorganic acids like hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromide, hydroiodide, etc., organic carboxylic acids like 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., and sulfonic acids like 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., and organic salts such as dicyclohexylamine, N-methyl-D-glucarmine, 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 conventional methods.

[0129] The term “hydrate” means a compound of the present invention or a salt thereof containing stoichiometric or non-stoichiometric amounts of water bound by non-covalent intermolecular forces.

[0130] The term “solvate” means a compound of the present invention or a salt thereof comprising stoichiometric or non-stoichiometric amounts of solvent bound by non-covalent intermolecular forces. Preferred solvents thereof include volatile, non-toxic, and / or solvents suitable for administration to humans.

[0131] The term “prodrug” refers to a substance that transforms into a 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 achieve viability via oral administration, 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”) that facilitates passage through the cell membrane, which is hydrolyzed by metabolism into an active carboxylic acid once water solubility is beneficial in the cell, although water solubility is detrimental to mobility. Another example of a prodrug could be a short peptide (polyamino acid) bound to an acid group that is converted by metabolism to expose the active site.

[0132] The term "tautomer" refers to a type of structural isomer that has the same chemical or molecular formula but differs in the way its constituent atoms are connected; for example, it signifies a structure that continuously alternates between the two isomers, such as in a keto-enol structure.

[0133] The terms “enantiomer” or “diastereomer” refer to isomers that have the same chemical or molecular formula but differ in the spatial arrangement of atoms within the molecule. The term “enantiomer” refers to an isomer that does not overlap with its mirror image, much like the relationship between a right hand and a left hand. Additionally, “diastereomer” refers to a stereoisomer that is not in a mirror image relationship, such as the trans form and the cis form; in this invention, the term is limited to pharmaceutically acceptable diastereomers. All of these isomers and mixtures thereof are also included within the scope of this invention.

[0134] The term “alkyl” refers to an aliphatic hydrocarbon group. In the present invention, “alkyl” is used as a concept that includes both “saturated alkyl,” which means not containing any alkene or alkyne groups, and “unsaturated alkyl,” which means containing at least one alkene or alkyne group; more specifically, it may be “saturated alkyl,” which means not containing any alkene or alkyne groups. The alkyl may include branched, straight-chain, or cyclic forms, and may also include structural isomers; for example, in the case of a C3 alkyl, it may mean propyl or isopropyl. In the present invention, the alkyl may be C1 to C20, C1 to C15, C1 to C12, C1 to C10, C1 to C8, C1 to C6, C1 to C5, C1 to C4, C1 to C3, or C1 to C2 alkyl, but is not limited thereto. For example, in the present invention, the alkyl may be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl, etc., and more specifically, for example, may be methyl or ethyl, etc.

[0135] The term “heteroalkyl” refers to an alkyl group comprising at least one heteroatom (e.g., oxygen, nitrogen, sulfur, etc.) in addition to carbon and hydrogen. Like alkyls, heteroalkyls may also include branched, straight-chain, or cyclic forms and include structural isomers.

[0136] The term “cycloalkyl” refers to a saturated hydrocarbon group in which three or more carbon atoms form a ring structure. In the present invention, the cycloalkyl may be C3 to C20, C3 to C15, C3 to C12, C3 to C10, C3 to C8, C3 to C6, C3 to C5, or C3 cycloalkyl, but is not limited thereto.

[0137] The term "heterocycloalkyl" means a cycloalkyl in which one or more ring carbons are substituted with oxygen, nitrogen, sulfur, etc.

[0138] The term "alkene" refers to a group in which at least two carbon atoms are connected by at least one carbon-carbon double bond, and "alkyne" refers to a group in which at least two carbon atoms are connected by at least one carbon-carbon triple bond. In the present invention, the alkene or alkyne may be C2 to C20, C2 to C15, C2 to C12, C2 to C10, C2 to C8, C2 to C6, C2 to C5, C2 to C4, C2 to C3, or C2 alkenes or alkynes, but is not limited thereto.

[0139] The term “alkoxy” refers to a substituent having a structure in which an alkyl group is connected through an oxygen atom. In the present invention, the alkoxy may be a C1 to C10, C1 to C8, C1 to C6, C1 to C5, C1 to C3, or C1 to C2 alkoxy, but is not limited thereto. Specifically, examples include methoxy (-OCH3), ethoxy (-OCH2CH3), etc.

[0140] The term "aryl" means an aromatic substituent having at least one ring having a shared pi electron system. The term includes monocyclic or fused ring polycyclic groups (i.e., rings sharing adjacent pairs of carbon atoms). When substituted, the substituent may be appropriately bonded to the ortho (o), meta (m), or para (p) positions. In the present invention, the aryl may be a C6 to C20 or C6 to C10 aryl, but is not limited thereto.

[0141] The term "aryloxy" refers to a group in which one carbon of an aromatic substituent is bonded to oxygen, and for example, when oxygen is bonded to a phenyl group, it can be represented as -O-C6H5 or -C6H4-O-.

[0142] The term "heteroaryl" refers to an aromatic group in which at least one of the ring carbons constituting the aryl is substituted with oxygen, nitrogen, sulfur, etc.

[0143] Examples of the above aryl or heteroaryl include phenyl, furan, pyran, pyridyl, pyrimidyl, triazyl, etc., but are not limited to these.

[0144] The term "halogen" refers to elements belonging to Group 17 of the periodic table, specifically fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0145] Other terms may be interpreted in the sense commonly understood in the field to which the present invention belongs.

[0146] In the present invention, the term "substitution" refers to the element introduced in place of a hydrogen atom when a derivative is formed by substituting one or more hydrogen atoms in an organic compound with another atomic group, and the substituent refers to the introduced atomic group. That is, in the present invention, the substitution of any functional group means that one or more hydrogen atoms of the said functional group are replaced by another atomic group. In the present invention, each functional group (alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, acetyl, etc.) may each independently have one or more hydrogen atoms substituted by another atomic group. In the present invention, "substitution" includes single substitution, double substitution, triple substitution, quadruple substitution, etc.

[0147]

[0148] In one embodiment of the present invention, R1 of Formula 1 may be hydrogen, a substituted or unsubstituted C1 to C4 alkyl, or a substituted or unsubstituted C3 to C6 cycloalkyl, but is not limited thereto.

[0149] In one embodiment of the present invention, the substituted alkyl or substituted cycloalkyl that may be R1 may be substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, nitro, amino, C1 to C4 alkyl, C1 to C14 haloalkyl, C1 to C4 alkoxy, C2 to C4 alkenyl, C6 to C10 aryl, 4 to 12 heterocycloalkyl and 4 to 12 heteroaryl (wherein the heterocycloalkyl or heteroaryl comprises one or more types selected from the group consisting of N, O and S, for example, 1 to 4, 1 to 3, or 1 to 2 substituents. In this case, the two or more substituents may be the same or different from each other.

[0150]

[0151] In one embodiment of the present invention, R2 of Formula 1 may be a substituted or unsubstituted C6 to C10 aryl, or a substituted or unsubstituted 4 to 12 heteroaryl.

[0152] More specifically, R2 of the above chemical formula 1 may be a substituted or unsubstituted C6 to C10 aryl, or a substituted or unsubstituted 4 to 9 heteroaryl.

[0153] The above heteroaryl may include one or more heteroatoms selected from the group consisting of N, O, and S, for example, 1 to 3 heteroatoms. In this case, two or more heteroatoms may be identical or different from each other.

[0154] In one embodiment of the present invention, R2 of Formula 1 may be a substituted aryl or a substituted heteroaryl, wherein the substituted aryl or substituted heteroaryl may be substituted with one or more substituents selected from the group consisting of substituted or unsubstituted C1 to C6 alkyls, substituted or unsubstituted C1 to C6 alkoxys, and halos, for example, 1 to 4, 1 to 3, or 1 to 2 substituents. In this case, the two or more substituents may be the same or different from each other.

[0155] Here, the halogen element may be, more specifically, fluorine, bromine, or chlorine, but is not limited thereto.

[0156] Here, the substituted or unsubstituted alkyl may be a C1 to C6 alkyl, more specifically a C1 to C4 alkyl, a C1 to C3 alkyl, or a C1 to C2 alkyl, but is not limited thereto.

[0157] Here, the alkyl of the substitution may be an alkyl (i.e., a haloalkyl) substituted with a halogen element. Additionally, the alkyl of the substitution may be substituted with one to three halogen elements. Here, two or more halogen elements may be of the same or different types. The halogen element may be fluorine, but is not limited thereto.

[0158] Here, the substituted or unsubstituted alkoxy may be C1 to C6 alkoxy, more specifically C1 to C4 alkoxy, C1 to C3 alkoxy, or C1 to C2 alkoxy, but is not limited thereto. For example, the alkoxy may be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, or tert-butoxy, and more specifically, may be methoxy or ethoxy, but is not necessarily limited thereto.

[0159] Here, the alkoxy of the substitution may be substituted with one or more substituents selected from the group consisting of halogen, cyano, C1 to C4 alkyl, C2 to C4 alkenyl, C6 to C10 aryl, 4 to 12 heterocycloalkyl and 4 to 12 heteroaryl (wherein the heterocycloalkyl or heteroaryl comprises one or more types selected from the group consisting of N, O and S, for example, 1 to 3 heteroatoms), for example, 1 to 4, 1 to 3, or 1 to 2. In this case, the two or more substituents may be identical or different from each other.

[0160] In another embodiment of the present invention, the substituted aryl or substituted heteroaryl may be any one selected from the group consisting of unsubstituted C1 to C3 alkyl, C1 to C3 alkyl substituted with 1 to 3 halogen elements, unsubstituted C1 to C3 alkoxy, and halogen elements, or substituted with any two or more identical or different substituents, but is not limited thereto.

[0161]

[0162] In one embodiment of the present invention, R3 of Formula 1 is -S(O)R'1, -S(O)2R'1, or -SO3H, and R'1 may be a C1 to C3 alkyl, more specifically R'1 may be CH3 or OH, but is not limited thereto.

[0163]

[0164] In the present invention, the scope of Formula 1 encompasses all compounds formed by combining the definitions of R1, R2, R3, and / or R'1 described in one embodiment of the present invention. For example, in Formula 1, R1 may be hydrogen, a substituted or unsubstituted alkyl, or a substituted or unsubstituted cycloalkyl; R2 may be a substituted or unsubstituted C6 to C10 aryl, or a substituted or unsubstituted 4 to 12 heteroaryl; R3 may be -S(O)R'1, -S(O)2R'1, or -SO3H; and R'1 may be a compound formed by other definitions of R1, R2, R3, and / or R'1.

[0165]

[0166]

[0167] In one embodiment of the present invention, the compound of Formula 1 may be selected from the group consisting of the following compounds 1 to 42.

[0168] However, the following compounds 1 to 42 correspond to some embodiments of compounds conceivable from this specification and are not necessarily limited thereto. The embodiments of compounds 1 to 42 demonstrate that the compounds of Formula 1 of the present invention exhibit certain utility even when various substituent changes are included:

[0169]

[0170]

[0171]

[0172]

[0173] In addition, the present invention comprises, as an active ingredient, the above compound, its pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer, NAD + The present invention provides a composition for the prevention, improvement, or treatment of diseases caused by a decrease in or mitochondrial dysfunction. The composition may be a pharmaceutical composition, a food composition, and / or a cosmetic composition. Preferably, the present invention comprises NAD, the above compound, etc., as an active ingredient. + Provides a pharmaceutical composition for the prevention or treatment of diseases caused by a decrease in or mitochondrial dysfunction.

[0174] In addition, the present invention relates to a NAD comprising the above-mentioned therapeutic composition. + Provides a kit for the prevention, improvement, or treatment of diseases caused by a decrease in or mitochondrial dysfunction.

[0175] In addition, the present invention comprises the step of administering the above compound, etc. to an individual requiring it, NAD + It provides a method for preventing, improving, or treating diseases caused by a decrease in or mitochondrial dysfunction.

[0176] In addition, the present invention is NAD + The above compounds, etc. are used for the prevention, improvement, or treatment of diseases caused by a decrease in or mitochondrial dysfunction.

[0177] In addition, the present invention is NAD + The above compounds, etc. are used for the manufacture of drugs for the prevention, improvement, or treatment of diseases caused by a decrease in or mitochondrial dysfunction.

[0178] In addition, the present invention provides a composition for enhancing the activity of NAD(P)H:quinone dehydrogenase 1 (NQO1), comprising the compound, a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer thereof as an active ingredient. The composition may be a pharmaceutical composition, a food composition, and / or a cosmetic composition.

[0179] In addition, the present invention provides a kit for enhancing the activity of NQO1, comprising the above composition.

[0180] In addition, the present invention provides a method for enhancing the activity of NQO1, comprising the step of administering the above compound, etc. to an individual requiring it.

[0181] In addition, the present invention provides a use of the above-mentioned compound, etc. for enhancing the activity of NQO1.

[0182] In addition, the present invention provides a use of the above-mentioned compound, etc. for the manufacture of a drug for enhancing the activity of NQO1.

[0183] The compound according to the present invention can increase the activity of NQO1, and the NQO1 with increased activity oxidizes NADH to increase intracellular NAD + Increases NAD + An increase in / NADH can increase the AMP / ATP ratio, and an increase in AMP activates AMP-activated protein kinase (AMPK), which induces mitophagy. In addition, NAD + It is used as a cofactor for enzymes related to glucose and fat metabolism in the body to promote metabolism, and NAD + cADPR, generated from the degradation of , is produced in the endoplasmic reticulum (ER) from Ca 2+By releasing [it] to induce synergistic activation of mitochondrial metabolism, it can bring about an in vivo motion-mimicking effect. Therefore, the compound of the present invention, through the effects described above, [induces] NAD + It is possible to achieve preventive, improved, and / or therapeutic effects for various diseases that may be caused by a decrease in or mitochondrial dysfunction.

[0184] In one embodiment of the present invention, the NAD + Diseases caused by a decrease in or mitochondrial dysfunction may be one or more selected from the group consisting of metabolic diseases, primary and secondary mitochondrial diseases, muscular diseases, neurodegenerative diseases, inflammatory diseases, fibrotic diseases, autoimmune diseases, cancer, and cognitive impairment, but are not limited thereto.

[0185] In another embodiment of the present invention, the metabolic disease may be one or more selected from the group consisting of obesity, diabetes, and metabolic disorder-related fatty liver disease, but is not limited thereto.

[0186] The content of the compound, etc. in the composition of the present invention can be appropriately adjusted according to the symptoms of the disease, the degree of progression of the symptoms, the condition of the patient, etc. For example, it may be 0.0001 to 99.9% by weight or 0.001 to 50% by weight based on the total weight of the composition, but is not limited thereto. The above content ratio is a value based on the dry weight after removing the solvent.

[0187] The pharmaceutical composition according to the present invention may further include a suitable carrier, excipient, and diluent commonly used in the manufacture of pharmaceutical compositions. The excipient may be one or more selected from the group consisting of, for example, diluents, binders, disintegrants, lubricants, adsorbents, humectants, film-coating materials, and controlled-release additives.

[0188] The pharmaceutical composition according to the present invention may be formulated and used in the form of external preparations such as powders, granules, sustained-release granules, enteric granules, liquids, eye drops, ellipsoids, emulsions, suspensions, ethanol tablets, troches, fragrances, limonades, tablets, sustained-release tablets, enteric tablets, sublingual tablets, hard capsules, soft capsules, sustained-release capsules, enteric capsules, pills, tinctures, soft extracts, dry extracts, fluid extracts, injections, capsules, irrigation solutions, warning agents, lotions, pastes, sprays, inhalants, patches, sterile injectable solutions, or aerosols, according to conventional methods, and the external preparations may have formulations such as creams, gels, patches, sprays, ointments, warning agents, lotions, liniments, pastes, or cataplasms.

[0189] Carriers, excipients, and diluents that may be included in the pharmaceutical composition according to the present invention include lactose, dextrose, sucrose, oligosaccharide, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil.

[0190] When formulating, it is prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants.

[0191] The pharmaceutical composition according to the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level may be determined according to factors including the type and severity of the patient's disease, drug activity, sensitivity to the drug, time of administration, route of administration and elimination rate, duration of treatment, concurrently used drugs, and other factors well known in the medical field.

[0192] The pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered as a single or multiple doses. It is important to administer an amount that obtains maximum effect with a minimum amount without side effects by considering all the above-mentioned factors, and this can be easily determined by a person skilled in the art to which the present invention belongs.

[0193] The pharmaceutical composition of the present invention may be administered to an individual by various routes. All modes of administration are expected, for example, oral administration, subcutaneous injection, intraperitoneal administration, intramuscular injection, intrathecal (intradural) injection, sublingual administration, buccal mucosal administration, rectal insertion, vaginal insertion, ocular administration, ear administration, nasal administration, inhalation, spray through the mouth or nose, skin administration, transdermal administration, etc.

[0194] The dosage of the pharmaceutical composition of the present invention is determined by the type of active ingredient drug, along with various relevant factors such as the disease to be treated, the route of administration, the patient's age, gender, weight, and the severity of the disease. Specifically, the effective dosage of the composition according to the present invention may vary depending on the patient's age, gender, and weight, and generally, 0.001 to 150 mg, preferably 0.01 to 100 mg per kg of body weight, may be administered daily or every other day, or divided into 1 to 3 doses per day. However, since the dosage may be increased or decreased depending on the route of administration, the severity of the disease, gender, weight, age, etc., the above dosage does not limit the scope of the present invention in any way.

[0195] In the present invention, the term “individual” refers to a subject requiring treatment for a disease, and more specifically, to mammals such as humans or non-human primates, mice, rats, dogs, cats, horses, and cattle.

[0196] In the present invention, “administration” means providing a predetermined composition of the present invention to an individual by any appropriate method.

[0197] In the present invention, “prevention” refers to any act of suppressing or delaying the onset of a target disease, “treatment” refers to any act of improving or beneficially altering the target disease and associated metabolic abnormality symptoms through the administration of a pharmaceutical composition according to the present invention, and “improvement” refers to any act of reducing parameters related to the target disease, such as the severity of symptoms, through the administration of a composition according to the present invention.

[0198] When the compounds of the present invention are used as food additives, they may be added as they are or used together with other foods or food ingredients, or used appropriately according to conventional methods. The amount of the active ingredient can be appropriately determined according to the purpose of use (prevention, health, or therapeutic treatment). Generally, when manufacturing food or beverages, the compounds of the present invention may be added in an amount of 15% by weight or less, or 10% by weight or less, relative to the raw materials. However, in the case of long-term consumption for the purpose of health and hygiene or health control, the above amount may be less than the above range, and since there are no issues regarding safety, the active ingredient may be used in an amount greater than the above range.

[0199] There are no specific restrictions on the types of the above-mentioned foods. Examples of foods to which the above-mentioned substance may be added include meat, sausage, bread, chocolate, candies, snacks, confectionery, pizza, ramen, other noodles, chewing gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages, and vitamin complexes, and include all health functional foods in the conventional sense.

[0200] The health beverage composition according to the present invention may contain various flavoring agents or natural carbohydrates as additional ingredients, as in conventional beverages. The natural carbohydrates described above are monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As sweeteners, natural sweeteners such as taumatin and stevia extract, or synthetic sweeteners such as saccharin and aspartame may be used. The proportion of the natural carbohydrates is generally about 0.01-0.20g or about 0.04-0.10g per 100 mL of the composition of the present invention.

[0201] In addition to the above, the composition of the present invention may contain various nutrients, vitamins, electrolytes, flavoring agents, coloring agents, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc. Furthermore, the composition of the present invention may contain fruit pulp for the production of natural fruit juices, fruit juice beverages, and vegetable beverages. These ingredients may be used independently or in combination. Although the proportion of these additives is not critical, it is generally selected in the range of 0.01 to 0.20 parts by weight per 100 parts by weight of the composition of the present invention.

[0202] The food composition of the present invention can be used as a composition for health functional foods. In this specification, the term “health functional food” is synonymous with “food for special health use (FoSHU)” and refers to a food with high medical or health effects that is processed to efficiently exhibit bio-regulatory functions in addition to nutritional supply. The food may be manufactured in various forms such as tablets, capsules, powders, granules, liquids, and pills to obtain useful effects for the prevention, improvement, and treatment of the aforementioned diseases.

[0203] The health functional food of the present invention can be manufactured by methods commonly used in the industry, and can be manufactured by adding raw materials and ingredients commonly added in the industry. In addition, unlike general pharmaceuticals, it has the advantage of not having side effects that may occur from long-term use of pharmaceuticals because it is made of food, and it can be highly portable.

[0204] The formulation of the cosmetic composition according to the present invention may be in the form of a skin lotion, skin softener, skin toner, astringent, lotion, milk lotion, moisture lotion, nourishing lotion, massage cream, nourishing cream, mist, moisture cream, hand cream, hand lotion, foundation, essence, nourishing essence, pack, soap, cleansing foam, cleansing lotion, cleansing cream, cleansing oil, cleansing balm, body lotion, or body cleanser.

[0205] The cosmetic composition of the present invention may further include a composition selected from the group consisting of water-soluble vitamins, oil-soluble vitamins, high molecular weight peptides, high molecular weight polysaccharides, and sphingolipids.

[0206] In the present invention, the term "Kit" refers to NAD using the compound according to the present invention. + It means a combination of materials or devices, etc., for the purpose of preventing, improving, and / or treating diseases caused by a decrease in or mitochondrial dysfunction of NAD(P)H quinone dehydrogenase 1, or for the purpose of enhancing the activity of NAD(P)H quinone dehydrogenase 1, and there are no limitations on the specific form. For the above-mentioned uses, the kit according to the present invention may include not only the compound according to the present invention but also one or more other constituent compositions, solutions, or devices suitable for the prevention, improvement, or treatment of diseases.

[0207]

[0208] In addition, the present invention provides a method for preparing a compound of Formula 1, comprising the following steps:

[0209] (S1) A step of reacting the compound of Formula 2 with HNO3 to obtain the compound of Formula 3;

[0210] (S2) A step of reducing the compound of Formula 3 above to obtain the compound of Formula 4;

[0211] (S3) A step of reacting the compound of Formula 4 with Glyoxal sodium bisulfite to obtain the compound of Formula 5;

[0212] (S4) A step of dissolving the compound of Formula 5 in acetonitrile and then reacting it with an oxidizing agent to obtain quinoxalin-5,8-dione of Formula 6;

[0213] (S5) A step of obtaining a compound of Formula 7 by performing a halogenation reaction of the quinazoline-5,8-dione of Formula 6 above;

[0214] (S6) A step of obtaining a compound of formula 9 by nucleophilically reacting the compound of formula 7 and the compound of formula 8;

[0215] (S7) A step of synthesizing a compound of the following formula 1 from a compound of the above formula 9, wherein the step is performed by a method comprising the following (a) or (b) step,

[0216] (a) a step of obtaining a compound of formula 10 by reacting NaZ1 with the compound of formula 9; and a step of obtaining formula 1 by oxidizing the compound of formula 10 using an oxidizing agent,

[0217] (b) a step of obtaining a compound of Formula 11 by reacting NaR3 with the compound of Formula 9 above; and a step of obtaining Formula 1 by oxidizing the compound of Formula 11 using an oxidizing agent,

[0218]

[0219] [Chemical Formula 2]

[0220]

[0221] [Chemical Formula 3]

[0222]

[0223] [Chemical Formula 4]

[0224]

[0225] [Chemical Formula 5]

[0226]

[0227] [Chemical Formula 6]

[0228]

[0229] [Chemical Formula 7]

[0230]

[0231] [Chemical Formula 8]

[0232] NHR1R2

[0233] [Chemical Formula 9]

[0234]

[0235] [Chemical Formula 10]

[0236]

[0237] [Chemical Formula 11]

[0238]

[0239] [Chemical Formula 1]

[0240]

[0241] (In the above chemical formulas,

[0242] The definitions of R1, R2, and R3 are the same as those in Chemical Formula 1 above, and

[0243] R a and R b Each is independently an H or a substituted or unsubstituted C1 to C10 alkyl, and

[0244] X1 and X2 are identical or different halogen elements, and

[0245] Z1 is -SR c, or -SOH and R c is a C1 to C4 alkyl.

[0246]

[0247] In one embodiment of the present invention, the R a and R b Each is independently H or a substituted or unsubstituted C1 to C10 alkyl, wherein the alkyl may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl, but is not limited thereto.

[0248] Here, the alkyl of the substitution may be substituted with one or more substituents selected from the group consisting of halogen, cyano, C1 to C4 alkyl, C1 to C4 alkoxy, C2 to C4 alkenyl, and C6 to C10 aryl.

[0249] In one embodiment of the present invention, Z1 is -SCH3 or is not limited thereto.

[0250] In one embodiment of the present invention, the step (S1) is a step of reacting HNO3 with a compound of Formula 2 to obtain a compound of Formula 3, which may be carried out by cooling an aqueous solution of HNO3, adding the compound of Formula 2 thereto, and heating to react, but is not limited thereto.

[0251] In one embodiment of the present invention, the step (S2) is to reduce a compound of Formula 3 to obtain a compound of Formula 4, which may be performed by dissolving the compound of Formula 3 in a suitable organic solvent, e.g., ethyl acetate, and then using a suitable reduction catalyst, e.g., Pd / C, Pd(OH)2 / C, PtO2, or Raney Ni, under a hydrogen atmosphere, but is not limited thereto.

[0252] In one embodiment of the present invention, the above (S3) is a step of reacting a compound of Formula 4 with Glyoxal sodium bisulfite to obtain a compound of Formula 5, and may further include, for example, a step of adding distilled water to the compound of Formula 4 and heating to prepare a solution, and separately adding distilled water to Glyoxal sodium bisulfite and heating to dissolve the aqueous solution, and then adding the solution to the solution containing Glyoxal sodium bisulfite and reacting, but is not limited thereto.

[0253] In one embodiment of the present invention, the step (S4) is a step of dissolving the compound of Formula 5 in acetonitrile and then reacting it with an oxidizing agent to obtain quinoxalin-5,8-dione of Formula 6. Specifically, this step may be performed by adding acetonitrile to the compound of Formula 5 and stirring at room temperature to prepare a solution, and separately adding ceric ammonium nitrate dissolved in distilled water slowly to the solution containing the compound of Formula 5 and stirring, but is not limited thereto. The oxidizing agent used in step (S4) may be one or more selected from the group consisting of, for example, ceric ammonium nitrate (CAN), MnO2, bis-[(trifluoroacetoxy)iodo]benzene (BTI), 2-iodoxybenzoic acid (IBX), and oxone, but is not limited thereto.

[0254] In one embodiment of the present invention, the halogenation of step (S5) may be performed using fluorine (F2), chlorine (Cl2), bromine (Br2), or iodine (I2), and specifically, through a reaction with bromine, but is not limited thereto.

[0255] In one embodiment of the present invention, the step (S6) is a step of obtaining a compound of formula 9 by nucleophilically reacting a compound of formula 7 and a compound of formula 8, and may be performed using cerium chloride hydrate, preferably cerium(III) chloride heptahydrate, as a catalyst, but is not limited thereto.

[0256] In one embodiment of the present invention, the step (S7) is a step of synthesizing a compound of Formula 1 from a compound of Formula 9, and the step is performed by a method comprising the following steps (a) or (b).

[0257] Specifically, step (a) is a process of obtaining a compound of formula 10 by reacting NaZ1 with a compound of formula 9, and then oxidizing Z1 using an oxidizing agent to finally obtain a compound of formula 1. As a specific example, the process may further include, but is not limited to, a step of stirring the compound of formula 8 with any one of THF, methanol (MeOH), and dichloromethane before the reaction between the compound of formula 9 and NaZ1. As a specific example, the step of obtaining formula 1 by oxidizing the compound of formula 10 using an oxidizing agent may be performed by sequentially adding chloroform and an oxidizing agent to the compound of formula 10 to carry out the oxidation reaction, but is not limited thereto. The oxidizing agent used in the above step may be one or more selected from the group consisting of, for example, meta-chloroperoxybenzoic acid (mCPBA), MnO2, and Oxone, but is not limited thereto.

[0258] Specifically, step (b) is a process of obtaining a compound of formula 11 by reacting NaR3 with the compound of formula 9, and then using an oxidizing agent thereon to oxidize the tetrahydroquinoxaline structure of formula 11 to obtain formula 1 having a dihydroquinoxaline group. The oxidizing agent used in the above step may be one or more selected from the group consisting of, for example, MnO2, SeO2, and Ag2O, but is not limited thereto.

[0259]

[0260] Preferred embodiments of the present invention will be described in detail below. However, the present invention is not limited to the embodiments described herein and may be embodied in other forms. Rather, the content introduced herein is provided to be thorough and complete and to sufficiently convey the concept of the present invention to those skilled in the art.

[0261]

[0262] <Example 1> Synthesis of Compound 1

[0263]

[0264] A 60% aqueous nitric acid solution (HNO3, 50.0 mL) was cooled at 0°C for 20 minutes, then 1,4-dimethoxybenzene (5.00 g, 36.2 mmol) was added and stirred at the same temperature for 1 hour. The reaction solution was stirred at room temperature for 1 hour, followed by further stirring at 80°C for 1 hour. The reaction solution was poured onto ice for quenching, and the resulting yellow solid was filtered and thoroughly washed with water. The obtained solid was cleanly dissolved in dichloromethane (DCM), dried with MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by recrystallization (ethyl acetate (EtOAc) / n-hexane (Hex)) to obtain the target compound (1,4-dimethoxy-2,3-dinitrobenzene, B).

[0265] Yellow solid, 6.84 g (82.8%)

[0266] 1 H NMR (400 MHz, CHLOROFORM-D) δ 7.20 (s, 2H), 3.93 (s, 6H).

[0267]

[0268] 1,4-dimethoxy-2,3-dinitrobenzene (3.42 g, 15.0 mmol) was dissolved in EtOAc (50.0 mL), then 10% Palladium on Carbon (Pd / C) (wetted with 55% water, 1.06 g, 450 μmol) was added and stirred under a hydrogen atmosphere. The reaction solution was stirred for 24 hours at room temperature. After removing Pd / C by filtration through a celite pad, the filtrate was concentrated under reduced pressure to obtain the target compound (3,6-dimethoxy-benzene-1,2-diamine, C).

[0269] Purple solid, 2.28 g (90.3%)

[0270] 1 H NMR (400 MHz, CHLOROFORM-D) δ 6.31(s, 2H), 3.81(s, 6H).

[0271]

[0272] Distilled water (27.0 mL) is added to 3,6-dimethoxy-benzene-1,2-diamine (2.28 g, 13.6 mmol) and heated to 50°C. Glyoxal sodium bisulfite (4.69 g, 17.6 mmol) is placed in another flask, distilled water (39.0 mL) is added, and the mixture is heated to 50°C to dissolve. The aqueous solution of glycoxal sodium bisulfite is added to the solution containing the starting material and stirred under a nitrogen atmosphere. The reaction solution is stirred for 2.5 hours at 100°C and then cooled to room temperature. The pH is adjusted to 8–9 using a saturated aqueous solution of NaHCO3, DCM is added, and extraction is performed several times. The separated organic layer is dried and filtered with MgSO4, followed by vacuum concentration. The concentrate was separated by silica gel column chromatography (EtOAc / Hex) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (5,8-dimethoxyquinoxaline, D).

[0273] Yellow solid, 2.07 g (80.0%)

[0274]

[0275] 1 H NMR (400 MHz, CHLOROFORM-D) δ 8.90 (s, 2H), 7.04 (s, 2H), 4.08 (s, 6H).

[0276]

[0277] Acetonitrile (MeCN, 29.0 mL) was added to 5,8-dimethoxyquinoxaline (1.94 g, 10.2 mmol) and stirred at room temperature. Ceric ammonium nitrate (CAN, 14.0 g, 25.5 mmol) dissolved in distilled water (29.0 mL) was slowly added to the solution containing the starting material over 10 minutes, and the mixture was stirred for an additional 12 minutes at room temperature. Saturated aqueous NaCl solution and DCM were added, and extraction was performed several times. The separated organic layer was dried and filtered with MgSO4, followed by vacuum concentration. The concentrate was separated by silica gel column chromatography (EtOAc / Hex) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (quinoxaline-5,8-dione, E).

[0278] Yellow solid, 1.20 g (73.5%)

[0279] 1 H NMR (400 MHz, CHLOROFORM-D) δ 9.08 (s, 2H), 7.27 (s, 2H).

[0280]

[0281] Acetic acid (AcOH, 25 mL) was added to quinoxaline-5,8-dione (2.47 g, 15.4 mmol) and stirred at room temperature. Bromine (Br2, 1.74 mL, 33.9 mmol) was added and stirred for 1.5 hours at 100°C. After cooling the reaction solution to room temperature, distilled water (100 mL) was added and quenched. The resulting solid was filtered and washed several times with distilled water. The obtained solid was cleanly dissolved in DCM, dried with MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6,7-dibromoquinoxaline-5,8-dione, F).

[0282] Ivory solid, 3.49 g (71.2%)

[0283] 1 H NMR (400 MHz, DMSO-D6) δ 9.09 (s, 2H).

[0284]

[0285] Ethanol (EtOH, 9.40 mL) was added to 6,7-dibromoquinoxaline-5,8-dione (300 mg, 944 μmol) and stirred at room temperature. At the same temperature, 2-fluoroaniline (136 μL, 1.42 mmol) and CeCl3·7H2O (35.2 mg, 94.4 μmol) were added and stirred for 19 hours at room temperature. After adding a saturated aqueous solution of NaCl and DCM and extracting several times, the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-((2-fluorophenyl)amino)quinoxaline-5,8-dione, 1a).

[0286] Red brown solid, 328 mg(99.8%)

[0287] 1 H NMR (400 MHz, DMSO-D6) δ 9.41 (s, 1H), 9.11 - 8.93 (m, 2H), 7.41 - 7.10 (m, 4H).

[0288]

[0289] Tetrahydrofuran (THF, 10.4 mL) was added to 6-bromo-7-((2-fluorophenyl)amino)quinoxaline-5,8-dione (325 mg, 934 μmol) and stirred at room temperature. At the same temperature, sodium thiomethoxide (NaSMe, 196 mg, 2.80 mmol) was added and stirred for 47 hours at room temperature. A saturated aqueous solution of NaCl was added to the reaction solution and extracted several times with DCM. The separated organic layer was washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((2-fluorophenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, 1b).

[0290] Red brown solid, 155 mg (52.7%)

[0291] 1 H NMR (400 MHz, DMSO-D6) δ 9.15 (s, 1H), 9.02 (d, J = 2.4 Hz, 1H), 8.99 (d, J = 2.3 Hz, 1H), 7.30 - 7.13 (m, 4H), 2.13 (s, 3H).

[0292]

[0293] Chloroform (CHCl3, 4.90 mL) was added and stirred at room temperature. At the same temperature, mCPBA (274 mg, 1.22 mmol) was added and stirred for another 7 hours. Distilled water was added to the reaction solution and extracted several times with DCM. The separated organic layer was dried and filtered with MgSO4, then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH was adjusted to 8 with a saturated aqueous solution of NaHCO3, DCM was added, and the mixture was extracted several times. The separated organic layer was washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((2-fluorophenyl)amino)-7-(methyl sulfonyl)quinoxaline-5,8-dione, Compound 1).

[0294] Red solid, 106 mg (62.2%)

[0295] 1 H NMR (500 MHz, DMSO-D6) δ 10.48 (s, 1H), 9.11 (d, J = 2.3 Hz, 1H), 9.03 (d, J = 2.6 Hz, 1H), 7.52 (t, J = 8.0 Hz, 1H), 7.37 - 7.29 (m, 2H), 7.20(dt,J= 8.4, 4.4 Hz, 1H), 3.43(s, 3H).

[0296]

[0297] <Example 2> Synthesis of Compound 2

[0298]

[0299] EtOH (9.40 mL) was added to 6,7-dibromoquinoxaline-5,8-dione (300 mg, 944 μmol) and stirred at room temperature. At the same temperature, p-anisidine (174 mg, 1.42 mmol) and CeCl3·7H2O (35.2 mg, 94.4 μmol) were added and stirred for 17.5 hours at room temperature. After adding a saturated aqueous solution of NaCl and DCM and extracting several times, the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-((4-methoxyphenyl)amino)quinoxaline-5,8-dione, 2a).

[0300] Dark brown solid, 338 mg(99.3%)

[0301] 1 H NMR (500 MHz, DMSO-D6) δ 9.45(s, 1H), 9.02(d,J= 2.4 Hz, 1H), 8.99(d,J= 2.3 Hz, 1H), 7.12(d,J= 9.0 Hz, 2H), 6.90(d,J= 9.0 Hz, 2H), 3.76(s, 3H).

[0302]

[0303] THF (9.30 mL) was added to 6-bromo-7-((4-methoxyphenyl)amino)quinoxaline-5,8-dione (334 mg, 927 μmol) and stirred at room temperature. NaSMe (260 mg, 3.71 mmol) was added at the same temperature and stirred for 22 hours at room temperature. The reaction solution was stirred for 6.5 hours at 40–50°C and then cooled to room temperature. A saturated aqueous solution of NaCl was added to the reaction solution and extracted several times with DCM. The separated organic layer was washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((4-methoxyphenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, 2b).

[0304] Black solid, 165 mg (54.4%)

[0305] 1 H NMR (400 MHz, CHLOROFORM-D) δ 8.99(d,J= 2.1 Hz, 1H), 8.93(d,J= 2.1 Hz, 1H), 7.93(s, 1H), 7.04(d,J= 8.9 Hz, 2H), 6.90(d,J= 8.9 Hz, 2H), 3.85(s, 3H), 2.21(s, 3H).

[0306]

[0307] CHCl3 (4.80 mL) is added to 6-((4-methoxyphenyl)amino)-7-(methylthio)quinoxaline-5,8-dione (157 mg, 480 μmol) and stirred at room temperature. At the same temperature, mCPBA (269 mg, 1.20 mmol) is added and stirred for 5.5 hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4, then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, DCM is added, and the mixture is extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((4-methoxyphenyl)amino)-7-(methyl sulfonyl)quinoxaline-5,8-dione, compound 2).

[0308] Dark violet solid, 102 mg(59.1%)

[0309] 1 H NMR (500 MHz, DMSO-D6) δ 10.62(s, 1H), 9.09(d,J= 2.3 Hz, 1H), 9.01(d,J= 2.3 Hz, 1H), 7.32(d,J= 9.0 Hz, 2H), 6.93(d,J= 9.0 Hz, 2H), 3.78(s, 3H), 3.38(s, 3H).

[0310]

[0311] <Example 3> Synthesis of Compound 3

[0312]

[0313] EtOH (9.40 mL) was added to 6,7-dibromoquinoxaline-5,8-dione (300 mg, 944 μmol) and stirred at room temperature. At the same temperature, 4-methoxy-3-(trifluoromethyl)aniline (271 mg, 1.42 mmol) and CeCl3·7H2O (35.2 mg, 94.4 μmol) were added and stirred for 17.5 hours at room temperature. After adding a saturated aqueous solution of NaCl and DCM and extracting several times, the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-((4-methoxy-3-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione, 3a).

[0314] Black solid, 415 mg (quantitative)

[0315] 1 H NMR (500 MHz, DMSO-D6) δ 9.52 (s, 1H), 9.02 (dd,J= 10.5, 2.3 Hz, 2H), 7.49 - 7.38 (m, 2H), 7.25 (d,J= 8.9 Hz, 1H), 3.89 (s, 3H).

[0316]

[0317] THF (9.40 mL) was added to 6-bromo-7-((4-methoxy-3-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione (412 mg, 944 μmol) and stirred at room temperature. At the same temperature, NaSMe (198 mg, 2.83 mmol) was added and stirred for 3.5 hours at room temperature. A saturated aqueous solution of NaCl was added to the reaction solution and extracted several times with DCM. The separated organic layer was washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (ether / Hex) to obtain the target compound (6-((4-methoxy-3-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, 3b).

[0318] Red violet solid, 212 mg (56.7%)

[0319] 1 H NMR (500 MHz, DMSO-D6) δ 9.39 (s, 1H), 8.99 (dd,J= 17.4, 2.3 Hz, 2H), 7.41 - 7.34 (m, 2H), 7.22 (d,J= 8.9 Hz, 1H), 3.88 (s, 3H), 2.04(s, 3H).

[0320]

[0321] CHCl3 (5.30 mL) is added to 6-((4-methoxy-3-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinoxaline-5,8-dione (210 mg, 531 μmol) and stirred at room temperature. At the same temperature, mCPBA (298 mg, 1.33 mmol) is added and stirred for 5 more hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, DCM is added, and the mixture is extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((4-methoxy-3-(trifluoromethyl)phenyl)amino)-7-(methylsulfonyl)quinoxaline-5,8-dione, compound 3).

[0322] Orange solid, 140 mg (61.7%)

[0323] 1 H NMR (500 MHz, DMSO-D6) δ 10.57(s, 1H), 9.10(d,J= 2.4 Hz, 1H), 9.03(d,J= 2.4 Hz, 1H), 7.73(s, 1H), 7.64(d,J= 8.9 Hz, 1H), 7.27(d,J= 9.0 Hz, 1H), 3.91(s, 3H), 3.34(s, 3H).

[0324]

[0325] <Example 4> Synthesis of Compound 4

[0326]

[0327] EtOH (9.40 mL) was added to 6,7-dibromoquinoxaline-5,8-dione (300 mg, 944 μmol) and stirred at room temperature. At the same temperature, 3,5-difluoro-4-methoxyaniline (225 mg, 1.42 mmol) and CeCl3·7H2O (35.2 mg, 94.4 μmol) were added and stirred for 23 hours at room temperature. After adding a saturated aqueous solution of NaCl and DCM and extracting several times, the separated organic layer was dried and filtered with Na2SO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-((3,5-difluoro-4-methoxyphenyl)amino)quinoxaline-5,8-dione, 4a).

[0328] Red brown solid, 338 mg(90.2%)

[0329] 1 H NMR (500 MHz, DMSO-D6) δ 9.48 (s, 1H), 9.05 (ddd,J= 7.6, 4.9, 2.1 Hz, 2H), 6.96 (t,J= 9.4 Hz, 2H), 3.90 (s, 3H).

[0330]

[0331] THF (8.40 mL) was added to 6-bromo-7-((3,5-difluoro-4-methoxyphenyl)amino)quinoxaline-5,8-dione (301 mg, 760 μmol) and stirred at room temperature. NaSMe (160 mg, 2.28 mmol) was added at the same temperature and stirred for another hour at room temperature. A saturated aqueous solution of NaCl was added to the reaction solution and extracted several times with DCM. The separated organic layer was dried and filtered with Na2SO4, followed by vacuum concentration. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((3,5-difluoro-4-methoxyphenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, 4b).

[0332] Black solid, 174 mg (63.0%)

[0333] 1 H NMR (500 MHz, DMSO-D6) δ 9.34 (s, 1H), 9.05 - 8.98 (m, 2H), 6.84 (d, J = 10.1 Hz, 2H), 3.88 (s, 3H), 2.14 (s, 3H).

[0334]

[0335] CHCl3 (3.30 mL) is added to 6-((3,5-difluoro-4-methoxyphenyl)amino)-7-(methylthio)quinoxaline-5,8-dione (121 mg, 333 μmol) and stirred at room temperature. At the same temperature, mCPBA (187 mg, 833 μmol) is added and stirred for 4 more hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4, then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, DCM is added, and the mixture is extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((3,5-difluoro-4-methoxyphenyl)amino)-7-(methylsulfonyl)quinoxaline-5,8-dione, compound 4).

[0336] Dark brown solid, 50.4 mg (38.3%)

[0337] 1 H NMR (500 MHz, DMSO-D6) δ 10.43(s, 1H), 9.12(d,J= 2.3 Hz, 1H), 9.05(d,J= 2.3 Hz, 1H), 7.28(d,J= 10.1 Hz, 2H), 3.92(s, 3H), 3.35(s, 3H).

[0338]

[0339] <Example 5> Synthesis of Compound 5

[0340]

[0341] EtOH (9.40 mL) was added to 6,7-dibromoquinoxaline-5,8-dione (300 mg, 944 μmol) and stirred at room temperature. At the same temperature, 3,4-difluoroaniline (140 μL, 1.42 mmol) and CeCl3·7H2O (35.2 mg, 94.4 μmol) were added and stirred at room temperature for 18 more hours. After adding a saturated aqueous solution of NaCl and DCM and extracting several times, the separated organic layer was dried and filtered with Na2SO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-((3,4-difluorophenyl)amino)quinoxaline-5,8-dione, 5a).

[0342] Dark brown solid, 306 mg (88.4%)

[0343] 1 H NMR (500 MHz, DMSO-D6) δ 9.52 (s, 1H), 9.07 - 9.00 (m, 2H), 7.41 (q,J= 9.7 Hz, 1H), 7.25 (ddd,J= 12.2, 7.3, 2.6 Hz, 1H), 7.06 - 6.98(m, 1H).

[0344]

[0345] THF (8.10 mL) was added to 6-bromo-7-((3,4-difluorophenyl)amino)quinoxaline-5,8-dione (268 mg, 732 μmol) and stirred at room temperature. NaSMe (154 mg, 2.20 mmol) was added at the same temperature and stirred for 4.5 hours at room temperature. A saturated aqueous solution of NaCl was added to the reaction solution and extracted several times with DCM. The separated organic layer was dried and filtered with Na2SO4, then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((3,4-difluorophenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, 5b).

[0346] Brown solid, 187 mg (76.6%)

[0347] 1 H NMR (500 MHz, DMSO-D6) δ 9.38 (s, 1H), 9.01 (dd,J= 13.9, 2.2 Hz, 2H), 7.37 (q,J= 9.8 Hz, 1H), 7.12 (ddd,J= 12.5, 7.2, 2.6 Hz, 1H), 6.98 - 6.91(m, 1H), 2.09(s, 3H).

[0348]

[0349] CHCl3 (3.60 mL) is added to 6-((3,4-difluorophenyl)amino)-7-(methylthio)quinoxaline-5,8-dione (121 mg, 363 μmol) and stirred at room temperature. At the same temperature, mCPBA (203 mg, 908 μmol) is added and stirred for 4.5 hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4, then concentrated under reduced pressure. After separating the target compound by C18 silicagel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, DCM is added, and extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((3,4-difluorophenyl)amino)-7-(methyl sulfonyl)quinoxaline-5,8-dione, compound 5).

[0350] Red solid, 78.3 mg (59.0%)

[0351] 1 H NMR (500 MHz, DMSO-D6) δ 10.51(s, 1H), 9.11(d,J= 2.3 Hz, 1H), 9.04(d,J= 2.3 Hz, 1H), 7.56(t,J= 8.5 Hz, 1H), 7.50 - 7.39(m, 1H), 7.25(d,J= 8.4 Hz, 1H), 3.35(s, 3H).

[0352]

[0353] <Example 6> Synthesis of Compound 6

[0354]

[0355] EtOH (9.40 mL) was added to 6,7-dibromoquinoxaline-5,8-dione (300 mg, 944 μmol) and stirred at room temperature. At the same temperature, 5-amino-2-chlorobenzotrifluoride (277 mg, 1.42 mmol) and CeCl3·7H2O (35.2 mg, 94.4 μmol) were added and stirred for 16.5 hours at room temperature. After adding a saturated aqueous solution of NaCl and DCM and extracting several times, the separated organic layer was dried and filtered with Na2SO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-((4-chloro-3-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione, 6a).

[0356] Red brown solid, 327 mg(80.1%)

[0357] 1 H NMR (500 MHz, DMSO-D6) δ 9.67 (s, 1H), 9.09 - 9.01 (m, 2H), 7.65 (ddd,J= 17.4, 8.0, 2.8 Hz, 2H), 7.42 (td,J= 8.3, 2.6 Hz, 1H).

[0358]

[0359] THF (6.90 mL) was added to 6-bromo-7-((4-chloro-3-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione) (270 mg, 624 μmol) and stirred at room temperature. At the same temperature, NaSMe (131 mg, 1.87 mmol) was added and stirred for another hour at room temperature. A saturated aqueous solution of NaCl was added to the reaction solution and extracted several times with DCM. The separated organic layer was dried and filtered with Na2SO4, followed by vacuum concentration. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (ether / Hex) to obtain the target compound (6-((4-chloro-3-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, 6b).

[0360] Dark brown solid, 135 mg (53.9%)

[0361] 1 H NMR (500 MHz, DMSO-D6) δ 9.56(s, 1H), 9.03(d,J= 2.4 Hz, 1H), 9.01(d,J= 2.3 Hz, 1H), 7.63(d,J= 8.7 Hz, 1H), 7.53(d,J= 2.7 Hz, 1H), 7.32(dd,J= 8.7, 3.2 Hz, 1H), 2.08(s, 3H).

[0362]

[0363] CHCl3 (2.50 mL) is added to 6-((4-chloro-3-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinoxaline-5,8-dione (99.9 mg, 250 μmol) and stirred at room temperature. At the same temperature, mCPBA (140 mg, 625 μmol) is added and stirred for 5 more hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, DCM is added, and the mixture is extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((4-chloro-3-(trifluoro methyl)phenyl)amino)-7-(methylsulfonyl)quinoxaline-5,8-dione, compound 6).

[0364] Orange solid, 56.3 mg (52.2%)

[0365] 1 H NMR (500 MHz, DMSO-D6) δ 10.55(s, 1H), 9.12(d,J= 2.4 Hz, 1H), 9.05(d,J= 2.4 Hz, 1H), 7.94(s, 1H), 7.75 - 7.63(m, 2H), 3.31(s, 3H).

[0366]

[0367] <Example 7> Synthesis of Compounds 7 and 8

[0368]

[0369] EtOH (9.40 mL) was added to 6,7-dibromoquinoxaline-5,8-dione (300 mg, 944 μmol) and stirred at room temperature. At the same temperature, 3-methoxy-4-(trifluoromethyl)aniline (271 mg, 1.42 mmol) and CeCl3·7H2O (35.2 mg, 94.4 μmol) were added and stirred for 19 hours at room temperature. After adding a saturated aqueous solution of NaCl and DCM and extracting several times, the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-((3-methoxy-4-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione, 7a).

[0370] Red brown solid, 295 mg(73.1%)

[0371] 1 H NMR (500 MHz, DMSO-D6) δ 9.61 (s, 1H), 9.09 - 9.02 (m, 2H), 7.52 (dd,J= 8.5, 4.7 Hz, 1H), 7.02 (dd,J= 7.3, 2.0 Hz, 1H), 6.82 (ddd,J= 10.8, 8.4, 1.9 Hz, 1H), 3.81(d,J= 2.1 Hz, 3H).

[0372]

[0373] THF (6.90 mL) was added to 6-bromo-7-((3-methoxy-4-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione (294 mg, 687 μmol) and stirred at room temperature. NaSMe (144 mg, 2.06 mmol) was added at the same temperature and stirred for 3.5 hours at room temperature. A saturated aqueous solution of NaCl was added to the reaction solution and extracted several times with DCM. The separated organic layer was dried and filtered with MgSO4, then concentrated under reduced pressure. The concentrate was separated using a silica gel filter (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((3-methoxy-4-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, 7b).

[0374] Red brown to purple solid, 174 mg (64.2%)

[0375] 1 H NMR (500 MHz, DMSO-D6) δ 9.46 (s, 1H), 9.06 - 9.00 (m, 2H), 7.48 (d, J = 8.4 Hz, 1H), 6.88 (s, 1H), 6.71 (d, J = 8.5 Hz, 1H), 3.81 (s, 3H), 2.16(s, 3H).

[0376]

[0377] CHCl3 (4.30 mL) is added to 6-((3-methoxy-4-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinoxaline-5,8-dione (170 mg, 430 μmol) and stirred at room temperature. At the same temperature, mCPBA (241 mg, 1.07 mmol) is added and stirred for 6 more hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, and then a saturated aqueous solution of NaCl and DCM are added and extracted several times. The separated organic layer is dried and filtered with Na2SO4 and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((3-methoxy-4-(trifluoromethyl)phenyl)amino)-7-(methylsulfonyl)quinoxaline-5,8-dione, compound 7) and (6-((3-methoxy-4-(trifluoromethyl)phenyl)amino)-7-(methylsulfinyl)quinoxaline-5,8-dione, compound 8).

[0378] Compound 7: Brown solid, 10.9 mg (5.93%)

[0379] 1 H NMR (500 MHz, DMSO-D6) δ 10.52 (s, 1H), 9.12 (d, J = 2.4 Hz, 1H), 9.05 (d, J = 2.6 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.35 (s, 1H), 7.08(d, J = 5.0 Hz, 1H), 3.82(s, 3H), 3.36(s, 3H).

[0380] Compound 8: Red brown solid, 19.4 mg (11.0%)

[0381] 1 H NMR (500 MHz, DMSO-D6) δ 10.92(s, 1H), 9.06(d,J= 2.3 Hz, 1H), 9.03(d,J= 2.3 Hz, 1H), 7.56(d,J= 8.4 Hz, 1H), 7.26(s, 1H), 6.98(d,J= 8.4 Hz, 1H), 3.82(s, 3H), 3.06(s, 3H).

[0382]

[0383] <Example 8> Synthesis of Compound 9

[0384]

[0385] EtOH (19.5 mL) is added to 6,7-dibromoquinoxaline-5,8-dione (618 mg, 1.94 mmol) and stirred at room temperature. At the same temperature, 4-methyl-3-(trifluoromethyl)aniline (400 μL, 2.91 mmol) and CeCl3·7H2O (72.0 mg, 194 μmol) are added, and the mixture is stirred for 17 more hours at room temperature. The reaction solution is concentrated under reduced pressure to remove EtOH, after which a saturated aqueous solution of NaCl and DCM are added and extracted several times. The separated organic layer is dried and filtered with MgSO4, followed by concentration under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-((4-methyl-3-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione, 9a).

[0386] Dark red violet solid, 654 mg (81.8%)

[0387] 1 H NMR (400 MHz, DMSO-D6) δ 9.57 (s, 1H), 9.06 - 9.00 (m, 2H), 7.49 (d, J = 2.3 Hz, 1H), 7.41 - 7.28 (m, 2H), 2.42 (d, J = 1.9 Hz, 3H).

[0388]

[0389] THF (15.6 mL) was added to 6-bromo-7-((4-methyl-3-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione (642 mg, 1.56 mmol) and stirred at room temperature. NaSMe (218 mg, 3.12 mmol) was added at the same temperature and stirred for 2 more hours at room temperature. A saturated aqueous solution of NaCl was added to the reaction solution and extracted several times with DCM. The separated organic layer was dried and filtered with MgSO4, then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((4-methyl-3-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, 9b).

[0390] Red brown solid, 302 mg(51.0%)

[0391] 1 H NMR (400 MHz, DMSO-D6) δ 9.44(s, 1H), 9.02(d,J= 2.3 Hz, 1H), 8.99(d,J= 2.3 Hz, 1H), 7.41(d,J= 2.3 Hz, 1H), 7.35(d,J= 8.3 Hz, 1H), 7.24(dd,J= 8.3, 2.3 Hz, 1H), 2.40(d,J= 2.0 Hz, 3H), 2.05(s, 3H).

[0392]

[0393] CHCl3 (2.60 mL) is added to 6-((4-methyl-3-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinoxaline-5,8-dione (100 mg, 264 μmol) and stirred at room temperature. At the same temperature, mCPBA (148 mg, 659 μmol) is added and stirred for 4 more hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, DCM is added, and the mixture is extracted several times. The separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((4-methyl-3-(trifluoromethyl)phenyl)amino)-7-(methylsulfonyl)quinoxaline-5,8-dione, compound 9).

[0394] Red solid, 55.9 mg (51.5%)

[0395] 1 H NMR (500 MHz, DMSO-D6) δ 10.57(s, 1H), 9.11(d,J= 2.3 Hz, 1H), 9.04(d,J= 2.3 Hz, 1H), 7.77(s, 1H), 7.55(d,J= 8.4 Hz, 1H), 7.43(d,J= 8.2 Hz, 1H), 3.34(s, 3H), 2.44(s, 3H).

[0396]

[0397] <Example 9> Synthesis of Compound 10

[0398]

[0399] Methanol (MeOH, 26.4 mL) and distilled water (5.30 mL) were added to 6-((4-methyl-3-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinoxaline-5,8-dione (1.00 g, 2.64 mmol) and stirred at 0°C. At the same temperature, Oxone monopersulfate (1.46 g, 2.37 mmol) was added and stirred for 20 hours at room temperature. The remaining solid was filtered and washed with MeOH. The filtrate was concentrated under reduced pressure, then extracted several times with a saturated aqueous solution of NaCl and DCM. The separated organic layer was dried and filtered with Na2SO4 and then concentrated under reduced pressure. The target compound was separated by C18 silicagel column chromatography (MeCN / Water), then extracted several times with a saturated aqueous solution of NaCl and DCM. The separated organic layer was dried and filtered with Na2SO4 and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((4-methyl-3-(trifluoromethyl)phenyl)amino)-7-(methylsulfinyl)quinoxaline-5,8-dione, Compound 10).

[0400] Brown solid, 480 mg (46.0%)

[0401] 1 H NMR (500 MHz, DMSO-D6) δ 10.95(s, 1H), 9.03(dd,J= 20.6, 2.3 Hz, 2H), 7.70(s, 1H), 7.55 - 7.35(m, 2H), 3.04(s, 3H), 2.44(s, 3H).

[0402]

[0403] <Example 10> Synthesis of Compound 11

[0404]

[0405] Distilled water (20.0 mL) was added to 6-bromo-7-((4-methyl-3-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione (2.00 g, 4.85 mmol), NaHSO3 (1.51 g, 14.6 mmol), and Na2SO3 (1.83 g, 14.6 mmol), and stirred at room temperature. After filling the reaction vessel with nitrogen, stirring was continued at 80°C for 12 hours. After filtering the solid in the reaction solution, the filtrate was concentrated under reduced pressure to obtain the target compound (7-((4-methyl-3-(trifluoromethyl)phenyl)amino)-5,8-dioxo-5,6,7,8-tetrahydroquinoxaline-6-sulfonic acid, 11a).

[0406] Red solid, 2.02 g (crude)

[0407]

[0408] THF (20.0 mL) and distilled water (20.0 mL) were added to 7-((4-methyl-3-(trifluoromethyl)phenyl)amino)-5,8-dioxo-5,6,7,8-tetrahydroquinoxaline-6-sulfonic acid (2.02 g, 4.86 mmol) and MnO2 (846 mg, 9.73 mmol), and stirred at room temperature. After filling the reaction vessel with nitrogen, stirring was continued at 60°C for 1 hour. The solid in the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM / MeOH) to obtain the target compound (7-((4-methyl-3-(trifluoromethyl)phenyl)amino)-5,8-dioxo-5,8-dihydroquinoxaline-6-sulfonic acid, Compound 11).

[0409] Red brown solid, 120 mg (40.0%)

[0410] 1H NMR (400 MHz, DMSO-D6) δ 9.00 (dd,J= 14.8, 2.0 Hz, 2 H), 8.60 (br d,J= 1.2 Hz, 1 H), 7.73 (br d,J= 7.6 Hz, 1 H), 7.63 (br t,J= 7.6 Hz, 1 H), 7.39(br t,J= 7.6 Hz, 1 H), 7.28(br d,J= 7.2 Hz, 1 H), 2.12(s, 3 H)

[0411]

[0412] <Example 11> Synthesis of Compound 12

[0413]

[0414] EtOH (9.40 mL) was added to 6,7-dibromoquinoxaline-5,8-dione (300 mg, 944 μmol) and stirred at room temperature. At the same temperature, 3-fluoro-4-methoxyaniline (200 mg, 1.42 mmol) and CeCl3·7H2O (35.2 mg, 94.4 μmol) were added and stirred for 21.5 hours at room temperature. After adding a saturated aqueous solution of NaCl and DCM and extracting several times, the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-((3-fluoro-4-methoxyphenyl)amino)quinoxaline-5,8-dione, 12a).

[0415] Dark brown solid, 350 mg(98.0%)

[0416] 1 H NMR (500 MHz, DMSO-D6) δ 9.45 (s, 1H), 9.06 - 8.99 (m, 2H), 7.17 - 7.05 (m, 2H), 7.01 - 6.95 (m, 1H), 3.84 (s, 3H).

[0417]

[0418] 6-bromo-7-((3-fluoro-4-methoxyphenyl)amino)quinoxaline-5,8-dione (344 mg, 910 μmol) was mixed with 9.10 mL of THF and stirred at room temperature. At the same temperature, NaSMe (191 mg, 2.73 mmol) was added and stirred for 47 hours at room temperature. A saturated aqueous solution of NaCl was added to the reaction solution and extracted several times with DCM. The separated organic layer was dried and filtered with MgSO4, followed by vacuum concentration. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) to obtain the target compound (6-((3-fluoro-4-methoxyphenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, 12b).

[0419] Dark brown solid, 204 mg(64.8%)

[0420] 1 H NMR (500 MHz, DMSO-D6) δ 9.29 (s, 1H), 8.99 (dd,J= 17.0, 2.3 Hz, 2H), 7.10 (t,J= 9.2 Hz, 1H), 7.00 (dd,J= 12.8, 2.5 Hz, 1H), 6.90(ddd,J= 8.9, 2.6, 1.3 Hz, 1H), 3.83(s, 3H), 2.07(s, 3H).

[0421]

[0422] CHCl3 (5.70 mL) is added to 6-((3-fluoro-4-methoxyphenyl)amino)-7-(methylthio)quinoxaline-5,8-dione (198 mg, 573 μmol) and stirred at room temperature. mCPBA (385 mg, 1.72 mmol) is added at the same temperature and stirred for 4 more hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, DCM is added, and the mixture is extracted several times. The separated organic layer is dried and filtered with Na2SO4 and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((3-fluoro-4-methoxyphenyl)amino)-7-(methylsulfonyl)quinoxaline-5,8-dione, compound 12).

[0423] Dark brown solid, 130 mg (60.0%)

[0424] 1 H NMR (500 MHz, DMSO-D6) δ 10.54(s, 1H), 9.10(d,J= 2.3 Hz, 1H), 9.02(d,J= 2.3 Hz, 1H), 7.36(d,J= 12.1 Hz, 1H), 7.21 - 7.11(m, 2H), 3.86(s, 3H), 3.36(s, 3H).

[0425]

[0426] <Example 12> Synthesis of Compound 13

[0427]

[0428] EtOH (9.40 mL) was added to 6,7-dibromoquinoxaline-5,8-dione (300 mg, 944 μmol) and stirred at room temperature. At the same temperature, 3-chloro-4-methoxyaniline (223 mg, 1.42 mmol) and CeCl3·7H2O (35.2 mg, 94.4 μmol) were added and stirred for 22 hours at room temperature. After adding a saturated aqueous solution of NaCl and DCM and extracting several times, the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-((3-chloro-4-methoxyphenyl)amino)quinoxaline-5,8-dione, 13a).

[0429] Dark brown solid, 360 mg(96.7%)

[0430] 1 H NMR (500 MHz, DMSO-D6) δ 9.45 (s, 1H), 9.07 - 8.97 (m, 2H), 7.27 (dd,J= 5.7, 1.8 Hz, 1H), 7.17 - 7.10 (m, 2H), 3.86 (s, 3H).

[0431]

[0432] 6-bromo-7-((3-chloro-4-methoxyphenyl)amino)quin-oxaline-5,8-dione (353 mg, 895 μmol) was mixed with 9.00 mL of THF and stirred at room temperature. At the same temperature, NaSMe (188 mg, 2.68 mmol) was added and stirred for 47.5 hours at room temperature. A saturated aqueous solution of NaCl was added to the reaction solution and extracted several times with DCM. The separated organic layer was dried and filtered with MgSO4, followed by vacuum concentration. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) to obtain the target compound (6-((3-chloro-4-methoxyphenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, 13b).

[0433] Dark brown solid, 141 mg(43.6%)

[0434] 1 H NMR (500 MHz, DMSO-D6) δ 9.30 (s, 1H), 9.01 (d, J = 2.4 Hz, 1H), 8.97 (d, J = 2.3 Hz, 1H), 7.19 (s, 1H), 7.09 (s, 2H), 3.84 (s, 3H), 2.06(s, 3H).

[0435]

[0436] CHCl3 (3.80 mL) is added to 6-((3-chloro-4-methoxyphenyl)amino)-7-(methylthio)quinoxaline-5,8-dione (138 mg, 381 μmol) and stirred at room temperature. At the same temperature, mCPBA (256 mg, 1.14 mmol) is added and stirred for 5.5 hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4, then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, then a saturated aqueous solution of NaCl and DCM are added and extracted several times. The separated organic layer is dried and filtered with MgSO4, then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((3-chloro-4-methoxyphenyl)amino)-7-(methylsulfonyl)quinoxaline-5,8-dione, compound 13).

[0437] Brown solid, 70.2 mg (46.8%)

[0438] 1 H NMR (500 MHz, DMSO-D6) δ 10.53(s, 1H), 9.10(d,J= 2.3 Hz, 1H), 9.02(d,J= 2.3 Hz, 1H), 7.55(s, 1H), 7.33(d,J= 7.2 Hz, 1H), 7.14(d,J= 9.0 Hz, 1H), 3.88(s, 3H), 3.35(s, 3H).

[0439]

[0440] <Example 13> Synthesis of Compound 14

[0441]

[0442] EtOH (9.40 mL) was added to 6,7-dibromoquinoxaline-5,8-dione (300 mg, 944 μmol) and stirred at room temperature. At the same temperature, 4-(trifluoromethyl)aniline (228 mg, 1.42 mmol) and CeCl3·7H2O (35.2 mg, 94.4 μmol) were added and stirred for 18 more hours at room temperature. After adding a saturated aqueous solution of NaCl and DCM and extracting several times, the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-((4-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione, 14a).

[0443] Red brown solid, 343 mg(91.2%)

[0444] 1 H NMR (500 MHz, DMSO-D6) δ 9.69 (s, 1H), 9.09 - 9.01 (m, 2H), 7.67 (d, J = 8.9 Hz, 2H), 7.30 (t, J = 8.5 Hz, 2H).

[0445]

[0446] 6-bromo-7-((4-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione (339 mg, 852 μmol) was mixed with 8.50 mL of THF and stirred at room temperature. At the same temperature, NaSMe (179 mg, 2.56 mmol) was added and stirred for 1.5 hours at room temperature. A saturated aqueous solution of NaCl was added to the reaction solution and extracted several times with DCM. The separated organic layer was dried and filtered with MgSO4, followed by vacuum concentration. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-(methylthio)-7-((4-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione, 14b).

[0447] Red brown solid, 186 mg(59.7%)

[0448] 1 H NMR (500 MHz, DMSO-D6) δ 9.54 (s, 1H), 9.02 (dd,J= 10.9, 2.4 Hz, 2H), 7.63 (d,J= 8.9 Hz, 2H), 7.19 (d,J= 8.7 Hz, 2H), 2.11 (s, 3H).

[0449]

[0450] CHCl3 (5.00 mL) is added to 6-(methylthio)-7-((4-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione (183 mg, 501 μmol) and stirred at room temperature. mCPBA (337 mg, 1.50 mmol) is added at the same temperature and stirred for 4 more hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, and then a saturated aqueous solution of NaCl and DCM are added and extracted several times. The separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-(methylsulfonyl)-7-((4-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione, compound 14).

[0451] Light orange solid, 137 mg (68.9%)

[0452] 1 H NMR (500 MHz, DMSO-D6) δ 10.58(s, 1H), 9.11(d,J= 2.2 Hz, 1H), 9.04(d,J= 2.3 Hz, 1H), 7.72(d,J= 8.3 Hz, 2H), 7.58(d,J= 8.2 Hz, 2H), 3.35(s, 3H).

[0453]

[0454] <Example 14> Synthesis of Compound 15

[0455]

[0456] EtOH (9.20 mL) was added to 6,7-dibromoquinoxaline-5,8-dione (293 mg, 922 μmol) and stirred at room temperature. At the same temperature, 3-aminobenzotrifluoride (170 μL, 1.38 mmol) and CeCl3·7H2O (34.3 mg, 92.2 μmol) were added and stirred for 18 more hours at room temperature. After adding a saturated aqueous solution of NaCl and DCM and extracting several times, the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-((3-(trifluoromethyl)phenyl)amino)quinoxaline 5,8-dione, 15a).

[0457] Dark violet solid, 329 mg (89.7%)

[0458] 1 H NMR (500 MHz, DMSO-D6) δ 9.64 (s, 1H), 9.09 - 9.00 (m, 2H), 7.59 - 7.41 (m, 4H).

[0459]

[0460] THF (8.20 mL) was added to 6-bromo-7-((3-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione (327 mg, 821 μmol) and stirred at room temperature. NaSMe (173 mg, 2.46 mmol) was added at the same temperature and stirred for 1.5 hours at room temperature. A saturated aqueous solution of NaCl was added to the reaction solution and extracted several times with DCM. The separated organic layer was dried and filtered with MgSO4, then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-(methylthio)-7-((3-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione, 15b).

[0461] Red brown solid, 165 mg (54.9%)

[0462] 1 H NMR (500 MHz, DMSO-D6) δ 9.51(s, 1H), 9.03(d,J= 2.2 Hz, 1H), 9.00(d,J= 2.3 Hz, 1H), 7.51(t,J= 7.9 Hz, 1H), 7.41 - 7.32(m, 3H), 2.07(d,J= 0.7 Hz, 3H).

[0463]

[0464] CHCl3 (4.50 mL) is added to 6-(methylthio)-7-((3-(trifluoro-methyl)phenyl)amino)quinoxaline-5,8-dione (162 mg, 443 μmol) and stirred at room temperature. mCPBA (298 mg, 1.33 mmol) is added at the same temperature and stirred for 5 more hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, and then a saturated aqueous solution of NaCl and DCM are added and extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-(methylsulfonyl)-7-((3-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione, compound 15).

[0465] Light orange solid, 106 mg (60.2%)

[0466] 1 H NMR (500 MHz, DMSO-D6) δ 10.59(s, 1H), 9.11(d,J= 2.2 Hz, 1H), 9.04(d,J= 2.3 Hz, 1H), 7.82(s, 1H), 7.67(d,J= 7.4 Hz, 1H), 7.61 - 7.55(m, 2H), 3.34(s, 3H).

[0467]

[0468] <Example 15> Synthesis of Compound 16

[0469]

[0470] EtOH (28.3 mL) was added to 6,7-dibromoquinoxaline-5,8-dione (900 mg, 2.83 mmol) and stirred at room temperature. At the same temperature, 4-chloroaniline (542 mg, 4.25 mmol) and CeCl3·7H2O (105 mg, 283 μmol) were added and stirred for 19.5 hours, after which the EtOH was removed by vacuum concentration. After adding a saturated aqueous solution of NaCl and DCM and extracting several times, the separated organic layer was dried and filtered with MgSO4 and then vacuum concentrated. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-((4-chlorophenyl)amino)quinoxaline-5,8-dione, 16a).

[0471] Dark brown solid, 869 mg (84.2%)

[0472]

[0473] THF (24.0 mL) was added to 6-bromo-7-((4-chlorophenyl)amino)quinoxaline-5,8-dione (863 mg, 2.37 mmol) and stirred at room temperature. NaSMe (498 mg, 7.10 mmol) was added at the same temperature and stirred for 15.5 hours at room temperature. A saturated aqueous solution of NaCl was added to the reaction solution and extracted several times with DCM. The separated organic layer was dried and filtered with MgSO4, then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((4-chlorophenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, 16b).

[0474] Brown solid, 503 mg (63.9%)

[0475] 1H NMR (500 MHz, DMSO-D6) δ 9.39 (s, 1H), 9.00 (m, 2H), 7.34 (d, J = 8.9 Hz, 2H), 7.09 (d, J = 8.7 Hz, 2H), 2.06 (s, 3H).

[0476]

[0477] CHCl3 (6.00 mL) is added to 6-((4-chlorophenyl)amino)-7-(methylthio)quino-xaline-5,8-dione (200 mg, 603 μmol) and stirred at room temperature. At the same temperature, mCPBA (405 mg, 1.81 mmol) is added and stirred for 5 more hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, and then a saturated aqueous solution of NaCl and DCM are added and extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((4-chlorophenyl)amino)-7-(methylsulfonyl)quinoxaline-5,8-dione, compound 16).

[0478] Brown solid, 145 mg (66.1%)

[0479] 1 H NMR (500 MHz, DMSO-D6) δ 10.54 (s, 1H), 9.10 (d, J = 2.3 Hz, 1H), 9.02 (d, J = 2.3 Hz, 1H), 7.43-7.39 (m, 4H), 3.35 (s, 3H).

[0480]

[0481] <Example 16> Synthesis of Compound 17

[0482]

[0483] EtOH (9.40 mL) was added to 6,7-dibromoquinoxaline-5,8-dione (300 mg, 944 μmol) and stirred at room temperature. At the same temperature, 4-fluoro-3-methoxyaniline (200 mg, 1.42 mmol) and CeCl3·7H2O (35.2 mg, 94.4 μmol) were added and stirred for 18 more hours at room temperature. After adding a saturated aqueous solution of NaCl and DCM and extracting several times, the separated organic layer was dried and filtered with Na2SO4 and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-((4-fluoro-3-methoxyphenyl)amino)quinoxaline-5,8-dione, 17a).

[0484] Purple solid, 323 mg (90.5%)

[0485] 1 H NMR (500 MHz, DMSO-D6) δ 9.45 (s, 1H), 9.07 - 9.00 (m, 2H), 7.17 (ddd,J= 11.2, 8.7, 1.4 Hz, 1H), 7.02 (td,J= 7.4, 2.5 Hz, 1H), 6.78 - 6.71(m, 1H), 3.77(s, 3H).

[0486]

[0487] THF (8.50 mL) was added to 6-bromo-7-((4-fluoro-3-methoxyphenyl)amino)quinoxaline-5,8-dione (322 mg, 851 μmol) and stirred at room temperature. NaSMe (179 mg, 2.55 mmol) was added at the same temperature and stirred for 24 hours at room temperature. A saturated aqueous solution of NaCl was added to the reaction solution and extracted several times with DCM. The separated organic layer was dried and filtered with MgSO4, then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((4-fluoro-3-methoxyphenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, 17b).

[0488] Black solid, 127 mg (43.3%)

[0489] 1 H NMR (500 MHz, DMSO-D6) δ 9.27 (s, 1H), 9.00 (dd,J= 16.0, 2.3 Hz, 2H), 7.13 (dd,J= 11.3, 8.7 Hz, 1H), 6.94 (dd,J= 7.8, 2.5 Hz, 1H), 6.69 - 6.63(m, 1H), 3.78(s, 3H), 2.09(s, 3H).

[0490]

[0491] CHCl3 (3.50 mL) is added to 6-((4-fluoro-3-methoxyphenyl)amino)-7-(methylthio)quinoxaline-5,8-dione (122 mg, 353 μmol) and stirred at room temperature. At the same temperature, mCPBA (198 mg, 883 μmol) is added and stirred for 4 more hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with Na2SO4, then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, DCM is added, and the mixture is extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with Na2SO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((4-fluoro-3-methoxyphenyl)amino)-7-(methylsulfonyl)quinoxaline-5,8-dione, compound 17).

[0492] Brown solid, 46.3 mg (34.8%)

[0493] 1 H NMR (500 MHz, DMSO-D6) δ 10.54(s, 1H), 9.11(d,J= 2.4 Hz, 1H), 9.03(d,J= 2.3 Hz, 1H), 7.30(d,J= 5.3 Hz, 1H), 7.20(dd,J= 11.3, 8.6 Hz, 1H), 6.99 - 6.90(m, 1H), 3.78(s, 3H), 3.38(s, 3H).

[0494]

[0495] <Example 17> Synthesis of Compound 18

[0496]

[0497] EtOH (9.40 mL) was added to 6,7-dibromoquinoxaline-5,8-dione (300 mg, 944 μmol) and stirred at room temperature. At the same temperature, 3-methyl-4-(trifluoromethyl)aniline (248 mg, 1.42 mmol) and CeCl3·7H2O (35.2 mg, 94.4 μmol) were added and stirred for 19 hours at room temperature. After adding a saturated aqueous solution of NaCl and DCM and extracting several times, the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-((3-methyl-4-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione, 18a).

[0498] Red brown solid, 333 mg (85.5%)

[0499] 1 H NMR (500 MHz, DMSO-D6) δ 9.61(s, 1H), 9.09 - 9.01(m, 2H), 7.60(dd,J= 8.6, 4.1 Hz, 1H), 7.17(d,J= 7.9 Hz, 1H), 7.10(t,J= 9.0 Hz, 1H), 2.40(s, 3H).

[0500]

[0501] 6-bromo-7-((3-methyl-4-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione (329 mg, 798 μmol) was mixed with 8.00 mL of THF and stirred at room temperature. At the same temperature, NaSMe (168 mg, 2.39 mmol) was added and stirred for 1.5 hours at room temperature. A saturated aqueous solution of NaCl was added to the reaction solution and extracted several times with DCM. The separated organic layer was dried and filtered with MgSO4, followed by vacuum concentration. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) to obtain the target compound (6-((3-methyl-4-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, 18b).

[0502] Dark brown solid, 212 mg(70.0%)

[0503] 1 H NMR (500 MHz, DMSO-D6) δ 9.45 (s, 1H), 9.02 (dd,J= 11.4, 2.3 Hz, 2H), 7.56 (d,J= 8.4 Hz, 1H), 7.06 - 6.98 (m, 2H), 2.39 (s, 3H), 2.13(s, 3H).

[0504]

[0505] CHCl3 (5.60 mL) is added to 6-((3-methyl-4-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinoxaline-5,8-dione (212 mg, 559 μmol) and stirred at room temperature. At the same temperature, mCPBA (313 mg, 1.40 mmol) is added and stirred for 5.5 hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with Na2SO4, then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, DCM is added, and extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with Na2SO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((3-methyl-4-(trifluoromethyl)phenyl)amino)-7-(methylsulfonyl)quinoxaline-5,8-dione, compound 18).

[0506] Orange solid, 143 mg (62.3%)

[0507] 1 H NMR (500 MHz, DMSO-D6) δ 10.52(s, 1H), 9.12(d,J= 2.3 Hz, 1H), 9.05(d,J= 2.3 Hz, 1H), 7.64(d,J= 8.5 Hz, 1H), 7.46(s, 1H), 7.38(d,J= 8.4 Hz, 1H), 3.35(s, 3H), 2.41(s, 3H).

[0508]

[0509] <Example 18> Synthesis of Compound 19

[0510]

[0511] EtOH (9.40 mL) was added to 6,7-dibromoquinoxaline-5,8-dione (300 mg, 944 μmol) and stirred at room temperature. At the same temperature, 3-fluoro-4-methylaniline (177 mg, 1.42 mmol) and CeCl3·7H2O (35.2 mg, 94.4 μmol) were added and stirred for 20 more hours at room temperature. After adding a saturated aqueous solution of NaCl and DCM and extracting several times, the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-((3-fluoro-4-methylphenyl)amino)quinoxaline-5,8-dione, 19a).

[0512] Dark brown solid, 335 mg(97.8%)

[0513] 1 H NMR (400 MHz, DMSO-D6) δ 9.47 (s, 1H), 9.08 - 8.98 (m, 2H), 7.21 (t, J = 8.0 Hz, 1H), 7.00 - 6.87 (m, 2H), 2.21 (d, J = 2.2 Hz, 3H).

[0514]

[0515] 6-bromo-7-((3-fluoro-4-methylphenyl)amino)quinoxaline-5,8-dione (331 mg, 914 μmol) was mixed with 9.10 mL of THF and stirred at room temperature. At the same temperature, NaSMe (192 mg, 2.74 mmol) was added and stirred for 16 hours at room temperature. A saturated aqueous solution of NaCl was added to the reaction solution and extracted several times with DCM. The separated organic layer was washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) to obtain the target compound (6-((3-fluoro-4-methylphenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, 19b).

[0516] Black solid, 206 mg (68.4%)

[0517] 1 H NMR (400 MHz, DMSO-D6) δ 9.31(s, 1H), 9.01(d,J= 2.3 Hz, 1H), 8.98(d,J= 2.4 Hz, 1H), 7.17(t,J= 8.7 Hz, 1H), 6.87 - 6.82(m, 2H), 2.19(d,J= 2.2 Hz, 3H), 2.08(s, 3H).

[0518]

[0519] CHCl3 (6.30 mL) is added to 6-((3-fluoro-4-methylphenyl)amino)-7-(methylthio)quinoxaline-5,8-dione (206 mg, 625 μmol) and stirred at room temperature. At the same temperature, mCPBA (350 mg, 1.56 mmol) is added and stirred for 6 more hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with Na2SO4 and then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, DCM is added, and the mixture is extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with Na2SO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((3-fluoro-4-methylphenyl)amino)-7-(methylsulfonyl)quinoxaline-5,8-dione, compound 19).

[0520] Red solid, 127 mg (56.4%)

[0521] 1 H NMR (500 MHz, DMSO-D6) δ 10.53(s, 1H), 9.10(d,J= 2.3 Hz, 1H), 9.03(d,J= 2.3 Hz, 1H), 7.26(t,J= 8.5 Hz, 2H), 7.12(d,J= 8.2 Hz, 1H), 3.37(s, 3H), 2.23(d, J = 2.0 Hz, 3H).

[0522]

[0523] <Example 19> Synthesis of Compound 20

[0524]

[0525] EtOH (9.40 mL) was added to 6,7-dibromoquinoxaline-5,8-dione (300 mg, 944 μmol) and stirred at room temperature. At the same temperature, 3-fluoroaniline (136 μL, 1.42 mmol) and CeCl3·7H2O (35.2 mg, 94.4 μmol) were added and stirred for 19 hours at room temperature. After adding a saturated aqueous solution of NaCl and DCM and extracting several times, the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-((3-fluorophenyl)amino)quinoxaline-5,8-dione, 20a).

[0526] Red brown solid, 314 mg(95.9%)

[0527] 1 H NMR (400 MHz, DMSO-D6) δ 9.55 (s, 1H), 9.07 - 8.99 (m, 2H), 7.34 (td,J= 8.3, 6.8 Hz, 1H), 7.04 - 6.90 (m, 3H).

[0528]

[0529] 6-bromo-7-((3-fluorophenyl)amino)quinoxaline-5,8-dione (313 mg, 899 μmol) was mixed with 9.00 mL of THF and stirred at room temperature. At the same temperature, NaSMe (189 mg, 2.70 mmol) was added and stirred for 23.5 hours at room temperature. A saturated aqueous solution of NaCl was added to the reaction solution and extracted several times with DCM. The separated organic layer was dried and filtered with Na2SO4, followed by vacuum concentration. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) to obtain the target compound (6-((3-fluorophenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, 20b).

[0530] Dark violet solid, 151 mg (53.4%)

[0531] 1 H NMR (400 MHz, DMSO-D6) δ 9.37(s, 1H), 8.98(d,J= 2.3 Hz, 1H), 8.96(d,J= 2.3 Hz, 1H), 7.27(td,J= 8.1, 6.4 Hz, 1H), 6.91 - 6.77(m, 3H), 2.06(s, 3H).

[0532]

[0533] CHCl3 (4.80 mL) is added to 6-((3-fluorophenyl)amino)-7-(methylthio)quinoxaline-5,8-dione (151 mg, 479 μmol) and stirred at room temperature. At the same temperature, mCPBA (268 mg, 1.20 mmol) is added and stirred for 5 more hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with Na2SO4, then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, DCM is added, and the mixture is extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with Na2SO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((3-fluorophenyl)amino)-7-(methyl sulfonyl)quinoxaline-5,8-dione, compound 20).

[0534] Light orange solid, 79.9 mg (48.0%)

[0535] 1H NMR (500 MHz, DMSO-D6) δ 10.53(s, 1H), 9.11(d,J= 2.3 Hz, 1H), 9.04(d,J= 2.3 Hz, 1H), 7.43 - 7.36(m, 1H), 7.32(d,J= 10.5 Hz, 1H), 7.23(d,J= 7.8 Hz, 1H), 7.07(td,J= 8.6, 2.7 Hz, 1H), 3.37(s, 3H).

[0536]

[0537] <Example 20> Synthesis of Compound 21

[0538]

[0539] EtOH (21.0 mL) was added to 6,7-dibromoquinoxaline-5,8-dione (682 mg, 2.15 mmol) and stirred at room temperature. At the same temperature, 4-fluoroaniline (310 μL, 3.22 mmol) and CeCl3·7H2O (80.0 mg, 215 μmol) were added and stirred for 16 more hours at room temperature. The reaction solution was concentrated under reduced pressure to remove EtOH, after which a saturated aqueous solution of NaCl and DCM were added and extracted several times. The separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-((4-fluorophenyl)amino)quinoxaline-5,8-dione, 21a).

[0540] Red purple solid, 659 mg (88.1%)

[0541] 1 H NMR (500 MHz, DMSO-D6) δ 9.50 (s, 1H), 9.06 - 8.96 (m, 2H), 7.24 - 7.15 (m, 4H).

[0542]

[0543] THF (19.0 mL) was added to 6-bromo-7-((4-fluorophenyl)amino)quinoxaline-5,8-dione (653 mg, 1.88 mmol) and stirred at room temperature. NaSMe (525 mg, 7.49 mmol) was added at the same temperature and stirred for 4.5 hours at room temperature. A saturated aqueous solution of NaCl was added to the reaction solution and extracted several times with DCM. The separated organic layer was dried and filtered with MgSO4, then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((4-fluorophenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, 21b).

[0544] Brown solid, 388 mg (65.4%)

[0545] 1 H NMR (400 MHz, CHLOROFORM-D) δ 9.02 - 8.92 (m, 2H), 7.88 (br s, 1H), 7.11 - 7.03 (m, 4H), 2.23 (s, 3H).

[0546]

[0547] CHCl3 (4.10 mL) is added to 6-((4-fluorophenyl)amino)-7-(methylthio)quinoxaline-5,8-dione (130 mg, 412 μmol) and stirred at room temperature. mCPBA (231 mg, 1.03 mmol) is added at the same temperature and stirred for 6 more hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with Na2SO4, then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, DCM is added, and the mixture is extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with Na2SO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((4-fluorophenyl)amino)-7-(methyl sulfonyl)quinoxaline-5,8-dione, compound 21).

[0548] Black solid, 85.5 mg (59.8%)

[0549] 1 H NMR (500 MHz, DMSO-D6) δ 10.57(s, 1H), 9.10(d,J= 2.3 Hz, 1H), 9.02(d,J= 2.3 Hz, 1H), 7.47 - 7.37(m, 2H), 7.25 - 7.17(m, 2H), 3.37(s, 3H).

[0550]

[0551] <Example 21> Synthesis of Compound 22

[0552]

[0553] EtOH (3.80 mL) was added to 6,7-dibromoquinoxaline-5,8-dione (120 mg, 377 μmol) and stirred at room temperature. At the same temperature, m-anisidine (70 mg, 566 μmol) and CeCl3·7H2O (7.00 mg, 18.9 μmol) were added and stirred for 16 more hours at room temperature. The reaction solution was concentrated under reduced pressure to remove EtOH, after which a saturated aqueous solution of NaCl and DCM were added and extracted several times. The separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / Hex) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-((3-methoxyphenyl)amino)quinoxaline-5,8-dione, 22a).

[0554] Red brown solid, 61.8 mg (45.5%)

[0555] 1 H NMR (500 MHz, DMSO-D6) δ 9.44 (s, 1H), 9.03 (d, J = 2.3 Hz, 1H), 9.01 (d, J = 2.3 Hz, 1H), 7.22 (t, J = 8.0 Hz, 1H), 6.81 - 6.68 (m, 3H), 3.72(s, 3H).

[0556]

[0557] 6-bromo-7-((3-methoxyphenyl)amino)quinoxaline-5,8-dione (320 mg, 888 μmol) was mixed with 10.0 mL of THF and stirred at room temperature. At the same temperature, NaSMe (200 mg, 2.65 mmol) was added and stirred for another hour at room temperature. The reaction solution was quenched with distilled water at 0 °C and extracted several times with EtOAc. The organic layer was washed with a saturated aqueous solution of NaCl, dried and filtered with Na2SO4, and then concentrated under reduced pressure. The crude product was triturated with MTBE for 30 minutes and then purified by Prep-HPLC (H2O / ACN). The primary purified compound was secondary purified with Prep-TLC (petroleum ether / EtOAc) to obtain the target compound (6-((3-methoxyphenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, 22b).

[0558] Black solid, 128 mg (43.8%)

[0559] 1 H NMR (400 MHz, CHLOROFORM-D) δ 9.09 - 8.90 (m, 2H), 7.92 (s, 1H), 7.30 (br s, 1H), 6.82 - 6.51 (m, 3H), 3.84 (s, 3H), 2.25 (s, 3H).

[0560]

[0561] CHCl3 (4.60 mL) is added to 6-((3-methoxyphenyl)amino)-7-(methylthio)quinoxaline-5,8-dione (150 mg, 458 μmol) and stirred at room temperature. At the same temperature, mCPBA (257 mg, 1.15 mmol) is added and stirred for 6 more hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with Na2SO4, then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, and then a saturated aqueous solution of NaCl and DCM are added and extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with Na2SO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((3-methoxyphenyl)amino)-7-(methylsulfonyl)quinoxaline-5,8-dione, compound 22).

[0562] Brown solid, 92.8 mg (56.4%)

[0563] 1 H NMR (500 MHz, DMSO-D6) δ 10.55(s, 1H), 9.10(d,J= 2.3 Hz, 1H), 9.02(d,J= 2.3 Hz, 1H), 7.27(t,J= 8.1 Hz, 1H), 7.03(s, 1H), 6.95(d,J= 7.3 Hz, 1H), 6.82(dd,J= 8.3, 2.5 Hz, 1H), 3.73(s, 3H), 3.39(s, 3H).

[0564]

[0565] <Example 22> Synthesis of Compound 23

[0566]

[0567] EtOH (9.40 mL) was added to 6,7-dibromoquinoxaline-5,8-dione (300 mg, 944 μmol) and stirred at room temperature. At the same temperature, o-toluidine (150 μL, 1.42 mmol) and CeCl3·7H2O (35.2 mg, 94.4 μmol) were added and stirred at room temperature for 22.5 hours. After adding a saturated aqueous solution of NaCl and DCM and extracting several times, the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-(o-tolylamino)quinoxaline-5,8-dione, 23a).

[0568] Red brown solid, 281 mg (86.6%)

[0569] 1 H NMR (500 MHz, DMSO-D6) δ 9.29 (s, 1H), 9.05 - 8.96 (m, 2H), 7.25 (dd,J= 6.9, 2.1 Hz, 1H), 7.22 - 7.12 (m, 3H), 2.23 (s, 3H).

[0570]

[0571] THF (8.00 mL) was added to 6-bromo-7-(o-tolylamino)quinoxaline-5,8-dione (275 mg, 799 μmol) and stirred at room temperature. NaSMe (168 mg, 2.40 mmol) was added at the same temperature and stirred for 27 hours at room temperature. A saturated aqueous solution of NaCl was added to the reaction solution and extracted several times with DCM. The separated organic layer was dried and filtered with MgSO4, followed by vacuum concentration. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) to obtain the target compound (6-(methylthio)-7-(o-tolylamino)quinoxaline-5,8-dione, 23b).

[0572] Red solid, 80.5 mg (32.4%)

[0573] 1 H NMR (500 MHz, DMSO-D6) δ 9.00(d,J= 2.3 Hz, 1H), 8.97(d,J= 2.3 Hz, 1H), 8.90(s, 1H), 7.22(dd,J= 7.2, 2.1 Hz, 1H), 7.13(pd,J= 7.3, 1.8 Hz, 2H), 7.03(dd,J= 7.5, 1.8 Hz, 1H), 2.28(s, 3H), 2.06(s, 3H).

[0574]

[0575] CHCl3 (2.40 mL) is added to 6-(methylthio)-7-(o-tolylamino)quinoxaline-5,8-dione (75.9 mg, 244 μmol) and stirred at room temperature. mCPBA (164 mg, 731 μmol) is added at the same temperature and stirred for 4 more hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. After separating the target compound by C18 silicagel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, and then a saturated aqueous solution of NaCl and DCM are added and extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-(methylsulfonyl)-7-(o-tolylamino)quin oxaline-5,8-dione, compound 23).

[0576] Brown solid, 31.4 mg (37.5%)

[0577] 1H NMR (500 MHz, DMSO-D6) δ 10.54(s, 1H), 9.09(d,J= 2.4 Hz, 1H), 9.00(d,J= 2.3 Hz, 1H), 7.31(t,J= 7.2 Hz, 2H), 7.19(dt,J= 21.2, 7.4 Hz, 2H), 3.39(s, 3H), 2.30(s, 3H).

[0578]

[0579] <Example 23> Synthesis of Compound 24

[0580]

[0581] EtOH (9.40 mL) was added to 6,7-dibromoquinoxaline-5,8-dione (300 mg, 944 μmol) and stirred at room temperature. At the same temperature, 4-amino-2-fluorobenzotrifluoride (254 mg, 1.42 mmol) and CeCl3·7H2O (35.2 mg, 94.4 μmol) were added and stirred for 19 hours at room temperature. After adding a saturated aqueous solution of NaCl and DCM and extracting several times, the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-((3-fluoro-4-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione, 24a).

[0582] Orange solid, 336 mg (85.6%)

[0583] 1 H NMR (500 MHz, DMSO-D6) δ 9.74 (s, 1H), 9.11 - 9.04 (m, 2H), 7.69 (t, J = 8.5 Hz, 1H), 7.22 - 7.06 (m, 2H).

[0584]

[0585] THF (8.00 mL) was added to 6-bromo-7-((3-fluoro-4-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione (333 mg, 800 μmol) and stirred at room temperature. NaSMe (168 mg, 2.40 mmol) was added at the same temperature and stirred for 4 more hours at room temperature. A saturated aqueous solution of NaCl was added to the reaction solution and extracted several times with DCM. The separated organic layer was dried and filtered with MgSO4, followed by vacuum concentration. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) to obtain the target compound (6-((3-fluoro-4-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, 24b).

[0586] Red violet solid, 172 mg (56.2%)

[0587] 1 H NMR (500 MHz, DMSO-D6) δ 9.61(s, 1H), 9.04(d,J= 2.3 Hz, 1H), 9.03(d,J= 2.3 Hz, 1H), 7.65(t,J= 8.4 Hz, 1H), 7.02(s, 1H), 7.01 - 6.98(m, 1H), 2.18(s, 3H).

[0588]

[0589] CHCl3 (4.30 mL) is added to 6-((3-fluoro-4-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinoxaline-5,8-dione (163 mg, 426 μmol) and stirred at room temperature. At the same temperature, mCPBA (286 mg, 1.28 mmol) is added and stirred for 6 more hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, and then a saturated aqueous solution of NaCl and DCM are added and extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((3-fluoro-4-(trifluoromethyl)phenyl)amino)-7-(methylsulfonyl)quinoxaline-5,8-dione, compound 24).

[0590] Light orange solid, 49.4 mg (27.9%)

[0591] 1 H NMR (500 MHz, DMSO-D6) δ 10.52(s, 1H), 9.13(d,J= 2.3 Hz, 1H), 9.07(d,J= 2.3 Hz, 1H), 7.76(t,J= 8.5 Hz, 1H), 7.56(d,J= 13.4 Hz, 1H), 7.41(d,J= 7.6 Hz, 1H), 3.33(s, 3H).

[0592]

[0593] <Example 24> Synthesis of Compound 25

[0594]

[0595] EtOH (12.6 mL) was added to 6,7-dibromoquinoxaline-5,8-dione (400 mg, 1.26 mmol) and stirred at room temperature. At the same temperature, 2-methyl-5-(trifluoromethyl)aniline (331 mg, 1.89 mmol) and CeCl3·7H2O (46.9 mg, 126 μmol) were added and stirred for 19.5 hours at room temperature. After adding a saturated aqueous solution of NaCl and DCM and extracting several times, the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) to obtain the target compound (6-bromo-7-((2-methyl-5-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione, 25a).

[0596] Red solid, 397 mg (76.4%)

[0597] 1 H NMR (500 MHz, DMSO-D6) δ 9.29 (s, 1H), 9.06 - 9.00 (m, 2H), 7.57 - 7.45 (m, 3H), 2.34 (s, 3H).

[0598]

[0599] THF (8.60 mL) was added to 6-bromo-7-((2-methyl-5-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione (355 mg, 861 μmol) and stirred at room temperature. NaSMe (181 mg, 2.58 mmol) was added at the same temperature and stirred for 4 more hours at room temperature. A saturated aqueous solution of NaCl was added to the reaction solution and extracted several times with DCM. The separated organic layer was dried and filtered with MgSO4, then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) to obtain the target compound (6-((2-methyl-5-(trifluoromethyl)phenyl)amino)-7-(methyl thio)quinoxaline-5,8-dione, 25b).

[0600] Red violet solid, 252 mg(77.1%)

[0601] 1 H NMR (500 MHz, DMSO-D6) δ 9.02 (d, J = 2.3 Hz, 1H), 8.99 (d, J = 2.4 Hz, 1H), 8.94 (s, 1H), 7.49 - 7.40 (m, 3H), 2.38 (s, 3H), 2.07 (s, 3H).

[0602]

[0603] CHCl3 (6.60 mL) is added to 6-((2-methyl-5-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinoxaline-5,8-dione (245 mg, 655 μmol) and stirred at room temperature. At the same temperature, mCPBA (440 mg, 1.97 mmol) is added and stirred for 6.5 hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, and then a saturated aqueous solution of NaCl and DCM are added and extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((2-methyl-5-(trifluoromethyl)phenyl)amino)-7-(methylsulfonyl)quinoxaline-5,8-dione, compound 25).

[0604] Orange solid, 167 mg (61.9%)

[0605] 1 H NMR (500 MHz, DMSO-D6) δ 10.46(s, 1H), 9.11(d,J= 2.3 Hz, 1H), 9.03(d,J= 2.4 Hz, 1H), 7.80(s, 1H), 7.53(d,J= 4.1 Hz, 2H), 3.33(s, 3H), 2.38(s, 3H).

[0606]

[0607] <Example 25> Synthesis of Compound 26

[0608]

[0609] EtOH (9.40 mL) was added to 6,7-dibromoquinoxaline-5,8-dione (300 mg, 944 μmol) and stirred at room temperature. At the same temperature, 3-fluoro-2-methylaniline (160 μL, 1.42 mmol) and CeCl3·7H2O (35.2 mg, 94.4 μmol) were added and stirred for 17 more hours at room temperature. After adding a saturated aqueous solution of NaCl and DCM and extracting several times, the separated organic layer was dried and filtered with Na2SO4 and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-((3-fluoro-2-methylphenyl)amino)quinoxaline-5,8-dione, 26a).

[0610] Solid, 292 mg (85.4%)

[0611] 1 H NMR (400 MHz, DMSO-D6) δ 9.35(s, 1H), 9.05 - 8.98(m, 2H), 7.20(q,J= 7.6 Hz, 1H), 7.10(t,J= 8.8 Hz, 1H), 7.03(d,J= 7.9 Hz, 1H), 2.14(m, 3H).

[0612]

[0613] 6-bromo-7-((3-fluoro-2-methylphenyl)amino)quinoxaline-5,8-dione (290 mg, 801 μmol) was mixed with THF (8.00 mL) and stirred at room temperature. At the same temperature, NaSMe (168 mg, 2.40 mmol) was added and stirred for 27 hours at room temperature. A saturated aqueous solution of NaCl was added to the reaction solution and extracted several times with DCM. The separated organic layer was dried and filtered with Na2SO4, followed by vacuum concentration. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) to obtain the target compound (6-((3-fluoro-2-methylphenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, 26b).

[0614] Solid, 144 mg (54.7%)

[0615] 1 H NMR (400 MHz, DMSO-D6) δ 9.01 (d, J = 2.3 Hz, 1H), 9.00 (s, 1H), 8.98 (d, J = 2.4 Hz, 1H), 7.21 - 7.12 (m, 1H), 7.01 (t, J = 8.3 Hz, 1H), 6.91(d,J= 7.9 Hz, 1H), 2.18(d,J= 2.2 Hz, 3H), 2.10(s, 3H).

[0616]

[0617] CHCl3 (4.40 mL) is added to 6-((3-fluoro-2-methylphenyl)amino)-7-(methylthio)quinoxaline-5,8-dione (144 mg, 437 μmol) and stirred at room temperature. At the same temperature, mCPBA (245 mg, 1.09 mmol) is added and stirred for 6 more hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, DCM is added, and the mixture is extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((3-fluoro-2-methylphenyl)amino)-7-(methylsulfonyl)quinoxaline-5,8-dione, compound 26).

[0618] Orange solid, 78.0 mg (49.4%)

[0619] 1 H NMR (400 MHz, DMSO-D6) δ 10.45(s, 1H), 9.10(d,J= 2.3 Hz, 1H), 9.01(d,J= 2.3 Hz, 1H), 7.25 - 7.15(m, 2H), 7.12(dt,J= 9.6, 3.8 Hz, 1H), 3.35(s, 3H), 2.21(d,J= 2.0 Hz, 3H).

[0620]

[0621] <Example 26> Synthesis of Compound 27

[0622]

[0623] EtOH (9.40 mL) was added to 6,7-dibromoquinoxaline-5,8-dione (300 mg, 944 μmol) and stirred at room temperature. At the same temperature, p-toluidine (152 mg, 1.42 mmol) and CeCl3·7H2O (35.2 mg, 94.4 μmol) were added and stirred for 22.5 hours at room temperature. After adding a saturated aqueous solution of NaCl and DCM and extracting several times, the separated organic layer was dried and filtered with Na2SO4 and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-(p-tolylamino)quinoxaline-5,8-dione, 27a).

[0624] Dark brown solid, 304 mg(93.6%)

[0625] 1 H NMR (500 MHz, DMSO-D6) δ 9.46 (s, 1H), 9.01 (dd,J= 10.5, 2.3 Hz, 2H), 7.13 (d,J= 8.2 Hz, 2H), 7.06 (d,J= 6.4 Hz, 2H), 2.29 (s, 3H).

[0626]

[0627] Add THF (8.80 mL) to 6-bromo-7-(p-tolylamino)quinoxaline-5,8-dione (301 mg, 875 μmol) and stir at room temperature. At the same temperature, add NaSMe (184 mg, 2.62 mmol) and stir for 22 hours at room temperature. Add a saturated aqueous solution of NaCl to the reaction solution and extract several times with DCM. Wash the separated organic layer once with distilled water, dry and filter with Na2SO4, and concentrate under reduced pressure. Dissolve the concentrate again in THF (8.80 mL), add NaSMe (61.3 mg, 875 μmol), and stir for 5 hours at room temperature. Add a saturated aqueous solution of NaCl to the reaction solution and extract several times with DCM. Dry and filter the separated organic layer with MgSO4, and concentrate under reduced pressure. The concentrate was purified by Silicagel column chromatography (EtOAc / DCM) to obtain the target compound (6-(methylthio)-7-(p-tolylamino)quinoxaline-5,8-dione, 27b).

[0628] Black solid, 172 mg (63.0%)

[0629] 1 H NMR (500 MHz, DMSO-D6) δ 9.27(s, 1H), 8.98(dd,J= 16.6, 2.4 Hz, 2H), 7.10(d,J= 8.5 Hz, 2H), 6.99(d,J= 8.4 Hz, 2H), 2.28(s, 3H), 2.03(s, 3H).

[0630]

[0631] CHCl3 (5.50 mL) is added to 6-(methylthio)-7-(p-tolylamino)quinoxaline-5,8-dione (172 mg, 552 μmol) and stirred at room temperature. At the same temperature, mCPBA (310 mg, 1.38 mmol) is added and stirred for 7 more hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4, then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, DCM is added, and the mixture is extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-(methylsulfonyl)-7-(p-tolylamino)quinoxaline-5,8-dione, compound 27).

[0632] Brown solid, 130 mg (68.5%)

[0633] 1 H NMR (400 MHz, DMSO-D6) δ 10.60 (s, 1H), 9.09 (dd,J= 2.3, 1.0 Hz, 1H), 9.01 (dd,J= 2.4, 0.8 Hz, 1H), 7.26 (d,J= 8.4 Hz, 2H), 7.17(d,J= 8.4 Hz, 2H), 3.39(s, 3H), 2.32(s, 3H).

[0634]

[0635] <Example 27> Synthesis of Compound 28

[0636]

[0637] EtOH (9.40 mL) was added to 6,7-dibromoquinoxaline-5,8-dione (300 mg, 944 μmol) and stirred at room temperature. At the same temperature, 2,4-dimethylaniline (180 μL, 1.42 mmol) and CeCl3·7H2O (35.2 mg, 94.4 μmol) were added and stirred at room temperature for 17 hours. After adding a saturated aqueous solution of NaCl and DCM and extracting several times, the separated organic layer was dried and filtered with Na2SO4 and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-((2,4-dimethylphenyl)amino)quinoxaline-5,8-dione, 28a).

[0638] Black solid, 307 mg (90.6%)

[0639] 1 H NMR (400 MHz, CHLOROFORM-D) δ 9.04 (d, J = 2.4 Hz, 1 H), 8.97 (d, J = 2.4 Hz, 1 H), 7.71 (br s, 1 H), 7.12 - 7.17 (m, 1 H), 7.04 - 7.10 (m, 1 H), 6.91(s, 1 H), 2.33(s, 3 H), 2.25(s, 3 H).

[0640]

[0641] THF (8.40 mL) was added to 6-bromo-7-((2,4-dimethylphenyl)amino)quinoxaline-5,8-dione (302 mg, 843 μmol) and stirred at room temperature. At the same temperature, NaSMe (177 mg, 2.53 mmol) was added and stirred for 26 hours at room temperature. A saturated aqueous solution of NaCl was added to the reaction solution and extracted several times with DCM. The separated organic layer was washed once with distilled water, dried and filtered with Na2SO4, and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) to obtain the target compound (6-((2,4-dimethylphenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, 28b).

[0642] Black solid, 192 mg (70.1%)

[0643] 1 H NMR (400 MHz, CHLOROFORM-D) δ 8.99(d,J= 2.0 Hz, 1 H), 8.93(d,J= 2.0 Hz, 1 H), 7.69(br s, 1 H), 7.13(br d,J= 8.0 Hz, 1 H), 6.99(br d,J= 8.0 Hz, 1 H), 6.73(s, 1 H), 2.32(s, 6 H), 2.22(s, 3 H).

[0644]

[0645] CHCl3 (5.90 mL) is added to 6-((2,4-dimethylphenyl)amino)-7-(methylthio)quinoxaline-5,8-dione (192 mg, 590 μmol) and stirred at room temperature. At the same temperature, mCPBA (331 mg, 1.48 mmol) is added and stirred for 5 more hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, DCM is added, and the mixture is extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((2,4-dimethylphenyl)amino)-7-(methylsulfonyl)quinoxaline-5,8-dione, compound 28).

[0646] Brown solid, 109 mg (51.8%)

[0647] 1 H NMR (400 MHz, DMSO-D6) δ 10.50(s, 1H), 9.09(d,J= 2.3 Hz, 1H), 9.00(d,J= 2.3 Hz, 1H), 7.19(d,J= 7.9 Hz, 1H), 7.11(s, 1H), 6.97(d,J= 7.6 Hz, 1H), 3.39(s, 3H), 2.29(s, 3H), 2.26(s, 3H).

[0648]

[0649] <Example 28> Synthesis of Compound 29

[0650]

[0651] EtOH (9.40 mL) was added to 6,7-dibromoquinoxaline-5,8-dione (300 mg, 944 μmol) and stirred at room temperature. At the same temperature, 3,5-dimethylaniline (180 μL, 1.42 mmol) and CeCl3·7H2O (35.2 mg, 94.4 μmol) were added and stirred for 17.5 hours at room temperature. After adding a saturated aqueous solution of NaCl and DCM and extracting several times, the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) to obtain the target compound (6-bromo-7-((3,5-dimethylphenyl)amino)quinoxaline-5,8-dione, 29a).

[0652] Red brown solid, 285 mg (84.4%)

[0653] 1 H NMR (500 MHz, DMSO-D6) δ 9.37 (s, 1H), 9.05 - 8.98 (m, 2H), 6.79 (s, 3H), 2.24 (s, 6H).

[0654]

[0655] 6-bromo-7-((3,5-dimethylphenyl)amino)quinoxaline-5,8-dione (285 mg, 796 μmol) is mixed with 8.00 mL of THF and stirred at room temperature. At the same temperature, NaSMe (223 mg, 3.18 mmol) is added and stirred for 48 more hours at room temperature. A saturated aqueous solution of NaCl is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with Na2SO4, then concentrated under reduced pressure. The concentrate is dissolved again in 8.00 mL of THF, NaSMe (55.8 mg, 796 μmol) is added, and stirred for 3 more hours at room temperature. A saturated aqueous solution of NaCl is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4, then concentrated under reduced pressure. The concentrate was purified by Silicagel column chromatography (EtOAc / DCM) to obtain the target compound (6-((3,5-dimethylphenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, 29b).

[0656] Dark violet solid, 130 mg (50.2%)

[0657] 1 H NMR (500 MHz, DMSO-D6) δ 9.17(s, 1H), 9.00(d,J= 2.3 Hz, 1H), 8.97(d,J= 2.4 Hz, 1H), 6.70(s, 3H), 2.23(s, 6H), 2.07(s, 3H).

[0658]

[0659] CHCl3 (4.00 mL) is added to 6-((3,5-dimethylphenyl)amino)-7-(methylthio)quinoxaline-5,8-dione (130 mg, 400 μmol) and stirred at room temperature. At the same temperature, mCPBA (224 mg, 999 μmol) is added and stirred for 5.5 hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4, then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, DCM is added, and the mixture is extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((3,5-dimethylphenyl)amino)-7-(methylsulfonyl)quinoxaline-5,8-dione, compound 29).

[0660] Orange solid, 85.7 mg (60.0%)

[0661] 1 H NMR (400 MHz, DMSO-D6) δ 10.54(s, 1H), 9.10(dd,J= 2.3, 0.9 Hz, 1H), 9.02(dd,J= 2.3, 0.9 Hz, 1H), 7.00(s, 2H), 6.89(s, 1H), 3.38(s, 3H), 2.25(s, 6H).

[0662]

[0663] <Example 29> Synthesis of Compound 30

[0664]

[0665] EtOH (9.40 mL) was added to 6,7-dibromoquinoxaline-5,8-dione (300 mg, 944 μmol) and stirred at room temperature. At the same temperature, 2-methyl-4-(trifluoromethyl)aniline (248 mg, 1.42 mmol) and CeCl3·7H2O (35.2 mg, 94.4 μmol) were added and stirred at room temperature for 24 hours. After adding a saturated aqueous solution of NaCl and DCM and extracting several times, the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) to obtain the target compound (6-bromo-7-((2-methyl-4-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione, 30a).

[0666] Solid, 289 mg (74.4%)

[0667]

[0668] 6-bromo-7-((2-methyl-4-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione (289 mg, 701 μmol) was mixed with 7.00 mL of THF and stirred at room temperature. At the same temperature, NaSMe (147 mg, 2.10 mmol) was added and stirred for 1.5 hours at room temperature. A saturated aqueous solution of NaCl was added to the reaction solution and extracted several times with DCM. The separated organic layer was dried and filtered with MgSO4, followed by vacuum concentration. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) to obtain the target compound (6-((2-methyl-4-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, 30b).

[0669] Solid, 180 mg (67.7%)

[0670]

[0671] CHCl3 (4.70 mL) is added to 6-((2-methyl-4-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinoxaline-5,8-dione (180 mg, 474 μmol) and stirred at room temperature. At the same temperature, mCPBA (266 mg, 1.19 mmol) is added and stirred for 6 more hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, and then a saturated aqueous solution of NaCl and DCM are added and extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((2-methyl-4-(trifluoromethyl)phenyl)amino)-7-(methylsulfonyl)quinoxaline-5,8-dione, compound 30).

[0672] Light orange solid, 107 mg (54.7%)

[0673] 1 H NMR (400 MHz, DMSO-D6) δ 10.48(s, 1H), 9.11(d,J= 2.3 Hz, 1H), 9.02(d,J= 2.3 Hz, 1H), 7.69(s, 1H), 7.55(s, 2H), 3.37(s, 3H), 2.38(s, 3H).

[0674]

[0675] <Example 30> Synthesis of Compound 31

[0676]

[0677] EtOH (9.40 mL) was added to 6,7-dibromoquinoxaline-5,8-dione (300 mg, 944 μmol) and stirred at room temperature. At the same temperature, 2,3-difluoroaniline (140 μL, 1.42 mmol) and CeCl3·7H2O (35.2 mg, 94.4 μmol) were added and stirred for 20 more hours at room temperature. After adding a saturated aqueous solution of NaCl and DCM and extracting several times, the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-((2,3-difluorophenyl)amino)quinoxaline-5,8-dione, 31a).

[0678] Red brown solid, 319 mg(92.2%)

[0679] 1 H NMR (400 MHz, DMSO-D6) δ 9.50 (s, 1H), 9.11 - 8.94 (m, 2H), 7.38 - 7.27 (m, 1H), 7.24 - 7.12 (m, 2H).

[0680]

[0681] THF (8.50 mL) was added to 6-bromo-7-((2,3-difluorophenyl)amino)quinoxaline-5,8-dione (312 mg, 852 μmol) and stirred at room temperature. At the same temperature, NaSMe (239 mg, 3.41 mmol) was added and stirred for 30 more hours at room temperature. A saturated aqueous solution of NaCl was added to the reaction solution and extracted several times with DCM. The separated organic layer was washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) to obtain the target compound (6-((2,3-difluorophenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, 31b).

[0682] Red brown solid, 85.6 mg (30.1%)

[0683] 1 H NMR (400 MHz, DMSO-D6) δ 9.26(s, 1H), 9.03(d,J= 2.3 Hz, 1H), 9.00(d,J= 2.2 Hz, 1H), 7.28 - 7.19(m, 1H), 7.15(tdd,J= 8.1, 5.8, 1.5 Hz, 1H), 7.08(ddt,J= 8.4, 6.8, 1.7 Hz, 1H), 2.17(s, 3H).

[0684]

[0685] CHCl3 (2.60 mL) is added to 6-((2,3-difluoro-phenyl)amino)-7-(methylthio)quinoxaline-5,8-dione (85.6 mg, 257 μmol) and stirred at room temperature. mCPBA (144 mg, 642 μmol) is added at the same temperature and stirred for 6 more hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, and then a saturated aqueous solution of NaCl and DCM are added and extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((2,3-difluorophenyl)amino)-7-(methylsulfonyl)quinoxaline-5,8-dione, compound 31).

[0686] Red brown solid, 34.5 mg (36.7%)

[0687] 1H NMR (400 MHz, DMSO-D6) δ 10.44(s, 1H), 9.12(d,J= 2.3 Hz, 1H), 9.04(d,J= 2.4 Hz, 1H), 7.35(d,J= 9.9 Hz, 2H), 7.19(q,J= 6.6 Hz, 1H), 3.38(s, 3H).

[0688]

[0689] <Example 31> Synthesis of Compound 32

[0690]

[0691] EtOH (12.6 mL) was added to 6,7-dibromoquinoxaline-5,8-dione (400 mg, 1.26 mmol) and stirred at room temperature. At the same temperature, 2-methoxy-5-(trifluoromethyl)aniline (361 mg, 1.89 mmol) and CeCl3·7H2O (46.9 mg, 126 μmol) were added and stirred for 20 more hours at room temperature. After adding a saturated aqueous solution of NaCl and DCM and extracting several times, the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) to obtain the target compound (6-bromo-7-((2-methoxy-5-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione, 32a).

[0692] Dark brown solid, 442 mg (81.9%)

[0693] 1 H NMR (500 MHz, DMSO-D6) δ 9.09(s, 1H), 9.04(d,J= 2.7 Hz, 1H), 9.01(d,J= 2.4 Hz, 1H), 7.61 - 7.49(m, 2H), 7.22(d,J= 8.5 Hz, 1H), 3.77(d,J=8.6 Hz, 3H).

[0694]

[0695] 6-bromo-7-((2-methoxy-5-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione (420 mg, 982 μmol) was mixed with 9.80 mL of THF and stirred at room temperature. At the same temperature, NaSMe (206 mg, 2.95 mmol) was added and stirred for 2 more hours at room temperature. A saturated aqueous solution of NaCl was added to the reaction solution and extracted several times with DCM. The separated organic layer was dried and filtered with MgSO4, followed by vacuum concentration. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) to obtain the target compound (6-((2-methoxy-5-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, 32b).

[0696] Red violet solid, 269 mg (69.3%)

[0697] 1 H NMR (500 MHz, DMSO-D6) δ 9.03(d,J= 2.3 Hz, 1H), 8.99(d,J= 2.3 Hz, 1H), 8.63(s, 1H), 7.49(dd,J= 8.2, 2.7 Hz, 1H), 7.38(d,J= 2.4 Hz, 1H), 7.21(d,J= 8.2 Hz, 1H), 3.84(s, 3H), 2.10(s, 3H).

[0698]

[0699] CHCl3 (6.60 mL) is added to 6-((2-methoxy-5-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinoxaline-5,8-dione (262 mg, 663 μmol) and stirred at room temperature. At the same temperature, mCPBA (446 mg, 1.99 mmol) is added and stirred for 6.5 hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, and then a saturated aqueous solution of NaCl and DCM are added and extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((2-methoxy-5-(trifluoromethyl)phenyl)amino)-7-(methylsulfonyl)quinoxaline-5,8-dione, compound 32).

[0700] Brown solid, 165 mg (58.3%)

[0701] 1 H NMR (500 MHz, DMSO-D6) δ 10.45(s, 1H), 9.12(d,J= 2.4 Hz, 1H), 9.04(d,J= 2.3 Hz, 1H), 7.87(s, 1H), 7.61(d,J= 7.8 Hz, 1H), 7.29(d,J= 8.7 Hz, 1H), 3.82(s, 3H), 3.45(s, 3H).

[0702]

[0703] <Example 32> Synthesis of Compound 33

[0704]

[0705] EtOH (9.40 mL) was added to 6,7-dibromoquinoxaline-5,8-dione (300 mg, 944 μmol) and stirred at room temperature. At the same temperature, 5-amino-2-fluorobenzotrifluoride (180 μL, 1.42 mmol) and CeCl3·7H2O (35.2 mg, 94.4 μmol) were added and stirred for 18.5 hours at room temperature. After adding a saturated aqueous solution of NaCl and DCM and extracting several times, the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-((4-fluoro-3-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione, 33a).

[0706] Red brown solid, 349 mg (88.9%)

[0707] 1 H NMR (500 MHz, DMSO-D6) δ 9.60 (s, 1H), 9.08 - 9.00 (m, 2H), 7.59 - 7.54 (m, 1H), 7.53 - 7.48 (m, 2H).

[0708]

[0709] THF (8.20 mL) was added to 6-bromo-7-((4-fluoro-3-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione (342 mg, 822 μmol) and stirred at room temperature. NaSMe (173 mg, 2.47 mmol) was added at the same temperature and stirred for 4 more hours at room temperature. A saturated aqueous solution of NaCl was added to the reaction solution and extracted several times with DCM. The separated organic layer was dried and filtered with MgSO4, then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((4-fluoro-3-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, 33b).

[0710] Red violet solid, 147 mg (46.7%)

[0711] 1 H NMR (500 MHz, DMSO-D6) δ 9.50 (s, 1H), 9.02 (dd,J= 14.4, 2.3 Hz, 2H), 7.51 - 7.37 (m, 3H), 2.06 (s, 3H).

[0712]

[0713] CHCl3 (3.70 mL) is added to 6-((4-fluoro-3-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinoxaline-5,8-dione (143 mg, 374 μmol) and stirred at room temperature. At the same temperature, mCPBA (252 mg, 1.12 mmol) is added and stirred for 6 more hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, and then a saturated aqueous solution of NaCl and DCM are added and extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((4-fluoro-3-(trifluoromethyl)phenyl)amino)-7-(methylsulfonyl)quinoxaline-5,8-dione, compound 33).

[0714] Orange solid, 76.7 mg (49.4%)

[0715] 1 H NMR (500 MHz, DMSO-D6) δ 10.55(s, 1H), 9.12(d,J= 2.3 Hz, 1H), 9.04(d,J= 2.3 Hz, 1H), 7.87(dd,J= 6.6, 2.6 Hz, 1H), 7.77 - 7.69(m, 1H), 7.53(t,J= 9.8 Hz, 1H), 3.32(s, 3H).

[0716]

[0717] <Example 33> Synthesis of Compound 34

[0718]

[0719] EtOH (9.40 mL) was added to 6,7-dibromoquinoxaline-5,8-dione (300 mg, 944 μmol) and stirred at room temperature. At the same temperature, o-anisidine (160 μL, 1.42 mmol) and CeCl3·7H2O (35.2 mg, 94.4 μmol) were added and stirred at room temperature for 22 hours. After adding a saturated aqueous solution of NaCl and DCM and extracting several times, the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-((2-methoxyphenyl)amino)quinoxaline-5,8-dione, 34a).

[0720] Red brown solid, 343 mg (quantitative)

[0721]

[0722] 6-bromo-7-((2-methoxyphenyl)amino)quinoxaline-5,8-dione (342 mg, 944 μmol) was mixed with 9.50 mL of THF and stirred at room temperature. At the same temperature, NaSMe (198 mg, 2.83 mmol) was added and stirred for 23 hours at room temperature. A saturated aqueous solution of NaCl was added to the reaction solution and extracted several times with DCM. The separated organic layer was dried and filtered with MgSO4, followed by vacuum concentration. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((2-methoxyphenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, 34b).

[0723] Indigo solid, 208 mg (67.4%)

[0724] 1H NMR (500 MHz, DMSO-D6) δ 9.04 - 8.89 (m, 2H), 7.97 (s, 1H), 7.23 - 7.17 (m, 1H), 7.01 - 6.92 (m, 3H), 3.90 (s, 3H), 2.16 (s, 3H).

[0725]

[0726] CHCl3 (6.30 mL) is added to 6-((2-methoxyphenyl)amino)-7-(methylthio)quinoxaline-5,8-dione (207 mg, 631 μmol) and stirred at room temperature. mCPBA (425 mg, 1.89 mmol) is added at the same temperature and stirred for 6.5 hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, and then a saturated aqueous solution of NaCl and DCM are added and extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((2-methoxyphenyl)amino)-7-(methylsulfonyl)quinoxaline-5,8-dione, compound 34).

[0727] Brown solid, 144 mg (63.5%)

[0728] 1H NMR (500 MHz, DMSO-D6) δ 10.43(s, 1H), 9.11(d,J= 2.3 Hz, 1H), 9.02(d,J= 2.3 Hz, 1H), 7.38(dd,J= 7.9, 1.8 Hz, 1H), 7.25(ddd,J= 8.7, 7.6, 1.7 Hz, 1H), 7.09(dd,J= 8.3, 1.3 Hz, 1H), 6.97(td,J= 7.6, 1.3 Hz, 1H), 3.69(s, 3H), 3.47(s, 3H).

[0729]

[0730] <Example 34> Synthesis of Compound 35

[0731]

[0732] EtOH (9.40 mL) was added to 6,7-dibromoquinoxaline-5,8-dione (300 mg, 944 μmol) and stirred at room temperature. At the same temperature, 3-amino-4-fluorobenzotrifluoride (180 μL, 1.42 mmol) and CeCl3·7H2O (35.2 mg, 94.4 μmol) were added and stirred at room temperature for 20 more hours. After adding a saturated aqueous solution of NaCl and DCM and extracting several times, the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-((2-fluoro-5-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione, 35a).

[0733] Orange solid, 347 mg (88.4%)

[0734]

[0735] 6-bromo-7-((2-fluoro-5-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione (345 mg, 829 μmol) was mixed with THF (8.30 mL) and stirred at room temperature. At the same temperature, NaSMe (174 mg, 2.49 mmol) was added and stirred for 4.5 hours at room temperature. A saturated aqueous solution of NaCl was added to the reaction solution and extracted several times with DCM. The separated organic layer was dried and filtered with MgSO4, followed by vacuum concentration. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) to obtain the target compound (6-((2-fluoro-5-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, 35b).

[0736] Red violet solid, 158 mg (49.8%)

[0737]

[0738] CHCl3 (4.10 mL) is added to 6-((2-fluoro-5-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinoxaline-5,8-dione (158 mg, 413 μmol) and stirred at room temperature. At the same temperature, mCPBA (278 mg, 1.24 mmol) is added and stirred for 5.5 hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, and then a saturated aqueous solution of NaCl and DCM are added and extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((2-fluoro-5-(trifluoromethyl)phenyl)amino)-7-(methylsulfonyl)quinoxaline-5,8-dione, compound 35).

[0739] Orange solid, 78.2 mg (45.6%)

[0740] 1 H NMR (500 MHz, DMSO-D6) δ 10.44 (s, 1H), 9.14 - 9.11 (m, 1H), 9.06 - 9.03 (m, 1H), 8.04 - 7.97 (m, 1H), 7.70 (d, J = 12.4 Hz, 1H), 7.55(t,J= 9.4 Hz, 1H), 3.37(s, 3H).

[0741]

[0742] <Example 35> Synthesis of Compound 36

[0743]

[0744] EtOH (9.40 mL) was added to 6,7-dibromoquinoxaline-5,8-dione (300 mg, 944 μmol) and stirred at room temperature. At the same temperature, 5-chloro-2-methylaniline (200 mg, 1.42 mmol) and CeCl3·7H2O (35.2 mg, 94.4 μmol) were added and stirred for 19.5 hours at room temperature. After adding a saturated aqueous solution of NaCl and DCM and extracting several times, the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-((5-chloro-2-methylphenyl)amino)quinoxaline-5,8-dione, 36a).

[0745] Orange solid, 297 mg (83.2%)

[0746] 1 H NMR (500 MHz, DMSO-D6) δ 9.23 (s, 1H), 9.05 - 9.02 (m, 1H), 9.01 (m, 1H), 7.30 - 7.21 (m, 3H), 2.23 (s, 3H).

[0747]

[0748] THF (7.70 mL) was added to 6-bromo-7-((5-chloro-2-methylphenyl)amino)quinoxaline-5,8-dione (292 mg, 772 μmol) and stirred at room temperature. At the same temperature, NaSMe (162 mg, 2.32 mmol) was added and stirred for 23.5 hours at room temperature. A saturated aqueous solution of NaCl was added to the reaction solution and extracted several times with DCM. The separated organic layer was dried and filtered with MgSO4, followed by vacuum concentration. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) to obtain the target compound (6-((5-chloro-2-methylphenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, 36b).

[0749] Red violet solid, 164 mg (61.7%)

[0750] 1 H NMR (500 MHz, DMSO-D6) δ 9.03 - 9.00 (m, 1H), 8.98 (dd,J= 2.4, 1.3 Hz, 1H), 8.84 (s, 1H), 7.26 - 7.22 (m, 1H), 7.16 - 7.12 (m, 2H), 2.27(s, 3H), 2.10(s, 3H).

[0751]

[0752] CHCl3 (4.60 mL) is added to 6-((5-chloro-2-methylphenyl)amino)-7-(methylthio)quinoxaline-5,8-dione (160 mg, 462 μmol) and stirred at room temperature. At the same temperature, mCPBA (311 mg, 1.39 mmol) is added and stirred for 6 more hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, and then a saturated aqueous solution of NaCl and DCM are added and extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((5-chloro-2-methylphenyl)amino)-7-(methylsulfonyl)quinoxaline-5,8-dione, compound 36).

[0753] Orange solid, 35.5 mg (20.3%)

[0754] 1H NMR (500 MHz, DMSO-D6) δ 10.42(s, 1H), 9.11(d,J= 2.3 Hz, 1H), 9.03(d,J= 2.3 Hz, 1H), 7.51(s, 1H), 7.32(d,J= 8.4 Hz, 1H), 7.25(dd,J= 8.2, 2.4 Hz, 1H), 3.36(s, 3H), 2.28(s, 3H).

[0755]

[0756] <Example 36> Synthesis of Compound 37

[0757]

[0758] EtOH (9.40 mL) was added to 6,7-dibromoquinoxaline-5,8-dione (300 mg, 944 μmol) and stirred at room temperature. At the same temperature, 4-fluoro-2-methylaniline (177 mg, 1.42 mmol) and CeCl3·7H2O (35.2 mg, 94.4 μmol) were added and stirred at room temperature for 24 hours. After adding a saturated aqueous solution of NaCl and DCM and extracting several times, the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-((4-fluoro-2-methylphenyl)amino)quinoxaline-5,8-dione, 37a).

[0759] Red brown solid, 318 mg(92.9%)

[0760] 1 H NMR (400 MHz, CHLOROFORM-D) δ 9.05(d,J= 2.4 Hz, 1 H), 8.99(d,J= 2.4 Hz, 1 H), 7.64(br s, 1 H), 7.10(dd,J= 8.8, 5.25 Hz, 1 H), 6.99(dd,J= 9.2, 2.69 Hz, 1 H), 6.90 - 6.96(m, 1 H), 2.29(s, 3 H).

[0761]

[0762] THF (8.70 mL) was added to 6-bromo-7-((4-fluoro-2-methylphenyl)amino)quinoxaline-5,8-dione (316 mg, 873 μmol) and stirred at room temperature. NaSMe (184 mg, 2.62 mmol) was added at the same temperature and stirred for 24 hours at room temperature. A saturated aqueous solution of NaCl was added to the reaction solution and extracted several times with DCM. The separated organic layer was dried and filtered with MgSO4, followed by vacuum concentration. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) to obtain the target compound (6-((4-fluoro-2-methylphenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, 37b).

[0763] Red violet solid, 160 mg (55.5%)

[0764] 1 H NMR (400 MHz, CHLOROFORM-D) δ 9.04 (d, J = 2.4 Hz, 1 H), 8.97 (d, J = 2.4 Hz, 1 H), 7.71 (br s, 1 H), 7.12 - 7.17 (m, 1 H), 7.04 - 7.10 (m, 1 H), 6.91(s, 1 H), 2.33(s, 3 H), 2.25(s, 3 H).

[0765]

[0766] CHCl3 (4.80 mL) is added to 6-((4-fluoro-2-methylphenyl)amino)-7-(methylthio)quinoxaline-5,8-dione (159 mg, 483 μmol) and stirred at room temperature. At the same temperature, mCPBA (325 mg, 1.45 mmol) is added and stirred for 6.5 hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, and then a saturated aqueous solution of NaCl and DCM are added and extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((4-fluoro-2-methyl phenyl)amino)-7-(methylsulfonyl)quinoxaline-5,8-dione, compound 37).

[0767] Brown solid, 57.5 mg (32.9%)

[0768] 1 H NMR (500 MHz, DMSO-D6) δ 10.43(s, 1H), 9.09(s, 1H), 9.01(d,J= 2.3 Hz, 1H), 7.37(dd,J= 8.6, 5.3 Hz, 1H), 7.18(dd,J= 9.6, 3.1 Hz, 1H), 7.06 - 6.97(m, 1H), 3.37(s, 3H), 2.30(s, 3H).

[0769]

[0770] <Example 37> Synthesis of Compound 38

[0771]

[0772] EtOH (9.40 mL) was added to 6,7-dibromoquinoxaline-5,8-dione (300 mg, 944 μmol) and stirred at room temperature. At the same temperature, 3,4-dimethylaniline (172 mg, 1.42 mmol) and CeCl3·7H2O (35.2 mg, 94.4 μmol) were added and stirred at room temperature for 24 hours. After adding a saturated aqueous solution of NaCl and DCM and extracting several times, the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-((3,4-dimethylphenyl)amino)quinoxaline-5,8-dione, 38a).

[0773] Red brown solid, 301 mg(89.0%)

[0774] 1 H NMR (500 MHz, DMSO-D6) δ 9.41(s, 1H), 9.02(dd,J= 5.0, 2.3 Hz, 1H), 9.00(d,J= 2.3 Hz, 1H), 7.08(d,J= 8.1 Hz, 1H), 6.96(dd,J= 6.4, 2.4 Hz, 1H), 6.90(dd,J= 7.9, 2.4 Hz, 1H), 2.20(s, 6H).

[0775]

[0776] THF (8.20 mL) was added to 6-bromo-7-((3,4-dimethylphenyl)amino)quinoxaline-5,8-dione (295 mg, 824 μmol) and stirred at room temperature. At the same temperature, NaSMe (173 mg, 2.47 mmol) was added and stirred for 24 hours at room temperature. A saturated aqueous solution of NaCl was added to the reaction solution and extracted several times with DCM. The separated organic layer was dried and filtered with MgSO4, followed by vacuum concentration. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) to obtain the target compound (6-((3,4-dimethylphenyl)amino)-7-(methyl thio)quinoxaline-5,8-dione, 38b).

[0777] Dark violet solid, 139 mg (52.0%)

[0778] 1 H NMR (500 MHz, DMSO-D6) δ 9.21(s, 1H), 9.00(d,J= 2.3 Hz, 1H), 8.96(d,J= 2.3 Hz, 1H), 7.04(d,J= 8.1 Hz, 1H), 6.89(s, 1H), 6.83(d,J= 8.1 Hz, 1H), 2.19(s, 6H), 2.05(s, 3H).

[0779]

[0780] CHCl3 (4.30 mL) is added to 6-((3,4-dimethylphenyl)amino)-7-(methylthio)quinoxaline-5,8-dione (139 mg, 427 μmol) and stirred at room temperature. At the same temperature, mCPBA (239 mg, 1.07 mmol) is added and stirred for 6 more hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4, then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, DCM is added, and extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((3,4-dimethylphenyl)amino)-7-(methylsulfonyl)quinoxaline-5,8-dione, compound 38).

[0781] Red brown solid, 91.3 mg (59.8%)

[0782] 1 H NMR (400 MHz, DMSO-D6) δ 10.58 (s, 1H), 9.10 (s, 1H), 9.01 (d, J = 2.3 Hz, 1H), 7.16 (s, 1H), 7.15 - 7.05 (m, 2H), 3.39 (s, 3H), 2.22(s, 3H), 2.20(s, 3H).

[0783]

[0784] <Example 38> Synthesis of Compound 39

[0785]

[0786] EtOH (9.40 mL) was added to 6,7-dibromoquinoxaline-5,8-dione (300 mg, 944 μmol) and stirred at room temperature. At the same temperature, 3-methoxy-5-(trifluoromethyl)aniline (271 mg, 1.42 mmol) and CeCl3·7H2O (35.2 mg, 94.4 μmol) were added and stirred for 23.5 hours at room temperature. After adding a saturated aqueous solution of NaCl and DCM and extracting several times, the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) to obtain the target compound (6-bromo-7-((3-methoxy-5-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione, 39a).

[0787] Red brown solid, 360 mg(89.1%)

[0788] 1 H NMR (500 MHz, DMSO-D6) δ 9.55(s, 1H), 9.07 - 9.04(m, 1H), 9.03(d,J= 2.3 Hz, 1H), 7.09(d,J= 8.2 Hz, 1H), 7.02(d,J= 5.3 Hz, 1H), 6.96(s, 1H), 3.80(s, 3H).

[0789]

[0790] THF (8.40 mL) was added to 6-bromo-7-((3-methoxy-5-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione (360 mg, 841 μmol) and stirred at room temperature. At the same temperature, NaSMe (177 mg, 2.52 mmol) was added and stirred for another hour at room temperature. A saturated aqueous solution of NaCl was added to the reaction solution and extracted several times with DCM. The separated organic layer was washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) to obtain the target compound (6-((3-methoxy-5-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, 39b).

[0791] Dark violet solid, 205 mg (61.6%)

[0792] 1 H NMR (500 MHz, DMSO-D6) δ 9.41(s, 1H), 9.03(d,J= 2.4 Hz, 1H), 9.00(d,J= 2.3 Hz, 1H), 7.01(s, 1H), 6.90(t,J= 2.3 Hz, 1H), 6.88(d,J= 1.6 Hz, 1H).

[0793]

[0794] CHCl3 (5.20 mL) is added to 6-((3-methoxy-5-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinoxaline-5,8-dione (205 mg, 519 μmol) and stirred at room temperature. At the same temperature, mCPBA (291 mg, 1.30 mmol) is added and stirred for 6.5 hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, and then a saturated aqueous solution of NaCl and DCM are added and extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((3-methoxy-5-(trifluoromethyl)phenyl)amino)-7-(methylsulfonyl)quinoxaline-5,8-dione, compound 39).

[0795] Orange solid, 132 mg (59.5%)

[0796] 1 H NMR (400 MHz, DMSO-D6) δ 10.52(s, 1H), 9.11(d,J= 2.4 Hz, 1H), 9.04(d,J= 2.4 Hz, 1H), 7.36(s, 1H), 7.28(s, 1H), 7.07(s, 1H), 3.81(s, 3H), 3.32(s, 3H).

[0797]

[0798] <Example 39> Synthesis of Compound 40

[0799]

[0800] EtOH (9.40 mL) was added to 6,7-dibromoquinoxaline-5,8-dione (300 mg, 944 μmol) and stirred at room temperature. At the same temperature, 4-chloro-2-methylaniline (200 mg, 1.42 mmol) and CeCl3·7H2O (35.2 mg, 94.4 μmol) were added and stirred for 23.5 hours at room temperature. After adding a saturated aqueous solution of NaCl and DCM and extracting several times, the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-((4-chloro-2-methylphenyl)amino)quinoxaline-5,8-dione, 40a).

[0801] Red brown solid, 282 mg(79.0%)

[0802] 1 H NMR (500 MHz, DMSO-D6) δ 9.24 (s, 1H), 9.05 - 8.99 (m, 2H), 7.35 (s, 1H), 7.25 (dd,J= 8.5, 2.5 Hz, 1H), 7.17 (dd,J= 8.5, 4.2 Hz, 1H), 2.24(d,J= 4.3 Hz, 3H).

[0803]

[0804] THF (7.30 mL) was added to 6-bromo-7-((4-chloro-2-methylphenyl)amino)quinoxaline-5,8-dione (276 mg, 729 μmol) and stirred at room temperature. At the same temperature, NaSMe (179 mg, 2.55 mmol) was added and stirred for 23.5 hours at room temperature. A saturated aqueous solution of NaCl was added to the reaction solution and extracted several times with DCM. The separated organic layer was washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) to obtain the target compound (6-((4-chloro-2-methylphenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, 40b).

[0805] Violet solid, 134 mg (53.3%)

[0806] 1 H NMR (500 MHz, DMSO-D6) δ 9.01(d,J= 2.3 Hz, 1H), 8.97(d,J= 2.3 Hz, 1H), 8.89(s, 1H), 7.31(d,J= 2.5 Hz, 1H), 7.21(dd,J= 8.4, 2.5 Hz, 1H), 7.05(d,J= 8.4 Hz, 1H), 2.28(s, 3H), 2.09(s, 3H).

[0807]

[0808] CHCl3 (3.70 mL) is added to 6-((4-chloro-2-methylphenyl)amino)-7-(methylthio)quinoxaline-5,8-dione (128 mg, 370 μmol) and stirred at room temperature. At the same temperature, mCPBA (207 mg, 925 μmol) is added and stirred for 6.5 hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, DCM is added, and the mixture is extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((4-chloro-2-methylphenyl)amino)-7-(methylsulfonyl)quinoxaline-5,8-dione, compound 40).

[0809] Red brown solid, 46.6 mg (33.3%)

[0810] 1 H NMR (400 MHz, DMSO-D6) δ 10.42(s, 1H), 9.10(d,J= 2.3 Hz, 1H), 9.01(d,J= 2.3 Hz, 1H), 7.40(d,J= 2.7 Hz, 1H), 7.36(d,J= 8.5 Hz, 1H), 7.24(dd,J= 8.5, 2.6 Hz, 1H), 3.36(s, 3H), 2.29(s, 3H).

[0811]

[0812] <Example 40> Synthesis of Compound 41

[0813]

[0814] EtOH (9.40 mL) was added to 6,7-dibromoquinoxaline-5,8-dione (300 mg, 944 μmol) and stirred at room temperature. At the same temperature, 2,5-dimethylaniline (180 μL, 1.42 mmol) and CeCl3·7H2O (35.2 mg, 94.4 μmol) were added and stirred for 17.5 hours at room temperature. After adding a saturated aqueous solution of NaCl and DCM and extracting several times, the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-((2,5-dimethylphenyl)amino)quinoxaline-5,8-dione, 41a).

[0815] Red brown solid, 308 mg(91.1%)

[0816] 1 H NMR (400 MHz, CHLOROFORM-D) δ 9.03 (d, J = 2.4 Hz, 1 H), 8.97 (d, J = 2.4 Hz, 1 H), 7.71 (br s, 1 H), 7.07 (s, 1 H), 7.00 (q, J = 8.0 Hz, 2 H), 2.36(s, 3 H), 2.25(s, 3 H).

[0817]

[0818] 6-bromo-7-((2,5-dimethylphenyl)amino)quinoxaline-5,8-dione (288 mg, 804 μmol) was mixed with 8.00 mL of THF and stirred at room temperature. At the same temperature, NaSMe (169 mg, 2.41 mmol) was added and stirred for 4.5 hours at room temperature. A saturated aqueous solution of NaCl was added to the reaction solution and extracted several times with DCM. The separated organic layer was dried and filtered with MgSO4, followed by vacuum concentration. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) to obtain the target compound (6-((2,5-dimethylphenyl)amino)-7-(methyl-thio)quinoxaline-5,8-dione, 41b).

[0819] Red violet solid, 102 mg(38.8%)

[0820] 1 H NMR (400 MHz, CHLOROFORM-D) δ 9.05(d,J= 2.4 Hz, 1 H), 9.01(d,J= 2.4 Hz, 1 H), 8.87(s, 1 H), 7.14(d,J= 7.6 Hz, 1 H), 6.97(dd,J= 7.6, 1.6 Hz, 1 H), 6.90(s, 1 H), 2.27(s, 6 H), 2.11(s, 3 H).

[0821]

[0822] CHCl3 (3.10 mL) is added to 6-((2,5-dimethylphenyl)amino)-7-(methyl-thio)quinoxaline-5,8-dione (101 mg, 312 μmol) and stirred at room temperature. At the same temperature, mCPBA (210 mg, 936 μmol) is added and stirred for 6.5 hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, and then a saturated aqueous solution of NaCl and DCM are added and extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((2,5-dimethylphenyl)amino)-7-(methylsulfonyl)quinoxaline-5,8-dione, compound 41).

[0823] Beige to light orange solid, 40.9 mg (36.7%)

[0824] 1 H NMR (500 MHz, DMSO-D6) δ 10.49(s, 1H), 9.09(d,J= 2.3 Hz, 1H), 9.01(d,J= 2.4 Hz, 1H), 7.20 - 7.12(m, 2H), 7.02(d,J= 8.1 Hz, 1H), 3.38(s, 3H), 2.24(s, 3H), 2.22(s, 3H).

[0825]

[0826] <Example 41> Synthesis of Compound 42

[0827]

[0828] EtOH (9.40 mL) was added to 6,7-dibromoquinoxaline-5,8-dione (300 mg, 944 μmol) and stirred at room temperature. At the same temperature, 5-fluoro-2-methylaniline (177 mg, 1.42 mmol) and CeCl3·7H2O (35.2 mg, 94.4 μmol) were added and stirred for 22.5 hours at room temperature. After adding a saturated aqueous solution of NaCl and DCM and extracting several times, the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) to obtain the target compound (6-bromo-7-((5-fluoro-2-methylphenyl)amino)quinoxaline-5,8-dione, 42a).

[0829] Dark brown solid, 265 mg (77.4%)

[0830] 1 H NMR (500 MHz, DMSO-D6) δ 9.24 (s, 1H), 9.06 - 8.99 (m, 2H), 7.31 - 7.23 (m, 1H), 7.09 - 6.98 (m, 2H), 2.21 (d, J = 4.3 Hz, 3H).

[0831]

[0832] THF (7.10 mL) was added to 6-bromo-7-((5-fluoro-2-methylphenyl)amino)quinoxaline-5,8-dione (257 mg, 710 μmol) and stirred at room temperature. At the same temperature, NaSMe (149 mg, 2.13 mmol) was added and stirred for 29 hours at room temperature. A saturated aqueous solution of NaCl was added to the reaction solution and extracted several times with DCM. The separated organic layer was dried and filtered with MgSO4, followed by vacuum concentration. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) to obtain the target compound (6-((5-fluoro-2-methylphenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, 42b).

[0833] Red violet solid, 177 mg (75.7%)

[0834] 1 H NMR (500 MHz, DMSO-D6) δ 9.02 (dd,J= 2.4, 0.9 Hz, 1H), 8.99(dd,J= 2.4, 0.9 Hz, 1H), 8.82(s, 1H), 7.26 - 7.20(m, 1H), 6.96 - 6.88(m, 2H), 2.26(s, 3H), 2.11(s, 3H).

[0835]

[0836] CHCl3 (5.40 mL) is added to 6-((5-fluoro-2-methylphenyl)amino)-7-(methylthio)quinoxaline-5,8-dione (177 mg, 537 μmol) and stirred at room temperature. At the same temperature, mCPBA (301 mg, 1.34 mmol) is added and stirred for 4.5 hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4, then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, DCM is added, and extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((5-fluoro-2-methylphenyl)amino)-7-(methylsulfonyl)quinoxaline-5,8-dione, compound 42).

[0837] Orange solid, 85.3 mg (44.0%)

[0838] 1 H NMR (400 MHz, DMSO-D6) δ 10.46(s, 1H), 9.11(d,J= 2.3 Hz, 1H), 9.03(d,J= 2.3 Hz, 1H), 7.32(t,J= 8.4 Hz, 2H), 7.05(dd,J= 8.7, 6.1 Hz, 1H), 3.40(s, 3H), 2.27(s, 3H).

[0839]

[0840] <Experimental Example 1> Elucidation of the NQO1 substrate effect of the compounds of the present invention and confirmation of the NQO1 activity enhancement effect (confirmation of chromium c reducing ability)

[0841] To analyze the efficacy of evaluation substances regarding NQO1 activity, a conventionally known method (Kang-Sik Seo, Jin-Hwan Kim, Ki-Nam Min, Jeong-A Moon et al. KL1333, a novel NAD + The experiment was performed by making some modifications to the study "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 a 1 mg / ml reagent 1 / 100; NADH was used dissolved in 0.01N NaOH at 20 mM; and cytochrome C was used dissolved in distilled water at 7.5 mM. ES936, an NQO1 inhibitor, was used for result correction, and 50 mM Tris-HCl containing 0.14% BSA was used as the reaction buffer. The reagents were prepared in advance, and 200 μl of reaction buffer was dispensed into 5 ml round tubes, ensuring that the amount dispensed did not touch the walls, corresponding to the number of drugs to be evaluated. NQO1, NADH, and cytochrome C were then added to the walls of the tubes containing the 200 μl of reaction buffer, ensuring they did not mix with each other. At this time, the final concentrations of each reagent added to 200 μl of reaction buffer were 10 ng NQO1, 0.4 mM NADH, and 75 nM cytochrome c; the evaluation substances were also added to final concentrations of 0.2, 1, and 5 μM, taking care not to mix them with the buffer. Since the reaction begins as soon as the reagents are mixed, vortex mixing was performed immediately before measurement, and 180 μl of each was added as quickly as possible to a 96-well plate. The efficacy of each evaluation substance on NQO1 enzyme activity was analyzed by measuring the absorbance at 550 nm. The results are shown in Table 1.

[0842] Cytochrome c reduction (nmole / min / mg) Compound Name 0.2 μM 1 μM 5 μM 1- -5382--77623--41214--13465--35046--32197--28448--63809871185604110131828461335711--158112--332713--426214--111415--893216--524817--643918--362419--674220--163221--1 57722--449823--41924--38625--905026--36927--928428--527329--1776030--114431--62932--726633--561434--331035--438136--527637--36138--793539--945940--287041--98542--982

Claims

1. Compounds represented by the following chemical formula 1, pharmaceutically acceptable salts, hydrates, solvates, prodrugs, tautomers, enantiomers, or diastereomers thereof: [Chemical Formula 1] In the above chemical formula 1, The above R1 is hydrogen, a substituted or unsubstituted alkyl, or a substituted or unsubstituted cycloalkyl, and R2 is a substituted or non-substituted aryl, or a substituted or non-substituted heteroaryl, and R3 is -S(O)R'1, -S(O)2R'1 or -SO3H, and R'1 is a C1 to C4 alkyl.

2. In Paragraph 1, The above R1 is a compound, pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer, wherein R1 is hydrogen, a substituted or unsubstituted C1 to C4 alkyl, or a substituted or unsubstituted C3 to C6 cycloalkyl.

3. In Paragraph 1, The above-mentioned substituted alkyl or substituted cycloalkyl is substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, nitro, amino, C1 to C4 alkyl, C1 to C14 haloalkyl, C1 to C4 alkoxy, C2 to C4 alkenyl, C6 to C10 aryl, 4 to 12 heterocycloalkyl, and 4 to 12 heteroaryl. At this time, the heterocycloalkyl or heteroaryl comprises one or more heteroatoms selected from the group consisting of N, O and S, a compound, a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer thereof.

4. In Paragraph 1, The above R2 is a compound, pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer, wherein R2 is a substituted or unsubstituted C6 to C10 aryl, or a substituted or unsubstituted 4 to 12 heteroaryl.

5. In Paragraph 4, A compound, pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer thereof, wherein the above-mentioned substituted C6 to C10 aryl or substituted 4-membered 12-membered heteroaryl is substituted with one or more substituents selected from the group consisting of substituted or unsubstituted C1 to C6 alkyl, substituted or unsubstituted C1 to C6 alkoxy, and halos.

6. In Paragraph 5, A compound, pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer thereof, wherein the C1 to C6 alkyl group of the above substitution is substituted with one or more halogens, and the C1 to C6 alkoxy group of the above substitution is substituted with one or more selected from the group consisting of halogens, cyanos, C1 to C4 alkyls, C2 to C4 alkenyls, C6 to C10 aryls, 4 to 12 heterocycloalkyls, and 4 to 12 heteroaryls, wherein the heterocycloalkyl or heteroaryl comprises one or more heteroatoms selected from the group consisting of N, O, and S.

7. In Paragraph 1, A compound, pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer thereof, wherein R'1 is CH3 or OH.

8. In Paragraph 1, The above compound is a compound, its pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer, selected from the group consisting of the following compounds 1 to 42: .

9. A NAD comprising, as an active ingredient, the compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer thereof. + A pharmaceutical composition for the prevention or treatment of diseases caused by a decrease in or mitochondrial dysfunction.

10. In Paragraph 9, The above NAD + A pharmaceutical composition wherein the disease caused by a decrease in or mitochondrial dysfunction is one or more selected from the group consisting of metabolic diseases, primary and secondary mitochondrial diseases, muscle diseases, neurodegenerative diseases, inflammatory diseases, fibrotic diseases, autoimmune diseases, cancer, and cognitive impairment.

11. In Paragraph 10, A pharmaceutical composition wherein the above metabolic disease is one or more selected from the group consisting of obesity, diabetes, and metabolic disorder-related fatty liver disease.

12. A NAD comprising, as an active ingredient, the compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer thereof. + A food composition for the prevention or improvement of diseases caused by a decrease in or mitochondrial dysfunction.

13. A composition for enhancing the activity of NQO1, comprising as an active ingredient a compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer thereof.

14. A method for preparing a compound represented by Chemical Formula 1, comprising the following steps: (S1) A step of reacting the compound of Chemical Formula 2 below with HNO3 to obtain the compound of Chemical Formula 3 below; (S2) A step of reducing the compound of Formula 3 above to obtain the compound of Formula 4; (S3) A step of reacting the compound of Formula 4 with Glyoxal sodium bisulfite to obtain the compound of Formula 5; (S4) A step of dissolving the compound of Formula 5 in acetonitrile and then reacting it with an oxidizing agent to obtain quinoxalin-5,8-dione of Formula 6; and (S5) A step of obtaining a compound of the following formula 7 by performing a halogenation reaction of the quinazoline-5,8-dione of formula 6 above; (S6) A step of obtaining a compound of formula 9 by nucleophilically reacting the compound of formula 7 and the compound of formula 8; (S7) A step of synthesizing a compound of the following formula 1 from a compound of formula 9, wherein the step is performed by a method comprising the following step (a) or (b), (a) a step of obtaining a compound of formula 10 by reacting NaZ1 with the compound of formula 9; and a step of obtaining formula 1 by oxidizing the compound of formula 10 using an oxidizing agent, (b) a step of obtaining a compound of Formula 11 by reacting NaR3 with the compound of Formula 9 above; and a step of obtaining Formula 1 by oxidizing the compound of Formula 11 using an oxidizing agent, [Chemical Formula 2] [Chemical Formula 3] [Chemical Formula 4] [Chemical Formula 5] [Chemical Formula 6] [Chemical Formula 7] [Chemical Formula 8] NHR1R2 [Chemical Formula 9] [Chemical Formula 10] [Chemical Formula 11] [Chemical Formula 1] In the above chemical formulas, R1 is hydrogen, a substituted or unsubstituted alkyl, or a substituted or unsubstituted cycloalkyl, and R2 is a substituted or non-substituted aryl, or a substituted or non-substituted heteroaryl, and R3 is -S(O)R'1, -S(O)2R'1 or -SO3H, and R'1 is a C1 to C4 alkyl, and R a and R b Each is independently an H or a substituted or unsubstituted C1 to C10 alkyl, and X1 and X2 are identical or different halogen elements, and Z1 is -SR c , or -SOH and R c It is a C1 to C4 alkyl.

15. A NAD comprising the step of administering to an individual a compound represented by Formula 1 according to claim 1, a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer thereof. + Method for preventing, improving, or treating diseases caused by a decrease in or mitochondrial dysfunction. 16.NAD + Use of a compound represented by Formula 1 according to claim 1, or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, tautomers, enantiomers, or diastereomers, for the prevention, improvement, or treatment of diseases caused by a decrease in or mitochondrial dysfunction. 17.NAD + Use of a compound represented by Formula 1 according to Claim 1, and its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, tautomers, enantiomers, or diastereomers, for preparing a pharmaceutical composition for the prevention, improvement, or treatment of diseases caused by a decrease in or mitochondrial dysfunction.

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