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

Abstract

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

Description

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

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

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

[0003] This application claims the benefit of priority based on Korean Patent Application No. 10-2024-0187364 filed on December 16, 2024, and all contents disclosed in the document of said Korean patent application are incorporated herein as part of this specification.

[0004] The research for the present invention was conducted with funding from the Ministry of Science and ICT, the Ministry of Trade, Industry and Energy, and the Ministry of Health and Welfare, through the National New Drug Development Project of the National New Drug Development Agency (RS-2024-00259507).

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

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

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

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

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

[0010] [Prior Art Literature]

[0011] [Patent Literature]

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

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

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

[0015] [Chemical Formula 1]

[0016]

[0017] The present disclosure is summarized as follows:

[0018] 1. Compounds represented by the following chemical formula 1, pharmaceutically acceptable salts, hydrates, solvates, prodrugs, tautomers, enantiomers, or diastereomers thereof:

[0019] [Chemical Formula 1]

[0020]

[0021] In the above chemical formula 1,

[0022] R1 is hydrogen, a substituted or unsubstituted alkyl, or a substituted or unsubstituted cycloalkyl, and

[0023] R2 is a substituted or non-substituted aryl, or a substituted or non-substituted heteroaryl, and

[0024] R3 is fluorine, bromine, iodine, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkoxy, a substituted or unsubstituted thioalkyl, a substituted or unsubstituted cycloalkyl, -S(O)R'1, -S(O)2R'1, or -SO3H, where R'1 is a C1 to C4 alkyl.

[0025]

[0026] 2. In the above Paragraph 1,

[0027] The above R1 is a compound, pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer, wherein R1 is hydrogen, a substituted or unsubstituted C1 to C4 alkyl, or a substituted or unsubstituted C3 to C6 cycloalkyl.

[0028]

[0029] 3. In any one of the preceding paragraphs,

[0030] A compound, pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer thereof, wherein the above-mentioned substituted aryl or substituted heteroaryl is substituted with one or more substituents selected from the group consisting of substituted or unsubstituted C1 to C6 alkyl, substituted or unsubstituted C1 to C6 alkoxy, and halogen elements.

[0031]

[0032] 4. In any one of the preceding paragraphs,

[0033] A compound, pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer thereof, wherein the alkyl group of the above substitution is substituted with a halogen element.

[0034]

[0035] 5. In any one of the preceding paragraphs,

[0036] A compound, pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer thereof, wherein the alkyl group of the above substitution is substituted with 1 to 3 halogen elements.

[0037]

[0038] 6. In any one of the preceding paragraphs,

[0039] A compound, pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer thereof, wherein the above-mentioned substituted aryl or substituted heteroaryl is substituted with one or more substituents selected from the group consisting of unsubstituted C1 to C3 alkyl, C1 to C3 alkyl substituted with a halogen element, unsubstituted C1 to C3 alkoxy, and halogen element.

[0040]

[0041] 7. In any one of the preceding paragraphs,

[0042] The above R'1 is a compound, pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer, wherein R'1 is methyl or ethyl.

[0043]

[0044] 8. In any one of the preceding paragraphs,

[0045] The above compound is a compound selected from the group consisting of compounds 1 to 137 disclosed herein, a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer thereof.

[0046]

[0047] 9. NAD comprising, as an active ingredient, the compound of any one of the preceding paragraphs, or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer. +A pharmaceutical composition for the prevention or treatment of diseases caused by a decrease in or mitochondrial dysfunction.

[0048]

[0049] 10. In the above paragraph 9,

[0050] The above NAD + A pharmaceutical composition wherein the disease caused by a decrease in or mitochondrial dysfunction is one or more selected from the group consisting of metabolic diseases, primary and secondary mitochondrial diseases, muscle diseases, neurodegenerative diseases, inflammatory diseases, fibrotic diseases, autoimmune diseases, cancer, and cognitive impairment.

[0051]

[0052] 11. In the above Paragraph 9 or 10,

[0053] A pharmaceutical composition wherein the above metabolic disease is one or more selected from the group consisting of obesity, diabetes, and metabolic disorder-related fatty liver disease.

[0054]

[0055] 12. NAD comprising, as an active ingredient, the compound of any one of the preceding paragraphs, or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer. + A food composition for the prevention or improvement of diseases caused by a decrease in or mitochondrial dysfunction.

[0056]

[0057] 13. A composition for enhancing the activity of NQO1, comprising as an active ingredient a compound of any one of the preceding claims, a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer thereof.

[0058]

[0059] 14. A method for preparing a compound represented by Chemical Formula 1, comprising the following steps:

[0060] A step of obtaining a compound of the following chemical formula 3 by reacting a compound of chemical formula 2 below with HNO3 under acidic conditions;

[0061] (S2) A step of reacting the compound of Formula 3 and formamide under acidic conditions to obtain the compound of Formula 4;

[0062] (S3) A step of obtaining a compound of Formula 5 by cyclizing the compound of Formula 4 under acidic conditions;

[0063] (S4) A step of dissolving the compound of Formula 5 in acetonitrile and then reacting it with an oxidizing agent to obtain quinazoline-5,8-dione of Formula 6;

[0064] (S5) A step of obtaining a compound of the following formula 7 by performing a halogenation reaction of the quinazoline-5,8-dione of formula 6 above;

[0065] (S6) A step of synthesizing a compound of the following formula 1 from a compound of the above formula 7, wherein the step is performed by a method comprising any one of the following steps (a) to (c).

[0066] (a) a step of reacting the compound of Formula 7 with the compound of Formula 8 to obtain the compound of Formula 1,

[0067] (b) a step of reacting the compound of Formula 7 with the compound of Formula 8 to obtain the compound of Formula 9; and a step of reacting NaZ1 with the compound of Formula 9 to obtain the compound of Formula 1;

[0068] (c) a step of obtaining a compound of formula 9 by reacting the compound of formula 7 with the compound of formula 8; a step of obtaining a compound of formula 10 by reacting NaZ1 with the compound of formula 9; and a step of obtaining a compound of formula 1 by reacting the compound of formula 10 with an oxidizing agent.

[0069] [Chemical Formula 2]

[0070]

[0071] [Chemical Formula 3]

[0072]

[0073] [Chemical Formula 4]

[0074]

[0075] [Chemical Formula 5]

[0076]

[0077] [Chemical Formula 6]

[0078]

[0079] [Chemical Formula 7]

[0080]

[0081] [Chemical Formula 8]

[0082]

[0083] [Chemical Formula 9]

[0084]

[0085] [Chemical Formula 10]

[0086]

[0087] [Chemical Formula 1]

[0088]

[0089] (In the above chemical formulas,

[0090] R1 is hydrogen, a substituted or unsubstituted alkyl, or a substituted or unsubstituted cycloalkyl, and

[0091] R2 is a substituted or non-substituted aryl, or a substituted or non-substituted heteroaryl, and

[0092] R3 is fluorine, bromine, iodine, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkoxy, a substituted or unsubstituted thioalkyl, a substituted or unsubstituted cycloalkyl, -S(O)R'1, -S(O)2R'1, or -SO3H, where R'1 is a C1 to C4 alkyl, and

[0093] R a and R b Each is independently an -OH or a substituted or unsubstituted alkoxy, and

[0094] X1 and X2 are identical or different halogen elements, and

[0095] The above n is an integer from 1 to 5, and Y is a substituted or unsubstituted alkyl, a substituted or unsubstituted alkoxy, or a halogen, wherein when n is 2 or more, the n Ys are each independent of each other, and

[0096] Z1 is a substituted or unsubstituted alkyl, a substituted or unsubstituted alkoxy, a substituted or unsubstituted thioalkyl, or a substituted or unsubstituted cycloalkyl.

[0097]

[0098] 15. A NAD comprising the step of administering to an individual the compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer thereof. + A method for the prevention, improvement, or treatment of diseases caused by a decrease in or mitochondrial dysfunction.

[0099]

[0100] 16. NAD + Use of any compound of the preceding claim, its pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer for the prevention, improvement, or treatment of diseases caused by a decrease in or mitochondrial dysfunction.

[0101]

[0102] 17. NAD+ Use of the compound of any one of the preceding claims, its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, tautomers, enantiomers, or diastereomers for the manufacture of a drug for the prevention, improvement, or treatment of diseases caused by a decrease in or mitochondrial dysfunction.

[0103]

[0104] However, the technical problems that the present invention aims to solve are not limited to those mentioned above, and other unmentioned problems will be clearly understood by those skilled in the art to which the present invention belongs from the description below.

[0105] The present invention provides a novel compound of Formula 1 that can serve as a substrate for NQO1, and a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer thereof.

[0106] In addition, the present invention comprises, as an active ingredient, the above compound, its pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer, NAD + A composition for the prevention, improvement, or treatment of diseases caused by a decrease in or mitochondrial dysfunction is provided.

[0107] In addition, the present invention provides a composition for enhancing the activity of NQO1, comprising the above compound, its pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer as an active ingredient.

[0108] In addition, the present invention provides a method for manufacturing the above compound.

[0109] The present invention relates to a novel 1,4-naphthoquinone derivative, which was completed by confirming that said derivative acts as a substrate for NQO1 and effectively increases enzyme activity. Accordingly, the compound according to the present invention increases NQO1 activity and consequently NAD + NAD through increase + It can achieve preventive, improved, and / or therapeutic effects for various diseases associated with a decrease in or mitochondrial dysfunction.

[0110] The present invention relates to a novel 1,4-naphthoquinone derivative, and was completed by confirming that the derivative acts as a substrate for NQO1 and effectively increases the activity of the enzyme.

[0111] The present invention will be described in detail below.

[0112] 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:

[0113] [Chemical Formula 1]

[0114]

[0115] In the above chemical formula 1,

[0116] R1 is hydrogen, a substituted or unsubstituted alkyl, or a substituted or unsubstituted cycloalkyl, and

[0117] R2 is a substituted or non-substituted aryl, or a substituted or non-substituted heteroaryl, and

[0118] R3 is fluorine, bromine, iodine, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkoxy, a substituted or unsubstituted thioalkyl, a substituted or unsubstituted cycloalkyl, -S(O)R'1, -S(O)2R'1, or -SO3H, where R'1 is a C1 to C4 alkyl.

[0119] Unless otherwise stated below, the compound of Formula 1 of the present invention includes all of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, tautomers, enantiomers, or diastereomers, all of which should be interpreted as being included within the scope of the present invention. For convenience of explanation, the compound of Formula 1, 1,4-naphthoquinone derivatives, etc., may be simply abbreviated in this specification.

[0120] The term “pharmaceuticalally acceptable salt” refers to a formulation of a compound that does not cause severe irritation to the organism to which it is administered and does not impair the biological activity and physical properties of the compound.

[0121] The terms "hydrate," "solvent," "prodrug," "tautomer," "enantiomer," or "diastereomer" in this specification also have the same meaning as above.

[0122] The above "pharmaceutically acceptable salt" includes acid addition salts formed by acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as inorganic acids like hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromide, hydroiodide, etc., organic carboxylic acids like tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid, etc., and sulfonic acids like methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. For example, pharmaceutically acceptable carboxylic acid salts include metal salts or alkaline earth metal salts formed by lithium, sodium, potassium, calcium, magnesium, etc., amino acid salts such as lysine, arginine, guanidine, etc., and organic salts such as dicyclohexylamine, N-methyl-D-glucarmine, tris(hydroxymethyl)methylamine, diethanolamine, choline, and triethylamine, etc. The compound of Formula 1 according to the present invention may also be converted into its salt by conventional methods.

[0123] The term “hydrate” means a compound of the present invention or a salt thereof containing stoichiometric or non-stoichiometric amounts of water bound by non-covalent intermolecular forces.

[0124] The term “solvate” means a compound of the present invention or a salt thereof comprising stoichiometric or non-stoichiometric amounts of solvent bound by non-covalent intermolecular forces. Preferred solvents thereof include volatile, non-toxic, and / or solvents suitable for administration to humans.

[0125] The term “prodrug” refers to a substance that transforms into a parent drug in vivo. Prodrugs are often used because, in some cases, they are easier to administer than the parent drug. For example, they may achieve viability via oral administration, whereas the parent drug may not. Prodrugs may also have improved solubility in pharmaceutical compositions compared to the parent drug. For example, a prodrug might be a compound administered as an ester (“prodrug”) that facilitates passage through the cell membrane, which is hydrolyzed by metabolism into an active carboxylic acid once water solubility is beneficial in the cell, although water solubility is detrimental to mobility. Another example of a prodrug could be a short peptide (polyamino acid) bound to an acid group that is converted by metabolism to expose the active site.

[0126] The term "tautomer" refers to a type of structural isomer that has the same chemical or molecular formula but differs in the way its constituent atoms are connected; for example, it signifies a structure that continuously alternates between the two isomers, such as in a keto-enol structure.

[0127] The terms “enantiomer” or “diastereomer” refer to isomers that have the same chemical or molecular formula but differ in the spatial arrangement of atoms within the molecule. The term “enantiomer” refers to an isomer that does not overlap with its mirror image, much like the relationship between a right hand and a left hand. Additionally, “diastereomer” refers to a stereoisomer that is not in a mirror image relationship, such as the trans form and the cis form; in this invention, the term is limited to pharmaceutically acceptable diastereomers. All of these isomers and mixtures thereof are also included within the scope of this invention.

[0128] The term “alkyl” refers to an aliphatic hydrocarbon group. In the present invention, “alkyl” is used as a concept that includes both “saturated alkyl,” which means not containing any alkene or alkyne groups, and “unsaturated alkyl,” which means containing at least one alkene or alkyne group; more specifically, it may be “saturated alkyl,” which means not containing any alkene or alkyne groups. The alkyl may include branched, straight-chain, or cyclic forms, and may also include structural isomers; for example, in the case of a C3 alkyl, it may mean propyl or isopropyl. In the present invention, the alkyl may be C1 to C20, C1 to C15, C1 to C12, C1 to C10, C1 to C8, C1 to C6, C1 to C5, C1 to C4, C1 to C3, or C1 to C2 alkyl, but is not limited thereto. For example, in the present invention, the alkyl may be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl, etc., and more specifically, for example, may be methyl or ethyl, etc.

[0129] The term “heteroalkyl” refers to an alkyl group comprising at least one heteroatom (e.g., oxygen, nitrogen, sulfur, etc.) in addition to carbon and hydrogen. Like alkyls, heteroalkyls may also include branched, straight-chain, or cyclic forms and include structural isomers.

[0130] The term “cycloalkyl” refers to a saturated hydrocarbon group in which three or more carbon atoms form a ring structure. In the present invention, the cycloalkyl may be C3 to C20, C3 to C15, C3 to C12, C3 to C10, C3 to C8, C3 to C6, C3 to C5, or C3 cycloalkyl, but is not limited thereto.

[0131] The term "heterocycloalkyl" refers to a cycloalkyl group in which a ring carbon is substituted with oxygen, nitrogen, sulfur, etc.

[0132] The term "alkene" refers to a group in which at least two carbon atoms are connected by at least one carbon-carbon double bond, and "alkyne" refers to a group in which at least two carbon atoms are connected by at least one carbon-carbon triple bond. In the present invention, the alkene or alkyne may be C1 to C20, C1 to C15, C1 to C12, C1 to C10, C1 to C8, C1 to C6, C1 to C5, C1 to C4, C1 to C3, or C1 to C2 alkenes or alkynes, but are not limited thereto.

[0133] The term “alkoxy” refers to a substituent having a structure in which an alkyl group is connected through an oxygen atom. In the present invention, the alkoxy may be a C1 to C10, C1 to C8, C1 to C6, C1 to C5, C1 to C3, or C1 to C2 alkoxy, but is not limited thereto. Specifically, examples include methoxy (-OCH3), ethoxy (-OCH2CH3), etc.

[0134] The term "aryl" refers to an aromatic substituent having at least one ring having a shared pi electron system. The term includes monocyclic or fused ring polycyclic groups (i.e., rings that share adjacent pairs of carbon atoms). When substituted, the substituent may be appropriately bonded to the ortho (o), meta (m), or para (p) positions.

[0135] The term "aryloxy" refers to a group in which one carbon of an aromatic substituent is bonded to oxygen, and for example, when oxygen is bonded to a phenyl group, it can be represented as -O-C6H5 or -C6H4-O-.

[0136] The term "heteroaryl" refers to an aromatic group in which at least one of the ring carbons constituting the aryl is substituted with oxygen, nitrogen, sulfur, etc.

[0137] Examples of the above aryl or heteroaryl include phenyl, furan, pyran, pyridyl, pyrimidyl, triazyl, etc., but are not limited to these.

[0138] The term "halogen" refers to elements belonging to Group 17 of the periodic table, specifically fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0139] The term “thioalkyl” refers to a substituent having a structure in which an alkyl group is connected through a sulfur atom. In the present invention, the thioalkyl may be C1 to C10, C1 to C8, C1 to C6, C1 to C5, C1 to C3, or C1 to C2 thioalkyl, but is not limited thereto. Specifically, examples include methylthio(-SCH3), ethylthio(-SCH2CH3), etc. The alkyl group included in the thioalkyl may have a straight-chain, branched-chain, or cyclic structure and is not particularly limited.

[0140] Other terms may be interpreted in the sense commonly understood in the field to which the present invention belongs.

[0141] In the present invention, the term "substitution" refers to the element introduced in place of a hydrogen atom when a derivative is formed by substituting one or more hydrogen atoms in an organic compound with another atomic group, and the substituent refers to the introduced atomic group. That is, in the present invention, the substitution of any functional group means that one or more hydrogen atoms of the said functional group are replaced by another atomic group. In the present invention, each functional group (alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, acetyl, etc.) may each independently have one or more hydrogen atoms substituted by another atomic group. In the present invention, "substitution" includes single substitution, double substitution, triple substitution, quadruple substitution, etc.

[0142] In one embodiment of the present invention, R1 of Formula 1 may be hydrogen, a substituted or unsubstituted C1 to C4 alkyl, or a substituted or unsubstituted C3 to C6 cycloalkyl, but is not limited thereto.

[0143] In one embodiment of the present invention, the substituted alkyl or substituted cycloalkyl that may be R1 may be substituted with one or more substituents selected from the group consisting of halogen, cyano, C1 to C4 alkyl, C1 to C4 alkoxy, C2 to C4 alkenyl, C6 to C10 aryl, 4 to 12 heterocycloalkyl and 4 to 12 heteroaryl (wherein the heterocycloalkyl or heteroaryl comprises one or more types selected from the group consisting of N, O and S, for example, 1 to 3 heteroatoms), for example, 1 to 4, 1 to 3, or 1 to 2. In this case, the two or more substituents may be the same or different from each other.

[0144] In one embodiment of the present invention, R2 of Formula 1 may be a substituted or unsubstituted C6 to C10 aryl, or a substituted or unsubstituted 4 to 12 heteroaryl.

[0145] More specifically, R2 of the above chemical formula 1 may be a substituted or unsubstituted C6 to C10 aryl, or a substituted or unsubstituted 4 to 9 heteroaryl, wherein the heteroaryl may include one or more heteroatoms selected from the group consisting of N, O, and S, for example, 1 to 3 heteroatoms. In this case, two or more heteroatoms may be identical or different from each other.

[0146] In one embodiment of the present invention, R2 of Formula 1 may be a substituted aryl or a substituted heteroaryl, wherein the substituted aryl or the substituted heteroaryl may be substituted with one or more substituents selected from the group consisting of substituted or unsubstituted C1 to C6 alkyls, substituted or unsubstituted C1 to C6 alkoxys, and halogen elements, for example, 1 to 4, 1 to 3, or 1 to 2 substituents. In this case, the two or more substituents may be the same or different from each other.

[0147] Here, the halogen element may be, more specifically, fluorine, bromine, or chlorine, but is not limited thereto.

[0148] Here, the substituted or unsubstituted alkyl may be a C1 to C6 alkyl, more specifically a C1 to C4 alkyl, a C1 to C3 alkyl, or a C1 to C2 alkyl, but is not limited thereto.

[0149] Here, the alkyl of the substitution may be an alkyl (i.e., a haloalkyl) substituted with a halogen element. Additionally, the alkyl of the substitution may be substituted with one to three halogen elements. Here, two or more halogen elements may be of the same or different types. The halogen element may be fluorine, but is not limited thereto. For example, the alkyl of the substitution may be -CF3.

[0150] Here, the substituted or unsubstituted alkoxy may be C1 to C6 alkoxy, more specifically C1 to C4 alkoxy, C1 to C3 alkoxy, or C1 to C2 alkoxy, but is not limited thereto. For example, the alkoxy may be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, or tert-butoxy, and more specifically, may be methoxy or ethoxy, but is not necessarily limited thereto.

[0151] Here, the alkoxy of the substitution may be substituted with one or more substituents selected from the group consisting of halogen, cyano, C1 to C4 alkyl, C2 to C4 alkenyl, C6 to C10 aryl, 4 to 12 heterocycloalkyl and 4 to 12 heteroaryl (wherein the heterocycloalkyl or heteroaryl comprises one or more types selected from the group consisting of N, O and S, for example, 1 to 3 heteroatoms), for example, 1 to 4, 1 to 3, or 1 to 2. In this case, the two or more substituents may be identical or different from each other.

[0152] In another embodiment of the present invention, the substituted aryl or substituted heteroaryl may be any one selected from the group consisting of unsubstituted C1 to C3 alkyl, C1 to C3 alkyl substituted with a halogen element, unsubstituted C1 to C3 alkoxy, and a halogen element, or substituted with any two or more identical or different substituents, but is not limited thereto.

[0153] In one embodiment of the present invention, R3 of the formula 1 may be fluorine, bromine, iodine, a substituted or unsubstituted C1 to C10 alkyl, a substituted or unsubstituted C1 to C10 alkoxy, a substituted or unsubstituted C1 to C10 thioalkyl, a substituted or unsubstituted C3 to C8 cycloalkyl, -S(O)R'1, -S(O)2R'1, or -SO3H, but is not limited thereto.

[0154] Here, the above R'1 may be a C1 to C4 alkyl or a C1 to C3 alkyl, and more specifically may be methyl or ethyl, but is not limited thereto.

[0155] Here, the alkyl may more specifically be a C1 to C8 alkyl, a C1 to C6 alkyl, a C1 to C4 alkyl, or a C1 to C3 alkyl, and more specifically may be methyl or ethyl, but is not limited thereto.

[0156] Here, the alkoxy may be more specifically a C1 to C8 alkoxy, a C1 to C6 alkoxy, a C1 to C4 alkoxy, or a C1 to C3 alkoxy, and more specifically a methoxy or ethoxy, but is not limited thereto.

[0157] Here, the alkyl in the thioalkyl may more specifically be a C1 to C8 alkyl, a C1 to C6 alkyl, a C1 to C4 alkyl, or a C1 to C3 alkyl, and more specifically, the thioalkyl may be methylthio or ethylthio, but is not limited thereto.

[0158] Here, the cycloalkyl may be more specifically C3 to C6 or C3 to C5 cycloalkyl, but is not limited thereto.

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

[0160] In the present invention, the range of Formula 1 encompasses all compounds that can be formed by combining the definitions of R1, R2, and / or R3 described in one embodiment of the present invention.

[0161] In one embodiment of the present invention, the compound of Formula 1 may be selected from the group consisting of the following compounds 1 to 137.

[0162] However, the following compounds 1 to 137 correspond to some embodiments of compounds conceivable from this specification and are not necessarily limited thereto. The embodiments of compounds 1 to 137 demonstrate that the compounds of Formula 1 of the present invention exhibit certain utility even when various substituent changes are included:

[0163]

[0164]

[0165]

[0166]

[0167]

[0168] In addition, the present invention comprises, as an active ingredient, the above compound, its pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer, NAD + The present invention provides a composition for the prevention, improvement, or treatment of diseases caused by a decrease in or mitochondrial dysfunction. The composition may be a pharmaceutical composition, a food composition, and / or a cosmetic composition. Preferably, the present invention comprises NAD, the above compound, etc., as an active ingredient. + Provides a pharmaceutical composition for the prevention or treatment of diseases caused by a decrease in or mitochondrial dysfunction.

[0169] In addition, the present invention relates to a NAD comprising the above-mentioned therapeutic composition. +Provides a kit for the prevention, improvement, or treatment of diseases caused by a decrease in or mitochondrial dysfunction.

[0170] In addition, the present invention comprises the step of administering the above compound, etc. to an individual, NAD + A method for preventing, improving, or treating diseases caused by a decrease in or mitochondrial dysfunction is provided. Herein, the individual is NAD + It may be an individual requiring prevention, improvement, or treatment of a disease caused by a decrease in or mitochondrial dysfunction. Here, the method comprises administering NAD prior to the administering step. + It may additionally include a step of identifying individuals requiring prevention, improvement, or treatment of diseases caused by a decrease in or mitochondrial dysfunction.

[0171] In addition, the present invention is NAD + The above compounds, etc. are used for the prevention, improvement, or treatment of diseases caused by a decrease in or mitochondrial dysfunction.

[0172] In addition, the present invention is NAD + The above compounds, etc. are used for the manufacture of drugs for the prevention, improvement, or treatment of diseases caused by a decrease in or mitochondrial dysfunction.

[0173] In addition, the present invention provides a composition for enhancing the activity of NAD(P)H quinone dehydrogenase 1 (NQO1), comprising the compound, a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer thereof as an active ingredient. The composition may be a pharmaceutical composition, a food composition, and / or a cosmetic composition.

[0174] In addition, the present invention provides a kit for enhancing the activity of NQO1, comprising the above composition.

[0175] In addition, the present invention provides a method for enhancing the activity of NQO1, comprising the step of administering the above-mentioned compound, etc. to an individual. Herein, the individual may be an individual requiring enhancement of the activity of NQO1. Herein, the method may further include the step of identifying an individual requiring enhancement of the activity of NQO1 prior to the step of administration.

[0176] In addition, the present invention provides a use of the above-mentioned compound, etc. for enhancing the activity of NQO1.

[0177] In addition, the present invention provides a use of the above-mentioned compound, etc. for the manufacture of a drug for enhancing the activity of NQO1.

[0178] The compound according to the present invention can increase the activity of NQO1, and the NQO1 with increased activity oxidizes NADH to increase intracellular NAD + Increases NAD + An increase in / NADH can increase the AMP / ATP ratio, and an increase in AMP activates AMP-activated protein kinase (AMPK), which induces mitophagy. In addition, NAD + It is used as a cofactor for enzymes related to glucose and fat metabolism in the body to promote metabolism, and NAD + cADPR, generated from the degradation of , is produced in the endoplasmic reticulum (ER) from Ca 2+ By releasing [it] to induce synergistic activation of mitochondrial metabolism, it can bring about an in vivo motion-mimicking effect. Therefore, the compound of the present invention, through the effects described above, [induces] NAD + It is possible to achieve preventive, improved, and / or therapeutic effects for various diseases that may be caused by a decrease in or mitochondrial dysfunction.

[0179] In one embodiment of the present invention, the NAD +Diseases caused by a decrease in or mitochondrial dysfunction may be one or more selected from the group consisting of metabolic diseases, primary and secondary mitochondrial diseases, muscular diseases, neurodegenerative diseases, inflammatory diseases, fibrotic diseases, autoimmune diseases, cancer, and cognitive impairment, but are not limited thereto.

[0180] In another embodiment of the present invention, the metabolic disease may be one or more selected from the group consisting of obesity, diabetes, and metabolic disorder-related fatty liver disease, but is not limited thereto.

[0181] The content of the compound, etc. in the composition of the present invention can be appropriately adjusted according to the symptoms of the disease, the degree of progression of the symptoms, the condition of the patient, etc. For example, it may be 0.0001 to 99.9% by weight or 0.001 to 50% by weight based on the total weight of the composition, but is not limited thereto. The above content ratio is a value based on the dry weight after removing the solvent.

[0182] The pharmaceutical composition according to the present invention may further include a suitable carrier, excipient, and diluent commonly used in the manufacture of pharmaceutical compositions. The excipient may be one or more selected from the group consisting of, for example, diluents, binders, disintegrants, lubricants, adsorbents, humectants, film-coating materials, and controlled-release additives.

[0183] The pharmaceutical composition according to the present invention may be formulated and used in the form of external preparations such as powders, granules, sustained-release granules, enteric granules, liquids, eye drops, oxylic agents, emulsions, suspensions, ethanol tablets, troches, fragrances, limonene adzes, tablets, sustained-release tablets, enteric tablets, sublingual tablets, hard capsules, soft capsules, sustained-release capsules, enteric capsules, pills, tinctures, soft extracts, dry extracts, fluid extracts, injections, capsules, irrigation solutions, warning agents, lotions, pastes, sprays, inhalants, patches, sterile injectable solutions, or aerosols, according to conventional methods, and the external preparations may have formulations such as creams, gels, patches, sprays, ointments, warning agents, lotions, liniments, pastes, or cataplasms.

[0184] Carriers, excipients, and diluents that may be included in the pharmaceutical composition according to the present invention include lactose, dextrose, sucrose, oligosaccharide, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil.

[0185] When formulating, it is prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants.

[0186] The pharmaceutical composition according to the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level may be determined according to factors including the type and severity of the patient's disease, drug activity, sensitivity to the drug, time of administration, route of administration and elimination rate, duration of treatment, concurrently used drugs, and other factors well known in the medical field.

[0187] The pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered as a single or multiple doses. It is important to administer an amount that obtains maximum effect with a minimum amount without side effects by considering all the above-mentioned factors, and this can be easily determined by a person skilled in the art to which the present invention belongs.

[0188] The pharmaceutical composition of the present invention may be administered to an individual by various routes. All modes of administration are expected, for example, oral administration, subcutaneous injection, intraperitoneal administration, intramuscular injection, intrathecal (intradural) injection, sublingual administration, buccal mucosal administration, rectal insertion, vaginal insertion, ocular administration, ear administration, nasal administration, inhalation, spray through the mouth or nose, skin administration, transdermal administration, etc.

[0189] The dosage of the pharmaceutical composition of the present invention is determined by the type of active ingredient drug, along with various relevant factors such as the disease to be treated, the route of administration, the patient's age, gender, weight, and the severity of the disease. Specifically, the effective dosage of the composition according to the present invention may vary depending on the patient's age, gender, and weight, and generally, 0.001 to 150 mg, preferably 0.01 to 100 mg per kg of body weight, may be administered daily or every other day, or divided into 1 to 3 doses per day. However, since the dosage may be increased or decreased depending on the route of administration, the severity of the disease, gender, weight, age, etc., the above dosage does not limit the scope of the present invention in any way.

[0190] In the present invention, the term “individual” refers to a subject requiring treatment for a disease, and more specifically, to mammals such as humans or non-human primates, mice, rats, dogs, cats, horses, and cattle.

[0191] In the present invention, “administration” means providing a predetermined composition of the present invention to an individual by any appropriate method.

[0192] In the present invention, “prevention” refers to any act of suppressing or delaying the onset of a target disease, “treatment” refers to any act of improving or beneficially altering the target disease and associated metabolic abnormality symptoms through the administration of a pharmaceutical composition according to the present invention, and “improvement” refers to any act of reducing parameters related to the target disease, such as the severity of symptoms, through the administration of a composition according to the present invention.

[0193] When the compounds of the present invention are used as food additives, they may be added as they are or used together with other foods or food ingredients, or used appropriately according to conventional methods. The amount of the active ingredient can be appropriately determined according to the purpose of use (prevention, health, or therapeutic treatment). Generally, when manufacturing food or beverages, the compounds of the present invention may be added in an amount of 15% by weight or less, or 10% by weight or less, relative to the raw materials. However, in the case of long-term consumption for the purpose of health and hygiene or health control, the above amount may be less than the above range, and since there are no issues regarding safety, the active ingredient may be used in an amount greater than the above range.

[0194] There are no specific restrictions on the types of the above-mentioned foods. Examples of foods to which the above-mentioned substance may be added include meat, sausage, bread, chocolate, candies, snacks, confectionery, pizza, ramen, other noodles, chewing gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages, and vitamin complexes, and include all health functional foods in the conventional sense.

[0195] The health beverage composition according to the present invention may contain various flavoring agents or natural carbohydrates as additional ingredients, as in conventional beverages. The natural carbohydrates mentioned above are monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As sweeteners, natural sweeteners such as taumatin and stevia extract, or synthetic sweeteners such as saccharin and aspartame may be used. The proportion of the natural carbohydrates is generally about 0.01-0.20g or about 0.04-0.10g per 100 mL of the composition of the present invention.

[0196] In addition to the above, the composition of the present invention may contain various nutrients, vitamins, electrolytes, flavoring agents, coloring agents, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc. Furthermore, the composition of the present invention may contain fruit pulp for the production of natural fruit juices, fruit juice beverages, and vegetable beverages. These ingredients may be used independently or in combination. Although the proportion of these additives is not critical, it is generally selected in the range of 0.01 to 0.20 parts by weight per 100 parts by weight of the composition of the present invention.

[0197] The food composition of the present invention can be used as a composition for health functional foods. In this specification, the term “health functional food” is synonymous with “food for special health use (FoSHU)” and refers to a food with high medical or health effects that is processed to efficiently exhibit bio-regulatory functions in addition to nutritional supply. The food may be manufactured in various forms such as tablets, capsules, powders, granules, liquids, and pills to obtain useful effects for the prevention, improvement, and treatment of the aforementioned diseases.

[0198] The health functional food of the present invention can be manufactured by methods commonly used in the industry, and can be manufactured by adding raw materials and ingredients commonly added in the industry. In addition, unlike general pharmaceuticals, it has the advantage of not having side effects that may occur from long-term use of pharmaceuticals because it is made of food, and it can be highly portable.

[0199] The formulation of the cosmetic composition according to the present invention may be in the form of a skin lotion, skin softener, skin toner, astringent, lotion, milk lotion, moisture lotion, nourishing lotion, massage cream, nourishing cream, mist, moisture cream, hand cream, hand lotion, foundation, essence, nourishing essence, pack, soap, cleansing foam, cleansing lotion, cleansing cream, cleansing oil, cleansing balm, body lotion, or body cleanser.

[0200] The cosmetic composition of the present invention may further include a composition selected from the group consisting of water-soluble vitamins, oil-soluble vitamins, high molecular weight peptides, high molecular weight polysaccharides, and sphingolipids.

[0201] In the present invention, the term "Kit" refers to NAD using the compound according to the present invention. + It refers to a combination of materials or devices, etc., for the purpose of preventing, improving, and / or treating diseases caused by a decrease in or mitochondrial dysfunction of NQO1, or for the purpose of enhancing the activity of NQO1, and there are no limitations on the specific form. For the above-mentioned uses, the kit according to the present invention may include not only the compound according to the present invention but also one or more other constituent compositions, solutions, or devices suitable for the prevention, improvement, or treatment of diseases.

[0202]

[0203] In addition, the present invention provides a method for preparing a compound of Formula 1, comprising the following steps:

[0204] (S1) A step of reacting the compound of Formula 2 below with HNO3 under acidic conditions to obtain the compound of Formula 3 below;

[0205] (S2) A step of reacting the compound of Formula 3 and formamide under acidic conditions to obtain the compound of Formula 4;

[0206] (S3) A step of obtaining a compound of Formula 5 by cyclizing the compound of Formula 4 under acidic conditions;

[0207] (S4) A step of dissolving the compound of Formula 5 in acetonitrile and then reacting it with an oxidizing agent to obtain quinazoline-5,8-dione of Formula 6;

[0208] (S5) A step of obtaining a compound of the following formula 7 by performing a halogenation reaction of the quinazoline-5,8-dione of formula 6 above;

[0209] (S6) A step of synthesizing a compound of the following formula 1 from a compound of the above formula 7, wherein the step is performed by a method comprising any one of the following steps (a) to (c).

[0210] (a) a step of reacting the compound of Formula 7 with the compound of Formula 8 to obtain the compound of Formula 1,

[0211] (b) a step of reacting the compound of Formula 7 with the compound of Formula 8 to obtain the compound of Formula 9; and a step of reacting NaZ1 with the compound of Formula 9 to obtain the compound of Formula 1,

[0212] (c) a step of obtaining a compound of formula 9 by reacting the compound of formula 7 with the compound of formula 8; a step of obtaining a compound of formula 10 by reacting NaZ1 with the compound of formula 9; and a step of obtaining a compound of formula 1 by reacting the compound of formula 10 with an oxidizing agent.

[0213] [Chemical Formula 2]

[0214]

[0215] [Chemical Formula 3]

[0216]

[0217] [Chemical Formula 4]

[0218]

[0219] [Chemical Formula 5]

[0220]

[0221] [Chemical Formula 6]

[0222]

[0223] [Chemical Formula 7]

[0224]

[0225] [Chemical Formula 8]

[0226]

[0227] [Chemical Formula 9]

[0228]

[0229] [Chemical Formula 10]

[0230]

[0231] [Chemical Formula 1]

[0232]

[0233] (In the above chemical formulas,

[0234] R1 is hydrogen, a substituted or unsubstituted alkyl, or a substituted or unsubstituted cycloalkyl, and

[0235] R2 is a substituted or non-substituted aryl, or a substituted or non-substituted heteroaryl, and

[0236] R3 is fluorine, bromine, iodine, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkoxy, a substituted or unsubstituted thioalkyl, a substituted or unsubstituted cycloalkyl, -S(O)R'1, -S(O)2R'1, or -SO3H, where R'1 is a C1 to C4 alkyl, and

[0237] The above R a and R b Each is independently an -OH or a substituted or unsubstituted alkoxy, and

[0238] X1 and X2 are identical or different halogen elements, and

[0239] The above n is an integer from 1 to 5, and Y is a substituted or unsubstituted alkyl, a substituted or unsubstituted alkoxy, or a halogen, wherein when n is 2 or more, the n Ys are each independent of each other, and

[0240] Z1 is a substituted or unsubstituted alkyl, a substituted or unsubstituted alkoxy, a substituted or unsubstituted thioalkyl, or a substituted or unsubstituted cycloalkyl.

[0241] In one embodiment of the present invention, the R a and R b Each may independently be an -OH or a substituted or unsubstituted C1 to C10 alkoxy. Here, the alkoxy may be, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, or tert-butoxy, but is not limited thereto.

[0242] Here, the alkoxy of the substitution may be substituted with one or more substituents selected from the group consisting of halogen, cyano, C1 to C4 alkyl, C1 to C4 alkoxy, C2 to C4 alkenyl, and C6 to C10 aryl.

[0243] In one embodiment of the present invention, n is an integer from 1 to 5, and Y is a substituted or unsubstituted alkyl, a substituted or unsubstituted alkoxy, or a halogen, wherein when n is 2 or more, the n Ys are each independent of each other. In other words, when n is 2 or more, each Y is independently a substituted or unsubstituted alkyl, a substituted or unsubstituted alkoxy, or a halogen. Specifically, n being 1 means that the formula 8 is substituted with one Y, and n being 2 means that the formula 8 is substituted with two Ys, wherein the two Ys can be represented as Y1 and Y2, respectively. Likewise, n being 3 means that the formula 8 is substituted with three Ys, wherein the three Ys can be represented as Y1 to Y3, respectively. A person skilled in the art can understand the meaning in accordance with the above when n is 4 or 5.

[0244] Here, the above Y is located at the ortho, meta, or para relative to NH2. Also, when n is 2 or greater, n Ys can be located independently at the ortho, meta, or para. Here, 2 or more Ys may be located at different positions (e.g., when n=2, Y1 is at the ortho and Y2 is at the meta relative to NH2), may be located at the same positions (e.g., when n=2, Y1 is at the 2nd ortho and Y2 is at the 6th ortho relative to NH2; or Y1 is at the 3rd meta and Y2 is at the 5th meta relative to NH2), or only some may be located at the same positions. For example, when n is 3 or greater, three or more Ys may all be located in different positions (e.g., when n=3, relative to NH2, Y1 is located ortho, Y2 is in meta, and Y3 is in para), but only some of them may be located in the same position (e.g., when n=3, relative to NH2, Y1 is in meta 3, Y2 is in para, and Y3 is in meta 5; when n=4, relative to NH2, Y1 is in ortho 2, Y2 is in meta 3, Y3 is in para, and Y4 is in meta 5).

[0245] In one embodiment of the present invention, the n Ys are each independently a substituted or unsubstituted alkyl, a substituted or unsubstituted alkoxy, or a halogen. More specifically, the n Ys may each independently be a substituted or unsubstituted C1 to C10 alkyl, a substituted or unsubstituted C1 to C10 alkoxy, or a halogen. Here, the alkyl may specifically be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl, and the alkoxy may be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, or tert-butoxy, but is not limited thereto.

[0246] Here, the substituted alkyl or substituted alkoxy may be substituted with one or more selected from the group consisting of halogen, cyano, C1 to C4 alkyl, C1 to C4 alkoxy, C2 to C4 alkenyl, and C6 to C10 aryl, 4 to 12 heterocycloalkyl and 4 to 12 heteroaryl (wherein the heterocycloalkyl or heteroaryl comprises one or more selected from the group consisting of N, O and S, for example, including 1 to 3 heteroatoms).

[0247] More specifically, the substituted alkyl or substituted alkoxy may be an alkyl or alkoxy substituted with one to three halogen elements. Here, two or more halogen elements may be of the same or different types. The halogen element may be fluorine, but is not limited thereto. For example, the substituted alkyl or substituted alkoxy may be -CF3 or -CF3O.

[0248] In one embodiment of the present invention, Z1 may be an unsubstituted C1 to C10 alkyl, an unsubstituted C1 to C10 alkoxy, an unsubstituted C1 to C10 thioalkyl, or a substituted or unsubstituted C3 to C8 cycloalkyl. More specifically, Z1 may be -CH3, -CH2CH3, -OCH3, -OCH2CH3, -SCH3, or -SCH2CH3.

[0249] Here, the substituted alkyl, substituted alkoxy, substituted thioalkyl, or substituted cycloalkyl may be substituted with one or more selected from the group consisting of halogen, cyano, C1 to C4 alkyl, C2 to C4 alkenyl, C6 to C10 aryl, 4 to 12 heterocycloalkyl and 4 to 12 heteroaryl (wherein the heterocycloalkyl or heteroaryl comprises one or more selected from the group consisting of N, O and S, for example, including 1 to 3 heteroatoms).

[0250] In the present invention, the acid conditions of steps (S1) to (S3) may be formed using nitric acid, hydrochloric acid, sulfuric acid, acetic acid, or acetic anhydride, but are not limited thereto.

[0251] In one embodiment of the present invention, step (S2) may further include the step of adding hydrogen chloride to the reactants of the compound of Formula 3 and formamide to react them. The hydrogen chloride may be dissolved in dioxane, but is not limited thereto.

[0252] In one embodiment of the present invention, step (S3) may be performed by adding a metal catalyst to the compound of Formula 4. For example, the metal catalyst may be selected from Fe, Zn, etc., but is not limited thereto.

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

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

[0255] In one embodiment of the present invention, the step (S6) is a step of synthesizing a compound of the following formula 1 from a compound of formula 7, wherein the step is performed by a method comprising any one of the following steps (a) to (c), and the specific details are as follows.

[0256] Step (a) above is a step of obtaining a compound of Formula 1 by reacting the compound of Formula 7 with the compound of Formula 8, and specifically, can be carried out by nucleophilic substitution of the compound of Formula 7 and the compound of Formula 8 under a Lewis acid catalyst in an ethanol solvent. Here, the catalyst may be cerium chloride hydrate, preferably cerium(III) chloride heptahydrate, but is not limited thereto. The compound of Formula 1 prepared through step (a) may have R3 as fluorine, bromine, or iodine, but is not limited thereto.

[0257] Step (b) above is a step of reacting the compound of Formula 7 with the compound of Formula 8 to obtain the compound of Formula 9, and then reacting the compound of Formula 9 with NaZ1 to obtain the compound of Formula 1. As a specific example, the method may further include a step of stirring the compound of Formula 9 with any one of THF, methanol (MeOH), and dichloromethane before the reaction between the compound of Formula 9 and NaZ1, but is not limited thereto. The compound of Formula 1 prepared through step (b) may have R3 as a substituted or unsubstituted alkyl, a substituted or unsubstituted alkoxy, a substituted or unsubstituted thioalkyl, or a substituted or unsubstituted cycloalkyl, but is not limited thereto. More specifically, the compound of Formula 1 prepared through step (b) may be -CH3, -CH2CH3, -OCH3, -OCH2CH3, -SCH3, or -SCH2CH3, but is not limited thereto.

[0258] Step (c) above is a step of reacting the compound of Formula 7 with the compound of Formula 8 to obtain the compound of Formula 9, then reacting the compound of Formula 9 with NaZ1 to obtain the compound of Formula 10, and subsequently reacting the compound of Formula 10 with an oxidizing agent to obtain the compound of Formula 1. As a specific example, the step of reacting the compound of Formula 10 with an oxidizing agent may be performed by sequentially adding chloroform and an oxidizing agent to the compound of Formula 10 and stirring, but is not limited thereto. The oxidizing agent used in the above step may be one or more selected from the group consisting of meta-chloroperoxybenzoic acid (mCPBA), MnO2, and Oxone, for example, but is not limited thereto. The compound of Formula 1 prepared through step (c) above is such that R3 is -S(O)R'1, -S(O)2R'1, or -SO3H, where R'1 may be a C1 to C4 alkyl, but is not limited thereto.

[0259]

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

[0261]

[0262] <Example 1> Synthesis of Compounds 1, 2, 107 and 108

[0263]

[0264]

[0265] Nitric acid (HNO3, 83 mL) and acetic anhydride (Ac2O, 81 mL) were placed in a flask and stirred at 0°C. At the same temperature, 2,5-dimethoxybenzaldehyde (40.0 g, 241 mmol) was slowly added over 30 minutes, followed by stirring for another hour. The reaction solution was poured onto ice and quenched; the resulting yellow solid was filtered and thoroughly washed with water. The obtained solid was dried under reduced pressure to obtain the target compound (3,6-dimethoxy-2-nitrobenzaldehyde, B).

[0266] Yellow solid, 65.0 g

[0267] 1 H NMR (400 MHz, DMSO-D6) δ 10.25(s, 1H), 7.69(d, 1H,J= 9.5 Hz), 7.47(d, 1H,J= 9.4 Hz), 3.94(s, 3H), 3.86(s, 3H)

[0268]

[0269] Formamide (NH2CHO, 320 mL) was added to 3,6-dimethoxy-2-nitrobenzaldehyde (76.0 g, 310 mmol) and stirred at 35°C. At the same temperature, hydrogen chloride solution (4 M in dioxane) (HCl·Diox, 400 mL) was added and stirred for another 10 hours. The reaction solution was cooled to room temperature and ice water (400 mL) was added. The resulting solid was filtered and thoroughly washed with water. The obtained solid was dried under reduced pressure to obtain the target compound (N,N'-((3,6-dimethoxy-2-nitrophenyl)methylene)diformamide, C).

[0270] Pale yellow solid, 81.5 g (81.6%)

[0271] 1H NMR (400 MHz, DMSO-D6) δ 8.68(br d, 2H,J= 8.0 Hz), 7.92(s, 2H), 7.27(s, 2H), 6.77(t, 1H,J= 8.1 Hz), 3.87(s, 3H), 3.81(s, 3H)

[0272]

[0273] Distilled water (970 mL) and acetic acid (AcOH, 360 mL) are added to N,N'-((3,6-dimethoxy-2-nitrophenyl)methylene)diformamide (81.0 g, 286 mmol) and stirred at 0°C. Zinc (Zn, 93.5 g, 1.43 mmol) is added at the same temperature and stirred for 2 hours, and then for 4 more hours at room temperature. After filtering the reaction solution, 50% NaOH aqueous solution (1.30 L) is slowly added to the filtrate. After stirring for 5 more minutes at the same temperature, the resulting solid is filtered. The obtained solid is triturated with ethyl acetate (EtOAc, 700 mL) for 30 minutes to remove soluble impurities. The obtained solid is then cleanly dissolved in EtOAc (4.00 L), dried with Na2SO4, and filtered. The target compound (5,8-dimethoxyquinazoline, D) was obtained by concentrating the filtrate under reduced pressure.

[0274] Brown solid, 33.5 g (61.0%)

[0275] 1 H NMR (400 MHz, DMSO-D6) δ 9.61(s, 1H), 9.26(s, 1H), 7.36(d, 1H,J= 8.8 Hz), 7.06(d, 1H,J= 8.6 Hz), 3.96(s, 3H), 3.93(s, 3H)

[0276]

[0277] 5,8-dimethoxyquinazoline (4.00 g, 21.0 mmol) was dissolved in acetonitrile (MeCN, 60 mL) and stirred at 0°C. Ceric ammonium nitrate (CAN, 28.8 g, 52.6 mmol) was dissolved in distilled water (60 mL) and slowly added over 10 minutes at the same temperature, followed by stirring for an additional 30 minutes. The reaction solution was concentrated under reduced pressure to remove MeCN. Saturated aqueous NaCl solution and dichloromethane (DCM) were added to the concentrate, and extraction was performed several times. The separated organic layer was dried and filtered with MgSO4, followed by reduced pressure concentration. The concentrate was purified by recrystallization (EtOAc / n-Hexane (Hex)) to obtain the target compound (quinazoline-5,8-dione, E).

[0278] Pale brown solid, 2.45 g (72.9%)

[0279] 1 H NMR (400 MHz, DMSO-D6) δ 9.68 (s, 1H), 9.42 (s, 1H), 7.28 (d, J = 10.5 Hz, 1H), 7.17 (d, J = 10.5 Hz, 1H).

[0280]

[0281] AcOH (28 mL) was added to quinazoline-5,8-dione (2.29 g, 14.3 mmol) and stirred at room temperature. Bromine (Br2, 1.47 mL, 28.6 mmol) was diluted in AcOH (28 mL) and slowly added at the same temperature. After stirring for another hour at room temperature, sodium acetate (NaOAc, 2.35 g, 28.6 mmol) was added, and the mixture was heated to 120–130°C for 10 minutes. The reaction solution was cooled to 90°C, and then quenched with distilled water (112 mL). After cooling the reaction solution to 0°C, the resulting solid was filtered and washed several times with distilled water. The obtained solid was cleanly dissolved in DCM, then dried and filtered with MgSO4. The filtrate was crystallized with Hex to obtain the target compound (6,7-dibromoquinazoline-5,8-dione, F).

[0282] Yellow solid, 1.93 g (56.3%)

[0283] 1 H NMR (400 MHz, DMSO-D6) δ 9.67(s, 1H), 9.49(s, 1H)

[0284]

[0285] Ethanol (EtOH, 8.90 mL) is added to 6,7-dibromoquinazoline-5,8-dione (282 mg, 887 μmol) and stirred at room temperature. At the same temperature, 5-amino-2-fluorobenzotrifluoride (169 μL, 1.33 mmol) and CeCl3·7H2O (16.5 mg, 44.4 μmol) are added and stirred for 22 hours at room temperature. The reaction solution is concentrated under reduced pressure to remove EtOH. Distilled water and DCM are added to the concentrate and extracted several times; the separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / Hex) and purified by recrystallization (DCM / Hex) to obtain the target compound (7-bromo-6-((4-fluoro-3-(trifluoromethyl)phenyl)amino)quinazoline-5,8-dione, compound 1).

[0286] Red brown solid, 270 mg(73.1%)

[0287] 1 H NMR (400 MHz, DMSO-D6) δ 9.63 (s, 2H), 9.41 (s, 1H), 7.60 - 7.55 (m, 1H), 7.54 - 7.47 (m, 2H).

[0288]

[0289] Tetrahydrofuran (THF, 2.40 mL) was added to 7-bromo-6-((4-fluoro-3-(trifluoromethyl)phenyl)amino)quinazoline-5,8-dione (100 mg, 240 μmol) and stirred at 0°C. At the same temperature, sodium thiomethoxide (NaSMe, 33.7 mg, 481 μmol) was added and stirred for 20 minutes at room temperature. After adding a saturated aqueous solution of NaCl and DCM to the reaction solution and extracting several times, the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / Hex) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((4-fluoro-3-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinazoline-5,8-dione, Compound 2).

[0290] Dark brown solid, 60.4 mg (65.7%)

[0291] 1 H NMR (400 MHz, DMSO-D6) δ 9.62 (s, 1H), 9.54 (s, 1H), 9.40 (s, 1H), 7.51 - 7.38 (m, 3H), 2.06 (s, 3H).

[0292]

[0293] Chloroform (CHCl3, Add 6.80 mL and stir at room temperature. At the same temperature, add mCPBA (612 mg, 2.73 mmol) and stir for another 5.5 hours. Add distilled water to the reaction solution and extract several times with DCM. The separated organic layer is dried and filtered with MgSO4, then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), adjust the pH to 8 with a saturated aqueous solution of NaHCO3, add a saturated aqueous solution of NaCl and DCM, and extract several times. Wash the separated organic layer once with distilled water, dry and filter with MgSO4, and then concentrate under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((4-fluoro-3-(trifluoromethyl)phenyl)amino)-7-(methylsulfinyl)quinazoline-5,8-dione, compound 107)(6-((4-fluoro-3-(trifluoromethyl)phenyl)amino)-7-(methylsulfonyl)quinazoline-5,8-dione, compound 108).

[0294] Compound 107: Orange solid

[0295] 1 H NMR (500 MHz, DMSO-D6) δ 10.98(s, 1H), 9.63(s, 1H), 9.31(s, 1H), 7.87(s, 1H), 7.70(s, 1H), 7.53(t,J= 9.7 Hz, 1H), 3.05(s, 3H).

[0296] Compound 108: Orange-brown solid, 15.6 mg (6.87%)

[0297] 1 H NMR (500 MHz, DMSO-D6) δ10.59(s, 1H), 9.68(s, 1H), 9.36(s, 1H), 7.84(s, 1H), 7.71(s, 1H), 7.53(t,J= 9.7 Hz, 1H), 3.30(s, 3H).

[0298]

[0299] <Example 2> Synthesis of Compounds 3, 4 and 125

[0300]

[0301] EtOH (6.30 mL) was added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, o-anisidine (116 mg, 944 μmol) and CeCl3·7H2O (12.0 mg, 31.5 μmol) were added and stirred for 18.5 hours at room temperature. The reaction solution was concentrated under reduced pressure to remove EtOH. Saturated aqueous NaCl solution and DCM were added to the concentrate and extracted several times; the separated organic layer was dried and filtered with MgSO4, followed by reduced pressure concentration. The concentrate was separated by silica gel column chromatography (EtOAc / Hex) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-bromo-6-((2-methoxyphenyl)amino)quinazoline-5,8-dione, Compound 3).

[0302] Dark orange solid, 172 mg (76.0%)

[0303] 1 H NMR (400 MHz, DMSO-D6) δ 9.60 (s, 1H), 9.34 (s, 1H), 9.17 (s, 1H), 7.30 - 7.14 (m, 2H), 7.03 (d, J = 8.2 Hz, 1H), 6.96 (t, J = 7.0 Hz, 1H), 3.68(s, 3H).

[0304]

[0305] THF (3.6 mL) was added to 7-bromo-6-((2-methoxyphenyl)amino)quinazoline-5,8-dione (130 mg, 361 μmol) and stirred at room temperature. At the same temperature, NaSMe (51.0 mg, 722 μmol) was added and stirred for another 20 minutes at room temperature. Saturated aqueous NaCl solution and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / Hex) and crystallized with Hex to obtain the target compound (7-bromo-6-((2-methoxyphenyl)amino)quinazoline-5,8-dione, Compound 4).

[0306] Dar brown solid, 74.5 mg (63.0%)

[0307] 1 H NMR (400 MHz, DMSO-D6) δ 9.61(s, 1H), 9.48(s, 1H), 9.38(s, 1H), 7.23(t,J= 7.9 Hz, 1H), 6.79 - 6.72(m, 3H), 3.73(s, 3H).

[0308]

[0309] CHCl3 (7.10 mL) is added to 7-bromo-6-((2-methoxyphenyl)amino)quinazoline-5,8-dione (187 mg, 571 μmol) and stirred at room temperature. mCPBA (640 mg, 2.86 mmol) is added at the same temperature and stirred for 5 more hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, and then a saturated aqueous solution of NaCl and DCM are added and extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((2-methoxyphenyl)amino)-7-(methylsulfonyl)quinazoline-5,8-dione, compound 125).

[0310] Red brown solid, 25.6 mg (12.5%)

[0311] 1 H NMR (500 MHz, DMSO-D6) δ 10.47(s, 1H), 9.68(s, 1H), 9.32(s, 1H), 7.39(d,J= 7.2 Hz, 1H), 7.26(t,J= 8.3 Hz, 1H), 7.09(d,J= 8.4 Hz, 1H), 6.97(t,J= 8.3 Hz, 1H), 3.71(s, 3H), 3.45(s, 3H).

[0312]

[0313] <Example 3> Synthesis of Compounds 5 and 6

[0314]

[0315] EtOH (6.30 mL) is added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, 2-methyl-3-trifluoromethyl aniline (165 mg, 944 μmol) and CeCl3·7H2O (11.7 mg, 31.5 μmol) are added and stirred for 17 more hours at room temperature. The reaction solution is concentrated under reduced pressure to remove EtOH. Distilled water and DCM are added to the concentrate and extracted several times; the separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / Hex) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-bromo-6-((2-methyl-3-(trifluoromethyl) phenyl)amino)quinazoline-5,8-dione, compound 5).

[0316] Red solid, 189 mg (73.0%)

[0317] 1 H NMR (400 MHz, DMSO-D6) δ 9.61(s, 1H), 9.41(s, 1H), 9.40(s, 1H), 7.64(d,J= 7.7 Hz, 1H), 7.48(d,J= 7.9 Hz, 1H), 7.40(t,J= 7.9 Hz, 1H), 2.34(s, 3H).

[0318]

[0319] EtOH (2.9 mL) was added to 7-bromo-6-((2-methyl-3-(trifluoromethyl)phenyl)amino)quinazoline-5,8-dione (121 mg, 294 μmol) and stirred at 0°C. At the same temperature, NaSMe (51.5 mg, 735 μmol) was added and stirred for 3 more hours at room temperature. After adding a saturated aqueous solution of NaCl and DCM to the reaction solution and extracting several times, the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / Hex) and purified by recrystallization (ether / Hex) to obtain the target compound (6-((2-methyl-3-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinazoline-5,8-dione, Compound 6).

[0320] Dark violet solid, 54.5 mg (48.9%)

[0321] 1 H NMR (400 MHz, DMSO-D6) δ 9.59(s, 1H), 9.37(s, 1H), 9.12(s, 1H), 7.56(dd,J= 6.1, 3.1 Hz, 1H), 7.39 - 7.32(m, 2H), 2.37(d,J= 1.7 Hz, 3H), 2.09(s, 3H).

[0322]

[0323] <Example 4> Synthesis of Compounds 7 and 8

[0324]

[0325] EtOH (6.30 mL) is added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, 2-methoxy-5-(trifluoromethyl) aniline (180 mg, 944 μmol) and CeCl3·7H2O (11.7 mg, 31.5 μmol) are added and stirred for 18.5 hours at room temperature. The reaction solution is concentrated under reduced pressure to remove EtOH. Distilled water and DCM are added to the concentrate and extracted several times; the separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / Hex) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-bromo-6-((2-methoxy-5-(trifluoromethyl)phenyl)amino)quinazoline-5,8-dione, compound 7).

[0326] Red brown solid, 225 mg (83.6%)

[0327] 1 H NMR (400 MHz, DMSO-D6) δ 9.62(s, 1H), 9.36(s, 1H), 9.18(s, 1H), 7.61 - 7.57(m, 1H), 7.56(d,J= 2.3 Hz, 1H), 7.22(d,J= 8.6 Hz, 1H), 3.78(s, 3H), 1.99(s, 3H).

[0328]

[0329] THF (2.90 mL) was added to 7-bromo-6-((2-methoxy-5-(trifluoromethyl)phenyl)amino)quinazoline-5,8-dione (123 mg, 287 μmol) and stirred at 0°C. At the same temperature, NaSMe (40.3 mg, 575 μmol) was added and stirred for 1.5 hours at room temperature. Saturated aqueous NaCl solution and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / Hex) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((2-methoxy-5-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinazoline-5,8-dione, Compound 8).

[0330] Dark violet solid, 51.4 mg (45.3%)

[0331] 1 H NMR (400 MHz, DMSO-D6) δ 9.61(s, 1H), 9.35(s, 1H), 8.76(s, 1H), 7.52(dd,J= 8.5, 1.6 Hz, 1H), 7.41(d,J= 1.9 Hz, 1H), 7.21(d,J= 8.6 Hz, 1H), 3.84(s, 3H), 2.10(s, 3H).

[0332]

[0333] <Example 5> Synthesis of Compound 9

[0334]

[0335] EtOH (6.30 mL) was added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, m-anisidine (110 μL, 944 μmol) and CeCl3·7H2O (23.4 mg, 62.9 μmol) were added, and the mixture was stirred for 17.5 hours at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4, followed by vacuum concentration. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-bromo-6-((3-methoxyphenyl)amino)quinazoline-5,8-dione, Compound 9).

[0336] Dark brown solid, 33.0 mg (14.6%)

[0337] 1 H NMR (500 MHz, DMSO-D6) δ 9.61(s, 1H), 9.50(s, 1H), 9.39(s, 1H), 7.23(t,J= 8.0 Hz, 1H), 6.81 - 6.71(m, 3H), 3.73(s, 3H).

[0338]

[0339] <Example 6> Synthesis of Compounds 10, 11, 111 and 112

[0340]

[0341] EtOH (6.30 mL) was added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, p-anisidine (116 mg, 944 μmol) and CeCl3·7H2O (12.0 mg, 31.5 μmol) were added and stirred for 16.5 hours at room temperature. The reaction solution was concentrated under reduced pressure to remove EtOH. Saturated aqueous NaCl solution and DCM were added to the concentrate and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / Hex) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-bromo-6-((4-methoxyphenyl)amino)quinazoline-5,8-dione, Compound 10).

[0342] Dark brown solid, 197 mg(87.0%)

[0343] 1 H NMR (400 MHz, DMSO-D6) δ 9.59(s, 1H), 9.50(s, 1H), 9.37(s, 1H), 7.12(d,J= 9.0 Hz, 2H), 6.91(d,J= 9.0 Hz, 2H), 3.77(s, 3H).

[0344]

[0345] THF (3.60 mL) was added to 7-bromo-6-((4-methoxyphenyl)amino)quinazoline-5,8-dione (130 mg, 361 μmol) and stirred at room temperature. At the same temperature, NaSMe (51.0 mg, 722 μmol) was added and stirred for 3.5 hours at room temperature. Saturated aqueous NaCl solution and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / Hex) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((4-methoxyphenyl)amino)-7-(methylthio)quinazoline-5,8-dione, Compound 11).

[0346] Dark brown solid, 55.6 mg (47.0%)

[0347] 1 H NMR (400 MHz, DMSO-D6) δ 9.57(s, 1H), 9.34(s, 1H), 9.31(s, 1H), 7.07(d,J= 9.0 Hz, 2H), 6.88(d,J= 9.0 Hz, 2H), 3.75(s, 3H), 2.03(s, 3H).

[0348] CHCl3 (7.00 mL) is added to 6-((4-methoxyphenyl)amino)-7-(methylthio)quinazoline-5,8-dione (230 mg, 703 μmol) and stirred at room temperature. mCPBA (394 mg, 1.76 mmol) is added at the same temperature and stirred for 5 more hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, and then a saturated aqueous solution of NaCl and DCM are added and extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((4-methoxyphenyl)amino)-7-(methylsulfonyl)quinazoline-5,8-dione, compound 111)(6-((4-methoxyphenyl)amino)-7-(methylsulfonyl)quinazoline-5,8-dione, compound 112).

[0349] Compound 111: Dark brown solid, 16.8 mg (6.96%)

[0350] 1 H NMR (500 MHz, DMSO-D6) δ 10.97(s, 1H), 9.61(s, 1H), 9.27(s, 1H), 7.25(d,J= 8.9 Hz, 2H), 6.93(d,J= 8.9 Hz, 2H), 3.78(s, 3H), 3.00(s, 3H).

[0351] Compound 112: Red-brown solid, 85.5 mg (33.8%)

[0352] 1H NMR (500 MHz, DMSO-D6) δ 10.66(s, 1H), 9.65(s, 1H), 9.28(s, 1H), 7.31(d,J= 9.0 Hz, 2H), 6.93(d,J= 9.0 Hz, 2H), 3.78(s, 3H), 3.37(s, 3H).

[0353]

[0354] <Example 7> Synthesis of Compounds 12, 13, 113 and 114

[0355]

[0356] EtOH (6.30 mL) was added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, 4-chloroaniline (120 mg, 944 μmol) and CeCl3·7H2O (11.7 mg, 31.5 μmol) were added and stirred for 18 more hours at room temperature. The reaction solution was concentrated under reduced pressure to remove EtOH. Distilled water and DCM were added to the concentrate and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-bromo-6-((4-chlorophenyl)amino)quinazoline-5,8-dione, Compound 12).

[0357] Dark brown solid, 199 mg (86.6%)

[0358] 1 H NMR (400 MHz, DMSO-D6) δ 9.61 (s, 1H), 9.58 (s, 1H), 9.39 (s, 1H), 7.41 - 7.36 (m, 2H), 7.21 - 7.16 (m, 2H).

[0359]

[0360] THF (3.30 mL) was added to 7-bromo-6-((4-chlorophenyl)amino)quinazoline-5,8-dione (120 mg, 329 μmol) and stirred at 0°C. At the same temperature, NaSMe (46.1 mg, 658 μmol) was added and stirred for 2.5 hours at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((4-chlorophenyl)amino)-7-(methylthio)quinazoline-5,8-dione, Compound 13).

[0361] Dark violet solid, 83.4 mg (76.4%)

[0362] 1 H NMR (400 MHz, DMSO-D6) δ 9.60 (s, 1H), 9.45 (s, 1H), 9.37 (s, 1H), 7.38 - 7.33 (m, 2H), 7.12 - 7.07 (m, 2H), 2.06 (s, 3H).

[0363]

[0364] CHCl3 (6.50 mL) is added to 6-((4-chlorophenyl)amino)-7-(methylthio)quin azoline-5,8-dione (214 mg, 645 μmol) and stirred at room temperature. At the same temperature, mCPBA (361 mg, 1.61 mmol) is added and stirred for 6.5 hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, and then a saturated aqueous solution of NaCl and DCM are added and extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((4-chlorophenyl)amino)-7-(methylsulfinyl)quinazoline-5,8-dione, compound 113)(6-((4-chlorophenyl)amino)-7-(methylsulfonyl)quinazoline-5,8-dione, compound 114).

[0365] Compound 113: Brown solid, 28.3 mg (12.6%)

[0366] 1 H NMR (500 MHz, DMSO-D6) δ 10.97 (s, 1H), 9.62 (s, 1H), 9.29 (s, 1H), 7.42 (d, J = 8.7 Hz, 2H), 7.35 (d, J = 8.9 Hz, 2H), 3.03 (s, 3H).

[0367] Compound 114: Red brown solid, 21.2 mg (9.04%)

[0368] 1H NMR (500 MHz, DMSO-D6) δ 10.60 (s, 1H), 9.67 (s, 1H), 9.33 (s, 1H), 7.45 - 7.37 (m, 4H), 3.34 (s, 3H).

[0369]

[0370] <Example 8> Synthesis of Compounds 14, 15, 109 and 110

[0371]

[0372] EtOH (6.30 mL) was added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, 4-fluoroaniline (90.0 μL, 944 μmol) and CeCl3·7H2O (12.0 mg, 31.5 μmol) were added and stirred for 17 more hours at room temperature. The reaction solution was concentrated under reduced pressure to remove EtOH. Saturated aqueous NaCl solution and DCM were added to the concentrate and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / Hex) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-bromo-6-((4-fluorophenyl)amino)quinazoline-5,8-dione, Compound 14).

[0373] Dark brown solid, 165 mg (75.5%)

[0374] 1 H NMR (400 MHz, DMSO-D6) δ 9.61 (s, 1H), 9.54 (s, 1H), 9.38 (s, 1H), 7.25 - 7.15 (m, 4H).

[0375]

[0376] THF (3.70 mL) was added to 7-bromo-6-((4-fluorophenyl)amino)quinazoline-5,8-dione (130 mg, 361 μmol) and stirred at room temperature. At the same temperature, NaSMe (51.0 mg, 722 μmol) was added and stirred for 2.5 hours at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((4-fluorophenyl)amino)-7-(methylthio)quinazoline-5,8-dione, Compound 15).

[0377] Brown solid, 83.0 mg (70.6%)

[0378] 1 H NMR (400 MHz, DMSO-D6) δ 9.59 (s, 1H), 9.40 (s, 1H), 9.36 (s, 1H), 7.15 (d, J = 2.7 Hz, 2H), 7.13 (s, 2H), 2.04 (s, 3H).

[0379]

[0380] CHCl3 (6.50 mL) is added to 6-((4-fluorophenyl)amino)-7-(methyl thio)quinazoline-5,8-dione (200 mg, 634 μmol) and stirred at room temperature. At the same temperature, mCPBA (355 mg, 1.59 mmol) is added and stirred for 4.5 hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4, then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, and then a saturated aqueous solution of NaCl and DCM are added and extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((4-fluorophenyl)amino)-7-(methylsulfinyl)quinazoline-5,8-dione, compound 109)(6-((4-fluorophenyl)amino)-7-(methylsulfonyl)quinazoline-5,8-dione, compound 110).

[0381] Compound 109: Dark brown solid, 13.0 mg (6.19%)

[0382] 1 H NMR (500 MHz, DMSO-D6) δ 10.97 (s, 1H), 9.62 (s, 1H), 9.29 (s, 1H), 7.42 - 7.34 (m, 2H), 7.21 (t, J = 8.8 Hz, 2H), 3.02 (s, 3H).

[0383] Compound 110: Red brown solid, 71.6 mg (32.5%)

[0384] 1H NMR (500 MHz, DMSO-D6) δ 10.62(s, 1H), 9.66(s, 1H), 9.31(s, 1H), 7.43(dd,J= 9.0, 4.9 Hz, 2H), 7.22(t,J= 8.8 Hz, 2H), 3.36(s, 3H).

[0385]

[0386] <Example 9> Synthesis of Compounds 16 and 17

[0387]

[0388] EtOH (6.30 mL) was added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, 2-amino-5-fluorobenzotrifluride (120 μL, 944 μmol) and CeCl3·7H2O (234 mg, 629 μmol) were added and stirred for 23.5 hours at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-bromo-6-((4-fluoro-2-(trifluoromethyl)phenyl)amino)quinazoline-5,8-dione, Compound 16).

[0389] Orange solid, 111 mg (42.6%)

[0390] 1 H NMR (400 MHz, DMSO-D6) δ 9.61 (s, 1H), 9.39 (d,J= 1.7 Hz, 1H), 9.25 (s, 1H), 7.72 (dd,J= 8.9, 2.9 Hz, 1H), 7.63 - 7.49 (m, 2H).

[0391]

[0392] THF (3.50 mL) was added to 7-bromo-6-((4-fluoro-2-(trifluoromethyl)phenyl)amino)quinazoline-5,8-dione (146 mg, 351 μmol) and stirred at room temperature. At the same temperature, NaSMe (49.0 mg, 702 μmol) was added and stirred for 50 minutes at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((4-fluoro-2-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinazoline-5,8-dione, Compound 17).

[0393] Violet-brown solid, 64.0 mg (47.7%)

[0394] 1 H NMR (400 MHz, DMSO-D6) δ 9.60 (s, 1H), 9.36 (s, 1H), 8.89 (s, 1H), 7.68 (dd,J= 8.9, 2.9 Hz, 1H), 7.56 (td,J= 8.5, 3.0 Hz, 1H), 7.42(dd,J= 8.9, 5.1 Hz, 1H), 2.11(s, 3H).

[0395]

[0396] <Example 10> Synthesis of Compound 18

[0397]

[0398] EtOH (6.30 mL) is added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, 2-Amino-5-chlorobenzotrifluride (130 μL, 944 μmol) and CeCl3·7H2O (235 mg, 630 μmol) are added and stirred for another 24 hours at room temperature. The reaction solution is concentrated under reduced pressure to remove EtOH. A saturated aqueous solution of NaCl and DCM are added to the concentrate and extracted several times; the separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-bromo-6-((4-chloro-2-(trifluoro methyl)phenyl)amino)quinazoline-5,8-dione, compound 18).

[0399] Red solid, 46.9 mg (17.2%)

[0400] 1 ¹H NMR(400 MHz, DMSO-D 6 ) δ 9.62(d,J= 4.9 Hz, 1H), 9.39(d,J= 2.4 Hz, 1H), 9.24(d,J= 27.8 Hz, 1H), 7.88(d,J= 2.4 Hz, 1H), 7.80(dd,J= 8.1, 3.2 Hz, 1H), 7.49(d,J= 8.6 Hz, 1H).

[0401]

[0402] <Example 11> Synthesis of Compounds 19 and 20

[0403]

[0404] EtOH (6.30 mL) is added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, 2-fluoro-3-(trifluoromethyl)aniline (120 μL, 944 μmol) and CeCl3·7H2O (23.4 mg, 62.9 μmol) are added and stirred for 28 hours at room temperature. The reaction solution is concentrated under reduced pressure to remove EtOH. A saturated aqueous solution of NaCl and DCM are added to the concentrate and extracted several times; the separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-bromo-6-((2-fluoro-3-(trifluoromethyl)phenyl)amino)quinazoline-5,8-dione, compound 19).

[0405] Red solid, 208 mg (79.3%)

[0406] 1 H NMR (400 MHz, DMSO-D6) δ 9.62(s, 1H), 9.55(s, 1H), 9.40(s, 1H), 7.67(t,J= 7.5 Hz, 2H), 7.41(t,J= 8.0 Hz, 1H).

[0407]

[0408] THF (2.80 mL) was added to 7-bromo-6-((2-fluoro-3-(trifluoromethyl)phenyl)amino)quinazoline-5,8-dione (117 mg, 281 μmol) and stirred at 0 °C. At the same temperature, NaSMe (39.4 mg, 562 μmol) was added and stirred for 35 minutes at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((2-fluoro-3-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinazoline-5,8-dione, Compound 20).

[0409] Red brown solid, 57.0 mg (52.9%)

[0410] 1 H NMR (400 MHz, DMSO-D6) δ 9.61(s, 1H), 9.38(s, 1H), 9.36(s, 1H), 7.58(t,J= 8.2 Hz, 2H), 7.37(t,J= 8.0 Hz, 1H), 2.15(s, 3H).

[0411]

[0412] <Example 12> Synthesis of Compounds 21, 22 and 117

[0413]

[0414] EtOH (6.30 mL) was added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, 2-Fluoroaniline (90 μL, 944 μmol) and CeCl3·7H2O (12.0 mg, 31.5 μmol) were added and stirred for 20 more hours at room temperature. The reaction solution was concentrated under reduced pressure to remove EtOH. A saturated aqueous solution of NaCl and DCM were added to the concentrate and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-bromo-6-((2-fluorophenyl)amino)quinazoline-5,8-dione, Compound 21).

[0415] Brown solid, 195 mg (89.0%)

[0416] 1 H NMR (400 MHz, DMSO-D6) δ 9.61 (s, 1H), 9.45 (s, 1H), 9.38 (s, 1H), 7.38 - 7.17 (m, 4H).

[0417]

[0418] THF (3.70 mL) was added to 7-bromo-6-((2-fluorophenyl)amino)quinazoline-5,8-dione (130 mg, 361 μmol) and stirred at room temperature. At the same temperature, NaSMe (53.0 mg, 747 μmol) was added and stirred for 1 hour at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((2-fluorophenyl)amino)-7-(methylthio)quinazoline-5,8-dione, Compound 22).

[0419] Dark brown solid, 83.2 mg (70.7%)

[0420] 1 H NMR (400 MHz, DMSO-D6) δ 9.60 (s, 1H), 9.36 (s, 1H), 9.22 (s, 1H), 7.29 - 7.14 (m, 4H), 2.12 (s, 3H).

[0421]

[0422] CHCl3 (7.20 mL) is added to 6-((2-fluorophenyl)amino)-7-(methylthio)quinazoline-5,8-dione (182 mg, 578 μmol) and stirred at room temperature. At the same temperature, mCPBA (648 mg, 2.89 mmol) is added and stirred for another 2 hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4, then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, and then a saturated aqueous solution of NaCl and DCM are added and extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((2-fluorophenyl)amino)-7-(methylsulfonyl)quinazoline-5,8-dione, compound 117).

[0423] Red brown solid, 31.6 mg (15.7%)

[0424] 1 H NMR (500 MHz, DMSO-D6) δ 10.51 (s, 1H), 9.68 (s, 1H), 9.33 (s, 1H), 7.51 (t, J = 8.1 Hz, 1H), 7.36 - 7.29 (m, 2H), 7.22 - 7.18 (m, 1H), 3.41(s, 3H).

[0425]

[0426] <Example 13> Synthesis of Compounds 23 and 24

[0427]

[0428] EtOH (6.30 mL) was added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, 3-fluoroaniline (90.0 μL, 944 μmol) and CeCl3·7H2O (12.0 mg, 31.5 μmol) were added and stirred for 18 more hours at room temperature. The reaction solution was concentrated under reduced pressure to remove EtOH. A saturated aqueous solution of NaCl and DCM were added to the concentrate and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-bromo-6-((3-fluorophenyl)amino)quinazoline-5,8-dione, Compound 23).

[0429] Brown solid, 190 mg (86.5%)

[0430] 1 H NMR (400 MHz, DMSO-D6) δ 9.62 (s, 1H), 9.59 (s, 1H), 9.40 (s, 1H), 7.35 (q, J = 7.9 Hz, 1H), 7.06 - 6.92 (m, 3H).

[0431]

[0432] THF (3.70 mL) was added to 7-bromo-6-((3-fluorophenyl)amino)quinazoline-5,8-dione (130 mg, 361 μmol) and stirred at room temperature. At the same temperature, NaSMe (53.0 mg, 747 μmol) was added and stirred for 1 hour at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((3-fluorophenyl)amino)-7-(methylthio)quinazoline-5,8-dione, Compound 24).

[0433] Black solid, 50.2 mg (42.7%)

[0434] 1 H NMR (400 MHz, DMSO-D6) δ 9.60 (s, 1H), 9.43 (s, 1H), 9.39 (s, 1H), 7.35 - 7.27 (m, 1H), 6.97 - 6.83 (m, 3H), 2.09 (s, 3H).

[0435]

[0436] <Example 14> Synthesis of Compounds 25, 26 and 131

[0437]

[0438] EtOH (6.30 mL) was added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, 3,4-difluoroaniline (122 mg, 944 μmol) and CeCl3·7H2O (12.0 mg, 31.5 μmol) were added and stirred for 22 hours at room temperature. The reaction solution was concentrated under reduced pressure to remove EtOH. A saturated aqueous solution of NaCl and DCM were added to the concentrate and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-bromo-6-((3,4-difluorophenyl)amino)quinazoline-5,8-dione, Compound 25).

[0439] Brown solid, 195 mg (84.8%)

[0440] 1 H NMR (400 MHz, DMSO-D6) δ 9.62(s, 1H), 9.58(s, 1H), 9.41(s, 1H), 7.49 - 7.35(m, 1H), 7.27(ddd,J= 12.1, 7.3, 2.6 Hz, 1H), 7.03(d, J = 8.9 Hz, 1H).

[0441]

[0442] THF (3.60 mL) was added to 7-bromo-6-((3,4-difluorophenyl)amino)quinazoline-5,8-dione (130 mg, 355 μmol) and stirred at room temperature. At the same temperature, NaSMe (50.0 mg, 710 μmol) was added and stirred for 1 hour at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((3,4-difluorophenyl)amino)-7-(methylthio)quinazoline-5,8-dione, Compound 26).

[0443] Brown solid, 78.1 mg (66.0%)

[0444] 1 H NMR (400 MHz, DMSO-D6) δ 9.60 (s, 1H), 9.43 (s, 1H), 9.39 (s, 1H), 7.37 (dt, J = 10.7, 9.0 Hz, 1H), 7.18 - 7.08 (m, 1H), 6.98 - 6.91(m, 1H), 2.08(s, 3H).

[0445]

[0446] CHCl3 (7.00 mL) is added to 6-((3,4-difluorophenyl)amino)-7-(methylthio)quinazoline-5,8-dione (186 mg, 558 μmol) and stirred at room temperature. mCPBA (625 mg, 2.79 mmol) is added at the same temperature and stirred for 4 more hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, and then a saturated aqueous solution of NaCl and DCM are added and extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((3,4-difluorophenyl)amino)-7-(methylsulfonyl)quinazoline-5,8-dione, compound 131).

[0447] Orange brown solid, 25.5 mg (12.5%)

[0448] 1 H NMR (500 MHz, DMSO-D6) δ 10.56(s, 1H), 9.68(s, 1H), 9.36(s, 1H), 7.56(s, 1H), 7.49 - 7.40(m, 1H), 7.25(s, 1H), 3.34(s, 3H).

[0449]

[0450] <Example 15> Synthesis of Compounds 27 and 28

[0451]

[0452] EtOH (6.30 mL) is added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, 2,3-difluoroaniline (100 μL, 944 μmol) and CeCl3·7H2O (12.0 mg, 31.5 μmol) are added and stirred for 16.5 hours at room temperature. The reaction solution is concentrated under reduced pressure to remove EtOH. A saturated aqueous solution of NaCl and DCM are added to the concentrate and extracted several times; the separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-bromo-6-((2,3-difluorophenyl)amino)quinazoline-5,8-dione, compound 27).

[0453] Red brown solid, 194 mg(84.1%)

[0454] 1 H NMR (400 MHz, DMSO-D6) δ 9.62 (s, 1H), 9.53 (s, 1H), 9.40 (s, 1H), 7.39 - 7.30 (m, 1H), 7.24 - 7.14 (m, 2H).

[0455]

[0456] THF (3.60 mL) was added to 7-bromo-6-((2,3-difluorophenyl)amino)quinazoline-5,8-dione (130 mg, 355 μmol) and stirred at room temperature. At the same temperature, NaSMe (50.0 mg, 710 μmol) was added and stirred for 1.5 hours at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((2,3-difluorophenyl)amino)-7-(methylthio)quinazoline-5,8-dione, Compound 28).

[0457] Orange brown solid, 62.0 mg (52.4%)

[0458] 1 H NMR (400 MHz, DMSO-D6) δ 9.60 (s, 1H), 9.37 (s, 1H), 9.31 (s, 1H), 7.30 - 7.21 (m, 1H), 7.20 - 7.12 (m, 1H), 7.12 - 7.04 (m, 1H), 2.16(s, 3H).

[0459]

[0460] <Example 16> Synthesis of Compounds 29, 30 and 121

[0461]

[0462] EtOH (6.30 mL) was added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, 3-fluoro-4-methylaniline (118 mg, 944 mmol) and CeCl3·7H2O (12.0 mg, 31.5 μmol) were added and stirred for 17 more hours at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-bromo-6-((3-fluoro-4-methylphenyl)amino)quinazoline-5,8-dione, Compound 29).

[0463] Dark brown solid, 202 mg (88.9%)

[0464] 1 H NMR (400 MHz, DMSO-D6) δ 9.61(s, 1H), 9.56(s, 1H), 9.39(s, 1H), 7.22(t,J= 8.5 Hz, 1H), 7.02 - 6.89(m, 2H), 2.21(s, 3H).

[0465]

[0466] THF (3.60 mL) was added to 7-bromo-6-((3-fluoro-4-methylphenyl)amino)quinazoline-5,8-dione (130 mg, 359 μmol) and stirred at room temperature. At the same temperature, NaSMe (50.3 mg, 718 μmol) was added and stirred for 1 hour at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((3-fluoro-4-methylphenyl)amino)-7-(methylthio)quinazoline-5,8-dione, Compound 30).

[0467] Indigo to black solid, 63.9 mg (54.0%)

[0468] 1 H NMR (400 MHz, DMSO-D6) δ 9.59(s, 1H), 9.38(s, 1H), 9.37(s, 1H), 7.18(t,J= 8.7 Hz, 1H), 6.90 - 6.81(m, 2H), 2.19(s, 3H), 2.07(s, 3H).

[0469]

[0470] CHCl3 (9.10 mL) is added to 6-((3-fluoro-4-methylphenyl)amino)-7-(methylthio)quinazoline-5,8-dione (241 mg, 731 μmol) and stirred at room temperature. At the same temperature, mCPBA (819 mg, 3.65 mmol) is added and stirred for 5 more hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4, then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, and then a saturated aqueous solution of NaCl and DCM are added and extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((3-fluoro-4-methylphenyl)amino)-7-(methylsulfonyl)quinazoline-5,8-dione, compound 121).

[0471] Orange brown solid, 36.7 mg (13.9%)

[0472] 1 H NMR (500 MHz, DMSO-D6) δ 10.57 (s, 1H), 9.67 (s, 1H), 9.34 (s, 1H), 7.29 - 7.22 (m, 2H), 7.13 (dd,J= 8.1, 2.3 Hz, 1H), 3.36 (s, 3H), 2.24(s, 3H).

[0473]

[0474] <Example 17> Synthesis of Compounds 31 and 32

[0475]

[0476] EtOH (6.30 mL) is added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, 2,5-difluoroaniline (100 μL, 944 μmol) and CeCl3·7H2O (23.4 mg, 62.9 μmol) are added and stirred for 19 hours at room temperature. The reaction solution is concentrated under reduced pressure to remove EtOH. A saturated aqueous solution of NaCl and DCM are added to the concentrate and extracted several times; the separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / Hex) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-bromo-6-((2,5-difluorophenyl)amino)quinazoline-5,8-dione, compound 31).

[0477] Red brown solid, 178 mg(77.1%)

[0478] 1 H NMR (400 MHz, DMSO-D6) δ 9.62 (s, 1H), 9.44 (s, 1H), 9.40 (s, 1H), 7.38 - 7.20 (m, 2H), 7.15 (ddd,J= 12.2, 6.2, 3.5 Hz, 1H).

[0479]

[0480] THF (4.00 mL) was added to 7-bromo-6-((2,5-difluorophenyl)amino)quinazoline-5,8-dione (145 mg, 396 μmol) and stirred at room temperature. At the same temperature, NaSMe (55.5 mg, 792 μmol) was added and stirred for 1.5 hours at room temperature. Saturated aqueous NaCl solution and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / Hex) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((2,5-difluorophenyl)amino)-7-(methylthio)quinazoline-5,8-dione, Compound 32).

[0481] Dark brown solid, 90.3 mg (68.4%)

[0482] 1 H NMR (400 MHz, DMSO-D6) δ 9.61(s, 1H), 9.38(s, 1H), 9.19(s, 1H), 7.28(ddd,J= 10.3, 9.1, 5.1 Hz, 1H), 7.18 - 7.01(m, 2H), 2.18(s, 3H).

[0483]

[0484] <Example 18> Synthesis of Compounds 33, 34 and 119

[0485]

[0486] EtOH (6.30 mL) is added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, 3-amino-4-fluorobenzotrifluoride (120 μL, 944 μmol) and CeCl3·7H2O (23.4 mg, 62.9 μmol) are added and stirred for 19 hours at room temperature. The reaction solution is concentrated under reduced pressure to remove EtOH. A saturated aqueous solution of NaCl and DCM are added to the concentrate and extracted several times; the separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-bromo-6-((2-fluoro-5-(trifluoromethyl)phenyl)amino)quinazoline-5,8-dione, compound 33).

[0487] Yellow solid, 170 mg (65.1%)

[0488] 1 H NMR (400 MHz, DMSO-D6) δ 9.63(s, 1H), 9.49(s, 1H), 9.41(s, 1H), 7.76(dd,J= 7.3, 2.3 Hz, 1H), 7.55(d,J= 9.5 Hz, 1H).

[0489]

[0490] THF (3.50 mL) was added to 7-bromo-6-((2-fluoro-5-(trifluoromethyl)phenyl)amino)quinazoline-5,8-dione (145 mg, 347 μmol) and stirred at room temperature. At the same temperature, NaSMe (49.0 mg, 695 μmol) was added and stirred for 1 hour at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((2-fluoro-5-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinazoline-5,8-dione, Compound 34).

[0491] Dark violet solid, 64.5 mg (48.5%)

[0492] 1 H NMR (400 MHz, DMSO-D6) δ 9.62(s, 1H), 9.39(s, 1H), 9.25(s, 1H), 7.65(dd, J = 7.3, 2.6 Hz, 1H), 7.62 - 7.57(m, 1H), 7.49(t, J = 9.3 Hz, 1H), 2.15(s, 3H).

[0493]

[0494] CHCl3 (6.20 mL) is added to 6-((2-fluoro-5-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinazoline-5,8-dione (190 mg, 496 μmol) and stirred at room temperature. At the same temperature, mCPBA (556 mg, 2.48 mmol) is added and stirred for 2.5 hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, and then a saturated aqueous solution of NaCl and DCM are added and extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((2-fluoro-5-(trifluoromethyl)phenyl)amino)-7-(methylsulfonyl)quinazoline-5,8-dione, compound 119).

[0495] Orange solid, 7.90 mg (3.83%)

[0496] 1 H NMR (500 MHz, DMSO-D6) δ 10.47(s, 1H), 9.68(s, 1H), 9.36(s, 1H), 7.96(s, 1H), 7.68(s, 1H), 7.55(q,J= 9.4 Hz, 1H), 3.34(s, 3H)

[0497]

[0498] <Example 19> Synthesis of Compounds 35 and 36

[0499]

[0500] EtOH (6.30 mL) is added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, 2,6-difluoroaniline (100 μL, 944 μmol) and CeCl3·7H2O (24.0 mg, 62.9 μmol) are added and stirred for 23 hours at room temperature. The reaction solution is concentrated under reduced pressure to remove EtOH. A saturated aqueous solution of NaCl and DCM are added to the concentrate and extracted several times; the separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-bromo-6-((2,6-difluorophenyl)amino)quinazoline-5,8-dione, compound 35).

[0501] Orange solid, 188 mg (81.6%)

[0502] 1 H NMR (400 MHz, DMSO-D6) δ 9.60 (s, 1H), 9.38 (s, 1H), 9.30 (s, 1H), 7.48 - 7.37 (m, 1H), 7.20 (t, J = 8.3 Hz, 2H).

[0503]

[0504] THF (3.60 mL) was added to 7-bromo-6-((2,6-difluorophenyl)amino)quinazoline-5,8-dione (130 mg, 355 μmol) and stirred at room temperature. At the same temperature, NaSMe (50.0 mg, 710 μmol) was added and stirred for 2 hours at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((2,6-difluorophenyl)amino)-7-(methylthio)quinazoline-5,8-dione, Compound 36).

[0505] Dark brown solid, 74.9 mg (63.3%)

[0506] 1 H NMR (400 MHz, DMSO-D6) δ 9.60(s, 1H), 9.35(s, 1H), 9.16(s, 1H), 7.37(tt,J= 8.9, 6.3 Hz, 1H), 7.16(t,J= 8.3 Hz, 2H), 2.15(s, 3H).

[0507]

[0508] <Example 20> Synthesis of Compounds 37 and 38

[0509]

[0510] EtOH (6.70 mL) is added to 6,7-dibromoquinazoline-5,8-dione (213 mg, 670 μmol) and stirred at room temperature. At the same temperature, 3-fluoro-2-methylaniline (110 μL, 1.00 mmol) and CeCl3·7H2O (25.0 mg, 67.0 μmol) are added and stirred for 17 more hours at room temperature. The reaction solution is concentrated under reduced pressure to remove EtOH. A saturated aqueous solution of NaCl and DCM are added to the concentrate and extracted several times; the separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-bromo-6-((3-fluoro-2-methylphenyl)amino) quinazoline-5,8-dione, compound 37).

[0511] Brown solid, 194 mg (79.9%)

[0512] 1 H NMR (400 MHz, DMSO-D6) δ 9.61(s, 1H), 9.44(s, 1H), 9.40(s, 1H), 7.26 - 7.08(m, 2H), 7.03(d,J= 7.9 Hz, 1H), 2.13(d,J= 2.1 Hz, 3H).

[0513]

[0514] THF (4.40 mL) was added to 7-bromo-6-((3-fluoro-2-methylphenyl)amino)quinazoline-5,8-dione (159 mg, 439 μmol) and stirred at room temperature. At the same temperature, NaSMe (92.3 mg, 1.32 mmol) was added and stirred for 3 hours at room temperature. Saturated aqueous NaCl solution and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (ether / Hex) to obtain the target compound (6-((3-fluoro-2-methylphenyl)amino)-7-(methylthio)quinazoline-5,8-dione, Compound 38).

[0515] Purple solid, 92.1 mg (63.7%)

[0516] 1 H NMR (400 MHz, DMSO-D6) δ 9.59(s, 1H), 9.36(s, 1H), 9.10(s, 1H), 7.23 - 7.12(m, 1H), 7.03(t,J= 8.9 Hz, 1H), 6.91(d,J= 7.8 Hz, 1H), 2.17(d,J= 2.1 Hz, 3H), 2.10(s, 3H).

[0517]

[0518] <Example 21> Synthesis of Compounds 39 and 40

[0519]

[0520] EtOH (6.30 mL) is added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, 3,5-bis(trifluoromethyl)aniline (150 μL, 944 μmol) and CeCl3·7H2O (23.4 mg, 62.9 μmol) are added and stirred for 16 more hours at room temperature. The reaction solution is concentrated under reduced pressure to remove EtOH. A saturated aqueous solution of NaCl and DCM are added to the concentrate and extracted several times; the separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((3,5-bis(trifluoromethyl)phenyl) amino)-7-bromoquinazoline-5,8-dione, compound 39).

[0521] Orange solid, 231 mg (78.8%)

[0522] 1 H NMR (400 MHz, DMSO-D6) δ 9.85(s, 1H), 9.66(s, 1H), 9.45(s, 1H), 7.80(s, 2H), 7.78(s, 1H).

[0523]

[0524] THF (4.00 mL) was added to 6-((3,5-bis(trifluoromethyl)phenyl)amino)-7-bromoquinazoline-5,8-dione (184 mg, 395 μmol) and stirred at room temperature. At the same temperature, NaSMe (83.0 mg, 1.18 mmol) was added and stirred for 4 hours at room temperature. Saturated aqueous NaCl solution and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((3,5-bis(trifluoromethyl)phenyl)amino)-7-(methylthio)quinazoline-5,8-dione, Compound 40).

[0525] Dark brown solid, 76.8 mg (44.9%)

[0526] 1 H NMR (400 MHz, DMSO-D6) δ 9.74(s, 1H), 9.64(s, 1H), 9.43(s, 1H), 7.78(d,J= 8.5 Hz, 1H), 7.68(d,J= 3.9 Hz, 3H), 2.09(s, 3H).

[0527]

[0528] <Example 22> Synthesis of Compounds 41 and 42

[0529]

[0530] EtOH (6.30 mL) was added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, 2-methyl-5-(trifluoromethyl)aniline (165 mg, 944 μmol) and CeCl3·7H2O (24.0 mg, 62.9 μmol) were added and stirred for 15.5 hours at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-bromo-6-((2-methyl-5-(trifluoromethyl)phenyl)amino)quinazoline-5,8-dione, Compound 41).

[0531] Orange solid, 186 mg (71.6%)

[0532] 1 H NMR (400 MHz, DMSO-D6) δ 9.62(s, 1H), 9.41(s, 1H), 9.38(s, 1H), 7.57 - 7.47(m, 3H), 2.32(s, 3H).

[0533]

[0534] THF (3.2 mL) was added to 7-bromo-6-((2-methyl-5-(trifluoromethyl)phenyl)amino)quinazoline-5,8-dione (130 mg, 315 μmol) and stirred at room temperature. At the same temperature, NaSMe (44.0 mg, 631 μmol) was added and stirred for 1.5 hours at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((2-methyl-5-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinazoline-5,8-dione, Compound 42).

[0535] Dark violet solid, 77.1 mg (64.5%)

[0536] 1 H NMR (400 MHz, DMSO-D6) δ 9.60(s, 1H), 9.38(s, 1H), 9.03(s, 1H), 7.46(d,J= 1.3 Hz, 2H), 7.43(s, 1H), 2.36(s, 3H), 2.06(s, 3H).

[0537]

[0538] <Example 23> Synthesis of Compounds 43, 44, 115 and 116

[0539]

[0540] EtOH (6.30 mL) is added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, 4-methyl-3-(trifluoromethyl)aniline (130 μL, 944 μmol) and CeCl3·7H2O (23.4 mg, 62.9 μmol) are added and stirred for 17 more hours at room temperature. The reaction solution is concentrated under reduced pressure to remove EtOH. A saturated aqueous solution of NaCl and DCM are added to the concentrate and extracted several times; the separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-bromo-6-((4-methyl-3-(trifluoromethyl)phenyl)amino)quinazoline-5,8-dione, compound 43).

[0541] Brown solid, 211 mg (81.5%)

[0542] 1 H NMR (400 MHz, DMSO-D6) δ 9.64(s, 1H), 9.62(s, 1H), 9.40(s, 1H), 7.49(d,J= 2.2 Hz, 1H), 7.40(d,J= 8.3 Hz, 1H), 7.33(dd,J= 8.3, 2.3 Hz, 1H), 2.42(d,J= 2.0 Hz, 3H).

[0543]

[0544] THF (4.20 mL) was added to 7-bromo-6-((4-methyl-3-(trifluoromethyl)phenyl)amino)quinazoline-5,8-dione (174 mg, 422 μmol) and stirred at room temperature. At the same temperature, NaSMe (88.8 mg, 1.27 mmol) was added and stirred for 3 hours at room temperature. Saturated aqueous NaCl solution and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((4-methyl-3-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinazoline-5,8-dione, Compound 44).

[0545] Dark brown solid, 88.0 mg (55.0%)

[0546] 1 H NMR (400 MHz, DMSO-D6) δ 9.60(s, 1H), 9.50(s, 1H), 9.38(s, 1H), 7.41(d,J= 2.3 Hz, 1H), 7.36(d,J= 8.3 Hz, 1H), 7.24(dd,J= 8.2, 2.3 Hz, 1H), 2.41(s, 3H), 2.05(s, 3H).

[0547]

[0548] CHCl3 (3.20 mL) is added to 6-((4-methyl-3-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinazoline-5,8-dione (120 mg, 316 μmol) and stirred at room temperature. At the same temperature, mCPBA (177 mg, 791 μmol) is added and stirred for another 24 hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4, then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, and then a saturated aqueous solution of NaCl and DCM are added and extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((4-methyl-3-(trifluoromethyl)phenyl)amino)-7-(methylsulfinyl)quinazoline-5,8-dione, compound 115)(6-((4-methyl-3-(trifluoromethyl)phenyl)amino)-7-(methylsulfonyl)quinazoline-5,8-dione, compound 116).

[0549] Compound 115: Red brown solid, 20.7 mg (16.6%)

[0550] 1 H NMR (500 MHz, DMSO-D6) δ 10.99(s, 1H), 9.62(s, 1H), 9.30(s, 1H), 7.69(s, 1H), 7.50(d,J= 7.9 Hz, 1H), 7.42(d,J= 8.1 Hz, 1H), 3.03(s, 3H), 2.44(s, 3H).

[0551] Compound 116: Orange solid, 21.7 mg (16.7%)

[0552] 1 H NMR (500 MHz, DMSO-D6) δ 10.61(s, 1H), 9.67(s, 1H), 9.34(s, 1H), 7.74(s, 1H), 7.55(d,J= 7.0 Hz, 1H), 7.43(d,J= 8.4 Hz, 1H), 3.32(s, 3H), 2.44(s, 3H).

[0553]

[0554] <Example 24> Synthesis of Compounds 45, 46 and 130

[0555]

[0556] EtOH (6.30 mL) was added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, 3-methoxy-5-(trifluoromethyl)aniline (180 mg, 944 μmol) and CeCl3·7H2O (24.0 mg, 62.9 μmol) were added and stirred for 23.5 hours at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-bromo-6-((3-methoxy-5-(trifluoromethyl)phenyl)amino)quinazoline-5,8-dione, Compound 45).

[0557] Red brown solid, 130 mg (48.2%)

[0558] 1 H NMR (400 MHz, DMSO-D6) δ 9.63(s, 1H), 9.62(s, 1H), 9.42(s, 1H), 7.11(s, 1H), 7.03(s, 1H), 6.99(s, 1H), 3.80(s, 3H).

[0559]

[0560] THF (2.6 mL) was added to 7-bromo-6-((3-methoxy-5-(trifluoromethyl)phenyl)amino)quinazoline-5,8-dione (110 mg, 257 μmol) and stirred at room temperature. At the same temperature, NaSMe (36.0 mg, 514 μmol) was added and stirred for 3 hours at room temperature. Saturated aqueous NaCl solution and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (Ether / Hex) to obtain the target compound (6-((3-methoxy-5-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinazoline-5,8-dione, Compound 46).

[0561] Red violet solid, 46.4 mg (45.7%)

[0562] 1 H NMR (400 MHz, DMSO-D6) δ 9.61(s, 1H), 9.47(s, 1H), 9.40(s, 1H), 7.02(s, 1H), 6.90(s, 2H), 3.80(s, 4H), 2.11(s, 3H).

[0563]

[0564] CHCl3 (7.00 mL) is added to 6-((3-methoxy-5-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinazoline-5,8-dione (220 mg, 556 μmol) and stirred at room temperature. At the same temperature, mCPBA (624 mg, 2.78 mmol) is added and stirred for 4 more hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4, then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, and then a saturated aqueous solution of NaCl and DCM are added and extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((3-methoxy-5-(trifluoromethyl)phenyl)amino)-7-(methylsulfonyl)quinazoline-5,8-dione, compound 130).

[0565] Orange solid, 7.80 mg (3.30%)

[0566] 1 H NMR (500 MHz, DMSO-D6) δ 10.56(s, 1H), 9.69(s, 1H), 9.38(s, 1H), 7.39(s, 1H), 7.31(s, 1H), 7.10(s, 1H), 3.82(s, 3H), 3.32(s, 3H).

[0567]

[0568] <Example 25> Synthesis of Compounds 47 and 48

[0569]

[0570] EtOH (6.30 mL) is added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, 3-amino-4-chlorobenzotrifluoride (130 μL, 944 μmol) and CeCl3·7H2O (23.4 mg, 62.9 μmol) are added and stirred for 23.5 hours at room temperature. The reaction solution is concentrated under reduced pressure to remove EtOH. A saturated aqueous solution of NaCl and DCM are added to the concentrate and extracted several times; the separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (ether / Hex) to obtain the target compound (7-bromo-6-((2-chloro-5-(trifluoromethyl)phenyl)amino)quinazoline-5,8-dione, compound 47).

[0571] Orange solid, 175 mg (64.3%)

[0572] 1 H NMR (400 MHz, DMSO-D6) δ 9.63 (d,J= 0.9 Hz, 1H), 9.42 (d,J= 9.7 Hz, 2H), 7.78 (d,J= 8.3 Hz, 2H), 7.66 (dd,J= 8.3, 2.3 Hz, 1H).

[0573]

[0574] THF (3.5 mL) was added to 7-bromo-6-((2-chloro-5-(trifluoromethyl)phenyl)amino)quinazoline-5,8-dione (151 mg, 349 μmol) and stirred at room temperature. At the same temperature, NaSMe (48.9 mg, 698 μmol) was added and stirred for 2 hours at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((2-chloro-5-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinazoline-5,8-dione, Compound 48).

[0575] Black solid, 69.1 mg (49.5%)

[0576] 1 H NMR (400 MHz, DMSO-D6) δ 9.63(s, 1H), 9.40(s, 1H), 9.01(s, 1H), 7.78 - 7.71(m, 1H), 7.63(d,J= 2.2 Hz, 1H), 7.57(dd,J= 8.4, 2.9 Hz, 1H), 2.14(s, 3H).

[0577]

[0578] <Example 26> Synthesis of Compounds 49 and 50

[0579]

[0580] EtOH (6.30 mL) is added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, 4-amino-3-chlorobenzotrifluoride (216 μL, 1.58 mmol) and CeCl3·7H2O (23.4 mg, 62.9 μmol) are added and stirred for 40 more hours at room temperature. The reaction solution is concentrated under reduced pressure to remove EtOH. A saturated aqueous solution of NaCl and DCM are added to the concentrate and extracted several times; the separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-bromo-6-((2-chloro-4-(trifluoromethyl)phenyl)amino)quinazoline-5,8-dione, compound 49).

[0581] Red solid, 148 mg (54.4%)

[0582] 1 H NMR (400 MHz, DMSO-D6) δ 9.63(s, 1H), 9.46(s, 1H), 9.40(s, 1H), 7.95(d,J= 2.1 Hz, 1H), 7.75(dd,J= 8.4, 2.1 Hz, 1H), 7.56(d,J= 8.4 Hz, 1H).

[0583]

[0584] THF (2.90 mL) was added to 7-bromo-6-((2-chloro-4-(trifluoromethyl)phenyl)amino)quinazoline-5,8-dione (125 mg, 289 μmol) and stirred at room temperature. At the same temperature, NaSMe (60.8 mg, 867 μmol) was added and stirred for 3 hours at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((2-chloro-4-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinazoline-5,8-dione, Compound 50).

[0585] Purple solid, 59.3 mg (51.3%)

[0586] 1 H NMR (400 MHz, DMSO-D6) δ 9.61 (dd,J= 6.4, 1.9 Hz, 1H), 9.39 (dd,J= 6.4, 2.0 Hz, 1H), 8.95 - 8.89 (m, 1H), 7.90 (d,J= 5.3 Hz, 1H), 7.69(t,J= 7.3 Hz, 1H), 7.35(t,J= 7.7 Hz, 1H), 2.22 - 2.15(m, 3H).

[0587]

[0588] <Example 27> Synthesis of Compounds 51 and 52

[0589]

[0590] EtOH (6.30 mL) was added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, 5-Amino-2-chlorobenzotrifluoride (185 mg, 944 μmol) and CeCl3·7H2O (24.0 mg, 62.9 μmol) were added and stirred for 16 more hours at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-bromo-6-((4-chloro-3-(trifluoromethyl)phenyl)amino)quinazoline-5,8-dione, Compound 51).

[0591] Red brown solid, 221 mg(81.2%)

[0592] 1 H NMR (400 MHz, DMSO-D6) δ 9.72(s, 1H), 9.64(s, 1H), 9.42(s, 1H), 7.68(d,J= 8.6 Hz, 1H), 7.64(d,J= 2.6 Hz, 1H), 7.43(dd,J= 8.6, 3.0 Hz, 1H).

[0593]

[0594] THF (3.50 mL) was added to 7-bromo-6-((4-chloro-3-(trifluoromethyl)phenyl)amino)quinazoline-5,8-dione (150 mg, 347 μmol) and stirred at room temperature. At the same temperature, NaSMe (49.0 mg, 694 μmol) was added and stirred for 4 hours at room temperature. Saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (Ether / Hex) to obtain the target compound (6-((4-chloro-3-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinazoline-5,8-dione, Compound 52).

[0595] Red brown solid, 37.8 mg (27.2%)

[0596] 1 H NMR (400 MHz, DMSO-D6) δ 9.62(s, 2H), 9.40(s, 1H), 7.64(d,J= 8.8 Hz, 1H), 7.54(d,J= 2.7 Hz, 1H), 7.33(dd,J= 8.6, 2.7 Hz, 1H), 2.07(s, 3H).

[0597]

[0598] <Example 28> Synthesis of Compounds 53, 54 and 118

[0599]

[0600] EtOH (6.30 mL) was added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, 3-aminobenzotrifluride (120 mg, 944 μmol) and CeCl3·7H2O (24.0 mg, 62.9 μmol) were added and stirred for 15.5 hours at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-bromo-6-((3-(trifluoromethyl)phenyl)amino)quinazoline-5,8-dione, Compound 53).

[0601] Red brown solid, 178 mg(71.1%)

[0602] 1 H NMR (400 MHz, DMSO-D6) δ 9.70 (s, 1H), 9.63 (s, 1H), 9.41 (s, 1H), 7.59 - 7.43 (m, 4H).

[0603]

[0604] THF (3.30 mL) was added to 7-bromo-6-((3-(trifluoromethyl)phenyl)amino)quinazoline-5,8-dione (130 mg, 327 μmol) and stirred at room temperature. At the same temperature, NaSMe (69.0 mg, 981 μmol) was added and stirred for 2 hours at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (Ether / Hex) to obtain the target compound (7-(methylthio)-6-((3-(trifluoromethyl)phenyl)amino)quinazoline-5,8-dione, Compound 54).

[0605] Red brown solid, 55.5 mg (46.5%)

[0606] 1 H NMR (400 MHz, DMSO-D6) δ 9.61(s, 1H), 9.54(s, 1H), 9.40(s, 1H), 7.54-7.52(m, 1H), 7.40-7.35(m, 3H), 2.07(s, 3H).

[0607]

[0608] CHCl3 (6.40 mL) is added to 7-(methylthio)-6-((3-(trifluoromethyl)phenyl)amino)quinazoline-5,8-dione (186 mg, 510 μmol) and stirred at room temperature. mCPBA (571 mg, 2.55 mmol) is added at the same temperature and stirred for 5 more hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, and then a saturated aqueous solution of NaCl and DCM are added and extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-(methylsulfonyl)-6-((3-(trifluoromethyl)phenyl)amino)quinazoline-5,8-dione, compound 118).

[0609] Orange brown solid, 16.5 mg (8.14%)

[0610] 1 H NMR (500 MHz, DMSO-D6) δ 10.63(s, 1H), 9.68(s, 1H), 9.35(s, 1H), 7.81(s, 1H), 7.67(d,J= 5.3 Hz, 1H), 7.59(dd,J= 5.0, 2.1 Hz, 2H), 3.32(s, 3H).

[0611]

[0612] <Example 29> Synthesis of Compounds 55, 56, 120 and 137

[0613]

[0614] EtOH (6.30 mL) was added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, 4-amino-2-fluorobenzotrifluoride (169 mg, 944 μmol) and CeCl3·7H2O (23.4 mg, 62.9 μmol) were added and stirred for 16 more hours at room temperature. Saturated aqueous NaCl solution and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (ether / Hex) to obtain the target compound (7-bromo-6-((3-fluoro-4-(trifluoromethyl)phenyl)amino)quinazoline-5,8-dione, Compound 55).

[0615] Dark red solid, 200 mg (76.3%)

[0616] 1 H NMR (400 MHz, DMSO-D6) δ 9.78(s, 1H), 9.65(s, 1H), 9.44(s, 1H), 7.70(t,J= 8.5 Hz, 1H), 7.20(d,J= 13.2 Hz, 1H), 7.13(d,J= 8.7 Hz, 1H).

[0617]

[0618] THF (3.60 mL) was added to 7-bromo-6-((3-fluoro-4-(trifluoromethyl)phenyl)amino)quinazoline-5,8-dione (151 mg, 363 μmol) and stirred at room temperature. At the same temperature, NaSMe (75.9 mg, 1.08 mmol) was added and stirred for 3 hours at room temperature. After adding a saturated aqueous solution of NaCl and DCM to the reaction solution and extracting several times, the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (ether / Hex) to obtain the target compound (6-((3-fluoro-4-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinazoline-5,8-dione, Compound 56).

[0619] Dark red solid, 55.0 mg (39.5%)

[0620] 1 H NMR (400 MHz, DMSO-D6) δ 9.66 - 9.58 (m, 2H), 9.44 - 9.37 (m, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.00 (t, J = 8.1 Hz, 2H), 2.20 - 2.13 (m, 3H).

[0621]

[0622] CHCl3 (7.40 mL) is added to 6-((3-fluoro-4-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinazoline-5,8-dione (227 mg, 591 μmol) and stirred at room temperature. At the same temperature, mCPBA (662 mg, 2.96 mmol) is added and stirred for 4.5 hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, and then a saturated aqueous solution of NaCl and DCM are added and extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((3-fluoro-4-(trifluoromethyl)phenyl)amino)-7-(methylsulfonyl)quinazoline-5,8-dione, compound 120)(6-((3-fluoro-4-(trifluoromethyl)phenyl)amino)-7-(methylsulfinyl)quinazoline-5,8-dione, compound 137).

[0623] Compound 120: Orange solid, 4.70 mg (1.91%)

[0624] 1 H NMR (500 MHz, DMSO-D6) δ 10.57 (s, 1H), 9.69 (s, 1H), 9.40 (s, 1H), 7.75-7.73 (m, 1H), 7.62 - 7.43 (m, 1H), 7.42 - 7.27 (m, 1H), 3.31(s, 3H).

[0625] Compound 137: Orange solid, 2.90 mg (1.23%)

[0626] 1H NMR (500 MHz, DMSO-D6) δ 10.96(s, 1H), 9.65(s, 1H), 9.36(s, 1H), 7.74(t,J= 8.5 Hz, 1H), 7.57(d,J= 12.1 Hz, 1H), 7.31(d,J= 7.8 Hz, 1H), 3.07(s, 3H).

[0627]

[0628] <Example 30> Synthesis of Compounds 57 and 58

[0629]

[0630] EtOH (12.5 mL) was added to 6,7-dibromoquinazoline-5,8-dione (400 mg, 1.26 mmol) and stirred at room temperature. At the same temperature, 2-aminobenzotrifluoride (0.24 mL, 1.89 mmol) and CeCl3·7H2O (24.0 mg, 62.9 μmol) were added and stirred for 88.5 hours at room temperature. After adding a saturated aqueous solution of NaCl and DCM to the reaction solution and extracting several times, the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (DCM / Hex) to obtain the target compound (7-bromo-6-((2-(trifluoromethyl)phenyl)amino)quinazoline-5,8-dione, Compound 57).

[0631] Orange solid, 134 mg (26.5%)

[0632] 1 H NMR (400 MHz, DMSO-D6) δ 9.61(s, 1H), 9.38(s, 1H), 9.21(s, 1H), 7.80-7.78(m, 1H), 7.70-7.65(m, 1H), 7.55-7.53(m, 1H), 7.46-7.44(m, 1H).

[0633]

[0634] THF (2.80 mL) was added to 7-bromo-6-((2-(trifluoromethyl)phenyl)amino)quinazoline-5,8-dione (110 mg, 276 μmol) and stirred at room temperature. At the same temperature, NaSMe (58.0 mg, 829 μmol) was added and stirred for 3 hours at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (Ether / Hex) to obtain the target compound (7-(methylthio)-6-((2-(trifluoromethyl)phenyl)amino)quinazoline-5,8-dione, Compound 58).

[0635] Red brown solid, 44.9 mg (44.5%)

[0636] 1 H NMR (400 MHz, DMSO-D6) δ 9.60(s, 1H), 9.36(s, 1H), 8.76(s, 1H), 7.76-7.73(m, 1H), 7.67-7.63(m, 1H), 7.45-7.41(m, 1H), 7.33-7.30(m, 1H), 2.11(s, 3H).

[0637]

[0638] <Example 31> Synthesis of Compounds 59 and 60

[0639]

[0640] EtOH (6.30 mL) was added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, 3-amino-5-bromobenzotrifluoride (130 μL, 944 μmol) and CeCl3·7H2O (23.4 mg, 62.9 μmol) were added and stirred for 23 hours at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-bromo-6-((3-bromo-5-(trifluoromethyl)phenyl)amino)quinazoline-5,8-dione, Compound 59).

[0641] Red solid, 226 mg (75.4%)

[0642] 1 H NMR (400 MHz, DMSO-D6) δ 9.70 (d,J= 5.5 Hz, 1H), 9.64 (dd,J= 4.8, 2.3 Hz, 1H), 9.46 - 9.40 (m, 1H), 7.65 (dd,J= 4.8, 2.6 Hz, 2H), 7.52(d,J= 4.4 Hz, 1H).

[0643]

[0644] THF (3.40 mL) is added to 7-bromo-6-((3-bromo-5-(trifluoromethyl)phenyl)amino)quinazoline-5,8-dione (162 mg, 340 μmol) and stirred at room temperature. At the same temperature, NaSMe (71.4 mg, 1.02 mmol) is added and stirred for 29 hours at room temperature. A saturated aqueous solution of NaCl and DCM are added to the reaction solution and extracted several times; the separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate is dissolved again in THF (3.40 mL), NaSMe (24.0 mg, 340 μmol) is added, and stirred for 17 hours at room temperature. A saturated aqueous solution of NaCl and DCM are added to the reaction solution and extracted several times; the separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (ether / Hex) to obtain the target compound (6-((3-bromo-5-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinazoline-5,8-dione, compound 60).

[0645] Red brown solid, 19.1 mg (12.6%)

[0646] 1 H NMR (400 MHz, DMSO-D6) δ 9.61 (d, J = 16.4 Hz, 2H), 9.42 (s, 1H), 7.53 (d, J = 17.5 Hz, 2H), 7.44 (s, 1H), 2.12 (s, 3H).

[0647]

[0648] <Example 32> Synthesis of Compounds 61 and 62

[0649]

[0650] EtOH (6.30 mL) was added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, 3-chloro-2-methylaniline (110 μL, 944 μmol) and CeCl3·7H2O (23.4 mg, 62.9 μmol) were added and stirred for 16 more hours at room temperature. After adding a saturated aqueous solution of NaCl and DCM to the reaction solution and extracting several times, the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-bromo-6-((3-chloro-2-methylphenyl)amino)quinazoline-5,8-dione, Compound 61).

[0651] Red brown solid, 193 mg (80.8%)

[0652] 1 H NMR (400 MHz, DMSO-D6) δ 9.60 (dd,J= 5.4, 1.9 Hz, 1H), 9.45 (d,J= 4.8 Hz, 1H), 9.38 (dd,J= 5.1, 2.0 Hz, 1H), 7.38(t,J= 6.3 Hz, 1H), 7.26 - 7.11(m, 2H), 2.25(d,J= 3.7 Hz, 3H).

[0653]

[0654] THF (3.50 mL) was added to 7-bromo-6-((3-chloro-2-methylphenyl)amino)quinazoline-5,8-dione (134 mg, 354 μmol) and stirred at room temperature. At the same temperature, NaSMe (99.2 mg, 1.42 mmol) was added and stirred for 23 hours at room temperature. After adding a saturated aqueous solution of NaCl and DCM to the reaction solution and extracting several times, the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((3-chloro-2-methylphenyl)amino)-7-(methylthio)quinazoline-5,8-dione, Compound 62).

[0655] Black solid, 29.7 mg (24.3%)

[0656] 1 H NMR (400 MHz, DMSO-D6) δ 9.59(s, 1H), 9.36(s, 1H), 9.14(s, 1H), 7.31(d,J= 7.8 Hz, 1H), 7.18(d,J= 7.1 Hz, 1H), 7.05(d,J= 9.4 Hz, 1H), 2.30(s, 3H), 2.13 - 2.07(m, 3H).

[0657]

[0658] <Example 33> Synthesis of Compounds 63 and 78

[0659]

[0660] EtOH (6.30 mL) was added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, 3,5-dimethylaniline (120 μL, 944 μmol) and CeCl3·7H2O (24.0 mg, 62.9 μmol) were added and stirred for 20 more hours at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (DCM / Hex) to obtain the target compound (7-bromo-6-((3,5-dimethylphenyl)amino)quinazoline-5,8-dione, Compound 63).

[0661] Pale violet solid, 200 mg (88.6%)

[0662] 1 H NMR (400 MHz, DMSO-D6) δ 9.60 (s, 1H), 9.46 (s, 1H), 9.37 (s, 1H), 6.91 - 6.67 (m, 3H), 2.25 (s, 6H).

[0663]

[0664] THF (4.20 mL) was added to 7-bromo-6-((3,5-dimethylphenyl)amino)quinazoline-5,8-dione (150 mg, 419 μmol) and stirred at room temperature. At the same temperature, NaSMe (88.0 mg, 1.26 mmol) was added and stirred for 2.5 hours at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (Ether / Hex) to obtain the target compound (6-((3,5-dimethylphenyl)amino)-7-(methylthio)quinazoline-5,8-dione, Compound 78).

[0665] Dark violet solid, 94.3 mg (69.2%)

[0666] 1 H NMR (400 MHz, DMSO-D6) δ 9.58(s, 1H), 9.35(s, 1H), 9.24(s, 1H), 6.77-6.70(m, 3H), 2.23(s, 6H), 2.06(s, 3H).

[0667]

[0668] <Example 34> Synthesis of Compounds 64 and 65

[0669]

[0670] EtOH (6.30 mL) was added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, 2,4-dimethylaniline (120 μL, 944 μmol) and CeCl3·7H2O (24.0 mg, 62.9 μmol) were added and stirred for 16.5 hours at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (DCM / Hex) to obtain the target compound (7-bromo-6-((2,4-dimethylphenyl)amino)quinazoline-5,8-dione, Compound 64).

[0671] Violet solid, 533 mg (84.8%)

[0672] 1 H NMR (400 MHz, DMSO-D6) δ 9.59 (s, 1H), 9.37 (s, 1H), 9.34 (s, 1H), 7.10 - 6.93 (m, 3H), 2.29 (s, 3H), 2.16 (s, 3H).

[0673]

[0674] THF (4.20 mL) was added to 7-bromo-6-((2,4-dimethylphenyl)amino)quinazoline-5,8-dione (150 mg, 419 μmol) and stirred at room temperature. At the same temperature, NaSMe (88.0 mg, 1.26 mmol) was added and stirred for 3 hours at room temperature. Saturated aqueous NaCl solution and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((2,4-dimethylphenyl)amino)-7-(methylthio)quinazoline-5,8-dione, Compound 65).

[0675] Dark violet solid, 60.4 mg (44.3%)

[0676] 1 H NMR (400 MHz, DMSO-D6) δ 9.57(s, 1H), 9.33(s, 1H), 8.98(s, 1H), 7.07-6.59(m, 3H), 2.28(s, 3H), 2.21(s, 3H), 2.06(s, 3H).

[0677]

[0678] <Example 35> Synthesis of Compounds 66 and 67

[0679]

[0680] EtOH (6.30 mL) was added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, 4-fluoro-2-methylaniline (110 μL, 944 μmol) and CeCl3·7H2O (23.4 mg, 62.9 μmol) were added and stirred for 16 more hours at room temperature. After adding a saturated aqueous solution of NaCl and DCM to the reaction solution and extracting several times, the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-bromo-6-((4-fluoro-2-methylphenyl)amino)quinazoline-5,8-dione, Compound 66).

[0681] Red brown solid, 198 mg (86.9%)

[0682] 1 H NMR (400 MHz, DMSO-D6) δ 9.60 (s, 1H), 9.38 (s, 1H), 9.34 (s, 1H), 7.18 (s, 2H), 7.04 (d, J = 7.5 Hz, 1H), 2.22 (s, 3H).

[0683]

[0684] THF (4.40 mL) was added to 7-bromo-6-((4-fluoro-2-methylphenyl)amino)quinazoline-5,8-dione (158 mg, 436 μmol) and stirred at room temperature. At the same temperature, NaSMe (123 mg, 1.75 mmol) was added and stirred for 23.5 hours at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((4-fluoro-2-methylphenyl)amino)-7-(methylthio)quinazoline-5,8-dione, Compound 67).

[0685] Dark violet solid, 43.2 mg (30.1%)

[0686] 1 H NMR (400 MHz, DMSO-D6) δ 9.58(d,J= 4.6 Hz, 1H), 9.35(d,J= 4.8 Hz, 1H), 9.02(s, 1H), 7.15 - 7.05(m, 2H), 7.00(dq,J= 9.5, 4.8 Hz, 1H), 2.26(d,J= 3.1 Hz, 3H), 2.08(d,J= 3.5 Hz, 3H).

[0687]

[0688] <Example 36> Synthesis of Compounds 68 and 69

[0689]

[0690] EtOH (6.30 mL) was added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, 3,4-dimethylaniline (114 mg, 944 μmol) and CeCl3·7H2O (23.4 mg, 62.9 μmol) were added and stirred for 16.5 hours at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-bromo-6-((3,4-dimethylphenyl)amino)quinazoline-5,8-dione, Compound 68).

[0691] Dark violet solid, 198 mg (87.9%)

[0692] 1 H NMR (400 MHz, DMSO-D6) δ 9.60(d,J= 1.1 Hz, 1H), 9.49(s, 1H), 9.37(d,J= 1.1 Hz, 1H), 7.09(d,J= 8.0 Hz, 1H), 6.97(d,J= 2.2 Hz, 1H), 6.90(dd,J= 8.0, 2.3 Hz, 1H), 2.20(d,J= 2.3 Hz, 6H).

[0693]

[0694] THF (4.70 mL) was added to 7-bromo-6-((3,4-dimethylphenyl)amino)quinazoline-5,8-dione (167 mg, 466 μmol) and stirred at room temperature. At the same temperature, NaSMe (98.0 mg, 1.40 mmol) was added and stirred for 3.5 hours at room temperature. Saturated aqueous NaCl solution and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((3,4-dimethylphenyl)amino)-7-(methylthio)quinazoline-5,8-dione, Compound 69).

[0695] Dark blue solid, 104 mg (68.4%)

[0696] 1 H NMR (400 MHz, DMSO-D6) δ 9.58(s, 1H), 9.35(s, 1H), 9.28(s, 1H), 7.05(d,J= 8.0 Hz, 1H), 6.89(d,J= 2.3 Hz, 1H), 6.83(dd,J= 8.0, 2.3 Hz, 1H), 2.19(s, 6H), 2.05(s, 3H).

[0697]

[0698] <Example 37> Synthesis of Compounds 70 and 71

[0699]

[0700] EtOH (6.30 mL) was added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, 2,5-dimethylaniline (120 μL, 944 μmol) and CeCl3·7H2O (24.0 mg, 62.9 μmol) were added and stirred for 20 more hours at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-bromo-6-((2,5-dimethylphenyl)amino)quinazoline-5,8-dione, Compound 70).

[0701] Red solid, 144 mg (64.0%)

[0702] 1 H NMR (400 MHz, DMSO-D6) δ 9.60(s, 1H), 9.38(s, 1H), 9.34(s, 1H), 7.14(d,J= 7.8 Hz, 1H), 7.02(d,J= 7.5 Hz, 1H), 6.96(s, 1H), 2.25(s, 3H), 2.16(s, 3H).

[0703]

[0704] THF (3.10 mL) was added to 7-bromo-6-((2,5-dimethylphenyl)amino)quinazoline-5,8-dione (110 mg, 307 μmol) and stirred at room temperature. At the same temperature, NaSMe (65.0 mg, 921 μmol) was added and stirred for 2.5 hours at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (petroleum ether) to obtain the target compound (6-((2,5-dimethylphenyl)amino)-7-(methylthio)quinazoline-5,8-dione, Compound 71).

[0705] Indigo solid, 46.3 mg(46.3%)

[0706] 1 H NMR (400 MHz, DMSO-D6) δ 9.58(s, 1H), 9.35(s, 1H), 8.96(s, 1H), 7.10(d,J= 7.5 Hz, 1H), 6.95(d,J= 7.5 Hz, 1H), 6.85(s, 1H), 2.23(s, 3H), 2.21(s, 3H), 2.06(s, 3H).

[0707]

[0708] <Example 38> Synthesis of Compounds 72 and 73

[0709]

[0710] EtOH (6.30 mL) was added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, 2,6-dimethylaniline (120 μL, 944 μmol) and CeCl3·7H2O (24.0 mg, 62.9 μmol) were added and stirred for 19.5 hours at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-bromo-6-((2,6-dimethylphenyl)amino)quinazoline-5,8-dione, Compound 72).

[0711] Dark violet to red brown solid, 174 mg(77.1%)

[0712] 1 H NMR (400 MHz, DMSO-D6) δ 9.66 (s, 1H), 9.44 (s, 1H), 6.91 (s, 2H), 5.18 (s, 2H), 2.13 (s, 6H).

[0713]

[0714] THF (3.90 mL) was added to 7-bromo-6-((2,6-dimethylphenyl)amino)quinazoline-5,8-dione (140 mg, 391 μmol) and stirred at room temperature. At the same temperature, NaSMe (82.0 mg, 1.17 mmol) was added and stirred for 2.5 hours at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((2,6-dimethylphenyl)amino)-7-(methylthio)quinazoline-5,8-dione, Compound 73).

[0715] Black solid, 58.4 mg (45.9%)

[0716] 1 H NMR (400 MHz, DMSO-D6) δ 9.62(s, 1H), 9.38(s, 1H), 6.79(s, 2H), 5.07(s, 2H), 2.30(s, 3H), 2.11(s, 7H).

[0717]

[0718] <Example 39> Synthesis of Compounds 74, 75 and 124

[0719]

[0720] EtOH (6.30 mL) was added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, o-toluidine (100 μL, 944 μmol) and CeCl3·7H2O (23.4 mg, 62.9 μmol) were added, and the mixture was stirred for 20 more hours at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4, followed by vacuum concentration. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-bromo-6-(o-tolylamino)quinazoline-5,8-dione, Compound 74).

[0721] Dark violet solid, 183 mg (84.6%)

[0722] 1 H NMR (400 MHz, DMSO-D6) δ 9.59 (s, 1H), 9.38 (s, 2H), 7.33 - 7.05 (m, 4H), 2.22 (s, 3H).

[0723]

[0724] THF (4.10 mL) was added to 7-bromo-6-(o-tolylamino)quinazoline-5,8-dione (140 mg, 407 μmol) and stirred at room temperature. At the same temperature, NaSMe (85.0 mg, 1.22 mmol) was added and stirred for 3 hours at room temperature. Saturated aqueous NaCl solution and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-(methylthio)-6-(o-tolylamino)quinazoline-5,8-dione, Compound 75).

[0725] Dark violet solid, 95.8 mg (75.6%)

[0726] 1 H NMR (400 MHz, DMSO-D6) δ 9.58(s, 1H), 9.34(s, 1H), 9.01(s, 1H), 7.23(dd,J= 6.4, 3.0 Hz, 1H), 7.18 - 7.09(m, 2H), 7.03(dd,J= 7.0, 2.4 Hz, 1H), 2.26(s, 3H), 2.06(s, 3H).

[0727]

[0728] CHCl3 (7.80 mL) is added to 7-(methylthio)-6-(o-tolylamino)quinazoline-5,8-dione (194 mg, 624 μmol) and stirred at room temperature. mCPBA (699 mg, 3.12 mmol) is added at the same temperature and stirred for 6 more hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, and then a saturated aqueous solution of NaCl and DCM are added and extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-(methylsulfonyl)-6-(o-tolylamino) quinazoline-5,8-dione, compound 124).

[0729] Orange solid, 48.9 mg (22.8%)

[0730] 1H NMR (500 MHz, DMSO-D6) δ 10.59(s, 1H), 9.66(s, 1H), 9.28(s, 1H), 7.33 - 7.30(m, 2H), 7.24 - 7.15(m, 2H), 3.38(s, 3H), 2.29(s, 3H).

[0731]

[0732] <Example 40> Synthesis of Compounds 76 and 77

[0733]

[0734] EtOH (6.30 mL) was added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, 2,3-dimethylaniline (110 μL, 944 μmol) and CeCl3·7H2O (23.4 mg, 62.9 μmol) were added and stirred for 21 hours at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-bromo-6-((2,3-dimethylphenyl)amino)quinazoline-5,8-dione, Compound 76).

[0735] Purple solid, 184 mg (81.8%)

[0736] 1 H NMR (400 MHz, DMSO-D6) δ 9.59(s, 1H), 9.41(s, 1H), 9.37(s, 1H), 7.09(dt,J= 15.2, 7.4 Hz, 2H), 6.99(d,J= 7.6 Hz, 1H), 2.28(s, 3H), 2.11(s, 3H).

[0737]

[0738] THF (4.30 mL) was added to 7-bromo-6-((2,3-dimethylphenyl)amino)quinazoline-5,8-dione (153 mg, 427 μmol) and stirred at room temperature. At the same temperature, NaSMe (89.8 mg, 1.28 mmol) was added and stirred for 3 hours at room temperature. Saturated aqueous NaCl solution and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((2,3-dimethylphenyl)amino)-7-(methylthio)quinazoline-5,8-dione, Compound 77).

[0739] Black solid, 80.1 mg (57.7%)

[0740] 1 H NMR (400 MHz, DMSO-D6) δ 9.57(s, 1H), 9.34(s, 1H), 9.05(s, 1H), 7.07 - 7.01(m, 2H), 6.93 - 6.86(m, 1H), 2.27(s, 3H), 2.15(s, 3H), 2.06(s, 3H).

[0741]

[0742] <Example 41> Synthesis of Compounds 79, 81 and 134

[0743]

[0744] EtOH (6.30 mL) was added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, 3-fluoro-4-methoxyaniline (133 mg, 944 μmol) and CeCl3·7H2O (24.0 mg, 62.9 μmol) were added and stirred for 21 more hours at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-bromo-6-((3-fluoro-4-methoxyphenyl)amino)quinazoline-5,8-dione, Compound 79).

[0745] Brown solid, 249 mg

[0746] 1 H NMR (400 MHz, DMSO-D6) δ 9.61 (s, 1H), 9.51 (s, 1H), 9.39 (s, 1H), 7.19 - 7.05 (m, 2H), 6.99 (d, J = 8.7 Hz, 1H), 3.85 (s, 3H).

[0747]

[0748] THF (3.20 mL) was added to 7-bromo-6-((3-fluoro-4-methoxyphenyl)amino)quinazoline-5,8-dione (120 mg, 317 μmol) and stirred at room temperature. At the same temperature, NaSMe (67.0 mg, 952 μmol) was added and stirred for 4 hours at room temperature. Saturated aqueous NaCl solution and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((3-fluoro-4-methoxyphenyl)amino)-7-(methyl-thio)quinazoline-5,8-dione, Compound 81).

[0749] Dark brown solid, 58.0 mg (53.0%)

[0750] 1 H NMR (400 MHz, DMSO-D6) δ 9.59(s, 1H), 9.36(s, 1H), 9.34(s, 1H), 7.10(t,J= 9.2 Hz, 1H), 7.01(d,J= 13.0 Hz, 1H), 6.91(d,J= 9.2 Hz, 1H), 3.83(s, 3H), 2.06(s, 3H).

[0751]

[0752] CHCl3 (8.00 mL) is added to 6-((3-fluoro-4-methoxyphenyl)amino)-7-(methyl-thio)quinazoline-5,8-dione (221 mg, 640 μmol) and stirred at room temperature. mCPBA (717 mg, 3.20 mmol) is added at the same temperature and stirred for 6 more hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, and then a saturated aqueous solution of NaCl and DCM are added and extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((3-fluoro-4-methoxyphenyl)amino)-7-(methylsulfonyl)quinazoline-5,8-dione, compound 134).

[0753] Orange brown solid, 18.3 mg(7.58%)

[0754] 1 H NMR (500 MHz, DMSO-D6) δ 10.59(s, 1H), 9.66(s, 1H), 9.32(s, 1H), 7.36(d,J= 12.4 Hz, 1H), 7.16(d,J= 8.2 Hz, 2H), 3.86(s, 3H), 3.35(s, 3H).

[0755]

[0756] <Example 42> Synthesis of Compounds 80, 82 and 127

[0757]

[0758] EtOH (6.30 mL) was added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, 4-fluoro-3-methoxyaniline (133 mg, 944 μmol) and CeCl3·7H2O (24.0 mg, 62.9 μmol) were added and stirred for 22 hours at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-bromo-6-((4-fluoro-3-methoxyphenyl)amino)quinazoline-5,8-dione, Compound 80).

[0759] Red brown solid, 209 mg(88.0%)

[0760] 1 H NMR (400 MHz, DMSO-D6) δ 9.61(s, 1H), 9.51(s, 1H), 9.39(s, 1H), 7.18(t,J= 10.0 Hz, 1H), 7.02(d,J= 7.9 Hz, 1H), 6.75(d,J= 9.8 Hz, 1H), 3.78(s, 3H).

[0761]

[0762] THF (2.60 mL) was added to 7-bromo-6-((4-fluoro-3-methoxyphenyl)amino)quinazoline-5,8-dione (100 mg, 264 μmol) and stirred at room temperature. At the same temperature, NaSMe (56.0 mg, 793 μmol) was added and stirred for 4 hours at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((4-fluoro-3-methoxyphenyl)amino)-7-(methylthio)quinazoline-5,8-dione, Compound 82).

[0763] Red brown to dark violet solid, 39.8 mg (43.7%)

[0764] 1 H NMR (400 MHz, DMSO-D6) δ 9.59(s, 1H), 9.37(s, 1H), 9.32(s, 1H), 7.14(t,J= 10.1 Hz, 1H), 6.94(d,J= 7.8 Hz, 1H), 6.66(d,J= 8.1 Hz, 1H), 3.78(s, 3H), 2.09(s, 3H).

[0765]

[0766] CHCl3 (8.00 mL) is added to 6-((4-fluoro-3-methoxyphenyl)amino)-7-(methyl-thio)quinazoline-5,8-dione (222 mg, 642 μmol) and stirred at room temperature. mCPBA (719 mg, 3.21 mmol) is added at the same temperature and stirred for 7 more hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, and then a saturated aqueous solution of NaCl and DCM are added and extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((4-fluoro-3-methoxyphenyl)amino)-7-(methylsulfonyl)quinazoline-5,8-dione, compound 127).

[0767] Orange brown solid, 33.1 mg (13.7%)

[0768] 1 H NMR (500 MHz, DMSO-D6) δ 10.60 (s, 1H), 9.67 (s, 1H), 9.34 (s, 1H), 7.29 (d, J = 6.1 Hz, 1H), 7.25 - 7.17 (m, 1H), 6.95 (s, 1H), 3.78(s, 3H), 3.37(s, 3H).

[0769]

[0770] <Example 43> Synthesis of Compounds 83, 85 and 133

[0771]

[0772] EtOH (6.30 mL) was added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, 3-methoxy-4-(trifluoromethyl) aniline (180 mg, 944 μmol) and CeCl3·7H2O (24.0 mg, 62.9 μmol) were added and stirred for 17.5 hours at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-bromo-6-((3-methoxy-4-(trifluoromethyl)phenyl)amino) quinazoline-5,8-dione, Compound 83).

[0773] Red brown solid, 244 mg(90.7%)

[0774] 1 H NMR (400 MHz, DMSO-D6) δ 9.64(s, 2H), 9.42(s, 1H), 7.53(d,J= 8.4 Hz, 1H), 7.02(s, 1H), 6.84(d,J= 8.4 Hz, 1H), 3.81(s, 3H).

[0775]

[0776] THF (2.8 mL) was added to 7-bromo-6-((3-methoxy-4-(trifluoromethyl)phenyl)amino)quinazoline-5,8-dione (120 mg, 280 μmol) and stirred at room temperature. At the same temperature, NaSMe (59.0 mg, 841 μmol) was added and stirred for 1.5 hours at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((3-methoxy-4-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinazoline-5,8-dione, Compound 85).

[0777] Red brown solid, 40.9 mg (36.9%)

[0778] 1 H NMR (400 MHz, DMSO-D6) δ 9.62(s, 1H), 9.48(s, 1H), 9.41(s, 1H), 7.49(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).

[0779]

[0780] CHCl3 (7.60 mL) is added to 6-((3-methoxy-4-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinazoline-5,8-dione (241 mg, 610 μmol) and stirred at room temperature. At the same temperature, mCPBA (683 mg, 3.05 mmol) is added and stirred for 5 more hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, and then a saturated aqueous solution of NaCl and DCM are added and extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((3-methoxy-4-(trifluoromethyl)phenyl)amino)-7-(methylsulfonyl)quinazoline-5,8-dione, compound 133).

[0781] Light orange solid, 9.40 mg (3.60%)

[0782] 1 H NMR (500 MHz, DMSO-D6) δ 10.58(s, 1H), 9.68(s, 1H), 9.38(s, 1H), 7.57(d,J= 8.1 Hz, 1H), 7.31(s, 1H), 7.06(s, 1H), 3.82(s, 3H), 3.34(s, 3H).

[0783]

[0784] <Example 44> Synthesis of Compounds 84, 86 and 136

[0785]

[0786] EtOH (6.30 mL) was added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, 4-methoxy-3-(trifluoromethyl) aniline (180 mg, 944 μmol) and CeCl3·7H2O (24.0 mg, 62.9 μmol) were added and stirred at room temperature for 18 more hours. Saturated aqueous NaCl solution and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-bromo-6-((4-methoxy-3-(trifluoromethyl)phenyl)amino) quinazoline-5,8-dione, Compound 84).

[0787] Violet solid, 260 mg (96.6%)

[0788] 1 H NMR (400 MHz, DMSO-D6) δ 9.61(s, 1H), 9.57(s, 1H), 9.39(s, 1H), 7.44(d,J= 9.6 Hz, 2H), 7.26(d,J= 8.5 Hz, 1H), 3.90(s, 3H).

[0789]

[0790] THF (2.80 mL) was added to 7-bromo-6-((4-methoxy-3-(trifluoromethyl)phenyl)amino)quinazoline-5,8-dione (120 mg, 280 μmol) and stirred at room temperature. At the same temperature, NaSMe (58.0 mg, 841 μmol) was added and stirred for 1 hour and 50 minutes at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((4-methoxy-3-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinazoline-5,8-dione, Compound 86).

[0791] Dark brown solid, 60.6 mg (54.7%)

[0792] 1 H NMR (400 MHz, DMSO-D6) δ 9.59 (s, 1H), 9.43 (s, 1H), 9.37 (s, 1H), 7.43 - 7.32 (m, 2H), 7.22 (d, J = 9.0 Hz, 1H), 3.88 (s, 3H), 2.04(s, 3H).

[0793]

[0794] CHCl3 (7.80 mL) is added to 6-((4-methoxy-3-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinazoline-5,8-dione (246 mg, 622 μmol) and stirred at room temperature. mCPBA (697 mg, 3.11 mmol) is added at the same temperature and stirred for 5.5 hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, and then a saturated aqueous solution of NaCl and DCM are added and extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((4-methoxy-3-(trifluoromethyl)phenyl)amino)-7-(methylsulfonyl)quinazoline-5,8-dione, compound 136).

[0795] Red brown solid, 27.0 mg (10.2%)

[0796] 1 H NMR (500 MHz, DMSO-D6) δ 10.61(s, 1H), 9.67(s, 1H), 9.33(s, 1H), 7.71(d,J= 2.7 Hz, 1H), 7.64(dd,J= 8.9, 2.7 Hz, 1H), 7.27(d,J= 8.9 Hz, 1H), 3.91(s, 3H), 3.33(s, 3H)

[0797]

[0798] <Example 45> Synthesis of Compounds 87, 88 and 128

[0799]

[0800] EtOH (6.30 mL) was added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, 3-methyl-4-(trifluoromethyl)aniline (165 mg, 944 μmol) and CeCl3·7H2O (23.4 mg, 62.9 μmol) were added and stirred for 21 hours at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-bromo-6-((3-methyl-4-(trifluoromethyl)phenyl)amino)quinazoline-5,8-dione, Compound 87).

[0801] Red solid, 207 mg (79.8%)

[0802] 1 H NMR (500 MHz, DMSO-D6) δ 9.63(s, 2H), 9.41(s, 1H), 7.60(d,J= 8.5 Hz, 1H), 7.18(s, 1H), 7.12(d,J= 8.4 Hz, 1H), 2.40(s, 3H).

[0803]

[0804] THF (2.70 mL) was added to 7-bromo-6-((3-methyl-4-(trifluoromethyl)phenyl)amino)quinazoline-5,8-dione (100 mg, 243 μmol) and stirred at room temperature. At the same temperature, NaSMe (51.0 mg, 728 μmol) was added and stirred for 5 hours at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((3-methyl-4-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinazoline-5,8-dione, Compound 88).

[0805] Red solid, 27.4 mg (29.7%)

[0806] 1 H NMR (500 MHz, DMSO-D6) δ 9.62(s, 1H), 9.47(s, 1H), 9.39(s, 1H), 7.57(d,J= 8.5 Hz, 1H), 7.05(s, 1H), 7.01(d,J= 8.5 Hz, 1H), 2.39(s, 3H), 2.13(s, 3H).

[0807]

[0808] CHCl3 (5.60 mL) is added to 6-((3-methyl-4-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinazoline-5,8-dione (211 mg, 556 μmol) and stirred at room temperature. At the same temperature, mCPBA (312 mg, 1.39 mmol) is added and stirred for 5 more hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, and then a saturated aqueous solution of NaCl and DCM are added and extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((3-methyl-4-(trifluoromethyl)phenyl)amino)-7-(methylsulfonyl)quinazoline-5,8-dione, compound 128).

[0809] Red brown solid, 13.9 mg (6.10%)

[0810] 1 H NMR (500 MHz, DMSO-D6) δ 10.67(s, 1H), 9.68(s, 1H), 9.37(s, 1H), 7.61-7.66(m, 1H), 7.31-7.45(m, 1H), 3.34(s, 3H), 2.41(s, 3H).

[0811]

[0812] <Example 46> Synthesis of Compounds 89, 90 and 129

[0813]

[0814] EtOH (6.30 mL) was added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, 2-methyl-4-(trifluoromethyl)aniline (165 mg, 944 μmol) and CeCl3·7H2O (23.4 mg, 62.9 μmol) were added and stirred for 17.5 hours at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried with MgSO4, filtered, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-bromo-6-((2-methyl-4-(trifluoromethyl)phenyl)amino)quinazoline-5,8-dione, Compound 89).

[0815] Red solid, 219 mg (84.5%)

[0816] 1 H NMR (500 MHz, DMSO-D6) δ 9.62 (s, 1H), 9.41 (s, 1H), 9.36 (s, 1H), 7.66 (s, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 2.32(s, 3H).

[0817]

[0818] THF (2.70 mL) was added to 7-bromo-6-((2-methyl-4-(trifluoromethyl)phenyl)amino)quinazoline-5,8-dione (100 mg, 243 μmol) and stirred at room temperature. At the same temperature, NaSMe (51.0 mg, 728 μmol) was added and stirred for 2 hours at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((2-methyl-4-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinazoline-5,8-dione, Compound 90).

[0819] Dark violet solid, 26.4 mg (28.6%)

[0820] 1 H NMR (500 MHz, DMSO-D6) δ 9.60(s, 1H), 9.37(s, 1H), 8.97(s, 1H), 7.61(s, 1H), 7.51(d,J= 8.9 Hz, 1H), 7.19(d,J= 8.5 Hz, 1H), 2.36(s, 3H), 2.12(s, 3H).

[0821]

[0822] CHCl3 (5.00 mL) is added to 6-((2-methyl-4-(trifluoromethyl)phenyl)amino)-7-(methylthio)quinazoline-5,8-dione (189 mg, 498 μmol) and stirred at room temperature. At the same temperature, mCPBA (558 mg, 2.49 mmol) is added and stirred for 6.5 hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, and then a saturated aqueous solution of NaCl and DCM are added and extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((2-methyl-4-(trifluoromethyl)phenyl)amino)-7-(methylsulfonyl)quinazoline-5,8-dione, compound 129).

[0823] Orange solid, 18.8 mg (9.20%)

[0824] 1 H NMR (500 MHz, DMSO-D6) δ 10.53(s, 1H), 9.67(s, 1H), 9.32(s, 1H), 7.69(s, 1H), 7.54(s, 2H), 3.36(s, 3H), 2.36(s, 3H).

[0825]

[0826] <Example 47> Synthesis of Compounds 91, 92 and 132

[0827]

[0828] EtOH (6.30 mL) was added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, 4-(Trifluoromethyl)aniline (152 mg, 944 μmol) and CeCl3·7H2O (24.0 mg, 62.9 μmol) were added and stirred for 18 more hours at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-bromo-6-((4-(trifluoromethyl)phenyl)amino)quinazoline-5,8-dione, Compound 91).

[0829] Orange to Red solid, 207 mg (82.8%)

[0830] 1 H NMR (400 MHz, DMSO-D6) δ 9.72 (s, 1H), 9.63 (s, 1H), 9.41 (s, 1H), 7.68 (d, J = 8.5 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H).

[0831]

[0832] THF (4.00 mL) was added to 7-bromo-6-((4-(trifluoromethyl)phenyl)amino)quinazoline-5,8-dione (160 mg, 402 μmol) and stirred at room temperature. At the same temperature, NaSMe (84.5 mg, 1.21 mmol) was added and stirred for 3.5 hours at room temperature. After adding a saturated aqueous solution of NaCl and DCM to the reaction solution and extracting several times, the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-(methylthio)-6-((4-(trifluoromethyl)phenyl)amino)quinazoline-5,8-dione, Compound 92).

[0833] Dark brown solid, 88.3 mg (60.1%)

[0834] 1 H NMR (400 MHz, DMSO-D6) δ 9.61(s, 1H), 9.57(s, 1H), 9.39(s, 1H), 7.64(d,J= 8.4 Hz, 2H), 7.20(d,J= 8.4 Hz, 2H), 2.11(s, 3H).

[0835]

[0836] CHCl3 (6.80 mL) is added to 7-(methylthio)-6-((4-(trifluoromethyl)phenyl)amino)quinazoline-5,8-dione (199 mg, 545 μmol) and stirred at room temperature. mCPBA (610 mg, 2.72 mmol) is added at the same temperature and stirred for 5 more hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, and then a saturated aqueous solution of NaCl and DCM are added and extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-(methylsulfonyl)-6-((4-(trifluoromethyl)phenyl)amino)quinazoline-5,8-dione, compound 132).

[0837] Orange solid, 10.2 mg (4.70%)

[0838] 1 H NMR (500 MHz, DMSO-D6) δ 10.63(s, 1H), 9.68(s, 1H), 9.36(s, 1H), 7.73(d,J= 8.7 Hz, 2H), 7.59(d,J= 7.6 Hz, 2H), 3.34(s, 3H).

[0839]

[0840] <Example 48> Synthesis of Compounds 93, 95 and 123

[0841]

[0842] EtOH (6.30 mL) was added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, p-toluidine (101 mg, 944 μmol) and CeCl3·7H2O (24.0 mg, 62.9 μmol) were added and stirred for 17 more hours at room temperature. After adding a saturated aqueous solution of NaCl and DCM to the reaction solution and extracting several times, the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-bromo-6-(p-tolylamino)quinazoline-5,8-dione, Compound 93).

[0843] Dark brown solid, 208 mg(96.2%)

[0844] 1 H NMR (400 MHz, DMSO-D6) δ 9.60 (s, 1H), 9.53 (s, 1H), 9.37 (s, 1H), 7.14 (d, J = 8.1 Hz, 2H), 7.07 (d, J = 8.1 Hz, 2H), 2.29 (s, 3H).

[0845]

[0846] THF (4.70 mL) was added to 7-bromo-6-(p-tolylamino)quinazoline-5,8-dione (160 mg, 465 μmol) and stirred at room temperature. At the same temperature, NaSMe (98.0 mg, 1.39 mmol) was added and stirred for 3 hours at room temperature. Saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-(methylthio)-6-(p-tolylamino)quinazoline-5,8-dione, Compound 95).

[0847] Dark violet to Indigo solid, 79.0 mg (54.6%)

[0848] 1 H NMR (400 MHz, DMSO-D6) δ 9.58(s, 1H), 9.35(s, 1H), 9.33(s, 1H), 7.10(d,J= 8.2 Hz, 2H), 7.00(d,J= 8.2 Hz, 2H), 2.28(s, 3H), 2.04(s, 3H).

[0849]

[0850] CHCl3 (7.30 mL) is added to 7-(methylthio)-6-(p-tolylamino)quinazoline-5,8-dione (183 mg, 588 μmol) and stirred at room temperature. mCPBA (659 mg, 2.94 mmol) is added at the same temperature and stirred for 4.5 hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, and then a saturated aqueous solution of NaCl and DCM are added and extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-(methylsulfonyl)-6-(p-tolylamino) quinazoline-5,8-dione, compound 123).

[0851] Red brown solid, 25.1 mg (12.4%)

[0852] 1H NMR (500 MHz, DMSO-D6) δ 10.65(s, 1H), 9.66(s, 1H), 9.29(s, 1H), 7.27(d,J= 8.4 Hz, 2H), 7.18(d,J= 8.4 Hz, 2H), 3.37(s, 3H), 2.32(s, 3H).

[0853]

[0854] <Example 49> Synthesis of Compounds 94 and 96

[0855]

[0856] EtOH (6.30 mL) was added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, 2,3-difluoro-4-methoxyaniline (150 mg, 944 μmol) and CeCl3·7H2O (24.0 mg, 62.9 μmol) were added and stirred for 16 more hours at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-bromo-6-((2,3-difluoro-4-methoxyphenyl)amino)quinazoline-5,8-dione, Compound 94).

[0857] Orange solid, 233 mg (93.3%)

[0858] 1 H NMR (400 MHz, DMSO-D6) δ 9.60(s, 1H), 9.42(s, 1H), 9.38(s, 1H), 7.12(t,J= 8.7 Hz, 1H), 7.03(t,J= 8.9 Hz, 1H), 3.90(s, 3H).

[0859]

[0860] THF (5.00 mL) was added to 7-bromo-6-((2,3-difluoro-4-methoxyphenyl)amino)quinazoline-5,8-dione (200 mg, 505 μmol) and stirred at room temperature. At the same temperature, NaSMe (110 mg, 1.51 mmol) was added and stirred for 1.5 hours at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((2,3-difluoro-4-methoxyphenyl)amino)-7-(methylthio)quinazoline-5,8-dione, Compound 96).

[0861] Dark brown solid, 117 mg(63.9%)

[0862] 1 H NMR (400 MHz, DMSO-D6) δ 9.59(s, 1H), 9.35(s, 1H), 9.23(s, 1H), 7.05(t,J= 8.8 Hz, 1H), 6.99(t,J= 8.9 Hz, 1H), 3.89(s, 3H), 2.13(s, 3H).

[0863]

[0864] <Example 50> Synthesis of Compounds 97, 99, and 122

[0865]

[0866] EtOH (6.30 mL) was added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, 5-chloro-2-methylaniline (134 mg, 944 μmol) and CeCl3·7H2O (23.4 mg, 62.9 μmol) were added and stirred at room temperature for 18 more 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 and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-bromo-6-((5-chloro-2-methylphenyl)amino)quinazoline-5,8-dione, Compound 97).

[0867] Red brown solid, 225 mg(94.4%)

[0868] 1 H NMR (500 MHz, DMSO-D6) δ 9.61 (s, 1H), 9.40 (s, 1H), 9.32 (s, 1H), 7.27 (q, J = 8.6 Hz, 3H), 2.21 (s, 3H).

[0869]

[0870] THF (3.20 mL) was added to 7-bromo-6-((5-chloro-2-methylphenyl)amino)quinazoline-5,8-dione (110 mg, 291 μmol) and stirred at room temperature. At the same temperature, NaSMe (61.1 mg, 872 μmol) was added and stirred for 4 hours at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and crystallized (Hex) to obtain the target compound (6-((5-chloro-2-methylphenyl)amino)-7-(methylthio)quinazoline-5,8-dione, Compound 99).

[0871] Black solid, 27.2 mg (27.0%)

[0872] 1 H NMR (500 MHz, DMSO-D6) δ 9.60 (s, 1H), 9.37 (s, 1H), 8.95 (s, 1H), 7.25 (d, J = 8.1 Hz, 1H), 7.19 - 7.12 (m, 2H), 2.26 (s, 3H), 2.10(s, 3H).

[0873]

[0874] CHCl3 (8.70 mL) is added to 6-((5-chloro-2-methylphenyl)amino)-7-(methylthio)quinazoline-5,8-dione (240 mg, 695 μmol) and stirred at room temperature. At the same temperature, mCPBA (779 mg, 3.47 mmol) is added and stirred for 4.5 hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, and then a saturated aqueous solution of NaCl and DCM are added and extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((5-chloro-2-methylphenyl)amino)-7-(methylsulfonyl)quinazoline-5,8-dione, compound 122).

[0875] Orange brown solid, 42.7 mg (16.3%)

[0876] 1 H NMR (500 MHz, DMSO-D6) δ 10.47(s, 1H), 9.67(s, 1H), 9.34(s, 1H), 7.49(s, 1H), 7.32(d,J= 8.2 Hz, 1H), 7.26(dd,J= 8.2, 2.3 Hz, 1H), 3.35(s, 3H), 2.26(s, 3H).

[0877]

[0878] <Example 51> Synthesis of Compounds 98 and 101

[0879]

[0880] EtOH (6.30 mL) was added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, 4-chloro-2-methylaniline (134 mg, 944 μmol) and CeCl3·7H2O (23.4 mg, 62.9 μmol) were added and stirred for 18 more hours at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-bromo-6-((4-chloro-2-methylphenyl)amino)quinazoline-5,8-dione, Compound 98).

[0881] Red brown solid, 225 mg(94.4%)

[0882] 1 H NMR (500 MHz, DMSO-D6) δ 9.60(s, 1H), 9.39(s, 1H), 9.33(s, 1H), 7.37(s, 1H), 7.26(d,J= 8.4 Hz, 1H), 7.17(d,J= 8.4 Hz, 1H), 2.22(s, 3H).

[0883]

[0884] THF (3.50 mL) was added to 7-bromo-6-((4-chloro-2-methylphenyl)amino)quinazoline-5,8-dione (120 mg, 317 μmol) and stirred at room temperature. At the same temperature, NaSMe (66.6 mg, 951 μmol) was added and stirred for 3 hours at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((4-chloro-2-methylphenyl)amino)-7-(methylthio)quinazoline-5,8-dione, Compound 101).

[0885] Black solid, 24.3 mg (22.2%)

[0886] 1 H NMR (500 MHz, DMSO-D6) δ 9.58 (s, 1H), 9.35 (s, 1H), 8.99 (s, 1H), 7.33 (s, 1H), 7.22 (d, J = 8.5 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 2.26(s, 3H), 2.09(s, 3H).

[0887]

[0888] <Example 52> Synthesis of Compounds 100 and 102

[0889]

[0890] EtOH (6.30 mL) was added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, 5-fluoro-2-methylaniline (134 mg, 944 μmol) and CeCl3·7H2O (23.4 mg, 62.9 μmol) were added and stirred for 18 more hours at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-bromo-6-((5-fluoro-2-methylphenyl)amino)quinazoline-5,8-dione, Compound 100).

[0891] Red brown solid, 204 mg (89.3%)

[0892] 1 H NMR (500 MHz, DMSO-D6) δ 9.61(s, 1H), 9.40(s, 1H), 9.32(s, 1H), 7.28(t,J= 7.9 Hz, 1H), 7.06(d,J= 8.4 Hz, 2H), 2.20(s, 3H).

[0893]

[0894] THF (4.6 mL) was added to 7-bromo-6-((5-fluoro-2-methylphenyl)amino)quinazoline-5,8-dione (150 mg, 414 μmol) and stirred at room temperature. At the same temperature, NaSMe (87.1 mg, 1.24 mmol) was added and stirred for 2 hours at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((5-fluoro-2-methylphenyl)amino)-7-(methylthio)quinazoline-5,8-dione, Compound 102).

[0895] Black solid, 63.9 mg (46.9%)

[0896] 1 H NMR (500 MHz, DMSO-D6) δ 9.59 (s, 1H), 9.37 (s, 1H), 8.93 (s, 1H), 7.24 (t, J = 7.5 Hz, 1H), 7.00 - 6.88 (m, 2H), 2.24 (s, 3H), 2.11(s, 3H).

[0897]

[0898] <Example 53> Synthesis of Compounds 103, 105, and 126

[0899]

[0900] EtOH (6.30 mL) was added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, 3-chloro-4-methoxyaniline (149 mg, 944 μmol) and CeCl3·7H2O (23.4 mg, 62.9 μmol) were added and stirred for 18 more hours at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-bromo-6-((3-chloro-4-methoxyphenyl)amino)quinazoline-5,8-dione, Compound 103).

[0901] Dark brown solid, 232 mg(93.6%)

[0902] 1 H NMR (500 MHz, DMSO-D6) δ 9.61 (s, 1H), 9.52 (s, 1H), 9.39 (s, 1H), 7.29 (s, 1H), 7.15 (d, J = 11.6 Hz, 2H), 3.86 (s, 3H).

[0903]

[0904] THF (5.10 mL) was added to 7-bromo-6-((3-chloro-4-methoxyphenyl)amino)quinazoline-5,8-dione (180 mg, 456 μmol) and stirred at room temperature. At the same temperature, NaSMe (95.9 mg, 1.37 mmol) was added and stirred for 1.5 hours at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((3-chloro-4-methoxyphenyl)amino)-7-(methylthio)quinazoline-5,8-dione, Compound 105).

[0905] Dark violet solid, 99.5 mg (60.3%)

[0906] 1 H NMR (500 MHz, DMSO-D6) δ 9.59(s, 1H), 9.36(s, 1H), 9.35(s, 1H), 7.20(s, 1H), 7.10(s, 2H), 3.85(s, 3H), 2.06(s, 3H).

[0907]

[0908] CHCl3 (8.60 mL) is added to 6-((3-chloro-4-methoxyphenyl)amino)-7-(methylthio)quinazoline-5,8-dione (250 mg, 691 μmol) and stirred at room temperature. mCPBA (774 mg, 3.45 mmol) is added at the same temperature and stirred for 6 more hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4 and then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, and then a saturated aqueous solution of NaCl and DCM are added and extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((3-chloro-4-methoxyphenyl)amino)-7-(methylsulfonyl)quinazoline-5,8-dione, compound 126).

[0909] Brown solid, 46.7 mg (17.2%)

[0910] 1 H NMR (500 MHz, DMSO-D6) δ 10.57(s, 1H), 9.67(s, 1H), 9.33(s, 1H), 7.55(d,J= 2.6 Hz, 1H), 7.34(dd,J= 8.9, 2.6 Hz, 1H), 7.15(d,J= 9.0 Hz, 1H), 3.88(s, 3H), 3.34(s, 3H).

[0911]

[0912] <Example 54> Synthesis of Compounds 104, 106, and 135

[0913]

[0914] EtOH (6.30 mL) was added to 6,7-dibromoquinazoline-5,8-dione (200 mg, 629 μmol) and stirred at room temperature. At the same temperature, 3,5-difluoro-4-methoxyaniline (150 mg, 944 μmol) and CeCl3·7H2O (23.4 mg, 62.9 μmol) were added and stirred for 17.5 hours at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (7-bromo-6-((3,5-difluoro-4-methoxyphenyl)amino)quinazoline-5,8-dione, Compound 104).

[0915] Red solid, 141 mg (56.7%)

[0916] 1 H NMR (500 MHz, DMSO-D6) δ 9.63 (s, 1H), 9.51 (s, 1H), 9.41 (s, 1H), 6.99 (d, J = 9.9 Hz, 2H), 3.90 (s, 3H).

[0917]

[0918] THF (3.10 mL) was added to 7-bromo-6-((3,5-difluoro-4-methoxyphenyl)amino)quinazoline-5,8-dione (110 mg, 278 μmol) and stirred at room temperature. At the same temperature, NaSMe (58.4 mg, 833 μmol) was added and stirred for 1.5 hours at room temperature. A saturated aqueous solution of NaCl and DCM were added to the reaction solution and extracted several times; the separated organic layer was dried and filtered with MgSO4 and then concentrated under reduced pressure. The concentrate was separated by silica gel column chromatography (EtOAc / DCM) and purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((3,5-difluoro-4-methoxyphenyl)amino)-7-(methylthio)quinazoline-5,8-dione, Compound 106).

[0919] Black solid, 37.4 mg (37.0%)

[0920] 1 H NMR (500 MHz, DMSO-D6) δ 9.61 (s, 1H), 9.39 (s, 1H), 9.36 (s, 1H), 6.86 (d, J = 10.1 Hz, 2H), 3.88 (s, 3H), 2.14 (s, 3H).

[0921]

[0922] CHCl3 (6.30 mL) is added to 6-((3,5-difluoro-4-methoxyphenyl)amino)-7-(methylthio)quinazoline-5,8-dione (183 mg, 504 μmol) and stirred at room temperature. At the same temperature, mCPBA (564 mg, 2.52 mmol) is added and stirred for 6.5 hours. Distilled water is added to the reaction solution and extracted several times with DCM. The separated organic layer is dried and filtered with MgSO4, then concentrated under reduced pressure. After separating the target compound by C18 silica gel column chromatography (MeCN / Water), the pH is adjusted to 8 with a saturated aqueous solution of NaHCO3, and then a saturated aqueous solution of NaCl and DCM are added and extracted several times. The separated organic layer is washed once with distilled water, dried and filtered with MgSO4, and then concentrated under reduced pressure. The concentrate was purified by recrystallization (EtOAc / Hex) to obtain the target compound (6-((3,5-difluoro-4-methoxyphenyl)amino)-7-(methylsulfonyl)quinazoline-5,8-dione, compound 135).

[0923] Orange solid, 15.3 mg (6.52%)

[0924] 1 H NMR (500 MHz, DMSO-D6) δ 10.48 (s, 1H), 9.68 (s, 1H), 9.39 (s, 1H), 7.28 (d, J = 9.5 Hz, 2H), 3.92 (s, 3H), 3.34 (s, 3H).

[0925]

[0926] <Experimental Example 1> Elucidation of the NQO1 substrate effect of the compounds of the present invention and confirmation of the NQO1 activity enhancement effect (confirmation of chromium c reducing ability)

[0927] Cytochrome c reduction (nmole / min / mg) Compound Name 0.2 μM 1 μM 5 μM11,0202263,37521,8242,63011,58631,5131,85112,0794801,6837, 50951,0331,5283,36164452,5263,13276783,35811,81585561,9328,5 0391,9825,84616,617104,23016,64441,549112473,15813,833120874 1,877132,3538,87536,4931403,10311,751151,3737,83234,31216938 1,8601,63817002,397181,8925901,568194303,473206293,5919,019211307454,776222514,44718,585231,3781,3066,742242,67010,83143,396251,1804511,473268237,85231,654279561,1953,8602801,86614,167295572801,156302,1846,76831,133311,2432,0291,383325182,8 7611,094335076152,7873407525,996352866751,480367388994,431371,0691511,60138832192,749396251,1443,262408066068,510418418184,918424762,3938,0184305983,817441,6466,08625,453454372,3816,801463713,70617,58747290514485875983,5004949300506946502,3 7451000525421,6969,806537891,2266,694541,3225,05624,9205502271,119561,2563,3823,788571,55402,263583171,2393,785591,2761,1634,753603273,44215,581617471,0353,224623649034,570631,0135,69218,2996401,0333,534658507184,139669381,5379,881671,0031,1734,142681,6632,27511,221691,7857,83530,879706545385,7737101,0308,811727147,87746,161733,1918,47330,247743181,3352,912754147533,1617602,1199,081778488592,74778--46,90079--24,07880--20,63781--23,18982--31,89983--10,24684--4,60885--32,17286--11,56487--1,89888--21,64889--6,02090--1,80291--1,83392--13,81293--2,82694--1,67195--29,97196--11,96297--5,91798--2,51899--13,159100--6,066101--3,084102--8,749103--4,862104--1,976105--8,675106--10,698107--1,346108--734109--952110--225111--2,232112--1,957113--1,221114--1,243115--2,695116--1,167117--436118--493119--383120--539121--846122--775123--1,103124--558125--502126--1,515127--579128--616129--457130--1,031131--627132--500133--798134--811135--719136--92137---,

Claims

Compounds represented by the following chemical formula 1, pharmaceutically acceptable salts, hydrates, solvates, prodrugs, tautomers, enantiomers, or diastereomers thereof: [Chemical Formula 1] In the above chemical formula 1, R1 is hydrogen, a substituted or unsubstituted alkyl, or a substituted or unsubstituted cycloalkyl, and R2 is a substituted or non-substituted aryl, or a substituted or non-substituted heteroaryl, and R3 is fluorine, bromine, iodine, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkoxy, a substituted or unsubstituted thioalkyl, a substituted or unsubstituted cycloalkyl, -S(O)R'1, -S(O)2R'1, or -SO3H, where R'1 is a C1 to C4 alkyl. In paragraph 1, The above R1 is a compound, pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer, wherein R1 is hydrogen, a substituted or unsubstituted C1 to C4 alkyl, or a substituted or unsubstituted C3 to C6 cycloalkyl. In paragraph 1, A compound, pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer thereof, wherein the above-mentioned substituted aryl or substituted heteroaryl is substituted with one or more substituents selected from the group consisting of substituted or unsubstituted C1 to C6 alkyl, substituted or unsubstituted C1 to C6 alkoxy, and halogen elements. In paragraph 3, A compound, pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer thereof, wherein the alkyl group of the above substitution is substituted with a halogen element. In paragraph 4, A compound, pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer thereof, wherein the alkyl group of the above substitution is substituted with 1 to 3 halogen elements. In paragraph 3, A compound, pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer thereof, wherein the above-mentioned substituted aryl or substituted heteroaryl is substituted with one or more substituents selected from the group consisting of unsubstituted C1 to C3 alkyl, C1 to C3 alkyl substituted with a halogen element, unsubstituted C1 to C3 alkoxy, and halogen element. In paragraph 1, The above R'1 is a compound, pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer, wherein R'1 is methyl or ethyl. In paragraph 1, The above compound is a compound, pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer thereof, selected from the group consisting of the following compounds 1 to 137: NAD comprising, as an active ingredient, a compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer thereof. + A pharmaceutical composition for the prevention or treatment of diseases caused by a decrease in or mitochondrial dysfunction. In Paragraph 9, The above NAD + A pharmaceutical composition wherein the disease caused by a decrease in or mitochondrial dysfunction is one or more selected from the group consisting of metabolic diseases, primary and secondary mitochondrial diseases, muscle diseases, neurodegenerative diseases, inflammatory diseases, fibrotic diseases, autoimmune diseases, cancer, and cognitive impairment. In Paragraph 10, A pharmaceutical composition wherein the above metabolic disease is one or more selected from the group consisting of obesity, diabetes, and metabolic disorder-related fatty liver disease. NAD comprising, as an active ingredient, a compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer thereof. + A food composition for the prevention or improvement of diseases caused by a decrease in or mitochondrial dysfunction. A composition for enhancing the activity of NQO1, comprising as an active ingredient a compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer thereof. A method for preparing a compound represented by Chemical Formula 1, comprising the following steps: A step of obtaining a compound of the following chemical formula 3 by reacting a compound of chemical formula 2 below with HNO3 under acidic conditions; (S2) A step of reacting the compound of Formula 3 and formamide under acidic conditions to obtain the compound of Formula 4; (S3) A step of obtaining a compound of Formula 5 by cyclizing the compound of Formula 4 under acidic conditions; (S4) A step of dissolving the compound of Formula 5 in acetonitrile and then reacting it with an oxidizing agent to obtain quinazoline-5,8-dione of Formula 6; (S5) A step of obtaining a compound of the following formula 7 by performing a halogenation reaction of the quinazoline-5,8-dione of formula 6 above; (S6) A step of synthesizing a compound of the following formula 1 from a compound of the above formula 7, wherein the step is performed by a method comprising any one of the following steps (a) to (c). (a) a step of reacting the compound of Formula 7 with the compound of Formula 8 to obtain the compound of Formula 1, (b) a step of reacting the compound of Formula 7 with the compound of Formula 8 to obtain the compound of Formula 9; and a step of reacting NaZ1 with the compound of Formula 9 to obtain the compound of Formula 1; (c) a step of obtaining a compound of formula 9 by reacting the compound of formula 7 with the compound of formula 8; a step of obtaining a compound of formula 10 by reacting NaZ1 with the compound of formula 9; and a step of obtaining a compound of formula 1 by reacting the compound of formula 10 with an oxidizing agent. [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 1] (In the above chemical formulas, R1 is hydrogen, a substituted or unsubstituted alkyl, or a substituted or unsubstituted cycloalkyl, and R2 is a substituted or non-substituted aryl, or a substituted or non-substituted heteroaryl, and R3 is fluorine, bromine, iodine, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkoxy, a substituted or unsubstituted thioalkyl, a substituted or unsubstituted cycloalkyl, -S(O)R'1, -S(O)2R'1, or -SO3H, where R'1 is a C1 to C4 alkyl, and R a and R b Each is independently an -OH or a substituted or unsubstituted alkoxy, and X1 and X2 are identical or different halogen elements, and The above n is an integer from 1 to 5, and Y is a substituted or unsubstituted alkyl, a substituted or unsubstituted alkoxy, or a halogen, wherein when n is 2 or more, the n Ys are each independent of each other, and Z1 is a substituted or unsubstituted alkyl, a substituted or unsubstituted alkoxy, a substituted or unsubstituted thioalkyl, or a substituted or unsubstituted cycloalkyl. NAD comprising the step of administering to an individual a compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer thereof. + A method for the prevention, improvement, or treatment of diseases caused by a decrease in or mitochondrial dysfunction. NAD + Use of the compound of any one of claims 1 to 8, or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer, for the prevention, improvement, or treatment of diseases caused by a decrease in or mitochondrial dysfunction. NAD + Use of the compound of any one of claims 1 to 8, or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer, or diastereomer, for the manufacture of a drug for the prevention, improvement, or treatment of diseases caused by a decrease in or mitochondrial dysfunction.

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