KR101741956B1 - Novel compound, process for the preparation thereof and pharmaceutical composition comprising the same - Google Patents

Abstract

The present invention relates to a novel compound controlling the phosphorylation of PPAR by CDK5, a process for the preparation thereof, and a pharmaceutical composition comprising the same. The novel compound of the present invention combines to PPAR with high affinity, but does not induce gene transcription (transcriptional activity), thereby not acting as an agonist. Additionally, the novel compound blocks the phosphorylation of CDK5 so side effects of conventional treatment agents for diabetes can be prevented from generating, and has an excellent pharmaceutical property. Therefore, a pharmaceutical composition comprising the novel compound of the present invention can be usefully utilized for treating PPAR-related metabolic diseases.

Description

TECHNICAL FIELD [0001] The present invention relates to a novel compound, a process for producing the same, and a pharmaceutical composition comprising the same. BACKGROUND OF THE INVENTION 1. Field of the Invention [0001]

The present invention relates to a novel compound which binds to a peroxisome proliferator activated receptor (Gamma) but does not act as an agonist, a process for its preparation, and a pharmaceutical composition containing it as an active ingredient.

As the number of diabetic patients has increased over the past decade, the market for diabetes therapies has also grown. Diabetes mellitus has mainly been treated with insulin injections, but insulin is a cumbersome task to inject using injections and is merely supplementing insufficient insulin in the body, and does not solve the fundamental treatment of diabetes.

Accordingly, a drug that promotes insulin secretion such as sulfonylurea, a drug that slowly releases glucose stored in the liver such as metformin, and a drug that slowly inhibits glucose absorption, such as acarbose, Drugs or drugs that enhance the sensitivity of insulin receptors such as rosiglitazone and pioglitazone have been developed and marketed.

The thiazolidinedione (TZD) drugs, such as rosiglitazone and pioglitazone, act on the peroxisome proliferator activated receptor gamma (PPARγ) receptor, a nuclear receptor, It activates transcription and increases the sensitivity of insulin to show an anti-diabetic effect.

However, the thiazolidinedione drug can increase the activity of 'PPARγ' to obtain an anti-diabetic effect, but the side effects such as weight gain, edema, and decrease in bone density are regulated by controlling the expression of genes causing various side effects, It is possible to induce disease and the like, and the use thereof in the market is limited. Therefore, PPARγ partial agonist and two of three subunits of PPAR (PPAR-α / γ or PPAR-γ / δ) and three (PPAR- α / γ / δ) have also been developed, but they have not been introduced to the market due to side effects and safety issues.

On the other hand, according to recent research results, it has been reported that a substance named 'SR-1664' exhibits sufficient antidiabetic and insulin resistance effects without side effects due to thiazolidinedione drugs (see Non-Patent Document 1 And 2). These results indicate that obesity-like insulin resistance in diabetic patients is caused by phosphorylation of PPARγ serine 273 amino acid of CDK5 (Cyclin-dependent kinase 5) due to mutation of several genes, and phosphorylation of PPARγ by CDK5 Blockade is an important approach to the development of diabetes therapies.

Accordingly, the present inventors have found that, although they bind to PPARγ at high affinity but do not induce transcriptional activity, they do not act as agonists, they block the phosphorylation by CDK5 and improve insulin resistance, And to provide compounds having excellent physical properties (solubility, metabolis stability, PK).

Non-Patent Document 1: Nature. 2010, 466, 451-456 Non-Patent Document 2: Nature, 2010. 477.477-481

It is an object of the present invention to provide a compound which binds to PPARy but does not act as an agonist, or a pharmaceutically acceptable salt thereof.

It is another object of the present invention to provide a process for producing the above compound.

It is another object of the present invention to provide a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof.

In order to accomplish the above object, the present invention provides a compound represented by the following formula (1), or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

In Formula 1,

R ₁ to R ₄ are the same or different and each independently represents a hydrogen atom, a halogen atom, a C ₁ to C ₁₀ alkyl group, a C ₁ to C ₁₀ alkoxy group, and a hetero atom selected from the group consisting of N, O, and S And a heteroaryl group having 5 to 10 ring atoms containing at least one heteroatom,

R ₅ to R ₉ are the same or different and are each independently selected from the group consisting of hydrogen, a halogen group and a C ₁ to C ₁₀ alkoxy group,

R ₁₀ is selected from the group consisting of a hydroxyl group, an amino group and a C ₁ to C ₁₀ alkoxy group,

R ₁₁ is selected from the group consisting of hydrogen, a halogen group, a nitro group, a thiol group, a C ₁ to C ₁₀ alkyl group, a C ₁ to C ₁₀ alkoxy group, a C ₆ to C ₁₀ aryl group, and N, And a heteroaryl group having 5 to 10 ring atoms containing at least one heteroatom selected from the group consisting of

L is selected from the group consisting of a single bond, a C ₁ to C ₁₀ alkylene group and a C ₆ to C ₁₀ arylene group,

A is selected from the group consisting of O and NR ₁₂ ,

R ₁₂ is selected from the group consisting of a hydroxyl group and a C ₁ to C ₁₀ alkoxy group,

Alkoxy group of said R ₁ to R ₄ of the C ₁ to C ₁₀ alkyl group, C ₁ to C ₁₀ alkoxy group and a heteroaryl group of from 5 to 10 ring atoms, wherein R ₅ to R ₉ in the C ₁ to C ₁₀ of , wherein R ₁₀ a C ₁ to C ₁₀ alkoxy group, wherein R ₁₁ of the thiol group, C ₁ to C ₁₀ alkyl group, C ₁ to C ₁₀ alkoxy groups, C ₆ to C ₁₀ aryl group and the number of ring atoms The C ₁ to C ₁₀ alkylene group and the C ₆ to C ₁₀ arylene group of L each independently represent a halogen, a C ₁ to C ₁₀ alkyl group, and a C ₁ to C ₁₀ An alkoxy group, and the like. When the substituent group is plural, the plurality of substituents may be the same as or different from each other.

The present invention also relates to a process for preparing a compound represented by the formula (1): a) synthesizing a compound represented by the following formula (2) or (3); b) cyclizing the compound of formula (2) synthesized in step a) in the presence of polyphosphoric acids, or cyclizing the compound of formula (3) in the presence of acetic acid to obtain a compound of formula Synthesizing a compound to be displayed; c) reacting the compound represented by formula (4) synthesized in step (b) with a compound represented by formula (5) to synthesize a compound represented by formula (6); d) synthesizing a compound represented by the following formula (7) by substituting hydrogen bonded to the nitrogen atom of the compound represented by the formula (6) synthesized in the step c); And e) reacting the compound of formula (7) synthesized in step d) with a strong base to synthesize a compound represented by the following formula (1).

(2)

(3)

[Chemical Formula 4]

[Chemical Formula 5]

[Chemical Formula 6]

(7)

[Chemical Formula 1]

In the above Chemical Formulas 1 to 7,

The definitions of R ₁ to R ₁₁ , L and A are the same as those described above.

The present invention also provides a pharmaceutical composition for the treatment of metabolic diseases comprising the compound represented by the above-mentioned formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to the present invention binds to PPARγ with high affinity but does not act as an agonist and does not induce gene transcription and blocks the phosphorylation by CDK5, It is possible to minimize the occurrence of side effects caused by drugs used for treatment. Accordingly, the present invention can provide a pharmaceutical composition capable of exhibiting an excellent effect in the treatment of PPARy-related metabolic diseases.

1 is a reference diagram for explaining Experimental Example 3 of the present invention.

Hereinafter, the present invention will be described.

1. A novel compound, or a pharmaceutically acceptable salt thereof, Acceptable  salt

The present invention relates to a compound which binds to PPARγ with high affinity but does not induce transcriptional activity and thus does not act as an agonist and can block the phosphorylation by CDK5 and thereby improve insulin resistance, And pharmaceutically acceptable salts thereof, wherein said compound is represented by the following formula (1).

[Chemical Formula 1]

In Formula 1,

R ₁ to R ₄ are the same or different and each independently represents a hydrogen atom, a halogen atom, a C ₁ to C ₁₀ alkyl group, a C ₁ to C ₁₀ alkoxy group, and a hetero atom selected from the group consisting of N, O, and S And a heteroaryl group having 5 to 10 ring atoms containing at least one heteroatom,

R ₅ to R ₉ are the same or different and are each independently selected from the group consisting of hydrogen, a halogen group and a C ₁ to C ₁₀ alkoxy group,

R ₁₀ is selected from the group consisting of a hydroxyl group, an amino group and a C ₁ to C ₁₀ alkoxy group,

R ₁₁ is selected from the group consisting of hydrogen, a halogen group, a nitro group, a thiol group, a C ₁ to C ₁₀ alkyl group, a C ₁ to C ₁₀ alkoxy group, a C ₆ to C ₁₀ aryl group, and N, And a heteroaryl group having 5 to 10 ring atoms containing at least one heteroatom selected from the group consisting of

L is selected from the group consisting of a single bond, a C ₁ to C ₁₀ alkylene group and a C ₆ to C ₁₀ arylene group,

A is selected from the group consisting of O and NR ₁₂ ,

R ₁₂ is selected from the group consisting of a hydroxyl group and a C ₁ to C ₁₀ alkoxy group,

Alkoxy group of said R ₁ to R ₄ of the C ₁ to C ₁₀ alkyl group, C ₁ to C ₁₀ alkoxy group and a heteroaryl group of from 5 to 10 ring atoms, wherein R ₅ to R ₉ in the C ₁ to C ₁₀ of , wherein R ₁₀ a C ₁ to C ₁₀ alkoxy group, wherein R ₁₁ of the thiol group, C ₁ to C ₁₀ alkyl group, C ₁ to C ₁₀ alkoxy groups, C ₆ to C ₁₀ aryl group and the number of ring atoms The C ₁ to C ₁₀ alkylene group and the C ₆ to C ₁₀ arylene group of L each independently represent a halogen, a C ₁ to C ₁₀ alkyl group, and a C ₁ to C ₁₀ An alkoxy group, and the like. When the substituent group is plural, the plurality of substituents may be the same as or different from each other.

The compound represented by Formula 1 is characterized in that an indole moiety has a specific substituent, that is, an aromatic ring group linked by a ketone group or an imino group. When the compound represented by the formula (1) of the present invention is used as an active ingredient of a pharmaceutical composition for treating a metabolic disease associated with PPARγ, transcriptional activity is not induced by the specific substituent, Can exert an excellent effect in the treatment of cancer.

Here, considering the therapeutic effect of the pharmaceutical composition, it is preferable that each of R ₁ to R ₄ in the general formula (1) is independently selected from the group consisting of hydrogen, a halogen group, a pyridine group and a trifluoromethyl group (-CF ₃ ).

Further, in the formula 1 R ₅ to R ₉ it may be selected from the group consisting of each independently hydrogen, a halogen group, a methoxy group (-OCH ₃₎ and trifluoro methoxy group (-OCF _3).

It is preferable that R ₁₀ is a hydroxyl group (-OH).

In addition, considering the therapeutic effect of the pharmaceutical composition, it is preferable that the structure represented by * -LR ₁₁ in the above formula (1) is selected from the group consisting of the structures represented by the following S1 to S30.

The compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof may be formulated with any one compound selected from the group consisting of the following formulas (C1) to (C77), or a pharmaceutically acceptable salt thereof, But are not limited thereto.

When the compound represented by formula (1) of the present invention is used in the form of a pharmaceutically acceptable salt, it is preferable that the compound is in the form of an acid addition salt formed by a pharmaceutically acceptable free acid. The acid to be used in the preparation of the acid addition salt is not particularly limited and may be selected from the group consisting of hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphorous acid, dicarboxylate, Acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, or fumaric acid.

The method for producing the acid addition salt is not particularly limited, but it is possible to dissolve the compound represented by the formula 1 in an organic solvent (for example, methanol, ethanol, acetone, methylene chloride, acetonitrile, etc.) Followed by filtration and drying of the resulting precipitate, or distillation of the organic solvent and excess acid by distillation, followed by drying.

2. Manufacturing Method

The present invention provides a process for preparing the compound represented by the above formula (1), which will be described in detail as follows.

First, a compound represented by the following general formula (2) or (3) is synthesized. The method for synthesizing the compound represented by the following general formula (2) or (3) is not particularly limited as long as it is well known in the art, and the starting material is added to an organic solvent (for example, acetate, alcohol, ether) For 15 hours, followed by drying and filtration.

(2)

(3)

Next, a compound represented by the general formula (2) synthesized above is subjected to a cyclization reaction in the presence of polyphosphoric acids, or a compound represented by the general formula (3) synthesized in the above is cyclized in the presence of acetic acid to obtain a compound represented by the following general formula Is synthesized.

[Chemical Formula 4]

Next, the compound represented by the formula (4) synthesized above is reacted with a compound represented by the following formula (5) to synthesize a compound represented by the following formula (6). The synthesis of the compound represented by the general formula (6) is carried out by adding the compound represented by the general formula (4) and the general formula (5) into an organic solvent (for example, dichloromethane), reacting for 10 to 15 hours, Can be synthesized. Catalysts such as aluminum chloride may also be used to facilitate the synthesis process.

[Chemical Formula 5]

[Chemical Formula 6]

Next, the compound represented by the following formula (7) is synthesized by substituting the hydrogen bonded to the nitrogen atom of the compound represented by the formula (6) synthesized above. That is, the hydrogen bonded to the nitrogen atom present in the indole moiety is replaced with a substituent represented by * -LR ₁₁ . At this time, the method of substituting the hydrogen with a substituent represented by * -LR ₁₁ is not particularly limited as long as it is a method known in the art.

(7)

Then, the compound represented by the formula (7) synthesized above is reacted with a strong base to synthesize the compound represented by the formula (1). Specifically, the compound of formula (7) is dissolved in an organic solvent (e.g., tetrahydrofuran, methanol, etc.) and reacted with a strong base (e.g., sodium hydroxide) for 30 minutes to 2 hours, Followed by filtration.

In the general formulas (1) to (7), the definitions of R ₁ to R ₁₁ , L and A are the same as those described above.

3. Pharmaceutical composition

The present invention provides a pharmaceutical composition for the treatment of metabolic diseases associated with PPARy comprising the compound represented by the above formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient. Specifically, the pharmaceutical composition of the present invention binds to PPARγ with high affinity, does not act as an agonist and does not induce gene transcription, can block the phosphorylation of the amino acid at position 273 of serine of PPARγ by CDK5, It does not cause side effects and can exert an excellent effect in treating metabolic diseases.

Specifically, the side effects include weight gain, edema, impairment of bone growth or formation, or cardiac hypertrophy.

In addition, metabolic diseases associated with phosphorylation of PPARy by CDK5 include insulin resistance, impaired glucose tolerance, pre-diabetes, hyperglycemia, hyperinsulinemia hyperinsulinemia), obesity or inflammation.

The pharmaceutical composition of the present invention can be formulated into oral or parenteral administration forms.

Examples of formulations for oral administration include tablets, pills, light / soft capsules, liquids, suspensions, emulsions, syrups, granules, elixirs and troches. These formulations may contain a diluent (E.g., silica, talc, stearic acid and its magnesium or calcium salt and / or polyethylene glycol), and the like, for example, ≪ / RTI >

The parenteral administration may include injecting the body by subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.

The pharmaceutical composition of the present invention is preferably used by adjusting the dose according to the patient's age, weight, sex, dosage form, health condition, and disease severity.

Hereinafter, the present invention will be described in detail with reference to examples. However, the following examples are illustrative of the present invention, and the present invention is not limited by the following examples.

In the following examples, all reagents were purchased from Sigma Aldrich, Fluka, and TCI. ¹ H NMR Spectra was prepared by using tetramethylsilane as an internal standard and using Bruker Biospin AVANCE II 400 instrument.

[ Example  1] 6- Chlooro -3- (4- Chlorobenzoyl ) -1- (4- Chlorophenyl ) -1H-indole-2-carboxylate Exceed  synthesis

<Step 1> (E) -Ethyl-2- (2- (3- Chlorophenyl ) Hydrazano ) Propanoate  synthesis

Add purified distilled water (520 ml) to a 2 L flask. (50 g, 0.6 mol) was dissolved in the flask, and then (3-chlorophenyl) hydrazine hydrochloride (52 g, 0.3 mol) was added thereto. The mixture was stirred at room temperature for 30 minutes and ethyl 2-oxopropanoate (35 ml, 0.3 mol) was slowly added thereto, followed by stirring for 6 hours. After completion of the reaction, the reaction product was filtered with a reduced pressure filter and then dried. A 3 L flask was charged with 2 L of dry solid and normal hexane and stirred for 1 hour and filtered to obtain 57 g of (E) -ethyl-2- (2- (3- chlorophenyl) hydrazano) propanoate , 0.24 mol, 81%).

^{1 H NMR (400 MHz, CDCl} 3) 7.66 (br, NH, 1H), 7.24 (m, 1H), 7.04 (m, 1H), 6.89 (d, J = 8.0 Hz, 1H), 6.84 (m, 1H ), 4.35 (q, 2H), 2.11 (s, 3H), 1.40 (t, J = 8.0 Hz, 3H).

&Lt; Step 2 > Ethyl-6- Chlooro -1H-indole-2- Carboxylate  synthesis

To a 500 ml flask was added toluene (110 ml), and to the solution of (E) -ethyl 2- (2- (3-chlorophenyl) hydrazano) propanoate (10.6 g, 0.044 mol). Then, polyphosphoric acid (52 g) was added thereto, followed by reflux reaction for 6 hours. After the reaction is completed, the reaction mixture is cooled to 50 ° C. and only the toluene layer is separated. The separated toluene layer was concentrated under reduced pressure. Then toluene (50 ml) was added to the solid formed, and the mixture was refluxed for 1 hour and cooled to room temperature. Thereafter, the recrystallized solid was filtered to obtain ethyl 6-chloro-1H-indole-2-carboxylate (3.4 g, 0.015 mol, 35%).

^{1 H NMR (400 MHz, CDCl3} ) 8.84 (br, NH, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.42 (s, 1H), 7.19 (s, 1H) 7.13 (d, J = 8.0 Hz, 1 H), 4.44 (q, 2H), 1.43 (t, J = 8.0 Hz, 3H).

&Lt; Step 3 > Ethyl 6- Chlooro -3- (4- Chlorobenzoyl ) -1H-indole-2- Carboxylate Synthesis of

In a 100 mL flask, ethyl 6-chloro-1H-indole-2-carboxylate (1 g, 4.47 mmol) synthesized in the above Step 2 and dichloromethane (10 mL) were dissolved and dissolved. Then, 4-chlorobenzoyl chloride (939 mg, 5.36 mmol) and aluminum chloride (714 mg, 5.36 mmol) were added and the mixture was refluxed for 12 hours. After completion of the reaction, the temperature was lowered to room temperature, and the organic layer was separated using dichloromethane and water, and the water contained in the organic layer was removed with magnesium sulfate. After filtration, the mixture was purified by column chromatography (EA / n-Hex = 1: 6) to give ethyl 6-chloro-3- (4- chlorobenzoyl) -1H-indole- (843 mg, 2.32 mmol, 52%).

^{1 H NMR (400 MHz, CDCl} 3) 9.17 (br, NH, 1H), 7.81 (d, J = 6.8 Hz, 2H), 7.60 (d, J = 8.4 Hz, 1H), 7.49-7.41 (m, 3H ), 7.21 (dd, J = 1.6,8.4 Hz, 1H), 4.13-4.08 (m, 2H), 0.97-0.94 (m, 3H).

<Step 4> Synthesis of ethyl-6- Chlooro -3- (4- Chlorobenzoyl ) -1- (4- Chlorophenyl ) -1H-indole-2-carboxylate

To a 25 mL flask was added ethyl 6-chloro-3- (4-chlorobenzoyl) -1H-indole-2-carboxylate (40 mg, 0.122 mmol) synthesized in the above Step 3 and dicloro Methane (1 mL) was added and dissolved. Then, 4- (chlorophenyl) boronic acid (39 mg, 0.246 mmol), copper (II) acetate (34 mg, 0.185 mmol) and triethylamine (25 mg, 0.246 mmol) . After completion of the reaction, the organic layer was separated using dichloromethane and water, and then the water contained in the organic layer was removed with magnesium sulfate. After filtration, the mixture was purified by column chromatography (EA / n-Hex = 1: 4) to give ethyl 6-chloro-3- (4- chlorobenzoyl) -1- (4- chlorophenyl) -1H-indole-2-carboxylate (34 mg, 0.072 mmol, 60%).

^{1 H NMR (400 MHz, CDCl} 3) 7.84 (d, J = 9.2 Hz, 2H), 7.67 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 9.6 Hz, 2H), 7.45 (d, J = 9.2 Hz, 2H), 7.34 (d, J = 9.6 Hz, 2H), 7.24 (dd, J = 2.0,8.8 Hz, 1H) 3.81 (m, 2H), 0.85-0.82 (m, 3H).

<Step 5> 6- Chlooro -3- (4- Chlorobenzoyl ) -1- (4- Chlorophenyl ) -1H-indole-2-carboxylate Exed's  synthesis

To a 25 mL flask was added ethyl 6-chloro-3- (4-chlorobenzoyl) -1- (4-chlorophenyl) -1H-indole-2-carboxylate mg, 0.072 mmol), and tetrahydrofuran (0.5 mL) and methanol (0.5 mL) were added and dissolved. Then sodium hydroxide (15 mg, 0.36 mmol) dissolved in water (0.5 mL) was added and stirred for 1 hour. After the reaction was completed, the solution was concentrated and adjusted to pH 5 with 2N HCl. Next, the organic layer was separated using ethyl acetate and water, and then the water contained in the organic layer was removed with magnesium sulfate. Then, after filtration, the mixture was purified by column chromatography (MeOH / CH ₂ Cl ₂ = 1: 9) to give 6-chloro-3- (4- chlorobenzoyl) -1- (4- chlorophenyl) -1H-indole-2-carboxylic acid (20 mg, 0.045 mmol, 62.5%).

^{1 H NMR (400 MHz, DMSO} -d 6) 13.56 (br, OH, 1H), 7.85-7.83 (d, J = 8.0 Hz, 2H), 7.67-7.57 (m, 7H), 7.32-7.30 (d, J = 8.0 Hz, 2H), 7.17 (s, 1H).

[ Example  2] 6- Chlooro -3- (4- Chlorobenzoyl ) -1- (3- Chlorophenyl ) -1H-indole-2-carboxylate Exed's  synthesis

The procedure of Example 1 was repeated except that (3-chlorophenyl) boronic acid was used instead of 4- (chlorophenyl) boronic acid used in <Step 4> to obtain the target compound .

^{1 H NMR (400 MHz, DMSO} -d 6) 13.53 (br, OH, 1H), 7.86-7.84 (d, J = 8.0 Hz, 2H), 7.50 (s, 1H), 7.65-7.58 (m, 5H) , 7.55-7.52 (m, 1H), 7.32-7.30 (d, J = 8.0 Hz, 1H), 7.16 (s, 1H).

[ Example  3] 6- Chlooro -3- (4- Chlorobenzoyl ) -1- (4- Rat - Butylphenyl ) -1H-indole-2-carboxylate Exed's  synthesis

The procedure of Example 1 was repeated, except that (4- (tert-butyl) phenyl) boronic acid was used instead of 4- (chlorophenyl) boronic acid used in <Step 4> Compound.

^{1 H NMR (400 MHz, DMSO} -d 6) 7.88 (d, J = 1.6 Hz, 1H), 7.76 (d, J = 3.6 Hz, 2H), 7.76-7.56 (m, 3H), 7.39 (d, J = 8.4 Hz, 2H), 7.25 (dd, J = 1.6,8.4 Hz, 1H), 7.12 (d, J = 11.2 Hz, 2H), 1.36 (s, 9H).

[ Example 4] 6 - Chlooro -3- (4- Chlorobenzoyl ) -1- (3,4- Difluorophenyl ) -1H-indole-2-carboxylate Exed's  synthesis

The same procedure as in Example 1 was carried out except that (3,4-difluorophenyl) boronic acid was used in place of the 4- (chlorophenyl) boronic acid used in <Step 4> Compound.

^{1 H NMR (400 MHz, DMSO} -d 6) 13.53 (br, OH, 1H), 7.84 (d, J = 8.0 Hz, 2H), 7.89 (t, J = 8.0 Hz, 1H), 7.70-7.60 (m J = 8.0 Hz, 1H), 7.57 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 8.0 Hz,

[ Example  5] 6- Chlooro -3- (4- Chlorobenzoyl ) -1- (3- ( Methyl thio ) Phenyl) -1H-indole-2-carboxylate Exed's  synthesis

The procedure of Example 1 was repeated except that (3- (methylthio) phenyl) boronic acid was used in place of the 4- (chlorophenyl) boronic acid used in <Step 4> Compound.

^{1 H NMR (400 MHz, DMSO} -d 6) 13.53 (br, OH, 1H), 7.81-7.76 (m, 3H), 7.49-7.45 (m, 3H), 7.37 (d, J = 8.0 Hz, 2H) , 7.25 (t, J = 8.0 Hz, 2H), 7.06 (s, IH), 2.35 (s, 3H).

[ Example  6] 6- Chlooro -3- (4- Chlorobenzoyl ) -1- (3- ( Triple aromethoxy ) Phenyl) -1H-indole-2-carboxylate Exed's  synthesis

The same procedure as in Example 1 was performed except that (3- (trifluoromethoxy) phenyl) boronic acid was used instead of 4- (chlorophenyl) boronic acid used in <Step 4> To obtain the target compound.

^{1 H NMR (400 MHz, DMSO} -d 6) 7.83 (d, J = 8.4 Hz, 2H), 7.72-7.54 (m, 7H), 7.28 (dd, J = 1.6, 8.4 Hz, 1H), 7.13 (d , &Lt; / RTI &gt; J = 1.6 Hz, 1H).

[ Example  7] 6- Chlooro -3- (4- Chlorobenzoyl ) -1- (3- ( Trifluoromethyl ) Phenyl) -1H-indole-2-carboxylate Exed's  synthesis

The procedure of Example 1 was repeated except that (3- (trifluoromethyl) phenyl) boronic acid was used instead of 4- (chlorophenyl) boronic acid used in <Step 4> To obtain the target compound.

^{1 H NMR (400 MHz, DMSO} -d 6) 8.01 (s, 1H), 7.93-7.80 (m, 5H), 7.64 (d, J = 8.8 Hz, 1H), 7.58 (d, J = 8.8 Hz, 2H ), 7.30 (dd, J = 2.0,8.8 Hz, 1H), 7.12 (d, J = 1.6 Hz, 1H).

[ Example  8] 6- Chlooro -3- (4- Chlorobenzoyl )-One-( Meta - Tollyill ) -1H-indole-2- Car Le Foxillic Exed's  synthesis

The procedure of Example 1 was repeated except that (meta-toluyl) boronic acid was used instead of 4- (chlorophenyl) boronic acid used in <Step 4> to obtain the target compound.

^{1 H NMR (400 MHz, DMSO} -d 6) 7.79 (d, J = 8.8 Hz, 2H), 7.71 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 8.4 Hz, 2H), 7.44 ( t, J = 7.6 Hz, 1H), 7.33-7.23 (m, 4H), 7.05 (s, 1H), 2.39 (s, 3H).

[ Example  9] 3- Benzoyl -6- Chlooro -1- (4- Chlorophenyl ) -1H-indole-2- Carboxylic  Synthesis of Exceed

<Step 1> (E) -Ethyl-2- (2- (3- Chlorophenyl ) Hydrazano ) Propanoate synthesis castle

Add purified distilled water (520 ml) to a 2 L flask. (50 g, 0.6 mol) was dissolved in the flask, and then (3-chlorophenyl) hydrazine hydrochloride (52 g, 0.3 mol) was added thereto. The mixture was stirred at room temperature for 30 minutes and ethyl 2-oxopropanoate (35 ml, 0.3 mol) was slowly added thereto, followed by stirring for 6 hours. After completion of the reaction, the reaction mixture was filtered with a reduced pressure filter and dried. A 3 L flask was charged with 2 L of dry solid and normal hexane and stirred for 1 hour and filtered to obtain 57 g of (E) -ethyl-2- (2- (3- chlorophenyl) hydrazano) propanoate , 0.24 mol, 81%).

^{1 H NMR (400 MHz, CDCl} 3) 7.66 (br, NH, 1H), 7.24 (m, 1H), 7.04 (m, 1H), 6.89 (d, J = 8.0 Hz, 1H), 6.84 (m, 1H ), 4.35 (q, 2H), 2.11 (s, 3H), 1.40 (t, J = 8.0 Hz, 3H).

&Lt; Step 2 > Ethyl-6- Chlooro -1H-indole-2- Carboxylate  synthesis

To a 500 ml flask was added toluene (110 ml), and 10.6 g (0.044 mmol) of the (E) -ethyl 2- (2- (3- chlorophenyl) hydrazano) propanoate synthesized in the above Step 1 mol). Then, the polyphosphoric acid (52 g) was added thereto, followed by reflux reaction for 6 hours. After the reaction is completed, the reaction mixture is cooled to 50 ° C. and only the toluene layer is separated. The separated toluene layer was concentrated under reduced pressure. Toluene (50 ml) was added to the formed solid and refluxed for 1 hour and then cooled to room temperature. Thereafter, the recrystallized solid was filtered to obtain ethyl-6-chloro-1H-indole-2-carboxylate (3.4 g, 0.015 mol, 35%).

^{1 H NMR (400 MHz, CDCl3} ) 8.84 (br, NH, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.42 (s, 1H), 7.19 (s, 1H) 7.13 (d, J = 8.0 Hz, 1 H), 4.44 (q, 2H), 1.43 (t, J = 8.0 Hz, 3H).

<Step 3> Synthesis of ethyl-3- Benzoyl -6- Chlooro -1H-indole-2- Carboxylate  synthesis

In a 100 ml flask, ethyl-6-chloro-1H-indole-2-carboxylate (3 g, 13.41 mmol) synthesized in the above Step 2 and dichloromethane (30 mL) were dissolved and dissolved. Then, benzoyl chloride (2.07 g, 14.75 mmol) and aluminum chloride (3.57 g, 26.82 mmol) were added and refluxed for 12 hours. After completion of the reaction, the temperature was lowered to room temperature, and the organic layer was separated using dichloromethane and water, and the water contained in the organic layer was removed with magnesium sulfate. After filtration, the mixture was purified by column chromatography (EA / n-Hex = 1: 6) to give ethyl-3-benzoyl-6-chloro-1H-indole- mmol, 57%).

^{1 H NMR (400 MHz, CDCl} 3) 9.48 (br, NH, 1H), 7.87 (d, J = 6.8 Hz, 2H), 7.66 (d, J = 8.8 Hz, 1H), 7.58 (d, J = 7.2 2H), 7.48 (s, 1H), 7.44 (d, J = 7.6 Hz, 2H), 7.2 (d, J = 4.03 (q, J = 7.2 Hz, 2H), 0.89-0.86 (t, J = 7.2 Hz, 3H).

<Step 4> Synthesis of ethyl-3- Benzoyl -6- Chlooro -1- (4- Chlorophenyl ) -1H-indole-2- Carboxyl Synthesis of Rate

To a 25 mL flask was added ethyl 3-benzoyl-6-chloro-1H-indole-2-carboxylate (150 mg, 0.46 mmol) synthesized in the above Step 3 and dichloromethane . Then, (4-chlorophenyl) boronic acid (71.6 mg, 0.46 mmol), copper (II) acetate (166 mg, 0.91 mmol) and triethylamine (93 mg, 0.91 mmol) . After completion of the reaction, the organic layer was separated using dichloromethane and water, and then the water contained in the organic layer was removed with magnesium sulfate. After filtration, the mixture was purified by column chromatography (EA / n-Hex = 1: 4) to give ethyl-3-benzoyl-6-chloro-1- (4-chlorophenyl) -2-carboxylate (78 mg, 0.18 mmol, 39%).

^{1 H NMR (400 MHz, CDCl} 3) 7.89 (d, J = 7.2 Hz, 2H), 7.07 (d, J = 8.8 Hz, 1H), 7.59-7.44 (m, 5H), 7.35 (d, J = 9.6 J = 1.6 Hz, 1H), 3.80-3.74 (m, 2H), 0.80-0.76 (m, 3H), 7.23 (dd, J = 1.6,8.4 Hz, 1H).

&Lt; Step 5 > 3- Benzoyl -6- Chlooro -1- (4- Chlorophenyl ) -1H-indole-2- Carboxylic Ex Synthesis of seed

Benzoyl-6-chloro-1- (4-chlorophenyl) -1H-indole-2-carboxylate (78 mg, 0.18 mmol) synthesized in the above Step 4 was added to a 25 mL flask, , And tetrahydrofuran (1 mL) and methanol (1 mL) were added and dissolved. Then, sodium hydroxide (36 mg, 0.89 mmol) dissolved in water (1 mL) was added and stirred for 1 hour. After the reaction was completed, the solution was concentrated and adjusted to pH 5 with 2N HCl. Next, the organic layer was separated using ethyl acetate and water, and then the water contained in the organic layer was removed with magnesium sulfate. After filtration, the mixture was purified by column chromatography (MeOH / CH ₂ Cl ₂ = 1: 9) to give 3-benzoyl-6-chloro-1- (4-chlorophenyl) -Carboxylic acid (48 mg, 0.12 mmol, 65%).

^{1 H NMR (400 MHz, DMSO} -d 6) 7.82 (d, J = 8.8 Hz, 2H), 7.61-7.51 (m, 6H), 7.42 (t, J = 8 Hz, 2H), 7.18 (dd, J = 2.0, 8.4 Hz, 1 H), 7.07 (d, J = 1.6 Hz, 1 H).

[ Example  10] 3- Benzoyl -6- Chlooro -1- (3- Methoxyphenyl ) -1H-indole-2- Carboxylic  Synthesis of Exceed

The procedure of Example 9 was repeated except that (3-methoxyphenyl) boronic acid was used instead of 4- (chlorophenyl) boronic acid used in <Step 4> to obtain the target compound .

^{1 H NMR (400 MHz, DMSO} -d 6) 7.84 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 7.2 Hz, 1H), 7.46 (t, 1H), 7.44 (t, 3H), 7.18 (d, J = 2.0 Hz, 1H), 7.07 (d, J = 7.6 Hz, 4H).

[ Example  11] 3- Benzoyl -6- Chlooro -1- (4- ( Rat - Butyl ) Phenyl) -lH-indole-2- Carlsbad Silic Exed's  synthesis

The procedure of Example 9 was repeated except that (4- (tert-butyl) phenyl) boronic acid was used instead of 4- (chlorophenyl) boronic acid used in <Step 4> Compound.

^{1 H NMR (400 MHz, DMSO} -d 6) 7.81 (dd, J = 7.2 Hz, 2H), 7.63-7.56 (m, 4H), 7.50 (t, J = 8.0 Hz, 2H), 7.42 (d, J = 6.8 Hz, 2H), 7.25 (dd, J = 1.6,8.4 Hz, 1H), 7.08 (d, J = 2.0 Hz, 1H), 1.37 (s, 9H).

[ Example  12] 3- Benzoyl -6- Chlooro -1- (3- ( Trifluoromethoxy ) Phenyl) -1H-indole-2-carboxylate Exed's  synthesis

The same procedure as in Example 9 was performed except that (3- (trifluoromethoxy) phenyl) boronic acid was used in place of the 4- (chlorophenyl) boronic acid used in <Step 4> To obtain the target compound.

^{1 H NMR (400 MHz, DMSO} -d 6) 7.85 (d, J = 7.2 Hz, 2H), 7.72 (t, J = 8.0 Hz, 1H), 7.64-7.45 (m, 7H), 7.25 (dd, J = 1.6, 8.4 Hz, 4H), 7.12 (d, J = 1.6 Hz, 1H).

[ Example  13] 3- Benzoyl -6- Chlooro -1- (4- ( Methyl thio ) Phenyl) -lH-indole-2- Carlsbad Silic Exed's  synthesis

The procedure of Example 9 was repeated except that (4- (methylthio) phenyl) boronic acid was used instead of 4- (chlorophenyl) boronic acid used in <Step 4> Compound.

^{1 H NMR (400 MHz, DMSO} -d 6) 7.81 (d, J = 6.8 Hz, 2H), 7.66 (d, J = 8.0 Hz 1H), 7.54 (t, J = 6.8 Hz, 1H), 7.41 (m , 6H), 7.19 (dd, J = 8 Hz, 1H), 7.05 (s, 1H), 2.55 (s, 3H).

[ Example  14] 3- Benzoyl -6- Chlooro -1- (4- ( Trifluoromethyl ) Phenyl) -1H-indole-2-carboxylate Exed's  synthesis

The same procedure as in Example 9 was carried out except that (4- (trifluoromethyl) phenyl) boronic acid was used instead of 4- (chlorophenyl) boronic acid used in <Step 4> To obtain the target compound.

^{1 H NMR (400 MHz, DMSO} -d 6) 7.91 (d, J = 8.4 Hz, 2H), 7.83 (d, J = 7.2 Hz 2H), 7.74 (d, J = 8.0 Hz, 2H), 7.63 (d J = 8.8 Hz, 6H), 7.55 (t, J = 7.2 Hz, 1H), 7.42 (t, J = 7.6 Hz, 2H), 7.20 , &Lt; / RTI &gt; J = 1.2 Hz, 1H).

[ Example  15] 3- Benzoyl -1- (4- Bromophenyl ) -6- Chlooro - lH-indole-2- Carboxylic  Synthesis of Exceed

The procedure of Example 9 was repeated except that (4-bromophenyl) boronic acid was used instead of 4- (chlorophenyl) boronic acid used in <Step 4> to obtain the target compound .

^{1 H NMR (400 MHz, DMSO} -d 6) 7.82 (d, J = 2.8 Hz, 2H), 7.74 (q, J = 3.2, 8.4 Hz, 1H), 7.54 (d, J = 6.4 Hz, 1H), (M, 2H), 7.48-7.42 (m, 2H), 7.41 (d, J = 7.6 Hz, 3H) 4H), 7.20 (dd, J = 1.6, 8.4 Hz, 1H), 7.10 (d, J = 2.0 Hz, 1H).

[ Example  16] 3- Benzoyl -6- Chlooro -1- (quinolin-3-yl) -lH-indole-2- Carboxylic  Synthesis of Exceed

The procedure of Example 9 was repeated except that (quinolin-3-yl) boronic acid was used instead of 4- (chlorophenyl) boronic acid used in <Step 4> .

^{1 H NMR (400 MHz, DMSO} -d 6) 9.03 (d, J = 2.4 Hz, 1H), 8.72 (d, J = 2.4 Hz, 1H), 8.18-8.11 (m, 2H), 7.93-7.30 (m , 10H).

[ Example  17] 3- Benzoyl -6- Chlooro -1- (para- Tollyill ) -1H-indole-2- Carboxylic Ex Synthesis of seed

The procedure of Example 9 was repeated except that (para-toluyl) boronic acid was used instead of 4- (chlorophenyl) boronic acid used in <Step 4> to obtain the target compound.

^{1 H NMR (400 MHz, DMSO} -d 6) 7.81 (d, J = 7.2 Hz, 2H), 7.60-7.55 (m, 2H), 7.46 (t, J = 7.6 Hz, 2H), 7.38-7.33 (m , 4H), 7.20 (dd, J = 1.6,8.4 Hz, 2H), 7.10 (d, J = 2.0 Hz, 1H).

[ Example  18] 3- Benzoyl -6- Chlooro -1- (3- Floro -4- Methoxyphenyl ) -1H-indole-2-carboxylate Exed's  synthesis

The same procedure as in Example 9 was carried out except that (3-fluoro-4-methoxyphenyl) boronic acid was used in place of the 4- (chlorophenyl) boronic acid used in <Step 4> To obtain the target compound.

^{1 H NMR (400 MHz, DMSO} -d 6) 7.82 (d, J = 7.2 Hz, 2H), 7.66 (d, J = 7.6 Hz, 1H), 7.54 (d, J = 6.4 Hz, 1H), 7.41 ( J = 7.6 Hz, 3H), 7.32-7.25 (m, 2H), 7.17 (dd, J = 1.6,8.4 Hz, 1H), 7.05 (s, 1H), 3.92 (s, 3H).

[ Example  19] 6- Chlooro -1- (4- Chlorophenyl ) -3- (4- Methoxybenzoyl ) -1H-indole-2-carboxylate Exceed  synthesis

<Step 1> (E) -Ethyl-2- (2- (3- Chlorophenyl ) Hydrazano ) Propanoate synthesis castle

Add purified distilled water (520 ml) to a 2 L flask. (50 g, 0.6 mol) was dissolved in the flask, and then (3-chlorophenyl) hydrazine hydrochloride (52 g, 0.3 mol) was added thereto. The mixture was stirred at room temperature for 30 minutes and ethyl 2-oxopropanoate (35 ml, 0.3 mol) was slowly added thereto, followed by stirring for 6 hours. After completion of the reaction, the reaction mixture was filtered with a reduced pressure filter and dried. A 3 L flask was charged with 2 L of dry solid and normal hexane and stirred for 1 hour and filtered to obtain 57 g of (E) -ethyl-2- (2- (3- chlorophenyl) hydrazano) propanoate , 0.24 mol, 81%).

^{1 H NMR (400 MHz, CDCl} 3) 7.66 (br, NH, 1H), 7.24 (m, 1H), 7.04 (m, 1H), 6.89 (d, J = 8.0 Hz, 1H), 6.84 (m, 1H ), 4.35 (q, 2H), 2.11 (s, 3H), 1.40 (t, J = 8.0 Hz, 3H).

&Lt; Step 2 > Ethyl-6- Chlooro -1H-indole-2- Carboxylate  synthesis

To a 500 ml flask was added toluene (110 ml), and 10.6 g (0.044 mmol) of the (E) -ethyl 2- (2- (3- chlorophenyl) hydrazano) propanoate synthesized in the above Step 1 mol). Then, polyphosphoric acid (52 g) was added thereto, followed by reflux reaction for 6 hours. After the reaction is completed, the reaction mixture is cooled to 50 ° C. and only the toluene layer is separated. The separated toluene layer was concentrated under reduced pressure. Toluene (50 ml) was added to the formed solid and refluxed for 1 hour and then cooled to room temperature. Thereafter, the recrystallized solid was filtered to obtain ethyl-6-chloro-1H-indole-2-carboxylate (3.4 g, 0.015 mol, 35%).

^{1 H NMR (400 MHz, CDCl3} ) 8.84 (br, NH, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.42 (s, 1H), 7.19 (s, 1H) 7.13 (d, J = 8.0 Hz, 1 H), 4.44 (q, 2H), 1.43 (t, J = 8.0 Hz, 3H).

<Step 3> Synthesis of ethyl-6- Chlooro -3- (4- Methoxybenzoyl ) -1H-indole-2- Carboxylate  synthesis

In a 25 mL flask, ethyl 6-chloro-1H-indole-2-carboxylate (7 g, 31.29 mmol) synthesized in the above Step 2 and dichloroethane (70 mL) were dissolved and dissolved. Then, 4-methoxybenzoyl chloride (6.04 g, 37.55 mmol) and aluminum chloride (5.07 g, 37.55 mmol) were added and the mixture was refluxed for 12 hours. After completion of the reaction, the temperature was lowered to room temperature, and the organic layer was separated using dichloroethane and water, and the water contained in the organic layer was removed with magnesium sulfate. After filtration, the mixture was purified by column chromatography (EA / n-Hex = 1: 6) to give ethyl 6-chloro-3- (4- methoxybenzoyl) -1H-indole- (6.51 g, 18.19 mmol, 58.17%).

^{1 H NMR (400 MHz, CDCl} 3) 9.31 (s, 1H), 7.81 (d, J = 9.2 Hz, 2H), 7.66 (d, J = 1.2 Hz, 1H), 7.55 (d, J = 8.8 Hz, J = 7.2 Hz, 2H), 7.43 (d, J = 9.2 Hz, 2H), 7.33 (dd, J = 8.8 Hz, 1H), 4.13-4.08 Hz, 3H).

<Step 4> Synthesis of ethyl-6- Chlooro -1- (4- Chlorophenyl ) -3- (4- Methoxybenzoyl ) -1H-indole-2-carboxylate

To a 25 mL flask was added ethyl-6-chloro-3- (4-methoxybenzoyl) -1H-indole-2-carboxylate (100 mg, 0.28 mmol) synthesized in the above Step 3 and dicloro Methane (1 mL) was added and dissolved. Then, 66 mg (0.42 mmol) of (4-chlorophenyl) boronic acid, copper (II) acetate (101 mg, 0.56 mmol) and triethylamine (57 mg, 0.56 mmol) . After completion of the reaction, the organic layer was separated using dichloromethane and water, and then the water contained in the organic layer was removed with magnesium sulfate. After filtration, the mixture was purified by column chromatography (EA / n-Hex = 1: 4) to give ethyl 6-chloro-1- (4-chlorophenyl) -3- (4-methoxybenzoyl ) -1H-indole-2-carboxylate (98 mg, 0.21 mmol, 74%).

^{1 H NMR (400 MHz, CDCl} 3) 7.88 (d, J = 7.2 Hz, 2H), 7.62 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.8 Hz, 2H), 7.20 (dd, J = 2.0, 8.8 Hz, 1H), 7.10 m, 5H), 0.88-0.81 (m, 3H).

<Step 5> 6- Chlooro -1- (4- Chlorophenyl ) -3- (4- Methoxybenzoyl ) -1H-indole-2- Car Le Foxillic Exed's  synthesis

To a 25 mL flask was added ethyl-6-chloro-1- (4-chlorophenyl) -3- (4-methoxybenzoyl) -1H-indole-2-carboxylate 98 mg, 0.21 mmol), and the mixture was dissolved by adding tetrahydrofuran (1 mL) and methanol (1 mL). Then sodium hydroxide (42 mg, 1.04 mmol) dissolved in water (1 mL) was added and stirred for 1 hour. After the reaction was completed, the solution was concentrated and adjusted to pH 5 with 2N HCl. Thereafter, the organic layer was separated using ethyl acetate and water, and then the water contained in the organic layer was removed with magnesium sulfate. Then, after filtration, the mixture was purified by column chromatography (MeOH / CH ₂ Cl ₂ = 1: 9) to give 6-chloro-1- (4-chlorophenyl) -3- (4-methoxybenzoyl) -1H-indole-2-carboxylic acid (56 mg, 0.13 mmol, 60%).

^{1 H NMR (400 MHz, DMSO} -d 6) 13.43 (br, OH, 1H), 7.83 (d, J = 8.0 Hz, 2H), 7.60-7.50 (m, 5H), 7.17 (d, J = 8.0 Hz , 7.07 (s, 1H), 6.96 (d, J = 8.0 Hz, 2H), 3.82 (s, 3H).

[ Example  20] 6- Chlooro -1- (3- Chlorophenyl ) -3- (4- Methoxybenzoyl ) -1H-indole-2-carboxylate Exed's  synthesis

The procedure of Example 19 was repeated except that (3-chlorophenyl) boronic acid was used instead of (4-chlorophenyl) boronic acid used in < Step 4 & I could.

^{1 H NMR (400 MHz, DMSO} -d 6) 13.43 (br, OH, 1H), 7.84 (d, J = 8.0 Hz, 2H), 7.70 (s, 1H), 7.61-7.60 (m, 2H), 7.53 (M, 2H), 7.25 (d, J = 8.0 Hz, 1H), 7.12 (s, 1H), 7.04 (d, J = 8.0 Hz, 2H), 3.84

[ Example  21] 6- Chlooro -3- (4- Methoxybenzoyl ) -1- (4- ( Methyl thio ) Phenyl) -1H-indole-2-carboxylate Exed's  synthesis

The same procedure as in Example 19 was carried out except that (4- (methylthio) phenyl) boronic acid was used instead of (4-chlorophenyl) boronic acid used in <Step 4> Compound.

^{1 H NMR (400 MHz, DMSO} -d 6) 7.83 (d, J = 8.8 Hz, 2H), 7.56 (d, J = 8.4 Hz, 1H), 7.43-7.37 (m, 4H), 7.14 (dd, J = 2.0, 8.8 Hz, 1H), 7.01 (d, J = 1.6 Hz, 1H), 6.95 (d, J = 8.8 Hz, 2H), 3.82 (s, 3H), 2.55

[ Example  22] 6- Chlooro -3- (4- Methoxybenzoyl ) -1- (4- ( Trifluoromethoxy ) Phenyl) -1H-indole-2-carboxylate Exed's  synthesis

The same procedure as in Example 19 was carried out except that (4- (trifluoromethoxy) phenyl) boronic acid was used in place of (4-chlorophenyl) boronic acid used in <Step 4> To obtain the target compound.

^{1 H NMR (400 MHz, DMSO} -d 6) 7.83 (d, J = 6.8 Hz, 2H), 7.64 (d, J = 8.8 Hz, 2H), 7.60 (d, J = 8.4 Hz, 1H) 7.54 (d 1H, J = 8.4 Hz, 2H), 7.19 (d, J = 10.0 Hz, 1H), 7.08 (s, 1H), 6.97 (d, J = 8.8 Hz, 2H), 3.82

[ Example  23] 6- Chlooro -3- (4- Methoxybenzoyl ) -1- (3- ( Methyl thio ) Phenyl) -1H-indole-2-carboxylate Exed's  synthesis

The procedure of Example 19 was repeated except that (3- (methylthio) phenyl) boronic acid was used instead of (4-chlorophenyl) boronic acid used in <Step 4> Compound.

¹ H NMR (400 MHz, DMSO-d ₆ ) 7.88 (d, J = 8.8 Hz, 2H), 7.55-7.36 (m, 4H), 7.26 2H), 7.00 (d, J = 8.8 Hz, 2H), 3.88 (s, 3H), 2.52 (s, 3H).

[ Example  24] 6- Chlooro -1- (3- Floro -4- Methylphenyl ) -3- (4- Methoxybenzoyl ) -1H-indole-2-carboxylate Exed's  synthesis

The procedure of Example 19 was repeated except that (3-fluoro-4-methylphenyl) boronic acid was used in place of (4-chlorophenyl) boronic acid used in <Step 4> Compound.

^{1 H NMR (400 MHz, DMSO} -d 6) 13.43 (br, OH, 1H), 7.83 (d, J = 8.0 Hz, 2H), 7.56 (d, J = 8.0 Hz, 1H), 7.45 (t, J 8.0 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 6.96 (d, J = 8.0 Hz, 2H), 3.82 (s, 3H), 2.32 (s, 3H).

[ Example  25] 6- Chlooro -3- (4- Methoxybenzoyl ) -1- (3,4,5- Trifluorophenyl ) -1H-indole-2-carboxylate Exed's  synthesis

The same procedure as in Example 19 was carried out except that (3,4,5-trifluoropropenyl) boronic acid was used in place of (4-chlorophenyl) boronic acid used in <Step 4> To obtain the target compound.

^{1 H NMR (400 MHz, DMSO} -d 6) 13.43 (br, OH, 1H), 7.83 (d, J = 8.0 Hz, 2H), 7.60-7.51 (m, 3H), 7.24 (s, 1H), 7.18 (d, J = 8.0 Hz, 1H), 6.96 (d, J = 8.0 Hz, 2H), 3.82 (s, 3H).

[ Example  26] 6- Chlooro -3- (4- Methoxybenzoyl ) -1- (3,5- Difluorophenyl ) -1H-indole-2-carboxylate Exed's  synthesis

The procedure of Example 19 was repeated except that (3,5-difluorophenyl) boronic acid was used instead of (4-chlorophenyl) boronic acid used in <Step 4> Compound.

^{1 H NMR (400 MHz, DMSO} -d 6) 13.43 (br, OH, 1H), 7.83 (d, J = 8.0 Hz, 2H), 7.53 (d, J = 8.0 Hz, 1H), 7.42-7.10 (m , 3H), 7.20-7.15 (m, 2H), 6.96 (d, J = 8.0 Hz, 2H), 3.82 (s, 3H).

[ Example  27] 1- (4- Bromophenyl ) -6- Chlooro -3- (4- Methoxybenzoyl ) -1H-indole-2- Car Le Foxillic Exed's  synthesis

The objective compound was obtained by following the procedure of Example 19 while using (4-bromophenyl) boronic acid instead of (4-chlorophenyl) boronic acid used in <Step 4> .

^{1 H NMR (400 MHz, DMSO} -d 6) 13.43 (br, OH, 1H), 7.83 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 8.0 Hz, 2H), 7.56 (d, J 8.0 Hz, 1H), 7.45 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.0 Hz, 3.82 (s, 3 H).

[ Example  28] 6- Chlooro -3- (4- Methoxybenzoyl ) -1- (4- ( Trifluoromethyl ) Phenyl) -1H-indole-2-carboxylate Exed's  synthesis

The same procedure as in Example 19 was carried out except that (4- (trifluoromethyl) phenyl) boronic acid was used instead of (4-chlorophenyl) boronic acid used in <Step 4> To obtain the target compound.

^{1 H NMR (400 MHz, DMSO} -d 6) 7.92 (d, J = 8.4 Hz, 2H), 7.84 (d, J = 6.8 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 7.57 ( (d, J = 8 Hz, 1H), 7.20 (dd, J = 1.6,8.4 Hz, 1H), 7.15 s, 3H).

[ Example  29] 6- Chlooro -3- (4- Methoxybenzoyl ) -1- (pyridin-4-yl) -1H-indole-2- Car Le Foxillic Exed's  synthesis

The procedure of Example 19 was repeated except that (pyridin-4-yl) boronic acid was used instead of (4-chlorophenyl) boronic acid used in <Step 4> .

^{1 H NMR (400 MHz, DMSO} -d 6) 8.72 (dd, J = 1.6, 6.4 Hz, 2H), 7.82 (d, J = 7.2 Hz, 2H), 7.63 (d, J = 8.4 Hz, 1H), (D, J = 6.8 Hz, 2H), 3.82 (s, 3H), 7.55 (dd, J = 1.6, 4.8 Hz, 2H) ).

[ Example  30] 6- Chlooro -1- (3- Fluorophenyl ) -3- (4- Methoxybenzoyl ) -1H-indole-2-carboxylate Exed's  synthesis

The procedure of Example 19 was repeated except that (3-fluorophenyl) boronic acid was used instead of (4-chlorophenyl) boronic acid used in <Step 4> to obtain the target compound .

^{1 H NMR (400 MHz, DMSO} -d 6) 7.84 (d, J = 8.8 Hz, 2H), 7.64 (d, J = 6.4 Hz, 2H), 7.44 (s, 1H), 7.36 (d, J = 7.2 1H), 7.21 (d, J = 8.8 Hz, 1H), 7.12 (s, 1H), 6.99 (d, J = 8.8 Hz, 2H), 3.83 (s, 3H).

[ Example  31] 6- Chlooro -3- (4- Methoxybenzoyl ) -1- (quinolin-3-yl) -lH-indole-2- Car Le Foxillic Exed's  synthesis

The procedure of Example 19 was repeated except that (quinolin-3-yl) boronic acid was used instead of (4-chlorophenyl) boronic acid used in <Step 4> .

^{1 H NMR (400 MHz, MeOD} ) 8.96 (d, J = 2.4, 1H), 8.53 (d, J = 2.4 Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H), 8.07 (d, J = 7.6 Hz, 1H), 7.93-7.87 (m, 3H), 7.38 (t, J = 7.2 Hz, 1H), 7.56 6.99 (m, 2 H), 3.88 (s, 3 H).

[ Example  32] 6- Chlooro -3- (4- Methoxybenzoyl ) -1- (3- Methoxyphenyl ) -1H-indole-2- Car Le Foxillic Exed's  synthesis

The procedure of Example 19 was repeated except that (3-methoxyphenyl) boronic acid was used instead of (4-chlorophenyl) boronic acid used in <Step 4> to obtain the target compound .

^{1 H NMR (400 MHz, DMSO} -d 6) 7.83 (d, J = 7.6 Hz, 2H), 7.59 (d, J = 8.4 Hz, 1H), 7.40 (d, J = 8.8 Hz, 2H), 7.15 ( (d, J = 1.6, 8.4 Hz, 1H), 7.07 (d, J = 8.8 Hz, 2H), 6.98 3.82 (s, 3 H).

[ Example  33] 6- Chlooro -3- (4- Methoxybenzoyl ) -1- (4- Methoxyphenyl ) -1H-indole-2- Car Le Foxillic Exed's  synthesis

The procedure of Example 19 was repeated except that (4-methoxyphenyl) boronic acid was used instead of (4-chlorophenyl) boronic acid used in < Step 4 & .

^{1 H NMR (400 MHz, DMSO} -d 6) 7.83 (d, J = 7.6 Hz, 2H), 7.60 (d, J = 8.4 Hz, 1H), 7.46 (t, 1H), 7.15 (dd, J = 1.6 , 8.4 Hz, 1H), 7.06-7.03 (m, 4H), 6.96 (d, J = 8.8 Hz, 2H), 3.82 (s, 3H), 3.80 (s, 3H).

[ Example  34] 6- Chlooro -3- (4- Methoxybenzoyl ) -1- (para- Tollyill ) -1H-indole-2- Car Le Foxillic Exed's  synthesis

The procedure of Example 19 was repeated except that (para-toluyl) boronic acid was used instead of (4-chlorophenyl) boronic acid used in <Step 4> to obtain the target compound.

^{1 H NMR (400 MHz, DMSO} -d 6) 7.84 (d, J = 8.8 Hz, 2H), 7.60 (d, J = 8.0 Hz, 1H), 7.35 (m, 4H), 7.69 (d, J = 8.8 1H), 7.01 (s, 1H), 6.97 (d, J = 8.4Hz, 2H), 3.82 (s, 3H), 2.40 (s, 3H).

[ Example  35] 6- Chlooro -3- (4- Methoxybenzoyl ) -1- (3- ( Trifluoromethyl ) Phenyl) -1H-indole-2-carboxylate Exed's  synthesis

The procedure of Example 19 was followed except that (3- (trifluoromethyl) phenyl) boronic acid was used instead of (4-chlorophenyl) boronic acid used in <Step 4> To obtain the target compound.

¹ H NMR (400 MHz, DMSO-d ₆ ) 7.88-7.78 (m, 6H), 7.58 (d, J = 8.4 Hz, 1H), 7.19 (dd, J = 1.6,8.8 Hz, 1H) , 6.98 (d, J = 8.8 Hz, 2H), 3.82 (s, 3H).

[ Example  36] 6- Chlooro -1- (3- Floro -4- Methoxyphenyl ) -3- (4- Methoxybenzoyl ) -1H-indole-2-carboxylate Exed's  synthesis

The same procedure as in Example 19 was carried out except that (3-fluoro-4-methoxyphenyl) boronic acid was used instead of (4-chlorophenyl) boronic acid used in <Step 4> To obtain the target compound.

^{1 H NMR (400 MHz, DMSO} -d 6) 7.83 (d, J = 8.8 Hz, 2H), 7.57 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 9.2 Hz, 1H), 7.32- 1H), 6.96 (d, J = 8.4 Hz, 2H), 3.92 (s, 3H), 3.82 (s, , 3H).

[ Example  37] 6- Chlooro -3- (4- Methoxybenzoyl ) -1- (3- ( Trifluoromethoxy ) Phenyl) -1H-indole-2-carboxylate Exed's  synthesis

The same procedure as in Example 19 was carried out except that (3- (trifluoromethoxy) phenyl) boronic acid was used in place of (4-chlorophenyl) boronic acid used in <Step 4> To obtain the target compound.

^{1 H NMR (400 MHz, DMSO} -d 6) 7.83 (d, J = 8.8 Hz, 2H), 7.71 (d, J = 8.8 Hz, 2H), 7.60 (d, J = 8.8 Hz, 2H), 7.53 ( (d, J = 8.4 Hz, 1H), 7.28 (dd, J = 1.6,8.4 Hz, 1H), 7.16 s, 3H).

[ Example  38] 6- Chlooro -3- (4- Methoxybenzoyl ) -1- (4- Nitrophenyl ) -1H-indole-2-carboxylate Exed's  synthesis

The objective compound was obtained by following the procedure of Example 19 while using (4-nitrophenyl) boronic acid instead of (4-chlorophenyl) boronic acid used in <Step 4> .

^{1 H NMR (400 MHz, DMSO} -d 6) 8.40 (d, J = 9.2 Hz, 2H), 7.84 (d, J = 6.8 Hz, 2H), 7.81 (d, J = 8.8 Hz, 2H), 7.58 ( (d, J = 8.8 Hz, 1H), 7.23 (d, J = 2 Hz, 2H), 7.21 (s, 1H), 7.00 (d, J = 8.8 Hz, 2H), 3.83

[ Example  39] 6- Chlooro -1- (4- Fluorophenyl ) -3- (4- Methoxybenzoyl ) -1H-indole-2-carboxylate Exed's  synthesis

The procedure of Example 19 was repeated except that (4-fluorophenyl) boronic acid was used instead of (4-chlorophenyl) boronic acid used in < Step 4 & .

^{1 H NMR (400 MHz, DMSO} -d 6) 7.86 (d, J = 9.2 Hz, 2H), 7.59 (d, J = 8.4 Hz, 1H), 7.54 (dd, J = 5.2, 8.8 Hz, 2H), 7.37 (t, 1H), 7.18 (dd, J = 1.6, 6.8 Hz, 1H), 7.03 (s, 1H), 6.97 (d, J = 8.8 Hz, 2H), 3.82 (s, 3H).

[ Example  40] 6- Chlooro -3- (3- Chlorobenzoyl ) -1- (4- Chlorophenyl ) -1H-indole-2-carboxylate Exed's  synthesis

<Step 1> (E) -Ethyl-2- (2- (3- Chlorophenyl ) Hydrazano ) Propanoate synthesis castle

Add purified distilled water (520 ml) to a 2 L flask. (50 g, 0.6 mol) was dissolved in the flask, and then (3-chlorophenyl) hydrazine hydrochloride (52 g, 0.3 mol) was added thereto. The mixture was stirred at room temperature for 30 minutes and ethyl 2-oxopropanoate (35 ml, 0.3 mol) was slowly added thereto, followed by stirring for 6 hours. After completion of the reaction, the reaction mixture was filtered with a reduced pressure filter and dried. A 3 L flask was charged with 2 L of dry solid and normal hexane and stirred for 1 hour and filtered to obtain 57 g of (E) -ethyl-2- (2- (3- chlorophenyl) hydrazano) propanoate , 0.24 mol, 81%).

^{1 H NMR (400 MHz, CDCl} 3) 7.66 (br, NH, 1H), 7.24 (m, 1H), 7.04 (m, 1H), 6.89 (d, J = 8.0 Hz, 1H), 6.84 (m, 1H ), 4.35 (q, 2H), 2.11 (s, 3H), 1.40 (t, J = 8.0 Hz, 3H).

&Lt; Step 2 > Ethyl-6- Chlooro -1H-indole-2- Carboxylate  synthesis

To a 500 ml flask was added toluene (110 ml), and 10.6 g (0.044 mmol) of the (E) -ethyl 2- (2- (3- chlorophenyl) hydrazano) propanoate synthesized in the above Step 1 mol). Then, polyphosphoric acid (52 g) was added thereto, followed by reflux reaction for 6 hours. After the reaction is completed, the reaction mixture is cooled to 50 ° C. and only the toluene layer is separated. The separated toluene layer was concentrated under reduced pressure. Toluene (50 ml) was added to the formed solid and refluxed for 1 hour and then cooled to room temperature. Thereafter, the recrystallized solid was filtered to obtain ethyl-6-chloro-1H-indole-2-carboxylate (3.4 g, 0.015 mol, 35%).

^{1 H NMR (400 MHz, CDCl} 3) 8.84 (br, NH, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.42 (s, 1H), 7.19 (s, 1H) 7.13 (d, J = 8.0 Hz, 1 H), 4.44 (q, 2H), 1.43 (t, J = 8.0 Hz, 3H).

<Step 3> Synthesis of ethyl-6- Chlooro -3- (3- Chlorobenzoyl ) -1H-indole-2- Carboxylate Synthesis of

In a 100 mL flask, ethyl-6-chloro-1H-indole-2-carboxylate (1 g, 4.47 mmol) synthesized in the above Step 2 and dichlooethane (10 mL) were dissolved and dissolved. Then, 3-chlorobenzoyl chloride (939 mg, 5.36 mmol) and aluminum chloride (715 mg, 5.36 mmol) were added and the mixture was refluxed for 12 hours. After completion of the reaction, the temperature was lowered to room temperature, and the organic layer was separated using dichloromethane and water, and then the water contained in the organic layer was removed with magnesium sulfate. After filtration, the mixture was purified by column chromatography (EA / Hx = 1: 6) to give ethyl 6-chloro-3- (3- chlorobenzoyl) -1H-indole-2-carboxylate 923 mg, 2.54 mmol, 57.6%).

^{1 H NMR (400 MHz, CDCl} 3) 9.19 (s, 1H), 7.84 (t, J = 1.6 Hz, 1H), 7.72-7.70 (m, 1H), 7.63 (d, J = 12.0 Hz, 1H), J = 8.0 Hz, 1H), 7.21 (dd, J = 2.0, 8.8 Hz, 1H), 4.20-4.07 (m, 2H), 1.05-0.93 (m, 3H).

<Step 4> Synthesis of ethyl-6- Chlooro -3- (3- Chlorobenzoyl ) -1- (4- Chlorophenyl ) -1H-indole-2-carboxylate

To a 25 mL flask was added ethyl-6-chloro-3- (3-chlorobenzoyl) -1H-indole-2-carboxylate (200 mg, 0.55 mmol) synthesized in the above Step 3 and dicloro Methane (2 mL) was added and dissolved. Then, 172 mg (1.10 mmol) of copper (IV) chloride (201 mg, 1.10 mmol) and triethylamine (112 mg, 1.10 mmol) were added thereto and stirred for 12 hours . After completion of the reaction, the organic layer was separated using dichloromethane and water, and then the water contained in the organic layer was removed with magnesium sulfate. After filtration, the mixture was purified by column chromatography (EA / n-Hex = 1: 4) to give ethyl 6-chloro-3- (3- chlorobenzoyl) -1- ) -1H-indole-2-carboxylate (75 mg, 0.16 mmol, 29%).

^{1 H NMR (400 MHz, CDCl} 3) 7.88 (t, J = 2 Hz, 1H), 7.75-7.70 (m, 2H), 7.56-7.52 (m, 3H), 7.42-7.34 (m, 3H), 7.26 (D, J = 2.0, 6.0 Hz, 1H), 7.12 (d, J = 2.0 Hz, 1H), 3.85-3.80 (m, 2H), 0.89-0.82 (m, 3H).

<Step 5> 6- Chlooro -3- (3- Chlorobenzoyl ) -1- (4- Chlorophenyl ) -1H-indole-2-carboxylate Exed's  synthesis

To a 25 mL flask was added ethyl 6-chloro-3- (3-chlorobenzoyl) -1- (4-chlorophenyl) -1H-indole-2-carboxylate 70 mg, 0.15 mmol), and the mixture was dissolved by adding tetrahydrofuran (1 mL) and methanol (1 mL). Then sodium hydroxide (30 mg, 0.74 mmol) dissolved in water (1 mL) was added and stirred for 1 hour. After the reaction was completed, the solution was concentrated and adjusted to pH 5 with 2N HCl. Thereafter, the organic layer was separated using ethyl acetate and water, and then the water contained in the organic layer was removed with magnesium sulfate. After filtration, the mixture was purified by column chromatography (MeOH / CH ₂ Cl ₂ = 1: 9) to give 6-chloro-3- (3- chlorobenzoyl) -1- (4- chlorophenyl) -1H-indole-2-carboxylic acid (52 mg, 0.12 mmol, 80%).

^{1 H NMR (400 MHz, DMSO} -d 6) 7.76-7.72 (m, 3H), 7.61-7.51 (m, 5H), 7.44 (t, J = 7.6 Hz, 1H), 7.21 (dd, J = 2.0, 8.4 Hz, 1 H), 7.08 (d, J = 2 Hz, 1 H).

[ Example  41] 1- (4- ( Rat - Butyl ) Phenyl) -6- Chlooro -3- (3- Chlorobenzoyl ) -1H-indole-2-carboxylate Exed's  synthesis

The procedure of Example 40 was repeated, except that (4- (tert-butyl) phenyl) boronic acid was used instead of 4- (chlorophenyl) boronic acid used in Step 4, Compound.

^{1 H NMR (400 MHz, DMSO} -d 6) 7.79 (t, J = 2.0 Hz, 1H), 7.74-7.71 (m, 2H), 7.67 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 8.8 Hz, 2H), 7.55 (t, J = 8.0 Hz, 1H), 7.45 (d, J = 8.8 Hz, 2H), 7.32 (dd, J = 2.0,8.8 Hz, 1H) = 1.6 Hz, 1 H), 1.36 (s, 9H).

[ Example  42] 6- Chlooro -3- (3- Chlorobenzoyl ) -1- (3- Fluorophenyl ) -1H-indole-2-carboxylate Exed's  synthesis

The procedure of Example 40 was repeated except that (3-fluorophenyl) boronic acid was used instead of 4- (chlorophenyl) boronic acid used in <Step 4> to obtain the target compound .

^{1 H NMR (400 MHz, DMSO} -d 6) 7.77-7.71 (m, 3H), 7.61 (d, J = 8.0 Hz, 1H), 7.56-7.52 (m, 2H), 7.45 (t, J = 8.0 Hz (D, J = 1.6, 8.4 Hz, 1H), 7.04 (d, J = 1.6 Hz, 1H).

[ Example  43] 1- (4- Bromophenyl ) -6- Chlooro -3- (3- Chlorobenzoyl ) -1H-indole-2-carboxylate Exed's  synthesis

The procedure of Example 40 was repeated except that (4-bromophenyl) boronic acid was used instead of 4- (chlorophenyl) boronic acid used in <Step 4> to obtain the target compound .

¹ H NMR (400 MHz, DMSO-d ₆ ) 7.83-7.71 (m, 5H), 7.65 (d, J = 8.8 Hz, 1H), 7.57-7.52 0, 8.8 Hz, 1H), 7.18 (d, J = 1.6 Hz, 1H).

[ Example  44] 6- Chlooro -3- (3- Chlorobenzoyl ) -1- (3- ( Methyl thio ) Phenyl) -1H-indole-2-carboxylate Exed's  synthesis

The procedure of Example 40 was repeated except that (3- (methylthio) phenyl) boronic acid was used in place of the 4- (chlorophenyl) boronic acid used in Step 4, Compound.

^{1 H NMR (400 MHz, DMSO} -d 6) 7.76-7.72 (m, 3H), 7.62 (d, J = 8.0 Hz, 1H), 7.47 (m, 2H), 7.37 (d, J = 2.0 Hz, 2H ), 7.25 (t, J = 8.4Hz, 2H), 7.07 (s, IH), 2.50 (s, 3H).

[ Example  45] 6- Chlooro -3- (3- Chlorobenzoyl ) -1- (4- ( Methyl thio ) Phenyl) -1H-indole-2-carboxylate Exed's  synthesis

The procedure of Example 40 was repeated except that (4- (methylthio) phenyl) boronic acid was used instead of 4- (chlorophenyl) boronic acid used in <Step 4> Compound.

^{1 H NMR (400 MHz, DMSO} -d 6) 7.76-7.71 (m, 3H), 7.63-7.61 (d, J = 8.0 Hz, 1H), 7.48-7.38 (m, 5H), 7.23 (dd, J = 1.6, 8.4 Hz, 1H), 7.07 (d, J = 1.6 Hz, 1H), 2.55 (s, 3H).

[ Example  46] 6- Chlooro -3- (3- Chlorobenzoyl ) -1- (4- Chlorophenyl ) -1H-indole-2-carboxylate Exed's  synthesis

<Step 1> (E) -Ethyl-2- (2- (3- Chlorophenyl ) Hydrazano ) Propanoate  synthesis

Add purified distilled water (520 ml) to a 2 L flask. (50 g, 0.6 mol) was dissolved in the flask, and then (3-chlorophenyl) hydrazine hydrochloride (52 g, 0.3 mol) was added thereto. The mixture was stirred at room temperature for 30 minutes and ethyl 2-oxopropanoate (35 ml, 0.3 mol) was slowly added thereto, followed by stirring for 6 hours. After completion of the reaction, the reaction product was filtered with a reduced pressure filter and then dried. A 3 L flask was charged with 2 L of dry solid and normal hexane and stirred for 1 hour and filtered to obtain 57 g of (E) -ethyl-2- (2- (3- chlorophenyl) hydrazano) propanoate , 0.24 mol, 81%).

^{1 H NMR (400 MHz, CDCl} 3) 7.66 (br, NH, 1H), 7.24 (m, 1H), 7.04 (m, 1H), 6.89 (d, J = 8.0 Hz, 1H), 6.84 (m, 1H ), 4.35 (q, 2H), 2.11 (s, 3H), 1.40 (t, J = 8.0 Hz, 3H).

&Lt; Step 2 > Ethyl-6- Chlooro -1H-indole-2- Carboxylate  synthesis

To a 500 ml flask was added toluene (110 ml), and to the (E) - (2- (3- chlorophenyl) hydrazano) propanoate synthesized in the above Step 1 (10.6 g, 0.044 mol). Then, polyphosphoric acid (52 g) was added thereto, followed by reflux reaction for 6 hours. After the reaction is completed, the reaction mixture is cooled to 50 ° C. and only the toluene layer is separated. The separated toluene layer was concentrated under reduced pressure. Toluene (50 ml) was added to the formed solid and refluxed for 1 hour and then cooled to room temperature. Thereafter, the recrystallized solid was filtered to obtain ethyl-6-chloro-1H-indole-2-carboxylate (3.4 g, 0.015 mol, 35%).

^{1 H NMR (400 MHz, CDCl3} ) 8.84 (br, NH, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.42 (s, 1H), 7.19 (s, 1H) 7.13 (d, J = 8.0 Hz, 1 H), 4.44 (q, 2H), 1.43 (t, J = 8.0 Hz, 3H).

<Step 3> Synthesis of ethyl-6- Chlooro -3- (2,4- Dichlorobenzoyl ) -1H-indole-2- Carboxyl Synthesis of Rate

Ethyl-6-chloro-1H-indole-2-carboxylate (10 g, 4.47 mmol) synthesized in the above Step 2 and dichloromethane (150 mL) were dissolved in a 500 mL flask. Then, 2,4-dichlorobenzoyl chloride (11.24 g, 53.6 mmol), aluminum chloride (7.154 mg, 53.65 mmol) was added and the mixture was refluxed for 12 hours. After completion of the reaction, the temperature was lowered to room temperature, and the organic layer was separated using dichloromethane and water, and the water contained in the organic layer was removed with magnesium sulfate. Then, after filtration, the mixture was purified by column chromatography (EA / n-Hex = 1: 6) to give ethyl 6-chloro-3- (2,4-dichlorobenzoyl) -Carboxylate (10.17 g, 25.64 mmol, 57%).

^{1 H NMR (400 MHz, CDCl} 3) 9.38 (s, 1H), 7.91-7.89 (m, 1H), 7.50-7.44 (m, 3H), 7.30-7.25 (m, 2H), 4.13-4.06 (m, 2H), 1.10-1.06 (m, 3H).

<Step 4> Synthesis of ethyl-6- Chlooro -1- (4- Chlorophenyl ) -3- (2,4- Dichlorobenzoyl ) -1H-indole-2-carboxylate

To a 25 mL flask was added ethyl-6-chloro-3- (2,4-dichlorobenzoyl) -1H-indole-2-carboxylate (300 mg, 0.756 mmol) synthesized in the above Step 3 Dichloromethane (3 mL) was added and dissolved. Then, 237 mg (1.51 mmol) of 4- (chlorophenyl) boronic acid, copper acetate (275 mg, 1.51 mmol) and triethylamine (153 mg, 1.51 mmol) . After completion of the reaction, the organic layer was separated using dichloromethane and 2N-HCl, and the water contained in the organic layer was removed with magnesium sulfate. After filtration, the mixture was purified by column chromatography (EA / n-Hex = 1: 4) to give ethyl 6-chloro-1- (4-chlorophenyl) -3- Chlorobenzoyl) -1H-indole-2-carboxylate.

<Step 5> 6- Chlooro -1- (4- Chlorophenyl ) -3- (2,4- Dichlorobenzoyl ) -1H-indole-2-carboxylate Acid  synthesis

To a 25 mL flask was added ethyl 6-chloro-1- (4-chlorophenyl) -3- (2,4-dichlorobenzoyl) -1H-indole- (165 mg, 0.325 mmol), and the mixture was dissolved by adding tetrahydrofuran (1 mL) and methanol (1 mL). Then, sodium hydroxide (65 mg, 1.63 mmol) dissolved in water (1 mL) was added and stirred for 1 hour. After the reaction was completed, the solution was concentrated and adjusted to pH 5 with 2N HCl. Thereafter, the organic layer was separated using ethyl acetate and water, and then the water contained in the organic layer was removed with magnesium sulfate. After filtration, the mixture was purified by column chromatography (MeOH / CH ₂ Cl ₂ = 1: 9) to give 6-chloro-1- (4-chlorophenyl) -3- Indole-2-carboxylic acid (120 mg, 0.250 mmol, 77%).

^{1 H NMR (400 MHz, DMSO} -d 6) 7.90 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 2.0 Hz, 1H), 7.67 (d, J = 9.6 Hz, 2H), 7.57- 7.48 (m, 4H), 7.41 (dd, J = 2.0,8.8 Hz, 1H), 7.22 (d, J = 2 Hz, 1H).

[ Example  47] 6- Chlooro -3- (3- Chlorobenzoyl ) -1- (4- Chlorophenyl ) -1H-indole-2-carboxylate Exed's  synthesis

<Step 1> (E) -Ethyl-2- (2- (3- Chlorophenyl ) Hydrazano ) Propanoate synthesis castle

Add purified distilled water (520 ml) to a 2 L flask. (50 g, 0.6 mol) was dissolved in the flask, and then (3-chlorophenyl) hydrazine hydrochloride (52 g, 0.3 mol) was added thereto. The mixture was stirred at room temperature for 30 minutes and ethyl 2-oxopropanoate (35 ml, 0.3 mol) was slowly added thereto, followed by stirring for 6 hours. After completion of the reaction, the reaction mixture was filtered with a reduced pressure filter and dried. A 3 L flask was charged with dry solid and 2 L of normal hexane and stirred for 1 hour and then filtered to obtain (E) -ethyl-2- (2- (3-chlorophenyl) hydrazano) propanoate g, 0.24 mol, 81%).

^{1 H NMR (400 MHz, CDCl} 3) 7.66 (br, NH, 1H), 7.24 (m, 1H), 7.04 (m, 1H), 6.89 (d, J = 8.0 Hz, 1H), 6.84 (m, 1H ), 4.35 (q, 2H), 2.11 (s, 3H), 1.40 (t, J = 8.0 Hz, 3H).

&Lt; Step 2 > Ethyl-6- Chlooro -1H-indole-2- Carboxylate  synthesis

To a 500 ml flask was added toluene (110 ml), and 10.6 g (0.044 mmol) of the (E) -ethyl 2- (2- (3- chlorophenyl) hydrazano) propanoate synthesized in the above Step 1 mol). Then, polyphosphoric acid (52 g) was added thereto, followed by reflux reaction for 6 hours. After the reaction is completed, the reaction mixture is cooled to 50 ° C. and only the toluene layer is separated. The separated toluene layer was concentrated under reduced pressure. Toluene (50 ml) was added to the formed solid and refluxed for 1 hour and then cooled to room temperature. Thereafter, the recrystallized solid was filtered to obtain ethyl-6-chloro-1H-indole-2-carboxylate (3.4 g, 0.015 mol, 35%).

^{1 H NMR (400 MHz, CDCl3} ) 8.84 (br, NH, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.42 (s, 1H), 7.19 (s, 1H) 7.13 (d, J = 8.0 Hz, 1 H), 4.44 (q, 2H), 1.43 (t, J = 8.0 Hz, 3H).

<Step 3> Synthesis of ethyl-6- Chlooro -3- (4- ( Trifluoromethoxy ) Benzoyl ) -1H-indole-2-carboxylate

Trifluoromethoxybenzoic acid (1.32 g, 6.706 mmol) and acetonitrile (5 ml) were added and dissolved in a 250-mL flask, and 85% phosphoric acid (0.43 ml, 0.75 mmol) and tri Fluoroacetic anhydride (941 mg, 6.706 mmol) was added and stirred for 10 minutes. Then, ethyl-6-chloro-1H-indole-2-carboxylate (500 mg, 2.23 mmol) synthesized in the above Step 2 was added thereto and stirred for 10 hours. After completion of the reaction, the organic layer was separated using ethyl acetate and water, and the organic layer was further treated with saturated sodium hydrogencarbonate and sodium chloride, and water was removed with magnesium sulfate. After filtration, the mixture was purified by column chromatography (EA / n-Hex = 1: 4) to give ethyl 6-chloro-3- (4- (trifluoromethoxy) benzoyl) -2-carboxylate (291 mg, 0.706 mmol, 31.61%).

^{1 H NMR (400 MHz, CDCl} 3) 9.21 (s, 1H), 7.93 (dd, J = 2.4, 8.8 Hz, 2H), 7.64 (d, J = 8.8 Hz, 1H), 7.50 (d, J = 1.6 J = 7.2 Hz, 2H), 0.91 (t, J = 8.8 Hz, 2H), 7.20 (dd, J = = 7.2 Hz, 3 H).

<Step 4> Synthesis of ethyl-6- Chlooro -1- (3- Chlorophenyl ) -3- (4- (Trifluoromethoxy)) Benzoyl) -1H-indole-2-carboxylate

To a 25 mL flask was added ethyl-6-chloro-3- (4- (trifluoromethoxy) benzoyl) -1H-indole-2-carboxylate (170 mg, 0.41 mmol ) And dichloromethane (1.7 mL) were added and dissolved. (129 mg, 0.82 mmol), copper (II) acetate (149 mg, 0.82 mmol) and triethylamine (0.115 ml, 0.82 mmol) were added and the mixture was stirred for 12 hours . After completion of the reaction, the organic layer was separated using dichloromethane and 2N HCl, and the water contained in the organic layer was removed with magnesium sulfate. After filtration, the mixture was purified by column chromatography (EA / n-Hex = 4: 1) to give ethyl 6-chloro-1- (3- chlorophenyl) -3- Benzoyl) -1H-indole-2-carboxylate (71.9 mg, 0.137 mmol, 33.34%).

^{1 H NMR (400 MHz, CDCl} 3) 7.96 (dd, J = 2.8, 8.8 Hz, 2H), 7.72 (d, J = 8 Hz, 1H), 7.55-7.39 (m, 3H), 7.33-7.22 (m , 5H), 7.14 (d, J = 2 Hz, 1H), 3.85 (q, J = 7.2 Hz, 2H), 0.81 (t, J = 7.2 Hz, 3H).

<Step 5> 6- Chlooro -1- (3- Chlorophenyl ) -3- (4- (Trifluoromethoxy) benzo &lt; RTI ID = 0.0 &gt; Yl) -1H-indole-2-carboxylate Exed's  synthesis

To a 100 mL flask was added ethyl-6-chloro-1- (3-chlorophenyl) -3- (4- (trifluoromethoxy) benzoyl) -1H- -Carboxylate (71.9 mg, 0.137 mmol), and the mixture was dissolved by adding tetrahydrofuran (1 mL) and methanol (1 mL). Then, 1N-sodium hydroxide (0.35 mL) was added, followed by stirring for 1 hour. After the reaction was completed, the solution was concentrated and adjusted to pH 5 with 2N HCl. Thereafter, the organic layer was separated using ethyl acetate and water, and then the water contained in the organic layer was removed with magnesium sulfate. The filtrate was then purified by column chromatography (MeOH / CH ₂ Cl ₂ = 1: 9) to give 6-chloro-1- (3- chlorophenyl) -3- (4- (trifluoromethoxy ) Benzoyl) -1H-indole-2-carboxylic acid (31 mg, 0.06 mmol, 45.56%).

^{1 H NMR (400 MHz, DMSO} -d 6) 7.94 (dd, J = 8.8 Hz, 2H), 7.76 (d, J = 8.4 Hz, 1H), 7.59-7.37 (m, 6H), 7.23 (dd, J = 2.0, 8.8 Hz, 1H), 7.06 (d, J = 1.6 Hz, 1H).

[ Example  48] 6- Chlooro -1- (4- Chlorophenyl ) -3- (4- ( Trifluoromethoxy ) Ben Yl) -1H-indole-2-carboxylate Exed's  synthesis

The procedure of Example 48 was repeated except that (4-chlorophenyl) boronic acid was used instead of 3- (chlorophenyl) boronic acid used in <Step 4> to obtain the target compound .

^{1 H NMR (400 MHz, DMSO} -d 6) 7.94 (dd, J = 2.8, 8.8 Hz, 2H), 7.76 (d, J = 8.4 Hz, 2H), 7.60-7.50 (m, 4H), 7.38 (d J = 8.0 Hz, 2H), 7.22 (dd, J = 1.6,8.4 Hz, 1H), 7.08 (d, J = 1.6 Hz, 1H).

[ Example  49] 3- Benzoyl -1- (4- Chlorophenyl ) -6- ( Trifluoromethyl ) -1H-indole-2-carboxylate Exed's  synthesis

<Step 1> (E) -Ethyl-2- (2- (3- Fluorophenyl ) Hydrazano ) Propanoate synthesis castle

(3- (trifluoromethyl) phenyl) hydrazine hydrochloride (25 g, 141.93 mmol) and ethanol (250 mL) were added and dissolved in a 100 mL flask. Then, ethyl-2-oxopropanoate (24.7 g, 212.89 mmol) and acetic acid (5 mL) were added and the mixture was refluxed with stirring for 5 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The organic layer was separated using ethyl acetate and water, and then the water contained in the organic layer was removed with magnesium sulfate. After filtration, the mixture was purified by column chromatography (EA / n-Hex = 1: 5) to obtain (E) -ethyl 2- (2- (3- fluorophenyl) hydrazano) propanoate 26 g, 94.8 mmol, 66%).

&Lt; Step 2 > Ethyl-6- ( Trifluoromethyl ) -1H-indole-2- Carboxylate synthesis

To a 1000 mL flask was added toluene (300 mL) and the (E) -ethyl-2- (2- (3- (trifluoromethyl) phenyl) hydrazano) propanoate synthesized in the above Step 1 26 g, 94.8 mmol). Then, polyphosphoric acid (150 g) was added thereto, followed by reflux reaction for 6 hours. When the reaction was completed, the reaction mixture was cooled to 50 deg. C and only the toluene layer was separated, and the separated toluene layer was concentrated under reduced pressure. Toluene (50 mL) was added to the formed solid, refluxed for 1 hour, and cooled to room temperature. Thereafter, the recrystallized solid was filtered to obtain ethyl-6- (trifluoromethyl) -1H-indole-2-carboxylate (1.25 g, 4.86 mmol, 5%).

<Step 3> Synthesis of ethyl-3- Benzoyl -6- ( Trifluoromethyl ) -1H-indole-2- Carboxylate  synthesis

Benzoic acid (1.63 g, 13.39 mmol) and acetonitrile (13 ml) were added to a 250-mL flask and dissolved. Then, 85% phosphoric acid (0.29 ml, 5.15 mmol) and trifluoroacetic acid hydride 7.27 ml, 51.51 mmol) was added and stirred for 10 minutes. Then, ethyl-6- (trifluoromethyl) -1H-indole-2-carboxylate (2.65 g, 10.30 mmol) synthesized in the above Step 2 was added thereto and stirred for 10 hours. After completion of the reaction, the organic layer was separated using ethyl acetate and water, and the organic layer was further treated with saturated sodium hydrogencarbonate and sodium chloride, and then water was removed with magnesium sulfate. Then, after filtration, the mixture was purified by column chromatography (EA / n-Hex = 1: 4) to obtain ethyl 3-benzoyl-6- (trifluoromethyl) -1H- indole-2-carboxylate , 0.86 mmol, 8.36%).

^{1 H NMR (400 MHz, CDCl} 3) 9.43 (s, 1H), 7.87-7.80 (m, 4H), 7.59 (t, J = 1.2, 7.6 Hz, 1H), 7.45 (t, J = 7.6 Hz, 3H ), 4.09 (q, J = 7.2 Hz, 2H), 0.90 (t, J = 7.2 Hz, 3H).

<Step 4> Synthesis of ethyl-3- Benzoyl -1- (4- ( Chlorophenyl ) -6- ( Trifluoromethyl ) -1H-indole-2-carboxylate

-1H-indole-2-carboxylate (150 mg, 0.41 mmol) synthesized in the above Step 3 and dichlooromethane (2 mL) were added to a 25 mL flask. mL) was added and dissolved. Then, 4- (chlorophenyl) boronic acid (129.8 mg, 0.83 mmol), copper (II) acetate (150.8 mg, 0.83 mmol) and triethylamine (116 μl, 0.83 mmol) Lt; / RTI &gt; After completion of the reaction, the organic layer was separated using dichloromethane and 2N HCl, and then the water contained in the organic layer was removed with magnesium sulfate. After filtration, the mixture was purified by column chromatography (EA / n-Hex = 1: 4) to obtain ethyl-3-benzoyl-1- (4- (chlorophenyl) -6- (trifluoromethyl) -1H-indole-2-carboxylate (31 mg, 0.06 mmol, 14.87%).

^{1 H NMR (400 MHz, CDCl} 3) 7.93-7.88 (m, 3H), 7.61-7.25 (m, 9H), 3.80 (q, J = 7.2 Hz, 2H), 0.81 (t, J = 7.2 Hz, 3H ).

&Lt; Step 5 > 3- Benzoyl -1- (4- Chlorophenyl ) -6- ( Trifluoromethyl ) -1H-indole-2-carboxylate Exed's  synthesis

To a 25 mL flask was added ethyl-3-benzoyl-1- (4- (chlorophenyl) -6- (trifluoromethyl) -1H-indole-2-carboxylate 1N sodium hydroxide (0.45 ml, 5 vol) was added to the solution, and the mixture was stirred for 1 hour. To the reaction mixture was added 1N sodium hydroxide (0.45 ml, 5 vol) After completion of the reaction, the reaction mixture was concentrated, and adjusted to pH 5 with 2N HCl. Then, the organic layer was separated using ethyl acetate and water, and then the water contained in the organic layer was removed with magnesium sulfate. The mixture was then purified by column chromatography (MeOH / CH ₂ Cl ₂ = 1: 9) to give 3-benzoyl-1- (4-chlorophenyl) -6- (trifluoromethyl) -Carboxylic acid (31 mg, 0.069 mmol, 14.87%).

^{1 H NMR (400 MHz, DMSO} -d 6) 7.84-7.80 (m, 3H), 7.65-7.45 (m, 8H), 7.37 (s, 1H).

[ Example  50] 3- Benzoyl -1- (3- Chlorophenyl ) -6- ( Trifluoromethyl ) -1H-indole-2-carboxylate Exed's  synthesis

The procedure of Example 49 was repeated except that (3-chlorophenyl) boronic acid was used instead of 4- (chlorophenyl) boronic acid used in <Step 4> to obtain the target compound .

^{1 H NMR (400 MHz, DMSO} -d 6) 7.85 (m, 3H), 7.64-7.42 (m, 8H), 7.31 (s, 1H).

[ Example  51] 1- (3- Chlorophenyl ) -3- (4- Chlorobenzoyl ) -1H-indole-2- Carboxyl Rick Exed's  synthesis

<Step 1> Synthesis of ethyl-3- (4- Methoxybenzoyl ) -1H-indole-2- Carboxylate  synthesis

Ethyl-1H-indole-2-carboxylate (1.5 g, 7.93 mmol) and dichloromethane (15 mL) were dissolved in a 25 mL flask. Then, 4-chlorobenzoyl chloride (1.39 g, 7.93 mmol), aluminum chloride (2.11 g, 15.85 mmol) was added and the mixture was refluxed for 12 hours. After completion of the reaction, the temperature was lowered to room temperature, and the organic layer was separated using dichloromethane and water, and the water contained in the organic layer was removed with magnesium sulfate. After filtration, the mixture was purified by column chromatography (EA / n-Hex = 6: 1) to obtain ethyl 3- (4-methoxybenzoyl) -1H- indole- 3.80 mmol, 34.6%).

^{1 H NMR (400 MHz, DMSO} -d 6) 12.59 (s, 1H), 7.77 (d, J = 6 Hz, 2H), 7.63 (s, 2H), 7.58 (s, 2H), 7.38 (t, J = 7.6 Hz, 1H), 7.18 (d, J = 9.2 Hz, 1H), 4.02-3.97 (q, J = 7.2 Hz, 2H), 0.89-0.85 (t, J = 7.2 Hz, 3H).

&Lt; Step 2 > Ethyl-1- (3- Chlorophenyl ) -3- (4- Chlorobenzoyl ) -1H-indole-2- Carlsbad Synthesis of silylate

-1H-indole-2-carboxylate (150 mg, 0.458 mmol) synthesized in the above Step 1 and dichloromethane (1.5 mL) were added to a 25 mL flask, And dissolved. Then, (3-chlorophenyl) boronic acid (71.6 mg, 0.458 mmol), copper (II) acetate (166.4 mg, 0.916 mmol) and triethylamine (92.7 mg, 0.916 mmol) Lt; / RTI &gt; After completion of the reaction, the organic layer was separated using dichloromethane and water, and then the water contained in the organic layer was removed with magnesium sulfate. After filtration, the mixture was purified by column chromatography (EA / n-Hex = 4: 1) to obtain ethyl-1- (3- chlorophenyl) -3- (4- chlorobenzoyl) -2-carboxylate (70 mg, 0.16 mmol, 35%).

^{1 H NMR (400 MHz, CDCl} 3) 7.88 (d, J = 8.8 Hz, 2H), 7.75 (d, J = 8Hz, 1H), 7.50 (d, J = 6 Hz, 2H), 7.46 (dd, J J = 8.4 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H) 3.89-3.83 (q, 2H), 0.86-0.83 (t, J = 7.2 Hz, 3H).

&Lt; Step 3 > 1- (3- Chlorophenyl ) -3- (4- Chlorobenzoyl ) -1H-indole-2- Carboxylic  Exceed

To a 100 mL flask was added ethyl-1- (3-chlorophenyl) -3- (4-chlorobenzoyl) -1H-indole-2-carboxylate synthesized in the above Step 2 (70 mg, 0.16 mmol ) Was added, and tetrahydrofuran (0.7 mL) and methanol (0.7 mL) were added to dissolve. Then, 4N sodium hydroxide aqueous solution (0.35 mL) was added, and the mixture was stirred for 1 hour. After completion of the reaction, the reaction mixture was concentrated and adjusted to pH 5 with 2N HCl. Thereafter, the organic layer was separated using ethyl acetate and water, and then the water contained in the organic layer was removed with magnesium sulfate. After filtration, the mixture was purified by column chromatography (MeOH / CH ₂ Cl ₂ = 1: 9) to give 1- (3-chlorophenyl) -3- (4- chlorobenzoyl) -1H- 2-carboxylic acid (38 mg, 0.093 mmol, 58%).

^{1 H NMR (400 MHz, DMSO} -d 6) 7.81 (d, J = 8.8 Hz, 2H), 7.68 (d, J = 8Hz, 1H), 7.43 (d, J = 6 Hz, 2H), 7.38 (d J = 8.4 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 7.20 ).

[ Example  52] 3- (4- Chlorobenzoyl ) -1- (3- Methoxyphenyl ) -1H-indole-2- Carboxylic  Synthesis of Exceed

The procedure of Example 51 was repeated except that (3-methoxyphenyl) boronic acid was used instead of (3-chlorophenyl) boronic acid used in <Step 2> to obtain the target compound .

^{1 H NMR (400 MHz, DMSO} -d 6) 7.83 (d, J = 9.2 Hz, 2H), 7.65 (d, J = 6.0 Hz, 1H), 7.60 (d, J = 6.8 Hz, 2H), 7.51- (D, J = 1.6, 8.4 Hz, 1H), 7.74 (t, 1H), 7.38-7.36 , 7.08 (s, 1 H), 7.06 (d, J = 8.4 Hz, 1 H), 3.81 (s, 3H).

[ Example  53] 1- (3- Chlorophenyl ) -3- (4- Methoxybenzoyl ) -1H-indole-2- Carboxylic  Synthesis of Exceed

<Step 1> Synthesis of ethyl-3- (4- Methoxybenzoyl ) -1H-indole-2- Carboxylate  synthesis

Ethyl-1H-indole-2-carboxylate (1 g, 5.29 mmol) and dichloroethane (10 mL) were dissolved in a 25 mL flask. Then, 4-methoxybenzoyl chloride (0.9 g, 5.29 mmol) and aluminum chloride (2.82 g, 10.58 mmol) were added and refluxed for 12 hours. After completion of the reaction, the temperature was lowered to room temperature, and the organic layer was separated using dichloromethane and water, and the water contained in the organic layer was removed with magnesium sulfate. After filtration, the mixture was purified by column chromatography (EA / n-Hex = 6: 1) to obtain ethyl 3- (4-methoxybenzoyl) -1H- indole- 2.78 mmol, 52.9%).

^{1 H NMR (400 MHz, CDCl} 3) 9.16 (s, 1H), 7.89 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 8.4 Hz, J = 7.2 Hz, 1H), 7.38 (t, J = 7.4 Hz, 1 H), 7.19 (t, J = 7.6 Hz, 2H), 3.87 (s, 3H), 0.97-0.94 (t, J = 7.2 Hz, 3H).

&Lt; Step 2 > Ethyl-1- (3- Chlorophenyl ) -3- (4- Methoxybenzoyl ) -1H-indole-2- Carboxyl Synthesis of Rate

-1H-indole-2-carboxylate (150 mg, 0.464 mmol) synthesized in the above Step 1 and dichloromethane (1.5 mL) were added to a 25 mL flask, And dissolved. (72.5 mg, 0.46 mmol), copper (II) acetate (168.6 mg, 0.93 mmol) and triethylamine (93.9 mg, 0.93 mmol) were added and the mixture was stirred for 12 hours Lt; / RTI &gt; After completion of the reaction, the organic layer was separated using dichloromethane and water, and then the water contained in the organic layer was removed with magnesium sulfate. After filtration, the mixture was purified by column chromatography (EA / n-Hex = 4: 1) to obtain ethyl-1- (3-chlorophenyl) -3- (4-methoxybenzoyl) -1H-indole -2-carboxylate (86 mg, 0.198 mmol, 42.8%).

^{1 H NMR (400 MHz, CDCl} 3) 7.92 (d, J = 4.4 Hz, 2H), 7.72 (dd, J = 8.4 Hz, 1H), 7.52 (d, J = 6.4 Hz, 2H), 7.36 (d, J = 6.4 Hz, 2H), 7.32 (dd, J = 8.4 Hz, 1H), 7.24 (t, J = 8.0 Hz, , 3.88-3.85 (q, J = 7.2 Hz, 2H), 3.85 (s, 3H), 0.85-0.82 (t, J = 7.2 Hz, 3H).

&Lt; Step 3 > 1- (3- Chlorophenyl ) -3- (4- Methoxybenzoyl ) -1H-indole-2- Carboxylic Ex Synthesis of seed

To a 100 mL flask was added ethyl-1- (3-chlorophenyl) -3- (4-methoxybenzoyl) -1H-indole-2-carboxylate (86 mg, 0.19 mmol ), And tetrahydrofuran (0.86 mL) and methanol (0.86 mL) were added to dissolve. Then, a 4N sodium hydroxide aqueous solution (0.43 mL) was added and stirred for 1 hour. After completion of the reaction, the reaction mixture was concentrated and adjusted to pH 5 with 2N HCl. Thereafter, the organic layer was separated using ethyl acetate and water, and then the water contained in the organic layer was removed with magnesium sulfate. Then, after filtration, the mixture was purified by column chromatography (MeOH / CH ₂ Cl ₂ = 1: 9) to give 1- (3-chlorophenyl) -3- (4-methoxybenzoyl) 2-carboxylic acid (39 mg, 0.096 mmol, 52.2%).

^{1 H NMR (400 MHz, DMSO} -d 6) 13.2 (s, 1H) 7.83 (d, J = 4.4 Hz, 2H), 7.69 (dd, J = 8.4 Hz, 1H), 7.41 (d, J = 6.4 Hz , 7.28 (d, J = 6.4 Hz, 2H), 7.23 (dd, J = 8.4 Hz, 1H), 7.15 , J = 6.8 Hz, 2 H) 3.85 (s, 3 H).

[ Example  54] 1- (4- ( Rat - Butyl ) Phenyl) -3- (4- Methoxybenzoyl ) -1H-indole-2- Carboxylic Exed's  synthesis

The procedure of Example 53 was repeated except that (4- (tert-butyl) phenyl) boronic acid was used in place of (3-chlorophenyl) boronic acid used in <Step 2> Compound.

^{1 H NMR (400 MHz, DMSO} -d 6) 13.22 (s, 1H), 7.81 (d, J = 8.8 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.0 J = 8.0 Hz, 1H), 7.41 (d, J = 8.0 Hz, 2H), 7.33 (t, Hz, 2H), 3.84 (s, 3H), 1.36 (s, 9H).

[ Example  55] 3- Benzoyl -6- Floro -1- (4- ( Methyl thio ) Phenyl) -lH-indole-2- Carlsbad Silic Exed's  synthesis

<Step 1> (E) -Ethyl-2- (2- (3- Fluorophenyl ) Hydrazano ) Propanoate synthesis castle

(3-Fluorophenyl) hydrazine hydrochloride (25 g, 153.75 mmol) and ethanol (250 mL) were added to a 1000 mL flask and dissolved. Then, ethyl 2-oxopropanoate (26.8 g, 230.62 mmol) and acetic acid (5 mL) were added, and the mixture was refluxed with stirring for 5 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The organic layer was separated using ethyl acetate and water, and then the water contained in the organic layer was removed with magnesium sulfate. Then, after filtration, the mixture was purified by column chromatography (EA / n-Hex = 1: 4) to obtain (E) -ethyl 2- (2- (3- fluorophenyl) hydrazano) propanoate (22.5 g, 100.34 mmol, 65%).

^{1 H NMR (400 MHz, CDCl} 3) 7.66 (br, NH, 1H), 7.26-7.20 (m, 1H), 7.02 (dt, J = 2.4, 10.8 Hz, 1H), 6.88 (dd, J = 1.6 Hz , 8.4 Hz, 1H), 6.84-6.63 (m, 1H), 4.35-4.29 (m, 2H), 2.11 (s, 3H), 1.55-1.36 (m, 3H).

&Lt; Step 2 > Ethyl-6- Floro -1H-indole-2- Carboxylate  synthesis

(E) -ethyl-2- (2- (3-fluorophenyl) hydrazano) propanoate synthesized in the above Step 1 (22.5 g, 100.34 mmol). Then, polyphosphoric acid (120 g) was added thereto, followed by reflux reaction for 6 hours. When the reaction was completed, the reaction solution was cooled to 50 DEG C and then the toluene layer was separated, and the separated toluene layer was concentrated under reduced pressure. Then toluene (50 mL) was added to the solid formed, and the mixture was refluxed for 1 hour and cooled to room temperature. The re-crystallized solid was then filtered to yield ethyl-6-fluoro-lH-indole-2-carboxylate (7.2 g, 34.7 mmol, 34%).

^{1 H NMR (400 MHz, CDCl} 3) 9.00 (br, NH, 1H), 7.63-7.59 (m, 1H), 7.22-7.20 (m, 1H), 7.08 (dd, J = 2.0, 9.6 Hz, 1H) , 6.95-6.90 (m, 1H), 4.45-4.38 (m, 2H), 1.44-1.40 (m, 3H).

<Step 3> Synthesis of ethyl-3- Benzoyl -6- Floro -1H-indole-2- Carboxylate  synthesis

Ethyl-6-fluoro-1H-indole-2-carboxylate (10 g, 48.26 mmol) synthesized in the above Step 2 and dichloroethane (150 mL) were dissolved in a 500 mL flask. Benzoyl chloride (8.14 g, 57.91 mmol), aluminum chloride (7.72 g, 57.91 mmol) was then added and refluxed for 12 hours. After completion of the reaction, the temperature was lowered to room temperature, and the organic layer was separated using dichloromethane and water, and the water contained in the organic layer was removed with magnesium sulfate. After filtration, the mixture was purified by column chromatography (EA / n-Hex = 1: 6) to give ethyl-3-benzoyl-6-fluoro-1H-indole-2-carboxylate (12 g, mmol, 80%).

^{1 H NMR (400 MHz, CDCl} 3) 9.26 (br, NH, 1H), 7.87 (d, J = 9.6 Hz, 2H), 7.69-7.64 (m, 1H), 7.59-7.55 (m, 1H), 7.43 (d, J = 2.4, 9.2 Hz, 1H), 7.02-6.95 (m, 1H), 4.07-4.02 (m, 2H), 0.90-0.85 ).

<Step 4> Synthesis of ethyl-3- Benzoyl -6- Floro -1- (4- ( Methyl thio ) Phenyl-lH-indole-2- Car Synthesis of the compound

To a 25 mL flask was added ethyl-3-benzoyl-6-fluoro-1H-indole-2-carboxylate (150 mg, 0.48 mmol) synthesized in the above Step 3 and dichloromethane . Next, (4-methylthiophenyl) boronic acid (162 mg, 0.96 mmol), copper (II) acetate (175 mg, 0.96 mmol) and triethylamine (134 .mu.l, 0.96 mmol) &Lt; / RTI > After completion of the reaction, the organic layer was separated using dichloromethane and 2N-HCl, and then the water contained in the organic layer was removed with magnesium sulfate. After filtration, the mixture was purified by column chromatography (EA / n-Hex = 1: 4) to obtain ethyl-3-benzoyl-6-fluoro-1- (4- (methylthio) -2-carboxylate (110 mg, 0.25 mmol, 52.66%).

^{1 H NMR (400 MHz, CDCl} 3) 7.91 (dd, J = 2.0, 8.0 Hz, 2H), 7.76 (q, J = 5.2, 8.8 Hz, 1H), 7.58-7.29 (m, 7H), 7.02 (dt J = 2.0, 8.8 Hz, 1H), 6.75 (dd, J = 2.4, 6.8 Hz, 1H), 3.76 (q, J = 7.2 Hz, 2H) 7.2 Hz, 3 H).

&Lt; Step 5 > 3- Benzoyl -6- Floro -1- (4- ( Methyl thio ) Phenyl) -lH-indole-2- Carboxyl Rick Exed's  synthesis

To a 25 mL flask was added ethyl-3-benzoyl-6-fluoro-1- (4- (methylthio) phenyl-1H-indole-2-carboxylate (110 mg, 0.25 1N sodium hydroxide (0.55 ml, 5 vol) was added thereto, and the mixture was stirred for 1 hour. After completion of the reaction, the reaction mixture was stirred at room temperature for 2 hours, , Concentrated, and adjusted to pH 5 with 2N HCl. Then, the organic layer was separated using ethyl acetate and water, and then the water contained in the organic layer was removed with magnesium sulfate. Purification by chromatography (MeOH / CH ₂ Cl ₂ = 1: 9) afforded 3-benzoyl-6-fluoro-1- (4- (methylthio) phenyl) -1H-indole-2-carboxylic acid 33 mg, 0.081 mmol, 32.07%).

^{1 H NMR (400 MHz, DMSO} -d 6) 7.80 (d, J = 7.2 Hz, 2H), 7.62-7.39 (m, 8H), 7.09 (dt, J = 2.0, 9.2 Hz, 1H), 6.88 (dd , J = 2.0, 9.5 Hz, IH), 2.55 (s, 3H).

[ Example  56] 3- Benzoyl -1- (3- ( Methyl thio ) Phenyl) -6- ( Trifluoromethyl ) -1H-indole-2-carboxylate Exed's  synthesis

The procedure of Example 55 was repeated except that (3-methylthiophenyl) boronic acid was used instead of (4-methylthiophenyl) boronic acid used in <Step 4> &Lt; / RTI &gt;

^{1 H NMR (400 MHz, DMSO} -d 6) 7.81 (d, J = 6.8 Hz, 2H), 7.60 (t, 2H), 7.48 (dt, J = 2.8, 8.4 Hz, 3H), 7.37 (d, J = 7.6 Hz, 2H), 7.24 (d, J = 6.8 Hz, 3H), 7.08 (t, J = 7.6 Hz, 1H), 6.89 (dd, J = 2.0, 10.0 Hz, 1H) ).

[ Example  57] 3- Benzoyl -6- Floro -1- (4- Fluorophenyl ) -1H-indole-2- Carboxylic  Synthesis of Exceed

The procedure of Example 55 was repeated except that (4-fluorophenyl) boronic acid was used instead of (4-methylthiophenyl) boronic acid used in <Step 4> to obtain the target compound .

^{1 H NMR (400 MHz, DMSO} -d 6) 13.3 (s, 1H), 7.83 (dd, J = 5.2, 7.2 Hz, 2H), 7.67-7.39 (m, 8H), 7.14 (dt, J = 2.4, 9.2 Hz, 1 H), 6.90 (dd, J = 2.4, 9.6 Hz, 1 H).

[ Example  58] 3- (4- Chlorobenzoyl ) -6- Floro -1- (4- ( Methyl thio ) Phenyl) -1H-indole-2-carboxylate Exed's  synthesis

<Step 1> (E) -Ethyl-2- (2- (3- Fluorophenyl ) Hydrazano ) Propanoate synthesis castle

(3-Fluorophenyl) hydrazine hydrochloride (25 g, 153.75 mmol) and ethanol (250 mL) were added to a 1000 mL flask and dissolved. Then, ethyl 2-oxopropanoate (26.8 g, 230.62 mmol) and acetic acid (5 mL) were added, and the mixture was refluxed with stirring for 5 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The organic layer was separated using ethyl acetate and water, and then the water contained in the organic layer was removed with magnesium sulfate. After filtration, the mixture was purified by column chromatography (EA / n-Hex = 1: 4) to obtain (E) -ethyl 2- (2- (3- fluorophenyl) hydrazano) propanoate 22.5 g, 100.34 mmol, 65%).

^{1 H NMR (400 MHz, CDCl} 3) 7.66 (br, NH, 1H), 7.26-7.20 (m, 1H), 7.02 (dt, J = 2.4, 10.8 Hz, 1H), 6.88 (dd, J = 1.6 Hz , 8.4 Hz, 1H), 6.84-6.63 (m, 1H), 4.35-4.29 (m, 2H), 2.11 (s, 3H), 1.55-1.36 (m, 3H).

&Lt; Step 2 > Ethyl-6- Floro -1H-indole-2- Carboxylate  synthesis

(E) -ethyl-2- (2- (3-fluorophenyl) hydrazano) propanoate synthesized in the above Step 1 (22.5 g, 100.34 mmol). Then, polyphosphoric acid (120 g) was added and the reflux reaction proceeded for 6 hours. When the reaction was completed, the reaction mixture was cooled to 50 DEG C, and only the toluene layer was separated, and then the separated toluene layer was concentrated under reduced pressure. Then toluene (50 mL) was added to the solid formed, and the mixture was refluxed for 1 hour and cooled to room temperature. The re-crystallized solid was then filtered to yield ethyl-6-fluoro-lH-indole-2-carboxylate (7.2 g, 34.7 mmol, 34%).

^{1 H NMR (400 MHz, CDCl} 3) 9.00 (br, NH, 1H), 7.63-7.59 (m, 1H), 7.22-7.20 (m, 1H), 7.08 (dd, J = 2.0, 9.6 Hz, 1H) , 6.95-6.90 (m, 1H), 4.45-4.38 (m, 2H), 1.44-1.40 (m, 3H).

<Step 3> Synthesis of ethyl-3- (4- Chlorobenzoyl ) -6- Floro -1H-indole-2- Carboxylate Synthesis of

Ethyl-6-fluoro-1H-indole-2-carboxylate (5 g, 22.3 mmol) synthesized in the above Step 2 and dichloroethane (50 mL) were dissolved in a 250 mL flask. Then, 4-chlorobenzoyl chloride (4.7 g, 26.8 mmol) and aluminum chloride (3.6 g, 26.8 mmol) were added and refluxed for 12 hours. After completion of the reaction, the temperature was lowered to room temperature, and the organic layer was separated using dichloromethane and water, and the water contained in the organic layer was removed with magnesium sulfate. Then, after filtration, the mixture was purified by column chromatography (EA / n-Hex = 1: 6) to obtain ethyl 3- (4-chlorobenzoyl) -6-fluoro-1H-indole- (4.5 g, 12.4 mmol, 55.6%).

^{1 H NMR (400 MHz, CDCl} 3) 9.27 (br, NH, 1H), 7.82 (d, J = 9.2 Hz, 2H), 7.65-7.62 (m, 1H), 7.42 (d, J = 9.2 Hz, 2H ), 7.16 (dd, J = 2.0,8.8 Hz, 1H), 7.02-6.97 (m, 1H), 4.12-4.07 (m, 2H), 0.97-0.93 (m, 3H).

<Step 4> Synthesis of ethyl-3- (4- Chlorobenzoyl ) -6- Floro -1- (4- Methyl thio ) Phenyl) -1H-indole-2-carboxylate

To a 25 mL flask was added ethyl-3- (4-chlorobenzoyl) -6-fluoro-1H-indole-2-carboxylate (200 mg, 0.41 mmol) synthesized in the above Step 3 and dicloro Methane (2 mL) was added and dissolved. Then, (4-methylthiophenyl) boronic acid (194 mg, 1.157 mmol), copper (II) acetate (210 mg, 1.157 mmol) and triethylamine (0.161 ml, 1.157 mmol) &Lt; / RTI > After completion of the reaction, the organic layer was separated using dichloromethane and 2N-HCl, and the water contained in the organic layer was removed with magnesium sulfate. After filtration, the mixture was purified by column chromatography (EA / n-Hex = 1: 4) to obtain ethyl 3- (4-chlorobenzoyl) -6- ) Phenyl) -1H-indole-2-carboxylate (97 mg, 0.207 mmol, 20.72%).

^{1 H NMR (400 MHz, CDCl} 3) 7.86 (d, J = 8.8 Hz, 2H), 7.73-7.69 (m, 1H), 7.45-7.22 (m, 6H), 7.05 (dt, J = 2.0, 9.2 Hz J = 7.2 Hz, 3H), 6.83 (dd, J = 1.5,9.2 Hz, 1H), 3.84 (q, J = 7.2 Hz, 2H).

<Step 5> Synthesis of 3- (4- Chlorobenzoyl ) -6- Floro -1- (4- ( Methyl thio ) Phenyl) -1H-indole-2-carboxylate Exed's  synthesis

To a 100 mL flask was added ethyl-3- (4-chlorobenzoyl) -6-fluoro-1- (4-methylthio) phenyl) -1H-indole-2-carboxyl (97 mg, 0.207 mmol) was added thereto, and the mixture was dissolved by adding tetrahydrofuran (1 mL) and methanol (1 mL). Next, 1N-sodium hydroxide (0.045 mL) was added and stirred for 1 hour. After completion of the reaction, the reaction mixture was concentrated and adjusted to pH 5 with 2N HCl. Thereafter, the organic layer was separated using ethyl acetate and water, and then the water contained in the organic layer was removed with magnesium sulfate. After filtration, the mixture was purified by column chromatography (MeOH / CH ₂ Cl ₂ = 1: 9) to give 3- (4-chlorobenzoyl) -6- ) Phenyl) -1H-indole-2-carboxylic acid (48 mg, 0.109 mmol, 52.64%).

^{1 H NMR (400 MHz, DMSO} -d 6) 13.4 (s, 1H), 7.82 (d, J = 8.8 Hz, 2H), 7.69-7.65 (m, 1H), 7.56 (d, J = 8.4 Hz, 2H ), 7.44-7.39 (m, 1H), 7.18 (dt, J = 2.4,9.2 Hz, 1H), 6.90 (dd, J = 2.0,9.6 Hz, 1H), 2.58 (s, 3H).

[ Example  59] 3- (4- Chlorobenzoyl ) -6- Floro -1- (4- ( Trifluoromethoxy ) Phenyl) -1H-indole-2-carboxylate Exed's  synthesis

The same procedure as in Example 58 was performed except that (4-trifluoromethoxyphenyl) boronic acid was used instead of (4-methylthiophenyl) boronic acid used in <Step 4> To obtain the target compound.

^{1 H NMR (400 MHz, DMSO} -d 6) 13.4 (s, 1H), 7.86 (dd, J = 2.4, 8.4 Hz, 2H), 7.70-7.53 (m, 7H), 7.18 (dt, J = 2.4, 9.2 Hz, 1H), 6.96 (dd, J = 2.4, 9.6 Hz 1H).

[ Example  60] 3- (4- Chlorobenzoyl ) -6- Floro -1- (3- Methyl thio ) Phenyl) -1H-indole-2-carboxylate Exed's  synthesis

The procedure of Example 58 was repeated except that (3-methylthiophenyl) boronic acid was used instead of (4-methylthiophenyl) boronic acid used in < Step 4 & &Lt; / RTI &gt;

^{1 H NMR (400 MHz, DMSO} -d 6) 7.82 (d, J = 2.0 Hz, 2H), 7.80-7.68 (m, 1H), 7.52-7.11 (m, 5H), 7.09 (d, J = 7.2 Hz (D, J = 2.0 Hz, 1H), 2.51 (s, 3H), 7.06 (t, J = 2.0 Hz,

[ Example  61] 6- Floro -1- (4- Fluorophenyl ) -3- (4- Methoxybenzoyl ) -1H-indole-2-carboxylate Exed's  synthesis

<Step 1> (E) -Ethyl-2- (2- (3- Fluorophenyl ) Hydrazano ) Propanoate synthesis castle

To a 1000 mL flask was added (3-fluorophenyl) hydrazine hydrochloride (25 g, 153.75 mmol) and ethanol (250 mL) to dissolve. Then, ethyl-2-oxopropanoate (26.8 g, 230.62 mmol) and acetic acid (5 mL) were added, and the mixture was refluxed with stirring for 5 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The organic layer was separated using ethyl acetate and water, and then the water contained in the organic layer was removed with magnesium sulfate. After filtration, the mixture was purified by column chromatography (EA / n-Hex = 1: 4) to obtain (E) -ethyl 2- (2- (3- fluorophenyl) hydrazano) propanoate 22.5 g, 100.34 mmol, 65%).

^{1 H NMR (400 MHz, CDCl} 3) 7.66 (br, NH, 1H), 7.26-7.20 (m, 1H), 7.02 (dt, J = 2.4, 10.8 Hz, 1H), 6.88 (dd, J = 1.6 Hz , 8.4 Hz, 1H), 6.84-6.63 (m, 1H), 4.35-4.29 (m, 2H), 2.11 (s, 3H), 1.55-1.36 (m, 3H).

&Lt; Step 2 > Ethyl-6- Floro -1H-indole-2- Carboxylate  Synthesis of compounds

(E) -ethyl-2- (2- (3-fluorophenyl) hydrazano) propanoate synthesized in the above Step 1 (22.5 g, 100.34 mmol). Then, polyphosphoric acid (120 g) was added and the reflux reaction proceeded for 6 hours. When the reaction was completed, the reaction mixture was cooled to 50 DEG C, and only the toluene layer was separated, and then the separated toluene layer was concentrated under reduced pressure. Then toluene (50 mL) was added to the solid formed, and the mixture was refluxed for 1 hour and cooled to room temperature. The re-crystallized solid was then filtered to yield ethyl-6-fluoro-lH-indole-2-carboxylate (7.2 g, 34.7 mmol, 34%).

^{1 H NMR (400 MHz, CDCl} 3) 9.00 (br, NH, 1H), 7.63-7.59 (m, 1H), 7.22-7.20 (m, 1H), 7.08 (dd, J = 2.0, 9.6 Hz, 1H) , 6.95-6.90 (m, 1H), 4.45-4.38 (m, 2H), 1.44-1.40 (m, 3H).

<Step 3> Synthesis of ethyl-6- Floro -3- (4- Methoxybenzoyl ) -1H-indole-2- Carboxylate  synthesis

(976 mg, 6.41 mmol) and acetonitrile (11 mL) were added to a 100 mL flask and dissolved. Then, 85% phosphoric acid (0.125 mL, 6.41 mmol) and trifluo The ro acetic anhydride (3 mL, 21.39 mmol) was added and stirred for 10 min. Then, ethyl-6-fluoro-1H-indole-2-carboxylate (1.1 g, 4.28 mmol) synthesized in the above Step 2 was added thereto and stirred for 10 hours. After completion of the reaction, the organic layer was separated using ethyl acetate and water, and the organic layer was further treated with saturated sodium hydrogencarbonate and sodium chloride, and then water was removed with magnesium sulfate. After filtration, the mixture was purified by column chromatography (EA / n-Hex = 1: 4) to give ethyl 6-fluoro-3- (4- methoxybenzoyl) -1H-indole- (1.2 g, 3.06 mmol, 71.8%).

^{1 H NMR (400 MHz, CDCl} 3) 9.34 (br, NH, 1H), 7.86 (d, J = 9.6 Hz, 2H), 7.60-7.57 (m, 1H), 7.14 (dd, J = 2.0, 9.2 Hz 2H), 3.87 (s, 3H), 0.98-0.94 (m, 3H).

<Step 4> Synthesis of ethyl-6- Floro -1- (4- Fluorophenyl ) -3- (4- Methoxybenzoyl ) -1H-indole-2-carboxylate

To a 25 mL flask was added ethyl-6-fluoro-3- (4-methoxybenzoyl) -1H-indole-2-carboxylate (150 mg, 0.44 mmol) synthesized in the above Step 3 and dicloro Methane (2 mL) was added and dissolved. Then, (4-fluorophenyl) boronic acid (92 mg, 0.66 mmol), copper (II) acetate (160 mg, 0.88 mmol) and triethylamine (89 mg, 0.88 mmol) Lt; / RTI &gt; After completion of the reaction, the organic layer was separated using dichloromethane and water, and then the water contained in the organic layer was removed with magnesium sulfate. Then, after filtration, the mixture was purified by column chromatography (EA / n-Hex = 1: 4) to give ethyl 6-fluoro-1- (4-fluorophenyl) -3- (4-methoxybenzoyl) -1H-indole-2-carboxylate (110 mg, 0.25 mmol, 57.6%).

^{1 H NMR (400 MHz, CDCl} 3) 7.90 (d, J = 10 Hz, 2H), 7.68-7.64 (m, 1H), 7.40-7.35 (m, 2H), 7.27- 7.21 (m, 2H), 7.00 (dt, J = 2.4,8.8 Hz, 1H), 6.94 (d, J = 10 Hz, 2H), 6.76 (dd, J = 2.4,9.6 Hz, 1H), 3.88-3.83 0.80 (m, 3 H).

<Step 5> 6- Floro -1- (4- Fluorophenyl ) -3- (4- Methoxybenzoyl ) -1H-indole-2- Car Le Foxillic Exed's  synthesis

To a 25 mL flask was added ethyl-6-fluoro-1- (4-fluorophenyl) -3- (4-methoxybenzoyl) -1H-indole-2-carboxylate 100 mg, 0.23 mmol), and the mixture was dissolved by adding tetrahydrofuran (1 mL) and methanol (1 mL). Then sodium hydroxide (46 mg, 1.15 mmol) dissolved in water (1 mL) was added and stirred for 1 hour. After completion of the reaction, the reaction mixture was concentrated and adjusted to pH 5 with 2N HCl. Thereafter, the organic layer was separated using ethyl acetate and water, and then the water contained in the organic layer was removed with magnesium sulfate. After filtration, the mixture was purified by column chromatography (MeOH / CH ₂ Cl ₂ = 1: 9) to give 6-fluoro-1- (4- fluorophenyl) -3- (4- methoxybenzoyl) -1H-indole-2-carboxylic acid (81.5 mg, 0.20 mmol, 87%).

^{1 H NMR (400 MHz, DMSO} -d 6) 7.83 (d, J = 9.6 Hz, 2H), 7.59-7.51 (m, 2H), 7.39-7.28 (m, 3H), 7.03-6.95 (m, 3H) , 6.88 (dd, J = 2.4,10 Hz, 1 H), 3.82 (s, 3H).

[ Example  62] 1- (3- Fluorophenyl ) -6- Floro -3- (4- Methoxybenzoyl ) -1H-indole-2-carboxylate Exed's  synthesis

The procedure of Example 61 was repeated except that (3-fluorophenyl) boronic acid was used instead of (4-fluorophenyl) boronic acid used in <Step 4> to obtain the target compound .

^{1 H NMR (400 MHz, DMSO} -d 6) 7.83 (d, J = 9.6 Hz, 2H), 7.57-7.49 (m, 3H), 7.35 (t, J = 8.8 Hz, 2H), 7.01-6.94 (m , 3H), 6.78 (dd, J = 2.4, 10.0 Hz, 1H), 3.82 (s, 3H).

[ Example  63] 1- (3- Chlorophenyl ) -6- Floro -3- (4- Methoxybenzoyl ) -1H-indole-2-carboxylate Exed's  synthesis

The procedure of Example 61 was repeated except that (3-chlorophenyl) boronic acid was used instead of (4-fluorophenyl) boronic acid used in <Step 4> to obtain the desired compound .

^{1 H NMR (400 MHz, DMSO} -d 6) 7.84 (d, J = 6.8 Hz, 2H), 7.59 (d, J = 7.6 Hz, 2H), 7.55 (s, 2H), 7.04 (tz, 1H), 7.28 (d, J = 6.8 Hz, 2H) 7.15 (d, J = 11.6 Hz, 1H)

[ Example  64] 3- (3- Chlorobenzoyl ) -6- Floro -1- (P- Tollyill ) -1H-indole-2- Car Foxy Rick Exed's  synthesis

<Step 1> (E) -Ethyl-2- (2- (3- Fluorophenyl ) Hydrazano ) Propanoate synthesis castle

(3-Fluorophenyl) hydrazine hydrochloride (25 g, 153.75 mmol) and ethanol (250 mL) were added to a 1000 mL flask and dissolved. Then, ethyl 2-oxopropanoate (26.8 g, 230.62 mmol) and acetic acid (5 mL) were added, and the mixture was refluxed with stirring for 5 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the organic layer was separated using ethyl acetate and water, and then the water contained in the organic layer was removed with magnesium sulfate. Then, after filtration, the mixture was purified by column chromatography (EA / n-Hex = 1: 4) to obtain (E) -ethyl 2- (2- (3- fluorophenyl) hydrazano) propanoate (22.5 g, 100.34 mmol, 65%).

^{1 H NMR (400 MHz, CDCl} 3) 7.66 (br, NH, 1H), 7.26-7.20 (m, 1H), 7.02 (dt, J = 2.4, 10.8 Hz, 1H), 6.88 (dd, J = 1.6 Hz , 8.4 Hz, 1H), 6.84-6.63 (m, 1H), 4.35-4.29 (m, 2H), 2.11 (s, 3H), 1.55-1.36 (m, 3H).

&Lt; Step 2 > Ethyl-6- Floro -1H-indole-2- Carboxylate  synthesis

(E) -ethyl-2- (2- (3-fluorophenyl) hydrazano) propanoate synthesized in the above Step 1 (22.5 g, 100.34 mmol). Then, polyphosphoric acid (120 g) was added and the reflux reaction proceeded for 6 hours. When the reaction was completed, the reaction mixture was cooled to 50 DEG C, and only the toluene layer was separated, and then the separated toluene layer was concentrated under reduced pressure. Then toluene (50 mL) was added to the solid formed, and the mixture was refluxed for 1 hour and cooled to room temperature. The re-crystallized solid was then filtered to yield ethyl-6-fluoro-lH-indole-2-carboxylate (7.2 g, 34.7 mmol, 34%).

^{1 H NMR (400 MHz, CDCl} 3) 9.00 (br, NH, 1H), 7.63-7.59 (m, 1H), 7.22-7.20 (m, 1H), 7.08 (dd, J = 2.0, 9.6 Hz, 1H) , 6.95-6.90 (m, 1H), 4.45-4.38 (m, 2H), 1.44-1.40 (m, 3H).

<Step 3> Synthesis of ethyl-3- (3- Chlorobenzoyl ) -6- Floro -1H-indole-2- Carboxylate Synthesis of

Ethyl-6-fluoro-1H-indole-2-carboxylate (10 g, 48.26 mmol) synthesized in the above Step 2 and dichloroethane (150 mL) were dissolved in a 500 mL flask. Then, 3-chlorobenzoyl chloride (10.1 g, 57.91 mmol), aluminum chloride (7.72 g, 57.91 mmol) was added and the mixture was refluxed for 12 hours. After completion of the reaction, the temperature was lowered to room temperature, and the organic layer was separated using dichloromethane and water, and the water contained in the organic layer was removed with magnesium sulfate. Then, after filtration, the mixture was purified by column chromatography (EA / n-Hex = 1: 6) to give ethyl 3- (3-chlorobenzoyl) -6-fluoro-1H-indole- (7 g, 20.24 mmol, 42%).

^{1 H NMR (400 MHz, CDCl} 3) 9.28 (br, NH, 1H), 7.85 (t, J = 2.0 Hz, 1H), 7.35 (dt, J = 1.2, 8.0 Hz, 1H), 7.67 (m, 1H ), 7.56-7.53 (m, 1 H), 7.38 (t, J = 8.0 Hz, 1 H), 7.16 (dd, J = 2.4,9.2 Hz, 1H), 7.04-6.99 m, 2H), 0.95-0.92 (m, 3H).

<Step 4> Synthesis of ethyl-3- (3- Chlorobenzoyl ) -6- Floro -1- (P- Tollyill ) -1H-indole-2- Car Synthesis of Lexylate

To a 100 mL flask was added ethyl-3- (3-chlorobenzoyl) -6-fluoro-1H-indole-2-carboxylate (200 mg, 0.57 mmol) synthesized in the above Step 3 and dicloro Methane (2 mL) was added and dissolved. Then, (3-methylphenyl) boronic acid (157 mg, 1.156 mmol), copper (II) acetate (210 mg, 1.156 mmol) and triethylamine (0.222 ml, 1.157 mmol) were added and stirred for 12 hours . After completion of the reaction, the organic layer was separated using dichloromethane and 2N-HCl, and the water contained in the organic layer was removed with magnesium sulfate. After filtration, the mixture was purified by column chromatography (EA / n-Hex = 1: 4) to obtain ethyl 3- (3- chlorobenzoyl) -6- -1H-indole-2-carboxylate (112 mg, 0.256 mmol, 44.42%).

^{1 H NMR (400 MHz, CDCl} 3) 7.89 (s, 1H), 7.79-7.73 (m, 2H), 7.53 (d, J = 6.8 Hz, 1H), 7.41-6.81 (m, 6H), 6.68 (d J = 8.4 Hz, 1H), 3.81 (q, J = 7.2 Hz, 2H), 0.83 (t, J = 7.2 Hz, 3H).

<Step 5> Synthesis of 3- (3- Chlorobenzoyl ) -6- Floro -1- (para- Tollyill ) -1H-indole-2- Car Foxy Rick Exed's  synthesis

To a 25 mL flask was added ethyl 3- (3-chlorobenzoyl) -6-fluoro-1- (P-toluyl) -1H-indole-2-carboxylate mg, 0.224 mmol), and tetrahydrofuran (1 mL) and methanol (1 mL) were added and dissolved. Then, 1N-sodium hydroxide (0.045 mL) was added and stirred for 1 hour. After completion of the reaction, the reaction mixture was concentrated and adjusted to pH 5 with 2N HCl. Thereafter, the organic layer was separated using ethyl acetate and water, and then the water contained in the organic layer was removed with magnesium sulfate. Then, after filtration, the mixture was purified by column chromatography (MeOH / CH ₂ Cl ₂ = 1: 9) to give 3- (3-chlorobenzoyl) -6-fluoro-1- (para- -Indole-2-carboxylic acid (38 mg, 0.093 mmol, 41.44%).

^{1 H NMR (400 MHz, DMSO} -d 6) 13.4 (s, 1H), 7.79 (t, J = 2.0 Hz, 1H), 7.74-7.68 (m, 3H), 7.55 (t, J = 8.0 Hz, 1H ), 7.38 (s, 4H), 7.18 (dt, J = 2.4,9.6 Hz, 1H), 6.88 (dd, J = 2.0, 9.6 Hz, 1H), 2.42 (s, 3H).

[ Example  65] 1- (4- Rat - Butyl ) Phenyl-3- (3- Chlorobenzoyl ) -6- Floro -1H-indole-2-carboxylate Exed's  synthesis

The procedure of Example 64 was repeated except that (4- (tert-butyl) phenyl) boronic acid was used instead of (3-methylphenyl) boronic acid used in <Step 4> .

^{1 H NMR (400 MHz, DMSO} -d 6) 7.77 (t, J = 1.6 Hz, 1H), 7.73 (m, 3H), 7.56 (d, J = 8.4 Hz, 2H), 7.51 (t, J = 7.6 Hz, 1H), 7.14 (dt, J = 2, 9.2 Hz, 1H), 6.86 (dd, J = 2.0, 9.6 Hz, 1H), 1.34 (s, 9H).

[ Example  66] 3- (3- Chlorobenzoyl ) -6- Floro -One-( Meta - Tollyill ) -1H-indole-2-carboxylate Exed's  synthesis

The procedure of Example 64 was repeated except that (meta-toluyl) boronic acid was used instead of (3-methylphenyl) boronic acid used in < Step 4 >.

^{1 H NMR (400 MHz, DMSO} -d 6) 13.5 (s, 1H), 7.78 (s, 1H), 7.73-7.67 (m, 3H), 7.54 (t, J = 8.0 Hz, 1H), 7.47 (t J = 8.0 Hz, 1H), 7.35 (d, J = 8.4 Hz, 2H), 7.28 , J = 2.0, 9.6 Hz, 1H), 2.39 (s, 3H).

[ Example  67] 3- (3- Chlorobenzoyl ) -6- Floro -1- (4- Methoxyphenyl ) -1H-indole-2-carboxylate Exed's  synthesis

The procedure of Example 64 was repeated except that (4-methoxyphenyl) boronic acid was used instead of (3-methylphenyl) boronic acid used in < Step 4 >.

^{1 H NMR (400 MHz, DMSO} -d 6) 7.81 (t, J = 1.6 Hz, 1H), 7.75-7.67 (m, 3H), 7.57 (t, J = 8.0 Hz, 1H), 7.46 (d, J = 8.8 Hz, 2H), 7.18-7.09 (m, 3H), 6.87 (dd, J = 2.4,9.6 Hz, 1H), 3.85 (s, 3H).

[ Example 68] 6 - Chlooro -1- (4- Chlorophenyl ) -3 - ((4- Chlorophenyl ) ( Hydlock Methyl) -1H-indole-2-carboxylate Exed's  synthesis

<Step 1> (E) -Ethyl-2- (2- (3- Chlorophenyl ) Hydrazano ) Propanoate synthesis castle

Add purified distilled water (520 ml) to a 2 L flask. (50 g, 0.6 mol) was dissolved in the flask, and then (3-chlorophenyl) hydrazine hydrochloride (52 g, 0.3 mol) was added thereto. The mixture was stirred at room temperature for 30 minutes and ethyl 2-oxopropanoate (35 ml, 0.3 mol) was slowly added thereto and stirred for 6 hours. After completion of the reaction, the reaction product was filtered with a reduced pressure filter and then dried. A 3 L flask was charged with 2 L of dry solid and normal hexane and stirred for 1 hour and filtered to obtain 57 g of (E) -ethyl-2- (2- (3- chlorophenyl) hydrazano) propanoate , 0.24 mol, 81%).

^{1 H NMR (400 MHz, CDCl} 3) 7.66 (br, NH, 1H), 7.24 (m, 1H), 7.04 (m, 1H), 6.89 (d, J = 8.0 Hz, 1H), 6.84 (m, 1H ), 4.35 (q, 2H), 2.11 (s, 3H), 1.40 (t, J = 8.0 Hz, 3H).

&Lt; Step 2 > Ethyl-6- Chlooro -1H-indole-2- Carboxylate  synthesis

To a 500 ml flask was added toluene (110 ml), and 10.6 g (0.044 mmol) of the (E) -ethyl 2- (2- (3- chlorophenyl) hydrazano) propanoate synthesized in the above Step 1 mol). Then, polyphosphoric acid (52 g) was added thereto, followed by reflux reaction for 6 hours. After the reaction is completed, the reaction mixture is cooled to 50 ° C. and only the toluene layer is separated. The separated toluene layer was concentrated under reduced pressure. Then toluene (50 ml) was added to the solid formed, and the mixture was refluxed for 1 hour and cooled to room temperature. Thereafter, the recrystallized solid was filtered to obtain ethyl-6-chloro-1H-indole-2-carboxylate (3.4 g, 0.015 mol, 35%).

^{1 H NMR (400 MHz, CDCl} 3) 8.84 (br, NH, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.42 (s, 1H), 7.19 (s, 1H) 7.13 (d, J = 8.0 Hz, 1 H), 4.44 (q, 2H), 1.43 (t, J = 8.0 Hz, 3H).

<Step 3> Synthesis of ethyl-6- Chlooro -3- (4- Chlorobenzoyl ) -1H-indole-2- Carboxylate Synthesis of

In a 100 mL flask, ethyl-6-chloro-1H-indole-2-carboxylate (1 g, 4.47 mmol) synthesized in the above Step 2 and dichloromethane , 4-chlorobenzoyl chloride (939 mg, 5.36 mmol) and aluminum chloride (714 mg, 5.36 mmol) were added and the mixture was refluxed for 12 hours. After completion of the reaction, the temperature was lowered to room temperature, and the organic layer was separated using dichloromethane and water, and the water contained in the organic layer was removed with magnesium sulfate. After filtration, the mixture was purified by column chromatography (EA / n-Hex = 1: 6) to give ethyl 6-chloro-3- (4- chlorobenzoyl) -1H-indole- (843 mg, 2.32 mmol, 52%).

^{1 H NMR (400 MHz, CDCl} 3) 9.17 (s, 1H), 7.81 (d, J = 6.8 Hz, 2H), 7.60 (d, J = 8.4 Hz, 1H), 7.49-7.41 (m, 3H), 7.21 (dd, J = 1.6,8.4 Hz, 1H), 4.13-4.08 (m, 2H), 0.97-0.94 (m, 3H).

<Step 4> Synthesis of ethyl-6- Chlooro -3- (4- Chlorobenzoyl ) -1- (4- Chlorophenyl ) -1H-indole-2-carboxylate

6-chloro-1H-indole-2-carboxylate (40 mg, 0.122 mmol) synthesized in the above Step 3 and dichloromethane (1 mL) were placed in a 25 mL flask. Then, 4- (chlorophenyl) boronic acid (39 mg, 0.246 mmol), copper (II) acetate (34 mg, 0.185 mmol) and triethylamine (25 mg, 0.246 mmol) Lt; / RTI &gt; After completion of the reaction, the organic layer was separated using dichloromethane and water, and then the water contained in the organic layer was removed with magnesium sulfate. After filtration, the mixture was purified by column chromatography (EA / n-Hex = 1: 4) to give ethyl 6-chloro-3- (4- chlorobenzoyl) ) -1H-indole-2-carboxylate (34 mg, 0.072 mmol, 60%).

^{1 H NMR (400 MHz, CDCl} 3) 7.84 (d, J = 9.2 Hz, 2H), 7.67 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 9.6 Hz, 2H), 7.45 (d, J = 9.2 Hz, 2H), 7.34 (d, J = 9.6 Hz, 2H), 7.24 (dd, J = 2.0,8.8 Hz, 1H) 3.81 (m, 2H), 0.85-0.82 (m, 3H).

<Step 5> 6- Chlooro -3- (4- Chlorobenzoyl ) -1- (4- Chlorophenyl ) -1H-indole-2-carboxylate Exed's  synthesis

To a 25 mL flask was added ethyl 6-chloro-3- (4-chlorobenzoyl) -1- (4-chlorophenyl) -1H-indole-2-carboxylate 34 mg, 0.072 mmol), and tetrahydrofuran (0.5 mL) and methanol (0.5 mL) were added and dissolved. Then sodium hydroxide (15 mg, 0.36 mmol) dissolved in water (0.5 mL) was added and stirred for 1 hour. After completion of the reaction, the reaction mixture was concentrated and adjusted to pH 5 with 2N HCl. Thereafter, the organic layer was separated using ethyl acetate and water, and then the water contained in the organic layer was removed with magnesium sulfate. Then, after filtration, the mixture was purified by column chromatography (MeOH / CH ₂ Cl ₂ = 1: 9) to give 6-chloro-3- (4- chlorobenzoyl) -1- (4- chlorophenyl) -1H-indole-2-carboxylic acid (20 mg, 0.045 mmol, 62.5%).

^{1 H NMR (400 MHz, DMSO} -d 6) 13.56 (br, OH, 1H), 7.85-7.83 (d, J = 8.0 Hz, 2H), 7.67-7.57 (m, 7H), 7.32-7.30 (d, J = 8.0 Hz, 2H), 7.17 (s, 1H).

<Step 6> 6- Chlooro -1- (4- Chlorophenyl ) -3 - ((4- Chlorophenyl ) ( Hydroxyoxy Amino) methyl) -1H-indole-2-carboxylate Exed's  synthesis

To a 5 mL flask was added 6-chloro-3- (4-chlorobenzoyl) -1- (4-chlorophenyl) -1H-indole-2-carboxylic acid mg, 0.1124 mmol) and ethanol (1.0 ml). Then, hydroxylamine hydrochloride (12 mg, 0.1686 mmol) and sodium acetate (18.4 mg, 0.2248 mmol) were added and the mixture was stirred under reflux for 5 hours, then cooled to room temperature and the reaction solution was concentrated. The obtained reaction product was diluted with water, and the organic layer was separated using ethyl acetate, and then the water contained in the organic layer was removed with magnesium sulfate. After filtration, the mixture was subjected to vacuum distillation and the mixture was purified by column chromatography (MC / MeOH / AcOH = 950: 50: 1) to obtain 6-chloro- 1- (4- chlorophenyl) -3- Chlorophenyl) (hydroxyimino) methyl) -1H-indole-2-carboxylic acid (30 mg, 0.0652 mmol, 58.1%).

^{1 H NMR (400 MHz, DMSO} -d 6) 13.10 (s, 1H), 11.61 (s, 1H), 7.71-7.40 (m, 8H), 7.26 (d, J = 8.4 Hz, 1H), 7.19 (d , J = 8.4 Hz, 1 H), 7.13 (s, 1 H).

[ Example  69] 6- Chlooro -1- (4- Chlorophenyl ) -3 - ((4- Chlorophenyl ) ( Methoxyimino ) Methyl) -1H-indole-2-carboxylic acid &lt; / RTI &gt;

<Step 1> (E) -Ethyl-2- (2- (3- Chlorophenyl ) Hydrazano ) Propanoate  synthesis

Add purified distilled water (520 ml) to a 2 L flask. (50 g, 0.6 mol) was dissolved in the flask, and then (3-chlorophenyl) hydrazine hydrochloride (52 g, 0.3 mol) was added thereto. The mixture was stirred at room temperature for 30 minutes and then ethyl 2-oxopropano Eight (35 ml, 0.3 mol) was slowly added thereto and stirred for 6 hours. After completion of the reaction, the reaction mixture was filtered with a reduced pressure filter and dried. A 3 L flask was charged with 2 L of dry solid and normal hexane and stirred for 1 hour and filtered to obtain 57 g of (E) -ethyl-2- (2- (3- chlorophenyl) hydrazano) propanoate , 0.24 mol, 81%).

^{1 H NMR (400 MHz, CDCl} 3) 7.66 (br, NH, 1H), 7.24 (m, 1H), 7.04 (m, 1H), 6.89 (d, J = 8.0 Hz, 1H), 6.84 (m, 1H ), 4.35 (q, 2H), 2.11 (s, 3H), 1.40 (t, J = 8.0 Hz, 3H).

&Lt; Step 2 > Ethyl-6- Chlooro -1H-indole-2- Carboxylate  synthesis

To a 500 ml flask was added toluene (110 ml), and 10.6 g (0.044 mmol) of the (E) -ethyl 2- (2- (3- chlorophenyl) hydrazano) propanoate synthesized in the above Step 1 mol). Then, polyphosphoric acid (52 g) was added, and the reflux reaction proceeded for 6 hours. After the reaction is completed, the reaction mixture is cooled to 50 ° C. and only the toluene layer is separated. The separated toluene layer was concentrated under reduced pressure. Then toluene (50 ml) was added to the solid formed, and the mixture was refluxed for 1 hour and then cooled to room temperature. Thereafter, the recrystallized solid was filtered to obtain ethyl-6-chloro-1H-indole-2-carboxylate (3.4 g, 0.015 mol, 35%).

^{1 H NMR (400 MHz, CDCl} 3) 8.84 (br, NH, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.42 (s, 1H), 7.19 (s, 1H) 7.13 (d, J = 8.0 Hz, 1 H), 4.44 (q, 2H), 1.43 (t, J = 8.0 Hz, 3H).

<Step 3> Synthesis of ethyl-6- Chlooro -3- (4- Chlorobenzoyl ) -1H-indole-2- Carboxylate Synthesis of

In a 100 mL flask, ethyl-6-chloro-1H-indole-2-carboxylate (1 g, 4.47 mmol) synthesized in the above Step 2 and dichloromethane (10 mL) were dissolved and dissolved. Then, 4-chlorobenzoyl chloride (939 mg, 5.36 mmol) and aluminum chloride (714 mg, 5.36 mmol) were added and the mixture was refluxed for 12 hours. After completion of the reaction, the temperature was lowered to room temperature, and the organic layer was separated using dichloromethane and water, and the water contained in the organic layer was removed with magnesium sulfate. After filtration, the mixture was purified by column chromatography (EA / n-Hex = 1: 6) to give ethyl 6-chloro-3- (4- chlorobenzoyl) -1H-indole- (843 mg, 2.32 mmol, 52%).

^{1 H NMR (400 MHz, CDCl} 3) 9.17 (s, 1H), 7.81 (d, J = 6.8 Hz, 2H), 7.60 (d, J = 8.4 Hz, 1H), 7.49-7.41 (m, 3H), 7.21 (dd, J = 1.6,8.4 Hz, 1H), 4.13-4.08 (m, 2H), 0.97-0.94 (m, 3H).

<Step 4> Synthesis of ethyl-6- Chlooro -3- (4- Chlorobenzoyl ) -1- (4- Chlorophenyl ) -1H-indole-2-carboxylate

6-chloro-1H-indole-2-carboxylate (40 mg, 0.122 mmol) synthesized in the above Step 3 and dichloromethane (1 mL) were dissolved in a 25 mL flask. Then, 4- (chlorophenyl) boronic acid (39 mg, 0.246 mmol), copper (II) acetate (34 mg, 0.185 mmol) and triethylamine (25 mg, 0.246 mmol) Lt; / RTI &gt; After completion of the reaction, the organic layer was separated using dichloromethane and water, and then the water contained in the organic layer was removed with magnesium sulfate. After filtration, the mixture was purified by column chromatography (EA / n-Hex = 1: 4) to give ethyl 6-chloro-3- (4- chlorobenzoyl) ) -1H-indole-2-carboxylate (34 mg, 0.072 mmol, 60%).

^{1 H NMR (400 MHz, CDCl} 3) 7.84 (d, J = 9.2 Hz, 2H), 7.67 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 9.6 Hz, 2H), 7.45 (d, J = 9.2 Hz, 2H), 7.34 (d, J = 9.6 Hz, 2H), 7.24 (dd, J = 2.0,8.8 Hz, 1H) 3.81 (m, 2H), 0.85-0.82 (m, 3H).

<Step 5> 6- Chlooro -3- (4- Chlorobenzoyl ) -1- (4- Chlorophenyl ) -1H-indole-2-carboxylate Exed's  synthesis

To a 25 mL flask was added ethyl 6-chloro-3- (4-chlorobenzoyl) -1- (4-chlorophenyl) -1H-indole-2-carboxylate 34 mg, 0.072 mmol), and tetrahydrofuran (0.5 mL) and methanol (0.5 mL) were added and dissolved. Then sodium hydroxide (15 mg, 0.36 mmol) dissolved in water (0.5 mL) was added and stirred for 1 hour. After completion of the reaction, the reaction mixture was concentrated and adjusted to pH 5 with 2N HCl. Thereafter, the organic layer was separated using ethyl acetate and water, and then the water contained in the organic layer was removed with magnesium sulfate. Then, after filtration, the mixture was purified by column chromatography (MeOH / CH ₂ Cl ₂ = 1: 9) to give 6-chloro-3- (4- chlorobenzoyl) -1- (4- chlorophenyl) -1H-indole-2-carboxylic acid (20 mg, 0.045 mmol, 62.5%).

^{1 H NMR (400 MHz, DMSO} -d 6) 13.56 (br, OH, 1H), 7.85-7.83 (d, J = 8.0 Hz, 2H), 7.67-7.57 (m, 7H), 7.32-7.30 (d, J = 8.0 Hz, 2H), 7.17 (s, 1H).

<Step 6> 6- Chlooro -1- (4- Chlorophenyl ) -3 - ((4- Chlorophenyl ) ( Methoxyimide Yl) methyl) -1H-indole-2-carboxylate Exed's  synthesis

To a 5 mL flask was added 6-chloro-3- (4-chlorobenzoyl) -1- (4-chlorophenyl) -1H-indole-2-carboxylic acid mg, 0.0675 mmol) and ethanol (0.5 ml) were added and dissolved. Then, methylhydroxylamine hydrochloride (8.5 mg, 0.1012 mmol) and sodium sulfate (19.2 mg, 0.1350 mmol) were added thereto, and the mixture was stirred under reflux, then cooled to room temperature and the reaction solution was concentrated. The obtained reaction product was diluted with water, and the organic layer was separated using ethyl acetate, and then the water contained in the organic layer was removed with magnesium sulfate. Then, the mixture was filtered and distilled under reduced pressure, and the mixture was purified by column chromatography (MC / MeOH / AcOH = 950: 50: 1) to obtain 6-chloro- 1- (4-chlorophenyl) -3- (Methoxyimino) methyl) -1H-indole-2-carboxylic acid (15 mg, 0.0317 mmol, 46.9%).

^{1 H NMR (400 MHz, DMSO} -d 6) 13.13 (s, 1H), 7.64 (d, J = 8.8 Hz, 2H), 7.56-7.51 (m, 4H), 7.44 (d, J = 8.8 Hz, 2H ), 7.30 (d, J = 8.4 Hz, 1 H), 7.22 (dd, J = 2.0,8.8 Hz,

[ Example  70] 6- Chlooro -3- (4- Chlorobenzoyl ) -1- (4- Chlorophenyl ) -1H-indole-2-carboxylate Exed's  synthesis

<Step 1> (E) -Ethyl-2- (2- (3- Chlorophenyl ) Hydrazano ) Propanoate synthesis castle

Add purified distilled water (520 ml) to a 2 L flask. (50 g, 0.6 mol) was dissolved in the flask, and then (3-chlorophenyl) hydrazine hydrochloride (52 g, 0.3 mol) was added thereto. The mixture was stirred at room temperature for 30 minutes and then ethyl 2-oxopropano Eight (35 ml, 0.3 mol) was slowly added thereto and stirred for 6 hours. After completion of the reaction, the reaction mixture was filtered with a reduced pressure filter and dried. A 3 L flask was charged with 2 L of dried solid and normal hexane and stirred for 1 hour and then filtered to obtain (E) -ethyl-2- (2- (3-chlorophenyl) hydrazano) propanoate g, 0.24 mol, 81%).

^{1 H NMR (400 MHz, CDCl} 3) 7.66 (br, NH, 1H), 7.24 (m, 1H), 7.04 (m, 1H), 6.89 (d, J = 8.0 Hz, 1H), 6.84 (m, 1H ), 4.35 (q, 2H), 2.11 (s, 3H), 1.40 (t, J = 8.0 Hz, 3H).

&Lt; Step 2 > Ethyl-6- Chlooro -1H-indole-2- Carboxylate  synthesis

To a 500 ml flask was added toluene (110 ml), and 10.6 g (0.044 mmol) of the (E) -ethyl 2- (2- (3- chlorophenyl) hydrazano) propanoate synthesized in the above Step 1 mol). Then, polyphosphoric acid (52 g) was added, and the reflux reaction proceeded for 6 hours. After the reaction is completed, the reaction mixture is cooled to 50 ° C, and only the toluene layer is separated. The separated toluene layer was concentrated under reduced pressure. Then toluene (50 ml) was added to the solid formed, and the mixture was refluxed for 1 hour and cooled to room temperature. Thereafter, the recrystallized solid was filtered to obtain ethyl-6-chloro-1H-indole-2-carboxylate (3.4 g, 0.015 mol, 35%).

^{1 H NMR (400 MHz, CDCl} 3) 8.84 (br, NH, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.42 (s, 1H), 7.19 (s, 1H) 7.13 (d, J = 8.0 Hz, 1 H), 4.44 (q, 2H), 1.43 (t, J = 8.0 Hz, 3H).

<Step 3> Synthesis of ethyl-6- Chlooro -3- (4- Chlorobenzoyl ) -1H-indole-2- Carboxylate Synthesis of

In a 100 mL flask, ethyl-6-chloro-1H-indole-2-carboxylate (1 g, 4.47 mmol) synthesized in the above Step 2 and dichloromethane (10 mL) were dissolved and dissolved. Then, 4-chlorobenzoyl chloride (939 mg, 5.36 mmol) and aluminum chloride (714 mg, 5.36 mmol) were added and the mixture was refluxed for 12 hours. After completion of the reaction, the temperature was lowered to room temperature, and the organic layer was separated using dichloromethane and water, and the water contained in the organic layer was removed with magnesium sulfate. After filtration, the mixture was purified by column chromatography (EA / n-Hex = 1: 6) to give ethyl 6-chloro-3- (4- chlorobenzoyl) -1H-indole- (843 mg, 2.32 mmol, 52%).

^{1 H NMR (400 MHz, CDCl} 3) 9.17 (s, 1H), 7.81 (d, J = 6.8 Hz, 2H), 7.60 (d, J = 8.4 Hz, 1H), 7.49-7.41 (m, 3H), 7.21 (dd, J = 1.6,8.4 Hz, 1H), 4.13-4.08 (m, 2H), 0.97-0.94 (m, 3H).

<Step 4> 6- Chlooro -3- (4- Chlorobenzoyl ) -1- (4- Chlorobenzyl ) -1H-indole-2-carboxylate

6-chloro-3- (4-chlorobenzoyl) -1H-indole-2-carboxylate (2 g, 6.10 mmol) synthesized in the above Step 3 was added to a 250 mL flask, Hydrofuran (10 mL) and N, N-dimethylformamide (10 mL) were added to dissolve. Then, 1 M lithium bis (trimethylsilyl) amide (13.5 mL, 13.4 mmol) was added at 0 ° C and stirred for 15 minutes. Then 1- (bromomethyl) -4-chlorobenzene (1.5 g, 7.32 mmol), and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the organic layer was separated using ethyl acetate and water, and the water contained in the organic layer was removed with magnesium sulfate. After filtration, the mixture was purified by column chromatography (EA / n-Hex = 4: 1) to give ethyl 6-chloro-3- (4- chlorobenzoyl) ) -1H-indole-2-carboxylate (1 g, 2.05 mmol, 45%).

¹ H NMR (400 MHz, CDCl ₃ ) 7.78 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.8 Hz, 1H), 7.44-7.42 (m, 3H), 7.28-7.26 2H), 3.90-3.84 (m, 2H), 0.88-0.83 (m, 2H), 7.22 (dd, J = 1.6,8.8 Hz, 3H).

<Step 5> 6- Chlooro -3- (4- Chlorobenzoyl ) -1- (4- Chlorophenyl ) -1H-indole-2-carboxylate Exed's  synthesis

To a 100 mL flask was added ethyl 6-chloro-3- (4-chlorobenzoyl) -1- (4-chlorobenzyl) -1H-indole-2-carboxylate 1 g, 2.05 mmol), and the mixture was dissolved by adding tetrahydrofuran (5 mL) and methanol (5 mL). Then, sodium hydroxide (329 mg, 8.21 mmol) dissolved in water (5 mL) was added and stirred for 1 hour. After the reaction was completed, the solution was concentrated and adjusted to pH 5 with 2N HCl. After the organic layer was separated using ethyl acetate and water, the water contained in the organic layer was removed with magnesium sulfate. After filtration, the mixture was purified by column chromatography (MeOH / CH ₂ Cl ₂ = 1: 9) to give 6-chloro-3- (4- chlorobenzoyl) -1- (4- chlorophenyl) Indole-2-carboxylic acid (1 g, 2.24 mmol, 77%).

^{1 H NMR (400 MHz, DMSO} -d 6) 7.88 (d, J = 1.6 Hz, 1H), 7.76 (d, J = 3.6 Hz, 2H), 7.76-7.56 (m, 3H), 7.39 (d, J = 8.4 Hz, 2H), 7.25 (dd, J = 1.6,8.4 Hz, 1H), 7.12 (d, J = 11.2 Hz, 2H), 5.83 (s, 2H).

[ Example  71] 6- Chlooro -3- (4- Chlorobenzoyl ) -1- (3-methoxybenzyl) -1H-indole-carboxylate Exceed  synthesis

The same procedure as in Example 70 was repeated, except that 1- (bromomethyl) -3-methoxybenzene was used instead of 1- (bromomethyl) -4-chlorobenzene used in <Step 4> To give the desired compound.

^{1 H NMR (400 MHz, MeOD} ) 7.80 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.4 Hz, 1H), 7.47-7.42 (m, 3H), 7.19-7.13 (m, 2H) , 6.78 - 6.73 (m, 3H), 5.70 (s, 2H), 3.71 (s, 3H).

[ Example  72] 6- Chlooro -3- (4- Chlorobenzoyl ) -1- (2- Chlorobenzyl ) -1H-indole-carboxylic &lt; / RTI &gt; Exed's  synthesis

The procedure of Example 70 was repeated except that 1- (bromomethyl) -2-chlorobenzene was used instead of 1- (bromomethyl) -4-chlorobenzene used in <Step 4> To give the desired compound.

^{1 H NMR (400 MHz, DMSO} -d 6) 7.83 (s, 1H), 7.80 (d, J = 8.0 Hz, 2H), 7.62 (t, 3H), 7.54 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.21 (t,

[Example 73] 6-claw oro-3- (4-claw oro benzoyl) -1- (pyridin-3-ylmethyl) -1H- indole-carboxylic acid: Synthesis of Acid Rick

The procedure of Example 70 was repeated except that 3- (bromomethyl) pyridine was used instead of 1- (bromomethyl) -4-chlorobenzene used in Step 4 to obtain the desired compound &Lt; / RTI >

^{1 H NMR (400 MHz, DMSO} -d 6) 12.73 (br, OH, 1H), 8.50-8.47 (m, 2H), 7.95 (s, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.60 (M, 3H), 7.50 (d, J = 8.0 Hz, 1H), 7.40 (m, 1H), 7.26 (d, J = 8.0 Hz, 1H), 5.88 (s, 2H).

[ Example  74] 6- Chlooro -3- (4- Chlorobenzoyl ) -1- (3- ( Trifluoromethoxy ) &Lt; / RTI &gt; benzyl) -lH-indole-carboxylate Exed's  synthesis

(Bromomethyl) -3- (trifluoromethoxy) benzene was used instead of 1- (bromomethyl) -4-chlorobenzene used in Step 4, 70, the target compound was obtained.

^{1 H NMR (400 MHz, DMSO} -d 6) 7.77 (d, J = 8.8 Hz, 2H), 7.71 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 6.0 Hz, 2H), 7.43 ( dd, J = 8.4 Hz, 2H), 7.28 (s, 1H), 7.25 (t, 1H) 7.15 (d, J = 8.0 Hz, 1H).

[ Example  75] 6- Bromo -3- (4- Chlorobenzoyl ) -1- (4- Chlorobenzyl ) -1H-indole-2-carboxyl Exed's  synthesis

<Step 1> Synthesis of ethyl-3- (4- Bromo -2- Nitrophenyl )-2- Oxopropanoate synthesis

After dissolving potassium ethoxide, ethanol (4 mL) and diethyl ether (16 mL) in a 100 mL flask, diethyl oxalate (1.5 mL, 11.1 mmol) dissolved in diethyl ether . Then, 4-bromo-1-methyl-2-nitrobenzene (2 g, 9.25 mmol) dissolved in diethyl ether (4 mL) was added and stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and adjusted to pH 5 with 2N HCl. Then, the reaction mixture was extracted with ethyl acetate, the water was removed with magnesium sulfate, and the filtrate was concentrated to obtain ethyl 3- (4-bromo-2-nitrophenyl) -2-oxopropanoate.

^{1 H NMR (400 MHz, CDCl} 3) 8.31 (d, J = 2.0 Hz, 1H), 8.15 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 2.0 Hz, 1H), 7.76 (dd, 2H, J = 2.0, 8.4 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 4.50 (s, 2H), 4.41-4.36 (m, 2H), 1.42-1.38 (m, 3H).

&Lt; Step 2 > Ethyl-6- Bromo -1H-indole-2- Carboxylate  synthesis

Ethyl-3- (4-bromo-2-nitrophenyl) -2-oxopropanoate (2.57 g, 8.15 mmol) synthesized in the above Step 1 was added to a 250 mL flask. Acetic acid 15 mL) and ethanol (15 mL) were added and dissolved. Then, iron powder (4.1 g, 73.4 mmol) was added and the mixture was stirred under reflux for 4 hours. After completion of the reaction, the temperature was lowered to 5 캜, the mixed solution was filtered using Celite, and then the filtrate was concentrated under reduced pressure. After adjusting to pH 5 with 2N HCl and extracting with ethyl acetate, the water was removed with magnesium sulfate and concentrated. Subsequently, recrystallization from dichloromethane gave ethyl 6-bromo-1H-indole-2-carboxylate (1.5 g, 5.59 mmol, 68.6%).

^{1 H NMR (400 MHz, CDCl} 3) 12.02 (s, 1H), 7.64-7.60 (m, 2H), 7.21 (dd, J = 2.0, 8.4 Hz, 1H), 4.37-4.31 (m, 2H), 1.35 -1.32 (m, 3H).

<Step 3> Synthesis of ethyl-6- Bromo -3- (4- Chlorobenzoyl ) -1H-indole-2- Carboxylate  synthesis

Ethyl 6-bromo-1H-indole-2-carboxylate (100 mg, 0.373 mmol) synthesized in the above Step 2 and dichloromethane (1 mL) were added and dissolved in a 25 mL flask , Chlorochlorobenzoyl chloride (78 mg, 0.448 mmol) and aluminum chloride (100 mg, 0.746 mmol) were added and the mixture was refluxed for 12 hours. After completion of the reaction, the temperature was lowered to room temperature, and the organic layer was separated using dichloromethane and water, and the water contained in the organic layer was removed with magnesium sulfate. After filtration, the mixture was purified by column chromatography (EA / n-Hex = 6: 1) to give ethyl 6-bromo-3- (4- chlorobenzoyl) -1H-indole- (47 mg, 0.115 mmol, 31%).

^{1 H NMR (400 MHz, CDCl} 3) 9.31 (s, 1H), 7.81 (d, J = 9.2 Hz, 2H), 7.66 (d, J = 1.2 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.43 (d, J = 9.2 Hz, 2H), 7.33 (dd, J = 8.8 Hz, 1H), 4.13-4.08 (m, 2H), 0.97-0.94 (m, 3H).

<Step 4> Synthesis of ethyl-6- Bromo -3- (4- Chlorobenzoyl ) -1- (4- Chlorobenzyl ) -1H-indole-2-carboxylate

-1H-indole-2-carboxylate (80 mg, 0.20 mmol) synthesized in the above <Step 3>, tetrahydrofuran (1 mL) and N, N-dimethylformamide (1 mL) were added and dissolved. Then, 1 M lithium bis (trimethylsilyl) amide (0.43 mL, 0.43 mmol) was added at 0 ° C. After stirring for 15 minutes, 1- (bromomethyl) -4-chlorobenzene (49 mg, 0.23 mmol) was added and stirred at room temperature for 2 hours. After completion of the reaction, the organic layer was separated using ethyl acetate and water, and the water contained in the organic layer was removed with magnesium sulfate. After filtration, the mixture was purified by column chromatography (EA / n-Hex = 4: 1) to give ethyl 6-bromo-3- (4- chlorobenzoyl) ) -1H-indole-2-carboxylate (95 mg, 0.18 mmol, 91%).

^{1 H NMR (400 MHz, CDCl} 3) 7.77 (d, J = 9.2 Hz, 2H), 7.61-7.55 (m, 2H), 7.43 (d, J = 9.2 Hz, 2H), 7.35-7.03 (m, 3H ), 7.02 (d, J = 8.8 Hz, 2H), 5.70 (s, 2H), 3.90-3.84 (m, 2H), 0.87-0.83 (m, 3H).

<Step 5> 6- Bromo -3- (4- Chlorobenzoyl ) -1- (4- Chlorobenzyl ) -1H-indole- Car Foxy Rick Exed's  synthesis

To a 25 mL flask was added ethyl 6-bromo-3- (4-chlorobenzoyl) -1- (4-chlorobenzyl) -1H-indole-2-carboxylate 95 mg, 0.18 mmol), tetrahydrofuran (1 mL), and methanol (1 mL). Then, sodium hydroxide (36 mg, 0.89 mmol) dissolved in water (1 mL) was added and stirred for 1 hour. After the reaction was completed, the solution was concentrated and adjusted to pH 5 with 2N HCl. Thereafter, the organic layer was separated using ethyl acetate and water, and then the water contained in the organic layer was removed with magnesium sulfate. After filtration, the mixture was purified by column chromatography (MeOH / CH ₂ Cl ₂ = 1: 9) to give 6-bromo-3- (4- chlorobenzoyl) -1- (4- chlorobenzyl) -1H-indole-carboxylic acid (20 mg, 0.040 mmol, 22%).

^{1 H NMR (400 MHz, DMSO} -d 6) 8.00 (d, J = 1.2 Hz, 1H), 7.56 (d, J = 1.6, 8.4 Hz, 2H), 7.58 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 8.8 Hz, 1H), 7.41-7.34 (m, 3H), 7.11 (d, J = 8.4 Hz, 2H), 5.82 (s, 2H).

[ Example  76] 6- Bromo -3- (4- Chlorobenzoyl ) -1- (4- Chlorophenyl ) -1H-indole-2-carboxylate Exed's  synthesis

<Step 1> Ethyl 3 -(4- Bromo -2- Nitrophenyl )-2- Oxopropanoate  synthesis

After dissolving potassium ethoxide, ethanol (4 mL) and diethyl ether (16 mL) in a 100 mL flask, diethyl oxalate (1.5 mL, 11.1 mmol) dissolved in diethyl ether (6 mL) . Then, 4-bromo-1-methyl-2-nitrobenzene (2 g, 9.25 mmol) dissolved in diethyl ether (4 mL) was added and stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and adjusted to pH 5 with 2N HCl. Then, the mixture was extracted with ethyl acetate, the water was removed with magnesium sulfate, and the mixture was concentrated to obtain ethyl 3- (4-bromo-2-nitrophenyl) -2-oxopropanoate.

^{1 H NMR (400 MHz, CDCl} 3) 8.31 (d, J = 2.0 Hz, 1H), 8.15 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 2.0 Hz, 1H), 7.76 (dd, 2H, J = 2.0, 8.4 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 4.50 (s, 2H), 4.41-4.36 (m, 2H), 1.42-1.38 (m, 3H).

&Lt; Step 2 > Ethyl-6- Bromo -1H-indole-2- Carboxylate  synthesis

2-oxopropanoate (2.57 g, 8.15 mmol) synthesized in the above Step 1 and acetic acid (15 mL ) And ethanol (15 mL) were added and dissolved. Then, iron powder (4.1 g, 73.4 mmol) was added and the mixture was stirred under reflux for 4 hours. After completion of the reaction, the temperature was lowered to 5 캜, and the mixed solution was filtered using celite, then concentrated under reduced pressure, and adjusted to pH 5 with 2N-HCl. Thereafter, the reaction mixture was extracted with ethyl acetate, and water was removed with magnesium sulfate, followed by concentration and recrystallization from dichloromethane to obtain ethyl 6-bromo-1H-indole-2-carboxylate (1.5 g, 5.59 mmol, 68.6% ).

^{1 H NMR (400 MHz, CDCl} 3) 12.02 (s, 1H), 7.64-7.60 (m, 2H), 7.21 (dd, J = 2.0, 8.4 Hz, 1H), 4.37-4.31 (m, 2H), 1.35 -1.32 (m, 3H).

<Step 3> Synthesis of ethyl-6- Bromo -3- (4- Chlorobenzoyl ) -1H-indole-2- Carboxylate  synthesis

Ethyl-6-bromo-1H-indole-2-carboxylate (100 mg, 0.373 mmol) and dichloromethane (1 mL) synthesized in the above Step 2 were dissolved in a 25 mL flask. Then, 4-chlorobenzoyl chloride (78 mg, 0.448 mmol) and aluminum chloride (100 mg, 0.746 mmol) were added and refluxed for 12 hours. After completion of the reaction, the temperature was lowered to room temperature, and the organic layer was separated using dichloromethane and water, and the water contained in the organic layer was removed with magnesium sulfate. After filtration, the mixture was purified by column chromatography (EA / n-Hex = 6: 1) to give ethyl 6-bromo-3- (4- chlorobenzoyl) -1H-indole- (47 mg, 0.115 mmol, 31%).

^{1 H NMR (400 MHz, CDCl} 3) 9.31 (s, 1H), 7.81 (d, J = 9.2 Hz, 2H), 7.66 (d, J = 1.2 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.43 (d, J = 9.2 Hz, 2H), 7.33 (dd, J = 8.8 Hz, 1H), 4.13-4.08 (m, 2H), 0.97-0.94 (m, 3H).

<Step 4> Synthesis of ethyl-6- Bromo -3- (4- Chlorobenzoyl ) -1- (4- Chlorophenyl ) -1H-indole-2-carboxylate

Ethyl-6-bromo-1H-indole-2-carboxylate (50 mg, 0.123 mmol) and dichloromethane (1 mL) synthesized in the above Step 3 were dissolved in a 25 mL flask. Then, 4- (chlorophenyl) boronic acid (39 mg, 0.246 mmol), copper (II) acetate (34 mg, 0.185 mmol) and triethylamine (25 mg, 0.246 mmol) Lt; / RTI &gt; After completion of the reaction, the organic layer was separated using dichloromethane and water, and then the water contained in the organic layer was removed with magnesium sulfate. After filtration, the mixture was purified by column chromatography (EA / n-Hex = 4: 1) to give ethyl 6-bromo-3- (4- chlorobenzoyl) ) -1H-indole-2-carboxylate (50 mg, 0.097 mmol, 78.6%).

^{1 H NMR (400 MHz, CDCl} 3) 7.84 (d, J = 9.2 Hz, 2H), 7.61 (d, J = 8.4 Hz, 1H), 7.54 (d, J = 8.8 Hz, 2H), 7.43 (d, J = 9.2 Hz, 2H), 7.38-7.28 (m, 3H), 6.92 (d, J = 6.8 Hz, 1H), 3.87-3.79 (m, 2H), 0.88-0.82 (m, 3H).

<Step 5> 6- Bromo -3- (4- Chlorobenzoyl ) -1- (4- Chlorophenyl ) -1H-indole-2- Car Le Foxillic Exed's  synthesis

To a 25 mL flask was added ethyl 6-bromo-3- (4-chlorobenzoyl) -1- (4-chlorophenyl) -1H-indole-2-carboxylate 45 mg, 0.087 mmol), tetrahydrofuran (0.5 mL), and methanol (0.5 mL). Then sodium hydroxide (17.4 mg, 0.43 mmol) dissolved in water (0.5 mL) was added and stirred for 1 hour. After the reaction was completed, the solution was concentrated and adjusted to pH 5 with 2N HCl. Thereafter, the organic layer was separated using ethyl acetate and water, and then the water contained in the organic layer was removed with magnesium sulfate. After filtration, the mixture was purified by column chromatography (MeOH / CH ₂ Cl ₂ = 1: 9) to give 6-bromo-3- (4- chlorobenzoyl) -1- (4- chlorophenyl) -1H-indole-2-carboxylic acid (21 mg, 0.043 mmol, 49.4%).

¹ H NMR (400 MHz, DMSO-d ₆ ) 7.84 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 9.6 Hz, 3H), 7.48 7.36 (dd, J = 2, 10.4 Hz, 1H), 7.29 (d, J = 1.6 Hz, 1H).

[ Example  77] 3- (4- Chlorobenzoyl ) -1- (4- Chlorophenyl ) -6- (pyridin-3-yl) -1H-indole-2-carboxylate Exed's  synthesis

<Step 1> Synthesis of ethyl-3- (4- Bromo -2- Nitrophenyl )-2- Oxopropanoate synthesis

After dissolving potassium ethoxide, ethanol (4 mL) and diethyl ether (16 mL) in a 100 mL flask, diethyl oxalate (1.5 mL, 11.1 mmol) dissolved in diethyl ether . Then, 4-bromo-1-methyl-2-nitrobenzene (2 g, 9.25 mmol) dissolved in diethyl ether (4 mL) was added and stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and adjusted to pH 5 with 2N HCl. Then, the mixture was extracted with ethyl acetate, the water was removed with magnesium sulfate, and the mixture was concentrated to obtain ethyl 3- (4-bromo-2-nitrophenyl) -2-oxopropanoate.

^{1 H NMR (400 MHz, CDCl} 3) 8.31 (d, J = 2.0 Hz, 1H), 8.15 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 2.0 Hz, 1H), 7.76 (dd, 2H, J = 2.0, 8.4 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 4.50 (s, 2H), 4.41-4.36 (m, 2H), 1.42-1.38 (m, 3H).

&Lt; Step 2 > Ethyl-6- Bromo -1H-indole-2- Carboxylate  synthesis

2-oxopropanoate (2.57 g, 8.15 mmol) synthesized in the above Step 1 and acetic acid (15 mL ) And ethanol (15 mL) were added and dissolved. Then, iron powder (4.1 g, 73.4 mmol) was added and the mixture was stirred under reflux for 4 hours. After completion of the reaction, the temperature was lowered to 5 캜, and the mixed solution was filtered using celite, then concentrated under reduced pressure, and adjusted to pH 5 with 2N-HCl. After extraction with ethyl acetate and removal of the water with magnesium sulfate, the mixture was concentrated and recrystallized from dichloromethane to give ethyl 6-bromo-1H-indole-2-carboxylate (1.5 g, 5.59 mmol, 68.6%).

^{1 H NMR (400 MHz, CDCl} 3) 12.02 (s, 1H), 7.64-7.60 (m, 2H), 7.21 (dd, J = 2.0, 8.4 Hz, 1H), 4.37-4.31 (m, 2H), 1.35 -1.32 (m, 3H).

<Step 3> Synthesis of ethyl-6- Bromo -3- (4- Chlorobenzoyl ) -1H-indole-2- Carboxylate  synthesis

Ethyl-6-bromo-1H-indole-2-carboxylate (100 mg, 0.373 mmol) and dichloromethane (1 mL) synthesized in the above Step 2 were dissolved in a 25 mL flask. Then, 4-chlorobenzoyl chloride (78 mg, 0.448 mmol) and aluminum chloride (100 mg, 0.746 mmol) were added and refluxed for 12 hours. After completion of the reaction, the temperature was lowered to room temperature, and the organic layer was separated using dichloromethane and water, and the water contained in the organic layer was removed with magnesium sulfate. After filtration, the mixture was purified by column chromatography (EA / n-Hex = 6: 1) to give ethyl 6-bromo-3- (4- chlorobenzoyl) -1H-indole- (47 mg, 0.115 mmol, 31%).

^{1 H NMR (400 MHz, CDCl} 3) 9.31 (s, 1H), 7.81 (d, J = 9.2 Hz, 2H), 7.66 (d, J = 1.2 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.43 (d, J = 9.2 Hz, 2H), 7.33 (dd, J = 8.8 Hz, 1H), 4.13-4.08 (m, 2H), 0.97-0.94 (m, 3H).

<Step 4> Synthesis of ethyl-6- Bromo -3- (4- Chlorobenzoyl ) -1- (4- Chlorophenyl ) -1H-indole-2-carboxylate

Ethyl-6-bromo-1H-indole-2-carboxylate (50 mg, 0.123 mmol) and dichloromethane (1 mL) synthesized in the above Step 3 were dissolved in a 25 mL flask. Then, 4- (chlorophenyl) boronic acid (39 mg, 0.246 mmol), copper (II) acetate (34 mg, 0.185 mmol) and triethylamine (25 mg, 0.246 mmol) Lt; / RTI &gt; After completion of the reaction, the organic layer was separated using dichloromethane and water, and then the water contained in the organic layer was removed with magnesium sulfate. After filtration, the mixture was purified by column chromatography (EA / n-Hex = 4: 1) to give ethyl 6-bromo-3- (4- chlorobenzoyl) ) -1H-indole-2-carboxylate (50 mg, 0.097 mmol, 78.6%).

^{1 H NMR (400 MHz, CDCl} 3) 7.84 (d, J = 9.2 Hz, 2H), 7.61 (d, J = 8.4 Hz, 1H), 7.54 (d, J = 8.8 Hz, 2H), 7.43 (d, J = 9.2 Hz, 2H), 7.38-7.28 (m, 3H), 6.92 (d, J = 6.8 Hz, 1H), 3.87-3.79 (m, 2H), 0.88-0.82 (m, 3H).

<Step 5> Synthesis of ethyl-3- (4- Chlorobenzoyl ) -1- (4- Chlorophenyl ) -6- (pyridin-3-yl) -1H-indole-2-carboxylate

To a 25 mL flask was added ethyl 6-bromo-3- (4-chlorobenzoyl) -1- (4-chlorophenyl) -1H-indole-2-carboxylate 50 mg, 0.096 mmol), tetrahydrofuran (0.5 mL), ethanol (0.5 mL) and water (0.5 mL). Then, pyridin-3-ylboronic acid (12 mg, 0.096 mmol), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (0.4 mg, 0.00048 mmol), tripotassium phosphate (41 mg, 0.19 mmol) was added and stirred at 70 [deg.] C for 4 hours. After completion of the reaction, the organic layer was separated using ethyl acetate and water, and the water contained in the organic layer was removed with magnesium sulfate. After filtration, the mixture was purified by column chromatography (EA / n-Hex = 4: 1) to give ethyl 3- (4-chlorobenzoyl) -1- (4- chlorophenyl) -6- Pyridin-3-yl) -1H-indole-2-carboxylate (34 mg, 0.066 mmol, 68%).

^{1 H NMR (400 MHz, CDCl} 3) 8.80 (s, 1H), 8.48 (d, J = 3.2 Hz, 1H), 7.90-7.82 (m, 4H) 7.57-7.54 (d, J = 14.4 Hz, 2H) , 7.50 (dd, J = 1.2, 10.0 Hz, 1H), 7.45 (d, J = 13.2 Hz, 2H), 7.41-7.27 (m, 4H).

<Step 6> Synthesis of 3- (4- Chlorobenzoyl ) -1- (4- Chlorophenyl ) -6- (pyridin-3-yl) -1H-indole-2-carboxylate Exed's  synthesis

To a 25 mL flask was added ethyl 3- (4-chlorobenzoyl) -1- (4-chlorophenyl) -6- (pyridin-3- -Carboxylate (30 mg, 0.058 mmol), tetrahydrofuran (0.5 mL) and methanol (0.5 mL) were added and dissolved. Then, sodium hydroxide (11.6 mg, 0.29 mmol) dissolved in water (0.5 mL) was added and stirred for 1 hour. After the reaction was completed, the solution was concentrated and adjusted to pH 5 with 2N HCl. Thereafter, the organic layer was separated using ethyl acetate and water, and then the water contained in the organic layer was removed with magnesium sulfate. After filtration, the mixture was purified by column chromatography (MeOH / CH ₂ Cl ₂ = 1: 9) to give 3- (4-chlorobenzoyl) -1- (4- chlorophenyl) -6- 3-yl) -1H-indole-2-carboxylic acid (20 mg, 0.041 mmol, 70.6%).

^{1 H NMR (400 MHz, DMSO} -d 6) 8.80 (d, J = 1.6 Hz, 1H), 8.56 (dd, J = 1.2, 6.0 Hz, 1H), 8.05 (dt, J = 3.6, 11.6 Hz, 1H ), 7.8 (d, J = 13.6 Hz, 2H), 7.70-7.59 (m, 8H), 7.48-7.45 (m, 1H), 7.42 (s, 1H).

[ Comparative Example  One]

The following Rosiglitazone compounds were used.

[ Comparative Example  2]

The following Pioglitazone compounds were used.

[ Comparative Example  3]

The following SR-1664 compound was used.

[ Experimental Example  One] Of PPARγ  Competitive binding evaluation

The competitive binding ability of the compounds of Examples 1 to 77 and the compounds of Comparative Examples 1 to 3 on PPARγ (Peroxisome proliferator activated receptor-Gamma) was evaluated by the following method. The results are shown in Table 1 below.

The experiment was performed using the LanthaScreen ^™ TR-FRET PPARγ Competitive Binding Assay Kit (Invitrogen / PV4894). 30 μl of each of the compounds of Examples 1 to 77 and Comparative Examples 1 to 3 diluted in assay buffer to a final concentration of 50 times in 96-well plate (SPL, 34096) was added to 5 nM Fluormone ^™ Pan-PPAR 15 μl of 5 nM GST-PPARG-LBD and 15 μl of 5 nM Tb-GST-antibody were further added, mixed, and transferred to 384-well plates (Greiner, 784075) in an amount of 20 μl each. Lt; / RTI &gt; After completion of the reaction, time-resolved fluorescence (RFU) mode, excitation 1 340 nm, emission 1 518 nm, excitation 2 340 nm, emission 2 488 nm, integration delay 50 us at Flexstation 3 (Molecular Devices) , integration 400 μs fluorescence values were read. Experimental results were calculated using 518 nm RFUs / 488 nm RFUs ratio. Specifically, the binding activity of each compound against vehicle was calculated as [100% - compound ratio / vehicle ratio].

[ Experimental Example  2] Of PPARγ  Evaluation of transcription activity

The transcriptional activity of the compounds of Examples 1 to 77 and the compounds of Comparative Examples 1 to 3 on PPARγ (Peroxisome proliferator activated receptor-Gamma) was evaluated by the following method. The results are shown in Table 1 below.

HEK293 cells were plated in 24-well plates (SPL, 30024) at 5 x 10 &lt; ⁴ &gt;. HEK293 cells were transfected with PPRE as FuGENE HD (Promega, E2312). After 24 hours of transfection, the compounds of Examples 1 to 77 and the compounds of Comparative Examples 1 to 3 were treated for 24 hours by concentration. After 24 hours of treatment, cells were collected and the activity of a reporter gene assay and a luciferase assay was calculated. At this time, the reporter gene analysis was performed using the Dual Reporter gene assay kit (Promega, E1980). The activity of the luciferase assay was calculated by normalizing the renilla activity.

compound Binding assay
(1 uM) PPRE
EC50 (nM) Example 1 96% NA Example 2 91% NA Example 3 100% NA Example 4 91% NA Example 5 95% NA Example 6 91% NA Example 7 92% NA Example 8 89% NA Example 9 56% NA Example 10 99% NA Example 11 69% NA Example 12 68% NA Example 13 91% NA Example 14 88% NA Example 15 81% NA Example 16 86% NA Example 17 61% NA Example 18 55% NA Example 19 95% NA Example 20 93% NA Example 21 96% NA Example 22 96% NA Example 23 93% NA Example 24 97% NA Example 25 88% NA Example 26 88% NA Example 27 96% NA Example 28 97% NA Example 29 29% NA Example 30 83% NA Example 31 98% NA Example 32 83% NA Example 33 91% NA Example 34 92% NA Example 35 96% NA Example 36 90% NA Example 37 89% NA Example 38 94% NA Example 39 76% NA Example 40 85% NA Example 41 81% NA Example 42 55% NA Example 43 80% NA Example 44 86% NA Example 45 94% NA Example 46 90% NA Example 47 98% NA Example 48 93% NA Example 49 32% NA Example 50 50% NA Example 51 72% NA Example 52 68% NA Example 53 98% NA Example 54 66% NA Example 55 86% NA Example 56 76% NA Example 57 19% NA Example 58 98% NA Example 59 85% NA Example 60 95% NA Example 61 49% NA Example 62 49% NA Example 63 74% NA Example 64 97% NA Example 65 67% NA Example 66 77% NA Example 67 60% NA Example 68 76% NA Example 69 66% NA Example 70 94% NA Example 71 89% NA Example 72 84% NA Example 73 59% NA Example 74 96% NA Example 75 95% NA Example 76 96% NA Example 77 87% NA Comparative Example 1 100% 90 nM Comparative Example 2 46% 520 nM Comparative Example 3 80% NA NA: No Activity

Referring to Table 1, it can be seen that the compound of the present invention has an excellent binding activity to PPARγ. The binding activity level refers to the presence or absence of binding, and is not directly related to pharmacological activity. In addition, it can be confirmed that the compounds of the present invention do not activate the transcription of PPARy, whereas the compounds of the comparative examples induce the transcription of PPARy.

These results support the fact that the compounds of the present invention specifically bind to PPAR gamma and do not induce gene transcription of PPAR gamma, so that the effect of preventing the side effects of PPAR gamma phosphorylation is excellent.

[ Experimental Example  3] CDK5 ( Cyclin -dependent kinase 5) of  Evaluation of phosphorylation inhibition activity

The compounds of Examples 1, 2, 19 and 20 and the compounds of Comparative Examples 1 and 3 bind to PPARγ but do not act as an enhancer of CDK5 (Cyclin-dependent kinase 5), and the amino acid at position 273 of serine of PPARγ The degree of suppression of phosphorylation was evaluated by the following method.

Compounds of Examples 1, 2, 19 and 20 and Comparative Examples 1 and 3 were diluted in DMSO (Dimethylsulfoxide) to a concentration of 2000 times the final test concentration, and the compound diluted 2,000 times was dissolved in 50% DMSO (DMSO: DW = 1: 1) at a ratio of 1/100. 100 ng of CDK5 / p35 active (millipore, 14-477), 10 times of kinase buffer (CellSignaling, 9802S) and DW (10 nM) of human PPARγ-LBD (human recombinant) Data warehousing) was prepared to a final volume of 36 μl (premix was prepared on ice and stored in ice). 2 μl of each compound was mixed with 36 μl of the above premix and reacted on ice for 10 minutes. Then, 2 μl of ATP (negative control: DW 2 μl) was added and the mixture was reacted in a 37 ° C water bath for 15 minutes . At the end of the reaction, they were immediately transferred to ice, allowed to cool for 1 to 2 minutes, mixed with 10 μl of a 5-fold sample buffer, and boiled for 8 to 10 minutes in a 95 ° C heat block. After the heat block treatment was completed, the sample was taken out for a while, and the protein was separated by SDS-PAGE (sodium dodecylsulfate-polyacrylamide gel electrophoresis) on a 10% SDS-gel.

Subsequently, PPARγ phosphorylation by CDK5 and inhibition by compound were confirmed by using Las4000mini (Fujifilm corp) using phospho-PPARγ Ser273 Antibody and PPARγ Antibody (Santacruz, sc-7273) 1.

Referring to FIG. 1, it can be seen that the compounds of Examples 1, 2, 19, and 20 inhibit the phosphorylation of PPARγ-induced serine 273 by PMA compared to the compounds of Comparative Examples 1 and 3.

[ Experimental Example  4] DIO (Diet-Induced Obesity) model Effectiveness evaluation

The blood glucose lowering effect of the pharmaceutical compositions containing the compounds of Examples 1, 2, 19 and 20 and the compound of Comparative Example 1 in the concentration of 10 mg / kg was evaluated by the following method. The results are shown in Table 2 below .

One) DIO (Diet-Induced Obesity) model selection and pharmaceutical composition administration

Diet-Induced Obesity (DIO) was induced by feeding a high fat diet (Lab. Diet co.) To approximately 4 weeks old male C57BL / 6 mice. Mice that weighed more than 40g of body weight in high fat diets were selected as obesity models and were randomly selected and grouped for each administration (n = 5).

DIO mice that had been separated from each other were dosed with the pharmaceutical composition for each dose for each week.

2) per load test ( Intraperitoneal  Glucose Tolerance Test; IPGTT )

DIO mice administered with each pharmaceutical composition for 1 week were orally administered glucose at a dose of 1 g / kg, and venous blood was measured using an Accu-chek active strip (Roche diagnostic Co.). At this time, the measurement time was -30 minutes, 0 minutes, 20 minutes, 40 minutes, 60 minutes, and 120 minutes based on the glucose administration time, and the values measured in each group were averaged.

3) Fasting glucose level after fasting

DIO mice that had finished dosing each pharmaceutical composition were over-night fasted. Next, the blood glucose of the DIO mice was measured using an Accu-chek active strip (Roche Diagnostic Co.), and the measured values were averaged in each group.

3) Fasting insulin level after fasting

DIO mice that had finished dosing each pharmaceutical composition were over-night fasted. Next, approximately 50 μl of blood was collected from the capillary of DIO mice (KIMBLE CHASE, USA) by orbital blood collection, and the blood was centrifuged at 3600 rpm for 10 minutes to separate the plasma. Then, the insulin was measured using an insulin ELISA kit (Miobs, Japan), and the measured values were averaged in each group.

Item Example 1
(10 mpk) Example 2
(10 mpk) Example 19
(10 mpk) Example 20
(10 mpk) Comparative Example 1
(10 mpk) IPGTT 40% ↓ 35% ↓ 43% ↓ 30% ↓ 28% ↓ Fasting glucose level 35% ↓ 37% ↓ 38% ↓ 25% ↓ 25% ↓ Fasting insulin level 40% ↓ 45% ↓ 50% ↓ 56% ↓ 34% ↓

Referring to the above Table 2, it can be seen that the pharmaceutical composition containing the compounds of Examples 1, 2, 19, and 20 exhibits a blood sugar reduction equal to or higher than that of the pharmaceutical composition containing the compound of Comparative Example 1, .

Claims (9)

Claims 1. A compound represented by the following formula (1): &lt; EMI ID =
[Chemical Formula 1]

In Formula 1,
R ₁ , R ₃ , R ₄ , R ₅ , R ₆ and R ₉ are all hydrogen,
R ₂ is hydrogen, a halogen group, a C ₁ to C ₁₀ alkyl group,

, &Lt; / RTI &gt;
R ₇ and R ₈ are the same or different and are each independently selected from the group consisting of hydrogen, a halogen group and a C ₁ to C ₁₀ alkoxy group,
R ₁₀ is selected from the group consisting of a hydroxyl group and a C ₁ to C ₁₀ alkoxy group,
L is selected from the group consisting of a single bond and a C ₁ to C ₁₀ alkylene group,
R &lt; _{11 &}

,

,

And

, &Lt; / RTI &gt;
Wherein R _a , R _b , R _c and R _d are the same or different and each independently represents hydrogen, a halogen group, a C ₁ to C ₁₀ alkyl group, a C ₁ to C ₁₀ alkoxy group, a C ₁ to C ₁₀ A thioalkyl group and a nitro group,
A is selected from the group consisting of O and NR ₁₂ ,
R ₁₂ is selected from the group consisting of a hydroxyl group and a C ₁ to C ₁₀ alkoxy group,
The C ₁ to C ₁₀ alkyl group, C ₁ to C ₁₀ alkoxy group and C ₁ to C ₁₀ thioalkyl groups of R ₂ , R ₇ , R ₈ , R _a , R _b , R _c and R _d are each independently Which may be substituted or unsubstituted with halogen, and when the substituent is plural, a plurality of substituents may be the same or different from each other. The method according to claim 1,
Wherein R ₂ is selected from the group consisting of a halogen group, a pyridine group and a trifluoromethyl group, or a pharmaceutically acceptable salt thereof. The method according to claim 1,
R ₇ and R ₈ are each independently selected from the group consisting of hydrogen, a halogen group, a methoxyl group and a trifluoromethoxy group, or a pharmaceutically acceptable salt thereof. The method according to claim 1,
R ₁₀ is a hydroxyl group, or a pharmaceutically acceptable salt thereof. The method according to claim 1,
Wherein the structure represented by * -LR ₁₁ in Formula 1 is selected from the group consisting of the structures represented by the following S1 to S30, or a pharmaceutically acceptable salt thereof.

The method according to claim 1,
The compound of the above formula (1) is represented by any one of the following formulas (C1) to (C77), or a pharmaceutically acceptable salt thereof.

a) synthesizing a compound represented by the following formula (2) or (3);
b) cyclizing the compound of formula (2) synthesized in step a) in the presence of polyphosphoric acids, or cyclizing the compound of formula (3) in the presence of acetic acid to obtain a compound of formula Synthesizing a compound to be displayed;
c) reacting the compound represented by formula (4) synthesized in step (b) with a compound represented by formula (5) to synthesize a compound represented by formula (6);
d) synthesizing a compound represented by the following formula (7) by substituting hydrogen bonded to the nitrogen atom of the compound represented by the formula (6) synthesized in the step c);
e) reacting the compound of formula (7) synthesized in step d) with a strong base to synthesize a compound of formula (1).
(2)

(3)

[Chemical Formula 4]

[Chemical Formula 5]

[Chemical Formula 6]

(7)

[Chemical Formula 1]

In the above Chemical Formulas 1 to 7,
The definitions of R ₁ to R ₁₁ , L and A are the same as those described in claim 1. A pharmaceutical composition for the treatment of metabolic diseases, comprising the compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof as an active ingredient. The method of claim 8,
The metabolic disease is a group consisting of diabetes, insulin resistance, impaired glucose tolerance, pre-diabetes, hyperglycemia, hyperinsulinemia, obesity and inflammation. &Lt; / RTI &gt; or a pharmaceutically acceptable salt thereof.

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