KR101448015B1 - Novel indole derivatives, preparation method thereof and pharmaceutical composition for the prevention or treatment of dyslipidemia containing the same as an active ingredient - Google Patents

Abstract

The present invention relates to a novel indole derivative or a pharmaceutically allowable salt thereof, a preparation method thereof, and a pharmaceutical composition for preventing or treating dyslipidemia containing the same as an active ingredient. The novel indole derivative according to the present invention combines a niacin GPR109A receptor, activates the receptor, and induces less activation of beta-arrestin signal transduction pathway, thereby minimizing a facial blushing side effect and being used as a composition for preventing, alleviating, or treating dyslipidemia such as hyperlipemia, hypercholesterinemia, hypertriglyceridemia, etc.

Description

TECHNICAL FIELD [0001] The present invention relates to a novel indole derivative, a process for producing the same, and a pharmaceutical composition for preventing or treating dyslipidemia containing the same as an active ingredient. ingredient}

The present invention relates to a novel indole derivative, a process for producing the same, and a pharmaceutical composition for preventing or treating dyslipidemia containing the same as an active ingredient.

Cholesterol is an essential component of essential organic molecules, such as steroids and bile acids, and cell membranes, but is known to cause cardiovascular disease. For example, cholesterol accumulates in the coronary arteries and becomes a major component of a plaque that causes abnormal lipidemia, in which the amount of serum lipids such as hyperlipidemia is abnormal.

Conventional dyslipidemic therapies have been shown to reduce the levels of low-density lipoproteins (LDL) cholesterol in the plasma and increase the levels of high-density lipoproteins (HDL) cholesterol, Niacin (nicotinic acid).

The niacin receptors GPR109A and GPR109B were first discovered by Lorenzen A et al. In 2001 (Non-Patent Document 1). GPR109A is a high affinity niacin receptor and GPR109B is a low affinity niacin receptor and 96% ).

The GPR109A receptor is widely expressed in adipose tissue, spleen, and immune cells, and is not expressed in liver, kidney, heart, or intestine. In addition, GPR109A (a human gene, HM74A) is a specific G-protein coupled receptor (GPCR) that binds to niacin to form intracellular 3'-5'-cyclic adenosine monophosphate Production is inhibited and transported into cells by beta-arrestin to activate the signaling pathway of mitogen-activated protein kinases (MAPKs). Therefore, when GPR109A is activated by the administration of niacin, the concentration of free fatty acid (FFA) and glycerol produced by degradation of TAG (triacylglyceride) is lowered, the synthesis of triglyceride of the liver is suppressed, (LDL), low-density lipoproteins (VLDL), and low-density lipoproteins (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol.

However, GPR109A activation by the above-mentioned niacin has a side effect of causing facial flushing with pharmacological action to lower the fat concentration. Therefore, studies have been conducted on substances capable of treating dyslipidemia by activating GPR109A without showing adverse side effects of facial flushing.

The cause of adverse facial flushing in niacin is that niacin activates GPR109A and activated GPR109A changes beta-arrestin, especially beta-arrestin 1, (PLD2, prostaglandin D2 and PLE2, prostaglandin E2), which is a cause of the chemical reaction of the G-protein, and it is expected that the development of the G-protein-based ligand to avoid this would reduce the side effect .

In addition, the activation of GPR109A can be transferred to a desensitization pathway, which is manifested by a signal transduction pathway linked to the G-protein and an intracellular pathway of beta-arrestin, and the two pathways can be independently controlled The structure - active correlation is still ambiguous.

Therefore, the development of a compound that induces the activation of the niacin receptor GPR109A mainly through the G-protein signal transduction pathway and the activation of the beta-arrestin signal transduction pathway leads to the development of a dyslipidemic therapeutic ingredient .

Recently, Merck has developed MK-6892 (biarylcyclohexanecarboxylic acid), a compound that acts as a powerful GPR109A agonist without showing adverse flushing side effects (Non-Patent Document 2).

In addition, MK-0354 (3- (1H-tetrazol-5-yl) -1,4,5,6-tetrahydro-cyclopentapyrazole) has a relatively weak affinity for MK-6892 It has been reported that vasodilation is not observed in animal experiments (Non-Patent Document 3).

Furthermore, a pyrazole-3-carboxylic acid derivative as shown below was developed as an agonist of GPR109A receptor in Arena (Patent Document 1 to Patent Document 3).

Merck also developed cyclopentapyrazole derivatives and anthranilic acid derivatives containing a pyrrole structure as shown below as GPR109A receptor agonists (Patent Documents 4 to 5).

However, indole derivatives have not yet been reported as GPR109A receptor agonists.

Therefore, in order to develop a therapeutic ingredient for dyslipidemia such as hyperlipidemia which can minimize side flushing adverse effects, the present inventors have found that the activity of the GPR109A receptor, which is a niacin receptor, is mainly transferred to the G- protein signal transduction pathway, While studying the less inducing signal transduction pathway, new indole derivatives are safe because they are not cytotoxic and bind to the GPR109A receptor to activate the receptor, while activation of the beta-arrestin signaling pathway is less likely to occur The present invention has been accomplished on the basis of the finding that it is possible to treat dyslipidemia such as hyperlipidemia, hypercholesterolemia and hypertriglyceridemia while minimizing side flushing side effects.

International Publication No. 2006/12795 International Patent Publication No. 2005/011677 International Patent Publication No. 2004/032928 WO 2007/092364 WO 2007/092364

Am. J. Cardiol. 2007, 100 (suppl), pp. 53N-61N J. Med. Chem., 2010, 53, pp. 2666-2670 J. Med. Chem., 2008, 51, pp. 5101-5108

It is an object of the present invention to provide a novel indole derivative or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a process for producing the novel indole derivative.

Still another object of the present invention is to provide a pharmaceutical composition for preventing or treating dyslipidemia which comprises the novel indole derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

Another object of the present invention is to provide a health food composition for preventing or ameliorating dyslipidemia comprising the novel indole derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

In order to achieve the above object,

There is provided a novel indole derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof:

[Chemical Formula 1]

(In the formula 1,

A is carbon (C) or sulfur (S)

R ¹ is -H, halogen, -COOH or C ₁ -C ₆ linear or branched alkyl,

R ² And R ³ are independently -H, C ₁ -C ₆ straight or branched chain alkyl or -C (= O) R ⁵ , wherein R ⁵ is -H, -OH, -OR ⁶ , -NH ₂ or -NHR ⁶ Wherein R ⁶ is C ₁ -C ₆ linear or branched alkyl or phenyl,

R ⁴ is -COOH, phenyl or 5- to 7-membered heteroaryl or heterocycloalkyl containing one or more heteroatoms selected from the group consisting of nitrogen (N), oxygen (O) and sulfur (S) Wherein said phenyl, heteroaryl or heterocycloalkyl is unsubstituted or substituted by one or more substituents selected from the group consisting of -OH, -NO ₂ , halogen, C ₁ -C ₆ linear or branched alkoxy, phenyl and nitrogen (N), oxygen (O) S), or a 5- to 7-membered heteroaryl or heterocycloalkyl containing one or more heteroatoms selected from the group consisting of C ₁ -C ₆ alkyl, C ₆ linear or branched alkoxy, phenyl, heteroaryl or heterocycloalkyl is unsubstituted or substituted by one or more substituents selected from the group consisting of -OH, -NO ₂ , halogen, C ₁ -C ₆ straight or branched chain alkyl, phenoxy and C ₁ -C ₆ alkoxy C ₆ -C ₁₀ aryl C ₁ -C ₆ al City may be further substituted with one or more substituents selected from the group consisting of,

는 단일 또는 이중결합이고,

Is a single or double bond,

n is an integer from 0 to 5, wherein each carbon of the alkylene between A and R < ⁴ > may be substituted with one or more C ₁ -C ₆ linear or branched alkyl.

Also, as shown in the following Reaction Scheme 1,

Reacting a compound represented by the general formula (2) with a compound represented by the general formula (3) to provide an indole derivative represented by the general formula (1)

[Reaction Scheme 1]

및 n은 상기 화학식 1에서 정의한 바와 같고, L은 이탈기로써, -0H 또는 할로겐이다).
(In the above Reaction Scheme 1, A, R ¹ , R ² , R ³ , R ⁴ ,

And n is as defined in Formula 1, and L is a leaving group, -OH or halogen.

Further, the present invention relates to a process for preparing a compound represented by the formula

(2) with a compound represented by the formula (13) and a carbonyl reagent to prepare a compound represented by the formula (1a), wherein the compound represented by the formula (1) :

[Reaction Scheme 4]

은 상기 화학식 1에서 정의한 바와 같고, R⁷은 상기 반응식 2에서 정의한 바와 같고, 화학식 1a로 표시되는 화합물은 상기 화학식 1로 표시되는 화합물의 유도체이다).
(In the above Reaction Scheme 4, R ¹ , R ² , R ³ And

Is as defined in Formula 1, R ⁷ is as defined in Reaction Scheme 2, and the compound represented by Formula (1a) is a derivative of the compound represented by Formula (1).

Also, as shown in the following Reaction Scheme 5,

There is provided a process for preparing a novel indole derivative represented by the formula (1), which comprises reacting a compound represented by the formula (2) with an anhydride compound represented by the formula (14) to prepare a compound represented by the formula (1b)

[Reaction Scheme 5]

은 상기 화학식 1에서 정의한 바와 같고, m은 0-5의 정수이고, 화학식 1b로 표시되는 화합물은 상기 화학식 1로 표시되는 화합물의 유도체이다).
(In the above Reaction Scheme 5, R ¹ , R ² , R ³ And

M is an integer of 0-5, and the compound represented by the formula (1b) is a derivative of the compound represented by the formula (1).

Further, the present invention relates to a process for preparing a compound represented by the following formula (6)

Halogenating a compound represented by the formula (1b) with a halogenating reagent to prepare a compound represented by the formula (15) (step 1); And

(Step 2) of cyclizing a compound represented by the formula (15) obtained in the above step 1 with a compound represented by the formula (16) to obtain a compound represented by the formula (1c) (step 2) Lt; RTI ID = 0.0 > of:

[Reaction Scheme 6]

및 n은 상기 화학식 1에서 정의한 바와 같고, E 및 R⁷은 상기 반응식 2에서 정의한 바와 같고, 화학식 1c로 표시되는 화합물은 상기 화학식 1로 표시되는 화합물의 유도체이다.)
(In the above Reaction Scheme 6, R ¹ , R ² , R ³ ,

And n are the same as defined in Formula 1, E and R ⁷ are as defined in Reaction Formula 2, and the compound represented by Formula 1c is a derivative of the compound represented by Formula 1.

Also, as shown in the following Reaction Scheme 7,

An amidation reaction of a compound represented by the formula (2) with a compound represented by the formula (17) under a base condition to prepare a compound represented by the formula (18) (step 1); And

(Step 2) of cyclizing a compound represented by the formula (18) obtained in the step 1 with sodium azide and a compound represented by the formula (19) to obtain a compound represented by the formula (1d) A process for the preparation of a novel indole derivative is provided:

[Reaction Scheme 7]

및 n은 상기 화학식 1에서 정의한 바와 같고, R⁷은 상기 반응식 2에서 정의한 바와 같고, 화학식 1d로 표시되는 화합물은 상기 화학식 1로 표시되는 화합물의 유도체이다).
(In the above Reaction Scheme 7, R ¹ , R ² , R ³ ,

And n are the same as defined in Formula 1, R ⁷ is as defined in Reaction Formula 2, and the compound represented by Formula 1d is a derivative of the compound represented by Formula 1.

Furthermore, the present invention provides a pharmaceutical composition for preventing or treating dyslipidemia, which comprises the novel indole derivative represented by the above-mentioned formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention also provides a health food composition for preventing or ameliorating dyslipidemia, which comprises the novel indole derivative represented by the above-mentioned formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

The novel indole derivative according to the present invention binds to the niacin GPR109A receptor to activate the receptor but less activates the beta-arrestin signal transduction pathway, thus minimizing the adverse effects of facial flushing and preventing hyperlipidemia, hypercholesterolemia, For the prevention, amelioration, or treatment of dyslipidemia such as hyperlipidemia and hyperlipidemia.

1 is a vector map of pCMV6-A-Hygro / GPR109A subcloned according to Experimental Example 2 of the present invention.
FIG. 2 is a graph showing the intracellular movement of beta-arrestin in the negative control group according to Experimental Example 2 of the present invention, Comparative Examples 1-2 and 12, 13 and 27 with green fluorescent protein (GFP) It is an image.

Hereinafter, the present invention will be described in detail.

The present invention provides a novel indole derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.

(In the formula 1,

A is carbon (C) or sulfur (S)

R ¹ is -H, halogen, -COOH or C ₁ -C ₆ linear or branched alkyl,

R ² And R ³ are independently -H, C ₁ -C ₆ straight or branched chain alkyl or -C (= O) R ⁵ , wherein R ⁵ is -H, -OH, -OR ⁶ , -NH ₂ or -NHR ⁶ Wherein R ⁶ is C ₁ -C ₆ linear or branched alkyl or phenyl,

R ⁴ is -COOH, phenyl or 5- to 7-membered heteroaryl or heterocycloalkyl containing one or more heteroatoms selected from the group consisting of nitrogen (N), oxygen (O) and sulfur (S) Wherein said phenyl, heteroaryl or heterocycloalkyl is unsubstituted or substituted by one or more substituents selected from the group consisting of -OH, -NO ₂ , halogen, C ₁ -C ₆ linear or branched alkoxy, phenyl and nitrogen (N), oxygen (O) S), or a 5- to 7-membered heteroaryl or heterocycloalkyl containing one or more heteroatoms selected from the group consisting of C ₁ -C ₆ alkyl, C ₆ linear or branched alkoxy, phenyl, heteroaryl or heterocycloalkyl is unsubstituted or substituted by one or more substituents selected from the group consisting of -OH, -NO ₂ , halogen, C ₁ -C ₆ straight or branched chain alkyl, phenoxy and C ₁ -C ₆ alkoxy C ₆ -C ₁₀ aryl C ₁ -C ₆ al City may be further substituted with one or more substituents selected from the group consisting of,

는 단일 또는 이중결합이고,

Is a single or double bond,

n is an integer from 0 to 5, wherein each carbon of the alkylene between A and R < ⁴ > may be substituted with one or more C ₁ -C ₆ linear or branched alkyl.

Preferably, in the above formula (1)

In Formula 1,

In Formula 1,

A is carbon (C) or sulfur (S)

R ¹ is -H, -Br, -Cl, -COOH or C ₁ -C ₄ linear or branched alkyl,

R ² And R ³ are independently -H, C ₁ -C ₄ linear or branched alkyl or -C (= O) R ⁵ , wherein R ⁵ is selected from the group consisting of -H, -OH, -NH ₂ or -OR ⁶ , wherein R ⁶ is C ₁ -C ₄ straight or branched chain alkyl,

R ⁴ is a 5- to 6-membered heteroaryl containing one or more heteroatoms selected from the group consisting of -COOH, phenyl, nitrogen (N), oxygen (O) and sulfur (S) Wherein said phenyl, heteroaryl or heterocycloalkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of: unsubstituted or substituted with one or more substituents selected from the group consisting of -OH, -Cl, -Br, C ₁ -C ₂ linear or branched alkoxy, phenyl, nitrogen (N), oxygen (O), 5- to 6-membered heteroaryl containing at least one heteroatom selected from the group consisting of oxygen (N), oxygen (O) and sulfur (S) and the substituents selected from the group consisting of heterocycloalkyl of 5 to 6 atoms which may be substituted, wherein the substituents of the alkyl, phenyl, heteroaryl, or heterocycloalkyl is -OH, -NO _2, -F, -Cl , C ₁ -C ₃ linear or branched alkyl, phenoxy and C ₁ - C ₄ alkoxyphenyl-C ₁ -C may be further substituted with one or more substituents selected from the group consisting of _4-alkoxy,

는 단일 또는 이중결합이고,

Is a single or double bond,

n is an integer from 0-3, wherein each carbon of the alkylene between A and R < ⁴ > may be substituted with one or more methyl or ethyl.

More preferably, in Formula 1,

A is carbon (C) or sulfur (S)

R ¹ is -H, halogen, -COOH or methyl,

R ² and R ³ are independently -H, methyl or -C (═O) R ⁵ , wherein R ⁵ is -H, -OH, -NH ₂ or -OMe, -OEt,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

, ,

,

,

,

,

,

,

,

또는

이고, R ⁴ is -COOH,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,,

,

,

,

,

,

,

,

or

ego,

는 단일 또는 이중결합이고,

Is a single or double bond,

n is an integer of 0-2, wherein each carbon of the alkylene between A and R < ⁴ > may be substituted with one or more methyl.

Further, the novel indole derivatives represented by the above formula (1) are more specifically exemplified as follows.

(1) Ethyl 5-methoxy-1- {3- [3- (4- (4-methoxybenzyloxy) phenyl) -1,2,4-oxadiazol- 1 H -indole-2-carboxylate;

(2) Ethyl 5-methoxy-1- {3- [3- (4- (4-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] propanoyl} -1 H - Indole-2-carboxylate;

(3) 5-Methoxy-1- {4- [3- (4 (4-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] propanoyl} -1 H - indole -2-carboxylic acid;

(4) Methyl 1- [4- (2-chlorophenyl) piperazine-1-carbonyl] indoline-2-carboxylate;

(5) 1- [4- (2-Chlorophenyl) piperazine-1-carbonyl] indoline-2-carboxylic acid;

(6) 1- [4- (2-Chlorophenyl) piperazine-1-carbonyl] indoline-2-carboxamide;

7 5-Bromo-1- (4-methoxybenzoyl) -1 H - indole-3-carbaldehyde;

8 5-Bromo-1- (4-methoxybenzoyl) -1 H - indole-3-carboxylic acid;

(9) methyl 1-nicotinoylindoline-2-carboxylate;

(10) 1-Nicotinoylindoline-2-carboxylic acid;

(11) 1-Nicotinoyl-1 H -indole-2-carboxylic acid;

(12) 2-Methyl-1-nicotinoyl-1 H -indole-3-carboxylic acid;

(13) 1-Nicotinoyl-1 H -indole-6-carboxylic acid;

(14) 1- (2-chloro-nicotinoyl) -1 H - indole-6-carboxylic acid;

(15) 1- (pyridin-3-yl-seolpayi carbonyl) -1 H-indole-3-carboxylic acid;

(16) 1- (6-chloro-nicotinoyl) -1 H - indole-3-carboxylic acid;

(17) 1- (6-morpholino-titanate say alkanoyl) -1 H - indole-3-carboxylic acid;

18 1- [6- (4-methylpiperazin-1-yl) nicotinoyl) -1 H - indole-3-carboxylic acid;

19 1- [6- (pyrrolidin-1-yl) nicotinoyl] -1 H - indole-3-carboxylic acid;

(20) 5-Bromo-1-nicotinoyl-1 H -indole-3-carboxylic acid;

21 1 - (pyrazine-2-carbonyl) -1 H - indole-3-carboxylic acid;

(22) 5-Methyl-1-nicotinoyl-1 H -indole-3-carboxylic acid;

(23) 5-Chloro-1-nicotinoyl-1 H -indole-3-carboxylic acid;

(24) 4- [2- (Methoxycarbonyl) indolin-1-yl] -4-oxobutanoic acid;

(25) Methyl 1- {3- [3- (5- (4-methoxybenzyloxy) pyridin-2-yl) -1,2,4-oxadiazol-5-yl] propanoyl} indoline -2-carboxylate;

(26) Methyl 1- {3- [3- (5-hydroxypyridin-2-yl) -1,2,4-oxadiazol-5-yl] propanoyl} indoline- ;

(27) 1- {3- [3- (5-Hydroxypyridin-2-yl) -1,2,4-oxadiazol-5-yl] propanoyl} indoline-2-carboxylic acid;

(28) 4- [2- (Methoxycarbonyl) indolin-1-yl] -3,3-dimethyl-4-oxobutanoic acid;

(29) Methyl 1- {3- [3- (5- (4-methoxybenzyloxy) pyridin-2-yl) -1,2,4-oxadiazol- Methylpropanoyl} indoline-2-carboxylate;

(30) 1- {3- [3- (5-Hydroxypyridin-2-yl) -1,2,4-oxadiazol-5-yl] -2,2-dimethylpropanoyl} indoline -2-carboxylic acid;

(31) Methyl 1- {3- [1- (pyridin-3-yl) -1,2,3-triazol-4-yl] propanoyl} indoline-2-carboxylate;

(32) 1- {3- [1- (Pyridin-3-yl) -1,2,3-triazol-4-yl] propanoyl} indoline-2-carboxylic acid;

33-methyl-1- {3- [1- (5- (4-methoxy-benzyloxy) pyridin-2-yl) -1 H - pyrazol-3-yl] propanoyl} indoline-2-carboxylic Decylate;

34 1- {3- [1- (5-hydroxy-pyridin-2-yl) -1 H - pyrazol-3-yl] propanoyl} indoline-2-carboxylic acid;

(35) Methyl 1- [3- (2-bromothiazol-5-yl) propanoyl] indoline-2-carboxylate;

(36) 1 - {[3- (2- (Pyridin-3-yl) thiazol-5-yl] propanoyl} indoline-2-carboxylic acid;

(37) 1 - {[3- (2- (3,5-Dichlorophenyl) thiazol-5-yl] propanoyl} indoline-2-carboxylic acid;

(38) 1 - {[3- (2- (3,5-Difluorophenyl) thiazol-5-yl] propanoyl} indoline-2-carboxylic acid;

(39) 1 - {[3- (2- (4-Chlorophenyl) thiazol-5-yl] propanoyl} indoline-2-carboxylic acid;

(40) 1 - {[3- (2- (2-Chlorophenyl) thiazol-5-yl] propanoyl} indoline-2-carboxylic acid;

(41) 1 - {[3- (2- (2-fluorophenyl) thiazol-5-yl] propanoyl} indoline-2-carboxylic acid;

(42) 1 - {[3- (2- (3-Fluorophenyl) thiazol-5-yl] propanoyl} indoline-2-carboxylic acid;

(43) 1- {[3- (2- (3-nitrophenyl) thiazol-5-yl] propanoyl} indoline-

(44) 1 - {[3- (2- (3-phenoxyphenyl) thiazol-5-yl] propanoyl} indoline-2-carboxylic acid.

The preferred structures of the novel indole derivatives represented by Formula 1 according to the present invention are shown in Table 1 below.

Example constitutional formula Example constitutional formula One

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

The indole derivative represented by the general formula (1) of the present invention can be used in the form of a pharmaceutically acceptable salt. As the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid and the like, aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, Citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid and the like, which are non-toxic organic acids such as hydrochloric acid, hydrobromic acid, Examples of such pharmaceutically non-toxic salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphate chlorides, bromides, But are not limited to, but are not limited to, but are not limited to, but are not limited to, but are not limited to, halides, halides, halides, halides, halides, halides, But are not limited to, lactose, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-diate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, Methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, Such as benzene sulfonate, benzene sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate,? -Hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene -1-sulfonate, naphthalene-2-sulfonate, mandelate and the like.

The acid addition salt according to the present invention can be prepared by a conventional method. For example, the indole derivative represented by the formula (1) is dissolved in an organic solvent such as methanol, ethanol, acetone, dichloromethane or acetonitrile, The precipitate formed by adding the inorganic acid may be filtered and dried. Alternatively, the precipitate may be dried by evaporating the solvent and excess acid under reduced pressure, followed by crystallization in an organic solvent.

In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt. In addition, the corresponding salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable salt (such as silver nitrate).

Further, the present invention includes all of the novel indole derivatives represented by the above formula (1) and pharmaceutically acceptable salts thereof, as well as solvates and hydrates thereof which can be prepared therefrom.

The present invention also provides a process for preparing a novel indole derivative represented by the general formula (1)

Production Method 1

The method for producing an indole derivative represented by the formula (1) according to the present invention is characterized in that,

Reacting a compound represented by the formula (2) with a compound represented by the formula (3) to prepare an indole compound represented by the formula (1).

[Reaction Scheme 1]

및 n은 상기 화학식 1에서 정의한 바와 같고, L은 이탈기로써, -0H 또는 할로겐이다.)
(In the above Reaction Scheme 1, A, R ¹ , R ² , R ³ , R ⁴ ,

And n is as defined in Formula 1, and L is a leaving group, -OH or halogen.

Hereinafter, the production method will be described in detail.

The process according to the present invention is characterized in that the indole compound represented by the general formula (2) is reacted with the compound represented by the general formula (3) under a condensing agent and a base, or the carboxylic acid represented by the general formula (3) is reacted with an acid halide or an acid anhydride And then reacted with an indole compound represented by the general formula (2) to prepare an indole derivative represented by the general formula (1).

In the above production process, the condensing agent is preferably a water-soluble carbodiamide condensing agent or the like, but it is preferable to use 1-ethyl- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride, N, N '-Dicyclohexylcarbodiimide and the like are more preferably used.

In the above production method, the base may be an organic compound such as pyridine, triethylamine, N, N-diisopropylethylamine (DIPEA), 1,8-diazabicyclo [5.4.0] Base, or an inorganic base such as sodium hydroxide, sodium hydride, sodium carbonate, potassium carbonate, cesium carbonate, etc. may be used in an equivalent amount or in an excess amount.

In the above production process, the reaction solvent is preferably dichloromethane, chloroform, dimethylformamide, dimethylsulfoxide, tetrahydrofuran, 1,2-dichloroethane, dioxane, etc., Deg.] C to 40 [deg.] C.

Starting material preparation method 1

The compound of Formula 3, which is the starting material of Reaction Scheme 1,

Reacting a compound represented by the formula (4) with a hydroxylamine to prepare a compound represented by the formula (5) (step a);

Reacting a compound represented by the formula (5) obtained in the step (a) with a compound represented by the formula (6) to prepare a compound represented by the formula (7) (step b); And

And a step (c) of reacting the compound represented by the formula (7) obtained in the step (b) under a base condition to prepare a compound represented by the formula (3a).

[Reaction Scheme 2]

(Wherein, in the above Reaction Scheme 2, n is an integer of 0-5, E is halogen,

R ⁷ is unsubstituted or substituted with _one or more groups selected from the group consisting of -OH, -NO ₂ , halogen, C ₁ -C ₄ linear or branched alkoxy, phenyl and nitrogen (N), oxygen (O) Or heteroaryl or heterocycloalkyl containing one or more heteroatoms selected from the group consisting of C ₁ -C ₄ linear or branched alkoxy, phenyl, heteroaryl or heterocyclo Alkyl is selected from the group consisting of unsubstituted or -OH, -NO ₂ , halogen, C ₁ -C ₅ straight or branched chain alkyl, phenoxy and C ₁ -C ₅ alkoxy C ₆ -C ₁₀ aryl C ₁ -C ₅ alkoxy Which may be substituted with one or more substituents,

The compound represented by the general formula (3a) is a derivative of the compound represented by the general formula (3) in the above Scheme 1.

Hereinafter, the manufacturing method will be described step by step.

First, step a according to the present invention is a step of reacting a nitrile compound represented by formula (4) with a hydroxylamine to prepare an N-hydroxyimidate compound represented by formula (5).

In step (a), the reaction solvent may be methanol, ethanol, propanol, butanol or the like, and the reaction temperature is preferably at room temperature.

Next, step b according to the present invention is a step of cyclizing a N-hydroxyimidate compound represented by the formula (5) obtained in the step (a) with a halogenoalkanoate compound represented by the formula (6) , 2,4-oxadiazole, and the like.

In the step (b), the halogenoalkanoate compound can be used as long as it is a compound having a halogenoalkanoate structure.

In the step b, the reaction solvent is an organic solvent such as pyridine, triethylamine, N, N-diisopropylethylamine (DIPEA), 1,8-diazabicyclo [5.4.0] The solvent may be a base or a solvent, and the reaction may be carried out at a temperature ranging from room temperature to the boiling point of the solvent.

Next, step c according to the present invention is carried out by reacting an ester compound containing 1,2,4-oxadiazole represented by the general formula (7) obtained in the above step b under basic conditions to obtain 1,2,4 - oxadiazole in the presence of a base.

In step c, the base may be lithium hydroxide, sodium hydroxide, etc. The reaction solvent may be an ether solvent such as tetrahydrofuran, dioxane or dichloromethane, or a solvent such as methanol, ethanol, propanol, Alcohol-based solvents, water, and the like may be used alone or in combination. Also, the reaction temperature is preferably 15 ° C to 35 ° C.

Starting material preparation method 2

The compound of Formula 3, which is the starting material of Reaction Scheme 1,

A step of reducing a compound represented by the formula (8) under a base condition to prepare a compound represented by the formula (9) (step a);

Halogenating the compound of formula (9) obtained in step (a) with a halogenating reagent to prepare a compound represented by formula (10) (step b);

Malonate-forming a compound represented by the formula (10) obtained in the step (b) under a base condition with a malonate reagent to prepare a compound represented by the formula (11) (step c);

A step (d) of reducing the compound represented by the formula (11) obtained in the step c under a base condition to prepare a compound represented by the formula (12); And

And a step (e) of reacting the compound represented by the formula (12) obtained in the step (d) under a base condition to prepare a compound represented by the formula (3b).

[Reaction Scheme 3]

Wherein X, Y, and Z are not simultaneously carbon, and E and R ⁷ are each independently a carbon (C) or nitrogen (N) in the above Reaction Scheme 3, And the compound represented by the formula (3b) is a derivative of the compound represented by the formula (3) in the above Reaction Scheme 1.

Hereinafter, the manufacturing method will be described step by step.

First, step a according to the present invention is a step of reducing an ester compound represented by the general formula (8) under a base condition to prepare an alcohol compound represented by the general formula (9).

In the step (a), the base may be selected from the group consisting of sodium hydride, sodium borohydride, lithium borohydride, and lithium diisopropyl amide. The reaction solvent is tetrahydrofuran, dioxane, dichloromethane, Ether solvents such as 2-dimethoxyethane and the like; Lower alcohols such as methanol, ethanol, propanol, butanol and the like, or dimethylformamide, dimethylsulfoxide, acetonitrile, etc. may be used alone or in combination. The reaction temperature is preferably from room temperature to the boiling point of the solvent.

Step b according to the present invention is a step of halogenating the alcohol compound represented by the formula (9) obtained in the step (a) with a halogenating reagent to prepare a halogen compound represented by the formula (10).

In the step b, the halogenating reagent may be a reagent such as NBS, N-bromosuccinimide, N-chlorosuccinimide, etc. The reaction solvent may be tetrahydrofuran Furan, dioxane, dichloromethane, 1,2-dimethoxyethane, and the like, alone or in combination. The reaction temperature is preferably -10 ° C to 10 ° C.

Next, step c according to the present invention is a step of malonate-forming a halogen compound represented by the formula (10) obtained in the step b) with a malonate reagent under a base condition to prepare a malonate compound represented by the formula (11).

In step c, the malonate reagent may be dimethylmalonate, diethylmalonate, or the like. The base may be selected from sodium hydride, sodium borohydride, lithium borohydride, lithium diisopropyl amide, etc. .

In step c, the reaction solvent may be dichloromethane, dichloroethane, chloroform, tetrahydrofuran, or the like. The reaction temperature is preferably 0 ° C to the boiling point of the solvent.

Next, step d according to the present invention is a step of reducing the malonate compound represented by the formula (11) obtained in the step (c) under the base condition to prepare the malonic acid compound represented by the formula (12).

In step d, the base may be lithium hydroxide, sodium hydroxide, potassium hydroxide, etc. The reaction solvent may be an ether solvent such as tetrahydrofuran, dioxane, dichloromethane, methanol, ethanol, Alcohol solvents such as methanol, ethanol, propanol, and butanol, and water may be used alone or in combination. The reaction temperature is preferably -10 ° C to 10 ° C.

Step e according to the present invention is a step of reacting the malonic acid compound represented by the formula (12) obtained in the above step d under basic conditions to prepare a carboxylic acid compound represented by the formula (3b).

In the step (e), the base is the same as the base which can be used in the step (d), and the reaction solvent is preferably used singly or in combination of dimethylformamide, dimethylsulfoxide and acetonitrile, Is preferably carried out at the boiling point of the solvent.

Production Method 2

Another method for producing an indole derivative represented by the formula (1) according to the present invention is a method for producing an indole derivative represented by the following formula (4)

And then subjecting the compound represented by the formula (2) to amidation reaction with a compound represented by the formula (13) and a carbonyl reagent to prepare a compound represented by the formula (1a).

[Reaction Scheme 4]

은 상기 화학식 1에서 정의한 바와 같고, R⁷은 상기 반응식 2에서 정의한 바와 같고, 화학식 1a로 표시되는 화합물은 상기 화학식 1로 표시되는 화합물의 유도체이다.)
(In the above Reaction Scheme 4, R ¹ , R ² , R ³ And

Is as defined in Formula 1, R ⁷ is as defined in Reaction Formula 2, and the compound represented by Formula (1a) is a derivative of the compound represented by Formula (1).

Hereinafter, the production method will be described in detail.

(2) with a piperazine compound represented by the formula (13) and a carbonyl reagent to prepare a compound containing piperazine represented by the formula (Ia), the indole derivative represented by the formula (1) Can be produced.

In the above production method, the carbonyl reagent may be triphosgene, phosgene, chloroacetyl chloride, trichloromethylcarbonyl chloridate, etc. The base may be triethylamine, N, N-diisopropylethylamine (DIPEA ) And 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) can be used.

In the above production method, dichloromethane, dichloroethane, chloroform and the like may be used alone or in combination as a reaction solvent, and it is preferably carried out at 15 to 35 ° C.

Production Method 3

Another method for producing an indole derivative represented by the formula (1) according to the present invention is a method for producing an indole derivative represented by the following formula (5)

Reacting a compound represented by the formula (2) with an anhydride compound represented by the formula (14) to prepare a compound represented by the formula (1b).

[Reaction Scheme 5]

은 상기 화학식 1에서 정의한 바와 같고, m은 0-5의 정수이고, 화학식 1b로 표시되는 화합물은 상기 화학식 1로 표시되는 화합물의 유도체이다.)
(In the above Reaction Scheme 5, R ¹ , R ² , R ³ And

M is an integer of 0-5, and the compound represented by the formula (1b) is a derivative of the compound represented by the formula (1).

Hereinafter, the production method will be described in detail.

The preparation method according to the present invention includes a step of reacting a compound represented by the formula (2) with an anhydride compound represented by the formula (14) to prepare a compound containing a carboxylic acid represented by the formula (1b) Indole derivatives can be prepared.

In the above production method, the anhydride compound may be succinic anhydride, 2,2-dimethylsuccinic anhydride or the like, and the reaction solvent may be ethyl acetate, tetrahydrofuran, dioxane, dichloromethane or the like Solvents may be used alone or in combination. Further, the reaction temperature is preferably carried out at the boiling point of the solvent.

Production method 4

Another method for producing an indole derivative represented by the formula (1) according to the present invention is as follows:

Halogenating a compound represented by the formula (1b) with a halogenating reagent to prepare a compound represented by the formula (15) (step 1); And

(Step 2) of cyclizing a compound represented by the formula (15) obtained in the above step 1 with a compound represented by the formula (16) to prepare a compound represented by the formula (1c) (step 2) .

[Reaction Scheme 6]

및 n은 상기 화학식 1에서 정의한 바와 같고, E 및 R⁷은 상기 반응식 2에서 정의한 바와 같고, 화학식 1c로 표시되는 화합물은 상기 화학식 1로 표시되는 화합물의 유도체이다.)
(In the above Reaction Scheme 6, R ¹ , R ² , R ³ ,

And n are the same as defined in Formula 1, E and R ⁷ are as defined in Reaction Formula 2, and the compound represented by Formula 1c is a derivative of the compound represented by Formula 1.

Hereinafter, the production method will be described in detail.

First, step 1 according to the present invention is a step of halogenating a carboxylic acid compound represented by formula (1b) with a halogenating reagent to prepare an acid halide compound represented by formula (15).

The halogenating reagent may be a reagent such as N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS) or the like in the step 1, and a reagent such as tetrahydrofuran, dioxane , Dichloromethane, 1,2-dimethoxyethane, and the like, alone or in combination. The reaction temperature is preferably -10 ° C to 10 ° C.

Step 2 according to the present invention is a step of cyclizing an acid halide compound represented by the formula (15) obtained in the above step 1 with an N-hydroxyimidate compound represented by the formula (16) 4-oxadiazole. ≪ / RTI >

In the step 2, the N-hydroxyimidate compound may be obtained by reacting it in the same manner as in the step a of Scheme 2, or a compound having a substituent of N-hydroxyimidate may be used.

In the step 2, the cyclization reaction can be carried out without a catalyst, but when a catalyst is used to promote the reaction, sodium ascorbate or the like can be used.

In the step 2, the reaction solvent is an ether solvent such as tetrahydrofuran, dioxane, dichloromethane, 1,2-dimethoxyethane and the like, a lower alcohol such as methanol, ethanol, propanol, butanol, dimethylformamide (DMF) Dimethyl sulfoxide (DMSO), acetonitrile, etc., may be used alone or in combination.

And lower alcohols such as methanol, ethanol, propanol, butanol, etc., and the reaction temperature is preferably from room temperature to the boiling point of the solvent.

Production method 5

Another method for producing an indole derivative represented by the general formula (1) according to the present invention is shown in Scheme 7,

(2) with a compound represented by formula (17) under basic conditions to prepare a compound represented by formula (18) (step 1); And

(Step 2) of cyclizing a compound represented by the formula (18) obtained in the step 1 with sodium azide and a compound represented by the formula (19) to prepare a compound represented by the formula (1d) .

[Reaction Scheme 7]

및 n은 상기 화학식 1에서 정의한 바와 같고, R⁷은 상기 반응식 2에서 정의한 바와 같고, 화학식 1d로 표시되는 화합물은 상기 화학식 1로 표시되는 화합물의 유도체이다.)
(In the above Reaction Scheme 7, R ¹ , R ² , R ³ ,

And n are the same as defined in Formula 1, R ⁷ is as defined in Reaction Scheme 2, and the compound represented by Formula 1d is a derivative of the compound represented by Formula 1.

Hereinafter, the production method will be described in detail.

First, step 1 according to the present invention is a step of producing an acetylene compound represented by the formula (18) by carrying out an amidation reaction of an indole compound represented by the formula (2) with a carboxylic acid compound containing acetylene represented by the formula (17) .

In the above step 1, the carboxylic acid compound containing acetylene may be used as long as it is a compound having a substituent group of acetylene and carboxylic acid, but it is preferable to use pentaamino acid, hexanoic acid, heptanoic acid, or the like.

In step 1, the base is an organic base such as triethylamine, N, N-diisopropylethylamine (DIPEA) or 1,8-diazabicyclo [5.4.0] -7-undecene The reaction solvent may be dichloromethane, dichloroethane, chloroform or the like, and it is preferably carried out at 15 to 35 ° C.

Next, step 2 according to the present invention is a step of cyclizing an acetylene compound represented by the formula (18) obtained in the above step 1 with sodium azide and a boronic acid compound represented by the formula (19) to obtain 1, 2, 3 -Triazole. ≪ / RTI >

In the step 2, the boronic acid compound may be used as long as it can react with sodium azide to form aryl azide. Copper such as capper sulfate, capper acetate, capper bromide, or the like may be used to promote the formation of aryl azide. Metal catalysts such as ruthenium and the like can be used.

In the step 2, the cyclization reaction can be carried out without a catalyst, but when a catalyst is used to promote the reaction, sodium ascorbate or the like can be used.

In the step 2, the reaction solvent may be a lower alcohol such as methanol, ethanol, propanol, butanol, etc., and is preferably carried out at 15 to 35 ° C.

Furthermore, the present invention provides a pharmaceutical composition for preventing or treating dyslipidemia, which comprises the novel indole derivative represented by the above-mentioned formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

Herein, the dyslipidemia may include hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, and the like.

The indole compound represented by Formula 1 according to the present invention has an excellent antinociceptive activity against the GPR109A receptor in a concentration-dependent manner. Compounds of Examples 22 and 23 exhibit more than 100% antagonistic activity at 10 [mu] M, and more than 90% at 1 [mu] M. MK6892 of Comparative Example 1, which is being developed as a therapeutic agent for hyperlipidemia, exhibited an activity of 104% at 10 μM and niacin of Comparative Example 2, which is a kind of vitamin B used as a therapeutic agent for hyperlipidemia, Activity. From these results, it can be seen that the indolizine compound represented by formula (1) according to the present invention has an antidiabetic activity similar to that of MK6892 and niacin, which have been used conventionally (see Table 2), for the GPR109A receptor.

In addition, the substance containing the indole derivative represented by the above formula (1) or a pharmaceutically acceptable salt thereof according to the present invention as an active ingredient can be used for measuring the movement of beta-arraysin into the cell, which is a signal transduction pathway associated with facial flushing side effects In one experiment, the migration of beta-arrestin into the cell was reduced by exhibiting a fluorescence ratio much lower than that of niacin or MK-6892 at high doses (see FIG. 2 and Table 3).

Furthermore, the substance containing the indole derivative represented by the above formula (1) or its pharmaceutically acceptable salt as an active ingredient according to the present invention shows excellent cytotoxicity at a high concentration of 10 μM in the GPR109A calcium cell line, (See Table 4).

Therefore, the indole derivative represented by Formula 1 according to the present invention is safe because it is free from cytotoxicity, has an excellent effect of binding to niacin GPR109A receptor to activate the receptor, and less activating the beta-arrestin signaling pathway Therefore, it can be usefully used as a composition for preventing or treating dyslipidemia such as hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, while minimizing side flushing side effects.

In the pharmaceutical composition according to the present invention, the indole derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof may be administered orally or parenterally in various dosage forms during clinical administration. In the case of formulation, Such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, and the like.

Solid formulations for oral administration include tablets, patients, powders, granules, capsules, troches and the like, and such solid preparations may contain one or more of the indole derivatives of Formula 1 of the present invention, The salt may be formulated by mixing at least one excipient, for example, starch, calcium carbonate, sucrose or lactose, or gelatin. In addition to simple excipients, lubricants such as magnesium stearate, talc, and the like may also be used. Liquid preparations for oral administration include suspensions, solutions, emulsions or syrups. Various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like are included in addition to commonly used simple diluents such as water and liquid paraffin. .

Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the non-aqueous solvent and suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. As a base for suppositories, witepsol, macrogol, tween 61, cacao paper, laurin, glycerol, gelatin and the like can be used.

The dosage of the indole derivative of the present invention represented by the formula (1) of the present invention or a pharmaceutically acceptable salt thereof to the human body may vary depending on the age, body weight, sex, dosage form, health condition and disease severity of the patient, Is generally 0.1 to 1000 mg / day, preferably 1 to 500 mg / day, based on an adult patient of 70 Kg, and may be administered once a day at a predetermined time interval according to the judgment of a doctor or pharmacist It may be divided into several doses.

The pharmaceutical composition of the present invention can be used alone or in combination with methods for the prevention or treatment of dyslipidemia or using surgery, hormone therapy, chemotherapy and biological response modifiers.

The present invention also provides a health food composition for preventing or ameliorating dyslipidemia, which comprises an indole derivative represented by the above formula (1) and a pharmaceutically acceptable salt thereof as an active ingredient.

Herein, the dyslipidemia may include hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, and the like.

The indole derivative represented by Formula 1 according to the present invention is safe because it is free from cytotoxicity, has an excellent effect of binding to niacin GPR109A receptor to activate the receptor, and less activates the beta-arrestin signaling pathway, An indole derivative represented by the above formula (1) may be added to a health supplement such as food, beverage or the like as a composition for preventing or ameliorating dyslipidemia such as hyperlipidemia, hypercholesterolemia and hypertriglyceridemia while minimizing side flushing side effects .

There is no particular limitation on the kind of the food. Examples of the foods to which the above substances can be added include dairy products including dairy products, meat, sausage, bread, biscuits, rice cakes, chocolate, candies, snacks, confectionery, pizza, ramen and other noodles, gums, ice cream, Beverages, alcoholic beverages and vitamin complexes, dairy products, and dairy products, all of which include health functional foods in a conventional sense.

INDUSTRIAL APPLICABILITY The indole derivative represented by the above formula (1) according to the present invention can be used as it is in food or in combination with other food or food ingredients, and can be suitably used according to conventional methods. The amount of the active ingredient to be mixed can be suitably determined according to the intended use (for prevention or improvement). Generally, the amount of the compound in the health food may be 0.1 to 90 parts by weight of the total food. However, in the case of long-term intake intended for health and hygiene purposes or for the purpose of controlling health, the amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount exceeding the above range.

In addition, the health functional beverage composition of the present invention has no particular limitation on other components other than the above-mentioned compounds as essential components in the indicated ratios, and may contain various flavoring agents or natural carbohydrates as additional components such as ordinary beverages have. Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And polysaccharides, for example, conventional sugars such as dextrin, cyclodextrin and the like, and sugar alcohols such as xylitol, sorbitol and erythritol. Natural flavors (tau martin, stevia extracts (e.g., rebaudioside A, glycyrrhizin, etc.) and synthetic flavors (saccharin, aspartame, etc.) can be advantageously used as flavors other than those described above The ratio of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 of the composition of the present invention.

In addition, the indole derivative represented by the formula (1) according to the present invention may further contain flavoring agents such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, coloring agents and intermediates such as cheese, Organic acids, protective colloid thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated drinks, and the like. In addition, the indole derivatives of the present invention may contain natural fruit juice and pulp for the production of fruit juice drinks and vegetable drinks.

These components may be used independently or in combination. Although the ratio of such additives is not so important, the derivatives of the present invention are generally selected in the range of 0.1 to about 20 parts by weight per 100 parts by weight.

Hereinafter, the present invention will be described in detail with reference to Examples and Experimental Examples.

However, the following Examples and Experimental Examples are merely illustrative of the present invention, and the present invention is not limited to the following Examples and Experimental Examples.

< Example  1 > Ethyl 5- Methoxy -1- {3- [3- (4- (4- Methoxybenzyloxy ) Phenyl ) -1,2,4- Oxadiazole -5 days] Propanoyl }-One H - indole-2- Carboxylate  Produce

Preparation Step 1: 5- (4- Methoxybenzyloxy ) Picolinonitrile  Produce

A solution of sodium hydride (NaH, 0.88 g, 37 mmol) in dimethylformamide (40 mL) was cooled to 0 ° C and 4-methoxybenzyl alcohol (4.3 g, 31 mmol) Lt; / RTI &gt; for 30 minutes, then stirred at room temperature for 30 minutes. Next, 5-bromo picolinonitrile (5 g, 27 mmol) was added to the reaction solution, stirred for 20 minutes at room temperature, and then the reaction was terminated. Next, the reaction solution was extracted with ethyl acetate (150 mL) and washed three times with water (100 mL). The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), concentrated under reduced pressure and purified by silica gel column chromatography (hexane: ethyl acetate = 1-3: 10) to obtain the desired compound (4.85 g, 74% .

_{^{1 H NMR (CDCl 3, 300}} MHz) δ 8.42 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.26-7.35 (m, 3H), 6.93 (m, 2H), 5.09 (s, 2H), 3.85 (s, 3H).

Preparation Step 2: N ' - Hydroxy -5- (4- Methoxybenzyloxy ) Picolinimidate  Produce

(4.85 g, 20 mmol) and dihydroxylamine hydrochloride (1.66 g, 24 mmol) obtained in the above preparation step 1 were dissolved in ethanol (100 mL) Aqueous solution of sodium hydroxide (0.96 g of NaOH, 24 mmol, 10 mL of H ₂ O) was added dropwise. The resulting mixture was stirred at room temperature for 8 hours, and the resulting solid was filtered and dried under reduced pressure to obtain the desired compound (4.85 g, 74%, white solid) without purification.

_{^{1 H NMR (DMSO-d 6}} , 300 MHz) δ 9.71 (s, 1H), 8.29 (s, 1H), 7.77 (d, 1H, J = 8.4 Hz), 7.48 (dd, J = 1.5, 7.5 Hz, 1H), 7.40 (d, J = 7.5 Hz, 2H), 6.95 (m, 2H).

Preparation Step 3: methyl  3- {3- [5- (4- Methoxybenzyloxy ) Pyridin-2-yl] -1,2,4- Oxadiazole -5 days} Propanoate  Produce

The N ' -hydroxy-5- (4-methoxybenzyloxy) picolinimidate compound (1.5 g, 5.5 mmol) obtained in the above preparation step 2 was dissolved in pyridine (4 mL) 4-Oxobutanoate (0.82 mL, 5.5 mol) was added and stirred at 130 캜 for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and water and dichloromethane were added to extract the reaction mixture. Next, the organic layer was separated, washed with water, dried over sodium sulfate (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. Methanol (3 mL) was added to the residue which was concentrated under reduced pressure, and the resulting solid was filtered, washed with methanol, and vacuum-dried to obtain the desired compound (1.4 g, 74%, pale pink solid).

_{^{1 H NMR (DMSO-d 6}} , 300 MHz) δ 8.51 (s, 1H), 8.03 (d, 1H, J = 8.7 Hz), 7.32-7.38 (m, 3H), 6.93 (d, J = 8.4 Hz, 2H), 5.10 (s, 2H), 3.82 (s, 3H), 3.72 (s, 3H), 3.28 (t, J = 7.2 Hz, 2H), 2.98 (t, J = 7.2 Hz, 2H).

Preparation Step 4: Preparation of 3- {3- [5- (4- Methoxybenzyloxy ) Pyridin-2-yl] -1,2,4- Oxadiazole -5 days} Propanoic  Produce

The methyl 3- {3- [5- (4-methoxybenzyloxy) pyridin-2-yl] -1,2,4-oxadiazol-5-yl} propanoate compound g, 3.4 mmol) was dissolved in a mixture of tetrahydrofuran, methanol and water (THF: MeOH: H ₂ O = 3: 1: 1, 35 mL) and lithium hydroxide aqueous solution (LiOH, 1N, 15 mL ), And the mixture was stirred at room temperature for 1 hour. After completion of the reaction, hydrochloric acid (HCl) was added to the residue concentrated under reduced pressure to adjust the pH to 3. Next, the resulting solid was filtered, washed with water and vacuum dried to obtain the desired compound (1.3 g, 90%, white solid).

_{^{1 H NMR (DMSO-d 6}} , 300 MHz) δ 8.53 (s, 1H), 8.03 (d, J = 8.7 Hz, 1H), 7.34-7.37 (m, 3H), 6.93 (d, J = 8.4 Hz, 2H), 5.10 (s, 2H), 3.82 (s, 3H), 3.27 (t, J = 7.2 Hz, 2H), 3.04 (t, J = 7.2 Hz, 2H).

Step 1: Ethyl 5- Methoxy -1- {3- [3- (4- (4- Methoxybenzyloxy ) Phenyl ) -1,2,4- Oxadiazole -5 days] Propanoyl }-One H - indole-2- Carboxylate  Produce

2-yl] -1,2,4-oxadiazol-5-yl} propanoic acid compound (16 mg, 0.046 mmol) was dissolved in dimethylformamide (1 mL), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (10 mg, 0.048 mmol) was added and the mixture was stirred at room temperature for 2 hours. To the reaction solution, ethyl 5-methoxyindole-2-carboxylate (10 mg, 0.046 mmol) was dissolved in dimethylformamide (1 mL), sodium hydride (NaH, 1.3 mg, 0.055 mmol) And the mixture was stirred for 30 minutes. The mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate and washed twice with saturated brine. The organic layer was dried with sodium sulfate (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain the desired compound (11 mg, 43% Solid).

_{^{1 H NMR (DMSO-d 6}} , 300 MHz) δ 8.48 (s, 1H), 8.02-8.04 (m, 1H), 7.75 (d, J = 9.5 Hz, 1H), 7.41-7.29 (m, 3H), 7.12-7.04 (m, 1H), 6.92 (d, J = 7.4 Hz, 2H), 5.31 (s, 2H), 5.13 (s, 2H), 4.39 (q, J = 8.5 Hz, 2H), 3.85 (q J = 7.2 Hz, 3H), 3.85 (d, J = 10.6 Hz, 3H), 3.47 (s, 2H), 1.41 (t, J = 7.2 Hz, 3H).

< Example  2 > Ethyl 5- Methoxy -1- {3- [3- (4- (4- Hydroxyphenyl ) -1,2,4- Oxadia 5-yl] Propanoyl }-One H - indole-2- Carboxylate  Produce

Compound of Example 1 (10 ㎎, 0.018 mmol) and dichloromethane (1 mL) was dissolved in, and cooled to 0 ℃ trifluoroacetic acid (10 ㎕) and triisopropylsilane (i -Pr ₃ SiH, 9 [mu] L, 0.045 mmol), and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain the desired compound (5 mg, 64%, yellow solid).

¹ H-NMR (CDCl _3, 1H, J = 9.50 Hz), 7.41-7.29 (m, 3H), 7.15-7.07 (m, 1H), 6.98 (m, d, 2H, J = 7.4 Hz ), 5.36 (s, 2H), 5.15 (s, 2H), 4.42 (q, 2H, J = 7.4 Hz), 3.87 (s, 3H), 3.48 (s, 2H), 1.45 (t, 3H, J = 7.4 Hz).

< Example  3> 5- Methoxy -1- {3- [3- (4- (4- Hydroxyphenyl ) -1,2,4- Oxadiazole -5 days] Propanoyl }-One H - indole-2- Carboxylic acid  Produce

After dissolving the compound of Example 2 (5 mg, 0.011 mmol) in tetrahydrofuran, methanol and water (THF: MeOH: H ₂ O = 3: 1: 1, 1 mL), potassium hydroxide (KOH, , 0.017 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, the pH was adjusted to 5 with an aqueous hydrochloric acid solution (HCl, 1N), extracted with dichloromethane (CH ₂ Cl ₂ ), washed twice with saturated brine Respectively. The organic layer was dried over sodium sulphate (Na2SO4) filtered and the filtrate was concentrated under reduced pressure and then the residue was subjected to silica gel column chromatography _{(CH 2 Cl 2: MeOH =} 10: 1) to give the desired compound (2 ㎎, 43%, yellow Solid).

¹ H-NMR (CDCl _3, (D, J = 9.4 Hz, 1H), 7.41-7.29 (m, 3H), 7.15-7.07 (m, m, 1H), 4.03-3.92 (m, 3H), 3.89 (s, 3H), 3.73-3.55 (m, 5H), 3.53 (s, 2H).

< Example  4> methyl  1- [4- (2- Chlorophenyl ) Piperazine-1-carbonyl] Indolin -2- Carlsbad Manufacture of silicate

(20 mg, 0.113 mmol) was dissolved in dichloromethane (CH ₂ Cl _2, 1 mL), then triphosgene (17 mg, 0.056 mmol) and diisopropylethylamine (24 L, 0.136 mmol) in dichloromethane (1 mL) was added, and the mixture was stirred at room temperature for 30 minutes. Next, a mixed solution obtained by dissolving 1- (2-chlorophenyl) piperazine (40 mg, 0.170 mmol) and diisopropylethylamine (30 μl, 0.17 mmol) in dichloromethane And the mixture was stirred at room temperature for 1 hour. Water was added to terminate the reaction, extracted with dichloromethane and washed twice with saturated brine. The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain the desired compound (40 mg, 89% Light yellow solid).

_{^{1 H-NMR (CDCl 3,}} 300 MHz) δ 7.37 (d, J = 7.3 Hz, 1H), 7.26-7.13 (m, 3H), 7.07-6.88 (m, 4H), 5.06 (t, J = 9.8 Hz (M, 1H), 3.78 (s, 3H), 3.56-3.37 (m, 5H), 3.14-3.11 (m, 4H), 3.07

< Example  5> 1- [4- (2- Chlorophenyl ) Piperazine-1-carbonyl] Indolin -2- Carboxylic acid  Produce

The objective compound (37 mg, 96%, pale yellow solid) was obtained by a similar method to that of Example 3, except that the compound of Example 4 (40 mg, 0.10 mmol) was used.

_{^{1 H-NMR (CDCl 3,}} 300 MHz) δ 7.36 (d, 1H, J = 7.9 Hz), 7.26-7.16 (m, 3H), 7.93-6.92 (m, 4H), 4.92 (m, 1H), 3.73 -3.51 (m, 5H), 3.32 (m, 1H), 3.15-3.03 (m, 4H).

< Example  6> 1- [4- (2- Chlorophenyl ) Piperazine-1-carbonyl] Indolin -2- Carboxamide Manufacture of de

The compound of Example 5 (35 mg, 0.091 mmol) was dissolved in dichloromethane (2 mL), oxalyl chloride (15 μL, 0.181 mmol) and dimethylformamide (2 drops) were added at 0 ° C., Lt; / RTI &gt; for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane (2 mL), cooled to 0 ° C, ammonium hydroxide (NH ₄ OH, 1 mL) was added and the mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction mixture was extracted with dichloromethane and washed twice with saturated brine. The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ) and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5-1: 1) %, White solid).

_{^{1 H-NMR (CDCl 3,}} 300 MHz) δ 7.37 (d, J = 7.9 Hz, 1H), 7.25-7.15 (m, 2H), 7.07-6.95 (m, 5H), 5.57 (brs, 1H), 4.86 (d, J = 4.9,5.4 Hz, 1H), 3.64-3.59 (m, 4H), 3.55-3.44 (m, 1H), 3.32 (m, 1H), 3.13-3.04 (m, 4H).

< Example  7> 5- Bromo -1- (4- Methoxybenzoyl )-One H - indol-3- Carbaldehyde  Produce

Phosphoryl chloride (62 μL, 0.699 mmol) was slowly added to dimethylformamide (5 mL) at 0 ° C. and stirred for 30 minutes. Then, 5-bromo-1- (4-methoxybenzoyl) -1 H -indole (0.1 g, 0.304 mmol) was added thereto, and the mixture was stirred at 80 ° C for 10 hours. Next, the reaction temperature was cooled to 0 占 폚, diluted with water (10 ml), basified to pH 11 with sodium hydroxide (NaOH, 1N) and extracted with dichloromethane. The organic layer was washed with water, dried over sodium sulfate (Na ₂ SO ₄ ) and then filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (50 mg, 46%, brown oil).

_{^{1 H-NMR (CDCl 3,}} 300 MHz) δ 9.75 (s, 1H), 8.01 (m, 1H), 7.78 (m, 1H), 7.68 (m, 2H), 7.41 (d, J = 8.9 Hz, 2H ), 7.25 (m, 1H), 7.02 (d, J = 8.9 Hz, 2H), 3.83 (s, 3H).

< Example  8> 5- Bromo -1- (4- Methoxybenzoyl )-One H - indol-3- Carboxylic acid  Manufacture of manufacturing

(50 mg, 0.140 mmol) was dissolved in a mixture of ethanol (1 mL) and water (1 mL), potassium hydroxide (8 mg, 0.140 mmol) and manganese dioxide (KMnO₄, 44 mg, 0.280 mmol) was added thereto, followed by stirring at 60 DEG C for 1 hour. After cooling to room temperature, the mixture was filtered through silylite, and the filtrate was concentrated under reduced pressure. The residue was adjusted to pH 4 with hydrochloric acid (HCl 1N), extracted with dichloromethane and washed twice with saturated brine. The organic layer was washed with sodium sulfate (Na₂SO₄The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain the desired compound (16 mg, 31%, white solid).

_{^{1 H-NMR (CD 3 OD}} , 300 MHz) δ 8.01-7.94 (m, 1H), 7.77-7.70 (m, 1H), 7.63 (m, 1H), 7.39 (d, J = 8.95 Hz, 2H), 7.16 (m, 1H), 6.98 (d, 2H, J = 8.66 Hz), 3.83 (s, 3H).

< Example  9> methyl  One- Nicotinoylindoline -2- Carboxylate  Produce

2-carboxylate (0.2 g, 1.129 mmol) was dissolved in dimethylformamide (10 mL) and then nicotinoyl chloride hydrochloride (221 mg, 1.242 mmol) and sodium hydride 60 mg, 2.484 mmol) was added, the temperature was raised to room temperature, and the mixture was stirred for 12 hours. Water was added to terminate the reaction, extracted with ethyl acetate and washed twice with saturated brine. The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3-1: 1) %, Yellow solid).

_{^{1 H-NMR (CDCl 3,}} 300 MHz) δ 8.79 (s, 1H), 8.75 (d, J = 3.9 Hz, 1H), 7.88 (m, 1H), 7.40 (m, 1H), 7.20 (m, 1H ), 3.78 (s, 3H), 3.65-3. 54 (m, 2H), 3.22 (m, 1H).

< Example  10> One- Nicotinoylindoline -2- Carboxylic acid  Produce

The target compound (170 mg, 89%) was obtained by a method similar to that of Example 3, except that the compound of Example 9 (0.2 g, 0.708 mmol) was used.

_{^{1 H-NMR (CD 3 OD}} , 500 MHz) δ 8.74 (s, 1H), 3.21-3.30 (m, 1H), 3.68-3.74 (m, 2H), 7.09 (brs, 1H), 7.29 (d, 1H J = 7.8 Hz), 7.59 (brs, 1H), 8.04 (d, 1H, J = 8.1 Hz), 8.29 (brs, 1H), 8.71 (brs, 1H).

< Example  11> One- Nicotinoyl -One H - indole-2- Carboxylic acid  Produce

Indole-2-carboxylic acid (0.1 g, 0.621 mmol) was dissolved in tetrahydrofuran (5 mL), sodium hydride (3 mg, 1.367 mmol) was added at 0 ° C and the mixture was stirred at room temperature for 30 minutes . To the reaction solution was added nicotinoyl chloride hydrochloride (122 mg, 0.683 mmol) and triethylamine (0.1 mL, 0.683 mmol), and the mixture was stirred at room temperature for 3 hours and then the reaction temperature was raised to 80 ° C and stirred for 5 hours . Water was added to terminate the reaction, extracted with dichloromethane and washed twice with saturated brine. The organic layer was dried with sodium sulfate (Na ₂ SO ₄ ), filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2-1: 1) to obtain the desired compound (20 mg, 12% , White solid).

_{^{1 H-NMR (CDCl 3,}} 300 MHz) δ 9.05 (s, 1H), 8.93 (d, J = 3.7 Hz, 1H), 8.41 (m, 1H), 8.25 (m, 1H), 8.13 (d, J = 7.9 Hz, IH), 8.02 (s, IH), 7.57 (m, IH), 7.50-7.45 (m, 2H).

< Example  12> 2- methyl -One- Nicotinoyl -One H - indol-3- Carboxylic acid  Produce

3-carboxylic acid (30 mg, 0.171 mmol) was dissolved in dichloromethane (2 mL), nicotinoyl chloride hydrochloride (67 mg, 0.376 mmol), N , N -dimethylamino Pyridine (10 mg, 0.090 mmol) and triethylamine (57 [mu] l, 0.410 mmol) were added and the mixture was stirred at room temperature for 10 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain the target compound (8 mg, 17%, yellow solid).

_{^{1 H-NMR (CDCl 3,}} 300 MHz) δ 9.00 (d, J = 12.3 Hz, 1H), 8.92 (m, 1H), 8.24 (d, J = 7.57 Hz, 1H), 8.17 (d, J = 7.57 1H), 7.02 (m, IH), 2.82 (s, 3H).

< Example  13> One- Nicotinoyl -One H -Indol-6- Carboxylic acid  Produce

(34 mg, 21%, pale green solid) was obtained in a similar manner to Example 12, except that indole-6-carboxylic acid (0.1 g, 0.621 mmol) was used.

_{^{1 H-NMR (CDCl 3,}} 300 MHz) δ 9.10 (s, 1H), 8.99 (s, 1H), 8.87 (d, J = 5.1 Hz, 1H), 8.08 (m, 2H), 7.66 (d, J = 8.3 Hz, 1H), 7.53 (m, 1H), 6.72 (d, J = 3.4 Hz, 1H), 7.40 (m, 1H).

< Example  14> 1- (2- Chloronicotinoyl )-One H -Indol-6- Carboxylic acid  Produce

Was reacted in the similar manner to Example 12, except that 2-chloronicotinoyl chloride (240 mg, 1.365) was used in place of indole-6-carboxylic acid (0.1 g, 0.621 mmol) , 11%, pale yellow solid).

_{^{1 H-NMR (CDCl 3,}} 300 MHz) δ 9.22 (brs, 1H), 8.59 (d, J = 4.4 Hz, 1H), 8.19 (d, J = 8.2 Hz, 1H), 7.93 (dd, J = 1.1 , 8.0 Hz, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.46 (m, 1H), 7.19 (s, 1H), 6.75 (d, J = 3.6 Hz, 1H).

< Example  15> 1- (Pyridin-3-yl- Sulfanyl )-One H - indol-3- Carboxylic acid  Produce

After dissolving 3-pyridine sulfonic acid (61 mg, 0.341 mmol) in anhydrous tetrahydrofuran (2 mL), 1-ethyl-3- (3- dimethylaminopropyl) carbodiimide (65 mg , 0.341 mmol) and hydroxybenzotriazole (46 mg, 0.341 mmol) were added and the mixture was stirred at room temperature for 30 minutes. Carboxylic acid (50 mg, 0.310 mmol) and sodium hydride (8 mg, 0.341 mmol) dissolved in anhydrous tetrahydrofuran (1 mL) were added to the reaction solution at 0 ° C for 30 minutes Was added to the reaction solution. After stirring at 80 DEG C for 10 hours, it was diluted with water, extracted with ethyl acetate and washed twice with saturated brine. The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1-2: 1) 11%, pale green solid).

_{^{1 H-NMR (CDCl 3,}} 300 MHz) δ 9.27 (brs, 1H), 8.31 (d, J = 2.3 Hz, 1H), 8.17 (m, 1H), 8.11 (d, J = 8.3 Hz, 1H), 7.51-7.57 (m, 2H), 7.45 (m, 1H), 7.37 (m, 2H).

< Example  16> 1- (6- Chloronicotinoyl )-One H - indol-3- Carboxylic acid  Produce

Preparation Step 1: 2- ( Trimethylsilyl ) Ethyl 1H-indole-3- Carboxylate  Produce

Indole-3-carboxylic acid (1 g, 6.21 mmol) Was dissolved in anhydrous dichloromethane (30 mL), and then 2- (trimethylsilyl) ethanol (1.1 mL, 7.45 mmol) and 1-ethyl-3- (3- dimethylaminopropyl) carbodiimide 1.3 g, 6.83 mmol) and N , N -dimethylaminopyridine (76 mg, 0.621 mmol) at 0 ° C, and the mixture was stirred at room temperature for 3 hours. Water was added to terminate the reaction, extracted with dichloromethane and washed twice with saturated brine. The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain the desired compound (1.2 g, 74% White solid).

_{^{1 H NMR (CDCl 3, 500MHz}} ) δ 8.56 (brs, 1H), 8.19 (d, J = 8.2 Hz, 1H), 8.24 (m, 1H), 7.93 (d, J = 3.1 Hz, 1H), 7.43 ( m, 1 H), 7.32-7.28 (m, 2H), 4.47 (m, 1H), 1.20 (m, 2H), 0.12 (s, 9H).

Step 1: 2- ( Trimethylsilyl ) Ethyl 1- (6- Chloronicotinoyl ) -1H-indole-3- Carboxylate  Produce

Except that 2- (trimethylsilyl) ethyl 1H-indole-3-carboxylate (0.3 g, 1.15 mmol) and 6-chloronicotinoyl chloride (242 mg, 1.38 mmol) Was reacted by a method similar to that of Example 12 to obtain the desired compound (300 mg, 65%, white oil).

_{^{1 H-NMR (CDCl 3,}} 300 MHz) δ 8.78 (s, 1H), 8.36 (m, 1H), 8.24 (m, 1H), 8.05 (d, J = 8.3 Hz, 1H), 7.86 (s, 1H ), 7.57 (d, J = 8.3 Hz, 1H), 7.46 (s, 2H), 4.43 (t, J = 8.5 Hz, 2H), 1.15 (t, J = 8.5 Hz, 2H), 0.08 (s, 9H ).

Step 1: 1- (6- Chloronicotinoyl ) -1H-indole-3- Carboxylic acid  Produce

Carboxylate (50 mg, 0.125 mmol) obtained in the above step 1 was added dropwise to a solution of 2- (trimethylsilyl) ethyl 1- (6-chloronicotinoyl) After dissolving in anhydrous dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added to the mixed solution at 0 ° C, and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5-1: 1) to obtain the title compound as a white solid (10 mg, 27%, white solid).

_{^{1 H-NMR (DMSO- d 6}} , 300 MHz) δ 12.84 (brs, 1H), 8.83 (s, 1H), 8.31 (m, 2H), 8.14 (d, J = 7.9 Hz, 1H), 7.97 (s 1H), 7.78 (d, 1H, J = 8.7Hz), 7.52-7.40 (m, 2H).

< Example  17> 1- (6- Molpolonikicotinoyl )-One H - indol-3- Carboxylic acid  Produce

Preparation Step 1: 2- ( Trimethylsilyl ) Ethyl 1- (6- Molpolonikicotinoyl ) -1H-indole-3- Carboxylate  Produce

2- (trimethylsilyl) ethyl 1- (6-chloronicotinoyl) -1H-indole-3-carboxylate (0.1 g, 0.219 mmol) obtained in the step 1 of Example 16 After dissolving in dimethylformamide (3 mL), morpholine (66 L, 0.747 mmol) was added to the mixed solution and reacted at 100 ° C for 20 minutes in a microwave reactor. After the reaction was terminated with water, the reaction solution was extracted with ethyl acetate and washed twice with saturated brine. The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ) and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10-3: 1) to obtain the desired compound (60 mg, 53% , White solid).

_{^{1 H-NMR (CDCl 3,}} 300 MHz) δ 8.61 (s, 1H), 8.30-8.19 (m, 2H), 8.07 (s, 1H), 7.92 (d, J = 8.5 Hz, 1H), 7.44-7.34 (m, 2H), 6.69 ( d, J = 9.4 Hz, 1H), 4.44 (t, J = 8.3 Hz, 2H), 3.86 (m, 4H), 3.76 (m, 4H), 1.17 (t, J = 8.3 Hz, 2H), 0.08 (s, 9H).

Step 1: 1- (6- Molpolonikicotinoyl ) -1H-indole-3- Carboxylate  Produce

Carboxylate (30 mg, 0.066 mmol) obtained in the above preparation step 1 was used instead of 2- (trimethylsilyl) ethyl 1- (6-morpholinonicotinonyl) -1H-indole- The target compound (20 mg, 86%, white solid) was obtained by a method similar to the step 2 of Example 16.

_{^{1 H-NMR (DMSO- d 6}} , 300 MHz) δ 9.30 (brs, 1H), 8.69 (d, J = 4.5 Hz, 1H), 8.28-8.15 (m, 2H), 8.09-7.92 (m, 2H) , 7.52-7.46 (m, 2H), 7.09 (m, 1H), 3.85 (m, 4H), 3.76 (m, 4H).

< Example  18> 1- [6- (4- Methylpiperazine -1 day) Nicotinoyl )-One H - indol-3- Carboxylic acid Manufacturing

Carboxylate (0.2 mg, 0.5 mmol) and 1-methylpiperazine (obtained in Step 1 of Example 16) obtained in Step 1 of Example 16 and 2- (trimethylsilyl) 0.5 mL, 1.48 mmol), the target compound (43 mg, 24%, white solid) was obtained by a method similar to Preparation 1 and Step 1 of Example 17.

_{^{1 H-NMR (CD 3 OD}} , 500 MHz) δ 8.58 (s, 1H), 8.28 (m, 1H), 8.23 (m, 1H), 8.01 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.37-7.32 (m, 2H). 6.93 (d, 1H, J = 8.43 Hz), 3.82 (m, 4H), 2.66 (m, 4H), 2.44 (s, 3H).

< Example  19> 1- [6- ( Pyrrolidine -1 day) Nicotinoyl ]-One H - indol-3- Carboxylic acid  Produce

(62 mg, 0.15 mmol) and pyrrolidine (40 [mu] L, 0.15 mmol) obtained in the step 1 of Example 16 and 2- (trimethylsilyl) , 0.48 mmol), the target compound (8 mg, 16%, white solid) was obtained by a method similar to Preparation 1 and Step 1 of Example 17.

¹ H-NMR (CD ₃ OD, 500 MHz)? 8.51 (s, 1H), 8.15-8.10 (m, 2H), 7.99 ), 6.61 (d, J = 6.8 Hz, IH), 3.53 (m, 4H), 1.98 (m, 4H).

< Example  20> 5- Bromo -One- Nicotinoyl -One H - indol-3- Carboxylic acid  Produce

The title compound (10 mg, 5%, yellow solid) was prepared by the reaction of Example 16 with the exception that 5-bromoindole-3-carboxylic acid (132 mg, 0.55 mmol) and nicotinoyl chloride were used. &Lt; / RTI &gt;

_{^{1 H-NMR (CD 3 OD}} , 500 MHz) δ 8.50 (s, 1H), 8.33 (s, 1H), 8.27 (s, 1H), 8.21 (d, J = 9.3 Hz, 1H), 8.09 (s, 1H), 7.50-7.39 (m, 3H).

< Example  21> 1- (Pyrazine-2-carbonyl) -1 H - indol-3- Carboxylic acid  Produce

Carboxylate (0.1 g, 0.62 mmol) and pyrazine-2-carbonyl chloride (0.1 g, 0.69 mmol) in the same manner as in Example 11, Mg, 15%, yellow solid).

_{^{1 H NMR (CD 3 OD,}} 300MHz) δ 9.34 (s, 1H), 8.86 (m, 1Hm), 8.69 (s, 1H), 8.52 (d, J = 7.8 Hz, 1H), 8.21 (d, J = 6.6 Hz, 1H), 7.46-7.39 (m, 2H).

< Example  22> 5- methyl -One- Nicotinoyl -One H - indol-3- Carboxylic acid  Produce

The title compound (50 mg, 16%, pale yellow solid) was obtained by a method similar to that of Example 12, except for using 5-methylindole-3-carboxylic acid (0.2 g, 1.14 mmol).

_{^{1 H-NMR (CDCl 3,}} 300 MHz) δ 8.97 (s, 1H), 8.85 (m, 1H), 8.26 (m, 2H), 8.02 (s, 1H), 7.93 (s, 1H), 7.69 (dd J = 6.0, 6.0 Hz, 1 H), 7.29 (d, J = 8.2 Hz, 1 H), 2.63 (s, 3H).

< Example  23> 5- Chloro -One- Nicotinoyl -One H - indol-3- Carboxylic acid  Produce

The target compound (34 mg, 11%, pale yellow solid) was obtained by a method similar to that of Example 12, except that 5-chloroindole-3-carboxylic acid (0.2 g, 1.02 mmol) was used.

_{^{1 H-NMR (DMSO- d 6}} , 300 MHz) δ 13.09 (brs, 1H), 8.97 (s, 1H), 8.87 (d, J = 4.0 Hz, 1H), 8.31 (d, J = 9.5 Hz, 1H ), 8.23 (d, J = 7.2 Hz, IH), 8.10 (s, IH), 7.91 (s, IH), 7.65 (m, IH).

< Example  24> 4- [2- ( Methoxycarbonyl ) Indolin -1-yl] -4- Oxobutanoic acid  Produce

Carboxylate (2.0 g, 11.2 mmol) and succinic anhydride (1.2 g, 11.3 mmol) were dissolved in ethyl acetate (40 mL), and the mixed solution was heated to reflux for 16 hours . Next, the reaction solution was washed three times with sodium bicarbonate (100 mL), the aqueous solution was acidified to pH 1, and the resulting solid was extracted three times with dichloromethane (100 mL). The organic layer was washed with saturated brine, dried over magnesium sulfate (MgSO ₄ ) and filtered, and the filtrate was concentrated under reduced pressure to give the desired compound (1.6 g, 54%, white solid).

_{^{1 H NMR (CD 3 OD,}} 300MHz) δ 8.10 (d, J = 8.1 Hz, 1H), 7.23-7.07 (m, 2H), 7.03 (d, J = 8.1 Hz, 1H), 5.15 (m, 1H) , 3.77 (s, 3H), 3.55 (m, 1H), 3.32-3.07 (m, 2H), 2.84-2.56 (m, 3H).

< Example  25> methyl  1- {3- [3- (5- (4- Methoxybenzyloxy ) Pyridin-2-yl) -1,2,4- Oxadiazole -5 days] Propanoyl } Indolin -2- Carboxylate  Produce

Preparation Step 1: methyl  1- [4- (lH-benzo [d] [1, 2, 3] Triazole -1-yl) - (4- Oxobutanoyl ] Indolin -2- Carboxylate  Produce

Sulfonyl chloride (SOCl ₂ , 0.86 g, 7.2 mmol) was added dropwise to a solution of benzotriazole (0.86 g, 7.2 mmol) in dichloromethane (50 mL) and refluxed for 30 minutes. The reaction solution was cooled in an ice water bath, and the compound of Example 24 (0.5 g, 1.8 mmol) was added dropwise thereto, followed by stirring at room temperature for 2 hours. The reaction solution was washed twice with a saturated sodium bicarbonate aqueous solution (50 mL), and the organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from dichloromethane and hexane to give the title compound (0.57 g, 85%, colorless crystals)

_{^{1 H NMR (CD 3 OD,}} 300MHz) δ 8.26 (d, J = 8.1 Hz, 1H), 8.18 (d, J = 7.8 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.64 (dd 1H, J = 7.2, 8.1 Hz, 1H), 7.33-7.18 (m, 2H), 7.05 (m, 3.72 (m, 2H), 3.51 (m, 1H), 3.17-2.83 (m, 2H).

Step 1: methyl  1- {3- [3- (5- (4- Methoxybenzyloxy ) Pyridin-2-yl) -1,2,4- Oxadiazole -5 days] Propanoyl } Indolin -2- Carboxylate  Produce

To a solution of methyl 1- [4- (1H-benzo (d) [1,2,3] triazol-1-yl) - (4-oxobutanoyl) indoline- 0.1 g, 0.36 mmol) was dissolved in dioxane (3 mL), and then N' -hydroxy-5- (4-methoxybenzyloxy) picolinimidate The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give the title compound as a colorless oil. 5-1: 1) to obtain the desired compound (0.11 g, 60%, white solid).

_{^{1 H NMR (CDCl 3, 300MHz}} ) δ 8.51 (s, 1H), 8.19 (d, J = 7.5 Hz, 1H), 8.05 (d, J = 8.7 Hz, 1H), 7.35 (m, 3H), 7.16 ( 2H), 7.02 (m, 1H), 6.93 (m, 2H), 5.20 (m, -3.30 (m, 4H), 3.08 (m, IH), 2.91 (m, IH).

< Example  26> methyl  1- {3- [3- (5- Hydroxypyridine Yl) -1,2,4- Oxadiazole -5 days] Propanoyl } Indolin -2- Carboxylate  Produce

The title compound (38 mg, 99%, pale yellow solid) was obtained by a method similar to that of Example 2, except that the compound of Example 25 (0.05 g, 0.097 mmol) was used.

_{^{1 H-NMR (CDCl 3,}} 300 MHz) δ 8.43 (s, 1H), 8.14 (d, J = 7.6 Hz, 1H), 8.01 (d, J = 8.7 Hz, 1H), 7.35 (m, 2H), 3H), 3.69 (m, 1H), 3.51-3.28 (m, 4H), 2.91 (m, 1H).

<Example 27> 1 - {4- [3- (5-hydroxy-pyridin-2-yl) -1,2,4-oxadiazol-5-yl] propanoyl} indoline-2-carboxylic Manufacture of acid

The objective compound (36 mg, 100%, white solid) was obtained by a similar method to that of Example 3, except that the compound of Example 26 (38 mg, 0.096 mmol) was used.

_{^{1 H-NMR (CD 3 OD}} , 300 MHz) δ 8.23 (s, 1H), 8.10 (d, J = 7.8 Hz, 1H), 8.01 (d, J = 8.7 Hz, 1H), 7.35 (m, 2H) , 7.24-7.15 (m, 2H), 7.04 (m, IH), 5.28 (m, IH), 3.68 (m, IH), 3.40-3.24 (m, 4H), 3.00

< Example  28 > 4- [2- ( Methoxycarbonyl ) Indolin -1-yl] -3,3- Dimethyl -4- Oxobutano Manufacture of Iksan

Preparation Step 1: 2,2- Dimethylsycinic Anhydride  Produce

Acetic anhydride (1.55 mL, 16.5 mmol) was added dropwise to a solution of 2,2-dimethylsuccinic acid (2.19 g, 15 mmol) in toluene (2 mL) and the mixture was stirred at 130 ° C for 3 hours . After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and toluene (2 mL) was added thereto. Crystallization at room temperature afforded the desired compound (1.67 g, 87%, light off-white oil).

_{^{1 H NMR (CDCl 3, 300MHz}} ) δ 2.83 (s, 2H), 1.45 (s, 6H).

Step 1: 4- [2- ( Methoxycarbonyl ) Indolin -1-yl] -3,3- Dimethyl -4- Oxobutanoic acid  Produce

Carboxylate (0.12 g, 0.7 mmol) obtained in Preparation 1 and 2,2-dimethylsuccinic anhydride obtained in Preparation 1 was used in the same manner as in Example 24 To give the desired compound (0.08 g, 38%, colorless solid).

_{^{1 H NMR (CDCl 3, 300MHz}} ) δ 8.20 (d, J = 8.1 Hz, 1H), 7.33-7.13 (m, 2H), 7.03 (m, 1H), 4.98 (m, 1H), 3.75 (s, 3H ), 3.58 (m, IH), 3.29-3.10 (m, 2H), 2.80-2. 46 (m, IH), 1.36 (brs, 6H).

< Example  29> methyl  1- {3- [3- (5- (4- Methoxybenzyloxy ) Pyridin-2-yl) -1,2,4- Oxada 5-yl] -2,2- Dimethyl propanoyl } Indolin -2- Carboxylate  Produce

The title compound (17 mg, 11%, colorless solid) was prepared by a method similar to that of Example 25 (Preparation 1 and Step 1) except that the compound of Example 28 (60 mg, 0.12 mmol) &Lt; / RTI &gt;

_{^{1 H NMR (CDCl 3, 300MHz}} ) δ 8.50 (d, J = 2.7 Hz, 1H), 8.07 (d, J = 8.7 Hz, 1H), 7.35-7.26 (m, 3H), 7.24-7.11 (m, 3H ), 7.02 (m, IH), 6.92 (m, 2H), 5.08 (s, 2H), 5.04 m, 2H), 1.70-1.62 (m, 6H).

< Example  30> 1- {3- [3- (5- Hydroxypyridine Yl) -1,2,4- Oxadiazole -5-yl] -2,2- This methylpropa Noille} Indolin -2- Carboxylic acid  Produce

(7 mg, 72%, white solid) was obtained in a similar manner to that of Example 26 and Example 27, except that the compound of Example 29 (13 mg, 0.024 mmol) was used.

_{^{1 H NMR (CD 3 OD,}} 300MHz) δ 8.23 (s, 1H), 8.03-7.95 (m, 2H), 7.33 (dd, J = 2.7, 6.0 Hz, 1H), 7.16 (d, J = 7.2 Hz, 1H), 7.08 (dd, J = 6.9,7.8 Hz, 1H), 6.98 (dd, J = 6.9,7.2 Hz, , 2H), 1.67 (brs, 3H), 1.21 (brs, 3H).

< Example  31> methyl  1- {3- [1- (Pyridin-3-yl) -1,2,3- Triazole Yl] Propanoyl } Indolin-2- Carboxylate  Produce

Preparation Step 1: methyl  One-( Pent -4- Inno ) Indolin -2- Carboxylate  Produce

(0.39 g, 2.2 mmol), pentaamino acid (0.43 g, 2.2 mmol) and 1-ethyl-3- (3- dimethylaminopropyl) carbodiimide (1.3 g, 6.83 mmol) in dichloromethane (10 mL) was added triethylamine (0.3 mL, 2.2 mmol), and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (60% -100% dichloromethane / hexane) to obtain the desired compound (0.18 g, 35%, light red solid).

_{^{1 H NMR (CDCl 3, 300MHz}} ) δ 8.23 (m, 2H), 7.23-7.15 (m, 2H), 7.04 (m, 1H), 5.09 (m, 1H), 3.77 (s, 3H), 3.67-3.00 (m, 2H), 2.64 (brs, 4H), 2.0 (brs, 1H).

Step 1: methyl  1- {3- [1- (Pyridin-3-yl) -1,2,3- Triazole Yl] Propanoyl } Indolin -2- Carboxylate  Produce

Sodium azide (NaN _{3 ,} 0.03 g, 0.48 mmol) and copper sulfate (II) pentahydrate (CuSO ₄ .5H ₂ O) were added to a solution of 3-pyridine boronic acid (0.05 g, 0.4 mmol) , 0.01 g, 10 mol%) was added, and the mixture was stirred at room temperature for 24 hours. To the reaction solution was added methyl 1- (pent-4-inoyl) indoline-2-carboxylate (0.28 g, 0.88 mmol) obtained in the above Step 1 and an aqueous solution of sodium ascorbate (0.08 g, 0.4 mmol, ) Was added thereto, followed by addition of ethanol (5 mL), followed by stirring at room temperature for 10 hours and at 55 ° C for 1 hour. The reaction solution was concentrated under reduced pressure, extracted twice with ethyl acetate (50 mL), and the organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain the desired compound (90 mg, 56%, white solid).

_{^{1 H NMR (CDCl 3, 300MHz}} ) δ 8.99 (d, J = 8.4 Hz, 1H), 8.66 (d, J = 4.2 Hz, 1H), 8.22 (d, J = 7.8 Hz, 1H), 8.12 (m, 1H), 7.96 (m, 1H), 7.46 (m, 1H), 7.21-7.16 (m, 2H), 7.02 (m, 5 H), 3.13 - 2.71 (m, 1 H).

< Example  32> 1- {3- [1- (Pyridin-3-yl) -1,2,3- Triazole Yl] Propanoyl } Indolin -2-car Lebic acid Manufacturing

The target compound (8 mg, 83%, white solid) was obtained by a similar method to that of Example 3, except that the compound obtained in Example 31 (10 mg, 0.026 mmol) was used.

_{^{1 H NMR (CDCl 3, 300MHz}} ) δ 8.73 (s, 1H), 8.33 (d, J = 4.5 Hz, 1H), 7.90-7.81 (m, 3H), 7.21 (d, J = 4.5 Hz, 1H), 6.85 (m, 2H), 6.69 (m, 1H), 4.71 (m, 1H), 3.34-2.92 (m, 5H), 2.69-2.

< Example  33> methyl  1- {3- [1- (5- (4- Methoxybenzyloxy ) Pyridin-2-yl) -1 H - Pyrazole -3 days] Propanoyl } Indolin -2- Carboxylate  Produce

Preparation Step 1: Ethyl 1- (5- Nitropyridine Yl) -1 H - Pyrazole -3- Carboxylate  Produce

Sodium hydride (0.34 g, 60%) was added to the solution at 0 &lt; 0 &gt; C and treated with 0 Lt; 0 &gt; C for 30 minutes and at room temperature for 40 minutes. 2-Bromo-5-nitropyridine (1.17 g, 5.8 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The reaction was terminated by the addition of water and extracted with dichloromethane. The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) , White solid).

_{^{1 H NMR (DMSO- d 6,}} 300MHz) δ 9.32 (d, J = 2.4 Hz, 1H), 8.79 (m, 2H), 8.18 (d, J = 9.3 Hz, 1H), 7.08 (d, J = 2.4 Hz, 1H), 4.35 (q, J = 7.2 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H).

Preparation Step 2: Ethyl 1- (5- Aminopyridine Yl) -1 H - Pyrazole -3- Carboxylate  Produce

(Pyridin-2-yl-5-nitro) -1 H ethyl 1 obtained in the preparing step 1-pyrazol-3-carboxylate (1.2 g, 4.57 mmol) and zinc (3 g, 4.57 mmol) acetic acid (40 mL), followed by stirring at 60 DEG C for 30 minutes. After completion of the reaction, the filtrate was concentrated under reduced pressure, then washed with a saturated sodium bicarbonate aqueous solution and extracted with dichloromethane. The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ), filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% methanol / dichloromethane) to obtain the desired compound (0.65 g, 61% Solid).

_{^{1 H NMR (CDCl 3, 300MHz}} ) δ 8.44 (m, 1H), 7.91 (m, 2H), 7.15 (dd, J = 2.9, 7.5 Hz, 1H), 6.94 (d, J = 2.9 Hz, 1H), 4.40 (q, J = 7.2 Hz, 2H), 3.75 (brs, 2H), 1.44 (t, J = 7.2 Hz, 3H).

Preparation Step 3: Ethyl 1- (5- Acetoxypyridine Yl) -1 H - Pyrazole -3- Carboxylate  Produce

Ethyl 1- (5-amino-2-yl) -1 H obtained in the above preparation step 2 was dissolved pyrazole-3-carboxylate (2.33 g, 10.7 mmol) in dichloromethane, -15 ℃ Boron trifluoride diethyl etherate (BF ₃ Et ₂ O, 2.27 g, 16 mmol) was added to the reaction mixture to form a solid amine-boron complex, which was added until a homogeneous solution Was added dichloromethane. T-Butylnitrite (1.53 mL, 12.8 mmol) dissolved in dichloromethane (5 mL) was added dropwise over 10 minutes while stirring at a high speed while maintaining the temperature of the mixed solution at -15 DEG C, The reaction temperature was raised to 5 캜 over 20 minutes in an ice bath. When a crystalline precipitate was formed, pentane (800 mL) was added, filtered and the solid was cooled, washed with ether, dried and used in the next reaction without purification. The resulting diazonium salt (3.5 g) was dissolved in acetic anhydride (200 mL) and stirred at 70 캜 for 12 hours. After completion of the reaction, the reaction product was dried under reduced pressure, and the residue was dissolved in dichloromethane and washed with sodium bicarbonate. The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ) and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane) to give the desired compound (1.9 g, 68%).

_{^{1 H NMR (CDCl 3, 300MHz}} ) δ 8.55 (d, J = 2.4 Hz, 1H), 8.24 (d, J = 2.1 Hz, 1H), 8.16 (d, J = 8.7 Hz, 1H), 7.64 (m, 1H), 6.96 (d, J = 2.4 Hz, 1H), 4.44 (q, J = 7.2 Hz, 2H), 2.36 (s, 3H), 1.44 (t, J = 7.2 Hz, 3H).

Preparation Step 4: Ethyl 1- (5- Hydroxypyridine Yl) -1 H - Pyrazole -3- Carboxylate  Produce

After dissolving the pyrazole-3-carboxylate (1.9 g, 6.9 mmol) in ethanol (200 mL), - ethyl 1- (5-acetoxy-2-yl) -1 H obtained in the above preparation steps 3 Sulfuric acid (a few drops) was added. The mixed solution was stirred at 90 DEG C for 12 hours, and after completion of the reaction, the mixture was dried under reduced pressure, and the pH of the residue was adjusted to 4-5 with sodium hydroxide, followed by extraction with water and chloroform. The organic layer was dried with sodium sulfate (Na ₂ SO ₄ ) and filtered, and the filtrate was concentrated under reduced pressure to obtain the desired compound (1.6 g, 100%).

_{^{1 H NMR (CDCl 3, 300MHz}} ) δ 8.43 (d, 1H, J = 2.4 Hz), 8.06 (d, J = 2.1 Hz, 1H), 7.84 (d, J = 8.7 Hz, 1H), 7.35 (m, 1H), 6.94 (d, J = 2.1 Hz, 1H), 4.44 (q, J = 7.2 Hz, 2H), 1.41 (t, J = 7.2 Hz, 3H).

Preparation Step 5: Ethyl 1- {5 - [(4-methoxybenzyl) Oxy ] Pyridin-2-yl} -1 H - Pyrazole -3- Carboxylate  Produce

Ethyl 1- (5-hydroxy-pyridin-2-yl) -1 H obtained in the above preparation steps 4 - pyrazole-3-carboxylate (1.6 g, 7.3 mmol) dissolved in dimethylformamide (30 mL) , Sodium hydride (0.38 g, 60%) was added at 0 &lt; 0 &gt; C and stirred for 30 minutes. 4- (Methoxybenzyl) oxychloride (1.19 mL, 8.76 mmol) and NaI (20 mg) were added to the reaction solution, and the mixture was stirred at 80 ° C for 30 minutes and then water (300 mL) was added to terminate the reaction. The organic layer was washed three times with saturated brine (300 mL), dried over sodium sulfate (Na ₂ SO ₄ ) and filtered. The filtrate was concentrated under reduced pressure to obtain the desired compound (2.5 g, 100%).

_{^{1 H NMR (CDCl 3, 300MHz}} ) δ 8.48 (d, J = 2.4 Hz, 1H), 8.14 (d, J = 2.7 Hz, 1H), 8.04 (d, J = 9.0 Hz, 1H), 7.43 (m, 3H), 6.95 (m, 3H ), 5.07 (s, 2H), 4.44 (q, J = 7.2 Hz, 2H), 3.83 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H).

Preparation Step 6: {1- {5 - [(4-methoxybenzyl) Oxy ] Pyridin-2-yl} -1 H - Pyrazole -3-yl} methanol

The preparation obtained in step 5, 1-ethyl {5 - [(4-methoxybenzyl) oxy] pyridin-2-yl} -1 H-pyrazole-3-tetrahydro of carboxylate (2.5 g, 7.0 mmol) After dissolving in furan (40 mL), lithium borohydride (LiBH ₄ , 0.3 g, 14.1 mmol) was added and stirred at 80 &lt; 0 &gt; C for 24 hours. The reaction was terminated by addition of hydrochloric acid (1N HCl) at 0 ° C until the pH of the reaction solution became 6, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, dried over sodium sulfate (Na ₂ SO ₄ ) and filtered, and the filtrate was concentrated under reduced pressure to obtain the desired compound (2.2 g, 100%).

_{^{1 H NMR (CDCl 3, 300MHz}} ) δ 8.38 (s, 1H), 8.12 (s, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.37 (m, 3H), 6.93 (d, J = 7.2 2H), 6.42 (s, 1H), 5.05 (s, 2H), 4.77 (s, 2H), 3.82 (s, 3H), 2.2 (brs, 1H).

Preparation 7: 2- [3- ( Bromomethyl )-One H - Pyrazole -3-yl] -5 - [(4-methoxybenzyl) Oxy ] Pyridine

Obtained in the above Step 6 Preparation of 1- {5 - [(4-methoxybenzyl) oxy] pyridin-2-yl} -1 H-pyrazol -3-yl} methanol (2.4 g, 7.7 mmol) in dichloromethane (NBS, 4.11 g, 23.1 mmol) in pyridine (0.74 mL, 9.25 mmol), triphenylphosphine (5.65 g, 21.5 mmol) Was added at 0 占 폚, and the mixture was stirred at 0 占 폚 for 1.5 hours. After completion of the reaction, the reaction solution was washed with saturated brine (200 mL), and the organic layer was dried with sodium sulfate (Na ₂ SO ₄ ) and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: hexane = 1: 1) to obtain the target compound (2.0 g, 70%, colorless solid).

_{^{1 H NMR (CDCl 3, 300MHz}} ) δ 8.38 (d, J = 2.4 Hz, 1H), 8.11 (d, J = 2.1 Hz, 1H), 7.84 (d, J = 9.0 Hz, 1H), 7.40 (m, 3H), 6.93 (d, J = 8.4Hz, 2H), 6.49 (d, J = 2.1Hz, 1H).

Preparation Step 8: Dimethyl  2 - {[1- (5 - ((4-methoxybenzyl) Oxy ) Pyridin-2-yl) -1 H - Pyrazole -3 days] methyl } Malonate  Produce

After dissolving dimethylmalonate (3 mL, 26.7 mmol) in dimethylformamide (50 mL), sodium hydride (1.2 g, 60%, 29.3 mmol) was added to the solution at 0 & after stirring for 1 hour, 2 obtained in the above preparation steps 7 [3- (bromomethyl) -1 H-pyrazol -3-yl] -5 - [(- 4-methoxybenzyl) oxy] pyridine ( 2 g, 5.34 mmol). The mixed solution was stirred at room temperature for 1 hour, and after completion of the reaction, extracted with ethyl acetate (500 mL) and aqueous ammonium chloride solution (300 mL). The organic layer was washed with saturated brine (200 mL), dried over sodium sulfate (Na ₂ SO ₄ ) and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give the desired compound (1.62 g, 72%, colorless solid).

_{^{1 H NMR (CDCl 3, 300MHz}} ) δ 8.30 (m, 1H), 8.08 (d, J = 1.5 Hz, 1H), 7.77 (d, J = 9.0 Hz, 1H), 7.37 (m, 3H), 6.91 ( d, J = 7.8 Hz, 2H ), 6.24 (d, J = 0.8 Hz, 1H), 5.05 (s, 2H), 3.82 (s, 3H), 3.75 (s, 6H), 3.32 (d, J = 7.6 Hz, 2H).

Preparation 9: 2 - {[1- (5 - ((4-methoxybenzyl) Oxy ) Pyridin-2-yl) -1 H - Pyrazole -3 days] methyl } Preparation of malonic acid

Dimethyl obtained in the above preparation steps 82 - {[1 - (5 - ((4-methoxybenzyl) oxy) pyridine-2-yl) -1 H-pyrazol -3-yl] methyl} malonate (1.62 g , 3.8 mmol) was added lithium hydroxide (LiOH, 1N, 65 mL) to a mixture of tetrahydrofuran, methanol and water (3: 1: 1, 120 mL), stirred at room temperature for 1 hour, Lt; / RTI &gt; The pH of the residue was acidified to 2 by adding hydrochloric acid (HCl, 1N) to the residue, extracted three times with ethyl acetate (50 mL), dried over sodium sulfate (Na ₂ SO ₄ ), filtered and the filtrate was concentrated under reduced pressure . The resulting compound proceeded directly to the next reaction.

Preparation 10: 3- {1- [5 - ((4-methoxybenzyl) Oxy ) Pyridin-2-yl] -1 H - Pyrazole -3 days} Propanoic  Produce

2 obtained in the above preparation steps 9 - {[1 - (5 - ((4-methoxybenzyl) oxy) pyridine-2-yl) -1 H-pyrazol -3-yl] methyl} malonic acid dimethyl formamide (20 mL), and the mixture was stirred at 130 DEG C for 30 minutes. After the reaction solution was cooled to room temperature to terminate the reaction, water (200 mL) was added and extracted with ethyl acetate (200 mL). The organic layer was washed three times with saturated brine (200 mL), dried over sodium sulfate (Na ₂ SO ₄ ) and filtered. The filtrate was concentrated under reduced pressure to give the desired compound (1.32 g, 98%, colorless solid).

_{^{1 H NMR (CDCl 3, 500MHz}} ) δ 8.36 (d, J = 2.5 Hz, 1H), 8.13 (d, J = 2.6 Hz, 1H), 7.78 (d, J = 8.9 Hz, 1H), 7.37 (m, 3H), 6.95 (d, J = 8.7 Hz, 2H), 6.30 (d, J = 2.6 Hz, 1H), 5.07 (s, 2H), 3.82 (s, 3H), 3.08 (t, J = 7.3 Hz, 2H), 2.86 (t, J = 7.25 Hz, 2H).

Step 1: Preparation of 1- {3- [1- (5- (4- Methoxybenzyloxy ) Pyridin-2-yl) -1 H - Pyrazole -3 days] Propanoyl } Indolin -2- Carboxylic acid  Produce

2 obtained in the preparation step 10 {1- [5 - ((4-methoxybenzyl) oxy) pyridine-2-yl] -1 H-pyrazol -3-yl} propanoic acid (25 mg, 0.07 mmol) and The title compound (14 mg, 40%, white solid) was prepared in a similar manner to the preparation of step 1 of Example 31, except that methyl indoline-2-carboxylate (14 mg, 0.077 mmol) &Lt; / RTI &gt;

_{^{1 H NMR (CDCl 3, 300MHz}} ) δ 8.29 (m, 2H), 8.10 (d, J = 2.7 Hz, 1H), 7.78 (m, 1H), 7.35 (d, J = 8.7 Hz, 2H), 7.21- 7.13 (m, 3H), 7.03 (m, 1H) 6.92 (d, J = 8.7 Hz, 2H), 6.28 (m, 1H), 5.14 (m, 1H), 5.04 (s, 2H), 3.82 (s, 3H), 3.73 (s, 3H), 3.29-3. 07 (m, 4H), 2.82 (m, 1H).

< Example  34> methyl  1- {3- [1- (5- Hydroxypyridine Yl) -1 H - Pyrazole -3 days] Pro Panoyl} Indolin -2- Carboxylate  Produce

Obtained in Example 33, 1- {3- [1- (5- (4-methoxy-benzyloxy) pyridin-2-yl) -1 H - pyrazol-3-yl] propanoyl} indoline -2 -Carboxylic acid (12 mg, 0.023 mmol), the title compound (8 mg, 91%, white solid) was obtained as a white solid &Lt; / RTI &gt;

_{^{1 H NMR (CD 3 OD,}} 300MHz) δ 8.31 (s, 1H), 8.15 (d, J = 7.8 Hz, 1H), 7.94 (s, 1H), 7.67 (d, J = 8.7 Hz, 1H), 7.32 (d, J = 9.6 Hz, IH), 7.20 (m, 2H), 7.05 (m, IH), 6.37 m, 4 H), 2.76 (m, 1 H).

< Example  35> methyl  1- [3- (2- Bromothiazole -5 days) Propanoyl ] Indolin -2- Carlsbad Manufacture of silicate

Preparation Step 1: methyl  2- Amiocathol -5- Carboxylate  Produce

Bromosuccinimide (NBS, 16.85 g, 0.086 mol) was added to a solution of? -Methoxyacrylate (10 g, 0.086 mol) in a mixture of water (40 mL) and dioxane (40 mL) 0.094 mmol), and the mixture was stirred at room temperature for 1 hour. Thiourea (6.54 g, 0.086 mol) was added to the reaction solution and stirred at 80 ° C. Next, after cooling to room temperature, concentrated aqueous ammonia (20 mL) was added to the reaction solution, followed by stirring at room temperature for 30 minutes to terminate the reaction. After filtration, the filtrate was concentrated under reduced pressure, and the resulting solid was washed with water and dried to obtain the desired compound (10.5 g, 77%, pale yellow solid).

¹ H NMR (CDCl ₃ )? 7.80 (s, 1 H), 5.37 (brs, 2H), 3.84 (s, 3H).

Preparation Step 2: methyl  2- Bromo isazole -5- Carboxylate  Produce

(H ₂ SO ₄ , 9 M, 125 mL), copper sulfate (CuSO ₄ , 49.7 g, 20.0 mmol), and the like were added to the methyl 2-amiazolacyl-5-carboxylate (10.5 g, (NaNO ₂ , 5.5 g, 79.6 mmol) was dissolved in water (40 mL), and the solution was added dropwise at -5 ° C to a solution of sodium bromite Respectively. The reaction solution was stirred at -5 DEG C for 20 minutes and at room temperature for 1.5 hours, and then the reaction was terminated. Water (200 mL) and ethyl acetate (200 mL) were added and extracted. The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (5% ethyl acetate / hexane) to obtain the desired compound (7.5 g, 51% ).

¹ H NMR (CDCl ₃ , 300 MHz) 隆 8.19 (s, 1 H), 3.95 (s, 3 H).

Preparation Step 3: (2- Bromothiazole -5-yl) methanol

Sodium fluoride in view of methyl 2-bromo-5-mosayi-carboxylate (4.0 g, 18 mmol) obtained in the preparation step 2 dissolved in methanol (50 mL) hydroxy _{(NaBH 4, 6.8 g, 180} mmol ) Was added dropwise over 30 minutes, and the mixed solution was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (20% ethyl acetate / hexane) to give the desired compound (3.0 g, 86% .

_{^{1 H NMR (CDCl 3, 300MHz}} ) δ 7.40 (s, 1H), 4.81 (s, 2H), 2.88 (brs, 1H).

Preparation Step 4: 2- Bromo -5- ( Bromomethyl ) Thiazole  Produce

Was obtained in a similar manner to the preparation of 7 in the above Example 33 except that (2-bromothiazol-5-yl) methanol (3 g, 15.4 mmol) obtained in the above preparation step 3 was used instead of 3.45 g, 85%, colorless solid).

¹ H NMR (CDCl ₃ , 300 MHz) 隆 7.53 (s, 1 H), 4.63 (s, 2H).

Preparation Step 5: Dimethyl  2 - [(2- Bromothiazole -5 days) methyl ] Malonate  Produce

(Bromomethyl) thiazole (3.4 g, 13.2 mmol) obtained in the above preparation step 4 was used instead of 2-bromo-5- (bromomethyl) thiazole (2.2 g, 62%, colorless oil).

_{^{1 H NMR (CDCl 3, 300MHz}} ) δ 7.33 (s, 1H), 3.75 (s, 6H), 3.63 (t, J = 2.7 Hz, 1H), 3.39 (d, J = 2.7 Hz, 2H).

Preparation Step 6: 3- (2- Bromothiazole -5 days) Propanoic  Produce

Preparative steps 9 and 10 of Example 33 were followed except that the dimethyl 2 - [(2-bromothiazol-5-yl) methyl] malonate (2.2 g, 7.5 mmol) 10, to obtain the title compound (1.3 g, 77%, colorless solid).

_{^{1 H NMR (CDCl 3, 300MHz}} ) δ11.2 (brs, 1H), 7.34 (s, 1H), 3.12 (t, J = 7.2 Hz, 2H), 2.72 (d, J = 7.2 Hz, 2H).

Step 1: methyl  1- [3- (2- Bromothiazole -5 days) Propanoyl ] Indolin -2- Carboxylate Manufacturing

(1.3 g, 5.5 mmol) and methyl indoline-2-carboxylate (0.97 g, 5.5 mmol) obtained in the above preparation step 6 , The target compound (1.2 g, 55%, white solid) was obtained in a similar manner to the preparation step 1 of Example 31.

_{^{1 H NMR (CDCl 3, 300MHz}} ) δ 8.25 (d, J = 7.5 Hz, 1H), 7.33 (s, 1H), 7.22-7.15 (m, 2H), 7.06 (m, 1H), 5.22-4.87 (m 1H), 3.73 (s, 3H), 3.65-3.44 (m, IH), 3.25 (brs, 3H), 3.11 (m,

< Example  36> 1 - {[3- (2- (Pyridin-3-yl) Thiazole -5 days] Propanoyl } Indolin -2- Car Preparation of Lexylic Acid

Carboxylate (39.5 mg, 0.1 mmol) obtained in Example 35 was dissolved in toluene and ethanol (2: 1) to obtain the title compound (16 mg, 1.3 mmol) and an aqueous potassium carbonate solution (K ₂ CO ₃ , 2M, 0.1 mL, 0.2 mmol) were added to the mixed solution, and the mixture was stirred for 30 minutes &Lt; / RTI &gt; Tetrakis triphenylphosphinopalladium (Pd (PPh ₃ ) ₄ , 0.005 mmol) was added to the reaction solution, followed by stirring at 85 ° C for 24 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was dried over sodium sulfate (Na ₂ SO ₄ ) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (20% methanol / ethyl acetate) to obtain the target compound (50%).

_{^{1 H NMR (CD 3 OD,}} 300MHz) δ 8.62 (brs, 1H), 8.36 (m, 1H), 8.16 (m, 1H), 7.75 (s, 1H), 7.60 (m, 1H), 7.21 (m, 2H), 7.05 (m, 1H), 5.16 (dd, 1H), 3.60 (m, 2H), 3.30 (m, 2H), 3.14-3.73 (m, 2H).

< Example  37> 1 - {[3- (2- (3,5- Dichlorophenyl ) Thiazole -5 days] Propanoyl } Indolin -2- Carboxylic acid  Produce

The procedure of Example 36 was repeated except that 3,5-dichlorophenylboronic acid was used to obtain the target compound (78%).

_{^{11 H NMR (DMSO- d 6,}} 300MHz) δ 8.08 (d, J = 7.8 Hz, 1H), 7.83 (s, 1H), 7.68 (s, 1H), 7.14 (m, 2H), 6.97 (m, 1H ), 5.02 (dd, 1H), 3.18 (m, 4H), 2.99-2.60 (m, 2H).

< Example  38 > 1 - {[3- (2- (3,5- Difluorophenyl ) Thiazole -5 days] Propanoyl } sign Turn-2- Carboxylic acid  Produce

(45%) was obtained in the same manner as in Example 36, except that 3,5-difluorophenylboronic acid was used.

_{^{11 H NMR (DMSO- d 6,}} 300MHz) δ 8.07 (d, J = 8.4 Hz, 1H), 7.74 (s, 1H), 7.54 (m, 2H), 7.33 (m, 1H), 7.11 (m, 2H ), 6.93 (m, IH), 4.74 (m, IH), 3.16 (m, 4H), 2.94-2.76 (m, 2H).

< Example  39> 1 - {[3- (2- (4- Chlorophenyl ) Thiazole -5 days] Propanoyl } Indolin -2- Car Preparation of Lexylic Acid

The procedure of Example 36 was repeated except for using 4-chlorophenylboronic acid to obtain the target compound (50%).

_{^{11 H NMR (CD 3 OD,}} 300MHz) δ 8.19 (d, J = 8.2 Hz, 1H), 7.85 (d, J = 7.8 Hz, 2H), 7.64 (s, 1H), 7.45 (d, J = 7.8 Hz 2H), 7.20 (m, 2H), 7.01 (m, 1H), 5.01 (m, 1H), 3.67 (m, 2H), 3.32 (m, 2H), 2.88

< Example  40> 1 - {[3- (2- (2- Chlorophenyl ) Thiazole -5 days] Propanoyl } Indolin -2- Car Preparation of Lexylic Acid

The procedure of Example 36 was repeated except that 2-chlorophenylboronic acid was used to obtain the target compound (77%).

_{^{11 H NMR (CD 3 OD,}} 300MHz) δ 8.19 (d, J = 7.8 Hz, 1H), 7.98 (m, 1H), 7.73 (s, 1H), 7.55 (m, 1H), 7.42 (m, 2H) , 7.16 (m, 2H), 7.00 (m, IH), 4.90 (m, IH), 3.63 (m, 2H), 3.31 (m, 2H), 2.95

< Example  41> 1 - {[3- (2- (2- Fluorophenyl ) Thiazole -5 days] Propanoyl } Indolin -2-carboxylic acid

The procedure of Example 36 was repeated except for using 2-fluorophenylboronic acid to obtain the target compound (yield: 50%).

_{^{11 H NMR (CD 3 OD,}} 300MHz) δ 8.16 (m, 2H), 7.72 (s, 1H), 7.46 (m, 1H), 7.32-7.15 (m, 4H), 7.03 (m, 1H), 5.01 ( m, 1 H), 3.58 (m, 2 H), 3.31 (m, 2 H), 2.94 (m, 2 H).

< Example  42 > 1 - {[3- (2- (3- Fluorophenyl ) Thiazole -5 days] Propanoyl } Indolin -2-carboxylic acid

The procedure of Example 36 was repeated except that 3-fluorophenylboronic acid was used to obtain the target compound (40%).

_{^{11 H NMR (CD 3 OD,}} 300MHz) δ 8.18 (d, J = 8.4 Hz, 1H), 7.67 (m, 3H), 7.47 (d, J = 7.8 Hz, 1H), 7.21 (m, 3H), 7.04 (m, 1H), 5.10 (m, 1H), 3.60 (m, 2H), 3.32 (m, 2H), 3.15-2.75 (m, 2H).

< Example  43> 1 - {[3- (2- (3- Nitrophenyl ) Thiazole -5 days] Propanoyl } Indolin -2-carboxylic acid

(40%) was obtained in the same manner as in Example 36, except that 3-nitrophenylboronic acid was used.

_{^{11 H NMR (CD 3 OD,}} 300MHz) δ 8.74 (s, 1H), 8.27 (m, 2H), 8.20 (d, J = 8.4 Hz, 1H), 7.74-7.69 (m, 2H), 7.16 (m, 1H), 7.00 (dd, J = 6.6, 6.6 Hz, 1H), 4.80 (m, 1H), 3.70-3.55 (m, 4H), 2.90 (m, 2H).

< Example  44> 1 - {[3- (2- (4- Phenoxyphenyl ) Thiazole -5 days] Propanoyl } Indolin -2- Carboxylic acid  Produce

The procedure of Example 36 was repeated except for using 4-phenoxyphenylboronic acid to obtain the target compound (90%).

_{^{11 H NMR (CD 3 OD,}} 300MHz) δ 8.17 (d, J = 8.1 Hz, 1H), 7.82 (d, J = 8.7 Hz, 1H), 7.58 (s, 1H), 7.39 (m, 2H), 7.16 2H), 3.26 (m, 2H), 2.99-2.65 (m, 2H), 7.03 (m, 5H), 4.99 (m,

< Experimental Example  1 > The indole derivative of the present invention GPR109A  Assessment of receptor agonistic activity

Experiments were carried out in the following manner to evaluate the effects of the indole derivatives of formula (I) according to the present invention on the prevention or treatment of dyslipidemia.

(One) GPR109A  Overexpression Search cell line  build

To construct cells overexpressing the GPR109A receptor, pCMV-XL6-GPR109A in which GPR109A gene was subcloned into CHO-K1 / G? 16 cells (Molecular Devices) was transformed (see Fig. 1). Vectors were transfected, and G418 antibiotics were added until the colonies were formed. After incubation for 2 weeks, each of the colony cells was cultured separately to measure the calcium signal increased by niacin in each colony.

Specifically, each colony was cultured and adhered to poly-D-lysine-coated 96-well plate at 40,000 cells / well. On the following day, cells were washed with PBS (phosphate buffered saline), replaced with serum-free medium, incubated for 2 hours, and washed again with HBSS (hank's balanced salt solution). Next, the Fluo-4NW solution was added, and further cultured at 37 ° C for 1 hour. Then, the ligand, niacin, was added and calcium signal was measured in a kinetic mode for 1 minute on a FlexStation II (Molecular Devices) When the concentration of calcium increased, the fluorescence (ex / em = 485/525) signal appeared. The colony with the highest increase in fluorescence signal was selected and used for calcium detection.

(2) Measurement of intracellular calcium concentration change by compound

The CHO-K1 / Ga16 / GPR109A cells selected above were used as the indole derivatives of Examples (12, 13, 20, 22, 23, 27, 40, 41 and 42) The calcium signal was measured using MK-6892 compound, a therapeutic agent for hyperlipemia developed by Merk, and Comparative Example 2, using niacin as a ligand. In addition, the% activity by the GPR109A receptor was calculated by subtracting the fluorescence value of the untreated group (signal measured in CHO-K1 / Ga16) from each measured fluorescence value, and is shown in Table 2.

% Hyperactivity 10 μM 3.2 [mu] M 1 [mu] M 316 nM 100 nM 32 nM Example 12 63 52 48 29 14 2 Example 13 65 55 51 39 15 3 Example 20 69 42 23 18 15 2 Example 22 102 102 89 66 27 2 Example 23 104 105 92 69 31 One Example 27 81 - 70 - - - Example 40 62 43 22 12 2 - Example 41 82 79 45 20 15 8 Example 42 58 53 25 20 11 One Comparative Example 1 104 101 98 103 89 75 Comparative Example 2 100 97 96 82 70 54

As shown in Table 2, the indole compound represented by Formula 1 according to the present invention has an excellent antinociceptive activity against the GPR109A receptor in a concentration-dependent manner. Compounds of Examples 22 and 23 exhibited more than 100% antagonistic activity at 10 [mu] M, and exhibited more than 90% at 1 [mu] M. MK6892 of Comparative Example 1, which is being developed as a therapeutic agent for hyperlipidemia, exhibited an activity of 104% at 10 μM, and niacin of Comparative Example 2, which is a kind of vitamin B, exhibited 100% . From these results, it can be seen that the 1-position substituted indole compound according to the present invention has an agonistic activity similar to that of MK6892 and niacin, which has been developed or used for the GPR109A receptor.

Therefore, the indole derivative represented by the formula (1) according to the present invention is excellent in the action of binding to the niacin GPR109A receptor and activating the receptor, so that the prevention or amelioration of dyslipidemia such as hyperlipidemia, hypercholesterolemia and hypertriglyceridemia It can be usefully used as a therapeutic composition.

Experimental Example 2 Effect of GPR109A receptor agonism on beta-arrestin migration of indole derivatives according to the present invention -1

In order to evaluate the prevention of facial flushing caused by the activation of the beta-arrestin signaling pathway by activation of the GPR109A receptor of the indole derivative represented by the formula 1 according to the present invention, the following experiment was conducted.

(1) Imaging expression vector construction of GPR109A receptor

As shown in Fig. 1, pCMV_neo / GPR109A (Origene) and pCMV_hygro shuttle vector were digested with restriction enzymes EcoR I and Not I to prepare pCMV6-A-Hygro / GPR109A vector. The vector was digested with 1% agarose gel The desired DNA band was separated and the DNA fragment was purified using a QIAquik gel extraction kit (QUIGEN). The purified insert DNA and vector were added at a molar ratio of 3: 1, and 10 μl of 2 × ligase buffer (Promega) and T4 DNA ligase were added to make a reaction product, which was reacted at room temperature for 10 minutes. DNA was then added to E. coli DH5α (RBC) competent cells, left on ice for 20 minutes, subjected to thermal shock for 1 minute in a hot block set at 42 ° C and then left on ice for 20 minutes. Ampicillin ) Was sprayed onto a selection agar plate (100 ㎍ / ml) and cultured overnight at 37 占 폚. The next day, the colonies were picked and placed in LB broth / amp + culture medium, cultured overnight at 37 ° C at 200 rpm, and plasmid DNA was isolated. The plasmid DNA was sequenced with a DNA sequencing primer (T7 sequencing primer (20 mer): TAA TAC GAC TCA CTA TAG GG, Hygro sequencing primer (20 mer): TCG CTG CGG CCG ATC TTA GC] Respectively.

(2) GPR109A  Receptor Imaging  Search Cell Construction

Imaging of GPR109A Receptor To construct a cell, pCMV6-A-Hygro / GPR109A, in which GPR109A gene was subcloned into U2OS-beta-arrestin2 RrGFP cells (Molecular Devices), was transformed, The moving GFP signal was imaged and screened.

Specifically, the colonies formed after the transplantation were dispensed into a 96-well plate at 15,000 cells / well. Cells were washed with PBS and replaced with serum and phenol red-free medium. Cells were cultured for 3 hours, treated with DRAQ5 solution and niacin, and fixed in 8% formaldehyde for 15 min. And then images were taken from Arrayscan II (Thermofisher). When the concentration of calcium increased, fluorescence (ex / em = 485/525) signal appeared. Therefore, colonies in which intracellular migration of the receptor was actively induced when niacin was treated were selected and used for image retrieval.

(3) Beta- Arrestin  move Imaging  Experiment

In order to image the migration of the indole derivatives represented by Formula 1 and the Comparative Examples 1 and 2 into beta-arrestin cells according to the present invention, the U2OS-beta-arrestin2 RrGFP / GPR109A cells selected above were subjected to MK-6892, a hyperlipemia therapeutic agent developed in Merck, Example 12, 13 and 17, and Comparative Example 1, niacin of Comparative Example 2 was fixed at a concentration of 10 μM, and images were taken at 30 minutes in the same manner as described above The results are shown in Fig.

FIG. 2 is an image obtained by measuring the intracellular migration of beta-arrestin to green control protein (GFP, Green fluorescent protein) against negative control, Comparative Examples 1-2 and Examples 12, 13 and 27.

As shown in Fig. 2, Examples 12, 13 and 17 according to the present invention reduced the formation of intracellular spots as compared to MK-6892 of Comparative Example 1 and niacin of Comparative Example 2. [

Therefore, the indole derivative represented by the formula (1) according to the present invention is excellent in the action of binding to the niacin GPR109A receptor to activate the receptor and less activating the beta-arrestin signaling pathway, For the prevention, amelioration or treatment of dyslipidemia such as hyperlipidemia, hypercholesterolemia, hypertriglyceridemia and the like.

Experimental Example 3 Effect of GPR109A receptor agonism on beta-arrestin migration of indole derivatives according to the present invention -2

Experiments were carried out in the following manner to evaluate the preventive effect of the indole derivative compound according to the present invention on facial flushing caused by activation of the beta-arrestin signaling pathway by activation of GPR109A receptor.

First, Tango-GPR109A-bla U2OS cell line (Invitrogen) was dispensed into a 384-well plate at 10,000 cells / well, followed by overnight application and incubated in the same manner as in Examples 12, 13, 20, 22, 23, 27, After 5 hours of treatment with MK-6892 of Comparative Example 1 and niacin of Comparative Example 2, 12 μl of the substrate mixture (Solution A (CCF4-AM substrate mix, 1 mM), 60 μl of Solution B, 925 μl of Solution C, (Ex / em = 409/460) and green fluorescence (ex / em = 409/530) were measured after addition of 8 쨉 l each at room temperature for 2 hours. Next, as shown in the following formula (1), the blue / green fluorescence ratio was calculated and shown in Table 3 below. At this time, when the ratio of blue / green fluorescence is larger than 1, it means that the migration ability of the compound in beta-arrestin cell is increased.

[Equation 1]

Blue / green fluorescence ratio (10 μM) Example 12 1.1 Example 13 1.5 Example 20 1.1 Example 22 3.6 Example 23 2.8 Example 27 1.7 Example 40 1.0 Example 41 1.9 Comparative Example 1 6.8 Comparative Example 2 3.9

As shown in Table 3, the indole derivatives represented by formula (I) according to the present invention exhibited fluorescence ratios of 1.0-3.6 at a high concentration of 10 μM, which is comparable to MK-6892 of Comparative Example 1 and Comparative Example 2 The fluorescence ratio of niacin is 6.8 or 3.9, which is much lower than that of niacin. From this, it can be seen that the indole derivatives according to the present invention reduce the migration of beta-arrestin into cells, which is a signal transduction pathway associated with facial flushing side effects.

Therefore, the indole derivative represented by the formula (1) according to the present invention is excellent in the action of binding to the niacin GPR109A receptor to activate the receptor and less activating the beta-arrestin signaling pathway, For the prevention, amelioration or treatment of dyslipidemia such as hyperlipidemia, hypercholesterolemia, hypertriglyceridemia and the like.

< Experimental Example  4> GPR109A  Cytotoxicity to calcium-screening cells

In order to examine the cytotoxicity of the indole derivative according to the present invention, experiments were carried out in the GPR109A calcium cell line as follows.

First, GPR109A calcium-scavenging cells were seeded onto 384-well plates coated with poly-D-lysine at a density of 1,500 cells / well and adhered. The following day, the compounds were treated at a desired concentration and cultured for 72 hours. 5 ㎕ of WST-1 (EZ-CYTOX, Daeil Lab Service) was treated and cultured for 4 hours, and the absorbance at 450 nm was measured. The results are shown in Table 4.

% Cytotoxicity 10 μM 3.2 [mu] M 1 μM 316nM 100 nM 32 nM Example 13 - - - - - - Example 22 - - - - - - Example 23 - - - - - - Example 27 - - - - - - Example 41 - - - - - - Comparative Example 1 18.2 13.4 16.8 18.5 14.2 6.8

In Table 4, "-" indicates no toxicity.

As shown in Table 4 above, the indole derivatives according to the present invention are all found to have low cytotoxicity. In the case of Examples 13, 22, 23, 27 and 41 according to the present invention, it was confirmed that no cytotoxicity was observed even at a high concentration of 10 μM. On the other hand, MK-6892 of Comparative Example 1 showed cytotoxicity of 18.2% or more at 10 μM. From these results, it can be seen that the 1-position substituted indole derivatives are significantly superior in toxicity to cells than MK-6892 of Comparative Example 1, which is conventionally known as a therapeutic agent for hyperlipidemia.

Therefore, the indole derivative represented by the formula (1) according to the present invention is excellent in the action of binding to the niacin GPR109A receptor to activate the receptor and less activating the beta-arrestin signaling pathway, For the prevention, amelioration or treatment of dyslipidemia such as hyperlipidemia, hypercholesterolemia, hypertriglyceridemia and the like.

Meanwhile, the derivatives according to the present invention can be formulated into various forms according to the purpose. Examples of formulations for the composition of the present invention are illustrated below.

&Lt; Formulation Example 1 > Preparation of pharmaceutical preparation

1. Manufacturing of powder

2 g of the indole derivative represented by the formula (1)

Lactose 1 g

The above components were mixed and packed in airtight bags to prepare powders.

2. Preparation of tablets

100 mg of the indole derivative represented by the formula (1)

Corn starch 100 mg

100 mg of milk

2 mg of magnesium stearate

After mixing the above components, tablets were prepared by tableting according to a conventional method for producing tablets.

3. Preparation of capsules

100 mg of the indole derivative represented by the formula (1)

Corn starch 100 mg

100 mg of milk

2 mg of magnesium stearate

After mixing the above components, the capsules were filled in gelatin capsules according to the conventional preparation method of capsules.

4. Manufacture of rings

1 g of the indole derivative represented by the formula (1)

Lactose 1.5 g

Glycerin 1 g

0.5 g of xylitol

After mixing the above components, they were prepared so as to be 4 g per one ring according to a conventional method.

5. Manufacture of granules

150 mg of the indole derivative represented by the formula (1)

Soybean extract 50 mg

200 mg of glucose

600 mg of starch

After mixing the above components, 100 mg of 30% ethanol was added and the mixture was dried at 60 캜 to form granules, which were then filled in a capsule.

< Formulation example  2> Manufacture of health food

1. Manufacture of beverages

Honey 522 mg

5 mg &lt; RTI ID = 0.0 &gt;

Nicotinic acid amide 10 mg

3 mg of sodium riboflavin hydrochloride

Pyridoxine hydrochloride 2 mg

Inositol 30 mg

Orthoic acid 50 mg

0.48-1.28 mg of the indole derivative represented by the formula (1)

200 ml of water

A beverage was prepared using the above-mentioned composition and content by a conventional method.

2. Of chewing gum  Produce

Gum base 20%

Sugar 76.36-76.76%

An indole derivative represented by the general formula (1): 0.24-0.64%

Fruit flavor 1%

Water 2%

Chewing gum was prepared using the above-mentioned composition and content by a conventional method.

3. Manufacture of candy

Sugar 50-60%

Starch syrup 39.26-49.66%

An indole derivative represented by the general formula (1): 0.24-0.64%

Orange fragrance 0.1%

The composition and the content of the candy were prepared using a conventional method.

4. Manufacture of flour food

0.5 to 5 parts by weight of an indole derivative represented by the formula (1) was added to 100 parts by weight of wheat flour, and a bread, a cake, a cookie, a cracker and a noodle were prepared by using the mixture.

5. Dairy products ( dairy products )

5 to 10 parts by weight of an indole derivative represented by the formula (1) was added to 100 parts by weight of milk, and various dairy products such as butter and ice cream were prepared using the milk.

6. Solar  Produce

Brown rice, barley, glutinous rice, and yulmu were alphalized by a known method and dried, and the powder was prepared into a powder having a particle size of 60 mesh by a pulverizer. Black beans, black sesame seeds, and perilla seeds were steamed and dried by a known method, and then powdered with a particle size of 60 meshes by a grinder. The grains and seeds prepared above were mixed with the indole derivatives represented by the formula (1) of the present invention in the following proportions.

Brown rice 30%

Yulmu 15%

Barley 20%

Perilla 7%

Black soybeans 7%

Black sesame 7%

The indole derivative 3% represented by the formula (1)

Manure 0.5%

0.5%

Claims (15)

1. An indole derivative represented by the following formula (1): &lt; EMI ID =
[Chemical Formula 1]

(In the formula 1,
A is carbon (C) or sulfur (S)
R ¹ is -H, halogen, -COOH or C ₁ -C ₆ linear or branched alkyl,
R ² and R ³ are independently -H, C ₁ -C ₆ linear or branched alkyl or -C (= O) R ⁵ , wherein R ⁵ is selected from the group consisting of -H, -OH, -OR ⁶ , -NH ₂ or -NHR ⁶ , wherein R ⁶ is C ₁ -C ₆ straight or branched chain alkyl or phenyl,
R ⁴ is -COOH, phenyl or 5- to 7-membered heteroaryl or heterocycloalkyl containing one or more heteroatoms selected from the group consisting of nitrogen (N), oxygen (O) and sulfur (S) Wherein said phenyl, heteroaryl or heterocycloalkyl is unsubstituted or substituted by one or more substituents selected from the group consisting of -OH, -NO ₂ , halogen, C ₁ -C ₆ linear or branched alkoxy, phenyl and nitrogen (N), oxygen (O) S), or a 5- to 7-membered heteroaryl or heterocycloalkyl containing one or more heteroatoms selected from the group consisting of C ₁ -C ₆ alkyl, C ₆ linear or branched alkoxy, phenyl, heteroaryl or heterocycloalkyl is unsubstituted or substituted by one or more substituents selected from the group consisting of -OH, -NO ₂ , halogen, C ₁ -C ₆ straight or branched chain alkyl, phenoxy and C ₁ -C ₆ alkoxy C ₆ -C ₁₀ aryl C ₁ -C ₆ al City may be further substituted with one or more substituents selected from the group consisting of,

Is a single or double bond,
n is an integer from 0 to 5, wherein each carbon of the alkylene between A and R &lt; ⁴ &gt; may be substituted with one or more C ₁ -C ₆ linear or branched alkyl,
When R ¹ , R ² and R ³ are -H and n is 2, R ⁴ is not phenyl,
When R ¹ is -Br, R ² and R ³ are -H and n is 2, then R ⁴ is not phenyl,
When R ¹ and R ³ are -H and R ² is -C (= O) OCH ₃ and n is 2, then R ⁴ is not phenyl,
When R ¹ and R ³ are -H, R ² is -CH ₃ and n is 2, R ⁴ is not phenyl,
When R ¹ is -CH ₃ , R ² and R ³ are -H and n is 2, then R ⁴ is not phenyl,
When R ¹ and R ² are -H, R ³ is -CH ₃ and n is 2, R ⁴ is not phenyl,
When R ¹ , R ² and R ³ are -H and n is 0, R ⁴ is not m-methoxyphenyl,
When R ¹ , R ² and R ³ are -H and n is 0, then R ⁴ is not phenyl,
When R ¹ and R ³ are -H, R ² is -C (= O) OH and n is 0, then R ⁴ is not phenyl,
Alternatively, the indole derivative represented by the formula (1) is any one of the following compounds:
(1) Ethyl 5-methoxy-1- {3- [3- (4- (4-methoxybenzyloxy) phenyl) -1,2,4-oxadiazol- 1 H -indole-2-carboxylate;
(2) Ethyl 5-methoxy-1- {3- [3- (4- (4-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] propanoyl} -1 H - Indole-2-carboxylate; and
(3) Synthesis of 5-methoxy-1- {3- [3- (4- (4-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] propanoyl} 2-carboxylic acid.).
The method according to claim 1,
In Formula 1,
A is carbon (C) or sulfur (S)
R ¹ is -H, -Br, -Cl, -COOH or C ₁ -C ₄ linear or branched alkyl,
R ² And R ³ are independently -H, C ₁ -C ₄ linear or branched alkyl or -C (= O) R ⁵ , wherein R ⁵ is selected from the group consisting of -H, -OH, -NH ₂ or -OR ⁶ , wherein R ⁶ is C ₁ -C ₄ straight or branched chain alkyl,
R ⁴ is a 5- to 6-membered heteroaryl containing one or more heteroatoms selected from the group consisting of -COOH, phenyl, nitrogen (N), oxygen (O) and sulfur (S) Wherein said phenyl, heteroaryl or heterocycloalkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of: unsubstituted or substituted with one or more substituents selected from the group consisting of -OH, -Cl, -Br, C ₁ -C ₂ linear or branched alkoxy, phenyl, nitrogen (N), oxygen (O), 5- to 6-membered heteroaryl containing at least one heteroatom selected from the group consisting of oxygen (N), oxygen (O) and sulfur (S) and the substituents selected from the group consisting of heterocycloalkyl of 5 to 6 atoms which may be substituted, wherein the substituents of the alkyl, phenyl, heteroaryl, or heterocycloalkyl is -OH, -NO _2, -F, -Cl , C ₁ -C ₃ linear or branched alkyl, phenoxy and C ₁ - C ₄ alkoxyphenyl-C ₁ -C may be further substituted with one or more substituents selected from the group consisting of _4-alkoxy,

Is a single or double bond,
n is an integer from 0 to 3, wherein each carbon of the alkylene between A and R &lt; ⁴ &gt; may be substituted with one or more methyl or ethyl; or a pharmaceutically acceptable salt thereof.
The method according to claim 1,
In Formula 1,
A is carbon (C) or sulfur (S)
R ¹ is -H, halogen, -COOH or methyl,
R ² And R ³ are independently -H, methyl or -C (= O) R ⁵ , wherein R ⁵ is -H, -OH, -NH ₂ Or -OMe, -OEt,
R ⁴ is -COOH,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,,

,

,

,

,

,

,

,

or

ego,

Is a single or double bond,
n is an integer from 0 to 2, wherein each carbon of the alkylene between A and R &lt; ⁴ &gt; can be substituted with one or more methyls; or a pharmaceutically acceptable salt thereof.
The method according to claim 1,
The indole derivative represented by the general formula (1)
(1) Ethyl 5-methoxy-1- {3- [3- (4- (4-methoxybenzyloxy) phenyl) -1,2,4-oxadiazol- 1 H -indole-2-carboxylate;
(2) Ethyl 5-methoxy-1- {3- [3- (4- (4-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] propanoyl} -1 H - Indole-2-carboxylate;
(3) 5-Methoxy-1- {4- [3- (4 (4-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] propanoyl} -1 H - indole -2-carboxylic acid;
(4) Methyl 1- [4- (2-chlorophenyl) piperazine-1-carbonyl] indoline-2-carboxylate;
(5) 1- [4- (2-Chlorophenyl) piperazine-1-carbonyl] indoline-2-carboxylic acid;
(6) 1- [4- (2-Chlorophenyl) piperazine-1-carbonyl] indoline-2-carboxamide;
7 5-Bromo-1- (4-methoxybenzoyl) -1 H - indole-3-carbaldehyde;
8 5-Bromo-1- (4-methoxybenzoyl) -1 H - indole-3-carboxylic acid;
(9) methyl 1-nicotinoylindoline-2-carboxylate;
(10) 1-Nicotinoylindoline-2-carboxylic acid;
(11) 1-Nicotinoyl-1 H -indole-2-carboxylic acid;
(12) 2-Methyl-1-nicotinoyl-1 H -indole-3-carboxylic acid;
(13) 1-Nicotinoyl-1 H -indole-6-carboxylic acid;
(14) 1- (2-chloro-nicotinoyl) -1 H - indole-6-carboxylic acid;
(15) 1- (pyridin-3-yl-seolpayi carbonyl) -1 H-indole-3-carboxylic acid;
(16) 1- (6-chloro-nicotinoyl) -1 H - indole-3-carboxylic acid;
(17) 1- (6-morpholino-titanate say alkanoyl) -1 H - indole-3-carboxylic acid;
18 1- [6- (4-methylpiperazin-1-yl) nicotinoyl) -1 H - indole-3-carboxylic acid;
19 1- [6- (pyrrolidin-1-yl) nicotinoyl] -1 H - indole-3-carboxylic acid;
(20) 5-Bromo-1-nicotinoyl-1 H -indole-3-carboxylic acid;
21 1 - (pyrazine-2-carbonyl) -1 H - indole-3-carboxylic acid;
(22) 5-Methyl-1-nicotinoyl-1 H -indole-3-carboxylic acid;
(23) 5-Chloro-1-nicotinoyl-1 H -indole-3-carboxylic acid;
(24) 4- [2- (Methoxycarbonyl) indolin-1-yl] -4-oxobutanoic acid;
(25) Methyl 1- {3- [3- (5- (4-methoxybenzyloxy) pyridin-2-yl) -1,2,4-oxadiazol-5-yl] propanoyl} indoline -2-carboxylate;
(26) Methyl 1- {3- [3- (5-hydroxypyridin-2-yl) -1,2,4-oxadiazol-5-yl] propanoyl} indoline- ;
(27) 1- {3- [3- (5-Hydroxypyridin-2-yl) -1,2,4-oxadiazol-5-yl] propanoyl} indoline-2-carboxylic acid;
(28) 4- [2- (Methoxycarbonyl) indolin-1-yl] -3,3-dimethyl-4-oxobutanoic acid;
(29) Methyl 1- {3- [3- (5- (4-methoxybenzyloxy) pyridin-2-yl) -1,2,4-oxadiazol- Methylpropanoyl} indoline-2-carboxylate;
(30) 1- {3- [3- (5-Hydroxypyridin-2-yl) -1,2,4-oxadiazol-5-yl] -2,2-dimethylpropanoyl} indoline -2-carboxylic acid;
(31) Methyl 1- {3- [1- (pyridin-3-yl) -1,2,3-triazol-4-yl] propanoyl} indoline-2-carboxylate;
(32) 1- {3- [1- (Pyridin-3-yl) -1,2,3-triazol-4-yl] propanoyl} indoline-2-carboxylic acid;
33-methyl-1- {3- [1- (5- (4-methoxy-benzyloxy) pyridin-2-yl) -1 H - pyrazol-3-yl] propanoyl} indoline-2-carboxylic Decylate;
34 1- {3- [1- (5-hydroxy-pyridin-2-yl) -1 H - pyrazol-3-yl] propanoyl} indoline-2-carboxylic acid;
(35) Methyl 1- [3- (2-bromothiazol-5-yl) propanoyl] indoline-2-carboxylate;
(36) 1 - {[3- (2- (Pyridin-3-yl) thiazol-5-yl] propanoyl} indoline-2-carboxylic acid;
(37) 1 - {[3- (2- (3,5-Dichlorophenyl) thiazol-5-yl] propanoyl} indoline-2-carboxylic acid;
(38) 1 - {[3- (2- (3,5-Difluorophenyl) thiazol-5-yl] propanoyl} indoline-2-carboxylic acid;
(39) 1 - {[3- (2- (4-Chlorophenyl) thiazol-5-yl] propanoyl} indoline-2-carboxylic acid;
(40) 1 - {[3- (2- (2-Chlorophenyl) thiazol-5-yl] propanoyl} indoline-2-carboxylic acid;
(41) 1 - {[3- (2- (2-fluorophenyl) thiazol-5-yl] propanoyl} indoline-2-carboxylic acid;
(42) 1 - {[3- (2- (3-Fluorophenyl) thiazol-5-yl] propanoyl} indoline-2-carboxylic acid;
(43) 1- {[3- (2- (3-nitrophenyl) thiazol-5-yl] propanoyl} indoline-
(44) A process for the preparation of a compound according to any one of (1) to (4), which is characterized in that the compound is any one selected from the group consisting of 1 - {[3- (2- (3-phenoxyphenyl) thiazol-5-yl] propanoyl} indoline- &Lt; / RTI &gt; or a pharmaceutically acceptable salt thereof.
As shown in Scheme 1 below,
A process for producing an indole derivative represented by the general formula (1), comprising the step of reacting a compound represented by the general formula (2) with a compound represented by the general formula (3) to prepare a compound represented by the general formula
[Reaction Scheme 1]

(In the above Reaction Scheme 1, A, R ¹ , R ² , R ³ , R ⁴ ,

And n is as defined in Chemical Formula 1 of claim 1, and L is a leaving group, -0H or halogen.
6. The method of claim 5,
The compound represented by the general formula (3)
Reacting a compound represented by the formula (4) with a hydroxylamine to prepare a compound represented by the formula (5) (step a);
Reacting a compound represented by the formula (5) obtained in the step (a) with a compound represented by the formula (6) to prepare a compound represented by the formula (7) (step b); And
(C) reacting a compound represented by the formula (7) obtained in the step (b) under a basic condition to prepare a compound represented by the formula (3a).
[Reaction Scheme 2]

(Wherein, in the above Reaction Scheme 2, n is an integer of 0-5, E is halogen,
R ⁷ is unsubstituted or substituted with _one or more groups selected from the group consisting of -OH, -NO ₂ , halogen, C ₁ -C ₄ linear or branched alkoxy, phenyl and nitrogen (N), oxygen (O) Or heteroaryl or heterocycloalkyl containing one or more heteroatoms selected from the group consisting of C ₁ -C ₄ linear or branched alkoxy, phenyl, heteroaryl or heterocyclo Alkyl is selected from the group consisting of unsubstituted or -OH, -NO ₂ , halogen, C ₁ -C ₅ straight or branched chain alkyl, phenoxy and C ₁ -C ₅ alkoxy C ₆ -C ₁₀ aryl C ₁ -C ₅ alkoxy Which may be substituted with one or more substituents,
The compound represented by the general formula (3a) is a derivative of the compound represented by the general formula (3) in the reaction formula (1).
6. The method of claim 5,
The compound represented by the general formula (3)
A step of reducing a compound represented by the formula (8) under a base condition to prepare a compound represented by the formula (9) (step a);
Halogenating the compound of formula (9) obtained in step (a) with a halogenating reagent to prepare a compound represented by formula (10) (step b);
Malonate-forming a compound represented by the formula (10) obtained in the step (b) under a base condition with a malonate reagent to prepare a compound represented by the formula (11) (step c);
A step (d) of reducing the compound represented by the formula (11) obtained in the step c under a base condition to prepare a compound represented by the formula (12); And
(E) reacting a compound represented by the formula (12) obtained in the step (d) under a base condition to prepare a compound represented by the formula (3b).
[Reaction Scheme 3]

(In the above scheme 3, and X, Y, and Z are each independently carbon (C) or nitrogen (N), wherein X, Y, and Z are all not simultaneously carbon, E, and R ⁷ is claim 6 Scheme 2, and the compound represented by the formula (3b) is a derivative of the compound represented by the formula (3) in the reaction formula (1) of claim 5.
As shown in Scheme 4 below,
1. A process for producing an indole derivative represented by the general formula (1), which comprises a step of carrying out an amidation reaction with a compound represented by the general formula (2) and a carbonyl reagent to prepare a compound represented by the general formula (1a)
[Reaction Scheme 4]

(In the above Reaction Scheme 4, R ¹ , R ² , R ³ And

Is as defined in formula (1) of claim 1, R ⁷ is as defined in scheme (2) of claim 6, and the compound of formula (1a) is a derivative of the compound of formula (1).
As shown in Scheme 5 below,
A process for preparing an indole derivative represented by the general formula (1), comprising the step of reacting a compound represented by the general formula (2) with an anhydride compound represented by the general formula (14) to prepare a compound represented by the general formula
[Reaction Scheme 5]

(In the above Reaction Scheme 5, R ¹ , R ² , R ³ And

(1), m is an integer of 0-5, and the compound represented by the formula (1b) is a derivative of the compound represented by the formula (1).
As shown in Scheme 6 below,
Halogenating a compound represented by the formula (1b) with a halogenating reagent to prepare a compound represented by the formula (15) (step 1); And
A step of cyclizing a compound represented by the formula (15) obtained in the above step 1 with a compound represented by the formula (16) to prepare a compound represented by the formula (1c) (step 2) Preparation of derivatives:
[Reaction Scheme 6]

(In the above Reaction Scheme 6, R ¹ , R ² , R ³ ,

And n are the same as defined in Formula 1 of Claim 1, and E and R ⁷ are as defined in Reaction Formula 2 of Claim 6, and the compound represented by Formula 1c is a derivative of the compound represented by Formula 1 of Claim 1.
As shown in the following Reaction Scheme 7,
An amidation reaction of a compound represented by the formula (2) with a compound represented by the formula (17) under a base condition to prepare a compound represented by the formula (18) (step 1); And
(Step 2) of cyclizing a compound represented by the formula (18) obtained in the step 1 with sodium azide and a compound represented by the formula (19) to obtain a compound represented by the formula (1d) &Lt; / RTI &gt;&lt; RTI ID =
[Reaction Scheme 7]

(In the above Reaction Scheme 7, R ¹ , R ² , R ³ ,

And n are the same as defined in Formula 1 of Claim 1, R ⁷ is as defined in Reaction Formula 2 of Claim 6, and the compound represented by Formula 1d is a derivative of the compound represented by Formula 1 of Claim 1.
A pharmaceutical composition for preventing or treating dyslipidemia comprising an indole derivative represented by the general formula (1) of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
13. The method of claim 12,
Wherein said dyslipidemia is any one selected from the group consisting of hyperlipidemia, hypercholesterolemia and hypertriglyceridemia.
A health food composition for preventing or ameliorating dyslipidemia comprising an indole derivative represented by the general formula (1) of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
15. The method of claim 14,
Wherein said dyslipidemia is any one selected from the group consisting of hyperlipidemia, hypercholesterolemia and hypertriglyceridemia.

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