WO2018021762A1

WO2018021762A1 - Novel compound, preparation method therefor, and pharmaceutical composition containing same

Info

Publication number: WO2018021762A1
Application number: PCT/KR2017/007853
Authority: WO
Inventors: 이인희; 김세환; 문순영; 장정인; 강승태; 윤현호; 이혁주; 이재걸
Original assignee: 현대약품 주식회사
Priority date: 2016-07-26
Filing date: 2017-07-20
Publication date: 2018-02-01
Also published as: KR101741956B1

Abstract

The present invention relates to a novel compound inhibiting CDK5-mediated PPARγ phosphorylation, a preparation method therefor, and a pharmaceutical composition containing the same. The novel compound of the present invention binds to PPARγ with high affinity but does not induce transcriptional activity so as not to act as an agonist, does not cause side effects of a conventional anti-diabetic by blocking the phosphorylation activity of CDK5, and has improved pharmacological properties. Therefore, a pharmaceutical composition containing the compound of the present invention as an active ingredient can be usable in the treatment of metabolic diseases associated with PPARγ.

Description

Novel compound, preparation method thereof and pharmaceutical composition comprising same

The present invention relates to a novel compound that binds to a peroxysome proliferator activated receptor (Gamma) but does not act as an agonist, a preparation method thereof, and a pharmaceutical composition comprising the same as an active ingredient.

As the number of diabetics has increased over the last decades, the market for diabetes treatments has grown together. Diabetes has been treated mainly with the introduction of insulin, but insulin has the trouble of using injections, and simply supplements the insulin that is lacking in the body, and does not solve the fundamental treatment of diabetes.

Accordingly, drugs that promote insulin secretion, such as sulfonylurea, drugs that slowly release glucose stored in the liver, such as metformin, which inhibits glycolysis, such as acarbose, which inhibit absorption. Drugs or drugs that enhance the sensitivity of insulin receptors, such as rosiglitazone and pioglitazone, have been developed and sold.

Thiazolidinedione (TZD) drugs, such as rosiglitazone and pioglitazone, act on the nuclear receptor peroxysome proliferator activated receptor-gamma (hereinafter referred to as 'PPARγ'). Anti-diabetic effect is shown by increasing the sensitivity of insulin by activating transcription.

However, the thiazolidinedione drug can obtain anti-diabetic effect by increasing the activity of 'PPARγ', but also controls the expression of genes causing various side effects, showing side effects such as weight gain, swelling, and bone mineral density, cardiovascular There is a problem that can cause diseases, such as the situation is limited to use in the market. Therefore, two of the three subunits (PPAR-α / γ or PPAR-γ / δ) and three (PPAR-) of the PPARγ partial agonist and PPAR as a solution to address the side effects of the PPARγ agonist. Drugs that act on α / γ / δ) are also being developed, but are not yet on the market due to side effects and safety issues.

On the other hand, recent studies have reported that the substance named SR-1664 has sufficient antidiabetic and insulin resistance effects without the side effects caused by conventional thiazolidinedione drugs (Nature. 2010, 466). , 451-456; Nature, 2010. 477.477-481). These findings indicate that the development of obesity-like insulin resistance in diabetic patients is caused by the phosphorylation of amino acid PPARγ serine 273 of CDK5 (Cyclin-dependant kinase 5) due to mutation of several genes. It has been found that blocking is an important approach for the development of diabetes treatments.

Therefore, the present inventors bind to PPARγ with high affinity, but do not induce gene transcription, thereby not acting as an agonist, blocking phosphorylation by CDK5, improving insulin resistance, and important pharmacology in developing new drugs. In order to provide a compound having excellent physical properties (solubility, metabolis stability, PK).

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

Another object of the present invention is to provide a method for preparing the 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 achieve the above object, the present invention provides a compound represented by the following formula (1), or a pharmaceutically acceptable salt thereof.

[Formula 1]

In Chemical Formula 1,

R ₁ to R ₄ are the same as or different from each other, and each independently hydrogen, a halogen group, 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 Is selected from the group consisting of 5 to 10 heteroaryl group containing one or more ring atoms,

R ₅ to R ₉ are the same as or different from each other, 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, O and S Is selected from the group consisting of 5 to 10 heteroaryl groups containing one or more hetero atoms,

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

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 heteroaryl group of 5 to 10, the C ₁ to C ₁₀ alkylene group and C ₆ to C ₁₀ arylene group of L are each independently halogen, C ₁ to C ₁₀ alkyl group and C ₁ to C ₁₀ It may be substituted or unsubstituted with one or more substituents selected from the group consisting of alkoxy groups. When the substituents are plural, the plural substituents are the same as or different from each other.

In addition, the present invention, a) synthesizing the compound represented by the formula (2) or 3; b) cyclization of the compound represented by Formula 2 synthesized in step a) in the presence of polyphosphoric acids, or by cyclization of the compound represented by Formula 3 in the presence of acetic acid Synthesizing the compound to be represented; c) synthesizing the compound represented by Chemical Formula 6 by reacting the compound represented by Chemical Formula 4 synthesized in step b) with the compound represented by Chemical Formula 5; d) synthesizing a compound represented by the following Chemical Formula 7 by substituting hydrogen bonded to a nitrogen atom of the compound represented by Chemical Formula 6 synthesized in step c); And e) reacting the compound represented by Formula 7 synthesized in step d) with a strong base to synthesize a compound represented by Formula 1 below.

[Formula 2]

[Formula 3]

[Formula 4]

[Formula 5]

[Formula 6]

[Formula 7]

[Formula 1]

In Chemical Formulas 1 to 7,

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

In another aspect, the present invention provides a pharmaceutical composition for treating metabolic disease comprising the compound represented by Formula 1, or a pharmaceutically acceptable salt thereof as an active ingredient.

The compound represented by Formula 1 according to the present invention, or a pharmaceutically acceptable salt thereof, binds to PPARγ with high affinity but does not act as an agent and thus does not induce gene transcription and blocks phosphorylation by CDK5, thereby preventing conventional diabetes mellitus. The occurrence of side effects caused by the drug used for treatment can be minimized. Accordingly, the present invention can provide a pharmaceutical composition that can exhibit an excellent effect in the treatment of PPARγ related metabolic diseases.

1 is a reference diagram for explaining an experimental example 3 of the present invention.

Hereinafter, the present invention will be described.

1. 신규 화합물, 또는 이의 약학적으로 1. a novel compound, or pharmaceutically thereof 허용가능한Acceptable 염 salt

The present invention binds to PPARγ with high affinity but does not induce gene transcriptional activity and thus does not act as an agonist, and may block phosphorylation by CDK5 to improve insulin resistance, or a pharmaceutical thereof. In regards to an acceptable salt, the compound is represented by the following Chemical Formula 1.

[Formula 1]

In Chemical Formula 1,

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

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

The compound represented by Formula 1 is characterized in that an aromatic ring group connected to an indole moiety by a specific substituent, that is, a ketone group or an imino group. When the compound represented by Formula 1 of the present invention is used as an active ingredient of a pharmaceutical composition for treating metabolic diseases related to PPARγ, metabolic diseases related to PPARγ are not induced because the transcriptional activity is not induced by the specific substituent. It can have an excellent effect on the treatment.

Here, in consideration of the therapeutic effect of the pharmaceutical composition, in Formula 1, R ₁ to R ₄ are each 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).

In addition, R ₁₀ is preferably a hydroxyl group (-OH).

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

Such a compound represented by Formula 1 of the present invention, or a pharmaceutically acceptable salt thereof may be embodied as any one compound selected from the group consisting of Formulas C1 to C77, or a pharmaceutically acceptable salt thereof. It is not limited to these.

On the other hand, when the compound represented by the formula (1) of the present invention is used in the form of a pharmaceutically acceptable salt, it is preferable that it is in the form of an acid addition salt formed by a pharmaceutically acceptable free acid. The acid used in the preparation of the acid addition salt is not particularly limited, but hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, dicarboxylate, phenyl-substituted alkanoate, hydroxy alkano Eate, alkanedioate, 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 preparing the acid addition salt is not particularly limited, but the compound represented by Chemical Formula 1 is dissolved in an organic solvent (for example, methanol, ethanol, acetone, methylene chloride, acetonitrile, etc.), and the organic or inorganic acid is dissolved. The precipitate formed by addition can be prepared by filtration and drying, or by drying the organic solvent and excess acid under reduced pressure and then drying.

2. 제조방법2. Manufacturing method

The present invention provides a method for preparing a compound represented by Chemical Formula 1, which will be described in detail below.

First, a compound represented by the following Chemical Formula 2 or 3 is synthesized. The method for synthesizing the compound represented by the following Chemical Formula 2 or 3 is not particularly limited as long as it is known in the art, and the raw material is added to an organic solvent (for example, acetate, alcohol, ether) and 5 at room temperature. After the reaction for 15 hours to dry and filtered it can be synthesized.

[Formula 2]

[Formula 3]

Next, the compound represented by Formula 2 synthesized above is cyclized in the presence of polyphosphoric acids, or the compound represented by Formula 3 synthesized above is cyclized in the presence of acetic acid The compound represented by it is synthesize | combined.

[Formula 4]

Then, the compound represented by the formula (6) is synthesized by reacting the compound represented by the formula (4) synthesized above with the compound represented by the formula (5). Synthesis of the compound represented by Formula 6 is carried out by drying the compound and the compound represented by Formula 4 and Formula 5 into an organic solvent (for example, dichloromethane) and reacted for 10 to 15 hours, followed by drying and filtration Can be synthesized. Catalysts such as aluminum chloride may also be used to facilitate the synthesis process.

[Formula 5]

[Formula 6]

Next, the compound represented by the following formula (7) is synthesized by substituting hydrogen bonded to the nitrogen atom of the compound represented by the formula (6). That is, hydrogen bonded to the nitrogen atom present in the indole moiety is substituted with a substituent represented by * -LR ₁₁ . In this case, the method for 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.

[Formula 7]

Thereafter, the compound represented by Chemical Formula 1 is synthesized by reacting the compound represented by Chemical Formula 7 synthesized above with a strong base. Specifically, the compound represented by Chemical Formula 7 is dissolved in an organic solvent (eg, tetrahydrofuran, methanol, etc.), reacted with a strong base (eg, sodium hydroxide, etc.) for 30 minutes to 2 hours, and then dried. And it can be synthesized through a process of filtration.

Here, in Formulas 1 to 7, the definitions for R ₁ to R ₁₁ , L, and A are the same as described above.

3. 약학 조성물3. Pharmaceutical Composition

The present invention provides a pharmaceutical composition for treating metabolic disease associated with PPARγ containing the compound represented by 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 thus does not induce gene transcription, and can block phosphorylation of the amino acid at position 273 of serine of PPARγ by CDK5, It does not cause side effects and can be effective in treating metabolic diseases.

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

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

Such pharmaceutical compositions of the present invention may be formulated and used in oral or parenteral dosage forms.

Formulations for oral administration include tablets, pills, hard / soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, troches, and the like. Lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine), glidants (e.g., silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols) It may contain.

The parenteral administration may be a method of injecting into the body by subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection.

Such a pharmaceutical composition of the present invention is preferably used to adjust the dosage according to the age, weight, sex, dosage form, health condition and degree of disease of the patient.

Hereinafter, the present invention will be described in detail with reference to the following Examples. However, the following examples are merely to illustrate the invention, the present invention is not limited by the following examples.

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

[[ 실시예Example 1] 6- 1] 6- 클로오로Claw -3-(4--3- (4- 클로오로벤조일Chlorobenzoyl )-1-(4-) -1- (4- 클로오로페닐Chlorophenyl )-1H-인돌-2-카르복실릭 ) -1H-indole-2-carboxylic 엑시드EXID 합성 synthesis

<Step 1> (E) -ethyl-2- (2- (3- Chlorophenyl ) Hydrazono ) Propanoate synthesis

Into a 2 L flask add purified distilled water (520 ml). After dissolving sodium acetate (50 g, 0.6 mol) in the flask, (3-chlorophenyl) hydrazine hydrochloride (52 g, 0.3 mol) was added thereto, stirred at room temperature for 30 minutes, and then ethyl 2-oxopropanoate. (35 ml, 0.3 mol) was slowly added and stirred for 6 hours. After the reaction was completed, the resultant was filtered with a vacuum filter and dried. To a 3 L flask, dried solid and 2 L of normal hexane were added and stirred for 1 hour, followed by filtration (E) -ethyl-2- (2- (3-chlorophenyl) hydrazono) propanoate (57 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).

Step 2 Synthesis of Ethyl-6-Chloro-1H-indole-2-carboxylate

Toluene (110 ml) was added to a 500 ml flask, and (E) -ethyl = 2- (2- (3-chlorophenyl) hydrazono) propanoate synthesized in the above <Step 1> (10.6 g, 0.044). mol) was added. Next, polyphosphoric acid (52 g) was added thereto, followed by reflux for 6 hours. After the reaction was completed, the mixture was cooled to 50 deg. C and only the toluene layer was separated. The separated toluene layer was concentrated under reduced pressure. Next, 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 give 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, 1H), 4.44 (q, 2H), 1.43 (t, J = 8.0 Hz, 3H).

<Step 3> Ethyl 6- Claw -3- (4- Chlorobenzoyl ) -1H-indole-2- Carboxylate synthesis

In a 100 mL flask, ethyl 6-chloro-1H-indole-2-carboxylate (1 g, 4.47 mmol) and dichloromethane (10 mL) synthesized in <Step 2> were added and dissolved. 4-chlorobenzoyl chloride (939 mg, 5.36 mmol) and aluminum chloride (714 mg, 5.36 mmol) were then added and stirred at reflux for 12 hours. After completion of the reaction, the temperature was lowered to room temperature, the organic layer was separated using dichloromethane and water, and then 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- (4-chlorobenzoyl) -1H-indole-2-carboxyl. Obtained the rate (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> Ethyl-6- Claw -3- (4- Chlorobenzoyl ) -1- (4- Chlorophenyl Synthesis of) -1H-indole-2-carboxylate

In a 25 mL flask, diethyl was added to ethyl-6-chloro-3- (4-chlorobenzoyl) -1H-indole-2-carboxylate (40 mg, 0.122 mmol) synthesized in step 3 above. Methane (1 mL) was added and dissolved. Next, 4- (chlorophenyl) boronic acid (39 mg, 0.246 mmol), copper (II) acetate (34 mg, 0.185 mmol) and triethylamine (25 mg, 0.246 mmol) were added thereto, and the mixture was stirred for 12 hours. . After completion of the reaction, the organic layer was separated using dichloromethane and water, and then 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-chloro-3- (4-chlorobenzoyl) -1- (4-chlorophenyl). -1H-indole-2-carboxylate (34 mg, 0.072 mmol, 60%) was obtained.

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), 7.11 (d, J = 2,0 Hz, 1H), 3.87- 3.81 (m, 2 H), 0.85-0.82 (m, 3 H).

<Step 5> 6- Claw -3- (4- Chlorobenzoyl ) -1- (4- Chlorophenyl ) -1H-indole-2-carboxylic Exsidic synthesis

In a 25 mL flask, ethyl-6-chloro-3- (4-chlorobenzoyl) -1- (4-chlorophenyl) -1H-indole-2-carboxylate (34 mg, 0.072 mmol) was added and dissolved by addition of tetrahydrofuran (0.5 mL) and methanol (0.5 mL). Next, sodium hydroxide (15 mg, 0.36 mmol) dissolved in water (0.5 mL) was added and then stirred for 1 hour. After the reaction was completed, the mixture was concentrated and adjusted to pH 5 using 2N-HCl. Next, after separating the organic layer using ethyl acetate and water, 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%) was obtained.

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).

[[ 실시예Example 2] 6- 2] 6- 클로오로Claw -3-(4--3- (4- 클로오로벤조일Chlorobenzoyl )-1-(3-) -1- (3- 클로오로페닐Chlorophenyl )-1H-인돌-2-카르복실릭 ) -1H-indole-2-carboxylic 엑시드의Exsidic 합성 synthesis

A target compound was obtained in the same manner as in Example 1, except that (3-chlorophenyl) boronic acid was used instead of 4- (chlorophenyl) boronic acid used in <Step 4>. .

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).

[[ 실시예Example 3] 6- 3] 6- 클로오로Claw -3-(4--3- (4- 클로오로벤조일Chlorobenzoyl )-1-(4-) -1- (4- 터트Tert -- 뷰틸페닐Butylphenyl )-1H-인돌-2-카르복실릭 ) -1H-indole-2-carboxylic 엑시드의Exsidic 합성 synthesis

The same procedure as in Example 1 was performed except that (4- (tert-butyl) phenyl) boronic acid was used instead of 4- (chlorophenyl) boronic acid used in <Step 4>. The compound was obtained.

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).

[[ 실시예Example 4] 64] 6 -- 클로오로Claw -3-(4--3- (4- 클로오로벤조일Chlorobenzoyl )-1-(3,4-) -1- (3,4- 다이플로오로페닐Difluorophenyl )-1H-인돌-2-카르복실릭 ) -1H-indole-2-carboxylic 엑시드의Exsidic 합성 synthesis

The same procedure as in Example 1 was carried out except that (3,4-difluorophenyl) boronic acid was used instead of 4- (chloroophenyl) boronic acid used in <Step 4>. The compound was obtained.

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 , 2H), 7.54 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.18 (s, 1H).

[[ 실시예Example 5] 6- 5] 6- 클로오로Claw -3-(4--3- (4- 클로오로벤조일Chlorobenzoyl )-1-(3-() -1- (3- ( 메틸싸이오Methylthio )페닐)-1H-인돌-2-카르복실릭 ) Phenyl) -1H-indole-2-carboxylic 엑시드의Exsidic 합성 synthesis

The same procedure as in Example 1 was carried out except that (3- (methylthio) phenyl) boronic acid was used instead of 4- (chloroophenyl) boronic acid used in <Step 4>. The compound was obtained.

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, 1H), 2.35 (s, 3H).

[[ 실시예Example 6] 6- 6] 6- 클로오로Claw -3-(4--3- (4- 클로오로벤조일Chlorobenzoyl )-1-(3-() -1- (3- ( 트리플로오로메톡시Trifluoromethoxy )페닐)-1H-인돌-2-카르복실릭 ) Phenyl) -1H-indole-2-carboxylic 엑시드의Exsidic 합성 synthesis

The same procedure as in Example 1 was performed except for using (3- (trifluoromethoxy) phenyl) boronic acid instead of 4- (chlorofluorophenyl) 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 , J = 1.6 Hz, 1H).

[[ 실시예Example 7] 6- 7] 6- 클로오로Claw -3-(4--3- (4- 클로오로벤조일Chlorobenzoyl )-1-(3-() -1- (3- ( 트리플로오로메틸Trifluoromethyl )페닐)-1H-인돌-2-카르복실릭 ) Phenyl) -1H-indole-2-carboxylic 엑시드의Exsidic 합성 synthesis

The same procedure as in Example 1 was performed except for using (3- (trifluoromethyl) phenyl) boronic acid instead of 4- (chlorofluorophenyl) boronic acid used in <Step 4>. The desired compound was obtained.

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).

[[ 실시예Example 8] 6- 8] 6- 클로오로Claw -3-(4--3- (4- 클로오로벤조일Chlorobenzoyl )-1-()-One-( 메타Meta -- 톨루일Toluyl )-1H-인돌-2-) -1H-indole-2- 카르복실릭Carboxylic 엑시드의Exsidic 합성 synthesis

The target compound was obtained in the same manner as in Example 1, except that (meth-toluyl) boronic acid was used instead of 4- (chloroophenyl) boronic acid used in <Step 4>.

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).

[[ 실시예Example 9] 3- 9] 3- 벤조일Benzoyl -6--6- 클로오로Claw -1-(4--1- (4- 클로오로페닐Chlorophenyl )-1H-인돌-2-) -1H-indole-2- 카르복실릭Carboxylic 엑시드의 합성 Synthesis of Exid

<Step 1> (E) -ethyl-2- (2- (3- Chlorophenyl ) Hydrazono ) Propanoate synthesis

Into a 2 L flask add purified distilled water (520 ml). After dissolving sodium acetate (50 g, 0.6 mol) in the flask, (3-chlorophenyl) hydrazine hydrochloride (52 g, 0.3 mol) was added thereto, stirred at room temperature for 30 minutes, and then ethyl 2-oxopropanoate. (35 ml, 0.3 mol) was slowly added and stirred for 6 hours. After the reaction was completed, the mixture was filtered through a vacuum filter and then dried. To a 3 L flask, dried solid and 2 L of normal hexane were added and stirred for 1 hour, followed by filtration to obtain (E) -ethyl-2- (2- (3-chlorophenyl) hydrazono) propanoate (57 g , 0.24 mol, 81%).

Step 2 Synthesis of Ethyl-6-Chloro-1H-indole-2-carboxylate

Toluene (110 ml) was added to a 500 ml flask and (E) -ethyl-2- (2- (3-chlorophenyl) hydrazono) propanoate (10.6 g, 0.044) synthesized in <Step 1> was used. mol) was added. Then, polyphosphoric acid (52 g) was added thereto, followed by reflux for 6 hours. After the reaction was completed, the mixture was cooled to 50 deg. C and only the toluene layer was 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. The recrystallized solid was then filtered to afford ethyl-6-chloro-1H-indole-2-carboxylate (3.4 g, 0.015 mol, 35%).

Step 3 Synthesis of Ethyl-3-benzoyl-6-chloro-1H-indole-2-carboxylate

Into a 100 ml flask, ethyl-6-chloro-1H-indole-2-carboxylate (3 g, 13.41 mmol) and dichloromethane (30 mL) synthesized in the above <Step 2> were added and dissolved. Next benzoyl chloride (2.07 g, 14.75 mmol), aluminum chloride (3.57 g, 26.82 mmol) were added and stirred at reflux for 12 hours. After completion of the reaction, the temperature was lowered to room temperature, the organic layer was separated using dichloromethane and water, and then 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-benzoyl-6-chloro-1H-indole-2-carboxylate (2.5 g, 7.62 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 Hz, 1H), 7.49 (d, J = 1.6 Hz, 2H), 7.46 (s, 1H), 7.44 (d, J = 7.6 Hz, 2H), 7.2 (d, J = 8.8 Hz, 2H), 4.08- 4.03 (q, J = 7.2 Hz, 2H), 0.89-0.86 (t, J = 7.2 Hz, 3H).

<Step 4> Ethyl-3- Benzoyl -6- Claw -1- (4- Chlorophenyl ) -1H-indole-2- Carboxylate synthesis

Into a 25 mL flask, add ethyl 3-benzoyl-6-chloro-1H-indole-2-carboxylate (150 mg, 0.46 mmol) and dichloromethane (1.5 mL) synthesized in <Step 3>. Dissolved. Next, (4-chlorophenyl) boronic acid (71.6 mg, 0.46 mmol), copper (II) acetate (166 mg, 0.91 mmol), triethylamine (93 mg, 0.91 mmol) were added thereto, and stirred for 12 hours. I was. After the reaction was completed, the organic layer was separated using dichloromethane and water, and then 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-3-benzoyl-6-chloro-1- (4-chlorophenyl) -1H-indole 2-carboxylate (78 mg, 0.18 mmol, 39%) was obtained.

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 Hz, 2H), 7.23 (dd, J = 1.6, 8.4 Hz, 1H), 7.11 (d, J = 1.6 Hz, 1H), 3.80-3.74 (m, 2H), 0.80-0.76 (m, 3H).

<Step 5> 3- Benzoyl -6- Claw -1- (4- Chlorophenyl ) -1H-indole-2- Carboxylic Exsidic synthesis

In a 25 mL flask, ethyl-3-benzoyl-6-chloro-1- (4-chlorophenyl) -1H-indole-2-carboxylate (78 mg, 0.18 mmol) synthesized in <Step 4> above Was added and dissolved by addition of tetrahydrofuran (1 mL) and methanol (1 mL). Next, sodium hydroxide (36 mg, 0.89 mmol) dissolved in water (1 mL) was added and then stirred for 1 hour. After the reaction was completed, the mixture was concentrated and adjusted to pH 5 using 2N-HCl. Next, after separating the organic layer using ethyl acetate and water, 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-benzoyl-6-chloro-1- (4-chlorophenyl) -1H-indole-2 -Carboxylic acid (48 mg, 0.12 mmol, 65%) was obtained.

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, 1H), 7.07 (d, J = 1.6 Hz, 1H).

[[ 실시예Example 10] 3- 10] 3- 벤조일Benzoyl -6--6- 클로오로Claw -1-(3--1- (3- 메톡시페닐Methoxyphenyl )-1H-인돌-2-) -1H-indole-2- 카르복실릭Carboxylic 엑시드의 합성 Synthesis of Exid

A target compound was obtained in the same manner as in Example 9, except that (3-methoxyphenyl) boronic acid acid was used instead of 4- (chlorophenyl) boronic acid acid used in <Step 4>. .

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).

[[ 실시예Example 11] 3- 11] 3- 벤조일Benzoyl -6--6- 클로오로Claw -1-(4-(-1- (4- ( 터트Tert -- 뷰틸Butyl )페닐)-1H-인돌-2-) Phenyl) -1H-indole-2- 카르복실릭Carboxylic 엑시드의Exsidic 합성 synthesis

The same procedure as in Example 9 was carried out except that (4- (tert-butyl) phenyl) boronic acid was used instead of 4- (chloroophenyl) boronic acid used in <Step 4>. The compound was obtained.

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).

[[ 실시예Example 12] 3- 12] 3- 벤조일Benzoyl -6--6- 클로오로Claw -1-(3-(-1- (3- ( 트라이플로오로메톡시Trifluoromethoxy )페닐)-1H-인돌-2-카르복실릭 ) Phenyl) -1H-indole-2-carboxylic 엑시드의Exsidic 합성 synthesis

The same procedure as in Example 9 was carried out except that (3- (trifluoromethoxy) phenyl) boronic acid was used instead of 4- (chlorofluorophenyl) 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).

[[ 실시예Example 13] 3- 13] 3- 벤조일Benzoyl -6--6- 클로오로Claw -1-(4-(-1- (4- ( 메틸싸이오Methylthio )페닐)-1H-인돌-2-) Phenyl) -1H-indole-2- 카르복실릭Carboxylic 엑시드의Exsidic 합성 synthesis

The same procedure as in Example 9 was carried out except for using (4- (methylthio) phenyl) boronic acid instead of 4- (chloroophenyl) boronic acid used in <Step 4>. The compound was obtained.

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).

[[ 실시예Example 14] 3- 14] 3- 벤조일Benzoyl -6--6- 클로오로Claw -1-(4-(-1- (4- ( 트라이플로오로메틸Trifluoromethyl )페닐)-1H-인돌-2-카르복실릭 ) Phenyl) -1H-indole-2-carboxylic 엑시드의Exsidic 합성 synthesis

The same procedure as in Example 9 was performed except for using (4- (trifluoromethyl) phenyl) boronic acid instead of 4- (chlorofluorophenyl) boronic acid used in <Step 4>. The desired compound was obtained.

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 (dd, J = 1.6, 8.4 Hz, 3H), 7.14 (d , J = 1.2 Hz, 1H).

[[ 실시예Example 15] 3- 15] 3- 벤조일Benzoyl -1-(4--1- (4- 브로모페닐Bromophenyl )-6-) -6- 클로오로Claw --1H-인돌-2---1H-indole-2- 카르복실릭Carboxylic 엑시드의 합성 Synthesis of Exid

A target compound was obtained in the same manner as in Example 9, except that (4-bromophenyl) boronic acid was used instead of 4- (chlorophenyl) boronic acid used in <Step 4>. .

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), 7.41 (t, J = 7.6 Hz, 3H), 7.32-7.25 (m, 2H), 7.17 (dd, J = 1.6, 8.4 Hz, 2H), 7.65-6.54 (m, 2H), 7.48-7.42 (m, 4H), 7.20 (dd. J = 1.6, 8.4 Hz, 1H), 7.10 (d, J = 2.0 Hz, 1H).

[[ 실시예Example 16] 3- 16] 3- 벤조일Benzoyl -6--6- 클로오로Claw -1-(퀴놀린-3-일)-1H-인돌-2--1- (quinolin-3-yl) -1H-indole-2- 카르복실릭Carboxylic 엑시드의Exsidic 합성 synthesis

A target compound was obtained in the same manner as in Example 9, except that (quinolin-3-yl) boronic acid was used instead of 4- (chloroophenyl) 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).

[[ 실시예Example 17] 3- 17] 3- 벤조일Benzoyl -6--6- 클로오로Claw -1-(파라--1- (para- 톨루일Toluyl )-1H-인돌-2-) -1H-indole-2- 카르복실릭Carboxylic 엑시드의Exsidic 합성 synthesis

The target compound was obtained in the same manner as in Example 9, except that (para-toluyl) boronic acid was used instead of 4- (chloroophenyl) boronic acid used in <Step 4>.

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).

[[ 실시예Example 18] 3- 18] 3- 벤조일Benzoyl -6--6- 클로오로Claw -1-(3--1- (3- 플로오로Floro -4--4- 메톡시페닐Methoxyphenyl )-1H-인돌-2-카르복실릭 ) -1H-indole-2-carboxylic 엑시드의Exsidic 합성 synthesis

The same procedure as in Example 9 was carried out except that (3-fluoro-4-methoxyphenyl) boronic acid was used instead of 4- (chlorofluoro) 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 ( t, 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).

[[ 실시예Example 19] 6- 19] 6- 클로오로Claw -1-(4--1- (4- 클로오로페닐Chlorophenyl )-3-(4-) -3- (4- 메톡시벤조일Methoxybenzoyl )-1H-인돌-2-카르복실릭 ) -1H-indole-2-carboxylic 엑시드EXID 합성 synthesis

<Step 1> (E) -ethyl-2- (2- (3- Chlorophenyl ) Hydrazono ) Propanoate synthesis

Into a 2 L flask add purified distilled water (520 ml). After dissolving sodium acetate (50 g, 0.6 mol) in the flask, (3-chlorophenyl) hydrazine hydrochloride (52 g, 0.3 mol) was added thereto, stirred at room temperature for 30 minutes, and then ethyl 2-oxopropanoate. (35 ml, 0.3 mol) was slowly added and stirred for 6 hours. After the reaction was completed, the mixture was filtered through a vacuum filter and then dried. To a 3 L flask, dried solid and 2 L of normal hexane were added and stirred for 1 hour, followed by filtration to obtain (E) -ethyl-2- (2- (3-chlorophenyl) hydrazono) propanoate (57 g , 0.24 mol, 81%) was obtained.

Step 2 Synthesis of Ethyl-6-Chloro-1H-indole-2-carboxylate

Toluene (110 ml) was added to a 500 ml flask and (E) -ethyl-2- (2- (3-chlorophenyl) hydrazono) propanoate (10.6 g, 0.044) synthesized in <Step 1> was used. mol) was added. Next, polyphosphoric acid (52 g) was added thereto, followed by reflux for 6 hours. After the reaction was completed, the mixture was cooled to 50 deg. C and only the toluene layer was 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. The recrystallized solid was then filtered to afford ethyl-6-chloro-1H-indole-2-carboxylate (3.4 g, 0.015 mol, 35%).

<Step 3> Ethyl-6- Claw -3- (4- Methoxybenzoyl ) -1H-indole-2- Carboxylate synthesis

Into a 25 mL flask, ethyl 6-chloro-1H-indole-2-carboxylate (7 g, 31.29 mmol) and dichloroethane (70 mL) synthesized in <Step 2> were added and dissolved. Then 4-methoxyrobenzoyl chloride (6.04 g, 37.55 mmol), aluminum chloride (5.07 g, 37.55 mmol) were added and stirred at reflux for 12 hours. After the reaction was completed, the temperature was lowered to room temperature, the organic layer was separated using dichloroethane and water, and then 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- (4-methoxybenzoyl) -1H-indole-2-carboxylate. (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, 1H), 7.43 (d, J = 9.2 Hz, 2H), 7.33 (dd, J = 8.8 Hz, 1H), 4.13-4.08 (q, J = 7.2 Hz, 2H), 0.97-0.94 (t, J = 7.2 Hz, 3H).

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

In a 25 mL flask, ethyl-6-chloro-3- (4-methoxybenzoyl) -1H-indole-2-carboxylate (100 mg, 0.28 mmol) synthesized in step <3> and dichloro Methane (1 mL) was added and dissolved. Next, (4-chlorophenyl) boronic acid (66 mg, 0.42 mmol), copper (II) acetate (101 mg, 0.56 mmol), triethylamine (57 mg, 0.56 mmol) were added thereto, and stirred for 12 hours. I was. After the reaction was completed, the organic layer was separated using dichloromethane and water, and then 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-chloro-1- (4-chlorophenyl) -3- (4-methoxybenzoyl ) -1H-indole-2-carboxylate (98 mg, 0.21 mmol, 74%) was obtained.

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 (d, J = 1.6 Hz, 1H), 6.94 (d, J = 8.8 Hz, 2H), 3.90-3.84 ( m, 5H), 0.88-0.81 (m, 3H).

<Step 5> 6- Claw -1- (4- Chlorophenyl ) -3- (4- Methoxybenzoyl ) -1H-indole-2- Carboxylic Exsidic synthesis

In a 25 mL flask, ethyl-6-chloro-1- (4-chlorophenyl) -3- (4-methoxybenzoyl) -1H-indole-2-carboxylate ( 98 mg, 0.21 mmol) was added and dissolved by addition of tetrahydrofuran (1 mL) and methanol (1 mL). Next, sodium hydroxide (42 mg, 1.04 mmol) dissolved in water (1 mL) was added and then stirred for 1 hour. After the reaction was completed, the mixture was concentrated and adjusted to pH 5 using 2N-HCl. Thereafter, the organic layer was separated using ethyl acetate and water, and then 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%) was obtained.

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 , 1H), 7.07 (s, 1H), 6.96 (d, J = 8.0 Hz, 2H), 3.82 (s, 3H).

[[ 실시예Example 20] 6- 20] 6- 클로오로Claw -1-(3--1- (3- 클로오로페닐Chlorophenyl )-3-(4-) -3- (4- 메톡시벤조일Methoxybenzoyl )-1H-인돌-2-카르복실릭 ) -1H-indole-2-carboxylic 엑시드의Exsidic 합성 synthesis

A target compound was obtained by the same procedure as in Example 19, except that (3-chlorophenyl) boronic acid was used instead of (4-chlorophenyl) boronic acid used in <Step 4>. 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 -7.50 (m, 2H), 7.25 (d, J = 8.0 Hz, 1H), 7.12 (s, 1H), 7.04 (d, J = 8.0 Hz, 2H), 3.84 (s, 3H).

[[ 실시예Example 21] 6- 21] 6- 클로오로Claw -3-(4--3- (4- 메톡시벤조일Methoxybenzoyl )-1-(4-() -1- (4- ( 메틸싸이오Methylthio )페닐)-1H-인돌-2-카르복실릭 ) Phenyl) -1H-indole-2-carboxylic 엑시드의Exsidic 합성 synthesis

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

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 (s, 3H).

[[ 실시예Example 22] 6- 22] 6- 클로오로Claw -3-(4--3- (4- 메톡시벤조일Methoxybenzoyl )-1-(4-() -1- (4- ( 트라이플로오로메톡시Trifluoromethoxy )페닐)-1H-인돌-2-카르복실릭 ) Phenyl) -1H-indole-2-carboxylic 엑시드의Exsidic 합성 synthesis

The same procedure as in Example 19 was carried out except that (4- (trifluoromethoxy) phenyl) boronic acid was used instead of the (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 , 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 (s, 3H).

[[ 실시예Example 23] 6- 23] 6- 클로오로Claw -3-(4--3- (4- 메톡시벤조일Methoxybenzoyl )-1-(3-() -1- (3- ( 메틸싸이오Methylthio )페닐)-1H-인돌-2-카르복실릭 ) Phenyl) -1H-indole-2-carboxylic 엑시드의Exsidic 합성 synthesis

The same procedure as in Example 19 was carried out except for using (3- (methylthio) phenyl) boronic acid instead of (4-chlorophenyl) boronic acid used in <Step 4>. The compound was obtained.

¹ H NMR (400 MHz, DMSO-d ₆ ) 7.88 (d, J = 8.8 Hz, 2H), 7.55-7.36 (m, 4H), 7.26 (d, J = 8.8 Hz, 1H), 7.18-7.14 (m , 2H), 7.00 (d, J = 8.8 Hz, 2H), 3.88 (s, 3H), 2.52 (s, 3H).

[[ 실시예Example 24] 6- 24] 6- 클로오로Claw -1-(3--1- (3- 플로오로Floro -4--4- 메틸페닐Methylphenyl )-3-(4-) -3- (4- 메톡시벤조일Methoxybenzoyl )-1H-인돌-2-카르복실릭 ) -1H-indole-2-carboxylic 엑시드의Exsidic 합성 synthesis

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

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, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.70 (s, 1H), 6.96 (d, J = 8.0 Hz, 2H), 3.82 (s, 3H), 2.32 (s, 3H).

[[ 실시예Example 25] 6- 25] 6- 클로오로Claw -3-(4--3- (4- 메톡시벤조일Methoxybenzoyl )-1-(3,4,5-) -1- (3,4,5- 트라이플로오로페닐Trifluorophenyl )-1H-인돌-2-카르복실릭 ) -1H-indole-2-carboxylic 엑시드의Exsidic 합성 synthesis

The same procedure as in Example 19 was carried out except that (3,4,5-trifluorophenyl) boronic acid was used instead of the (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).

[[ 실시예Example 26] 6- 26] 6- 클로오로Claw -3-(4--3- (4- 메톡시벤조일Methoxybenzoyl )-1-(3,5-) -1- (3,5- 다이플로오로페닐Difluorophenyl )-1H-인돌-2-카르복실릭 ) -1H-indole-2-carboxylic 엑시드의Exsidic 합성 synthesis

The same procedure as in Example 19 was carried out except for using (3,5-difluorophenyl) boronic acid instead of (4-chlorophenyl) boronic acid used in <Step 4>. The compound was obtained.

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).

[[ 실시예Example 27] 1-(4- 27] 1- (4- 브로모페닐Bromophenyl )-6-) -6- 클로오로Claw -3-(4--3- (4- 메톡시벤조일Methoxybenzoyl )-1H-인돌-2-) -1H-indole-2- 카르복실릭Carboxylic 엑시드의Exsidic 합성 synthesis

A target compound was obtained in the same manner as in Example 19, except that (4-bromophenyl) boronic acid was used 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, 1H), 7.07 (s, 1H), 6.96 (d, J = 8.0 Hz, 2H), 3.82 (s, 3 H).

[[ 실시예Example 28] 6- 28] 6- 클로오로Claw -3-(4--3- (4- 메톡시벤조일Methoxybenzoyl )-1-(4-() -1- (4- ( 트라이플로오로메틸Trifluoromethyl )페닐)-1H-인돌-2-카르복실릭 ) Phenyl) -1H-indole-2-carboxylic 엑시드의Exsidic 합성 synthesis

The same procedure as in Example 19 was carried out except for using (4- (trifluoromethyl) phenyl) boronic acid instead of (4-chlorophenyl) boronic acid used in <Step 4>. The desired compound was obtained.

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 (d, J = 1.6 Hz, 1H), 6.98 (d, J = 8.8 Hz, 2H), 3.82 ( s, 3H).

[[ 실시예Example 29] 6- 29] 6- 클로오로Claw -3-(4--3- (4- 메톡시벤조일Methoxybenzoyl )-1-(피리딘-4-일)-1H-인돌-2-) -1- (pyridin-4-yl) -1H-indole-2- 카르복실릭Carboxylic 엑시드의Exsidic 합성 synthesis

The target compound was obtained in the same manner as in Example 19, 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), 7.55 (dd, J = 1.6, 4.8 Hz, 2H), 7.25 (s, 1H), 7.19 (d, J = 8.8 Hz, 1H), 6.95 (d, J = 6.8 Hz, 2H), 3.82 (s, 3H ).

[[ 실시예Example 30] 6- 30] 6- 클로오로Claw -1-(3--1- (3- 플로오로페닐Fluorophenyl )-3-(4-) -3- (4- 메톡시벤조일Methoxybenzoyl )-1H-인돌-2-카르복실릭 ) -1H-indole-2-carboxylic 엑시드의Exsidic 합성 synthesis

A target compound was obtained in the same manner as in Example 19, except that (3-fluorophenyl) boronic acid was used instead of (4-chlorophenyl) boronic acid used in <Step 4>. .

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 Hz, 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).

[[ 실시예Example 31] 6- 31] 6- 클로오로Claw -3-(4--3- (4- 메톡시벤조일Methoxybenzoyl )-1-(퀴놀린-3-일)-1H-인돌-2-) -1- (quinolin-3-yl) -1H-indole-2- 카르복실릭Carboxylic 엑시드의Exsidic 합성 synthesis

A target compound was obtained in the same manner as in Example 19, 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 (d, J = 8.8 Hz, 1H), 7.23-7.20 (m, 2H), 7.02- 6.99 (m, 2 H), 3.88 (s, 3 H).

[[ 실시예Example 32] 6- 32] 6- 클로오로Claw -3-(4--3- (4- 메톡시벤조일Methoxybenzoyl )-1-(3-) -1- (3- 메톡시페닐Methoxyphenyl )-1H-인돌-2-) -1H-indole-2- 카르복실릭Carboxylic 엑시드의Exsidic 합성 synthesis

A target compound was obtained in the same manner as in Example 19, except that (3-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), 7.59 (d, J = 8.4 Hz, 1H), 7.40 (d, J = 8.8 Hz, 2H), 7.15 ( dd, J = 1.6, 8.4 Hz, 1H), 7.07 (d, J = 8.8 Hz, 2H), 6.98 (s, 1H), 6.96 (d, J = 8.8 Hz, 2H), 3.83 (s, 3H), 3.82 (s, 3 H).

[[ 실시예Example 33] 6- 33] 6- 클로오로Claw -3-(4--3- (4- 메톡시벤조일Methoxybenzoyl )-1-(4-) -1- (4- 메톡시페닐Methoxyphenyl )-1H-인돌-2-) -1H-indole-2- 카르복실릭Carboxylic 엑시드의Exsidic 합성 synthesis

A target compound was obtained in the same manner as in Example 19, 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).

[[ 실시예Example 34] 6- 34] 6- 클로오로Claw -3-(4--3- (4- 메톡시벤조일Methoxybenzoyl )-1-(파라-) -1- (para- 톨루일Toluyl )-1H-인돌-2-) -1H-indole-2- 카르복실릭Carboxylic 엑시드의Exsidic 합성 synthesis

A target compound was obtained in the same manner as in Example 19, except for using (para-toluyl) boronic acid instead of (4-chlorophenyl) boronic acid used in <Step 4>.

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 Hz, 1H), 7.01 (s, 1H), 6.97 (d, J = 8.4 Hz, 2H), 3.82 (s, 3H), 2.40 (s, 3H).

[[ 실시예Example 35] 6- 35] 6- 클로오로Claw -3-(4--3- (4- 메톡시벤조일Methoxybenzoyl )-1-(3-() -1- (3- ( 트라이플로오로메틸Trifluoromethyl )페닐)-1H-인돌-2-카르복실릭 ) Phenyl) -1H-indole-2-carboxylic 엑시드의Exsidic 합성 synthesis

The same procedure as in Example 19 was carried out except for using (3- (trifluoromethyl) phenyl) boronic acid instead of (4-chlorophenyl) boronic acid used in <Step 4>. The desired compound was obtained.

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), 7.04 (s , 1H), 6.98 (d, J = 8.8 Hz, 2H), 3.82 (s, 3H).

[[ 실시예Example 36] 6- 36] 6- 클로오로Claw -1-(3--1- (3- 플로오로Floro -4--4- 메톡시페닐Methoxyphenyl )-3-(4-) -3- (4- 메톡시벤조일Methoxybenzoyl )-1H-인돌-2-카르복실릭 ) -1H-indole-2-carboxylic 엑시드의Exsidic 합성 synthesis

The same procedure as in Example 19 was carried out except that (3-fluoro-4-methoxyphenyl) boronic acid was used instead of the (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- 25 (m, 2H), 7.15 (dd, J = 2, 8.4 Hz, 1H), 7.04 (s, 1H), 6.96 (d, J = 8.4 Hz, 2H), 3.92 (s, 3H), 3.82 (s , 3H).

[[ 실시예Example 37] 6- 37] 6- 클로오로Claw -3-(4--3- (4- 메톡시벤조일Methoxybenzoyl )-1-(3-() -1- (3- ( 트라이플로오로메톡시Trifluoromethoxy )페닐)-1H-인돌-2-카르복실릭 ) Phenyl) -1H-indole-2-carboxylic 엑시드의Exsidic 합성 synthesis

The same procedure as in Example 19 was carried out 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 ) 7.83 (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 (d, J = 6.8 Hz, 1H), 7.06 (d, J = 8.8 Hz, 2H), 3.84 ( s, 3H).

[[ 실시예Example 38] 6- 38] 6- 클로오로Claw -3-(4--3- (4- 메톡시벤조일Methoxybenzoyl )-1-(4-) -1- (4- 나이트로페닐Nitrophenyl )-1H-인돌-2-카르복실릭 ) -1H-indole-2-carboxylic 엑시드의Exsidic 합성 synthesis

A target compound was obtained in the same manner as in Example 19, except that (4-nitrophenyl) boronic acid was used 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 (s, 3H).

[[ 실시예Example 39] 6- 39] 6- 클로오로Claw -1-(4--1- (4- 플로오로페닐Fluorophenyl )-3-(4-) -3- (4- 메톡시벤조일Methoxybenzoyl )-1H-인돌-2-카르복실릭 ) -1H-indole-2-carboxylic 엑시드의Exsidic 합성 synthesis

A target compound was obtained in the same manner as in Example 19, 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, 1 H), 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).

[[ 실시예Example 40] 6- 40] 6- 클로오로Claw -3-(3--3- (3- 클로오로벤조일Chlorobenzoyl )-1-(4-) -1- (4- 클로오로페닐Chlorophenyl )-1H-인돌-2-카르복실릭 ) -1H-indole-2-carboxylic 엑시드의Exsidic 합성 synthesis

<Step 1> (E) -ethyl-2- (2- (3- Chlorophenyl ) Hydrazono ) Propanoate synthesis

Step 2 Synthesis of Ethyl-6-Chloro-1H-indole-2-carboxylate

Toluene (110 ml) was added to a 500 ml flask and (E) -ethyl-2- (2- (3-chlorophenyl) hydrazono) propanoate (10.6 g, 0.044) synthesized in <Step 1> was used. mol) was added. Next, polyphosphoric acid (52 g) was added thereto, followed by reflux for 6 hours. After the reaction was completed, the mixture was cooled to 50 DEG C, and only the toluene layer was 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. The recrystallized solid was then filtered to afford 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, 1H), 4.44 (q, 2H), 1.43 (t, J = 8.0 Hz, 3H).

<Step 3> Ethyl-6- Claw -3- (3- Chlorobenzoyl ) -1H-indole-2- Carboxylate synthesis

In a 100 mL flask, ethyl-6-chloro-1H-indole-2-carboxylate (1 g, 4.47 mmol) and dichloroethane (10 mL) synthesized in <Step 2> were added and dissolved. 3-chlorobenzoyl chloride (939 mg, 5.36 mmol) and aluminum chloride (715 mg, 5.36 mmol) were then added and stirred at reflux for 12 hours. After the reaction was completed, the temperature was lowered to room temperature, the organic layer was separated using dichloromethane and water, and then water contained in the organic layer was removed with magnesium sulfate. Then, 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), 7.58-7.50 (m, 2H), 7.38 (t, 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> Ethyl-6- Claw -3- (3- Chlorobenzoyl ) -1- (4- Chlorophenyl Synthesis of) -1H-indole-2-carboxylate

In a 25 mL flask, add diethyl with ethyl-6-chloro-3- (3-chlorobenzoyl) -1H-indole-2-carboxylate (200 mg, 0.55 mmol) synthesized in step 3 above. Methane (2 mL) was added and dissolved. Next, (4-chlorophenyl) boronic acid (172 mg, 1.10 mmol), copper (II) acetate (201 mg, 1.10 mmol), triethylamine (112 mg, 1.10 mmol) were added thereto, and stirred for 12 hours. I was. After the reaction was completed, the organic layer was separated using dichloromethane and water, and then 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-chloro-3- (3-chlorobenzoyl) -1- (4-chlorophenyl ) -1H-indole-2-carboxylate (75 mg, 0.16 mmol, 29%) was obtained.

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 -7.23 (dd, 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- Claw -3- (3- Chlorobenzoyl ) -1- (4- Chlorophenyl ) -1H-indole-2-carboxylic Exsidic synthesis

In a 25 mL flask, ethyl-6-chloro-3- (3-chlorobenzoyl) -1- (4-chlorophenyl) -1H-indole-2-carboxylate ( 70 mg, 0.15 mmol) was added and dissolved by addition of tetrahydrofuran (1 mL) and methanol (1 mL). Next, sodium hydroxide (30 mg, 0.74 mmol) dissolved in water (1 mL) was added and then stirred for 1 hour. After the reaction was completed, the mixture was concentrated and adjusted to pH 5 using 2N-HCl. Thereafter, the organic layer was separated using ethyl acetate and water, and then 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- (3-chlorobenzoyl) -1- (4-chlorophenyl) -1H-indole-2-carboxylic acid (52 mg, 0.12 mmol, 80%) was obtained.

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, 1H), 7.08 (d, J = 2 Hz, 1H).

[[ 실시예Example 41] 1-(4-( 41] 1- (4- ( 터트Tert -- 뷰틸Butyl )페닐)-6-) Phenyl) -6- 클로오로Claw -3-(3--3- (3- 클로오로벤조일Chlorobenzoyl )-1H-인돌-2-카르복실릭 ) -1H-indole-2-carboxylic 엑시드의Exsidic 합성 synthesis

The same procedure as in Example 40 was carried out except that (4- (tert-butyl) phenyl) boronic acid was used instead of 4- (chlorophenyl) boronic acid used in <Step 4>. The compound was obtained.

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), 7.11 (d, J = 1.6 Hz, 1H), 1.36 (s, 9H).

[[ 실시예Example 42] 6- 42] 6- 클로오로Claw -3-(3--3- (3- 클로오로벤조일Chlorobenzoyl )-1-(3-) -1- (3- 플로오로페닐Fluorophenyl )-1H-인돌-2-카르복실릭 ) -1H-indole-2-carboxylic 엑시드의Exsidic 합성 synthesis

A target compound was obtained in the same manner as in Example 40, except that (3-fluorophenyl) boronic acid was used instead of 4- (chlorofluoro) boronic acid used in <Step 4>. .

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 , 1H), 7.37 (t, J = 8.8 Hz, 2H), 7.23 (dd, J = 1.6, 8.4 Hz, 1H), 7.04 (d, J = 1.6 Hz, 1H).

[[ 실시예Example 43] 1-(4- 43] 1- (4- 브로모페닐Bromophenyl )-6-) -6- 클로오로Claw -3-(3--3- (3- 클로오로벤조일Chlorobenzoyl )-1H-인돌-2-카르복실릭 ) -1H-indole-2-carboxylic 엑시드의Exsidic 합성 synthesis

A target compound was obtained in the same manner as in Example 40, except that (4-bromophenyl) boronic acid was used instead of 4- (chlorophenyl) boronic acid used in <Step 4>. .

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 (m, 3H), 7.31 (dd, J = 2, 0, 8.8 Hz, 1H), 7.18 (d, J = 1.6 Hz, 1H).

[[ 실시예Example 44] 6- 44] 6- 클로오로Claw -3-(3--3- (3- 클로오로벤조일Chlorobenzoyl )-1-(3-() -1- (3- ( 메틸싸이오Methylthio )페닐)-1H-인돌-2-카르복실릭 ) Phenyl) -1H-indole-2-carboxylic 엑시드의Exsidic 합성 synthesis

The same procedure as in Example 40 was carried out except that (3- (methylthio) phenyl) boronic acid was used instead of 4- (chloroophenyl) boronic acid used in <Step 4>. The compound was obtained.

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 = 8.4 Hz, 2H), 7.07 (s, 1H), 2.50 (s, 3H).

[[ 실시예Example 45] 6- 45] 6- 클로오로Claw -3-(3--3- (3- 클로오로벤조일Chlorobenzoyl )-1-(4-() -1- (4- ( 메틸싸이오Methylthio )페닐)-1H-인돌-2-카르복실릭 ) Phenyl) -1H-indole-2-carboxylic 엑시드의Exsidic 합성 synthesis

The same procedure as in Example 40 was carried out except that (4- (methylthio) phenyl) boronic acid was used instead of 4- (chloroophenyl) boronic acid used in <Step 4>. The compound was obtained.

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).

[[ 실시예Example 46] 6- 46] 6- 클로오로Claw -3-(3--3- (3- 클로오로벤조일Chlorobenzoyl )-1-(4-) -1- (4- 클로오로페닐Chlorophenyl )-1H-인돌-2-카르복실릭 ) -1H-indole-2-carboxylic 엑시드의Exsidic 합성 synthesis

<Step 1> (E) -ethyl-2- (2- (3- Chlorophenyl ) Hydrazono ) Propanoate synthesis

Into a 2 L flask add purified distilled water (520 ml). After dissolving sodium acetate (50 g, 0.6 mol) in the flask, (3-chlorophenyl) hydrazine hydrochloride (52 g, 0.3 mol) was added thereto, stirred at room temperature for 30 minutes, and then ethyl 2-oxopropanoate. (35 ml, 0.3 mol) was slowly added and stirred for 6 hours. After the reaction was completed, the resultant was filtered with a vacuum filter and dried. To a 3 L flask, dried solid and 2 L of normal hexane were added and stirred for 1 hour, followed by filtration to obtain (E) -ethyl-2- (2- (3-chlorophenyl) hydrazono) propanoate (57 g , 0.24 mol, 81%).

Step 2 Synthesis of Ethyl-6-Chloro-1H-indole-2-carboxylate

Toluene (110 ml) was added to a 500 ml flask and (E) -e--2- (2- (3-chlorophenyl) hydrazono) propanoate (10.6 g, 0.044 mol) was added. Next, polyphosphoric acid (52 g) was added thereto, followed by reflux for 6 hours. After the reaction was completed, the mixture was cooled to 50 DEG C, and only the toluene layer was 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. The recrystallized solid was then filtered to afford ethyl-6-chloro-1H-indole-2-carboxylate (3.4 g, 0.015 mol, 35%).

<Step 3> Ethyl-6- Claw -3- (2,4- Dichlorobenzoyl ) -1H-indole-2- Carboxylate synthesis

In a 500 mL flask, ethyl-6-chloro-1H-indole-2-carboxylate (10 g, 4.47 mmol) and dichloromethane (150 mL) synthesized in <Step 2> were added and dissolved. 2,4-Dichlorobenzoyl chloride (11.24 g, 53.6 mmol) and aluminum chloride (7.154 mg, 53.65 mmol) were then added and stirred at reflux for 12 hours. After completion of the reaction, the temperature was lowered to room temperature, the organic layer was separated using dichloromethane and water, and then 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) -1H-indole-2 -Carboxylate (10.17 g, 25.64 mmol, 57%) was obtained.

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> Ethyl-6- Claw -1- (4- Chlorophenyl ) -3- (2,4- Dichlorobenzoyl Synthesis of) -1H-indole-2-carboxylate

In a 25 mL flask, with ethyl-6-chloro-3- (2,4-dichlorobenzoyl) -1H-indole-2-carboxylate (300 mg, 0.756 mmol) synthesized in <Step 3> above Dichloromethane (3 mL) was added and dissolved. Next, 4- (chlorophenyl) boronic acid (237 mg, 1.51 mmol), copper (II) acetate (275 mg, 1.51 mmol), triethylamine (153 mg, 1.51 mmol) were added thereto, and stirred for 12 hours. I was. After the reaction was completed, the organic layer was separated using dichloromethane and 2N-HCl, and then 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-chloro-1- (4-chlorophenyl) -3- (2,4-di Chlorobenzoyl) -1H-indole-2-carboxylate was obtained.

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

In a 25 mL flask, ethyl-6-chloro-1- (4-chlorophenyl) -3- (2,4-dichlorobenzoyl) -1H-indole-2-car synthesized in step 4 above. A carboxylate (165 mg, 0.325 mmol) was added and dissolved by addition of tetrahydrofuran (1 mL) and methanol (1 mL). Next, sodium hydroxide (65 mg, 1.63 mmol) dissolved in water (1 mL) was added and then stirred for 1 hour. After the reaction was completed, the mixture was concentrated and adjusted to pH 5 using 2N-HCl. Thereafter, the organic layer was separated using ethyl acetate and water, and then 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- (2,4-dichloro Orobenzoyl) -1H-indole-2-carboxylic acid (120 mg, 0.250 mmol, 77%) was obtained.

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).

[[ 실시예Example 47] 6- 47] 6- 클로오로Claw -3-(3--3- (3- 클로오로벤조일Chlorobenzoyl )-1-(4-) -1- (4- 클로오로페닐Chlorophenyl )-1H-인돌-2-카르복실릭 ) -1H-indole-2-carboxylic 엑시드의Exsidic 합성 synthesis

<Step 1> (E) -ethyl-2- (2- (3- Chlorophenyl ) Hydrazono ) Propanoate synthesis

Into a 2 L flask add purified distilled water (520 ml). After dissolving sodium acetate (50 g, 0.6 mol) in the flask, (3-chlorophenyl) hydrazine hydrochloride (52 g, 0.3 mol) was added thereto, stirred at room temperature for 30 minutes, and then ethyl 2-oxopropanoate. (35 ml, 0.3 mol) was slowly added and stirred for 6 hours. After the reaction was completed, the mixture was filtered through a vacuum filter and then dried. To a 3 L flask, dried solid and 2 L of normal hexane were added and stirred for 1 hour, followed by filtration to obtain (E) -ethyl-2- (2- (3-chlorophenyl) hydrazono) propanoate (57 g, 0.24 mol, 81%).

Step 2 Synthesis of Ethyl-6-Chloro-1H-indole-2-carboxylate

Toluene (110 ml) was added to a 500 ml flask and (E) -ethyl-2- (2- (3-chlorophenyl) hydrazono) propanoate (10.6 g, 0.044) synthesized in <Step 1> was used. mol) was added. Next, polyphosphoric acid (52 g) was added thereto, followed by reflux for 6 hours. After the reaction was completed, the mixture was cooled to 50 DEG C, and only the toluene layer was 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%).

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

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

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 Hz, 1H), 7.29 (d, J = 8.8 Hz, 2H), 7.20 (dd, J = 2,0, 12.8 Hz, 1H), 4.13 (q, J = 7.2 Hz, 2H), 0.91 (t, J = 7.2 Hz, 3H).

<Step 4> Ethyl-6- Claw -1- (3- Chlorophenyl ) -3- (4- (Trifluoromethoxy)) benzoyl Synthesis of) -1H-indole-2-carboxylate

In a 25 mL flask, ethyl-6-chloro-3- (4- (trifluoromethoxy) benzoyl) -1H-indole-2-carboxylate (170 mg, 0.41 mmol) synthesized in <Step 3> above ) And dichloromethane (1.7 mL) were added and dissolved. Next, 3- (chlorophenyl) boronic acid (129 mg, 0.82 mmol), copper (II) acetate (149 mg, 0.82 mmol), triethylamine (0.115 ml, 0.82 mmol) were added thereto, and stirred for 12 hours. . After the reaction was completed, the organic layer was separated using dichloromethane and 2N HCl, and then water contained in the organic layer was removed with magnesium sulfate. Then, after filtration, the mixture was purified by column chromatography (EA / n-Hex = 4: 1) to give ethyl-6-chloro-1- (3-chlorophenyl) -3- (4- (triflo Oromethoxy) benzoyl) -1H-indole-2-carboxylate (71.9 mg, 0.137 mmol, 33.34%) was obtained.

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- Claw -1- (3- Chlorophenyl ) -3- (4- (Trifluoromethoxy)) benzoyl ) -1H-indole-2-carboxylic Exsidic synthesis

In a 100 mL flask, ethyl-6-chloro-1- (3-chlorophenyl) -3- (4- (trifluoromethoxy) benzoyl) -1H-indole-2 synthesized in <Step 4> above -Carboxylate (71.9 mg, 0.137 mmol) was added and dissolved by addition of tetrahydrofuran (1 mL) and methanol (1 mL). Then 1N-sodium hydroxide (0.35 mL) was added and then stirred for 1 hour. After completion of the reaction, it was concentrated and adjusted to pH 5 using 2N-HCl. Thereafter, the organic layer was separated using ethyl acetate and water, and then 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- (3-chlorophenyl) -3- (4- (trifluoromethoxy ) Benzoyl) -1H-indole-2-carboxylic acid (31 mg, 0.06 mmol, 45.56%) was obtained.

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).

[[ 실시예Example 48] 6- 48] 6- 클로오로Claw -1-(4--1- (4- 클로오로페닐Chlorophenyl )-3-(4-() -3- (4- ( 트라이플로오로메톡시Trifluoromethoxy )) 벤조일Benzoyl )-1H-인돌-2-카르복실릭 ) -1H-indole-2-carboxylic 엑시드의Exsidic 합성 synthesis

A target compound was obtained in the same manner as in Example 48, except that (4-chlorophenyl) boronic acid was used instead of 3- (chlorophenyl) boronic acid used in <Step 4>. .

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).

[[ 실시예Example 49] 3- 49] 3- 벤조일Benzoyl -1-(4--1- (4- 클로오로페닐Chlorophenyl )-6-() -6- ( 트라이플로오로메틸Trifluoromethyl )-1H-인돌-2-카르복실릭 ) -1H-indole-2-carboxylic 엑시드의Exsidic 합성 synthesis

<Step 1> (E) -ethyl-2- (2- (3- Fluorophenyl ) Hydrazono ) Propanoate synthesis

In a 100 mL flask, (3- (trifluoromethyl) phenyl) hydrazine hydrochloride (25 g, 141.93 mmol) and ethanol (250 mL) were added and dissolved. Next, ethyl-2-oxopropanoate (24.7 g, 212.89 mmol) and acetic acid (5 mL) were added thereto, and the mixture was stirred under reflux 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 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 give (E) -ethyl-2- (2- (3-fluorophenyl) hydrazono) propanoate ( 26 g, 94.8 mmol, 66%).

Step 2 Synthesis of Ethyl-6- (trifluoromethyl) -1H-indole-2-carboxylate

Toluene (300 mL) was added to a 1000 mL flask, and (E) -ethyl-2- (2- (3- (trifluoromethyl) phenyl) hydrazono) propanoate synthesized in the above <Step 1> ( 26 g, 94.8 mmol) was added. Next, polyphosphoric acid (150 g) was added thereto, followed by a reflux reaction for 6 hours. After the reaction was completed, the mixture was cooled to 50 ° C., and only the toluene layer was separated. Toluene (50 mL) was added to the formed solid and refluxed for 1 hour, and then cooled to room temperature. The recrystallized solid was then filtered to give ethyl-6- (trifluoromethyl) -1H-indole-2-carboxylate (1.25 g, 4.86 mmol, 5%).

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

In a 250 mL flask, benzoic acid (1.63 g, 13.39 mmol) and acetonitrile (13 ml) were added and dissolved, followed by 85% phosphoric acid (0.29 ml, 5.15 mmol) and trifluoroacetic anhydride ( 7.27 ml, 51.51 mmol) was added and stirred for 10 minutes. Next, ethyl-6- (trifluoromethyl) -1H-indole-2-carboxylate (2.65 g, 10.30 mmol) synthesized in <Step 2> was added thereto, followed by stirring for 10 hours. After completion of the reaction, the organic layer was separated using ethyl acetate and water, and the organic layer was treated once more 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 give ethyl-3-benzoyl-6- (trifluoromethyl) -1H-indole-2-carboxylate (311 mg , 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> Ethyl-3- Benzoyl -1- (4- ( Chlorophenyl ) -6- ( Trifluoromethyl Synthesis of) -1H-indole-2-carboxylate

In a 25 mL flask, ethyl-3-benzoyl-6- (trifluoromethyl) -1H-indole-2-carboxylate (150 mg, 0.41 mmol) and dichloromethane (2) synthesized in step 3 were prepared. mL) was added and dissolved. Next, 4- (chlorophenyl) boronic acid (129.8 mg, 0.83 mmol), copper (II) acetate (150.8 mg, 0.83 mmol), triethylamine (116 μl, 0.83 mmol) are added, and for 12 hours Stirred. After the reaction was completed, the organic layer was separated using dichloromethane and 2N HCl, and then 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-3-benzoyl-1- (4- (chlorophenyl) -6- (trifluoromethyl) -1H-indole-2-carboxylate (31 mg, 0.06 mmol, 14.87%) was obtained.

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 ).

<Step 5> 3- Benzoyl -1- (4- Chlorophenyl ) -6- ( Trifluoromethyl ) -1H-indole-2-carboxylic Exsidic synthesis

In a 25 mL flask, ethyl-3-benzoyl-1- (4- (chlorophenyl) -6- (trifluoromethyl) -1H-indole-2-carboxylate synthesized in step <4> (92 mg, 0.46 mmol) was added and dissolved by addition of tetrahydrofuran (1 mL) and methanol (1 mL), then 1N sodium hydroxide (0.45 ml, 5 vol) was added and stirred for 1 hour. After completion of the reaction, the mixture was concentrated and adjusted to pH 5 using 2N-HCl, after which the organic layer was separated using ethyl acetate and water, and then 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) -1H-indole-2 -Carboxylic acid (31 mg, 0.069 mmol, 14.87%) was obtained.

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

[[ 실시예Example 50] 3- 50] 3- 벤조일Benzoyl -1-(3--1- (3- 클로오로페닐Chlorophenyl )-6-() -6- ( 트라이플로오로메틸Trifluoromethyl )-1H-인돌-2-카르복실릭 ) -1H-indole-2-carboxylic 엑시드의Exsidic 합성 synthesis

A target compound was obtained in the same manner as in Example 49, except for using (3-chlorophenyl) boronic acid instead of 4- (chlorophenyl) boronic acid used in <Step 4>. .

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

[[ 실시예Example 51] 1-(3- 51] 1- (3- 클로오로페닐Chlorophenyl )-3-(4-) -3- (4- 클로오로벤조일Chlorobenzoyl )-1H-인돌-2-) -1H-indole-2- 카르복실릭Carboxylic 엑시드의Exsidic 합성 synthesis

Step 1 Synthesis of Ethyl-3- (4-methoxybenzoyl) -1H-indole-2-carboxylate

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) were added and stirred at reflux for 12 hours. After completion of the reaction, the temperature was lowered to room temperature, the organic layer was separated using dichloromethane and water, and then water contained in the organic layer was removed with magnesium sulfate. After filtration, the mixture was then purified by column chromatography (EA / n-Hex = 6: 1) to give ethyl-3- (4-methoxybenzoyl) -1H-indole-2-carboxylate (0.9 g, 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).

<Step 2> Ethyl-1- (3- Chlorophenyl ) -3- (4- Chlorobenzoyl ) -1H-indole-2- Carboxylate synthesis

In a 25 mL flask, ethyl-3- (4-chlorobenzoyl) -1H-indole-2-carboxylate (150 mg, 0.458 mmol) and dichloromethane (1.5 mL) synthesized in <Step 1> above were used. Was added and dissolved. Then (3-chlorophenyl) boronic acid (71.6 mg, 0.458 mmol), copper (II) acetate (166.4 mg, 0.916 mmol), triethylamine (92.7 mg, 0.916 mmol) was added and for 12 hours Stirred. After completion of the reaction, the organic layer was separated using dichloromethane and water, and then water contained in the organic layer was removed with magnesium sulfate. Then, after filtration, the mixture was purified by column chromatography (EA / n-Hex = 4: 1) to give ethyl-1- (3-chlorophenyl) -3- (4-chlorobenzoyl) -1H-indole 2-carboxylate (70 mg, 0.16 mmol, 35%) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) 7.88 (d, J = 8.8 Hz, 2H), 7.75 (d, J = 8 Hz, 1H), 7.50 (d, J = 6 Hz, 2H), 7.46 (dd, J = 8.4 Hz, 3H), 7.37 (t, 1H), 7.27 (d, J = 8 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 3.89-3.83 (q, 2H), 0.86-0.83 (t, J = 7.2 Hz, 3H).

<Step 3> 1- (3- Chlorophenyl ) -3- (4- Chlorobenzoyl ) -1H-indole-2- Carboxylic EXID

In 100 mL flask, ethyl-1- (3-chlorophenyl) -3- (4-chlorobenzoyl) -1H-indole-2-carboxylate (70 mg, 0.16 mmol) synthesized in <Step 2> above ) Was added and dissolved by addition of tetrahydrofuran (0.7 mL) and methanol (0.7 mL). Next, 4N-sodium hydroxide aqueous solution (0.35 mL) was added, followed by stirring for 1 hour. After completion of the reaction, it was concentrated and adjusted to pH 5 using 2N-HCl. Thereafter, the organic layer was separated using ethyl acetate and water, and then 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-chlorobenzoyl) -1H-indole- 2-carboxylic acid (38 mg, 0.093 mmol, 58%) was obtained.

¹ H NMR (400 MHz, DMSO-d ₆ ) 7.81 (d, J = 8.8 Hz, 2H), 7.68 (d, J = 8 Hz, 1H), 7.43 (d, J = 6 Hz, 2H), 7.38 (d , J = 8.4 Hz, 3H), 7.30 (t, 1H), 7.26 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 8 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H ).

[[ 실시예Example 52] 3-(4- 52] 3- (4- 클로오로벤조일Chlorobenzoyl )-1-(3-) -1- (3- 메톡시페닐Methoxyphenyl )-1H-인돌-2-) -1H-indole-2- 카르복실릭Carboxylic 엑시드의 합성 Synthesis of Exid

A target compound was obtained in the same manner as in Example 51, except for using (3-methoxyphenyl) boronic acid instead of (3-chlorophenyl) boronic acid used in <Step 2>. .

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- 7.74 (t, 1H), 7.38-7.36 (t, 1H), 7.28-7.25 (t, 1H), 7.21 (d, J = 8.4 Hz, 1H), 7.13 (dd, J = 1.6, 8.4 Hz, 1H) , 7.08 (s, 1 H), 7.06 (d, J = 8.4 Hz, 1 H), 3.81 (s, 3 H).

[[ 실시예Example 53] 1-(3- 53] 1- (3- 클로오로페닐Chlorophenyl )-3-(4-) -3- (4- 메톡시벤조일Methoxybenzoyl )-1H-인돌-2-) -1H-indole-2- 카르복실릭Carboxylic 엑시드의 합성 Synthesis of Exid

Step 1 Synthesis of Ethyl-3- (4-methoxybenzoyl) -1H-indole-2-carboxylate

In a 25 mL flask, ethyl-1H-indole-2-carboxylate (1 g, 5.29 mmol) and dichloroethane (10 mL) were added and dissolved. Then 4-methoxybenzoyl chloride (0.9 g, 5.29 mmol), aluminum chloride (2.82 g, 10.58 mmol) were added and stirred at reflux for 12 hours. After completion of the reaction, the temperature was lowered to room temperature, the organic layer was separated using dichloromethane and water, and then water contained in the organic layer was removed with magnesium sulfate. After filtration, the mixture was then purified by column chromatography (EA / n-Hex = 6: 1) to give ethyl-3- (4-methoxybenzoyl) -1H-indole-2-carboxylate (0.9 g, 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, 1H), 7.38 (t, J = 7.4 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 6.93 (d, J = 9.2 Hz, 2H), 4.13-4.08 (q, J = 7.2 Hz, 2H), 3.87 (s, 3H), 0.97-0.94 (t, J = 7.2 Hz, 3H).

<Step 2> Ethyl-1- (3- Chlorophenyl ) -3- (4- Methoxybenzoyl ) -1H-indole-2- Carboxylate synthesis

In a 25 mL flask, ethyl-3- (4-methoxybenzoyl) -1H-indole-2-carboxylate (150 mg, 0.464 mmol) and dichloromethane (1.5 mL) synthesized in <Step 1> were used. Was added and dissolved. Next, (3-chlorophenyl) boronic acid (72.5 mg, 0.46 mmol), copper (II) acetate (168.6 mg, 0.93 mmol), triethylamine (93.9 mg, 0.93 mmol) are added and for 12 hours Stirred. After completion of the reaction, the organic layer was separated using dichloromethane and water, and then water contained in the organic layer was removed with magnesium sulfate. Then, after filtration, the mixture was purified by column chromatography (EA / n-Hex = 4: 1) to give ethyl-1- (3-chlorophenyl) -3- (4-methoxybenzoyl) -1H-indole 2-carboxylate (86 mg, 0.198 mmol, 42.8%) was obtained.

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, 1H), 7.12 (d, 2H), 6.94 (d, J = 6.8 Hz, 2H) , 3.88-3.85 (q, J = 7.2 Hz, 2H), 3.85 (s, 3H), 0.85-0.82 (t, J = 7.2 Hz, 3H).

<Step 3> 1- (3- Chlorophenyl ) -3- (4- Methoxybenzoyl ) -1H-indole-2- Carboxylic Exsidic synthesis

In a 100 mL flask, ethyl-1- (3-chlorophenyl) -3- (4-methoxybenzoyl) -1H-indole-2-carboxylate (86 mg, 0.19 mmol) synthesized in <Step 2> above ) Was added and dissolved by addition of tetrahydrofuran (0.86 mL) and methanol (0.86 mL). Next, an aqueous 4N-sodium hydroxide solution (0.43 mL) was added and stirred for 1 hour. After completion of the reaction, it was concentrated and adjusted to pH 5 using 2N-HCl. Thereafter, the organic layer was separated using ethyl acetate and water, and then 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) -1H-indole- 2-carboxylic acid (39 mg, 0.096 mmol, 52.2%) was obtained.

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 , 2H), 7.27 (d, J = 6.4 Hz, 2H), 7.23 (dd, J = 8.4 Hz, 1H), 7.15 (t, J = 8 Hz, 1H), 7.03 (d, 2H), 6.85 (d , J = 6.8 Hz, 2H) 3.85 (s, 3H).

[[ 실시예Example 54] 1-(4-( 54] 1- (4- ( 터트Tert -- 뷰틸Butyl )페닐)-3-(4-) Phenyl) -3- (4- 메톡시벤조일Methoxybenzoyl )-1H-인돌-2-) -1H-indole-2- 카르복실릭Carboxylic 엑시드의Exsidic 합성 synthesis

The same procedure as in Example 53 was carried out except for using (4- (tert-butyl) phenyl) boronic acid instead of (3-chlorophenyl) boronic acid used in <Step 2>. The compound was obtained.

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 Hz, 1H), 7.41 (d, J = 8.0 Hz, 2H), 7.33 (t, 1H), 7.23 (t, 1H), 7.14 (d, J = 8.4 Hz, 1H), 7.06 (d, J = 8.8 Hz, 2H), 3.84 (s, 3H), 1.36 (s, 9H).

[[ 실시예Example 55] 3- 55] 3- 벤조일Benzoyl -6--6- 플로오로Floro -1-(4-(-1- (4- ( 메틸싸이오Methylthio )페닐)-1H-인돌-2-) Phenyl) -1H-indole-2- 카르복실릭Carboxylic 엑시드의Exsidic 합성 synthesis

<Step 1> (E) -ethyl-2- (2- (3- Fluorophenyl ) Hydrazono ) Propanoate synthesis

In a 1000 mL flask, (3-fluorophenyl) hydrazine hydrochloride (25 g, 153.75 mmol) and ethanol (250 mL) were added and dissolved. Next, ethyl 2-oxopropanoate (26.8 g, 230.62 mmol) and acetic acid (5 mL) were added and stirred at reflux 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 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 (E) -ethyl-2- (2- (3-fluorophenyl) hydrazono) propanoate (22.5 g, 100.34 mmol, 65%) was obtained.

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).

Step 2 Synthesis of Ethyl-6-Fluoro-1H-indole-2-carboxylate

Toluene (200 mL) was added to a 500 mL flask, and (E) -ethyl-2- (2- (3-fluorophenyl) hydrazono) propanoate (22.5 g, 100.34) synthesized in Step 1 was used. mmol) was added. Next, polyphosphoric acid (120 g) was added thereto, followed by a reflux reaction for 6 hours. After the reaction was completed, the mixture was cooled to 50 ° C., and only the toluene layer was separated, and the separated toluene layer was concentrated under reduced pressure. Next, toluene (50 mL) was added to the formed solid, and refluxed for 1 hour, and then cooled to room temperature. The recrystallized solid was then filtered to afford ethyl-6-fluoro-1H-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-fluoro-1H-indole-2-carboxylate

In a 500 mL flask, ethyl-6-fluoro-1H-indole-2-carboxylate (10 g, 48.26 mmol) and dichloroethane (150 mL) synthesized in <Step 2> were added and dissolved. Benzoyl chloride (8.14 g, 57.91 mmol) and aluminum chloride (7.72 g, 57.91 mmol) were then added and stirred at reflux for 12 hours. After completion of the reaction, the temperature was lowered to room temperature, the organic layer was separated using dichloromethane and water, and then 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-benzoyl-6-fluoro-1H-indole-2-carboxylate (12 g, 38.54 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 (t, J = 8.0 Hz, 2H), 7.16 (dd, J = 2.4, 9.2 Hz, 1H), 7.02-6.95 (m, 1H), 4.07-4.02 (m, 2H), 0.90-0.85 (m, 3H ).

<Step 4> Ethyl-3- Benzoyl -6- Floro -1- (4- ( Methylthio ) Phenyl-1H-indole-2- Carboxylate synthesis

Into a 25 mL flask, add ethyl-3-benzoyl-6-fluoro-1H-indole-2-carboxylate (150 mg, 0.48 mmol) and dichloromethane (2 mL) synthesized in step 3. Dissolved. Next, (4-methylthiophenyl) boronic acid (162 mg, 0.96 mmol), copper (II) acetate (175 mg, 0.96 mmol), triethylamine (134 μl, 0.96 mmol) were added and 12 hours Was stirred. After the reaction was completed, the organic layer was separated using dichloromethane and 2N-HCl, and then 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 purify ethyl-3-benzoyl-6-fluoro-1- (4- (methylthio) phenyl-1H-indole 2-carboxylate (110 mg, 0.25 mmol, 52.66%) was obtained.

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), 2.54 (s, 3H), 0.773 (t, J = 7.2 Hz, 3H).

<Step 5> 3- Benzoyl -6- Floro -1- (4- ( Methylthio ) Phenyl) -1H-indole-2- Carboxylic Exsidic synthesis

In a 25 mL flask, ethyl-3-benzoyl-6-fluoro-1- (4- (methylthio) phenyl-1H-indole-2-carboxylate (110 mg, 0.25) synthesized in <Step 4> above mmol) was added and dissolved by addition of tetrahydrofuran (1 mL) and methanol (1 mL), then 1N sodium hydroxide (0.55 ml, 5 vol) was added and stirred for 1 hour. The mixture was concentrated and adjusted to pH 5 using 2N-HCl, after which the organic layer was separated using ethyl acetate and water, and then the water contained in the organic layer was removed with magnesium sulfate, and then the mixture was filtered. Purification by chromatography (MeOH / CH ₂ Cl ₂ = 1: 9) gave 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, 1H), 2.55 (s, 3H).

[[ 실시예Example 56] 3- 56] 3- 벤조일Benzoyl -1-(3-(-1- (3- ( 메틸싸이오Methylthio )페닐)-6-() Phenyl) -6- ( 트라이플로오로메틸Trifluoromethyl )-1H-인돌-2-카르복실릭 ) -1H-indole-2-carboxylic 엑시드의Exsidic 합성 synthesis

The same procedure as in Example 55 was carried out except that (3-methylthiophenyl) boronic acid was used instead of (4-methylthiophenyl) boronic acid used in <Step 4>. Got.

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), 2.51 (s, 3H ).

[[ 실시예Example 57] 3- 57] 3- 벤조일Benzoyl -6--6- 플로오로Floro -1-(4--1- (4- 플로오로페닐Fluorophenyl )-1H-인돌-2-) -1H-indole-2- 카르복실릭Carboxylic 엑시드의 합성 Synthesis of Exid

A target compound was obtained in the same manner as in Example 55 except for using (4-fluorophenyl) boronic acid instead of (4-methylthiophenyl) boronic acid used in <Step 4>. .

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, 1H), 6.90 (dd, J = 2.4, 9.6 Hz, 1H).

[[ 실시예Example 58] 3-(4- 58] 3- (4- 클로오로벤조일Chlorobenzoyl )-6-) -6- 플로오로Floro -1-(4-(-1- (4- ( 메틸싸이오Methylthio )페닐)-1H-인돌-2-카르복실릭 엑시드의 합성Synthesis of Phenyl) -1H-indole-2-carboxylic Acid

<Step 1> (E) -ethyl-2- (2- (3- Fluorophenyl ) Hydrazono ) Propanoate synthesis

In a 1000 mL flask, (3-fluorophenyl) hydrazine hydrochloride (25 g, 153.75 mmol) and ethanol (250 mL) were added and dissolved. Next, ethyl 2-oxopropanoate (26.8 g, 230.62 mmol) and acetic acid (5 mL) were added and stirred at reflux 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 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 (E) -ethyl-2- (2- (3-fluorophenyl) hydrazono) propanoate ( 22.5 g, 100.34 mmol, 65%).

Step 2 Synthesis of Ethyl-6-Fluoro-1H-indole-2-carboxylate

Toluene (200 mL) was added to a 500 mL flask, and (E) -ethyl-2- (2- (3-fluorophenyl) hydrazono) propanoate (22.5 g, 100.34) synthesized in Step 1 was used. mmol) was added. Next, polyphosphoric acid (120 g) was added thereto, followed by a reflux reaction for 6 hours. After the reaction was completed, the mixture was cooled to 50 ° C, and only the toluene layer was separated, and the separated toluene layer was concentrated under reduced pressure. Next, toluene (50 mL) was added to the formed solid, and refluxed for 1 hour, and then cooled to room temperature. The recrystallized solid was then filtered to afford ethyl-6-fluoro-1H-indole-2-carboxylate (7.2 g, 34.7 mmol, 34%).

<Step 3> Ethyl-3- (4- Chlorobenzoyl ) -6- Floro -1H-indole-2- Carboxylate synthesis

In a 250 mL flask, ethyl-6-fluoro-1H-indole-2-carboxylate (5 g, 22.3 mmol) and dichloroethane (50 mL) synthesized in <Step 2> were added and dissolved. 4-chlorobenzoyl chloride (4.7 g, 26.8 mmol) and aluminum chloride (3.6 g, 26.8 mmol) were then added and stirred at reflux for 12 hours. After completion of the reaction, the temperature was lowered to room temperature, the organic layer was separated using dichloromethane and water, and then 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-2-carboxylate. (4.5 g, 12.4 mmol, 55.6%) was obtained.

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> Ethyl-3- (4- Chlorobenzoyl ) -6- Floro -1- (4- Methylthio Synthesis of Phenyl) -1H-indole-2-carboxylate

In a 25 mL flask, ethyl-3- (4-chlorobenzoyl) -6-fluoro-1H-indole-2-carboxylate (200 mg, 0.41 mmol) synthesized in step <3> and dichloro 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), triethylamine (0.161 ml, 1.157 mmol) was added and 12 h Was stirred. After the reaction was completed, the organic layer was separated using dichloromethane and 2N-HCl, and then 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-3- (4-chlorobenzoyl) -6-fluoro-1- (4-methylthio ) Phenyl) -1H-indole-2-carboxylate (97 mg, 0.207 mmol, 20.72%) was obtained.

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 , 1H), 6.83 (dd, J = 1.5, 9.2 Hz, 1H), 3.84 (q, J = 7.2 Hz, 2H), 0.84 (t, J = 7.2 Hz, 3H).

<Step 5> 3- (4- Chlorobenzoyl ) -6- Floro -1- (4- ( Methylthio ) Phenyl) -1H-indole-2-carboxylic Exsidic synthesis

In a 100 mL flask, ethyl-3- (4-chlorobenzoyl) -6-fluoro-1- (4-methylthio) phenyl) -1H-indole-2-carboxyl synthesized in step <4> above. Rate (97 mg, 0.207 mmol) was added and dissolved by addition of tetrahydrofuran (1 mL) and methanol (1 mL). Then 1N-sodium hydroxide (0.045 mL) was added and stirred for 1 hour. After completion of the reaction, it was concentrated and adjusted to pH 5 using 2N-HCl. Thereafter, the organic layer was separated using ethyl acetate and water, and then 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- (4-chlorobenzoyl) -6-fluoro-1- (4- (methylthio). ) Phenyl) -1H-indole-2-carboxylic acid (48 mg, 0.109 mmol, 52.64%) was obtained.

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).

[[ 실시예Example 59] 3-(4- 59] 3- (4- 클로오로벤조일Chlorobenzoyl )-6-) -6- 플로오로Floro -1-(4-(-1- (4- ( 트라이플로오로메톡시Trifluoromethoxy )페닐)-1H-인돌-2-카르복실릭 ) Phenyl) -1H-indole-2-carboxylic 엑시드의Exsidic 합성 synthesis

The same procedure as in Example 58 was performed except for using (4-trifluoromethoxyphenyl) boronic acid instead of (4-methylthiophenyl) boronic acid used in <Step 4>. The desired compound was obtained.

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).

[[ 실시예Example 60] 3-(4- 60] 3- (4- 클로오로벤조일Chlorobenzoyl )-6-) -6- 플로오로Floro -1-(3--1- (3- 메틸싸이오Methylthio )페닐)-1H-인돌-2-카르복실릭 ) Phenyl) -1H-indole-2-carboxylic 엑시드의Exsidic 합성 synthesis

The same procedure as in Example 58 was carried out except that (3-methylthiophenyl) boronic acid was used instead of (4-methylthiophenyl) boronic acid used in <Step 4>. Got.

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 , 1H), 7.06 (t, J = 2.0 Hz, 1H), 6.85 (d, J = 2.0 Hz, 1H), 2.51 (s, 3H).

[[ 실시예Example 61] 6- 61] 6- 플로오로Floro -1-(4--1- (4- 플로오로페닐Fluorophenyl )-3-(4-) -3- (4- 메톡시벤조일Methoxybenzoyl )-1H-인돌-2-카르복실릭 ) -1H-indole-2-carboxylic 엑시드의Exsidic 합성 synthesis

<Step 1> (E) -ethyl-2- (2- (3- Fluorophenyl ) Hydrazono ) Propanoate synthesis

(3-fluorophenyl) hydrazine hydrochloride (25 g, 153.75 mmol) and ethanol (250 mL) were added and dissolved in a 1000 mL flask. Then ethyl-2-oxopropanoate (26.8 g, 230.62 mmol) and acetic acid (5 mL) were added and stirred at reflux 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 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 (E) -ethyl-2- (2- (3-fluorophenyl) hydrazono) propanoate ( 22.5 g, 100.34 mmol, 65%).

Step 2 Synthesis of Ethyl-6-Fluoro-1H-indole-2-carboxylate Compound

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

Into a 100 mL flask was dissolved (4-methoxybenzoic) exit (976 mg, 6.41 mmol) and acetonitrile (11 mL), followed by 85% phosphoric acid (0.125 mL, 6.41 mmol) and trifluoride. Loacetic anhydride (3 mL, 21.39 mmol) was added and stirred for 10 minutes. Next, ethyl-6-fluoro-1H-indole-2-carboxylate (1.1 g, 4.28 mmol) synthesized in <Step 2> was added thereto, followed by stirring for 10 hours. After completion of the reaction, the organic layer was separated using ethyl acetate and water, and the organic layer was treated with saturated sodium hydrogencarbonate and sodium chloride once more, and then water 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-3- (4-methoxybenzoyl) -1H-indole-2-carboxyl. Obtained (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 , 1H), 6.98-6.90 (m, 3H), 4.15-4.09 (m, 2H), 3.87 (s, 3H), 0.98-0.94 (m, 3H).

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

In a 25 mL flask, ethyl-6-fluoro-3- (4-methoxybenzoyl) -1H-indole-2-carboxylate (150 mg, 0.44 mmol) synthesized in <Step 3> and dichloro Methane (2 mL) was added and dissolved. Next, (4-fluorophenyl) boronic acid (92 mg, 0.66 mmol), copper (II) acetate (160 mg, 0.88 mmol), triethylamine (89 mg, 0.88 mmol) were added, and for 12 hours Stirred. After the reaction was completed, the organic layer was separated using dichloromethane and water, and then 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%) was obtained.

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 (m, 5H), 0.88- 0.80 (m, 3 H).

<Step 5> 6- Floro -1- (4- Fluorophenyl ) -3- (4- Methoxybenzoyl ) -1H-indole-2- Carboxylic Exsidic synthesis

In a 25 mL flask, ethyl-6-fluoro-1- (4-fluorophenyl) -3- (4-methoxybenzoyl) -1H-indole-2-carboxylate synthesized in step <4> ( 100 mg, 0.23 mmol) was added and dissolved by addition of tetrahydrofuran (1 mL) and methanol (1 mL). Next, sodium hydroxide (46 mg, 1.15 mmol) dissolved in water (1 mL) was added and stirred for 1 hour. After completion of the reaction, it was concentrated and adjusted to pH 5 using 2N-HCl. Thereafter, the organic layer was separated using ethyl acetate and water, and then 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-fluoro-1- (4-fluorophenyl) -3- (4-methoxybenzoyl) -1H-indole-2-carboxylic acid (81.5 mg, 0.20 mmol, 87%) was obtained.

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, 3 H).

[[ 실시예Example 62] 1-(3- 62] 1- (3- 플로오로페닐Fluorophenyl )-6-) -6- 플로오로Floro -3-(4--3- (4- 메톡시벤조일Methoxybenzoyl )-1H-인돌-2-카르복실릭 ) -1H-indole-2-carboxylic 엑시드의Exsidic 합성 synthesis

A target compound was obtained in the same manner as in Example 61, except that (3-fluorophenyl) boronic acid was used instead of (4-fluorophenyl) boronic acid used in <Step 4>. .

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).

[[ 실시예Example 63] 1-(3- 63] 1- (3- 클로오로페닐Chlorophenyl )-6-) -6- 플로오로Floro -3-(4--3- (4- 메톡시벤조일Methoxybenzoyl )-1H-인돌-2-카르복실릭 ) -1H-indole-2-carboxylic 엑시드의Exsidic 합성 synthesis

A target compound was obtained by the same procedure as in Example 61, except that (3-chlorophenyl) boronic acid was used instead of (4-fluorophenyl) boronic acid used in <Step 4>. It was.

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 (s, 1H) 7.25 (d, J = 6.8 Hz, 2H) 7.15 (d, J = 11.6 Hz, 1H)

[[ 실시예Example 64] 3-(3- 64] 3- (3- 클로오로벤조일Chlorobenzoyl )-6-) -6- 플로오로Floro -1-(P--1- (P- 톨루일Toluyl )-1H-인돌-2-) -1H-indole-2- 카르복실릭Carboxylic 엑시드의Exsidic 합성 synthesis

<Step 1> (E) -ethyl-2- (2- (3- Fluorophenyl ) Hydrazono ) Propanoate synthesis

In a 1000 mL flask, (3-fluorophenyl) hydrazine hydrochloride (25 g, 153.75 mmol) and ethanol (250 mL) were added and dissolved. Next, ethyl 2-oxopropanoate (26.8 g, 230.62 mmol) and acetic acid (5 mL) were added and stirred at reflux for 5 hours. After the completion of the reaction, the mixture was concentrated under reduced pressure, and the organic layer was separated using ethyl acetate and water, and then 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 (E) -ethyl-2- (2- (3-fluorophenyl) hydrazono) propanoate (22.5 g, 100.34 mmol, 65%) was obtained.

Step 2 Synthesis of Ethyl-6-Fluoro-1H-indole-2-carboxylate

<Step 3> Ethyl-3- (3- Chlorobenzoyl ) -6- Floro -1H-indole-2- Carboxylate synthesis

In a 500 mL flask, ethyl-6-fluoro-1H-indole-2-carboxylate (10 g, 48.26 mmol) and dichloroethane (150 mL) synthesized in <Step 2> were added and dissolved. 3-chlorobenzoyl chloride (10.1 g, 57.91 mmol) and aluminum chloride (7.72 g, 57.91 mmol) were then added and stirred at reflux for 12 hours. After completion of the reaction, the temperature was lowered to room temperature, the organic layer was separated using dichloromethane and water, and then 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-2-carboxyl. Obtained (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, 1H), 7.38 (t, J = 8.0 Hz, 1H), 7.16 (dd, J = 2.4, 9.2 Hz, 1H), 7.04-6.99 (m, 1H), 4.12-4.06 ( m, 2H), 0.95-0.92 (m, 3H).

<Step 4> Ethyl-3- (3- Chlorobenzoyl ) -6- Floro -1- (P- Toluyl ) -1H-indole-2- Carboxylate synthesis

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

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> 3- (3- Chlorobenzoyl ) -6- Floro -1- (para- Toluyl ) -1H-indole-2- Carboxylic Exsidic synthesis

In a 25 mL flask, ethyl-3- (3-chlorobenzoyl) -6-fluoro-1- (P-toluyl) -1H-indole-2-carboxylate (98 mg, 0.224 mmol) was added and dissolved by addition of 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, it was concentrated and adjusted to pH 5 using 2N-HCl. Thereafter, the organic layer was separated using ethyl acetate and water, and then 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-toluyl) -1H. -Indole-2-carboxylic acid (38 mg, 0.093 mmol, 41.44%) was obtained.

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).

[[ 실시예Example 65] 1-(4- 65] 1- (4- 터트Tert -- 뷰틸Butyl )페닐-3-(3-) Phenyl-3- (3- 클로오로벤조일Chlorobenzoyl )-6-) -6- 플로오로Floro -1H-인돌-2-카르복실릭 -1H-indole-2-carboxylic 엑시드의Exsidic 합성 synthesis

Except for using (4- (tert-butyl) phenyl) boronic acid used in place of (3-methylphenyl) boronic acid used in <step 4> the same procedure as in Example 64 was carried out Got it.

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).

[[ 실시예Example 66] 3-(3- 66] 3- (3- 클로오로벤조일Chlorobenzoyl )-6-) -6- 플로오로Floro -1-(-One-( 메타Meta -- 톨루일Toluyl )-1H-인돌-2-카르복실릭 ) -1H-indole-2-carboxylic 엑시드의Exsidic 합성 synthesis

The target compound was obtained in the same manner as in Example 64, except that (meth-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 (d, J = 8.0 Hz, 1H), 7.16 (dt, J = 2.0, 9.2 Hz, 1H), 6.89 (dd , J = 2.0, 9.6 Hz, 1H), 2.39 (s, 3H).

[[ 실시예Example 67] 3-(3- 67] 3- (3- 클로오로벤조일Chlorobenzoyl )-6-) -6- 플로오로Floro -1-(4--1- (4- 메톡시페닐Methoxyphenyl )-1H-인돌-2-카르복실릭 ) -1H-indole-2-carboxylic 엑시드의Exsidic 합성 synthesis

The target compound was obtained in the same manner as in Example 64, 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).

[[ 실시예Example 68] 668] 6 -- 클로오로Claw -1-(4--1- (4- 클로오로페닐Chlorophenyl )-3-((4-) -3-((4- 클로오로페닐Chlorophenyl )() ( 하이드록시이미노Hydroxyimino )메틸)-1H-인돌-2-카르복실릭 Methyl) -1H-indole-2-carboxylic 엑시드의Exsidic 합성 synthesis

<Step 1> (E) -ethyl-2- (2- (3- Chlorophenyl ) Hydrazono ) Propanoate synthesis

Step 2 Synthesis of Ethyl-6-Chloro-1H-indole-2-carboxylate

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

<Step 3> Ethyl-6- Claw -3- (4- Chlorobenzoyl ) -1H-indole-2- Carboxylate synthesis

Into a 100 mL flask was dissolved by adding ethyl-6-chloro-1H-indole-2-carboxylate (1 g, 4.47 mmol) and dichloromethane (10 mL) synthesized in <Step 2>. , 4-chlorobenzoyl chloride (939 mg, 5.36 mmol) and aluminum chloride (714 mg, 5.36 mmol) were added and stirred at reflux for 12 hours. After completion of the reaction, the temperature was lowered to room temperature, the organic layer was separated using dichloromethane and water, and then 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- (4-chlorobenzoyl) -1H-indole-2-carboxyl. Obtained the rate (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).

Into a 25 mL flask was added with ethyl-6-chloro-1H-indole-2-carboxylate (40 mg, 0.122 mmol) and dichloromethane (1 mL) synthesized in <Step 3>. Next, 4- (chlorophenyl) boronic acid (39 mg, 0.246 mmol), copper (II) acetate (34 mg, 0.185 mmol), triethylamine (25 mg, 0.246 mmol) are added and for 12 hours Stirred. After completion of the reaction, the organic layer was separated using dichloromethane and water, and then 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-chloro-3- (4-chlorobenzoyl) -1- (4-chlorophenyl ) -1H-indole-2-carboxylate (34 mg, 0.072 mmol, 60%) was obtained.

In a 25 mL flask, ethyl-6-chloro-3- (4-chlorobenzoyl) -1- (4-chlorophenyl) -1H-indole-2-carboxylate ( 34 mg, 0.072 mmol) was added and dissolved by addition of tetrahydrofuran (0.5 mL) and methanol (0.5 mL). Next, sodium hydroxide (15 mg, 0.36 mmol) dissolved in water (0.5 mL) was added and then stirred for 1 hour. After completion of the reaction, it was concentrated and adjusted to pH 5 using 2N-HCl. Thereafter, the organic layer was separated using ethyl acetate and water, and then 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%) was obtained.

<Step 6> 6- Claw -1- (4- Chlorophenyl ) -3-((4- Chlorophenyl ) ( Hydroxyimino Methyl) -1H-indole-2-carboxylic Exsidic synthesis

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

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, 1H), 7.13 (s, 1H).

[[ 실시예Example 69] 6- 69] 6- 클로오로Claw -1-(4--1- (4- 클로오로페닐Chlorophenyl )-3-((4-) -3-((4- 클로오로페닐Chlorophenyl )() ( 메톡시이미노Methoxyimino )메틸)-1H-인돌-2-카르복실릭 Methyl) -1H-indole-2-carboxylic 엑시드의Exsidic 합성 synthesis

<Step 1> (E) -ethyl-2- (2- (3- Chlorophenyl ) Hydrazono ) Propanoate synthesis

Into a 2 L flask add purified distilled water (520 ml). After dissolving sodium acetate (50 g, 0.6 mol) in the flask, (3-chlorophenyl) hydrazine hydrochloride (52 g, 0.3 mol) was added thereto, stirred at room temperature for 30 minutes, and then ethyl-2-oxopropano. Add slowly (35 ml, 0.3 mol) and stir for 6 hours. After the reaction was completed, the mixture was filtered through a vacuum filter and then dried. To a 3 L flask, dried solid and 2 L of normal hexane were added and stirred for 1 hour, followed by filtration to obtain (E) -ethyl-2- (2- (3-chlorophenyl) hydrazono) propanoate (57 g , 0.24 mol, 81%).

Step 2 Synthesis of Ethyl-6-Chloro-1H-indole-2-carboxylate

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

In a 100 mL flask, ethyl-6-chloro-1H-indole-2-carboxylate (1 g, 4.47 mmol) and dichloromethane (10 mL) synthesized in <Step 2> were added and dissolved. 4-chlorobenzoyl chloride (939 mg, 5.36 mmol) and aluminum chloride (714 mg, 5.36 mmol) were then added and stirred at reflux for 12 hours. After completion of the reaction, the temperature was lowered to room temperature, the organic layer was separated using dichloromethane and water, and then 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- (4-chlorobenzoyl) -1H-indole-2-carboxyl. Obtained the rate (843 mg, 2.32 mmol, 52%).

Ethyl-6-chloro-1H-indole-2-carboxylate (40 mg, 0.122 mmol) and dichloromethane (1 mL) synthesized in the above <Step 3> were added and dissolved in a 25 mL flask. Next, 4- (chlorophenyl) boronic acid (39 mg, 0.246 mmol), copper (II) acetate (34 mg, 0.185 mmol), triethylamine (25 mg, 0.246 mmol) are added and for 12 hours Stirred. After completion of the reaction, the organic layer was separated using dichloromethane and water, and then 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-chloro-3- (4-chlorobenzoyl) -1- (4-chlorophenyl ) -1H-indole-2-carboxylate (34 mg, 0.072 mmol, 60%) was obtained.

<Step 6> 6- Claw -1- (4- Chlorophenyl ) -3-((4- Chlorophenyl ) ( Methoxyimino Methyl) -1H-indole-2-carboxylic Exsidic synthesis

In a 5 mL flask, 6-chloro-3- (4-chlorobenzoyl) -1- (4-chlorophenyl) -1H-indole-2-carboxylic acid (30) synthesized in <Step 5> above (30) mg, 0.0675 mmol) and ethanol (0.5 ml) were added and dissolved. Next, methylhydroxylamine hydrochloride (8.5 mg, 0.1012 mmol) and sodium sulfate (19.2 mg, 0.1350 mmol) were added and stirred under reflux, and then the temperature was lowered to room temperature and the reaction solution was concentrated. The resulting reaction was diluted with water and the organic layer was separated using ethyl acetate, and then water contained in the organic layer was removed with magnesium sulfate. After filtration and distillation under reduced pressure, the mixture was purified by column chromatography (MC / MeOH / AcOH = 950: 50: 1) to give 6-chloro-1- (4-chlorophenyl) -3-((4 -Chlorophenyl) (methoxyimino) methyl) -1H-indole-2-carboxylic acid (15 mg, 0.0317 mmol, 46.9%) was obtained.

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, 1H), 7.22 (dd, J = 2.0, 8.8 Hz, 1H), 7.15 (s, 1H), 3.89 (s, 3H)

[[ 실시예Example 70] 6- 70] 6- 클로오로Claw -3-(4--3- (4- 클로오로벤조일Chlorobenzoyl )-1-(4-) -1- (4- 클로오로페닐Chlorophenyl )-1H-인돌-2-카르복실릭 ) -1H-indole-2-carboxylic 엑시드의Exsidic 합성 synthesis

<Step 1> (E) -ethyl-2- (2- (3- Chlorophenyl ) Hydrazono ) Propanoate synthesis

Into a 2 L flask add purified distilled water (520 ml). After dissolving sodium acetate (50 g, 0.6 mol) in the flask, (3-chlorophenyl) hydrazine hydrochloride (52 g, 0.3 mol) was added thereto, stirred at room temperature for 30 minutes, and then ethyl-2-oxopropano. Add slowly (35 ml, 0.3 mol) and stir for 6 hours. After the reaction was completed, the mixture was filtered through a vacuum filter and then dried. Into a 3 L flask, dried solid and 2 L of normal hexane were added, stirred for 1 hour, and filtered to give (E) -ethyl-2- (2- (3-chlorophenyl) hydrazono) propanoate (57 g, 0.24 mol, 81%).

Step 2 Synthesis of Ethyl-6-Chloro-1H-indole-2-carboxylate

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

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

Into a 250 mL flask was added ethyl-6-chloro-3- (4-chlorobenzoyl) -1H-indole-2-carboxylate (2 g, 6.10 mmol) synthesized in step <3>, followed by tetra 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, stirred for 15 minutes, and then 1- (bromomethyl) -4-chlorobenzene (1.5 g, 7.32 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 then water contained in the organic layer was removed with magnesium sulfate. Then, after filtration, the mixture was purified by column chromatography (EA / n-Hex = 4: 1) to give ethyl-6-chloro-3- (4-chlorobenzoyl) -1- (4-chlorobenzyl ) -1H-indole-2-carboxylate (1 g, 2.05 mmol, 45%) was obtained.

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 (m, 2H ), 7.22 (dd, J = 1.6, 8.8 Hz, 1H), 7.03 (d, J = 8.4 Hz, 2H), 5.7 (s, 2H), 3.90-3.84 (m, 2H), 0.88-0.83 (m, 3H).

<Step 5> 6- Claw -3- (4- Chlorobenzoyl ) -1- (4- Chlorophenyl Synthesis of) -1H-indole-2-carboxylic acid

In a 100 mL flask, ethyl-6-chloro-3- (4-chlorobenzoyl) -1- (4-chlorobenzyl) -1H-indole-2-carboxylate ( 1 g, 2.05 mmol) is added and dissolved by addition of tetrahydrofuran (5 mL) and methanol (5 mL). Next, sodium hydroxide (329 mg, 8.21 mmol) dissolved in water (5 mL) is added and then stirred for 1 hour. After the reaction was completed, the mixture was concentrated and adjusted to pH 5 using 2N-HCl. After separating the organic layer 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)- 1H-indole-2-carboxylic acid (1 g, 2.24 mmol, 77%) was obtained.

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).

[[ 실시예Example 71] 6- 71] 6- 클로오로Claw -3-(4--3- (4- 클로오로벤조일Chlorobenzoyl )-1-(3-메톡시벤질)-1H-인돌―카르복실릭 ) -1- (3-methoxybenzyl) -1H-indole-carboxylic 엑시드EXID 합성 synthesis

The same procedure as in Example 70 was carried out 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, 3 H), 5.70 (s, 2 H), 3.71 (s, 3 H).

[[ 실시예Example 72] 6- 72] 6- 클로오로Claw -3-(4--3- (4- 클로오로벤조일Chlorobenzoyl )-1-(2-) -1- (2- 클로오로벤질Chlorobenzyl )-1H-인돌-카르복실릭 ) -1H-indole-carboxylic 엑시드의Exsidic 합성 synthesis

The same procedure as in 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, 1H), 6.32 (d, J = 7.6 Hz, 1H).

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

The same procedure as in Example 70 was carried out except that 3- (bromomethyl) pyididine was used instead of 1- (bromomethyl) -4-chlorobenzene used in <Step 4>. Got.

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 -7.56 (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).

[[ 실시예Example 74] 6- 74] 6- 클로오로Claw -3-(4--3- (4- 클로오로벤조일Chlorobenzoyl )-1-(3-() -1- (3- ( 트라이플로오로메톡시Trifluoromethoxy )벤질)-1H-인돌-카르복실릭 ) Benzyl) -1H-indole-carboxylic 엑시드의Exsidic 합성 synthesis

Example 1 except that 1- (bromomethyl) -3- (trifluoromethoxy) benzene was used instead of 1- (bromomethyl) -4-chlorobenzene used in <Step 4>. The same procedure as in 70 was carried out to obtain the target compound.

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).

[[ 실시예Example 75] 6- 75] 6- 브로모Bromo -3-(4--3- (4- 클로오로벤조일Chlorobenzoyl )-1-(4-) -1- (4- 클로오로벤질Chlorobenzyl )-1H-인돌-2-카르복실 ) -1H-indole-2-carboxyl 엑시드의Exsidic 합성 synthesis

Step 1 Synthesis of Ethyl-3- (4-bromo-2-nitrophenyl) -2-oxopropanoate

Potassium ethoxide, ethanol (4 mL) and diethyl ether (16 mL) were dissolved in a 100 mL flask, and diethyl oxalate (1.5 mL, 11.1 mmol) dissolved in diethyl ether (6 mL) was dissolved. Added. 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 the reaction was completed, the mixture was concentrated under reduced pressure and adjusted to pH 5 using 2N-HCl. Next, the mixture was extracted with ethyl acetate, water was removed with magnesium sulfate, and then concentrated to give 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, 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).

Step 2 Synthesis of Ethyl-6-bromo-1H-indole-2-carboxylate

Into a 250 mL flask was added ethyl-3- (4-bromo-2-nitrophenyl) -2-oxopropanoate (2.57 g, 8.15 mmol) synthesized in <Step 1>, followed by acetic acid ( 15 mL) and ethanol (15 mL) were added to dissolve, then iron powder (4.1 g, 73.4 mmol) was added and stirred at reflux for 4 h. After the reaction was completed, the temperature was lowered to 5 ° C., and the mixed solution was filtered using Celite, and then concentrated under reduced pressure. The mixture was adjusted to pH 5 using 2N-HCl, extracted with ethyl acetate, and then dried over magnesium sulfate and concentrated. Then recrystallized with 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, 3 H).

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

Into a 25 mL flask was dissolved with ethyl-6-bromo-1H-indole-2-carboxylate (100 mg, 0.373 mmol) and dichloromethane (1 mL) synthesized in <Step 2>. , 4-chlorobenzoyl chloride (78 mg, 0.448 mmol), aluminum chloride (100 mg, 0.746 mmol) were added and stirred at reflux for 12 hours. After completion of the reaction, the temperature was lowered to room temperature, the organic layer was separated using dichloromethane and water, and then water contained in the organic layer was removed with magnesium sulfate. Then, after filtration, the mixture was purified by column chromatography (EA / n-Hex = 6: 1) to give ethyl-6-bromo-3- (4-chlorobenzoyl) -1H-indole-2-carboxyl Obtained (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> Ethyl-6- Bromo -3- (4- Chlorobenzoyl ) -1- (4- Chlorobenzyl Synthesis of) -1H-indole-2-carboxylate

In a 25 mL flask, ethyl-6-bromo-3- (4-chlorobenzoyl) -1H-indole-2-carboxylate (80 mg, 0.20 mmol), tetrahydrofuran, synthesized in <Step 3> above (1 mL) and N, N-dimethylformamide (1 mL) were added and dissolved, followed by addition of 1 M lithium bis (trimethylsilyl) amide (0.43 mL, 0.43 mmol) 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 then water contained in the organic layer was removed with magnesium sulfate. Then, after filtration, the mixture was purified by column chromatography (EA / n-Hex = 4: 1) to give ethyl-6-bromo-3- (4-chlorobenzoyl) -1- (4-chlorobenzyl ) -1H-indole-2-carboxylate (95 mg, 0.18 mmol, 91%) was obtained.

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- Carboxylic Exsidic synthesis

In a 25 mL flask, 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) were added and dissolved. Next, sodium hydroxide (36 mg, 0.89 mmol) dissolved in water (1 mL) was added and then stirred for 1 hour. After the reaction was completed, the mixture was concentrated and adjusted to pH 5 using 2N-HCl. Thereafter, the organic layer was separated using ethyl acetate and water, and then 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-bromo-3- (4-chlorobenzoyl) -1- (4-chlorobenzyl) -1H-indole-carboxylic acid (20 mg, 0.040 mmol, 22%) was obtained.

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).

[[ 실시예Example 76] 6- 76] 6- 브로모Bromo -3-(4--3- (4- 클로오로벤조일Chlorobenzoyl )-1-(4-) -1- (4- 클로오로페닐Chlorophenyl )-1H-인돌-2-카르복실릭 ) -1H-indole-2-carboxylic 엑시드의Exsidic 합성 synthesis

<Step 1> Synthesis of ethyl 3- (4-bromo-2-nitrophenyl) -2-oxopropanoate

Into a 100 mL flask, add potassium ethoxide, ethanol (4 mL), diethyl ether (16 mL), dissolve, and diethyl oxalate (1.5 mL, 11.1 mmol) dissolved in diethyl ether (6 mL). Added. 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 mixture was concentrated under reduced pressure and adjusted to pH 5 using 2N-HCl. Next, the mixture was extracted with ethyl acetate, water was removed with magnesium sulfate, and the mixture was concentrated to give ethyl-3- (4-bromo-2-nitrophenyl) -2-oxopropanoate.

Step 2 Synthesis of Ethyl-6-bromo-1H-indole-2-carboxylate

In a 250 mL flask, ethyl-3- (4-bromo-2-nitrophenyl) -2-oxopropanoate (2.57 g, 8.15 mmol) and acetic acid (15 mL) synthesized in <Step 1> were used. ), Ethanol (15 mL) was added to dissolve, 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 ° C., and then the mixed solution was filtered using Celite, concentrated under reduced pressure, and adjusted to pH 5 using 2N-HCl. Then extracted with ethyl acetate, water was removed with magnesium sulfate, concentrated and recrystallized with dichloromethane to ethyl-6-bromo-1H-indole-2-carboxylate (1.5 g, 5.59 mmol, 68.6% )

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

<Step 4> Ethyl-6- Bromo -3- (4- Chlorobenzoyl ) -1- (4- Chlorophenyl Synthesis of) -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 added and dissolved in a 25 mL flask. Next, 4- (chlorophenyl) boronic acid (39 mg, 0.246 mmol), copper (II) acetate (34 mg, 0.185 mmol), triethylamine (25 mg, 0.246 mmol) are added and for 12 hours Stirred. After completion of the reaction, the organic layer was separated using dichloromethane and water, and then water contained in the organic layer was removed with magnesium sulfate. Then, after filtration, the mixture was purified by column chromatography (EA / n-Hex = 4: 1) to give ethyl-6-bromo-3- (4-chlorobenzoyl) -1- (4-chlorophenyl ) -1H-indole-2-carboxylate (50 mg, 0.097 mmol, 78.6%) was obtained.

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- Carboxylic Exsidic synthesis

In a 25 mL flask, 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) were added and dissolved. Next, sodium hydroxide (17.4 mg, 0.43 mmol) dissolved in water (0.5 mL) was added and then stirred for 1 hour. After the reaction was completed, the mixture was concentrated and adjusted to pH 5 using 2N-HCl. Thereafter, the organic layer was separated using ethyl acetate and water, and then 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-bromo-3- (4-chlorobenzoyl) -1- (4-chlorophenyl) -1H-indole-2-carboxylic acid (21 mg, 0.043 mmol, 49.4%) was obtained.

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 (dd, J = 1.2, 10.4 Hz, 4H), 7.36 (dd, J = 2, 10.4 Hz, 1H), 7.29 (d, J = 1.6 Hz, 1H).

[[ 실시예Example 77] 3-(4- 77] 3- (4- 클로오로벤조일Chlorobenzoyl )-1-(4-) -1- (4- 클로오로페닐Chlorophenyl )-6-(피리딘-3-일)-1H-인돌-2-카르복실릭 ) -6- (pyridin-3-yl) -1H-indole-2-carboxylic 엑시드의Exsidic 합성 synthesis

Step 1 Synthesis of Ethyl-3- (4-bromo-2-nitrophenyl) -2-oxopropanoate

Potassium ethoxide, ethanol (4 mL) and diethyl ether (16 mL) were dissolved in a 100 mL flask, and diethyl oxalate (1.5 mL, 11.1 mmol) dissolved in diethyl ether (6 mL) was dissolved. Added. 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 the reaction was completed, the mixture was concentrated under reduced pressure, and adjusted to pH 5 using 2N-HCl. Then, the mixture was extracted with ethyl acetate, water was removed with magnesium sulfate, and the mixture was concentrated to give ethyl-3- (4-bromo-2-nitrophenyl) -2-oxopropanoate.

Step 2 Synthesis of Ethyl-6-bromo-1H-indole-2-carboxylate

In a 250 mL flask, ethyl-3- (4-bromo-2-nitrophenyl) -2-oxopropanoate (2.57 g, 8.15 mmol) and acetic acid (15 mL) synthesized in <Step 1> were used. ), Ethanol (15 mL) was added to dissolve, iron powder (4.1 g, 73.4 mmol) was added, and the mixture was stirred under reflux for 4 hours. After the reaction was completed, the temperature was lowered to 5 ° C., the mixed solution was filtered using Celite, and then concentrated under reduced pressure, and adjusted to pH 5 using 2N-HCl. Then extracted with ethyl acetate, water was removed with magnesium sulfate, the mixture was concentrated and recrystallized from dichloromethane to ethyl-6-bromo-1H-indole-2-carboxylate (1.5 g, 5.59 mmol, 68.6%).

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

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

In a 25 mL flask, 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) were added and dissolved. 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 ° C. for 4 h. After completion of the reaction, the organic layer was separated using ethyl acetate and water, and then water contained in the organic layer was removed with magnesium sulfate. Then, 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%) was obtained.

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> 3- (4- Chlorobenzoyl ) -1- (4- Chlorophenyl ) -6- (pyridin-3-yl) -1H-indole-2-carboxylic Exsidic synthesis

In a 25 mL flask, ethyl-3- (4-chlorobenzoyl) -1- (4-chlorophenyl) -6- (pyridin-3-yl) -1H-indole-2 synthesized in <Step 5> above Carboxylate (30 mg, 0.058 mmol), tetrahydrofuran (0.5 mL) and methanol (0.5 mL) were added and dissolved. Next, sodium hydroxide (11.6 mg, 0.29 mmol) dissolved in water (0.5 mL) was added and then stirred for 1 hour. After the reaction was completed, the mixture was concentrated and adjusted to pH 5 using 2N-HCl. Thereafter, the organic layer was separated using ethyl acetate and water, and then 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- (4-chlorobenzoyl) -1- (4-chlorophenyl) -6- (pyridine 3-yl) -1H-indole-2-carboxylic acid (20 mg, 0.041 mmol, 70.6%) was obtained.

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).

[[ 비교예Comparative example 1] One]

The following Rosiglitazone compound was used.

[비교예 2]Comparative Example 2

The following Pioglitazone compound was used.

[비교예 3]Comparative Example 3

The following SR-1664 compound was used.

[실험예 1] PPARγ의 경쟁 결합 능력(Competitive binding) 평가Experimental Example 1 Evaluation of Competitive Binding Capacity of PPARγ

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

Using the LanthaScreen ^™ TR-FRET PPARγ Competitive Binding Assay Kit (manufacturer: Invitrogen / Model name: PV4894), the experiment was performed using the test method provided by the kit. 30 μl of each of the compounds of Examples 1 to 77 and the compounds of Comparative Examples 1 to 3 diluted in assay buffer to 50 times the final concentration in 96-well plates (SPL, 34096) was 5 nM Fluormone ^™ Pan-PPAR After mixing with 15 µl of Green, 15 µl of 5nM GST-PPARG-LBD and 15 µl of 5nM Tb-GST-antibody were added and mixed. Reacted. After the reaction is completed, Time-Resolved Fluorescence (RFU) mode in Flexstation 3 (Molecular Devices), excitation1 340 nm, emission1 518 nm, excitation2 340 nm, emission2 488 nm, integration delay 50 us The fluorescence values were read under the integration 400 us condition. Experimental results were calculated using the 518 nm RFUs / 488 nm RFUs ratio value. Specifically, the binding activity of each compound relative to the vehicle (binding activity) was calculated by the formula [100%-each compound ratio / vehicle ratio].

[[ 실험예Experimental Example 2] 2] PPARγ의PPARγ 전사 활성(Transcription activity) 평가 Transcription activity assessment

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

HEK293 cells were plated at 5 × 10 ⁴ in 24-well plates (SPL, 30024). HEK293 cells were transfected with PPPAR (PPAR Response Element) as FuGENE HD (Promega, E2312). 24 hours after transduction, 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 to calculate the activity of the reporter gene assay and the Luciferase assay. In this case, the reporter gene analysis was performed using a Dual Reporter gene assay kit (Promega, E1980), and the activity of the luciferase assay was calculated by normalizing renilla activity.

Referring to Table 1, it can be seen that the compound of the present invention has excellent activity of binding to PPARγ. The binding activity level indicates the presence or absence of binding, and is not directly related to pharmacological activity. Further, the compounds of the present invention do not induce the transcriptional activity of PPARγ, while the compounds of the comparative examples can be seen to induce the transcriptional activity of PPARγ.

These results support that the compound of the present invention does not induce the gene transcription activity of PPARγ while specifically binding to PPARγ, and thus has an excellent effect of preventing side effects due to phosphorylation of PPARγ.

[[ 실험예Experimental Example 3] 3] CDK5CDK5 (( CyclinCyclin -dependant -dependant kinasekinase 5)의5) 인산화 억제 활성 평가 Evaluation of phosphorylation inhibitory 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 Cyclin-dependant kinase 5 (CDK5). In order to determine the degree of inhibition of phosphorylation was evaluated by the following method.

After diluting the compounds of Examples 1, 2, 19 and 20 and the compounds of Comparative Examples 1 and 3 in DMSO (Dimethylsulfoxide) to be 2000 times the final test concentration, the compound diluted to 2000 times was 50% DMSO (DMSO: DW = 1: 1) was prepared by diluting at a 1/100 ratio. PPARγ-Ligand binding domain (human recombinant) (Cayman, 10007941) 0.43 mg, CDK5 / p35 active (millipore, 14-477) 100 ng, 10-fold kinase buffer (CellSignaling, 9802S) and DW ( The premix was prepared to have a final volume of 36 μl of data warehousing (premix was prepared on ice and stored in ice). 2 μl of each compound was mixed in 36 μl of the premix and reacted for 10 minutes on ice. Then, 2 μl of ATP 10 mM (2 μl of DW for negative control) was added and reacted for 15 minutes in a 37 ° C. water bath. I was. After the reaction, it was immediately transferred to ice and cooled for 1 to 2 minutes. After mixing 10 μl of 5-fold sample buffer, sample was boiled for 8 to 10 minutes in a 95 ° C. heat block. After the heat block treatment was taken out and cooled for a while, the protein was separated by SDS-PAGE (Sodium dodecylsulfate-polyacryl amide gel electrophoresis) in 10% SDS-gel.

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

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

[[ 실험예Experimental Example 4] 4] DIODIO (Diet-Induced Obesity) 모델을 통한 약학 조성물의 효력평가(Efficacy Evaluation of Pharmaceutical Compositions Using a Diet-Induced Obesity Model)

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

One) DIO Diet-Induced Obesity Selection and Pharmaceutical Composition Administration

About 4 weeks old male C57BL / 6 mice were fed a high fat diet (Lab. Diet co.) To induce a high fat diet obesity mouse model (Diet-Induced Obesity, DIO). Mice with a weight greater than 40 g among the mice gaining weight in a high fat diet were selected as the obesity model, and randomly selected among them were subjected to group separation (n = 5) for each administration.

DIO mice with group separation completed were administered a pharmaceutical composition for each group for one week at each dose.

2) Intraperitoneal Glucose Tolerance Test (IPGTT)

DIO mice to which each pharmaceutical composition was administered for 1 week were orally administered 1 g / kg of glucose, and the blood glucose was measured by Accu-chek active strip (Roche diagnostic Co.) by puncture of the microvenous veins. 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 terminated the administration of each pharmaceutical composition were fasted over-night. Next, blood glucose of DIO mice was measured by Accu-chek active strip (Roche diagnostic Co.) and recorded as fasting blood glucose, and then the values measured in each group were averaged.

4) Fasting insulin level after fasting

DIO mice that terminated the administration of each pharmaceutical composition were fasted over-night. Next, about 50 μl of blood was drawn through the capillary (KIMBLE CHASE, USA) of DIO mice by orbital blood collection, and blood was centrifuged at 3600 rpm for 10 minutes to separate plasma. Thereafter, insulin was measured using an insulin ELISA kit (Miobs, Japan), and then averaged values measured in each group.

Referring to Table 2 above, the pharmaceutical compositions containing the compounds of Examples 1, 2, 19, and 20 exhibited equivalent or more blood glucose reductions compared to the pharmaceutical compositions containing the compounds of Comparative Example 1, confirming that the effect was excellent. Can be.

Claims

A compound represented by Formula 1, or a pharmaceutically acceptable salt thereof:

[Formula 1]

In Chemical Formula 1,

R 1 to R 4 are the same as or different from each other, and each independently a hydrogen atom, a halogen group, 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 Is selected from the group consisting of 5 to 10 heteroaryl group containing one or more ring atoms,

R 5 to R 9 are the same as or different from each other, 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, O and S Is selected from the group consisting of 5 to 10 heteroaryl groups containing one or more hetero atoms,

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

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 heteroaryl group of 5 to 10, the C 1 to C 10 alkylene group and C 6 to C 10 arylene group of L are each independently halogen, C 1 to C 10 alkyl group and C 1 to C 10 It may be substituted or unsubstituted with one or more substituents selected from the group consisting of alkoxy groups. When the substituents are plural, the plural substituents are the same as or different from each other.
The method according to claim 1,

Wherein each of R 1 to R 4 is independently selected from the group consisting of hydrogen, a halogen group, a pyridine group, and a trifluoromethyl group, or a pharmaceutically acceptable salt thereof.
The method according to claim 1,

R 5 to R 9 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,

Compound represented by * -LR 11 of Formula 1 is selected from the group consisting of the structure represented by S1 to S30, or a pharmaceutically acceptable salt thereof.
The method according to claim 1,

The compound of 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 Formula 2 or 3 below;

b) cyclization of the compound represented by Formula 2 synthesized in step a) in the presence of polyphosphoric acids, or by cyclization of the compound represented by Formula 3 in the presence of acetic acid Synthesizing the compound to be represented;

c) synthesizing the compound represented by Chemical Formula 6 by reacting the compound represented by Chemical Formula 4 synthesized in step b) with the compound represented by Chemical Formula 5;

d) synthesizing a compound represented by the following Chemical Formula 7 by substituting hydrogen bonded to a nitrogen atom of the compound represented by Chemical Formula 6 synthesized in step c);

e) A method for preparing a compound comprising the step of reacting the compound represented by the formula (7) synthesized in step d) with a strong base to synthesize a compound represented by the following formula (1).

[Formula 2]

[Formula 3]

[Formula 4]

[Formula 5]

[Formula 6]

[Formula 7]

[Formula 1]

In Chemical Formulas 1 to 7,

The definitions for R 1 to R 11 , L and A are as defined in claim 1.
A pharmaceutical composition for treating metabolic disease comprising the compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof as an active ingredient.
The method according to claim 8,

The metabolic disease comprises diabetes, insulin resistance, impaired glucose tolerance, pre-diabetes, hyperglycemia, hyperinsulinemia, obesity and inflammation Pharmaceutical composition for treating metabolic disease selected from.