1,4-naphthoquinone derivatives and preparation methods thereof

Abstract

The present invention relates to novel 1,4-naphthoquinone derivatives, preparation methods thereof, and uses thereof. When the compounds of the present invention are used, it is possible to achieve enhanced NQO1 activity, increased NAD+, increased ATP, and mitochondrial function improvement, thus achieving the effect of preventing or treating related diseases.

Description

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

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

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

[0003] NAD(P)H:quinone oxidoreductase 1 (NQO1) is a protein that maintains cellular homeostasis by removing external substances or oxidative stress. It is expressed in all tissues of the human body and exists at relatively low levels under normal conditions. However, it is known that the activity and expression of NQO1 are significantly increased in various diseases such as obesity, steatohepatitis related to metabolic disorders, muscle diseases, degenerative neurodegenerative diseases, cancer, and diseases caused by mitochondrial dysfunction. Meanwhile, NQO1 converts NADH to NAD through its enzymatic activity. + can be converted to and increased NAD + can induce effects such as improvement of cellular energy metabolism and mitochondrial function through sirtuins and AMP-activated protein kinase (AMPK). As a specific example, substrate compounds of NQO1, including β-Lapachone, can induce effects such as improvement of cellular energy metabolism and mitochondrial function through sirtuins and AMP-activated protein kinase (AMPK). + It shows therapeutic effects on various diseases such as metabolic diseases, neurodegenerative diseases, age-related diseases, mitochondrial diseases, inflammatory diseases and fibrotic diseases such as obesity, muscular dystrophy, Parkinson's disease, Huntington's disease, cancer, kidney disease, hypertension, hearing loss, heart disease, pulmonary fibrosis, MELAS syndrome and primary sclerosing cholangitis through increase. By utilizing the phenomenon of increased activity and expression of NQO1 in disease states, intracellular NAD + Although some attempts have been reported to treat diseases through effective increases in , their therapeutic effects are limited, and there is a growing need for new, more effective and safer substrate compounds.

[0004] Mitochondria are double-membrane organelles found in most eukaryotic cells, including animals, plants, and fungi. They generate cellular energy (adenosine triphosphate, ATP) through aerobic respiration. Mitochondria also play a crucial role in maintaining cellular homeostasis, including cell signaling, cell differentiation, apoptosis, the cell cycle, and growth control. Furthermore, mitochondrial dysfunction is well-known to be closely associated with various diseases, including metabolic diseases, muscle diseases, cancer, neurodegenerative diseases, and mitochondrial diseases. Among these, over 300 mitochondrial diseases are caused by mutations in nuclear DNA (nDNA) or mitochondrial DNA (mtDNA), which directly disrupt the expression and function of mitochondrial complex proteins. ATP synthesis disorders are the most common cause. Except for Leber hereditary optic neuropathy (LHON), all mitochondrial diseases have no approved treatments yet, and patients receive symptomatic treatment with antioxidants and vitamin cocktails. LHON is caused by a deficiency of mitochondrial complex I. Idebenone, a known NQO1 substrate, is approved in Europe under the brand name Raxone for treatment. Idebenone is known to treat the disease by inducing ATP synthesis by bypassing the dysfunction of mitochondrial complex I by transferring electrons obtained through reduction by NQO1 to mitochondrial complex III. However, existing compounds still have limitations in terms of bioavailability, target selectivity, and safety, and thus the development of more effective and improved novel drugs is necessary. Therefore, based on the characteristics of increased NQO1 activity and expression associated with various diseases mentioned above, intracellular NAD + There has been a need to develop novel drugs that optimize the ability of electron transport to the mitochondrial electron transport chain.

[0005] [Prior Art Literature]

[0006] [Patent Document]

[0007] (Patent Document 1) KR 10-2008-0039361 A

[0008] To meet the above-mentioned needs, the present inventors have developed NAD that acts as a substrate for NQO1. + We have conducted extensive research to develop novel compounds capable of preventing or treating diseases associated with decreased or impaired mitochondrial function and their associated symptoms. As a result, we have synthesized novel compounds exhibiting the aforementioned effects, thereby completing the present invention.

[0009] Accordingly, the object of the present invention is to provide a novel compound capable of acting as a substrate of NQO1, a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer or diastereomer thereof.

[0010] Another object of the present invention is to provide a pharmaceutical composition, cosmetic composition or food composition comprising the novel compound described above, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer or diastereomer thereof.

[0011] Another object of the present invention is to provide a method for producing the novel compound described above.

[0012]

[0013] According to one aspect of the present invention, the present invention provides a compound represented by the following chemical formula 1, a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer or diastereomer thereof:

[0014] [Chemical Formula 1]

[0015]

[0016] In the above formula,

[0017] The above R1 and R2 are each independently hydrogen, a halogen element, hydroxy, a substituted or unsubstituted alkoxy, a substituted or unsubstituted alkyl, or a substituted or unsubstituted cycloalkyl,

[0018] The above R3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl,

[0019] The above R4 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -COR'1, -CO(O)R'1, -COCH2-R' 1, -COCH2CH2-R'1 or -CO(CH2) n NR'1R'2 (wherein n is an integer from 1 to 3, and -(CH2) n - part may be substituted with a substituted or unsubstituted alkyl group),

[0020] The above R'1 and R'2 are each independently hydrogen, hydroxy, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or the above R'1 and R'2 together may form heterocycloalkyl,

[0021] When the above R4 is a substituted or unsubstituted aryl, the above R5 is a halogen element, hydroxy, a substituted or unsubstituted alkyl, a substituted or unsubstituted thioalkyl, a substituted or unsubstituted cycloalkyl, -NO2, -CN, or -NR'3R'4,

[0022] wherein R4 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroaryl, -COR'1, -CO(O)R'1, -COCH2-R'1, -COCH2CH2-R'1 or -CO(CH2) n NR'1R'2 (wherein n is an integer from 1 to 3, and -(CH2) n- If the portion may be substituted with a substituted or unsubstituted alkyl group), the R5 is hydrogen, a halogen element, hydroxy, a substituted or unsubstituted alkyl, a substituted or unsubstituted thioalkyl, a substituted or unsubstituted cycloalkyl, -NO2, -CN, or -NR'3R'4,

[0023] The above R'3 and R'4 are each independently hydrogen, hydroxy, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl,

[0024] When the above R4 is an aryl substituted with -NO2, R5 is not selected as Cl,

[0025] When the above R4 is -COR'1, R5 is selected as hydrogen.

[0026]

[0027] The features and advantages of the present invention are summarized as follows:

[0028] (a) The present invention provides novel compounds for preventing, improving or treating related symptoms and diseases due to enhancement of NQO1 activity.

[0029] (b) When using a composition containing the compound of the present invention as an active ingredient, intracellular NAD + It can achieve the effect of preventing, improving or treating diseases accompanied by a decrease or mitochondrial dysfunction.

[0030]

[0031] The present invention is described in more detail below.

[0032]

[0033] When the “substituted or unsubstituted” functional group in the present specification is substituted, the functional group may be substituted with any one or more selected from the group consisting of a halogen element, hydroxy, straight-chain or branched C1-C10 alkyl, straight-chain or branched C2-C10 alkenyl, straight-chain or branched C2-C10 alkynyl, straight-chain or branched C1-C10 alkoxy, straight-chain or branched C1-C10 alkoxycarbonyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C4-C10 aryl, and C2-C10 heteroaryl.

[0034] In another specific embodiment of the present invention, the “substituted” functional group in the present specification may be substituted with at least one selected from the group consisting of a halogen atom, hydroxy, straight or branched C1-C6 alkyl, straight or branched C1-C6 alkoxy, C6-C10 aryl, and C6-C10 heteroaryl.

[0035] Additionally, the above-described “substituting” functional group may be substituted as many times as possible within the range of, for example, 1 to 4.

[0036] The term "pharmaceutically acceptable salt" as used herein means a formulation of a compound that does not cause serious irritation to an organism to which the compound is administered and does not impair the biological activity and physical properties of the compound.

[0037] The terms “hydrate”, “solvate”, “prodrug”, “tautomer”, “enantiomer” or “diastereoisomer” in this specification also have the same meanings as above.

[0038] The above "pharmaceutically acceptable salt" includes acid addition salts formed by acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, etc., organic carboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid, etc., sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. For example, pharmaceutically acceptable carboxylic acid salts include metal salts or alkaline earth metal salts formed by lithium, sodium, potassium, calcium, magnesium, etc.; amino acid salts such as lysine, arginine, guanidine, etc.; organic salts such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline, and triethylamine, etc. The compound of formula 1 according to the present invention may also be converted into its salt by a conventional method.

[0039] The term "hydrate" means a compound of the present invention or a salt thereof containing a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[0040] The term "solvate" refers to a compound of the present invention or a salt thereof that contains a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents include those that are volatile, non-toxic, and / or suitable for human administration.

[0041] The term "prodrug" refers to a substance that is transformed into the parent drug in vivo. Prodrugs are often used because, in some cases, they are easier to administer than the parent drug. For example, they may be bioactive when administered orally, whereas the parent drug may not. Prodrugs may also have improved solubility in pharmaceutical compositions compared to the parent drug. For example, a prodrug might be a compound administered as an ester ("prodrug"), which facilitates membrane passage, although water solubility would impede mobility. Once in cells where water solubility is beneficial, the prodrug is metabolized to the active carboxylic acid, which facilitates membrane passage.

[0042] The term "tautomer" refers to a type of structural isomer that has the same chemical or molecular formula but different ways in which its constituents are connected, such as the keto-enol structure, which continuously changes its structure by shuttling between the two isomers.

[0043] The term "enantiomers or pharmaceutically acceptable diastereomers" refers to isomers that have the same chemical formula or molecular formula but are formed due to different spatial arrangements of atoms within the molecule. The term "enantiomer" refers to an isomer that is not superimposable with its mirror image, like the relationship between right and left hands, and further, "diastereomer" refers to a stereoisomer that is not a mirror image relationship, such as trans or cis. All of these isomers and mixtures thereof are also included in the scope of the present invention.

[0044] The term "alkyl" refers to an aliphatic hydrocarbon group. In the present invention, alkyl is used as a concept including both "saturated alkyl" meaning that it does not contain any alkene or alkyne moiety, and "unsaturated alkyl" meaning that it contains at least one alkene or alkyne moiety, and specifically, it may be a "saturated alkyl" meaning that it does not contain any alkene or alkyne moiety. The alkyl may include a branched, straight-chain, or cyclic type, and also includes structural isomers, so for example, in the case of C3 alkyl, it may mean propyl, isopropyl, or cyclopropyl.

[0045] The term "heteroalkyl" refers to an alkyl group that contains at least one heteroatom (e.g., oxygen, nitrogen, sulfur, etc.) in addition to carbon and hydrogen. Like alkyl, heteroalkyl groups can be branched, straight-chain, or cyclic, and include structural isomers.

[0046] The term "alkene" refers to a group of at least two carbon atoms with at least one carbon-carbon double bond, and "alkyne" refers to a group of at least two carbon atoms with at least one carbon-carbon triple bond.

[0047] The term "alkoxy" refers to a substituent having a structure in which an alkyl group is connected through an oxygen atom. Specific examples include methoxy (-OCH3) and ethoxy (-OCH2CH3).

[0048] The term “cycloalkyl” refers to a saturated hydrocarbon group in which three or more carbon atoms form a ring structure.

[0049] The term "heterocycloalkyl" refers to a cycloalkyl in which a ring carbon is replaced by oxygen, nitrogen, sulfur, etc.

[0050] The term "aryl" refers to an aromatic substituent having at least one ring with a shared pi electron system. The term includes monocyclic or fused ring polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) groups. When substituted, the substituent may be attached at the ortho (o), meta (m), or para (p) positions, as appropriate.

[0051] The term "heteroaryl" refers to an aromatic group in which at least one of the ring carbon atoms constituting the aryl is replaced with oxygen, nitrogen, sulfur, etc.

[0052] Examples of the above aryl or heteroaryl include, but are not limited to, phenyl, furan, pyran, pyridyl, pyrimidyl, triazyl, etc.

[0053] The term "thioalkyl" refers to a substituent having a structure in which an alkyl group is connected via a sulfur atom. Specific examples include methylthio (-SCH3), ethylthio (-SCH2CH3), etc. The alkyl included in thioalkyl may have a straight-chain, branched-chain, or cyclic structure, and is not particularly limited.

[0054] The term "halogen" refers to elements in group 17 of the periodic table, specifically fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0055] The term "aryloxy" refers to a group in which one of the carbons forming the aromatic substituent is bonded to oxygen, for example, when oxygen is bonded to a phenyl group, it can be expressed as -O-C6H5, -C6H4-O-.

[0056] Other terms may be interpreted as having the meaning commonly understood in the field to which the present invention belongs.

[0057] In one embodiment of the present invention, R1 and R2 of formula 1 may each independently be hydrogen, a halogen element, hydroxy, a substituted or unsubstituted C1 to C10 alkoxy, a substituted or unsubstituted C1 to C10 alkyl, or a substituted or unsubstituted C3 to C8 cycloalkyl.

[0058] In another embodiment of the present invention, R1 and R2 of formula 1 can each independently be hydrogen, a substituted or unsubstituted C1 to C10 alkyl, or a substituted or unsubstituted C3 to C8 cycloalkyl.

[0059] In another embodiment of the present invention, R1 and R2 of formula 1 can each independently be hydrogen, a substituted or unsubstituted C1 to C6 alkyl, or a substituted or unsubstituted C5 to C8 cycloalkyl.

[0060] In another embodiment of the present invention, R1 and R2 of formula 1 may each independently be hydrogen, or substituted or unsubstituted C1 to C4 alkyl.

[0061] For example, R1 and R2 in the formula 1 can each independently be hydrogen or an unsubstituted C1 to C4 alkyl, and the unsubstituted C1 to C4 alkyl can have a straight or branched chain structure. The unsubstituted C1 to C4 alkyl as described above can be specifically, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl.

[0062] In another specific embodiment, R1 and R2 of formula 1 can each independently be hydrogen or methyl.

[0063] In embodiments of the present invention, R1 and R2 of chemical formula 1 may be bonded as substituents on carbon or nitrogen constituting the pyrazine ring, and in one specific example, may be bonded by replacing hydrogen bonded to carbon constituting the pyrazine ring.

[0064] In another embodiment of the present invention, R3 of formula 1 may be hydrogen, substituted or unsubstituted C1 to C6 alkyl, or substituted or unsubstituted C3 to C8 cycloalkyl.

[0065] More specifically, for example, R3 in chemical formula 1 can be hydrogen or unsubstituted C1 to C4 alkyl, and the unsubstituted C1 to C4 alkyl can have a straight or branched chain structure. The unsubstituted C1 to C4 alkyl as described above can be specifically, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl.

[0066] In another embodiment, R3 of formula 1 can be hydrogen or methyl.

[0067] In one embodiment of the present invention, R4 of chemical formula 1 is substituted or unsubstituted phenyl, -COR'1, -CO(O)R'1, -COCH2-R'1, -COCH2CH2-R'1 or -CO(CH2) n NR'1R'2 (wherein n is an integer from 1 to 3, and -(CH2) n - part may be substituted with a substituted or unsubstituted C1 to C4 alkyl group), and R'1 and R'2 are each independently hydrogen, hydroxy, substituted or unsubstituted C1 to C6 alkoxy, substituted or unsubstituted C1 to C6 alkyl, substituted or unsubstituted C3 to C8 cycloalkyl, substituted or unsubstituted C4 to C10 aryl, or substituted or unsubstituted C4 to C10 heteroaryl, or R'1 and R'2 together may form a C2 to C8 heterocycloalkyl. -CO(CH2) which may be selected as R4 as described above n NR'1R'2 (wherein n is an integer from 1 to 3, and -(CH2) n- The part may be substituted with a substituted or unsubstituted C1 to C4 alkyl group) may be, but is not limited to, specifically, -COCH2NR'1R'2, -COCH2CH2NR'1R'2, -COCH(CH3)NR'1R'2, or -COCH(CH2CH3)NR'1R'2.

[0068] The substituted C1 to C6 alkoxy, substituted C1 to C6 alkyl, substituted C3 to C8 cycloalkyl, substituted C4 to C10 aryl, or substituted C4 to C10 heteroaryl that may be selected as the above R'1 and R'2 may be substituted with any one or more selected from the group consisting of a halogen element, hydroxy, straight-chain or branched C1-C10 alkyl, straight-chain or branched C2-C10 alkenyl, straight-chain or branched C2-C10 alkynyl, straight-chain or branched C1-C10 alkoxy, straight-chain or branched C1-C10 alkoxycarbonyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C4-C10 aryl, and C2-C10 heteroaryl, as defined above.

[0069] The 'alkyl' and 'substituted or unsubstituted C1 to C6 alkyl' included in the 'substituted or unsubstituted C1 to C6 alkoxy' that can be selected as the above R'1 or R'2 include both straight-chain and branched-chain structures.

[0070] The substituted or unsubstituted C3 to C8 cycloalkyl that may be selected as R'1 or R'2 may be specifically, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0071] The substituted or unsubstituted C4 to C10 aryl that may be selected as R'1 or R'2 may be, specifically, for example, a substituted or unsubstituted C5 to C6 aryl. The substituted C5 to C6 aryl may be substituted with one or two or more substituents, which are the same or different, selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, and halogen elements.

[0072] The substituted or unsubstituted C4 to C10 heteroaryl that may be selected as R'1 or R'2 may be, specifically, for example, a substituted or unsubstituted C5 to C6 heteroaryl. The substituted or unsubstituted C5 to C6 heteroaryl may be, specifically, for example, a heteroaryl in which a ring carbon is substituted with oxygen, nitrogen, or sulfur, and may be a heteroaryl in which not only one ring carbon is substituted but also two or more ring carbon atoms are substituted with heteroatoms. More specifically, for example, the heteroaryl may be selected from the group consisting of furanyl, thiophenyl, pyridinyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl, or isothiazolyl.

[0073] More specifically, for example, the heteroaryl may be selected from the group consisting of:

[0074] , , , , , , , , , , , , , or .

[0075] When R'1 and R'2 together constitute a C2 to C8 heterocycloalkyl, the heterocycloalkyl may be, for example, a 5- or 6-membered ring heterocycloalkyl. The heterocycloalkyl may further include, for example, an additional heteroatom in addition to the nitrogen to which R'1 and R'2 are bonded within the 5- or 6-membered ring. The heteroatom may be oxygen, nitrogen, or sulfur, and may be, for example, oxygen.

[0076] The R'1 or R'2 may be specifically selected from, for example, methyl, ethyl, isopropyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-ethylpropyl, neopentyl, fluorophenyl, chlorophenyl, thiophenyl, morpholino, morpholinomethyl, morpholinoethyl, dimethylamino, 1-piperidinyl, 2-furanyl, 2-thiophenyl, 5-isoxazolyl, 3-pyridinyl, fluorophenyl, methoxyphenyl, dimethoxyphenyl, trifluoromethylphenyl, or 1-bromoethyl.

[0077] In one embodiment of the present invention, the above-described substituted phenyl that can be selected as R4 of Chemical Formula 1 may be substituted with any one, or two or more substituents that are the same or different, selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, amido, and halogen elements. The halogen element may be fluorine, chlorine, bromine, or iodine, and more specifically, for example, fluorine or chlorine. The substituted or unsubstituted alkyl that can be bonded to the phenyl may be specifically, for example, C1 to C4 alkyl, and may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl, and more specifically, may be, for example, methyl or ethyl.

[0078] In one embodiment of the present invention, the above-described substituted alkyl that may be substituted for the substituted phenyl selected as R4 of Chemical Formula 1 may be substituted with one to three halogen elements. The halogen elements may be fluorine, chlorine, bromine, or iodine.

[0079] In one embodiment of the present invention, the above-described substituted phenyl that can be selected as R4 of Chemical Formula 1 may be substituted with one or more substituents selected from the group consisting of unsubstituted C1 to C4 alkyl, unsubstituted C1 to C4 alkoxy, C1 to C4 alkyl substituted with 1 to 3 halogen elements, acetamido, and halogen elements. The unsubstituted C1 to C4 alkyl may be specifically, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl. The above unsubstituted C1 to C4 alkoxy includes a C1 to C4 alkyl group bonded to oxygen, and specifically, for example, may be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl, and more specifically, may be methyl or ethyl, and thus, the alkoxy may be methoxy or ethoxy, but is not necessarily limited thereto.

[0080] In one embodiment of the present invention, the halogen element in the 'C1 to C4 alkyl substituted with 1 to 3 halogen elements' that may be substituted for the phenyl of the substitution that may be selected as R4 of the chemical formula 1 may be fluorine.

[0081] When R4 according to one embodiment of the present invention is substituted or unsubstituted aryl, R5 is selected from a halogen element, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted thioalkyl, substituted or unsubstituted cycloalkyl, -NO2, -CN, or -NR'3R'4, and R4 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroaryl, -COR'1, -CO(O)R'1, -COCH2-R'1, -COCH2CH2-R'1, or -CO(CH2) n NR'1R'2 (wherein n is an integer from 1 to 3, and -(CH2)n - When the part may be substituted with a substituted or unsubstituted alkyl group), the R5 may be selected from hydrogen, a halogen element, hydroxy, a substituted or unsubstituted alkyl, a substituted or unsubstituted thioalkyl, a substituted or unsubstituted cycloalkyl, -NO2, -CN, or -NR'3R'4, and the halogen element that may be selected as R5 may be specifically, for example, fluorine, chlorine, bromine, or iodine, and more specifically, fluorine, chlorine, or bromine, provided that when the R4 is -NO2-substituted aryl, R5 is not selected as Cl. In addition, the substituted or unsubstituted alkyl that may be selected as R5 may be selected from C1 to C4 alkyl, and the alkyl in the substituted or unsubstituted thioalkyl may be C1 to C4 alkyl, and more specifically, the thioalkyl may be methylthio or ethylthio. The above R'3 and R'4 are each independently hydrogen, hydroxy, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and when the above R4 is -COR'1, R5 is selected as hydrogen.

[0082] In one embodiment of the present invention, the compound of formula 1 may be at least one compound selected from the group consisting of compounds 1 to 121, but compounds 1 to 121 correspond to some embodiments of compounds that can be assumed from the detailed description of the invention described above and are not necessarily limited thereto. The embodiments of compounds 1 to 121 demonstrate that the compound of formula 1 of the present invention exhibits certain usefulness even when including various substituent changes:

[0083]

[0084]

[0085]

[0086]

[0087]

[0088]

[0089] According to another aspect of the present invention, the present invention provides a composition for enhancing NQO1 activity comprising the compound described above.

[0090] The composition of the present invention specifically comprises NAD(P)H:quinone oxidoreductase (NQO1) as a redox enzyme, which is an in vivo NAD + / It can increase the AMP / ATP ratio by inducing an increase in the ratio of NADH. This increase in AMP in the cell activates AMPK, which acts as an energy gauge, and promotes fat metabolism by activating the expression of PGC1a, which activates energy metabolism in mitochondria, thereby replenishing the insufficient ATP energy. In addition, the composition reduced by NQO1 plays a role in inducing ATP synthesis by transferring electrons to mitochondrial complex III. Meanwhile, the NAD increased by the composition + It is used as a cofactor for enzymes related to glucose and fat metabolism in the body, promoting metabolism and NAD + cADPR, which is generated by the breakdown of Ca, is released into the endoplasmic reticulum (ER). 2+ It can have an in vivo exercise-mimetic effect by synergistically activating mitochondrial metabolism by releasing mitochondrial peptides. Through this, it can exhibit preventive or therapeutic activities for various metabolic diseases and diseases related to mitochondrial activity.

[0091] In one embodiment of the present invention, the composition of the present invention may be provided in the form of a pharmaceutical composition, a cosmetic composition, or a food composition.

[0092] According to another aspect of the present invention, the present invention provides a pharmaceutical composition for preventing or treating a disease related to NQO1, comprising the compound described above.

[0093] In one embodiment of the present invention, the NQO1-related disease of the present invention may be any one selected from the group consisting of metabolic diseases such as obesity, diabetes, and metabolic disorder-related steatohepatitis, primary and secondary mitochondrial diseases, muscle diseases, degenerative neurodegenerative diseases, inflammatory diseases, fibrotic diseases, autoimmune diseases, and cancer, but is not limited thereto.

[0094] When the present invention is provided in the form of a pharmaceutical composition, the composition of the present invention comprises a pharmaceutically acceptable carrier in addition to the active ingredient. The pharmaceutically acceptable carrier contained in the pharmaceutical composition of the present invention is one commonly used in formulation, and includes, but is not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. In addition to the above components, the pharmaceutical composition of the present invention may further comprise a lubricant, a wetting agent, a sweetener, a flavoring agent, an emulsifier, a suspending agent, a preservative, and the like. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington's Pharmaceutical Sciences (19th ed., 1995).

[0095] The appropriate dosage of the pharmaceutical composition of the present invention may vary depending on factors such as the formulation method, administration method, patient age, body weight, sex, pathological condition, food, administration time, administration route, excretion rate, and response sensitivity. Meanwhile, the dosage of the pharmaceutical composition of the present invention is preferably 0.001-1000 mg / kg (body weight) per day.

[0096] The pharmaceutical composition of the present invention can be administered orally or parenterally. When administered parenterally, it can be administered by topical application to the skin, intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal administration, etc. Considering that the pharmaceutical composition of the present invention is applied to enhance NQO1 activity, oral administration or parenteral administration in the form of an injection is preferable.

[0097] The pharmaceutical composition of the present invention can be manufactured in a unit dose form or can be manufactured by placing it in a multi-dose container by formulating it using a pharmaceutically acceptable carrier and / or excipient according to a method that can be easily performed by a person having ordinary skill in the art to which the present invention pertains.

[0098] Conventional dosage forms include, for example, oral (tablets, capsules, powders), buccal, sublingual, rectal, vaginal, intranasal, topical or parenteral (including intravenous, intracavernosal, intramuscular, subcutaneous and intraductal) administration dosage forms. For example, the compounds according to the present invention may be administered orally, buccally or sublingually in the form of tablets containing starch or lactose, or in the form of capsules alone or with excipients, or in the form of elixirs or suspensions containing chemicals for flavoring or coloring. Liquid preparations are prepared with pharmaceutically acceptable excipients such as suspending agents (e.g., methylcellulose, semi-synthetic glycerides such as witepsol, or glyceride mixtures such as mixtures of apricot kernel oil and PEG-6 esters or mixtures of PEG-8 and caprylic / capric glycerides). In addition, when injected parenterally, for example, intravenously, intracavernosally, intramuscularly, subcutaneously, and intraductally, it is most preferable to use it in the form of a sterile aqueous solution, and in this case, the solution may contain other substances (for example, salt or monosaccharides such as mannitol or glucose) to have isotonicity with blood.

[0099] When the pharmaceutical composition of the present invention is administered orally, solid preparations for oral administration include tablets, pills, powders, granules, capsules, troches, etc., and these solid preparations are prepared by mixing one or more compounds of the present invention with at least one excipient, such as starch, calcium carbonate, sucrose, lactose, or gelatin. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, oral solutions, emulsions, or syrups, and in addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included.

[0100] Formulations for oral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solutions and suspensions can include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases include witepsol, macrogol, Tween 61, cocoa butter, laurin, glycerol, and gelatin.

[0101] The compound of the present invention can be used in the form of a pharmaceutically acceptable salt, and as a salt, an acid addition salt formed by a pharmaceutically acceptable free acid can be used. The acid addition salt is obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, non-toxic organic acids such as aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates and alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids, organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid and fumaric acid. These pharmaceutically non-toxic salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphate chlorides, bromides, iodides, fluorides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caprates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyn-1,4-dioate, hexane-1,6-dioate, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, Including, but not limited to, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate or mandelate.

[0102] The acid addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the compound of the present invention in an organic solvent, for example, methanol, ethanol, acetone, methylene chloride, acetonitrile, etc., adding an organic acid or inorganic acid, filtering and drying the resulting precipitate, or by distilling the solvent and an excess of acid under reduced pressure and then drying or crystallizing the same in an organic solvent.

[0103] Additionally, pharmaceutically acceptable metal salts can be prepared using bases. Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering out the undissolved compound salt, and evaporating and drying the filtrate. Among the metal salts, sodium, potassium, or calcium salts are pharmaceutically suitable. Furthermore, the corresponding silver salts are obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

[0104] The composition of the present invention can also be manufactured in the form of a cosmetic composition. The cosmetic composition of the present invention can be manufactured in any formulation commonly manufactured in the art, and for example, can be formulated as a solution, suspension, emulsion, paste, gel, cream, lotion, powder, soap, surfactant-containing cleansing, oil, powder foundation, emulsion foundation, wax foundation, and spray, etc., but is not limited thereto. More specifically, it can be manufactured in the form of a flexible toner, a nourishing toner, a lotion, a nourishing cream, a massage cream, an essence, an eye cream, a cleansing cream, a cleansing foam, a cleansing water, a pack, a spray, or a powder.

[0105] When the formulation of the present invention is a paste, cream, lotion, or gel, animal oil, vegetable oil, wax, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silica, talc, or zinc oxide may be used as a carrier component.

[0106] When the formulation of the present invention is a powder or spray, lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used as a carrier component, and particularly in the case of a spray, a propellant such as chlorofluorohydrocarbon, propane / butane or dimethyl ether may be additionally included.

[0107] When the formulation of the present invention is a solution or emulsion, a solvent, solubilizer or emulsifier is used as a carrier component, and examples thereof include water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylglycol oil, glycerol aliphatic ester, polyethylene glycol or fatty acid ester of sorbitan.

[0108] When the formulation of the present invention is a suspension, a liquid diluent such as water, ethanol or propylene glycol, a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar or tragacanth may be used as a carrier component.

[0109] When the formulation of the present invention is a surfactant-containing cleansing agent, aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyl taurate, sarcosinate, fatty acid amide ether sulfate, alkylamidobetaine, fatty alcohol, fatty acid glyceride, fatty acid diethanolamide, vegetable oil, lanolin derivative, or ethoxylated glycerol fatty acid ester may be used as a carrier component.

[0110] The components included in the cosmetic composition of the present invention include, in addition to the active ingredient and the carrier component, components commonly used in cosmetic compositions, and may include conventional excipients such as antioxidants, stabilizers, solubilizers, vitamins, pigments, and fragrances. The cosmetic composition of the present invention may be prepared in a form with enhanced percutaneous permeability, depending on the purpose, and can realize percutaneous permeation of the active ingredient through topical application on the skin, thereby achieving the desired effect.

[0111] The cosmetic composition of the present invention may be more suitable for achieving the NQO1 activation effect on a local area. For example, NAD + It can achieve the effect of preventing or improving symptoms or diseases caused by decreased or impaired mitochondrial function.

[0112] The composition of the present invention can be manufactured in the form of a food composition. The food composition of the present invention includes ingredients commonly added during food manufacturing, such as proteins, carbohydrates, fats, nutrients, and seasonings. For example, when manufactured as a drink, flavoring agents or natural carbohydrates may be included as additional ingredients in addition to the active ingredient. For example, natural carbohydrates include monosaccharides (e.g., glucose, fructose, etc.); disaccharides (e.g., maltose, sucrose, etc.); oligosaccharides; polysaccharides (e.g., dextrin, cyclodextrin, etc.); and sugar alcohols (e.g., xylitol, sorbitol, erythritol, etc.). Natural flavoring agents (e.g., thaumatin, stevia extract, etc.) and synthetic flavoring agents (e.g., saccharin, aspartame, etc.) can be used.

[0113] The food composition of the present invention comprises NAD + It can achieve the effect of preventing or improving symptoms or diseases caused by decreased or impaired mitochondrial function.

[0114] According to another aspect of the present invention, the present invention provides a method for preparing compounds according to one embodiment of the present invention, comprising the following steps:

[0115] (S1) A step of reacting a compound of chemical formula 2 with an aqueous nitric acid solution to obtain a compound of chemical formula 3;

[0116] (S2) A step of reducing the compound of the above chemical formula 3 to obtain a compound of the chemical formula 4;

[0117] (S3) A step of reacting the compound of the above chemical formula 4 with glyoxal sodium bisulfite or a substituted or unsubstituted C1 to C10 alkane dione or a substituted or unsubstituted C1 to C10 oxalate to obtain a compound of the chemical formula 5;

[0118] (S4) A step of synthesizing a compound of the following formula 1 from a compound of the above formula 5, wherein the step is performed by a method including the following steps (a-1) to (a-3), (b-1) to (b-4), (c-1) to (c-3), (d-1) to (d-2) and (e-1) to (e-3).

[0119] (a-1) A step of reacting the compound of chemical formula 5 with an oxidizing agent to obtain a compound of chemical formula 6;

[0120] (a-2) A step of reacting the compound of chemical formula 6 with sodium azide to obtain a compound of chemical formula 7;

[0121] (a-3) A step of obtaining a compound of chemical formula 1 by subjecting the compound of chemical formula 7 and the compound of chemical formula 8 to a nucleophilic reaction;

[0122] (b-1) A step of reacting the compound of the above chemical formula 5 with an aqueous nitric acid solution to obtain a compound of the chemical formula 9;

[0123] (b-2) A step of reducing the compound of chemical formula 9 to obtain a compound of chemical formula 10;

[0124] (b-3) A step of obtaining a compound of chemical formula 11 by subjecting the compound of chemical formula 10 and the compound of chemical formula 8 to a nucleophilic reaction;

[0125] (b-4) A step of reacting the compound of the above chemical formula 11 with an oxidizing agent to obtain a compound of the chemical formula 1;

[0126] (c-1) A step of obtaining a compound of chemical formula 13 by subjecting the compound of chemical formula 10 and the compound of chemical formula 12 to a nucleophilic reaction;

[0127] (c-2) A step of obtaining a compound of chemical formula 15 by subjecting the compound of chemical formula 13 to a nucleophilic reaction with a compound of chemical formula 14;

[0128] (c-3) A step of reacting the compound of the above chemical formula 15 with an oxidizing agent to obtain a compound of the chemical formula 1;

[0129] (d-1) A step of reacting the compound of the above chemical formula 13 with an oxidizing agent to obtain a compound of the chemical formula 16;

[0130] (d-2) A step of obtaining a compound of chemical formula 1 by subjecting the compound of chemical formula 16 and the compound of chemical formula 14 to a nucleophilic reaction;

[0131] (e-1) A step of performing a halogenation reaction on the compound of the above chemical formula 6 to obtain a compound of the chemical formula 17;

[0132] (e-2) A step of obtaining a compound of chemical formula 19 by subjecting the compound of chemical formula 17 and the compound of chemical formula 18 to a nucleophilic reaction;

[0133] (e-3) A step of reacting NaR5 with the compound of the above chemical formula 19 to obtain a compound of the chemical formula 1;

[0134] [Chemical Formula 1]

[0135]

[0136]

[0137] [Chemical Formula 2]

[0138]

[0139] [Chemical Formula 3]

[0140]

[0141] [Chemical Formula 4]

[0142]

[0143] [Chemical Formula 5]

[0144]

[0145] [Chemical Formula 6]

[0146]

[0147] [Chemical Formula 7]

[0148]

[0149] [Chemical Formula 8]

[0150]

[0151] [Chemical Formula 9]

[0152]

[0153] [Chemical Formula 10]

[0154]

[0155] [Chemical Formula 11]

[0156]

[0157] [Chemical Formula 12]

[0158]

[0159] [Chemical Formula 13]

[0160]

[0161] [Chemical Formula 14]

[0162] NR'1R'2

[0163] [Chemical Formula 15]

[0164]

[0165] [Chemical Formula 16]

[0166]

[0167] [Chemical Formula 17]

[0168]

[0169] [Chemical Formula 18]

[0170] NHR3R4

[0171] [Chemical Formula 19]

[0172]

[0173] In the above chemical formulas,

[0174] R a and R b are each independently H or substituted or unsubstituted C1 to C10 alkyl, and X1 to X4 are the same or different halogen elements. R1 to R5 and R'1 and The definition of R'2 is the same as in the above chemical formula 1, and n is an integer from 1 to 3.

[0175]

[0176] In a specific embodiment, in a specific example of the step (S3), when the substituted or unsubstituted C1 to C10 alkane dione or the substituted or unsubstituted C1 to C10 oxalate of the step (S3) is substituted, it may be substituted by R1 and / or R2.

[0177]

[0178] In one embodiment of the present invention, compounds 1 to 121 can be prepared by performing steps (S1) to (S4).

[0179]

[0180] Hereinafter, the present invention will be described in more detail through examples. These examples are intended solely to illustrate the present invention more specifically, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples, in accordance with the gist of the present invention.

[0181]

[0182] Example

[0183] Example 1: Synthesis of Compound 1

[0184]

[0185] A 60% nitric acid aqueous solution (50 mL) was cooled at 0°C for 20 minutes, 1,4-dimethoxybenzene (5.00 g, 36.2 mmol) was added, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was stirred at room temperature for 1 hour and then stirred for another hour at 80°C. The reaction solution was poured onto ice to quench, and the resulting yellow solid was filtered and washed thoroughly with water. The obtained solid was dissolved cleanly in DCM, dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (1,4-dimethoxy-2,3-dinitrobenzene, B).

[0186] Yellow solid, 6.84 g (82.8%)

[0187] 1 H NMR (400 MHz, CHLOROFORM-D) δ 7.20 (s, 2H), 3.93 (s, 6H).

[0188]

[0189] B (3.42 g, 15.0 mmol) was dissolved in EtOAc (50 mL), 10% Pd / C (wetted with 55% water, 1.06 g, 450 μmol) was added, and the mixture was stirred under a hydrogen atmosphere. The reaction solution was further stirred at room temperature for 24 h. The Pd / C was removed by filtration through a celite pad, and the filtrate was concentrated under reduced pressure to obtain the target compound (3,6-dimethoxy-benzene-1,2-diamine, crude C).

[0190] Purple solid, 2.28 g (90.3%)

[0191] 1 H NMR (400 MHz, CHLOROFORM-D) δ 6.31 (s, 2H), 3.81 (s, 6H).

[0192]

[0193] Add distilled water (27 mL) to crude C (2.28 g, 13.6 mmol) and heat to 50°C. In another flask, add glyoxal sodiumbisulfite (4.69 g, 17.6 mmol), add distilled water (39 mL), and heat to 50°C to dissolve. Add the aqueous glyoxal sodiumbisulfite solution to the reaction solution and stir under a nitrogen atmosphere. The reaction solution is stirred at 100°C for another 2.5 hours and then cooled to room temperature. Adjust the pH to 8–9 with saturated NaHCO3 aqueous solution, add DCM, and extract several times. The separated organic layer is dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate is purified by recrystallization (EtOAc / Hex) after being separated by silica gel column chromatography (EtOAc / Hex) to obtain the target compound (5,8-dimethoxyquinoxaline, D).

[0194] Yellow solid, 2.07 g (80.0%)

[0195] 1 H NMR (400 MHz, CHLOROFORM-D) δ 8.90 (s, 2H), 7.04 (s, 2H), 4.08 (s, 6H).

[0196]

[0197] D (1.94 g, 10.2 mmol) was dissolved in acetonitrile (MeCN, 29 mL), and then ceric ammonium nitrate (CAN, 14.0 g, 25.5 mmol) aqueous solution (water, 29 mL) was slowly added over 10 minutes. The reaction solution was stirred at room temperature for an additional 12 minutes. Saturated NaCl aqueous solution and DCM were added and extracted several times. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / Hex) and recrystallized (EtOAc / Hex) to obtain the target compound (quinoxaline-5,8-dione, E).

[0198] Yellow solid, 1.20 g (73.5%)

[0199] 1 H NMR (400 MHz, CHLOROFORM-D) δ 9.08 (s, 2H), 7.27 (s, 2H).

[0200]

[0201] To E (385 mg, 2.40 mmol) was added THF (5.7 mL) and AcOH (2.3 mL) and stirred at 40°C for 10 min under a nitrogen atmosphere. Sodium azide (NaN3) (188 mg, 2.89 mmol) dissolved in distilled water (1 mL) was added to the reaction solution and stirred at the same temperature for another 2.5 h. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (EtOAc / Hex) to obtain the target compound (6-aminoquinoxaline-5,8-dione, 1a).

[0202] Red purple solid, 110 mg (26.2%)

[0203] 1H NMR (400 MHz, DMSO-D6) δ 8.98 (d,J= 2.4 Hz, 1H), 8.93 (d,J= 2.4 Hz, 1H), 5.97 (s, 1H).

[0204]

[0205] Add DCM (6.2 mL) to 1a (108 mg, 617 μmol) and stir at 0°C. Pyridine (1.2 mL, 14.8 mmol) and isobutyryl chloride (0.32 mL, 3.08 mmol) are slowly added at the same temperature. The reaction solution is stirred at room temperature for another 1 h. After quenching the reaction solution by pouring it onto ice, saturated aqueous NaCl solution and EtOAc are added and extracted several times. The separated organic layer is dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / Hex) and purified by recrystallization (EtOAc / DCM / Hex) to obtain the target compound (N-(5,8-dioxo-5,8-dihydroquinoxalin-6-yl)isobuty ramide, compound 1).

[0206] Yellowish solid, 70 mg (46.3%)

[0207] 1 H NMR (400 MHz, CHLOROFORM-D) δ 9.07 (d,J= 2.3 Hz, 1H), 9.03 (d,J= 2.2 Hz, 1H), 8.42 (s, 1H), 8.18 (s, 1H), 2.72 (sep,J= 6.9 Hz, 1H), 1.31 (d,J=6.9 Hz, 6H).

[0208]

[0209] Example 2: Synthesis of Compound 2

[0210]

[0211] Crude C (8.16 mmol) was dissolved in EtOH (33 mL), and 2,3-Butanedione (0.81 mL, 9.19 mmol) was added. The reaction solution was stirred at 90°C for 30 minutes and then concentrated. The concentrate was separated by silica gel column chromatography (EtOAc / Hex) and purified by recrystallization (EtOAc / DCM / Hex) to obtain the target compound (5,8-dimethoxy-2,3-dimethylquinoxaline, D').

[0212] Yellow green solid, 1.64 g (91.9%)

[0213] 1 H NMR (400 MHz, CHLOROFORM-D) δ 6.93 (s, 2H), 4.04 (s, 6H), 2.78 (s, 6H).

[0214]

[0215] Add MeCN (15 mL) and water (15 mL) to D' (1.47 g, 6.75 mmol) and stir. Dissolve ceric ammonium nitrate (CAN) (9.27 g, 16.9 mmol) in MeCN (62 mL) and water (3 mL) and add to the reaction solution. Stir at room temperature for 1 h, then concentrate to remove MeCN. Add saturated NaCl aqueous solution and DCM and extract several times, then dry the separated organic layer over MgSO4 and filter. The filtrate was concentrated under reduced pressure and purified by recrystallization (DCM / Ether) to obtain the target compound (2,3-dimethylquinoxaline-5,8-dione, E').

[0216] Yellow solid, 934 mg (73.5%)

[0217] 1 H NMR (400 MHz, CHLOROFORM-D) δ 7.15 (s, 2H), 2.80 (s, 6H).

[0218]

[0219] E' (927 mg, 4.93 mmol) was mixed with THF (11 mL) and AcOH (4.5 mL) and stirred at 40°C for 10 min under a nitrogen atmosphere. Sodium azide (NaN3) (352 mg, 5.42 mmol) dissolved in water (2.3 mL) was added to the reaction solution and stirred at the same temperature for 4 h and then at room temperature for an additional 64.5 h. EtOAc (50 mL) and MeOH (10 mL) were added to the reaction solution and filtered through Celite. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (EtOAc / MeOH) to obtain the target compound (6-amino-2,3-dimethylquinoxaline-5,8-dione, 2a).

[0220] Red brown solid, 323 mg (32.3%)

[0221] 1 H NMR (400 MHz, DMSO-D6) δ 5.87 (s, 1H), 2.63 (s, 3H), 2.62 (s, 3H).

[0222]

[0223] Add DCM (9.8 mL) to 2a (100 mg, 492 μmol) and stir at 0°C. Slowly add pyridine (1.34 mL) and isobutyryl chloride (186 μL, 1.72 mmol) at the same temperature. Stir for 15 h at room temperature and then for another 10 min at 50°C. At the same temperature, add DCM (4.9 mL) and isobutyryl chloride (250 μL, 2.46 mmol) and stir for another 20 min at room temperature. Quench the reaction solution by pouring it onto ice, then extract several times with saturated aqueous NaCl solution and EtOAc. The separated organic layer is dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / Hex) and purified by recrystallization (EtOAc / DCM / Hex) to obtain the target compound (N-(2,3-dimethyl-5,8-dioxo-5,8-dihydroquinoxalin-6-yl)isobutyramide, compound 2).

[0224] Yellow solid, 77.6 mg, (57.7%)

[0225] 1 H NMR (400 MHz, CHLOROFORM-D) δ 8.39 (s, 1H), 8.05 (s, 1H), 2.80 (s, 3H), 2.78 (s, 3H), 2.70 (p,J= 6.9 Hz, 1H), 1.29 (d,J= 6.9 Hz, 6H).

[0226]

[0227] Example 3: Synthesis of Compound 3

[0228]

[0229] Add Ac2O (31.5 mL) to D (1.20 g, 6.30 mmol) and stir at 0℃. In another round-bottom flask, add Ac2O (6.3 mL) and 60% HNO3 (0.53 mL) and H2SO4 (1 drop) at 0℃. At the same temperature, slowly add the HNO3 solution to the A-1 solution over 5 minutes. Stir at the same temperature for 30 minutes and then at room temperature for another 3.5 hours. After quenching the reaction solution by pouring it onto ice, add a saturated NaCl aqueous solution and DCM and extract several times. Adjust the pH of the aqueous layer to 8 with a saturated NaHCO3 aqueous solution, add DCM and extract several times. The separated organic layer is dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / Hex) and purified by recrystallization (EtOAc / Hex) to obtain (5,8-dimethoxy-6-nitroquinoxaline, F).

[0230] Yellow solid, 1.03 g (69.2%)

[0231] 1 H NMR (400 MHz, CHLOROFORM-D) δ 9.04 (d, J= 1.8 Hz, 1H), 9.00 (d, J= 1.8 Hz, 1H), 7.43 (s, 1H), 4.29 (s, 3H), 4.15 (s, 3H).

[0232]

[0233] Add MeOH (129 mL) to F (684 mg, 2.91 mmol) and heat to 80 °C to dissolve. At the same temperature, add an aqueous solution of Na2S2O4 (2.53 g, 14.5 mmol) (16 mL of water) and stir for another hour at 80 °C. Cool the reaction solution to room temperature and concentrate under reduced pressure. Add water to the concentrate, adjust the pH to 8–9 with a saturated aqueous solution of NaHCO3, add DCM, and extract several times. The separated organic layer was washed with a saturated aqueous solution of NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (5,8-dimethoxyquinoxalin-6-amine, G).

[0234] Orange solid, 328 mg (54.9%)

[0235] 1 H NMR (400 MHz, CHLOROFORM-D) δ 8.74 (d, J= 1.9 Hz, 1H), 8.55 (d, J= 1.9 Hz, 1H), 6.62 (s, 1H), 4.37 (s, 2H), 4.04 (s, 3H), 4.01 (s, 3H).

[0236]

[0237] Add DCM (2.7 mL) to G (55.0 mg, 268 μmol) and stir at 0°C. At the same temperature, slowly add pyridine (40 ml, 495 μmol) and trimethylacetyl chloride (34 μL, 398 μmol). After stirring at room temperature for 3 h, extract several times with distilled water and DCM. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / Hex) to obtain the target compound (N-(5,8-dimethoxyquinoxalin-6-yl)pivalamide, 3a).

[0238] Yellow solid, 60.8 mg (78.4%)

[0239] 1 H NMR (400 MHz, CHLOROFORM-D) δ 8.84 (d, J= 1.8 Hz, 1H), 8.75 (d, J= 1.8 Hz, 1H), 8.53 (s, 1H), 4.13 (s, 3H), 4.12 (s, 3H), 1.41 (s, 9H).

[0240]

[0241] 3a (55.6 mg, 192 μmol) was stirred with MeCN (0.7 mL) and distilled water (0.3 mL). Ceric ammonium nitrate (CAN) (263 mg, 480 μmol) was added to the reaction solution and stirred at room temperature for 3 h. The reaction solution was concentrated to remove MeCN, and the concentrate was purified by silica gel column chromatography (EtOAc / DCM) to obtain the target compound (N-(5,8-dioxo-5,8-dihydroquinoxalin-6-yl)pivalamide, compound 3).

[0242] Yellow solid, 24.6 mg (49.4%)

[0243] 1 H NMR (400 MHz, CHLOROFORM-D) δ 9.07 (d,J= 2.2 Hz, 1H), 9.03 (d,J= 2.2 Hz, 1H), 8.72 (s, 1H), 8.17 (s, 1H), 1.37 (s, 9H).

[0244]

[0245] Example 4: Synthesis of compound 4

[0246]

[0247] G (350 mg, 1.71 mmol) was dissolved in DCM (17 mL) and stirred at 0°C. At the same temperature, pyridine (0.42 mL, 5.12 mmol) and cyclopropane carbonyl chloride (190 μL, 2.05 mmol) were slowly added. After stirring at room temperature for 1.5 h, the reaction solution was poured onto ice to quench. After extraction several times with saturated aqueous NaCl solution and DCM, the separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / Hex) to obtain the target compound (N-(5,8-dimethoxyquinoxalin-6-yl)cyclopropanecarboxamide, 4a).

[0248] Yellow solid, 441 mg (94.3%)

[0249] 1 H NMR (400 MHz, CHLOROFORM-D) δ 8.83 (d,J= 1.8 Hz, 1H), 8.75 (d,J= 1.8 Hz, 1H), 8.51 (s, 1H), 8.38 (s, 1H), 4.16 (s, 3H), 4.09 (s, 3H), 1.69 (ddd,J= 12.3, 7.8, 4.5 Hz, 1H), 1.20 - 1.14 (m, 2H), 1.00 - 0.93 (m, 2H).

[0250]

[0251] 4a (440 mg, 1.61 mmol) was stirred with MeCN (3.5 mL) and water (3.5 mL). Ceric ammonium nitrate (CAN) (2.21 mg, 4.02 mmol) was dissolved in MeCN (14.7 mL) and water (0.74 mL) and added to the reaction solution. Stirred at room temperature for 1 h, concentrated to remove MeCN. Extracted several times with saturated aqueous NaCl solution and DCM, the separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) and recrystallized (DCM / Hex) to obtain the target compound (N-(5,8-dioxo-5,8-dihydroquinoxalin-6-yl)cyclopropanecarboxamide, compound 4).

[0252] Yellow solid, 218 mg (55.7%)

[0253] 1 H NMR (400 MHz, CHLOROFORM-D) δ 9.07 (d,J= 2.2 Hz, 1H), 9.02 (d,J= 2.2 Hz, 1H), 8.60 (s, 1H), 8.13 (s, 1H), 1.76 (ddd,J= 12.3, 7.7, 4.5 Hz, 1H), 1.22 - 1.15 (m, 2H), 1.06 - 0.98 (m, 2H).

[0254]

[0255] Example 5: Synthesis of Compound 5

[0256]

[0257] G (131 mg, 637 μmol) was dissolved in DCM (6.4 mL) and stirred at 0°C. At the same temperature, pyridine (0.1 mL, 1.27 mmol) and cyclohexanecarbonyl chloride (0.11 mL, 828 μmol) were slowly added. After stirring at room temperature for 21.5 h, distilled water and DCM were added and extracted several times. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / Hex) to obtain the target compound (N-(5,8-dimethoxyquinoxalin-6-yl)cyclohexanecarboxamide, 5a).

[0258] Yellow solid, 176 mg (87.8%)

[0259] 1 H NMR (400 MHz, CHLOROFORM-D) δ 8.83 (d,J= 1.8 Hz, 1H), 8.75 (d,J= 1.8 Hz, 1H), 8.53 (s, 1H), 8.20 (s, 1H), 4.13 (s, 3H), 4.11 (s, 3H), 2.45 - 2.34 (m, 1H), 2.09 - 2.00 (m, 2H), 1.89 (dt,J= 12.7, 3.3 Hz, 2H), 1.75 (dd,J= 11.9, 4.3 Hz, 1H), 1.67 - 1.60 (m, 1H), 1.56-1.60 (m, 1H), 1.45 - 1.23 (m, 3H).

[0260]

[0261] 5a (173 mg, 549 μmol) was stirred at room temperature with MeCN (1.4 mL) and water (1.4 mL). At the same temperature, ceric ammonium nitrate (CAN) (752 mg, 1.37 mmol) was dissolved in MeCN (5.2 mL) and water (0.26 mL) and added to the reaction solution. After stirring at room temperature for 1.5 h, the solution was concentrated to remove MeCN. After extraction several times with saturated aqueous NaCl solution and DCM, the separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) to obtain the target compound (N-(5,8-dioxo-5,8-dihydroquinoxalin-6-yl)cyclohexanecarboxamide, compound 5).

[0262] Yellow solid, 20 mg (12.8%)

[0263] 1 H NMR (400 MHz, CHLOROFORM-D) δ 9.07 (d,J= 2.2 Hz, 1H), 9.02 (d,J= 2.2 Hz, 1H), 8.41 (s, 1H), 8.19 (s, 1H), 2.43 (tt,J= 11.6, 3.5 Hz, 1H), 2.04 - 1.94 (m, 2H), 1.91 - 1.83 (m, 2H), 1.74 (dd,J= 11.7, 4.2 Hz, 1H), 1.57-1.61 (m, 1H), 1.53 (dd,J= 12.2, 3.4 Hz, 1H), 1.43 - 1.22 (m, 3H).

[0264]

[0265] Example 6: Synthesis of compound 6

[0266]

[0267] G (120 mg, 585 μmol) was dissolved in DCM (5.9 mL) and stirred at 0°C. At the same temperature, pyridine (0.14 mL, 1.76 mmol) and propionyl chloride (61 μL, 702 μmol) were slowly added. After stirring at room temperature for 1.5 h, the reaction solution was quenched by pouring it onto ice. After extracting several times with saturated aqueous NaCl solution and DCM, the separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / Hex) to obtain the target compound (N-(5,8-dimethoxyquinoxalin-6-yl)propionamide, 6a).

[0268] Light yellow solid, 149 mg (97.2%)

[0269] 1 H NMR (400 MHz, CHLOROFORM-D) δ 8.83 (d,J= 1.8 Hz, 1H), 8.75 (d,J= 1.8 Hz, 1H), 8.53 (s, 1H), 8.14 (s, 1H), 4.13 (s, 3H), 4.11 (s, 3H), 2.56 (q,J= 7.5 Hz, 2H), 1.32 (t,J= 7.5 Hz, 3H).

[0270]

[0271] 6a (147 mg, 563 μmol) was stirred at 0°C with MeCN (1.3 mL) and water (1.3 mL). At the same temperature, ceric ammonium nitrate (CAN) (770 mg, 1.41 mmol) was dissolved in MeCN (5.1 mL) and water (0.30 mL) and added to the reaction solution. Stirred at room temperature for 15 minutes, concentrated to remove MeCN, and extracted several times with saturated aqueous NaCl solution and DCM. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) and recrystallized (DCM / Hex) to obtain the target compound (N-(5,8-dioxo-5,8-dihydroquinoxalin-6-yl)propionamide, compound 6).

[0272] Yellow solid, 71.5 mg (54.9%)

[0273] 1 H NMR (400 MHz, CHLOROFORM-D) δ 9.07 (d,J= 2.3 Hz, 1H), 9.02 (d,J= 2.3 Hz, 1H), 8.36 (s, 1H), 8.18 (s, 1H), 2.58 (q,J= 7.5 Hz, 2H), 1.28 (t,J= 7.5 Hz, 3H).

[0274]

[0275] Example 7: Synthesis of Compound 7

[0276]

[0277] G (132 mg, 643 μmol) was dissolved in DCM (6.4 mL) and stirred at 0°C. At the same temperature, pyridine (0.1 mL, 1.29 mmol) and isovaleryl chloride (0.1 mL, 836 μmol) were slowly added. After stirring at room temperature for 1 h, distilled water and DCM were added and extracted several times. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / Hex) to obtain the target compound (N-(5,8-dimethoxyquinoxalin-6-yl)-3-methylbutanamide, 7a).

[0278] Yellow solid, 182 mg (97.9%)

[0279] 1 H NMR (400 MHz, CHLOROFORM-D) δ 8.83 (d,J= 1.8 Hz, 1H), 8.76 (d,J= 1.8 Hz, 1H), 8.51 (s, 1H), 8.11 (s, 1H), 4.12 (s, 3H), 4.12 (s, 3H), 2.38 (d,J= 6.7 Hz, 2H), 2.34 - 2.21 (m, 1H), 1.08 (d,J= 6.5 Hz, 6H).

[0280]

[0281] 7a (180 mg, 623 μmol) was stirred at 0°C with MeCN (1.6 mL) and distilled water (1.6 mL). At the same temperature, ceric ammonium nitrate (CAN) (855 mg, 1.56 mmol) was dissolved in MeCN (5.9 mL) and distilled water (0.3 mL) and added to the reaction solution. Stirred at room temperature for 1 hour, concentrated to remove MeCN, and extracted several times with saturated NaCl aqueous solution and DCM. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) and recrystallized (DCM / Hex) to obtain the target compound (N-(5,8-dioxo-5,8-dihydroquinoxalin-6-yl)-3-methylbutan amide, compound 7).

[0282] Yellow solid, 69 mg (42.7%)

[0283] 1 H NMR (400 MHz, CHLOROFORM-D) δ 9.07 (d,J= 2.1 Hz, 1H), 9.02 (d,J= 2.1 Hz, 1H), 8.33 (s, 1H), 8.20 (s, 1H), 2.41 (d,J= 7.1 Hz, 2H), 2.24 (dp,J= 13.7, 6.8 Hz, 1H), 1.04 (d,J= 6.6 Hz, 6H).

[0284]

[0285] Example 8: Synthesis of Compound 8

[0286]

[0287] G (120 mg, 585 μmol) was dissolved in DCM (5.9 mL) and stirred at 0°C. At the same temperature, pyridine (0.14 mL, 1.76 mmol) and 2-Ethylbutyryl chloride (100 μL, 702 μmol) were slowly added. After stirring at room temperature for 1 h, the reaction solution was quenched by pouring it onto ice. After extracting several times with saturated aqueous NaCl solution and DCM, the separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / Hex) to obtain the target compound (N-(5,8-dimethoxy-quinoxalin-6-yl)-2-ethylbutanamide, 8a).

[0288] Yellow solid, 170 mg (95.8%)

[0289] 1 H NMR (400 MHz, CHLOROFORM-D) δ 8.83 (d,J= 1.8 Hz, 1H), 8.75 (d,J= 1.8 Hz, 1H), 8.53 (s, 1H), 4.12 (s, 3H), 4.12 (s, 3H), 2.22 (tt,J= 8.8, 5.3 Hz, 1H), 1.85 - 1.72 (m, 2H), 1.71 - 1.59 (m, 2H), 1.02 (t,J= 7.4 Hz, 6H).

[0290]

[0291] 8a (167 mg, 550 μmol) was stirred at 0°C with MeCN (1.2 mL) and water (1.2 mL). At the same temperature, ceric ammonium nitrate (CAN) (753 mg, 1.37 mmol) was dissolved in MeCN (5.1 mL) and water (0.25 mL) and added to the reaction solution. Stirred at room temperature for 15 minutes, concentrated to remove MeCN, and extracted several times with saturated NaCl aqueous solution and DCM. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) and recrystallized (Hex) to obtain the target compound (N-(5,8-dioxo-5,8-dihydroquinoxalin-6-yl)-2-ethylbutanamide, compound 8).

[0292] Dark yellow solid, 76.0 mg (50.6%)

[0293] 1 H NMR (400 MHz, CHLOROFORM-D) δ 9.07 (d,J= 2.3 Hz, 1H), 9.02 (d,J= 2.2 Hz, 1H), 8.36 (s, 1H), 8.22 (s, 1H), 2.30 (tt,J= 8.5, 5.5 Hz, 1H), 1.82 - 1.69 (m, 2H), 1.69 - 1.58 (m, 2H), 0.96 (t,J= 7.4 Hz, 6H).

[0294]

[0295] Example 9: Synthesis of compound 9

[0296]

[0297] G (123 mg, 599 μmol) was dissolved in DCM (6.0 mL) and stirred at 0°C. At the same temperature, pyridine (97 μL, 1.20 mmol) and tert-butylacetyl chloride (110 μL, 779 μmol) were slowly added. After stirring at room temperature for 1 h, distilled water and DCM were added and extracted several times. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / Hex) to obtain the target compound (5,8-dimethoxyquinoxalin-6-yl)-3,3-dimethylbutanamide, 9a).

[0298] Yellow solid, 180 mg (98.8%)

[0299] 1 H NMR (400 MHz, CHLOROFORM-D) δ 8.83 (d,J= 1.8 Hz, 1H), 8.75 (d,J= 1.8 Hz, 1H), 8.51 (s, 1H), 8.08 (s, 1H), 4.12 (s, 3H), 4.12 (s, 3H), 2.37 (s, 2H), 1.17 (s, 9H).

[0300]

[0301] 9a (177 mg, 583 μmol) was stirred at 0°C with MeCN (1.5 mL) and distilled water (1.5 mL). At the same temperature, ceric ammonium nitrate (CAN) (800 mg, 1.46 mmol) was dissolved in MeCN (5.6 mL) and distilled water (0.28 mL) and added to the reaction solution. Stirred at room temperature for 15 minutes, concentrated to remove MeCN, and extracted several times with saturated NaCl aqueous solution and DCM. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) and recrystallized (DCM / Hex) to obtain the target compound (N-(5,8-dioxo-5,8-dihydroquinoxalin-6-yl)-3,3-dimethyl-butanamide, compound 9).

[0302] Yellow solid, 83.2 mg (52.2%)

[0303] 1 H NMR (400 MHz, CHLOROFORM-D) δ 9.07 (d,J= 2.3 Hz, 1H), 9.02 (d,J= 2.2 Hz, 1H), 8.29 (s, 1H), 8.20 (s, 1H), 2.40 (s, 2H), 1.12 (s, 9H).

[0304]

[0305] Example 10: Synthesis of compound 10

[0306]

[0307] G (130 mg, 633 μmol) was dissolved in DCM (6.3 mL) and stirred at 0°C. At the same temperature, pyridine (0.1 mL, 1.27 mmol) and cyclobutanecarbonyl chloride (94 μL, 824 μmol) were slowly added. After stirring at room temperature for 1 h, distilled water and DCM were added and extracted several times. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / Hex) to obtain the target compound (N-(5,8-dimethoxyquinoxalin-6-yl)cyclobutanecarboxamide, 10a).

[0308] Yellow solid, 174 mg (95.5%)

[0309] 1 H NMR (400 MHz, CHLOROFORM-D) δ 8.83 (d,J= 1.8 Hz, 1H), 8.75 (d,J= 1.8 Hz, 1H), 8.56 (s, 1H), 8.05 (s, 1H), 4.12 (s, 3H), 4.11 (s, 3H), 3.32 (pd,J= 8.5, 1.0 Hz, 1H), 2.53 - 2.39 (m, 2H), 2.39 - 2.27 (m, 2H), 2.16 - 1.93 (m, 2H).

[0310]

[0311] 10a (170 mg, 592 μmol) was stirred at 0°C with MeCN (1.5 mL) and distilled water (1.5 mL). At the same temperature, ceric ammonium nitrate (CAN) (811 mg, 1.48 mmol) was dissolved in MeCN (5.6 mL) and distilled water (0.3 mL) and added to the reaction solution. Stirred at room temperature for 15 minutes, concentrated to remove MeCN, and extracted several times with saturated NaCl aqueous solution and DCM. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) and recrystallized (DCM / Hex) to obtain the target compound (N-(5,8-dioxo-5,8-dihydroquinoxalin-6-yl)cyclobutane-carboxamide, compound 10).

[0312] Yellow solid, 75.6 mg (49.6%)

[0313] 1 H NMR (400 MHz, CHLOROFORM-D) δ 9.07 (d,J= 2.2 Hz, 1H), 9.02 (d,J= 2.2 Hz, 1H), 8.25 (s, 1H), 8.20 (s, 1H), 3.32 (qd,J= 8.5, 1.0 Hz, 1H), 2.50 - 2.25 (m, 4H), 2.16 - 1.91 (m, 2H).

[0314]

[0315] Example 11: Synthesis of compound 11

[0316]

[0317] G (163 mg, 792 μmol) was dissolved in DCM (8.0 mL) and stirred at 0°C. At the same temperature, pyridine (190 μL, 2.38 mmol) and 4-Fluorobenzoyl chloride (120 μL, 953 μmol) were slowly added. After stirring at room temperature for 1 h, the reaction solution was quenched by pouring it onto ice. After extracting several times with saturated aqueous NaCl solution and DCM, the separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / Hex) to obtain the target compound (N-(5,8-dimethoxy-quinoxalin-6-yl)-4-fluorobenzamide, 11a).

[0318] Yellow solid, 264 mg

[0319] 1 H NMR (400 MHz, CHLOROFORM-D) δ 8.87 (s, 1H), 8.86 (d,J= 1.8 Hz, 1H), 8.79 (d,J= 1.8 Hz, 1H), 8.59 (s, 1H), 8.02 - 7.95 (m, 2H), 7.28 - 7.21 (m, 2H), 4.20 (s, 3H), 4.16 (s, 3H).

[0320]

[0321] 11a (261 mg, 799 μmol) was stirred at 0°C with MeCN (1.8 mL) and water (1.8 mL). At the same temperature, ceric ammonium nitrate (CAN) (1.10 g, 2.00 mmol) was dissolved in MeCN (7.3 mL) and water (0.37 mL) and added to the reaction solution. Stirred at room temperature for 15 minutes, concentrated to remove MeCN, and extracted several times with saturated NaCl aqueous solution and DCM. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) and recrystallized (DCM / Hex) to obtain the target compound (N-(5,8-dioxo-5,8-dihydroquinoxalin-6-yl)-4-fluorobenz amide, compound 11).

[0322] Yellow solid, 122 mg (51.9%, yield for two steps)

[0323] 1 H NMR (400 MHz, CHLOROFORM-D) δ 9.12 (s, 1H), 9.10 (d,J= 2.2 Hz, 1H), 9.05 (d,J= 2.2 Hz, 1H), 8.32 (s, 1H), 8.04 - 7.96 (m, 2H), 7.30 - 7.22 (m, 2H).

[0324]

[0325] Example 12: Synthesis of Compound 12

[0326]

[0327] G (132 mg, 643 μmol) was dissolved in DCM (6.4 mL) and stirred at 0°C. At the same temperature, pyridine (100 μL, 1.29 mmol) and 4-chlorophenylacetyl chloride (120 μL, 836 μmol) were slowly added. After stirring at room temperature for 1 h, distilled water and DCM were added and extracted several times. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / Hex) and recrystallized (DCM / Hex) to obtain the target compound (2-(4-chlorophenyl)-N-(5,8-dimethoxyquinoxalin-6-yl)acetamide, 12a).

[0328] Yellow solid, 229 mg (99.6%)

[0329] 1 H NMR (400 MHz, CHLOROFORM-D) δ 8.81 (d,J= 1.8 Hz, 1H), 8.74 (d,J= 1.8 Hz, 1H), 8.44 (s, 1H), 8.16 (s, 1H), 7.43 (d,J= 8.6 Hz, 2H), 7.34 (d,J= 8.7 Hz, 2H), 4.10 (s, 3H), 3.90 (s, 3H), 3.83 (s, 2H).

[0330]

[0331] 12a (227 mg, 634 μmol) was stirred at 0°C with MeCN (1.6 mL) and distilled water (1.6 mL). At the same temperature, ceric ammonium nitrate (CAN) (870 mg, 1.59 mmol) was dissolved in MeCN (6.0 mL) and distilled water (0.3 mL) and added to the reaction solution. Stirred at room temperature for 25 minutes, concentrated to remove MeCN, and extracted several times with saturated NaCl aqueous solution and DCM. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / Hex) and recrystallized (DCM / Hex) to obtain the target compound (2-(4-chlorophenyl)-N-(5,8-dioxo-5,8-dihydroquinoxalin-6-yl)acetamide, compound 12).

[0332] Yellow solid, 71.4 mg (34.4%)

[0333] 1 H NMR (400 MHz, CHLOROFORM-D) δ 9.06 (d,J= 2.2 Hz, 1H), 9.01 (d,J= 2.2 Hz, 1H), 8.43 (s, 1H), 8.13 (s, 1H), 7.45 - 7.37 (m, 2H), 7.31 - 7.27 (m, 2H), 3.84 (s, 2H).

[0334]

[0335] Example 13: Synthesis of Compound 13

[0336]

[0337] G (120 mg, 585 μmol) was dissolved in DCM (5.9 mL) and stirred at 0°C. At the same temperature, pyridine (140 μL, 1.76 mmol) and 2-Thiopheneacetyl chloride (88 μL, 702 μmol) were slowly added. After stirring at room temperature for 1.5 h, the reaction solution was poured onto ice to quench. After extraction several times with saturated aqueous NaCl solution and DCM, the separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / Hex) to obtain the target compound (N-(5,8-dimethoxy-quinoxalin-6-yl)-2-(thiophen-2-yl)acetamide, 13a).

[0338] Pale yellow solid, 188 mg (97.7%)

[0339] 1 H NMR (400 MHz, CHLOROFORM-D) δ 8.80 (d,J= 1.8 Hz, 1H), 8.73 (d,J= 1.8 Hz, 1H), 8.46 (s, 1H), 8.41 (s, 1H), 7.37 (dd,J= 4.6, 1.8 Hz, 1H), 7.15 - 7.04 (m, 2H), 4.11 (s, 3H), 4.07 (s, 2H), 3.86 (s, 3H).

[0340]

[0341] 13a (185 mg, 560 μmol) was stirred at 0°C with MeCN (1.3 mL) and water (1.3 mL). At the same temperature, ceric ammonium nitrate (CAN) (770 mg, 1.40 mmol) was dissolved in MeCN (5.0 mL) and water (0.25 mL) and added to the reaction solution. Stirred at room temperature for 15 minutes, concentrated to remove MeCN, and extracted several times with saturated aqueous NaCl solution and DCM. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / Hex) and recrystallized (EtOAc / Hex) to obtain the target compound (N-(5,8-dioxo-5,8-dihydroquinoxalin-6-yl)-2-(thiophen-2-yl)acetamide, compound 13).

[0342] Yellow solid, 79.5 mg (47.4%)

[0343] 1 H NMR (400 MHz, CHLOROFORM-D) δ 9.09 - 9.04 (m, 1H), 9.03 - 8.97 (m, 1H), 8.63 (s, 1H), 8.16 (d,J= 4.8 Hz, 1H), 7.39 - 7.33 (m, 1H), 7.14 - 7.06 (m, 2H), 4.08 (d,J= 5.4 Hz, 2H).

[0344]

[0345] Example 14: Synthesis of Compound 14

[0346]

[0347] G (120 mg, 585 μmol) was dissolved in DCM (5.9 mL) and stirred at 0°C. At the same temperature, pyridine (140 μL, 1.76 mmol) and acetyl chloride (50 μL, 702 μmol) were slowly added. After stirring at room temperature for 1.5 h, the reaction solution was quenched by pouring it onto ice. After extracting several times with saturated aqueous NaCl solution and DCM, the separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / Hex) to obtain the target compound (N-(5,8-dimethoxyquinoxalin-6-yl)acetamide, 14a).

[0348] Pale yellow solid, 136 mg (94.0%)

[0349] 1 H NMR (400 MHz, CHLOROFORM-D) δ 8.83 (s, 1H), 8.75 (s, 1H), 8.47 (s, 1H), 8.14 (s, 1H), 4.13 (s, 3H), 4.11 (s, 3H), 2.32 (s, 3H).

[0350]

[0351] 14a (133 mg, 538 μmol) was stirred at 0°C with MeCN (1.2 mL) and water (1.2 mL). At the same temperature, ceric ammonium nitrate (CAN) (740 mg, 1.34 mmol) was dissolved in MeCN (4.9 mL) and water (0.25 mL) and added to the reaction solution. Stirred at room temperature for 15 minutes, concentrated to remove MeCN, and extracted several times with saturated aqueous NaCl solution and DCM. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / Hex) and recrystallized (EtOAc / Hex) to obtain the target compound (N-(5,8-dioxo-5,8-dihydroquinoxalin-6-yl)acetamide, compound 14).

[0352] Pale orange solid, 56.5 mg (48.4%)

[0353] 1 H NMR (400 MHz, CHLOROFORM-D) δ 9.08 (t,J= 2.5 Hz, 1H), 9.03 (t,J= 2.5 Hz, 1H), 8.38 (s, 1H), 8.18 (d,J= 2.6 Hz, 1H), 2.35 (d,J= 2.7 Hz, 3H).

[0354]

[0355] Example 15: Synthesis of Compound 15

[0356]

[0357] Dissolve G (700 mg, 3.41 mmol) in DCM (34 mL) and stir at 0°C. Slowly add pyridine (0.55 mL, 6.82 mmol) and bromoacetyl chloride (0.37 mL, 4.43 mmol) at the same temperature. After stirring at room temperature for 2.5 h, extract several times with distilled water and DCM. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / Hex) to obtain the target compound (2-bromo-N-(5,8-dimethoxyquinoxalin-6-yl)acetamide, H).

[0358] Yellow solid, 956.7 mg (86.0%)

[0359] 1 H NMR (400 MHz, CHLOROFORM-D) δ 9.28 (d,J= 58.5 Hz, 1H), 8.87 (dd,J= 1.8, 0.8 Hz, 1H), 8.79 (dd,J= 1.8, 1.1 Hz, 1H), 8.40 (d,J= 10.2 Hz, 1H), 4.29 (s, 1H), 4.17 (s, 3H), 4.12 (s, 3H).

[0360]

[0361] Add THF (4.8 mL) and DCM (2.4 mL) to H (237 mg, 727 μmol) and stir at 0°C. At the same temperature, add Morpholine (0.19 mL, 2.18 mmol), Potassium iodide (KI) (12 mg, 72.3 μmol), and Potassium carbonate (K2CO3) (100 mg, 724 μmol) and stir for 23.5 h. After adjusting the pH to 7–8 with 1 M HCl aqueous solution, add DCM and extract several times. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc) to obtain the target compound (N-(5,8-dimethoxyquinoxalin-6-yl)-2-morpholinoacetamide, 15a).

[0362] Yellow solid, 242 mg (quantitative)

[0363] 1 H NMR (400 MHz, CHLOROFORM-D) δ 10.24 (s, 1H), 8.85 (d,J= 1.8 Hz, 1H), 8.76 (d,J= 1.8 Hz, 1H), 8.52 (s, 1H), 4.16 (s, 3H), 4.12 (s, 3H), 3.86 (t,J= 4.6 Hz, 4H), 3.26 (s, 2H), 2.71 (t,J= 4.6 Hz, 4H).

[0364]

[0365] 15a (240 mg, 721 μmol) was mixed with MeCN (1.8 mL) and distilled water (1.8 mL) and stirred at 0°C. At the same temperature, ceric ammonium nitrate (CAN) (988 mg, 1.80 mmol) was dissolved in MeCN (6.9 mL) and water (0.34 mL) and added to the reaction solution. Stirred at room temperature for 25 minutes, concentrated to remove MeCN. Adjusted to pH 6 with saturated aqueous NaHCO3 solution, then extracted several times with saturated aqueous NaCl solution and DCM. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (DCM / MeOH) and purified by recrystallization (DCM / Hex) to obtain the target compound (N-(5,8-dioxo-5,8-dihydroquinoxalin-6-yl)-2-morpholinoacetamide, compound 15).

[0366] Yellowish brown solid, 115 mg (52.5%)

[0367] 1 H NMR (400 MHz, CHLOROFORM-D) δ 10.52 (s, 1H), 9.08 (d,J= 1.7 Hz, 1H), 9.03 (d,J= 1.7 Hz, 1H), 8.16 (s, 1H), 3.86 (s, 4H), 3.26 (s, 2H), 2.66 (s, 4H).

[0368]

[0369] Example 16: Synthesis of compound 16

[0370]

[0371] Add MeCN (4.6 mL) to H (151 mg, 463 μmol) and stir at 0℃. At the same temperature, add KI (7.7 mg, 46.3 μmol), dimethylamine hydrochloride (49.1 mg, 602 μmol), and K2CO3 (128 mg, 926 μmol) and stir for 23.5 h. Add distilled water and DCM to the reaction solution and extract several times. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM / MeOH) to obtain the target compound (N-(5,8-dimethoxyquinoxalin-6-yl)-2-(dimethylamino)acet amide, 16a).

[0372] Yellow solid, 135 mg (quantitative)

[0373] 1 H NMR (400 MHz, CHLOROFORM-D) δ 10.12 (s, 1H), 8.84 (dd,J= 1.9, 0.9 Hz, 1H), 8.75 (dd,J= 1.8, 1.0 Hz, 1H), 8.53 (s, 1H), 4.12 (s, 3H), 4.11 (s, 3H), 3.19 (s, 2H), 2.47 (s, 6H).

[0374]

[0375] 16a (133 mg, 458 μmol) was stirred at 0°C with MeCN (1.1 mL) and distilled water (1.1 mL). At the same temperature, ceric ammonium nitrate (CAN) (628 mg, 1.15 mmol) was dissolved in MeCN (4.4 mL) and distilled water (0.22 mL) and added to the reaction solution. Stirred at room temperature for 20 minutes, concentrated to remove MeCN. Adjusted to pH 7–8 with saturated NaHCO3 aqueous solution, then extracted several times with saturated NaCl aqueous solution and DCM. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (DCM / MeOH) and purified by recrystallization (DCM / Hex) to obtain the target compound (N-(2-(dimethylamino)-N-(5,8-dioxo-5,8-dihydroquinoxalin-6-yl)acetamide, compound 16).

[0376] Yellowish brown solid, 14.3 mg (12.0 %)

[0377] 1 H NMR (400 MHz, CHLOROFORM-D) δ 10.33 (s, 1H), 9.07 (d,J= 2.2 Hz, 1H), 9.03 (d,J= 2.2 Hz, 1H), 3.20 (s, 2H), 2.43 (s, 6H)

[0378]

[0379] Example 17: Synthesis of compound 17

[0380]

[0381] G (299 mg, 1.46 mmol) was dissolved in DCM (14.6 mL) and stirred at 0°C. At the same temperature, pyridine (0.36 mL, 4.38 mmol) and 3-Bromopropionyl chloride (0.18 mL, 1.75 mmol) were slowly added. After stirring at room temperature for 1.5 h, the reaction solution was poured onto ice to quench. After extraction several times with saturated aqueous NaCl solution and DCM, the separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / Hex) to obtain the target compound (3-bromo-N-(5,8-dimethoxyquinoxalin-6-yl)propanamide, I).

[0382] Yellow solid, 452 mg (91.1%)

[0383]

[0384] Add MeCN (2.9 mL) to I (100 mg, 294 μmol) and stir at room temperature. At the same temperature, add Morpholine (77 μL, 882 μmol), Potassium iodide (KI) (5 mg, 29.4 μmol), and Potassium carbonate (K2CO3) (45 mg, 323 μmol) and stir for 23 h. After extracting several times with saturated aqueous NaCl solution and DCM, the separated organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / MeOH) to obtain the target compound (N-(5,8-dimethoxyquinoxalin-6-yl)-3-morpholinopropanamide, 17a).

[0385] Yellow solid, 96.1 mg (94.4%)

[0386] 1H NMR (400 MHz, CHLOROFORM-D) δ 11.06 (s, 1H), 8.85 - 8.83 (m, 1H), 8.76 - 8.75 (m, 1H), 8.51 (s, 1H), 4.10 (s, 3H), 4.08 (s, 3H), 3.89 (t,J= 4.7 Hz, 4H), 2.79 (t,J= 5.9 Hz, 2H), 2.67 (dd,J= 10.5, 5.9 Hz, 6H).

[0387]

[0388] Add MeCN (0.6 mL) and water (0.6 mL) to 17a (94.6 mg, 273 μmol) and stir at 0°C. At the same temperature, dissolve ceric ammonium nitrate (CAN) (380 mg, 683 μmol) in MeCN (2.5 mL) and water (0.13 mL) and add to the reaction solution. Stir at room temperature for 30 minutes, then concentrate to remove MeCN. Adjust the pH to 8–9 with saturated NaHCO3 aqueous solution, then add saturated NaCl aqueous solution and DCM and extract several times. The separated organic layer is dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / MeOH) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (N-(5,8-dioxo-5,8-dihydroquinoxalin-6-yl)-3-morpholinopropanamide, compound 17).

[0389] Khaki solid, 36.9 mg (42.7%)

[0390] 1H NMR (400 MHz, CHLOROFORM-D) δ 12.09 (s, 1H), 9.06 (d,J= 2.3 Hz, 1H), 9.02 (d,J= 2.3 Hz, 1H), 8.24 (s, 1H), 4.01 (t,J= 4.7 Hz, 4H), 2.80 - 2.71 (m, 2H), 2.71 - 2.56 (m, 6H).

[0391]

[0392] Example 18: Synthesis of compound 18

[0393]

[0394] Add MeCN (6.5 mL) to I (222 mg, 653 μmol) and stir at room temperature. At the same temperature, add piperidine (190 μL, 1.96 mmol), potassium iodide (KI) (11 mg, 65.3 μmol), and potassium carbonate (K2CO3) (99 mg, 718 μmol) and stir for 2 h. After extracting several times with saturated aqueous NaCl solution and DCM, the separated organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (N-(5,8-dimethoxyquinoxalin-6-yl)-3-(piperidin-1-yl)propanamide, 18a).

[0395] Yellow solid, 193 mg (85.6%)

[0396] 1H NMR (400 MHz, CHLOROFORM-D) δ 11.49 (s, 1H), 8.83 (dt,J= 1.8, 0.8 Hz, 1H), 8.74 (dt,J= 1.7, 0.7 Hz, 1H), 8.50 (s, 1H), 4.10 (s, 3H), 4.05 (s, 3H), 2.75 - 2.68 (m, 2H), 2.68 - 2.62 (m, 2H), 2.56 (s, 4H), 1.76 (p,J= 5.6 Hz, 4H), 1.52 (s, 2H).

[0397]

[0398] Add MeCN (1.2 mL) and water (1.2 mL) to 18a (189 mg, 550 μmol) and stir at 0°C. At the same temperature, dissolve ceric ammonium nitrate (CAN) (754 mg, 1.37 mmol) in MeCN (5.0 mL) and water (0.25 mL) and add to the reaction solution. Stir at room temperature for 40 minutes and concentrate to remove MeCN. Adjust the pH to 8–9 with saturated NaHCO3 aqueous solution, then add saturated NaCl aqueous solution and DCM and extract several times. The separated organic layer is dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (DCM / MeOH) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (N-(5,8-dioxo-5,8-dihydroquinoxalin-6-yl)-3-(piperidin-1-yl)propanamide, compound 18).

[0399] Yellow brown solid, 87.5 mg (50.6%)

[0400] 1H NMR (400 MHz, CHLOROFORM-D) δ 12.44 (s, 1H), 9.05 (d,J= 2.2 Hz, 1H), 9.01 (d,J= 2.2 Hz, 1H), 8.26 (s, 1H), 2.73 - 2.43 (m, 8H), 1.88 (t,J= 5.8 Hz, 4H), 1.58 (m, 2H).

[0401]

[0402] Example 19: Synthesis of Compound 19

[0403]

[0404] Add MeCN (3.5 mL) to I (120 mg, 353 μmol) and stir at room temperature. At the same temperature, add dimethylamine hydrochloride (37 mg, 459 μmol), potassium iodide (KI) (6 mg, 35.3 μmol), and potassium carbonate (K2CO3) (98 mg, 706 μmol) and stir for 16 h. After extracting several times with saturated aqueous NaCl solution and DCM, the separated organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM / MeOH) to obtain the target compound (N-(5,8-dimethoxy-quinoxalin-6-yl)-3-(dimethylamino)propanamide, 19a).

[0405] Yellow solid, 108 mg (quantitative)

[0406] 1H NMR (400 MHz, CHLOROFORM-D) δ 11.92 (s, 1H), 8.82 (d,J= 1.8 Hz, 1H), 8.73 (d,J= 1.8 Hz, 1H), 8.58 (s, 1H), 4.11 (s, 3H), 4.04 (s, 3H), 2.73 (t,J= 5.7 Hz, 2H), 2.62 (t,J= 5.5 Hz, 2H), 2.45 (s, 6H).

[0407]

[0408] Add MeCN (0.8 mL) and water (0.8 mL) to 19a (107 mg, 351 μmol) and stir at 0°C. At the same temperature, dissolve ceric ammonium nitrate (CAN) (480 mg, 876 μmol) in MeCN (3.2 mL) and water (0.16 mL) and add to the reaction solution. Stir at room temperature for 1.5 h and concentrate to remove MeCN. Adjust the pH to 8–9 with saturated aqueous NaHCO3 solution, then add saturated aqueous NaCl solution and DCM and extract several times. The separated organic layer is dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / MeOH) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (3-(dimethylamino)-N-(5,8-dioxo-5,8-dihydroquinoxalin-6-yl)propanamide, compound 19).

[0409] Yellow solid, 19.4 mg (20.2%)

[0410] 1 H NMR (400 MHz, CHLOROFORM-D) δ 9.05 (d,J= 2.3 Hz, 1H), 8.99 (d,J= 2.3 Hz, 1H), 8.18 (s, 1H), 2.72 - 2.66 (m, 2H), 2.61 - 2.55 (m, 2H), 2.46 (s, 6H).

[0411]

[0412] Example 20: Synthesis of Compound 20

[0413]

[0414] Add MeCN (4.6 mL) to H (150 mg, 460 μmol) and stir at 0°C. At the same temperature, add KI (7.6 mg, 46.0 μmol), piperidine (68 μL, 690 μmol), and K2CO3 (69.9 mg, 506 μmol) and stir for 18.5 h. Add saturated NaCl aqueous solution and DCM to the reaction solution and extract several times. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / Hex) to obtain the target compound (N-(5,8-dimethoxyquinoxalin-6-yl)-2-(piperidin-1-yl)acet amide, 20a).

[0415] Yellow solid, 136 mg (89.2%)

[0416] 1 H NMR (400 MHz, CHLOROFORM-D) δ 10.39 (s, 1H), 8.84 (d,J= 1.8 Hz, 1H), 8.75 (d,J= 1.8 Hz, 1H), 8.54 (s, 1H), 4.14 (s, 3H), 4.12 (s, 3H), 3.18 (s, 2H), 2.62 (s, 4H), 1.73 (p,J= 5.7 Hz, 4H), 1.54 (d,J= 7.7 Hz, 2H).

[0417]

[0418] Add MeCN (1.0 mL) and distilled water (1.0 mL) to 20a (133 mg, 403 μmol) and stir at 0°C. At the same temperature, dissolve ceric ammonium nitrate (CAN) (552 mg, 1.01 mmol) in MeCN (3.8 mL) and water (0.19 mL) and add to the reaction solution. Stir at room temperature for 30 minutes and concentrate to remove MeCN. Adjust the pH to 8–9 with saturated aqueous NaHCO3 solution, then add saturated aqueous NaCl solution and DCM and extract several times. The separated organic layer is dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / MeOH) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (N-(5,8-dioxo-5,8-dihydroquinoxalin-6-yl)-2-(piperidin-1-yl)acetamide, compound 20).

[0419] Yellowish brown solid, 60.4 mg (49.9%)

[0420] 1 H NMR (400 MHz, CHLOROFORM-D) δ 10.71 (s, 1H), 9.07 (d,J= 2.2 Hz, 1H), 9.02 (d,J= 2.3 Hz, 1H), 8.17 (s, 1H), 3.18 (s, 2H), 2.57 (t,J= 5.3 Hz, 4H), 1.74 (p,J= 5.7 Hz, 4H), 1.53 (d,J= 6.7 Hz, 2H).

[0421]

[0422] Example 21: Synthesis of Compound 21

[0423]

[0424] Add MeCN (8.4 mL) to H (957 mg, 2.93 mmol) and stir at 0℃. At the same temperature, dissolve ceric ammonium nitrate (CAN) (4.02 g, 7.34 mmol) in distilled water (8.4 mL) and add to the reaction solution. After stirring at the same temperature for 15 minutes, extract several times by adding saturated NaCl aqueous solution and DCM. The separated organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (DCM / MeOH) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (2-bromo-N-(5,8-dioxo-5,8-dihydroquinoxalin-6-yl)acetamide, J).

[0425] Yellow solid, 631 mg (72.7%)

[0426] 1 H NMR (400 MHz, CHLOROFORM-D) δ 9.40 (d,J= 83.4 Hz, 1H), 9.09 (d,J= 2.2 Hz, 1H), 9.05 (dd,J= 2.2, 1.4 Hz, 1H), 8.16 (d,J= 11.6 Hz, 1H), 4.28 (s, 1H), 4.09 (s, 1H).

[0427]

[0428] Add MeCN (4.1 mL) to J (121 mg, 409 μmol) and stir at room temperature. At the same temperature, add KI (6.8 mg, 40.9 μmol), 4-fluoroaniline (51 μL, 531 μmol), and K2CO3 (62.1 mg, 450 μmol) and stir for another 18.5 h at 50–60 °C. Cool the reaction solution to room temperature, add distilled water and DCM, and extract several times. The separated organic layer is dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / MeOH) and recrystallization (EtOAc / Hex) to obtain the target compound (N-(5,8-dioxo-5,8-dihydroquinoxalin-6-yl)-2-((4-fluorophenyl)amino)acetamide, compound 21).

[0429] Dark purple solid, 73.7 mg (55.2%)

[0430] 1 H NMR (400 MHz, CHLOROFORM-D) δ 9.76 (s, 1H), 9.05 (d,J= 2.2 Hz, 1H), 9.00 (d,J= 2.2 Hz, 1H), 8.23 ​​(s, 1H), 7.00 - 6.91 (m, 2H), 6.69 - 6.61 (m, 2H), 4.38 (d,J= 5.5 Hz, 1H), 4.01 (d,J= 5.5 Hz, 2H).

[0431]

[0432] Example 22: Synthesis of Compound 22

[0433]

[0434] G (120 mg, 585 μmol) was dissolved in DCM (5.9 mL) and stirred at 0°C. At the same temperature, pyridine (140 μL, 1.76 mmol) and 2-Furoyl chloride (69 μL, 702 μmol) were slowly added. After stirring at room temperature for 45 min, the reaction solution was poured onto ice to quench. After extraction several times with saturated aqueous NaCl solution and DCM, the separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / Hex) to obtain the target compound (N-(5,8-dimethoxyquinoxalin-6-yl)furan-2-carboxamide, 22a).

[0435] Light yellow solid, 156 mg (89.4%)

[0436] 1 H NMR (400 MHz, CHLOROFORM-D) δ 9.14 (s, 1H), 8.86 (d,J= 1.8 Hz, 1H), 8.77 (d,J= 1.8 Hz, 1H), 8.61 (s, 1H), 7.63 (dd,J= 1.8, 0.9 Hz, 1H), 7.32 (dd,J= 3.5, 0.8 Hz, 1H), 6.63 (dd,J= 3.5, 1.8 Hz, 1H), 4.20 (s, 3H), 4.14 (s, 3H).

[0437]

[0438] 22a (153 mg, 513 μmol) was stirred at 0°C with MeCN (1.2 mL) and water (1.2 mL). At the same temperature, ceric ammonium nitrate (CAN) (703 mg, 1.28 mmol) was dissolved in MeCN (4.7 mL) and water (0.23 mL) and added to the reaction solution. Stirred at room temperature for 1 h, concentrated to remove MeCN, and extracted several times with saturated NaCl aqueous solution and DCM. The separated organic layer was dried over MgSO4, filtered, and 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 (N-(5,8-dioxo-5,8-dihydroquinoxalin-6-yl)furan-2-carbox amide, compound 22).

[0439] Yellow solid, 76.1 mg (55.1%)

[0440] 1 H NMR (400 MHz, CHLOROFORM-D) δ 9.34 (s, 1H), 9.09 (d,J= 2.2 Hz, 1H), 9.05 (d,J= 2.2 Hz, 1H), 8.28 (s, 1H), 7.67 (dd,J= 1.7, 0.8 Hz, 1H), 7.39 (dd,J= 3.7, 0.8 Hz, 1H), 6.65 (dd,J= 3.6, 1.8 Hz, 1H).

[0441]

[0442] Example 23: Synthesis of Compound 23

[0443]

[0444] G (120 mg, 585 μmol) was dissolved in DCM (5.9 mL) and stirred at 0°C. At the same temperature, pyridine (140 μL, 1.76 mmol) and Thiophene-2-carbonyl chloride (75 μL, 702 μmol) were slowly added. After stirring at room temperature for 1 h, the reaction solution was quenched by pouring it onto ice. After extracting several times with saturated aqueous NaCl solution and DCM, the separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) to obtain the target compound (N-(5,8-dimethoxy-quinoxalin-6-yl)thiophene-2-carboxamide, 23a).

[0445] Yellow solid, 175 mg (95.1%)

[0446] 1 H NMR (400 MHz, CHLOROFORM-D) δ 8.85 (d,J= 1.8 Hz, 1H), 8.80 (s, 1H), 8.78 (d,J= 1.8 Hz, 1H), 8.56 (s, 1H), 7.73 (dd,J= 3.8, 1.1 Hz, 1H), 7.64 (dd,J= 5.0, 1.2 Hz, 1H), 7.21 (dd,J= 4.9, 3.8 Hz, 1H), 4.20 (s, 3H), 4.14 (s, 3H).

[0447]

[0448] 23a (172 mg, 544 μmol) was stirred at 0°C with MeCN (1.2 mL) and water (1.2 mL). At the same temperature, ceric ammonium nitrate (CAN) (746 mg, 1.36 mmol) was dissolved in MeCN (5.0 mL) and water (0.25 mL) and added to the reaction solution. Stirred at room temperature for 1 h, concentrated to remove MeCN, and extracted several times with saturated aqueous NaCl solution and DCM. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / Hex) to obtain the target compound (N-(5,8-dioxo-5,8-dihydroquinoxalin-6-yl)thiophene-2-carboxamide, compound 23).

[0449] Yellow solid, 80.8 mg (52.1%)

[0450] 1 H NMR (400 MHz, CHLOROFORM-D) δ 9.09 (d,J= 2.2 Hz, 1H), 9.04 (d,J= 2.2 Hz, 1H), 9.00 (s, 1H), 8.24 (s, 1H), 7.79 (dd,J= 3.8, 1.2 Hz, 1H), 7.71 (dd,J= 4.9, 1.1 Hz, 1H), 7.22 (dd,J= 5.0, 3.8 Hz, 1H).

[0451]

[0452] Example 24: Synthesis of Compound 24

[0453]

[0454] G (121 mg, 590 μmol) was dissolved in DCM (5.9 mL) and stirred at 0°C. At the same temperature, pyridine (95 μL, 1.18 mmol) and isoxazole-5-carbonyl chloride (74 μL, 766 μmol) were slowly added. After stirring at room temperature for 1.5 h, distilled water and DCM were added and extracted several times. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by recrystallization (DCM / Hex) to obtain the target compound (N-(5,8-dimethoxyquinoxalin-6-yl)isoxazole-5-carboxamide, 24a).

[0455] Light yellow solid, 173 mg (97.5%)

[0456] 1 H NMR (400 MHz, CHLOROFORM-D) δ 9.32 (s, 1H), 8.89 (d,J= 1.8 Hz, 1H), 8.82 (d,J= 1.8 Hz, 1H), 8.52 (s, 1H), 8.46 (d,J= 1.8 Hz, 1H), 7.10 (d,J= 1.8 Hz, 1H), 4.25 (s, 3H), 4.15 (s, 3H).

[0457]

[0458] 24a (172 mg, 573 μmol) was stirred at 0°C with MeCN (1.4 mL) and distilled water (1.4 mL). At the same temperature, ceric ammonium nitrate (CAN) (785 mg, 1.43 mmol) was dissolved in MeCN (5.5 mL) and distilled water (0.27 mL) and added to the reaction solution. Stirred at room temperature for 15 minutes, concentrated to remove MeCN, and extracted several times with distilled water and DCM. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) and recrystallized (EtOAc / Hex) to obtain the target compound (N-(5,8-dioxo-5,8-dihydroquinoxalin-6-yl)isoxazole-5-carboxamide, compound 24).

[0459] Light yellow solid, 95.5 mg (61.7 %)

[0460] 1 H NMR (400 MHz, CHLOROFORM-D) δ 9.49 (s, 1H), 9.11 (dd,J= 2.2, 0.8 Hz, 1H), 9.08 (dd,J= 2.3, 0.8 Hz, 1H), 8.48 (dd,J= 1.9, 0.7 Hz, 1H), 8.28 (d,J= 0.8 Hz, 1H), 7.17 (dd,J= 1.8, 0.7 Hz, 1H).

[0461]

[0462] Example 25: Synthesis of Compound 25

[0463]

[0464] J (108 mg, 365 μmol) was stirred at room temperature with MeCN (3.7 mL). At the same temperature, KI (6.1 mg, 36.5 μmol), p-anisidine (53.9 mg, 438 μmol), and K2CO3 (55.5 mg, 401 μmol) were added, and the mixture was stirred at 50°C for further 15 h. After cooling the reaction solution to room temperature, distilled water and DCM were added, and extraction was performed several times. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / MeOH) and recrystallization (EtOAc / Hex) to obtain the target compound (N-(5,8-dioxo-5,8-dihydroquinoxalin-6-yl)-2-((4-methoxyphenyl)amino)acetamide, compound 25).

[0465] Dark brown solid, 46.1 mg (37.3%)

[0466] 1 H NMR (400 MHz, CHLOROFORM-D) δ 9.91 (s, 1H), 9.05 (d,J= 2.2 Hz, 1H), 8.99 (d,J= 2.2 Hz, 1H), 8.24 (s, 1H), 6.84 - 6.79 (m, 2H), 6.69 - 6.62 (m, 2H), 3.98 (d,J= 5.3 Hz, 2H), 3.74 (s, 3H).

[0467]

[0468] Example 26: Synthesis of compound 26

[0469]

[0470] G (120 mg, 585 μmol) was dissolved in DCM (5.9 mL) and stirred at 0°C. At the same temperature, pyridine (140 μL, 1.76 mmol) and Nicotinoyl chloride hydrochloride (125 mg, 702 μmol) were slowly added. After stirring at room temperature for 1.5 h, the reaction solution was poured onto ice to quench. After extraction several times with saturated aqueous NaCl solution and DCM, the separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / MeOH) to obtain the target compound (N-(5,8-dimethoxyquinoxalin-6-yl)nicotinamide, 26a).

[0471] Yellow solid, 167 mg (92.2%)

[0472] 1 H NMR (400 MHz, CHLOROFORM-D) δ 9.21 (d,J= 2.4 Hz, 1H), 8.94 (s, 1H), 8.88 - 8.84 (m, 2H), 8.80 (d,J= 1.8 Hz, 1H), 8.58 (s, 1H), 8.29 (dt,J= 8.0, 2.0 Hz, 1H), 7.53 (dd,J= 8.7, 4.9 Hz, 1H), 4.22 (s, 3H), 4.17 (s, 3H).

[0473]

[0474] 26a (164 mg, 529 μmol) was mixed with MeCN (1.2 mL) and water (1.2 mL) and stirred at 0°C. At the same temperature, ceric ammonium nitrate (CAN) (480 mg, 876 μmol) was dissolved in MeCN (3.2 mL) and water (0.16 mL) and added to the reaction solution. Stirred at room temperature for 1 h, concentrated to remove MeCN. Adjusted to pH 8–9 with saturated aqueous NaHCO3 solution, then extracted several times with saturated aqueous NaCl solution and DCM. The separated organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / MeOH) to obtain the target compound (N-(5,8-dioxo-5,8-dihydroquinoxalin-6-yl)nicotinamide, compound 26).

[0475] Yellow solid, 88.2 mg (59.5%)

[0476] 1 H NMR (400 MHz, CHLOROFORM-D) δ 9.22 (d,J= 3.3 Hz, 1H), 9.17 (s, 1H), 9.11 (d,J= 2.2 Hz, 1H), 9.06 (d,J= 2.2 Hz, 1H), 8.89 (dd,J= 4.9, 1.7 Hz, 1H), 8.33 (s, 1H), 8.27 (ddd,J= 8.0, 2.5, 1.7 Hz, 1H), 7.54 (ddd,J= 8.0, 4.9, 0.9 Hz, 1H).

[0477]

[0478] Example 27: Synthesis of compound 27

[0479]

[0480] G (200 mg, 975 μmol) was dissolved in DCM (9.8 mL) and stirred at 0°C. At the same temperature, pyridine (140 μL, 1.76 mmol) and 4-(Trifluoromethyl)benzoyl chloride (170 μL, 1.17 mmol) were slowly added. After stirring at room temperature for 1.5 h, the reaction solution was poured onto ice to quench. After extraction several times with saturated aqueous NaCl solution and DCM, the separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / Hex) to obtain the target compound (N-(5,8-dimethoxyquinoxalin-6-yl)-4-(trifluoromethyl)benzamide, 27a).

[0481] Yellow solid, 348 mg (94.6%)

[0482] 1 H NMR (400 MHz, CHLOROFORM-D) δ 8.94 (s, 1H), 8.87 (d,J= 1.8 Hz, 1H), 8.80 (d,J= 1.8 Hz, 1H), 8.59 (s, 1H), 8.08 (d,J= 9.5 Hz, 2H), 7.84 (d,J= 9.5 Hz, 2H), 4.21 (s, 3H), 4.17 (s, 3H).

[0483]

[0484] 27a (120 mg, 318 μmol) was mixed with MeCN (0.7 mL) and water (0.7 mL) and stirred at 0°C. At the same temperature, ceric ammonium nitrate (CAN) (436 mg, 795 μmol) was dissolved in MeCN (2.9 mL) and water (0.15 mL) and added to the reaction solution. Stirred at room temperature for 2 h, concentrated to remove MeCN, and extracted several times with saturated aqueous NaCl solution and DCM. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / Hex) to obtain the target compound (N-(5,8-dioxo-5,8-dihydroquinoxalin-6-yl)-4-(trifluoromethyl)benzamide, compound 27).

[0485] Light yellow solid, 62.8 mg (56.9%)

[0486] 1 H NMR (400 MHz, CHLOROFORM-D) δ 9.19 (s, 1H), 9.11 (d,J= 2.3 Hz, 1H), 9.06 (d,J= 2.3 Hz, 1H), 8.34 (s, 1H), 8.09 (d,J= 8.1 Hz, 2H), 7.85 (d,J=8.1 Hz, 2H).

[0487]

[0488] Example 28: Synthesis of compounds 28 and 29

[0489]

[0490] G (500 mg, 2.44 mmol) was dissolved in DCM (24.4 mL) and stirred at 0°C. At the same temperature, pyridine (0.59 mL, 7.31 mmol) and 2-Bromopropionyl chloride (0.30 mL, 2.92 mmol) were slowly added. After stirring at room temperature for 3 h, the reaction solution was poured onto ice to quench. After extraction several times with saturated aqueous NaCl solution and DCM, the separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / Hex) and recrystallized (EtOAc / Hex) to obtain the target compound (2-bromo-N-(5,8-dimethoxyquinoxalin-6-yl)propanamide, 29a).

[0491] Yellow solid, 694 mg (83.6%)

[0492] 1 H NMR (400 MHz, CHLOROFORM-D) δ 9.06 (s, 1H), 8.85 (d,J= 1.8 Hz, 1H), 8.78 (d,J= 1.8 Hz, 1H), 8.39 (s, 1H), 4.65 (q,J= 7.0 Hz, 1H), 4.16 (s, 3H), 4.12 (s, 3H), 2.02 (d,J= 7.0 Hz, 3H).

[0493]

[0494] 29a (670 mg, 1.97 mmol) was mixed with MeCN (4.3 mL) and water (4.3 mL) and stirred at 0°C. At the same temperature, ceric ammonium nitrate (CAN) (2.70 g, 4.92 mmol) was dissolved in MeCN (18 mL) and water (0.9 mL) and added to the reaction solution. Stirred at room temperature for 30 minutes, concentrated to remove MeCN. After extracting several times with saturated aqueous NaCl solution and DCM, the separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / Hex) and recrystallized (EtOAc / Hex) to obtain the target compound (2-bromo-N-(5,8-dioxo-5,8-dihydroquinoxalin-6-yl)propan amide, compound 29).

[0495] Yellow solid, 365 mg (59.7%)

[0496] 1 H NMR (400 MHz, CHLOROFORM-D) δ 9.13 (s, 1H), 9.08 (d,J= 2.2 Hz, 1H), 9.04 (d,J= 2.2 Hz, 1H), 8.13 (s, 1H), 4.61 (q,J= 7.0 Hz, 1H), 1.97 (d,J= 7.0 Hz, 3H).

[0497] Add MeCN (3.9 mL) to 29 (120 mg, 387 μmol) and stir at room temperature. At the same temperature, add p-Anisidine (57.2 mg, 464 μmol), potassium iodide (KI) (6.4 mg, 38.7 μmol), and potassium carbonate (K2CO3) (58.8 mg, 426 μmol) and stir for 20.5 h. After extracting several times with saturated aqueous NaCl solution and DCM, the separated organic layer was dried over MgSO4, filtered, and 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 (N-(5,8-dimethoxyquinoxalin-6-yl)-2-((4-methoxyphenyl)amino)propanamide, compound 28).

[0498] Brown solid, 12.7 mg (9.3%)

[0499] 1 H NMR (400 MHz, DMSO-D6) δ 10.07 (s, 1H), 9.06 (d,J= 2.3 Hz, 1H), 9.03 (d,J= 2.3 Hz, 1H), 7.79 (s, 1H), 6.75 (d,J= 9.0 Hz, 2H), 6.61 (d,J= 9.1 Hz, 2H), 5.93 - 5.89 (m, 1H), 4.20 - 4.10 (m, 1H), 3.62 (s, 3H), 1.41 (d,J= 7.0 Hz, 3H).

[0500]

[0501] Example 29: Synthesis of compound 30

[0502]

[0503] Add MeCN (3.7 mL) to J (110 mg, 372 μmol) and stir at room temperature. At the same temperature, add KI (6.2 mg, 37.2 μmol), o-anisidine (50.4 μL, 446 μmol), and K2CO3 (56.5 mg, 409 μmol), and stir for 17.5 hours at room temperature and 5.5 hours at 50°C. Cool the reaction solution to room temperature, add distilled water and DCM, and extract several times. The separated organic layer is dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (DCM / MeOH) and purified by recrystallization (EtOAc) to obtain the target compound (N-(5,8-dioxo-5,8-dihydroquinoxalin-6-yl)-2-((2-methoxyphenyl)amino)acetamide, compound 30).

[0504] Black solid, 38.3 mg (30.4%)

[0505] 1 H NMR (400 MHz, DMSO-D6) δ 10.06 (s, 1H), 9.10 - 9.01 (m, 2H), 7.80 (s, 1H), 6.88 (dd,J= 7.9, 1.4 Hz, 1H), 6.77 (td,J= 7.6, 1.3 Hz, 1H), 6.64 (td,J= 7.7, 1.5 Hz, 1H), 6.45 (dd,J= 7.8, 1.5 Hz, 1H), 5.72 (t,J= 6.2 Hz, 1H), 4.08 (d,J= 6.2 Hz, 2H), 3.85 (s, 3H).

[0506]

[0507] Example 30: Synthesis of compound 31

[0508]

[0509] J (110 mg, 372 μmol) was stirred at room temperature with MeCN (3.7 mL). At the same temperature, KI (6.2 mg, 37.2 μmol), 3,5-dimethoxyaniline (74.0 mg, 483 μmol), and K2CO3 (56.5 mg, 409 μmol) were added, and the mixture was stirred at 50°C for further 21 h. After cooling the reaction solution to room temperature, distilled water and DCM were added, and extraction was performed several times. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / MeOH) and recrystallized (EtOAc) to obtain the target compound (2-((3,5-dimethoxyphenyl)amino)-N-(5,8-dioxo-5,8-dihydroquinoxalin-6-yl)acetamide, compound 31).

[0510] Dark brown solid, 54.6 mg (39.8%)

[0511] 1 H NMR (500 MHz, DMSO-D6) δ 10.00 (s, 1H), 9.09 - 9.03 (m, 2H), 7.81 (s, 1H), 6.32 (t,J= 6.2 Hz, 1H), 5.82 (s, 3H), 4.05 (d,J= 6.1 Hz, 2H), 3.65 (s, 6H).

[0512]

[0513] Example 31: Synthesis of compound 32

[0514]

[0515] Add MeCN (3.7 mL) to J (110 mg, 372 μmol) and stir at room temperature. At the same temperature, add KI (6.2 mg, 37.2 μmol), m-anisidine (54 μL, 483 μmol), and K2CO3 (56.5 mg, 409 μmol) and stir at 55°C for further 25.5 h. Cool the reaction solution to room temperature, add saturated NaCl aqueous solution and DCM, and extract several times. The separated organic layer is dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / Hex) and recrystallized (EtOAc) to obtain the target compound (N-(5,8-dioxo-5,8-dihydroquinoxalin-6-yl)-2-((3-methoxyphenyl)amino)acetamide, compound 32).

[0516] Dark brown solid, 48.5 mg (38.5%)

[0517] 1 H NMR (500 MHz, DMSO-D6) δ 10.01 (s, 1H), 9.10 - 9.00 (m, 2H), 7.81 (s, 1H), 7.02 (t,J= 8.1 Hz, 1H), 6.33 (t,J= 6.3 Hz, 1H), 6.29 - 6.13 (m, 3H), 4.06 (d,J= 6.1 Hz, 2H), 3.67 (s, 3H).

[0518]

[0519] Example 32: Synthesis of compounds 33 and 34

[0520]

[0521] Add AcOH (22 mL) to E (1.74 g, 10.8 mmol) and stir at room temperature. Dilute bromine (1.11 mL, 21.7 mmol) in AcOH (11 mL) and slowly add it at the same temperature. After stirring for 1.5 hours at room temperature, add sodium acetate (NaOAc) (1.78 g, 21.7 mmol) and heat at 120-130℃ for 10 minutes. Cool the reaction solution to 90℃ and quench it by adding water (88 mL). After cooling the reaction solution to 0℃, filter the formed solid and wash it several times with water. Dry the obtained solid under reduced pressure under P2O5 to obtain the target compound (6,7-dibromoquinoxaline-5,8-dione, K).

[0522] Yellow solid, 1.93 g (56.3%)

[0523] 1 H NMR (400 MHz, DMSO-D6) δ 9.09 (s, 2H).

[0524]

[0525] Add EtOH (6.3 mL) to K (200 mg, 629 μmol) and stir at room temperature. At the same temperature, add 3-aminobenzotrifluoride (117 μL, 944 μmol) and CeCl3·7H2O (11.7 mg, 31.5 μmol), stir at room temperature for another 23.5 h, and then concentrate to remove EtOH. After adding saturated aqueous NaCl solution and DCM and extracting several times, the separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOH / Ether) to obtain the target compound (6-bromo-7-((3-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione, compound 34).

[0526] Dark violet solid, 108 mg (43.2%)

[0527] 1 H NMR (500 MHz, DMSO-D6) δ 9.64 (s, 1H), 9.09 - 9.00 (m, 2H), 7.59 - 7.41 (m, 4H).

[0528]

[0529] Add EtOH (1.2 mL) to 34 (92.4 mg, 232 μmol) and stir at 0℃. At the same temperature, add sodium thiomethoxide (NaSMe) (32.5 mg, 464 μmol). The reaction solution is stirred at room temperature for 3 more hours and then concentrated under reduced pressure to remove EtOH. Add distilled water, adjust the pH to 7-8 with 1 M HCl, and extract several times with DCM. The separated organic layer is dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / MeOH) to obtain the target compound (6-(methylthio)-7-((3-(trifluoro-methyl)phenyl)amino)quinoxaline-5,8-dione, compound 33).

[0530] Red solid, 18.4 mg (21.7%)

[0531] 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).

[0532]

[0533] Example 33: Synthesis of compound 35

[0534]

[0535] E (198 mg, 1.24 mmol) was dissolved in CHCl3 (25 mL) and stirred at 0°C. At the same temperature, pyridine (1.0 mL, 12.4 mmol) and SOCl2 (406 μL, 5.56 mmol) were added. The reaction solution was stirred under reflux conditions for 5 hours. After the reaction was completed, the hot solution was filtered and the filtrate was cooled to room temperature. The filtrate was washed twice with a small amount of water, and the obtained organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by recrystallization (DCM / Hex) to obtain the target compound (6,7-dichloroquinoxaline-5,8-dione, L).

[0536] Orange solid, 99.8 mg (35.1%)

[0537] 1 H NMR (500 MHz, DMSO-D6) δ 9.13 (s, 2H).

[0538]

[0539] Add EtOH (4.2 mL) to L (95.0 mg, 415 μmol) and stir at room temperature. At the same temperature, add 3-aminobenzotrifluoride (77 μL, 622 μmol) and CeCl3·7H2O (7.7 mg, 20.7 μmol), stir at room temperature for another 26 h, and then concentrate to remove EtOH. Add distilled water and DCM, and extract several times. The separated organic layer is dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate is purified by recrystallization (EtOH / Ether) to obtain the target compound (6-chloro-7-((3-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione, compound 35).

[0540] Dark violet solid, 109 mg (74.5%)

[0541] 1H NMR (500 MHz, DMSO-D6) δ 9.70 (s, 1H), 9.06 (d,J= 2.3 Hz, 1H), 9.04 (d,J= 2.3 Hz, 1H), 7.56 (t,J= 7.9 Hz, 1H), 7.50 - 7.41 (m, 3H).

[0542]

[0543] Example 34: Synthesis of compounds 36 and 38

[0544]

[0545] Add EtOH (6.3 mL) to K (200 mg, 629 μmol) and stir at room temperature. At the same temperature, add 5-amino-2-fluorobenzotrifluoride (120 μL, 944 μmol) and CeCl3·7H2O (11.7 mg, 31.5 μmol), stir at room temperature for another 15 h, and then concentrate to remove EtOH. After adding distilled water and DCM and extracting several times, the separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / Hex) and recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo -7-((4-fluoro-3-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione, compound 36).

[0546] Red solid, 218 mg (83.4%)

[0547] 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).

[0548]

[0549] Add EtOH (2.1 mL) to 36 (172 mg, 413 μmol) and stir at 0℃. At the same temperature, add sodium thiomethoxide (NaSMe) (57.9 mg, 827 μmol). The reaction solution is stirred at room temperature for 3 more hours and then concentrated under reduced pressure to remove EtOH. Distilled water is added, pH is adjusted to 7-8 with 1 M HCl aqueous solution, and extracted several times with DCM. The separated organic layer is dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography (EtOAc / Hex) to obtain the target compound (6-((4-fluoro-3-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, compound 38).

[0550] Red solid, 43.9 mg (27.7%)

[0551] 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).

[0552]

[0553] Example 35: Synthesis of compound 37

[0554]

[0555] Add EtOH (6.3 mL) to K (200 mg, 629 μmol) and stir at room temperature. At the same temperature, add 4-fluoroaniline (91 μL, 944 μmol) and CeCl3·7H2O (11.7 mg, 31.5 μmol), stir at room temperature for another 18 h, and then concentrate to remove EtOH. After adding distilled water and DCM and extracting several times, the separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / Hex) and recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-((4-fluoro-phenyl)amino)quinoxaline-5,8-dione, compound 37).

[0556] Red purple solid, 161 mg (73.4%)

[0557] 1 H NMR (500 MHz, DMSO-D6) δ 9.50 (s, 1H), 9.06 - 8.96 (m, 2H), 7.24 - 7.15 (m, 4H).

[0558]

[0559] Example 36: Synthesis of compound 39

[0560]

[0561] Add EtOH (6.3 mL) to K (200 mg, 629 μmol) and stir at room temperature. At the same temperature, add 2,6-Dimethoxyaniline (145 mg, 944 μmol) and CeCl3·7H2O (12 mg, 31.5 μmol), stir at room temperature for another 15 h, and then concentrate to remove EtOH. After adding saturated NaCl aqueous solution and DCM and extracting several times, the separated organic layer was dried over MgSO4, filtered, and 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-((2,6-dimethoxyphenyl)amino)quinoxaline-5,8-dione, compound 39).

[0562] Dark violet solid, 193 mg (78.7%)

[0563] 1 H NMR (500 MHz, DMSO-D6) δ 9.01 (d,J= 2.3 Hz, 1H), 8.98 (d,J= 2.4 Hz, 1H), 8.56 (s, 1H), 7.25 (t,J= 8.3 Hz, 1H), 6.70 (d,J= 8.5 Hz, 2H), 3.72 (s, 6H).

[0564]

[0565] Example 37: Synthesis of compound 40

[0566]

[0567] Add EtOH (6.3 mL) to K (200 mg, 629 μmol) and stir at room temperature. At the same temperature, add 3,4-Dimethoxyaniline (145 mg, 944 μmol) and CeCl3·7H2O (12 mg, 31.5 μmol), stir at room temperature for another 16 h, and then concentrate to remove EtOH. After adding saturated NaCl aqueous solution and DCM and extracting several times, the separated organic layer was dried over MgSO4, filtered, and 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-((3,4-dimethoxyphenyl)amino)quinoxaline-5,8-dione, compound 40).

[0568] Dark brown solid, 93.4 mg (38.1%)

[0569] 1 H NMR (500 MHz, DMSO-D6) δ 9.41 (s, 1H), 9.02 (d,J= 2.3 Hz, 1H), 9.00 (d,J= 2.3 Hz, 1H), 6.91 (d,J= 8.5 Hz, 1H), 6.86 (d,J= 2.4 Hz, 1H), 6.73 (dd,J= 8.6, 2.5 Hz, 1H), 3.76 (s, 3H), 3.70 (s, 3H).

[0570]

[0571] Example 38: Synthesis of compound 41

[0572]

[0573] Add EtOH (3.8 mL) to K (120 mg, 377 μmol) and stir at room temperature. At the same temperature, add p-Anisidine (70 mg, 566 μmol) and CeCl3·7H2O (7 mg, 18.9 μmol), stir at room temperature for another 16 h, and then concentrate to remove EtOH. After adding saturated NaCl aqueous solution and DCM and extracting several times, the separated organic layer was dried over MgSO4, filtered, and 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-((4-methoxyphenyl)amino)quinoxaline-5,8-dione, compound 41).

[0574] Dark brown solid, 105 mg (77.3%)

[0575] 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).

[0576]

[0577] Example 39: Synthesis of compound 42

[0578]

[0579] Add EtOH (3.8 mL) to K (120 mg, 377 μmol) and stir at room temperature. At the same temperature, add o-Anisidine (70 mg, 566 μmol) and CeCl3·7H2O (7 mg, 18.9 μmol), stir at room temperature for another 16 h, and then concentrate to remove EtOH. After adding saturated aqueous NaCl solution and DCM and extracting several times, the separated organic layer was dried over MgSO4, filtered, and 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-((2-methoxyphenyl)amino)quinoxaline-5,8-dione, compound 42).

[0580] Dark orange solid, 96 mg (70.7%)

[0581] 1 H NMR (500 MHz, DMSO-D6) δ 9.05 (s, 1H), 9.02 (d,J= 2.3 Hz, 1H), 8.99 (d,J= 2.3 Hz, 1H), 7.21 (d,J= 7.5 Hz, 2H), 7.02 (d,J= 7.5 Hz, 1H), 6.95 (t,J= 7.6 Hz, 1H), 3.67 (s, 3H).

[0582]

[0583] Example 40: Synthesis of compound 43

[0584]

[0585] Add EtOH (3.8 mL) to K (120 mg, 377 μmol) and stir at room temperature. At the same temperature, add m-Anisidine (70 mg, 566 μmol) and CeCl3·7H2O (7 mg, 18.9 μmol), stir at room temperature for another 16 h, and then concentrate to remove EtOH. After adding saturated NaCl aqueous solution and DCM and extracting several times, the separated organic layer was dried over MgSO4, filtered, and 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, compound 43).

[0586] Red brown solid, 61.8 mg (45.5%)

[0587] 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).

[0588]

[0589] Example 41: Synthesis of compounds 44 and 46

[0590]

[0591] Add EtOH (6.3 mL) to K (200 mg, 629 μmol) and stir at room temperature. At the same temperature, add 3-Methoxy-5-(trifluoromethyl)aniline (180 mg, 944 μmol) and CeCl3·7H2O (12 mg, 31.5 μmol), stir at room temperature for another 17 h, and then concentrate to remove EtOH. After adding saturated NaCl aqueous solution and DCM and extracting several times, the separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / Hex) and recrystallization (Ether / Hex) to obtain the target compound (6-bromo-7-((3-methoxy-5-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione, compound 44).

[0592] Red brown solid, 188 mg (69.7%)

[0593] 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).

[0594]

[0595] Add EtOH (3.5 mL) to 44 (150 mg, 350 μmol) and stir at 0°C. At the same temperature, add sodium thiomethoxide (NaSMe) (49 mg, 701 μmol) and stir for 5 minutes. The reaction solution is stirred at room temperature for another 10 minutes and then poured onto ice to quench. After adding saturated NaCl aqueous solution and DCM and extracting several times, the separated organic layer is dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / Hex) and purified by recrystallization (Ether / Hex) to obtain the target compound (6-((3-methoxy-5-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, compound 46).

[0596] Dark violet solid, 64.3 mg (46.5%)

[0597] 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).

[0598]

[0599] Example 42: Synthesis of compounds 45 and 47

[0600]

[0601] Add EtOH (6.3 mL) to K (200 mg, 629 μmol) and stir at room temperature. At the same temperature, add 2-Methoxy-5-(trifluoromethyl)aniline (180 mg, 944 μmol) and CeCl3·7H2O (12 mg, 31.5 μmol), stir at room temperature for another 19 h, and then concentrate to remove EtOH. After adding saturated aqueous NaCl solution and DCM and extracting several times, the separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / Hex) and recrystallization (Ether / Hex) to obtain the target compound (6-bromo-7-((2-methoxy-5-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione, compound 45).

[0602] burgundy solid, 181 mg (67.0%)

[0603] 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).

[0604]

[0605] Add EtOH (3.3 mL) to 45 (140 mg, 327 μmol) and stir at 0°C. At the same temperature, add sodium thiomethoxide (NaSMe) (46 mg, 654 μmol) and stir for 5 minutes. The reaction solution is stirred at room temperature for another 30 minutes and then poured onto ice to quench. After adding saturated NaCl aqueous solution and DCM and extracting several times, the separated organic layer is dried over MgSO4, filtered, and 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-((2-methoxy-5-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, compound 47).

[0606] Dark violet solid, 68.1 mg (52.7%)

[0607] 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).

[0608]

[0609] Example 43: Synthesis of compounds 48 and 50

[0610]

[0611] Add EtOH (6.3 mL) to K (200 mg, 629 μmol) and stir at room temperature. At the same temperature, add 2-Methyl-3-trifluoromethylaniline (165 mg, 944 μmol) and CeCl3·7H2O (12 mg, 31.5 μmol), stir at room temperature for another 17.5 h, and then concentrate to remove EtOH. After adding saturated NaCl aqueous solution and DCM and extracting several times, the separated organic layer was dried over MgSO4, filtered, and 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-((2-methyl-3-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione, compound 48).

[0612] Red solid, 135 mg (52.1%)

[0613] 1 H NMR (500 MHz, DMSO-D6) δ 9.35 (s, 1H), 9.04 - 9.02 (m, 1H), 9.01 (d,J= 2.4 Hz, 1H), 7.62 (d,J= 7.1 Hz, 1H), 7.48 (d,J= 7.5 Hz, 1H), 7.39 (t,J= 7.8 Hz, 1H), 2.35 (s, 3H).

[0614]

[0615] Add EtOH (2.4 mL) to 48 (100 mg, 243 μmol) and stir at 0℃. At the same temperature, add sodium thiomethoxide (NaSMe) (34 mg, 485 μmol) and stir for 5 minutes. The reaction solution is stirred at room temperature for 10 more minutes and then poured onto ice to quench. After adding saturated NaCl aqueous solution and DCM and extracting several times, the separated organic layer is dried over MgSO4, filtered, and 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-((2-methyl-3-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, compound 50).

[0616] Red brown solid, 53.2 mg (57.7%)

[0617] 1 H NMR (500 MHz, DMSO-D6) δ 9.03 (s, 1H), 9.02 (d,J= 2.4 Hz, 1H), 8.98 (d,J= 2.4 Hz, 1H), 7.54 (dd,J= 6.8, 2.5 Hz, 1H), 7.36 (d,J= 6.4 Hz, 2H), 2.39 (s, 3H), 2.09 (s, 3H).

[0618]

[0619] Example 44: Synthesis of compound 49

[0620]

[0621] Add EtOH (6.3 mL) to K (200 mg, 629 μmol) and stir at room temperature. At the same temperature, add 4'-Amino-3'-(trifluoromethyl)acetanilide (206 mg, 944 μmol) and CeCl3·7H2O (12 mg, 31.5 μmol), stir for another 40 hours at room temperature, and then concentrate to remove EtOH. Add saturated NaCl aqueous solution and DCM, extract several times, and separate the organic layer, dry over MgSO4, filter, and concentrate 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 (N-(4-((7-bromo-5,8-dioxo-5,8-dihydroquinoxalin-6-yl)amino)-3-(trifluoromethyl)phenyl)acetamide, compound 49).

[0622] Orange brown solid, 61 mg (21.3%)

[0623] 1 H NMR (500 MHz, DMSO-D6) δ 10.32 (s, 1H), 9.10 (d,J= 21.3 Hz, 1H), 9.06 - 8.95 (m, 2H), 8.13 - 8.04 (m, 1H), 7.75 (dt,J= 8.7, 2.8 Hz, 1H), 7.38 (dd,J= 8.6, 2.6 Hz, 1H), 2.09 (s, 3H).

[0624]

[0625] Example 45: Synthesis of compounds 51 and 53

[0626]

[0627] Add EtOH (7.8 mL) to K (249 mg, 783 μmol) and stir at room temperature. At the same temperature, add 4-methyl-2-(trifluoromethyl)aniline (160 μL, 1.17 mmol) and CeCl3·7H2O (15.0 mg, 39.2 μmol), stir at room temperature for another 22.5 h, and then concentrate to remove EtOH. After adding distilled water and DCM and extracting several times, the separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / Hex) and recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-((4-methyl-3-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione, compound 51).

[0628] Dark red violet solid, 266 mg (82.4%)

[0629] 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).

[0630]

[0631] Add EtOH (2.9 mL) to 51 (120 mg, 291 μmol) and stir at 0°C. At the same temperature, add sodium thiomethoxide (NaSMe) (40.8 mg, 582 μmol) and stir. The reaction solution is stirred at room temperature for 10 more minutes and then poured onto ice to quench. After adding saturated NaCl aqueous solution and DCM and extracting several times, the separated organic layer is dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate is separated by silica gel column chromatography (EtOAc / Hex) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((4-methyl-3-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, compound 53).

[0632] Reddish brown solid, 30.0 mg (27.2%)

[0633] 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).

[0634]

[0635] Example 46: Synthesis of compound 52

[0636]

[0637] Add EtOH (9.4 mL) to K (300 mg, 944 μmol) and stir at room temperature. At the same temperature, add 2-aminobenzotrifluoride (239 μL, 1.93 mmol) and CeCl3·7H2O (54.0 mg, 145 μmol), stir at room temperature for another week, and then concentrate to remove EtOH. After adding distilled water and DCM and extracting several times, the separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / Hex) and recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-((4-fluorophenyl)amino)quinoxaline-5,8-dione, 52a).

[0638] Red solid, 112 mg (29.8%)

[0639] 1 H NMR (400 MHz, DMSO-D6) δ 9.09 (d,J= 30.3 Hz, 1H), 9.05 - 9.00 (m, 2H), 7.78 (dd,J= 7.9, 1.5 Hz, 1H), 7.72 - 7.64 (m, 1H), 7.55 - 7.42 (m, 2H).

[0640]

[0641] Add EtOH (2.3 mL) to 52a (91.0 mg, 229 μmol) and stir at 0°C. At the same temperature, add sodium thiomethoxide (NaSMe) (32.0 mg, 457 μmol) and stir for 10 minutes. The reaction solution is stirred for another 10 minutes at room temperature and then poured onto ice to quench. After adding saturated NaCl aqueous solution and DCM and extracting several times, the separated organic layer is dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography (EtOAc / Hex) to obtain the target compound (6-(methylthio)-7-((2-(trifluoromethyl) phenyl)amino)quinoxaline-5,8-dione, compound 52).

[0642] Red purple solid, 43.7 mg (52.2%)

[0643] 1 H NMR (400 MHz, DMSO-D6) δ 9.03 (d,J= 2.3 Hz, 1H), 9.00 (d,J= 2.3 Hz, 1H), 8.60 (s, 1H), 7.76 - 7.71 (m, 1H), 7.64 (t,J= 7.7 Hz, 1H), 7.41 (t,J= 7.7 Hz, 1H), 7.30 (d,J= 8.0 Hz, 1H), 2.12 (s, 3H).

[0644]

[0645] Example 47: Synthesis of compounds 54 and 55

[0646]

[0647] Add EtOH (9.5 mL) to K (303 mg, 953 μmol) and stir at room temperature. At the same temperature, add 4-amino-2-fluorobenzotrifluoride (256 mg, 1.43 mmol) and CeCl3·7H2O (17.8 mg, 47.7 μmol), stir at room temperature for another 24.5 h, and then concentrate to remove EtOH. After adding distilled water and DCM and extracting several times, the separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / Hex) and recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-((3-fluoro-4-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione, compound 54).

[0648] Orange solid, 307 mg (77.3%)

[0649] 1 H NMR (400 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).

[0650]

[0651] Add EtOH (3.6 mL) to 54 (150 mg, 360 μmol) and stir at 0°C. At the same temperature, add sodium thiomethoxide (NaSMe) (32.0 mg, 457 μmol) and stir for 10 minutes. The reaction solution is stirred for another 10 minutes at room temperature and then poured onto ice to quench. After adding saturated NaCl aqueous solution and DCM and extracting several times, the separated organic layer is dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography (EtOAc / Hex) to obtain the target compound (6-((3-fluoro-4-(trifluoromethyl)phenyl) amino)-7-(methylthio)quinoxaline-5,8-dione, compound 55).

[0652] Reddish brown solid, 61.1 mg (44.3%)

[0653] 1 H NMR (400 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).

[0654]

[0655] Example 48: Synthesis of compound 56

[0656]

[0657] 54 (109 mg, 262 μmol) was dissolved in MeOH (6.6 mL) and DMF (6.6 mL), NaN3 (25.5 mg, 393 μmol) was added, and the mixture was stirred at room temperature for 18.5 h (darkness). After extracting several times with distilled water and DCM, the separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude intermediate was dissolved in EtOH (2.6 mL), NaBH4 (14.9 mg, 393 μmol) was added, and the mixture was stirred at room temperature for 2 h. After extracting several times with distilled water and DCM, the separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (DCM / MeOH) and purified by recrystallization (EtOH) to obtain the target compound (6-amino-7-((3-fluoro-4-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione, compound 56).

[0658] Black solid, 49.5 mg (53.6%)

[0659] 1 H NMR (400 MHz, DMSO-D6) δ 8.96 (d,J= 2.3 Hz, 1H), 8.92 (d,J= 2.3 Hz, 1H), 8.14 (s, 1H), 7.42 (t,J= 8.6 Hz, 1H), 7.07 (s, 2H), 6.69 - 6.55 (m, 2H).

[0660]

[0661] Example 49: Synthesis of compound 57

[0662]

[0663] Add EtOH (5.6 mL) to L (127 mg, 555 μmol) and stir at room temperature. At the same temperature, add p-anisidine (136 mg, 1.10 mmol) and CeCl3·7H2O (10.3 mg, 27.7 μmol), stir at room temperature for another 21 h, and then concentrate to remove EtOH. Add distilled water and DCM, and extract several times. The separated organic layer is dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / Hex) and recrystallized (EtOAc / Hex) to obtain the target compound (6-chloro-7-((4-methoxyphenyl) amino)quinoxaline-5,8-dione, compound 57).

[0664] Black solid, 78.6 mg (44.9%)

[0665] 1 H NMR (400 MHz, DMSO-D6) δ 9.45 (s, 1H), 9.03 (d,J= 2.3 Hz, 1H), 8.99 (d,J= 2.4 Hz, 1H), 7.13 - 7.08 (m, 2H), 6.93 - 6.88 (m, 2H), 3.77 (s, 3H).

[0666]

[0667] Example 50: Synthesis of compound 58

[0668]

[0669] Add EtOH (5.3 mL) to L (122 mg, 533 μmol) and stir at room temperature. At the same temperature, o-anisidine (90 μL, 799 μmol) and CeCl3·7H2O (9.92 mg, 26.6 μmol) are added, stirred at room temperature for another 22 h, and then concentrated to remove EtOH. After adding distilled water and DCM and extracting several times, the separated organic layer is dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / Hex) and recrystallization (EtOAc / Hex) to obtain the target compound (6-chloro-7-((2-methoxy phenyl)amino)quinoxaline-5,8-dione, compound 58).

[0670] Red solid, 42.2 mg (25.1%)

[0671] 1 H NMR (400 MHz, DMSO-D6) δ 9.09 (s, 1H), 9.03 (d,J= 2.4 Hz, 1H), 8.99 (d,J= 2.4 Hz, 1H), 7.27 - 7.13 (m, 2H), 7.03 (dd,J= 8.3, 1.3 Hz, 1H), 6.99 - 6.91 (m, 1H), 3.69 (s, 3H).

[0672]

[0673] Example 51: Synthesis of compound 59

[0674]

[0675] Add EtOH (5.9 mL) to L (135 mg, 589 μmol) and stir at room temperature. At the same temperature, add m-anisidine (130 μL, 1.18 mmol) and CeCl3·7H2O (11 mg, 29.5 μmol), stir for another 12.5 h at room temperature, and then concentrate to remove EtOH. After adding distilled water and DCM and extracting several times, the separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / Hex) and recrystallization (EtOAc / Hex) to obtain the target compound (6-chloro-7-((3-methoxyphenyl)amino) quinoxaline-5,8-dione, compound 59).

[0676] Red solid, 130 mg (70.0%)

[0677] 1 H NMR (400 MHz, DMSO-D6) δ 9.49 (s, 1H), 9.04 (d,J= 2.4 Hz, 1H), 9.01 (d,J= 2.3 Hz, 1H), 7.22 (t,J= 8.3 Hz, 1H), 6.77 - 6.70 (m, 3H), 3.73 (s, 3H).

[0678]

[0679] Example 52: Synthesis of compound 60

[0680]

[0681] Add EtOH (5.6 mL) to L (127 mg, 555 μmol) and stir at room temperature. At the same temperature, add 3,4-Dimethoxyaniline (127 mg, 832 μmol) and CeCl3·7H2O (10.3 mg, 27.7 μmol), stir at room temperature for another 19 hours, and then concentrate to remove EtOH. Add distilled water and DCM and extract several times. The separated organic layer is dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / Hex) and recrystallization (EtOAc / Hex) to obtain the target compound (6-chloro-7-((3,4-dimethoxyphenyl)amino)quinoxaline-5,8-dione, compound 60).

[0682] Black solid, 76.8 mg (40.0%)

[0683] 1 H NMR (400 MHz, DMSO-D6) δ 9.41 (s, 1H), 9.03 (d,J= 2.3 Hz, 1H), 9.00 (d,J= 2.3 Hz, 1H), 6.91 (d,J= 8.6 Hz, 1H), 6.85 (d,J= 2.4 Hz, 1H), 6.71 (dd,J= 8.5, 2.4 Hz, 1H), 3.76 (s, 3H), 3.70 (s, 3H).

[0684]

[0685] Example 53: Synthesis of compound 61

[0686]

[0687] Add EtOH (5.2 mL) to L (120 mg, 524 μmol) and stir at room temperature. At the same temperature, add 2,6-Dimethoxyaniline (120 mg, 786 mmol) and CeCl3·7H2O (10.0 mg, 26.2 μmol), stir at room temperature for another 19 hours, and then concentrate to remove EtOH. Add distilled water and DCM and extract several times. The separated organic layer is dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / Hex) and recrystallization (EtOAc / Hex) to obtain the target compound (6-chloro-7-((2,6-dimethoxyphenyl)amino)quinoxaline-5,8-dione, compound 61).

[0688] Dark violet solid, 76.1 mg (42.0%)

[0689] 1 H NMR (400 MHz, DMSO-D6) 9.02 (d,J= 2.4 Hz, 1H), 8.97 (d,J= 2.3 Hz, 1H), 8.69 (s, 1H), 7.25 (t,J= 8.4 Hz, 1H), 6.70 (d,J= 8.5 Hz, 2H), 3.72 (s, 6H).

[0690]

[0691] Example 54: Synthesis of compound 62

[0692]

[0693] 37 (310 mg, 890 μmol) was dissolved in THF (10.0 mL), sodium thiomethoxide (NaSMe) (120 mg, 1.59 mmol) was added, and the mixture was stirred at room temperature for 1 h. 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 over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was triturated with MTBE for 30 min and purified by Prep-HPLC (H2O / ACN) for the first time. The purified compound was purified again by Prep-TLC (petroleum ether / EtOAc) to obtain the target compound (6-((4-fluorophenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, compound 62).

[0694] Brown solid, 73.5 mg (26.2%)

[0695] 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).

[0696]

[0697] Example 55: Synthesis of compound 63

[0698]

[0699] K (5.00 g, 15.7 mmol) was dissolved in THF (50.0 mL), and then NaOMe (2.83 g, 15.7 mmol) was added. The mixture was stirred at room temperature for 1 h, and then distilled water was added at 0 °C. After several extractions with EtOAc, the separated organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the target compound (6-bromo-7-methoxyquinoxaline-5,8-dione, M).

[0700] Yellow solid, 3.60 g (80.8%)

[0701] 1 H NMR (400 MHz, DMSO-D6) δ 9.07 (dd,J= 2.3, 12.0 Hz, 2H), 4.26 (s, 3H).

[0702] M (200 mg, 743 μmol) and 4-chloroaniline (114 mg, 892 μmol) were added to MeOH (2.00 mL), degassed, and filled with nitrogen. The mixture was stirred at 60 °C for 1 h and then concentrated under reduced pressure to remove MeOH. The crude product was triturated with MTBE and petroleum ether for 15 min to obtain the target compound (6-bromo-7-((4-chlorophenyl)amino)quinoxaline-5,8-dione, 63a).

[0703] Red brown solid, 230 mg (69.6%)

[0704]

[0705] 63a (335 mg, 919 μmol) was dissolved in THF (10.0 mL), sodium thiomethoxide (NaSMe) (130 mg, 1.72 mmol) was added, and the mixture was stirred at room temperature for 1 h. 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 over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was triturated with MTBE for 30 min and purified by Prep-TLC (petroleum ether / EtOAc) to obtain the target compound (6-((4-chlorophenyl)amino)-7-(methylthio)quino-xaline-5,8-dione, compound 63).

[0706] Brown solid, 59.99 mg (19.5%)

[0707] 1 H NMR (400 MHz, CHLOROFORM-D) δ 9.04 - 8.93 (m, 2H), 7.87 (s, 1H), 7.37 - 7.33 (m, 2H), 6.99 (d,J= 8.6 Hz, 2H), 2.23 (s, 3H).

[0708]

[0709] Example 56: Synthesis of compound 64

[0710]

[0711] 42 (330 mg, 916 μmol) was dissolved in THF (10.0 mL), sodium thiomethoxide (NaSMe) (120 mg, 1.59 mmol) was added, and the mixture was stirred at room temperature for 1 h. 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 over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was triturated with MTBE for 30 min and purified by Prep-HPLC (H2O / ACN) for the first time. The purified compound was purified again by Prep-TLC (petroleum ether / EtOAc) to obtain the target compound (6-((2-methoxyphenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, compound 64).

[0712] Black solid, 96.8 mg (32.3%)

[0713] 1 H NMR (400 MHz, CHLOROFORM-D) 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).

[0714]

[0715] Example 57: Synthesis of compound 65

[0716]

[0717] 43 (320 mg, 888 μmol) was dissolved in THF (10.0 mL), sodium thiomethoxide (NaSMe) (200 mg, 2.65 mmol) was added, and the mixture was stirred at room temperature for 1 h. 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 over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was triturated with MTBE for 30 min and purified by Prep-HPLC (H2O / ACN). The purified compound was purified again by Prep-TLC (petroleum ether / EtOAc) to obtain the target compound (6-((3-methoxyphenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, compound 65).

[0718] Black solid, 128 mg (43.8%)

[0719] 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).

[0720]

[0721] Example 58: Synthesis of compound 66

[0722]

[0723] Add EtOH (6.3 mL) to K (200 mg, 629 μmol) and stir at room temperature. At the same temperature, add 3-fluoroaniline (90 μL, 944 μmol) and CeCl3·7H2O (11.7 mg, 31.5 μmol), stir at room temperature for 19 h, and then concentrate to remove EtOH. After adding distilled water and DCM and extracting several times, the separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / Hex) and recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-((3-fluorophenyl)amino)quinoxaline-5,8-dione, compound 66).

[0724] Red brown solid, 176 mg (80.3%)

[0725] 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).

[0726]

[0727] Example 59: Synthesis of compound 67

[0728]

[0729] 41 (100 mg, 277 μmol) was dissolved in THF (1.0 mL), sodium thiomethoxide (NaSMe) (40.1 mg, 572 μmol) was added, and the mixture was stirred at 40 °C for 2 h. 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 over Na2SO4, filtered, and concentrated under reduced pressure. The concentrate was purified by SFC (CO2-ACN / i-PrOH) to obtain the target compound (6-((4-methoxyphenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, compound 67).

[0730] Black solid, 247 mg (90.5%)

[0731] 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).

[0732]

[0733] Example 60: Synthesis of compound 68

[0734]

[0735] M (1.27 g, 4.72 mmol) and 2,4-dimethoxyaniline (867 mg, 5.66 mmol) were added to MeOH (10.0 mL), degassed, and then filled with nitrogen. The mixture was stirred at 60 °C for 3 h, filtered, and concentrated under reduced pressure. The concentrate was triturated with MTBE and petroleum ether for 50 min to obtain the target compound (6-bromo-7-((2,4-dimethoxyphenyl)amino)quinoxaline-5,8-dione, 68a).

[0736] brown to black solid, 1.10 g (59.7%)

[0737]

[0738] 68a (500 mg, 1.28 mmol) was dissolved in THF (5.0 mL), sodium thiomethoxide (NaSMe) (269 mg, 3.84 mmol) was added, and the mixture was degassed and filled with nitrogen. The mixture was stirred at 30 °C for 2 h. 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 over Na2SO4, filtered, and concentrated under reduced pressure. The concentrate was purified by Prep-TLC (petroleum ether / EtOAc) to obtain the target compound (6-((2,4-dimethoxyphenyl)amino)-7-(methyl thio)quinoxaline-5,8-dione, compound 68).

[0739] brown to black solid, 121 mg (25.8%)

[0740] 1H NMR (400 MHz, DMSO-D6) δ 9.01 (d,J= 2.4 Hz, 1H), 8.95 (d,J= 2.4 Hz, 1H), 8.67 (br s, 1H), 7.04 (d,J= 8.4 Hz, 1H), 6.59 (d,J= 2.8 Hz, 1H), 6.51 (dd,J= 2.8, 8.7 Hz, 1H), 3.78 (s, 3H), 3.71 (s, 3H), 2.08 (s, 3H).

[0741]

[0742] Example 61: Synthesis of compound 69

[0743]

[0744] 40 (200 mg, 512 μmol) was dissolved in THF (3.0 mL), sodium thiomethoxide (NaSMe) (71.8 mg, 1.03 mmol) was added, and the mixture was degassed and filled with nitrogen. The mixture was stirred at room temperature for 1 h. 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 over Na2SO4, filtered, and concentrated under reduced pressure. The concentrate was purified by Prep-TLC (petroleum ether / EtOAc) to obtain the target compound (6-((3,4-dimethoxyphenyl)amino)-7-(methylthio) quinoxaline-5,8-dione, compound 69).

[0745] brown to black solid, 63.0 mg (33.1%)

[0746] 1H NMR (400 MHz, DMSO-D6) δ 9.21 (br s, 1H), 9.00 (d,J= 2.3 Hz, 1H), 8.96 (d,J= 2.3 Hz, 1H), 6.88 (d,J= 8.6 Hz, 1H), 6.81 (d,J= 2.4 Hz, 1H), 6.67 - 6.61 (m, 1H), 3.74 (s, 3H), 3.71 - 3.70 (m, 3H), 2.06 (s, 3H).

[0747]

[0748] Example 62: Synthesis of compound 70

[0749]

[0750] M (300 mg, 1.12 mmol) and 3,5-dimethoxyaniline (205 mg, 1.34 mmol) were added to MeOH (5.0 mL), degassed, and filled with nitrogen. The mixture was stirred at 80 °C for 2 h, extracted several times with distilled water and EtOAc at room temperature, and the organic layer was washed with a saturated aqueous solution of NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrate was purified by Prep-TLC (petroleum ether / EtOAc) to obtain the target compound (6-((3,4-dimethoxyphenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, 70a).

[0751] Purple solid, 400 mg (77.2%)

[0752]

[0753] 70a (326 mg, 836 μmol) was dissolved in THF (1.0 mL), sodium thiomethoxide (NaSMe) (90.0 mg, 1.28 mmol) was added, and the mixture was stirred at room temperature for 3 h. 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 over Na2SO4, filtered, and concentrated under reduced pressure. The concentrate was purified by Prep-HPLC (Hex / EtOH) to obtain the target compound (6-((3,5-dimethoxyphenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, compound 70).

[0754] Purple solid, 61.8 mg (18.4%)

[0755] 1 H NMR (400 MHz, CHLOROFORM-D) δ 8.99 (s, 1H), 8.94 (s, 1H), 7.87 (s, 1H), 6.32 (s, 1H), 6.19 (s, 1H), 6.18 (s, 1H), 3.81 (s, 6H), 2.27 (s, 3H).

[0756]

[0757] Example 63: Synthesis of compound 71

[0758]

[0759] Add EtOH (6.3 mL) to K (200 mg, 629 μmol) and stir at room temperature. At the same temperature, add 2-fluoroaniline (90 μL, 944 μmol) and CeCl3·7H2O (11.7 mg, 31.5 μmol), stir at room temperature for 22.5 h, and then concentrate to remove EtOH. After adding distilled water and DCM and extracting several times, the separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) and recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-((2-fluorophenyl)amino)quinoxaline-5,8-dione, compound 71).

[0760] Red brown solid, 185 mg (84.7%)

[0761] 1 H NMR (400 MHz, DMSO-D6) δ 9.41 (s, 1H), 9.11 - 8.93 (m, 2H), 7.41 - 7.10 (m, 4H).

[0762]

[0763] Example 64: Synthesis of compound 72

[0764]

[0765] Add EtOH (6.3 mL) to K (200 mg, 629 μmol) and stir at room temperature. At the same temperature, add 2-fluoroaniline (90 μL, 944 μmol) and CeCl3·7H2O (11.7 mg, 31.5 μmol), stir at room temperature for 22.5 h, and then concentrate to remove EtOH. After adding saturated NaCl aqueous solution and DCM and extracting several times, the separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / Hex) and recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-((2,3-difluorophenyl)amino)quinoxaline-5,8-dione, compound 72).

[0766] Red brown solid, 178 mg (77.2%)

[0767] 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).

[0768]

[0769] Example 65: Synthesis of compound 73

[0770]

[0771] 66 (128 mg, 368 μmol) was stirred in THF (3.7 mL) at 0°C. Sodium thiomethoxide (NaSMe) (51.5 mg, 735 μmol) was added at the same temperature and stirred for 5 minutes. The reaction solution was stirred for an additional 19 hours at room temperature and then quenched by pouring onto ice. After extraction several times with saturated aqueous NaCl solution and DCM, the separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) and purified by silica gel column chromatography (EtOAc / Hex) to obtain the target compound (6-((3-fluorophenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, compound 73).

[0772] Dark violet solid, 12.7 mg (10.9%)

[0773] 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).

[0774]

[0775] Example 66: Synthesis of compound 74

[0776]

[0777] 71 (132 mg, 379 μmol) was stirred at 0°C with THF (3.8 mL). At the same temperature, sodium thiomethoxide (NaSMe) (79.8 mg, 1.14 mmol) was added and stirred for 5 minutes. The reaction solution was stirred at room temperature for an additional 54 hours and then quenched by pouring onto ice. After adding a saturated aqueous solution of NaCl and DCM and extracting several times, the separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was dissolved in THF (3.8 mL), sodium thiomethoxide (NaSMe) (26.8 mg, 382 μmol) was added, and the mixture was stirred at room temperature for 4.5 hours. After adding a saturated aqueous solution of NaCl and DCM to the reaction solution and extracting several times, the separated organic layer was dried over MgSO4, filtered, and 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-((2-fluorophenyl) amino)-7-(methylthio)quinoxaline-5,8-dione, compound 74).

[0778] Red brown solid, 33.9 mg (28.4%)

[0779] 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).

[0780]

[0781] Example 67: Synthesis of compound 75

[0782]

[0783] Add THF (3.6 mL) to 72 (130 mg, 355 μmol) and stir at 0°C. At the same temperature, add sodium thiomethoxide (NaSMe) (74.6 mg, 1.06 mmol) and stir for 5 minutes. The reaction solution is stirred at room temperature for 23 hours and then quenched by pouring onto ice. After adding saturated aqueous NaCl solution and DCM and extracting several times, the separated organic layer is dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate is dissolved in THF (3.6 mL), and sodium thiomethoxide (NaSMe) (24.9 mg, 355 μmol) is added and stirred at room temperature for 6 hours. After adding saturated aqueous NaCl solution and DCM to the reaction solution and extracting several times, the separated organic layer is dried over MgSO4, filtered, and 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-((2,3-difluoro-phenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, compound 75).

[0784] Red brown solid, 36.3 mg (30.7%)

[0785] 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).

[0786]

[0787] Example 68: Synthesis of compound 76

[0788]

[0789] Add EtOH (6.3 mL) to K (200 mg, 629 μmol) and stir at room temperature. At the same temperature, add 3-fluoro-2-methylaniline (100 μL, 944 μmol) and CeCl3·7H2O (11.7 mg, 31.5 μmol), stir at room temperature for 21 h, and then concentrate to remove EtOH. After adding distilled water and DCM and extracting several times, the separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / Hex) and recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-((3-fluoro-2-methylphenyl)amino)quinoxaline-5,8-dione, compound 76).

[0790] Solid, 185 mg (81.3%)

[0791] 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).

[0792]

[0793] Example 69: Synthesis of compounds 77 and 78

[0794]

[0795] K (200 mg, 629 μmol) was stirred at room temperature with EtOH (6.3 mL). 2-Methyl-5-(trifluoromethyl)aniline (165 mg, 944 μmol) and CeCl3·7H2O (12.0 mg, 31.5 μmol) were added at the same temperature and stirred at room temperature for an additional 17 h. After extracting several times with distilled water and DCM, the separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) and recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-((2-methyl-5-(trifluoromethyl) phenyl)amino)quinoxaline-5,8-dione, compound 77).

[0796] Orange solid, 139 mg (53.5%)

[0797] 1 H NMR (400 MHz, DMSO-D6) 9.29 (s, 1H), 9.06 - 9.00 (m, 2H), 7.57 - 7.45 (m, 3H), 2.34 (s, 3H).

[0798]

[0799] Add THF (2.7 mL) to 77 (109 mg, 264 μmol) and stir at room temperature. At the same temperature, add sodium thiomethoxide (NaSMe) (37.1 mg, 529 μmol) and stir at room temperature for another 1 hour. After adding saturated aqueous NaCl solution and DCM to the reaction solution and extracting several times, the separated organic layer was dried over MgSO4, filtered, and 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-((2-methyl-5-(trifluoromethyl)phenyl)amino)-7-(methyl thio)quinoxaline-5,8-dione, compound 78).

[0800] Red brown solid, 57.5 mg (57.4%)

[0801] 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).

[0802]

[0803] Example 70: Synthesis of compound 79

[0804]

[0805] 76 (147 mg, 406 μmol) was stirred at room temperature with THF (4.1 mL). At the same temperature, sodium thiomethoxide (NaSMe) (85.3 mg, 1.22 mmol) was added and stirred at room temperature for another 18 hours. The reaction solution was extracted several times with saturated aqueous NaCl solution and DCM, and the separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was dissolved in THF (4.1 mL), sodium thiomethoxide (NaSMe) (28.5 mg, 406 μmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was extracted several times with saturated aqueous NaCl solution and DCM, and the separated organic layer was dried over MgSO4, filtered, and 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-((3-fluoro-2-methylphenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, compound 79).

[0806] Solid, 72.5 mg (54.2%)

[0807] 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).

[0808]

[0809] Example 71: Synthesis of compound 80

[0810]

[0811] Add EtOH (6.3 mL) to K (200 mg, 629 μmol) and stir at room temperature. At the same temperature, add N-methyl-4-(trifluoromethyl)aniline (130 μL, 944 μmol) and CeCl3·7H2O (46.7 mg, 125 μmol), stir at room temperature for 27 h, and then concentrate to remove EtOH. After adding distilled water and DCM and extracting several times, the separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / Hex) and recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-(methyl(4-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione, compound 80).

[0812] Purple solid, 166 mg (63.9%)

[0813] 1 H NMR (400 MHz, DMSO-D6) δ 9.12 (s, 2H), 7.64 - 7.47 (m, 2H), 7.21 - 7.01 (m, 2H), 3.34 (s, 3H).

[0814]

[0815] Example 72: Synthesis of compounds 81 and 88

[0816]

[0817] Add EtOH (9.4 mL) to K (300 mg, 944 μmol) and stir at room temperature. At the same temperature, add 2-Amino-5-fluorobenzotrifluoride (180 μL, 1.42 mmol) and CeCl3·7H2O (12.0 mg, 31.5 μmol) and stir at room temperature for another 43.5 h. Concentrate under reduced pressure to remove EtOH. The concentrate was extracted several times with saturated aqueous NaCl solution and DCM, and the separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) and recrystallized (DCM / Hex) to obtain the target compound (6-bromo-7-((4-fluoro-2-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione, compound 81).

[0818] Light orange solid, 161 mg (40.9%)

[0819] 1 H NMR (500 MHz, DMSO-D6) δ 9.17 (s, 1H), 9.01 - 9.03 (m, 2H), 7.70 (dd,J= 8.9, 2.9 Hz, 1H), 7.55 - 7.60 (m, 1H), 7.52 - 7.53 (m, 1H).

[0820]

[0821] 81 (213 mg, 512 μmol) was stirred at room temperature with THF (5.2 mL). At the same temperature, sodium thiomethoxide (NaSMe) (110 mg, 1.54 mmol) was added and stirred at room temperature for another 3 hours. The reaction solution was extracted several times with saturated aqueous NaCl solution and DCM, and the separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) and recrystallized (DCM / Hex) to obtain the target compound (6-((4-fluoro-2-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, compound 88).

[0822] Red brown solid, 161 mg (82.1%)

[0823] 1 H NMR (500 MHz, DMSO-D6) δ 9.03 (d,J= 2.3 Hz, 1H), 8.99 (d,J= 2.3 Hz, 1H), 8.75 (s, 1H), 7.66 (dd,J= 8.9, 2.9 Hz, 1H), 7.55 (td,J= 8.5, 3.0 Hz, 1H), 7.41 (dd,J= 9.1, 5.0 Hz, 1H), 2.12 (s, 3H).

[0824]

[0825] Example 73: Synthesis of compounds 82 and 83

[0826]

[0827] Add EtOH (6.3 mL) to K (200 mg, 629 μmol) and stir at room temperature. At the same temperature, add 4-(Fluoromethyl)aniline (152 mg, 944 μmol) and CeCl3·7H2O (24.0 mg, 62.9 μmol) and stir at room temperature for another 19.5 h. Concentrate under reduced pressure to remove EtOH. The concentrate was extracted several times with saturated aqueous NaCl solution and DCM, and the separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) and recrystallized (DCM / Hex) to obtain the target compound (6-bromo-7-((4-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione, compound 82).

[0828] Violet brown solid, 209 mg (83.3%)

[0829] 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).

[0830]

[0831] 82 (150 mg, 377 μmol) was stirred at room temperature with THF (3.8 mL). At the same temperature, sodium thiomethoxide (NaSMe) (79.0 mg, 1.13 mmol) was added and stirred at room temperature for another 3 hours. The reaction solution was extracted several times with saturated aqueous NaCl solution and DCM, and the separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by recrystallization (DCM / Hex) and purified by silica gel column chromatography (EtOAc / DCM) to obtain the target compound (6-(methylthio)-7-((4-(trifluoromethyl)phenyl)amino) quinoxaline-5,8-dione, compound 83).

[0832] Red brown solid, 76.7 mg (55.7%)

[0833] 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).

[0834]

[0835] Example 74: Synthesis of compounds 84 and 85

[0836]

[0837] Add EtOH (6.3 mL) to K (200 mg, 629 μmol) and stir at room temperature. At the same temperature, add p-Toluidine (100 mg, 944 mmol) and CeCl3·7H2O (23.4 mg, 62.9 μmol) and stir at room temperature for another 18.5 h. Concentrate under reduced pressure to remove EtOH. The concentrate was extracted several times with saturated aqueous NaCl solution and DCM, and the separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) and recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-(p-tolylamino)quinoxaline-5,8-dione, compound 84).

[0838] Dark brown solid, 178 mg (82.0%)

[0839] 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).

[0840]

[0841] To 84 (140 mg, 407 μmol) was added THF (4.1 mL) and stirred at room temperature. At the same temperature, sodium thiomethoxide (NaSMe) (85.5 mg, 1.22 mmol) was added and stirred at room temperature for another 23 h. After adding saturated aqueous NaCl solution and DCM to the reaction solution and extracting several times, the separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) and recrystallized (DCM / Hex) to obtain the target compound (6-(methylthio)-7-(p-tolylamino)quinoxaline-5,8-dione, compound 85).

[0842] Black solid, 77.5 mg (61.2%)

[0843] 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).

[0844]

[0845] Example 75: Synthesis of compounds 86 and 87

[0846]

[0847] Add EtOH (6.3 mL) to K (200 mg, 629 μmol) and stir at room temperature. At the same temperature, add 4-Methoxy-3-(trifluoromethyl)aniline (180 mg, 944 μmol) and CeCl3·7H2O (23.4 mg, 62.9 μmol) and stir at room temperature for 2 more hours. After adding saturated NaCl aqueous solution and DCM to the concentrate and extracting several times, the separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) and recrystallization (DCM / Hex) to obtain the target compound (6-bromo-7-((4-methoxy-3-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione, compound 86).

[0848] Black solid, 220 mg (81.8%)

[0849] 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).

[0850]

[0851] 86 (170 mg, 397 μmol) was stirred at room temperature with THF (4.0 mL). At the same temperature, sodium thiomethoxide (NaSMe) (83.5 mg, 1.19 mmol) was added and stirred at room temperature for another 3.5 hours. The reaction solution was extracted several times with saturated aqueous NaCl solution and DCM, and the separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) and recrystallization (EtOAc / Hex) to obtain the target compound (6-((4-methoxy-3-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, compound 87).

[0852] Red violet solid, 91.5 mg (58.3%)

[0853] 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).

[0854]

[0855] Example 76: Synthesis of compounds 89 and 90

[0856]

[0857] Add EtOH (6.3 mL) to K (200 mg, 629 μmol) and stir at room temperature. At the same temperature, add o-Toluidine (100 μL, 944 mmol) and CeCl3·7H2O (23.4 mg, 62.9 μmol) and stir at room temperature for another 18.5 h. After extracting several times with saturated aqueous NaCl solution and DCM, the separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) and recrystallized (DCM / Hex) to obtain the target compound (6-bromo-7-(o-tolylamino)quinoxaline-5,8-dione, compound 89).

[0858] Red brown solid, 166 mg (76.8%)

[0859] 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).

[0860]

[0861] 89 (134 mg, 388 μmol) was stirred at room temperature with THF (3.9 mL). At the same temperature, sodium thiomethoxide (NaSMe) (81.6 mg, 1.16 mmol) was added and stirred at room temperature for another 24 h. The reaction solution was extracted several times with saturated aqueous NaCl solution and DCM, and the separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) and recrystallized (DCM / Hex) to obtain the target compound (6-(methylthio)-7-(o-tolylamino)quinoxaline-5,8-dione, compound 90).

[0862] Red violet solid, 40.6 mg (33.6%)

[0863] 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).

[0864]

[0865] Example 77: Synthesis of compound 91

[0866]

[0867] Add EtOH (6.3 mL) to K (200 mg, 629 μmol) and stir at room temperature. At the same temperature, add 3,4-Dimethylaniline (114 mg, 944 μmol) and CeCl3·7H2O (23.4 mg, 62.9 μmol) and stir at room temperature for another 23.5 h. After extracting several times with saturated aqueous NaCl solution and DCM, the separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) and recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-((3,4-dimethylphenyl)amino) quinoxaline-5,8-dione, compound 91).

[0868] Red brown solid, 184 mg (81.8%)

[0869] 1H 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).

[0870]

[0871] Example 78: Synthesis of compounds 92 and 98

[0872]

[0873] Add EtOH (6.3 mL) to K (200 mg, 629 μmol) and stir at room temperature. At the same temperature, add 3,5-Dimethylaniline (120 μL, 944 μmol) and CeCl3·7H2O (23.4 mg, 62.9 μmol) and stir at room temperature for another 19.5 h. After extracting several times with saturated aqueous NaCl solution and DCM, the separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) and recrystallized (DCM / Hex) to obtain the target compound (6-bromo-7-((3,5-dimethylphenyl)amino) quinoxaline-5,8-dione, compound 92).

[0874] Red brown solid, 133 mg (59.2%)

[0875] 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).

[0876]

[0877] Add THF (3.0 mL) to 92 (108 mg, 302 μmol) and stir at room temperature. At the same temperature, add sodium thiomethoxide (NaSMe) (63.4 mg, 905 μmol). The reaction solution is stirred at room temperature for an additional 23 h, then saturated aqueous NaCl solution is added and extracted several times with DCM. The separated organic layer is dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography (EtOAc / DCM) and recrystallization (EtOAc / Hex) to obtain the target compound (6-((3,5-dimethylphenyl)amino)-7-(methylthio) quinoxaline-5,8-dione, compound 98).

[0878] Dark violet solid, 40.5 mg (41.2%)

[0879] 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).

[0880]

[0881] Example 79: Synthesis of compounds 93 and 94

[0882]

[0883] Add EtOH (6.3 mL) to K (200 mg, 629 μmol) and stir at room temperature. At the same temperature, add 3-methoxy-4-(trifluoromethyl)aniline (180 mg, 944 μmol) and CeCl3·7H2O (23.4 mg, 62.9 μmol), stir at room temperature for another 20.5 h, and then concentrate to remove EtOH. Add saturated aqueous NaCl solution, extract several times with DCM, and then dry the separated organic layer with Na2SO4, filter, and concentrate under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) and recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-((3-methoxy-4-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione, compound 93).

[0884] Purple solid, 234 mg (87.0%)

[0885] 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).

[0886]

[0887] Add THF (5.2 mL) to 93 (202 mg, 472 μmol) and stir at room temperature. At the same temperature, add sodium thiomethoxide (NaSMe) (99.2 mg, 1.42 mmol). The reaction solution is stirred at room temperature for 1 more hour, saturated aqueous NaCl solution is added, and the mixture is extracted several times with DCM. The separated organic layer is dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography (EtOAc / DCM) and recrystallization (EtOAc / Hex) to obtain the target compound (6-((3-methoxy-4-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, compound 94).

[0888] Purple solid, 109 mg (58.4%)

[0889] 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).

[0890]

[0891] Example 80: Synthesis of compounds 95 and 97

[0892]

[0893] Add EtOH (6.3 mL) to K (200 mg, 629 μmol) and stir at room temperature. At the same temperature, add 3-fluoro-4-methoxyaniline (133 mg, 944 μmol) and CeCl3·7H2O (23.4 mg, 62.9 μmol), stir at room temperature for another 20 hours, and then concentrate to remove EtOH. Add saturated aqueous NaCl solution and extract several times with DCM. The separated organic layer is dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) and recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-((3-fluoro-4-methoxyphenyl)amino)quinoxaline-5,8-dione, compound 95).

[0894] Purple solid, 211 mg (88.7%)

[0895] 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).

[0896]

[0897] Add THF (5.2 mL) to 95 (176 mg, 465 μmol) and stir at room temperature. At the same temperature, add sodium thiomethoxide (NaSMe) (97.9 mg, 1.40 mmol). The reaction solution is stirred at room temperature for another 24 h, saturated aqueous NaCl solution is added, and the mixture is extracted several times with DCM. The separated organic layer is dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography (EtOAc / DCM) and recrystallization (EtOAc / Hex) to obtain the target compound (6-((3-fluoro-4-methoxyphenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, compound 97).

[0898] Dark violet solid, 109 mg (67.8%)

[0899] 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).

[0900]

[0901] Example 81: Synthesis of compounds 96 and 105

[0902]

[0903] Add EtOH (6.3 mL) to K (200 mg, 629 μmol) and stir at room temperature. At the same temperature, add 4-fluoro-3-methoxyaniline (133 mg, 944 μmol) and CeCl3·7H2O (23.4 mg, 62.9 μmol), stir at room temperature for another 19 hours, and then concentrate to remove EtOH. Add saturated aqueous NaCl solution and extract several times with DCM. The separated organic layer is dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) and recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-((4-fluoro-3-methoxyphenyl)amino)quinoxaline-5,8-dione, compound 96).

[0904] Purple solid, 191 mg (80.2%)

[0905] 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).

[0906]

[0907] Add THF (4.7 mL) to 96 (161 mg, 426 μmol) and stir at room temperature. At the same temperature, add sodium thiomethoxide (NaSMe) (89.5 mg, 1.28 mmol). The reaction solution is stirred at room temperature for another 24 h, saturated aqueous NaCl solution is added, and the mixture is extracted several times with DCM. The separated organic layer is dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography (EtOAc / DCM) and recrystallization (EtOAc / Hex) to obtain the target compound (6-((4-fluoro-3-methoxyphenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, compound 105).

[0908] Black solid, 73.6 mg (50.0%)

[0909] 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).

[0910]

[0911] Example 82: Synthesis of compounds 99 and 100

[0912]

[0913] M (500 mg, 1.86 mmol) was dissolved in MeOH (5.0 mL), 4-fluoro-2-methylaniline (279 mg, 2.23 mmol) was added, and the mixture was stirred at 60°C for 2 hours. Distilled water and petroleum ether were added to the reaction solution and extracted several times. The organic layer was washed with a saturated aqueous solution of NaCl, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to obtain the target compound (6-bromo-7-((4-fluoro-2-methylphenyl)amino)quinoxaline-5,8-dione, compound 99).

[0914] Black solid, 500 mg (crude)

[0915] 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).

[0916]

[0917] 99 (500 mg, 1.38 mmol) was dissolved in THF (5.0 mL), sodium thiomethoxide (NaSMe) (290 mg, 4.14 mmol) was added, and the mixture was stirred at 40°C for 2 h. 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 over Na2SO4, filtered, and concentrated under reduced pressure. The concentrate was purified by Prep-HPLC [water(FA)-ACN] to obtain the target compound (6-((4-fluoro-2-methylphenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, compound 100).

[0918] Black solid, 58.0 mg (12.4%)

[0919] 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).

[0920]

[0921] Example 83: Synthesis of compounds 101 and 102

[0922]

[0923] M (500 mg, 1.86 mmol) was dissolved in MeOH (5.0 mL), 2,4-dimethylaniline (270 mg, 2.23 mmol) was added, and the mixture was stirred at 60°C for 1 h. Distilled water and EtOAc were added to the reaction solution and extracted several times. The organic layer was washed with a saturated aqueous solution of NaCl, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to obtain the target compound (6-bromo-7-((2,4-dimethylphenyl)amino)quinoxaline-5,8-dione, compound 101).

[0924] Black solid, 500 mg (crude)

[0925] 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).

[0926]

[0927] 101 (500 mg, 1.40 mmol) was dissolved in THF (5.00 mL), sodium thiomethoxide (NaSMe) (293 mg, 4.19 mmol) was added, and the mixture was stirred at 40°C for 2 h. 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 over Na2SO4, filtered, and concentrated under reduced pressure. The concentrate was purified by reversed-phase HPLC [water(FA)-ACN] to obtain the target compound (6-((2,4-dimethylphenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, compound 102).

[0928] Black solid, 100 mg (21.8%)

[0929] 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).

[0930]

[0931] Example 84: Synthesis of compounds 103 and 104

[0932]

[0933] M (500 mg, 1.86 mmol) was dissolved in MeOH (5.0 mL), 2,5-dimethylaniline (270 mg, 2.23 mmol) was added, and the mixture was stirred at 60°C for 1 h. Distilled water and EtOAc were added to the reaction solution and extracted several times. The organic layer was washed with a saturated aqueous solution of NaCl, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to obtain the target compound (6-bromo-7-((2,5-dimethylphenyl)amino)quinoxaline-5,8-dione, compound 103).

[0934] Black solid, 500 mg (crude)

[0935] 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).

[0936]

[0937] 103 (1.00 g, 2.79 mmol) was dissolved in THF (10.0 mL), sodium thiomethoxide (NaSMe) (610 mg, 8.70 mmol) was added, and the mixture was stirred at 40°C for 2 h. 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 over Na2SO4, filtered, and concentrated under reduced pressure. The concentrate was purified by prep-HPLC [water(FA)-ACN] to obtain the target compound (6-((2,5-dimethylphenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, compound 104).

[0938] Black solid, 80.0 mg (8.74%)

[0939] 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).

[0940]

[0941] Example 85: Synthesis of compounds 106 and 107

[0942]

[0943] Add EtOH (6.3 mL) to K (200 mg, 629 μmol) and stir at room temperature. At the same temperature, add 3,4-dimethylaniline (114 mg, 944 μmol) and CeCl3·7H2O (24.0 mg, 62.9 μmol), stir at room temperature for another 23.5 hours, and then concentrate to remove EtOH. Add saturated NaCl aqueous solution, extract several times with DCM, and then dry the separated organic layer over MgSO4, filter, and concentrate under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) and recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-((3,4-dimethylphenyl)amino)quinoxaline-5,8-dione, compound 106).

[0944] Red brown solid, 184 mg (81.8%)

[0945] 1H 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).

[0946]

[0947] 106 (139 mg, 387 μmol) was stirred at room temperature with THF (3.9 mL). At the same temperature, sodium thiomethoxide (NaSMe) (81.4 mg, 1.16 mmol) was added. The reaction solution was stirred at room temperature for an additional 24 h, saturated aqueous NaCl solution was added, and the mixture was extracted several times with DCM. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) and recrystallized (DCM / Hex) to obtain the target compound (6-((3,4-dimethylphenyl)amino)-7-(methylthio) quinoxaline-5,8-dione, compound 107).

[0948] Dark violet solid, 58.0 mg (46.1%)

[0949]

[0950] 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).

[0951]

[0952] Example 86: Synthesis of compounds 108 and 109

[0953]

[0954] Add EtOH (9.4 mL) to K (300 mg, 944 μmol) and stir at room temperature. At the same temperature, add 2-Amino-5-chlorobenzotrifluoride (190 μL, 1.42 mmol) and CeCl3·7H2O (700 mg, 1.89 mmol), stir at room temperature for 4 more days, and then concentrate to remove EtOH. Add saturated aqueous NaCl solution and extract several times with DCM. The separated organic layer is dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) and recrystallized (DCM / Hex) to obtain the target compound (6-bromo-7-((4-chloro-2-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione, compound 108).

[0955] Light orange solid, 97.1 mg (23.8%)

[0956] 1 H NMR (500 MHz, DMSO-D6) δ 9.13 (s, 1H), 9.04 (d,J= 2.3 Hz, 1H), 9.02 (d,J= 2.3 Hz, 1H), 7.86 (s, 1H), 7.79 (d,J= 8.5 Hz, 1H), 7.49 (d,J=8.5 Hz, 1H).

[0957]

[0958] 108 (81.7 mg, 189 μmol) was stirred at room temperature with THF (1.9 mL). At the same temperature, sodium thiomethoxide (NaSMe) (39.7 mg, 567 μmol) was added. The reaction solution was stirred at room temperature for 3 more hours, saturated aqueous NaCl solution was added, and extracted several times with DCM. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) and recrystallized (DCM / Hex) to obtain the target compound (6-((4-chloro-2-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, compound 109).

[0959] Red brown solid, 48.2 mg (63.8%)

[0960] 1 H NMR (500 MHz, DMSO-D6) δ 9.03 (d,J= 2.3 Hz, 1H), 9.00 (d,J= 2.3 Hz, 1H), 8.64 (s, 1H), 7.81 (d,J= 2.6 Hz, 1H), 7.75 (d,J= 8.5 Hz, 1H), 7.34 (d,J= 8.7 Hz, 1H), 2.15 (s, 3H).

[0961]

[0962] Example 87: Synthesis of compounds 110 and 112

[0963]

[0964] Add EtOH (6.3 mL) to K (200 mg, 629 μmol) and stir at room temperature. At the same temperature, add 3-Chlro-4-methoxyaniline (149 mg, 944 μmol) and CeCl3·7H2O (23.4 mg, 62.9 μmol), stir at room temperature for another 27 hours, and then concentrate to remove EtOH. Add saturated aqueous NaCl solution and extract several times with DCM. The separated organic layer is dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) and recrystallized (DCM / Hex) to obtain the target compound (6-bromo -7-((3-chloro-4-methoxyphenyl)amino)quinoxaline-5,8-dione, compound 110).

[0965] Dark brown solid, 216 mg (87.2%)

[0966] 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).

[0967]

[0968] 110 (190 mg, 481 μmol) was stirred at room temperature with THF (4.8 mL). At the same temperature, sodium thiomethoxide (NaSMe) (100 mg, 1.44 mmol) was added. The reaction solution was stirred at room temperature for an additional 20.5 h, saturated aqueous NaCl solution was added, and the mixture was extracted several times with DCM. The separated organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) and recrystallization (EtOAc / Hex) to obtain the target compound (6-((3-chloro-4-methoxyphenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, compound 112).

[0969] Dark violet solid, 33.0 mg (19.0%)

[0970] 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).

[0971]

[0972] Example 88: Synthesis of compounds 111 and 113

[0973]

[0974] Add EtOH (5.3 mL) to K (200 mg, 629 μmol) and stir at room temperature. At the same temperature, dissolve 3-methyl-4-(trifluoromethyl)aniline (165 mg, 944 μmol) in EtOH (1.0 mL), add CeCl3·7H2O (23.4 mg, 62.9 μmol), and stir at room temperature for another 18 h. Add saturated NaCl aqueous solution, extract several times with DCM, and then dry the separated organic layer with Na2SO4, filter, and concentrate under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) and recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-((3-methyl-4-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione, compound 111).

[0975] Red brown solid, 225 mg (86.8%)

[0976] 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).

[0977]

[0978] 111 (187 mg, 454 μmol) was stirred at room temperature with THF (5.0 mL). At the same temperature, sodium thiomethoxide (NaSMe) (95.4 mg, 1.36 mmol) was added. The reaction solution was stirred at room temperature for 1 more hour, saturated aqueous NaCl solution was added, and the mixture was extracted several times with DCM. The separated organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) and then crystallized (Hex) to obtain the target compound (6-((3-methyl-4-(trifluoromethyl)phenyl)amino)-7-(methylthio) quinoxaline-5,8-dione, compound 113).

[0979] Dark brown solid, 57.5 mg (33.4%)

[0980] 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).

[0981]

[0982] Example 89: Synthesis of compounds 114 and 116

[0983]

[0984] Add EtOH (9.4 mL) to K (300 mg, 944 μmol) and stir at room temperature. At the same temperature, add 3,4-difluoroaniline (140 μL, 1.42 mmol) and CeCl3·7H2O (35.2 mg, 94.4 μmol) and stir at room temperature for another 18 h. Add saturated NaCl aqueous solution and extract several times with DCM. The separated organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) and recrystallized (EtOAc / Hex) to obtain the target compound (6-bromo-7-((3,4-difluorophenyl) amino)quinoxaline-5,8-dione, compound 114).

[0985] Dark brown solid, 306 mg (88.4%)

[0986] 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).

[0987]

[0988] 114 (268 mg, 732 μmol) was stirred at room temperature with THF (8.1 mL). At the same temperature, sodium thiomethoxide (NaSMe) (154 mg, 2.20 mmol) was added. The reaction solution was stirred at room temperature for an additional 4.5 hours, saturated aqueous NaCl solution was added, and the mixture was extracted several times with DCM. The separated organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) and recrystallization (EtOAc / Hex) to obtain the target compound (6-((3,4-difluorophenyl)amino)-7-(methylthio) quinoxaline-5,8-dione, compound 116).

[0989] Brown solid, 187 mg (76.6%)

[0990] 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).

[0991]

[0992] Example 90: Synthesis of compounds 115 and 117

[0993]

[0994] Add EtOH (9.4 mL) to K (300 mg, 944 μmol) and stir at room temperature. At the same temperature, add 3,5-difluoro-4-methoxyaniline (225 mg, 1.42 mmol) and CeCl3·7H2O (35.2 mg, 94.4 μmol) and stir at room temperature for another 23 h. Add saturated NaCl aqueous solution and extract several times with DCM. The separated organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) and recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-((3,5-difluoro-4-methoxyphenyl)amino)quinoxaline-5,8-dione, compound 115).

[0995] Red brown solid, 338 mg (90.2%)

[0996] 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).

[0997]

[0998] 115 (301 mg, 760 μmol) was stirred at room temperature with THF (8.4 mL). At the same temperature, sodium thiomethoxide (NaSMe) (160 mg, 2.28 mmol) was added. The reaction solution was stirred at room temperature for 1 more hour, saturated aqueous NaCl solution was added, and the mixture was extracted several times with DCM. The separated organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) and recrystallization (EtOAc / Hex) to obtain the target compound (6-((3,5-difluoro-4-methoxyphenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, compound 117).

[0999] Black solid, 174 mg (63.0%)

[1000] 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).

[1001]

[1002] Example 91: Synthesis of compounds 118 and 120

[1003]

[1004] Add EtOH (9.4 mL) to K (300 mg, 944 μmol) and stir at room temperature. At the same temperature, add 5-amino-2-chlorobenzotrifluoride (277 mg, 1.42 mmol) and CeCl3·7H2O (35.2 mg, 94.4 μmol) and stir at room temperature for another 16.5 h. Add saturated NaCl aqueous solution and extract several times with DCM. The separated organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) and recrystallization (EtOAc / Hex) to obtain the target compound (6-bromo-7-((4-chloro-3-(trifluoromethyl)phenyl)amino)quinoxaline-5,8-dione, compound 118).

[1005] Red brown solid, 327 mg (80.1%)

[1006] 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).

[1007]

[1008] 118 (270 mg, 624 μmol) was stirred at room temperature with THF (6.9 mL). At the same temperature, sodium thiomethoxide (NaSMe) (131 mg, 1.87 mmol) was added. The reaction solution was stirred at room temperature for 1 more hour, saturated aqueous NaCl solution was added, and the mixture was extracted several times with DCM. The separated organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) and recrystallization (ether / Hex) to obtain the target compound (6-((4-chloro-3-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinoxaline-5,8-dione, compound 120).

[1009] Dark brown solid, 135 mg (53.9%)

[1010] 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).

[1011]

[1012] Example 92: Synthesis of compounds 119 and 121

[1013]

[1014] Add EtOH (9.4 mL) to K (300 mg, 944 μmol) and stir at room temperature. At the same temperature, add 3-Fluoro-4-methylaniline (177 mg, 1.42 mmol) and CeCl3·7H2O (35.0 mg, 94.4 μmol), stir at room temperature for another 15.5 h, and then concentrate to remove EtOH. Add saturated aqueous NaCl solution, extract several times with DCM, and then dry the separated organic layer over MgSO4, filter, and concentrate under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) and recrystallization (DCM / Hex) to obtain the target compound (6-bromo -7-((3-fluoro-4-methylphenyl)amino)quinoxaline-5,8-dione, compound 119).

[1015] Dark brown solid, 308 mg (90.1%)

[1016] 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).

[1017]

[1018] 119 (293 mg, 810 μmol) was stirred at room temperature with THF (8.1 mL). At the same temperature, sodium thiomethoxide (NaSMe) (170 mg, 2.43 mmol) was added. The reaction solution was stirred at room temperature for another 24 h, saturated aqueous NaCl solution was added, and the mixture was extracted several times with DCM. The separated organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / DCM) and recrystallized (DCM / Hex) to obtain the target compound (6-((3-fluoro-4-methylphenyl)amino)-7-(methylthio) quinoxaline-5,8-dione, compound 121).

[1019] Black solid, 98.4 mg (36.9%)

[1020] 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).

[1021]

[1022] Example 93: NQO1 activity assay (cytochrome c reduction)

[1023] In order to analyze the efficacy of the evaluation substances on NQO1 activity, a previously known method (Kang-Sik Seo, Jin-Hwan Kim, Ki-Nam Min, Jeong-A Moon et al. KL1333, a novel NAD +This study was performed with some improvements on the previous method (a modulator, improves energy metabolism and mitochondrial dysfunction in MELAS fibroblasts. Front. Neurol. 9:552 (2018)). More specifically, human NQO1 recombinant protein was used after diluting 1 / 100 of the reagent at 1 mg / ml, NADH was used after dissolving in 0.01 N NaOH at 20 mM, and cytochrome C was used after dissolving in distilled water at 7.5 mM. To verify the specificity of the enzymatic reaction, the results were corrected using ES936, an NQO1 selective inhibitor. The reaction buffer used in the experiment was 50 mM Tris-HCl containing 0.14% BSA. The reagents were prepared in advance, and 200 μl of the reaction buffer was dispensed into a 5 ml round tube without touching the wall, equal to the number of drugs to be evaluated for activity. NQO1, NADH, and cytochrome c were added to the wall of a tube containing 200 μl of reaction buffer without mixing them. The final concentrations of each reagent added to the 200 μl of reaction buffer were 10 ng NQO1, 0.4 mM NADH, and 75 nM cytochrome c. Care was taken to ensure that the test substances did not mix with the buffer, and the final concentrations were 0.2, 1, and 5 μM. Since the enzyme reaction was initiated simultaneously with the mixing of each reagent, the tube was gently vortexed immediately after the addition of all reagents, and 180 μl per sample was dispensed into a 96-well plate without delay. The absorbance was measured at 550 nm, and the effect of the test substances on NQO1 enzyme activity was quantitatively analyzed based on the rate of change in absorbance according to the reduction of cytochrome c. The related results are presented in Table 1.

[1024] Cytochrome C Reduction (nmole / min / mg) Compound Name 0.2 μM 1 μM 5 μM 130 5,226 32,161 20 0 1,773 30 7,249 29,383 410,101 52,155 132,468 55,482 36,150 88,220 612,826 68,554 164,749 77,691 40,807 110,071 85,143 29,926 125,184 98,111 43,255 137,141 105,738 33,348 73,957 112,668 10,483 32,328 123,359 17,168 24,567 133,748 13,574 39,950 148,598 55,179 143,341 157,480 43,637 100,513 162,949 19,146 68,699 178,313 35,416 84,250 185,646 26,951 86,125 192,252 9,450 44,535 205,606 21,562 59,045 214,101 17,480 56,036 229,395 44,650 84,578 236,960 29,102 36,977 247,454 43,544 110,032 2510,041 53,023 150,730 268,481 50,066 114,066 271,852 9,830 25,569 283,165 15,351 59,214 296,453 40,506 127,840 302,735 23,313 76,567 315,420 16,675 73,971 328,947 33,838 108,053 338,712 35,904 96,289 347,261 18,347 24,857 357,754 9,706 9,715 363,242 1,474 24,251 3711,876 22,834 68,137 386,727 17,101 93,306 393,892 4,466 58,732 4011,748 19,760 56,415 4118,320 58,148 85,673 426,366 28,621 59,948 4311,646 35,794 24,727 443,859 8,850 5,838 453,542　15,983　19,835　466,399　29,932　67,191　474,384　16,805　37,274　485,421　18,217　27,258　493,588　14,674　28,589　503,909　20,531　82,369　513,349　13,668　16,090　523,414　14,059　60,753　536,737　30,829　65,094　54452　1,804　7,863　551,884　8,529　40,433　563,492　5,835　4,744　5711,964　31,061　31,514　588,712　26,824　45,797　5910,198　21,492　18,226　6013,252　26,067　24,866　614,427　18,702　60,414　6210,066　41,740　94,663　637,062　30,230　78,248　644,213　19,802　50,360　6511,234　37,964　82,676　6611,109　34,120　39,392　676,32327,97273,207685,89722,25852,857694,47619,04457,651707,48829,68260,529716,99431,54348,898723,78420,40541,145739,49040,16390,078749,08336,92298,058757,53734,187103,927764,17525,26067,753773,06811,69218,120784,08816,85563,686796,50922,42875,8538026547611,994813,068　11,692　18,120　824,088　16,855　63,686　836,509　22,428　75,853　84265　476　11,994　8554512,07138,055862,93014,57328,786874,94320,09675,890889,02728,38455,775896,99929,65763,932904,3897,15317,795919,38525,72153,897921,6339,21545,502933,48314,89664,198942,53912,04448,394957,24721,26731,750965,76320,72634,715972,84510,03313,400984,34819,36961,977999,60626,36136,663100--29,433101--72,112102--57,291103--23,923104--35,514105--38,527106--70,684107--54,998108--16,374109--40,361110--24,300111--17,356112--68,085113--85,654114--15,676115--14,376116--134,143117--130,096118--15,705119--12,652120--81,164121--71,722,

Claims

1. A compound represented by the following chemical formula 1, a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer or diastereomer thereof: [Chemical Formula 1] In the above formula, The above R1 and R2 are each independently hydrogen, a halogen element, hydroxy, a substituted or unsubstituted alkoxy, a substituted or unsubstituted alkyl, or a substituted or unsubstituted cycloalkyl, The above R3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, The above R4 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -COR'1, -CO(O)R'1, -COCH2-R'1, -COCH2CH2-R'1 or -CO(CH2) n NR'1R'2 (wherein n is an integer from 1 to 3, and -(CH2) n - part may be substituted with a substituted or unsubstituted alkyl group), The above R'1 and R'2 are each independently hydrogen, hydroxy, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or the above R'1 and R'2 together may form heterocycloalkyl, When the above R4 is a substituted or unsubstituted aryl, the above R5 is a halogen element, hydroxy, a substituted or unsubstituted alkyl, a substituted or unsubstituted thioalkyl, a substituted or unsubstituted cycloalkyl, -NO2, -CN or -NR'3R'4, wherein R4 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroaryl, -COR'1, -CO(O)R'1, -COCH2-R'1, -COCH2CH2-R'1 or -CO(CH2) n NR'1R'2 (wherein n is an integer from 1 to 3, and -(CH2) n - If the portion may be substituted with a substituted or unsubstituted alkyl group), the R5 is hydrogen, a halogen element, hydroxy, a substituted or unsubstituted alkyl, a substituted or unsubstituted thioalkyl, a substituted or unsubstituted cycloalkyl, -NO2, -CN, or -NR'3R'4, The above R'3 and R'4 are each independently hydrogen, hydroxy, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, When the above R4 is an aryl substituted with -NO2, R5 is not selected as Cl, When the above R4 is -COR'1, R5 is selected as hydrogen.

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

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

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

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

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

7. In paragraph 1, The above R4 is substituted or unsubstituted phenyl, -COR'1, -CO(O)R'1, -COCH2-R'1, -COCH2CH2-R'1 or -CO(CH2) n NR'1R'2 (wherein n is an integer from 1 to 3, and -(CH2) n - part may be substituted with a substituted or unsubstituted C1 to C4 alkyl group), A compound, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer or diastereoisomer thereof, wherein R'1 and R'2 are each independently hydrogen, hydroxy, a substituted or unsubstituted C1 to C6 alkoxy, a substituted or unsubstituted C1 to C6 alkyl, a substituted or unsubstituted C3 to C8 cycloalkyl, a substituted or unsubstituted C4 to C10 aryl, or a substituted or unsubstituted C4 to C10 heteroaryl, or wherein R'1 and R'2 together constitute a C2 to C8 heterocycloalkyl.

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

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

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

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

12. In the first paragraph, the compound is at least one compound selected from the group consisting of the following compounds 1 to 121, a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer or diastereomer thereof: .

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

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

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

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

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

18. A method for preparing a compound according to any one of claims 1 to 12, comprising the following steps: (S1) A step of reacting a compound of chemical formula 2 with an aqueous nitric acid solution to obtain a compound of chemical formula 3; (S2) A step of reducing the compound of the above chemical formula 3 to obtain a compound of the chemical formula 4; (S3) A step of reacting the compound of the above chemical formula 4 with glyoxal sodium bisulfite or a substituted or unsubstituted C1 to C10 alkane dione or a substituted or unsubstituted C1 to C10 oxalate to obtain a compound of the chemical formula 5; (S4) A step of synthesizing a compound of formula 1 from a compound of formula 5, wherein the step is performed by a method including the following steps (a-1) to (a-3), (b-1) to (b-4), (c-1) to (c-3), (d-1) to (d-2) and (e-1) to (e-3). (a-1) A step of reacting the compound of chemical formula 5 with an oxidizing agent to obtain a compound of chemical formula 6; (a-2) A step of reacting the compound of chemical formula 6 with sodium azide to obtain a compound of chemical formula 7; (a-3) A step of obtaining a compound of chemical formula 1 by subjecting the compound of chemical formula 7 and the compound of chemical formula 8 to a nucleophilic reaction; (b-1) A step of reacting the compound of the above chemical formula 5 with an aqueous nitric acid solution to obtain a compound of the chemical formula 9; (b-2) A step of reducing the compound of chemical formula 9 to obtain a compound of chemical formula 10; (b-3) A step of obtaining a compound of chemical formula 11 by subjecting the compound of chemical formula 10 and the compound of chemical formula 8 to a nucleophilic reaction; (b-4) A step of reacting the compound of the above chemical formula 11 with an oxidizing agent to obtain a compound of the chemical formula 1; (c-1) A step of obtaining a compound of chemical formula 13 by subjecting the compound of chemical formula 10 and the compound of chemical formula 12 to a nucleophilic reaction; (c-2) A step of obtaining a compound of chemical formula 15 by subjecting the compound of chemical formula 13 to a nucleophilic reaction with a compound of chemical formula 14; (c-3) A step of reacting the compound of the above chemical formula 15 with an oxidizing agent to obtain a compound of the chemical formula 1; (d-1) A step of reacting the compound of the above chemical formula 13 with an oxidizing agent to obtain a compound of the chemical formula 16; (d-2) A step of obtaining a compound of chemical formula 1 by subjecting the compound of chemical formula 16 and the compound of chemical formula 14 to a nucleophilic reaction; (e-1) A step of performing a halogenation reaction on the compound of the above chemical formula 6 to obtain a compound of the chemical formula 17; (e-2) A step of obtaining a compound of chemical formula 19 by subjecting the compound of chemical formula 17 and the compound of chemical formula 18 to a nucleophilic reaction; (e-3) A step of reacting NaR5 with the compound of the above chemical formula 19 to obtain a compound of the chemical formula 1; [Chemical Formula 1] [Chemical Formula 2] [Chemical Formula 3] [Chemical Formula 4] [Chemical Formula 5] [Chemical Formula 6] [Chemical Formula 7] [Chemical Formula 8] [Chemical Formula 9] [Chemical Formula 10] [Chemical Formula 11] [Chemical Formula 12] [Chemical Formula 13] [Chemical Formula 14] NR'1R'2 [Chemical Formula 15] [Chemical Formula 16] [Chemical Formula 17] [Chemical Formula 18] NHR3R4 [Chemical Formula 19] In the above chemical formulas, R a and R b are each independently H or substituted or unsubstituted C1 to C10 alkyl, and X1 to X4 are the same or different halogen elements. R1 to R5 and R'1 and The definition of R'2 is the same as in the above chemical formula 1, and n is an integer from 1 to 3.

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