KR20130087283A - Composition containing indole and indazole derivatives for inhibition of cancer metastasis - Google Patents

Abstract

PURPOSE: A composition containing indole and indazole derivatives as active ingredients is provided to suppress cancer metastasis and to effectively enhance a cancer therapeutic effect. CONSTITUTION: A pharmaceutical composition for suppressing cancer metastasis contains a compound of chemical formula 1 or an optical isomer thereof as an active ingredient. The compound of chemical formula 1 has an indole or indazole structure of chemical formula 2 or 3. The compound of chemical formula 1 is cyclopentyl-[2-(4,5-dihydro-1,3-thiazole-2-yl)-1H-indole-7-yl]-amine, [2-(4,5-dihydro-thiazole-2-yl)-1H-indole-7-yl]-(4-methyl-cyclohexyl)-amine, or [2-(4,5-dihydro-thiazole-2-yl)-1H-indole-7-yl]-piperidine-4-yl-amine.

Description

Composition for inhibiting cancer metastasis comprising indole and indazole derivatives as active ingredients {Composition containing indole and indazole derivatives for inhibition of cancer metastasis}

The present invention relates to a composition for inhibiting cancer metastasis comprising an indole and an indazole derivative or an isomer thereof as an active ingredient, and more particularly, an indole and indazole compound represented by the following [Formula 1] or an optical isomer thereof as an active ingredient. It relates to a pharmaceutical composition for inhibiting cancer metastasis comprising.

[Formula 1]

Cancer refers to a population of abnormal cells caused by continuous division and proliferation due to the disruption of the balance between cell division and death by various causes, also called tumors or neoplasms. It usually affects more than 100 different parts of the body, including organs, white blood cells, bones, lymph nodes, etc., and develops severe symptoms through infiltration into surrounding tissues and metastases to other organs (WHO, 2006).

Tumor metastasis refers to the migration of early tumors into blood vessels or lymphatic vessels to other organs with respect to the growth and proliferation of cancer cells (Cavallaro U, Christofori G. Cell adhesion in tumor invasion and metastasis: loss of the glue is not enough Biochim Biophys Acta 2001; 1552: 39-45). Based on the statistical results that more than 90% of cancer deaths are due to cancer metastasis, cancer metastasis is the leading cause of deterioration of the efficiency of cancer treatment and should be considered as a priority in cancer treatment. In other words, the development of cancer metastasis inhibitors is the most important study to reduce mortality from cancer (Hanahan, D. et. Al. Cell 100: 57-70, 2000, Jemal A. et. Al. CA Cancer J Clin. 54: 8 -29, 2004).

The research on the mechanism of cancer metastasis is mainly done in the pure scientific aspect, especially the research using molecular biological methods. As a method for treating, preventing and inhibiting cancer from a molecular biological point of view, there are methods using antibodies or peptides, but the effects thereof have been questioned, and the problem of effective drug delivery and the body during administration There is a problem that an antibody is produced. Moreover, the conventional anticancer agent aims at the anticancer effect which suppresses the proliferation of cancer in a primary or metastasis place, and the cancer metastasis suppression effect is not reported as an anticancer agent currently put into practical use. Therefore, combining them, it can be seen that the anticancer effect and cancer metastasis inhibitory effect is due to a different action, it is urgent to develop a cancer metastasis inhibitor separately from the anticancer agent.

To date, the expectation for the development of a drug having such a cancer metastasis inhibitory effect is very high, but in practice, there are very few examples of the development of a drug for the purpose of inhibiting cancer metastasis. Sulfated polysaccharides, N-diazoacetylglycine derivatives, noiraminitase and fibronectin degrading enzymes (FNS) have been reported to have such inhibitory effects, but there are no reports of their practical use, and they have anticancer effects themselves. There is no. In addition, Arg-Gly-Asp (RGD) analog, a common binding peptide of the integrin molecule, which is a mediator of cell adhesion, has been focused on developing cancer metastasis inhibitors. As a result, RGD peptidomimetics, RGD Disintegrins isolated from polymers and snake venom have been developed, but these peptides and proteins are easily hydrolyzed, which makes them difficult to oral administration, has a very short half-life of action, and shock due to immune activity when intraperitoneally administered. There is this. Therefore, there is an urgent need to develop new drugs that have cancer metastasis suppression effects without side effects.

Accordingly, the present inventors have searched for compounds having cancer metastasis inhibitory effect among known indole and indazole compounds, and have found that some of the compounds have cancer metastasis inhibitory effect, thereby completing the present invention.

Therefore, an object of the present invention is to provide a pharmaceutical composition for inhibiting cancer metastasis comprising the compound of Formula 1 or an optical isomer thereof as an active ingredient.

[Formula 1]

In order to achieve the above object, the present invention provides a pharmaceutical composition for inhibiting cancer metastasis comprising the compound of Formula 1 or an optical isomer thereof as an active ingredient.

In the above formula (1)

X represents C or N,

n is 0 or 1, n is 1 when X is C, n is 0 when X is N,

A represents a direct bond, represents C ₃ -C ₈ -cycloalkyl, represents phenyl, or a 5-6 membered heteroaryl containing 1 to 3 heteroatoms each selected from N, O and S atoms or Represents a heterocycle,

R1 represents hydrogen, -C (O) -BX-R7 or-(CR5R6) _m -BX-R7,

m is from 0 to 4,

R 5 and R 6 each independently represent hydrogen or C ₁ -C ₅ -alkyl,

B represents a direct bond, optionally represents C ₃ -C ₈ -cycloalkyl comprising oxo, or a 3 to 10 membered heterocycle including 1 to 3 heteroatoms each selected from O, S and N atoms or Heteroaryl,

X represents a direct bond or -C (O)-, -SO _2- , -CO ₂ -or -C (O) NR5-,

R7 represents hydrogen, C ₁ -C ₆ -alkyl, halogeno-C ₁ -C ₆ -alkyl, halogen, (CR ₅ R ₆ ) _m -phenyl, (CR 5 R 6) _m -hydroxy or (CR 5 R 6) _m -heterocycle, Wherein the heterocycle is a 3-10 membered ring optionally containing oxo and containing 1 to 3 heteroatoms selected from N, O and S atoms,

R2 represents-(CR5R6) _m -DX-R8,

D represents a direct bond or a 3-10 membered heterocycle or heteroaryl, each optionally including oxo and optionally fused and containing 1-4 heteroatoms selected from N, O and S atoms,

X represents a direct bond or -C (O)-, -C (O) O-, -NR5C (O)-, -C (O) NR5- or -O-,

R8 represents hydrogen, halogen, C ₁ -C ₆ -alkyl, halogeno-C ₁ -C ₆ -alkyl, tri (C ₁ -C ₆ -alkyl) silane or hydroxy-C ₁ -C ₆ -alkyl,

R3 represents hydrogen, halogen, cyano, nitro, aryl-R9 or (CR5R6) _m -D-R9,

R9 represents hydrogen, halogen, C ₁ -C ₆ -alkyl, cyano, nitro or C ₁ -C ₆ -alkoxy,

R4 represents-(CR5R6) _m -YD-R10,

Y represents a direct bond, -C (O) O- or -O-,

R 10 represents hydrogen, nitro, halogen, C ₁ -C ₆ -alkyl, carboxy-C ₁ -C ₆ -alkyl, aryl or —C (O) O—R 5,

In the above, alkyl, alkoxy, aryl, cycloalkyl, heterocycle and heteroaryl may be optionally substituted, and the substituents are hydroxy, halogen, nitrile, amino, C ₁ -C ₆ -alkylamino, di (C ₁ -C _In the group consisting of ₆ -alkyl) amino, C ₁ -C ₆ -alkyl, halogeno-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkylsulfonyl, aryl-C ₁ -C ₆ -alkoxy and oxo One or more to be selected.

In the definition for the substituent of the compound of formula 1, the term alkyl means an aliphatic hydrocarbon radical. Alkyl may be saturated alkyl that does not include alkenyl or alkynyl moieties, or unsaturated alkyl that includes at least one alkenyl or alkynyl moieties. Alkenyl refers to a group containing at least one carbon-carbon double bond, and alkynyl refers to a group containing at least one carbon-carbon triple bond. Alkyl may be branched or straight chain, respectively, when used alone or in combination, such as alkoxy.

Alkyl groups 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, n-butyl, isobutyl, t-butyl, pentyl, hexyl, ethenyl, propenyl, butenyl and the like. For example, C ₁ -C ₄ -alkyl has 1 to 4 carbon atoms in the alkyl chain and consists of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and t-butyl Is selected from the group.

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

The term cycloalkyl means a saturated aliphatic 3-10 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 shared pi electron system and includes, for example, a monocyclic or fused polycyclic (ie rings that divide adjacent pairs of carbon atoms) groups. That is, aryl in the present specification means a 4-10 membered, preferably 6-10 membered aromatic monocyclic or multicyclic ring including phenyl, naphthyl and the like unless otherwise defined.

The term heteroaryl includes 1 to 3 heteroatoms selected from the group consisting of N, O and S atoms, unless otherwise defined, and benzo or C ₃ -C ₈ Aromatic 3 to 10 member, preferably 4 to 8 member, more preferably 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, oxadia Sol, pyridine, pyridazine, pyrimidine, pyrazine and similar groups, but is not limited thereto. Examples of bicyclic heteroaryl include indole, indolin, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzthiazole, benzthiadiazole, benztriazole, quinoline, isoquinoline, purine , Furypyridine and similar groups, but are not limited to these.

The term heterocycle includes one to three heteroatoms selected from the group consisting of N, O and S atoms, unless defined otherwise, and can be fused with benzo or C ₃ -C ₈ -cycloalkyl, saturated or 1 or 2 It means a 3 to 10 member, preferably 4 to 8 member, more preferably a 5 to 6 membered ring containing two double bonds. Examples of heterocycles include pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, pyran, piperidine, morpholine, thiomorpholine, piperazine, hydrofuran and the like. However, it is not limited only to these.

Other terms and abbreviations used herein may be interpreted as meanings commonly understood by those skilled in the art to which the present invention belongs unless otherwise defined.

Among the compounds of Formula 1 according to the present invention, preferred compounds are

X represents C or N,

n is 0 or 1, n is 1 when X is C, n is 0 when X is N,

A represents a direct bond, represents phenyl, or represents a 5-6 membered heteroaryl or heterocycle comprising 1 to 3 heteroatoms each selected from N, O and S atoms,

R1 represents hydrogen, -C (O) -BX-R7 or-(CR5R6) _m -BX-R7,

m is 0 to 2,

R 5 and R 6 each independently represent hydrogen or C ₁ -C ₅ -alkyl,

B represents a direct bond, optionally containing oxo and optionally halogen substituted C ₄ -C ₇ -cycloalkyl, or 4 to 8 containing 1 to 3 heteroatoms each selected from O, S and N atoms A membered heterocycle or heteroaryl,

X represents a direct bond, or -C (O)-, -SO _2- , -CO ₂ -or -C (O) NH-,

R7 represents hydrogen, C ₁ -C ₆ -alkyl, halogeno-C ₁ -C ₆ -alkyl, halogen, (CR ₅ R ₆ ) _m -phenyl, (CR 5 R 6) _m -hydroxy, (CR 5 R 6) _m -heterocycle, Wherein the heterocycle is a 4-8 membered ring optionally containing oxo and containing 1 to 3 heteroatoms selected from N, O and S atoms,

R2 represents-(CR5R6) _m -DX-R8,

D represents a direct bond or a 4-8 membered heterocycle or heteroaryl, each optionally including oxo and optionally fused and containing 1-4 heteroatoms selected from N, O and S atoms,

X represents -C (O)-, -C (O) O-, -NR5C (O)-, -C (O) NR5- or -O-,

R8 represents hydrogen, halogen, C ₁ -C ₆ -alkyl, halogeno-C ₁ -C ₆ -alkyl, tri (C ₁ -C ₆ -alkyl) silane or hydroxy-C ₁ -C ₆ -alkyl,

R3 represents hydrogen, halogen, cyano, nitro, aryl-R9 or (CR5R6) _m -D-R9,

R9 represents hydrogen, halogen, C ₁ -C ₆ -alkyl, cyano, nitro or C ₁ -C ₆ -alkoxy,

R4 represents-(CR5R6) _m -YD-R10,

Y represents a direct bond, -C (O) O- or -O-,

R 10 represents hydrogen, nitro, halogen, C ₁ -C ₆ -alkyl, carboxy-C ₁ -C ₆ -alkyl, aryl or —C (O) O—R 5.

In the compound of [Formula 1] according to the present invention, X is C or N, and the structure of the compound for each case may be represented by the following [Formula 2] or [Formula 3].

Substituent A in the compound of Formula 1 according to the present invention is more preferably phenyl, pyridine, 1,4-pyrazine, 4,5-dihydro-thiazole, thiazole, 4,5-dihydrooxazole, [1,2,4] oxadiazole and [1,3,4] oxadiazole.

Substituent R 1 more preferably represents —C (O) —BX—R 7 or — (CHR 5) _m —BX—R 7, wherein m is 0 to 2, R 5 represents C ₁ -C ₃ -alkyl, B represents a direct bond, optionally containing oxo and optionally halogen substituted C ₅ -C ₆ -cycloalkyl, or 5 to 6 each comprising one to three heteroatoms selected from O, S and N atoms A membered heterocycle or heteroaryl, X represents a direct bond, or -C (O)-, -SO _2- , -CO ₂ -or -C (O) NH-, and R7 is hydrogen, C ₁ -C ₃ -alkyl, halogeno-C ₁ -C ₃ -alkyl, halogen, (CH ₂ ) _m -phenyl, (CH ₂ ) _m -hydroxy, (CH ₂ ) _m- heterocycle, where hetero The cycle is a 5-6 membered ring optionally containing oxo and containing 1 to 3 heteroatoms selected from N, O and S atoms. B in substituent R1 is most preferably selected from the group consisting of cyclopentyl, cyclohexyl, piperidine, tetrahydropyran, oxocyclohexyl, pyrrolidine, difluorocyclohexyl and tetrahydrofuran, and R7 is most Preferably hydrogen, methyl, ethyl, isopropyl, benzyl, hydroxymethyl, (morpholin-4-yl) -ethyl, tetrahydrofuran, 2,2,2-trifluoroethyl, hydroxyethyl, 1, 1-dioxothiomorpholine, tetrahydropyran, (tetrahydropyran-4-yl) -methyl and trifluoromethyl.

D in the substituent R2 more preferably represents a direct bond or is selected from the group consisting of piperazine, pyrrolidine, morpholine, 1,1-dioxothiomorpholine and oxopiperazine, and R8 is more preferably Is selected from the group consisting of hydrogen, ethyl, hydroxymethyl, methyl and fluorine.

Substituent R3 more preferably represents hydrogen or halogen, represents phenyl optionally substituted by alkoxy, or contains 1 to 3 heteroatoms selected from N, S and O atoms as ring members and optionally comprises oxo 6-membered heterocyclylmethyl. R 3 is most preferably hydrogen, bromine, phenyl, methoxy-phenyl, morpholin-4-yl-methyl, oxopiperazin-4-yl-methyl, 1,1-dioxo-thiomorpholin-4-yl -Methyl is selected from the group consisting of.

Substituent R4 more preferably represents-(CH ₂ ) _m -YD-R10, m is 0 to 2, Y represents a direct bond or -C (O) O- or -O-, D is Pyridine or optionally 5 to 6 membered heterocycle comprising oxo and containing 1 to 3 heteroatoms selected from N, S and O atoms, R 10 is hydrogen, halogen, C ₁ -C ₃ -alkyl,- (CH ₂ ) —CO ₂ H, aryl or —C (O) O—R 5, wherein R 5 represents hydrogen or C ₁ -C ₃ -alkyl. D in the substituent R4 is most preferably selected from the group consisting of 1,1-dioxo-thio-morpholine, oxopiperazine, pyridine, morpholine and 4,5-dihydro-thiazole, and R10 is most preferably Is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl, ethyl and-(CH ₂ ) -CO ₂ H.

 Representative compounds of Formula 1 according to the present invention include the following compounds.

Cyclopentyl- [2- (4,5-dihydro-1,3-thiazol-2-yl) -1H-indol-7-yl] -amine;

[2- (4,5-Dihydro-thiazol-2-yl) -1H-indol-7-yl]-(4-methyl-cyclohexyl) -amine;

[2- (4,5-Dihydro-thiazol-2-yl) -1H-indol-7-yl] -piperidin-4-yl-amine;

2-5- [7- (tetrahydro-pyran-4-ylamino) -1H-indol-2-yl]-[1,2,4] oxadiazol-3-yl} -ethanol;

[(R) -2- (7-cyclopentylamino-1 H-indol-2-yl) -4,5-dihydro-1,3-thiazol-4-yl] -methanol;

Cyclopentyl- [2-((R) -4-pyrrolidin-1-ylmethyl-4,5-dihydro-thiazol-2-yl) -1H-indol-7-yl] -amine;

{(R) -2- [7- (tetrahydro-pyran-4-ylamino) -1H-indol-2-yl] -4,5-dihydro-thiazol-4-yl} -methanol;

[(R) -2- (7-cyclopentylamino-5-fluoro-1 H-indol-2-yl) -4,5-dihydro-thiazol-4-yl] -methanol;

{(R) -2- [5-fluoro-7- (tetrahydro-pyran-4-ylamino) -1H-indol-2-yl] -4,5-dihydro-thiazol-4-yl} Methanol;

{(R) -2- [5- (pyridin-3-yloxy) -7- (tetrahydro-pyran-4-ylamino) -1H-indol-2-yl] -4,5-dihydro-thia Zol-4-yl} -methanol;

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

[(R) -2- (5-Chloro-7-cyclopentylamino-1 H-indol-2-yl) -4,5-dihydro-thiazol-4-yl] -acetic acid ethyl ester;

2-{(R) -2- [5-chloro-7- (tetrahydro-pyran-4-ylamino) -1H-indol-2-yl] -4,5-dihydro-thiazol-4-yl }-ethanol;

1- [4- (2-{(R) -2- [5-chloro-7- (tetrahydro-pyran-4-ylamino) -1H-indol-2-yl] -4,5-dihydro- Thiazol-4-yl} -ethyl) -piperazin-1-yl] -2-hydroxy-ethanone;

1- (2-{(R) -2- [5-Chloro-7- (tetrahydro-pyran-4-ylamino) -1H-indol-2-yl] -4,5-dihydro-thiazole- 4-yl} -ethyl) -pyrrolidin-3-ol;

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

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

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

[2- (7-cyclopentylamino-5-phenoxy-1H-indol-2-yl) -4,5-dihydro-thiazol-4-yl] -acetic acid;

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

[(S) -2- (7-cyclopentylamino-5-phenoxy-1H-indol-2-yl) -4,5-dihydro-thiazol-4-yl] -acetic acid;

3-[(R) -2- (5-chloro-7-cyclopentylamino-1 H-indol-2-yl) -4,5-dihydro-thiazol-4-yl] -propionic acid ethyl ester;

3-[(R) -2- (5-chloro-7-cyclopentylamino-1 H-indol-2-yl) -4,5-dihydro-thiazol-4-yl] -propionic acid;

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

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

(2-pyrazin-2-yl-1H-indol-7-yl)-(tetrahydropyran-4-yl) -amine;

Cyclopentyl- (2-thiazol-2-yl-1H-indol-7-yl) -amine;

2- (7-cyclopentylamino-5-methyl-1H-indol-2-yl) -thiazole-4-carboxylic acid ethyl ester;

2- (7-cyclopentylamino-5-methyl-1 H-indol-2-yl) -thiazole-4-carboxylic acid;

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

[2- (7-cyclopentylamino-5-methyl-1 H-indol-2-yl) -thiazol-5-yl] -methanol;

Cyclopentyl- (5-methyl-2- [1,3,4] oxadiazol-2-yl-1H-indol-7-yl) -amine;

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

(5-methyl-2-pyridin-2-yl-1H-indol-7-yl)-(tetrahydro-pyran-4-yl) -amine;

Cyclohexyl- (5-methyl-2-pyridin-2-yl-1H-indol-7-yl) -amine;

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

(1-methyl-piperidin-4-yl)-(5-methyl-2-pyridin-2-yl-1H-indol-7-yl) -amine;

4- (5-methyl-2-pyridin-2-yl-1H-indol-7-ylamino) -cyclohexanone;

(1-benzyl-pyrrolidin-3-yl)-(5-methyl-2-pyridin-2-yl-1H-indol-7-yl) -amine;

Cyclopentylmethyl- (5-methyl-2-pyridin-2-yl-1H-indol-7-yl) -amine;

N- (5-methyl-2-pyridin-2-yl-1H-indol-7-yl) -benzamide;

Cyclopentyl- (5-methyl-2-pyrazin-2-yl-1H-indol-7-yl) -amine;

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

Cyclopentyl- (5-phenoxy-2-pyridin-2-yl-1H-indol-7-yl) -amine;

Cyclopentyl- (3,5-dimethyl-2-phenyl-1H-indol-7-yl) -amine;

Cyclopentyl- (5-methyl-2-phenyl-1H-indol-7-yl) -amine;

(2-cyclohexyl-5-methyl-1H-indol-7-yl) -cyclopentyl-amine;

Cyclopentyl- [5-methyl-2- (6-methyl-pyridin-2-yl) -1H-indol-7-yl] -amine;

(5-methyl-2-phenyl-1H-indol-7-yl)-(tetrahydro-pyran-4-yl) -amine;

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

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

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

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

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

4- (5-Methyl-2-phenyl-1 H-indol-7-ylamino) -cyclohexanecarboxylic acid;

4- (5-Methyl-2-phenyl-1H-indol-7-ylamino) -cyclohexanecarboxylic acid (2-morpholin-4-yl-ethyl) -amide;

Cyclopentylmethyl- (5-methyl-2-phenyl-1H-indol-7-yl) -amine;

(5-methyl-2-phenyl-1H-indol-7-yl)-(tetrahydro-pyran-4-ylmethyl) -amine;

(5-chloro-2-phenyl-1 H-indol-7-yl) -cyclopentyl-amine;

(5-chloro-2-phenyl-1 H-indol-7-yl)-(tetrahydro-pyran-4-yl) -amine;

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

(5-chloro-2-phenyl-1 H-indol-7-yl) -cyclohexyl-amine;

(1-benzyl-pyrrolidin-3-yl)-(5-chloro-2-phenyl-1H-indol-7-yl) -amine;

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

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

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

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

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

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

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

7-cyclopentylamino-2-phenyl-1H-indole-5-carboxylic acid ethyl ester;

7-cyclopentylamino-2-phenyl-1H-indole-5-carboxylic acid;

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

(7-cyclopentylamino-2-phenyl-1H-indol-5-yl) -acetic acid ethyl ester;

(7-cyclopentylamino-2-phenyl-1H-indol-5-yl) -acetic acid;

2-[(4S) -2- [5-methyl-7- (oxan-4-ylmethylamino) -1H-indol-2-yl] -4,5-dihydro-1,3-thiazole-4 -Yl] acetic acid;

2-[(4S) -2- [5-chloro-7- (oxan-4-ylmethylamino) -1H-indol-2-yl] -4,5-dihydro-1,3-thiazole-4 -Yl] acetic acid;

2-[(4S) -2- [7-[(4,4-difluorocyclohexyl) amino] -5-methyl-1H-indol-2-yl] -4,5-dihydro-1,3 -Thiazol-4-yl] acetic acid;

2-[(4S) -2- [7- (oxan-4-ylamino) -5-phenoxy-1H-indol-2-yl] -4,5-dihydro-1,3-thiazole-4 -Yl] acetic acid;

2-[(4R) -2- [7- (oxan-4-ylamino) -5-phenoxy-1H-indol-2-yl] -4,5-dihydro-1,3-thiazole-4 -Yl] acetic acid;

2-[(4R) -2- [7- (oxan-4-ylmethylamino) -5-phenoxy-1H-indol-2-yl] -4,5-dihydro-1,3-thiazole- 4-yl] acetic acid;

2-[(4S) -2- [7- (cyclopentylamino) -1H-indol-2-yl] -4,5-dihydro-1,3-thiazol-4-yl] acetic acid;

2-[(4S) -2- [7-[(1-acetylpyrrolidin-3-yl) amino] -5-methyl-1H-indol-2-yl] -4,5-dihydro-1, 3-thiazol-4-yl] acetic acid;

2-[(4S) -2- [7- (oxan-4-ylmethylamino) -1H-indol-2-yl] -4,5-dihydro-1,3-thiazol-4-yl] acetic acid ;

2-[(4S) -2- [7- (oxan-4-ylamino) -1H-indol-2-yl] -4,5-dihydro-1,3-thiazol-4-yl] acetic acid;

2-[(4S) -2- [7- (oxan-2-ylmethylamino) -1H-indol-2-yl] -4,5-dihydro-1,3-thiazol-4-yl] acetic acid ;

2-[(4S) -2- [5-methyl-7-[[1- (3,3,3-trifluoropropanoyl) piperidin-4-yl] amino] -1 H-indole-2 -Yl] -4,5-dihydro-1,3-thiazol-4-yl] acetic acid;

2-[(4R) -2- [7- (cyclopentylamino) -5-methyl-1H-indol-2-yl] -4,5-dihydro-1,3-thiazol-4-yl] acetic acid ;

2-[(4R) -2- [5-methyl-7- (oxan-4-ylmethylamino) -1H-indol-2-yl] -4,5-dihydro-1,3-thiazole-4 -Yl] acetic acid;

4- [2-[(4S) -2- [5-methyl-7- (oxan-4-ylmethylamino) -1H-indol-2-yl] -4,5-dihydro-1,3-thia Sol-4-yl] ethyl] piperazin-2-one;

2-[(4S) -4- [2- (1,1-dioxo-1,4-siazinan-4-yl) ethyl] -4,5-dihydro-1,3-thiazole-2- Il] -5-methyl-N- (oxan-4-ylmethyl) -1H-indol-7-yl-amine;

N- (4,4-difluorocyclohexyl) -5-methyl-2-[(4S) -4- (2-morpholin-4-ylethyl) -4,5-dihydro-1,3- Thiazol-2-yl] -1 H-indol-7-yl-amine;

4- [2-[(4S) -2- [7-[(4,4-difluorocyclohexyl) amino] -5-methyl-1H-indol-2-yl] -4,5-dihydro- 1,3-thiazol-4-yl] ethyl] piperazin-2-one;

4- [2-[(4S) -2- [7- (oxan-4-ylmethylamino) -5-phenoxy-1H-indol-2-yl] -4,5-dihydro-1,3- Thiazol-4-yl] ethyl] piperazin-2-one;

2-[(4S) -4- (2-morpholin-4-ylethyl) -4,5-dihydro-1,3-thiazol-2-yl] -N- (oxan-4-ylmethyl) -5-phenoxy-1H-indol-7-amine;

5-methyl-2-[(4S) -4- (2-morpholin-4-ylethyl) -4,5-dihydro-1,3-thiazol-2-yl] -N- (oxan-4 -Ylmethyl) -1H-indol-7-amine;

1- [2-[(4S) -2- [5-methyl-7- (oxan-4-ylmethylamino) -1H-indol-2-yl] -4,5-dihydro-1,3-thia Sol-4-yl] ethyl] piperidine-4-carboxyamide;

[(2R) -1- [2-[(4S) -2- [5-methyl-7- (oxan-4-ylmethylamino) -1H-indol-2-yl] -4,5-dihydro- 1,3-thiazol-4-yl] ethyl] pyrrolidin-2-yl] methanol;

(2S) -1- [2-[(4S) -2- [5-methyl-7- (oxan-4-ylmethylamino) -1H-indol-2-yl] -4,5-dihydro-1 , 3-thiazol-4-yl] ethyl] pyrrolidine-2-carboxyamide;

4- [2-[(4R) -2- [7- (cyclopentylamino) -5-methyl-1H-indol-2-yl] -4,5-dihydro-1,3-thiazole-4- Il] ethyl] piperazin-2-one;

2-[(4S) -2- [7- (cyclopentylamino) -5-methyl-1H-indol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl] acetic acid ;

{(S) -2- [5-methyl-7- (tetrahydropyran-4-ylamino) -1H-indol-2-yl] -4,5-dihydro-oxazol-4-yl} -acetic acid ;

2-[(4S) -2- [5-methyl-7- (tetrahydropyran-4-ylamino) -1H-indol-2-yl] -4,5-dihydro-1,3-oxazole- 4-yl] ethanol;

{5-Methyl-2-[(S) -4- (2-morpholin-4-yl-ethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1 H-indole- 7-yl}-(tetrahydro-pyran-4-yl) amine;

4-[(5-chloro-2-phenyl-1H-indol-7-yl) amino] -N-ethylpiperidine-1-carboxyamide;

[4-[(5-chloro-2-phenyl-1H-indol-7-yl) amino] piperidin-1-yl]-(oxoran-3-yl) methanone;

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

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

5-fluoro-N- (1-methylpiperidin-4-yl) -2-phenyl-1H-indol-7-amine;

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

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

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

N- (oxan-4-yl) -5-phenoxy-2-phenyl-1H-indol-7-amine;

Methyl 2-[(5-fluoro-2-phenyl-1H-indol-7-yl) amino] acetate;

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

Methyl 2-[(5-chloro-2-phenyl-1H-indol-7-yl) amino] propanoate;

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

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

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

2-[(4S) -2- [7- (oxan-4-ylmethylamino) -2-phenyl-1H-indol-5-yl] -4,5-dihydro-1,3-thiazole-4 -Yl] acetic acid;

2-[(4S) -2- [7- (cyclopentylamino) -2-phenyl-1H-indol-5-yl] -4,5-dihydro-1,3-thiazol-4-yl] acetic acid ;

Methyl 2- [4- [5-chloro-7- (oxan-4-ylamino) -1H-indol-2-yl] phenyl] acetate;

Methyl 2- [4- [5-chloro-7- (oxan-4-ylmethylamino) -1H-indol-2-yl] phenyl] acetate;

2- [4- [5-chloro-7- (oxan-4-ylamino) -1H-indol-2-yl] phenyl] acetic acid;

5-[(1,1-dioxo-1,4-siazinan-4-yl) methyl] -N- (oxan-4-yl) -2-phenyl-1H-indol-7-amine;

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

4-[[7- (oxan-4-ylamino) -2-phenyl-1H-indol-5-yl] methyl] piperazin-2-one;

5-[(1,1-dioxo-1,4-siazinan-4-yl) methyl] -2-phenyl-N-piperidin-4-yl-1H-indol-7-amine;

[4-[[5-[(1,1-dioxo-1,4-siazinan-4-yl) methyl] -2-phenyl-1H-indol-7-yl] amino] piperidine-1- Il]-(oxoran-3-yl) methanone;

N- [4- [5-[(1,1-dioxo-1,4-siazinan-4-yl) methyl] -7- (oxan-4-ylamino) -1H-indol-2-yl] Phenyl] acetamide;

N- [4- [7- (dicyclopentylamino) -5-[(1,1-dioxo-1,4-siazinan-4-yl) methyl] -1H-indol-2-yl] phenyl] Acetamide;

N- [4- [5-[(1,1-dioxo-1,4-siazinan-4-yl) methyl] -7- (oxan-4-ylmethylamino) -1H-indol-2-yl ] Phenyl] acetamide;

N-cyclopentyl-5-[(1,1-dioxo-1,4-siazinan-4-yl) methyl] -2- (4-methoxyphenyl) -1H-indol-7-amine;

5-[(1,1-dioxo-1,4-siazinan-4-yl) methyl] -2- (4-methoxyphenyl) -N- (oxan-4-yl) -1H-indole-7 Amines;

5-[(1,1-dioxo-1,4-siazinan-4-yl) methyl] -N- (3-methoxybutyl) -2-phenyl-1H-indol-7-amine;

5-[(1,1-dioxo-1,4-siazinan-4-yl) methyl] -2- (3-fluorophenyl) -N- (oxan-4-yl) -1H-indole-7 Amines;

N-cyclopentyl-5-[(1,1-dioxo-1,4-siazinan-4-yl) methyl] -2- (3-fluorophenyl) -1H-indol-7-amine;

3-bromo-5-[(1,1-dioxo-1,4-siazinan-4-yl) methyl] -N- (oxan-4-yl) -2-phenyl-1H-indole-7- Amines;

3-bromo-5- (morpholin-4-ylmethyl) -N- (oxan-4-yl) -2-phenyl-1H-indol-7-amine;

3-bromo-N-cyclopentyl-5-[(1,1-dioxo-1,4-siazinan-4-yl) methyl] -2-phenyl-1H-indol-7-amine;

3-bromo-5-[(1,1-dioxo-1,4-siazinan-4-yl) methyl] -N- (oxan-4-yl) -2-phenyl-1H-indole-7- Amines;

5-chloro-N- (oxan-4-yl) -3-phenyl-1H-indol-7-amine;

5-chloro-N-cyclopentyl-3-phenyl-1H-indol-7-amine;

5-chloro-N- (oxan-4-ylmethyl) -3-phenyl-1H-indol-7-amine;

5-[(1,1-dioxo-1,4-thiazinan-4-yl) methyl] -N- (oxan-4-yl) -3-phenyl-2-trimethylsilyl-1H-indole-7- Amines;

4-[[5-chloro-7- (cyclopentylamino) -2-phenyl-1H-indol-3-yl] methyl] piperazin-2-one;

4-[[5-chloro-7- (oxan-4-ylamino) -2-phenyl-1H-indol-3-yl] methyl] piperazin-2-one;

4-[[5-chloro-7- (oxan-4-ylmethylamino) -2-phenyl-1H-indol-3-yl] methyl] piperazin-2-one;

N-cyclopentyl-3- (4-methoxyphenyl) -1H-indazol-7-amine;

3- (4-methoxyphenyl) -N- (oxan-4-yl) -1H-indazol-7-amine;

3- (4-methoxyphenyl) -N- (oxan-4-ylmethyl) -1H-indazol-7-amine; And

2- (7-cyclopentylamino-2-phenyl-1H-indol-5-yl) -ethanol.

Among the above compounds, the representative compound of [Formula 1] is preferably 5-[(1,1-dioxo-thiomorpholin-4-ylmethyl) -2-phenyl-1H-indol-7-yl]-( Tetrahydropyran-4-ylmethyl) -amine.

Also more preferably 5-[(1,1-dioxo-thiomorpholin-4-ylmethyl) -2-phenyl-1H-indol-7-yl]-(tetrahydropyran-4-ylmethyl)- It may be an amine.

In addition, the terms and abbreviations used herein have their original meanings unless defined otherwise.

Among the indole and indazole compounds, the present inventors describe '5-[(1,1-dioxo-thiomorpholin-4-ylmethyl) -2-phenyl-1H-indol-7-yl]-(tetrahydropyran It was found that -4-ylmethyl) -amine 'has the effect of inhibiting cancer metastasis, which can be found in Experimental Example 1 of the present invention.

After the oral administration of the compound for 3 weeks to the mice to which the cancer cells were administered, lungs were removed, and the number of cancer cells was significantly reduced (ANOVA TEST (p <0.05)) as compared with the control group. That is, it shows that the compound of the present invention functions as an inhibitor of cancer cell lung metastasis. However, this potency is not limited to the above compounds, but also includes the indole and indazole compounds of the above-listed (Korean Patent Registration 10-1098583).

Therefore, the present invention provides a pharmaceutical composition for inhibiting cancer metastasis comprising the indole and indazole compounds as an active ingredient.

The pharmaceutical composition for inhibiting cancer metastasis of the present invention may further include suitable carriers, excipients and diluents which are used alone or in the manufacture of pharmaceutical compositions.

The compositions comprising the compounds according to the invention are each formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral preparations, suppositories, and sterile injectable solutions according to conventional methods. Carriers, excipients and diluents which may be used in combination with the compound, and which may be included in the composition comprising the compound include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin , Calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations may contain at least one excipient such as starch, calcium carbonate, sucrose, or the like. ) Or lactose, gelatin and the like are mixed. In addition to simple excipients, lubricants such as magnesium stearate talc are also used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, and syrups. In addition to water and liquid paraffin, simple diluents commonly used, various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included . Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.

Preferred dosages of the compounds of the present invention depend on the condition and weight of the patient, the extent of the disease, the form of the drug, the route of administration and the duration, but may be appropriately selected by those skilled in the art. However, for the desired effect, the compound of the present invention is preferably administered at 0.5 mg / kg to 300 mg / kg, preferably at 1 mg / kg to 200 mg / kg. Administration can be from one day to seven days a week, an effective amount can be administered at one time, or divided into several times. Accordingly, the dosage is not limited in any way to the scope of the present invention.

The composition of the present invention may be administered to mammals such as rats, mice, livestock, humans, and the like in various routes. All modes of administration can be expected, for example by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebroventricular injection.

The present invention relates to a composition for inhibiting cancer metastasis comprising indole and indazole derivatives or isomers thereof as an active ingredient, and more particularly, a pharmaceutical for inhibiting cancer metastasis comprising indole and indazole compounds or optical isomers as an active ingredient. To provide a composition. The present invention has been found to be effective in inhibiting cancer metastasis, and thus, is effective in increasing cancer treatment efficiency by inhibiting cancer metastasis.

1A is a graph of an experimental group in which 1 × 10 ⁵ CELL / ml B16 melanoma cells were injected into mice.
(Y axis: Nodule count, X axis: con is control, Necro-X is Necro-X group)
1B is a graph of an experimental group in which 2 × 10 ⁵ CELL / ml B16 melanoma cells were injected into mice.
(Y axis: Nodule count, X axis: con is control, Necro-X is Necro-X group)

Hereinafter, the present invention will be described in more detail with reference to Preparation Examples, Examples, and Experimental Examples, but the scope of the present invention is not limited thereto. In the following Preparation Examples and Examples, M means molarity, and N means normal concentration.

Preparation Example 1 Synthesis of 2-[(4-fluoro-2-nitro-phenyl-) hydrazono] -propionic acid ethyl ester

Dissolve 10 g (64 mmol) of 4-fluoro-2-nitroaniline in 64 ml (0.27 mol) of 6N hydrochloric acid, and slowly add dropwise 4.4 g (64 mmol) of sodium nitrate dissolved in 50 ml of water at 0 ° C. Was stirred. At the same time, 9.2 ml (64 mmol) of ethyl 2-methylacetoacetate and 19 g (0.34 mol) of sodium hydroxide were dissolved in 95 ml of 80% ethanol aqueous solution and stirred at 0 ° for 10 minutes. The prepared two solutions were mixed and stirred for 8 hours at 0 ° C. to room temperature. Water was added to the reaction to collect the insoluble solid. Washing with water and drying gave 7.9 g (46% yield) of the title compound.

Preparation Example 2 Synthesis of 5-Fluoro-7-nitro-1H-indole-2-carboxylic acid ethyl ester

8.8 g (33 mmol) of the compound obtained in Preparation Example 1 were mixed with 50 ml of polyphosphoric acid and stirred at 60 ° C for 7 hours. Water was added to the reaction to collect the insoluble solid. Washing with water and drying gave 3.4 g (41% yield) of the title compound.

Preparation Example 3 Synthesis of (4-chloro-2-nitro-phenyl) -hydrazine hydrochloride

40 g (0.23 mol) of 4-chloro-2-nitroaniline was dissolved in 100 ml of 12N hydrochloric acid. 16 g (0.23 mol) of sodium nitrate dissolved in 50 ml of water at 0 ° C. was slowly added dropwise, followed by stirring at 0 ° C. to room temperature for 30 minutes. 132 g (0.70 mol) of tin (II) chloride dissolved in 100 ml of 12N hydrochloric acid was slowly added dropwise at 0 ° C. It stirred for 3 hours at 0 degree-room temperature. The resulting reaction in the form of a yellow solid was filtered, washed with a small amount of 6N-HCl and dried to give 30 g (yield, 63%) of the title compound.

Preparation Example 4 Synthesis of 2-[(4-chloro-2-nitro-phenyl) -hydrazono] -propionic acid methyl ester

Hydrazine (30 g, 0.14 mol) and methyl pyruvate (14.4 ml, 0.16 mol) obtained in Preparation Example 3 were dissolved in 300 ml of methanol, and sodium acetate (14.2 g, 0.17 mol) was added thereto. The yellow solid obtained by stirring for 8 hours at room temperature was filtered, washed with water and methanol and dried to give 30 g (yield 82%) of the title compound.

Preparation Example 5 Synthesis of 5-chloro-7-nitro-1H-indole-2-carboxylic acid methyl ester

100 ml of polyphosphoric acid was added to the compound (13 g, 46 mmol) obtained in Preparation Example 4 and heated at 100 ° C. for 4 hours. After completion of the reaction, water was added to the reaction to collect the undissolved solid. Washing with water and drying gave 6.0 g (49% yield) of the title compound.

Preparation Example 6 Synthesis of 5-bromo-7-nitro-1H-indole-2-carboxylic acid methyl ester

By the method described in Preparation Examples 3 to 5, 7.2 g (yield 73%) of the title compound were obtained using 15.6 g (71.9 mmol) of 4-bromo-2-nitroaniline.

Preparation Example 7 Synthesis of 5-methyl-7-nitro-1H-indole-2-carboxylic acid methyl ester

By the method described in Production Examples 3 to 5, 40 g (0.26 mol) of 4-methyl-2-nitroaniline was used to obtain 20 g (yield 32%) of the title compound.

Preparation Example 8 Synthesis of 4-ethoxy-2-nitro-phenylamine

40 g (0.29 mol) of 4-ethoxyaniline and 61 ml (0.44 mol) of triethylamine were dissolved in 200 ml of dichloromethane. 30 ml (0.32 mmol) of acetic anhydride was added dropwise, followed by stirring at 0 ° C. to room temperature for 1 hour. 1N hydrochloric acid solution was added and extracted with ethyl acetate. Washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate.

The obtained acetamide compound was dissolved in 200 ml of dichloromethane, and 13 ml (0.29 mol) of fuming nitric acid was added dropwise at 0 degree. Stirred at 0 ° C. to room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added and extracted with ethyl acetate. Washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate.

The obtained nitrate compound was dissolved in 100 ml of methanol and 100 ml of tetrahydrofuran, and 6N-sodium hydride was added dropwise. Stir at room temperature for 6 hours. After completion of the reaction, the mixture was neutralized with 6N hydrochloric acid solution to pH 7 and extracted with ethyl acetate. Washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate to give 44 g (yield 83%) of the title compound.

Preparation Example 9 Synthesis of 5-ethoxy-7-nitro-1H-indole-2-carboxylic acid methyl ester

By the method described in Preparation Examples 3 to 5, 13 g (yield 22%) of the title compound were obtained using 40 g (0.22 mol) of 4-ethoxy-2-nitroaniline obtained in Preparation Example 8.

Preparation Example 10 Synthesis of 7-nitro-5-phenoxy-1H-indole-2-carboxylic acid methyl ester

Using the methods described in Preparation Example 8 and Preparation Examples 3 to 5 sequentially, 5 g (yield 15%) of the title compound were obtained from 20 g (0.11 mol) of 4-aminophenyl phenyl ether.

Preparation Example 11 Synthesis of 7-nitro-5- (pyridin-3-yloxy) -1H-indole-2-carboxylic acid ethyl ester

(Step 1)

40 g (0.25 mol) of 1-chloro-4-nitrobenzene and 36 g (0.38 mol) of 3-hydroxypyridine were dissolved in 100 ml of N, N-dimethylformamide. 52.6 g (0.38 mol) of potassium carbonate was added thereto and stirred at 100 ° C. for 20 hours. 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 3- (4-nitro-phenoxy) -pyridine.

The obtained compound was dissolved using 100 ml of water, 100 ml of tetrahydrofuran and 100 ml of methanol. 103 g (1.84 mol) of iron powder and 99 g (1.84 mol) of ammonium chloride were added and stirred using a mechanical stirrer at 80 ° C. for 3 hours. After completion of the reaction, the mixture was filtered through celite, washed with methanol and concentrated. The resulting solid was filtered, washed with ether and dried to give 17 g of 4- (pyridin-3-yloxy) -phenylamine (yield 36%).

(Step 2)

4.2 g (yield 10%) of the title compound were obtained from 25 g (0.13 mol) of 4- (pyridin-3-yloxy) -phenylamine sequentially using the method of manufacture example 8 and the manufacture examples 3-5.

Manufacturing example  12: 5- methyl -7-nitro-2-pyridin-2-yl-1H- Indole  synthesis

10 g (49 mmol) of (4-methyl-2-nitrophenyl) hydrazine hydrochloride and 5.5 ml (49 mmol) of 2-acetylpyridine by the method described in Preparation Examples 4 to 5 (yield 16%) Got.

Preparation Example 13 Synthesis of 5-methyl-7-nitro-2-pyrazin-2-yl-1H-indole

0.3 g (yield 19%) of the title compound using the method described in Preparation Examples 4 to 5 using 2 g (9.8 mmol) of (4-methyl-2-nitrophenyl) hydrazine hydrochloride and 1.2 ml (9.8 mmol) of 2-acetylpyrazine. )

Manufacturing example  14: 7-nitro-2-pyridin-2-yl-1H- Indole  synthesis

By the method described in Production Examples 4 to 5, 5 g (26 mmol) of 2-nitrophenylhydrazine hydrochloride and 2.5 ml (26 mmol) of 2-acetylpyridine were used to obtain 1 g (yield 16%) of the title compound.

Preparation Example 15 Synthesis of 7-nitro-2-pyrazin-2-yl-1H-indole

By the method described in Preparation Examples 4 to 5, 3.1 g (16 mmol) of 2-nitrophenylhydrazine hydrochloride and 2.0 ml (16 mmol) of 2-acetylpyrazine were used to obtain 0.5 g (yield 13%) of the title compound.

Preparation Example 16 Synthesis of 5-ethoxy-7-nitro-2-pyridin-2-yl-1H-indole

By the method described in Preparation Examples 4 to 5, 5 g (21 mmol) of (4-ethoxy-2-nitrophenyl) hydrazine hydrochloride and 2.4 ml (21 mmol) of 2-acetylpyridine were used to yield 0.5 g of the title compound (yield 8). %) Was obtained.

Preparation Example 17 Synthesis of 7-nitro-5-phenoxy-2-pyridin-2-yl-1H-indole

By the method described in Preparation Examples 4 to 5, 10 g (49 mmol) of (4-phenoxy-2-nitrophenyl) hydrazine hydrochloride and 5.5 ml (49 mmol) of 2-acetylpyridine were used to give 2 g of the title compound (yield 16%). )

Preparation Example 18 Synthesis of 3,5-dimethyl-7-nitro-2-phenyl-1H-indole

150 mg of the title compound (yield 11) using 1.0 g (4.9 mmol) of (4-methyl-2-nitrophenyl) hydrazine hydrochloride and 0.7 ml (4.9 mmol) of 2-propiophenone by the method described in Preparation Examples 4-5. %) Was obtained.

Preparation Example 19 Synthesis of 5-methyl-7-nitro-2-phenyl-1H-indole

 (Step 1)

20 g (131.5 mmol) of 4-methyl-2-nitroaniline was dissolved in 300 ml of ethanol, and 27 g (157.7 mmol) of silver nitrate and 40 g (157.7 mmol) of iodine were added thereto, followed by stirring at room temperature for 8 hours. After completion of the reaction, the mixture was filtered through celite, washed with 100 ml of ethyl acetate and concentrated. Water was added and extracted with ethyl acetate. Washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate to obtain 29 g (69%) of 2-iodo-4-methyl-6-nitro-phenylamine.

(Step 2)

7 g (25.2 mmol) of the compound obtained in Step 1 and 3.3 ml (30,22 mmol) of phenylacetylene were dissolved in 100 ml of tetrahydrofuran, 11 ml (75.5 mmol) of triethylamine, and dichloro (bistriphenylphosphine) palladium (II) 1.8g (2.52 mmol) and 0.48 g (2.52 mmol) of copper (I) iodide were added thereto, followed by stirring at room temperature for 8 hours. After completion of the reaction, water was added and extracted with ethyl acetate. Washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Separation by column chromatography gave 4.5 g (71% yield) of 4-methyl-2-nitro-6-phenylethynyl-phenylamine.

(Step 3)

4.5 g (17.8 mmol) of the compound obtained in Step 2 was dissolved in 120 ml of tetrahydrofuran and 30 ml of N-methyl-pyrrolidinone. 4 g (35.7 mmol) of potassium thi-butoxide was added thereto, followed by stirring at room temperature for 3 hours. After completion of the reaction, water was added and extracted with ethyl acetate. Washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Separation by column chromatography gave 1.0 g (yield 22%) of 5-methyl-7-nitro-2-phenyl-1H-indole.

Preparation Example 20 Synthesis of 2-cyclohexyl-5-methyl-7-nitro-1H-indole

By the method described in Preparation Example 19, 290 mg (yield 62%) of the title compound were obtained using 500 mg (1.8 mmol) of 6-iodo-4-methyl-2-nitroaniline and 0.23 ml (1.8 mmol) of cyclohexylacetylene. .

Preparation Example 21 Synthesis of 5-methyl-2- (6-methyl-pyridin-2-yl) -7-nitro-1H-indole

170 mg of the title compound using the method described in Preparation Example 19 using 500 mg (1.8 mmol) of 6-iodo-4-methyl-2-nitroaniline and 210 mg (1.8 mmol) of 2-ethynyl-6-methylpyridine. (Yield 35%) was obtained.

Preparation Example 22 Synthesis of (R) -3-Amino-4- (4-methoxy-benzylsulfanyl) -butyric acid methyl ester hydrochloride

(Step 1)

In a mixed solution of 400 ml of diethyl ether and 400 ml of concentrated hydrochloric acid, 280 g (1780 mmol) of 4-methoxybenzyl chloride was dissolved in 400 ml of diethyl ether, and added dropwise for 2 hours and stirred for 1 hour. The organic layer was separated, and 197 g (1625 mmol) of L-cystine and 980 ml of 2N caustic soda solution were added to a solution made by dissolving 1890 ml of ethanol. Stir at room temperature for 2 hours. After the reaction was completed, the mixture was cooled to 0 ° C, and neutralized to pH 7 using 3N aqueous hydrochloric acid solution. The resulting solid was filtered and dried to give 250 g (1035 mmol, 64% yield) of (R) -2-amino-3- (4-methoxy-benzylsulfanyl) -propionic acid.

(Step 2)

30.7 g (127.3 mmol) of the compound obtained in Step 1 were dissolved in 150 ml of tetrahydrofuran and 150 ml of water. 26.4 g (190 mmol) of potassium carbonate and 27.7 g (127.3 mmol) of di-thi-butyloxy-dicarbonyl were added thereto, followed by stirring at room temperature for 2 hours. After completion of the reaction, distillation under reduced pressure was carried out to remove tetrahydrofuran. Cool to 0 ° and acidify to pH 3 with 3N aqueous hydrochloric acid solution. The resulting solid was washed with water and dried to give 43 g (126 mmol, yield 99%) of (R) -2-ti-butoxycarbonylamino-3- (4-methoxy-benzylsulfanyl) -propionic acid.

(Step 3)

43 g of the compound obtained in Step 2, 14.5 ml (132 mmol) of 1-methylmorpholine, and 14.1 ml (132 mmol) of ethylchloroformate were dissolved in 500 ml of tetrahydrofuran and stirred at -25 ° C for 1 hour. At the same time, 75 g (1336 mmol) of potassium hydroxide was dissolved in 75 ml of water and 750 ml of diethyl ether, and 26 g (252 mmol) of N-methyl-nitrosourea was added dropwise at 0 ° C. for 2 hours and stirred for 30 minutes. The two solutions were mixed and stirred for 3 hours at -25 ~ room temperature. After completion of the reaction, water was added, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous ammonium chloride solution, and then the organic layer was concentrated to give [(R) -3-diazo-1- (4-methoxy-benzylsulfanylmethyl)-. 2-oxo-propyl] -carbamic acid thi-butyl ester was obtained.

(Step 4)

The compound obtained in step 3 was dissolved in 1000 ml of methanol, 7.1 g (31.1 mmol) of silver benzoate was added, and the mixture was sonicated for 1 hour using ultrasonic waves. After completion of the reaction, the reaction mixture was concentrated and separated by column chromatography. (R) -3-T-butoxycarbonylamino-4- (4-methoxy-benzylsulfanyl) -butyric acid methyl ester 35.2 g (95.3 mmol, yield 76% )

(Step 5)

35.2 g of the compound obtained in Step 4 was dissolved in 70 ml of dichloromethane, 71 ml of 4N hydrochloric acid / 1,4-dioxane solution was added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction was concentrated. 30 ml of dichloromethane and 150 ml of diethyl ether were added, and the resulting solid was filtered and dried to give 25.5 g (83.3 mmol, 87% yield) of the title compound.

Preparation Example 23 Synthesis of (R) -3-Amino-4- (4-methoxy-benzylsulfanyl) -butyric acid ethyl ester hydrochloride

By the method described in Preparation 22, 5.2 g (yield 40%) of the title compound were obtained from 50 g (0.41 mol) of L-cystine using ethanol instead of methanol in Step 4 of Preparation Example 22.

Preparation Example 24 Synthesis of (R) -4-Amino-5- (4-methoxy-benzylsulfanyl) -pentanoic acid ethyl ester hydrochloride

(Step 1)

36 g (137.8 mmol) of (R) -4-thi-butoxycarbonylamino-5-hydroxy-pentanoic acid ethyl ester and 38.4 ml (275.5 mol) of triethylamine can be prepared in 200 ml of dichloromethane. Melted. 11.7 ml (151.5 mmol) of methanesulfonyl chloride was added dropwise, followed by stirring at 0 ° C to room temperature for 1 hour. 1N hydrochloric acid solution was added thereto, followed by extraction with ethyl acetate. Washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate to give (R) -4-ti-butoxycarbonylamino-5-methanesulfonyloxy-pentanoic acid ethyl ester.

(Step 2)

A solution made by dissolving 5.5 g (137.8 mmol) of sodium hydride and 15.4 ml (110.2 mmol) of 4-methoxybenzyl mercaptan in 150 ml of N, N-dimethylformamide and stirring at 0 ° for 10 minutes. Dropped in Stir at 0 degrees for 4 hours. After completion of the reaction, water was added and extracted with ethyl acetate. Washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Separation by column chromatography yielded 21.0 g (yield 38%) of (R) -4-ti-butoxycarbonylamino-5- (4-methoxy-benzylsulfanyl) -pentanoic acid ethyl ester.

(Step 3)

11 g (62.7 mmol) of the compound obtained in Step 2 was dissolved in 200 ml of dichloromethane, and 20 ml of 4-normal hydrochloric acid / ethyl acetate solution was added thereto. Stir at room temperature for 2 hours. After completion of the reaction, the reaction solution was completely concentrated and 150 ml of diethyl ether was added thereto. The obtained solid was filtered and dried to give 20 g (yield 96%) of the title compound.

Preparation Example 25 Synthesis of (S) -3-Amino-4- (4-methoxy-benzylsulfanyl) -butyric acid isopropyl ester hydrochloride

By the method of Production Example 24, (S) -3-thi-butoxycarbonylamino-4-hydroxy instead of (R) -4-thi-butoxycarbonylamino-5-hydroxy-pentanoic acid ethyl ester 22.0 g (84.2 mmol) of butyric acid isopropyl ester were used to obtain 21.0 g (yield 75%) of the title compound.

Preparation Example 26 Synthesis of (R) -2-Amino-3- (4-methoxy-benzylsulfanyl) propionic acid ethyl ester hydrochloride

20 g (83 mmol) of the seed compound obtained in Step 1 of Preparation Example 22 was dissolved in 100 ml of ethanol. 12 ml (166 mmol) of acetyl chloride was added dropwise, followed by stirring at 50 degrees for 12 hours. After completion of the reaction, the reaction mixture was completely concentrated and diethyl ether was added thereto. The obtained solid was filtered and dried to give 16.8 g (yield 69%) of the title compound.

Preparation Example 27 Synthesis of (R) -2,2-Dimethyl-propionic Acid 2-Amino-3- (4-methoxy-benzylsulfanyl) -propyl Ester

(Step 1)

50 g (207.2 mmol) of the compound obtained in Step 1 of Preparation Example 22 were dissolved in 300 ml of methanol. 21 ml (207.2 mmol) of acetyl chloride was added dropwise, followed by stirring at 50 degrees for 12 hours. After completion of the reaction, the mixture was concentrated completely and diethyl ether was added. The obtained solid was filtered and dried to obtain (R) -2-amino-3- (4-methoxy-benzylsulfanyl) -propionic acid methyl ester.

(Step 2)

200 ml of tetrahydrofuran and 200 ml of water were added and dissolved in the compound obtained in Step 1. 87 ml (621.6 mmol) of triethylamine were added thereto, and 43.0 g (196.8 mmol) of di-thi-butyloxy-dicarbonyl was added dropwise to 100 ml of tetrahydrofuran with stirring. Stir at room temperature for 8 hours. After completion of the reaction, 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 (R) -2-ti-butoxycarbonylamino-3- (4-methoxy-benzylsulfanyl) -propionic acid methyl ester.

(Step 3)

The compound obtained in the step 2 was dissolved in 300 ml of tetrahydrofuran. 9.0 g (414.4 mmol) of lithium borohydride was added thereto, followed by stirring at 0 ° C. for 3 hours. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. Washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate to obtain [(R) -2-hydroxy-1- (4-methoxy-benzylsulfanylmethyl) -ethyl] -carbamic acid thi-butyl ester.

(Step 4)

The alcohol compound obtained in the step 3 was dissolved in 300 ml of dichloromethane. 58 ml (414.4 mmol) of triethylamine and 28 ml (227.9 mmol) of trimethylacetyl chloride were added thereto, followed by stirring at 0 ° C. for 6 hours. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. Washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Separation by column chromatography gave 81.0 g (yield 95%) of 2,2-dimethyl-propionic acid (R) -2-thi-butoxycarbonylamino-3- (4-methoxy-benzylsulfanyl) -propyl ester. Got it.

(Step 5)

81 g (196 mmol) of the trimethyl acetate compound obtained in Step 4 were dissolved in 300 ml of dichloromethane. 100 ml of 4N hydrochloric acid / 1,4-dioxane solution was added and stirred at room temperature for 8 hours. After completion of the reaction, the mixture was concentrated completely and diethyl ether was added. The obtained solid was filtered and dried to give 68 g (yield 95%) of the title compound.

Preparation Example 28 Synthesis of 2- (4,5-dihydro-thiazol-2-yl) -1H-indol-7-ylamine

(Step 1)

500 mg (2.14 mmol) of ethyl 7-nitroindole-2-carboxylate was dissolved in 20 ml of a 1: 1 mixed solution of tetrahydrofuran and water, and then 448 mg (10.7 mmol) of lithium hydroxide hydrate were added. After stirring at room temperature for 8 hours, 1N-hydrochloric acid was added and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the filtrate was filtered under reduced pressure to obtain 7-nitro-1H-indole-2-carboxylic acid.

(Step 2)

The compound obtained in the step 1 and 371 mg (3.2 mmol) of 2-chloroethylamine hydrochloride were dissolved in 10 ml of N, N-dimethylformamide. 0.6 ml (4.3 mmol) of triethylamine, EDC (614 mg, 3.2 mmol) and HOBT (433 mg, 3.2 mmol) were added. After stirring at room temperature for 8 hours, 1N-hydrochloric acid was added and extracted with ethyl acetate. The mixture was washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and the filtrate was filtered under reduced pressure to obtain 7-nitro-1H-indole-2-carboxylic acid (2-chloro-ethyl) -amide.

(Step 3)

The compound obtained in Step 2 was dissolved in 10 ml of dichloroethane and 10 ml of toluene, and 1.29 g (3.2 mmol) of Laensone reagent was added. After refluxing for 4 hours, distillation under reduced pressure and water were added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered and the filtrate was distilled under reduced pressure. The concentrate was separated by column chromatography to obtain 100 mg (yield 22%) of compound 2- (4,5-dihydro-thiazol-2-yl) -7-nitro-1H-indole obtained as a result of the cyclization reaction.

(Step 4)

The thiazolin compound obtained in step 3 was dissolved in 50 ml of methanol. 10% Pd / C was added and stirred under hydrogen gas for 8 hours. After completion of the reaction, the reaction mixture was filtered through celite and distilled under reduced pressure. Separation by column chromatography gave 80 mg (91%) of the title compound.

Example 1: cyclopentyl- [2- (4,5-dihydro-1,3-thiazol-2-yl) -1 H-indol-7-yl]- Amine  synthesis

15 mg (0.07 mmol) of the compound obtained in Preparation Example 28 was dissolved in 10 ml of 1,2-dichloroethane. 12 mg (0.14 mmol) of cyclopentanone and 29 mg (0.14 mmol) of sodium triacetoxyborohydride were added and stirred at room temperature for 3 hours. After completion of the reaction, water was added and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate and filtration, the filtrate was distilled under reduced pressure. The residue was purified by column chromatography to give 6.7 mg (34% yield) of the title compound.

Example 2: [2- (4,5-Dihydro-thiazol-2-yl) -1 H-indol-7-yl]-(4-methyl-cyclohexyl)- Amine  synthesis

In the same manner as in Example 1, two diastereomers were obtained by 9.1 mg and 7.4 mg (total yield 60%), respectively, using 19 mg (0.09 mmol) of the compound obtained in Preparation Example 28 and 4-methyl-cyclohexanone.

Example  3: [2- (4,5- Dihydro -Thiazol-2-yl) -1H-indol-7-yl] -piperidin-4-yl- Amine  synthesis

Dichloromethane and trifluorocarboxylic acid solution in a compound made using 20 mg (0.09 mmol) of the compound obtained in Preparation Example 28 and 1- (thi-butylcarbonyl) -4-piperidone in the same manner as in Example 1 5 ml (5: 1, v / v) were added. After stirring for 1 hour at room temperature, the mixture was distilled under reduced pressure. Saturated sodium bicarbonate solution was added and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure. Column chromatography gave 4.9 mg (18% yield) of the title compound.

Preparation Example 29 Synthesis of 7- (tetrahydro-pyran-4-ylamino) -1H-indole-2-carboxylic acid

2.5 g (10.7 mmol) of ethyl 7-nitroindole-2-carboxylate were dissolved in 50 ml of methanol. 200 mg of 10% Pd / C was added and stirred under hydrogen gas for 1 hour. Filtration was carried out using Celite and distilled under reduced pressure. The distillate was dissolved in 50 ml of 1,2-dichloroethane and tetrahydro- 4H -pyran-4-one (1.3 ml, 12.8 mmol) and sodium triacetoxyborohydride (3.4 g, 16.1 mmol) were added. Stir at room temperature for 8 hours. After completion of the reaction, water was added and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate and filtration, the filtrate was distilled under reduced pressure. After concentration the residue was purified by column chromatography. The obtained compound was dissolved in 50 ml of methanol and 50 ml of tetrahydrofuran, and 43 ml (42.8 mmol) of 1N-sodium hydroxide was added and stirred at room temperature for 8 hours. 1N hydrochloric acid solution was added and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the filtrate was filtered under reduced pressure to obtain 2.1 g (yield 76%) of the title compound.

Preparation Example 30: {5- [7- (tetrahydro-pyran-4-ylamino) -1H-indol-2-yl]-[1,2,4] oxadiazol-3-yl} acetic acid ethyl ester synthesis

300 mg (1.15 mmol) of the compound obtained in Preparation Example 29 were dissolved in 20 ml of dimethylformamide. 202 mg (1.38 mmol) of ethyl 3- (hydroxyamino) -3-iminopropionate, EDC (265 mg, 1.38 mmol) and HOBT (187 mg, 1.38 mmol) were added. After stirring for 8 hours at room temperature, saturated sodium bicarbonate solution was added and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure. After concentration the residue was purified by column chromatography. The obtained compound was dissolved in 20 ml of toluene and 10 ml of dichloroethane and refluxed at 120 degrees for 8 hours. After distillation under reduced pressure, the residue was purified by column chromatography to obtain 80 mg (yield 19%) of the title compound.

Example 4 of 2-5- [7- (tetrahydro-pyran-4-ylamino) -1H-indol-2-yl]-[1,2,4] oxadiazol-3-yl} -ethanol synthesis

20 mg (0.05 mmol) of the compound obtained in Preparation Example 30 was dissolved in 2 ml of tetrahydrofuran, and lithium borohydride (2.4 mg, 0.10 mmol) was added. After stirring for 2 hours at room temperature saturated ammonium chloride solution was added and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered and the filtrate was distilled under reduced pressure. Purification by column chromatography gave 4.7 mg (27%) of the title compound.

Preparation Example 31 Synthesis of 2,2-Dimethyl-propionic Acid (R) -2- (7-Amino-1H-indol-2-yl) -4,5-dihydro-thiazol-4-ylmethyl ester

(Step 1)

8.2 g (22.7 mmol) of the 7-nitroindole-carboxylic acid compound obtained in Step 1 of Preparation Example 28 and 13.2 g (27.2 mmol) of the amine compound obtained in Preparation Example 27 were dissolved in 100 ml of dimethylformamide, and 6.6 g (25.0 mmol) of EDC was used. 4.6 g (25.0 mmol) of HOBT were added. After stirring for 8 hours at room temperature saturated sodium bicarbonate solution was added and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure. After concentration the residue was purified by column chromatography to give 2,2-dimethyl-propionic acid (R) -3- (4-methoxy-benzylsulfanyl) -2-[(7-nitro-1H-indole-2-car 8.1 g (71% yield) of carbonyl) -amino-propyl ester were obtained.

(Step 2)

1.6 g (3.2 mmol) of the compound obtained in the method of Step 1 were dissolved in 50 ml of dichloromethane. Phosphorus pentachloride (1.3 g, 6.4 mmol) was added and stirred at room temperature for 5 hours. After completion of the reaction, saturated sodium bicarbonate solution was added and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure. After concentration the residue was purified by column chromatography to give 2,2-dimethyl-propionic acid (R) -2- (7-nitro-1H-indol-2-yl) -4,5-dihydro-thiazole-4- 0.8 g (yield 69%) of monomethyl ester was obtained.

(Step 3)

2.7 g (7.5 mmol) of the compound obtained by the method of Step 2 were dissolved in 150 ml of a 1: 1: 1 mixed solution of tetrahydrofuran, methanol, and water. 4.2 g (74.7 mmol) of iron powder and 4.0 g (74.7 mmol) of ammonium chloride were added and stirred using a mechanical stirrer at 60 ° C. for 30 minutes. After completion of the reaction, water was added and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure. Column chromatography was used to give 2.0 g (yield 81%) of the title compound.

Preparation 32: Synthesis of 2,2-dimethyl-propionic acid (R) -2- (7-cyclopentylamino-1H-indol-2-yl) -4,5-dihydro-thiazol-4-ylmethyl ester

In the same manner as in Example 1, 1.3 g (yield 54%) of the title compound was obtained by using 2.0 g of the compound obtained in Preparation Example 31.

Example 5: Synthesis of [(R) -2- (7-cyclopentylamino-1H-indol-2-yl) -4,5-dihydro-1,3-thiazol-4-yl] -methanol

1.3 g (3.3 mmol) of the compound obtained in Preparation Example 32 were dissolved in 10 ml of tetrahydrofuran, 10 ml of methanol, and 10 ml of water. 0.4 g (9.8 mmol) of lithium hydroxide hydrate was added and stirred at room temperature for 4 hours. After distilling under reduced pressure and concentration, 1N hydrochloric acid was added and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure. Column chromatography gave 820 mg (80% yield) of the title compound.

Preparation Example 33 Synthesis of Methanesulfonic Acid (R) -2- (7 -cyclopentylamino- 1H-indol-2-yl) -4,5 -dihydro -thiazol-4- ylmethyl ester

820 mg (2.6 mmol) of the compound obtained in the method of Example 5 were dissolved in 50 ml of dichloromethane. 0.24 ml (3.1 mmol) of methanesulfonyl chloride and 0.81 ml (3.1 mmol) of triethylamine were added thereto and stirred at 0 ° C. for 30 minutes. After completion of the reaction, saturated sodium bicarbonate solution was added and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the filtrate was filtered under reduced pressure. Column chromatography gave 600 mg (60% yield) of the title compound.

Example  6: Cyclopentyl -[2-((R) -4- Pyrrolidine -One- Yl methyl -4,5- Dihydro -Thiazol-2-yl) -1H-indol-7-yl]- Amine  synthesis

150 mg (0.38 mmol) of the compound obtained in Preparation Example 33 was dissolved in 5 ml of N, N-dimethylformamide. 0.08 ml (1.1 mmol) of pyrrolidine was added and stirred at 70 ° C. for 4 hours. After completion of the reaction, water was added and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the filtrate was filtered under reduced pressure. Column chromatography gave 20 mg (14% yield) of the title compound.

Example 7: {(R) -2- [7- (tetrahydro-pyran-4-ylamino) -1H-indol-2-yl] -4,5-dihydro-thiazol-4-yl}- Synthesis of Methanol

(Step 1)

900 mg (2.7 mmol) of the compound obtained in Preparation Example 31 was dissolved in 100 ml of 1,2-dichloroethane. Tetrahydro- 4H -pyran-4-one (0.8 ml, 8.13 mmol), sodium triacetoxyborohydride (1.72 g, 8.13 mmol) and acetic acid (0.47 ml, 8.13 mmol) were added and at room temperature for 48 hours. Stirred. After completion of the reaction, the mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate solution. After drying over anhydrous magnesium sulfate, the filtrate was filtered under reduced pressure. Purification by column chromatography to give 2,2-dimethylpropionic acid (R) -2- [7- (tetrahydro-pyran-4-ylamino) -1H-indol-2-yl] -4,5-dihydro-thia Zol-4-ylmethyl ester was obtained.

(Step 2)

The compound obtained in the step 1 was dissolved in 32 ml of methanol, 32 ml of tetrahydrofuran and 16 ml of water. 7 ml of 1N sodium hydroxide was added thereto and stirred at room temperature for 4 hours. After completion of the reaction, the mixture was distilled under reduced pressure and extracted with dichloromethane. Washed with saturated sodium chloride and dried over anhydrous magnesium sulfate, and the filtrate was distilled under reduced pressure. Purification by column chromatography gave 700 mg (yield 78%) of the title compound.

Example  8: [(R) -2- (7- Cyclopentylamino -5- Fluoro -1H-indol-2-yl) -4,5- Dehydro Synthesis of Rho-thiazol-4-yl] -methanol

According to the method of Example 5, 600 mg (yield 15%) of the title compound was obtained using 3.0 g (11.9 mmol) of ethyl 5-fluoro-7-nitro-1H-indole-2-carboxylate prepared in Preparation Example 2. Got it.

Example 9: {(R) -2- [5-Fluoro-7- (tetrahydro-pyran-4-ylamino) -1H-indol-2-yl] -4,5-dihydro-thiazole- 4-yl} -methanol synthesis

According to the method of Example 7, 750 mg (yield 18%) of the title compound was obtained using 3.0 g (11.9 mmol) of ethyl 5-fluoro-7-nitro-1H-indole-2-carboxylate prepared in Preparation Example 2. Got it.

Example  10: {(R) -2- [5- (pyridine-3- Sake ) -7- ( Tetrahydro -Pyran-4- Amino ) -1H-Indol-2-yl] -4,5-dihydro-thiazol-4-yl} -methanol

40 mg of the title compound according to the method of Example 7, using 500 mg (1.5 mmol) of 7-nitro-5- (pyridin-3-yloxy) -1H-indole-2-carboxylic acid ethyl ester prepared in Preparation Example 11 (Yield 6%) was obtained.

Preparation Example 34 Synthesis of 5-chloro-7-nitro-1H-indole-2-carboxylic acid

15.0 g (59.1 mmol) of the compound obtained in Preparation Example 5 were dissolved in 300 ml of tetrahydrofuran and 100 ml of methanol. 7.43 g (177 mmol) of lithium hydroxide was dissolved in 100 ml of water, added to the reaction solution, and stirred at room temperature for 3 hours. After completion of the reaction, tetrahydrofuran and methanol were removed by distillation under reduced pressure. The solution was neutralized to pH 6 using 3N hydrochloric acid solution. The resulting solid was filtered and dried to give 13.1 g (92% yield) of the title compound.

Preparation Example 35 Synthesis of [(R) -2- (7-Amino-5-chloro-1 H-indol-2-yl) -4,5-dihydro-thiazol-4-yl] -acetic acid methyl ester

(Step 1)

12.5 g (52.0 mmol) of the compound obtained in Preparation Example 34 and 19.1 g (62.4 mmol) of the compound obtained in Preparation Example 22 were dissolved in 200 ml of N, N-dimethylformamide. 8.7 ml (62.4 mmol) of triethylamine, 14.0 g (104 mmol) of HOBT, and 16.9 g (88.4 mmol) of EDC were added and stirred at room temperature for 4 hours. After completion of the reaction, the mixture was concentrated and extracted with ethyl acetate. Each was washed with saturated aqueous sodium bicarbonate solution and saturated aqueous ammonium chloride solution. The organic layer was concentrated and separated by column chromatography to give (R) -3-[(5-chloro-7-nitro-1H-indole-2-carbonyl) -amino] -4- (4-methoxy-benzylsulfa 20.2 g (41.0 mmol, yield 79%) of methyl) -butyric acid methyl ester were obtained.

(Step 2)

The compound obtained in step 1 was dissolved in 200 ml of dichloromethane. Phosphorus pentachloride (17.1 g, 82 mmlol) was added and stirred at room temperature for 1 hour. After completion of the reaction, the resultant was concentrated, 200 ml of diethyl ether was added, the solid formed was filtered and dried to obtain [(R) -2- (5-chloro-7-nitro-1H-indol-2-yl) -4,5-dihydro- Thiazol-4-yl] -acetic acid methyl ester was obtained.

(Step 3)

The compound obtained in step 2 was dissolved using 200 ml of tetrahydrofuran, 200 ml of methanol and 200 ml of water. 22.9 g (410 mmol) of iron powder and 21.9 g (410 mmol) of ammonium chloride were added and stirred at 60 ° C. for 1 hour using a mechanical stirrer. After completion of the reaction, 300 ml of tetrahydrofuran was added, filtered through Celite, and washed with 100 ml of tetrahydrofuran. After distillation under reduced pressure, the mixture was extracted using ethyl acetate. Washed with saturated sodium chloride and dried over anhydrous magnesium sulfate, and the filtrate was distilled under reduced pressure. Separation by column chromatography gave 9.0 g (yield 68%) of the title compound.

Preparation Example 36: [(R) -2- (5-chloro-7-cyclopentylamino-1 H-indol-2-yl) -4,5-dihydro-thiazol-4-yl] -acetic acid methyl ester synthesis

4.9 g (15.1 mmol) of the compound obtained in Preparation Example 35 was dissolved in 100 ml of dichloroethane. 2.7 ml (30.3 mmol) of cyclopentanone, 0.86 ml (15.1 mmol) of glacial acetic acid, and 6.42 g (30.3 mmol) of sodium triacetoxyborohydride were added and stirred at room temperature for 36 hours. After completion of the reaction, the mixture was washed with 200 ml of saturated aqueous sodium hydrogen carbonate solution and then concentrated. Separation by column chromatography gave 5.15 g (87%) of the title compound.

Example  11: [(R) -2- (5- Chloro -7- Cyclopentylamino -1H-indol-2-yl) -4,5- Dihydro Synthesis of -thiazol-4-yl] -acetic acid

1.5 g (3.83 mmol) of the compound obtained in Preparation Example 36 was dissolved in 100 ml of tetrahydrofuran and 50 ml of methanol. 640 mg (15.3 mmol) of lithium hydroxide monohydrate was dissolved in 50 ml of water, added to the reaction solution, and stirred at room temperature for 4 hours. After completion of the reaction, tetrahydrofuran and methanol were removed by distillation under reduced pressure. 1N hydrochloric acid solution was added and extracted with ethyl acetate. Washed with saturated sodium chloride and dried over anhydrous magnesium sulfate, and the filtrate was distilled under reduced pressure. Separation by column chromatography gave 13.1 g (yield 92%) of the title compound.

Example  12: [(R) -2- (5- Chloro -7- Cyclopentylamino -1H-indol-2-yl) -4,5- Dihydro Synthesis of -thiazol-4-yl] -acetic acid ethyl ester

By the method described in Production Examples 34 to 36, 840 mg (yield 11%) of the title compound were obtained using 5.0 g (19.7 mmol) of the compound obtained in Preparation Example 5 and 6.3 g (19.7 mmol) of the compound obtained in Preparation Example 23.

Example 13: 2-{(R) -2- [5-chloro-7- (tetrahydro-pyran-4-ylamino) -1H-indol-2-yl] -4,5-dihydro-thiazole Synthesis of -4-yl} -ethanol

(Step 1)

By the method of Step 1 of Example 7, 4.1 g (10.0 mmol, yield; 81%) of the tetrahydropyran-4-ylamine compound was obtained using 4.0 g (12.4 mmol) of the compound obtained in Preparation Example 35.

(Step 2)

By the method of Example 4, 2.5 g (6.12 mmol) of the compound obtained in Step 1 was used to obtain 2.19 g (5.76 mmol, 94% yield) of the title compound.

Manufacturing example  37: {5- Chloro -2-[(R) -4- (2- Iodo Ethyl) -4,5- Dihydro -Thiazol-2-yl] -1H-indol-7-yl}-( Tetrahydro -Pyran-4-yl)- Amine  synthesis

3.7 g (10.2 mmol) of the compound obtained in Example 13 were dissolved in 100 ml of tetrahydrofuran. Imidazole 2.1g (30.6mmol), triphenylphosphine 4.0g (15.3mmol), iodine 3.9g (15.3mmol) was added and stirred for 8 hours at 0 ~ room temperature. After completion of the reaction, 100 ml of ethyl acetate was added and washed twice with 100 ml of water. The organic layer was concentrated and separated by column chromatography to give 2.0 g (4.07 mmol, 40% yield) of the title compound.

Example 14 1- [4- (2-{(R) -2- [5-chloro-7- (tetrahydro-pyran-4-ylamino) -1H-indol-2-yl] -4,5 Synthesis of -dihydro-thiazol-4-yl} -ethyl) -piperazin-1-yl] -2-hydroxy-ethanone

(Step 1)

100 mg (0.2 mmol) of the compound obtained in Preparation Example 37 and 270 mg (1.4 mmol) of 1-ti-butoxycarbonyl-piperazine were dissolved in 20 ml of N, N-dimethylformamide. 200 mg (1.4 mmol) of potassium carbonate was added thereto and stirred at room temperature for 4 hours. After completion of the reaction, water was added and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the filtered filtrate was distilled under reduced pressure and concentrated to give 4- (2-{(R) -2- [5-chloro-7- (tetrahydro-pyran-4-ylamino) -1H-indole- 2-yl] -4,5-dihydro-thiazol-4-yl} -ethyl) -piperazine-1-carboxylic acid thi-butyl ester was obtained.

(Step 2)

The concentrated compound obtained in step 1 was dissolved in 10 ml of dichloromethane. 0.5 ml of 4N-hydrochloric acid solution was added dropwise and stirred at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated by distillation under reduced pressure. The concentrate was dissolved in 5 ml of N, N-dimethylformamide, glycolic acid (15.1 mg, 0.2 mmol), triethylamine (28 ul, 0.2 mmol), EDC (45 mg, 0.23 mmol) and HOBT (40 mg, 0.29). mmol) was added. Stir at room temperature for 8 hours. 1N hydrochloric acid solution was added and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure. Purification by column chromatography gave 5.1 mg (5% yield) of the title compound.

Example  15: 1- (2-{(R) -2- [5- Chloro -7- ( Tetrahydro -Pyran-4- Amino ) -1H-indol-2-yl] -4,5- Dihydro -Thiazol-4-yl} -ethyl)- Pyrrolidine 3-ol

100 mg (0.2 mmol) of the compound obtained in Preparation Example 37 and 0.35 ml (4.2 mmol) of 3-pyrrolidinol were dissolved in 20 ml of N, N-dimethylformamide. Potassium carbonate 580mg (4.2mmol) was added and stirred at room temperature for 4 hours. After completion of the reaction, water was added and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the filtrate was concentrated by distillation under reduced pressure. Purification by column chromatography gave 2 mg (2%) of the title compound.

Example  16: [(R) -2- (5- Bromo -7- Cyclopentylamino -1H-indol-2-yl) -4,5- Dihydro Synthesis of -thiazol-4-yl] -acetic acid

As a method of preparing the compound of Example 11, using the methyl 5-bromo-7-nitro-1H-indole-2-carboxylate 1.1g (3.7mmol) prepared in Preparation Example 6 250mg (16% yield) of the title compound )

Example 17 Synthesis of [(R) -2- (7-cyclopentylamino-5-ethoxy-1H-indol-2-yl) -4,5-dihydro-thiazol-4-yl] -acetic acid

150 mg (5.7% yield) of the title compound using 1.5 g (5.7 mmol) of methyl 5-ethoxy-7-nitro-1H-indole-2-carboxylate prepared in Preparation Example 9 as a method for preparing the compound of Example 11 )

Example 18 Synthesis of [(S) -2- (7-cyclopentylamino-5-ethoxy-1H-indol-2-yl) -4,5-dihydro-thiazol-4-yl] -acetic acid

(Step 1)

In the method of Preparation Example 22, (S) -3-amino-4- (4-methoxy-benzylsulfanyl) -butyric methyl ester 1.2 using 5.0 g (31.7 mmol) of D-cystine instead of L-cystine g (yield 12%) was obtained.

(Step 2)

The method described in Production Examples 34 to 36 and the method for producing the compound of Example 11, and 1.0 g (3.8 mmol) of 5-ethoxy-7-nitro-1H-indole-2-carboxylate prepared in Production Example 9 27 mg (2% yield) of the title compound were obtained using the compound prepared in 1.

Example 19 Synthesis of [2- (7-cyclopentylamino-5-phenoxy-1H-indol-2-yl) -4,5-dihydro-thiazol-4-yl] -acetic acid

(Step 1)

By the method of Production Example 24, 3-thi-butoxycarbonylamino-4-hydroxy-butyric acid ethyl ester instead of (R) -4-thi-butoxycarbonylamino-5-hydroxy-pentanoic acid ethyl ester 15.0 g (60.7 mmol) was used to obtain 12.0 g (61% yield) of 3-amino-4- (4-methoxy-benzylsulfanyl) -butyric acid ethyl ester.

(Step 2)

The method described in Production Examples 34 to 36 and the method for producing the compound of Example 11, wherein the compound produced in Step 1 and the 7-nitro-5-phenoxy-1H-indole-2-carboxylic acid methyl ester made in Production Example 10 500 g (17% yield) of the title compound were obtained using 2.0 g (6.7 mmol).

Example  20: [(R) -2- (7- Cyclopentylamino -5- Phenoxy -1H-indol-2-yl) -4,5- Dihydro Synthesis of -thiazol-4-yl] -acetic acid

101.5 g (264.7 mmol) of 7-nitro-5-phenoxy-1H-indole-2-carboxylic acid methyl ester produced in Preparation Example 10 by the method described in Preparation Examples 34 to 36 and the method for producing the compound of Example 11. 51.0 g (yield 44%) of the title compound were obtained using (R) -3-amino-4- (4-methoxy-benzylsulfanyl) -butyric acid ethyl ester hydrochloride prepared in Preparation Example 23.

Example  21: [(S) -2- (7- Cyclopentylamino -5- Phenoxy -1H-indol-2-yl) -4,5- Dihydro Synthesis of -thiazol-4-yl] -acetic acid

55.5 g (185.9 mmol) of 7-nitro-5-phenoxy-1H-indole-2-carboxylic acid methyl ester produced in Preparation Example 10 by the method described in Preparation Examples 34 to 36 and the method for producing the compound of Example 11. 21.0 g (yield 26%) of the title compound were obtained using (S) -3-amino-4- (4-methoxy-benzylsulfanyl) -butyric acid isopropyl ester hydrochloride prepared in Preparation Example 25.

Manufacturing example  38: 3-[(R) -2- (7-amino-5- Chloro -1H-indol-2-yl) -4,5- Dihydro Synthesis of -thiazol-4-yl] -propionic acid ethyl ester

By the method described in Production Example 35, 2.0 g (8.3 mmol) of the export compound obtained in Production Example 34 and compound (R) -4-amino-5- (4-methoxy-benzylsulfanyl) -penta obtained in Production Example 24 3.4 g (10.2 mmol) of no-acid ethyl ester hydrochloride were used to obtain 0.76 g (yield 26%) of the title compound.

Example  22: 3-[(R) -2- (5- Chloro -7- Cyclopentylamino -1H-indol-2-yl) -4,5- Dihydro Synthesis of -thiazol-4-yl] -propionic acid ethyl ester

By the method described in Example 1, 450 mg (yield 51%) of the title compound were obtained using 760 mg (2.1 mmol) of the compound prepared in Preparation Example 38.

Example 23 of 3-[(R) -2- (5-chloro-7-cyclopentylamino-1 H-indol-2-yl) -4,5-dihydro-thiazol-4-yl] -propionic acid synthesis

By the method described in Example 11, 400 mg (yield 85%) of the title compound were obtained using 500 mg (1.2 mmol) of the ester prepared in the method of Example 22.

Preparation Example 39 Synthesis of 2-pyridin-2-yl-1H-indol-7-ylamine

By the method described in Step 3 of Preparation Example 31, 800 mg (yield 92%) of the title compound were obtained using 1.0 g (4.2 mmol) of the compound prepared in Preparation Example 14.

Example 24 Synthesis of Cyclopentyl- (2-pyridin-2-yl-1H-indol-7-yl) -amine

By the method described in Example 1, 55 mg (yield 28%) of the title compound were obtained using 150 mg (0.7 mmol) of the compound prepared in Preparation Example 39.

Preparation Example 40 Synthesis of 2-pyrazin-2-yl-1H-indol-7-ylamine

By the method described in Step 3 of Preparation Example 31, 500 mg (2.1 mmol) of the compound prepared in Preparation Example 15 were used to obtain 430 mg (yield 98%) of the title compound.

Example 25 Synthesis of Cyclopentyl- (2-pyrazin-2-yl-1H-indol-7-yl) amine

By the method described in Example 1, 33 mg (yield 31%) of the title compound were obtained using 80 mg (0.38 mmol) of the compound prepared in Preparation Example 40.

Example  26: (2-pyrazin-2-yl-1H-indol-7-yl)-( Tetrahydropyran Yl) - Amine  synthesis

By the method described in Step 1 of Example 7, 35 mg (yield 31%) of the title compound were obtained using 80 mg (0.38 mmol) of the compound prepared in Preparation Example 40.

Manufacturing example  41: 7-nitro-lH-indole-2- Carbothioic acid  Synthesis of Amide

2.0 g (9.7 mmol) of the 7-nitroindole-2-carboxylic acid compound obtained in Step 1 of Preparation Example 28 was dissolved in 100 ml of dichloromethane. 2 ml (29.1 mmol) of cionyl chloride were added thereto and stirred at 60 ° C. for 1 hour. After completion of the reaction, the mixture was concentrated by distillation under reduced pressure. This compound was dissolved in 100 ml of tetrahydrofuran, and 5.0 g (14.6 mmol) of Laensone reagent was added thereto. Stir at 80 degrees for 3 hours. After completion of the reaction, the resulting solid was washed with 100 ml of dichloromethane to give 1.5 g (71% yield) of the title compound.

Manufacturing example  42: 7-nitro-2-thiazol-2-yl-1 H- Indole  synthesis

1.1 g (5.0 mmol) of the compound obtained in Preparation Example 41 were dissolved in 20 ml of ethanol and 1 ml of N, N-dimethylformamide. 3.7 ml (25 mmol) of bromoacetalaldehyde diethyl acetal was added thereto, followed by stirring at 100 ° C. for 8 hours. After completion of the reaction, water was added and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the filtrate was concentrated by distillation under reduced pressure. The obtained solid was washed with diethyl ether to give 800 mg (yield 67%) of the title compound.

Manufacturing example  43: 2-thiazol-2-yl-1H-indole-7- Thiamine  synthesis

In the method described in Step 3 of Preparation Example 31, 650 mg (yield 93%) of the title compound was obtained using 800 mg (3.3 mmol) of the compound obtained in Preparation Example 42.

Example  27: Cyclopentyl -(2-thiazol-2-yl-1 H-indol-7-yl)- Amine  synthesis

By the method described in Example 1, 20 mg (yield 51%) of the title compound were obtained using 30 mg (3.3 mmol) of the compound obtained in Preparation Example 43.

Manufacturing example  44: 5- methyl -7-nitro-1H-indole-2- Carboxylic acid  synthesis

6.5 g (27.8 mmol) of the compound obtained in Preparation Example 7 were dissolved in 200 ml of a 1: 1: 1 mixed solution of methanol, tetrahydrofuran and water. 3.5 g (83.3 mmol) of lithium hydroxide hydrate were added. After stirring for 8 hours at room temperature, 1N-hydrochloric acid solution was added and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the filtrate was filtered under reduced pressure to obtain 5.7 g (yield 94%) of the title compound.

Manufacturing example  45: (R) -3- (4- Methoxy - Benzylsulfanyl ) -2-[(5- methyl Synthesis of -7-nitro-1H-indole-2-carbonyl) -amino] -propionic acid ethyl ester

3 g (13.6 mmol) of the compound obtained in Preparation Example 44 and (R) -2-amino-3- (4-methoxy-benzylsulfanyl) propionic acid ethyl ester hydrochloride (5.8 g, 19.1 mmol) obtained in Preparation Example 26 were prepared. It was dissolved in 100 ml of dimethylformamide. Triethylamine (1.9 g, 19.1 mmol), EDC (4.4 g, 23.2 mmol) and HOBT (3.7 g, 27.3 mmol) were added. After stirring for 8 hours at room temperature 1N hydrochloric acid solution was added and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure. Purification by column chromatography gave 4.1 g (64%) of the title compound.

Manufacturing example  46: (R) -2- (7-amino-5- methyl -1H-indol-2-yl) -4,5- Dihydro -Thiazole-4- Carboxylic acid  Synthesis of Ethyl Ester

(Step 1)

4.1 g (8.7 mmol) of the compound obtained in Preparation Example 45 was dissolved in 200 ml of dichloromethane, and 3.6 g (17.4 mmol) of phosphorus pentachloride was added thereto and stirred at room temperature for 4 hours. Saturated aqueous sodium bicarbonate solution was added and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the filtered filtrate was distilled under reduced pressure to obtain (R) -2- (5-methyl-7-nitro-1H-indol-2-yl) -4,5-dihydro-thiazole-4-car The ethyl acid ester was obtained.

(Step 2)

The compound obtained in Step 1 was dissolved in 300 ml of a mixed solution of water, tetrahydrofuran and methanol 1: 1: 1. 4.6 g (86.9 mmol) of ammonium chloride and 4.9 g (86.9 mmol) of iron were added and stirred at 60 ° C. for 30 minutes. Celite filter and distillation under reduced pressure. Saturated aqueous sodium bicarbonate solution was added to the concentrate and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the filtrate was filtered under reduced pressure. Purification by column chromatography gave 400 mg (15%) of the title compound.

Manufacturing example  47: (R) -2- (7- Cyclopentylamino -5- methyl -1H-indol-2-yl) -4,5- Dihydro -Thiazole-4- Carboxylic acid  Synthesis of Ethyl Ester

In the same manner as in Example 1, 590 mg (yield 12%) of the title compound were obtained using 4.0 g (0.91 mmol) of the compound obtained in Preparation Example 46.

Example  28: 2- (7- Cyclopentylamino -5- methyl -1H-indol-2-yl) -thiazole-4- Carboxylic acid  Synthesis of Ethyl Ester

560 mg (1.51 mmol) of the compound obtained in Preparation Example 47 were dissolved in 20 ml of dichloromethane. Bromotrichloromethane (330 mg, 1.7 mmol) and DBU (250 mg, 1.7 mmol) were added and stirred at 0 ° C. for 2 hours. After completion of the reaction, saturated aqueous sodium bicarbonate solution was added and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure. Purification by column chromatography gave 450 mg (81%) of the title compound.

Example  29: 2- (7- Cyclopentylamino -5- methyl -1H-indol-2-yl) -thiazole-4- Carboxylic acid  synthesis

In the same manner as in Production Example 44, 70 mg (yield 76%) of the title compound were obtained using 100 mg (0.27 mmol) of the compound obtained in Example 28.

Example  30: [2- (7- Cyclopentylamino -5- methyl Synthesis of -1H-indol-2-yl) -thiazol-4-yl] -methanol

In the same manner as in Example 4, 200 mg (yield 75%) of the title compound were obtained using 300 mg (0.81 mmol) of the compound obtained in Example 28.

Preparation Example 48 Synthesis of 5-methyl-7-nitro-1H-indole-2-carbothioic acid amido

By the method of Preparation Example 41, 2.4g (yield 75%) of the title compound was obtained using 3.2 g (1.4 mmol) of the carboxylic acid compound obtained in Preparation Example 44.

Preparation 49: Synthesis of 2- (5-methyl-7-nitro-1H-indol-2-yl) -thiazole-5-carbaldehyde

2.5 g (11.3 mmol) of the compound obtained in Preparation Example 48 were dissolved in 50 ml of N, N-dimethylformamide. 2.56 g (17 mmol) of 2-bromomalonaldehyde was added thereto and stirred at 100 ° C. for 6 hours. After the reaction was completed, the reaction was placed in ice water. The resulting solid was collected and dried to give 2.45 g (77% yield) of the title compound.

Preparation 50: Synthesis of [2- (7-Amino-5-methyl-1 H-indol-2-yl) -thiazol-5-yl] -methanol

1.75 g (6.1 mmol) of the compound obtained in Preparation Example 49 were dissolved in 300 ml of a mixed solution of water, tetrahydrofuran and methanol 1: 1: 1. 3.26 g (60.9 mmol) of ammonium chloride and 3.4 g (60.9 mmol) of iron were added and stirred at 60 ° C. for 30 minutes, followed by a celite filter and distillation under reduced pressure. Saturated aqueous sodium bicarbonate solution was added to the concentrate and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure. Purification by column chromatography gave 300 mg (19%) of the title compound.

Example 31 Synthesis of [2- (7-cyclopentylamino-5-methyl-1H-indol-2-yl) -thiazol-5-yl] -methanol

By the method described in Example 1, 380 mg (yield 100%) of the title compound were obtained using 300 mg (1.16 mmol) of the compound obtained in Preparation Example 50.

Preparation Example 51 Synthesis of 5-methyl-7-nitro-1H-indole-2-carboxylic acid hydrazide

5.0 g (21.3 mmol) of the compound obtained in Preparation Example 7 were dissolved in 100 ml of ethanol. 2 ml (40 mmol) of hydrazine hydrate was added and stirred at 100 ° C. for 4 hours. After completion of the reaction, the mixture was cooled to precipitate a solid. The solids were collected and washed with dichloromethane to give 2.34 g (47% yield) of the title compound.

Preparation Example 52 Synthesis of 5-methyl-7-nitro-2- [1,3,4] oxadiazol-2-yl-1H-indole

2.3 g (9.8 mmol) of the compound obtained in Preparation Example 51 and 100 ml of triethyl orthoformate were mixed and stirred at 120 ° C. for 8 hours. After completion of the reaction, water was added and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the filtrate was filtered under reduced pressure to obtain 600 mg (25% yield) of the title compound.

Example 32 Synthesis of Cyclopentyl- (5-methyl-2- [1,3,4] oxadiazol-2-yl-1H-indol-7-yl) -amine

Using the method described in Production Example 43 and Example 1, 300 mg (1.2 mmol) of the compound obtained in Preparation Example 52 were used to obtain 50 mg (yield 14%) of the title compound.

Preparation Example 53 Synthesis of 5-methyl-2-pyridin-2-yl-1H-indol-7-ylamine

300 mg (1.2 mmol) of the compound obtained in Preparation Example 12 were dissolved in 100 ml of a mixed solution of methanol and ethyl acetate 1: 1. 10 mg Pd / C 40mg was added and stirred under hydrogen gas for 1 hour. After completion of the reaction, the reaction mixture was filtered through celite and distilled under reduced pressure. Separation by column chromatography gave 170 mg (64%) of the title compound.

Example 33 Synthesis of Cyclopentyl- (5-methyl-2-pyridin-2-yl-1H-indol-7-yl) -amine

By the method described in Example 1, 20 mg (yield 46%) of the title compound were obtained using 50 mg (0.22 mmol) of the compound obtained in Preparation Example 53.

Example 34 Synthesis of (5-methyl-2-pyridin-2-yl-1H-indol-7-yl)-(tetrahydro-pyran-4-yl) -amine

By the method described in Step 1 of Example 7, 25 mg (yield 36%) of the title compound were obtained using 50 mg (0.22 mmol) of the compound obtained in Preparation Example 53.

Example 35 Synthesis of Cyclohexyl- (5-methyl-2-pyridin-2-yl-1H-indol-7-yl) -amine

Cyclohexanone was used instead of cyclopentanone in the method described in Example 1, and 50 mg (0.22 mmol) of the compound obtained in Preparation 53 was used to obtain 25 mg (yield 36%) of the title compound.

Example  36: 1- [4- (5- methyl -2-pyridin-2-yl-1H-indole-7- Amino ) -Piperidin-1-yl]- Ethanon  synthesis

In the method described in Example 1, 1-acetyl-4-piperidone was used instead of cyclopentanone, and 10 mg (yield 21%) of the title compound was obtained using 30 mg (0.13 mmol) of the compound obtained in Preparation Example 53.

Example 37 Synthesis of (1-Methyl-piperidin-4-yl)-(5-methyl-2-pyridin-2-yl-1H-indol-7-yl) -amine

In the method described in Example 1, 1-methyl-4-piperidone was used instead of cyclopentanone and 17 mg (yield 40%) of the title compound was obtained using 30 mg (0.13 mmol) of the compound obtained in Preparation 53.

Example 38 Synthesis of 4- (5-methyl-2-pyridin-2-yl-1H-indol-7-ylamino) -cyclohexanone

Obtained using 30 mg (0.13 mmol) of the compound obtained in Preparation Example 53 using 1,4-cyclohexanedione monoethylene acetal instead of cyclopentanone in the method described in Example 1. The compound was dissolved in 10 ml of acetone and 5 ml of water. 1 ml of 1 N hydrochloric acid solution was added and stirred at 80 ° C. for 8 hours. After completion of the reaction was added saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure. Purification by column chromatography gave 10 mg (23%) of the title compound.

Example 39 Synthesis of (1-benzyl-pyrrolidin-3-yl)-(5-methyl-2-pyridin-2-yl-1H-indol-7-yl) -amine

In the method described in Example 1, 1-benzyl-3-pyrrolidone was used instead of cyclopentanone and 10 mg (yield 20%) of the title compound was obtained using 30 mg (0.13 mmol) of the compound obtained in Preparation Example 53.

Example  40: Cyclopentylmethyl - (5- methyl -2-pyridin-2-yl-1H-indol-7-yl)- Amine  synthesis

Cyclopentanecarboxaldehyde was used instead of cyclopentanone in the method described in Example 1, and 10 mg (yield 20%) of the title compound was obtained using 30 mg (0.13 mmol) of the compound obtained in Preparation Example 53.

Example  41: N- (5- methyl -2-pyridin-2-yl-1H-indol-7-yl)- Benjamid  synthesis

45 mg (0.20 mmol) of the compound obtained in Preparation Example 53 was dissolved in 10 ml of dichloromethane. 0.2 ml of triethylamine and 0.03 ml (0.22 mmol) of benzoyl chloride were added and stirred at room temperature for 2 hours. After completion of the reaction, water was added and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the filtrate was filtered under reduced pressure. Purification by column chromatography gave 18 mg (27%) of the title compound.

Example  42: Cyclopentyl - (5- methyl -2-pyrazin-2-yl-1H-indol-7-yl)- Amine  synthesis

25 mg (yield 22%) of the title compound was obtained using 100 mg (0.39 mmol) of the compound obtained in Preparation Example 13 by the method described in Preparation Example 53 and Example 1.

Example  43: Cyclopentyl - (5- Ethoxy -2-pyridin-2-yl-1H-indol-7-yl)- Amine  synthesis

By the method described in Preparation Example 53 and Example 1, 4.5 mg (yield 19%) of the title compound were obtained using 20 mg (0.07 mmol) of the compound obtained in Preparation Example 16.

Example  44: Cyclopentyl - (5- Phenoxy -2-pyridin-2-yl-1H-indol-7-yl)- Amine  synthesis

120 mg (yield 43%) of the title compound were obtained using 250 mg (0.75 mmol) of the compound obtained in Preparation Example 17 by the method described in Preparation Example 53 and Example 1.

Example 45 Synthesis of Cyclopentyl- (3,5-dimethyl-2-phenyl-1H-indol-7-yl) -amine

By the method described in Preparation Example 53 and Example 1, 35 mg (yield 31%) of the title compound were obtained using 100 mg (0.38 mmol) of the compound obtained in Preparation Example 18.

Example 46 Synthesis of Cyclopentyl- (5-methyl-2-phenyl-1H-indol-7-yl) -amine

By the method described in Preparation Example 53 and Example 1, 50 mg (yield 36%) of the title compound were obtained using 120 mg (0.48 mmol) of the compound obtained in Preparation Example 19.

Example 47 Synthesis of (2-cyclohexyl-5-methyl-1H-indol-7-yl) -cyclopentyl-amine

By the method described in Preparation Example 53 and Example 1, 21 mg (yield 37%) of the title compound were obtained using 50 mg (0.19 mmol) of the compound obtained in Preparation Example 20.

Example 48 Synthesis of Cyclopentyl- [5-methyl-2- (6-methyl-pyridin-2-yl) -1 H-indol-7-yl] -amine

By the method described in Preparation Example 53 and Example 1, 35 mg (yield 40%) of the title compound were obtained using 50 mg (0.19 mmol) of the compound obtained in Preparation Example 21.

Example 49 Synthesis of (5-methyl-2-phenyl-1H-indol-7-yl)-(tetrahydro-pyran-4-yl) -amine

Using the compound (70 mg, 0.28 mmol) obtained in Preparation Example 19 using tetrahydro- 4H -pyran-4-one in place of cyclopentanone in the method described in Preparation Example 53 and the method described in Example 1 50 mg (yield, 57%) of compound were obtained.

Example 50 Synthesis of (5-methyl-2-phenyl-1H-indol-7-yl)-(1-methyl-piperidin-4-yl) -amine

In the method described in Preparation Example 53 and 1-methyl-4-piperidone in place of cyclopentanone in the method described in Example 1, using the compound (70 mg, 0.28 mmol) obtained in Preparation Example 19, 24 mg ( Yield 29%).

Example  51: 1- [4- (5- methyl -2- Phenyl -1H-indole-7- Amino ) -Piperidin-1-yl]- Ethanon  synthesis

18 mg of the title compound was obtained using the compound (96 mg, 0.38 mmol) obtained in Preparation Example 19 using 1-acetyl-4-piperidone instead of cyclopentanone in the method described in Preparation Example 53 and the method described in Example 1. Yield 13%).

Example  52: (5- methyl -2- Phenyl -1H-indol-7-yl) -piperidin-4-yl-amine Of hydrochloride  synthesis

By the method described in Preparation Example 53 and Example 3, using the compound (140 mg, 0.56 mmol) obtained in Preparation Example 19 to obtain 50 mg (yield 21%) of the title compound.

Example  53: 2- Hydroxy -1- [4- (5- methyl -2- Phenyl -1H-indole-7- Amino ) -Piperidin-1-yl]- Ethanon  synthesis

The compound obtained in Example 52 (50 mg, 0.13 mmol) was dissolved in 3 ml of N, N-dimethylformamide, glycolic acid (15 mg, 0.20 mmol), triethylamine (0.06 ml, 0.43 mmol), EDC ( 38 mg, 0.20 mmol) and HOBT (27 mg, 0.20 mmol) were added. Stir at room temperature for 8 hours. 1N hydrochloric acid solution was added and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure. Purification by column chromatography gave 20 mg (43%) of the title compound.

Example  54: (1- Methanesulfonyl -Piperidin-4-yl)-(5- methyl -2- Phenyl -1H-indole-7-yl)- Amine  synthesis

The compound obtained in Example 52 was dissolved in 10 ml of dichloromethane, triethylamine (0.02 ml, 0.14 mmol) and methanesulfonylchloride (10 mg, 0.09 mmol) were added. Stir at 0 degrees for 1 hour. 1N hydrochloric acid solution was added and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure. Purification by column chromatography gave 18 mg (67% yield) of the title compound.

Preparation Example 54 Synthesis of 4- (5-methyl-2-phenyl-1H-indol-7-ylamino) -cyclohexanecarboxylic acid ethyl ester

Using the compound (200 mg, 0.90 mmol) obtained in Preparation Example 19 using 4-oxo-cyclohexanecarboxylic acid ethyl ester instead of cyclopentanone in the method described in Preparation Example 53 and the method described in Example 1 170 mg (50% yield) of compound were obtained.

Example 55: Synthesis of 4- (5-methyl-2-phenyl-1H-indol-7-ylamino) -cyclohexanecarboxylic acid

The compound (170 mg, 0.45 mmol) obtained in Preparation Example 54 was dissolved in 12 ml of a 5: 1 mixed solution of tetrahydrofuran and methanol. 0.4 ml of 6N sodium hydroxide was added and stirred at room temperature for 8 hours. After completion of the reaction, distilled under reduced pressure, 1N hydrochloric acid solution was added and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure. Column chromatography gave 120 mg (77% yield) of the title compound.

Example  56: 4- (5- methyl -2- Phenyl -1H-indole-7- Amino ) - Cyclohexanecarboxylic acid  (2- Morpholine Synthesis of 4-yl-ethyl) -amide

The compound obtained in Example 55 (30 mg, 0.09 mmol) was dissolved in 5 ml of N, N-dimethylformamide, 2-morpholin-4-yl-ethylamine (22 mg, 0.17 mmol), EDC (25 mg, 0.19 mmol) and HOBT. (18 mg, 0.19 mmol) was added. Stir at room temperature for 8 hours. Saturated aqueous chloride solution was added and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure. Purification by column chromatography gave 40 mg (100% yield) of the title compound.

Example  57: Cyclopentylmethyl - (5- methyl -2- Phenyl -1H-indole-7-yl)- Amine  synthesis

36 mg (yield 40%) of the title compound was obtained using the compound (70 mg, 0.28 mmol) obtained in Preparation Example 19 using cyclopentanecarbaldehyde instead of cyclopentanone in the method described in Preparation Example 53 and the method described in Example 1. Got it.

Example  58: (5- methyl -2- Phenyl -1H-indole-7-yl)-( Tetrahydro -Pyran-4- Yl methyl ) - Amine  synthesis

In the method described in Preparation Example 53 and in the method described in Example 1, using tetrahydro-pyran-4-carbaldehyde instead of cyclopentanone, using the compound (70 mg, 0.28 mmol) obtained in Preparation Example 19, 19 mg ( Yield 21%).

Manufacturing example  55: 5- Chloro -7-nitro-2- Phenyl -1H- Indole  synthesis

In the method of Preparation Example 19, 4-chloro-2-nitroaniline (1.0 g, 3.67 mmol) was used instead of 4-methyl-2-nitroaniline to obtain 750 mg (yield 75%) of the title compound.

Example  59: (5- Chloro -2- Phenyl -1H-indole-7-yl)- Cyclopentyl - Amine  synthesis

By the method of Example 46, the title compound was substituted with 5-chloro-7-nitro-2-phenyl-1H-indole (225 mg, 0.83 mmol) instead of 5-methyl-7-nitro-2-phenyl-1H-indole. 230 mg (89% yield) were obtained.

Example  60: (5- Chloro -2- Phenyl -1H-indole-7-yl)-( Tetrahydro -Pyran-4-yl)- Amine  synthesis

As in Example 49, the title compound was substituted with 5-chloro-7-nitro-2-phenyl-1H-indole (337 mg, 1.23 mmol) instead of 5-methyl-7-nitro-2-phenyl-1H-indole. 200 mg (50% yield) were obtained.

Example 61 Synthesis of (5-Chloro-2-phenyl-1H-indol-7-yl)-(1-methyl-piperidin-4-yl) -amine

As in Example 50, the title compound was obtained using 5-chloro-7-nitro-2-phenyl-1H-indole (337 mg, 1.23 mmol) instead of 5-methyl-7-nitro-2-phenyl-1H-indole. 288 mg (69% yield) were obtained.

Example 62 Synthesis of (5-chloro-2-phenyl-1H-indol-7-yl) -cyclohexyl-amine

98 mg (yield, 49%) of the title compound using the compound (170 mg, 0.62 mmol) obtained in Preparation Example 55 using cyclohexanone instead of cyclopentanone in the method described in Preparation Example 53 and the method described in Example 1. Got.

Example 63 Synthesis of (1-benzyl-pyrrolidin-3-yl)-(5-chloro-2-phenyl-1H-indol-7-yl) -amine

Using 1-benzyl-pyrrolidin-3-one instead of cyclopentanone in the method described in Preparation Example 53 and the method described in Example 1, using compound (225 mg, 0.83 mmol) obtained in Preparation Example 55 50 mg (15% yield) of compound was obtained.

Preparation 56 Synthesis of 4-ethynyl-benzoic acid methyl ester

(Step 1)

20.60 g (78.61 mmol) of 4-iodobenzoic acid methyl ester and 9.26 g (94.33 mmol) of ethynyltrimethylsilane are dissolved in 200 ml of tetrahydrofuran, 23.86 g (235.83 mmol) of triethylamine, and dichloro (bistriphenylphosph). 1.65 g (2.36 mmol) of pin) palladium (II) and 0.45 g (2.36 mmol) of cupper (I) iodide were added and stirred at room temperature for 8 hours. After completion of the reaction, water was added and extracted with ethyl acetate. Washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Separation by column chromatography gave 18.30 g (yield 100%) of trimethylsilylethynylbenzoic acid methyl ester.

(Step 2)

18.30 g (78.61 mmol) of the compound obtained in Step 1 was dissolved in 300 ml of a mixed solution of methanol and dichloromethane 2: 1, and 5.44 g (39.3 mmol) of potassium carbonate was added thereto and stirred at room temperature for 1 hour. After completion of the reaction, water was added and extracted with ethyl acetate. Washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Separation by column chromatography gave 11.90 g (95% yield) of the title compound.

Manufacturing example  57: 4- (5- Chloro 2-nitro-1H-indol-2-yl) -benzoic acid Methyl ester  synthesis

(Step 1)

10.0 g (33.50 mmol) of 2-iodo-4-chloro-6-nitro-phenylamine was dissolved in 200 ml of tetrahydrofuran. 3.97 g (50.25 mmol) of pyridine and 7.74 g (36.85 mmol) of trifluoroacetic hydride were added thereto, followed by stirring for 9 hours at 0 ° C. to room temperature. After completion of the reaction, water was added and extracted with ethyl acetate. Washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Separation by column chromatography gave 12.3 g (yield 85%) of trifluoroacetamide.

(Step 2)

12.3 g (31.18 mmol) of the compound obtained in Step 1 and 6.0 g (37.42 mmol) of 4-ethynylbenzoic acid methyl ester were dissolved in 200 ml of N, N-dimethylformamide, 9.47 g (93.54 mmol) of triethylamine, and tetrabutylammonium Add 11.51 g (31.18 mmol) of iodide, 1.09 g (1.56 mmol) of dichloro (bistriphenylphosphine) palladium (II), 0.30 g (1.56 mmol) of cupper (I) iodide for 8 hours at 80 ° C. Stirred. After completion of the reaction, water was added and extracted with ethyl acetate. Washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Separation by column chromatography gave 7.6 g (yield 81%) of the title compound.

Example  64: 4- (5- Chloro -7- Cyclopentylamino -1H-indol-2-yl) -benzoic acid methyl  Synthesis of esters

In the method of Example 46, 1.25 g (yield 15%) of the title compound were obtained using 7.60 g (22.98 mmol) of the compound obtained in Preparation Example 57 instead of 5-methyl-7-nitro-2-phenyl-1H-indole. .

Example 65 Synthesis of 4- (5-Chloro-7-cyclopentylamino-1 H-indol-2-yl) -benzoic acid

300 mg (0.81 mmol) of the compound obtained in Example 64 was dissolved in 15 ml of tetrahydrofuran, 5 ml of water, and 5 ml of methanol. 100 mg (2.44 mmol) of lithium hydroxide monohydrate was added and stirred at room temperature for 21 hours. After completion of the reaction, tetrahydrofuran and methanol were removed by distillation under reduced pressure. 1N hydrochloric acid solution was added and extracted with ethyl acetate. Washed with saturated sodium chloride and dried over anhydrous magnesium sulfate, and the filtrate was distilled under reduced pressure. Separation by column chromatography gave 20 mg (7%) of the title compound.

Example  66: [4- (5- Chloro -7- Cyclopentylamino -1H-indol-2-yl)- Phenyl ]-Synthesis of Methanol

760 mg (2.06 mmol) of the compound obtained in Example 64 were dissolved in 30 ml of tetrahydrofuran, and a tetrahydrofuran solution (2.06 ml, 4.12 mmol) of 2M-lithium borohydride was added. After stirring at 80 ° C. for 3 hours, saturated ammonium chloride solution was added and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered and the filtrate was distilled under reduced pressure. Purification by column chromatography gave 60 mg (9%) of the title compound.

Example  67: 4- (7- Cyclopentylamino -5- methyl -1H-indol-2-yl) -benzoic acid Methyl ester  synthesis

In the method of Preparation Example 57 and Example 64, 2-iodo-4-methyl-6-nitro-phenylamine (500 mg, 1.80 mmol) was substituted for 2-iodo-4-chloro-6-nitro-phenylamine. 30 mg (3% yield) of the title compound were obtained.

Manufacturing example  58: 2- (5- Chloro -7-nitro-1H-indol-2-yl) -benzoic acid Methyl ester  synthesis

In the method of Preparation Example 57, 1.8 g (yield 15%) of the title compound was obtained using 2-ethynyl-benzoic acid methyl ester (6.0 g 37.42 mmol) instead of 4-ethynyl-benzoic acid methyl ester.

Example  68: 2- (5- Chloro -7- Cyclopentylamino -1H-indol-2-yl) -benzoic acid methyl  Synthesis of esters

In the method of Example 46, 1.80 g (5.44 mmol) of the compound obtained in Preparation 58 was obtained instead of 5-methyl-7-nitro-2-phenyl-1H-indole, to obtain 800 mg (yield 40%) of the title compound.

Example 69 Synthesis of 2- (5-Chloro-7-cyclopentylamino-1 H-indol-2-yl) -benzoic acid

By the method of Example 65, 120 mg (yield 42%) of the title compound were obtained using 300 mg (0.81 mmol) of the compound obtained in Example 68.

Example 70 Synthesis of [2- (5-Chloro-7-cyclopentylamino-1 H-indol-2-yl) -phenyl] -methanol

By the method of Example 66, 150 mg (yield 54%) of the title compound were obtained using 300 mg (0.81 mmol) of the compound obtained in Example 68.

Preparation Example 59 Synthesis of 7-nitro-2-phenyl-1H-indole-5-carboxylic acid ethyl ester

In the method of Preparation Example 19, 1.6 g (yield 58%) of the title compound was obtained by using 4-amino-3-nitro-benzoic acid ethyl ester (3.0 g, 8.9 mmol) instead of 4-methyl-2-nitroaniline.

Example 71: Synthesis of 7-cyclopentylamino-2-phenyl-1H-indole-5-carboxylic acid ethyl ester

In the method of Example 46, 100 mg (yield 15%) of the title compound were obtained using 600 mg (1.9 mmol) of the compound obtained in Preparation Example 59 instead of 5-methyl-7-nitro-2-phenyl-1H-indole.

Example 72: Synthesis of 7-cyclopentylamino-2-phenyl-1H-indole-5-carboxylic acid

In the method of Example 65, 350 mg (1.0 mmol) of the compound obtained in Example 71 were used to obtain 300 mg (yield 94%) of the title compound.

Example  73: (7- Cyclopentylamino -2- Phenyl Synthesis of -1H-indol-5-yl) -methanol

In the method of Example 66, 21 mg (yield 40%) of the title compound were obtained using 60 mg (0.17 mmol) of the compound obtained in Example 71.

Manufacturing example  60: (7-nitro-2- Phenyl -1H-indol-5-yl) -acetic acid Ethyl ester  synthesis

In the method of Preparation Example 19, 3.0 g (yield 68%) of the title compound using (4-amino-3-nitro-phenyl) acetate ethyl ester (4.8 g, 13.7 mmol) instead of 4-methyl-2-nitroaniline. Got.

Example  74: (7- Cyclopentylamino -2- Phenyl -1H-indol-5-yl) -acetic acid Ethyl ester  synthesis

By the method of Example 46, 3.0 g (9.2 mmol) of the compound obtained in Preparation Example 60 were obtained instead of 5-methyl-7-nitro-2-phenyl-1H-indole to obtain 2.0 g (yield 60%) of the title compound. .

Example  75: (7- Cyclopentylamino -2- Phenyl Synthesis of -1H-indol-5-yl) -acetic acid

In the method of Example 65, 65 mg (yield 78%) of the title compound were obtained using the compound (90 mg, 0.25 mmol) obtained in Example 74.

Example  76: 2- (7- Cyclopentylamino -2- Phenyl Synthesis of -1H-indol-5-yl) -ethanol

In the method of Example 66, 40 mg (yield 89%) of the title compound were obtained using the compound (50 mg, 0.14 mmol) obtained in Example 74.

Example  77 to 90

Using the nitro indole compounds synthesized in Preparation Examples 5, 7, and 10, the compounds obtained in Preparation Examples 23 and 25, and commercially available ketone compounds, the methods of Preparation Examples 34, 35, 36 and Example 11 were sequentially used. The following example compounds were obtained.

Example  91 to 101:

Using the ester obtained in the middle of synthesizing Examples 21, 77, 79, 89, 78, it was reduced as in Example 4 and reacted as in Preparation Example 37 and Example 15 to obtain the following Example compounds.

Manufacturing example  61: [(S) -2- (5- methyl -7-nitro-1H-indol-2-yl) -4,5- Dihydro - Oxazole 4-yl] -synthesis of isopropyl acetate

(Step 1)

The 5-methyl-7-nitro-1H-indole-2-carboxylic acid methyl ester obtained in Preparation Example 7 was hydrolyzed in the same manner as in Step 1 of Preparation Example 28 using LiOH and Preparation Example 28 to 5-methyl- 7-nitro-1H-indole-2-carboxylic acid was obtained.

(Step 2)

(S) -3-T-butoxycarbonylamino-4-hydroxybutyric acid-isopropyl ester used in Preparation Example 25 was deprotected in the same manner as in Step 3 of Preparation Example (S) -3- Amino-4-hydroxy-butyric acid isopropyl ester was obtained.

(Step 3)

The compounds obtained in Steps 1 and 2 were reacted as in Step 2 of Preparation Example 28 to obtain (S) -4-hydroxy-3-[(5-methyl-7-nitro-1H-indole-2-carbonyl) -amino ] -Butyric acid isopropyl ester was obtained.

(Step 4)

The compound obtained in Step 3 and methanesulfonyl chloride were reacted in the same manner as in Production Example 33 to give (S) -4-methanesulfonyloxy-3-[(5-methyl-7-nitro-1H-indole-2- Carbonyl) -amino] -butyric acid isopropyl ester.

(Step 5)

Compound (890 mg, 2 mmol) obtained in step 4 was added to THF (10 mL) and K ₂ CO ₃ (330 mg, 10 mmol) was added and stirred at 80 degrees for 2 hours. Water was added to terminate the reaction, the organics were extracted with EtOAc, dried over MgSO ₄ and the solvent was removed under reduced pressure. The residue was purified by column chromatography (eluent: EtOAc / n-Hex / DMC = 1/4/1) to give the title compound (445 mg, 61% yield).

Example  102: [(S) -2- (7- Cyclopentylamino -5- methyl -1H-indol-2-yl) -4,5- Dihydro - Oxazole 4-yl] -synthesis of acetic acid

Step 3 of Preparation Example 31, Preparation Example 36 and Preparation Example 28 in Step 1 of the compound obtained in Preparation Example 61 and cyclopentanone were continuously performed to obtain the title compound.

Example 103: {(S) -2- [5-methyl-7- (tetrahydropyran-4-ylamino) -1H-indol-2-yl] -4,5-dihydro-oxazole-4- Synthesis of Il-Acetic Acid

The title compound was obtained in Example 102 using tetrahydropyran-4-one instead of cyclopentanone.

Example  104: 2-{(S) -2- [5- methyl -7- ( Tetrahydropyran -4- Amino ) -1H-indol-2-yl] -4,5- Dihydro Synthesis of -oxazol-4-yl} -ethanol

The compound obtained in Example 103 was reduced in the same manner as in Example 66 to obtain the title compound.

Example  105: {5- methyl -2-[(S) -4- (2- Morpholine -4-yl-ethyl) -4,5- Dihydro - Oxazole -2-yl] -1 H-indol-7-yl}-(te Trahidro -Pyran-4-yl) Amine  synthesis

The compound obtained in Example 104 and the morpholine were sequentially reacted in the same manner as in Preparation Example 33 and Example 15 to obtain the title compound.

Example  106 to 125:

The following Example compounds were obtained by reacting in the same manner as in Preparation Example 19, Preparation Example 35, and Step 3 and Preparation Example 36.

Preparation 62: Synthesis of 5- (1,1-dioxo-thiomorpholin-4-ylmethyl) -2-phenyl-1H-indol-7-ylamine

(Step 1)

7-nitro-2-phenyl-1H-indole-5-carboxylic acid ethyl ester obtained in Preparation Example 59 was reacted according to Preparation Example 66 (7-nitro-2-phenyl-1H-indol-5-yl)- Methanol was obtained.

(Step 2)

The compound obtained in Step 1, iodine, and 1,1-dioxo-thiomorpholine were sequentially reacted according to Preparation Examples 37 and 15 to 5- (1,1-dioxo-thiomorpholin-4-ylmethyl ) -7-nitro-2-phenyl-1H-indole was obtained.

(Step 3)

The compound obtained in Step 2 and iron were reacted according to Step 3 of Preparation Example 35 to obtain the title compound.

Example  126: [5- (1,1- Dioxo - Thiomorpholine -4- Yl methyl )-2- Phenyl -1H-indole-7-yl]-( Tetrahydropyran Yl) - Amine  synthesis

The compound obtained in Preparation Example 62 and tetrahydropyran-4-one were reacted according to Preparation Example 36 to obtain the title compound.

Example  127 to 138:

The indole compound synthesized in the same manner as in Preparation Example 59 and the commercially available amine and carbonyl compound were sequentially reacted in the same manner as in Preparation Examples 62 and 126 to obtain the Example Compounds in the Table below.

Manufacturing example  63: 3- Bromo -5- (1,1- Dioxo - Thiomorpholine Yl) methyl -7-nitro-2- Phenyl -1H- Indole  synthesis

(Step 1)

5-methyl-7-nitro-2-phenyl-1H-indole and (BOC) ₂ O obtained in the preparation of Example 46 were reacted according to Preparation Example 23 to thereby prepare 1-BOC-5-methyl-7-nitro-2. -Phenyl-indole was obtained.

(Step 2)

1-BOC-5-methyl-7-nitro-2-phenyl-indole (3.5 g, 10 mmol) obtained in step 1 was dissolved in carbon tetrachloride (30 mL), and then N-bromosuccinimide (NBS, 2.3 g, 13 mmol) and benzoyl peroxide (100 mg) were added thereto, followed by stirring at reflux for 4 hours at 80 ° C. The solid was removed by filtration, water was added, and the organics were extracted with DCM. The solvent was removed under reduced pressure and then purified by column chromatography to give 1-BOC-3-bromo-5-bromomethyl-7-nitro-2-phenyl-indole (2.3 g, 46%).

(Step 3)

1-BOC-3-bromo-5-bromomethyl-7-nitro-2-phenyl-indole (1.0 g, 2 mmol) obtained in step 2 was dissolved in DCM (10 mL), and Et ₃ N (560 uL, 4 mmol) was added and 1,1-dioxo-thio-morpholine (300 mg, 3 mmol) was added, followed by stirring at room temperature for 12 hours. After the reaction was terminated, saturated NH ₄ Cl aqueous solution was added thereto, and the organics were extracted with DCM. After drying, the solvent was removed under reduced pressure and purified by column chromatography to give 1-BOC-3-bromo-5- (1,1-dioxo-thiomorpholin-4-yl) methyl-7-nitro-2-phenyl -1H-indole (825 mg, 78%) was obtained.

(Step 4)

1-BOC-3-bromo-5- (1,1-dioxo-thiomorpholin-4-yl) methyl-7-nitro-2-phenyl-1H-indole (825 mg, 1.6 mmol) obtained in step 3 ) Was dissolved in diethyl ether (5 mL), dissolved in HCl (4M dioxane solution, 5 mL), and stirred at room temperature for 2 hours. At the end of the reaction, the solvent was removed under reduced pressure and dried to afford 3-bromo-5- (1,1-dioxo-thiomorpholin-4-yl) methyl-7-nitro-2-phenyl-1H-indole And used for the next reaction without further purification.

Manufacturing example  64: 4-[(3- Bromo -7-nitro-2- Phenyl -1H-indole-5-day) methyl ] - Morpholine  synthesis

1-BOC-3-bromo-5-bromomethyl-7-nitro-2-phenyl-indole and morpholine obtained in Step 2 of Preparation Example 63 were reacted according to Steps 3 and 4 of Preparation Example 63 to obtain the title compound. Got.

Example  139: [3- Bromo -5- (1,1- Dioxo - Thiomorpholine -4- Yl methyl )-2- Phenyl -1H-indole-7-yl]-( Tetrahydropyran Yl) - Amine  synthesis

The compound obtained in Preparation Example 63 and tetrahydropyran-4-one were reacted according to Step 3 of Preparation Example 35 and Preparation Example 36 to obtain the title compound.

Example 140: Synthesis of [3-bromo- (5-morpholin-4-yl) methyl-2-phenyl-1H-indol-7-yl]-(tetrahydropyran-4-yl) -amine

The compound obtained in Preparation Example 64 and tetrahydropyran-4-one were reacted according to Step 3 of Preparation Example 35 and Preparation Example 36 to obtain the title compound.

Example 141: Synthesis of [3-bromo-5- (1,1-dioxo-thiomorpholin-4-ylmethyl) -2-phenyl-1H-indol-7-yl] -cyclopentyl-amine

The compound obtained in Preparation Example 63 and cyclopentanone were reacted according to Step 3 of Preparation Example 35 and Preparation Example 36 to obtain the title compound.

Example 142: [3-bromo-5- (1,1-dioxo-thiomorpholin-4-ylmethyl) -2-phenyl-1H-indol-7-yl]-(tetrahydro-pyran-4 Synthesis of -ylmethyl) -amine

The compound obtained in Preparation Example 63 and tetrahydropyran-4-carboxyaldehyde were reacted according to Step 3 of Preparation Example 35 and Preparation Example 36 to obtain the title compound.

Preparation 65: Synthesis of 5-chloro-3-phenyl-7-nitro-1H-indole

(Step 1)

Commercially available 4-chloro-2-nitro-phenylamine (17.4 g, 131.5 mmol) was dissolved in ethanol (300 mL), silver nitrate (27 g, 157.7 mmol) and iodine (40 g, 157.7 mmol) Put and stirred for 8 hours at room temperature. After completion of the reaction, the mixture was filtered through celite, washed with 100 mL of ethyl acetate and concentrated. Water was added and extracted with ethyl acetate. Washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate to give 2-amino-5-chloro-3-nitro-phenyliodide (27.4 g, 69% yield).

(Step 2)

2-amino-5-chloro-3-nitro-phenyliodide (1.5 g, 4.90 mmol) and 1-phenyl-2-trimethylsilylacetylene (4.3 g, 24.50 mmol) obtained in step 1 were added with DMF (50 mL). 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 thereto, and the mixture was heated and stirred at 100 ° C. for 3 hours. After completion of the reaction, water was added, 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 5-chloro-7-nitro-3-phenyl-2-trimethylsilyl-1H-indole (1.05 g, 87% yield).

(Step 3)

5-Chloro-7-nitro-3-phenyl-2-trimethylsilyl-1H-indole (1.5 g, 4.35 mmol) obtained in step 2 was dissolved in tetrahydrofuran (30 mL) and a 1M solution of tetrabutylammonium fluoride (5.2) mL, 5.2 mmol) was added dropwise at 0 ° C. After completion of the reaction, 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 separated by column chromatography to give 5-chloro-3-phenyl-7-nitro-1H-indole (1.2 g, yield 100%).

Example  143: (5- Chloro -3- Phenyl -1H-indole-7-yl)-( Tetrahydro -Pyran-4-yl)- Amine  synthesis

5-chloro-3-phenyl-7-nitro-1H-indole and tetrahydropyran-4-one obtained in Preparation Example 65 were reacted according to Preparation 3 and Preparation Example 36 of Preparation Example 35 to obtain the title compound.

Example  144: (5- Chloro -3- Phenyl -1H-indole-7-yl)-( Cyclopentyl ) - Amine  synthesis

Using the 5-chloro-3-phenyl-7-nitro-1H-indole and cyclopentanone obtained in Preparation Example 65 was carried out in the same manner as in Process 3 of Preparation Example 35 and Preparation Example 36 to obtain the title compound.

Example  145: (5- Chloro -3- Phenyl -1H-indole-7-yl)-( Tetrahydropyran -4- Yl methyl ) - Amine  synthesis

5-Chloro-3-phenyl-7-nitro-1H-indole and tetrahydropyran-4-carboxyaldehyde obtained in Preparation Example 65 were reacted according to Preparation 3 and Preparation 36 of Preparation Example 35 to obtain the title compound.

Example 146: [5- (1,1-Dioxo-thiomorpholin-4-ylmethyl) -3-phenyl-2-trimethylsilanyl-1H-indol-7-yl]-(tetrahydropyran-4 Synthesis of -yl) -amine

(Step 1)

4-Amino-3-nitro-benzoic acid ethyl ester and trimethyl-phenylethynyl-silane were reacted in the same manner as in Preparation Example 7 to 7-nitro-3-phenyl-2-trimethylsilanyl-1H-indole-5-car The ethyl acid ester was obtained.

(Step 2)

The compound obtained in Step 1, 1,1-dioxo-thiomorpholine and tetrahydropyran-4-one were reacted sequentially according to Preparation Examples 62 and 36 to obtain the title compound.

Preparation Example 66 Synthesis of 5-chloro-7-nitro-3- (2-oxo-piperazin-4-yl) methyl-2-phenyl-1H-indole

(Step 1)

7-nitro-5-chloro-2-phenyl-1H-indole (1.0 g, 3.67 mmol) obtained in the process of obtaining the compound of Example 59 was dissolved in dichloromethane (20 mL) and phosphoryloxychloride (at 0 ° C) 0.84 g, 5.50 mmol) and DMF (0.80 g, 11.01 mmol) were added dropwise, followed by stirring at room temperature for 6 hours. After completion of the reaction, the reaction was terminated with saturated aqueous sodium hydrogen carbonate solution and the organics were 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 5-chloro-3-formyl-7-nitro-2-phenyl-1H-indole (0.5 g, 45% yield).

(Step 2)

5-chloro-3-formyl-7-nitro-2-phenyl-1H-indole (0.5 g, 1.66 mmol) obtained in step 1 was dissolved in dichloroethane (20 mL), and acetic acid (0.10 g, 1.66 mmol), 2- Oxopiperazine (0.3 g, 3.32 mmol) and sodium triacetoxyborohydride (0.71 g, 3.32 mmol) were added dropwise and stirred at room temperature for 4 hours. After completion of the reaction, the reaction was diluted with water and 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 5-chloro-7-nitro-3- (2-oxo-piperazin-4-yl) methyl-2-phenyl-1H-indole (0.55 g, Yield 86%).

Example 147: Synthesis of 4- (5-chloro-7-cyclopentylamino-2-phenyl-1H-indol-3-ylmethyl) -piperazin-2-one

The compound obtained in Preparation Example 66 and cyclopentanone were reacted according to Step 3 of Preparation Example 35 and Preparation Example 36 to obtain the title compound.

Example 148: Synthesis of 4- [5-chloro-2-phenyl-7- (tetrahydropyran-4-ylamino) -1H-indol-3-ylmethyl] -piperazin-2-one

The compound obtained in Preparation Example 66 and tetrahydropyran-4-one were reacted according to Step 3 of Preparation Example 35 and Preparation Example 36 to obtain the title compound.

Example 149: Synthesis of 4- {5-chloro-2-phenyl-7-[(tetrahydropyran-4-ylmethyl) -amino] -1H-indol-3-ylmethyl} -piperazin-2-one

The compound obtained in Preparation Example 66 and tetrahydropyran-4-carboxyaldehyde were reacted according to Step 3 of Preparation Example 35 and Preparation Example 36 to obtain the title compound.

Preparation 67: Synthesis of 3- (4-methoxy-phenyl-1-yl) -7-nitro-1H-indazole

(Step 1)

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, the mixture was diluted with 10% aqueous sodium bisulfite solution. The resulting solids were collected and dried to give 3-iodo-7-nitro-1H-indazole (2.50 g, yield 88%).

(Step 2)

3-iodo-7-nitro-1H-indazole (2.50 g, 8.65 mmol) obtained in step 1 was dissolved in acetone (50 mL), followed by potassium hydroxide (0.73 g, 12.97 mmol) and 4-methoxybenzylchloride. (1.63 g, 10.38 mmol) was added dropwise at 0 ° C. and stirred for 2 hours. After completion of the reaction, the reaction was diluted with water and the organics 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 3-iodo-7-nitro-1- (4-methoxybenzyl) -1H-indazole (3.2 g, 91% yield).

(Step 3)

3-iodo-7-nitro-1- (4-methoxybenzyl) -1H-indazole (1.50 g, 3.67 mmol) obtained in step 2 was dissolved in dimethoxyethane (20 mL) and 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 stirred under reflux for 2 hours. After cooling the solution, the reaction was diluted with water and the organics 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 taken up in trifluoroacetic acid (20 mL) and stirred at reflux for 5 hours, then the solvent was removed under reduced pressure. The residue was diluted with water and the organics 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 3- (4-methoxy-phenyl-1-yl) -7-nitro-1H-indazole (0.85 g, yield 86%).

Example  150: Cyclopentyl - [3- (4- Methoxyphenyl ) -1H- Indazole -7 days]- Amine  synthesis

The compound obtained in Preparation Example 67 and cyclopentanone were reacted according to Step 3 of Preparation Example 35 and Preparation Example 36 to obtain the title compound.

Example  151: [3- (4- Methoxyphenyl ) -1H- Indazole -7 days]-( Tetrahydropyran Yl) - Amine  synthesis

The compound obtained in Preparation Example 67 and tetrahydropyran-4-one were reacted according to Step 3 of Preparation Example 35 and Preparation Example 36 to obtain the title compound.

Example  152: [3- (4- Methoxyphenyl ) -1H- Indazole -7 days]-( Tetrahydropyran -4- Yl methyl ) - Amine  synthesis

The compound obtained in Preparation Example 67 and tetrahydropyran-4-carboxyaldehyde were reacted according to Step 3 of Preparation Example 35 and Preparation Example 36 to obtain the title compound.

Hereinafter, the effect to be provided by the present invention will be described through the following experimental example. However, the effects of the present invention are not limited only by the following experimental examples.

Experimental Example 1 Confirmation of Inhibition of Cancer Metastasis

Cancer cells 1X10 ⁵ , 2X10 ⁵ Determine each experimental group and control group to be administered at the concentration of cells / ml, and prepare 5 8-12 week old B6 background male mice (central laboratory animals) for each group. The cancer cells are B16 melanoma cells (donated by the Department of Dermatology, Seoul National University College of Medicine), which are mouse metastatic skin cancer cells, and injected 200 μl into the tail vein of the mouse at concentrations of 1 × ^{10 5} and 2 × 10 ⁵ cells / ml, respectively. 5-[(1,1-dioxo-thiomorpholin-4-ylmethyl) -2-phenyl-1H-indol-7-yl]-(tetrahydropyran-4-ylmethyl) -amine 'for 3 weeks It was administered orally to the experimental group twice a week in the amount of 25mg / Kg (dose by weight of the subject), and the control group was administered only saline.

Three weeks after the cell transplantation, the mice were autopsied, and lungs from which cancer cells had metastasized were removed. The result is shown in FIG. The statistical significance of the experiment was tested by STUDENT TEST (p <0.05), which showed a significant decrease compared to the control.

The experimental results confirmed the function of the indole and indazole compounds of the present invention as Lung metastasis inhibitor of melanoma.

The present invention relates to a composition for inhibiting cancer metastasis comprising indole and indazole derivatives or isomers thereof as an active ingredient, and more particularly, a pharmaceutical for inhibiting cancer metastasis comprising indole and indazole compounds or optical isomers as an active ingredient. To provide a composition. The present invention has been found to be effective in inhibiting cancer metastasis of the compound, and thus is effective in suppressing cancer metastasis to increase the efficiency of cancer treatment, and thus has high industrial applicability.

Claims (18)

A pharmaceutical composition for inhibiting cancer metastasis comprising the compound of Formula 1 below or an optical isomer thereof as an active ingredient.
[Formula 1]

According to claim 1, wherein the cancer is small bowel cancer, rectal cancer, anal cancer, esophageal cancer, lymph gland cancer, thyroid cancer, skin cancer, ovarian cancer, gallbladder cancer, liver cancer, colon cancer, gastric cancer, prostate cancer, breast cancer, kidney cancer, brain tumor, lung cancer, The composition, characterized in that any one selected from the group consisting of uterine cancer, colon cancer, bladder cancer, hematologic cancer and pancreatic cancer.
According to claim 1, In the compound of [Formula 1],
X represents C or N,
n is 0 or 1, n is 1 when X is C, n is 0 when X is N,
A represents a direct bond, represents C ₃ -C ₈ -cycloalkyl, represents phenyl, or a 5-6 membered heteroaryl containing 1 to 3 heteroatoms each selected from N, O and S atoms or Represents a heterocycle,
R1 represents hydrogen, -C (O) -BX-R7 or-(CR5R6) _m -BX-R7,
m is from 0 to 4,
R 5 and R 6 each independently represent hydrogen or C ₁ -C ₅ -alkyl,
B represents a direct bond, optionally represents C ₃ -C ₈ -cycloalkyl comprising oxo, or a 3 to 10 membered heterocycle including 1 to 3 heteroatoms each selected from O, S and N atoms or Heteroaryl,
X represents a direct bond or -C (O)-, -SO _2- , -CO ₂ -or -C (O) NR5-,
R7 represents hydrogen, C ₁ -C ₆ -alkyl, halogeno-C ₁ -C ₆ -alkyl, halogen, (CR ₅ R ₆ ) _m -phenyl, (CR 5 R 6) _m -hydroxy or (CR 5 R 6) _m -heterocycle, Wherein the heterocycle is a 3-10 membered ring optionally containing oxo and containing 1 to 3 heteroatoms selected from N, O and S atoms,
R2 represents-(CR5R6) _m -DX-R8,
D represents a direct bond or a 3-10 membered heterocycle or heteroaryl, each optionally including oxo and optionally fused and containing 1-4 heteroatoms selected from N, O and S atoms,
X represents a direct bond or -C (O)-, -C (O) O-, -NR5C (O)-, -C (O) NR5- or -O-,
R8 represents hydrogen, halogen, C ₁ -C ₆ -alkyl, halogeno-C ₁ -C ₆ -alkyl, tri (C ₁ -C ₆ -alkyl) silane or hydroxy-C ₁ -C ₆ -alkyl,
R3 represents hydrogen, halogen, cyano, nitro, aryl-R9 or (CR5R6) _m -D-R9,
R9 represents hydrogen, halogen, C ₁ -C ₆ -alkyl, cyano, nitro or C ₁ -C ₆ -alkoxy,
R4 represents-(CR5R6) _m -YD-R10,
Y represents a direct bond, -C (O) O- or -O-,
R 10 represents hydrogen, nitro, halogen, C ₁ -C ₆ -alkyl, carboxy-C ₁ -C ₆ -alkyl, aryl or —C (O) O—R 5,
In the above, alkyl, alkoxy, aryl, cycloalkyl, heterocycle and heteroaryl may be optionally substituted, and the substituents are hydroxy, halogen, nitrile, amino, C ₁ -C ₆ -alkylamino, di (C ₁ -C _In the group consisting of ₆ -alkyl) amino, C ₁ -C ₆ -alkyl, halogeno-C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkylsulfonyl, aryl-C ₁ -C ₆ -alkoxy and oxo A composition representing one or more selected.
According to claim 1, In the compound of [Formula 1],
X represents C or N,
n is 0 or 1, n is 1 when X is C, n is 0 when X is N,
A represents a direct bond, represents phenyl, or represents a 5-6 membered heteroaryl or heterocycle comprising 1 to 3 heteroatoms each selected from N, O and S atoms,
R1 represents hydrogen, -C (O) -BX-R7 or-(CR5R6) _m -BX-R7,
m is 0 to 2,
R 5 and R 6 each independently represent hydrogen or C ₁ -C ₅ -alkyl,
B represents a direct bond, optionally represents C ₄ -C ₇ -cycloalkyl comprising oxo, or a 4-8 membered heterocycle comprising 1 to 3 heteroatoms each selected from O, S and N atoms or Heteroaryl,
X represents a direct bond, or -C (O)-, -SO _2- , -CO ₂ -or -C (O) NH-,
R7 represents hydrogen, C ₁ -C ₆ -alkyl, halogeno-C ₁ -C ₆ -alkyl, halogen, (CR ₅ R ₆ ) _m -phenyl, (CR 5 R 6) _m -hydroxy, (CR 5 R 6) _m -heterocycle, Wherein the heterocycle is a 4-8 membered ring optionally containing oxo and containing 1 to 3 heteroatoms selected from N, O and S atoms,
R2 represents-(CR5R6) _m -DX-R8,
D represents a direct bond or a 4-8 membered heterocycle or heteroaryl, each optionally including oxo and optionally fused and containing 1-4 heteroatoms selected from N, O and S atoms,
X represents -C (O)-, -C (O) O-, -NR5C (O)-, -C (O) NR5- or -O-,
R8 represents hydrogen, halogen, C ₁ -C ₆ -alkyl, halogeno-C ₁ -C ₆ -alkyl, tri (C ₁ -C ₆ -alkyl) silane or hydroxy-C ₁ -C ₆ -alkyl,
R3 represents hydrogen, halogen, cyano, nitro, aryl-R9 or (CR5R6) _m -D-R9,
R9 represents hydrogen, halogen, C ₁ -C ₆ -alkyl, cyano, nitro or C ₁ -C ₆ -alkoxy,
R4 represents-(CR5R6) _m -YD-R10,
Y represents a direct bond, -C (O) O- or -O-,
R 10 represents hydrogen, nitro, halogen, C ₁ -C ₆ -alkyl, carboxy-C ₁ -C ₆ -alkyl, aryl or —C (O) O—R 5.
The composition of claim 4, wherein the compound of formula (1) has an indole or indazole structure of the formula [Formula 2] or [Formula 3]:
(2)

(3)

The compound of claim 2, wherein in the compound of Formula 2, A is phenyl, pyridine, 1,4-pyrazine, 4,5-dihydro-thiazole, thiazole, 4,5-dihydrooxazole, 1 A composition selected from the group consisting of 2,4-oxadiazole and 1,3,4-oxadiazole.
A compound according to claim 4, wherein in the compound of [Formula 2] or [Formula 1b], R 1 represents -C (O) -BX-R 7 or-(CHR 5) _m -BX-R 7, wherein m is 0 to Number of 2, R 5 represents C ₁ -C ₃ -alkyl, B represents a direct bond, optionally represents C ₅ -C ₆ -cycloalkyl comprising oxo, or each of O, S and N atoms 5-6 membered heterocycle or heteroaryl containing 1 to 3 heteroatoms selected, X represents a direct bond, or -C (O)-, -SO _2- , -CO ₂ -or -C ( O) NH-, R7 is hydrogen, C ₁ -C ₃ -alkyl, halogeno-C ₁ -C ₃ -alkyl, halogen, (CH ₂ ) _m -phenyl, (CH ₂ ) _m -hydroxy, ( CH ₂ ) _m -heterocycle, wherein the heterocycle is a 5-6 membered ring optionally comprising oxo and containing 1 to 3 heteroatoms selected from N, O and S atoms.
8. The composition of claim 7, wherein said B is selected from the group consisting of cyclopentyl, cyclohexyl, piperidine, tetrahydropyran, oxocyclohexyl, pyrrolidine, difluorocyclohexyl and tetrahydrofuran. 8. A compound according to claim 7, wherein R7 is hydrogen, methyl, ethyl, isopropyl, benzyl, hydroxymethyl, (morpholin-4-yl) -ethyl, tetrahydrofuran, 2,2,2-trifluoroethyl, Composition selected from the group consisting of hydroxyethyl, 1,1-dioxothiomorpholine, tetrahydropyran, (tetrahydropyran-4-yl) -methyl and trifluoromethyl.
The composition of claim 4, wherein D represents a direct bond or is selected from the group consisting of piperazine, pyrrolidine, morpholine, 1,1-dioxothiomorpholine, and oxopiperazine.
The composition of claim 4, wherein R 8 is selected from the group consisting of hydrogen, ethyl, hydroxymethyl, methyl and fluorine.
5. The compound of claim 4, wherein R 3 represents hydrogen or halogen, represents phenyl optionally substituted by alkoxy, or contains 1 to 3 heteroatoms selected from N, S and O atoms as ring members and optionally oxo. A composition representing a 6 membered heterocyclylmethyl comprising. 13. The compound of claim 12, wherein R3 is hydrogen, bromine, phenyl, methoxy-phenyl, morpholin-4-yl-methyl, oxopiperazin-4-yl-methyl, 1,1-dioxo-thiomorpholine- A composition selected from the group consisting of 4-yl-methyl.
The compound of claim 4, wherein R 4 represents-(CH ₂ ) _m -YD-R 10, wherein m is 0 to 2 and Y represents a direct bond or -C (O) O- or -O- D represents pyridine or optionally 5-6 membered heterocycle comprising oxo and containing 1 to 3 heteroatoms selected from N, S and O atoms, R10 is hydrogen, halogen, C ₁ -C ₃ A composition representing -alkyl,-(CH ₂ ) -CO ₂ H, aryl or -C (O) O-R5.
15. The composition of claim 14, wherein D is selected from the group consisting of 1,1-dioxo-thio-morpholine, oxopiperazine, pyridine, morpholine and 4,5-dihydro-thiazole.
The composition of claim 14, wherein R 10 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl, ethyl and — (CH ₂ ) —CO ₂ H.
The method of claim 4, wherein the compound of [Formula 1]
Cyclopentyl- [2- (4,5-dihydro-1,3-thiazol-2-yl) -1H-indol-7-yl] -amine;
[2- (4,5-Dihydro-thiazol-2-yl) -1H-indol-7-yl]-(4-methyl-cyclohexyl) -amine;
[2- (4,5-Dihydro-thiazol-2-yl) -1H-indol-7-yl] -piperidin-4-yl-amine;
2-5- [7- (tetrahydro-pyran-4-ylamino) -1H-indol-2-yl]-[1,2,4] oxadiazol-3-yl} -ethanol;
[(R) -2- (7-cyclopentylamino-1 H-indol-2-yl) -4,5-dihydro-1,3-thiazol-4-yl] -methanol;
Cyclopentyl- [2-((R) -4-pyrrolidin-1-ylmethyl-4,5-dihydro-thiazol-2-yl) -1H-indol-7-yl] -amine;
{(R) -2- [7- (tetrahydro-pyran-4-ylamino) -1H-indol-2-yl] -4,5-dihydro-thiazol-4-yl} -methanol;
[(R) -2- (7-cyclopentylamino-5-fluoro-1 H-indol-2-yl) -4,5-dihydro-thiazol-4-yl] -methanol;
{(R) -2- [5-fluoro-7- (tetrahydro-pyran-4-ylamino) -1H-indol-2-yl] -4,5-dihydro-thiazol-4-yl} Methanol;
{(R) -2- [5- (pyridin-3-yloxy) -7- (tetrahydro-pyran-4-ylamino) -1H-indol-2-yl] -4,5-dihydro-thia Zol-4-yl} -methanol;
[(R) -2- (5-Chloro-7-cyclopentylamino-1 H-indol-2-yl) -4,5-dihydro-thiazol-4-yl] -acetic acid;
[(R) -2- (5-Chloro-7-cyclopentylamino-1 H-indol-2-yl) -4,5-dihydro-thiazol-4-yl] -acetic acid ethyl ester;
2-{(R) -2- [5-chloro-7- (tetrahydro-pyran-4-ylamino) -1H-indol-2-yl] -4,5-dihydro-thiazol-4-yl }-ethanol;
1- [4- (2-{(R) -2- [5-chloro-7- (tetrahydro-pyran-4-ylamino) -1H-indol-2-yl] -4,5-dihydro- Thiazol-4-yl} -ethyl) -piperazin-1-yl] -2-hydroxy-ethanone;
1- (2-{(R) -2- [5-Chloro-7- (tetrahydro-pyran-4-ylamino) -1H-indol-2-yl] -4,5-dihydro-thiazole- 4-yl} -ethyl) -pyrrolidin-3-ol;
[(R) -2- (5-Bromo-7-cyclopentylamino-1 H-indol-2-yl) -4,5-dihydro-thiazol-4-yl] -acetic acid;
[(R) -2- (7-cyclopentylamino-5-ethoxy-1H-indol-2-yl) -4,5-dihydro-thiazol-4-yl] -acetic acid;
[(R) -2- (7-cyclopentylamino-5-ethoxy-1H-indol-2-yl) -4,5-dihydro-thiazol-4-yl] -acetic acid;
[2- (7-cyclopentylamino-5-phenoxy-1H-indol-2-yl) -4,5-dihydro-thiazol-4-yl] -acetic acid;
[(R) -2- (7-cyclopentylamino-5-phenoxy-1H-indol-2-yl) -4,5-dihydro-thiazol-4-yl] -acetic acid;
[(S) -2- (7-cyclopentylamino-5-phenoxy-1H-indol-2-yl) -4,5-dihydro-thiazol-4-yl] -acetic acid;
3-[(R) -2- (5-chloro-7-cyclopentylamino-1 H-indol-2-yl) -4,5-dihydro-thiazol-4-yl] -propionic acid ethyl ester;
3-[(R) -2- (5-chloro-7-cyclopentylamino-1 H-indol-2-yl) -4,5-dihydro-thiazol-4-yl] -propionic acid;
Cyclopentyl- (2-pyridin-2-yl-1H-indol-7-yl) -amine;
Cyclopentyl- (2-pyrazin-2-yl-1H-indol-7-yl) amine;
(2-pyrazin-2-yl-1H-indol-7-yl)-(tetrahydropyran-4-yl) -amine;
Cyclopentyl- (2-thiazol-2-yl-1H-indol-7-yl) -amine;
2- (7-cyclopentylamino-5-methyl-1H-indol-2-yl) -thiazole-4-carboxylic acid ethyl ester;
2- (7-cyclopentylamino-5-methyl-1 H-indol-2-yl) -thiazole-4-carboxylic acid;
[2- (7-cyclopentylamino-5-methyl-1 H-indol-2-yl) -thiazol-4-yl] -methanol;
[2- (7-cyclopentylamino-5-methyl-1 H-indol-2-yl) -thiazol-5-yl] -methanol;
Cyclopentyl- (5-methyl-2- [1,3,4] oxadiazol-2-yl-1H-indol-7-yl) -amine;
Cyclopentyl- (5-methyl-2-pyridin-2-yl-1H-indol-7-yl) -amine;
(5-methyl-2-pyridin-2-yl-1H-indol-7-yl)-(tetrahydro-pyran-4-yl) -amine;
Cyclohexyl- (5-methyl-2-pyridin-2-yl-1H-indol-7-yl) -amine;
1- [4- (5-methyl-2-pyridin-2-yl-1H-indol-7-ylamino) -piperidin-1-yl] -ethanone;
(1-methyl-piperidin-4-yl)-(5-methyl-2-pyridin-2-yl-1H-indol-7-yl) -amine;
4- (5-methyl-2-pyridin-2-yl-1H-indol-7-ylamino) -cyclohexanone;
(1-benzyl-pyrrolidin-3-yl)-(5-methyl-2-pyridin-2-yl-1H-indol-7-yl) -amine;
Cyclopentylmethyl- (5-methyl-2-pyridin-2-yl-1H-indol-7-yl) -amine;
N- (5-methyl-2-pyridin-2-yl-1H-indol-7-yl) -benzamide;
Cyclopentyl- (5-methyl-2-pyrazin-2-yl-1H-indol-7-yl) -amine;
Cyclopentyl- (5-ethoxy-2-pyridin-2-yl-1H-indol-7-yl) -amine;
Cyclopentyl- (5-phenoxy-2-pyridin-2-yl-1H-indol-7-yl) -amine;
Cyclopentyl- (3,5-dimethyl-2-phenyl-1H-indol-7-yl) -amine;
Cyclopentyl- (5-methyl-2-phenyl-1H-indol-7-yl) -amine;
(2-cyclohexyl-5-methyl-1H-indol-7-yl) -cyclopentyl-amine;
Cyclopentyl- [5-methyl-2- (6-methyl-pyridin-2-yl) -1H-indol-7-yl] -amine;
(5-methyl-2-phenyl-1H-indol-7-yl)-(tetrahydro-pyran-4-yl) -amine;
(5-methyl-2-phenyl-1H-indol-7-yl)-(1-methyl-piperidin-4-yl) -amine;
1- [4- (5-methyl-2-phenyl-1H-indol-7-ylamino) -piperidin-1-yl] -ethanone;
(5-methyl-2-phenyl-1H-indol-7-yl) -piperidin-4-yl-amine hydrochloride;
2-hydroxy-1- [4- (5-methyl-2-phenyl-1H-indol-7-ylamino) -piperidin-1-yl] -ethanone;
(1-methanesulfonyl-piperidin-4-yl)-(5-methyl-2-phenyl-1H-indol-7-yl) -amine;
4- (5-Methyl-2-phenyl-1 H-indol-7-ylamino) -cyclohexanecarboxylic acid;
4- (5-Methyl-2-phenyl-1H-indol-7-ylamino) -cyclohexanecarboxylic acid (2-morpholin-4-yl-ethyl) -amide;
Cyclopentylmethyl- (5-methyl-2-phenyl-1H-indol-7-yl) -amine;
(5-methyl-2-phenyl-1H-indol-7-yl)-(tetrahydro-pyran-4-ylmethyl) -amine;
(5-chloro-2-phenyl-1 H-indol-7-yl) -cyclopentyl-amine;
(5-chloro-2-phenyl-1 H-indol-7-yl)-(tetrahydro-pyran-4-yl) -amine;
(5-chloro-2-phenyl-1H-indol-7-yl)-(1-methyl-piperidin-4-yl) -amine;
(5-chloro-2-phenyl-1 H-indol-7-yl) -cyclohexyl-amine;
(1-benzyl-pyrrolidin-3-yl)-(5-chloro-2-phenyl-1H-indol-7-yl) -amine;
4- (5-Chloro-7-cyclopentylamino-1 H-indol-2-yl) -benzoic acid methyl ester;
4- (5-Chloro-7-cyclopentylamino-1 H-indol-2-yl) -benzoic acid;
[4- (5-Chloro-7-cyclopentylamino-1 H-indol-2-yl) -phenyl] -methanol;
4- (7-cyclopentylamino-5-methyl-1 H-indol-2-yl) -benzoic acid methyl ester;
2- (5-Chloro-7-cyclopentylamino-1 H-indol-2-yl) -benzoic acid methyl ester;
2- (5-Chloro-7-cyclopentylamino-1 H-indol-2-yl) -benzoic acid;
[2- (5-Chloro-7-cyclopentylamino-1 H-indol-2-yl) -phenyl] -methanol;
7-cyclopentylamino-2-phenyl-1H-indole-5-carboxylic acid ethyl ester;
7-cyclopentylamino-2-phenyl-1H-indole-5-carboxylic acid;
(7-cyclopentylamino-2-phenyl-1 H-indol-5-yl) -methanol;
(7-cyclopentylamino-2-phenyl-1H-indol-5-yl) -acetic acid ethyl ester;
(7-cyclopentylamino-2-phenyl-1H-indol-5-yl) -acetic acid;
2-[(4S) -2- [5-methyl-7- (oxan-4-ylmethylamino) -1H-indol-2-yl] -4,5-dihydro-1,3-thiazole-4 -Yl] acetic acid;
2-[(4S) -2- [5-chloro-7- (oxan-4-ylmethylamino) -1H-indol-2-yl] -4,5-dihydro-1,3-thiazole-4 -Yl] acetic acid;
2-[(4S) -2- [7-[(4,4-difluorocyclohexyl) amino] -5-methyl-1H-indol-2-yl] -4,5-dihydro-1,3 -Thiazol-4-yl] acetic acid;
2-[(4S) -2- [7- (oxan-4-ylamino) -5-phenoxy-1H-indol-2-yl] -4,5-dihydro-1,3-thiazole-4 -Yl] acetic acid;
2-[(4R) -2- [7- (oxan-4-ylamino) -5-phenoxy-1H-indol-2-yl] -4,5-dihydro-1,3-thiazole-4 -Yl] acetic acid;
2-[(4R) -2- [7- (oxan-4-ylmethylamino) -5-phenoxy-1H-indol-2-yl] -4,5-dihydro-1,3-thiazole- 4-yl] acetic acid;
2-[(4S) -2- [7- (cyclopentylamino) -1H-indol-2-yl] -4,5-dihydro-1,3-thiazol-4-yl] acetic acid;
2-[(4S) -2- [7-[(1-acetylpyrrolidin-3-yl) amino] -5-methyl-1H-indol-2-yl] -4,5-dihydro-1, 3-thiazol-4-yl] acetic acid;
2-[(4S) -2- [7- (oxan-4-ylmethylamino) -1H-indol-2-yl] -4,5-dihydro-1,3-thiazol-4-yl] acetic acid ;
2-[(4S) -2- [7- (oxan-4-ylamino) -1H-indol-2-yl] -4,5-dihydro-1,3-thiazol-4-yl] acetic acid;
2-[(4S) -2- [7- (oxan-2-ylmethylamino) -1H-indol-2-yl] -4,5-dihydro-1,3-thiazol-4-yl] acetic acid ;
2-[(4S) -2- [5-methyl-7-[[1- (3,3,3-trifluoropropanoyl) piperidin-4-yl] amino] -1 H-indole-2 -Yl] -4,5-dihydro-1,3-thiazol-4-yl] acetic acid;
2-[(4R) -2- [7- (cyclopentylamino) -5-methyl-1H-indol-2-yl] -4,5-dihydro-1,3-thiazol-4-yl] acetic acid ;
2-[(4R) -2- [5-methyl-7- (oxan-4-ylmethylamino) -1H-indol-2-yl] -4,5-dihydro-1,3-thiazole-4 -Yl] acetic acid;
4- [2-[(4S) -2- [5-methyl-7- (oxan-4-ylmethylamino) -1H-indol-2-yl] -4,5-dihydro-1,3-thia Sol-4-yl] ethyl] piperazin-2-one;
2-[(4S) -4- [2- (1,1-dioxo-1,4-siazinan-4-yl) ethyl] -4,5-dihydro-1,3-thiazole-2- Il] -5-methyl-N- (oxan-4-ylmethyl) -1H-indol-7-yl-amine;
N- (4,4-difluorocyclohexyl) -5-methyl-2-[(4S) -4- (2-morpholin-4-ylethyl) -4,5-dihydro-1,3- Thiazol-2-yl] -1 H-indol-7-yl-amine;
4- [2-[(4S) -2- [7-[(4,4-difluorocyclohexyl) amino] -5-methyl-1H-indol-2-yl] -4,5-dihydro- 1,3-thiazol-4-yl] ethyl] piperazin-2-one;
4- [2-[(4S) -2- [7- (oxan-4-ylmethylamino) -5-phenoxy-1H-indol-2-yl] -4,5-dihydro-1,3- Thiazol-4-yl] ethyl] piperazin-2-one;
2-[(4S) -4- (2-morpholin-4-ylethyl) -4,5-dihydro-1,3-thiazol-2-yl] -N- (oxan-4-ylmethyl) -5-phenoxy-1H-indol-7-amine;
5-methyl-2-[(4S) -4- (2-morpholin-4-ylethyl) -4,5-dihydro-1,3-thiazol-2-yl] -N- (oxan-4 -Ylmethyl) -1H-indol-7-amine;
1- [2-[(4S) -2- [5-methyl-7- (oxan-4-ylmethylamino) -1H-indol-2-yl] -4,5-dihydro-1,3-thia Sol-4-yl] ethyl] piperidine-4-carboxyamide;
[(2R) -1- [2-[(4S) -2- [5-methyl-7- (oxan-4-ylmethylamino) -1H-indol-2-yl] -4,5-dihydro- 1,3-thiazol-4-yl] ethyl] pyrrolidin-2-yl] methanol;
(2S) -1- [2-[(4S) -2- [5-methyl-7- (oxan-4-ylmethylamino) -1H-indol-2-yl] -4,5-dihydro-1 , 3-thiazol-4-yl] ethyl] pyrrolidine-2-carboxyamide;
4- [2-[(4R) -2- [7- (cyclopentylamino) -5-methyl-1H-indol-2-yl] -4,5-dihydro-1,3-thiazole-4- Il] ethyl] piperazin-2-one;
2-[(4S) -2- [7- (cyclopentylamino) -5-methyl-1H-indol-2-yl] -4,5-dihydro-1,3-oxazol-4-yl] acetic acid ;
{(S) -2- [5-methyl-7- (tetrahydropyran-4-ylamino) -1H-indol-2-yl] -4,5-dihydro-oxazol-4-yl} -acetic acid ;
2-[(4S) -2- [5-methyl-7- (tetrahydropyran-4-ylamino) -1H-indol-2-yl] -4,5-dihydro-1,3-oxazole- 4-yl] ethanol;
{5-Methyl-2-[(S) -4- (2-morpholin-4-yl-ethyl) -4,5-dihydro-1,3-oxazol-2-yl] -1 H-indole- 7-yl}-(tetrahydro-pyran-4-yl) amine
4-[(5-chloro-2-phenyl-1H-indol-7-yl) amino] -N-ethylpiperidine-1-carboxyamide;
[4-[(5-chloro-2-phenyl-1H-indol-7-yl) amino] piperidin-1-yl]-(oxoran-3-yl) methanone;
2- [7- (oxan-4-ylamino) -2-phenyl-1H-indol-5-yl] acetic acid;
2- [7- (cyclopentylmethylamino) -2-phenyl-1H-indol-5-yl] acetic acid;
5-fluoro-N- (1-methylpiperidin-4-yl) -2-phenyl-1H-indol-7-amine;
2- [4-[(5-fluoro-2-phenyl-1H-indol-7-yl) amino] piperidin-1-yl] ethanone;
5-fluoro-N- [1- (oxan-4-yl) piperidin-4-yl] -2-phenyl-1H-indol-7-amine;
N- [1- (1,1-dioxyan-4-yl) piperidin-4-yl] -5-fluoro-2-phenyl-1H-indol-7-amine;
N- (oxan-4-yl) -5-phenoxy-2-phenyl-1H-indol-7-amine;
Methyl 2-[(5-fluoro-2-phenyl-1H-indol-7-yl) amino] acetate;
2-[(5-fluoro-2-phenyl-1H-indol-7-yl) amino] acetic acid;
Methyl 2-[(5-chloro-2-phenyl-1H-indol-7-yl) amino] propanoate;
2-[(5-chloro-2-phenyl-1H-indol-7-yl) amino] propanoic acid;
2-[(5-phenoxy-2-phenyl-1H-indol-7-yl) amino] acetic acid;
2-[(5-phenoxy-2-phenyl-1H-indol-7-yl) amino] propanoic acid;
2-[(4S) -2- [7- (oxan-4-ylmethylamino) -2-phenyl-1H-indol-5-yl] -4,5-dihydro-1,3-thiazole-4 -Yl] acetic acid;
2-[(4S) -2- [7- (cyclopentylamino) -2-phenyl-1H-indol-5-yl] -4,5-dihydro-1,3-thiazol-4-yl] acetic acid ;
Methyl 2- [4- [5-chloro-7- (oxan-4-ylamino) -1H-indol-2-yl] phenyl] acetate;
Methyl 2- [4- [5-chloro-7- (oxan-4-ylmethylamino) -1H-indol-2-yl] phenyl] acetate;
2- [4- [5-chloro-7- (oxan-4-ylamino) -1H-indol-2-yl] phenyl] acetic acid;
5-[(1,1-dioxo-1,4-siazinan-4-yl) methyl] -N- (oxan-4-yl) -2-phenyl-1H-indol-7-amine;
5-[(1,1-dioxo-thiomorpholin-4-ylmethyl) -2-phenyl-1H-indol-7-yl]-(tetrahydropyran-4-ylmethyl) -amine;
4-[[7- (oxan-4-ylamino) -2-phenyl-1H-indol-5-yl] methyl] piperazin-2-one;
5-[(1,1-dioxo-1,4-siazinan-4-yl) methyl] -2-phenyl-N-piperidin-4-yl-1H-indol-7-amine;
[4-[[5-[(1,1-dioxo-1,4-siazinan-4-yl) methyl] -2-phenyl-1H-indol-7-yl] amino] piperidine-1- Il]-(oxoran-3-yl) methanone;
N- [4- [5-[(1,1-dioxo-1,4-siazinan-4-yl) methyl] -7- (oxan-4-ylamino) -1H-indol-2-yl] Phenyl] acetamide;
N- [4- [7- (dicyclopentylamino) -5-[(1,1-dioxo-1,4-siazinan-4-yl) methyl] -1H-indol-2-yl] phenyl] Acetamide;
N- [4- [5-[(1,1-dioxo-1,4-siazinan-4-yl) methyl] -7- (oxan-4-ylmethylamino) -1H-indol-2-yl ] Phenyl] acetamide;
N-cyclopentyl-5-[(1,1-dioxo-1,4-siazinan-4-yl) methyl] -2- (4-methoxyphenyl) -1H-indol-7-amine;
5-[(1,1-dioxo-1,4-siazinan-4-yl) methyl] -2- (4-methoxyphenyl) -N- (oxan-4-yl) -1H-indole-7 Amines;
5-[(1,1-dioxo-1,4-siazinan-4-yl) methyl] -N- (3-methoxybutyl) -2-phenyl-1H-indol-7-amine;
5-[(1,1-dioxo-1,4-siazinan-4-yl) methyl] -2- (3-fluorophenyl) -N- (oxan-4-yl) -1H-indole-7 Amines;
N-cyclopentyl-5-[(1,1-dioxo-1,4-siazinan-4-yl) methyl] -2- (3-fluorophenyl) -1H-indol-7-amine;
3-bromo-5-[(1,1-dioxo-1,4-siazinan-4-yl) methyl] -N- (oxan-4-yl) -2-phenyl-1H-indole-7- Amines;
3-bromo-5- (morpholin-4-ylmethyl) -N- (oxan-4-yl) -2-phenyl-1H-indol-7-amine;
3-bromo-N-cyclopentyl-5-[(1,1-dioxo-1,4-siazinan-4-yl) methyl] -2-phenyl-1H-indol-7-amine;
3-bromo-5-[(1,1-dioxo-1,4-siazinan-4-yl) methyl] -N- (oxan-4-yl) -2-phenyl-1H-indole-7- Amines;
5-chloro-N- (oxan-4-yl) -3-phenyl-1H-indol-7-amine;
5-chloro-N-cyclopentyl-3-phenyl-1H-indol-7-amine;
5-chloro-N- (oxan-4-ylmethyl) -3-phenyl-1H-indol-7-amine;
5-[(1,1-dioxo-1,4-thiazinan-4-yl) methyl] -N- (oxan-4-yl) -3-phenyl-2-trimethylsilyl-1H-indole-7- Amines;
4-[[5-chloro-7- (cyclopentylamino) -2-phenyl-1H-indol-3-yl] methyl] piperazin-2-one;
4-[[5-chloro-7- (oxan-4-ylamino) -2-phenyl-1H-indol-3-yl] methyl] piperazin-2-one;
4-[[5-chloro-7- (oxan-4-ylmethylamino) -2-phenyl-1H-indol-3-yl] methyl] piperazin-2-one;
N-cyclopentyl-3- (4-methoxyphenyl) -1H-indazol-7-amine;
3- (4-methoxyphenyl) -N- (oxan-4-yl) -1H-indazol-7-amine;
3- (4-methoxyphenyl) -N- (oxan-4-ylmethyl) -1H-indazol-7-amine; And
A composition characterized in that it is selected from the group consisting of 2- (7-cyclopentylamino-2-phenyl-1H-indol-5-yl) -ethanol.
18. The compound of claim 17, wherein in the compound '5-[(1,1-dioxo-thiomorpholin-4-ylmethyl) -2-phenyl-1H-indol-7-yl]-(tetrahydropyran-4' -Ylmethyl) -amine '.

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