KR20180088627A - 1,2-Naphthoquinone-based Derivatives and Methods for Preparing them - Google Patents

Abstract

The present invention provides a compound represented by chemical formula (1), a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer or a pharmaceutically acceptable diastereomer thereof. X_1 to X_4 in the chemical formula (1) are as defined in claim 1. The present invention aims to provide a composition for treating and preventing metabolic diseases by comprising a novel pharmacologically effective amount of the novel compound as an active ingredient.

Description

1,2-Naphthoquinone Derivatives and Methods for Their Preparation {1,2-Naphthoquinone-based Derivatives and Methods for Preparing Them,

The present invention relates to a 1,2-naphthoquinone derivative, a process for producing the same, and a composition having a therapeutic and preventive effect on a metabolic disease containing the same.

Metabolic Syndrome refers to a syndrome in which risk factors such as hypertriglyceridemia, hypertension, glucose metabolism abnormality, blood clotting abnormality, and obesity coexist, and includes heart failure, ischemic heart disease, type 2 diabetes, hypercholesterolemia, , Cholelithiasis, arthritis, arthralgia, respiratory diseases, sleep apnea, enlargement of the prostate gland, menstrual irregularities, and the like. According to the US National Cholesterol Education Program (NCEP) standard published in 2001, ① waist circumference is 40 inches (102 cm) for men and 35 inches (88 cm) for women. Abdominal obesity; ② triglycerides 150 mg / dL Of the risk factors for HDL cholesterol were 40 mg / dL for men, 50 mg / dL for women, ≥ 130/85 mmHg for blood pressure, and 110 mg / dL for fasting glucose. If three or more are shown, the disease is judged to be a metabolic disease. In Oriental medicine, when the waist circumference is 90 cm for men and 80 cm for women or more, it is somewhat adjusted to abdominal obesity. According to recent research report, about 25% of Koreans have metabolic disease have.

This metabolic disorder is considered to be a major risk factor for chronic long-term high caloric intake. Metabolic efficiency is decreased in the process of excess energy intake, lack of exercise, prolongation of life and aging, and it is known that it deepens the problem of energy overload and shifts to obesity, diabetes and metabolic diseases.

However, because the cause of the disease has not been clarified, the current effect is insignificant, only to alleviate the symptoms or delay the progress of the disease. Therapeutic targets for the development of therapeutic agents have also been presented in various ways.

On the other hand, when NAD ⁺ / NADH and NADP ⁺ / NADPH ratios are reduced in vivo or in vitro, and NADH and NADPH remain as surplus, they are used not only for the fat biosynthesis process, (ROS), it is also a cause of important diseases including inflammatory diseases caused by ROS. For this reason, if the in vivo or in vitro environment can be established to stably maintain the increased NAD ⁺ / NADH and NADP ⁺ / NADPH ratios, the fat content by NAD ⁺ and NADP ⁺ Oxidation and various energy expenditure metabolism can be activated. As a result, if it is possible to activate the action mechanism that keeps the concentration of NAD (P) H constantly low, it is considered that it will be possible to treat various diseases including obesity by inducing exhaustion of excess energy.

Such a method of increasing the concentration and the ratio of the known signal communicator of NAD (P) by a variety of features ⁺ is, first, NAD (P) ⁺ Biosynthesis processes the salvage method for controlling the synthesis process, and second, NAD (P) H (P) ⁺ or its analogs, derivatives, precursors and prodrugs from the outside to activate NAD (P) ^{+ in} vivo by activating the gene or protein of the enzyme using the enzyme as a substrate or coenzyme. A method of increasing the concentration of (P) ⁺ can be considered.

NAD (P) H: quinone oxidoreductase (EC1.6.99.2) is called DT-diaphorase, quinone reductase, menadione reductase, vitamin K reductase or azo-dye reductase. These NQOs are two isoforms: NQO1 And NQO2 (ROM. J. INTERN. MED. 2000-2001, vol. 38-39, 33-50). NQO is a flavoprotein that catalyzes two electron reduction and decontamination of quinone or quinone derivatives. NQO uses both NADH and NADPH as electron donors. The activity of NQO prevents the formation of highly reactive quinone metabolites, detoxifies benzo (d) pyrene, quinone, and reduces the toxicity of chromium. The activity of NQO is present in all tissues, but the activity varies from tissue to tissue. In general, the expression level of NQO was found to be high in tissues such as cancer cell tissue, liver, stomach, and kidney. The gene expression of NQO is induced by xenobiotics, antioxidants, oxidants, heavy metals, ultraviolet rays, radiation and the like. NQO is part of a number of cellular defense mechanisms induced by oxidative stress. Associated expression of genes involved in these defense mechanisms, including NQO, plays a role in protecting cells against oxidative stress, free radicals and neoplasia. NQO has a very broad substrate specificity, and besides quinone, quinone-imines, nitro and azo compounds can be used as substrates.

Among them, NQO1 is mainly distributed in epithelial cells and endothelial cells. This means that it can act as a defense mechanism against compounds absorbed through air, esophagus or blood vessels. Recently, the gene expression of NQO1 has been shown to increase significantly in adipose tissues of people with metabolic diseases. Especially, the expression level of NQO1 was significantly higher in adipocytes with large fat cells. When weight loss was induced through diet, weight loss and proportion of NQO1 expression decreased proportionally. There was a correlation between the amount of mRNA of NQO1 and GOT and GPT, which are known to be related to the degree of fatty liver. Therefore, NQO1 may play a role in obesity-related metabolic diseases when the expression of NQO1 in adipose tissue is correlated with adiposity, glucose tolerance, and liver function index (The Journal of Clinical Endocrinology & Metabolism 92 (6): 2346 2352).

SUMMARY OF THE INVENTION The present invention has been made in view of the above problems, and it is an object of the present invention to solve the technical problems required from the past and the past.

Specifically, the present invention provides a 1,2-naphthoquinone derivative having a novel structure.

It is another object of the present invention to provide a process for preparing such novel compounds.

It is a further object of the present invention to provide a composition for the treatment and prevention of metabolic diseases comprising as active ingredients such novel compounds in a pharmacologically effective amount.

Another object of the present invention is to provide a method for the treatment and prevention of metabolic diseases, using such a novel compound as an active ingredient.

The present invention provides a compound represented by the following formula (1), a pharmaceutically acceptable salt, a hydrate, a solvate, a prodrug, a tautomer, an enantiomer or a pharmaceutically acceptable diastereomer thereof .

(1)

(One)

i) X ₂ and X ₃ are each independently -NW ' ₁ W' ₂ , Or _{-NW '1 (CO (O)} W' 2), -NW '1 (C (O) NW' 1 W '2), or _{-NW' 1 (SO (O)} W '2), or X ₂ And X < ₃ > form a cyclic structure of substituted or unsubstituted C3-C10 heteroaryl by mutual bonding,

X ₁ and X ₄ are each independently selected from the group consisting of hydrogen, a halogen atom, a substituted or unsubstituted C 1 -C 10 alkoxy, a substituted or unsubstituted C 1 -C 10 alkyl, a substituted or unsubstituted C 3 -C 8 cycloalkyl, a substituted or unsubstituted C 2 -C 8 hetero cycloalkyl, substituted or unsubstituted C4-C10 aryl, substituted or unsubstituted C4-C10 aryloxy, substituted or unsubstituted C4-C10 heteroaryl group, -NX _'1 X' _{2, -NX '1 (CO (O)} X' 2), -NX '1 (C (O) NX' 1 X '2), -CO (O) X' 1, -C (O) NX '1 X' _{2, -CN, -SO (O)} X is a _{'1, -SO (O) NX} ' 1 X '2, -NX' 1 (SO (O) X '2), or -CSNX' ₁ X _'2,

Wherein W ' ₁ and W' ₂ each independently represent hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 4 -C 10 aryl, substituted or unsubstituted C 4 -C 10 aryloxy , substituted or unsubstituted C4-C8 heteroaryl group, a substituted or unsubstituted - and _{(CW '' 1 W ''} 2) m'-C4-C10 aryl, or a substituted or unsubstituted _{NW '' 1 W '' 2} , where W '' ₁ and W '' ₂ each independently is hydrogen or C1-C3 alkyl, or W '' ₁ and W '' ₂ is to achieve a substituted or unsubstituted cyclic structure of C4-C10 aryl, by mutual coupling Have;

ii) when X ₃ and X ₄ are a cyclic structure of a substituted or unsubstituted C3-C10 heteroaryl by a mutual bond or a substituted or unsubstituted C2-C8 heterocycloalkyl,

X ₁ and X ₂ are each independently selected from the group consisting of hydrogen, a halogen atom, a substituted or unsubstituted C 1 -C 10 alkoxy, a substituted or unsubstituted C 1 -C 10 alkyl, a substituted or unsubstituted C 3 -C 8 cycloalkyl, a substituted or unsubstituted C 2 -C 8 hetero cycloalkyl, substituted or unsubstituted C4-C10 aryl, substituted or unsubstituted C4-C10 aryloxy, substituted or unsubstituted C4-C10 _{heteroaryl, -NO 2, -NX '1 X} ' 2, _{-NX '1 (CO (O)} X' 2), -NX '1 (C (O) NX' 1 X '2), -CO (O) X' 1, -C (O) NX '1 X' _{2, -CN, -SO (O)} X '1, -SO (O) NX' 1 X '2, -NX' 1 (SO (O) X '2), or -CSNX' or ₁ X _'2, Or X ₁ and X ₂ may form a cyclic structure of substituted or unsubstituted C4-C10 cycloalkyl, substituted or unsubstituted C4-C10 aryl or C2-C10 heteroaryl by mutual bonding,

Wherein X _'1 and X' ₂ each is independently hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C4-C10 aryl, substituted or unsubstituted C4-C10 aryloxy and _{(CX '' 1 X ''} 2) m'-C4-C10 aryl, or a substituted or unsubstituted _{NX '' 1 X '' 2} , where - a substituted or unsubstituted C4-C8 heteroaryl group, a substituted or unsubstituted X '' ₁ and X '' ₂ each independently is hydrogen or C1-C3 alkyl, or X '' ₁ and X '' ₂ is to achieve a substituted or unsubstituted cyclic structure of C4-C10 aryl, by mutual coupling Have;

In the substituents is hydroxy, halogen atom, -NO _2, C2-C8 cycloalkyl substituted by C1-C20 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C20 alkoxy, C1-C10 alkoxycarbonyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C8 heterocycloalkyl, C4-C10 aryl, C4-C10 aryl substituted with halogen, C4-C10 aryloxy C4-C10 heteroaryl, - (CQ ₁ Q ₂ ) _{m "} -C ₁ -C10 alkoxycarbonyl, - CQ ₁ Q ₂ ) _{m "} -C 4 -C 10 aryl, - (CQ ₁ Q ₂ ) _m" -C 4 -C 10 aryloxy, - (CQ ₁ Q ₂ ) _{m " CQ 1 Q 2) m ''} -C4-C10 _{heterocycloalkyl, - (CQ 1 Q 2)} m '' -NQ 3 Q 4, - (CQ 1 Q 2) m '' -OQ 3, -CO (O _{) Q 3, -CONQ 3 Q 4} , -NQ 3 Q 4, -NQ 3 (C (O) Q 4), -SO (O) Q 3, -SO (O) NQ 3 Q 4, -NQ 3 ( _{SO (O) Q 4),} -CSNQ 3 Q 4, _{-NQ 5 (CO (O) Q} 6), -NQ 5 (C (O) NQ 5 Q 6), -C (O) NQ 5 Q 6, -CN, compound "A" one of the formula (I) when -CH ₂ a, or a cyclic structure, or a C2-C10 ring structure heteroaryl of C4-C10 aryl or by a -A, or more than one substituent when the compound is "a" in the formula (1) in mutual engagement ;

Wherein Q ₁ and Q ₂ are independently hydrogen or C ₁ -C 3 alkyl,

Q ₃ and Q ₄ are each independently hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 4 -C 10 aryl, substituted or unsubstituted C 4 -C 10 aryloxy, substituted (CQ ' ₃ Q' ₄ ) _{m '' - C} 4 -C 10 aryl, substituted or unsubstituted - (CQ ' ₃ Q' ₄ ) _{m '''} - substituted or unsubstituted C 1 -C 8 heteroaryl, C4-C10 aryloxy, or -CO (O) Q _'3, substituted or unsubstituted NQ' Q _{3 '4,} Or Q ₃ and Q ₄ may form a cyclic structure of a substituted or unsubstituted C4-C10 heterocycloalkyl or a substituted or unsubstituted C4-C10 heteroaryl ring by mutual bonding, wherein Q ' ₃ and Q' _And Q ' ₃ and Q ' ₄ may form a cyclic structure of substituted or unsubstituted C4-C10 aryl by mutual bonding, wherein the substituent is selected from the group consisting of hydroxy, halogen, C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, C1-C10 alkoxycarbonyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C10heteroaryl; < / RTI >

Q ₅ and Q ₆ are Substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C4-C10 aryl, substituted or unsubstituted C4-C10 aryloxy, substituted or unsubstituted C1- Substituted or unsubstituted - (CQ ' ₅ Q' ₆ ) m '''- C 4 -C 10 aryl or substituted or unsubstituted NQ' ₅ Q ' ₆ , wherein Q' ₅ and Q ' ₆ are each independently Or Q ' ₅ and Q ' ₆ may be taken together to form a cyclic structure of substituted or unsubstituted C4-C10 aryl, wherein the substituent is selected from the group consisting of hydroxy, halogen, C1- , C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, C1-C10 alkoxycarbonyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C4-C10 aryl and C2-C10 heteroaryl At least one selected from the group consisting of;

m ', m' ', and m' '' are each independently a natural number of 1 to 4; And

The hetero atom is at least one selected from N, O and S.

Unless otherwise specified hereinafter, the compound of formula (I) as the active ingredient of the therapeutic agent may be combined with a pharmaceutically acceptable salt, hydrate, solvate, prodrug, tautomer, enantiomer or pharmacological , All of which are to be construed as being included within the scope of the present invention. For convenience of explanation, the compound of the formula (1) may be simply abbreviated herein.

The compound of the formula (1) according to the present invention has a novel structure which is not known in the prior art. As can be seen from the following experimental examples, the compound of the formula (1) according to the present invention is excellent in the treatment and prevention of metabolic diseases .

Specifically, the compound of formula (1) according to the present invention induces NAD (P) H: quinone oxidoreductase (NQO1) as an oxidoreductase to increase the ratio of NAD + / NADH in vivo to increase the ratio of AMP / ATP . The increase of AMP in these cells activates AMPK, which acts as an energy gauge, and promotes fat metabolism by PGC1a expression, which activates energy metabolism in mitochondria, to supplement deficient ATP energy. In addition, increased NAD ⁺ is used as a cofactor of glucose and lipid metabolism enzymes in the body to promote metabolism. CADPR produced by degradation of NAD ⁺ releases Ca ²⁺ from the endoplasmic reticulum (ER) Synergistic activation of the action of the in vivo motion mimetic effect can be obtained.

The terms used herein are briefly described.

The term " pharmaceutically acceptable salt " means a formulation of a compound that does not cause serious irritation to the organism to which the compound is administered and does not impair the biological activity and properties of the compound.

The terms "hydrate", "solvate", "prodrug", "tautomer", "enantiomer or pharmaceutically acceptable diastereomer" have the same meaning as above.

The above-mentioned "pharmaceutically acceptable salt" means an acid which forms a non-toxic acid addition salt containing a pharmaceutically acceptable anion such as inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, Organic carboxylic acids such as acetic acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid and salicinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p- Sulfonic acids such as sulfonic acids and the like. For example, pharmaceutically acceptable carboxylic acid salts include metal salts or alkaline earth metal salts formed with lithium, sodium, potassium, calcium, magnesium and the like, amino acid salts such as lysine, arginine and guanidine, dicyclohexylamine, N Organic salts such as methyl-D-glucamine, tris (hydroxymethyl) methylamine, diethanolamine, choline and triethylamine, and the like. The compound of formula (1) according to the present invention may be converted into its salt by a conventional method.

The term " hydrate " refers to a compound of the present invention comprising a stoichiometric or non-stoichiometric amount of water combined by non-covalent intermolecular forces Or a salt thereof.

The term " solvate " means a compound of the present invention or a salt thereof, comprising a stoichiometric or non-stoichiometric amount of a solvent bound by noncovalent intermolecular forces. Preferred solvents therefor are volatile, non-toxic, and / or solvents suitable for administration to humans.

The term " prodrug " refers to a substance that is transformed into a parent drug in vivo. Prodrugs are often used in some cases because they are easier to administer than parent drugs. For example, they may achieve viability by oral administration, whereas parent drugs may not. Prodrugs may also have improved solubility in pharmaceutical compositions over the parent drug. For example, a prodrug is an ester that facilitates the passage of a cell membrane, which is hydrolyzed to a carboxylic acid that is active by metabolism in a cell whose water solubility is once beneficial, Drug "). ≪ / RTI > Another example of a prodrug may be a short peptide (polyamino acid) that is attached to an acid group that is converted by metabolism so that the peptide reveals its active site.

The term " tautomer " is a type of structural isomer that has the same chemical or molecular formula but has a different configuration of constituent atoms, such as a keto-eno structure, Is changed.

The term " enantiomer or pharmaceutically acceptable diastereomer " refers to an isomer that has the same chemical or molecular formula but is formed as a result of a change in the spatial arrangement of atoms in a molecule. The term " enantiomer "Quot; and " diastereomer " are stereoisomers which are not in mirror image relationship, such as trans form and cis form, and are defined as pharmaceutically acceptable diastereomers in the present invention. All of these isomers and mixtures thereof are also included within the scope of the present invention.

The term " alkyl " means an aliphatic hydrocarbon group. In the present invention, the term "alkyl" refers to a "saturated alkyl" meaning that it does not contain any alkene or alkyne moieties and an "unsaturated alkyl" meaning that the alkyl includes at least one alkene or alkyne moiety. Quot; and " saturated alkyl ", which is used in the concept that includes no alkene or alkyne moiety in detail. The alkyl may include branched, straight, or cyclic, and may also include structural isomers, for example, in the case of C3 alkyl, may mean propyl, isopropyl.

The term " alkene " means a group in which at least two carbon atoms are composed of at least one carbon-carbon double bond, and " alkyne " means that at least two carbon atoms are composed of at least one carbon- Group.

The term " heterocycloalky " refers to a substituent wherein the ring carbon is replaced by oxygen, nitrogen, sulfur, or the like.

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

The term " heteroaryl " means an aromatic group containing at least one heterocyclic ring.

Examples of the aryl or heteroaryl include, but are not limited to, phenyl, furan, pyran, pyridyl, pyrimidyl, triazyl and the like.

The term " halogen " refers to elements belonging to group 17 of the periodic table, in particular fluorine, chlorine, bromine, iodine.

The term " aryloxy " means a group bonded to any one of carbon and oxygen constituting an aromatic substituent. For example, when oxygen is bonded to a phenyl group, -OC ₆ H ₅ , -C ₆ H ₄ -O- As shown in FIG.

Other terms may be construed as meaning commonly understood in the field to which the present invention belongs.

In a preferred example according to the present invention,

The compound of the formula (1) may be a compound represented by the following formula (2).

(2)

(2)

Wherein R ₁ , R ₂ , and R ₃ are each independently hydrogen, C 1 -C 10 alkyl, C 4 -C 10 aryl, or - (CQ ₁ Q ₂ ) _{m "} , -C4-C10 aryl;

Wherein Q ₁ and Q ₂ are independently hydrogen or C ₁ -C 3 alkyl;

m " are each independently a natural number of 1 to 2;

X ₂ and X ₃ are each independently N, O or S, and

X ₁ and X ₄ are the same as defined in claim 1.

는 단일결합 또는 결합이 형성되지 않을 수 있음을 의미하며,

는 단일 결합 또는 이중결합을 의미한다.In the above formula

Quot; means that a single bond or bond may not be formed,

Quot; means a single bond or a double bond.

Specifically,

The compound of the formula (2) may be a compound represented by the following formula (2-1).

(2-1)

(2-1)

In another example according to the present invention,

X ₂ and X ₃ are each independently -NW ' ₁ W' ₂ , Or _{-NW '1 (CO (O)} W' 2) and;

Wherein W ' ₁ and W' ₂ each independently may be hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 4 -C 10 aryl.

More specifically,

The compound of formula (1) may be represented by the following formula (3).

(3)

(3)

In another example according to the present invention,

The compound of formula (1) may be represented by the following formula (4).

(4)

(4)

Wherein R ₄ , R ₅ and R ₆ are each independently selected from the group consisting of hydrogen, a halogen element, substituted or unsubstituted C 1 -C 9 alkyl, substituted or unsubstituted C 1 -C 20 alkoxy, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted Substituted or unsubstituted C -C 10 heterocycloalkyl, substituted or unsubstituted C 4 -C 10 aryl, substituted or unsubstituted C 4 -C 10 aryloxy, substituted or unsubstituted C 1 -C 10 heteroaryl, substituted or unsubstituted - (CQ ₁ Q ₂ ) _{m ''} -C4-C10 aryl, substituted or unsubstituted _{- (CQ 1 Q 2) m} '' -C4-C10 aryloxy, substituted or unsubstituted _{- (CQ 1 Q 2) m} '' -C4-C10 heteroaryl, Substituted or unsubstituted - (CQ ₁ Q ₂ ) _{m "} -C 4 -C 10 heterocycloalkyl, substituted or unsubstituted - (CQ ₁ Q ₂ ) _m" -NQ ₃ Q ₄ , substituted or unsubstituted - _{1 Q 2) m '' -OQ} 3, -CO (O) Q 3, -CONQ 3 Q 4, -NQ 3 Q 4, -NQ 3 (C (O) Q 4), -SO (O) Q 3 _{, -SO (O) NQ 3 Q} 4, -NQ 3 (SO (O) Q 4), or -CSNQ ₃ Q _4, when the compound is "B" of the formula (4) -CH ₂ B, or formula Is -B when the compound of formula (1) is " B ";

Q ₁ , Q ₂ , Q ₃ and Q ₄ are as defined in claim 1;

Wherein the substituent is selected from the group consisting of hydroxy, halogen, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, C1-C10 alkoxycarbonyl, C3-C8 cycloalkyl, C2-C8 heterocyclo Alkyl, C4-C10 aryl, and C2-C10 heteroaryl;

m " are each independently a natural number of 1 to 2;

는 단일결합 또는 이중결합이고,

는 단일결합 또는 결합이 형성되지 않을 수 있음을 의미하며,

Is a single bond or a double bond,

Quot; means that a single bond or bond may not be formed,

X ₁ and X ₂ are as defined in claim 1;

X ₃ , X ₄ and X ₅ are each independently N (H), O, S or C;

Specifically,

The compound of formula (4) may be a compound selected from the group consisting of compounds represented by the following formulas (4-1) and (4-2).

Wherein R ₄ , R ₅ , and R ₆ are as defined in claim 4;

X ₁ and X ₂ are each independently selected from the group consisting of hydrogen, a halogen atom, a substituted or unsubstituted C 1 -C 10 alkoxy, a substituted or unsubstituted C 1 -C 10 alkyl, a substituted or unsubstituted C 3 -C 8 cycloalkyl, a substituted or unsubstituted C 2 -C 8 hetero Cycloalkyl, substituted or unsubstituted C4-C10 aryl, or substituted or unsubstituted C4-C10 aryloxy, or X ₁ and X ₂ are each independently a substituted or unsubstituted C4-C10 aryl or a substituted or unsubstituted C2 Lt; RTI ID = 0.0 > C10heteroaryl < / RTI >

Wherein the substituent is selected from the group consisting of hydroxy, halogen, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, C1-C10 alkoxycarbonyl, C3-C8 cycloalkyl, C2-C8 heterocyclo Alkyl, C4-C10 aryl, C4-C10 aryloxy, or C2-C10 heteroaryl;

The hetero atom is at least one selected from N, O and S.

Or more specifically,

The compound of formula (4) may be a compound selected from the group consisting of compounds represented by the following formulas (4-3) and (4-4).

In this formula,

R < ₅ > is as defined in claim 4;

X ₁ and X ₂ are each independently selected from the group consisting of hydrogen, a halogen atom, a substituted or unsubstituted C 1 -C 10 alkoxy, a substituted or unsubstituted C 1 -C 10 alkyl, a substituted or unsubstituted C 3 -C 8 cycloalkyl, a substituted or unsubstituted C 2 -C 8 hetero Cycloalkyl, substituted or unsubstituted C4-C10 aryl, or substituted or unsubstituted C4-C10 aryloxy, or X ₁ and X ₂ are each independently a substituted or unsubstituted C4-C10 aryl or a substituted or unsubstituted C2 Lt; RTI ID = 0.0 > C10heteroaryl < / RTI >

Wherein the substituent is selected from the group consisting of hydroxy, halogen, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, C1-C10 alkoxycarbonyl, C3-C8 cycloalkyl, C2-C8 heterocyclo Alkyl, C4-C10 aryl, C4-C10 aryloxy, or C2-C10 heteroaryl;

The hetero atom is at least one selected from N, O and S.

Or more specifically,

The compound of formula (4) may be a compound selected from the group consisting of compounds represented by the following formulas (4-5) to (4-7).

In this formula,

R ₅ and R ₆ are as defined in claim 4;

X ₁ and X ₂ are each independently selected from the group consisting of hydrogen, a halogen atom, a substituted or unsubstituted C 1 -C 10 alkoxy, a substituted or unsubstituted C 1 -C 10 alkyl, a substituted or unsubstituted C 3 -C 8 cycloalkyl, a substituted or unsubstituted C 2 -C 8 hetero Cycloalkyl, substituted or unsubstituted C4-C10 aryl, or substituted or unsubstituted C4-C10 aryloxy, or X ₁ and X ₂ are each independently a substituted or unsubstituted C4-C10 aryl or a substituted or unsubstituted C2 Lt; RTI ID = 0.0 > C10heteroaryl < / RTI >

Wherein the substituent is selected from the group consisting of hydroxy, halogen, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, C1-C10 alkoxycarbonyl, C3-C8 cycloalkyl, C2-C8 heterocyclo Alkyl, C4-C10 aryl, C4-C10 aryloxy, or C2-C10 heteroaryl;

The hetero atom is at least one selected from N, O and S.

Specifically,

In the above formulas (4-1) to (4-7), R ₄ , R ₅ and R ₆ each independently may be hydrogen, C 2 -C 10 alkyl, or C 4 -C 10 aryl,

X ₁ and X ₂ are each independently selected from the group consisting of hydrogen, a halogen atom, a substituted or unsubstituted C 1 -C 10 alkyl, a substituted or unsubstituted C 2 -C 8 heterocycloalkyl, a substituted or unsubstituted C 4 -C 10 aryl, C10 aryloxy, or X ₁ and X ₂ may achieve a substituted or unsubstituted cyclic structure of the C5-C6 aryl, or a substituted or unsubstituted C3-C4-heteroaryl by a mutual bond,

Here, the substituent is a halogen atom, C1-C10 alkyl; And

The heteroatom may be one or more selected from N, O, and S.

More specifically,

In the formulas (4-1) to (4-7), X ₁ and X ₂ are each independently selected from the group consisting of hydrogen, a halogen atom, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 2 -C 8 heterocycloalkyl, or unsubstituted C4-C10 aryl, substituted or unsubstituted C4-C10 aryloxy, or X ₁ and X ₂ is a substituted or unsubstituted C6 aryl, or a substituted or unsubstituted imidazole (imidazole) by cross coupling, or a substituted or Can form an annular structure of an unsubstituted thiazole,

Here, the substituent is a halogen atom, C1-C10 alkyl; And

The heteroatom may be one or more selected from N, O, and S.

More specifically,

The compound of formula (4-1) or (4-2) may be one of the compounds represented by the following formulas.

The compound of formula (4-3) or (4-4) may be one of the compounds represented below.

The compound of formula (4-5), formula (4-6) or formula (4-7) may be one of the compounds represented below.

Or more specifically,

The compound of formula (4) may be a compound selected from the group consisting of compounds represented by the following formulas (4-8) to (4-10).

In this formula,

R ₄ , R ₅ and R ₆ are as defined in claim 4;

R ₁₁ and R ₁₂ are each independently selected from the group consisting of hydrogen, a halogen atom, a substituted or unsubstituted C 1 -C 20 alkoxy, a substituted or unsubstituted C 1 -C 20 alkyl, a substituted or unsubstituted C 4 -C 10 aryl, a substituted or unsubstituted C 4 -C 10 aryloxy , substituted or unsubstituted C2-C10 _{heteroaryl, -NO 2, -NQ 3 Q 4} , _{-NQ 5 (CO (O) Q} 6), -NQ 5 (C (O) NQ 5 Q 6), -CO (O) Q 3, -C (O) NQ 5 Q 6, -CN, -SO ( _{O) Q 3, -SO (O} ) NQ 3 Q 4, -NQ 3 (SO (O) Q 4), or -CSNQ ₃ Q _4, or is R ₁₁ and R ₁₂ is a substituted or unsubstituted ring by a mutual bond A cyclic structure of C4-C10 aryl, or a substituted or unsubstituted C2-C10 heteroaryl ring structure,

Where Q ₃ through Q ₆ are Substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C4-C10 aryl, substituted or unsubstituted C4-C10 aryloxy, substituted or unsubstituted C1- Substituted or unsubstituted - (CQ ' ₅ Q' ₆ ) m '''- C 4 -C 10 aryl or substituted or unsubstituted NQ' ₅ Q ' ₆ , wherein Q' ₅ and Q ' ₆ are each independently Or Q ' ₅ and Q ' ₆ may form a cyclic structure of substituted or unsubstituted C4-C10 aryl by mutual bonding, m "'each independently represents a natural number of 1 to 4 ego;

Wherein the substituent is selected from the group consisting of hydroxy, halogen, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, C1-C10 alkoxycarbonyl, C3-C8 cycloalkyl, C2-C8 heterocyclo Alkyl, C4-C10 aryl, and C2-C10 heteroaryl;

X ₁ , X ₂ , X ₆ and X ₇ are each independently C (H) or N;

The hetero atom is at least one selected from N, O and S.

More specifically,

R _4, R ₅ and R ₆ are each independently substituted or unsubstituted C 1 -C 3 alkyl, or substituted or unsubstituted - (CH ₂ ) -C 6 aryl;

Here, the substituent may be at least one selected from the group consisting of hydroxy, halogen element, C1-C3 alkyl, and C1-C3 alkoxy.

As a specific example,

The compound of formula (4-8), formula (4-9), or formula (4-10) may be one of the compounds represented below.

In another example according to the present invention,

The compound of the formula (1) may be a compound represented by the following formula (5).

(5)

(5)

In this formula,

X ₁ and X ₂ may be a cyclic structure of substituted or unsubstituted C4-C10 aryl,

X ₃ and X ₄ are selected from NH, O and S;

R ₇ , R ₈ , R ₉ and R ₁₀ are each independently hydrogen or substituted or unsubstituted C 1 -C 10 alkyl;

Here, the substituent is a halogen atom, C1-C10 alkyl; And

n is 0, 1 or 2;

Specifically, the compound of formula (5) may be a compound represented by the following formula.

The present invention also provides a process for preparing a compound of formula (1).

Those of ordinary skill in the art ("those skilled in the art") will be able to prepare the compounds by various methods based on the structure of formula (1), and all of these methods are within the scope of the present invention . That is, within the scope of the present invention, it is possible to prepare the compound of the formula (1) by arbitrarily combining various synthetic methods described in the present specification or disclosed in the prior art. Therefore, the scope of the present invention is not limited thereto.

As an example, the compound of formula (1)

(A) reacting a compound of the formula (6) and a compound of the formula (7) in the presence of a base;

(B) Step (A) a compound with HNO after the introduction of -NO ₂ in the resulting compound by reacting ₃ in acid conditions in step A), -NO ₂ through the reducing reaction generating on the -NH ₂ ;

(C) subjecting the compound produced in step (B) to a cyclization reaction under acidic conditions; And

(D) selectively reducing the compound produced in step (C), and then producing an end product through an oxidation reaction;

. ≪ / RTI >

In this formula,

X ₁ and X ₂ are as defined in claim 1;

R < ₅ > is hydrogen, C1-C10 alkyl, or C4-C10 aryl;

Y ₁ is hydrogen, methyl, ethyl, propyl, or benzyl;

R ₁₃ is -OH, OCH ₃ , -OC ₂ H _5, -OC ₃ H ₇ , -OCH ₂ C ₆ H ₅ or -NH ₂ ;

Z is a halogen element.

In the present invention, the basic condition can be formed using triethylamine, diisopropylethylamine, 1,10-phenanthroline, or pyridine, but is not limited thereto.

In the present invention, acid conditions can be formed using nitric acid, sulfuric acid, acetic acid, or acetic anhydride, but are not limited thereto.

In the present invention, the reduction reaction can proceed through, for example, a hydrogenation reaction, and the hydrogenation reaction is a process of reacting hydrogen with a metal catalyst such as Pd / C or Zn, Will be omitted below. Alternatively, the reduction reaction may be performed under conditions such as K ₂ CO _3, Na ₂ S ₂ O _4, cHBr, and the like, but is not limited thereto.

In the present invention, the oxidation reaction may be performed under conditions such as, for example, IBX, but is not limited thereto.

In the present invention, " optional " means that the corresponding reaction may or may not be included depending on the case.

The present invention, as another example,

A process for preparing a compound of formula (1)

(A ₁ ) reacting a compound of the following formula (6) with a compound of the following formula (7) in a base condition;

(B ₁ ) reacting the compound produced in step (A ₁ ) with Lawesson's reagent;

(C ₁ ) subjecting the compound produced in step (B ₁ ) to a cyclization reaction under basic conditions; And

(E ₁ ) a step of reducing the compound produced in step (D ₁ ) and then producing an end product through an oxidation reaction;

≪ RTI ID = 0.0 > *. ≪ / RTI >

In this formula,

X ₁ and X ₂ are as defined in claim 1;

R < ₅ > is hydrogen, C1-C10 alkyl, or C4-C10 aryl;

Y ₁ is hydrogen, methyl, ethyl, propyl, or benzyl;

R ₁₃ is -OH, OCH ₃ , -OC ₂ H _5, -OC ₃ H ₇ , -OCH ₂ C ₆ H ₅ or -NH ₂ ; And

Z is a halogen element.

의 구조식을 가진다. The Lawesson's reagent is generally known in the art as a reagent for introducing sulfur into a compound,

.

Specifically,

The step (A ₁ ) may comprise the following steps (A ' ₁ ) to (A' ₃ ).

(A ' ₁ ) After introducing -NO ₂ by reacting the compound of formula (6) with HNO ₃ under acidic conditions, -NO ₂ -NH ₂ ;

(A ' ₂ ) halogenating the compound produced in step (A' ₁ ) to give a halogenated compound; And

(A ' ₃ ) reacting the compound formed in step (A' ₂ ) with the compound of formula (7) in a base condition;

The compound of formula (6) and the compound of formula (7) are as defined in claim 11.

The present invention, as another example,

A process for preparing a compound of formula (1)

(A ₂ ) introducing -NO ₂ by reacting a compound of the following formula (6) with HNO ₃ under acidic conditions;

(B ₂ ) reacting the compound produced in step (A ₂ ) with a compound of the following formula (7) in a base condition;

(C ₂ ) The compound produced in the step (B ₂ ) is reduced through -NR ₂ -NH ₂ ;

(D ₂ ) cyclizing the compound produced in step (C ₂ ) under an acidic condition, and then performing a reduction reaction; And

(E ₂ ) reacting the compound produced in step (D ₂ ) with X ₁ H or X ₂ H (X ₁ or X ₂ is as defined in claim 1) to produce the final product;

. ≪ / RTI >

In this formula,

R < ₅ > is hydrogen, C1-C10 alkyl, or C4-C10 aryl;

Y ₁ is hydrogen, methyl, ethyl, propyl, or benzyl;

R ₁₃ is -OH, OCH ₃ , -OC ₂ H _5, -OC ₃ H ₇ , -OCH ₂ C ₆ H ₅ or -NH ₂ ;

Z is a halogen element.

The present invention, as another example,

A process for preparing a compound of formula (1)

(A ₃ ) reacting a compound of the following formula (6) with HNO ₃ under acidic conditions to introduce -NO ₂ , followed by halogenation;

(B ₃ ) The compound produced in step (A ₃ ) is reduced to -NO ₂ -NH ₂ ;

(C ₃ ) subjecting the compound produced in step (B ₃ ) to a cyclization reaction under acid conditions; And

(D ₃ ) The compound produced in step (C ₃ ) is reacted with a substituted or unsubstituted phenylboric acid (wherein the substituent is a halogen element or a C ₁ -C 5 alkyl), R ₁ Z 'or R ₃ Z And then reacting in an acidic condition;

By oxidizing the compound produced from (E ₃₎ step (D ₃₎ to produce an end product;

Comprising the steps of:

In this formula,

R ₁ and R ₃ are each independently hydrogen, C 1 -C 10 alkyl, C 4 -C 10 aryl, or - (CQ ₁ Q ₂ ) _{m "C} 4 -C 10 aryl wherein Q ₁ and Q ₂ are independently hydrogen or C1 And m " are each independently a natural number of 1 to 2;

R < ₅ > is hydrogen, C1-C10 alkyl, or C4-C10 aryl;

Y ₁ is hydrogen, methyl, ethyl, propyl, or benzyl;

R ₁₃ is -OH, OCH ₃ , -OC ₂ H _5, -OC ₃ H ₇ , -OCH ₂ C ₆ H ₅ or -NH ₂ ;

Z and Z 'are each independently a halogen atom.

Specifically,

Between the step (E ₃₎ and step (F _3), may comprise the steps of (E _'3).

(E ' ₃ ) reacting the compound produced in step (E ₃ ) with X ₁ M or X ₂ M (X ₁ and X ₂ are as defined in claim 1 and M is Na or K).

The present invention, as another example,

A process for preparing a compound of formula (1)

(A ₄ ) introducing -NO ₂ by reacting a compound of the following formula (6) with HNO ₃ under acidic conditions;

(B ₄ ) reacting the compound formed in step (A ₄ ) with camphorsulfonic acid after reacting in a hydrogen atmosphere,

(C ₄ ) a step of subjecting the compound produced in the step (B ₄ ) to a reduction reaction followed by an oxidation reaction to produce an end product;

. ≪ / RTI >

In this formula,

X ₁ and X ₂ are as defined in claim 1;

Y ₁ is hydrogen, methyl, ethyl, propyl, or benzyl; And

R ₁₃ is -OH, OCH ₃ , -OC ₂ H _5, -OC ₃ H ₇ , -OCH ₂ C ₆ H ₅ or -NH ₂ .

The present invention, as another example,

A process for preparing a compound of formula (1)

(A ₅ ) reacting a compound of the formula (6) and a compound of the formula (7)

(B ₅ ) reacting the compound produced in step (A ₅ ) with BF ₃ .Et ₂ O and then reacting with NH ₂ OH; And

(C ₅₎ step of the step and cyclization in acid and the resulting compound in the conditions (B _5), the oxidation reaction;

. ≪ / RTI >

In this formula,

R < ₅ > is hydrogen, C1-C10 alkyl, or C4-C10 aryl;

Y ₁ is hydrogen, methyl, ethyl, propyl, or benzyl;

R ₁₃ is -OH, OCH ₃ , -OC ₂ H _5, -OC ₃ H ₇ , -OCH ₂ C ₆ H ₅ or -NH ₂ ; And

Z is a halogen element.

The BF ₃ and Et ₂ O may be in a coordinated state.

It said step (C ₅₎ is then specifically, after the cyclization in acid and the resulting compound conditions in step (B _5), introducing a hydroxy group is reacted with BBr ₃ may comprise an oxidation reaction .

The present invention, as another example,

(D ₅₎ introducing a -NO ₂ was reacted in the above step (C ₅₎ the acid compound and HNO ₃ generated in the conditions;

(E ₅₎ a -NO ₂ through a reduction reaction of the compound produced in the step (D ₅₎ -NH ₂ ; And

(F ₅ ) reacting the compound produced in step (E ₅ ) with MZ ₁ (provided that M is hydrogen or a divalent metal and Z ₁ is a halogen element) under acidic conditions to produce the final product;

≪ RTI ID = 0.0 > and / or < / RTI >

"One or more steps to be sequentially selected for" in the field, step (D _5), or step (D ₅₎ and Step (E _5), or step (D ₅₎ step (E ₅₎ and step (F ₅₎ is It can be selected.

The present invention, as another example,

A process for preparing a compound of formula (1)

(A ₆ ) reacting a compound of the following formula (6) with HNO ₃ in an acidic condition to introduce -NO ₂ and then reducing -NO ₂ -NH ₂ ;

(B ₆₎ and to the resulting compound in step (A ₆₎ reacting a compound of formula (7) in basic conditions;

(C ₆ ) cyclizing the compound produced in step (B ₆ ) under acidic conditions, followed by a reduction reaction;

(D ₆ ) The compound produced in step (C ₆ ) is reacted with HNO ₃ in the presence of acid to introduce -NO ₂ , followed by reduction of -NO ₂ -NH ₂ ;

(E ₆₎ and to the resulting compound in step (D ₆₎ reacting a compound of formula (7) in basic conditions; And

(F ₆₎ steps to produce an end product of the compound produced from (E ₆₎ to the oxidation reaction and then an oxidation reaction and a reductive cyclization;

. ≪ / RTI >

In this formula,

R < ₅ > is hydrogen, C1-C10 alkyl, or C4-C10 aryl;

Y ₁ is hydrogen, methyl, ethyl, propyl, or benzyl;

R ₁₃ is -OH, OCH ₃ , -OC ₂ H _5, -OC ₃ H ₇ , -OCH ₂ C ₆ H ₅ or -NH ₂ ; And

Z is a halogen element.

Said step (F ₆₎ is specifically, for the compound produced in step (E ₆₎ CAN: and then proceed with the oxidation reaction over a Cerium Ammonium Nitrate (cerium ammonium nitrate), and the reaction, and the reduction and cyclization Followed by an oxidation reaction to introduce a carbonyl group.

The present invention, as another example,

A process for preparing the compound of formula (1)

(A ₇ ) reacting a compound of the following formula (6) with C ₆ H ₅ CH ₂ Z ₂ (Z ₂ is a halogen element) under basic conditions;

(B ₇ ) reacting the compound produced in step A ₇ ) with NH ₂ OH; And

(C ₇ ) reducing the compound produced in step B ₇ ), subjecting the resulting compound to a cyclization reaction, and carrying out an oxidation reaction;

. ≪ / RTI >

In this formula,

Y ₁ is hydrogen, methyl, ethyl, propyl, or benzyl; And

R ₁₃ is -OH, OCH ₃ , -OC ₂ H _5, -OC ₃ H ₇ , -OCH ₂ C ₆ H ₅ or -NH ₂ .

As another example of the present invention,

A process for preparing a compound of formula (1)

(A ₈ ) A compound of the following formula (6) is reacted with HNO ₃ in an acidic condition to introduce -NO ₂ , followed by reducing the -NO ₂ -NH ₂ ;

(B ₈ ) reacting the compound produced in step (A ₈ ) with CAN (Cerium Ammonium Nitrate)

(C ₈ ) reacting the compound formed in step (B ₈ ) with a compound of the following formula (7) in a base condition; And

(D ₈₎ phase (C ₈₎ after the cyclization of the compound produced in step to produce a final product by oxidation;

. ≪ / RTI >

In this formula,

X ₁ and X ₂ are as defined in claim 1;

R < ₅ > is hydrogen, C1-C10 alkyl, or C4-C10 aryl;

Y ₁ is hydrogen, methyl, ethyl, propyl, or benzyl;

R ₁₃ is -OH, OCH ₃ , -OC ₂ H _5, -OC ₃ H ₇ , -OCH ₂ C ₆ H ₅ or -NH ₂ ; And

Z is a halogen element.

The present invention also provides a process for preparing a compound of formula (4) as a specific example of formula (1).

It will be appreciated by those skilled in the art (" those skilled in the art ") that the preparation of compounds by various methods based on the structure of formula (4) will be possible, . That is, within the scope of the present invention, it is possible to prepare the compound of the formula (4) by arbitrarily combining various synthetic methods described in the present specification or disclosed in the prior art. Therefore, the scope of the present invention is not limited thereto.

As an example, the compound of formula (4)

(A ₉ ) reacting a compound of formula (8) or a compound of formula (8-1) with R ₄ Z ", R ₅ Z", or R ₆ Z "; And

After reduction of the compound produced in (B ₉₎ step (A ₉₎ oxidizing;

. ≪ / RTI >

In this formula,

R ₄ to R ₆ , R ₁₁ , R ₁₂ and X ₁ to X ₅ are as defined in claim 4;

X ₆ and X ₇ are each independently C (H) or N;

Y ₂ is hydrogen, methyl, ethyl, propyl, or benzyl; And

Z "is a halogen atom, an alkoxy group, a sulfate group, a substituted or unsubstituted sulfonate group, wherein the substituent is C4-C10 aryl substituted with an alkyl group.

Specifically,

Wherein X _3, X _4, and X ₅ may be N (H), respectively.

The above-

(C ₉₎ reacting in Step (B ₉₎ a compound with a HNO ₃ acid conditions generated in;

May be further included,

The above-

(D ₉ ) The compound produced in step (C ₉ ) is reduced through -NR ₂ -NH ₂ ;

May be further included,

The above-

(E ₉₎ The compound produced in step _{(D 9) HZ 3 (Z} 3 is a halogen atom) and reacting;

May be further included.

As another example of the present invention,

A process for preparing a compound of formula (4)

(A ₁₀ ) reducing and oxidizing a compound of the formula (8) or a compound of the formula (8-1) below; And

(B ₁₀ ) reacting the compound produced in step (A ₁₀ ) with R ₄ Z ", R ₅ Z", or R ₆ Z ";

. ≪ / RTI >

In this formula,

R ₄ to R ₆ , R ₁₁ , R ₁₂ and X ₁ to X ₅ are as defined in claim 4;

X ₆ and X ₇ are each independently C (H) or N;

Y ₂ is hydrogen, methyl, ethyl, propyl, or benzyl; And

Z "is a halogen atom, an alkoxy group, a sulfate group, a substituted or unsubstituted sulfonate group, wherein the substituent is C4-C10 aryl substituted with an alkyl group.

Specifically,

Wherein X _3, X _4, and X ₅ may be N (H), respectively.

The present invention, as another example,

A process for preparing a compound of formula (4)

(헤테로시클로알케닐)를 반응시키는 단계; 및(A ₁₁ ) a compound of the formula (8) or a compound of the formula (8-1)

(Heterocycloalkenyl); And

After reduction of the compound produced in (B ₁₁₎ step (A ₁₁₎ oxidizing;

. ≪ / RTI >

In this formula,

R ₁₁ , R ₁₂ and X ₁ to X ₅ are as defined in claim 4;

X ₆ and X ₇ are each independently C (H) or N;

Y ₂ is hydrogen, methyl, ethyl, propyl, or benzyl.

Specifically,

Wherein X _3, X _4, and X ₅ may be N (H), respectively.

In the present invention,

The compound of formula (8) or the compound of formula (8-1)

(A ₁₂ ) reacting a compound of the formula (9-1) or a compound of the formula (9-2) with (Y ₄ ) ₂ O, or Y ₄ Z ''';

(B ₁₂₎ reacting a compound from the acid conditions of HNO ₃ generated in step (A _12);

The step of reducing the compound produced in (C ₁₂₎ step (B _12);

(D ₁₂ ) reacting the compound produced in step (C ₁₂ ) with Y ₅ Z '''; And

(E ₁₂₎ and then reducing the compound produced in step (D _12), the step of the ring closure reaction;

. ≪ / RTI >

Gt;

R ₁₁ , R ₁₂ and X ₁ , and X ₂ are as defined in claim 4;

X ₆ and X ₇ are each independently C (H) or N;

Y ₂ and Y ₅ are each independently hydrogen, methyl, ethyl, propyl, or benzyl;

Y ₃ is -NH ₂ , -NH ₃ Z ₄ (Z ₄ is a halogen element) or -NO ₂ ; And

Y ₄ is R'COO-, wherein R 'is a substituted or unsubstituted C 1 -C 9 alkyl, a substituted or unsubstituted - (CH ₂ ) _m -C 4 -C 10 aryl, a substituted or unsubstituted - (CH ₂ ) _m- C10 aryloxy, or substituted or unsubstituted C4-C10 aryl wherein the substituent is selected from the group consisting of hydroxy, halogen, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C10 alkoxycarbonyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C4-C10 aryl, and C5-C10 heteroaryl;

m is a natural number of 1 to 4;

Z " 'is a halogen element.

As another example of the present invention,

A process for preparing a compound of formula (4)

(A ₁₃ ) A compound of the following formula (9-1) or a compound of the formula (9-2) is reacted with R ₄ Z ", R ₅ Z", or R ₆ Z "step; And

( _B13 ) cyclizing the compound produced in step ( _A13 ) to form a triazole;

( _C13 ) reducing and oxidizing the compound produced in step ( _B13 );

. ≪ / RTI >

In this formula,

R ₄ to R ₆ , R ₁₁ , R ₁₂ and X ₁ , and X ₂ are as defined in claim 4;

X ₆ and X ₇ are each independently C (H) or N;

Y ₂ is hydrogen, methyl, ethyl, propyl, or benzyl;

Y ₃ is -NH ₂ , - H ₃ Z ''' Or -NO _2, and; And

Z " is -NH ₂ .

After completion of the reaction according to the present invention, separation of a typical mixture can be carried out by conventional post treatment methods such as tube chromatography, recrystallization, HPLC and the like.

The details are described in the following embodiments and experimental examples.

The present invention also provides a pharmaceutical composition comprising (a) a pharmacologically effective amount of a compound of formula (1) above, a pharmaceutically acceptable salt, hydrate, solvate, tautomer, enantiomer and / or pharmaceutically acceptable diastereomer ; And (b) a pharmaceutically acceptable carrier, diluent, or excipient, or a combination thereof. The present invention also provides a pharmaceutical composition for the treatment and prevention of metabolic diseases.

The term " pharmaceutical composition " means a mixture of compounds of the present invention and other chemical components such as diluents or carriers. The pharmaceutical composition facilitates administration of the compound into the organism. Various techniques exist for administering the compounds, including, but not limited to, oral, injectable, aerosol, parenteral, and topical administration. The pharmaceutical composition may be obtained by reacting acid compounds such as hydrochloric acid, bromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.

The term " therapeutically effective amount " means that the amount of the compound administered will alleviate or reduce to some extent one or more symptoms of the disorder being treated, delay the onset of clinical markers or symptoms of the disease in need of prevention, Quot; means the amount of active ingredient that is effective to effect. Thus, a pharmacologically effective amount can be any amount effective to (1) reverse the rate of progression of the disease, (2) to some extent inhibit further progression of the disease, and / or (3) (Preferably, eliminating) the degree of the effect. A pharmacologically effective amount can be determined empirically by testing compounds in known in vivo and in vitro model systems for diseases in need of treatment.

The term " carrier " is defined as a compound that facilitates the addition of a compound into a cell or tissue. For example, dimethylsulfoxide (DMSO) is a commonly used carrier that facilitates the introduction of many organic compounds into cells or tissues of an organism.

The term " diluent " is defined as a compound that not only stabilizes the biologically active form of the compound of interest, but also dilutes in water to which the compound is dissolved. Salts dissolved in buffer solutions are used as diluents in the art. A commonly used buffer solution is phosphate buffered saline, since it mimics the salt state of the human solution. Since buffer salts can control the pH of the solution at low concentrations, buffer diluents rarely modify the biological activity of the compounds.

The compounds used herein can be administered to a human patient either as such, or as a pharmaceutical composition mixed with other active ingredients, such as in a combination therapy, or with suitable carriers or excipients. A description of the formulation and administration of the compounds in this application can be found in " Remington ' s Pharmaceutical Sciences, " Mack Publishing Co., Easton, PA, 18th edition,

The pharmaceutical compositions of the present invention can be prepared in a known manner, for example by means of conventional mixing, dissolving, granulating, sugar-making, pulverizing, emulsifying, encapsulating, trapping or lyophilizing processes .

The pharmaceutical compositions for use according to the invention thus comprise one or more pharmacologically acceptable excipients which comprise excipients or auxiliaries which facilitate the treatment of the active compounds with pharmaceutically usable formulations Or may be prepared by a conventional method using a carrier. Suitable formulations depend on the route of administration chosen. Any of the known techniques, carriers and excipients may be used as appropriate and as understood in the art, for example, Remingston's Pharmaceutical Sciences, supra. In the present invention, the compound of formula (1) may be formulated into injectable preparations and oral preparations according to the purpose.

For injection, the components of the present invention may be formulated as a liquid solution, preferably a pharmacologically compatible buffer such as a Hank solution, Ringer solution, or physiological saline solution. For mucosal permeation administration, a non-permeabilizing agent suitable for the barrier to be passed is used in the formulation. Such impermeabilizers are generally known in the art.

For oral administration, the compounds can be formulated readily by combining the pharmacologically acceptable carriers known in the art with the active compounds. Such carriers enable the compounds of the present invention to be formulated into tablets, pills, powders, granules, sugars, capsules, liquids, gels, syrups, slurries, suspensions and the like. Preferably, capsules, tablets, pills, powders and granules are possible, and in particular, capsules and tablets are useful. Tablets and pills are preferably prepared as preservative. Pharmaceutical preparations for oral use can be prepared by mixing one or two or more compounds of the present invention with one or more excipients, optionally milling such mixture, and if necessary passing the appropriate adjuvant, then treating the mixture of granules Tablets or sugar cores can be obtained. Suitable excipients include fillers such as lactose, sucrose, mannitol, or sorbitol; Corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone PVP), and the like. If necessary, a carrier such as a crosslinking polyvinylpyrrolidone, a starch or a disintegrating agent such as alginic acid or sodium alginate and a lubricant such as magnesium stearate, a binder and the like may be added.

Pharmaceutical preparations which can be used orally may include soft seal capsules made of gelatin and a plasticizer such as glycol or sorbitol, as well as push-fix capsules made of gelatin. Capsules for push-fixing may also contain active ingredients, such as a filler such as lactose, a binder such as starch, and / or a mixture with talc or a lubricant such as magnesium stearate. In soft capsules, the active compounds may be dissolved or dispersed in suitable solvents such as fatty acids, liquid paraffin, or liquid polyethylene glycols. A stabilizer may also be included. All formulations for oral administration should be in amounts suitable for such administration.

The compounds may be formulated for parenteral administration by injection, for example, by large pill injection or continuous infusion. The injectable formulation may be presented in unit dosage form, for example, as an ampoule or a multi-dose container with an added preservative. The compositions may take such forms as suspensions, solutions, emulsions on oily or liquid vehicles, and may also contain components for the formulation, such as suspending, stabilizing and / or dispersing agents.

The active ingredient may also be in the form of a powder for constitution with a suitable vehicle, such as sterile pyrogen-free water, before use.

The compounds may also be formulated into rectal administration compositions such as suppositories or rectal enema containing, for example, conventional suppository bases such as cocoa butter or other glycerides.

Pharmaceutical compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an amount effective to achieve its intended purpose. More specifically, a therapeutically effective amount refers to an amount of a compound that is effective to prolong the survival of an object to be treated or to prevent, alleviate, or alleviate symptoms of the disease. The determination of a therapeutically effective amount is well within the ability of those skilled in the art, particularly in light of the detailed disclosure provided herein.

When formulated in unit dose form, the compound of formula (1) as an active ingredient is preferably contained in a unit dose of about 0.1 to 1,000 mg. The dosage of the compound of formula (1) will depend upon the physician's prescription depending on factors such as the patient's weight, age and the particular nature and severity of the disease. However, the dosage required for adult therapy is usually in the range of about 1 to 1000 mg per day depending on the frequency and intensity of administration. A total dosage of about 1 to 500 mg per day, separated by a single dose when administered intramuscularly or intravenously to an adult, may be sufficient, but in some patients a higher daily dose may be desirable.

In the present invention, the objective disease may be obesity, fatty liver, arteriosclerosis, stroke, myocardial infarction, cardiovascular disease, ischemic disease, diabetes, hyperlipidemia, hypertension, retinopathy or renal failure, Huntington's disease or inflammation, Or a Huntington's disease, but is not limited thereto.

The present invention also relates to a pharmaceutical composition comprising a compound of formula (1) according to claim 1, a pharmaceutically acceptable salt, hydrate, solvate, tautomer, enantiomer or pharmaceutically acceptable diastereomer thereof in a pharmacologically effective amount As an effective amount, to treat or prevent a metabolic disease. The term " treatment " as used herein refers to stopping or delaying the progression of a disease when used in an object having an onset symptom. The term " prevention " Delay.

As described above, the novel 1,2-naphthoquinone derivative according to the present invention can enhance the NAD (P) + / NAD (P) H ratio through in vivo NQO1 activity, (AMPK activation of energy consumption, activation of mitochondrial energy metabolism, PGC1a expression, etc.) and long-term calorie restriction and induction of genetic changes during exercise, resulting in mitochondrial biosynthesis due to mitochondrial activation, Since the improvement of the system brings about the exercise mimetic treatment effect which increases the physical activity of the body, the medicines using it as an active ingredient can be usefully used for treating or preventing metabolic diseases.

1 is a graph showing weight gain, weight change, and intake of obesity rat ( ob / ob ) for the compound according to Example 12 of Experimental Example 3 and for the compound according to Example 13 and the control.
2 is a graph showing weight gain, weight change, and intake of obesity rat ( ob / ob ) for the compound according to Example 24 of Experimental Example 4 and a control group;
3 is a graph showing weight gain, weight change, and intake of diabetic rats ( db / db ) for the compounds according to Examples 24, 30, and 31 of Experimental Example 5 and a control group;
FIG. 4 is a graph showing the glucose level in the fasting condition of diabetic rats ( db / db ) for the compounds according to Examples 24, 30, and 31 of Experimental Example 6 and the control group; And
FIG. 5 is a graph showing the glycated hemoglobin (Hb1Ac) of a diabetic rat ( db / db ) relative to the compound according to Examples 24, 30, and 31 of Experimental Example 6 and a control group.

The present invention will be described in detail with reference to the following examples and experimental examples, but the scope of the present invention is not limited thereto. In the following, the examples describe methods for synthesizing an intermediate for making a final compound and for synthesizing a final compound using the compounds in the examples.

Example 1 [Synthesis of Compound 1]

1) 1-> 2

Compound 1 (4-amino-2,3-dimethylphenol, 5.0 g, 36.45 mmol) was dissolved in methylene chloride (180 ml), followed by addition of triethylamine (15.4 ml, 109.34 mmol) and stirring for 10 minutes. Slowly add isobutyryl chloride (8.4 ml, 80.19 mmol) to the reaction and stir for 1 hour. The reaction is quenched with aqueous NaHCO ₃ solution and extracted with MC. The organic layer is washed three times with aqueous NaHCO ₃ solution. The organic layer is dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The precipitated solid was filtered off by EA and hexane and dried to obtain compound 2 (8.84 g, 88%).

^{1 H NMR (300 MHz, CDCl} 3) δ 7.41-7.38 (d, J = 8.7 Hz, 1H), 7.07 (s, NH, 1H), 6.83-6.80 (d, J = 8.7 Hz, 1H), 2.87- (M, 1H), 2.10 (s, 3H), 2.06 (s, 3H), 1.35 - 1.33 (d, J = 6.9 Hz, 6H), 1.27 - J = 6.9 Hz, 6H)

2) 2-> 3

Compound 2 (2.5 g, 9.01 mmol) is dissolved in Ac ₂ O (45 ml) and stirred in an ice bath for 20 minutes. Add HNO ₃ (0.51 ml, 10.82 mmol) slowly to the reaction. After quenching with methanol, concentrate under reduced pressure. The concentrated reaction product is dissolved in EA and washed several times with aqueous NaHCO ₃ solution. The EA layer is dried with Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The concentrated reaction product is recrystallized with EA and hexane, and the precipitated solid is filtered and dried. compound 3 ( 1.3 g, 45%).

^{1 H NMR (300 MHz, CDCl} 3) δ 8.48 (s, NH, 1H), 7.63 (s, 1H), 2.90-2.85 (m, 1H), 2.68-2.63 (m, 1H), 2.18 (s, 6H ), 1.37-1.35 (d, J = 6.9 Hz, 6H), 1.31-1.28 (d, J = 6.9 Hz, 6H)

3) 3-> 4-> 5

Compound 3 (1.25 g, 3.88 mmol) is dissolved in MeOH (38 mL) and then 5% Pd / C (0.05 g, 0.05 mol%) is added to the round bottom flask. After purge the inside of the flask with H ₂ balloon, react overnight at room temperature. After the reaction, the mixture is filtered using celite and then concentrated under reduced pressure. The reaction is dissolved in AcOH (80 mL) and refluxed for 2 h. Remove the AcOH as much as possible by decompression and dissolve in EA. After washing 3 times with NaHCO ₃ aqueous solution, the EA layer is dried with Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude compound 5 ( 1.0 g, 98%) is obtained.

4) 5-> 6-> 7

Crude Compound 5 (1.0 g, 3.8 mmol) was dissolved in MeOH (32 ml), K ₂ CO ₃ (0.59 g, 4.27 mmol) was added thereto, and the mixture was stirred for 12 hours. Concentrate the reaction mixture under reduced pressure, add 1N HCl, and extract three times with EA. The EA layer is dried with Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The concentrated compound (0.08 g) is dissolved in DMF (5 mL), and the temperature is lowered to 0 캜. 47% IBX (0.28 g, 0.47 mmol) was added thereto and stirred for 3 hours. After quenching with NaHCO ₃ aqueous solution, it is extracted with EA. The EA layer was separated, treated with Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound 7 ( 40 mg, 50%).

Ex.1

^{1 H NMR (300 MHz, CDCl} 3) δ 11.04 (br, 1H), 3.23-3.14 (m, 1H), 2.28 (s, 3H), 1.94 (s, 3H), 1.41-1.39 (d, J = 6.9 Hz, 6H)

Example 2 [Synthesis of Compound 2]

1) 1-> 2

Compound 1 (4-amino-2,3-dimethylphenol, 5.0 g, 36.45 mmol) was dissolved in methylene chloride (180 ml), followed by addition of triethylamine (15.4 ml, 109.34 mmol) and stirring for 10 minutes. Slowly add isobutyryl chloride (8.4 ml, 80.19 mmol) to the reaction and stir for 1 hour. The reaction is quenched with aqueous NaHCO ₃ solution and extracted with MC. The organic layer is washed three times with aqueous NaHCO ₃ solution. The organic layer is dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The precipitated solid was filtered off by EA and hexane and dried to obtain compound 2 (8.84 g, 88%).

^{1 H NMR (300 MHz, CDCl} 3) δ 7.41-7.38 (d, J = 8.7 Hz, 1H), 7.07 (s, NH, 1H), 6.83-6.80 (d, J = 8.7 Hz, 1H), 2.87- (M, 1H), 2.10 (s, 3H), 2.06 (s, 3H), 1.35 - 1.33 (d, J = 6.9 Hz, 6H), 1.27 - J = 6.9 Hz, 6H)

2) 2-> 3

Dissolve Compound 2 (2.5 g, 9.01 mmol) in toluene (90 ml), add Lawesson's reagent (2.55 g, 6.31 mmol) and reflux for 12 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound 3 ( 930 mg, 35%).

^{1 H NMR (300 MHz, CDCl} 3) δ 8.91 (s, NH, 1H), 7.00-6.97 (d, J = 8.4 Hz, 1H), 6.83-6.80 (d, J = 8.4 Hz, 1H), 3.05- (S, 3H), 2.02 (s, 3H), 1.35-1. 30 (m, 12H)

3) 3-> 4

Compound 3 (930 mg, 3.17 mmol), FeCl ₃ (50 mg, 0.317 mmol) and Na ₂ S ₂ O ₈ (750 mg, 3.17 mmol) were placed in a round bottom flask, ₂ to purge. Add DMSO (9 mL) to the round bottom flask and add pyridine (0.51 mL, 6.34 mmol). The reaction is heated to 40 占 폚 for 12 hours. The reaction is quenched with aqueous NaCl solution and extracted with EA. Wash the EA layer 3 times with NaCl solution. The EA layer is dried with Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Dissolve the concentrated reaction in MC and short silica filter and wash with MC. The filtrate was concentrated under reduced pressure to obtain compound 4 ( 0.71 g, 77%, yellowish oil).

^{1 H NMR (300 MHz, CDCl} 3) δ 7.41 (s, 1H), 3.48-3.31 (m, 1H), 2.95-2.81 (m, 1H), 2.69 (s, 3H), 2.19 (s, 3H), 1.43-1.41 (d, J = 6.9 Hz, 6H), 1.40-1.38 (d, J = 6.9 Hz, 6H)

4) 4-> 5

Compound 4 (0.71 g, 2.4 mmol) was dissolved in MeOH (20 ml), K ₂ CO ₃ (0.37 g, 2.68 mmol) was added thereto and stirred for 1 hour. Concentrate the reaction mixture under reduced pressure, add 1N HCl, and extract three times with EA. The EA layer is dried with Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The concentrated compound is purified by short silica filter to obtain compound 5 ( 0.52 g, 96%).

5) 5-> 6

Compound 5 (0.51 g, 2.3 mmol) is dissolved in DMF (46 mL), and the temperature is lowered to 0 ° C. 47% IBX (1.65 g, 2.77 mmol) was added thereto, followed by stirring for 15 minutes. After quenching with NaHCO ₃ aqueous solution, it is extracted with EA. The EA layer was separated, treated with Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give compound 6 ( 0.42 g, 78%).

Ex.2

^{1 H NMR (300 MHz, CDCl} 3) δ 3.40-3.31 (m, 1H), 2.42 (s, 3H), 2.03 (s, 3H), 1.45-1.43 (d, J = 6.9 Hz, 6H)

Example 3 [Synthesis of Compound 3]

1) 1-> 2

Compound 1 (4-amino-2,3-dimethylphenol, 3.2 g, 23.33 mmol) is dissolved in methylene chloride (125 ml), followed by addition of triethylamine (9.8 ml, 69.98 mmol) and stirring for 10 minutes. Add propionyl chloride (4.5 ml, 51.32 mmol) slowly to the reaction mixture and stir for 2 hours. The reaction is quenched with aqueous NaHCO ₃ solution and extracted with MC. The organic layer is washed three times with aqueous NaHCO ₃ solution. The organic layer is dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The precipitated solid was filtered off by EA and hexane and dried to obtain compound 2 (5.49 g, 94%).

^{1 H NMR (300 MHz, CDCl} 3) δ 7.44-7.42 (d, J = 8.4 Hz, 1H), 6.98 (s, NH, 1H), 6.87-6.85 (d, J = 8.4 Hz, 1H), 2.66- 2H), 2.14 (s, 3H), 2.08 (s, 3H), 1.31-1. 23 (m, 6H)

2) 2-> 3

Dissolve Compound 2 (2.0 g, 8.02 mmol) in toluene (80 ml), add Lawesson's reagent (1.95 g, 4.81 mmol) and reflux for 12 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound 3 ( 1.76 g, 83%).

^{1 H NMR (300 MHz, CDCl} 3) δ 8.55 (s, NH, 1H), 7.14-7.11 (m, 1H), 6.92-6.90 (m, 1H), 2.90-2.83 (m, 2H), 2.68-2.60 (m, 2H), 2.12 (s, 3H), 2.09 (s, 3H), 1.45-1.

3) 3-> 4-> 5

Compound 3 (1.7 g, 6.41 mmol), FeCl ₃ (0.1 g, 0.641 mmol) and Na ₂ S ₂ O ₈ (1.53 g, 6.41 mmol) were placed in a round bottom flask, ₂ to purge. DMSO (18 mL) is added to the round bottom flask and then pyridine (1.0 mL, 12.81 mmol) is added. The reaction is heated to 40 占 폚 for 12 hours. After the reaction product is quenched with an aqueous solution of NaCl, the precipitated solid is filtered and dissolved with EA. The reaction product is purified by short silica filter to obtain crude compound 4 . Compound 4 was dissolved in MeOH (50 ml), K ₂ CO ₃ (0.97 g, 7.04 mmol) was added thereto, and the mixture was stirred for 1 hour. Concentrate the reaction mixture under reduced pressure, add 1N HCl, and extract three times with EA. The EA layer is dried with Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The concentrated compound is purified by short silica filter to obtain compound 5 ( 0.18 g, 14%).

^{1 H NMR (300 MHz, CDCl} 3) δ 7.08 (s, 1H), 3.14-3.06 (m, 2H), 2.68 (s, 3H), 2.29 (s, 3H), 1.44-1.39 (m, 3H)

4) 5-> 6

Compound 5 (0.18 g, 0.87 mmol) is dissolved in DMF (17 mL), and the temperature is lowered to 0 ° C. 47% IBX (0.62 g, 1.04 mmol) was added and the mixture was stirred for 30 minutes. After quenching with NaHCO ₃ aqueous solution, it is extracted with EA. The EA layer is separated, treated with Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography gives compound 6 ( 19 mg, 10%).

Ex.3

^{1 H NMR (300 MHz, CDCl} 3) δ 3.14-3.06 (q, J = 7.5 Hz, 2H), 2.42 (s, 3H), 2.02 (s, 3H), 1.47-1.42 (t, J = 7.5 Hz, 3H)

Example 4 [Synthesis of compound 4]

1) 1step:

Dry to Compound 1 (1.5 g, 9.732 mmol). Dichloromethane (48 ml, 0.2 M) was added and Et3N (6.8 ml, 48.66 mmol) was added under an ice bath. Then, isobutyryl chloride (2.258 ml, 21.41 mmol) is added and stirred for 18 hours. H2O is added, neutralized and then extracted with EA. The separated organic layer is dried over MgSO4, filtered, distilled under reduced pressure, and subjected to silica gel column to obtain the target compound. 1.3 g (45%)

2) Step 2:

To compound 2 (1.3 g, 4.392 mmol) is added EtOH (22 ml, 0.2 M). Add 260 mg of Pd / C, degass, and replace with H2. The reaction is carried out at room temperature for 4 hours. After filtration through celite, the desired compound is obtained by distillation under reduced pressure.

3) Step 3:

AcOH (55 ml, 0.08 M) was added to Compound 3 , and the mixture was refluxed with stirring for 1.5 hours. After distillation under reduced pressure, the product is subjected to silica gel column chromatography to obtain the target compound. Brown oil: 1 g (2,3 step yield: 92%)

4) 4 steps:

CHCl (6 ml, 0.6M) was added to Compound 4 (900 mg, 3.659 mmol), followed by stirring at 60 ° C for 1 hour. The reaction was cooled and aq. After neutralization with NaHCO3, extract with EA. Crude product 600 mg (93%, brown oil)

5) 5 step:

THF / H2O (1: 1, 4.6 ml) and pyrrolidine (93 ul, 1.135 mmol) were added to Compound 5 (40 mg, 0.227 mmol), degassed and replaced with O ₂ and stirred at room temperature for 7 days. The reaction product is extracted with EA, and the EA layer is dried with MgSO4, filtered, and distilled under reduced pressure. The concentrated reaction product separates the target compound through Prep TLC. Violet solid: 6 mg (10%)

Ex.4

2H), 3.51-3.35 (m, 2H), 3.09-3.02 (m, 1H), 1.97-1.81 (m, IH) m, 4H), 1.26 (d, J = 7.2 Hz, 6H)

Example 5 [Synthesis of Compound 5]

The Compound 1 (3 g, 20.24 mmol ) dissolved in CH ₃ CN (100 ml). Add K ₂ CO ₃ (8.4 g, 60.72 mmol) and stir at room temperature for 10 minutes. Benzyl bromide (2.5 ml, 21.25 mmol) was added, and the mixture was refluxed for 1.5 hours. The reaction solution is cooled to room temperature and the solid is filtered. Add EA and distilled water, then wash several times. The separated organic layer is dried with MgSO ₄ and filtered. The filtrate is concentrated under reduced pressure and purified by silica gel column chromatography.

Colorless oil 4.5 g (93%)

Compound 2 (4.47 g, 18.76 mmol) is dissolved in Ac ₂ O (62 ml, 0.3 M) in an ice bath. AcOH (3 ml) and HNO3 (90%) (1.1 ml, 22.51 mmol) were added, and the mixture was stirred at room temperature for 1 hour. The reaction solution is poured into ice and neutralized by adding a saturated aqueous NaHCO ₃ solution. EA and NaHCO ₃ saturated aqueous solution are added and extracted several times. The separated organic layer was dried over MgSO ₄ and filtered. The filtrate is concentrated under reduced pressure and purified by silica gel column chromatography.

Orange oil 3.62 g (68%) (Compound 3 + Compound 4 )

Compound 3 + Compound 4 (0.45 g, 1.59 mmol) is dissolved in Acetone (13 ml) and distilled water (3.2 ml) and then heated to 45 ° C. NH ₄ Cl (0.51 g, 9.53 mmol) and Fe (0.86 g, 15.9 mmol) were added and refluxed for 2 hours. NaCl saturated aqueous solution and EA are added, and the separated organic layer is dried with MgSO ₄ and filtered. The filtrate is concentrated under reduced pressure and then separated by silica gel column chromatography.

Brown oil 0.36 g (90%) (Compound 5 + Compound 6 )

In an ice bath, dissolve Compound 6 (1.4 g, 5.52 mmol) in MC (55 ml) and add Et ₃ N (2.3 ml, 16.6 mmol). Isobutyryl chloride (0.7 ml, 6.63 mmol) was slowly added at the same temperature and stirred for 1 hour. Add distilled water and MC and extract several times. The separated organic layer is dried with MgSO ₄ and filtered. The filtrate is concentrated under reduced pressure and purified by recrystallization.

Ivory solid 1.25 g (70%)

In an ice bath, dissolve Compound 7 (0.5 g, 1.55 mmol) in Ac ₂ O (30 ml) and add HNO ₃ (90%) (93 μl, 1.86 mmol). After stirring for 1 hour, the reaction solution is poured into ice. NaHCO ₃ saturated aqueous solution is added to neutralize and extracted several times with MC and saturated aqueous NaHCO ₃ solution. The separated organic layer was dried over MgSO ₄ and filtered. The filtrate is concentrated under reduced pressure and purified by recrystallization.

Ivory solid 0.42 g (74%)

Compound 8 (0.4 g, 1.09 mmol) is dissolved in EA (11 ml) and MeOH (5.5 ml). 5% Pd / C (0.23 g, 10 mol%) was added and stirred under a hydrogen atmosphere for 14.5 hours. The reaction solution is filtered through a Celite filter (MC, THF) and concentrated under reduced pressure.

Ivory solid 0.26 g (98%)

Compound 9 (0.2 g, 0.81 mmol) is dissolved in AcOH (16 ml, 0.05 M) and refluxed for 30 minutes. The reaction solution is poured into ice, neutralized with a saturated aqueous solution of NaHCO ₃ , and extracted several times with MC. The separated organic layer is dried with MgSO ₄ and filtered. The filtrate is concentrated under reduced pressure and purified by recrystallization.

White solid 0.13 g (70%)

Compound 10 (50 mg, 0.22 mmol) was dissolved in DMF (4.4 ml) and then IBX (0.16 g, 0.26 mmol) was added. After reacting at room temperature for 1 hour, NaHCO ₃ saturated aqueous solution and EA are added and extracted several times. The separated organic layer is dried with MgSO ₄ and filtered. The filtrate is concentrated under reduced pressure and purified by silica gel column chromatography.

Dark-red solid 38 mg (70%)

Ex.5

^{1 H NMR (300 MHz, DMSO} ) δ 3.05-2.98 (m, 1H), 2.54 (br, s, 2H), 2.18 (br, s, 2H), 1.64-1.62 (m, 4H), 1.24 (d, J = 7.0 Hz, 6H)

Example 6 [Synthesis of Compound 6]

1) 1-> 2

Compound 1 (4-amino-3-methylphenol, 5.0 g, 40.60 mmol) is dissolved in methylene chloride (200 ml), followed by addition of triethylamine (17.1 ml, 121.79 mmol) and stirring for 10 minutes. Slowly add isobutyryl chloride (9.4 ml, 89.31 mmol) to the reaction mixture and stir for 1 hour. The reaction is quenched with aqueous NaHCO ₃ solution and extracted with MC. The organic layer is washed three times with aqueous NaHCO ₃ solution. The organic layer is dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The precipitated solid was filtered off by EA and hexane and dried to obtain compound 2 (9.75 g, 91%).

^{1 H NMR (300 MHz, CDCl} 3) δ 7.82-7.79 (m, 1H), 6.96 (s, NH, 1H), 6.91-6.90 (m, 2H), 2.81-2.76 (m, 1H), 2.59-2.54 (m, 1 H), 2.23 (s, 3H), 1.31 - 1.27 (m, 12H)

2) 2-> 3

Compound 2 (4.0 g, 15.19 mmol) was dissolved in Ac ₂ O (75 ml) and stirred in an ice bath for 20 minutes. Add HNO ₃ (0.86 ml, 18.23 mmol) slowly to the reaction. After quenching with methanol, concentrate under reduced pressure. The concentrated reaction product is dissolved in EA and washed several times with aqueous NaHCO3 solution. The EA layer is dried with Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The concentrated reaction product is recrystallized with EA and hexane, and the precipitated solid is filtered and dried. compound 3 ( 1.63 g, 35%).

^{1 H NMR (300 MHz, CDCl} 3) δ 8.30 (s, NH, 1H), 7.64 (s, 1H), 7.27 (s, 1H), 2.84-2.80 (m, 1H), 2.67-2.62 (m, 1H ), 2.30 (s, 3H), 1.33-1.27 (m, 12H)

3) 3-> 4-> 5

Add Compound 3 (1.6 g, 5.19 mmol) to a round bottom flask in MeOH (50 mL) and add 5% Pd / C (0.55 g, 0.05 mol%). After purge the inside of the flask with H ₂ balloon, react overnight at room temperature. After the reaction, the mixture is filtered using celite and then concentrated under reduced pressure. The reaction is dissolved in AcOH (50 mL) and refluxed for 2 h. Remove the AcOH as much as possible by decompression and dissolve in EA. After washing 3 times with NaHCO ₃ aqueous solution, the EA layer is dried with Na ₂ SO ₄ , filtered and concentrated under reduced pressure. compound 5 ( 1.4 g, 99%).

^{1 H NMR (300 MHz, CDCl} 3) δ 10.16 (br, NH, 1H), 7.03 (s, 1H), 6.68 (s, 1H), 3.17-3.12 (m, 1H), 2.90-2.80 (m, 1H ), 2.46 (s, 3H), 1.44-1. 34 (m, 12H)

4) 5-> 6

Compound 4 (1.4 g, 5.38 mmol) was dissolved in MeOH (40 ml), K ₂ CO ₃ (0.82 g, 5.92 mmol) was added thereto, and the mixture was stirred for 1 hour. Concentrate the reaction mixture under reduced pressure, add 1N HCl, and extract three times with EA. The EA layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give compound 6 ( 1.1 g, 99%).

5) 6-> 7

Compound 6 (1.1 g, 5.78 mmol) is dissolved in DMF (110 mL), and the temperature is lowered to 0 ° C. 47% IBX (4.1 g, 6.94 mmol) was added thereto, followed by stirring for 12 hours. After quenching with NaHCO ₃ aqueous solution, it is extracted with EA. The EA layer was separated, treated with Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound 7 ( 0.25 g, 25%).

Ex.6

^{1 H NMR (300 MHz, CDCl} 3) δ 11.30 (br, 1H), 5.91 (s, 1H), 3.21-3.16 (m, 1H), 2.29 (s, 3H), 1.41-1.39 (d, J = 6.9 Hz, 6H)

Example 7 [Synthesis of Compound 7]

1) 1-> 2

Compound 1 (4-amino-3-methylphenol, 5.0 g, 40.60 mmol) is dissolved in methylene chloride (200 ml), followed by addition of triethylamine (17.1 ml, 121.79 mmol) and stirring for 10 minutes. Slowly add isobutyryl chloride (9.4 ml, 89.31 mmol) to the reaction mixture and stir for 1 hour. The reaction is quenched with aqueous NaHCO ₃ solution and extracted with MC. The organic layer is washed three times with aqueous NaHCO ₃ solution. The organic layer is dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The precipitated solid was filtered off by EA and hexane and dried to obtain compound 2 (9.75 g, 91%).

^{1 H NMR (300 MHz, CDCl} 3) δ 7.82-7.79 (m, 1H), 6.96 (s, NH, 1H), 6.91-6.90 (m, 2H), 2.81-2.76 (m, 1H), 2.59-2.54 (m, 1 H), 2.23 (s, 3H), 1.31 - 1.27 (m, 12H)

2) 2-> 3

Dissolve Compound 2 (3.0 g, 11.39 mmol) in toluene (110 ml), add Lawesson's reagent (2.76 g, 6.84 mmol) and reflux for 12 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound 3 ( 2.74 g, 86%).

^{1 H NMR (300 MHz, CDCl} 3) δ 8.79 (s, NH, 1H), 7.27-7.22 (m, 1H), 6.93-6.87 (m, 2H), 3.04-3.00 (m, 1H), 2.85-2.76 (m, 1 H), 2.14 (s, 3 H), 1.34 - 1.29 (m, 12 H)

3) 3-> 4

Compound 3 (2.8 g, 10.02 mmol), FeCl ₃ (0.17 g, 1.02 mmol) and Na ₂ S ₂ O ₈ (2.39 g, 10.02 mmol) were placed in a round bottom flask and vacuumed to give a vacuum state. N ₂ to purge. DMSO (30 mL) is added to the round bottom flask, and then pyridine (1.62 mL, 20.04 mmol) is added. The reaction is heated to 40 占 폚 for 12 hours. The reaction is quenched with aqueous NaCl solution and extracted with EA. Wash the EA layer 3 times with NaCl solution. The EA layer is dried with Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Dissolve the concentrated reaction in MC and short silica filter and wash with MC. The filtrate is concentrated under reduced pressure to obtain compound 4 ( 1.35 g, 49%).

^{1 H NMR (300 MHz, CDCl} 3) δ 7.40 (s, 1H), 6.96 (s, 1H), 3.48-3.39 (m, 1H), 2.87-2.78 (m, 1H), 2.71 (s, 3H), 1.47-1.44 (m, 6H), 1.34-1.32 (m, 6H)

4) 4-> 5

Compound 4 (1.35 g, 4.87 mmol) was dissolved in MeOH (40 ml), K ₂ CO ₃ (0.74 g, 5.35 mmol) was added thereto and stirred for 1 hour. Concentrate the reaction mixture under reduced pressure, add 1N HCl, and extract three times with EA. The EA layer is dried with Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The concentrated compound is purified by short silica filter to obtain compound 5 ( 0.94 g, 94%).

5) 5-> 6

Compound 5 (0.94 g, 4.54 mmol) is dissolved in DMF (90 mL), and the temperature is lowered to 0 캜. 47% IBX (3.24 g, 5.44 mmol) was added thereto, followed by stirring for 12 hours. After quenching with NaHCO ₃ aqueous solution, it is extracted with EA. The EA layer is separated, treated with Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography gives compound 6 ( 0.25 g, 25%).

Ex.7

^{1 H NMR (300 MHz, CDCl} 3) δ 6.25 (s, 1H), 3.42-3.33 (m, 1H), 2.44 (s, 3H), 1.47-1.45 (d, J = 6.6 Hz, 6H)

* Examples 8 and 9 [Synthesis of compounds 8 and 9]

1) 1step:

To compound 1 (5 g, 29.735 mmol) is added CH ₂ Cl ₂ (50 ml, 0.6 M) and Br ₂ is dropwise at -15 ° C. React at that temperature for 30 minutes. Aq. NaHCO ₃ is added to neutralize and extracted with MC. The separated organic layer is dried with MgSO ₄ , filtered, distilled under reduced pressure and short-columned to obtain the target compound. 3.2 g (43%)

2) 2 step

NH ₄ Cl (650 mg, 12.144 mmol) was added to Compound 2 (500 mg, 2.024 mmol), and acetone and water were added. After Fe was added, the mixture was refluxed with stirring for 2 hours. The reaction was filtered through celite, and then Aq. NaHCO ₃ is added to neutralize and extracted with MC. The separated organic layer is dried with MgSO ₄ , filtered, distilled under reduced pressure and short-columned to obtain the target compound. 200 mg (46%)

3) 3 steps

Compound 6 (200 mg, 0.921 mmol) was added with 6 ml of AcOH and the mixture was refluxed for 15 hours. After vacuum distillation to remove some of the AcOH, aq. Add NaHCO ₃ and neutralize. EA is added thereto, and the mixture is extracted with distillation under reduced pressure, followed by recrystallization to obtain the target compound. Light orange solid: 81 mg (36%)

4) 4 step

Compound 4 (80 mg, 0.332 mmol), Phenyl boric acid and Pd (PPh ₃ ) ₄ are replaced with N ₂ after vaccum. THF and 2 M Na ₂ CO ₃ are added, and the mixture is refluxed for 17 hours. After completion of the reaction, Aq. NaHCO ₃ is added to neutralize and extracted with EA. The separated organic layer is dried over MgSO ₄ , filtered, and distilled under reduced pressure. (Compound 5: Compound 4 = 1: 1)

5) 5 step

CHBr (1.5 ml) was added to Compound 5 (60 mg, 0.268 mmol), and the mixture was stirred at 100 ° C for 5 hours. After completion of the reaction, Aq. NaHCO ₃ is added to neutralize and extracted with EA. The separated organic layer is dried over MgSO ₄ , filtered, and distilled under reduced pressure. (25 mg, 44%).

6) 6 step

Back into the Compound 6 DMF (1.1 ml) in (25 mg), put the 47% IBX 73 mg. After stirring at room temperature for 45 min, Aq. NaHCO ₃ is added to neutralize and extracted with EA. The separated organic layer is dried over MgSO ₄ , filtered through silica gel, distilled under reduced pressure, and then the desired compound is obtained by Prep TLC.

Ex.8 : 12 mg

_{1H NMR (300 MHz, CDCl 3} ) δ 6.63 (s, 1H), 2.59 (s, 3H)

Ex.9 : 6 mg

_{1H NMR (300 MHz, CDCl 3} ) δ 7.91-7.89 (m, 2H), 7.55-7.49 (m, 3H), 6.30 (s, 1H), 2.59 (s, 3H)

Examples 10 and 11 [Synthesis of compounds 10 and 11]

Add 4 N HCl (10 ml, 0.46 M) to compound 1 (1 g, 4.607 mmol) and add propionic acid (0.41 ml, 5.52 mmol). The reaction is refluxed with stirring for 1.5 hours. Aq. Add NaHCO ₃ to neutralize, then add EA to extract. The separated organic layer is dried over MgSO ₄ , filtered, distilled under reduced pressure, and the desired compound is obtained on a silica gel column. Solid: 921 mg (78%)

Compound 2 (200 mg, 0.784 mmol), Phenyl boric acid (143 mg, 1.176 mmol) and Pd (PPh ₃ ) ₄ (90 mg) are replaced with N ₂ after vaccum. Toluene (5.2 ml, 0.15 M) and 2 M Na ₂ CO ₃ (0.8 ml, 1 M) were added and the mixture was refluxed for 5 hours. After completion of the reaction, Aq. Add NaHCO ₃ and extract with EA. The separated organic layer is dried with MgSO ₄ , filtered, distilled under reduced pressure and short-columned to obtain the target compound. (oil, 198 mg, quantitative yield)

48% HBr (3.5 ml) was added to Compound 3-1 (170 mg, 0.17 mmol), and the mixture was stirred at 100 ° C for 7 hours. After completion of the reaction, Aq. NaHCO ₃ is added to neutralize and extracted with EA. The separated organic layer is dried over MgSO ₄ , filtered, and distilled under reduced pressure. (179 mg, quantitative yield)

DMF (3.8 ml) is added to Compound 4-1 (170 mg, 0.759 mmol) and 47% IBX (497 mg, 0.835 mmol) is added. After stirring at room temperature for 1 hour, Aq. NaHCO ₃ is added to neutralize and extracted with EA. The separated organic layer is dried over MgSO ₄ , filtered, and distilled under reduced pressure to obtain the desired compound in a short column. (41 mg, 21%).

Ex.10

_{1H NMR (300 MHz, CDCl 3} ) δ 10.39 (s, 1H), 7.94-7.91 (m, 2H), 7.51-7.47 (m, 3H), 6.31 (s, 1H), 2.92 (q, J = 7.5 Hz , 2H), 1.40 (t, J = 7.5 Hz, 3H)

Compound 2 (200 mg, 0.784 mmol), 4-fluorophenyl boric acid (164 mg, 1.17 mmol) and Pd (PPh ₃ ) ₄ (90 mg) are replaced with N ₂ after vaccum. Toluene (5.2 ml, 0.15 M) and 2 M Na ₂ CO ₃ (0.8 ml, 1 M) were added and the mixture was refluxed for 5 hours. After completion of the reaction, Aq. Add NaHCO ₃ and extract with EA. The separated organic layer is dried with MgSO ₄ , filtered, distilled under reduced pressure and short-columned to obtain the target compound. (White solid, 198 mg, 99%).

48% HBr (3.5 ml) was added to Compound 3-2 (183 mg, 0.678 mmol), and the mixture was stirred at 100 ° C for 7 hours. After completion of the reaction, Aq. NaHCO ₃ is added to neutralize and extracted with EA. The separated organic layer is dried over MgSO ₄ , filtered, and distilled under reduced pressure. (158 mg, 91%).

DMF (5.8 ml) is added to Compound 4-2 (151 mg, 0.589 mmol) and 47% IBX (386 mg, 0.648 mmol) is added. After stirring at room temperature for 1 hour, Aq. NaHCO ₃ is added to neutralize and extracted with EA. The separated organic layer is dried over MgSO ₄ , filtered, and distilled under reduced pressure to obtain the desired compound in a short column. (40 mg, 25%).

Ex.11

9.05 (s, 1H), 2.72 (q, J = 7.5 Hz, 2H), 7.33 (d, J = 9.0 Hz, 2H). 1H NMR (300 MHz, DMSO) , 2H), 1.23 (t, J = 7.5 Hz, 3H)

Example 12 [Synthesis of Compound 12]

1) 1step

DMF (12 ml, 0.1 M) was added to Compound 1 (307 mg, 1.204 mmol), K ₂ CO ₃ (500 mg, 3.612 mmol) was added and the mixture was stirred for 5 minutes. BnBr (247 mg, 1.445 mmol) was added and stirred at room temperature for 16 hours. H ₂ O is added and extracted with EA. The separated organic layer is dried over MgSO ₄ , filtered, and distilled under reduced pressure. (Ivory solid, 351 mg, 69%).

2) 2 step

48% HBr (4 ml, 0.2 M) was added to Compound 2 (350 mg, 1.014 mmol), and the mixture was stirred at 100 ° C for 24 hours. After completion of the reaction, Aq. NaHCO ₃ is added to neutralize and extracted with EA. The separated organic layer is dried over MgSO ₄ , filtered, distilled under reduced pressure, and recrystallized to obtain the target compound. (295 mg, 87%).

3) 3 steps

Compound 3 (200 mg, 0.604 mmol) and CuBr (104 mg, 0.725 mmol) in vacuo were placed in anhydrous DMF (3 ml, 0.2 M). Add NaOMe (1 ml) and react at 120 ° C for 3 hours. Add water and extract with EA. The separated organic layer is dried over MgSO ₄ , filtered, distilled under reduced pressure, and recrystallized to obtain the target compound. (61 mg, 36%).

4) 4 step

DMF (1 ml, 0.1 M) was added to Compound 4 (30 mg, 0.106 mmol), IBX (76 mg, 0.128 mmol) was added thereto, and the mixture was reacted at room temperature for 30 minutes. Aq. NaHCO ₃ is added to neutralize and extracted with EA. The separated organic layer is dried over MgSO ₄ , filtered, and distilled under reduced pressure to obtain the desired compound in a short column. (16 mg, 51%).

Ex.12

_{1H NMR (300 MHz, CDCl 3} ) δ 7.35-7.30 (m, 3H), 7.16-7.13 (m, 2H), 5.62 (s, 1H), 5.53 (s, 2H), 3.99 (s, 3H), 2.74 (q, J = 7.5 Hz, 2H), 1.30 (t, J = 7.5 Hz, 3H)

Example 13 [Synthesis of Compound 13]

1) 1-> 2

Compound 1 (1-chloro-2,5-dimethoxy-4-nitrobenzene, 3.0 g, 13.79 mmol) is dissolved in methylene chloride (140 ml), purged with N ₂ and stirred at 0 ° C for 10 minutes. Slowly add boron trichloride (1 M in MC, 14 ml, 14.00 mmol) to the reaction and stir for 1 hour. Quench the reaction mixture with ice and neutralize with Na ₂ SO ₃ to pH = 7. The reaction product is extracted with EA, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. compound 2 (2.83 g, 99%).

^{1 H NMR (300 MHz, CDCl} 3) δ 10.36 (s, 1H), 7.56 (s, 1H), 7.24 (s, 1H), 3.93 (s, 3H)

2) 2-> 3

Compound 2 (2.83 g, 14.00 mmol) was dissolved in acetonitrile (70 ml), K ₂ CO ₃ (5.8 g, 42.00 mmol) was added, and the mixture was stirred for 10 minutes. Add benzylbromide (1.75 mL, 14.7 mmol) to the reaction and reflux for 2 h. After quenching with water, lower the temperature and filter the precipitated solid, wash it with water, and wash it with hexane. And dried under reduced pressure to obtain compound 3 ( 4.03 g, 98%).

^{1 H NMR (300 MHz, CDCl} 3) δ 7.51 (s, 1H), 7.47-7.34 (m, 5H), 7.20 (s, 1H), 5.18 (s, 2H), 3.92 (s, 3H)

3) 3-> 4

Compound 4 (4.03 g, 13.72 mmol) is dissolved in EtOH (140 mL) and H ₂ O (28 mL) and then NH ₄ Cl (4.4 g, 82.32 mmol) is added to a round bottom flask. The reaction was heated to 60 ° C, and then Fe (3.83 g, 68.61 mmol) was added thereto, followed by stirring for 3 hours. The reaction is filtered through celite and then concentrated under reduced pressure. Add NaHCO ₃ aqueous solution to the filtrate and extract 3 times with EA. The extracted EA layer was dried with Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain compound 4 ( 3.61 g, 99%).

^{1 H NMR (300 MHz, CDCl} 3) δ 7.41-7.34 (m, 5H), 6.88 (s, 1H), 6.38 (s, 1H), 5.00 (s, 2H), 3.81 (s, 3H)

4) 4-> 5

After dissolving Compound 4 (3.61 g, 13.69 mmol) in MC (105 mL) and MeOH (70 mL), tetrabutylammonium bromide (7.92 g, 16.43 mmol) was added and stirred for 12 hours. Concentrate the reaction mixture under reduced pressure, add water and extract three times with ether. The ether layer is dried with Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The concentrated compound is purified by short silica filter to obtain compound 5 ( 3.37 g, 72%).

^{* 1 H NMR (300 MHz,} CDCl 3) δ 7.35-7.30 (m, 5H), 6.78 (s, 1H), 4.94 (s, 2H), 4.26 (s, NH, 2H), 3.78 (s, 3H)

5) 5-> 6

After dissolving Compound 5 (3.37 g, 9.84 mmol) in methylene chloride (50 ml), add triethylamine (2.1 ml, 14.75 mmol) and stir for 10 minutes. Slowly add isobutyryl chloride (1.1 ml, 10.82 mmol) to the reaction and reflux for 2 hours. The reaction is quenched with aqueous NaHCO ₃ solution and extracted with MC. The organic layer is washed three times with aqueous NaHCO ₃ solution. The organic layer is dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. After recrystallization with MC and hexane, the precipitated solid was filtered and dried to obtain compound 6 (2.95 g, 72%).

^{1 H NMR (300 MHz, CDCl} 3) δ 7.40-7.33 (m, 5H), 7.00 (s, 1H), 6.72 (s, 1H), 5.29 (s, 2H), 3.85 (s, 3H), 2.55- 2.54 (m, 1 H), 1.23 - 1.20 (m, 6 H)

6) 6-> 7

Dissolve Compound 6 (1.43 g, 3.47 mmol) in toluene (35 ml), add Lawesson's reagent (0.70 g, 1.73 mmol) and reflux for 1 hour. The reaction mixture was concentrated under reduced pressure, followed by short silica filter and washing with MC to obtain crude compound 7 ( 1.48 g, 99%).

^{1 H NMR (300 MHz, CDCl} 3) δ 8.06 (s, 1H), 7.38-7.34 (m, 5H), 7.04 (s, 1H), 5.00 (s, 2H), 3.86 (s, 3H), 3.00- 2.95 (m, 1 H), 1.31-1.25 (m, 6 H)

7) 7-> 8

Compound 7 (3.92 g, 9.14 mmol), CsCO ₃ (4.47 g, 13.71 mmol), 1,10-phenanthroline (0.16 g, 0.91 mmol) and CuI (0.09 g, 0.46 mmol) were placed in a round bottom flask, Make vaccum and purge with N ₂ . DME (90 mL) was added, the mixture was heated to 90 DEG C and stirred for 12 hours. After quenching with water, extract with EA. The EA layer was separated, treated with Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain compound 8 ( 2.89 g, 99%).

^{1 H NMR (300 MHz, CDCl} 3) δ 7.49-7.46 (m, 2H), 7.39-7.35 (m, 3H), 6.88 (s, 1H), 5.34 (s, 2H), 3.92 (s, 3H), 3.53-3.44 (m, 1 H), 1.48-1.46 (m, 6 H)

8) 8-> 9

Compound 8 (2.89 g, 7.9 mmol) was dissolved in EtOH (80 mL), conc. HCl (40 mL) was added, and the mixture was refluxed for 8 hours. Cool the reaction mixture at room temperature, add water, and extract with EA. The EA layer was separated, treated with Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain compound 9 ( 2.14 g, 99%).

¹ H NMR (300 MHz, CDCl ₃ )? 6.98 (s, IH), 3.93 (s, 3H), 3.40-3.36

9) 9-> 10

Compound 9 (2.49 g, 9.66 mmol) is dissolved in DMF (190 mL), and the temperature is lowered to 0 ° C. 47% IBX (6.91 g, 11.59 mmol) was added and the mixture was stirred for 1 hour. After quenching with NaHCO ₃ aqueous solution, it is extracted with EA. Wash the EA layer several times with aqueous NaHCO ₃ solution. Processing the EA layer Na ₂ SO _4, filtered, and concentrated under reduced pressure. Recrystallization from EA / HX gave compound 10 ( 1.23 g, 47%).

Ex.13

^{1 H NMR (300 MHz, CDCl} 3) δ 4.47 (s, 3H), 3.40-3.36 (m, 1H), 1.48-1.44 (d, J = 6.9 Hz, 6H)

Example 14 [Synthesis of Compound 14]

1) 1step

DMF (38 ml, 0.5 M) was added to Compound 1 (3 g, 19.096 mmol), K ₂ CO ₃ (3.8 g, 27.288 mmol) and BnBr (2.7 ml, 22.915 mmol) And reacts. Add 1 N HCl to neutralize and extract with EA. The separated organic layer was dried with MgSO ₄ , filtered, distilled under reduced pressure, and recrystallized with Hex / EA to obtain the target compound. (Ivory solid, 3.759 g, 80%)

2) 2 step

Phenol (460 mg, 4.859 mmol), K ₂ CO ₃ (1.7 g, 12.145 mmol) and DMF (40 ml, 0.1 M) were mixed and stirred at 60 ° C for 30 minutes. Compound 2 (1 g, 4.049 mmol) was added at the same temperature, followed by reaction for 15 hours. After extracting with water and EA, the separated organic layer is dried with MgSO ₄ , filtered, distilled under reduced pressure, and recrystallized with Hex / EA to obtain the target compound. (pale yellow solid, 1.44 g, quantitative yield)

3) 3 steps

Compound 3 (1.44 g, 4.481 mmol ) in EtOH (45 ml, 0.1M), H 2 O into the (9 ml, 0.5 M), NH 4 Cl (1.44 g, 26.88 mmol) and Fe (1.2 g, 22.407 mmol ), And the mixture is refluxed with stirring for 2 hours. After celite filtration, the filtrate is distilled under reduced pressure. Aq. After neutralizing with NaHCO ₃ , it is extracted with EA. The separated organic layer is dried over MgSO ₄ , filtered, distilled under reduced pressure, and subjected to silica gel column chromatography to obtain the target compound. (ivory solid, 788 mg, 60%).

4) 4 step

Anhydrous CH ₂ Cl ₂ is added to Compound 4 (755 mg, 2.59 mmol), Et ₃ N (1.8 ml, 12.975 mmol) and propionyl chloride (0.27 ml, 3.108 mmol) are added under an ice bath. After stirring at room temperature for 15 hours, aq. Neutralize with NaHCO ₃ , and extract with EA. The separated organic layer is dried over MgSO4, filtered, and distilled under reduced pressure to obtain the target compound. (Crude oil, 1 g, quantitative yield)

5) 5 step

AcOH (3.4 ml, 0.25 M) was added to Compound 5 (300 mg, 0.864 mmol), HNO ₃ (49 μl, 1.036 mmol) was added at 10 ° C and the mixture was stirred for 5 minutes. aq. After neutralization with NaHCO ₃ and extraction with EA, the separated organic layer is dried over MgSO ₄ , filtered and distilled under reduced pressure to obtain the target compound. (Yellow solid, 260 mg, 77%).

6) 6 step

To the compound 6 (244 mg, 0.622 mmol) was added EtOH (6.2 ml, 0.1 M) and H ₂ O (1.24 ml, 0.5 M), NH ₄ Cl (200 mg, 3.732 mmol) do. Fe (168 mg, 3.11 mmol) was added thereto, followed by stirring under reflux for 2.5 hours. After celite filtration, the filtrate is distilled under reduced pressure. Aq. After neutralizing with NaHCO ₃ , it is extracted with EA. The separated organic layer is dried over MgSO ₄ , filtered, distilled under reduced pressure, and subjected to silica gel column chromatography to obtain the target compound. (ivory solid, 200 mg, 88%).

7) 7step

AcOH (6.9 ml, .08 M) was added to Compound 7 (200 mg, 0.552 mmol) and reacted at 100 ° C for 18 hours. After vacuum distillation, Aq. NaHCO ₃ is added to neutralize and extracted with EA. The separated organic layer is dried over MgSO ₄ , filtered, distilled under reduced pressure, and subjected to silica gel column chromatography to obtain the target compound. (violet solid, 110 mg, 49%).

8) 8 step

To a solution of Compound 8 (110 mg, 0.319 mmol) in MeOH (3 ml, 0.1 M) was added Pd / C (20 mg). The inside air is replaced with H ₂ , and then the mixture is stirred at room temperature for 4 hours. After filtration through celite, the filtrate is distilled under reduced pressure, and the concentrate is again silicagel filtered to remove the bottom spot. (light violet solid, 75 mg, 75%).

9) 9step

After dissolving Compound 9 (75 mg, 0.239 mmol) in DMF (2.9 ml, 0.1 M), add IBX (170 mg, 0.286 mmol) and react at room temperature for 30 min. Add Aq.NaHCO ₃ and extract with EA. The EA layer is dried over MgSO ₄ , filtered, and distilled under reduced pressure, followed by silicagel filtration. The filtrate is distilled again under reduced pressure and recrystallized with EA / Hex. (yellow-green solid, 44 mg, 56%).

Ex.14

_{1H NMR (300 MHz, CDCl 3} ) δ 8.15 (brs, 1H), 7.68 (s, 1H), 7.48-7.29 (m, 3H), 7.10 (d, J = 9.0 Hz, 2H), 5.64 (s, 1H ), 2.63 (q, J = 7.5 Hz, 2H), 2.21 (s, 3H)

Example 15 [Synthesis of compound 15]

EtOH and THF (17 ml, 1: 1) were added to Compound 1 (1 g, 3.4 mmol) and PtO ₂ (96 mg, 0.34 mmol) and the mixture was stirred under a hydrogen atmosphere for 3 hours. The reaction solution is filtered through Celite fliter and concentrated under reduced pressure. The concentrate is redissolved in Acetone (70 ml) and CSA (0.8 g, 4.1 mmol) is added. After stirring at room temperature for 48 h, aqueous NaCl solution and EA were added and extracted several times. The separated organic layer is dried over MgSO ₄ and filtered. The filtrate is concentrated under reduced pressure and purified by recrystallization.

Gold solid 0.93 g (79%)

Compound 2 (0.5 g, 1.45 mmol) is dissolved in MeOH (14.5 ml) and MC (14.5 ml) and then Pd (OH) ₂ (20t%) (0.1 g, 0.145 mmol) is added. After stirring for 16 hours under a hydrogen atmosphere, Celite filter is applied. The filtrate is concentrated under reduced pressure and purified by recrystallization.

Ivory solid 0.356 g (96%)

Compound 3 (0.1 g, 0.393 mmol) was dissolved in DMF (8 ml) and then IBX (0.28 g, 0.47 mmol) was added. After reacting at room temperature for 1 hour, NaHCO ₃ saturated aqueous solution and EA are added and extracted several times. The separated organic layer is dried with MgSO ₄ and filtered. The filtrate is concentrated under reduced pressure and purified by silica gel column chromatography.

Brown liquid (or solid) 44 mg (42%)

Ex.15

^{1 H NMR (300 MHz, CD} 3 OD) δ 8.00-7.97 (m, 2H), 7.89-7.86 (m, 1H), 7.51-7.45 (m, 2H), 4.04-3.97 (m, 1H), 2.05- (M, 2H), 1.39 (d, J = 6.6 Hz, 3H), 1.35

Example 16 [Synthesis of Compound 16]

Compound 3 (3,6-dimethoxybenzene-1,2-diamine, 0.63 g, 3.75 mmol) is dissolved in MC (37 ml) in an ice bath. Add Et ₃ N (1.05 ml, 7.5 mmol) under nitrogen atmosphere. Isobutyryl chloride (0.4 ml, 3.75 mmol) was slowly added and stirred at room temperature for 1 hour. Add MC and distilled water to the reaction solution, and extract several times. The separated organic layer was dried over MgSO ₄ and filtered. The filtrate is concentrated under reduced pressure and purified by silica gel column chromatography.

Ivory solid 0.7 g (79%)

Compound 2 (0.7 g, 2.94 mmol) is dissolved in AcOH (58 ml) and refluxed for 30 minutes. The reaction solution is concentrated under reduced pressure, and then MC and NaHCO ₃ saturated aqueous solution are added to extract several times. The separated organic layer is dried over MgSO4 and filtered. The filtrate is concentrated under reduced pressure and purified by recrystallization.

Ivory solid 0.57 g (88%)

Compound 3 (1.2 g, 5.45 mmol) is dissolved in Ac ₂ O (11 ml, 0.5 M) in an ice bath. AcOH (1.5 ml) and HNO3 (60%) (0.5 ml, 6.54 mmol) were added, and the mixture was stirred at room temperature for 20 hours. The reaction solution is poured into ice, and a saturated aqueous solution of NaHCO ₃ is added to neutralize it. MC and NaHCO ₃ saturated aqueous solution. The separated organic layer was dried over MgSO ₄ and filtered. The filtrate is concentrated under reduced pressure and purified by silica gel column chromatography.

Yellow solid 0.7 g (51%)

Compound 4 (0.39 g, 1.47 mmol) was dissolved in MC (15 ml) and MeOH (7.5 ml). 5% Pd / C (78 mg, 20 wt%) was added thereto and stirred under a hydrogen atmosphere for 18 hours. The reaction solution is filtered through a Celite filter (MC) and concentrated under reduced pressure. Re-dissolve in MC (7.5 ml, 0.2 M) in an ice bath and add pyridine (0.36 ml, 4.41 mmol). Isobutyryl chloride (0.19 ml, 1.76 mmol) was slowly added and stirred at room temperature for 1 hour. Add MC and distilled water to the reaction solution, and extract several times. The separated organic layer was dried over MgSO ₄ and filtered. The filtrate is concentrated under reduced pressure and purified by recrystallization.

Ivory solid 0.26 g (59%)

In Ice bath Compound 6 (0.26 g, 0.86 mmol) is dissolved in a CH ₃ CN (12.5 ml) and distilled water (4.5 ml). Add CAN (Cerium Ammonium Nitrate: cerium ammonium nitrate) (1.42 g, 2.6 mmol) and stir for 30 minutes at the same temperature. Add EA and distilled water, and extract several times. The separated organic layer was dried over MgSO ₄ and filtered. The filtrate is concentrated under reduced pressure and purified by recrystallization.

Orange solid 0.15 g (61%)

* Compound 7 (0.14 g, 0.51 mmol) is dissolved in AcOH (5 ml). Zinc (0.17 g, 2.54 mmol) was added thereto, followed by heating to 100 占 폚. HBr (33 wt% in AcOH) (0.45 ml, 2.54 mmol) was slowly added thereto, followed by stirring for 21 hours. Add EA and rinse with distilled water several times. The separated organic layer is washed several times with a saturated aqueous solution of NaHCO ₃ , then washed again with distilled water. The separated organic layer is dried with MgSO ₄ and filtered. The filtrate is concentrated under reduced pressure to crystallize.

Ivory solid 60.5 mg (46%)

Compound 8 (60.5 mg, 0.23 mmol) is dissolved in DMF (4.5 ml) and then IBX (0.17 g, 0.28 mmol) is added. After reacting at room temperature for 2 hours, a saturated aqueous solution of NaHCO ₃ and EA are added and extracted. The separated organic layer is dried with MgSO ₄ and filtered. The filtrate is concentrated under reduced pressure and purified by silica gel column chromatography.

Dark red solid 12 mg (18%)

Ex.16

^{1 H NMR (300 MHz, CDCl} 3) δ 11.43 (br, s, 1H), 3.22-3.15 (m, 2H), 1.43 (d, J = 7.0 Hz, 6H), 1.42 (d, J = 7.0 Hz, 6H)

Examples 17, 18, 19, and 21 [Synthesis of Compounds 17, 18, 19, and 21]

1) 1-> 3

After adding MeOH (100 ml) to 1,4-naphthoquinone 1 (7.9 g, 0.05 mol), a solution of SnCl ₂ (33.3 g, 0.18 mol) in cHCl (35 ml) was added dropwise at room temperature for 20 minutes . The reaction solution is refluxed for 3 hours and then cooled to room temperature. Concentrate MeOH to the 1/5 volume of the first volume through vacuum distillation and pour cold water to solidify. After filtration, the obtained solid was dissolved in MC, dried over MgSO ₄ , filtered, and distilled under reduced pressure to obtain Compound 2 (77% yield)

Mixture of 4-methoxy-1-naphthol 2 (5 g, 0.029 mol), isobutyryl chloride (10 mL) and pyridine (15 mL) in a flask is stirred at room temperature for 24 hours. The reaction is poured into cold water, extracted twice with EA, and the collected EA layer is washed with 2M HCl. Dried over MgSO ₄ , filtered, and distilled under reduced pressure to obtain Compound 3 . (6 g, 97% yield)

^{_{1 H NMR (CDCl 3) δ}} H (300 MHz; CDCl 3) 8.26 (dd, 1H, J = 6.75, J = 2.74), 7.76 (dd, 1H, J = 6.78, J = 2.73), 7.54 - 7.46 ( m, 2H), 7.11 (d , 1H, J = 8.43), 6.76 (d, 1H, J = 8.43), 3.99 (s, 3H), 2.97 (sep, 1H, J = 6.96), 1.43 (d, 6H , J = 7.32)

2) 3-> 4

Add 4-methoxynaphthalen-1-yl isobutyrate 3 (2 g, 8.19 mmol) to the flask and warm to 140 ° C. Then add BF ₃ .Et ₂ O (5 mL). After 5 minutes, the reaction is poured into cold water and extracted with EA. At this time, NaHCO ₃ is added to neutralize. The EA layer is dried with MgSO ₄ , filtered, distilled under reduced pressure, and purified by flash chromatography to obtain Compound 4 . (1.8 g, 96%).

^{_{1 H NMR (CDCl 3) δ}} H (300 MHz; CDCl 3) 14.04 (s, 1H), 8.45 (d, 1H, J = 7.68), 8.18 (d, 1H, J = 8.07), 7.66 (t, 1H , J = 6.96), 7.57 ( t, 1H, J = 6.96), 6.92 (s, 1H), 3.99 (s, 3H), 3.62 (sep, 1H, J = 6.96), 1.31 (d, 6H, J = 6.96)

3) 4-> 6

Put 1- (1-hydroxy-4- methoxynaphthalen-2-yl) -2-methylpropan-1-one 4 2 N NaOH (60 mL) and NH ₄ OH.HCl (0.7 g) in stirred and refluxed for 3 hours do. After cooling to room temperature, neutralize with aq. NaHCO ₃ and extract with EA. The EA layer is dried with MgSO ₄ , filtered, and distilled under reduced pressure to obtain Compound 5 .

Ac ₂ O (20 ml) was added to 1- (1-hydroxy-4-methoxynaphthalen-2-yl) -2-methylpropan-1-one oxime 5 (0.9 g, 0.029 mol) and stirred at 100 ° C. for 4 hours do. The reaction is poured into cold water, neutralized with NaHCO ₃ and extracted with EA. The EA layer is dried with MgSO ₄ , filtered, distilled under reduced pressure, and purified by flash chromatography to obtain Compound 6 . (0.7 g, 56% yield)

_{δ H (300 MHz; CDCl 3} ) 8.34 (d, 1H, J = 2.55), 8.32 (d, 1H, J = 2.22), 7.68 - 7.64 (m, 2H), 6.82 (s, 1H), 4.05 (s , 3H), 3.44 (sep, 1H, J = 6.96), 1.53 (d, 6H, J = 6.96)

4) 6-> 7

3-isopropyl-5-methoxynaphtho [2,1-d] isoxazole 6 (0.7 g, 2.9 mmol) was dissolved in MC and BBr ₃ was dropwise added at 0 ° C. and stirred for 4 hours. When the reaction is complete, the reaction is poured into cold water, neutralized with NaHCO ₃ , and extracted with EA. The EA layer is dried with MgSO ₄ , filtered, and distilled under reduced pressure to obtain Compound 7 . (0.67 g, 99% yield)

_{* Δ H (300 MHz; CDCl} 3) 8.37 - 8.34 (m, 1H), 8.31 - 8.28 (m, 1H), 7.72 - 7.76 (m, 2H), 6.96 (s, 1H), 5.60 (br, s, 1H), 3.41 (sep, 1H, J = 6.96), 1.50 (d, 6H, J = 6.96)

5) 7-> 8

IBX (0.7 g) was added to 3-isopropylnaphtho [2,1-d] isoxazol-5-ol 7 (0.6 g, 2.64 mmol) dissolved in DMF (29 ml) and the mixture was stirred at room temperature for 1 hour. Add Aq.NaHCO ₃ and extract with EA. The EA layer is dried with MgSO ₄ , filtered, and distilled under reduced pressure to obtain Compound 8 . (0.58 g, 81%)

Ex.21

_{δ H (300 MHz; CDCl 3} ) 8.20 (dd, 1H, J = 7.51, J = 0.91), 7.96 (dd, 1H, J = 7.69, J = 0.73), 7.80 (1H, td, J = 7.5, J = 1.3), 7.69 (1H, td, J = 7.7, J = 1.1), 3.44 (sep, 1H, J = 6.96), 1.42 (d, 6H, J = 6.6)

6) 8-> 9

3-isopropylnaphtho [2,1-d] isoxazole-4,5-dione (0.1 g, 4.13 mmol) was added to sulfuric acid (8 ml) at 0 ° C. and HNO ₃ (0.08 ml) was added thereto and stirred for 4 hours . The reaction is poured into ice, neutralized with NaHCO ₃ , and extracted with EA. The organic layer is evaporated after washing with water once, dried with MgSO _4, filtered, and reduced pressure. The concentrated reaction product is separated by flash column chromatography (EA-HX 1: 4) to obtain Compound 9 3-isopropyl-7-nitronaphtho [2,1-d] isoxazole-4,5-dione. (0.13 g, 99%).

Ex.17

_{δ H (300 MHz; CDCl 3} ) 9.00 (d, 1H, J = 2.55), 8.64 (dd, 1H, J = 8.43, J = 2.19), 8.19 (d, 1H, J = 8.4), 3.48 (sep, 1H, J = 6.96), 1.44 (d, 6H, J = 6.96)

7) 9-> 10

3-isopropyl-7-nitronaphtho [2,1-d] isoxazole-4,5-dione (0.1 g, 0.35 mmol) in MeOH (7 ml) and add (10% / C, 0.01 g). The reaction was purged with H ₂ and stirred at room temperature for 4 h. After celite filtration, the filtrate is distilled under reduced pressure to obtain Compound 10 7-amino-3-isopropylnaphtho [2,1-d] isoxazole-4,5-dione in solid form. (0.82 g, 87%).

Ex.18

_{δ H (300 MHz; CDCl 3} ) 7.49 (d, 1H, J = 8.43), 7.39 (d, 1H, J = 2.19), 6.91 (dd, 1H, J = 6.06, J = 2.19), 4.36 (br, s, 2H), 3.39 (sep, 1H, J = 6.96), 1.40 (d, 6H, J = 6.93)

8) 10-> 11

7-amino-3-isopropylnaphtho [2,1-d] isoxazole-4,5-dione (0.07 g, 0.27 mmol) in 1N HCl (3 ml) with added thereto and then, sodium nitrite (0.03 g, 0.41 mmol) in H ₂ O (0.4 mL) the rear semi put into solution in CuCl ₂ H ₂ O (0.7 ml) is added. The reaction is carried out at room temperature for 10 minutes and then at 60 ° C for 3 hours. The reaction is poured into ice water, neutralized with NaHCO ₃ and extracted with MC. The organic layer is dried over MgSO ₄ , filtered and distilled under reduced pressure. The concentrated reaction product is separated by flash column chromatography (EA-HX 1: 4) to obtain Compound 11 in solid form. (yield: 52%)

Ex.19

_{δ H (300 MHz; CDCl 3} ): 8.16 (d, 1H, J = 2.2), 7.91 (d, 1H, J = 8.4), 7.77 (dd, 1H, J = 8.4, J = 2.2), 3.44 (sep , 1H, J = 7.0), 1.42 (d, 6H, J = 7.0)

Example 20 [Synthesis of Compound 20]

1) 1-> 2

Compound 1 (3.0 g, 14.69 mmol) was dissolved in DMF (75 ml), KI (1.49 g, 8.82 mmol) and K ₂ CO ₃ (9.1 g, 66.12 mmol) were added thereto and stirred for 10 minutes. Benzylbromide (5.7 ml, 48.49 mmol) was slowly added to the reaction mixture and stirred for 4 hours. The reaction is quenched with H ₂ O and extracted several times with EA. The organic layer is dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The precipitated solid was filtered and dried to give compound 2 (4.44 g, 64%).

^{1 H NMR (300 MHz, CDCl} 3) δ 8.35-8.32 (m, 1H), 8.21-8.19 (m, 1H), 7.60-7.32 (m, 20H), 5.39 (s, 2H), 5.25 (s, 2H ), 5.06 (s, 2 H)

2) 2-> 3

NH ₂ OH HCl (3.9 g, 55.56 mmol) is dissolved in MeOH (20 ml) and KOH (4.6 g, 81.92 mmol) is dissolved in MeOH (11.5 ml) slowly. After stirring for 30 minutes, filter the solution, remove the generated KCl, add Compound 2 (3.38 g, 7.12 mmol) to the filtrate, and stir for 16 hours. After quenching with NH ₄ Cl _{(aq), it} is extracted several times with EA. The EA layer is dried with Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The concentrated reaction product is recrystallized with MeOH, and the precipitated solid is filtered and dried. compound 3 ( 1.7 g, 60%).

¹ H NMR (300 MHz, CDCl ₃ )? 10.51 (s, IH), 8.71 (br, IH), 8.37-8.34 (m, IH), 8.19-8.16 (m, IH), 7.64-7.33 ), 5.19 (s, 2 H), 5.03 (s, 2 H)

3) 3-> 4-> 5-> 6 (crude)

3-> 4

Compound 3 (0.7 g, 2.08 mmol) is dissolved in MeOH (20 ml) and then 5% Pd / C (0.2 g, 0.094 mmol) is added. After degassing the reaction mixture, H ₂ 1 atm is applied, and the mixture is stirred at room temperature for 18 hours. After removing Pd / C by Celite filiter, it is concentrated under reduced pressure.

4-> 5

Crude-Compound 4 (0.456 g, 2.08 mmol) was dissolved in THF (20 ml), and CDI (1.01 g, 6.24 mmol) was added thereto. The mixture is refluxed for 30 minutes and stirred. TEA (0.44 ml, 3.12 mmol) was added to the reaction mixture and stirred for 2 hours. The THF is removed by concentration under reduced pressure. 1N-HCl aqueous solution is added to the concentrated reaction product and then extracted several times with EA. The EA layer is dried with Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The concentrated reaction product is separated by flash column chromatography.

5-> 6

Compound 5 (0.2 mg, 0.99 mmol) is dissolved in DMF (10 ml), the temperature is lowered with an ice bath, and the mixture is stirred for 30 minutes. To the reaction was added 47% IBX (1.18 g, 2.0 mmol) and stirred for 1 hour. The reaction is diluted with EA and washed several times with aqueous NaHCO ₃ solution. The EA layer is dried with Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The concentrated reaction product is purified by prep-TLC to obtain compound 6 ( 20 mg, 10%).

Ex.20

^{1 H NMR (300 MHz, CDCl} 3) δ 10.73 (br, 1H), 8.23-8.21 (m, 1H), 8.12-8.09 (m, 1H), 7.85-7.80 (m, 1H), 7.71-7.66 (m , 1H)

Example 22 [Synthesis of Compound 22]

1) 1-> 3

After adding MeOH (100 ml) to 1,4-naphthoquinone 1 (7.9 g, 0.05 mol), a solution of SnCl ₂ (33.3 g, 0.18 mol) in cHCl (35 ml) was added dropwise at room temperature for 20 minutes . The reaction solution is refluxed for 3 hours and then cooled to room temperature. Concentrate MeOH to the 1/5 volume of the first volume through vacuum distillation and pour cold water to solidify. After filtration, the obtained solid is dissolved in MC, dried over MgSO ₄ , filtered, and distilled under reduced pressure to obtain Compound 2

Mixture of 4-methoxy-1-naphthol 2 (5 g, 0.029 mol), Pivaloyl chloride (14.3 mL) and pyridine (15 mL) in a flask is stirred at room temperature for 24 hours. The reaction is poured into cold water, extracted twice with EA, and the collected EA layer is washed with 2 M HCl. Dried over MgSO ₄ , filtered, and distilled under reduced pressure to obtain Compound 3 . (8 g, 1,2 step yield: 62%)

2) 3-> 4

Add 4-methoxynaphthalen-1-yl pivalate 3 (2 g, 7.74 mmol) to the flask and warm to 140 ° C. Then add BF ₃ .Et ₂ O (5 mL). After 5 minutes, the reaction is poured into cold water and extracted with EA. At this time, NaHCO ₃ is added to neutralize. The EA layer is dried with MgSO ₄ , filtered, distilled under reduced pressure, and purified by flash chromatography to obtain Compound 4 . (1.74 g, 87%)

3) 4-> 6

1- (1-hydroxy-4- methoxynaphthalen-2-yl) -2,2-dimethylpropan-1-one 4 in 2N NaOH (55 mL) and _{NH 4 OH.HCl (0.7 g) (} 1.2 g, 4.65 mmol) And the mixture is refluxed with stirring for 3 hours. After cooling to room temperature, neutralize with aq. NaHCO ₃ and extract with EA. The EA layer is dried with MgSO ₄ , filtered, and distilled under reduced pressure to obtain the target compound 5. (1.9 g)

Ac ₂ O (20 ml) was added to (E) -1- (1-hydroxy-4-methoxynaphthalen-2-yl) -2,2-dimethylpropan-1-one oxime 5 (1 g, 3.66 mmol) Lt; 0 > C for 4 hours. The reaction is poured into cold water, neutralized with NaHCO3 and extracted with EA. The EA layer is dried with MgSO ₄ , filtered, distilled under reduced pressure, and purified by flash chromatography to obtain Compound 6 . (0.7 g, 4-6 step yield: 50%)

4) 6-> 7

After dissolving 3- (tert-butyl) -5-methoxynaphtho [2,1-d] isoxazole 6 (0.7 g, 2.74 mmol) in MC, BBr ₃ was dropwise added at 0 ° C and stirred for 4 hours. When the reaction is complete, the reaction is poured into cold water, neutralized with NaHCO ₃ , and extracted with EA. The EA layer is dried with MgSO ₄ , filtered, and distilled under reduced pressure to obtain Compound 7 . (0.64 g, 97% yield)

5) 7-> 8

IBX (0.5 g) was added to 3- (tert-butyl) naphtho [2,1-d] isoxazol-5-ol 7 (0.4 g, 1.66 mmol) dissolved in DMF (29 ml) and stirred at room temperature for 1 hour do. Add Aq.NaHCO ₃ and extract with EA. The EA layer is dried with MgSO ₄ , filtered, and distilled under reduced pressure to obtain Compound 8 . (0.31 g, 75%)

Example 23 [Synthesis of Compound 23]

1) 1step

Pyridine (3.1 ml) was added to 6-amino-2-methylbenzo [d] thiazole-4,7-dione (0.3 g, 1.55 mmol) and stirred under a nitrogen atmosphere. The ice bath was added dropwise to isobutyryl chloride (0.2 ml, 6.89 mmol) and the mixture was stirred at room temperature for 3 hours. After adding EA and distilled water, wash the organic layer several times with aqueous NaCl solution and distilled water. The separated organic layer is dried with MgSO ₄ , filtered and concentrated under reduced pressure. Crude is purified by silicagel column chromatography to obtain N- (2-methyl-4,7-dioxo-4,7-dihydrobenzo [d] thiazol-6-yl) isobutyramide.

0.15 g (37%)

2) 2 step

Zinc (0.1 g, 1.46 mmol) and acetic acid (2.5 ml, 0.488 mmol) were added to N- (2-methyl-4,7-dioxo-4,7-dihydrobenzo [d] thiazol- ) And the mixture is stirred at room temperature. The reaction solution was heated to 100 ° C and HBr / HOAc (33 wt%) (0.27 ml, 1.46 mmol) was added. The reaction solution is refluxed for 3 hours. After adding EA and distilled water, wash the organic layer several times with distilled water and aqueous NaHCO ₃ solution. The separated organic layer is dried with MgSO ₄ , filtered and concentrated under reduced pressure.

0.12 g (96%)

3) 3 steps

Add DMF (9 ml) to SM (Chemigraw naming X) (0.1 g, 0.438 mmol) and stir in an ice bath. Add IBX (0.31 g, 0.526 mmol) and stir for an additional 30 min. After adding EA and distilled water, wash the organic layer several times with distilled water and aqueous NaHCO ₃ solution. The separated organic layer is dried with MgSO ₄ , filtered and concentrated under reduced pressure. Crude is purified by recrystallization and Silicagel filter to obtain product [naming X from chemdraw] .

48 mg (46%)

Ex.23

^{1 H NMR (300 MHz, CDCl} 3) 3.26-3.29 (m, 1H), 2.84 (s, 3H) 1.44 (d, J = 7.0Hz, 6H)

Production Example 1 [Synthesis of triazole intermediate]

One) 1-> 2

Compound 1 (4-amino-1-naphthol hydrochloride, 15.0 g, 69.0 mmol) is dissolved in methylene chloride (230 ml) and stirred in an ice bath for 20 minutes. Add triethylamine (33.9 ml, 241.5 mmol) and stir for 10 min. Add acetic anhydride (13.7 ml, 144.9 mmol) slowly to the reaction mixture and stir for 1 hour. The reaction is quenched with H ₂ O and extracted with MC. Wash the organic layer 3 times with H ₂ O. The organic layer is dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. After recrystallization with MC and hexane, the precipitated solid was filtered and dried to obtain compound 2 (14.41 g, 86%).

^{1 H NMR (300 MHz, DMSO} ) δ 9.97 (s, 1H), 8.10-8.08 (m, 1H), 7.92-7.89 (m, 1H), 7.66-7.56 (m, 3H), 7.29-7.26 (m, 1H), 2.45 (s, 3H), 2.19 (s, 3H)

2) 2-> 3

Compound 2 (14.41 g, 59.24 mmol) was dissolved in MC (300 ml) and stirred in an ice bath for 20 minutes. Add Ac ₂ O (3.35 ml, 35.48 mmol) to the reaction and slowly add HNO ₃ (3.2 ml, 65.16 mmol). After adding 250 ml of hexane, the precipitated solid is filtered, washed with H ₂ O and washed with hexane. Dry at room temperature to give compound 3 (11.87 g, 69%).

^{1 H NMR (300 MHz, DMSO} ) δ 10.56 (s, 1H), 8.32-8.29 (m, 1H), 8.10-8.07 (m, 1H), 7.84-7.81 (m, 2H), 2.49 (s, 3H) , 2.18 (s, 3 H)

3) 3-> 4-> 5

Compound 3 (11.87 g, 41.18 mmol) was dissolved in MeOH (205 ml), K ₂ CO ₃ (8.54 g, 61.77 mmol) was added thereto and stirred for 1 hour. After adding H ₂ O (50 ml), concentrate under reduced pressure and extract three times with EA. The EA layer is dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give crude compound 4 . Dissolve in DMF (205 ml), add K ₂ CO ₃ (8.54 g, 61.77 mmol), and slowly add benzylbromide (5.4 ml, 45.30 ml). After completion of the reaction, add H ₂ O (200 ml), add ice (100 ml), filter the precipitated solid, and wash with water and hexane. Dry to obtain compound 5 . (13.10 g, 95%, 2 step yield)

Compound 4

^{1 H NMR (300 MHz, DMSO} ) δ 10.12 (s, 1H), 8.23-8.20 (m, 1H), 8.10-8.08 (m, 1H), 7.74-7.69 (m, 2H), 7.24 (s, 1H) , 2.11 (s, 3 H)

Compound 5

^{1 H NMR (300 MHz, CDCl} 3) δ 8.44 (s, 1H), 8.40-8.37 (m, 1H), 7.70-7.68 (m, 1H), 7.67-7.65 (m, 2H), 7.54-7.52 (m , 2H), 7.48-7.39 (m, 4H), 5.31 (s, 2H), 2.36 (s, 3H)

4) 5-> 6

Compound 5 (10.0 g, 29.73 mmol) is dissolved in acetone (240 ml) and H ₂ O (60 ml), NH ₄ Cl (9.54 g, 178.38 mmol) is added and the mixture is heated to 60 ° C. Fe (16.6 g, 297.3 mmol) was added thereto and reacted for 12 h. The reaction is filtered through celite and washed with MeOH. The reaction mixture is concentrated under reduced pressure, and then NaHCO _{3 (aq) is} added thereto, followed by extraction three times with EA. The EA layer is dried with Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The concentrated compound was recrystallized from EA / Hexane, filtered and dried to obtain compound 6 (5.56 g, 61%).

Compound 6

¹ H NMR (300 MHz, DMSO)? 9.02 (s, 1H), 7.98-7.95 (m, 1H), 7.55-7.31 (m, 7H), 7.13-7.08 , 5.21 (s, 2H), 5.15 (s, 2H), 2.11 (s, 3H)

5) 6-> 7-> 8

After dissolving Compound 6 (5.56 g, 18.15 mmol) in conc-HCl / H ₂ O (1/4, 180 ml), 1M NaNO _{2 (aq)} (1.45 g, 21.05 mmol) was added and stirred for 10 minutes . The precipitated compound is filtered, washed with water and dried to obtain compound 7. [ Compound 7 was dissolved in MeOH (180 ml), K ₂ CO ₃ (5.02 g, 36.30 mmol) was added thereto and stirred for 1 hour. The reaction product is filtered, concentrated under reduced pressure, and then water is added thereto and extracted three times with EA. The EA layer is dried with Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The concentrated compound was recrystallized from EA / Hexane, filtered and dried to obtain compound 8 (4.37 g, 88%).

Compound 7

^{1 H NMR (300 MHz, CDCl} 3) δ 9.31-9.28 (m, 1H), 8.51-8.49 (m, 1H), 7.72-7.65 (m, 2H), 7.57-7.54 (m, 2H), 7.47-7.35 (m, 4H), 5.32 (s, 2H), 3.12 (s, 3H)

Compound 8

^{1 H NMR (300 MHz, CDCl} 3) δ 8.64-8.61 (m, 1H), 7.43-7.40 (m, 1H), 7.76-7.71 (m, 1H), 7.65-7.60 (m, 1H), 7.55-7.53 (m, 2H), 7.47-7.38 (m, 4H), 7.04 (s, IH), 5.28

Examples 24, 25 and 26 [Synthesis of Compounds 24, 52 and 26]

1) 1-> 2

Compound 1 (0.337 g, 1.22 mmol) was dissolved in DMF (6 ml), K ₂ CO ₃ (0.30 g, 2.19 mmol) was added thereto and stirred for 10 minutes. 2-iodopropane (0.18 ml, 1.84 mmol) was added thereto, followed by stirring for 2 hours. The reaction is quenched with H ₂ O and extracted with EA. Wash the organic layer 3 times with H ₂ O. The organic layer is dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Crude Compound 2 is obtained.

2) 2-> 3

Crude Compound 2 (1.22 mmol) was dissolved in MeOH / MC (1/1, 12 ml), Pd / C (0.06 g, 0.06 mmol) was added and hydrogen was added. After completion of the reaction, filtration, and concentration under reduced pressure, Crude Compound 3 is obtained.

3) 3-> 4

Crude Compound 3 (1.22 mmol) was dissolved in DMF (12 ml), then IBX (0.87 g, 1.46 mmol) was added thereto and stirred for 2 hours. The reaction is quenched with NaHCO _{3 (aq)} and extracted with EA. The organic layer is dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Compound 4a (0.194 g, 66%) was obtained by drying the precipitated solid by recrystallization with EA and hexane. The compound 4b (trace amount) and compound 4c (trace amount) were obtained by column chromatography on the filtrate.

Ex. ^{24 3step yield: 66%, 1} H NMR (300 MHz, CDCl 3) δ 8.19 (d, J = 7.5 Hz, 1H), 8.02 (d, J = 7.5 Hz, 1H), 7.73 (t, J = 7.5 Hz (D, J = 6.6 Hz, 6H), 7.53 (t, J = 7.5 Hz, 1H), 5.04-4.96

Ex. ^{25 3step yield: trace amount, 1} H NMR (300 MHz, CDCl 3) δ 8.22 (d, J = 7.5 Hz, 1H), 8.14 (d, J = 7.5 Hz, 1H), 7.75 (t, J = 7.5 Hz , 7.52 (t, J = 7.5 Hz, 1H), 5.42-5.30 (m,

Ex 26 3 step yield: trace amount, ¹ H NMR (300 MHz, CDCl ₃ )? 8.32 (d, J = 7.5 Hz, 1H), 7.87-7.77 ), 5.23-5.14 (m, IH), 1.86 (d, J = 6.6 Hz, 6H)

Examples 27, 28 and 29 [Synthesis of compounds 27, 28 and 29]

1) 1-> 2

Cool H ₂ SO ₄ (8.3 ml) in an ice bath and add Compound 1 (Example 1, 1.0 g, 4.15 mmol). Add 90% HNO ₃ (0.25 ml, 4.97 mmol) slowly and stir for another 30 min. Pour the reaction solution into ice and adjust pH = 5-6 with 2N NaOH. The reaction is extracted several times with EA. The organic layer is dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Recrystallized with EA and hexane, and the precipitated solid was filtered and dried to obtain compound 2 (0.993 g, 84%).

Ex. 27

_{1H NMR (300 MHz, CDCl 3} ) δ 9.00 (d, J = 2.4 Hz, 1H), 8.58 (dd, J = 8.4, 2.4 Hz, 1H), 8.26 (d, J = 8.4 Hz, 1H), 5.11- 5.02 (m, 1 H), 1.74 (d, J = 6.6 Hz, 6 H)

2) 2-> 3

Compound 2 was dissolved in MeOH / MC (2/1, 51 ml) and 5% Pd / C (0.18 g, 5 mol%) was added. After the Celite filter was purified by EA / Hx recrystallization, compound 3 (0.805 g, 92%) was obtained.

Ex. 28

^{1 H NMR (300 MHz, CDCl} 3) δ 8.22-8.19 (m, 1H), 7.40 (s, 1H), 6.92-6.88 (m, 1H), 5.11-5.06 (m, 1H), 1.72-1.69 (d , ≪ / RTI > J = 6.6 Hz, 6H)

3) 3-> 4

Add HF-Pyridine (11.7 ml) to the cornical tube, add compound 3 (0.75 g, 2.93 mmol) at 0 ° C, and stir for 15 minutes. Add NaNO ₂ (0.28 g, 4.10 mmol) and stir at room temperature for 15 minutes. After stirring overnight at 110 ° C, cool at room temperature. Ice is added and EA is added to extract. The EA layer is treated with MgSO ₄ , and after silicagel filter, it is concentrated under reduced pressure. It is obtained by recrystallization with EA / Hex.

49 mg (6%)

Ex. 29

^{1 H NMR (300 MHz, CDCl} 3) δ 8.03 (dd, J = 8.4, 4.8 Hz, 1H), 7.86 (dd, J = 8.4, 2.7 Hz, 1H), 7.43 (dt, J = 8.1, 2.7 Hz, 1H), 5.04-4.95 (m, 1H), 1.70 (d, J = 6.6 Hz, 6H)

Examples 30 and 31 [Synthesis of compounds 30 and 31]

1) 1-> 2

Compound 1 (5.9 g, 21.5 mmol) was dissolved in DMF (107.5 ml), K ₂ CO ₃ (4.46 g, 32.25 mmol) was added thereto and stirred for 10 minutes. Iodomethane (1.6 ml, 25.71 mmol) was added thereto and stirred for 3 hours. The reaction is quenched with H ₂ O and extracted with EA. Wash the organic layer 3 times with H ₂ O. The organic layer is dried over MgSO ₄ , filtered, and concentrated under reduced pressure. Recrystallized with EA and hexane, and the precipitated solid was filtered and dried to obtain Compound 2a (1.1 g, 42%). The filtrate is concentrated under reduced pressure. Recrystallized with EA and Hexane, and the precipitated solid was filtered and dried to obtain Compound 2b (0.9 g, 35%).

Compound 2a

^{1 H NMR (300 MHz, CDCl} 3) δ 8.47-8.44 (m, 1H), 8.39-8.36 (m, 1H), 7.69-7.59 (m, 2H), 7.57-7.53 (m, 2H), 7.45- 7.32 (m, 3H), 7.02 (s, IH), 5.28 (s, 2H), 4.46

Compound 2b

^{1 H NMR (300 MHz, CDCl} 3) δ 8.74-8.71 (d, J = 8.1 Hz, 1H), 8.42-8.39 (d, J = 8.2 Hz, 1H),

2H), 4.29 (s, 3H), 7.79-7.73 (m, 1H), 7.62-7.55

2) 2-> 3

Compound 2a (0.36 g, 1.24 mmol) was dissolved in MeOH / MC (1/1, 12.4 ml), Pd / C (0.26 g, 0.12 mmol) was added and hydrogen was added. After confirming the completion of the reaction, filtration and concentration under reduced pressure. After recrystallization from EA and hexane, the precipitated solid was filtered and dried to obtain Compound 3a (0.19 g, 80%).

Compound 3a

^{1 H NMR (300 MHz, DMSO} ) δ 8.51-8.48 (m, 1H), 8.33-8.23 (m, 1H), 7.76-7.69 (m, 2H), 7.61-7.56 (m, 1H) 6.95 (s, 1H ), 4.26 (s, 3H)

Compound 2b (0.42 g, 1.45 mmol) was dissolved in MeOH / MC (1/1, 14.4 ml), Pd / C (0.30 g, 0.14 mmol) was added and hydrogen was added. After confirming the completion of the reaction, filtration and concentration under reduced pressure. Recrystallized with EA and hexane, and the precipitated solid was filtered and dried to obtain Compound 3b (0.21 g, 74%).

Compound 3b

^{1 H NMR (300 MHz, DMSO} ) δ 8.36-8.20 (m, 2H), 7.76-7.57 (m, 3H), 6.95 (s, 1H), 4.39 (s, 3H)

3) 3-> 4

Compound 3a (0.21 g, 1.07 mmol) was dissolved in DMF (21 ml), followed by addition of IBX (0.77 g, 1.29 mmol) and stirring for 2 hours. The reaction is quenched with NaHCO _{3 (aq)} and extracted with EA. The organic layer is dried over MgSO ₄ , filtered, and concentrated under reduced pressure. The precipitated solid was filtered off by EA and hexane and dried to obtain compound 4a (0.126 g, 57%).

Ex. 30

^{1 H NMR (300 MHz, CDCl} 3) δ 8.20 (d, J = 9.3 Hz, 1H), 7.98 (d, J = 9.3 Hz, 1H), 7.74 (t, J = 7.7 Hz, 1H), 7.54 (t , J = 7.7 Hz, 1 H), 4.38 (s, 3 H)

Compound 3b (0.21 g, 1.07 mmol) was dissolved in DMF (21 ml), followed by addition of IBX (0.77 g, 1.29 mmol) and stirring for 2 hours. The reaction is quenched with NaHCO _{3 (aq)} and extracted with EA. The organic layer is dried over MgSO ₄ , filtered, and concentrated under reduced pressure. The precipitated solid was filtered off by EA and hexane and dried to obtain compound 4b (0.09 g, 41%).

Ex. 31

^{1 H NMR (300 MHz, CDCl} 3) δ 8.16 (q, J = 7.7 Hz, 2H), 7.75 (t, J = 7.5 Hz, 1H), 7.52 (t, J = 7.5 Hz, 1H), 4.40 (s , 3H)

Examples 32 and 33 [Synthesis of compounds 32 and 33]

1) 1-> 2

Compound 1 (2.5 g, 9.08 mmol) was dissolved in DMF (45 ml), K ₂ CO ₃ (1.88 g, 13.62 mmol) was added thereto and stirred for 10 minutes. Ethyl bromide (0.8 ml, 10.89 mmol) was added and stirred for 4 hours. The reaction is quenched with H ₂ O and extracted with EA. Wash the organic layer 3 times with H ₂ O. The organic layer was dried over MgSO ₄ , filtered, concentrated under reduced pressure and then dried to give Crude compounds 2a and 2b (2.29 g, 80%).

1) 2-> 3

Crude compound 2 (2.29 g, 7.25 mmol) was dissolved in MeOH / MC (1/1, 72 ml), Pd / C (1.54 g, 0.73 mmol) was added and hydrogen was added. After confirming the completion of the reaction, filtration and concentration under reduced pressure. Recrystallization with EA and Hexane was performed to filter out the precipitated solid. column chromatography, and dried under reduced pressure to obtain Crude compounds 3a and 3b (1.55 g, 96%).

1) 3-> 4

Compound 3a (1.03 g, 4.83 mmol) was dissolved in DMF (96 ml), followed by addition of IBX (3.45 g, 5.79 mmol) and stirring for 2 hours. The reaction mixture is quenched with NaHCO _{3 (aq)} and extracted with EA. The organic layer is dried over MgSO ₄ , filtered, and concentrated under reduced pressure. column chromatography, and dried under reduced pressure to obtain compound 4a (0.87 g, 79%).

Ex. 33

^{1 H NMR (300 MHz, CDCl} 3) δ 8.19 (d, J = 7.5 Hz, 1H), 8.00 (d, J = 7.5 Hz, 1H), 7.73 (t, J = 7.5 Hz, 1H), 7.53 (t , J = 7.5 Hz, 1H) , 4.64 (q, J = 7.3 Hz, 2H), 1.68 (t, J = 7.3 Hz, 1H)

Compound 3b (0.52 g, 2.43 mmol) was dissolved in DMF (48 ml), IBX (1.74 g, 2.92 mmol) was added thereto and stirred for 2 hours. The reaction mixture is quenched with NaHCO _{3 (aq)} and extracted with EA. The organic layer is dried over MgSO ₄ , filtered, and concentrated under reduced pressure. After separation by column chromatography, it was dried under reduced pressure to obtain compound 4b (0.45 g, 81%).

Ex. 32

^{1 H NMR (300 MHz, CDCl} 3) δ 8.07-8.00 (m, 1H), 7.78-7.75 (m, 1H), 7.41-7.35 (m, 1H), 7.14-7.09 (m, 1H), 4.37 (q , J = 7.3 Hz, 2H), 1.40 (t, J = 7.3 Hz, 1H)

Examples 34 and 35 [Synthesis of compounds 34 and 35]

1) 1-> 2

Compound 1 (5.5 g, 19.9 mmol) is dissolved in MeOH / MC (1/1, 200 ml), Pd / C (4.25 g, 1.99 mmol) is added and hydrogen is added. After confirming the completion of the reaction, filtration and concentration under reduced pressure. The precipitated solid was filtered off by EA and hexane and dried to obtain compound 2 (2.3 g, 60%).

Compound 2

¹ H NMR (300 MHz, CDCl ₃ )? 8.59-8.57 (m, 1 H), 8.35-8.32 (m, 1 H), 7.67-7.56

2) 2-> 3

Compound 2 (2.2 g, 11.8 mmol) was dissolved in DMF (236 ml), followed by addition of IBX (8.5 g, 14.29 mmol) and stirring for 2 hours. The reaction is quenched with NaHCO _{3 (aq)} and extracted with EA. The organic layer is dried over MgSO ₄ , filtered, and concentrated under reduced pressure. The precipitated solid was filtered off by EA and Hexane, and dried to obtain compound 3 (1.09 g, 43%).

Compound 3

^{1 H NMR (300 MHz, DMSO} ) δ 7.82-7.79 (m, 1H), 7.71-7.69 (m, 1H), 7.39-7.24 (m, 1H), 6.91-6.69 (m, 1H)

3) 3-> 4

Compound 3 (0.5 g, 2.5 mmol) was dissolved in DMF (25.0 ml), K ₂ CO _{3 -} (0.52 g, 3.7 mmol) was added thereto and stirred for 10 minutes. Benzyl bromide (0.36 ml, 3.0 mmol) was added thereto and stirred for 3 hours. The reaction is quenched with H ₂ O and extracted with EA. Wash the organic layer 3 times with H ₂ O. The organic layer is dried over MgSO ₄ , filtered, and concentrated under reduced pressure. The precipitated solid was filtered off by EA and hexane and dried to obtain Compound 4a (1.19 g, 38%). Compound 4b (trace amount) .

Ex. 35

^{1 H NMR (300 MHz, CDCl} 3) δ 8.08 (d, J = 7.5 Hz, 1H), 7.94 (d, J = 7.5 Hz, 1H), 7.79 (t, J = 7.5 Hz, 1H), 7.45-7.31 (m, 5 H), 7.09 (t, J = 7.5 Hz, 1 H), 4.65

* Ex. 34

^{1 H NMR (300 MHz, CDCl} 3) δ 8.18 (d, J = 7.5 Hz, 1H), 8.00 (d, J = 7.5 Hz, 1H), 7.71 (t, J = 7.5 Hz, 1H), 7.52 (t , J = 7.5 Hz, 1H) , 7.48-7.45 (m, 2H), 7.53-7.34 (m, 3H) 5.71 (s, 2H)

Example 36 [Synthesis of Compound 36]

1) 1-> 2

Compound 1 (2 g, 7.27 mmol) was dissolved in DMF (36 ml), K ₂ CO ₃ (1.8 g, 13.1 mmol) was added thereto and stirred for 10 minutes. Iodomethane (0.68 ml, 10.9 mmol) was added thereto, followed by stirring for 2 hours. The reaction is quenched with H ₂ O and extracted with EA. Wash the organic layer with H ₂ O several times. The organic layer is dried over MgSO ₄ , filtered, and concentrated under reduced pressure. Recrystallized with EA and hexane, and the precipitated solid was filtered and dried to obtain Compound 2a (1.1 g, 42%). The filtrate is concentrated under reduced pressure. After separation by column chromatography (EA: HX = 1: 2), the compound 2b + Compound 2c (1.05 g, 51%) was obtained by recrystallization from EA and hexane.

2) 2-> 3

Compound 2b + Compound 2c (1 g, 3.46 mmol) was dissolved in MeOH / MC (1/1, 34 ml), Pd / C (0.73 g, 0.35 mmol) was added and hydrogen was added. After completion of the reaction, the reaction mixture was filtered through a Celite filter and concentrated under reduced pressure to obtain Compound 3b + Compound 3c (0.7 g, quantitative yield).

3) 3-> 4

Compound 3b + Compound 3c (0.7 g, 3.51 mmol) was dissolved in DMF (18 ml), IBX (2.3 g, 3.87 mmol) was added thereto and stirred for 2.5 hours. The reaction is quenched with NaHCO _{3 (aq)} and extracted with EA. The organic layer is dried over MgSO ₄ , filtered, and concentrated under reduced pressure. column chromatography (EA: HX = 1: 1), followed by recrystallization with EA and hexane to obtain Compound 4c (53.8 mg, 7%).

Ex. 36

¹ H NMR (300 MHz, CDCl ₃ )? 8.32 (d, J = 7.7 Hz, 1H), 7.88-7.79 (m, 2H), 7.69-7.64

Example 37 [Synthesis of Compound 37]

1) 1-> 2

Compound 1 (0.1 g, 0.363 mmol) was dissolved in DMF (3.6 ml), K ₂ CO ₃ (0.09 g, 0.653 mmol) was added thereto and stirred for 10 minutes. Dimethylsulfamoyl chloride (0.059 ml, 0.545 mmol) was added thereto and stirred for 2 hours. The reaction is quenched with H ₂ O and extracted with EA. Wash the organic layer 3 times with H ₂ O. The organic layer is dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The concentrated compound is dissolved only in MC, followed by short silica fliter, washed with MC, and concentrated under reduced pressure to obtain Crude Compound 2 .

2) 2-> 3

Crude Compound 2 is dissolved in MeOH / MC (1/1, 0.1 M), Pd / C (5 mol%) is added and hydrogen is added. After completion of the reaction, the reaction mixture is filtered through a Celite filter and concentrated under reduced pressure to obtain Crude Compound 3 .

3) 3-> 4

Crude Compound 3 was dissolved in DMF (3 ml), IBX (0.19 g, 0.314 mmol) was added thereto, and the mixture was stirred for 30 minutes. The reaction is quenched with NaHCO _{3 (aq)} and extracted with EA. The organic layer is dried over MgSO ₄ , filtered, and concentrated under reduced pressure. Purify by column chromatography and dry to give compound 4 (0.01 g).

Ex. 37

¹ H NMR (300 MHz, CDCl ₃ )? 8.26-8.18 (m, 2H), 7.79 (m,

Example 38 [Synthesis of Compound 38]

1) 1-> 2

Compound 1 (0.1 g, 0.363 mmol) was dissolved in DMF (3.6 ml) and 2,2-dimethoxy propane (0.45 ml, 3.63 mmol) and TsOH (6.3 mg, 0.036 mmol), and the mixture was stirred for 20 minutes. The reaction is poured into ice, quenched with H ₂ O and extracted with EA. Wash the organic layer with H ₂ O several times. The organic layer is dried over MgSO ₄ , filtered, and concentrated under reduced pressure. Purified by column chromatography and dried to give compound 2 (91 mg, 72%).

2) 2-> 3

Compound 2 was dissolved in MeOH / MC (1/1, 3 ml), Pd / C (56 mg, 0.026 mmol) was added and hydrogen was added. After completion of the reaction, the reaction mixture is filtered through a Celite filter and concentrated under reduced pressure to obtain Crude Compound 3 .

3) 3-> 4

Crude Compound 3 is dissolved in DMF (0.1 M), then IBX (0.436 mmol) is added thereto and stirred for 2 hours. The reaction is quenched with NaHCO _{3 (aq)} and extracted with EA. The organic layer is dried over MgSO ₄ , filtered, and concentrated under reduced pressure. Recrystallization from EA and hexane gave Compound 4 (19.8 mg, 28%).

Ex.38

^{1 H NMR (300 MHz, CDCl} 3) δ 8.20 (d, J = 7.7 Hz, 1H), 8.10 (d, J = 7.7 Hz, 1H), 7.74 (t, J = 7.7 Hz, 1H), 7.55 (t , J = 7.7 Hz, 1 H), 3.21 (s, 3 H), 2.02 (s, 6 H)

Examples 39 and 40 [Synthesis of compounds 39 and 40]

1) 1-> 2

Compound 1 (0.5 g, 1.81 mmol) was dissolved in DMF (9 ml), K ₂ CO ₃ (0.37 g, 2.71 mmol) was added thereto and stirred for 10 minutes. 4-Morpholinecarbonyl chloride (0.24 ml, 2.18 mmol) was added and stirred for 10 hours. The reaction is quenched with H ₂ O and extracted with EA. Wash the organic layer 3 times with H ₂ O. The organic layer is dried over MgSO ₄ , filtered, and concentrated under reduced pressure. EA, and HX to obtain crystalline Compound 2a . After crystallization, the filtrate is concentrated under reduced pressure to obtain Compound 2b .

Compound 2a

^{1 H NMR (300 MHz, CDCl} 3) δ 8.72 (d, J = 8.0 Hz, 1H), 8.42 (d, J = 8.0 Hz, 1H), 7.79 (t, J = 7.5 Hz, 1H), 7.63 (t 2H, J = 7.5 Hz, 1H), 7.57-7.54 (m, 2H), 7.48-7.37 (m, 4H)

Compound 2b

^{1 H NMR (300 MHz, CDCl} 3) δ 8.57-8.54 (m, 1H), 8.39-8.36 (m, 1H), 7.72-7.66 (m, 2H), 7.55-7.53 (m, 2H), 7.47-7.35 (m, 3H), 7.48-7.37 (m, 4H), 6.97 (s,

2) 2-> 3

Compound 2a (0.3 g, 0.77 mmol) was dissolved in MeOH / MC (1/1, 7.72 ml), Pd / C (0.16 g, 0.07 mmol) was added and hydrogen was added. After completion of the reaction, the reaction mixture is filtered through Celite and concentrated under reduced pressure to obtain Crude Compound 3a .

Compound 3a

^{1 H NMR (300 MHz, CDCl} 3) δ 8.72 (d, J = 8.0 Hz, 1H), 8.34 (d, J = 8.0 Hz, 1H), 7.81-7.66 (m, 2H), 7.44 (s, 1H) , 3.93-3.91 (m, 8H)

Compound 2b (0.3 g, 0.77 mmol) was dissolved in MeOH / MC (1/1, 7.72 ml), Pd / C (0.16 g, 0.07 mmol) was added and hydrogen was added. After confirming the completion of the reaction, the mixture is filtered through Celite and then concentrated under reduced pressure to obtain Crude Compound 3b .

Compound 3b

^{1 H NMR (300 MHz, CDCl} 3) δ 8.57-8.54 (m, 1H), 8.57-8.54 (m, 1H), 7.30-8.28 (m, 1H), 7.73-7.67 (m, 2H), 6.97 (s , ≪ / RTI > 1H), 3.89-3.86 (m, 8H)

3) 3-> 4

Compound 3a (0.16 g, 0.56 mmol) was dissolved in DMF (11 ml), followed by addition of IBX (0.39 g, 0.66 mmol) and stirring for 3 hours. The reaction is quenched with NaHCO _{3 (aq)} and extracted with EA. The organic layer is dried over MgSO ₄ , filtered, and concentrated under reduced pressure. After recrystallization with EA and hexane, the precipitated solid was filtered and dried to obtain compound 4a (0.068 g, 40%).

Ex.39

^{1 H NMR (300 MHz, CDCl} 3) δ 8.24 (d, J = 7.7 Hz, 1H), 8.18 (d, J = 7.7 Hz, 1H), 7.80 (t, J = 7.7 Hz, 1H), 7.57 (t 2H, J = 7.7 Hz, 1H), 3.92 (s, 4H), 3.78-3.73

Compound 3b (0.05 g, 0.17 mmol) was dissolved in DMF (3 ml), followed by addition of IBX (0.12 g, 0.21 mmol) and stirring for 3 hours. The reaction is quenched with NaHCO _{3 (aq)} and extracted with EA. The organic layer is dried over MgSO ₄ , filtered, and concentrated under reduced pressure. After recrystallization with EA and hexane, the precipitated solid was filtered and dried to obtain compound 4b (0.035 g, 66%).

Ex.40

^{1 H NMR (300 MHz, CDCl} 3) δ 8.26 (d, J = 7.7 Hz, 1H), 8.17 (d, J = 7.7 Hz, 1H), 7.80 (t, J = 7.7 Hz, 1H), 7.64 (t , J = 7.7 Hz, 1 H), 3.88 - 3.72 (m, 8 H)

Examples 41 and 42 [Synthesis of compounds 41 and 42]

1) 1-> 2

Compound 1 (0.5 g, 1.81 mmol) was dissolved in DMF (9 ml), K ₂ CO ₃ (0.37 g, 2.71 mmol) was added thereto and stirred for 10 minutes. dimethylcarbamic chloride (0.2 ml, 2.18 mmol) were added and stirred for 10 hours. The reaction is quenched with H ₂ O and extracted with EA. Wash the organic layer 3 times with H ₂ O. The organic layer is dried over MgSO ₄ , filtered, and concentrated under reduced pressure. EA, and HX to obtain crystalline Compound 2a (0.38 g, 61%). After crystallization, the filtrate is concentrated under reduced pressure to obtain Compound 2b (0.12 g, 20%).

2) 2-> 3

Compound 2a (0.38 g, 1.09 mmol) was dissolved in MeOH / MC (1/1, 10.8 ml), Pd / C (0.23 g, 0.11 mmol) was added and hydrogen was added. After completion of the reaction, the reaction mixture is filtered through Celite and concentrated under reduced pressure to obtain Crude Compound 3a .

Compound 2b (0.12 g, 0.35 mmol) was dissolved in MeOH / MC (1/1, 3.4 ml), Pd / C (0.074 g, 0.035 mmol) was added and hydrogen was added. After confirming the completion of the reaction, the mixture is filtered through Celite and then concentrated under reduced pressure to obtain Crude Compound 3b .

3) 3-> 4

Compound 3a (0.23 g, 0.89 mmol) was dissolved in DMF (17 ml), followed by addition of IBX (0.64 g, 1.07 mmol) and stirring for 3 hours. The reaction is quenched with NaHCO _{3 (aq)} and extracted with EA. The organic layer is dried over MgSO ₄ , filtered, and concentrated under reduced pressure. After recrystallization with EA and hexane, the precipitated solid was filtered and dried to obtain compound 4a (0.09 g, 37%).

Ex.41

^{1 H NMR (300 MHz, CDCl} 3) δ 8.25 (d, J = 7.5 Hz, 1H), 8.17 (d, J = 7.5 Hz, 1H), 7.78 (t, J = 7.5 Hz, 1H), 7.57 (t , J = 7.5 Hz, 1 H), 3.32 (s, 1 H), 3.01 (s,

Compound 3b (0.06 g, 0.23 mmol) was dissolved in DMF (5 ml), followed by addition of IBX (0.17 g, 0.28 mmol) and stirring for 3 hours. The reaction is quenched with NaHCO _{3 (aq)} and extracted with EA. The organic layer is dried over MgSO ₄ , filtered, and concentrated under reduced pressure. After recrystallization with EA and hexane, the precipitated solid was filtered and dried to obtain compound 4b (0.035 g, 56%).

Ex.42

^{1 H NMR (300 MHz, CDCl} 3) δ 8.25 (d, J = 7.7 Hz, 1H), 8.16 (d, J = 7.7 Hz, 1H), 7.79 (t, J = 7.7 Hz, 1H), 7.62 (t , J = 7.7 Hz, 1 H), 3.29 (s, 1 H), 3.19 (s,

Example 43 [Synthesis of Compound 43]

1) 1-> 2

3,4-dihydro-2H-pyran (3.6 ml) and TsOH (12.5 mg, 0.073 mmol) were added to Compound 1 (0.2 g, 0.73 mmol) and refluxed for 3.5 hours. The reaction is poured into ice, quenched with H ₂ O and extracted with EA. Wash the organic layer with H ₂ O several times. The organic layer is dried over MgSO ₄ , filtered, and concentrated under reduced pressure. Purify by column chromatography and dry to give compound 2 (0.2 g, 75%).

2) 2-> 3

Compound 2 was dissolved in MeOH / MC (1/1, 11 ml), Pd / C (0.12 g, 0.055 mmol) was added and hydrogen was added. After completion of the reaction, the reaction mixture is filtered through a Celite filter and concentrated under reduced pressure to obtain Crude Compound 3 .

3) 3-> 4

Crude Compound 3 was dissolved in DMF (5.5 ml), IBX (0.36 g, 0.603 mmol) was added thereto, and the mixture was stirred for 30 minutes. The reaction is quenched with NaHCO _{3 (aq)} and extracted with EA. The organic layer is dried over MgSO ₄ , filtered, and concentrated under reduced pressure. After silica filtration, recrystallized with EA and HX to obtain Compound 4 (35.4 mg, 23%).

Ex. 43

^{1 H NMR (300 MHz, CDCl} 3) δ 8.21 (d, J = 7.9 Hz, 1H), 8.08 (d, J = 7.9 Hz, 1H), 7.77-7.72 (m, 1H), 7.58-7.53 (m, 1H), 5.91 (dd, J = 2.7 Hz, 5.3 Hz, IH), 4.11-4.06 (m, IH), 3.87-3.79 (m, IH), 2.52-2.49 , ≪ / RTI > 2H), 1.81-1.73 (m, 3H)

Examples 44 and 45 [Synthesis of compounds 44 and 45]

1) 1-> 2

Compound 1 (0.2 g, 0.73 mmol) was dissolved in DMF (7.5 ml), K ₂ CO ₃ (0.3 g, 2.18 mmol) and KI (12 mg, 0.073 mmol) were added thereto and stirred for 20 minutes. 1-Bromo-2-methylpropane (0.12 ml, 0.87 mmol) was added and the mixture was stirred at 60 ^° C for 3 hours. The reaction is poured into ice, quenched with H ₂ O and extracted with EA. Wash the organic layer with H ₂ O several times. The organic layer is dried over MgSO ₄ , filtered, and concentrated under reduced pressure. Compound 2a (0.15 g, 62%) and Compound 2b + Compound 2c (0.07 g, 29%) are obtained after column chromatography (EA: HX = 1: 3).

2) 2-> 3

Compound 2a (0.14 g, 0.422 mmol) was dissolved in MeOH / MC (1/1, 8 ml), Pd / C (90 mg, 0.042 mmol) was added and hydrogen was added. After completion of the reaction, the reaction mixture was filtered through a Celite filter and concentrated under reduced pressure to obtain crude Compound 3a .

Compound 2b + Compound 2c (70 mg, 0.21 mmol) was dissolved in MeOH / MC (1/1, 4 ml), Pd / C (45 mg, 0.021 mmol) was added and hydrogen was added. After completion of the reaction, the reaction mixture is filtered through a Celite filter and concentrated under reduced pressure to obtain crude Compound 3b + Compound 3c .

3) 3-> 4

Crude Compound 3a was dissolved in DMF (4 ml), IBX (0.28 g, 0.465 mmol) was added thereto, and the mixture was stirred for 17.5 hours. The reaction is quenched with NaHCO _{3 (aq)} and extracted with EA. The organic layer is dried over MgSO ₄ , filtered, and concentrated under reduced pressure. After silica filtration, purified by hexane to obtain Compound 4a (51.1 mg, 47%).

Ex. 44

^{1 H NMR (300 MHz, CDCl} 3) δ 8.19 (d, J = 7.5 Hz, 1H), 8.00 (d, J = 7.5 Hz, 1H), 7.73 (t, J = 7.7 Hz, 1H), 7.53 (t , J = 7.7 Hz, 1H) , 4.39 (d, J = 7.3 Hz, 2H), 2.56-2.42 (m, 1H), 1.02 (d, J = 6.8 Hz, 6H)

Compound 3b + Compound 3c (70 mg, 0.211 mmol) was dissolved in DMF (4 ml), followed by addition of IBX (0.14 g, 0.232 mmol) and stirring for 16 hours. The reaction is quenched with NaHCO _{3 (aq)} and extracted with EA. The organic layer is dried over MgSO ₄ , filtered, and concentrated under reduced pressure. column chromatography (EA: HX = 1: 3) followed by drying to obtain Compound 4b (36 mg, 67%).

Ex.45

^{1 H NMR (300 MHz, CDCl} 3) δ 8.21 (d, J = 7.5 Hz, 1H), 8.14 (d, J = 7.9 Hz, 1H), 7.75 (t, J = 7.7 Hz, 1H), 7.52 (t , J = 7.7 Hz, 1H) , 4.56 (d, J = 7.3 Hz, 2H), 2.74-2.39 (m, 1H), 1.00 (d, J = 6.8 Hz, 6H)

Example 46 [Synthesis of Compound 46]

1) 1-> 2

Compound 1 (2.0 g, 7.26 mmol) and TsOH (0.125 g, 0.72 mmol) were dissolved in 3,4-dihydro-2H-pyran (36 ml) and stirred for 3 hours. After completion of the reaction, quenching with NaCl (aq) and extraction with EA. Wash the organic layer 3 times with H ₂ O. The organic layer is dried over MgSO ₄ , filtered, and concentrated under reduced pressure. Crude compound 2 was obtained.

2) 2-> 3

Crude compound 2 (2.0 g, 5.56 mmol) was dissolved in MeOH / MC (1/1, 54 ml), Pd / C (1.1 g, 0.56 mmol) was added and hydrogen was added. After completion of the reaction, the reaction mixture was filtered through a Celite filter to obtain a reduced pressure Crude compound 3 .

3) 3-> 4

Crude compound 3 (1.05 g, 3.9 mmol) was dissolved in DMF (80 ml), IBX (1.3 g, 4.68 mmol) was added thereto and stirred for 2 hours. The reaction is quenched with NaHCO _{3 (aq)} and extracted with EA. The organic layer is dried over MgSO ₄ , filtered, and concentrated under reduced pressure. The precipitated solid was filtered off by EA and Hexane and dried to obtain compound 4 (0.19 g, 18%).

Ex. 46

^{1 H NMR (300 MHz, CDCl} 3) δ 8.23 (d, J = 7.5 Hz, 1H), 8.14 (d, J = 7.5 Hz, 1H), 7.74 (t, J = 7.5 Hz, 1H), 7.52 (t 1H, J = 7.5 Hz, 1H), 6.24-6.19 (m, 1H), 4.08-4.04 (m, 1H), 3.86-3.79 (m, 1H), 2.53-2.48 , ≪ / RTI > 2H), 1.84-1.70 (m, 3H)

Example 47 [Synthesis of compound 47]

1) 1-> 2

Compound 1 (2.0 g, 7.26 mmol) was dissolved in KOH (4.06 g, 7.26 mmol) and H ₂ O (7.26 ml) and stirred for 10 minutes. Hydroxylamine-O-sulfonic acid (4.1 g, 3.6 mmol) is slowly added and heated to 60 ° C. Stir for 12 hours. The reaction is quenched with H ₂ O and extracted with EA. Wash the organic layer 3 times with H ₂ O. The organic layer is dried over MgSO ₄ , filtered, and concentrated under reduced pressure. Column chromatography (EA: Hexane = 1: 3) separates the compound. The separated compound was concentrated under reduced pressure to obtain compound 2 (0.3 g, 14%).

Compound 2

^{1 H NMR (300 MHz, CDCl} 3) δ 8.45-8.38 (m, 2H), 7.70-7.54 (m, 4H), 7.47-7.37 (m, 3H), 6.99 (s, 1H), 6.25 (s, 2H ), 5.29 (s, 2 H)

2) 2-> 3

Compound 2 (0.08 g, 0.27 mmol) is dissolved in MeOH / MC (1/1, 2.7 ml), Pd / C (0.058 g, 0.027 mmol) is added and hydrogen is added. After completion of the reaction, the reaction mixture was filtered through Celite and then concentrated under reduced pressure to obtain Crude Compound 3 (0.05 g, 91%).

Compound 3

^{1 H NMR (300 MHz, CDCl} 3) δ 8.40-8.30 (m, 2H), 7.65-7.54 (m, 2H), 7.01 (s, 1H), 6.90 (s, 2H)

3) 3-> 4

Compound 3 (0.05 g, 0.25 mmol) was dissolved in DMF (5 ml), followed by addition of IBX (0.18 g, 0.29 mmol) and stirring for 3 hours. The reaction mixture is quenched with NaHCO _{3 (aq)} and extracted with EA. The organic layer is dried over MgSO ₄ , filtered, and concentrated under reduced pressure. After recrystallization from EA and hexane, the precipitated solid was filtered and dried to obtain compound 4 (0.049 g, 92%).

Ex.47

^{1 H NMR (300 MHz, CDCl} 3) δ 7.73 (d, J = 7.7 Hz, 1H), 7.44 (d, J = 7.7 Hz, 1H), 7.27 (t, J = 7.7 Hz, 1H), 6.91 (t , J = 7.7 Hz, 1 H), 3.15 (s, 2 H)

Examples 48 and 49 [Synthesis of compounds 48 and 49]

1) 1-> 2

Compound 1 (0.2 g, 0.73 mmol) was dissolved in DMF (1.8 ml), K ₂ CO ₃ (0.1 g, 0.73 mmol) was added thereto and stirred for 10 minutes. tert-Butyl bromoacetate (0.12 ml, 0.80 mmol) was added and the mixture was stirred at room temperature for 12 hours. The reaction is quenched with H ₂ O and extracted with EA. Wash the organic layer 3 times with H ₂ O. The organic layer is dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Column chromatography (EA: Hexane = 1: 4) separates the compound. The separated compounds were each obtained by concentration under reduced pressure. Compound 2b (141 mg, 62%) Compound 1 (38.9 mg), compound 2a (62 mg, 27%

Compound 2a

^{1 H NMR (300 MHz, CDCl} 3) δ 8.49 (d, J = 7.5 Hz, 1H), 8.39 (d, J = 7.5 Hz, 1H), 7.67-7.37 (m, 7H), 7.04 (s, 1H) , 5.38 (s, 2H), 5.29 (s, 2H), 1.49 (s, 9H)

Compound 2b

^{1 H NMR (300 MHz, CDCl} 3) δ 8.73 (d, J = 8.1 Hz, 1H), 8.41 (d, J = 8.1 Hz, 1H), 7.78-7.36 (m, 7H), 6.75 (s, 1H) , 5.32 (s, 2H), 5.30 (s, 2H), 1.44 (s, 9H)

2) 2-> 3

Compound 2a, Compound 2b (1.0 eq) is dissolved in MeOH / MC (1/1, 0.1M) and 5% Pd / C (10 mol%) is added and hydrogen is added. After completion of the reaction, filtration and concentration under reduced pressure were carried out to obtain Crude compound 3a and Crude compound 3b was obtained.

3) 3-> 4

Crude Compound 3a, Crude Compound 3b (1.0 eq) is dissolved in DMF (0.1 M), then IBX (1.2 eq) is added and stirred for 3 hours. The reaction is quenched with NaHCO _{3 (aq)} and extracted with EA. The organic layer is dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The precipitated solid was filtered off by recrystallization with EA and hexane and dried to give compound 4a compound 4b was obtained.

Ex.48

^{2step yield: 77%, 1 H} NMR (300 MHz, CDCl 3) δ 8.21 (d, J = 7.5 Hz, 1H), 8.03 (d, J = 7.5 Hz, 1H), 7.74 (t, J = 7.5 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 5.27 (s, 2H), 1.51

Ex.49

^{2step yield: 17%, 1 H} NMR (300 MHz, CDCl 3) δ 8.21 (d, J = 7.5 Hz, 1H), 8.165 (d, J = 7.5 Hz, 1H), 7.76 (t, J = 7.5 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 5.37 (s, 2H), 1.50

Production Example 2 [Synthesis of triazole intermediate 2]

1) 1-> 2

After dissolving 4-amino-1-naphthol (5.0 g, 26.43 mmol) in DMF (132 ml), K ₂ CO ₃ (11.0 g, 79.29 mmol) was added and then benzylbromide (7.5 ml, 63.44 ml) . After completion of the reaction, quenching with NH ₄ Cl (aq) (200 ml) and extraction with EA. The organic layer is dried over MgSO ₄ , filtered, and concentrated under reduced pressure. Recrystallized with EA and hexane, and the precipitated solid was filtered and dried to obtain compound 2 (5.3 g, 72%).

Compound 2

^{1 H NMR (300 MHz, CDCl} 3) δ 8.79 (d, J = 8.5 Hz, 1H), 8.46 (d, J = 8.5 Hz, 1H), 8.38 (d, J = 8.5 Hz, 1H), 7.77-7.39 (m, 6 H), 6.90 (d, J = 8.5 Hz, 1 H), 5.36 (s,

1) 2-> 3

Compound 2 (5.0 g, 17.9 mmol) is dissolved in THF (179 ml) and then PtO ₂ (0.5 g, 1.79 mmol) is added. After completion of the reaction, the reaction mixture was filtered through PtO ₂ and concentrated under reduced pressure to obtain Compound 3 .

Compound 3

¹ H NMR (300 MHz, CDCl ₃ )? 8.35-8.32 (m, IH), 7.84-7.81 (m, IH), 7.53-7.48 (m, 4H), 7.48-7.31 (m, 2 H), 5.18 (s, 2 H)

Example 50 [Synthesis of Compound 50]

1) 1-> 2

Dilute 4-Fluoroaniline (0.30 ml, 3.10 mmol) and 35% Conc.HCl (1.24 ml, 9.30 mmol) in H ₂ O (10 ml, 0.3 M) in one round bottle flask. NaNO ₂ (0.21 g, 3.10 mmol) was then added Dilute to H ₂ O (1.5 ml, 2M) and allow to stand for 20 minutes. Compound 1 (0.77 g, 3.10 mmol) is dissolved in EtOH (15 ml) in the other round bottem flask and slowly added to the prepared solution for 30 min. After confirming the completion of the reaction, the reaction product is quenched with NaHCO _{3 (aq)} and extracted with EA. The organic layer is dried over MgSO ₄ , filtered, and concentrated under reduced pressure. After recrystallization with EA and hexane, the precipitated solid was filtered and dried to obtain compound 2 (0.56 g, 49%).

Compound 2

^{1 H NMR (300 MHz, CDCl} 3) δ 8.35-8.32 (m, 1H), 8.00-7.96 (m, 1H), 7.90-8.87 (m, 2H), 7.62-7.55 (m, 4H), 7.46-7.36 (s, 2H), 5.24 (s, 2H), < RTI ID =

2) 2-> 3

Compound 2 (0.5 g, 1.34 mmol) was dissolved in CH ₃ CN (34 ml) and copper acetate (1.41 g, 9.69 mmol) was added. Heat to 60 캜. After confirming the termination of the reaction, quenching with NaCl and extraction with EA. The organic layer is dried over MgSO ₄ , filtered, and concentrated under reduced pressure. After recrystallization with EA and hexane, the precipitated solid was filtered and dried to obtain compound 3 (0.45 g, 90%).

Compound 3

^{1 H NMR (300 MHz, CDCl} 3) δ 8.58 (d, J = 7.7 Hz, 1H), 8.40 (d, J = 7.7 Hz, 1H), 8.32-8.27 (m, 2H), 7.73-7.67 (m, 2H), 7.62-7.55 (m, 2H), 7.23-7.20 (m, 2H), 7.08 (s,

3) 3-> 4-> 5

Compound 3 (0.44 g, 1.19 mmol) was dissolved in MeOH / MC (1/1, 12 ml), 20% PdOH ₂ (0.09 g, 0.119 mmol) was added and hydrogen was added. After completion of the reaction, the reaction solution was filtered through Celite and then concentrated under reduced pressure to obtain compound 4 (0.26 g, 78%). Compound 4 (0.02 g, 0.93 mmol) was dissolved in DMF (19 ml), followed by addition of IBX (0.66 g, 1.17 mmol) and stirring for 3 hours. The reaction is quenched with NaHCO _{3 (aq)} and extracted with EA. The organic layer is dried over MgSO ₄ , filtered, and concentrated under reduced pressure. After recrystallization with EA and hexane, the precipitated solid was filtered and dried to obtain compound 5 (0.23 g, 86%).

Ex.50

^{2step yield: 59%, 1 H} NMR (300 MHz, CDCl 3) δ 8.29-8.22 (m, 3H), 8.14 (d, J = 7.7 Hz, 1H), 7.79 (t, J = 7.7 Hz, 1H), 7.60 (t, J = 7.7 Hz, 1 H), 7.29 - 7.17 (m, 2 H)

Example 51 [Synthesis of Compound 51]

1) 1-> 2

Dilute 4-fluoroaniline (0.29 ml, 3.01 mmol) and 35% Conc.HCl (0.78 ml, 9.03 mmol) in H ₂ O (11 ml, 0.3 M) in one round bottle flask. NaNO ₂ (0.20 g, 3.01 mmol) was then added Dilute to H ₂ O (1.5 ml, 2M) and allow to stand for 20 minutes. Dissolve Compound 1 (0.75 g, 3.01 mmol) in EtOH (15 ml) in the other round bottem flask and slowly add to the prepared solution for 30 min. After confirming the completion of the reaction, the reaction product is quenched with NaHCO _{3 (aq)} and extracted with EA. The organic layer is dried over MgSO ₄ , filtered, and concentrated under reduced pressure. After recrystallization with EA and hexane, the precipitated solid was filtered and dried to obtain compound 2 (0.97 g, 87%).

Compound 2

^{1 H NMR (300 MHz, CDCl} 3) δ 8.35-8.32 (m, 1H), 7.80-7.78 (m, 1H), 7.58-8.35 (m, 11H), 5.26 (s, 2H)

2) 2-> 3

Compound 2 (0.97 g, 2.61 mmol) was dissolved in CH ₃ CN (66 ml) and then copper acetate (2.74 g, 13.72 mmol) was added. Heat to 60 캜. After confirming the termination of the reaction, quenching with NaCl and extraction with EA. The organic layer is dried over MgSO ₄ , filtered, and concentrated under reduced pressure. After recrystallization with EA and hexane, the precipitated solid was filtered and dried to obtain compound 3 (0.90 g, 93%).

Compound 3

^{1 H NMR (300 MHz, CDCl} 3) δ 8.60 (d, J = 7.7 Hz, 1H), 8.41 (d, J = 7.7 Hz, 1H), 7.73-7.62 (m, 2H), 7.45-7.31 (m, 9H), 7.11 (s, 1 H), 5.33 (s, 2 H)

3) 3-> 4-> 5

Compound 3 (0.90 g, 2.43 mmol) is dissolved in MeOH / MC (1/1, 24 ml), 20% PdOH ₂ (0.17 g, 0.24 mmol) is added and hydrogen is added. After completion of the reaction, the mixture was filtered through Celite and then concentrated under reduced pressure to obtain compound 4 (0.27 g, 43%). Compound 4 (0.25 g, 0.96 mmol) was dissolved in DMF (18 ml), followed by addition of IBX (0.68 g, 1.15 mmol) and stirring for 3 hours. The reaction is quenched with NaHCO _{3 (aq)} and extracted with EA. The organic layer is dried over MgSO ₄ , filtered, and concentrated under reduced pressure. After recrystallization with EA and hexane, the precipitated solid was filtered and dried to obtain compound 5 (0.15 g, 72%).

Ex.51

^{2step yield: 30%, 1 H} NMR (300 MHz, CDCl 3) δ 8.24 (d, J = 7.7 Hz, 1H), 8.15 (d, J = 7.7 Hz, 1H), 8.97 (t, J = 7.7 Hz, 1H), 7.79 (t, J = 7.7 Hz, 1H), 7.62-7.50 (m, 2H), 7.40-7.24

Examples 52, 53, 53-1, 54, 54-1 and 55 [Synthesis of compounds 52, 53, 53-1, 54, 54-1 and 55]

1) 1-> 2

Compound 1 (0.2 g, 0.726 mmol) was dissolved in DMF (3.6 ml), Cs ₂ CO ₃ (0.94 g, 2.9 mmol) was added thereto and stirred for 20 minutes. 1-tert-Butoxycarbonyl-4- (p-toluenesulfonyloxy) piperidine (0.26 ml, 0.726 mmol) was added and the mixture was stirred at 80 ° C for 15.5 hours. The resulting solid is filtered and washed several times with EA. The reaction is quenched with H ₂ O and extracted with EA. Wash the organic layer 3 times with H ₂ O. The organic layer is dried over MgSO ₄ , filtered, and concentrated under reduced pressure. Compound 2b and compound 2c (Orange solid, 70.6 mg, 21%) were obtained by column chromatography and then dried to yield compound 2a (yellow solid, 0.2 g, 60%).

2) 2-> 3

Compound 2a (0.14 g, 0.422 mmol) was dissolved in MeOH / MC (1/1, 0.1 M), then 5% Pd / C (92 mg, 0.043 mmol) was added and hydrogen was added. After completion of the reaction, filtration and concentration under reduced pressure are carried out to obtain Crude Compound 3a .

Compound 2b and Compound 2c (51.7 mg, 0.011 mmol) were dissolved in MeOH / MC (1/1, 0.05 M), followed by addition of 5% Pd / C (24 mg, 0.011 mmol) and hydrogenation. After completion of the reaction, filtration and concentration under reduced pressure are performed to obtain Crude Compounds 3b and 3c .

3) 3-> 4

Crude Compound 3a is dissolved in DMF (4.4 ml), then IBX (0.3 g, 0.475 mmol) is added thereto and stirred for 2 hours. The reaction is quenched with NaHCO _{3 (aq)} and extracted with EA. The organic layer is dried over MgSO ₄ , filtered and concentrated under reduced pressure. EA: Recrystallization from hexane gave compound 4a (yellow solid, 0.12 g, 72%).

Ex.52

^{1 H NMR (300 MHz, CDCl} 3) δ 8.20 (d, J = 7.7 Hz, 1H), 8.00 (d, J = 7.5 Hz, 1H) 7.74 (t, J = 7.6 Hz, 1H) 7.54 (t, J 2H), 2.26-2.20 (m, 4H), 1.49 (s, 9H)

Crude Compounds 3b and 3c were dissolved in DMF (2.2 ml), IBX (77 mg, 0.124 mmol) was added thereto, and the mixture was stirred for 2.5 hours. The reaction is quenched with NaHCO _{3 (aq)} and extracted with EA. The organic layer is dried over MgSO ₄ , filtered, and concentrated under reduced pressure. After purification by column chromatography and drying, compound 4b (Orange solid, 26.8 mg, 62%) and compound 4c (Yellow solid, 7.1 mg, 16%) were obtained.

Ex.54

^{1 H NMR (300 MHz, CDCl} 3) δ 8.21 (d, J = 7.7 Hz, 1H), 8.14 (d, J = 7.7 Hz, 1H), 7.75 (t, J = 7.6 Hz, 1H) 7.53 (t, J = 7.7 Hz, 1H), 5.17-5.10 (m, 1H), 4.30 (m, 2H), 3.01 (m, 2H), 2.26-2.18 (m, 4H), 1.50 (s, 9H)

Ex.53

^{1 H NMR (300 MHz, CDCl} 3) δ 8.31 (d, J = 7.9 Hz, 1H), 7.82-7.77 (m, 2H), 7.66 (t, J = 7.5 Hz, 1H), 4.92 (m, 1H) , 4.35 (m, 2H), 3.09 (m, 2H), 2.32 (m, 4H)

4) 4-> 5

Compound 4a was dissolved in DCM (2.2 ml), TFA (0.44 ml, 0.3 M) was added, and the mixture was stirred for 2 hours. Ether and EA are added to the reaction mixture, and the mixture is concentrated under reduced pressure several times. MC: Recrystallized with hexane to obtain compound 5 (yellow solid, 30 mg, 81%).

Ex.55

^{1 H NMR (300 MHz, DMSO} ) δ 8.04 (d, J = 7.5 Hz, 1H), 7.92 (d, J = 7.5 Hz, 1H) 7.78 (t, J = 7.6 Hz, 1H) 7.60 (t, J = 6.6 Hz, 7.6 Hz, 1H), 5.09 (m, 1H), 3.47-3.35 (m, 2H), 3.20-3.12 (m, 2H), 2.49-2.39 )

Compound 4b (1.67 mmol) Was dissolved in DCM (28 ml), TFA (5.5 ml, 0.3 M) was added thereto, and the mixture was stirred for 2 hours. Ether and EA are added to the reaction mixture, and the mixture is concentrated under reduced pressure several times. MC: Compound 5b (yellow solid, 662 mg, 99%) was obtained by recrystallization from hexane.

Ex.54-1

^{1 H NMR (300 MHz, DMSO} ) δ 8.85 (br, 1H), 8.56 (br, 1H), 8.08 (d, J = 7.5 Hz, 1H), 8.01 (d, J = 7.5 Hz, 1H) 7.79 (t , J = 7.2 Hz, 1H) 7.58 (t, J = 7.2 Hz, 1H), 5.29 (m, 1H), 3.47 (m, 2H), 3.25 (m, 2H), 2.30 (m, 4H)

Compound 4c (0.371 mmol) Was dissolved in DCM (6.2 ml), TFA (1.2 ml, 0.3 M) was added thereto, and the mixture was stirred for 2 hours. Ether and EA are added to the reaction mixture, and the mixture is concentrated under reduced pressure several times. MC: Recrystallized as hexane to obtain compound 5c (yellow solid, 138 mg, 94%).

Ex.53-1

^{1 H NMR (300 MHz, DMSO} ) δ 8.92 (br, 1H), 8.59 (br, 1H), 8.13 (m, 2H), 7.85 (t, J = 7.2 Hz, 1H) 7.70 (t, J = 7.2 Hz (M, IH), 5.45 (m, IH), 3.32 (m, 4H), 2.40

Example 56 [Synthesis of Compound 56]

1) 1-> 2

Compound 1 (0.3 g, 1.09 mmol) was dissolved in DMF (5.5 ml), Cs ₂ CO ₃ (1.42 g, 4.36 mmol) was added thereto and stirred for 20 minutes. 3-Oxetanyl p-toluenesulfonate (0.25 ml, 1.09 mmol) was added and the mixture was stirred at 80 ° C for 16 hours. The resulting solid is filtered and washed several times with EA. The reaction is quenched with H ₂ O and extracted with EA. Wash the organic layer 3 times with H ₂ O. The organic layer is dried over MgSO ₄ , filtered, and concentrated under reduced pressure. After purification by column chromatography and drying, Crude compound 2 (compound 2: Oxetanyl p-toluenesylphonate = 1: 1, Yellow oil, 0.26 g) was obtained.

2) 2-> 3

Crude Compound 2 (0.25 g) was dissolved in MeOH / MC (1/1, 15 ml), then 5% Pd / C (0.16 g) was added and hydrogen was added. After completion of the reaction, filtration, and concentration under reduced pressure, Crude Compound 3 is obtained.

3) 3-> 4

Crude Compound 3 is dissolved in DMF (7.5 ml), IBX (0.51 g) is added, and the mixture is stirred for 2 hours. The reaction is quenched with NaHCO _{3 (aq)} and extracted with EA. The organic layer is dried over MgSO ₄ , filtered and concentrated under reduced pressure. Compound 4 (yellow solid, 46.5 mg, 17% [from Compound 1] ) was obtained by recrystallization from EA: hexane.

Ex.56

^{1 H NMR (300 MHz, CDCl} 3) δ 8.22 (d, J = 7.9 Hz, 1H), 8.06 (d, J = 7.7 Hz, 1H) 7.77 (t, J = 7.6 Hz, 1H) 7.58 (t, J = 7.5 Hz, 7.9 Hz, 1H ), 5.98-5.89 (m, 1H), 5.29 (t, J = 6.9 Hz, 6.4 Hz, 2H), 5.17 (t, J = 7.5 Hz, 7.3 Hz, 2H)

Examples 57, 58 and 59 [Synthesis of compounds 57, 58 and 59]

Tetrahydropyran-4-ol (3 ml, 31.55 mmol) is dissolved in pyridine (32 ml) at 0 ° C and p-toluenesulfonyl chloride is added slowly. After the temperature was raised to room temperature, stirring was continued for 18 hours. After confirming the termination of the reaction, quenching with 1 M HCl and extracting with EA. The extracted EA was washed once with NaHCO ₃ , and the organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure to obtain compound 1 (7.27 g, 90%).

Compound 1

^{1 H NMR (300 MHz, CDCl} 3) δ 7.80 (d, J = 8.2 Hz, 1H), 7.35 (d, J = 8.2 Hz, 1H), 4.72-4.64 (m, 1H), 3.90-3.83 (m, 2H), 3.51-3.43 (m, 2H), 2.45 (s, 3H), 1.90-1.64 (m, 4H)

1) 2-> 3

Compound 2 (4.5 g, 16.34 mmol) was dissolved in DMF (82 ml) and stirred for 10 minutes. Cs ₂ is heated to _{CO 3 (21.3 g, 65.38 mmol} ) then gave put tetrahydro-2H-pyran-4- yl 4-methylbenzene-sulfonate after 80 ℃ gave put (4.20 g, 16.34 mmol). Stir for 12 hours. After completion of the reaction, the reaction product is quenched with NaHCO ₃ and extracted with EA. Wash the organic layer 3 times with H ₂ O. The organic layer was dried over MgSO ₄ , filtered, and concentrated under reduced pressure to obtain crude compounds 3a, 3b and 3c (4.84 g, 82%).

2) 3-> 4

Crude compounds 3a, 3b and 3c (4.84 g, 13.34 mmol) were dissolved in MeOH / MC (1/1, 134 ml), Pd / C (2.85 g, 1.33 mmol) was added and hydrogen was added. After completion of the reaction, the reaction mixture was filtered through Celite and then concentrated under reduced pressure to obtain crude compounds 4a, 4b and 4c (3.02 g, 83%).

3) 4-> 5

Crude compounds 4a, 4b and 4c (3.02 g, 11.2 mmol) were dissolved in DMF (222 ml), IBX (8.31 g, 13.3 mmol) was added thereto and stirred for 2 hours. After completion of the reaction, the reaction product is quenched with NaHCO _{3 (aq)} and extracted with EA. The organic layer is dried over MgSO ₄ , filtered, and concentrated under reduced pressure. After recrystallization with MC and hexane, the precipitated solid was filtered and dried to obtain compound 5a (2.05 g, 91%) and compound 5b and compound 5c .

Ex.57

^{1 H NMR (300 MHz, CDCl} 3) δ 8.20 (d, J = 7.5 Hz, 1H), 8.01 (d, J = 7.5 Hz, 1H), 7.74 (t, J = 7.5 Hz, 1H), 7.54 (t , J = 7.5 Hz, 1H) , 4.90-4.80 (m, 1H), 4.17-4.13 (m, 2H), 3.66-3.57 (m, 2H), 2.44-2.25 (m, 4H)

Ex.58

^{* 1 H NMR (300 MHz,} CDCl 3) δ 8.22 (d, J = 7.5 Hz, 1H), 8.14 (d, J = 7.5 Hz, 1H), 7.75 (t, J = 7.5 Hz, 1H), 7.53 ( t, J = 7.5 Hz, 1H ), 5.25-5.17 (m, 1H), 4.20-4.11 (m, 2H), 3.68-3.5760m, 2H), 2.47-2.35 (m, 2H), 2.17-2.13 (m , 2H)

Ex.59

^{1 H NMR (300 MHz, CDCl} 3) δ 8.19 (d, J = 7.5 Hz, 1H), 8.01 (d, J = 7.5 Hz, 1H), 7.74 (t, J = 7.5 Hz, 1H), 7.54 (t , J = 7.5 Hz, 1H) , 4.85-4.83 (m, 1H), 4.19-4.14 (m, 2H), 3.68-3.57 (m, 2H), 2.43-2.28 (m, 4H)

Examples 60, 61 and 62 [Synthesis of compounds 60, 61 and 62]

1) 1-> 2

Compound 1 (0.05 g, 0.235 mmol) was dissolved in AcOH (0.1 M, 2.4 ml), Zn dust (0.154 g, 2.35 mmol), and the mixture was stirred for 20 minutes. Ac ₂ O (0.044 ml, 0.470 mmol) was added and the mixture was refluxed with stirring for 3 hours. The reaction is filtered, washed with EA, and then washed three times with a saturated aqueous NaHCO ₃ solution. The EA layer is dried with NaSO ₄ , filtered and concentrated under reduced pressure. EA: recrystallized with hexane to obtain compound 2 compound.

Ex.60

^{yield: 74%, 1 H NMR} (300 MHz, CDCl 3) δ 8.38-8.35 (m, 1H), 7.98-7.95 (m, 1H), 7.73-7.66 (m, 2H), 4.67 (s, 3H), 2.51 (s, 3H), 2.50 (s, 3H)

Ex.61

^{yield: 52%, 1 H NMR} (300 MHz, CDCl 3) δ 8.79 (d, J = 8.1 Hz, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.76 (t, J = 7.8 Hz, 1H ), 7.65 (t, J = 7.8 Hz, 1 H), 4.38 (s, 3H)

Ex.62

^{yield: 18%, 1 H NMR} (300 MHz, CDCl 3) δ 8.51 (d, J = 7.2 Hz, 1H), 7.86 (d, J = 7.2 Hz, 1H), 7.68-7.63 (m, 2H), 4.52 (s, 3H), 2.50 (s, 3H), 2.46 (s, 3H)

Examples 63, 64 and 65 [Synthesis of compounds 63, 64 and 65]

1) 1-> 2

Compound 1 (0.05 g, 0.235 mmol) was dissolved in CHCl ₃ (0.1 M, 2.4 ml) and pyridine (0.057 ml, 0.705 mmol), dimethylcarbamyl chloride (0.065 ml, (0.154 g, 2.35 mmol) in that order. And refluxed for 3 hours. The reaction is filtered, rinsed with EA, and washed 3 times with H ₂ O. The EA layer is dried with NaSO ₄ , filtered and concentrated under reduced pressure. EA: recrystallized with hexane to obtain compound 2 compound.

Ex.63

^{yield: 13%, 1 H NMR} (300 MHz, CDCl 3) δ 8.40-8.36 (m, 1H), 8.07-8.03 (m, 1H), 7.70-7.67 (m, 2H), 4.69 (s, 3H), 3H), 3.25 (s, 3H), 3.10 (s, 3H), 3.09 (s, 3H)

Ex.64

^{yield: 53%, 1 H NMR} (300 MHz, CDCl 3) δ 8.76 (d, J = 8.1 Hz, 1H), 7.95 (d, J = 8.1 Hz, 1H), 7.72 (t, J = 6.9 Hz, 1H ), 7.62 (t, J = 6.9 Hz, 1H), 4.39 (s, 3H), 3.28 (s, 3H), 3.22 (s, 3H), 3.11 (s, 3H), 3.10 (s, 3H)

Ex.65

^{yield: 23%, 1 H NMR} (300 MHz, CDCl 3) δ 8.48 (d, J = 7.2 Hz, 1H), 7.92 (d, J = 7.2 Hz, 1H), 7.64-7.61 (m, 2H), 4.52 (s, 3H), 3.27 (s, 3H), 3.21 (s, 3H)

Examples 66, 67, and 68 [synthesis of compounds 66, 67, and 68]

1-BOC-3-hydroxyazetidine (5.0 g, 28.86 mmol) is dissolved in pyridine (28 ml) at 0 ° C and p-toluenesulfonyl chloride is added slowly. The temperature was raised to room temperature and then stirred for 8 hours. After confirming the termination of the reaction, quenching with 1 M HCl and extracting with EA. After washing the extracted EA with NaCl (aq), the organic layer was dried over MgSO ₄ , filtered, and concentrated under reduced pressure to obtain compound 1 (9.44 g, 99%).

Compound 1

^{1 H NMR (300 MHz, CDCl} 3) δ 7.79-7.70 (m, 2H), 7.38-7.30 (m, 2H), 5.00-4.98 (m, 1H), 4.12-4.07 (m, 2H), 3.90 (m , 2H), 2.46 (s, 3H), 1.41 (s, 9H)

1) 2-> 3

Compound 2 (2.5 g, 9.08 mmol) was dissolved in DMF (45 ml) and stirred for 10 minutes. And heated to (tosyloxy) -azetidine (2.97 g, 9.08 mmol) gave after 80 ℃ put _{- Cs 2 CO 3 (11.83 g} , 36.32 mmol) then gave into 1 - Boc - 3. Stir for 12 hours. After completion of the reaction, the reaction product is quenched with NaCl (aq) and extracted with EA. Wash the organic layer 3 times with H ₂ O. The organic layer was dried over MgSO ₄ , filtered, and concentrated under reduced pressure to give compound 3a (1.32 g, 34%), crude compound 3b, 3c (0.99 g, 26%).

2) 3-> 4

Compound 3a (1.3 g, 3.02 mmol) was dissolved in MeOH / MC (1/1, 30 ml), Pd / C (0.64 g, 0.30 mmol) was added and hydrogen was added. After completion of the reaction, the mixture was filtered through Celite and then concentrated under reduced pressure to obtain compound 4a (0.95 g, 92%).

Crude compound 3 (0.99 g, 2.29 mmol) was dissolved in MeOH / MC (1/1, 22 ml), Pd (OH) ₂ (0.16 g, 0.23 mmol) was added and hydrogen was added. After completion of the reaction, the reaction mixture was filtered through Celite and concentrated under reduced pressure to obtain crude compound 4b, 4c (0.701 g, 89%).

3) 4-> 5

Compound 4 (0.92 g, 2.70 mmol) was dissolved in DMF (54 ml), followed by addition of IBX (1.93 g, 3.24 mmol) and stirring for 3 hours. After completion of the reaction, the reaction product is quenched with NaHCO _{3 (aq)} and extracted with EA. The organic layer is dried over MgSO ₄ , filtered, and concentrated under reduced pressure. After purification by column chromatography, it was dried to obtain compound 5a (0.69 g, 73%).

Ex.66

^{1 H NMR (300 MHz, CDCl} 3) δ 8.21 (d, J = 7.7 Hz, 1H), 8.03 (d, J = 7.7 Hz, 1H), 7.76 (t, J = 7.7 Hz, 1H), 7.57 (t , J = 7.7 Hz, 1H) , 5.58-5.49 (m, 1H), 4.59-4.48 (m, 4H), 1.49 (s, 9H)

Crude compound 4b, 4c (0.70 g, 2.06 mmol) was dissolved in DMF (46 ml), IBX (1.6 g, 2.47 mmol) was added thereto and stirred for 3 hours. After completion of the reaction, the reaction product is quenched with NaHCO _{3 (aq)} and extracted with EA. The organic layer is dried over MgSO ₄ , filtered, and concentrated under reduced pressure. The product was purified by column chromatography and dried to obtain compound 5b (0.13 g 30%) and compound 5c (0.07 g, 10%).

Ex.67

^{1 H NMR (300 MHz, CDCl} 3) δ 8.23 (d, J = 7.5 Hz, 1H), 8.15 (d, J = 7.5 Hz, 1H), 7.77 (t, J = 7.5 Hz, 1H), 7.54 (t , J = 7.5 Hz, 1H) , 5.83-5.75 (m, 1H), 4.60-4.53 (m, 4H), 1.48 (s, 9H)

Ex.68

^{1 H NMR (300 MHz, CDCl} 3) δ 8.23 (d, J = 7.5 Hz, 1H), 8.04 (d, J = 7.5 Hz, 1H), 7.76 (t, J = 7.5 Hz, 1H), 7.57 (t , J = 7.5 Hz, 1H) , 5.55-5.51 (m, 1H), 4.56-4.48 (m, 4H) 1.48 (s, 9H)

Experimental Example 1: Measurement of NQO1 activity

The enzyme reaction solution contained 25 mM Tris / HCl (pH 7.4), 0.14% bovine serum albumin, 200 uM NADH, 77 uM Cytochrome C and 5 ng of NQO1 protein. The enzyme reaction is initiated with NADH addition and is performed at 37 ° C. At this time, the reaction rate was observed at 550 nm for 10 min that the absorbance was increased by reducing Cytochrome C, and the NQO1 activity was expressed as the amount of reduced cytochrome C [nmol cytochrome C reduced / min / ug protein].

Extinction coefficient for cytochrome C: 21.1 mmol / L / cm = 21.1 [mu] mol / ml / cm

NQO1 activity (5 uM, [nmol cytochrome C reduced / min / ug protein]).

The results are shown in Table 1 below.

compound NQO1 active compound NQO1 active compound NQO1 active Example 1 202.5 Example 24 256.8 Example 47 14.3 Example 2 330.4 Example 25 204.8 Example 48 218.3 Example 3 14.8 Example 26 181.5 Example 49 241.6 Example 4 3.8 Example 27 153.8 Example 50 217 Example 5 127.2 Example 28 244.6 Example 51 234.1 Example 6 187.6 Example 29 233.3 Example 52 235.2 Example 7 515.3 Example 30 232.5 Example 53 98.2 Example 8 240.3 Example 31 186.8 Example 53-1 111.8 Example 9 275.8 Example 32 209.8 Example 54 191.4 Example 10 222.7 Example 33 233.8 Example 54-1 271.6 Example 11 273.1 Example 34 156.5 Example 55 183 Example 12 173.0 Example 35 171.7 Example 56 227.1 Example 13 49.1 Example 36 143.5 Example 57 235.1 Example 14 19.4 Example 37 214.7 Example 58 205.2 Example 15 132.6 Example 38 106.5 Example 59 206.8 Example 16 40.0 Example 39 240.2 Example 60 31.8 Example 17 173.8 Example 40 202.8 Example 61 53.3 Example 18 235.4 Example 41 237.2 Example 62 55.4 Example 19 217.2 Example 42 218.9 Example 63 7.8 Example 20 12.8 Example 43 219.7 Example 64 14.0 Example 21 222.9 Example 44 234.1 Example 65 10.4 Example 22 236.4 Example 45 121.3 Example 66 182.2 Example 23 145.1 Example 46 233.2 Example 67 169.3 Example 68 158

As shown in Table 1, the compounds according to the present invention show NQO1 activity. Experimental Example 2: Measurement of Lactate Change in Cells

Cells are treated with 400 μl 6% PCA and recovered and extracted. Centrifuge (13,000 rpm, 10 min). The precipitate is dried by speed-vac, dried and the cell dry weight is measured. The supernatant is neutralized using 400 μl 1 M KOH, and the final volume is adjusted to 1 ml using 0.33 M KH ₂ PO ₄ / K ₂ HPO ₄ , pH 7.5. Centrifuge (13,000 rpm, 10 min) and measure the amount of lactate (Megazyme, K-LATE) in the supernatant.

The results are shown in Table 2 below.

compound Lactate change in cell
(nmol / mg cell) Example 1 (Compound 1) 8.0 Example 2 (Compound 2) 9.5 Example 3 (Compound 3) 9.8 Example 4 (Compound 4) 9.5 Example 5 (Compound 5) 9.8 Example 6 (Compound 6) 9.8 Example 7 (Compound 7) 10.7 Example 8 (Compound 8) 10.9 Example 9 (Compound 9) 11.7 Example 10 (Compound 10) 11.5 Example 11 (Compound 11) 9.7 Example 12 (Compound 12) 6.7 Example 13 (Compound 13) 8.9 Example 14 (Compound 14) 10.3 Example 15 (Compound 15) 6.4 Example 16 (Compound 16) 9.2 Example 17 (Compound 17) 5.3 Example 18 (Compound 18) 5.4 Example 19 (Compound 19) 5.1 Example 20 (Compound 20) 8.8 Example 21 (Compound 21) 5.5 Example 22 (Compound 22) 5.8 Example 23 (Compound 23) One

As shown in Table 2, it can be seen that Lactate activity in cells according to the embodiment of the present invention is shown. Since the ratio of NAD / NADH in Cytosol is similar to that of pyruvate / lactate, the ratio of NAD / NADH in the cytosol can be measured with pyruvate / lactate ratio. Therefore, when the amount of lactate decreases, the ratio of NAD / NADH in the cell increases. Experimental Example 3: Effect of the compound according to Example 12 and the compound according to Example 13 on weight loss in obese rats ( ob / ob )

A 10-week-old C57BL / 6J Lep ob / ob mouse with characteristics of genetic obesity of Charles River Laboratories, Japan (CRJ) was prepared and incubated at 20-24 ° C, 35-65% relative humidity, 150-300 lux, (200W × 260L × 130H (mm), Three-shine) kept in a breeding environment of 12 hours of light-dark cycle and 10-15 times / hr of evacuation. Two rats were kept in each box of CHARLES RIVER LABORATORIES, The low fat diet (11.9 kcal% fat, 5053, Labdiet, USA) of JAPAN (CRJ) was purchased and freely taken in the feeder. The drinking water was filtered using a filter and a water sterilizer. The sterilized purified water was dissolved in polycarbonate (250 mL) for free ingestion.

The compound according to Example 12 and the compound according to Example 13 synthesized in the present invention were administered to three C57BL / 6J Lep ob / ob mice at a dose of 100 mg / kg once a day for a total of 2 weeks for oral administration. Orally in the stomach using an attached disposable syringe. As a control, 0.1% SLS sodium lauryl sulfate: Soudium Lauryl Sulfate was administered to three C57BL / 6J Lep ob / ob mice at a dose of 10 mg / kg using the same method. The body weight gain, weight change, and intake amount according to the administration time were measured and are shown in FIG.

The body weight of the test animals was measured at the time of group separation (immediately before administration of the test substance) and from the start of administration to the end of the test, and the total weight gain was calculated by subtracting the body weight at the start of the experiment from the body weight measured on the day before the end. Dietary intake was measured twice a week from the beginning of the test substance administration to the end of the test.

As shown in the graph of FIG. 1, weight gain, body weight change and intake after 2 weeks of C57BL / 6J Lep ob / ob mice administered with the compound according to Example 12 were significantly decreased in some sections compared with the control .

Experimental Example 4: Obesity rat (Compound ob / ob ) Weight loss effect

C57BL / 6J Lep ob / ob mice, which have the characteristics of genetic obesity of CHARLES RIVER LABORATORIES, JAPAN (CRJ), were prepared at the temperature of 20 ~ 24 ℃, relative humidity 35 ~ 65%, illumination 150 ~ 300 lux, (200W × 260L × 130H (mm), Three-shine) kept in a breeding environment of 12 hours of light-dark cycle and 10-15 times / hr of evacuation. Two rats were kept in each box of CHARLES RIVER LABORATORIES, The low fat diet (11.9 kcal% fat, 5053, Labdiet, USA) of JAPAN (CRJ) was purchased and freely taken in the feeder. The drinking water was filtered using a filter and a water sterilizer. The sterilized purified water was dissolved in polycarbonate (250 mL) for free ingestion.

The compound according to Example 24 synthesized in the present invention was administered to three C57BL / 6J Lep ob / ob mice at a dosage of 100 mg / kg once a day for a total of 2 weeks using a disposable syringe with a sonde for oral administration Orally in the stomach. As a control, 0.1% SLS (Sodium Lauryl Sulfate) was administered to three C57BL / 6J Lep ob / ob mice at a dose of 100 mg / kg using the same method. Weight gain, weight change, and intake were measured according to the administration time, and the results are shown in FIG.

The body weight of the test animals was measured at the time of group separation (immediately before administration of the test substance) and from the start of administration to the end of the test, and the total weight gain was calculated by subtracting body weight at the start of the experiment from the body weight measured before the end. Dietary intake was measured twice a week from the beginning of the test substance administration to the end of the test.

As shown in the graph of FIG. 2, weight gain, weight change, and intake of the C57BL / 6J Lep ob / ob mice administered with the compound according to Example 24 were significantly decreased in the whole group compared with the control group .

Experimental Example 5: Compounds according to Examples 24, 30 and 31 in diabetic rats ( db / db ) Weight loss effect

C57BLKS / J-Lepr ^{db / db} mice with characteristics of genetic diabetes of CHARLES RIVER LABORATORIES, JAPAN (CRJ) were prepared for 5 weeks of age. Temperature was 22 ~ 24 degrees, relative humidity was 50 ~ 30%, illumination was 150 ~ 300 lux (200W × 260L × 130H (mm), Three-shine), which were kept in a breeding environment of 10-15 times / hr for 12 hours of light and dark cycle, were fed two rabbits per box. The feeds were CHARLES RIVER LABORATORIES , And low fat diet (11.9 kcal% fat, 5053, Labdiet) of JAPAN (CRJ Co.) were purchased and freely taken into the feeder. The drinking water was filtered using a filter and a water sterilizer. The sterilized purified water was filtered through a polycarbonate- (250 mL) for free ingestion.

The compounds according to Examples 24, 30 and 31 synthesized in the present invention were administered once daily for three times each at a dosage of 80 mg / kg for each of C57BLKS / J-Lepr ^{db / db} mice for a total of 2 weeks. The amount of the administration solution was forcedly orally administered in the stomach using a syringe. Three control C57BLKS / J-Lepr ^{db / db} mice were administered 0.1% SLS at a dose of 80 mg / kg using the same method. The body weight gain, weight change, and intake amount according to the administration time were measured and are shown in FIG.

The body weight of the test animals was measured at the time of group separation (immediately before administration of the test substance) and from the start of administration to the end of the test, and the total weight gain was calculated by subtracting the body weight at the start of the experiment from the body weight measured on the day before the end. Dietary intake was measured twice a week from the beginning of the test substance administration to the end of the test.

As shown in the graph of FIG. 2, weight gain, weight change, and intake and blood sugar levels of C57BLKS / J-Lepr ^{db / db} mice administered with the compounds according to Examples 24, 30 and 31 were lower It can be seen that it is significantly reduced.

Experimental Example 6: Compounds according to Examples 24, 30 and 31 in diabetic rats ( db / db ) And Glucose Level and HbAAc (Fasting)

C57BLKS / J-Lepr ^{db / db} mice with characteristics of genetic diabetes of CHARLES RIVER LABORATORIES, JAPAN (CRJ) were prepared for 5 weeks of age. Temperature was 22 ~ 24 degrees, relative humidity was 50 ~ 30%, illumination was 150 ~ 300 lux (200W × 260L × 130H (mm), Three-shine), which were kept in a breeding environment of 10-15 times / hr for 12 hours of light and dark cycle, were fed two rabbits per box. The feeds were CHARLES RIVER LABORATORIES , And low fat diet (11.9 kcal% fat, 5053, Labdiet) of JAPAN (CRJ Co.) were purchased and freely taken in the feeder. The drinking water was filtered using a filter and a water sterilizer and sterilized purified water was poured into a polycarbonate- (250 mL) for free ingestion.

The compounds according to Examples 24, 30, and 31 synthesized in the present invention were administered to each of three C57BLKS / J-Lepr ^{db / db} mice at a dosage of 80 mg / kg, using a disposable syringe with a sonde for oral administration. Was orally administered in the stomach. As a control, 0.1% SLS was administered to three C57BLKS / J Lepr ^{db / db} mice at a dose of 80 mg / kg using the same method. Glucose level and Hb1Ac were measured once a week under the fasting condition for 6 hours. The results are shown in FIGS. 4 and 5 (the charts are changed to C57BLKS / J Lepr ^{db / db} , respectively).

To Figures 4 and 5 Glucose in fasting conditions (reference respectively C57BLKS / J Lepr ^{db /} change in ^db) embodiment as shown in Examples 24, 30, and administering a compound according to 31 the C57BLKS ^/ J-Lepr ^db / ^db mouse Level and glycated hemoglobin (Hb1Ac) were significantly decreased compared to the control group.

Claims (13)

A compound, or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, enantiomer or pharmaceutically acceptable diastereomer thereof, which is a compound represented by the formula (2)

(2)

In this formula,
Wherein each of R ₁ , R ₂ and R ₃ is independently hydrogen, C 1 -C 4 alkyl, or - (CQ ₁ Q ₂ ) _{m "} -C 4 -C 10 aryl wherein Q ₁ and Q ₂ are independently hydrogen or C1-C3 alkyl, and m " are each independently a natural number of 1 to 2;
X ₂ and X ₃ are each independently N, O or S;
X ₁ is or C ₁ -C 4 alkoxy, and X ₄ is hydrogen;

Is a single bond or a double bond,

Quot; means that a single bond or bond may not be formed A compound, or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, enantiomer or pharmaceutically acceptable diastereomer thereof, which is a compound represented by the formula (4)

(4)
Wherein R ₄ , R ₅ and R ₆ are each independently selected from the group consisting of hydrogen, a halogen atom, C 1 -C 6 alkyl substituted or unsubstituted with C 1 -C 3 alkoxy, substituted or unsubstituted C 2 -C 8 heterocycloalkyl, (CQ ₁ Q ₂ ) _{m "} -C 4 -C 8 aryl, - (CQ ₁ Q ₂ ) _m" -OQ ₃ , - (CQ ₁ Q ₂ ) _{m " 1} Q ₂ ) _{m ',} -CO (O) Q ₃ , -CO (O) Q ₃ , -CONQ ₃ Q ₄ , -NQ ₃ Q ₄ , or -SO (O) NQ ₃ Q ₄ ;
Wherein Q ₁ and Q ₂ are independently hydrogen or C ₁ -C 3 alkyl,
Q ₃ and Q ₄ are each independently hydrogen or unsubstituted C1-C4 alkyl, Or Q ₃ and Q ₄ may form a cyclic structure of unsubstituted C4-C6 heterocycloalkyl by a mutual bond, wherein the substituent is selected from the group consisting of a halogen atom, NH2, COO, and C1- Or more;
m " are each independently a natural number of 1 to 2;

Is a single bond or a double bond,

Quot; means that a single bond or bond may not be formed,
X ₁ and X ₂ are each independently selected from the group consisting of hydrogen, halogen, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 alkyl, unsubstituted C 2 -C 6 heterocycloalkyl wherein the heterocycloalkyl contains one or more heteroatoms It can be included), or a halogen-substituted or unsubstituted C4-C10 aryl, or X ₁ and X ₂ is an unsubstituted C4-C8, by mutual coupling-cycloalkyl, substituted or unsubstituted C4-C10 aryl, or a substituted or unsubstituted C 2 -C 6 heteroaryl, wherein the substituents are halogen elements, C 1 -C 4 alkyl, amino or nitro;
The heteroatom is at least one selected from N, O and S;
X ₃ , X ₄ and X ₅ are each independently N (H), O, S or C; Is a compound selected from the group consisting of compounds represented by the following formulas (4-3) and (4-4), a pharmaceutically acceptable salt, a hydrate, a solvate thereof, Enantiomer or pharmaceutically acceptable diastereomer thereof:

In this formula,
R ₅ is selected from the group consisting of hydrogen, a halogen atom, C 1 -C 6 alkyl substituted or unsubstituted with C 1 -C 3 alkoxy, substituted or unsubstituted C 2 -C 8 heterocycloalkyl, substituted or unsubstituted C 4 -C 8 aryl, (CQ ₁ Q ₂ ) _{m "} -C 4 -C 8 aryl, - (CQ ₁ Q ₂ ) _m" -OQ ₃ , - (CQ ₁ Q ₂ ) _{m '} Q ₃ , -CO (O) Q ₃ , -CONQ ₃ Q ₄ , -NQ ₃ Q ₄ , or -SO (O) NQ ₃ Q ₄ ;
X ₁ and X ₂ are each independently selected from the group consisting of hydrogen, halogen, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 alkyl, unsubstituted C 2 -C 6 heterocycloalkyl wherein the heterocycloalkyl contains one or more heteroatoms It can be included), or a halogen-substituted or unsubstituted C4-C10 aryl, or X ₁ and X ₂ is an unsubstituted C4-C8, by mutual coupling-cycloalkyl, substituted or unsubstituted C4-C10 aryl, or a substituted or unsubstituted C 2 -C 6 heteroaryl, wherein the substituents are halogen elements, C 1 -C 4 alkyl, amino or nitro;
The hetero atom is at least one selected from N, O and S. A compound selected from the group consisting of compounds represented by the following formulas (4-5) to (4-7), a pharmaceutically acceptable salt, hydrate, solvate, tautomer, enantiomer or pharmacological Enantiomerically acceptable diastereomers:

In this formula,
R ₅ and R ₆ are each independently selected from the group consisting of hydrogen, a halogen atom, a C 1 -C 6 alkyl substituted or unsubstituted with C 1 -C 3 alkoxy, a substituted or unsubstituted C 2 -C 8 heterocycloalkyl, a substituted or unsubstituted C 4 -C 8 aryl, (CQ ₁ Q ₂ ) _{m "} -C 4-C 8 aryl, - (CQ ₁ Q ₂ ) _m" -OQ ₃ , - (CQ ₁ Q ₂ ) _{m ',} unsubstituted C1-C6 heteroaryl _{, '-CO (O) Q 3,} -CO (O) Q 3, -CONQ 3 Q 4, -NQ 3 Q 4, or -SO (O) NQ ₃ Q _4, and ;;
X ₁ and X ₂ are each independently selected from the group consisting of hydrogen, halogen, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 -C 4 alkyl, unsubstituted C 2 -C 6 heterocycloalkyl wherein the heterocycloalkyl contains one or more heteroatoms It can be included), or a halogen-substituted or unsubstituted C4-C10 aryl, or X ₁ and X ₂ is an unsubstituted C4-C8, by mutual coupling-cycloalkyl, substituted or unsubstituted C4-C10 aryl, or a substituted or unsubstituted C 2 -C 6 heteroaryl, wherein the substituents are halogen elements, C 1 -C 4 alkyl, amino or nitro;
The hetero atom is at least one selected from N, O and S. Is a compound selected from the group consisting of compounds represented by the following formulas (4-8) to (4-10), a pharmaceutically acceptable salt, hydrate, solvate thereof, Enantiomer or pharmaceutically acceptable diastereomer thereof:

In this formula,
R ₄ , R ₅ and R ₆ are each independently selected from the group consisting of hydrogen, a halogen atom, a C 1 -C 6 alkyl substituted or unsubstituted with C 1 -C 3 alkoxy, a substituted or unsubstituted C 2 -C 8 heterocycloalkyl, a substituted or unsubstituted C 4 -C 8 aryl (CQ ₁ Q ₂ ) _{m "} -C 4 -C 8 aryl, - (CQ ₁ Q ₂ ) _m" -OQ ₃ , - (CQ ₁ Q ₂ ) _{m ',' -CO (O)} Q 3, -CO (O) Q 3, -CONQ 3 Q 4, -NQ 3 Q 4, or -SO (O) NQ ₃ Q _4, and;
R ₁₁ and R ₁₂ are each independently hydrogen, halogen element, substituted or unsubstituted C 1 -C 20 alkyl, amino or nitro;
X ₁ , X ₂ , X ₆ and X ₇ are each independently C (H) or N;
The hetero atom is at least one selected from N, O and S. A compound represented by the following formula (5), a pharmaceutically acceptable salt, hydrate, solvate, tautomer, enantiomer or pharmaceutically acceptable diastereomer thereof:

(5)
In this formula,
X ₁ and X ₂ are capable of forming a cyclic structure of a substituted or unsubstituted C4-C8 aryl;
X ₃ and X ₄ are each independently selected from NH, O and S;
R ₇ , R ₈ , R ₉ and R ₁₀ are each independently hydrogen or unsubstituted C 1 -C 3 alkyl;
Here, the substituent is a halogen atom or C1-C3 alkyl;
n is 0, 1 or 2; A process for preparing a compound of formula (4) according to claim 2,
(A) reacting a compound of the formula (6) and a compound of the formula (7) in the presence of a base;
(B) Step (A) a compound with HNO after the introduction of -NO ₂ in the resulting compound by reacting ₃ in acid conditions in step A), -NO ₂ through the reducing reaction generating on the -NH ₂ ;
(C) subjecting the compound produced in step (B) to a cyclization reaction under acidic conditions; And
(D) selectively reducing the compound produced in step (C), and then producing an end product through an oxidation reaction;
Comprising the steps of:

In this formula,
X ₁ and X ₂ are as defined in claim 4;
R ₅ is hydrogen, C 1 -C 6 alkyl, or C 4 -C 8 aryl;
Y ₁ is hydrogen, methyl, ethyl, propyl, or benzyl;
R ₁₃ is -OH, OCH ₃ , -OC ₂ H _5, -OC ₃ H ₇ , -OCH ₂ C ₆ H ₅ or -NH ₂ ;
Z is a halogen element. A process for preparing a compound of formula (4) according to claim 2,
(A ₁ ) reacting a compound of the following formula (6) with a compound of the following formula (7) in a base condition;
(B ₁ ) reacting the compound produced in step (A ₁ ) with Lawesson's reagent;
(C ₁ ) subjecting the compound produced in step (B ₁ ) to a cyclization reaction under basic conditions; And
(D ₁ ) hydrolyzing the compound produced in step (C ₁ ) under basic conditions; And
(E ₁ ) a step of reducing the compound produced in step (D ₁ ) and then producing an end product through an oxidation reaction;
Comprising the steps of:

In this formula,
X ₁ and X ₂ are as defined in claim 4;
R ₅ is hydrogen, C 1 -C 6 alkyl, or C 4 -C 8 aryl;
Y ₁ is hydrogen, methyl, ethyl, propyl, or benzyl;
R ₁₃ is -OH, OCH ₃ , -OC ₂ H _5, -OC ₃ H ₇ , -OCH ₂ C ₆ H ₅ or -NH ₂ ; And
Z is a halogen element. A process for preparing a compound of formula (4) according to claim 2 or a compound of formula (4-7) according to claim 4,
(A ₅ ) reacting a compound of the formula (6) and a compound of the formula (7)
(B ₅ ) reacting the compound produced in step (A ₅ ) with BF ₃ .Et ₂ O and then reacting with NH ₂ OH; And
(C ₅₎ step of the step and cyclization in acid and the resulting compound in the conditions (B _5), the oxidation reaction;
Comprising the steps of:

In this formula,
R < ₅ > is hydrogen, C1-C10 alkyl, or C4-C10 aryl;
Y ₁ is hydrogen, methyl, ethyl, propyl, or benzyl;
R ₁₃ is -OH, OCH ₃ , -OC ₂ H _5, -OC ₃ H ₇ , -OCH ₂ C ₆ H ₅ or -NH ₂ ; And
Z is a halogen element. A method for producing the compound of formula (4-8), (4-9) or (4-10) of claim 5,
(A ₆ ) reacting a compound of the formula (6) and a compound of the formula (7) in the presence of a base;
(B ₆ ) reacting a compound represented by the following formula (A ₆ ) with HNO ₃ in an acidic condition to introduce -NO ₂ , followed by hydrolysis under basic conditions;
(C ₆ ) reacting the compound produced in step (B ₆ ) with C ₆ H ₅ CH ₂ Z ₂ (Z ₂ is a halogen element) in a base condition;
(D ₆₎ after the reduction in acid and the resulting compound condition in step (C _6), and the cyclization reaction conditions from the acid comprising: hydrolyzing with a base;
(E ₆ ) is characterized in that the compound produced in the step (D ₆ ) is reacted with RX (X is halogen) or acid to introduce R, followed by reduction and cyclization, Lt; / RTI >

In this formula,
R < ₅ > is hydrogen, C1-C10 alkyl, or C4-C10 aryl;
Y ₁ is hydrogen, methyl, ethyl, propyl, or benzyl;
R ₁₃ is -OH, OCH ₃ , -OC ₂ H _5, -OC ₃ H ₇ , -OCH ₂ C ₆ H ₅ or -NH ₂ ; And
Z is a halogen element. A process for preparing a compound of formula (4-6) according to claim 4,
(A ₇ ) reacting a compound of the following formula (6) with C ₆ H ₅ CH ₂ Z ₂ (Z ₂ is a halogen element) under basic conditions;
(B ₇₎ The compound produced in step (A ₇₎ reacting with NH ₂ OH; And
(C ₇ ) reducing the compound produced in step (B ₇ ), subjecting the compound to a cyclization reaction, and performing an oxidation reaction;
Comprising the steps of:

In this formula,
Y ₁ is hydrogen, methyl, ethyl, propyl, or benzyl; And
R ₁₃ is -OH, OCH ₃ , -OC ₂ H _5, -OC ₃ H ₇ , -OCH ₂ C ₆ H ₅ or -NH ₂ . A process for preparing a compound of formula (4-5) according to claim 4,
(A ₈ ) A compound of the following formula (6) is reacted with HNO ₃ in an acidic condition to introduce -NO ₂ , followed by reducing the -NO ₂ -NH ₂ ;
(B ₈₎ and to the resulting compound in step (A ₈₎ reacting a compound of formula (7) in basic conditions;
(C ₈ ) reacting the compound produced in step (B ₈ ) with CAN (Cerium Ammonium Nitrate); And
(D ₈₎ phase (C ₈₎ after the cyclization of the compound produced in step to produce a final product by oxidation;
Comprising the steps of:

In this formula,
X ₁ and X ₂ are as defined in claim 7;
R ₅ is hydrogen, C 1 -C 10 alkyl, or C 4 -C 8 0 aryl;
Y ₁ is hydrogen, methyl, ethyl, propyl, or benzyl;
R ₁₃ is -OH, OCH ₃ , -OC ₂ H _5, -OC ₃ H ₇ , -OCH ₂ C ₆ H ₅ or -NH ₂ ; And
Z is a halogen element. (a) a pharmacologically effective amount of at least one compound selected from the group consisting of compounds of formulas (2), (4), (4-3), (4-4), (4-5) (4-7), (4-8), (4-9), (4-10) or (5), a pharmaceutically acceptable salt, hydrate, solvate, An enantiomer and a pharmaceutically acceptable diastereomer; And (b) a pharmaceutically acceptable carrier, diluent, or excipient, or a combination thereof.

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