KR101511771B1 - Indole and indazole compounds as an inhibitor of cellular necrosis - Google Patents

Abstract

상기 식에서 R¹, R², R³, R⁴, R⁵, R⁶, A, X, n 및 m은 명세서에 정의한 바와 같다.The present invention relates to a method and a composition for preventing or treating cell necrosis and related diseases, which comprises a compound of the following formula (1), a pharmaceutically acceptable salt or isomer thereof, and an active ingredient thereof.
[Chemical Formula 1]

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , A, X, n and m are as defined in the specification.

Description

Indole and indazole compounds as an inhibitor of cellular necrosis [

The present invention relates to a method and a composition for preventing or treating cell necrosis and related diseases characterized by comprising an indole or indazole compound of the formula (1), a pharmaceutically acceptable salt or isomer thereof, and an active ingredient thereof .

Many studies related to apoptosis have focused on the apoptosis of cells known as programmed cell death (PCD), and the discovery of an enzyme called caspase has led to the development of drugs using caspase inhibitors by many pharmaceutical companies It has been going on for 10 years. However, few drugs have yet been approved by the FDA. This is because the natural history of a cell is likely to be caused by a cell death that occurs in a physiological situation and is due to a defensive period that maintains homeostasis in the body. In contrast, necrosis is a cell death that occurs mainly in pathologic conditions, and in the vast majority of cases, it is characterized by an inflammation reaction. Although cell death is known to be uncontrolled cell death for a long period of time, recent studies (Proskurykakov SY et al., 2002, Biochemistry) have reported cell necrosis as an active / controlled cell death phenomenon . Diseases caused by cell necrosis are ischemic (eg, myocardial infarction, stroke, nerve color), neurodegenerative, and inflammatory diseases. Since cell death is an unadjusted accident history in pathological conditions, its mechanisms of action, molecular targets, and signal transduction systems are rarely studied. Therefore, treatment of ischemic, neurodegenerative, and inflammatory diseases caused by cell necrosis, It is very urgent to find and develop such inhibitors of cell necrosis to identify biological and pathological causes.

Indole derivatives according to the present invention are very useful structures medically, and there are many research results on these structures. Among them, Patent Document WO2006 / 112549 which reports activity against glucokinase, antitumor and cardiovascular production inhibitor Patent WO95 / 07276 reported to be useful, and WO2004 / 018428 reported to be useful as an antibiotic.

Accordingly, the present inventors conducted intensive and extensive studies to develop compounds useful for prevention or treatment and improvement of cell necrosis and related diseases as well as prevention or treatment of liver diseases under the technical background described above. As a result, It has been found that the substituted indole or indazole derivative of the formula (1) as described below has an excellent effect for the prevention and treatment of cell necrosis and related diseases, and the present invention has been completed.

Accordingly, it is an object of the present invention to provide novel indole or indazole derivatives of formula (1).

The present invention also relates to the use of a compound of formula (I), a pharmaceutically acceptable salt or isomer thereof as an active ingredient together with a pharmaceutically acceptable carrier or diluent for the treatment of cell necrosis and related diseases, The present invention also provides a composition for preventing or treating chronic liver disease, a method for producing the same, and a method for producing the same.

The present invention also aims at providing a method for preventing or treating cell necrosis and related diseases, particularly liver protection, liver function improvement, and acute and chronic liver diseases, using the above composition.

In order to achieve this object, the present invention provides an indole or indazole compound represented by the following formula (1), a pharmaceutically acceptable salt or an isomer thereof:

[Chemical Formula 1]

In this formula,

n is a number from 1 to 3,

m is 0 or 1,

A represents a direct bond or represents a phenyl or 6-membered heteroaryl containing 1 to 2 nitrogen atoms,

X represents C or N, provided that when X is N, m is 0 and when X is C, m is 1,

R ¹ represents hydrogen, alkyl, - (CH ₂ ) _r NR ⁷ R ⁸ , or - (CH ₂ ) _r CO ₂ H wherein r is a number from 1 to 5, and R ⁷ and R ⁸ are each independently Alkyl, or alkylcarbonyl, or, together, optionally, one methylene may be replaced by an N atom and form an alkylene chain optionally substituted by alkyl,

R ² is hydrogen, halogen, cyano, nitro, hydroxyl, or represent alkyl, alkoxy or _{trialkylsilyl, - (CH 2) p CO} 2 R 7, - (CH 2) p OR 7, - (CH 2 _{^{) p NR 7 R 8, -NHR}} 10, -N (H) S (O) 2 R 7, -NHC (O) R 10, - (CH 2) p S (O) 2 R 7 or (CH _{2) p} -heterocycle-R ¹⁰ wherein p is a number from 0 to 3, R ⁷ and R ⁸ are as defined above, and R ¹⁰ is hydrogen, oxo, alkylsulfonyl, alkylcarbonyl, alkyloxycarbonyl Alkyl, alkoxy, alkyl or heterocycle, < RTI ID = 0.0 >

R ³ represents hydrogen, cyano, halogen, alkyl or phenyl, - (CH ₂ ) _n -heterocycle or - (CH ₂ ) _n -aryl, n is a number from 1 to 3,

R ⁴ represents -YR ¹¹ , wherein Y is a direct bond or represents - (CR ⁷ R ⁸ ) _p Y '-, p is a number from 0 to 3, and R ⁷ And R < ⁸ > are as defined above,

Y 'is ^{-O-, -S-, -NR 12 -,} -NR 12 C (O) -, -C (O) -, -C (O) O-, -C (O) NR 12 -, - S (O) _q -, and -S (O) _q NR ¹² - is selected from the group consisting of, R ¹² is a hydrogen, alkyl, aryl or heteroaryl, q is a number from 0 to 2, R ¹¹ is T is selected from the group consisting of hydrogen, cyano, halogen, hydroxy, thiol, carboxy, alkyl and - (CH ₂ ) _t BR ¹³ , t is a number from 0 to 3, and B is a heterocycle, heteroaryl, R ¹³ represents hydrogen, cyano, halogen, hydroxy, oxo, thiol, carboxy, carboxyalkyl, alkylcarbonyloxy, alkyl, alkoxy, alkylthio, alkylcarbonyl or alkylsulfonyl,

R < ⁵ > represents hydrogen, alkyl, cycloalkyl, heterocycle or heterocyclylalkyl,

R ⁶ is _{^{- (CR 7 R 8) p}} -ZDWR represents a ^14, Z is a direct bond, or represents -C (O) -, -C ( O) O-, -C (O) NR 12 -, -S (O) _y - is selected from the group, y is a number 1 or 2, D represents a direct bond, or represents cycloalkyl, heteroaryl or heterocyclyl, W is a direct bond, or represents -NR consisting of ⁷ -. -C (O) -, -C ( O) O-, -C (O) NR 12 -, -S (O) y -, -S (O) y NR 12 - or -NR ¹² S (O) _y -, R ¹⁴ represents hydrogen, hydroxy, alkyl, alkoxy, heterocycle, heteroaryl, aryl or aralkyl,

R ⁵ and R ⁶ together represent an alkylene chain,

Wherein the alkyl, alkoxy, aryl, cycloalkyl, heterocycle and heteroaryl may optionally be substituted and the substituent is selected from the group consisting of hydroxy, halogen, nitrile, amino, alkylamino, dialkylamino, carboxy, alkyl, alkoxy, carboxyalkyl , Alkylcarbonyloxy, alkylthio, alkyloxycarbonyl, alkylaminocarbonyl, arylalkoxy, and oxo.

In the definition of the substituent of the compound of formula (1) according to the present invention, the term "alkyl" means an aliphatic hydrocarbon radical. Alkyl may be a " saturated alkyl " containing no alkenyl or alkynyl moiety, or an " unsaturated alkyl " containing at least one alkenyl or alkynyl moiety. &Quot; Alkenyl " means a group comprising at least one carbon-carbon double bond, and " alkynyl " means a group comprising at least one carbon-carbon triple bond. Alkyl, when used alone or in combination with alkoxy, may be branched or straight chain, respectively.

The alkyl group may have from 1 to 20 carbon atoms, unless otherwise defined. The alkyl group may be a medium-sized alkyl having 1 to 10 carbon atoms. The alkyl group may be lower alkyl having 1 to 6 carbon atoms. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, ethenyl, propenyl, butenyl and the like. For example, C ₁ -C ₄ -alkyl has from 1 to 4 carbon atoms in the alkyl chain and is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and t- Group.

The term " alkoxy " means alkyloxy having 1 to 10 carbon atoms unless otherwise specified.

The term " cycloalkyl " means a saturated aliphatic 3- to 10-membered ring unless otherwise defined. Typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The term " aryl " includes at least one ring having a covalent pi electron system and includes, for example, a monocyclic or fused ring polycyclic (i.e., rings that divide adjacent pairs of carbon atoms) groups . That is, in the present specification, aryl means 4- to 10-membered, preferably 6- to 10-membered aromatic monocyclic or multicyclic ring including phenyl, naphthyl and the like unless otherwise defined.

The term "heteroaryl" comprises from 1 to 3 heteroatoms selected from the group consisting of one N, O, and S that do not otherwise defined, benzoyl or C ₃ -C ₈ Means an aromatic 3- to 10-membered ring, preferably a 4- to 8-membered ring, more preferably a 5- to 6-membered ring which can be fused with cycloalkyl. Examples of monocyclic heteroaryl include thiazole, oxazole, thiophene, furan, pyrrole, imidazole, isoxazole, isothiazole, pyrazole, triazole, triazine, thiadiazole, tetrazole, oxadiazole Sol, pyridine, pyridazine, pyrimidine, pyrazine, and similar groups. Examples of bicyclic heteroaryls include indole, indoline, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzthiazole, benzthiadiazole, benztriazole, quinoline, isoquinoline, purine , Furopyridine, and similar groups.

And the term 'heterocyclic' includes from 1 to 3 heteroatoms selected from the group consisting of one N, O, and S that do not otherwise defined, benzoyl or C ₃ -C ₈ Means a 3- to 10-membered ring, preferably a 4- to 8-membered ring, more preferably a 5- to 6-membered ring which may be fused with cycloalkyl and is saturated or contains one or two double bonds. Examples of the heterocycle include pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, pyran, piperidine, morpholine, thiomorpholine, piperazine, However, the present invention is not limited to these.

Other terms and abbreviations used herein can be interpreted as commonly understood by a person skilled in the art to which the present invention belongs, unless otherwise defined.

Also preferred as the compound of the formula (1)

n is a number from 1 to 3,

m is 0 or 1,

A represents a direct bond or represents a phenyl or 6-membered heteroaryl containing 1 to 2 nitrogen atoms,

X represents C or N, provided that when X is N, m is 0 and when X is C, m is 1,

R ¹ represents hydrogen, C ₁ -C ₆ -alkyl or - (CH ₂ ) _r NR ⁷ R ⁸ , r is a number from 2 to 3, and R ⁷ And R ⁸ are each independently hydrogen or C ₁ -C ₃ - alkyl, optionally together and one methylene is replaced by N atom, C ₁ -C ₆ - alkyl optionally substituted by a C ₂ -C ₆ - alkyl May form a chain,

R ² is hydrogen, halogen, C ₁ -C ₆ - _{alkyl, - (CH 2) p CO} 2 R 7, - (CH 2) p OR 7, - (CH 2) p NR 7 R 8, -NHR 10, -N (H) S (O) ₂ R ⁷ , -NHC (O) R ¹⁰ , - (CH ₂ ) _p S (O) ₂ R ⁷ or - (CH ₂ ) _p -heterocycle-R ¹⁰ ,

p is a number from 0 to 3,

R ¹⁰ is selected from the group consisting of hydrogen, oxo, C ₁ -C ₆ -alkylsulfonyl, C ₁ -C ₆ -alkylcarbonyl, C ₁ -C ₆ -alkyloxycarbonyl, C ₁ -C ₆ -alkylaminocarbonyl, C ₁ -C ₆ - alkoxy, C ₁ -C ₆ - alkyl, hydroxy -C ₁ -C ₆ - alkyl, or represent, and contains 1 or 2 nitrogen atoms as a hetero atom C ₁ -C ₃ - alkyl, by An optionally substituted 5- to 6-membered heterocycle,

R ³ represents hydrogen, halogen or C ₁ -C ₆ -alkyl or represents phenyl optionally substituted by C ₁ -C ₆ -alkoxy, or wherein the heterocycle represents one or two heteroatoms selected from N and O atoms C ₁ -C ₅ -alkyl which is a 5 to 6 membered ring optionally substituted by one or two oxo groups,

R ⁴ represents -YR ¹¹ , wherein Y is a direct bond or - (CR ⁷ R ⁸ ) _p Y'- and Y 'is -O-, -C (O) -, -C (O) O-, -NHC (O) -, ¹² -NR -, -C (O) NR ¹² -, -S (O) _q -, and -S (O) NR ¹² _q - is selected from the group, R ¹² is hydrogen consisting of Or C ₁ -C ₃ -alkyl, q is a number from 0 to 2 and R ¹¹ is hydrogen, halogen, hydroxy, thiol, carboxy, C ₁ -C ₆ -alkyl, hydroxy-C ₁ -C ₆ -Alkyl, or - (CH ₂ ) _t BR ¹³ , t is a number from 0 to 3, B is C ₆ -C ₁₀ -aryl, or is selected from the group consisting of N, O and S atoms, or Or a 5 to 6 membered heteroaryl comprising one or two N atoms, and R ¹³ represents hydrogen, halogen, hydroxy, oxo, thiol, carboxy , Carboxy-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkylcarbonyloxy, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkylthio, C C ₁ -C ₆ -halogenoalkyl, C ₁ -C ₆ -alkylcarbonyl or C ₁ -C ₆ -alkylsulfonyl,

R ⁵ represents hydrogen, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -cycloalkyl, heterocycle or heterocyclyl-C ₁ -C ₆ -alkyl wherein the heterocycle is selected from N and O atoms Is a 3 to 8 membered ring optionally containing one to three heteroatoms, optionally substituted by one or two oxo groups,

R ⁶ represents - (CR ⁷ R ⁸ ) _p -ZDWR ¹⁴ ,

Z is a direct bond, or represents -C (O) -, -C ( O) O-, -C (O) NR 12 -, -S (O) y - is selected from the group consisting of, y is 1 to 2 Lt; / RTI >

D represents C ₄ -C ₆ -cycloalkyl, or a 5 to 6 membered heterocycle optionally containing one or two heteroatoms selected from N, O and S, and optionally containing an oxo group,

W represents a direct bond or -NR < ^{7 >} -. -C (O) -, -C ( O) O-, -C (O) NR 12 -, -S (O) y -, -S (O) y NR 12 - or -NR ¹² S (O) _y -, < / RTI >

R ¹⁴ is hydrogen, hydroxy, C ₁ -C ₆ - alkyl, hydroxy -C ₁ -C ₆ - alkyl, carboxy -C ₁ -C ₆ - alkyl, C ₆ -C ₁₀ - aryl or C ₆ -C ₁₀ -Ar-C ₁ -C ₆ -alkyl, or a 5 to 6 membered heterocycle containing from 1 to 3 heteroatoms selected from N, O and S and optionally substituted by one or two oxo groups, , 5 to 6 membered heteroaryl optionally containing one to three heteroatoms selected from N, O and S and optionally substituted by C ₁ -C ₆ -alkyl,

R ⁵ and R ⁶ together form a C ₂ -C ₆ -alkylene chain.

In the compound of formula (1) according to the present invention, X is C or N, and the structure of the compound in each case may be represented by the following formula (1a) or (1b).

[Formula 1a]

[Chemical Formula 1b]

In the compound of formula (1) according to the present invention, substituent A more preferably represents phenyl, pyridine or 1,4-pyrazine.

The substituent R ¹ is more preferably hydrogen, C ₁ -C ₆ -alkyl or di (C ₁ -C ₃ -alkyl) amino-C ₂ -C ₃ -alkyl, most preferably hydrogen, methyl or (dimethyl Amino) ethyl.

The substituent R ² is more preferably hydrogen, amino, halogen, C ₁ -C ₃ - alkyl, carboxy, carboxy -C ₁ -C ₃ - alkyl, C ₁ -C ₃ - alkoxycarbonyl, C ₁ -C ₃ - alkoxycarbonyl -C ₁ -C ₃ - alkyl, hydroxy -C ₁ -C ₃ - alkyl, C ₁ -C ₃ - _{alkoxy, - (CH 2) p NR} 7 R 8, -NHR 10, -N (H ) S (O) R ⁷ _2, -NHC (O) R ¹⁰ or - (CH _{2) p} - represents a heterocycle -R ^10, p, R ^7, R ¹⁰ is ^8, and R as defined in the preferable range And most preferably hydrogen, methyl, methoxy, fluoro, -NH ₂ , -NHAc, -NHSO ₂ Me, -NHBOC, -NH (1-methyl-piperidine) hydroxy-ethyl, dimethylaminomethyl, hydroxymethyl, hydroxyethyl, carboxy, carboxymethyl, carboxyethyl, -CH ₂ - (2- oxo) piperazine, -CH ₂ - piperazine, -CH ₂ - morpholine, -CH ₂ - [1,1-dioxo-thiomorpholin-4-yl], -CH ₂ - [4-acetyl-piperazin-1-yl].

Substituent R ³ is more preferably hydrogen, methyl or bromo, or represents phenyl optionally substituted by C ₁ -C ₃ -alkoxy, or wherein the heterocycle represents one or two heteroatoms selected from N and O atoms, C ₁ -C ₃ -alkyl which is a 5 to 6 membered ring optionally substituted by one or two oxo groups and is most preferably selected from the group consisting of hydrogen, methyl, bromo, phenyl, 4-MeO-phenyl , -CH ₂ - (2-oxo-piperazin-4-yl), and -CH ₂ - (morpholin-4-yl).

The substituent R ⁴ is more preferably -YR ¹¹ , Y is a direct bond, -O-, -C (O) -, -NH-, -CONH-, -SO ₂ NH-, -NHC , -CH ₂ CONH-, -CH ₂ C (O) -, and -CH ₂ SO ₂ -, and most preferably a direct bond, -O-, -C (O) -, -CH ₂ C (O) - and NHC (O) - ≪ / RTI > R ¹¹ is selected from the group consisting of hydrogen, halogen, hydroxy, C ₁ -C ₆ -alkyl or - (CH ₂ ) _t BR ¹³ , t, B and R ¹³ are as defined in the above preferred examples, Most preferably hydrogen, methyl, ethyl, phenyl, fluoro, chloro, hydroxy, 2-carboxy-pyrrolidin-1-yl, pyrrolidin- 2-yl, -CH ₂ - (1,1-dioxo-thiomorpholin-4-yl), and -CH ₂ - (2-oxopiperazin-4-yl).

Substituent R ⁵ is more preferably hydrogen, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -cycloalkyl, heterocycle or heterocyclyl-C ₁ -C ₆ -alkyl, wherein the heterocycle is N And O atoms, and is preferably a 5- to 6-membered ring optionally substituted by one or two oxo groups, most preferably hydrogen, methyl, cyclopentyl, tetrahydropyran-4-yl And CH ₂ - (tetrahydropyran-4-yl).

The substituent R ⁶ more preferably represents - (CR ⁷ R ⁸ ) _p -ZDWR ¹⁴ , wherein Z represents a direct bond or represents -C (O) -, -C (O) O-, -C O) NH- or -S (O) ₂ -. D is more preferably selected from the group consisting of cyclopentyl, cyclohexyl, pyrrolidine, tetrahydropyran, tetrahydrofuran or piperidine. W represents a direct bond or represents -SO ₂ -, -CO-, -C (O) O- or -CONR ¹² -, wherein R ¹² is as defined in the above preferred examples. Substituent W is most preferably -SO ₂ - is selected from the group consisting of, -CONH- -, -CO-, -C ( O) O-, -CON (Me). R ¹⁴ is more preferably hydrogen, hydroxy, C ₁ -C ₆ - alkyl, hydroxy -C ₁ -C ₆ - alkyl, C ₆ -C ₁₀ - aryl or C ₆ -C ₁₀ - aralkyl -C ₁ - C ₃ -alkyl, or a 5 to 6 membered heterocycle containing 0 or S atoms optionally substituted by 1 or 2 oxo groups, or 1 or 2 heteroatoms selected from N, O and S, And 5 to 6 membered heteroaryl optionally substituted by C ₁ -C ₃ -alkyl and most preferably represents hydrogen, hydroxy, methyl, ethyl, isobutyl, hydroxymethyl, hydroxyethyl, phenyl, benzyl , Thiophene, tetrahydrofuran, tetrahydropyran, 1,1-dioxo-tetrahydro-thiopyran, furan, pyridine and 5-methyl-pyridine.

On the other hand, R < ⁵ > and R < ⁶ > may more preferably form a piperidine together with the N atom to which they are attached.

The compounds according to the invention can also form pharmaceutically acceptable salts. Such "pharmaceutically acceptable salts" include those acids which form non-toxic acid addition salts containing a pharmaceutically acceptable anion, for example inorganic acids such as sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid and the like; Organic carboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid and the like; Methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, and the like. In addition, pharmaceutically acceptable base addition salts include, for example, alkali metal or alkaline earth metal salts formed by lithium, sodium, potassium, calcium, magnesium and the like; Amino acid salts such as lysine, arginine and guanidine; Organic salts such as dicyclohexylamine, N-methyl-D-glucamine, tris (hydroxymethyl) methylamine, diethanolamine, choline, triethylamine and the like. The compound of formula (1) according to the present invention can be converted into its salt by a conventional method, and the preparation of the salt can be easily carried out by a person skilled in the art based on the structure of the above formula (1) have.

As used herein, an "isomer" means a compound or salt thereof that has the same chemical or molecular formula but is optically or sterically different. The compound of formula (1) according to the present invention may have an asymmetric carbon center, and therefore may exist as an optical isomer (R or S isomer), a racemate, a mixture of diastereomers, individual diastereoisomers, When present, geometric isomers (trans, cis isomers) may also be present. All of these isomers and mixtures thereof are also included within the scope of the present invention.

Unless otherwise stated hereinafter, the compounds of formula (1) include pharmaceutically acceptable salts and isomers thereof, all of which should be construed as being included within the scope of the present invention. For convenience of explanation, these compounds are simply referred to as compounds of the formula (1).

Representative compounds of formula (1) according to the present invention include the following compounds:

Cyclopentyl- [5-methyl-2- (pyridin-2-yl) -lH-indol-7-yl] -amine;

Cyclopentyl- [5-methyl-2-phenyl-lH-indol-7-yl] -amine;

5-Chloro-2- (pyridin-2-yl) -1H-indol-7-yl] -amine;

(Tetrahydropyran-4-yl) - [5-methyl-2- (pyridin-2-yl) -lH-indol-7-yl] -amine;

Cyclopentyl- [2- (pyrazin-2-yl) -1H-indol-7-yl] -amine;

Cyclopentyl- [5-methyl-2- (pyrazin-2-yl) -lH-indol-7-yl] -amine;

Cyclopentyl- [2- (pyridin-2-yl) -1H-indol-7-yl] -amine;

(Tetrahydropyran-4-yl) - [2- (pyridin-2-yl) -1H-indol-7-yl] -amine;

Cyclopentyl- [5-phenoxy-2- (pyridin-2-yl) -lH-indol-7-yl] -amine;

Cyclopentyl- [5-ethoxy-2- (pyridin-2-yl) -1H-indol-7-yl] -amine;

Cyclohexyl- [5-methyl-2- (pyridin-2-yl) -lH-indol-7-yl] -amine;

1- [4 - [(5-methyl-2- (pyridin-2-yl) -1H-indol-7-yl) amino] piperidin-1-yl] ethanone;

(1-methylpiperidin-4-yl) - [5-methyl-2- (pyridin-2-yl) -1H-indol-7-yl] -amine;

(1-Benzylpyrrolidin-3-yl) - [5-methyl-2- (pyridin-2-yl) -1H-indol-7-yl] -amine;

Cyclopentylmethyl- [5-methyl-2- (pyridin-2-yl) -lH-indol-7-yl] -amine;

5-Methyl- (7-piperidin-1-yl) amino-2- (pyridin-2-yl) -1H-indole;

Dimethyl- [5-methyl-2- (pyridin-2-yl) -1H-indol-7-yl] -amine;

Cyclopentyl- [1,5-dimethyl-2- (pyridin-2-yl) -indol-7-yl] -amine;

Cyclopentyl- [5-methyl-2- (6-methylpyridin-2-yl) -lH-indol-7-yl] -amine;

(1-cyclohexanon-4-yl) - [5-methyl-2- (pyridin-2-yl) -lH-indol-7-yl] -amine;

4 - [(5-chloro-2-phenyl-1H-indol-7-yl) amino] -cyclohexan-1-one;

N- (5-Methyl-2- (pyridin-2-yl) -lH-indol-7-yl) -benzamide;

1-ethyl-3- [5-methyl-2- (pyridin-2-yl) -1H-indol-7-yl] -urea;

1-phenyl-3- [5-methyl-2- (pyridin-2-yl) -1H-indol-7-yl] -urea;

Thiophene-2-sulfonic acid (2-pyridin-2-yl-lH-indol-7-yl) -amide;

Thiophene-2-sulfonic acid [5-methyl-2- (pyridin-2-yl) -1H-indol-7-yl] -amide;

Cyclopentyl-methyl- [5-methyl-2- (pyridin-2-yl) -1H-indol-7-yl] -amine;

7- (Cyclopentyl) amino-2-phenyl-1H-indole-5-carboxylic acid ethyl ester;

Cyclopentyl- [5-hydroxymethyl-2-phenyl-lH-indol-7-yl] -amine;

7- (Cyclopentyl) amino-2-phenyl-1H-indole-5-carboxylic acid;

2- [7- (Cyclopentyl) amino-2-phenyl-1H-indol-5-yl] -acetic acid ethyl ester;

2- [7- (Cyclopentylamino) -2-phenyl-1H-indol-5-yl] ethanol;

2- [7- (Cyclopentyl) amino-2-phenyl-1H-indol-5-yl] acetic acid;

2- [2-Phenyl-7- (tetrahydropyran-4-yl) amino-1H-indol-5-yl] -acetic acid;

2- [2-Phenyl-7- (1,1-dioxo-tetrahydro-thiopyran-4-yl) amino-1H-indol-5-yl] -acetic acid;

(Tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin-4-yl) methyl- 1 H-indol-7-yl] amine;

(Tetrahydropyran-4-yl) - [2-phenyl-5- (2-oxo-piperazin-4-yl) methyl- 1 H-indol-7-yl] amine;

Cyclopentyl- [2- (3-fluoro) phenyl-5- (2-oxo-piperazin-4-yl) methyl- 1 H-indol-7-yl] amine;

(Tetrahydropyran-4-yl) - [2- (4-methoxy) phenyl-5- (1,1-dioxo-thiomorpholin- ;

Cyclopentyl- [3,5-dimethyl-2-phenyl-lH-indol-7-yl] -amine;

(Tetrahydropyran-4-yl) - (5-methyl-2-phenyl-lH-indol-7-yl) -amine;

Cyclopentylmethyl- (5-methyl-2-phenyl-lH-indol-7-yl) -amine;

(Tetrahydropyran-4-ylmethyl) - (5-methyl-2-phenyl-lH-indol-7-yl) -amine;

(L-Methylpiperidin-4-yl) - (5-methyl-2-phenyl-lH-indol-7-yl) -amine;

1 - [- 4 - [(5-methyl-2-phenyl-1H-indol-7-yl) amino] piperidin-1-yl] ethanone;

Cyclopentyl- (5-chloro-2-phenyl-lH-indol-7-yl) -amine;

Cyclohexyl- (5-chloro-2-phenyl-lH-indol-7-yl) -amine;

(Tetrahydropyran-4-yl) - (5-chloro-2-phenyl-lH-indol-7-yl) -amine;

Cyclopentylmethyl- (5-chloro-2-phenyl-lH-indol-7-yl) -amine;

(Tetrahydropyran-4-ylmethyl) - (5-chloro-2-phenyl-lH-indol-7-yl) -amine;

(L-Benzylpyrrolidin-3-yl) - (5-chloro-2-phenyl-lH-indol-7-yl) -amine;

(L-Methylpiperidin-4-yl) - (5-chloro-2-phenyl-lH-indol-7-yl) -amine;

(1,4-dioxaspiro [4.5] decan-8-yl) - (5-chloro-2-phenyl-1H-indol-7-yl) -amine;

2 - [(5-chloro-2-phenyl-1H-indol-7-yl) amino] propane-1,3-diol;

(Tetrahydropyran-4-yl) - (5-methyl-2-phenyl-lH-indol-7-yl) -methyl- amine;

(Tetrahydropyran-4-ylmethyl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin-4-yl) methyl- 1 H-indol-7-yl] amine;

Di (tetrahydropyran-4-ylmethyl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin-4-yl) methyl- 1 H-indol-7-yl] amine;

Di (tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin-4-yl) methyl- 1 H-indol-7-yl] amine;

(L-methyl-piperidinemethyl-4-yl) - [5-fluoro-2-phenyl-lH-indol-7-yl] amine;

2- [4 - [(5-fluoro-2-phenyl-1H-indol-7-yl) amino] piperidin-1-yl] ethanol;

[1- (Tetrahydropyran-4-yl) piperidin-4-yl] - (5-fluoro-2-phenyl-1H-indol-7-yl) amine;

(Tetrahydropyran-4-yl) - (5-phenoxy-2-phenyl-lH-indol-7-yl) -amine;

(Tetrahydropyran-4-ylmethyl) - [2-phenyl-5- (2-oxo-piperazin-4-yl) methyl- 1 H-indol-7-yl] amine;

(Tetrahydropyran-4-yl) - [5-chloro-l- (2-diethylaminoethyl) -2-phenyl-lH-indol-7-yl] amine;

Dimethyl- (5-chloro-l-methyl-2-phenyl-lH-indol-7-yl) amine;

(Tetrahydropyran-4-yl) - (5-chloro-l-methyl-2-phenyl-lH-indol-7-yl) -methylamine;

(Tetrahydropyran-4-yl) - (5-chloro-3-phenyl-lH-indol-7-yl) -amine;

Cyclopentyl- (5-chloro-3-phenyl-lH-indol-7-yl) -amine;

(Tetrahydropyran-4-ylmethyl) - (5-chloro-3-phenyl-lH-indol-7-yl) -amine;

Cyclopentyl- (5-chloro-3- (morpholin-4-yl) methyl-2-phenyl-lH-indol-7-yl) -amine;

(Tetrahydropyran-4-yl) - (5-chloro-3- (morpholin-4-yl) methyl-2-phenyl-1H-indol-7-yl) -amine;

(Tetrahydropyran-4-yl) - (5-chloro-3- (2-oxo-piperazin-4-yl) methyl-2-phenyl-1H-indol-7-yl) -amine;

Cyclopentyl- (5-chloro-3- (2-oxo-piperazin-4-yl) methyl-2-phenyl-lH-indol-7-yl) -amine;

(Tetrahydropyran-4-ylmethyl) - (5-chloro-3- (2-oxo-piperazin-4-yl) methyl-2-phenyl-lH-indol-7-yl) -amine;

(Tetrahydropyran-4-yl) - (3-bromo-5- (1,1-dioxo-thiomorpholin- ;

Cyclopentyl- (3-bromo-5- (1,1-dioxo-thiomorpholin-4-yl) methyl-2-phenyl-1H-indol-7-yl) -amine;

(Tetrahydropyran-4-ylmethyl) - (3-bromo-5- (1,1-dioxo-thiomorpholin- Amine;

(Tetrahydropyran-4-yl) - (5- (1,1-dioxo-thiomorpholin-4- yl) methyl- 2- (3- fluorophenyl) Amine;

(Tetrahydropyran-4-yl) - (5-chloro-3-phenyl-lH-indol-7-yl) -amine;

(3-methylbutyl) - [5- (1,1-dioxo-thiomorpholin-4-yl) methyl-2- (4-methoxyphenyl) -lH-indol-7-yl] -amine;

t-butyl N- [4- [5-chloro-7- (cyclopentylamino) -1H-indol-2-yl] phenyl] carbamate;

Cyclopentyl- [2- (4-aminophenyl) -5-chloro-lH-indol-7-yl] -amine;

Cyclopentyl- {5-chloro-2- [4- (1-methyl-piperidin-4-yl) aminophenyl] -1H-indol-7-yl} -amine;

N- [4- (5-Chloro-7-cyclopentylamino-1H-indol-2-yl) -phenyl] -methanesulfonamide;

Cyclopentyl- {5- (1,1-dioxo-thiomorpholin-4-yl) methyl-2- [4- (acetyl) aminophenyl] -1H-indol-7-yl} -amine;

Dicyclopentyl- {5- (1,1-dioxo-thiomorpholin-4-yl) methyl-2- [4- (acetyl) aminophenyl] -1H-indol-7-yl} -amine;

(Tetrahydropyran-4-yl) methyl- {5- (1,1-dioxo-thiomorpholin-4-yl) methyl- 2- [4- (acetyl) aminophenyl] Yl} -amine;

Di (tetrahydropyran-4-yl) methyl- {5- (1,1-dioxo-thiomorpholin-4- yl) methyl- 2- [4- (acetyl) aminophenyl] - yl} -amine;

(Tetrahydropyran-4-yl) - {5- (1,1-dioxo-thiomorpholin-4-yl) methyl- 2- [4- (acetyl) aminophenyl] -1H-indol- } -Amine;

(5-methyl-2-phenyl-lH-indol-7-yl) -piperidin-4-yl-amine;

[1- (Methanesulfonyl) piperidin-4-yl] - (5-methyl-2-phenyl-1H-indol-7-yl) -amine;

2-Hydroxy-1- [4- (5-methyl-2-phenyl-1H-indol-7-yl) amino-piperidin-l-yl] -ethanone;

(5-Chloro-2-phenyl-lH-indol-7-yl) -piperidin-4-yl-amine;

4- (5-Chloro-2-phenyl-1H-indol-7-yl) amino-piperidin-l-yl-carboxylic acid phenylamide;

L- [4- (5-Chloro-2-phenyl-lH-indol-7-yl) amino-piperidin-l-yl] -2-dimethylamino-ethanone;

[5- (1,1-Dioxo-thiomorpholin-4-yl) methyl-2-phenyl-1H-indol-7-yl] - (piperidin-4-yl) methyl-amine;

Yl) - (1 -methanesulfonyl-piperidin-4-yl) -methyl-2-phenyl-lH-indol- Amine;

Yl} amino-piperidin-1-yl} - (tetrahydro-furan-2-ylmethyl) Furan-2-yl) -methanone;

(5-fluoro-2-phenyl-1H-indol-7-yl) - [1- (1,1- dioxo-tetrahydrothiopyran-4- yl) -piperidin- ;

N- (5-chloro-2-phenyl-1H-indol-7-yl) -N ', N'-dimethyl-cyclohexane-1,4-diamine;

N- (5-Chloro-2-phenyl-1H-indol-7-yl) -N'-methyl-cyclohexane-1,4-diamine;

4- (5-Chloro-2-phenyl-1 H-indol-7-yl) amino-cyclohexane-1-carboxylic acid;

4- (5-Methyl-2-phenyl-lH-indol-7-yl) amino-cyclohexane-1-carboxylic acid;

4- (5-Chloro-2-phenyl-lH-indol-7-yl) amino-cyclohexane-1-carboxylic acid amide;

4- (5-Chloro-2-phenyl-1 H-indol-7-yl) amino-cyclohexanecarboxylic acid methylamide;

(2- (5-Fluoro-2-phenyl-1H-indol-7-yl) amino-acetic acid methyl ester;

2- (5-Fluoro-2-phenyl-lH-indol-7-yl) amino-acetic acid;

2- (5-phenoxy-2-phenyl-1H-indol-7-yl) amino-acetic acid methyl ester;

2 - [(5-phenoxy-2-phenyl-1H-indol-7-yl) amino] -acetic acid;

2 - [(5-phenoxy-2-phenyl-1H-indol-7-yl) amino] -propionic acid methyl ester;

2- (5-Phenoxy-2-phenyl-1H-indol-7-yl) amino-propionic acid;

2- (5-Chloro-2-phenyl-1H-indol-7-yl) amino-propionic acid;

(5-Chloro-2-phenyl-lH-indol-7-yl) -pyridin-2-yl-amine;

(5-Chloro-2-phenyl-lH-indol-7-yl) -5-methyl-pyridin-2-yl-amine;

(5-Chloro-3-phenyl-lH-indol-7-yl) - (5-methyl-pyridin-2-yl) -amine;

(2S) -1- (7-Cyclopentylamino-2-phenyl-lH-indole-5-carbonyl) -pyrrolidine-2-carboxylic acid methyl ester;

(2S) -1- (7-Cyclopentylamino-2-phenyl-lH-indole-5-carbonyl) -pyrrolidine-2-carboxylic acid;

(2S) -1- [2-Phenyl-7- (tetrahydropyran-4-yl) amino-1H-indole-5-carbonyl] -pyrrolidine-2-carboxylic acid;

2- (7-Cyclopentylamino-2-phenyl-1H-indol-5-yl] -1-pyrrolidin-1-yl-ethanone;

Cyclopentyl- [2-phenyl-5- (2-pyrrolidin-1-yl-ethyl) -lH-indol-7-yl] -amine;

2 - [(R) -2- (7-Cyclopentylamino-2-phenyl-1H-indol-5-yl) -4,5-dihydro-thiazol-4-yl] -acetic acid;

(2-phenyl-7- (tetrahydropyran-4-yl) methylamino-1 H-indol-5-yl) -4,5-dihydro-thiazol- ] -Acetic acid;

3- (7-Cyclopentylamino-5-chloro-1 H-indol-2-yl) -benzoic acid methyl ester;

3- (7-Cyclopentylamino-5-chloro-1 H-indol-2-yl) -benzoic acid;

[3- (5-Chloro-7-cyclopentylamino-1H-indol-2-yl) -phenyl] -methanol;

{3- [5-Chloro-7- (tetrahydropyran-4-yl) amino-1H-indol-2-yl] -phenyl} -methanol;

2- {3- [5-Chloro-7- (tetrahydropyran-4-ylmethyl) amino-1H-indol-2-yl] -phenyl} -acetic acid;

2- [3- (5-Chloro-7-cyclopentylamino-1H-indol-2-yl) -phenyl] -acetic acid;

2- {3- [5-Chloro-7- (tetrahydropyran-4-yl) amino-1H-indol-2-yl] -phenyl} -acetic acid;

2- {3- [5-Chloro-7- (tetrahydropyran-4-ylmethyl) amino-1H-indol-2-yl] -phenyl} -acetic acid methyl ester;

2- [3- (5-Chloro-7-cyclopentylamino-1H-indol-2-yl) -phenyl] -acetic acid methyl ester;

2- {3- [5-Chloro-7- (tetrahydropyran-4-yl) amino) -lH-indol-2-yl] -phenyl} -acetic acid methyl ester;

[2- (5-Chloro-7-cyclopentylamino-1H-indol-2-yl) -phenyl] -methanol;

2- (5-Chloro-7-cyclopentylamino-1H-indol-2-yl) -benzoic acid;

2- (5-Chloro-7-cyclopentylamino-1H-indol-2-yl) -benzoic acid methyl ester;

[4- (5-Chloro-7-cyclopentylamino-1H-indol-2-yl) -phenyl] -methanol;

2- {4- [5-Chloro-7- (tetrahydropyran-4-yl) amino-1H-indol-2-yl] phenyl} -ethanol;

4- (5-Chloro-7-cyclopentylamino-1H-indol-2-yl) -benzoic acid;

2- {4- [5-Chloro-7- (tetrahydropyran-4-ylmethyl) amino-1H-indol-2-yl] phenyl} -acetic acid;

2- [4- (5-Chloro-7-cyclopentylamino-1H-indol-2-yl) phenyl] -acetic acid;

2- {4- [5-Chloro-7- (tetrahydropyran-4-yl) amino-1H-indol-2-yl] phenyl} -acetic acid;

4- (5-Chloro-7-cyclopentylamino-1H-indol-2-yl) benzoic acid methyl ester;

4- (7-Cyclopentylamino-5-methyl-lH-indol-2-yl) benzoic acid methyl ester;

2- {4- [5-Chloro-7- (tetrahydropyran-4-ylmethyl) amino-1H-indol-2-yl] phenyl} -acetic acid methyl ester;

2- [4- (5-Chloro-7-cyclopentylamino-1H-indol-2-yl) phenyl] acetic acid methyl ester;

2- {4- [5-Chloro-7- (tetrahydropyran-4-yl) amino-1H-indol-2-yl] phenyl} -acetic acid methyl ester;

[5-chloro-2- (3-dimethylaminoethylphenyl) -1H-indol-7-yl] - (tetrahydropyran-4-yl) -amine;

[5-chloro-2- (3-morpholin-4-ylmethylphenyl) -1H-indol-7-yl] - (tetrahydropyran-4-yl) -amine;

[5-Chloro-2- (3-pyrrolidin-4-ylmethylphenyl) -1H-indol-7-yl] - (tetrahydropyran-4-yl) -amine;

L- {4- [3- (5-Chloro-7-tetrahydropyran-4-ylamino-lH-indol-2-yl) -benzyl] -piperazin-1-yl} -ethanone;

{5-Chloro-2- [3- (2-oxo-piperazin-4-yl) ethylphenyl] -lH-indol-7-yl} - (tetrahydropyran-4-yl) -amine;

Yl} - (tetrahydropyran-4-yl) -amine (prepared as described in Example 1) ;

Cyclopentyl- (lH-indazol-7-yl) -amine;

(Tetrahydropyran-4-yl) - (1H-indazol-7-yl) -amine;

Cyclopentyl- (5-methyl-lH-indazol-7-yl) -amine;

(5-methyl-lH-indazol-7-yl) - (tetra-hydropyran-4-yl) -amine;

Cyclopentyl- [3- (4-methoxyphenyl) -lH-indazol-7-yl) -amine;

[3- (4-methoxyphenyl) -lH-indazol-7-yl)] - (tetrahydropyran-4-yl) -amine;

[3- (4-methoxyphenyl) -1H-indazol-7-yl) - (tetrahydropyran-4-ylmethyl) -amine;

(Tetrahydropyran-4-yl) - [5- (1,1-dioxo-thiomorpholin-4-yl) methyl-3-phenyl-2-trimethylsilyl- ;

(Tetrahydropyran-4-yl) - [5- (1,1-dioxo-thiomorpholin-4-yl) methyl-3-phenyl-1H-indol-7-yl) -amine; And

(Tetrahydropyran-4-yl) - [3-bromo-5- (morpholin-4-yl) methyl-2-phenyl-lH-indol-7-yl] -amine.

The present invention also provides a process for preparing a compound of formula (1). Hereinafter, a method for producing the compound of formula (1) will be described based on an exemplary reaction formula to help understand the present invention. However, those skilled in the art will recognize that compounds of formula (1) can be prepared by various methods based on the structure of formula (1), all of which are included within the scope of the present invention Should be interpreted as being. That is, it is understood that the compounds of formula (1) can be prepared by any combination of the synthesis methods described in the present specification or disclosed in the prior art, which is understood to fall within the scope of the present invention, But is not limited to what has been described.

First, the compound of the formula (1) can be obtained by reducing the nitro group of the compound (2) according to the following reaction scheme (1) to prepare an amine compound of the compound (3) A reductive amination reaction or a coupling reaction in the presence of a base.

[Reaction Scheme 1]

In the above reaction formula (1)

m, X, R ¹ , R ³ , R ⁴ and R ⁶ are as defined above,

R ^{2 '} represents (R ² ) _n -A-,

E represents a leaving group or linking group, preferably chlorine, bromine or iodine, or a mixed anhydride form, isocyanate or isothiocyanate.

In Scheme (1), the reduction reaction can be carried out using an acid catalyst and a metal, or using a metal catalyst in the presence of hydrogen gas. As the metal, iron, zinc, lithium, sodium, tin (commonly, tin chloride) can be used. Examples of the acid catalyst include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid; Organic carboxylic acids such as acetic acid, trifluoroacetic acid and the like; Or ammonium chloride. In addition, examples of the metal catalyst that can be used in the reduction reaction using a metal catalyst in the presence of hydrogen gas include palladium, nickel, platinum, ruthenium, rhodium, etc., Is usually 1 to 3 atmospheres.

R ⁶ in compound (4) includes a carbonyl group, wherein the carbonyl means an aldehyde or a ketone. For reductive amination, sodium triacetoxyborohydride {NaBH (OAc) ₃ } or sodium cyanoborohydride (NaBH ₃ CN) may be used.

The coupling reaction is carried out by reacting compound (3) with compound (5) using a base such as Et ₃ N, EtN (iPr) ₂ , DBU, N-methyl-morpholine, methyl-pyrrolidine, K ₂ CO ₃ You can proceed.

In the case of indole compounds wherein X is C, compounds with simple substituents (7-nitro-indole, 2,3-dimethyl-7-nitro-indole, etc.) Can be synthesized by cyclizing an acetylene intermediate such as the compound (8). Compound (8) can also be synthesized through a coupling reaction from a halobenzene compound (6) and an acetylene compound (7).

[Reaction Scheme 2]

In the above reaction formula (2)

R ^{2 '} and R ⁴ are as defined above,

Q represents iodine or bromine.

The compound (2-1) can be produced by cyclizing the acetylene compound (8) in the presence of a base such as KOBu ^t , K ₂ CO _{3 ,} DBU, or a metal catalyst such as CuI or Pd (II).

The acetylene compound (8) can be prepared by adding a base in the presence of a metal catalyst, and Pd (II) or Cu (I) is used as the metal catalyst. Et ₃ N, Et ₂ N ), DBU, N-methyl-morpholine, methyl-pyrrolidine, K ₂ CO ₃ and the like.

Acetylene compounds (7) are commercially available or can be prepared according to the methods described in Synthesis, 2004 59-61; Bioorganic & Medicinal Chemistry, 13, 2005, 197-209; Journal of Organic Chemistry, 71, 2006, 167-175] According to a known method, Pd (II) or Cu (I) can be prepared by coupling acetylene in the presence of a base. The acetylene used is trimethylsilylacetylene or 2-methyl-3-butyn-2-ol, and the base used is diethylamine, triethylamine, diisopropylethyl Amine.

The halobenzene compound (6) can be synthesized from the nitroaniline compound (13) by using iodine or bromine as shown in the following reaction formula (3).

[Reaction Scheme 3]

In the above reaction formula (3), R ⁴ and Q are as defined above.

The nitroaniline compound (13) can be synthesized from a commercially available nitro compound (11) or an aniline compound (12), which is commercially available, through acetylation, nitration and deacetylation. The aniline compound (12), which is difficult to obtain commercially, can be synthesized from the nitro compound (11), and similarly, the nitro compound (11) can also be commercially available or synthesized from the 4-fluoro-nitrobenzene compound have. In Scheme (2), compound (10) of the formula R ⁴ -H means commercially available alcohols and amines.

The halogenated material for preparing the compound (6) may be selected from iodine, bromine, iodine monobromide and iodine monochloride, and silver ions such as silver nitrate (AgNO ₃ ), silver carbonate (AgCO ₃ ) Silver sulfate (Ag ₂ SO ₄ ) and the like can be used together.

Conventional acetylation and nitration reactions can be used to obtain compound (13) from compound (12). The nitration reaction can be carried out at low temperatures (-15 to 0 占 폚) using nitric acid as the raw solution, or in combination with various solvents such as dichloroethane or dichloromethane. Further, the reduction reaction of the nitro group can be carried out in the same manner as the method for obtaining the compound (3) in the reaction formula (1).

In the case of the compound (6-1) substituted with trifluoroacetyl as shown in the following reaction formula (4), the indole compound may be synthesized by reacting directly with the acetylene compound (7).

[Reaction Scheme 4]

On the other hand, the indole compound (2-2) can be synthesized from the nitroaniline compound (13) according to the method of Fischer indole synthesis as shown in the following reaction formula (5).

[Reaction Scheme 5]

In the above reaction formula (5)

R ^{2 '} , R ³ and R ⁴ are as defined above.

Compound (14) can be prepared by a commercially available compound or by modifying an amine group of formula (13) to a hydrazine group using a method known from Journal of the American Chemical Society, 198 (48), 15374-75, 2006.

The hydrazine can be prepared by reacting an amine group with NaNO ₂ in the presence of hydrochloric acid to introduce a nitro group and then reducing using SnCl ₂ , wherein the reaction is carried out using a 1 to 12N aqueous hydrochloric acid solution, preferably a 4 to 8N aqueous hydrochloric acid solution .

The hydrazone compound (15) can be prepared by coupling a hydrazine compound (14) with a ketone compound under a base condition. Examples of the base include metal hydroxides such as sodium hydroxide and lithium hydroxide, metal carbonates such as sodium bicarbonate and potassium carbonate, metal acetates such as sodium acetate, organic acids such as triethylamine and pyridine, Base and the like can be used. Preferably, sodium acetate, sodium bicarbonate or the like is used.

The preparation of the compound (2-2) through cyclization can be carried out in the presence of an acid catalyst, and the acid used in the synthesis is polyphosphoric acid, hydrochloric acid, p-toluenesulfonic acid, sulfuric acid, acetic acid and the like, preferably polyphosphoric acid. Polyphosphoric acid itself, or mixed with an aromatic hydrocarbon such as benzene or toluene. The reaction temperature is 25 to 150 캜, and the reaction time is usually 5 minutes to 60 hours, preferably 5 minutes to 12 hours.

The compound (2-3) having a substituent at the 3-position of the indole ring can be synthesized by cyclizing a compound (6) and an acetylene compound (18) substituted with TMS as shown in the following reaction formula (6).

[Reaction Scheme 6]

In the above reaction formula (6), R < ³ > And R < ⁴ > are as defined above.

Compounds (16), (17) and (20) are commercially available, and compound (19) can be synthesized from alcohol or phenol through a common tosylation reaction. The method of obtaining TMS compound (18) or synthesizing compound (21) is the same as that used to obtain compound (2-1) in reaction formula (2). The compound (2-3) can be obtained by removing the TMS group, wherein TBNF (tetrabutylammonium fluoride) and a base can be used.

The compound (2-4) in which the position 3 of the indole ring is substituted can be obtained by introducing a formyl group into the indole compound (22) to obtain an aldehyde compound (23) and then performing a reductive amino reaction.

[Reaction Scheme 7]

In the above reaction formula (7)

R < ⁴ > is as defined above,

R ^{3 '} represents a heterocycle containing an amine.

The formylation reaction can be carried out using DMF in the presence of a base. Examples of the base include normal butyllithium, t-butyllithium, LDA (lithium diisopropylamine), KHMDS (potassium hexamethyldisilane) Can be mentioned. The reductive amino reaction can be carried out in the same manner as the compound (1) in the reaction scheme (1).

The indazole compound (27) or (33) can be synthesized by a method similar to the following reaction formula (8). The indanthrone ring itself can be easily obtained by heating the nitroaniline compound in the presence of acetic acid in a conventional manner, and the compound (33) substituted at the 3-position of the indazole ring can be obtained through a substitution reaction using an iodo compound.

[Reaction Scheme 8]

A compound in which the preparation method is not particularly described herein is a compound known per se or a compound which can be synthesized from a known compound by a known synthesis method or the like.

Separation of a mixture generally used in the production method according to the present invention is carried out by using a column chromatography, and after completion of the reaction for the final compound, recrystallization, normal or reverse state HPLC (Waters, Delta Pack, 300x50 mm ID, Mu m, 100A). In the case of purification through recrystallization or HPLC, a compound can be obtained in the form of a trifluoroacetic acid salt, and in the case of obtaining a hydrochloride, an ion exchange resin can be used.

As described above, the compounds according to the present invention, starting materials for the preparation thereof, intermediates and the like can be synthesized by various methods, and these methods are included in the scope of the present invention in connection with the preparation of the compound of formula (1) .

The present invention also relates to a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt or isomer thereof, together with a pharmaceutically acceptable carrier or diluent, Or a pharmaceutically acceptable salt thereof.

The present invention also provides a method for preventing or treating cell necrosis and related diseases using the composition.

Cellular necrosis and related diseases that can be treated and / or prevented according to the present invention include, but are not limited to, acute / chronic liver disease (such as hepatitis, liver fibrosis, cirrhosis), neurodegenerative diseases (such as dementia, Parkinson's disease, Huntington's disease) , Ischemic heart disease, reperfusion injury, ischemic stroke or ischemic injury, pancreatitis, bacterial / viral septicemia, diabetes or diabetic complications, diabetic vascular disease [such as diabetes, especially due to pancreatic cell- (Such as hyperglycemia, fatty acids, diets, toxins, streptozotocin, etc.), necrotizing procolitis, cystic fibrosis, rheumatoid arthritis, degenerative arthritis, nephritis, bacterial infections, HIV), multiple sclerosis, leukemia, lymphoma, neonatal respiratory distress syndrome, asphyxia, tuberculosis, endometriosis, vasculopathy, psoriasis, bronchitis, Atherosclerosis, mycoplasma disease, mycoplasma disease, anthrax, Anderson's disease, congenital myotocardia, myocardial infarction, myocardial infarction, myocardial infarction, Leiosis, phenylketonuria, placental infarction, syphilis, aseptic necrosis, and the like. In addition, cell necrosis and related diseases caused by drugs and toxic substances include alcohol poisoning, cocaine, drugs (for example, paracetamol, antibiotics, anticancer drugs, adriamycin, puromycin, bleomycin, , NSAIDs, cyclosporine, chemical toxins (e.g., carbon tetrachloride, cyanide, methanol, ethylene glycol), poisons, pesticides, heavy metals (e.g. lead, mercury, cadmium) and / Or necrosis associated with self administration, damage due to radiation / UV exposure, and associated cell necrosis.

Particularly, the composition according to the present invention not only shows the effect of improving liver protection and liver function, but also has the effect of preventing or treating chronic liver diseases such as fatty liver, liver fibrosis and chronic liver diseases such as cirrhosis, hepatitis caused by viruses or drugs, . As a result, the complication of liver diseases such as portal hypertension can be prevented or treated, but the present invention is not limited thereto. More particularly, the pharmaceutical composition according to the present invention is also effective for the treatment or prevention of liver diseases selected from liver transplantation, alcoholic or non-alcoholic fatty liver disease, hepatic fibrosis, liver cirrhosis, viral or hepatitis caused by drugs, It is effective for chronic liver disease.

The composition according to the present invention is also effective for the treatment or prevention of acute and chronic liver diseases derived from fatty acids or fatty acids derived from fatty acids.

In the present specification, " treatment " refers to stopping or delaying the progress of a disease when used in an object exhibiting an onset symptom, and " prevention " means stopping or stopping the onset symptom Delay.

The " pharmaceutical composition " may include a pharmaceutically acceptable carrier, diluent, excipient, or a combination thereof, together with a compound of the present invention if necessary. The pharmaceutical composition facilitates the administration of the compound into the organism. There are a variety of techniques for administering the compounds, including, but not limited to, oral, injectable, aerosol, parenteral and topical administration, and the like.

As used herein, " carrier " means a substance that facilitates the addition of a compound into a cell or tissue. For example, dimethylsulfoxide (DMSO) is a carrier commonly used to facilitate the introduction of many organic compounds into cells or tissues of an organism.

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

As used herein, " pharmaceutically acceptable " means a property that does not impair the biological activity and physical properties of the compound.

The compounds of the present invention may be formulated into various pharmaceutical dosage forms as desired. In preparing the pharmaceutical composition according to the present invention, a variety of pharmaceutically acceptable salts may be selected depending on the active ingredient, specifically the formulation of the compound of formula (1), its pharmaceutically acceptable salt or isomer, Lt; / RTI > For example, the pharmaceutical composition according to the present invention can be formulated into injectable preparations, oral preparations and the like as desired.

The compound of the present invention can be formulated in a known manner using known pharmaceutical carriers and excipients and introduced into a unit dose form or a multi-dose container. The form of the preparation may be in the form of a solution, suspension or emulsion in an oil or aqueous medium, and may contain conventional dispersing agents, suspending agents or stabilizing agents. It may also be in the form of a dry powder, for example, dissolved in sterile, pyrogen-free water before use. The compounds of the present invention may also be formulated in suppository form using conventional suppository bases such as cocoa butter or other glycerides. Solid dosage forms for oral administration may be capsules, tablets, pills, powders, and granules, with capsule and tablet being particularly useful. Tablets and pills are preferably prepared as preservative. Solid dosage forms can be prepared by mixing the compounds of the present invention with carriers such as lubricants, disintegrants, binders, etc., such as magnesium stearate and one or more inert diluents such as sucrose, lactose, starch and the like.

If desired, the compounds according to the invention or pharmaceutical compositions containing them may also be used in combination with other active agents, for example, cytoprotective agents with a variety of different mechanisms of action, in particular for the protection of the liver, It may also be administered in combination with existing medicaments used - hepatocyte regeneration promoter, liver function adjuvant, antiviral agent, immunosuppressant, and fibrosis inhibitor.

The compound according to the present invention or the pharmaceutical composition containing the same can be administered in combination with a prophylactic or therapeutic agent for all drug-induced cell necrosis and related diseases. Such medicaments may be used as antibiotics, anticancer agents, antiviral agents, antiinfectives, antiinflammatory agents, anticoagulants, lipid modifying agents, cell death inhibitors, antihypertensive agents, diabetes / obesity treatment agents, cardiovascular disease agents, degenerative neurological disease agents, And drugs for all kinds of diseases such as drugs.

The compounds according to the present invention or pharmaceutical compositions containing them can be used for preventing cell damage induced by various causes such as toxins and the related necrosis and related diseases, reactive oxygen species, heavy metals, alcohol, food, supplements, radiation, diets, and the like.

The dosage of the compound of formula (1) may vary depending on factors such as the patient's body weight, sex, age, health condition, diet, specific nature of the disease, time of administration, method of administration, Follow. However, the dosage required for adult therapy is usually in the range of about 1.0 mg to 2,000 mg per day depending on the frequency and intensity of administration. A total dosage of about 1.0 mg to 300 mg per day, separated by a single dose at the time of intramuscular or intravenous administration to an adult would suffice, but in some patients a higher daily dosage may be desirable.

The present invention also relates to the use of a compound of formula (I), a pharmaceutically acceptable salt or isomer thereof as an active ingredient, in combination with a pharmaceutically acceptable carrier or diluent, for the prophylaxis or treatment of cell necrosis and related diseases A method for preparing a composition is provided.

The present invention will be described more specifically by the following Production Examples and Examples, but the scope of the present invention is not limited thereto. In the following Preparation Examples and Examples, M means the molar concentration and N means the normal concentration.

The following preparations illustrate more specifically the preparation of intermediates necessary for the synthesis of the compounds of the examples according to the invention. The abbreviations used in the following Preparations and Examples are as follows.

Ac: acetyl

BOC: t-Butoxycarbonyl

Bu: butyl

Bn: benzyl

c-Pen: cyclopentyl

c-Hex: Cyclohexyl

DME: Dimethoxyethane

DCM: dichloromethane

DIPEA: Diisopropylethylamine

DMAP: 4-dimethylaminopyridine

DMF: N, N-dimethylformamide

EDC: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, hydrochloride

Et: ethyl

Hex: Normal hexane

HOBT: Hydroxybenzotriazole

HBTU: 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate

i-Pr: isopropyl

i-Pen: isopentyl

KHMDS: Potassium bis (trimethylsilyl) amide

LDA: Lithium diisopropylamine

Me: methyl

Ph: phenyl

Pid: Piperidine

Piz: Piperazine

Pyd: pyrrolidine

Pro: Proline

PMB: para-methoxybenzyl

TEA: Triethylamine

TFA: Trifluoroacetic acid

THF: tetrahydrofuran

THP: tetrahydropyran

TMS: trimethylsilyl

TBNF: tetrabutylammonium fluoride

Manufacturing example  1: 2-Nitro-4- Phenoxy - Phenylamine

Step A: Preparation of N- (4- Phenoxy - Phenyl ) - Acetamide

A solution of commercially available 4-phenoxy-aniline (4.16 g, 20.8 mmol) was dissolved in dichloromethane (100 mL), and triethylamine (3.05 g, 31.1 mmol) and acetonic hydride (2.22 g, And the mixture was stirred at 0 ° C to room temperature for 1 hour. After completion of the reaction, the reaction product was filtered using dichloromethane and crystallized to obtain the title compound (4.50 g, 18.6 mmol).

Step B: Preparation of N- (2-nitro-4- Phenoxy - Phenyl ) Acetamide

N- (4-phenoxy-phenyl) -acetamide obtained in Step A (1.00 g, 4.03 mmol) was dissolved in fuming nitric acid (2 mL), and the mixture was stirred at -15 ° C for 2 hours. After completion of the reaction, the reaction product was poured into 100 mL of ice water, and the organic material was extracted with ethyl acetate. The extracted organic solution was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, and the resultant product was separated by column chromatography to obtain the title compound (0.67 g, 2.33 mmol).

Step C: Preparation of 2-nitro-4- Phenoxy - Phenylamine

(0.67 g, 2.33 mmol) obtained in Step B was dissolved in methanol (5 mL), 6.0N sodium hydroxide (1.5 mL) was added thereto, and the mixture was stirred at room temperature for 18 Lt; / RTI > After completion of the reaction, 1.3 mL of a 6.0N aqueous hydrochloric acid solution and 100 mL of an ammonium chloride solution were added, and then organic material was extracted with ethyl acetate. Dried over magnesium sulfate and recrystallized from dichloromethane and hexane to give the title compound (521 mg, 2.12 mmol).

Mass [M + H] = 230

Manufacturing example  2 to 7:

The preparation example compounds of the following table were synthesized according to the method of Preparation Example 1 using commercially available aniline.

Manufacturing example  8: 5- methyl -2- (pyridin-2-yl) -7-nitro-1H-indole

Step A: (2-Nitro-4- methyl - Phenyl ) - Hydrazine Hydrochloride

The commercially available 4-methyl-2-nitro-phenylamine (40 g, 0.23 mol) was dissolved in 12 N hydrochloric acid (100 mL) and sodium nitrite (16 g, 0.23 mol) mol) was slowly added dropwise, followed by stirring at 0 ° C for 30 minutes. Tin (II) chloride (132 g, 0.70 mol), dissolved in 100 mL of 12N-hydrochloric acid, was slowly added dropwise at 0 ° C. 0 > C to room temperature for 3 hours. The resulting yellow solid form reaction was filtered, washed with a small amount of 6N-HCl and then dried to give the title compound (30 g, yield 63%).

Step B: Preparation of N - [(4- methyl -2-nitro- Phenyl ) -N '- [l- (pyridin-2-yl) - Ethylidene ] Hi Drained Hydrochloride

(30 g, 0.14 mol) and pyridine methyl ketone (14.4 mL, 0.16 mol) obtained in Step A were dissolved in methanol (300 mL), and sodium acetate (14.2 g, 0.17 mol). The yellow solid formed by stirring at room temperature for 8 hours was filtered, washed with water and methanol and dried to obtain the title compound (30 g, yield 82%).

Step C: 5- methyl -2- (pyridin-2-yl) -7-nitro-1H-indole

Hydrazine hydrochloride (13 g, 46 mmol), which was obtained in Step B, was added dropwise to a solution of polyphosphoric acid (100 mL), and the mixture was heated at 100 占 폚 for 4 hours. After completion of the reaction, water was added to the reaction product and the undissolved solid was collected. Washed with water and then dried to give the title compound (6.0 g, yield 49%).

Mass [M + H] = 253

Manufacturing example  9 to 15:

The preparation examples of the compounds shown in the following table were synthesized according to the method of Preparation Example 8 using commercially available nitroaniline and the compound obtained in Preparation Example 3, pyridine and pyrazine ketone.

Manufacturing example  16: 2- Bromo -6-nitro-4- Phenoxy - Phenylamine

2-nitro-4-phenoxy-phenylamine (2.3 g, 10 mmol) obtained in Preparation Example 1 was dissolved in DCM (30 mL), Br ₂ (720 μL, 35% Lt; / RTI > After the reaction was completed, an aqueous saturated sodium thiosulfate solution was added, and the organic was extracted with EtOAc, dried over MgSO ₄ , and the solvent was removed under reduced pressure. The residue was purified by column chromatography to obtain the title compound (2.84 g, yield 92% Respectively.

Mass [M + H] = 309

Manufacturing example  17: 2-Amino-5- methyl -3-nitro- Phenyl iodide

(20 g, 131.5 mmol) was dissolved in ethanol (300 mL), silver nitrate (27 g, 157.7 mmol) and iodine (40 g, 157.7 mmol) And the mixture was stirred at room temperature for 8 hours. After completion of the reaction, the reaction mixture was filtered through celite, washed with 100 mL of ethyl acetate, and then concentrated. Water was added and the mixture was extracted with ethyl acetate. Washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate to give the title compound (29 g, 69% yield).

Manufacturing example  18 to 22:

Commercially available nitroaniline and the compounds obtained in Preparative Examples 1 to 7 were reacted according to Preparative Example 17 to synthesize the following Preparative Examples.

Manufacturing example  23: p- ( BOC - amino) - Phenyl -acetylene

p-Aminophenyl-acetylene (1.17 g, 10 mmol) was added to DCM (30 mL) and Et ₃ N (2.8 mL, 20 mmol) was added. (BOC) ₂ O (2.3 g, 10 mmol) was added thereto, followed by stirring at room temperature for 2 hours. When the reaction was complete, 1N HCl was added and the organics were extracted with EtOAc and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography to give the title compound.

Mass [M + H] = 117

Manufacturing example  24: 5- methyl -7-nitro-2- Phenyl -1H-indole

Step A: 4- methyl Nitro-6- ( Phenylacetylene ) - Phenylamine

Amino-5-methyl-3-nitro-phenyl iodide (7 g, 25.2 mmol) and phenylacetylene (3.3 mL, 30.22 mmol) obtained in Production Example 17 were dissolved in 100 mL of tetrahydrofuran, (1.8 g, 2.52 mmol) and copper (I) iodide (0.48 g, 2.52 mmol) were added to a solution of the amine (11 mL, 75.5 mmol), dichloro (bistriphenylphosphine) palladium Lt; / RTI > After completion of the reaction, the reaction mixture was diluted with water, extracted with ethyl acetate, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure and the residue was separated by column chromatography to give the title compound (4.5 g, yield 71%).

Step B: 5- methyl -7-nitro-2- Phenyl -1H-indole

Methyl-2-nitro-6- (phenylacetylene) -phenylamine (4.5 g, 17.8 mmol) obtained in Step A was dissolved in tetrahydrofuran (120 mL) and N- methyl- After dissolving, potassium t-butoxide (4 g, 35.7 mmol) was added thereto, followed by stirring at room temperature for 3 hours. After completion of the reaction, the reaction product was diluted with water, and the organic matter was extracted with ethyl acetate, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure and the residue was separated by column chromatography to give the title compound (1.0 g, yield 22%).

Manufacturing example  25 to 40:

The compounds obtained in Preparations 16, 18-22, commercially available acetylene compounds and the compounds obtained in Preparative Example 23 were reacted according to Preparative Example 24 to synthesize the following Preparative Examples.

Manufacturing example  41: 5- Chloro -3- Phenyl -7-nitro-1H-indole

Step A: 5- Chloro -7-nitro-3- Phenyl -2- Trimethylsilyl -1H-indole

(1.5 g, 4.90 mmol) and 1-phenyl-2-trimethylsilylacetylene (4.3 g, 24.50 mmol) obtained in Preparative Example 19 were dissolved in DMF ), Palladium acetate (0.11 g, 0.5 mmol), lithium chloride (0.21 g, 4.90 mmol) and triethylamine (2.48 g, 24.50 mmol) were added and the mixture was stirred at 100 ° C for 3 hours. After completion of the reaction, water was added and the organic matter was extracted with ethyl acetate, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure and the residue was separated by column chromatography to give the title compound (1.05 g, yield 87%).

Step B: 5- Chloro -3- Phenyl -7-nitro-1H-indole

7-nitro-3-phenyl-2-trimethylsilyl-1H-indole (1.5 g, 4.35 mmol) obtained in Step A was dissolved in tetrahydrofuran (30 mL) and a 1M solution of tetrabutylammonium fluoride 5.2 mL, 5.2 mmol) at 0 < 0 > C. After completion of the reaction, the reaction was diluted with water, the organic was extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The solvent was removed under reduced pressure and the residue was separated by column chromatography to give the title compound (1.2 g, yield 100%).

Manufacturing example  42: [3- Phenyl -7-nitro-lH-indol-5-yl] - Carboxylic acid

Iodo-4-amino-5-nitro-1-benzoic acid ethyl ester obtained in Preparation Example 20 was reacted according to the steps A and B in Production Example 41 to give the title compound.

Manufacturing example  43: 5- Chloro -7-nitro-3- (2-oxo-piperazin-4-yl) methyl -2- Phenyl -1H-indole

Step A: 5- Chloro -3- Formyl -7-nitro-2- Phenyl -1H-indole

(1.0 g, 3.67 mmol) obtained in Preparation 26 was dissolved in dichloromethane (20 mL), and phosphoryl oxychloride (0.84 g, 5.50 mmol) was added at 0 ° C. And DMF (0.80 g, 11.01 mmol) were added dropwise thereto, followed by stirring at room temperature for 6 hours. After completion of the reaction, the reaction was terminated with a saturated aqueous solution of sodium hydrogencarbonate, the organic matter was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give the title compound (0.5 g, 45% yield).

Step B: 5- Chloro -7-nitro-3- (2-oxo-piperazin-4-yl) methyl -2- Phenyl -1H-indole

(0.5 g, 1.66 mmol) obtained in Step A was dissolved in dichloroethane (20 mL), acetic acid (0.10 g, 1.66 mmol), 2 (0.3 g, 3.32 mmol) and sodium triacetoxyborohydride (0.71 g, 3.32 mmol) were added dropwise and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction was diluted with water, the organics were extracted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The solvent was removed under reduced pressure and the residue was separated by column chromatography to give the title compound (0.55 g, yield 86%).

Manufacturing example  44: 5- Chloro -3- ( Morpholine Yl) methyl -7-nitro-2- Phenyl -1H-indole

Chloro-3-formyl-7-nitro-2-phenyl-1H-indole obtained in Step A of Preparation 43 was reacted with morpholine according to the method of Preparation 43, Step B, to give the title compound.

Manufacturing example  45: 5- methyl -7-nitro-1H- Indazole

Step A: 4,6-Dimethyl-2-nitro- Phenylamine

2,4-Dimethylaniline (8.0 g, 66.0 mmol) was dissolved in acetone hydride (50 mL) and nitric acid (5 mL) was slowly added dropwise at 0 ° C. After stirring for 30 minutes, the mixture was diluted with ice water (200 mL), concentrated hydrochloric acid (10 mL) was added dropwise thereto, and the mixture was refluxed with stirring for 4 hours. After cooling to room temperature, the solution was removed under reduced pressure and diluted with aqueous ammonium hydroxide solution. The resulting orange solid was filtered and dried to give the title compound (10.6 g, yield 97%).

Step B: 5- methyl -7-nitro-1H- Indazole

Dimethyl-2-nitro-phenylamine (10.6 g, 64.08 mmol) obtained in Step A was dissolved in acetic acid (150 mL), sodium nitrite (5.3 g, 76.90 mmol) was added dropwise and the mixture was stirred for 12 hours . After completion of the reaction, the reaction mixture was diluted with ammonium hydroxide, the organic matter was extracted with dichloromethane, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The solvent was removed under reduced pressure and the residue was separated by column chromatography to give the title compound (1.0 g, yield 9%).

Manufacturing example  46: 3- (4- Methoxy - Phenyl -1-yl) -7-nitro-1H- Indazole

Step A: 3- Iodo -7-nitro-1H- Indazole

7-Nitroindazole (1.60 g, 9.80 mmol) was dissolved in DMF (100 mL), and potassium hydroxide (2.20 g, 39.20 mmol) and iodine (4.98 g, 19.61 mmol) were added dropwise. After stirring for 2 hours, it was diluted with 10% sodium bisulfite aqueous solution. The resulting solid was collected and dried to give the title compound (2.50 g, yield 88%).

Step B: 3- Iodo -7-nitro-l- (4-methoxybenzyl) -lH- Indazole

7-nitro-1H-indazole (2.50 g, 8.65 mmol) obtained in Step A was dissolved in acetone (50 mL), and potassium hydroxide (0.73 g, 12.97 mmol) and 4-methoxybenzyl Chloride (1.63 g, 10.38 mmol) was added dropwise at 0 占 폚, followed by stirring for 2 hours. After completion of the reaction, the reaction was diluted with water, the organic was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure and the residue was separated by column chromatography to give the title compound (3.2 g, yield 91%).

Step C: 3- (4- Methoxy - Phenyl -1-yl) -7-nitro-1H- Indazole

7-nitro-1- (4-methoxybenzyl) -1H-indazole (1.50 g, 3.67 mmol) obtained in Step B was dissolved in dimethoxyethane (20 mL), sodium carbonate (1.17 g, 11.01 mmol), 4-methoxyphenylboronic acid (0.84 g, 5.50 mmol) and tetrakis (triphenylphosphine) palladium (0) (0.43 g, 0.37 mmol) were added dropwise and the mixture was refluxed with stirring for 2 hours. After cooling the solution, the reaction was diluted with water and the organics were extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The solvent was removed under reduced pressure, and the residue was dissolved in trifluoroacetic acid (20 mL), refluxed and stirred for 5 hours, and then the solvent was removed under reduced pressure. The residue was diluted with water and the organics were extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The solvent was removed under reduced pressure and the residue was separated by column chromatography to give the title compound (0.85 g, yield 86%).

Manufacturing example  47: 4 - [(3- Bromo -7-nitro-2- Phenyl Indol-5-yl) methyl ] -Piperazin-2-one

Step A: 1- BOC -5- methyl -7-nitro-2- Phenyl - Indole

Methyl-7-nitro-2-phenyl-1H-indole obtained in Production Example 24 with (BOC) ₂ O and DMAP according to Preparation 23, the title compound was obtained.

Step B: 1- BOC -3- Bromo -5- Bromomethyl -7-nitro-2- Phenyl - Indole

(3.5 g, 10 mmol) obtained in Step A was dissolved in carbon tetrachloride (30 mL), and then N-bromosuccinimide (NBS, 2.3 g, 13 mmol) and benzoyl peroxide (100 mg) were added, followed by reflux stirring at 80 ° C for 4 hours. The solid was filtered off, water was added, and organic matter was extracted with DCM. Removal of the solvent under reduced pressure followed by purification by column chromatography gave the title compound (2.3 g, yield 46%).

Step C: Preparation of 4 - [(1- BOC -3- Bromo -7-nitro-2- Phenyl Indol-5-yl) methyl ] -Piperazin-2-one

Obtained in Step B [(3- bromo-5-bromomethyl-7-nitro-2-phenyl -1H- indole (1.0 g, 2 mmol) was dissolved in _{DCM (10 mL) Et 3 N} (560 uL (300 mg, 3 mmol) was added thereto, and the mixture was stirred at room temperature for 12 hours. When the reaction was completed, saturated aqueous NH ₄ Cl solution was added thereto, and the organic material was extracted with DCM. After drying, the solvent was removed under reduced pressure and purification by column chromatography gave the title compound (825 mg, yield 78%).

Step D: [(3- Bromo -7-nitro-2- Phenyl Indol-5-yl) methyl ] -Piperazin-2-one

Yl) methyl] -piperazin-2-one (825 mg, 1.6 mmol) obtained in Step C, Was dissolved in diethyl ester (5 mL), dissolved in HCl (4M in dioxane solution, 5 mL), and stirred at room temperature for 2 hours. When the reaction was completed, the solvent was removed under reduced pressure and dried to be used in the next reaction.

Mass [M + H] = 429

Manufacturing example  48: 4 - [(3- Bromo -7-nitro-2- Phenyl Indol-5-yl) methyl ] - Morpholine

Bromo-5-bromomethyl-7-nitro-2-phenyl-indole obtained in Step B of Preparation 47 and morpholine was used according to the procedures of Preparation 47, Steps C and D. To give the title compound.

Mass [M + H] = 416

Example  One: Cyclopentyl - [5- methyl -2- (pyridin-2-yl) -lH-indol-7-yl] -amine

Step A: 7-Amino-5- methyl -2- (pyridin-2-yl) -1H-indole

1H-indole (6.9 g, 27.3 mmol) obtained in Production Example 8 was dissolved in tetrahydrofuran (130 mL), methanol (1 mL), and tetrahydrofuran Was dissolved in a mixed solution of water (130 mL) and NH ₄ Cl (14.6 g, 27.3 mmol) was added. The temperature of the reaction was raised to 60 DEG C, and iron (15.2 g, 273 mmol) was added and stirred for 30 minutes. When the reaction was completed, the solid was filtered off with celite, the solvent was removed from the remaining solution under reduced pressure, and organic matters were extracted with EtOAc. The extracted organic was dried over MgSO ₄ and the solvent was removed under reduced pressure to give the title compound (5.0 g, yield 40%).

Step B: Cyclopentyl - [5- methyl -2- (pyridin-2-yl) -lH-indol-7-yl] -amine

Amino-5-methyl-2- (pyridin-2-yl) -1H-indole (5 g, 22.4 mmol) and cyclopentanone (1.88 g, 22.4 mmol) were added to dichloroethane (50 mL), NaBH (OAc) ₃ (9.5 g, 44.8 mmol) was added and the mixture was stirred at room temperature for 12 hours . When the reaction was complete, it was diluted with a saturated aqueous NaHCO ₃ solution and extracted with dichloromethane and EtOAc. The extract was washed with water and an aqueous NaCl solution and dried over MgSO _{4. The} solvent was removed under reduced pressure, and the residue was purified by column chromatography (eluent EtOAc / n-Hex = 1/5) to give the title compound (3.77 g , Yield: 58%).

Example  2: Cyclopentyl - [5- methyl -2- Phenyl -LH-indol-7-yl] -amine

Methyl-7-nitro-2-phenyl-1H-indole obtained in Preparation 24 was reacted according to the steps A and B of Example 1 to give the title compound.

Example  3: [5- Chloro -2- Phenyl -LH-indol-7-yl] -amine

The 5-chloro-7-nitro-2-phenyl-1H-indole obtained in Preparation 26 was reacted according to the method described in Step A of Example 1 to obtain the title compound.

Example 4: ( tetrahydropyran- 4-yl) - [5- methyl -2- (pyridin- 2- yl) -lH- indol-

4-oxo-tetrahydropyran obtained in Step A of Example 1 was reacted according to Step B of Example 1 to give the title compound (25 mg, yield 36%).

Example  5 to 19:

The compounds obtained in Preparations 8 to 15 and commercially available ketones or aldehydes were reacted according to Example 1 to synthesize the following example compounds.

Example  20: (1- Cyclohexanone Yl) - [5- methyl -2- (pyridin-2-yl) -lH-indol-7-yl] -amine

Step A: (1,4- Dioxa - [4.5] dec-8-yl) - [5- methyl -2- (pyridin-2-yl) -1H-indol-7-yl) amine

Amino-5-methyl-2- (pyridin-2-yl) -1H-indole obtained in Step A of Example 1 and 1,4- cyclohexanedione monoethylene acetal Was reacted according to step B of example 1 to yield the title compound.

Step B: (1- Cyclohexanone Yl) - [5- methyl -2- (pyridin-2-yl) -lH-indol-7-yl] -amine

(5-methyl-2- (pyridin-2-yl) -1H-indol-7-yl) amine obtained in Step A , 0.13 mmol) was dissolved in acetone (10 mL) and water (5 mL), and a 1N hydrochloric acid solution (1 mL) was added thereto, followed by stirring at 80 ° C for 8 hours. After completion of the reaction, saturated aqueous NaHCO ₃ solution was added, and the organic matter was extracted with EtOAc and dried over anhydrous MgSO ₄ . The solvent was removed under reduced pressure and the residue was purified by column chromatography (eluent EtOAc / n-Hex = 1/5) to give the title compound (10 mg, yield 23%).

Example  21: 4 - [(5- Chloro -2- Phenyl -LH-indol-7-yl) amino] - Cyclohexane -1-one

Amino-5-chloro-2-phenyl-1H-indole obtained in Example 3 was reacted according to Example 20 to give the title compound.

Example  22: N- (5- methyl -2- (pyridin-2-yl) -lH-indol-7-yl) - Benzamide

(45 mg, 0.20 mmol) obtained in Step A of Example 1 was dissolved in dichloromethane (10 mL), Et ₃ N (0.56 mL, 0.4 mmol) and benzoyl chloride (0.03 mL, 0.22 mmol) were added thereto, followed by stirring at room temperature for 2 hours. When the reaction was complete, the reaction was diluted with water, extracted with EtOAc, and dried over anhydrous MgSO ₄ . The solvent was removed under reduced pressure and the residue was purified by column chromatography (eluent EtOAc / n-Hex = 1/5) to give the title compound (18 mg, yield 27%).

Example  23: 1-Ethyl-3- [5- methyl -2- (pyridin-2-yl) -1H-indol-7-yl] - Urea

Amino-5-methyl-2- (pyridin-2-yl) -1H-indole obtained in Step A of Example 1 and ethyl isocyanate were reacted according to Example 22 to give the title compound.

Example  24: 1- Phenyl -3- [5- methyl -2- (pyridin-2-yl) -1H-indol-7-yl] - Urea

Amino-5-methyl-2- (pyridin-2-yl) -1H-indole obtained in Step A of Example 1 was reacted with phenyl isocyanate according to Example 22 to give the title compound.

Example  25: Thiophene-2- Sulfonic acid  (2-pyridin-2-yl-lH-indol-7-yl) -amide

The 2-pyridin-2-yl-7-nitro-1H-indole obtained in Production Example 9 and 2-thiophenesulfonyl chloride were reacted sequentially according to the procedure of Step A of Example 1 and Example 22 to give the title compound Respectively.

Example  26: Thiophene-2- Sulfonic acid  [5- methyl -2- (pyridin-2-yl) -lH-indol-7-yl] -amide

Amino-5-methyl-2- (pyridin-2-yl) -1H-indole and 2-thiophenesulfonyl chloride obtained in Step A of Example 1 were reacted according to the method of Example 22 to give the title compound Respectively.

Example  27: Cyclopentyl - methyl - [5- methyl -2- (pyridin-2-yl) -lH-indol-7-yl] -amine

1H-indol-7-yl] -amine obtained in Example 1 and formaldehyde were reacted according to Step B of Example 1 to obtain the title compound ≪ / RTI >

Example  28: 7- ( Cyclopentyl ) Amino-2- Phenyl -1H-indole-5- Carboxylic acid  Ethyl ester

Step A: 2- Phenyl -7-nitro-lH-indol-5- Carboxylic acid  Ethyl ester

(14.1 g, 50 mmol) obtained in Production Example 30 was dissolved in ethanol (40 mL), followed by addition of concentrated sulfuric acid (10 mL), followed by the addition of 2 Lt; / RTI > When the reaction is complete, 1N NaOH is added and the organics are extracted with EtOAc, dried over anhydrous magnesium sulfate and filtered. The solvent was removed under reduced pressure and the residue was recrystallized from EtOAc and hexanes to give the title compound (14.1 g, 95% yield).

Step B: 7- ( Cyclopentyl ) Amino-2- Phenyl -1H-indole-5- Carboxylic acid  Ethyl ester

The 2-phenyl-7-nitro-1H-indole-5-carboxylic acid ethyl ester obtained in Step A and cyclopentanone were reacted according to Example 1 to give the title compound.

Example  29: Cyclopentyl - [5- Hydroxymethyl -2- Phenyl -LH-indol-7-yl] -amine

Step A: 5- Hydroxymethyl -2- Phenyl -7-nitro-1H-indole

2-phenyl-7-nitro-1H-indole-5-carboxylic acid ethyl ester (10 g, 29 mmol) obtained in step A of Example 28 was dissolved in methanol (100 mL) and LiBH ₄ ) At 0 < 0 > C. After the temperature was raised to room temperature, the mixture was stirred for 3 hours. A small amount of water was added to terminate the reaction, methanol was removed under reduced pressure, and 1N HCl was added. The organics were extracted with EtOAc, dried and used in the next reaction without further purification.

Step B: Cyclopentyl - [5- Hydroxymethyl -2- Phenyl -LH-indol-7-yl] -amine

The 5-hydroxymethyl-2-phenyl-7-nitro-1H-indole obtained in Step A was reacted according to Example 1 to give the title compound.

Example  30: 7- ( Cyclopentyl ) Amino-2- Phenyl -1H-indole-5- Carboxylic acid

5-carboxylic acid ethyl ester (5 g, 14.3 mmol) obtained in Example 28 was dissolved in a mixed solution of MeOH (20 mL) and water (20 mL) And NaOH (1.3 g, 33.8 mmol) was added thereto, followed by stirring at room temperature for 4 hours. When the reaction is complete, MeOH is removed under reduced pressure, 1N HCl is added to the residue, the organic is extracted with EtOAc, dried over anhydrous magnesium sulfate, filtered and the solvent removed under reduced pressure. The residue was recrystallized from EtOAc and n-Hex to give the title compound.

Example  31: 2- [7- ( Cyclopentyl ) Amino-2- Phenyl -LH-indol-5-yl] -acetic acid ethyl ester

The 2- (2-phenyl-7-nitro-1H-indol-5-yl) acetic acid obtained in Preparation 29 was reacted according to Example 28 to give the title compound.

Example  32: 2- [7- ( Cyclopentylamino )-2- Phenyl -1H-indol-5-yl] ethanol

Amino-2-phenyl-1H-indol-5-yl] acetic acid ethyl ester and cyclopentanone obtained in Example 31 according to the procedure described in Example 29 to give the title compound 257 mg, yield 80%).

Example  33: 2- [7- ( Cyclopentyl ) Amino-2- Phenyl -1H-indol-5-yl] acetic acid

2- [7-Cyclopentyl) amino-2-phenyl-1H-indol-5-yl] acetic acid ethyl ester obtained in Example 31 was reacted according to Example 30 to give the title compound.

Example  34: 2- [2- Phenyl -7- ( Tetrahydropyran Yl) amino-1H-indol-5-yl] -acetic acid

(2-Phenyl-7-amino-1H-indol-5-yl) -acetic acid ethyl ester and 4-oxo-tetrahydropyran produced in the intermediate to synthesize Example 31, Lt; / RTI > to give the title compound.

Example  35: 2- [ 2- Phenyl -7- (1,1- Dioxo - Tetrahydro - Thiopyran Yl) amino-1H-indol-5-yl] -acetic acid

(2-phenyl-7-amino-1H-indol-5-yl) acetic acid ethyl ester and 1,1-dioxo-tetrahydro-thiopyran- Step B of Example 1 and Example 30 provided the title compound.

Example  36: ( Tetrahydropyran -4-yl) - [2- Phenyl -5- (1,1- Dioxo - Thiomorpholine Yl) methyl -LH-indol-7-yl] amine

Step A: 5- Iodomethyl -2- Phenyl -7-nitro-1H-indole

5-hydroxymethyl-2-phenyl-7-nitro-1H-indole (804 mg, 3 mmol) obtained in step A of Example 29 was dissolved in THF (10 mL), imidazole (408 mg, ) And triphenylphosphine (1.52 g, 6 mmol). Iodine (453 mg, 3.9 mmol) was added thereto, followed by stirring for 2 hours. When the reaction was complete, it was filtered through celite and used for the next reaction without further purification.

Step B: 5- (l, l- Dioxo - Thiomorpholine Yl) methyl -2- Phenyl -7-nitro-1H-indole

5-iodomethyl-2-phenyl-7-nitro-1H-indole (850 mg, 2.5 mmol) obtained in Step A was dissolved in THF (10 mL), 1,1-dioxo-thiomorpholine mg, 2.25 mmol) was added thereto, followed by stirring for 2 hours. When the reaction is complete, it is diluted with water and the organics are extracted with EtOAc, dried over anhydrous magnesium sulfate and filtered. The residue was recrystallized from DCM and hexane to give the title compound (625 mg, 65% yield).

Step C: ( Tetrahydropyran -4-yl) - [2- Phenyl -5- (1,1- Dioxo - Thiomorpholine Yl) methyl -LH-indol-7-yl] amine

The resulting 5- (1,1-dioxo-thiomorpholin-4-yl) methyl-2-phenyl-7-nitro-1H-indole obtained in Step B and tetrahydropyran- To give the title compound.

Example  37: ( Tetrahydropyran -4-yl) - [2- Phenyl -5- (2-oxo-piperazin-4-yl) methyl-lH-indol-7-

5-hydroxymethyl-2-phenyl-7-nitro-1H-indole, 2-oxopiperazine and 4-oxo-tetrahydropyran obtained in step A of Example 29 were reacted in accordance with the procedure of Example 36 The title compound was obtained.

Example  38: Cyclopentyl - [2- (3- Fluoro ) Phenyl -5- (2-oxo-piperazin-4-yl) methyl-lH-indol-7-

2- (3-Fluorophenyl) -7-nitro-1H-indole-5-carboxylic acid obtained in Production Example 39 was reacted according to the procedure described in Step A of Example 28, Examples 32 and 36 to obtain the title compound.

Example  39: ( Tetrahydropyran -4-yl) - [2- (4- Methoxy ) Phenyl -5- (1,1- Dioxo -Thiomorpholin-4-yl) methyl -LH-indol-7-yl] amine

The title compound was obtained by reacting 2- (4-methoxy-phenyl) -7-nitro-1H-indole-5-carboxylic acid obtained in Preparative Example 40 according to Step A of Example 28, Examples 32 and 36 .

Example  40 to 78:

The compounds of Examples 26 to 37 were selectively performed on the compounds obtained in Preparations 24 to 40, 43, 44 and 47 and commercially available ketones or aldehydes to synthesize the following example compounds.

Example  79: ( Tetrahydropyran Yl) - (5- Chloro -3- Phenyl -LH-indol-7-yl) -amine

Chloro-7-nitro-3-phenyl-1H-indole obtained in Production Example 41 and tetrahydropyran-4-one according to Example 1, the title compound was obtained.

Example  80: Cyclopentyl - (5- Chloro -3- Phenyl -LH-indol-7-yl) -amine

Using the 5-chloro-7-nitro-3-phenyl-1H-indole obtained in Production Example 41 and cyclopentanone according to Example 1, the title compound was obtained.

Example  81: ( Tetrahydropyran Yl) methyl - (5- Chloro -3- Phenyl -LH-indol-7-yl) -amine

Chloro-7-nitro-3-phenyl-1H-indole obtained in Production Example 41 and tetrahydropyran-4-carboxyaldehyde were reacted according to the method of Example 1 to obtain the title compound.

Example  82: Cyclopentyl - [2- (4- Aminophenyl ) -5- Chloro -LH-indol-7-yl] -amine

7-yl] -amine (430 mg, 1 mmol) obtained in Example 78 was dissolved in DCM (5 mL), and a solution of TFA (5 mL) was added and stirred for 2 hours. Upon completion of the reaction, TFA was removed under reduced pressure and purification by column chromatography gave the title compound (310 mg, yield 95%).

Example  83: Cyclopentyl - {5- Chloro -2- [4- (1- methyl -Piperidin-4-yl) Aminophenyl ] -LH-indol-7-yl} -amine

1H-indol-7-yl] -amine obtained in Example 82 and 1-methyl-piperidin-4-one were reacted with 1- Step B to give the title compound.

Example  84: N- [4- (5- Chloro -7- Cyclopentylamino Indol-2-yl) - Phenyl ] - Methanesulfonamide

The title compound was obtained by reacting cyclopentyl- [2- (4-aminophenyl) -5-chloro-1H-indol-7-yl] -amine obtained in Example 82 with methanesulfonyl chloride according to Example 22 Respectively.

Example  85: Cyclopentyl - {5- (1,1- Dioxo - Thiomorpholine Yl) methyl -2- [4- (acetyl) Aminophenyl ] -LH-indol-7-yl} -amine

(4-BOC-amino-phenyl) -7-nitro-1H-indole-5-carboxylic acid obtained in Production Example 40 was reacted sequentially according to Example 28, Step A of Example 29 and Example 36 To give the title compound.

Example  86 to 89:

Amino-5- (1,1-dioxo-thiomorpholin-4-yl) methyl-2- [4- (acetyl) aminophenyl] -1H- Were reacted according to Step B of Example 1 to give the example compounds of the following Tables.

Example  90: (5- methyl -2- Phenyl -LH-indol-7-yl) -piperidin-4-yl-amine

Step A: 1- BOC - (5- methyl -2- Phenyl -LH-indol-7-yl) -piperidin-4-yl-amine

Amino-5-methyl-2-phenyl-1H-indole obtained in Example 2 and 1-BOC-piperidinone were reacted according to Production Example 23 to give the title compound.

Step B: (5- methyl -2- Phenyl -LH-indol-7-yl) -piperidin-4-yl-amine

The title compound was obtained by reacting 1-BOC- (5-methyl-2-phenyl-1H-indol-7-yl) -piperidin-4-yl-amine obtained in Step A according to Example 82.

Example  91: [1- ( Methanesulfonyl ) Piperidin-4-yl] - (5- methyl -2- Phenyl -LH-indol-7-yl) -amine

(5-methyl-2-phenyl-1H-indol-7-yl) -piperidin-4-yl-amine obtained in Example 90 and methanesulfonyl chloride were reacted according to the method of Example 22 to give the title compound Respectively.

Example  92: 2- Hydroxy -1- [4- (5- methyl -2- Phenyl -LH-indol-7-yl) amino-piperidin-l-yl] - Ethanone

(305 mg, 1 mmol) obtained in Example 90 was dissolved in DMF (5 mL), and a solution of hydroxy (5-methyl-2-phenyl-1H-indol-7-yl) -piperidin- Acetic acid (76 mg, 1 mmol), EDC (232 mg, 1.3 mmol), HOBT (229 mg, 1.5 mmol) and Et ₃ N (280 uL, 2 mmol) were stirred at room temperature for 4 hours. When the reaction was completed, saturated aqueous NaHCO ₃ solution was added, and the organic matter was extracted with EtOAc, washed with saturated aqueous NaCl solution and 1N HCl, dried over anhydrous magnesium sulfate, and filtered. After removal of the solvent under reduced pressure, the residue was purified by column chromatography to give the title compound.

Example  93: (5- Chloro -2- Phenyl -LH-indol-7-yl) -piperidin-4-yl-amine

Amino-5-chloro-2-phenyl-1H-indole obtained in Example 3 and 1-BOC-4-piperidinone were reacted according to the step B of Example 1 to give the title compound.

Example 94: 4- (5-chloro-2-phenyl -1H- indole-7-yl) amino-piperidin-1-yl-carboxylic acid phenylamide

(5-chloro-2-phenyl-1H-indol-7-yl) -piperidin-4-yl-amine obtained in Example 93 and phenyl isocyanate were reacted according to the method of Example 22 to give the title compound .

Example  95: 1- [4- (5- Chloro -2- Phenyl -LH-indol-7-yl) amino-piperidin-l-yl] -2-dimethylamino- Ethanone

Step A: 1- [4- (5- Chloro -2- Phenyl -LH-indol-7-yl) amino-piperidin-l-yl] -2-BOC- Ethanone

(5-chloro-2-phenyl-1H-indol-7-yl) -piperidin-4-yl- amine obtained in Example 93 was reacted with N-BOC- Lt; / RTI >

Step B: 1- [4- (5- Chloro -2- Phenyl -LH-indol-7-yl) amino-piperidin-l-yl] Ethanone

Amino-piperidin-l-yl] -2-BOC-amino-ethanone obtained in step A was converted to l- [4- (5-chloro-2-phenyl- To give the title compound.

Step C: 1- [4- (5- Chloro -2- Phenyl -LH-indol-7-yl) amino-piperidin-l-yl] -2-dimethylamino- Ethanone

Amino-piperidin-1-yl] -2-amino-ethanone obtained in Step B and formaldehyde were reacted with 1- 1, step B to give the title compound.

Example  96: [5- (1,1- Dioxo - Thiomorpholine Yl) methyl -2- Phenyl -LH-indol-7-yl] - (piperidin-4-yl) methyl - amine

(1, 1-dioxo-thiomorpholin-4-yl) methyl-2-phenyl-7-nitro-1H-indole obtained in Example 36, Step B and 1-BOC-piperidin- -Carboxyaldehyde were reacted sequentially according to Example 1 and Example 90 to give the title compound.

Example  97: (5- (1,1- Dioxo - Thiomorpholine Yl) methyl -2- Phenyl -1H-indol-7-yl) - (1- Bullet sulphone Yl-piperidin-4-yl) -amine

Methyl-2-phenyl-1H-indol-7-yl) - (piperidin-4-yl) methyl ester obtained in Example 96 -Amine and methanesulfonyl chloride were reacted according to example 22 to yield the title compound.

Example  98: {4- [5- (1,1- Dioxo - Thiomorpholine Yl) methyl -2- Phenyl -LH-indol-7-yl] amino-piperidin-l-yl} - ( Tetrahydrofuran -2 days)- Methanone

Methyl-2-phenyl-1H-indol-7-yl) - (piperidin-4-yl) methyl ester obtained in Example 96 -Amine and tetrahydrofuran-2-carboxylic acid were reacted according to example 92 to yield the title compound.

Example  99: (5- Fluoro -2- Phenyl -1H-indol-7-yl) - [1- (1,1- Dioxo - Tetrahydrothiopyran -4-yl) -piperidin-4-yl] -amine

Step A: (5- Fluoro -2- Phenyl -LH-indol-7-yl) -piperidin-4-yl-amine

Fluoro-7-nitro-2-phenyl-1H-indole obtained in Production Example 25 and 1-BOC-piperidinone were reacted according to Example 90 to give the title compound.

Step B: (5- Fluoro -2- Phenyl -1H-indol-7-yl) - [1- (1,1- Dioxo - Tetrahydrothiopyran -4-yl) -piperidin-4-yl] -amine

(5-fluoro-2-phenyl-1H-indol-7-yl) -piperidin-4-yl- amine obtained in step A and 1,1-dioxo-tetrahydro- 1, step B to give the title compound.

Example  100: N- (5- Chloro -2- Phenyl -LH-indol-7-yl) -N ', N'dimethyl- Cyclohexane -1,4-diamine

Amino-5-chloro-2-phenyl-1H-indole obtained in Example 3 and 4-dimethylaminohexanone were reacted according to the step B of Example 1 to give the title compound.

Example  101: N- (5- Chloro -2- Phenyl -LH-indol-7-yl) -N'- methyl - Cyclohexane -1,4- Diamine

The monoalkylated title compound was obtained in the process of obtaining the compound of Example 100.

Example  102: 4- (5- Chloro -2- Phenyl -LH-indol-7-yl) amino- Cyclohexane -One- Carboxylic acid

2-phenyl-1H-indole obtained in Example 3 and 4-oxo-cyclohexane-1-carboxylic acid methyl ester were reacted sequentially according to Step B of Example 1 and Example 30 To give the title compound.

Example  103: 4- (5- methyl -2- Phenyl -LH-indol-7-yl) amino- Cyclohexane -One- Carboxylic acid

Methyl-7-nitro-2-phenyl-1H-indole obtained in Production Example 24 and 4-oxo-cyclohexyl-1-carboxylic acid were sequentially reacted according to Example 1 and Example 30 to give the title compound Respectively.

Example  104: 4- (5- Chloro -2- Phenyl -LH-indol-7-yl) amino- Cyclohexane -One- Car Bicylic acid amide

Reaction of 4- (5-chloro-2-phenyl-1H-indol-7-yl) amino-cyclohexane-1-carboxylic acid and NH ₄ Cl obtained in Example 102 according to Example 92 provided the title compound .

Example  105: 4- (5- Chloro -2- Phenyl -LH-indol-7-yl) amino- Cyclohexanecarboxylate mountain Methylamide

Amino-cyclohexane-1-carboxylic acid and methylamine (HCl salt) were reacted according to the procedure described in Example 92 to give the title compound ≪ / RTI >

Example  106: 2- (5- Fluoro -2- Phenyl -LH-indol-7-yl) amino-acetic acid methyl  ester

The 7-nitro-5-fluoro-2-phenyl-1H-indole obtained in Production Example 27 and methyl bromoacetate were reacted sequentially according to the procedure of Step A of Example 1 and Example 22 to obtain the title compound.

Example  107: 2- (5- Fluoro -2- Phenyl -LH-indol-7-yl) amino-acetic acid

2- (5-fluoro-2-phenyl-1H-indol-7-yl) amino-acetic acid methyl ester obtained in Example 106 was reacted according to Example 30 to give the title compound.

Example  108: 2- (5- Phenoxy -2- Phenyl -LH-indol-7-yl) amino-acetic acid methyl  ester

The 7-nitro-5-phenoxy-2-phenyl-1H-indole obtained in Production Example 27 and methyl bromoacetate were reacted sequentially according to the procedure of Step A of Example 1 and Example 22 to give the title compound.

Example  109: 2 - [(5- Phenoxy -2- Phenyl -LH-indol-7-yl) amino] -acetic acid

The (5-phenoxy-2-phenyl-1H-indol-7-yl) amino-acetic acid methyl ester obtained in Example 108 was reacted according to Example 30 to give the title compound.

Example  110: 2 - [(5- Phenoxy -2- Phenyl -LH-indol-7-yl) amino] -propionic acid methyl  ester

The 2-phenyl-5-phenoxy-7-nitro-1H-indole obtained in Production Example 27 and methyl 2-bromopropionic acid ester were reacted sequentially according to the procedure of Step A of Example 1 and Example 22 to give the title compound .

Example  111: 2- (5- Phenoxy -2- Phenyl -LH-indol-7-yl) amino-propionic acid

2- (5-phenoxy-2-phenyl-1H-indol-7-yl) amino-propionic acid methyl ester obtained in Example 110 was reacted according to Example 30 to give the title compound.

Example  112: 2- (5- Chloro -2- Phenyl -LH-indol-7-yl) amino-propionic acid

Amino-5-chloro-2-phenyl-1H-indole obtained in Example 3 and methyl 2-bromopropionic acid ester were reacted sequentially according to Example 22 and Example 30 to give the title compound.

Example  113: (5- Chloro -2- Phenyl -LH-indol-7-yl) -pyridin-2-yl-amine

(200 mg, 0.82 mmol) obtained in Example 3 was dissolved in toluene (30 mL), and 2-bromopyridine (182 mg, 1.15 mmol) Pd ₂ (dba) ₃ , Xanthophos (Xantphos, 42 mg, 0.07 mmol) and Na ₂ CO ₃ were added. The reaction was degassed and stirred at 100 < 0 > C for 12 h. When the reaction was complete, it was filtered through celite and the solvent was removed under reduced pressure. Purification by column chromatography (eluent: EtOAc / n-Hex = 1/3) afforded the title compound (25 mg, yield 13%).

Example  114: (5- Chloro -2- Phenyl -1H-indol-7-yl) -5- methyl -Pyridin-2-yl-amine

Amino-5-chloro-2-phenyl-1H-indole obtained in Example 3 and 2-bromo-5-methyl-pyridine were reacted according to Example 113 to give the title compound.

Example  115: (5- Chloro -3- Phenyl -LH-indol-7-yl) - (5- methyl - pyridin-2-yl) -amine

Chloro-3-phenyl-7-nitro-1H-indole obtained in Production Example 41 was reacted according to the method described in Step A of Example 1 and Example 113 to obtain the title compound.

Example  116: (2S) -1- (7- Cyclopentylamino -2- Phenyl -1H-indole-5- Carbonyl ) - blood Lt; / RTI > Carboxylic acid Methyl ester

Cyclopentylamino-2-phenyl-1H-indole-5-carboxylic acid and (2S) -Pro-OMe obtained in Example 30 were reacted according to Example 92 to give the title compound.

Example  117: (2S) -1- (7- Cyclopentylamino -2- Phenyl -1H-indole-5- Carbonyl ) - Pyrrolidine Carboxylic acid

(2S) -1- (7-Cyclopentylamino-2-phenyl-1H-indole-5-carbonyl) -pyrrolidine-2-carboxylic acid methyl ester obtained in Example 116 was reacted according to Example 30 to give The title compound was obtained.

Example  118: (2S) -1- [2- Phenyl -7- ( Tetrahydropyran Yl) amino-1H-indole-5-car Bo Nyl] - Pyrrolidine -2- Carboxylic acid

(2S) -Pro-OMe and tetrahydropyran-4-one obtained in Production Example 28 were reacted with 2-phenyl-7-nitro-1H-indole-5-carboxylic acid, , The title compound was obtained.

Example  119: 2- (7- Cyclopentylamino -2- Phenyl -1H-indol-5-yl] -1- Pyrrolidine -1 day- Ethanone

2- [7-Cyclopentyl) amino-2-phenyl-1H-indol-5-yl] -acetic acid and pyrrolidine obtained in Example 33 were reacted according to Example 92 to give the title compound.

Example  120: Cyclopentyl -[2- Phenyl -5- (2- Pyrrolidine Yl-ethyl) -lH-indol-7-yl] -amine

The title compound was obtained by reacting 2- [7-cyclopentylamino-2-phenyl-1H-indol-5-yl] -ethanol and pyrrolidine obtained in Example 32 according to Step A, Respectively.

Example  121: 2 - [(R) -2- (7- Cyclopentylamino -2- Phenyl -LH-indol-5-yl) -4,5-dihydro-thiazol-4-yl] -acetic acid

Step A: (R) -4- (4- Methoxy - Benzylsulfanyl ) -3 - [(7-nitro-2- Phenyl -1H-indole-5- Carbonyl ) -Amino] -butyric acid methyl  ester

(R) -3-amino-4- (4-methoxy-benzylsulfanyl) -butyric acid obtained in Production Example 47 and 2-phenyl- Methyl ester hydrochloride was reacted according to example 92 to yield the title compound.

Step B: Preparation of 2 - [(R) -2- (7-nitro-2- Phenyl Indol-5-yl) -4,5- Dihydro -Thiazol-4-yl] -acetic acid methyl  ester

Benzylsulfanyl) -3 - [(7-nitro-2-phenyl-1H-indole-5-carbonyl) -amino] -butyric acid methyl ester (533 mg, 1 mmol) was dissolved in DCM (10 mL), phosphorus pentachloride (406 mg, 2 mmol) was added, and the mixture was stirred at room temperature for 5 hours. The reaction was terminated with an aqueous saturated sodium bicarbonate solution and the organic was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography to give the title compound (240 mg, yield 60%).

Step C: Preparation of 2 - [(R) -2- (7- Cyclopentylamino -2- Phenyl Indol-5-yl) -4,5- Dihydro -Thiazol-4-yl] -acetic acid

(R) -2- (7-nitro-2-phenyl-1H-indol-5-yl) -4,5-dihydro-thiazol-4-yl] -acetic acid methyl ester And cyclopentanone were reacted according to example 1 and example 30 to yield the title compound.

Example  122: 2 - [(R) -2- (2- Phenyl -7- ( Tetrahydropyran Yl) Methyl amino Indol-5-yl) -4,5- Dihydro -Thiazol-4-yl] -acetic acid

(R) -2- (7-nitro-2-phenyl-1H-indol-5-yl) -4,5-dihydro-thiazol- -Acetic acid methyl ester and tetrahydropyran-4-one were reacted sequentially according to Example 1 and Example 30 to give the title compound.

Example  123: 3- (7- Cyclopentylamino -5- Chloro -LH-indol-2-yl) -benzoic acid Me Yl ester

Step A: 3- (5- Chloro Amino-1H-indol-2-yl) benzoic acid methyl  ester

3- (5-Chloro-7-nitro-1H-indol-2-yl) benzoic acid obtained in Production Example 32 was reacted according to Example 28 to give the title compound.

Step B: 3- (7- Cyclopentylamino -5- Chloro -LH-indol-2-yl) -benzoic acid Methyl ester

3- (5-Chloro-7-amino-1H-indol-2-yl) benzoic acid methyl ester obtained in Step A was reacted according to Example 1 to give the title compound.

Example  124: 3- (7- Cyclopentylamino -5- Chloro -LH-indol-2-yl) -benzoic acid

3-yl) -benzoic acid methyl ester obtained in Example 123 was reacted according to Example 30 to give the title compound.

Example  125: [3- (5- Chloro -7- Cyclopentylamino Indol-2-yl) - Phenyl ] -Methanol

3- (7-Cyclopentylamino-5-chloro-1 H-indol-2-yl) -benzoic acid methyl ester obtained in Example 123 was reacted according to Example 32 to give the title compound.

Example  126 to 146:

The indole derivatives obtained in Production Examples 31 to 37 were selectively subjected to the methods of Examples 123 to 125 to synthesize the following example compounds.

Example  147: [5- Chloro -2- (3- Dimethylaminomethylphenyl ) -LH-indol-7-yl] - ( Tetrahydropyran -4-yl) -amine

The title compound was obtained by reacting [3- (5-chloro-7- (tetrahydropyran-4-yl) -phenyl]] - methanol obtained in Example 126 and dimethylamine (HCl salt) Respectively.

Example  148: [5- Chloro -2- (3- Morpholine -4- Ylmethylphenyl ) -LH-indol-7-yl] - ( Tetrahydropyran -4-yl) -amine

Chloro-7- (tetrahydropyran-4-yl) -phenyl)] - methanol obtained in Example 126 and morpholine was reacted according to Example 36 to give the title compound.

Example  149: [5- Chloro -2- (3- Pyrrolidine -4- Ylmethylphenyl ) -LH-indol-7-yl] - ( Tetrahydropyran -4-yl) -amine

-Benzyl] -piperazine obtained in Example 126 and 1-BOC-piperazine were reacted according to the procedures described in Examples 36 and 82 to give the title compound ≪ / RTI >

Example  150: 1- {4- [3- (5- Chloro -7- Tetrahydropyran -4- Amino -LH-indol-2-yl) -benzyl] -piperazin-l-yl} - Ethanone

The title compound was obtained by reacting [3- (5-chloro-7- (tetrahydropyran-4-yl) -phenyl]] - methanol obtained in Example 126 and 1-acetyl- Respectively.

Example  151: {5- Chloro -2- [3- (2-oxo-piperazin-4-yl) Ethyl phenyl ] -1H-indol-7-yl} - ( Tetrahydropyran -4-yl) -amine

1-yl) -phenyl] -acetic acid methyl ester obtained in Example 132 and 2-oxo-piperazine was obtained as a colorless oil from a mixture of 2- [3- (7-tetrahydropyran- Step A and B according to Example 32 and Example 36 were reacted sequentially to give the title compound.

Example  152: {5- Chloro -2- [3- (1,1- Dioxo - Thiomorpholine Yl) Ethyl phenyl ] -1H-indol-7-yl} - ( Tetrahydropyran -4-yl) -amine

1-yl) -phenyl] -acetic acid methyl ester obtained in Example 132 and 1,1-dioxo-pyridine-2-carboxylic acid methyl ester Thiomorpholine were reacted sequentially according to steps A and B of Example 32 and Example 36 to give the title compound.

Example  153 to 161:

The indole and indazole derivatives obtained in Preparations 44, 48 and 49 were reacted according to Example 1 to synthesize the example compounds of the following table.

Example  162: ( Tetrahydropyran Yl) - [3- Bromo -5- ( Morpholine Yl) methyl -2-phenyl-lH-indol-7-yl] -amine

The title compound was prepared according to Example 1 using 4- [3-bromo-2-phenyl-7-nitro-1H-indol-5-yl] -morpholine and tetrahydropyran- To give the title compound.

Experimental Example  1: For hepatocyte toxicity inducers Example  Measurement and analysis of hepatocyte protective effect of compounds

When cells are subjected to various attacks from inside and outside, the apoptosis mechanism works in two forms, apoptosis or necrosis. The present experimental example shows that primary hepatocytes isolated from rats using this apoptosis mechanism are treated with various chemicals that induce serious side effects of hepatotoxicity in the clinic or drugs that induce cell death And after 24 to 48 hours, the hepatocyte protective effects of the compounds synthesized in the Examples were measured. Liver apoptosis inducer include _{CCl 4, ActD, H 2 O} 2, doxorubicin (doxorubicin), wherein -Fas antibody / dactinomycin D (anti-Fas Ab / Actinomycin D), acetaminophen (acetoaminophen), EtOH, CdCl ₂ , palmitate, stearate, cyclophosphamide, terfenadine, diclofenac, simvastatin, and adefovir were used. Segregation of primary hepatic cells was performed by the method of Seglen PO (Experimental Cell Research 74 (1972) pp450-454). Briefly, hepatocytes were separated according to a two-step collagenase perfusion method followed by percoll gradient (Kreamer BL et al., In Vitro Cellular & Developmental Biology 22 (1986) pp201-211) for 10 min at low speed (500 rpm) to remove dead cells. At this time, the viability of the cells was maintained at 90% or more. The number of cells was calculated by adding to HepatoZYME media (Gibco BRL). 1.5X10 ⁴ cells to collagen (collagen) to adhere the cells to the bottom during the 100㎕ put in a 96-well plate (BD biocoat) that are coated for 3 to 4 hours.

The attached cells were pretreated with the compound of Example for 30 minutes in order to confirm the hepatocyte protective effect. At this time, the concentration of the compound of the example was continuously diluted by 5 or more times in the range of 30 μM, 10 μM or 1 μM according to the experiment, twice or three times, and the final DMSO concentration was adjusted to 0.2%. Thirty minutes after the treatment with the compound, hepatocyte apoptosis inducing substance or hepatotoxic drug was treated with the concentrations shown in Table 1 and the survival rate of the cells was measured 24 hours or 48 hours to evaluate the hepatocyte protective effect. Cell viability was measured at 440 nm absorbance using WST-1 (MK-400, Takeda) method. The hepatocyte protective effect of the example compounds is expressed as " EC ₅₀ " calculated from the measured values. &Quot; EC ₅₀ " means the concentration of the compound representing 50% of the maximum protective effect seen in the experiment.

The preferred EC ₅₀ of the example compound is 30 uM or less, more preferably 10 uM or less, particularly preferably 1.0 uM or less.

Table 1 shows the treatment concentration of the various hepatotoxic inducers, the hepatocyte protective effect of the compound of Example 41, and Table 2 shows the cytoprotective effect of the example compounds against the hepatotoxicity inducing substance doxorubicin.

Experimental Example  2: In liver cells and various other tissue-derived cells tBHP  ( tert - Butyl  Hydroxy Peroxide ; t- BuOOH ), The protective effect

One) Liver cells primary hepatocyte )on tBHP The protective effect when treated

Hepatocyte separation was carried out in the same manner as described in Experimental Example 1, and hepatocytes were dispensed onto plates using a DMEM (Gibco + 10% FBS + 1X antibiotics) medium. Twenty-four hours after the liver cells were planted, the cells were serially diluted three times with final concentrations of 30, 10, 3, 1, 0.3, and 0.1 uM, and pretreated for 30 min. tBHP was treated with a final concentration of 300 uM and protection effect was measured after 1 hour. WST-1 (Takeda, 10 uL) was treated for 1 hour 30 minutes as in Experimental Example 1, and the absorbance was measured at 440 nm using SpectraMax (Molecular Device) to calculate the EC ₅₀ value.

The preferred EC ₅₀ of the example compound is 30 uM or less, more preferably 10 uM or less, particularly preferably 1.0 uM or less.

2) In pancreatic cells (Linm5F) tBHP The protective effect when treated

To measure the protective effect against pancreatic cells, Linm5F cells, one of the beta cells, were divided into ² × 10 ⁴ 96-well plates and cultured for 24 hours. The final concentration of the compound of Example was diluted 3-fold to 30, 10, 3, 1, 0.3, and 0.1 uM, and treated for 1 hour in each well. tBHP was treated to a final concentration of 400 uM and further cultured for 5 hours. The protective effect was measured using the SRB (Sulforhodamine B Protein) method, which stains the total protein amount of the cells. Briefly, the cells were incubated for 5 hours, and then 50 μL of 4% formaldehyde solution was added to each well and fixed at room temperature for 30 minutes. The medium was discarded and each well was washed 2 to 3 times with distilled water, and the plate was then dried in an oven at 50 ° C. SRB solution was added to each well in an amount of 50 μL, and the mixture was allowed to stand at room temperature for about 30 minutes. The SRB solution was removed and the plate was washed 2 to 3 times with 1% acetic acid solution. The plate was dried in an oven at 50 ° C and 100 μL of 10 mM Tris was added to elute the SRB staining the intracellular protein. The absorbance was measured at 590 nm and 650 nm using SpectrMax, and the absorbance at 650 nm was subtracted from the absorbance at 590 nm to calculate the EC ₅₀ value.

The preferred EC ₅₀ of the example compound is 30 uM or less, more preferably 10 uM or less, particularly preferably 1.0 uM or less. As a representative example compound, the compounds of Examples 56, 106 and 107 and the like showed excellent activity in this experiment, and their EC ₅₀ value is 0.1 μM or less.

3) cardiac cells ( H9C2 , Rat myocardial cells) tBHP The protective effect when treated

H9C2 cells were divided into ^four 1.5 × 10 ⁴ cells and cultured for 24 hours. The wells were serially diluted in triplicate to a final concentration of 30, 10, 3, 1, 0.3, 0.1 uM of the compound of the example, treated in each well, and cultured for 45 minutes. tBHP was treated to a final concentration of 400 uM and incubated for 2 hours. The protective effect of each compound was measured by the same SRB method as in Linm5F in 2) above.

The preferred EC ₅₀ of the example compound is 30 uM or less, more preferably 10 uM or less, particularly preferably 1.0 uM or less. As a representative example compound, for example, the EC ₅₀ value of the compound of Example 86 was 0.5 uM, and the compounds of Examples 39, 74, 86, 97 and 117 showed excellent activity in this experiment, and their EC ₅₀ value is 0.2 uM or less.

4) kidney cells ( LLC - PK1 )on tBHP The protective effect when treated

To measure the protective effect on kidney cells, ⁴ × 10 ⁴ Were seeded into each well and cultured for 24 hours. Example compounds were treated to final concentrations of 30, 10, 3, 1, 0.3, 0.1 uM and incubated for 30 min. 400 uM tBHP was further treated and cultured for 6 hours. The protective effect of each compound was measured by the same SRB method as in Linm5F in 2) above.

The preferred EC ₅₀ of the example compound is 30 uM or less, more preferably 10 uM or less, particularly preferably 1.0 uM or less. Typically, the EC ₅₀ value of the compound of Example 56 is 0.66 uM.

5) Chondrocytes ( chondrocyte )on tBHP The protective effect when treated

To measure the protective effect of chondrocytes, chondrocytes were first isolated from two hind legs of a 16-week-old SD rats (body weight: 450-460 g). The separation method is as follows. The cartilage was removed from the knee area of the rat hind leg and transferred to a 100 pi plate containing PBS (+ 1X antibiotics). PBS was kept in an ice bath at 4 ° C. Exchanged with fresh PBS and centrifuged at 1000 rpm. PBS was removed and 3 mL of 1X trypsin (Gibco) at 37 ° C was added and treated for 15 minutes. After centrifugation, the supernatant was discarded and washed again with PBS. Centrifuged and the supernatant was discarded. Cells were harvested by incubation in a 37 ° C incubator overnight with 0.2% collagenase (Worthington, type II). The filtered cell solution was centrifuged and the supernatant discarded. After washing with PBS, 2 × 10 ⁴ cells were added to each well and cultured for 24 hours in 10 mL DMEM / F-12 (Gibco, 10% FBS). The final concentration of the compound of Example was diluted 3 times to 30, 10, 3, 1, 0.3, 0.1 uM, treated for 1 hour, treated with tBHP to a final concentration of 500 uM and incubated for 3 hours. The protective effect of each compound was measured by the same SRB staining method as in Linm5F of 2).

The preferred EC ₅₀ of the example compound is 30 uM or less, more preferably 10 uM or less, particularly preferably 1.0 uM or less. Representatively, the compounds of Examples 56 and 63 showed excellent activity in this experiment, and their EC ₅₀ value is 0.1 μM or less.

6) brain cells ( SK -N- MC )on tBHP The protective effect when treated

To confirm the protective effect of the compounds on brain cells, ⁴ brain cells (2 × 10 ⁴ ) were divided into 96 wells using DMEM medium (Gibco, 10% FBS) and cultured for 24 hours. The final concentration of the compound of the Example was continuously diluted by 3 times to 30, 10, 3, 1, 0.3, and 0.1 uM and treated for 1 hour. tBHP was treated to a final concentration of 400 uM and incubated for 6 hours. The LDH assay (Promega) was performed by taking 50 uL of the medium in each well. In LDH assay (Promega), 50 μL of the assay solution was mixed with 50 μL of the assay solution, reacted at room temperature for 30 minutes, and the absorbance was measured at 490 nm using SpectraMax (Molecular Device).

The preferred EC ₅₀ of the example compound is 30 uM or less, more preferably 10 uM or less, particularly preferably 1.0 uM or less. Representatively, the EC ₅₀ of Example 115 compound Value was 0.26 uM, and the compounds of Examples 37, 55 and 63 exhibited excellent activity in this experiment, and their EC ₅₀ values were 0.1 uM or less.

As can be seen from the above results, the novel compounds according to the present invention not only show the effect of improving liver protection and liver function, but also can be used for the treatment of chronic liver diseases such as fatty liver, liver fibrosis, cirrhosis, hepatitis induced by viruses or drugs, Can be usefully used for preventing or treating diseases. The compounds of the present invention also exhibited cytotoxic inhibitory activity in the pancreas, kidney, brain, cartilage, and heart cells.

Therefore, the compound of the present invention can be usefully used for prevention or treatment of cell necrosis and related diseases.

It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.

Claims (33)

An indole or indazole compound of the formula (1), a pharmaceutically acceptable salt or optical isomer thereof:
[Chemical Formula 1]

In this formula,
n is an integer of 1 to 3,
m is 0 or 1,
A represents phenyl,
X represents C or N, provided that m is 0 when X is N and m is 1 when X is C,
R ¹ represents hydrogen, C ₁ -C ₆ -alkyl or - (CH ₂ ) _r NR ⁷ R ⁸ wherein r is an integer from 2 to 5 and R ⁷ and R ⁸ are each independently hydrogen or C ₁ -C ₆ -alkyl, -C ₃ - when represents alkyl, with the proviso that X is N R ¹ is hydrogen,
R ² represents hydrogen, halogen or C ₁ -C ₆ -alkoxy or represents - (CH ₂ ) _p CO ₂ R ⁷ , - (CH ₂ ) _p OR ⁷ , - (CH ₂ ) _p NR ⁷ R ⁸ , ^{NHR 10, -N (H) S} (O) 2 R 7 or -NHC (O) R ¹⁰ represent, or heterocyclic portion containing one or two heteroatoms selected from N, O or S atoms of 5 to (CH ₂ ) _p -heterocycle-R ¹⁰ wherein p is an integer from 0 to 3, R ⁷ and R ⁸ are as defined above, and R ¹⁰ is hydrogen, oxo, C ₁ - C ₆ - alkylcarbonyl, C ₁ -C ₆ - alkoxy or C ₁ -C ₆ - represents an alkyl or represents a 5 to 6 membered heterocycle containing one or two nitrogen atoms as a hetero atom,
R ³ represents hydrogen, halogen, C ₁ -C ₆ -alkyl or phenyl, or - (CH ₂ ) _n - _{wherein the} heterocycle comprises one or two heteroatoms selected from N and O atoms and is a 5- to 6-membered ring, Where n is an integer from 1 to 3, with the proviso that when X is N, R < ³ > is hydrogen or phenyl,
R ⁴ represents -YR ¹¹ , wherein Y is a direct bond or - (CR ⁷ R ⁸ ) _p Y '-, wherein p is an integer from 0 to 3 and R ⁷ and R ⁸ are as defined above In addition,
Y 'is -O-, -C (O) -, and -C (O) is selected from the group consisting of O-, R ¹¹ is hydrogen, halogen, C ₁ -C ₆ - alkyl and - (CH _{2) t} BR ¹³ , t is an integer from 0 to 3, B represents a heterocycle having 5 to 6 carbon atoms, containing 1 or 2 heteroatoms selected from N, O and S atoms, or C ₆ -C ₁₀ -, wherein R ¹³ represents hydrogen, cyano, halogen, hydroxy, oxo, thiol, carboxy or carboxy-C ₁ -C ₆ -alkyl, provided that when X is N then R ⁴ is hydrogen or C ₁ -C ₆ - represents an alkyl,
R ⁵ represents hydrogen, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -cycloalkyl, heterocycle or heterocyclyl-C ₁ -C ₆ -alkyl wherein the heterocycle is selected from N and O atoms Is a 3 to 8 membered ring containing 1 to 3 heteroatoms, provided that when X is N, R < ⁵ > is hydrogen,
R ⁶ represents - (CR ⁷ R ⁸ ) _p -ZDWR ¹⁴ , Z represents a direct bond or is selected from the group consisting of -C (O) - and -C (O) O-, D represents a direct bond Or represents C ₄ -C ₆ -cycloalkyl, or represents 5 to 6 membered heteroaryl containing 1 or 2 N atoms, or contains 1 or 2 heteroatoms selected from N, O and S atoms represents a 5 to 6 membered heterocycle, W is a direct bond, or represents ^{-NR 7 -, -C (O)} -, -C (O) O-, -C (O) NR 12 - or -S (O ) _y- , R ¹² represents hydrogen, C ₁ -C ₃ -alkyl or C ₆ -C ₁₀ -aryl, y is an integer of 1 or 2, and R ¹⁴ represents hydrogen, hydroxy, C ₁ -C ₆ -alkyl, 5 to 6 membered heterocycle comprising 1 to 3 heteroatoms selected from N, O and S atoms, or C ₆ -C ₁₀ -aryl-C ₁ -C ₆ -alkyl,
With the proviso that when X is N, R ⁶ represents C ₄ -C ₆ -cycloalkyl or a 5 to 6 membered heterocycle comprising one or two heteroatoms selected from N, O and S atoms,
Wherein the alkyl, alkoxy, aryl, cycloalkyl, heterocycle and heteroaryl can be optionally substituted and wherein the substituent is selected from the group consisting of hydroxy, C ₁ -C ₆ -alkylamino, di (C ₁ -C ₆ -alkyl) amino, Carboxy, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, carboxy-C ₁ -C ₆ -alkyl and oxo. The compound according to claim 1, wherein R ¹ represents hydrogen, C ₁ -C ₆ -alkyl or di (C ₁ -C ₃ -alkyl) amino-C ₂ -C ₃ -alkyl. According to claim 1 wherein, R ² is hydrogen, halogen, carboxy, carboxy -C ₁ -C ₃ - alkyl, C ₁ -C ₃ - alkoxycarbonyl, C ₁ -C ₃ - alkoxycarbonyl -C ₁ -C ₃ -alkyl, optionally substituted by one oxo group, hydroxy -C ₁ -C ₃ -alkyl, C ₁ -C ₃ - _{alkoxy, - (CH 2) p NR} 7 R 8, -NHR 10, -N (H ), S (O) ₂ R ⁷ or -NHC (O) R ¹⁰ , or - (CH ₂ ) _p -heterocycle -R ¹⁰ wherein the heterocycle, p, R ⁷ , R ⁸ and R ¹⁰ , 11. A compound as defined in claim 1. The compound according to claim 1, wherein Y is selected from the group consisting of a direct bond, -O-, -C (O) - and -CH ₂ C (O) -. A compound according to claim 1, wherein R ¹¹ is selected from the group consisting of hydrogen, methyl, ethyl, phenyl, fluoro, chloro, 2-carboxy-pyrrolidin- thiazol 2-yl, -CH ₂ - (1,1- dioxo-thio morpholine-4-yl), and -CH ₂ - (2- oxo-piperazin-4-yl) compound is selected from the group consisting of . 2. The compound of claim 1, wherein D is selected from the group consisting of cyclopentyl, cyclohexyl, pyrrolidine, tetrahydropyran, tetrahydrofuran and piperidine. According to claim 1, W represents a direct bond or _{-SO 2 -, -CO-, -C (} O) O- or -CONR ¹² - represents a, where R ¹² is a compound as defined in claim 1, . Indole or indazole compounds selected from the following compounds, pharmaceutically acceptable salts or optical isomers thereof:
Cyclopentyl- [5-methyl-2-phenyl-lH-indol-7-yl] -amine;
4 - [(5-chloro-2-phenyl-1H-indol-7-yl) amino] -cyclohexan-1-one;
7- (Cyclopentyl) amino-2-phenyl-1H-indole-5-carboxylic acid ethyl ester;
Cyclopentyl- [5-hydroxymethyl-2-phenyl-lH-indol-7-yl] -amine;
7- (Cyclopentyl) amino-2-phenyl-1H-indole-5-carboxylic acid;
2- [7- (Cyclopentyl) amino-2-phenyl-1H-indol-5-yl] -acetic acid ethyl ester;
2- [7- (Cyclopentylamino) -2-phenyl-1H-indol-5-yl] ethanol;
2- [7- (Cyclopentyl) amino-2-phenyl-1H-indol-5-yl] acetic acid;
2- [2-Phenyl-7- (tetrahydropyran-4-yl) amino-1H-indol-5-yl] -acetic acid;
2- [2-Phenyl-7- (1,1-dioxo-tetrahydro-thiopyran-4-yl) amino-1H-indol-5-yl] -acetic acid;
(Tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin-4-yl) methyl- 1 H-indol-7-yl] amine;
(Tetrahydropyran-4-yl) - [2-phenyl-5- (2-oxo-piperazin-4-yl) methyl- 1 H-indol-7-yl] amine;
Cyclopentyl- [2- (3-fluoro) phenyl-5- (2-oxo-piperazin-4-yl) methyl- 1 H-indol-7-yl] amine;
(Tetrahydropyran-4-yl) - [2- (4-methoxy) phenyl-5- (1,1-dioxo-thiomorpholin- ;
Cyclopentyl- [3,5-dimethyl-2-phenyl-lH-indol-7-yl] -amine;
(Tetrahydropyran-4-yl) - (5-methyl-2-phenyl-lH-indol-7-yl) -amine;
Cyclopentylmethyl- (5-methyl-2-phenyl-lH-indol-7-yl) -amine;
(Tetrahydropyran-4-ylmethyl) - (5-methyl-2-phenyl-lH-indol-7-yl) -amine;
(L-Methylpiperidin-4-yl) - (5-methyl-2-phenyl-lH-indol-7-yl) -amine;
1- [4 - [(5-methyl-2-phenyl-1H-indol-7-yl) amino] piperidin-1-yl] ethanone;
Cyclopentyl- (5-chloro-2-phenyl-lH-indol-7-yl) -amine;
Cyclohexyl- (5-chloro-2-phenyl-lH-indol-7-yl) -amine;
(Tetrahydropyran-4-yl) - (5-chloro-2-phenyl-lH-indol-7-yl) -amine;
Cyclopentylmethyl- (5-chloro-2-phenyl-lH-indol-7-yl) -amine;
(Tetrahydropyran-4-ylmethyl) - (5-chloro-2-phenyl-lH-indol-7-yl) -amine;
(L-Benzylpyrrolidin-3-yl) - (5-chloro-2-phenyl-lH-indol-7-yl) -amine;
(L-Methylpiperidin-4-yl) - (5-chloro-2-phenyl-lH-indol-7-yl) -amine;
(1,4-dioxaspiro [4.5] decan-8-yl) - (5-chloro-2-phenyl-1H-indol-7-yl) -amine;
2 - [(5-chloro-2-phenyl-1H-indol-7-yl) amino] propane-1,3-diol;
(Tetrahydropyran-4-yl) - (5-methyl-2-phenyl-lH-indol-7-yl) -methyl- amine;
(Tetrahydropyran-4-ylmethyl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin-4-yl) methyl- 1 H-indol-7-yl] amine;
Di (tetrahydropyran-4-ylmethyl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin-4-yl) methyl- 1 H-indol-7-yl] amine;
Di (tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin-4-yl) methyl- 1 H-indol-7-yl] amine;
(L-methyl-piperidinemethyl-4-yl) - [5-fluoro-2-phenyl-lH-indol-7-yl] amine;
2- [4 - [(5-fluoro-2-phenyl-1H-indol-7-yl) amino] piperidin-1-yl] ethanol;
[1- (Tetrahydropyran-4-yl) piperidin-4-yl] - (5-fluoro-2-phenyl-1H-indol-7-yl) amine;
(Tetrahydropyran-4-yl) - (5-phenoxy-2-phenyl-lH-indol-7-yl) -amine;
(Tetrahydropyran-4-ylmethyl) - [2-phenyl-5- (2-oxo-piperazin-4-yl) methyl- 1 H-indol-7-yl] amine;
(Tetrahydropyran-4-yl) - [5-chloro-l- (2-diethylaminoethyl) -2-phenyl-lH-indol-7-yl] amine;
Dimethyl- (5-chloro-l-methyl-2-phenyl-lH-indol-7-yl) amine;
(Tetrahydropyran-4-yl) - (5-chloro-l-methyl-2-phenyl-lH-indol-7-yl) -methylamine;
(Tetrahydropyran-4-yl) - (5-chloro-3-phenyl-lH-indol-7-yl) -amine;
Cyclopentyl- (5-chloro-3-phenyl-lH-indol-7-yl) -amine;
(Tetrahydropyran-4-ylmethyl) - (5-chloro-3-phenyl-lH-indol-7-yl) -amine;
Cyclopentyl- (5-chloro-3- (morpholin-4-yl) methyl-2-phenyl-lH-indol-7-yl) -amine;
(Tetrahydropyran-4-yl) - (5-chloro-3- (morpholin-4-yl) methyl-2-phenyl-1H-indol-7-yl) -amine;
(Tetrahydropyran-4-yl) - (5-chloro-3- (2-oxo-piperazin-4-yl) methyl-2-phenyl-1H-indol-7-yl) -amine;
Cyclopentyl- (5-chloro-3- (2-oxo-piperazin-4-yl) methyl-2-phenyl-lH-indol-7-yl) -amine;
(Tetrahydropyran-4-ylmethyl) - (5-chloro-3- (2-oxo-piperazin-4-yl) methyl-2-phenyl-lH-indol-7-yl) -amine;
(Tetrahydropyran-4-yl) - (3-bromo-5- (1,1-dioxo-thiomorpholin- ;
Cyclopentyl- (3-bromo-5- (1,1-dioxo-thiomorpholin-4-yl) methyl-2-phenyl-1H-indol-7-yl) -amine;
(Tetrahydropyran-4-ylmethyl) - (3-bromo-5- (1,1-dioxo-thiomorpholin- Amine;
(Tetrahydropyran-4-yl) - (5- (1,1-dioxo-thiomorpholin-4- yl) methyl- 2- (3- fluorophenyl) Amine;
(Tetrahydropyran-4-yl) - (5-chloro-3-phenyl-lH-indol-7-yl) -amine;
(3-methylbutyl) - [5- (1,1-dioxo-thiomorpholin-4-yl) methyl-2- (4-methoxyphenyl) -lH-indol-7-yl] -amine;
t-butyl N- [4- [5-chloro-7- (cyclopentylamino) -1H-indol-2-yl] phenyl] carbamate;
Cyclopentyl- [2- (4-aminophenyl) -5-chloro-lH-indol-7-yl] -amine;
Cyclopentyl- {5-chloro-2- [4- (1-methyl-piperidin-4-yl) aminophenyl] -1H-indol-7-yl} -amine;
N- [4- (5-Chloro-7-cyclopentylamino-1H-indol-2-yl) -phenyl] -methanesulfonamide;
Cyclopentyl- {5- (1,1-dioxo-thiomorpholin-4-yl) methyl-2- [4- (acetyl) aminophenyl] -1H-indol-7-yl} -amine;
Dicyclopentyl- {5- (1,1-dioxo-thiomorpholin-4-yl) methyl-2- [4- (acetyl) aminophenyl] -1H-indol-7-yl} -amine;
(Tetrahydropyran-4-yl) methyl- {5- (1,1-dioxo-thiomorpholin-4-yl) methyl- 2- [4- (acetyl) aminophenyl] Yl} -amine;
Di (tetrahydropyran-4-yl) methyl- {5- (1,1-dioxo-thiomorpholin-4- yl) methyl- 2- [4- (acetyl) aminophenyl] - yl} -amine;
(Tetrahydropyran-4-yl) - {5- (1,1-dioxo-thiomorpholin-4-yl) methyl- 2- [4- (acetyl) aminophenyl] -1H-indol- } -Amine;
(5-methyl-2-phenyl-lH-indol-7-yl) -piperidin-4-yl-amine;
[1- (Methanesulfonyl) piperidin-4-yl] - (5-methyl-2-phenyl-1H-indol-7-yl) -amine;
2-Hydroxy-1- [4- (5-methyl-2-phenyl-1H-indol-7-yl) amino-piperidin-l-yl] -ethanone;
(5-Chloro-2-phenyl-lH-indol-7-yl) -piperidin-4-yl-amine;
4- (5-Chloro-2-phenyl-1H-indol-7-yl) amino-piperidin-l-yl-carboxylic acid phenylamide;
L- [4- (5-Chloro-2-phenyl-lH-indol-7-yl) amino-piperidin-l-yl] -2-dimethylamino-ethanone;
[5- (1,1-Dioxo-thiomorpholin-4-yl) methyl-2-phenyl-1H-indol-7-yl] - (piperidin-4-yl) methyl-amine;
Yl) - (1 -methanesulfonyl-piperidin-4-yl) -methyl-2-phenyl-lH-indol- Amine;
Yl} amino-piperidin-1-yl} - (tetrahydro-furan-2-ylmethyl) Furan-2-yl) -methanone;
(5-fluoro-2-phenyl-1H-indol-7-yl) - [1- (1,1- dioxo-tetrahydrothiopyran-4- yl) -piperidin- ;
N- (5-chloro-2-phenyl-1H-indol-7-yl) -N ', N'-dimethyl-cyclohexane-1,4-diamine;
N- (5-Chloro-2-phenyl-1H-indol-7-yl) -N'-methyl-cyclohexane-1,4-diamine;
4- (5-Chloro-2-phenyl-1 H-indol-7-yl) amino-cyclohexane-1-carboxylic acid;
4- (5-Methyl-2-phenyl-lH-indol-7-yl) amino-cyclohexane-1-carboxylic acid;
4- (5-Chloro-2-phenyl-lH-indol-7-yl) amino-cyclohexane-1-carboxylic acid amide;
4- (5-Chloro-2-phenyl-1 H-indol-7-yl) amino-cyclohexanecarboxylic acid methylamide;
2- (5-Fluoro-2-phenyl-1H-indol-7-yl) amino-acetic acid methyl ester;
2- (5-Fluoro-2-phenyl-lH-indol-7-yl) amino-acetic acid;
2- (5-phenoxy-2-phenyl-1H-indol-7-yl) amino-acetic acid methyl ester;
2 - [(5-phenoxy-2-phenyl-1H-indol-7-yl) amino] -acetic acid;
2 - [(5-phenoxy-2-phenyl-1H-indol-7-yl) amino] -propionic acid methyl ester;
2- (5-Phenoxy-2-phenyl-1H-indol-7-yl) amino-propionic acid;
2- (5-Chloro-2-phenyl-1H-indol-7-yl) amino-propionic acid;
(5-Chloro-2-phenyl-lH-indol-7-yl) -pyridin-2-yl-amine;
(5-Chloro-2-phenyl-lH-indol-7-yl) -5-methyl-pyridin-2-yl-amine;
(5-Chloro-3-phenyl-lH-indol-7-yl) - (5-methyl-pyridin-2-yl) -amine;
(2S) -1- (7-Cyclopentylamino-2-phenyl-lH-indole-5-carbonyl) -pyrrolidine-2-carboxylic acid methyl ester;
(2S) -1- (7-Cyclopentylamino-2-phenyl-lH-indole-5-carbonyl) -pyrrolidine-2-carboxylic acid;
(2S) -1- [2-Phenyl-7- (tetrahydropyran-4-yl) amino-1H-indole-5-carbonyl] -pyrrolidine-2-carboxylic acid;
2- (7-Cyclopentylamino-2-phenyl-1H-indol-5-yl] -1-pyrrolidin-1-yl-ethanone;
Cyclopentyl- [2-phenyl-5- (2-pyrrolidin-1-yl-ethyl) -lH-indol-7-yl] -amine;
2 - [(R) -2- (7-Cyclopentylamino-2-phenyl-1H-indol-5-yl) -4,5-dihydro-thiazol-4-yl] -acetic acid;
(2-phenyl-7- (tetrahydropyran-4-yl) methylamino-1 H-indol-5-yl) -4,5-dihydro-thiazol- ] -Acetic acid;
3- (7-Cyclopentylamino-5-chloro-1 H-indol-2-yl) -benzoic acid methyl ester;
3- (7-Cyclopentylamino-5-chloro-1 H-indol-2-yl) -benzoic acid;
[3- (5-Chloro-7-cyclopentylamino-1H-indol-2-yl) -phenyl] -methanol;
{3- [5-Chloro-7- (tetrahydropyran-4-yl) amino-1H-indol-2-yl] -phenyl} -methanol;
2- {3- [5-Chloro-7- (tetrahydropyran-4-ylmethyl) amino-1H-indol-2-yl] -phenyl} -acetic acid;
2- [3- (5-Chloro-7-cyclopentylamino-1-H-indol-2-yl) -phenyl] -acetic acid;
2- {3- [5-Chloro-7- (tetrahydropyran-4-yl) amino-1H-indol-2-yl] -phenyl} -acetic acid;
2- {3- [5-Chloro-7- (tetrahydropyran-4-ylmethyl) amino-1-H-indol-2-yl] -phenyl} -acetic acid methyl ester;
2- [3- (5-Chloro-7-cyclopentylamino-1H-indol-2-yl) -phenyl] -acetic acid methyl ester;
2- {3- [5-Chloro-7- (tetrahydropyran-4-yl) amino) -lH-indol-2-yl] -phenyl} -acetic acid methyl ester;
[2- (5-Chloro-7-cyclopentylamino-1H-indol-2-yl) -phenyl] -methanol;
2- (5-Chloro-7-cyclopentylamino-1H-indol-2-yl) -benzoic acid;
2- (5-Chloro-7-cyclopentylamino-1H-indol-2-yl) -benzoic acid methyl ester;
[4- (5-Chloro-7-cyclopentylamino-1H-indol-2-yl) -phenyl] -methanol;
2- {4- [5-Chloro-7- (tetrahydropyran-4-yl) amino-1H-indol-2-yl] phenyl} -ethanol;
4- (5-Chloro-7-cyclopentylamino-1H-indol-2-yl) -benzoic acid;
2- {4- [5-Chloro-7- (tetrahydropyran-4-ylmethyl) amino-1H-indol-2-yl] phenyl} -acetic acid;
2- [4- (5-Chloro-7-cyclopentylamino-1H-indol-2-yl) phenyl] -acetic acid;
2- {4- [5-Chloro-7- (tetrahydropyran-4-yl) amino-1H-indol-2-yl] phenyl} -acetic acid;
4- (5-Chloro-7-cyclopentylamino-1H-indol-2-yl) benzoic acid methyl ester;
4- (7-Cyclopentylamino-5-methyl-lH-indol-2-yl) benzoic acid methyl ester;
2- {4- [5-Chloro-7- (tetrahydropyran-4-ylmethyl) amino-1H-indol-2-yl] phenyl} -acetic acid methyl ester;
2- [4- (5-Chloro-7-cyclopentylamino-1H-indol-2-yl) phenyl] acetic acid methyl ester;
2- {4- [5-Chloro-7- (tetrahydropyran-4-yl) amino-1H-indol-2-yl] phenyl} -acetic acid methyl ester;
[5-chloro-2- (3-dimethylaminomethylphenyl) -1H-indol-7-yl] - (tetrahydropyran-4-yl) -amine;
[5-chloro-2- (3-morpholin-4-ylmethylphenyl) -1H-indol-7-yl] - (tetrahydropyran-4-yl) -amine;
L- {4- [3- (5-Chloro-7-tetrahydropyran-4-ylamino-lH-indol-2-yl) -benzyl] -piperazin-1-yl} -ethanone;
{5-Chloro-2- [3- (2-oxo-piperazin-4-yl) ethylphenyl] -lH-indol-7-yl} - (tetrahydropyran-4-yl) -amine;
Yl} - (tetrahydropyran-4-yl) -amine (prepared as described in Example 1) ;
Cyclopentyl- (lH-indazol-7-yl) -amine;
(Tetrahydropyran-4-yl) - (1H-indazol-7-yl) -amine;
Cyclopentyl- (5-methyl-lH-indazol-7-yl) -amine;
(5-methyl-lH-indazol-7-yl) - (tetrahydropyran-4-yl) -amine;
Cyclopentyl- [3- (4-methoxyphenyl) -lH-indazol-7-yl) -amine;
[3- (4-methoxyphenyl) -lH-indazol-7-yl)] - (tetrahydropyran-4-yl) -amine;
[3- (4-methoxyphenyl) -1H-indazol-7-yl) - (tetrahydropyran-4-ylmethyl) -amine;
(Tetrahydropyran-4-yl) - [5- (1,1-dioxo-thiomorpholin-4-yl) methyl-3-phenyl-1H-indol-7-yl) -amine; And
(Tetrahydropyran-4-yl) - [3-bromo-5- (morpholin-4-yl) methyl-2-phenyl-lH-indol-7-yl] -amine. 10. The compound according to claim 8, which is (tetrahydropyran-4-yl) - [2-phenyl-5- (1,1-dioxo-thiomorpholin- , A pharmaceutically acceptable salt thereof or an optical isomer thereof. A pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound according to claims 1 or 8, a pharmaceutically acceptable salt or optical isomer thereof, in combination with a pharmaceutically acceptable carrier or diluent. A pharmaceutical composition for preventing or treating cell necrosis and related diseases comprising:
Wherein the disease is selected from the group consisting of acute or chronic liver disease, dementia, Parkinson's disease, Huntington's disease, ischemic disease, diabetes, pancreatitis, bacterial or viral septicemia, necrotizing procolitis, cystic fibrosis, rheumatoid arthritis, , Bacterial infections, viral infections, multiple sclerosis, leukemia, lymphoma, neonatal respiratory distress syndrome, asphyxia, tuberculosis, endometriosis, vasculopathy, psoriasis, bronchitis, steroid treatment complications, syphilis, tenderness, hemoglobinuria, burns, hyperthermia, Crohn's disease , Celiac disease, compartment syndrome, vasospasm, glomerulonephritis, myelopathy, mycoplasma disease, anthrax, Anderson's disease, congenital myotocondial disease, phenylketonuria, placental infarction, syphilis and aseptic necrosis; And necrosis associated with alcoholism and exposure to cocaine, antibiotics, anticancer drugs, NSAIDs, cyclosporine, chemical toxins, poisons, pesticides, heavy metals or their administration or self-administration, radioactivity or UV Damage due to exposure to, and associated cell necrosis. 11. The composition of claim 10 wherein the antibiotic is leucomycin or puromycin and the anticancer agent is adriamycin or bleomycin. delete 11. The composition of claim 10, wherein the liver disease is selected from the group consisting of liver transplantation, alcoholic or nonalcoholic fatty liver, liver fibrosis, liver cirrhosis, viral or hepatitis caused by the drug. 11. The composition of claim 10, wherein the liver disease is an alcoholic, chronic liver disease. 11. The composition of claim 10, wherein the liver disease is a chronic or chronic liver disease derived from fatty liver or fatty liver derived from fatty acids. 11. The composition of claim 10, wherein the liver disease is mediated by reactive oxygen species (ROS). 11. The composition of claim 10, wherein the liver disease is mediated by heavy metals. 11. The method of claim 10, further comprising administering to the patient an antibiotic, an anticancer agent, an antiviral agent, an antiinfective agent, an antiinflammatory agent, an anticoagulant, a lipid improvement agent, a cell death inhibitor, an antihypertensive agent, Wherein the composition is administered in combination with a prophylactic or therapeutic agent for drug-induced cell necrosis and related diseases selected from the group consisting of therapeutic agents. 11. The composition according to claim 10, wherein the composition is administered in combination with a drug selected from the group consisting of a hepatocyte regeneration promoter, liver function supplements, an antiviral agent and an immunosuppressive agent. 11. The composition of claim 10 wherein the ischemic disease is heart disease, reperfusion injury, ischemic stroke or ischemic injury. 11. The composition of claim 10 wherein the diabetes is diabetes mellitus, diabetic complications or diabetic vascular disease due to pancreatic cell destruction material. 22. The composition according to claim 21, wherein the diabetes is mediated by a virus, hyperglycemia, fatty acid, diet, toxin or streptozotocin. The method according to claim 10, characterized in that it comprises the step of mixing the compound according to claims 1 or 8, a pharmaceutically acceptable salt or optical isomer thereof as an active ingredient with a pharmaceutically acceptable carrier Necrosis and related diseases. delete delete delete delete delete delete delete delete delete delete