KR101664281B1 - 34- - Novel acetamide derivatives containing 34-dichlorophenyl group or pharmaceutically acceptable salts thereof preparation method therof and pharmaceutical composition for use in preventing or treating Urotensin- receptor activity related diseases containing the same as an active ingredient - Google Patents

34- - Novel acetamide derivatives containing 34-dichlorophenyl group or pharmaceutically acceptable salts thereof preparation method therof and pharmaceutical composition for use in preventing or treating Urotensin- receptor activity related diseases containing the same as an active ingredient Download PDF

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KR101664281B1
KR101664281B1 KR1020150047056A KR20150047056A KR101664281B1 KR 101664281 B1 KR101664281 B1 KR 101664281B1 KR 1020150047056 A KR1020150047056 A KR 1020150047056A KR 20150047056 A KR20150047056 A KR 20150047056A KR 101664281 B1 KR101664281 B1 KR 101664281B1
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dichlorophenyl
acetamide
amino
methyl
ethyl
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이규양
임채조
김낙정
이병호
오광석
이정현
서호원
김수희
김성환
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한국화학연구원
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole

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Abstract

The present invention relates to an acetamide derivative containing a 3,4-dichlorophenyl group or a pharmaceutically acceptable salt thereof, a process for producing the same, and a pharmaceutical composition for the prophylactic or therapeutic treatment of a disease associated with the activity of a urotensin- ≪ / RTI > The acetamide derivative containing the 3,4-dichlorophenyl group according to the present invention acts as an antagonist to the urotensin-II receptor and thus can be used for the treatment of congestive heart failure, cardiac ischemia, myocardial infarction, cardiac hypertrophy, cardiac fibrosis, II receptor activity-related diseases such as inflammation, scleroderma, hypertension, asthma, renal failure, diabetes, vascular inflammation, neurodegenerative diseases, stroke, pain, depression, psychosis, cancer and the like.

Description

The present invention relates to an acetamide derivative containing a 3,4-dichlorophenyl group, a pharmaceutically acceptable salt thereof, a process for producing the same, and a pharmaceutical composition for preventing or treating a disease associated with the activity of a urotensin- acetamide derivatives containing 3,4-dichlorophenyl group or pharmaceutically acceptable salts thereof, preparation method thereof, and pharmaceutical composition for use in preventing or treating Urotensin-II receptor activity,

The present invention relates to an acetamide derivative containing a 3,4-dichlorophenyl group or a pharmaceutically acceptable salt thereof, a process for producing the same, and a pharmaceutical composition for the prophylactic or therapeutic treatment of a disease associated with the activity of a urotensin- ≪ / RTI >

Eurotensin-II is a cysteine-linked cyclic peptide, and is known to be one of the most potent vasoconstrictors known to date, 10 times stronger than endothelin-1 (Non-Patent Document 1). Eurotensin-II is composed of 14 amino acids in rats from eleven amino acids in humans and was first found in goby fish, but is now identified in all vertebrates (non-patent document 2).

It is reported that urotensin-II induces myocardial cell hypertrophy and proliferation of smooth muscle cells, indicating that it is involved in chronic vascular diseases such as heart failure and arteriosclerosis (Non-Patent Document 3). In addition, it has been reported that urotensin-II increases the peripheral vascular tone characteristic of chronic heart failure (Non-Patent Document 4). And urotensin-II is highly expressed in the plasma of patients with renal dysfunction (Non-Patent Document 5). Eurotensin-II has also been reported to be associated with diabetes (Non-Patent Document 6). It has been reported that Eurotensin-II is also involved in central nervous system disorders (Non-Patent Document 7). Specific tumor cell line overexpresses the urotensin-II receptor (Non-Patent Document 8).

The physiological activity of urotensin-II is mediated through the activation of the urotensin-II receptor (UT). Previously, the orphan receptor GPR14, which is a G-protein-coupled-receptor (GPCR) as a seven-domain transmembrane receptor, was identified as the urotensin-II receptor (non-patent document 9). The urotensin-II receptor is expressed in various tissues such as blood vessels, heart, liver, kidney, muscle and lung (Non-Patent Document 10).

The urotensin-II receptor antagonist may be useful in the treatment of congestive heart failure, cardiac ischemia, myocardial infarction, cardiac hypertrophy, cardiac fibrosis, coronary artery disease, arteriosclerosis, hypertension, asthma, renal failure, diabetes and vascular inflammation. In addition, the urotensin-II receptor antagonist may be useful for the treatment of disorders of the central nervous system, for example, neurodegenerative diseases, stroke, pain, depression, psychosis and the like, and may be useful for the treatment of certain cancers.

Research on the development of the urotensin-II receptor antagonist is underway to derive low molecular weight synthetic compounds with various chemical skeletons from the study of peptidomimetics based on urandtide.

Accordingly, the present inventors have made efforts to develop a compound having an antagonistic effect on the urotensin-II receptor, and have found that an acetamide derivative containing a 3,4-dichlorophenyl group having a specific structure acts as an antagonist of the urotensin-II receptor The present invention can be used as a pharmaceutical composition for the prevention and treatment of diseases related to the activity of the urotensin-II receptor, thereby completing the present invention.

Ames et al., Nature 1999, 401, 282 Onan et al., Trends Endocrinol. Metab. 2004, 15, 175 Zou et al., FEBS Letters 2001, 508, 57 Lim et al., Circulation 2004, 109, 1212 Totsune et al., Lanceet 2001, 358, 810 Totsune et al., Clin. Sci. 2003, 104, 1 Matsumoto et al., Neurosci. Lett., 2004, 358, 99 Takahashi et al., Peptides, 2003, 24, 301 Elshourbagy et al., Br. J. Pharmacol. 2002, 36, 9 Proulx et al., Peptides 2008, 29, 691

It is an object of the present invention to provide an acetamide derivative containing a 3,4-dichlorophenyl group or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a process for preparing an acetamide derivative containing the 3,4-dichlorophenyl group.

It is still another object of the present invention to provide a method for preventing or treating an urotensin-II receptor activity-related disease comprising an acetamide derivative containing the 3,4-dichlorophenyl group, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient, And to provide a therapeutic pharmaceutical composition.

Another object of the present invention is to provide a method for the prevention or amelioration of a disease related to the activity of the urotensin-II receptor comprising an acetamide derivative containing the 3,4-dichlorophenyl group, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient And to provide a health functional food composition containing the same.

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

[Chemical Formula 1]

Figure 112015032633366-pat00001

In Formula 1,

R < 1 > is a 5- to 8-membered heteroaryl which is unsubstituted or is substituted by one or more halogens containing at least one heteroatom selected from the group consisting of N, O and S;

R 2 and R 3 are each independently hydrogen or straight or branched chain alkyl of C 1 -10 or together with the N atom to which they are attached form a 5 to 8-membered heterocycloalkyl, Lt; / RTI > may further comprise at least one heteroatom selected from the group consisting of N, O and S; And

A is O, S, -CH 2 -, -SO 2 - or -NR 4 -, wherein said R 4 is - (CH 2) n R 5 Wherein n is an integer from 0 to 5, and R 5 is selected from the group consisting of hydrogen, -CN, straight or branched alkoxy of C 1-5 , C 5-8 aryl,

Figure 112015032633366-pat00002
or
Figure 112015032633366-pat00003
Wherein R 6 is -OH, C 1-5 linear or branched alkyl, C 1-5 straight or branched alkoxy, C 5-8 aryl or
Figure 112015032633366-pat00004
And R 7 and R 8 are each independently hydrogen or C 1-5 straight chain alkyl.

Also, as shown in the following Reaction Scheme 1,

There is provided a process for preparing a compound represented by the formula (1), which comprises a step of reacting a compound represented by the formula (2) and a compound represented by the formula (3) in the presence of a condensing agent and a base to prepare a compound represented by the formula .

[Reaction Scheme 1]

Figure 112015032633366-pat00005

In the above Reaction Scheme 1, R 1 , R 2 , R < 3 > and A are as defined in the above formula (1).

Further, the present invention provides a pharmaceutical composition for preventing or treating a disease associated with the activity of the urotensin-II receptor, which comprises the compound represented by the formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention also provides a health functional food composition for preventing or ameliorating a disease associated with the activity of a urotensin-II receptor, which comprises the compound represented by the formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient .

The acetamide derivative containing the 3,4-dichlorophenyl group according to the present invention acts as an antagonist to the urotensin-II receptor and thus can be used for the treatment of congestive heart failure, cardiac ischemia, myocardial infarction, cardiac hypertrophy, cardiac fibrosis, II receptor activity-related diseases such as inflammation, scleroderma, hypertension, asthma, renal failure, diabetes, vascular inflammation, neurodegenerative diseases, stroke, pain, depression, psychosis, cancer and the like.

Hereinafter, the present invention will be described in detail.

The present invention provides a compound represented by the following general formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

Figure 112015032633366-pat00006

In Formula 1,

R < 1 > is a 5- to 8-membered heteroaryl which is unsubstituted or is substituted by one or more halogens containing at least one heteroatom selected from the group consisting of N, O and S;

R 2 and R 3 are each independently hydrogen or straight or branched chain alkyl of C 1 -10 or together with the N atom to which they are attached form a 5 to 8-membered heterocycloalkyl, Lt; / RTI > may further comprise at least one heteroatom selected from the group consisting of N, O and S; And

A is O, S, -CH 2 -, -SO 2 - or -NR 4 -, wherein said R 4 is - (CH 2) n R 5 Wherein n is an integer from 0 to 5, and R 5 is selected from the group consisting of hydrogen, -CN, straight or branched alkoxy of C 1-5 , C 5-8 aryl,

Figure 112015032633366-pat00007
or
Figure 112015032633366-pat00008
Wherein R 6 is -OH, C 1-5 linear or branched alkyl, C 1-5 straight or branched alkoxy, C 5-8 aryl or
Figure 112015032633366-pat00009
And R 7 and R 8 are each independently hydrogen or C 1-5 straight chain alkyl.

Preferably,

Wherein R 1 is unsubstituted or at least one substituted 5- to 8-membered heteroaryl selected from the group consisting of chloro, fluoro and bromo, comprising at least one heteroatom selected from the group consisting of N, O and S ;

R 2 and R 3 are each independently hydrogen or C 1-5 straight or branched chain alkyl,

Figure 112015032633366-pat00010
,
Figure 112015032633366-pat00011
,
Figure 112015032633366-pat00012
,
Figure 112015032633366-pat00013
,
Figure 112015032633366-pat00014
or
Figure 112015032633366-pat00015
Lt; / RTI >

A is O, S, -SO 2 - or -NR 4 -, wherein said R 4 is - (CH 2) n R 5 , N is an integer from 0 to 3, and R 5 is hydrogen, -CN, C 1-3 linear or branched alkoxy, C 5-8 aryl,

Figure 112015032633366-pat00016
or
Figure 112015032633366-pat00017
Wherein R 6 is -OH, C 1-5 linear or branched alkyl, C 1-5 straight or branched alkoxy, C 5-8 aryl or
Figure 112015032633366-pat00018
And R 7 and R 8 are each independently hydrogen or C 1-3 straight chain alkyl.

More preferably,

Wherein R < 1 &

Figure 112015032633366-pat00019
,
Figure 112015032633366-pat00020
,
Figure 112015032633366-pat00021
or
Figure 112015032633366-pat00022
ego;

R 2 and R 3 together with the N atom to which they are attached

Figure 112015032633366-pat00023
or
Figure 112015032633366-pat00024
Lt; / RTI > And

A is O, S or -NR < 4 >-; Wherein R < 4 > is hydrogen, methyl,

Figure 112015032633366-pat00025
,
Figure 112015032633366-pat00026
,
Figure 112015032633366-pat00027
,
Figure 112015032633366-pat00028
,
Figure 112015032633366-pat00029
,
Figure 112015032633366-pat00030
,
Figure 112015032633366-pat00031
,
Figure 112015032633366-pat00032
,
Figure 112015032633366-pat00033
,
Figure 112015032633366-pat00034
,
Figure 112015032633366-pat00035
or
Figure 112015032633366-pat00036
to be.

Preferable examples of the compound represented by the formula (1) according to the present invention include the following compounds:

(1) Synthesis of 2 - [(cyanomethyl) (3,4-dichlorophenyl) amino] -N-methyl-N- [1- [4- (pyridin- 1-yl) ethyl] acetamide;

(2) Synthesis of 2 - [(methyl) (3,4-dichlorophenyl) amino] -N-methyl-N- [1- [4- (pyridin- 1-yl) ethyl] acetamide;

(3) Synthesis of 2 - [(2-methoxyethyl) (3,4-dichlorophenyl) amino] Pyrrolidin-1-yl) ethyl] acetamide;

(4) Synthesis of 2 - [(acetyl) (3,4-dichlorophenyl) amino] -N-methyl-N- [1- [4- (pyridin- 1-yl) ethyl] acetamide;

(5) Synthesis of 2 - [(methanesulfonyl) (3,4-dichlorophenyl) amino] -N-methyl-N- [1- [4- (pyridin- 1-yl) ethyl] acetamide;

(6) Synthesis of 2 - [(benzyl) (3,4-dichlorophenyl) amino] -N-methyl-N- [1- [4- (pyridin- 1-yl) ethyl] acetamide;

(7) Synthesis of 2 - [(phenylsulfonyl) (3,4-dichlorophenyl) amino] -N-methyl-N- [1- [4- (pyridin- 1-yl) ethyl] acetamide;

(8) Synthesis of 2 - [(benzoyl) (3,4-dichlorophenyl) amino] -N-methyl-N- [1- [4- (pyridin- 1-yl) ethyl] acetamide;

(9) Synthesis of 2 - [[(t-butoxycarbonyl) methyl] (3,4-dichlorophenyl) amino] -2- (pyrrolidin-1-yl) ethyl] acetamide;

(10) Synthesis of 2 - [(carboxymethyl) (3,4-dichlorophenyl) amino] -N-methyl-N- [1- [4- (pyridin- -1-yl) ethyl] acetamide;

(11) 2- [(2-Amino-2-oxoethyl) (3,4-dichlorophenyl) amino] 2- (pyrrolidin-1-yl) ethyl] acetamide;

(12) Synthesis of 2 - [(3,4-dichlorophenyl) amino] -N-methyl-N- [1- [4- (pyridin- ) Ethyl] acetamide;

(13) Synthesis of 2- (3,4-dichlorophenoxy) -N-methyl-N- [1- [4- (pyridin- ] Acetamide;

(14) Synthesis of 2 - [(3,4-dichlorophenyl) [2- (dimethylamino) -2-oxoethyl] ) Phenyl] -2- (pyrrolidin-1-yl) ethyl] acetamide;

(15) Synthesis of 2 - [(3,4-dichlorophenyl) [2- (methylamino) -2-oxoethyl] Phenyl] -2- (pyrrolidin-1-yl) ethyl] acetamide;

(16) 2- [(3,4-dichlorophenyl) thio] -N-methyl-N- [1- [4- (pyridin- Yl) ethyl] acetamide;

(17) Synthesis of 2 - [(methyl) (3,4-dichlorophenyl) amino] -N- Acetamide;

(18) Synthesis of 2 - [(benzyl) (3,4-dichlorophenyl) amino] -N- Acetamide;

(19) Synthesis of 2 - [(cyanomethyl) (3,4-dichlorophenyl) amino] -N-methyl-N- [1- [4- (thiophen- Lt; / RTI > yl) ethyl] acetamide;

(20) 2- [(methyl) (3,4-dichlorophenyl) amino] -N-methyl-N- [1- [4- (thiophen- -1-yl) ethyl] acetamide;

(21) Synthesis of 2 - [(3,4-dichlorophenyl) (2-methoxyethyl) amino] -N-methyl-N- [1- [4- (thiophen- (Pyrrolidin-1-yl) ethyl] acetamide;

(22) Synthesis of 2 - [(acetyl) (3,4-dichlorophenyl) amino] -N-methyl-N- [1- [4- (thiophen- -1-yl) ethyl] acetamide;

(23) Synthesis of 2 - [(methanesulfonyl) (3,4-dichlorophenyl) amino] -N-methyl-N- [1- [4- (thiophen- Lt; / RTI > yl) ethyl] acetamide;

(24) Synthesis of 2 - [(benzyl) (3,4-dichlorophenyl) amino] -N-methyl-N- [1- [4- (thiophen- -1-yl) ethyl] acetamide;

(25) Synthesis of 2 - [(phenylsulfonyl) (3,4-dichlorophenyl) amino] -N-methyl-N- [1- [4- (thiophen- Lt; / RTI > yl) ethyl] acetamide;

(26) Synthesis of 2 - [(benzoyl) (3,4-dichlorophenyl) amino] -N-methyl-N- [1- [4- (thiophen- -1-yl) ethyl] acetamide;

(27) Synthesis of 2 - [[(t-butoxycarbonyl) methyl] (3,4-dichlorophenyl) amino] -N- ] -2- (pyrrolidin-1-yl) ethyl] acetamide;

(28) Synthesis of 2 - [(carboxymethyl) (3,4-dichlorophenyl) amino] -N-methyl-N- [1- [4- (thiophen- 1-yl) ethyl] acetamide;

(29) Synthesis of 2 - [(cyanomethyl) (3,4-dichlorophenyl) amino] -N-methyl-N- [2-morpholino- ] Ethyl] acetamide;

(30) Synthesis of 2 - [(2-amino-2-oxoethyl) (3,4-dichlorophenyl) amino] -2- (pyrrolidin-1-yl) ethyl] acetamide;

(31) 2- [(benzoyl) (3,4-dichlorophenyl) amino] -N-methyl-N- [1- [4- (2- chloropyridin- Lt; / RTI > yl) ethyl] acetamide;

(32) Synthesis of 2 - [(cyanomethyl) (3,4-dichlorophenyl) amino] -N-methyl-N- [1- [4- (2- chloropyridin- (Pyrrolidin-1-yl) ethyl] acetamide;

(33) Synthesis of 2 - [(methyl) (3,4-dichlorophenyl) amino] -N-methyl-N- [1- [4- (2-chloropyridin- Lt; / RTI > yl) ethyl] acetamide;

(34) Synthesis of 2 - [(2-methoxyethyl) (3,4-dichlorophenyl) amino] 2- (pyrrolidin-1-yl) ethyl] acetamide;

(35) Synthesis of 2 - [(methanesulfonyl) (3,4-dichlorophenyl) amino] -N-methyl-N- [1- [4- (2- chloropyridin- (Pyrrolidin-1-yl) ethyl] acetamide;

(36) Synthesis of 2 - [(phenylsulfonyl) (3,4-dichlorophenyl) amino] -N-methyl-N- [1- [4- (2- chloropyridin- (Pyrrolidin-1-yl) ethyl] acetamide;

(37) Synthesis of 2 - [(benzyl) (3,4-dichlorophenyl) amino] -N-methyl-N- [1- [4- (2-chloropyridin- Lt; / RTI > yl) ethyl] acetamide;

(38) Synthesis of 2 - [(cyanomethyl) (3,4-dichlorophenyl) amino] -N- ) Phenyl] ethyl] acetamide;

(39) Synthesis of 2 - [(methyl) (3,4-dichlorophenyl) amino] -N-methyl-N- [2-morpholino- ] Ethyl] acetamide.

The compound represented by the formula (1) of the present invention can be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid and the like, aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, Derived from organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid and the like. Examples of such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, But are not limited to, but are not limited to, but are not limited to, but are not limited to, but are not limited to, halides, halides, halides, halides, halides, halides, But are not limited to, lactose, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, Methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, chlorobenzene Sulfonates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, and the like, as well as sulfonates such as benzyl sulfonate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, -Sulfonate, naphthalene-2-sulfonate, mandelate, and the like.

The acid addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the derivative of Chemical Formula 1 in an organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile, etc., The precipitate may be filtered and dried, or the solvent and excess acid may be distilled off under reduced pressure, followed by drying and crystallization in an organic solvent.

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

Furthermore, the present invention encompasses the compounds represented by the formula (1) and pharmaceutically acceptable salts thereof as well as solvates, optical isomers and hydrates thereof which can be prepared therefrom.

Also, as shown in the following Reaction Scheme 1,

There is provided a process for preparing a compound represented by the formula (1), which comprises the step of reacting a compound represented by the formula (2) and a compound represented by the formula (3) in the presence of a condensing agent and a base to prepare a compound represented by the formula

[Reaction Scheme 1]

Figure 112015032633366-pat00037

(In the above Reaction Scheme 1,

R 1 , R 2 , R < 3 > and A are the same as defined in formula (1) of claim 1).

Hereinafter, a method for preparing the compound represented by Formula 1 according to the present invention will be described in detail.

The method for preparing a compound represented by the formula (1) according to the present invention comprises reacting a compound represented by the formula (2) and a compound represented by the formula (3) in the presence of a condensing agent and a base, The compound can be produced, and specific examples are as follows.

Preparation 1-A

As shown in Reaction Scheme 1, the compound represented by Formula (2) and the compound represented by Formula (3) may be condensed in the presence of a condensing agent and a base to prepare a compound represented by Formula (1).

The condensing agent may be bis (2-oxo-3-oxazolidinyl) phosphinic chloride (BOP-Cl), benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate Dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-ethyl-3- (3-methylphenyl) (N, N-carbonyldiimidazole), O- benzotriazole-N, N, N ', N (N, N'-diethylaminopropyl) carbodiimide '-Tetramethyl-uronium-hexafluorophosphate (HBTU) may be used alone or in combination.

Examples of the base include N, N-dimethylaminopyridine (DMAP), pyridine, triethylamine, N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] (DBU), or inorganic bases such as sodium bicarbonate, sodium hydroxide, and potassium hydroxide, which may be used alone or in combination.

Further, as the solvent usable in the above reaction, ether solvents such as tetrahydrofuran, dioxane, dichloromethane and 1,2-dimethoxyethane, aromatic hydrocarbon solvents such as benzene, toluene and xylene, dimethylformamide DMF), dimethylsulfoxide (DMSO), acetonitrile, etc., which may be used alone or in combination. The reaction temperature is from 0 ° C to the boiling point of the solvent.

Preparation 1-B

The compound represented by the general formula (2) in the above Reaction Scheme 1 may be reacted with an acyl halide, a carboxylic acid anhydride or an active ester (for example, p-nitrophenyl ester, N-hydroxysuccinimide ester, Fluorophenyl ester, etc.), and then reacting the compound represented by formula (3) in the presence of a base to obtain a compound represented by formula (1).

At this time, examples of the base include an inorganic base such as a tertiary amine organic base such as triethylamine or diisopropylethylamine and an inorganic base such as sodium carbonate, potassium carbonate, potassium hydroxide, sodium hydroxide, cesium carbonate, barium hydroxide, .

Examples of the solvent which can be used in the above reaction include ether-based solvents such as dioxane, tetrahydrofuran and 1,2-dimethoxyethane, and halogen-containing solvents such as 1,2-dichloromethane or 1,2- And aromatic hydrocarbon solvents such as benzene and toluene, which can be used singly or in combination, and can be reacted without a solvent. The reaction temperature is from 0 ° C to the boiling point of the solvent.

Production method 1 of starting material (compound represented by formula (2)) 1

The compound of Formula 2, which is a starting material of Reaction Scheme 1, can be prepared and used as shown in Reaction Scheme 2-1 or Reaction Scheme 2-2.

Specifically, in the case of a compound of formula (2) wherein A is O, S and N, as shown in the following reaction formula (2-1)

Reacting a compound represented by the formula (4) with a compound represented by the formula (5) in the presence of a base to obtain a compound represented by the formula (6) (step 1) and

And a step (step 2) of hydrolyzing the compound represented by the formula (6) obtained in the step 1 in the presence of an acid or base to obtain a compound represented by the formula (2a).

[Reaction Scheme 2-1]

Figure 112015032633366-pat00038

(In the above Reaction Scheme 2-1, A is O, S and N, X is halogen, and 2a is a derivative of the above formula 2).

Hereinafter, the method for preparing the compound represented by Formula 2a will be described in detail.

In step (1), the compound represented by formula (4) is reacted with a compound represented by formula (5) in the presence of a base to obtain a compound represented by formula (6).

Examples of the base include organic bases such as pyridine, triethylamine, N, N-diisopropylethylamine and 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) There are inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate and the like, and they can be used in an equivalent amount or in an excess amount.

Examples of the solvent that can be used in the reaction include ether solvents such as tetrahydrofuran, dioxane, dichloromethane and 1,2-dimethoxyethane, dimethylformamide (DMF), dimethylsulfoxide (DMSO), acetonitrile These can be used singly or in combination. The reaction temperature is from 0 ° C to the boiling point of the solvent.

In the method for preparing the compound represented by the general formula (2) according to the present invention, the step (2) is a step for hydrolyzing the compound represented by the general formula (6) obtained in the step 1 in the presence of an acid or a base to obtain a compound represented by the general formula to be.

At this time, examples of the base include inorganic bases such as sodium carbonate, potassium carbonate, potassium hydroxide, sodium hydroxide, cesium carbonate, barium hydroxide, and the like.

As the acid, hydrochloric acid, sulfuric acid, methanesulfonic acid and the like can be used.

Further, as the solvent which can be used in the above reaction, ether solvents such as tetrahydrofuran, dioxane, dichloromethane and 1,2-dimethoxyethane, aromatic hydrocarbon solvents such as benzene, toluene and xylene, methanol, The same alcoholic solvent, dimethylformamide (DMF), dimethylsulfoxide (DMSO), acetonitrile and the like, which can be used singly or in combination. The reaction temperature is from 0 ° C to the boiling point of the solvent.

In particular, in the case of a compound wherein A is -NR 4 - in the general formula (2), as shown in the following reaction formula 2-2,

Reacting a compound represented by the formula (6a) with a compound represented by the formula (7) in the presence of a base to obtain a compound represented by the formula (8) (step 1) and

And a step (step 2) of hydrolyzing the compound represented by the formula 8 obtained in the step 1 in the presence of an acid or base to obtain a compound represented by the formula 2b.

[Reaction Scheme 2-2]

Figure 112015032633366-pat00039

(In the above Scheme 2-2,

R 4 is as defined in Formula 1; 6a is a derivative of the above formula (6); X is halogen; And 2b is a derivative of the above formula (2).

Hereinafter, the method of preparing the compound represented by Formula 2b will be described in detail.

In step (1), the compound represented by formula (6a) is reacted with a compound represented by formula (7) in the presence of a base to obtain a compound represented by formula (8).

Examples of the base include organic bases such as pyridine, triethylamine, N, N-diisopropylethylamine and 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) There are inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate and the like, and they can be used in an equivalent amount or in an excess amount.

Further, as the solvent which can be used in the above reaction, ether solvents such as tetrahydrofuran, dioxane, dichloromethane and 1,2-dimethoxyethane, dimethylformamide (DMF), dimethylsulfoxide (DMSO), acetonitrile These can be used singly or in combination. The reaction temperature is from 0 ° C to the boiling point of the solvent.

In the method for preparing the compound represented by the general formula (2) according to the present invention, the step (2) is a step of hydrolyzing the compound represented by the general formula (8) obtained in the step (1) in the presence of an acid or base to obtain a compound represented by the general formula to be.

The specific production method of the step 2 can be carried out in the same manner as the production method of the step 2 of the reaction formula 2-1.

Production method 2 (starting material) of the starting material

The compound of Formula 3, which is a starting material of Reaction Scheme 1, can be prepared and used as shown in Reaction Scheme 3 below.

(9) with a compound represented by formula (10) in the presence of a base to obtain a compound represented by formula (11) (step 1);

A step of reducing the compound of the formula 11 obtained in the step 1 in the presence of a metal reducing agent to obtain a compound represented by the formula 12 (step 2);

(Step 3) of substituting the compound of formula (12) obtained in step 2 with the compound of formula (13) in the presence of a base to obtain a compound of formula (14); And

A step of subjecting a compound represented by the formula (14) obtained in the above step 3 to a Suzuki coupling reaction with a compound represented by the formula (15) under a transition metal catalyst and a base to obtain a compound represented by the formula (3) (step 4) . ≪ / RTI >

[Reaction Scheme 3]

Figure 112015032633366-pat00040

(In the above scheme 3,

R 1 , R 2 and R 3 are the same as defined in Formula 1; X is halogen; Y is

Figure 112015032633366-pat00041
or
Figure 112015032633366-pat00042
to be).

Hereinafter, the method for preparing the compound represented by the above formula (3) will be described step by step.

In the process for preparing the compound represented by the general formula (3) according to the present invention, the step (1) is a step of substituting the compound represented by the general formula (9) with the compound represented by the general formula (10) in the presence of a base to obtain a compound represented by the general formula .

Examples of the base include organic bases such as pyridine, triethylamine, N, N-diisopropylethylamine and 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) There are inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate and the like, and they can be used in an equivalent amount or in an excess amount.

Examples of the solvent that can be used in the reaction include ether solvents such as tetrahydrofuran, dioxane, dichloromethane and 1,2-dimethoxyethane, dimethylformamide (DMF), dimethylsulfoxide (DMSO), acetonitrile These can be used singly or in combination. The reaction temperature is from 0 ° C to the boiling point of the solvent.

In the process for preparing a compound represented by the general formula (3) according to the present invention, the step (2) is a step of reducing the compound represented by the general formula (11) obtained in the step (1) in the presence of a metal reducing agent to obtain a compound represented by the general formula (12).

At this time, sodium borohydride (NaBH 4 ) and lithium aluminum hydride (LiAlH 4 ) may be used as the metal reducing agent.

Examples of the solvent that can be used in the above reaction include alcohol solvents such as methanol and ethanol, ether solvents such as tetrahydrofuran, dioxane and 1,2-dimethoxyethane, etc. These solvents may be used alone or in combination . The reaction temperature is from 0 ° C to the boiling point of the solvent.

In the method for producing the compound represented by the general formula (3) according to the present invention, the step (3) is a step of substituting the compound represented by the formula (12) obtained in the step 2 with the compound represented by the formula To obtain a compound.

Specifically, in step 3, the compound represented by formula (14) can be prepared by replacing the alcohol group in the compound represented by formula (12) with a leaving group in the presence of a base and then substituting with a methylamine compound represented by formula (13).

At this time, chloro or sulfonate compounds such as phosphorus oxychloride (POCl 3 ) or phosphorus trichloride (PCl 3 ), methanesulfonyl chloride, p -toluenesulfonyl chloride and the like can be used as the leaving group.

Examples of the base include organic bases such as pyridine, triethylamine, N, N-diisopropylethylamine and 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) There are inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate and the like, and they can be used in an equivalent amount or in an excess amount.

Further, as the solvent which can be used in the above-mentioned reaction, an ether solvent such as tetrahydrofuran, dioxane, dimethoxyethane, dimethylformamide (DMF), dimethylsulfoxide (DMSO) Nitrile and the like, which can be used alone or in combination. The reaction temperature is from 0 ° C to the boiling point of the solvent.

In step (4), the compound represented by the formula (14) is reacted with the compound represented by the formula (15) in the presence of a transition metal catalyst and base, Coupling reaction to obtain a compound of formula (3).

Specifically, Step 4 can be carried out by reacting the compound represented by the formula (14) with a boronic acid compound represented by the formula (15), which is commercially available or prepared from the corresponding halide compound by a known method, in the presence of a transition metal catalyst and a base such as Suzuki ) Type coupling reaction to prepare a compound represented by the general formula (3).

At this time, the transition metal catalyst may be palladium, nickel or a platinum derivative, but it is preferable to use a palladium catalyst. The palladium catalyst is tetrakis (triphenylphosphine) palladium (Pd (PPh 3) 4) , palladium charcoal (Pd-C), bis (triphenylphosphine) palladium dichloride (PdCl 2 (PPh 3) 2 ), tris (Dibenzylideneacetone) palladium (Pd 2 (dba) 3 ), [1,1-bis (diphenylphosphino) ferrocene] dichloropalladium (PdCl 2 (dppf)), allylpalladium chloride dimer allyl)] 2 ), palladium acetate (Pd (OAc) 2 ), and palladium chloride (PdCl 2 ).

Examples of the base include inorganic bases such as sodium carbonate, potassium carbonate, potassium hydroxide, sodium hydroxide, cesium carbonate, barium hydroxide and the like, and they can be used in an equivalent amount or in an excess amount.

Further, promoting the reaction in the above step 4, and to enhance the yield, such as triphenylphosphine (PPh 3), trio shoot tolylphosphine (P- (O- tolyl) 3) , tributylphosphine (PBu 3) Phosphine compounds or salts such as lithium chloride, lithium bromide, lithium iodide and the like can be used as adducts.

Examples of the solvent which can be used in the above reaction include ether solvents such as tetrahydrofuran, dioxane and 1,2-dimethoxyethane, aromatic hydrocarbon solvents such as benzene, toluene and xylene, alcohols such as methanol, ethanol, Lower alcohol, dimethylformamide (DMF), dimethylsulfoxide (DMSO), acetonitrile, water and the like, which may be used alone or in combination. The reaction temperature is from 0 ° C to the boiling point of the solvent.

In addition, the present invention provides a pharmaceutical composition for preventing or treating a disease associated with the activity of a urotensin-II receptor comprising the compound represented by the formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

Herein, the above-mentioned urotensin-II receptor activity-related diseases are selected from the group consisting of congestive heart failure, cardiac ischemia, myocardial infarction, cardiac hypertrophy, cardiac fibrosis, coronary artery disease, arteriosclerosis, hypertension, asthma, renal failure, diabetes, Stroke, pain, depression, psychosis, cancer, and the like.

As a result of measuring the inhibitory activity of the compound represented by Formula 1 according to the present invention on the urotensin-II receptor binding, the compounds of Examples 1, 2, 3, 5, 6, 11, 13, 15, 19, 32 Of the compounds of the present invention are antagonistic to the urotensin-II receptor at an IC 50 value of 0.1 μM or less. In particular, the compound of Example 1 has an IC 50 value of 0.005 μM or less, which is excellent for the urotensin- (See Experimental Example 1).

Therefore, the pharmaceutical composition of the present invention acts as an antagonist to the urotensin-II receptor and thus can be used as an antagonist for the urotensin-II receptor, II receptor activity-related diseases such as diabetes, vascular inflammation, neurodegenerative diseases, stroke, pain, depression, psychosis, cancer and the like.

In the pharmaceutical composition according to the present invention, the compound represented by the formula (1), its optical isomer or pharmaceutically acceptable salt thereof may be administered in various formulations for oral administration and parenteral administration at the time of clinical administration. May be prepared by using diluents or excipients such as fillers, extenders, binders, humectants, disintegrants, surfactants, etc. which are usually used.

Examples of formulations for oral administration include tablets, pills, light / soft capsules, liquids, suspensions, emulsions, syrups, granules, elixirs and troches, , Dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine), lubricants (such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols). The tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine and may optionally contain binders such as starch, agar, alginic acid or sodium salts thereof Release or boiling mixture and / or absorbent, colorant, flavor, and sweetening agent.

The pharmaceutical composition comprising the compound of Formula 1, its optical isomer or its pharmaceutically acceptable salt as an active ingredient according to the present invention can be administered parenterally, and parenteral administration can be carried out by subcutaneous injection, intravenous injection, muscle Intravenous injection or intra-thoracic injection.

In this case, in order to formulate the composition for parenteral administration, the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof may be mixed with water or a stabilizer or a buffer to prepare a solution or suspension, . The compositions may contain sterilized and / or preservatives, stabilizers, wettable or emulsifying accelerators, adjuvants such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, Or may be formulated according to the coating method.

The dose of the pharmaceutical composition containing the compound represented by the formula (1) of the present invention, its optical isomer or a pharmaceutically acceptable salt thereof as an active ingredient to the human body depends on the age, body weight, sex, May be varied depending on the health condition and the degree of disease, preferably 0.01 to 200 mg / kg / day, depending on the judgment of the physician or pharmacist, at intervals of several times a day, preferably once to three times a day May be administered by oral or parenteral route.

Furthermore, the pharmaceutical composition comprising the compound represented by the above-mentioned formula (1) of the present invention, its optical isomer or its pharmaceutically acceptable salt as an active ingredient may be used alone or in combination with a pharmaceutically acceptable salt, solvate or prodrug for the prophylactic or therapeutic treatment of a urotensin- Or in combination with methods using surgery, hormone therapy, chemotherapy, and biological response modifiers.

The present invention also provides a health food composition for preventing or ameliorating a disease associated with the activity of the urotensin-II receptor, which comprises the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

Herein, the above-mentioned urotensin-II receptor activity-related diseases are selected from the group consisting of congestive heart failure, cardiac ischemia, myocardial infarction, cardiac hypertrophy, cardiac fibrosis, coronary artery disease, arteriosclerosis, hypertension, asthma, renal failure, diabetes, Stroke, pain, depression, psychosis, cancer, and the like.

The compound represented by the formula 1 according to the present invention acts as an antagonist to the urotensin-II receptor and thus can be used as an antagonist for the urotensin-II receptor, The present invention relates to a health functional food composition for preventing or ameliorating a disease associated with urotensin-II receptor activity such as renal failure, diabetes, vascular inflammation, neurodegenerative diseases, stroke, pain, depression, Can be added.

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

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

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

In addition, in addition to the above, the compound represented by the formula (1) according to the present invention can be used as a flavoring agent such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, coloring agents and intermediates such as cheese, Acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated beverages and the like. In addition, the compound represented by formula (1) of the present invention may contain natural fruit juice and pulp for the production of fruit juice drinks and vegetable drinks.

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

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

< Manufacturing example  1 > 2 - [( Cyanomethyl ) (3,4- Dichlorophenyl ) Amino] Acetic Acid's  Produce

Step 1: Preparation of ethyl 2 - [(3,4-dichlorophenyl) amino] acetate

Figure 112015032633366-pat00043

After dissolving 3,4-dichloroaniline (5.6 g, 34.56 mmol) in N-methyl-2-pyrrolidone (50 ml), ethyl bromoacetate (3.8 ml, 34.56 mmol) and diisopropylethylamine 7.2 ml), which was stirred for 12 hours at 90 deg. After completion of the reaction, the mixture was extracted twice with ethyl acetate (40 ml) and washed twice with water. The organic layer was dried over anhydrous sodium sulfate (Na 2 SO 4 ), concentrated under reduced pressure, and then purified by silica gel column chromatography (normal hexane: ethyl acetate = 9: 1) to obtain the desired compound in 74% yield (6.3 g, 25.39 mmol).

R f = 0.37 (n-hexane and ethyl acetate, 6/1, v / v)

One&Lt; 1 &gt; H NMR (300 MHz, CDCl33)δ 7.22 (d,J = 8.6 Hz, 1 H), 6.66 (s, 1 H), 6.46 (d,J = 8.6 Hz, IH), 4.40 (brs, IH), 4.38 (q, 2H), 3.86J = 5.3 Hz, 2H), 1.33 (t, 3H).

Step 2: Preparation of ethyl 2 - [(cyanomethyl) (3,4-dichlorophenyl) amino] acetate

Figure 112015032633366-pat00044

After dissolving the ethyl 2 - [(3,4-dichlorophenyl) amino] acetate (1.0 g, 4.30 mmol) obtained in the above step 1 in N-methyl-2-pyrrolidone (10 ml), bromoacetonite Reil (0.84 ml, 12.09 mmol), diisopropylethylamine (2.1 ml) and sodium iodide (1.2 g) were added and the mixture was stirred at 120 ° C for 12 hours. After completion of the reaction, the mixture was extracted twice with ethyl acetate (40 ml) and washed twice with water. The organic layer was dried over anhydrous sodium sulfate (Na 2 SO 4 ), concentrated under reduced pressure, and then purified by silica gel column chromatography (normal hexane: ethyl acetate = 9: 1) to obtain the target compound in a yield of 57% (657 mg, 2.28 mmol).

Rf = 0.31 (n-hexane and ethyl acetate, 3/1, v / v)

One&Lt; 1 &gt; H NMR (500 MHz, CDCl33)δ 7.37 (d,J = 8.8 Hz, 1 H), 6.89 (s, 1 H), 6.67 (d,J = 8.8 Hz, 1 H), 4.30 (s, 2H), 4.27 (q, 2H), 4.10 (s, 2H), 1.33 (t, 3H).

Step 3: Preparation of 2 - [(cyanomethyl) (3,4-dichlorophenyl) amino] acetic acid

Figure 112015032633366-pat00045

To a solution of ethyl 2 - [(cyanomethyl) (3,4-dichlorophenyl) amino] acetate (657 mg, 2.28 mmol) obtained in the above step 2 in tetrahydrofuran (5 ml) was dissolved in a small amount of water Lithium hydroxide (74 mg) was added and stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was acidified with 3N hydrochloric acid, extracted twice with ethyl acetate (20 ml), and washed twice with water. After drying over anhydrous sodium sulfate (Na 2 SO 4 ) and concentration under reduced pressure, the desired compound was obtained in a yield of 82% (480 mg, 1.85 mmol).

Rf = 0.17 (dichloromethane and methanol, 10/1, v / v)

One&Lt; 1 &gt; H NMR (500 MHz, CD3OD)δ 7.40 (d,J = 8.9 Hz, 1 H), 6.98 (s, 1 H), 6.79 (d,J = 8.9 Hz, 1 H), 4.51 (s, 2H), 4.08 (s, 2H).

PREPARATION EXAMPLE 2 Preparation of 2- [N- (3,4-dichlorophenyl) acetamido] acetic acid

Step 1: Preparation of ethyl 2- [N- (3,4-dichlorophenyl) acetamido] acetate

Figure 112015032633366-pat00046

(500 mg, 2.01 mmol) obtained in the above Step 1 of Preparation Example 1 was dissolved in dichloromethane (5 ml), and then acetyl chloride (0.22 ml, 3.02 mmol) and triethylamine (0.84 ml) were added, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was extracted twice with ethyl acetate (20 ml) and washed twice with water. The organic layer was dried over anhydrous sodium sulfate (Na 2 SO 4 ), concentrated under reduced pressure, and then purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain the target compound in a yield of 26% (152 mg, 0.52 mmol).

Rf = 0.25 (hexane: ethyl acetate = 3/1, v / v)

One&Lt; 1 &gt; H NMR (300 MHz, CDCl33)δ 2H), 1.94 (s, 3H), 1.31 (t, 3H), 7.51 (m, 2H), 7.22 (s,

Step 2: Preparation of 2- [N- (3,4-dichlorophenyl) acetamido] acetic acid

Figure 112015032633366-pat00047

The objective compound was prepared by carrying out the same procedure as in the step 3 of Preparation Example 1 using ethyl 2- [N- (3,4-dichlorophenyl) acetamido] acetate (152 mg, 0.52 mmol) Yield (120 mg, 0.45 mmol).

Rf = 0.32 (dichloromethane and methanol, 10/1, v / v)

One&Lt; 1 &gt; H NMR (500 MHz, CD3OD)δ7.66 (m, 2H), 7.39 (s, 1H), 4.39 (s, 2H), 2.16 (s, 3H).

< Manufacturing example  3> N- methyl -1- [4- (pyridin-3-yl) phenyl] -2- ( Pyrrolidine -1 day) Ethanamine  Produce

Step 1: Preparation of 1- (4-bromophenyl) -2- (pyrrolidin-1-yl) ethanone

Figure 112015032633366-pat00048

(12 g, 43.17 mmol) was dissolved in tetrahydrofuran (100 ml), and then diisopropylethylamine (15 ml, 86.34 mmol) and pyrrolidine (5.3 ml, 64.76 mmol ) And the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was extracted with ethyl acetate (150 ml) and washed with saturated sodium bicarbonate aqueous solution (100 ml). The organic layer was dried over anhydrous sodium sulfate (Na 2 SO 4 ) and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (5% methanol / dichloromethane) to obtain the target compound in a yield of 79% (9.25 g, 34.49 mmol).

Rf = 0.23 (5% MeOH / MC)

One&Lt; 1 &gt; H NMR (300 MHz, CDCl33) [delta] 7.88 (d,J = 8.5 Hz, 2H), 7.61 (d,J = 8.5 Hz, 2H), 3.98 (s, 2H), 2.75-2.71 (m, 4H), 1.87-1.83 (m, 4H).

Step 2: Preparation of 1- (4-bromophenyl) -2- (pyrrolidin-1-yl) ethanol

Figure 112015032633366-pat00049

1- (4-Bromophenyl) -2- (pyrrolidin-1-yl) ethanone (10.55 g, 39.34 mmol) obtained in the above step 1 was dissolved in ethanol (70 ml) and sodium borohydride 4.46 g, 118.03 mmol), and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent, followed by extraction with chloroform (50 ml) and washing with water (40 ml). The organic layer was dried over anhydrous sodium sulfate (Na 2 SO 4 ) and concentrated under reduced pressure to give the title compound (10.4 g, 38.49 mmol).

One&Lt; 1 &gt; H NMR (300 MHz, CDCl33) [delta] 7.49 (d,J = 5.0 Hz, 2H), 7.29 (d,J = 5.0 Hz, 2H), 4.68-4.66 (m, 1H), 2.79-2.71 (m, 3H), 2.56-2.47 (m, 3H), 1.84-1.80 (m, 4H).

Step 3: Preparation of l- (4-bromophenyl) -N-methyl-2- (pyrrolidin-l-yl) ethanamine

Figure 112015032633366-pat00050

1- (4-Bromophenyl) -2- (pyrrolidin-1-yl) ethanol (6.32 g, 23.39 mmol) obtained in the above step 2 was dissolved in tetrahydrofuran (40 ml) 8.2 ml, 58.48 mmol) and methanesulfonyl chloride (2.2 ml, 28.07 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. Triethylamine (4.9 ml, 35.09 mmol) and methylamine (17 ml, 350.88 mmol) were added and stirred for 20 hours. After the reaction was completed, the reaction mixture was extracted with ethyl acetate (100 ml) and washed with water (300 ml). The organic layer was dried over anhydrous sodium sulfate (Na 2 SO 4 ) and concentrated under reduced pressure to give the object compound (5.5 g, 19.42 mmol).

One&Lt; 1 &gt; H NMR (300 MHz, CDCl33) [delta] 7.49 (d,J = 8.2 &lt; / RTI &gt; Hz, 2H), 7.27 (d,J = 8.2 Hz, 2H), 3.57-3.54 (m, 1H), 2.78 (t,J 2H), 2.29 (s, 3H), 2.27-2.24 (m, 1H), 1.80-1.77 (m, 4H) .

Step 4: Preparation of N-methyl-1- [4- (pyridin-3-yl) phenyl] -2- (pyrrolidin-

Figure 112015032633366-pat00051

The compound (200 mg, 0.71 mmol) obtained in the above step 3 was dissolved in 1,4-dioxane (10 ml), and PdCl 2 (Dppf) 2 .CH 2 Cl 2 (33 mg, (96 mg, 0.78 mmol) and 2M sodium carbonate aqueous solution (1.06 ml, 2.12 mmol) were added thereto, and the mixture was refluxed at 110 占 폚 for 4 hours. After completion of the reaction, the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (dichloromethane: methanol = 3: 1, v / v) to obtain the target compound in a yield of 69% (137 mg, 0.49 mmol).

Rf = 0.17 (dichloromethane and methanol, 3/1, v / v)

One&Lt; 1 &gt; H NMR (300 MHz, CDCl33) [delta] 8.85 (s, IH), 8.57 (d,J= 3.4 Hz, 1 H), 7.86 (d,J= 8.0 Hz, 2H), 7.56 (d,J= 8.2 &lt; / RTI &gt; Hz, 2H), 7.47 (d,J= 8.2 Hz, 2H), 7.34 (dd,J= 8.0, 3.4 Hz, 2H), 3.62-3.67 (m, 1H), 2.90 (t,J= 11.3 Hz, 1H), 2.82-2.86 (m, 2H), 2.64-2.69 (m, 2H), 2.33 (s, 3H), 2.29-2.30 (m, 1H), 1.77-1.81 (m, 4H).

< Manufacturing example  4> N- methyl -1- [4- ( Thiophene Yl) phenyl] -2- ( Pyrrolidine -1 day) Ethanamine  Produce

Figure 112015032633366-pat00052

1- (4-bromophenyl) -N-methyl-2- (pyrrolidin-1-yl) ethanamine (200 mg, 0.71 mmol) obtained in the above Step 3 of Preparation Example 3 was dissolved in 1,4- were dissolved in 10ml), PdCl 2 (dppf) 2 .CH 2 Cl 2 (33 mg, 0.04 mmol) and 3-thiophene beam Nick acid (100 mg, 0.78 mmol), 2M aqueous sodium carbonate solution (1.06 ml, 2.12 mmol) were added and the mixture was refluxed at 110 DEG C for 4 hours. After completion of the reaction, the reaction mixture was filtered using celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane and methanol, 3/1, v / v) to obtain 57% (116 mg, 0.41 mmol).

Rf = 0.16 (dichloromethane and methanol, 3/1, v / v)

One&Lt; 1 &gt; H NMR (300 MHz, CDCl33)δ 7.56 (d,J= 8.2 Hz, 2H), 7.38-7.43 (m, 5H), 3.71-3.76 (m,J= 10.9 Hz, 1H), 2.75-2.79 (m, 2H), 2.63-2.67 (m, 2H), 2.44-2. 48 (m, 1H), 2.34 (s, 3H), 1.82-1.88 (m, 4H).

< Manufacturing example  5> N- methyl -1- [4- (2- Chloropyridine Yl) phenyl] -2- ( Pyrrolidine -1 day) Ethanamine  Produce

Step 1: N-Methyl-2- (pyrrolidin-1-yl) -1- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaballolan- ] Ethaneamine Production

Figure 112015032633366-pat00053

1- (4-bromophenyl) -N-methyl-2- (pyrrolidin-1-yl) ethanamine (1.0 g, 3.53 mmol) obtained in the above Step 3 of Preparation Example 2 was dissolved in 1,4- 30 ml), and then potassium acetylated (1.04 g, 10.59 mmol), PdCl 2 (dppf) 2 .CH 2 Cl 2 (144 mg, 0.18 mmol) and bis (pinacolato) diboron (1.79 g, 7.09 mmol) were added and refluxed at 110 ° C for 2 hours. After completion of the reaction, the reaction mixture was filtered using celite, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (dichloromethane and methanol, 3/1, v / v) to obtain the target compound in a yellow solid form at a yield of 22% 236 mg, 0.72 mmol).

Rf = 0.18 (dichloromethane and methanol, 3/1, v / v)

One&Lt; 1 &gt; H NMR (300 MHz, CDCl33) [delta] 7.79 (d,J= 7.7 Hz, 2H), 7.37 (d,J= 7.7 Hz, 2H), 3.60-3.64 (m, 1H), 2.85 (t,J2H), 2.24-2.26 (m, 2H), 2.28 (s, 3H), 1.71-1.81 (m, 4H) 1.34 (s, 12 H).

Step 2: Preparation of N-methyl-1- [4- (2-chloropyridin-4-yl) phenyl] -2- (pyrrolidin-

Figure 112015032633366-pat00054

To a solution of N-methyl-2- (pyrrolidin-1-yl) -1- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan- ) phenyl] ethanamine (670 mg, 2.03 mmol), PdCl 2 (dppf) were dissolved in 1,4-dioxane (10 ml) 2 .CH 2 Cl 2 (163 mg, 0.20 mmol), 4-bromo-2-chloropyridine (1.16 g, 6.09 mmol) and 2M sodium carbonate aqueous solution (3.05 ml, 6.09 mmol) were added and refluxed at 110 ° C for 4 hours. After completion of the reaction, the reaction mixture was filtered using celite, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (dichloromethane: methanol = 3: 1, v / v) to obtain the desired compound in the form of a yellow solid in a yield of 60% 380 mg, 1.20 mmol).

Rf = 0.16 (dichloromethane and methanol, 3/1, v / v)

One&Lt; 1 &gt; H NMR (300 MHz, CDCl33) [delta] 8.41 (d,J= 5.3 Hz, 1H), 7.47-7.61 (m, 5H), 7.43 (d,J= 5.3 Hz, 1H), 3.63-3.68 (m, 1H), 2.85 (t,J= 11.3 Hz, 1H), 2.62-2.67 (m, 2H), 2.46-2.52 (m, 2H), 2.27-2.37 (m, 4H), 1.75-1.84 (m, 4H).

< Example  1 > 2 - [( Cyanomethyl ) (3,4- Dichlorophenyl ) Amino] -N- methyl (Pyridin-3-yl) phenyl] -2- (pyrrolidin-1-yl) ethyl] acetamide

Figure 112015032633366-pat00055

Amino] acetic acid (53 mg, 0.20 mmol) obtained in Preparation Example 1 was dissolved in dimethylformamide (4 ml), and the resulting mixture was reacted with 2- (pyrrolidin-1-yl) ethanamine (48 mg, 0.17 mmol) obtained in Example 3 and bis (2-oxo- 3-oxazolidinyl) phosphinic chloride (65 mg) and triethylamine (0.071 ml) were added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was extracted twice with ethyl acetate (20 ml) and washed twice with water. After drying over anhydrous sodium sulfate (Na 2 SO 4) and concentrated under reduced pressure was purified by silica gel column chromatography (dichloromethane: methanol = 30: 1, v / v ) to give the desired compound in 43% yield (38 mg, 0.072 mmol) of &Lt; / RTI &gt;

Rf = 0.49 (dichloromethane and methanol, 10/1, v / v)

One&Lt; 1 &gt; H NMR (300 MHz, CD3OD)δ 8.80 (s, 1 H), 8.54 (m, 1 H), 8.12 (d,J = 7.5 Hz, 1 H), 7.74 (d,J = 7.7 Hz, 2H), 7.54 (m, IH), 7.45 (d,J = 7.7 Hz, 2H), 7.37 (d,J = 8.9 Hz, 1 H), 6.99 (m, 1 H), 6.81 (d,J 2H), 3.65 (m, 3H), 2.82 (s, 3H), 2.82 (s, 3H) (m, 2 H), 1.90 (m, 4 H).

< Example  2 > 2 - [( methyl ) (3,4- Dichlorophenyl ) Amino] -N- methyl (Pyridin-3-yl) phenyl] -2- (pyrrolidin-1-yl) ethyl] acetamide

Figure 112015032633366-pat00056

The procedure of Example 1 was repeated except for using 2 - [(3,4-dichlorophenyl) (methyl) amino] acetic acid (50 mg, 0.21 mmol) Yield (41 mg).

Rf = 0.23 (dichloromethane and methanol, 10/1, v / v)

One&Lt; 1 &gt; H NMR (500 MHz, CD3OD)δ 8.81 (s, 1 H), 8.53 (d,J = 3.9 Hz, 1 H), 8.10 (d,J = 5.3 Hz, 1 H), 7.70 (d,J = 7.9 Hz, 2H), 7.52-7.55 (m, 1H), 7.40 (d,J = 7.9 Hz, 2H), 7.26 (d,J = 9.3 Hz, 1 H), 6.81 (d,J = 2.6 Hz, 1 H), 6.64 (dd,J = 9.3, 2.6 Hz, IH), 6.04-6.08 (m, IH), 4.27-4.37 (dd,J (M, 2H), 2.86-2. 70 (m, 2H), 3.86-3.50 (m, 1.90 (m, 4H).

< Example  3 > 2 - [(2- Methoxyethyl ) (3,4- Dichlorophenyl ) Amino] -N- methyl (Pyridin-3-yl) phenyl] -2- (pyrrolidin-1-yl) ethyl] acetamide

Figure 112015032633366-pat00057

The procedure of Example 1 was repeated except for using 2 - [(2-methoxyethyl) (3,4-dichlorophenyl) amino] acetic acid (58 mg, 0.21 mmol) Was obtained in 46% yield (44 mg, 0.081 mmol).

Rf = 0.47 (dichloromethane and methanol, 10/1, v / v)

One&Lt; 1 &gt; H NMR (500 MHz, CD3OD)δ1H), 8.71 (d, 1H), 8.83 (s, 1H)J = 8.1 Hz, 2H), 7.55 (m, 1H), 7.48 (d,J = 8.1 Hz, 1 H), 7.24 (d,J = 8.9 Hz, IH), 6.81 (m, IH), 6.66 (d,J 3H), 2.83 (s, 3H), 2.83 (m, 3H), 2.64 (m, (m, 2 H), 1.87 (m, 4 H).

< Example  4 > 2 - [(acetyl) (3,4- Dichlorophenyl ) Amino] -N- methyl (Pyridin-3-yl) phenyl] -2- (pyrrolidin-1-yl) ethyl] acetamide

Figure 112015032633366-pat00058

The procedure of Example 1 was repeated except that 2- [N- (3,4-dichlorophenyl) acetamido] acetic acid (50 mg, 0.19 mmol) obtained in Preparation Example 2 was used, (10 mg, 0.019 mmol).

Rf = 0.47 (dichloromethane and methanol, 10/1, v / v)

One&Lt; 1 &gt; H NMR (500 MHz, CD3OD)δ 1H), 8.50 (m, 2H), 7.74 (m, 4H), 7.63 (m, (m, 2H), 1.88 (m, 4H), 2.65 (m,

< Example  5 > 2 - [( Methanesulfonyl ) (3,4- Dichlorophenyl ) Amino] -N- methyl (Pyridin-3-yl) phenyl] -2- (pyrrolidin-1-yl) ethyl] acetamide

Figure 112015032633366-pat00059

(64 mg, 0.21 mmol) was used in place of 2- [N- (3,4-dichlorophenyl) methanesulfonylamino] acetic acid Yield (15 mg, 0.026 mmol).

Rf = 0.45 (dichloromethane and methanol, 10/1, v / v)

One&Lt; 1 &gt; H NMR (500 MHz, CD3OD)δ 8.82 (s, 1 H), 8.54 (m, 1 H), 8.12 (d,J = 7.8 Hz, 1 H), 7.78 (s, 1 H), 7.72 (d,J = 8.2 Hz, 2H), 7.56 (m, 3H), 7.42 (d,J2H), 6.06 (m, IH), 4.84 (m, IH), 4.67 (m, IH), 3.43 , &Lt; / RTI &gt; 2.62 (m, 2H), 1.82 (m, 4H).

< Example  6 > 2 - [( benzyl ) (3,4- Dichlorophenyl ) Amino] -N- methyl (Pyridin-3-yl) phenyl] -2- (pyrrolidin-1-yl) ethyl] acetamide

Figure 112015032633366-pat00060

The procedure of Example 1 was repeated except for using 2- [benzyl (3,4-dichlorophenyl) amino] acetic acid (53 mg, 0.17 mmol) to obtain the desired compound in a yield of 46% , 0.064 mmol).

Rf = 0.57 (dichloromethane and methanol, 10/1, v / v)

One&Lt; 1 &gt; H NMR (300 MHz, CD3OD)δ 8.80 (s, 1 H), 8.53 (m, 1 H), 8.11 (d,J = 7.8 Hz, 1 H), 7.69 (d,J= 8.1 Hz, 2H), 7.52 (m, 1H), 7.48 (d,J = 8.1 Hz, 2H), 7.21-7.30 (m, 6H), 6.76 (s,J = 8.5 Hz, IH), 6.05 (m, IH), 4.63 (s, 2H), 4.38 (m, 2H), 3.53 (m, 4H).

< Example  7 > 2 - [( Phenylsulfonyl ) (3,4- Dichlorophenyl ) Amino] -N- methyl (Pyridin-3-yl) phenyl] -2- (pyrrolidin-1-yl) ethyl] acetamide

Figure 112015032633366-pat00061

The procedure of Example 1 was repeated except for using 2 - [(phenylsulfonyl) (3,4-dichlorophenyl) amino] acetic acid (62 mg, 0.17 mmol) Yield (30 mg, 0.048 mmol).

Rf = 0.49 (dichloromethane and methanol, 10/1, v / v)

One&Lt; 1 &gt; H NMR (500 MHz, CDCl33)δ (M, 3H), 7.51 (m, 4H), 7.39 (m, 3H), 7.23 (d,J= 8.0 Hz, 2H), 7.10 (m, IH), 5.90 (m, IH), 4.66 (m, IH), 4.39 -2.79 (m, 5H), 2.47 (m, 2H), 1.75 (m, 4H).

< Example  8 > 2 - [( Benzoyl ) (3,4- Dichlorophenyl ) Amino] -N- methyl (Pyridin-3-yl) phenyl] -2- (pyrrolidin-1-yl) ethyl] acetamide

Figure 112015032633366-pat00062

The procedure of Example 1 was repeated except for using [(benzoyl) (3,4-dichlorophenyl) amino] acetic acid (55 mg, 0.17 mmol) to obtain the title compound in a yield of 53% , 0.074 mmol).

Rf = 0.46 (dichloromethane and methanol, 10/1, v / v)

One&Lt; 1 &gt; H NMR (500 MHz, CDCl33)δ 2H), 7.24 (m, 2H), 7.86 (m, 2H), 7.86 (m, , 7.01 (m, 1 H), 6.11 (m, 1 H), 4.87 (m, 1 H), 4.55 ), 2.56 (m, 2H), 1.79 (m, 4H).

< Example  9 > 2 - [[(t- Butoxycarbonyl ) methyl ] (3,4- Dichlorophenyl ) Amino] -N- methyl (Pyridin-3-yl) phenyl] -2- (pyrrolidin-1-yl) ethyl] acetamide

Figure 112015032633366-pat00063

amino] acetic acid (70 mg, 0.21 mmol) was used as a starting material, to thereby yield the title compound Was obtained in a yield of 34% (35 mg, 0.058 mmol).

Rf = 0.52 (dichloromethane and methanol 10/1, v / v)

One&Lt; 1 &gt; H NMR (500 MHz, CD3OD)δ 8.82 (s, 1 H), 8.55 (s, 1 H), 8.13 (d,J = 8.1 Hz, 1 H), 7.71 (d,J= 8.2 Hz, 2H), 7.56 (m, 1H), 7.49 (d,J = 8.2 Hz, 2H), 7.28 (d,J = 8.9 Hz, 1 H), 6.74 (s, 1 H), 6.57 (d,J 3H), 2.84 (m, 3H), 2.67 (m, IH) (m, 2H), 1.88 (m, 4H), 1.50 (s, 9H).

< Example  10 > 2 - [( Carboxymethyl ) (3,4- Dichlorophenyl ) Amino] -N- methyl (Pyridin-3-yl) phenyl] -2- (pyrrolidin-1-yl) ethyl] acetamide

Figure 112015032633366-pat00064

Methyl] -N- [1- [4- (pyridin-3-yl) methyl] -N-methyl-N- ) Phenyl] -2- (pyrrolidin-1-yl) ethyl] acetamide (25 mg, 0.041 mmol) was dissolved in a mixed solution of trifluoroacetic acid / dichloromethane The mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was adjusted to pH 6 with 3N sodium hydroxide aqueous solution, extracted twice with dichloromethane (30 ml) and washed twice with water. The organic layer was dried over anhydrous magnesium sulfate (MgSO 4 ) and concentrated under reduced pressure to give the target compound in a yield of 90% (20 mg, 0.036 mmol).

Rf = 0.02 (dichloromethane and methanol 10/1, v / v)

One&Lt; 1 &gt; H NMR (500 MHz, CD3OD)δ 8.84 (s, 1 H), 8.57 (s, 1 H), 8.14 (d,J = 7.9 Hz, 1 H), 7.77 (d,J= 8.2 Hz, 2 H), 7.57 (m, 1 H), 7.48 (d,J = 8.2 Hz, 2H), 7.26 (d,J = 8.9 Hz, 1 H), 6.90 (s, 1 H), 6.70 (d,J 1H), 3.66 (m, IH), 3.46 (m, IH), 4.60 (m, 4H), 2.70 (s, 3H), 2.15 (m, 4H).

< Example  11 > 2 - [(2-Amino-2- Oxoethyl ) (3,4- Dichlorophenyl ) Amino] -N- methyl (Pyridin-3-yl) phenyl] -2- (pyrrolidin-1-yl) ethyl] acetamide

Figure 112015032633366-pat00065

Methyl] -N- [l- [4- (pyridin-3-yl) phenyl] -2- (methylsulfanyl) (11 mg, 0.021 mmol) by carrying out the same processes as in the step 3 of the above-mentioned Production Example 1, except for using (pyrrolidin-1-yl) ethyl] acetamide mmol).

Rf = 0.20 (dichloromethane and methanol 10/1, v / v)

One&Lt; 1 &gt; H NMR (500 MHz, CD3OD)δ8.83 (s, 1 H), 8.56 (s, 1 H), 8.13 (d,J = 7.9 Hz, 1 H), 7.75 (d,J = 8.1 Hz, 2H), 7.57 (m, 1H), 7.52 (d,J = 8.1 Hz, 2H), 7.32 (d,J = 8.9 Hz, 1 H), 6.70 (s, 1 H), 6.54 (d,J 3H), 3.00 (s, 3H), 2.89 (m, IH) (m, 2 H), 1.98 (m, 4 H).

< Example  12 > 2 - [(3,4- Dichlorophenyl ) Amino] -N- methyl (Pyridin-3-yl) phenyl] -2- (pyrrolidin-1-yl) ethyl] acetamide

Figure 112015032633366-pat00066

The procedure of Example 1 was repeated except for using 2 - [(3,4-dichlorophenyl) amino] acetic acid (43 mg, 0.19 mmol) to obtain the desired compound in a yield of 62% 0.09 mmol).

Rf = 0.40 (dichloromethane and methanol 10/1, v / v)

One&Lt; 1 &gt; H NMR (300 MHz, CD3OD)δ 8.81 (s, 1 H), 8.52 (s, 1 H), 8.07 (d,J = 7.9 Hz, 1 H), 7.72 (d,J = 8.1 Hz, 2H), 7.54 (m, 1H), 7.43 (d,J = 8.1 Hz, 2H), 7.16 (d,J = 8.9 Hz, 1 H), 6.78 (s, 1 H), 6.60 (d,J (M, 2H), 1.90 (m, 2H), 2.40 (s, 3H) (m, 4H).

< Example  13 > 2- (3,4- Dichlorophenoxy ) -N- methyl (Pyridin-3-yl) phenyl] -2- (pyrrolidin-1-yl) ethyl] acetamide

Figure 112015032633366-pat00067

(27 mg, 0.055 mmol) by carrying out the same procedures as in Example 1, except for using 2- (3,4-dichlorophenoxy) acetic acid (42 mg, 0.19 mmol) &Lt; / RTI &gt;

Rf = 0.48 (dichloromethane and methanol 10/1, v / v)

One&Lt; 1 &gt; H NMR (500 MHz, CD3OD)δ 8.81 (s, 1 H), 8.54 (s, 1 H), 8.11 (d,J = 7.9 Hz, 1 H), 7.68 (d,J = 8.1 Hz, 2H), 7.54 (m, IH), 7.45 (d,J = 8.1 Hz, 2H), 7.42 (d,J = 8.9 Hz, 1 H), 7.20 (s, 1 H), 6.97 (d,J 2H), 1.85 (m, 2H), 2.85 (s, 3H), 2.85 (m, 4H).

< Example  14 > 2 - [(3,4- Dichlorophenyl )[2-( Dimethylamino )-2- Oxoethyl ] Amino] -N-methyl-N- [1- [4- (pyridin-3- yl) phenyl] -2- (pyrrolidin- 1 -yl) ethyl] acetamide

Figure 112015032633366-pat00068

Methyl] -N- [1- [4- (pyridin-3-yl) phenyl] -2- ( (45 mg, 0.083 mmol) was dissolved in dimethylformamide (4 ml), followed by the addition of dimethylamine hydrochloride (14 mg, 0.166 mmol), N- (3- (26 mg, 0.166 mmol), 1-hydroxybenzotriazole hydrate (23 mg, 0.166 mmol) and triethylamine (0.034 ml, 0.249 mmol) were added to a solution of The mixture was stirred at room temperature for 8 hours. After completion of the reaction, the reaction mixture was extracted twice with ethyl acetate (30 ml), washed twice with saturated sodium chloride aqueous solution (30 ml), dried over anhydrous magnesium sulfate (MgSO 4 ) and concentrated under reduced pressure. Purification by chromatography (dichloromethane and methanol 10/1, v / v) afforded the target compound in 42% yield (20 mg, 0.035 mmol).

Rf = 0.28 (dichloromethane and methanol 10/1, v / v)

One&Lt; 1 &gt; H NMR (500 MHz, CD3OD)δ 8.83 (s, 1 H), 8.55 (s, 1 H), 8.14 (d,J = 7.9 Hz, 1 H), 7.72 (d,J = 8.1 Hz, 2H), 7.56 (m, 1H), 7.50 (d,J = 8.1 Hz, 2H), 7.25 (d,J = 8.9 Hz, 1 H), 6.71 (s, 1 H), 6.54 (d,J 3H), 2.88 (s, 3H), 2.79 (s, 3H), 3.79 (m, 2H) (m, 3 H), 2.67 (m, 2 H), 1.92 (m, 4 H).

< Example  15 > 2 - [(3,4- Dichlorophenyl )[2-( Methyl amino )-2- Oxoethyl ] Amino] -N-methyl-N- [1- [4- (pyridin-3- yl) phenyl] -2- (pyrrolidin- 1 -yl) ethyl] acetamide

Figure 112015032633366-pat00069

Methyl] -N- [1- [4- (pyridin-3-yl) phenyl] -2- ( (45 mg, 0.083 mmol) and methylamine hydrochloride (12 mg, 0.166 mmol) in the same manner as in Example 14, the desired compound was obtained from 33 % Yield (15 mg, 0.027 mmol).

Rf = 0.25 (dichloromethane and methanol 10/1, v / v)

One&Lt; 1 &gt; H NMR (500 MHz, CD3OD)δ 8.83 (s, 1 H), 8.55 (s, 1 H), 8.14 (d,J = 7.9 Hz, 1 H), 7.73 (d,J = 8.1 Hz, 2H), 7.56 (m, 1H), 7.51 (d,J = 8.1 Hz, 2H), 7.31 (d,J = 8.9 Hz, 1 H), 6.67 (s, 1 H), 6.50 (d,J 2H), 2.91 (s, 3H), 2.84 (m, 3H), 2.80 (s, 2H) (s, 3H), 2.66 (m, 2H), 1.89 (m, 4H).

< Example  16> 2- [ (3,4-dichlorophenyl) thio ] -N- methyl (Pyridin-3-yl) phenyl] -2- (pyrrolidin-1-yl) ethyl] acetamide

Figure 112015032633366-pat00070

(51 mg, 0.213 mmol) was used in place of 2 - [(3,4-dichlorophenyl) thio] acetic acid (50 mg, 0.10 mmol).

Rf = 0.40 (dichloromethane and methanol 10/1, v / v)

One&Lt; 1 &gt; H NMR (500 MHz, CD3OD)δ8.83 (s, 1 H), 8.55 (d,J = 4.7 Hz, 1 H), 8.13 (d,J = 7.6 Hz, 1 H), 7.68 (d,J = 8.2 Hz, 2H), 7.62 (s, 1H), 7.56 (dd, J = 4.7 Hz, 7.6 Hz, 1H), 7.44J = 8.4 Hz, 1 H), 7.40 (d,J = 8.2 Hz, 2H), 7.38 (d,J = 8.4 Hz, 1 H), 6.05 (d,J = 10.6 Hz, 1 H), 4.09 (d,J = 14.9 Hz, 1 H), 3.98 (d,J = 14.9 Hz, 1 H), 3.42 (dd,J= 12.4 Hz, 10.6 Hz, 1H), 2.91 (s, 3H), 2.85 (d,J = 12.4 Hz, 1H), 2.78 (m, 2H), 2.62 (m, 2H), 1.82 (m, 4H).

< Example  17 > 2 - [( methyl ) (3,4- Dichlorophenyl ) Amino] -N- methyl -N- [2- Morpolino -1- [4- (pyridin-3-yl) phenyl] ethyl] acetamide

Figure 112015032633366-pat00071

2-morpholino-1- [4- (pyridin-3-yl) phenyl] ethane (1.2 eq. Amine (36 mg, 0.12 mmol), the target compound was obtained in a yield of 19% (12 mg, 0.023 mmol).

Rf = 0.36 (dichloromethane: methanol = 100: 7, v / v)

One&Lt; 1 &gt; H NMR (500 MHz, CDCl33) [delta] = 8.84 (s, IH), 8.60 (d,J = 4.4 Hz, 1 H), 7.86 (d,J = 7.4 Hz, 1 H), 7.56 (d,J = 8.0 Hz, 2H), 7.40 (d,J = 8.0 Hz, 2H), 7.37 (d,J = 8.8 Hz, 1 H), 7.23 (dd,J = 7.4, 4.4 Hz, 1 H), 6.72 (s, 1 H), 6.50 (d,J = 8.8 Hz, 1 H), 6.12 (dd,J 2H), 3.73-3.64 (m, 4H), 3.08 (s, 3H), 2.96 (dd,J = 11.2, 5.1 Hz, 1H), 2.80 (s, 3H), 2.76 (dd,J = 11.2, 5.1 Hz, 1H), 2.75-2.71 (m, 2H), 2.44-2.39 (m, 2H).

< Example  18 > 2 - [( benzyl ) (3,4- Dichlorophenyl ) Amino] -N- methyl -N- [2- Morpolino -1- [4- (pyridin-3-yl) phenyl] ethyl] acetamide

Figure 112015032633366-pat00072

2-morpholino-1- [4- (pyridin-3-yl) phenyl] ethanamine (1 eq. (33 mg, 0.11 mmol), the target compound was obtained in a yield of 64% (27 mg, 0.046 mmol).

Rf = 0.37 (dichloromethane: methanol = 100: 7, v / v)

One&Lt; 1 &gt; H NMR (500 MHz, CDCl33)δ = 8.84 (s, 1 H), 8.60 (d,J = 4.9 Hz, 1 H), 7.86 (d,J = 7.7 Hz, 1 H), 7.56 (d,J = 8.2 Hz, 2H), 7.38 (d,J = 8.2 Hz, 2H), 7.38 (d,J = 8.2 Hz, 2H), 7.36 (d,J = 8.6 Hz, 1H), 7.34-7.35 (m, 2H), 7.27-7.30 (m, 3H), 7.19 (dd,J = 7.7, 4.9 Hz, 1 H), 6.72 (s, 1 H), 6.50 (d,J = 8.6 Hz, 1 H), 6.17 (dd,J 2H), 4.16 (q, 2H), 3.37-3.74 (m, 4H), 2.96 (dd,J = 11.2, 4.6 Hz, 1H), 2.77-2.78 (m, 2H), 2.76 (dd,J = 11.2, 4.6 Hz, 1 H), 2.75 (s, 3H), 2.40 - 2.45 (m, 2H).

< Example  19> 2 - [( Cyanomethyl ) (3,4- Dichlorophenyl ) Amino] -N- methyl Phenyl] -2- (pyrrolidin-1-yl) ethyl] acetamide The title compound was prepared in accordance with the general method of example 1,

Figure 112015032633366-pat00073

Except that the N-methyl-1- [4- (thiophen-3-yl) phenyl] -2- (pyrrolidin- 1 -yl) ethanamine (45 mg, 0.15 mmol) , The target compound was obtained in a yield of 46% (36 mg, 0.07 mmol) in the same manner as in Example 1.

Rf = 0.48 (dichloromethane and methanol, 10/1, v / v)

One&Lt; 1 &gt; H NMR (500 MHz, CD3OD)δ 7.68 (d,J = 8.1 Hz, 1H), 7.64 (s, 1H), 7.50 (m, 2H), 7.54J = 8.1 Hz, 3 H), 7.01 (s, 1 H), 6.82 (d,J 2H), 2.76 (s, 3H), 2.85 (m, 2H), 2.76 (m, 1 H), 1.87 (m, 4 H).

< Example  20 > 2 - [( methyl ) (3,4- Dichlorophenyl ) Amino] -N- methyl -N- [1- [4- ( Thiophene Yl) phenyl] -2- (pyrrolidin-1-yl) ethyl] acetamide

Figure 112015032633366-pat00074

The procedure of Example 19 was repeated except for using 2 - [(methyl) (3,4-dichlorophenyl) amino] acetic acid (56 mg, 0.23 mmol) Yield (54 mg).

Rf = 0.35 (dichloromethane and methanol, 10/1, v / v)

One&Lt; 1 &gt; H NMR (500 MHz, CD3OD)δ7.67 (d,J = 8.1 Hz, 1H), 7.64 (s, 1H), 7.46-7.50 (m, 2H), 7.36J = 8.1 Hz, 2H), 7.25 (d,J = 9.1 Hz, 1 H), 6.81 (d,J = 2.7 Hz, 1 H), 6.64 (dd,J = 2.7, 9.1 Hz, 1H), 6.00-6.03 (m, 1H), 4.25-4.35 (dd,J 2H), 1.84-7.81 (m, 2H), 3.45-3.49 (m, 1H), 3.06 (s, 3H) 1.89 (m, 4 H).

< Example  21 > 2 - [(3,4- Dichlorophenyl )(2- Methoxyethyl ) Amino] -N- methyl Phenyl] -2- (pyrrolidin-1-yl) ethyl] acetamide The title compound was prepared in accordance with the general method of example 1,

Figure 112015032633366-pat00075

The procedure of Example 19 was repeated except for using 2 - [(3,4-dichlorophenyl) (2-methoxyethyl) amino] acetic acid (58 mg, 0.21 mmol) Was obtained in a yield of 28% (26 mg, 0.047 mmol).

Rf = 0.45 (dichloromethane and methanol, 10/1, v / v)

One&Lt; 1 &gt; H NMR (300 MHz, CD3OD)δ 7.73 (m, 3H), 7.48 (m, 2H), 7.36 (d,J = 8.1 Hz, 2H), 7.22 (d,J = 8.9 Hz, 1 H), 6.78 (s, 1 H), 6.59 (d,J = 8.1 Hz, 1H), 5.98 (m, IH), 4.24 (m, IH), 3.40 (s, 3H), 3.42 (m, 1 H), 2.52 (m, 2 H), 1.82 (m, 4 H).

< Example  22 > 2 - [(acetyl) (3,4- Dichlorophenyl ) Amino] -N- methyl -N- [1- [4- ( Thiophene Yl) phenyl] -2- (pyrrolidin-1-yl) ethyl] acetamide

Figure 112015032633366-pat00076

The same procedure as in Example 19 was carried out except that 2- [N- (3,4-dichlorophenyl) acetamido] acetic acid (50 mg, 0.19 mmol) obtained in Preparation Example 2 was used The desired compound was obtained in a yield of 32% (25 mg, 0.05 mmol).

Rf = 0.50 (dichloromethane and methanol, 10/1, v / v)

One&Lt; 1 &gt; H NMR (300 MHz, CD3OD)δ (M, 3H), 7.50 (m, 3H), 7.47 (m, 2H), 7.34 (m, 2H), 6.02 (s, 3H), 2.62 (m, 3H), 2.58 (m, 2H), 2.18 (s, 3H), 1.84 (m, 4H).

< Example  23 > 2 - [( Methanesulfonyl ) (3,4- Dichlorophenyl ) Amino] -N- methyl Phenyl] -2- (pyrrolidin-1-yl) ethyl] acetamide The title compound was prepared in accordance with the general method of example 1,

Figure 112015032633366-pat00077

The procedure of Example 19 was repeated except for using 2 - [(methanesulfonyl) (3,4-dichlorophenyl) amino] acetic acid (60 mg, 0.20 mmol) % Yield (50 mg, 0.09 mmol).

Rf = 0.47 (dichloromethane and methanol, 10/1, v / v)

One&Lt; 1 &gt; H NMR (500 MHz, CD3OD)δ 7.75 (s, 1H), 7.63 (m, 3H), 7.50-7.55 (m, 4H), 7.27J2H), 6.00 (m, 1H), 4.81 (m, 1H), 4.64 (m, , 2.58 (m, 2 H), 1.79 (m, 4 H).

< Example  24 > 2 - [( benzyl ) (3,4- Dichlorophenyl ) Amino] -N- methyl -N- [1- [4- ( Thiophene Yl) phenyl] -2- (pyrrolidin-1-yl) ethyl] acetamide

Figure 112015032633366-pat00078

The procedure of Example 19 was repeated except for using 2 - [(benzyl) (3,4-dichlorophenyl) amino] acetic acid (52 mg, 0.16 mmol) Yield (49 mg, 0.084 mmol).

Rf = 0.58 (dichloromethane and methanol, 10/1, v / v)

One&Lt; 1 &gt; H NMR (500 MHz, CD3OD)δ 7.70 (d,J 2H), 7.63 (s, 1H), 7.50 (m, 2H), 7.30-7. 37 (m, 6H), 7.22J 2H), 2.78 (s, 2H), 2.77 (m, 2H), 2.62 (m, 2H), 1.86 m, 4H).

< Example  25 > 2 - [( Phenylsulfonyl ) (3,4- Dichlorophenyl ) Amino] -N- methyl Phenyl] -2- (pyrrolidin-1-yl) ethyl] acetamide The title compound was prepared in accordance with the general method of example 1,

Figure 112015032633366-pat00079

The procedure of Example 19 was repeated except for using 2 - [(phenylsulfonyl) (3,4-dichlorophenyl) amino] acetic acid (61 mg, 0.16 mmol) % Yield (70 mg, 0.11 mmol).

Rf = 0.52 (dichloromethane and methanol, 10/1, v / v)

One&Lt; 1 &gt; H NMR (500 MHz, CDCl33)δ 1H), 7.64 (m, 3H), 7.57-7.61 (m, 5H), 7.43 , 4.37 (m, 1H), 3.06 (m, 1H), 2.88 (s, 3H), 2.67-2.77 (m, 5H), 2.46 (m, 2H), 1.78

< Example  26 > 2 - [( Benzoyl ) (3,4- Dichlorophenyl ) Amino] -N- methyl -N- [1- [4- ( Thiophene Yl) phenyl] -2- (pyrrolidin-1-yl) ethyl] acetamide

Figure 112015032633366-pat00080

The procedure of Example 19 was repeated except for using 2 - [(benzoyl) (3,4-dichlorophenyl) amino] acetic acid (54 mg, 0.16 mmol) Yield (59 mg, 0.09 mmol).

Rf = 0.48 (dichloromethane and methanol, 10/1, v / v)

One&Lt; 1 &gt; H NMR (500 MHz, CDCl33)δ 1H), 4.88 (m, 1H), 7.41 (m, 2H), 7.63 (m, , 4.59 (m, 1H), 3.15 (m, 1H), 2.81 (s, 3H), 2.63-2.65 (m, 5H), 2.53 (m, 2H), 1.77

< Example  27 > 2 - [[(t- Butoxycarbonyl ) methyl ] (3,4- Dichlorophenyl ) Amino] -N- methyl Phenyl] -2- (pyrrolidin-1-yl) ethyl] acetamide The title compound was prepared in accordance with the general method of example 1,

Figure 112015032633366-pat00081

The procedure of Example 19 was repeated except for using 2 - [[(t-butoxycarbonyl) methyl] (3,4-dichlorophenyl) amino] acetic acid, (25 mg, 0.041 mmol).

Rf = 0.51 (dichloromethane and methanol 10/1, v / v)

One&Lt; 1 &gt; H NMR (500 MHz, CD3OD)δ7.69 (d,J = 8.1 Hz, 1 H), 7.65 (s, 1 H), 7.50 (d,J= 8.2 Hz, 2H), 7.39 (d,J = 8.0 Hz, 2H), 7.28 (d,J = 8.9 Hz, 1 H), 6.74 (s, 1 H), 6.57 (d,J 3H), 2.73 (m, 3H), 2.64 (m, IH) (m, 2 H), 1.90 (m, 4 H), 1.50 (s, 9 H).

< Example  28 > 2 - [( Carboxymethyl ) (3,4- Dichlorophenyl ) Amino] -N- methyl Phenyl] -2- (pyrrolidin-1-yl) ethyl] acetamide The title compound was prepared in accordance with the general method of example 1,

Figure 112015032633366-pat00082

Methyl] -N- [1- [4- (thiophene-3-carboxaldehyde &lt; / RTI &gt; Yl) ethyl] acetamide (13 mg, 0.021 mmol) was used in place of the compound obtained in the previous step to give the desired compound in 86% yield (10 mg, 0.018 mmol).

Rf = 0.02 (dichloromethane and methanol 10/1, v / v)

One&Lt; 1 &gt; H NMR (500 MHz, CD3OD)δ 7.67 (d,J = 8.1 Hz, 1 H), 7.51 (s, 1 H), 7.44 (d,J= 8.2 Hz, 2H), 7.25 (d,J = 8.0 Hz, 2H), 7.21 (d,J = 8.9 Hz, 1 H), 6.86 (s, 1 H), 6.58 (d,J 1H), 4.00 (m, 1H), 3.63 (m, 2H), 4.00 (m, (m, IH), 3.05 (m, 2H), 2.52 (m, 2H), 2.09 (s, 3H), 1.31 (m, 4H).

< Example  29 > 2 - [( Cyanomethyl ) (3,4- Dichlorophenyl ) Amino] -N- methyl -N- [2- Morpolino -1- [4- (thiophen-3-yl) phenyl] ethyl] acetamide

Figure 112015032633366-pat00083

(70 mg, 0.23 mmol) obtained in Preparation Example 1 and 2 - [(cyanomethyl) (2-fluorophenyl) 3,4-dichlorophenyl) amino] acetic acid (1.2 eq.) Was used in the same manner as in Example 1 to obtain the desired compound in a yield of 35% (44 mg, 0.08 mmol) .

Rf = 0.19 (dichloromethane: methanol = 20: 1, v / v)

One&Lt; 1 &gt; H NMR (500 MHz, CD3OD)δ 7.63 (d,J (M, 1H), 6.96 (m, 1H), 6.78 (m, 1H), 7.46-7.47 dd,J = 9.0 Hz, 1 H), 6.02 (dd,J = 11.2, 4.3 Hz, 1 H), 4.47 (s, 1 H), 4.40 (d,J = 6.8 Hz, 1H), 3.64-3.71 (m, 4H), 3.08 (t,J = 12.5 Hz, 1 H), 2.82 (s, 3H), 2.69-2.72 (m, 3H), 2.43-2.44 (m, 2H).

< Example  30 > 2 - [(2-Amino-2- Oxoethyl ) (3,4- Dichlorophenyl ) Amino] -N- methyl Phenyl] -2- (pyrrolidin-1-yl) ethyl] acetamide The title compound was prepared in accordance with the general method of example 1,

Figure 112015032633366-pat00084

Methyl] -N- [l- [4- (thiophen-3-yl) phenyl] -2 - [(cyanomethyl) (13 mg, 0.023 mmol) by carrying out the same procedures as in the above Example 11, except for using 2- (pyrrolidin-1-yl) ethyl] acetamide (20 mg, &Lt; / RTI &gt;

Rf = 0.17 (dichloromethane and methanol 10/1, v / v)

One&Lt; 1 &gt; H NMR (300 MHz, CD3OD)δ 7.72 (d,J = 4.4 Hz, 2H), 7.68 (s, 1H), 7.49 (m, 3H), 7.35 (d,J = 8.1 Hz, 2H), 7.31 (d,J = 8.9 Hz, 1 H), 6.66 (s, 1 H), 6.51 (d,J 2H), 3.79 (m, 3H), 2.85 (s, 3H), 2.83 (s, (m, 2 H), 1.90 (m, 4 H).

< Example  31 > 2 - [( Benzoyl ) (3,4- Dichlorophenyl ) Amino] -N- methyl -N- [1- [4- (2- Chloropyridine Yl) phenyl] -2- (pyrrolidin-1-yl) ethyl] acetamide

Figure 112015032633366-pat00085

Amino] acetic acid (45 mg, 0.14 mmol) obtained in Preparation Example 5 and N-methyl-1- [4- (2-chloropyridin- 1-yl) ethanamine (34 mg, 0.11 mmol) was used in place of 2-pyrrolidin-1-ylmethyl- (25.4 mg, 0.04 mmol).

Rf = 0.54 (dichloromethane and methanol, 10/1, v / v)

One&Lt; 1 &gt; H NMR (300 MHz, CD3OD)δ 8.39 (d,J = 5.3 Hz, 1 H), 7.70-7.79 (m, 3 H), 7.64 (d,J 1H), 4.97 (d, IH), 7.44-7.52 (m, 3H), 7.24-7.42 (m, 6H), 7.13-7.19J = 16.6 Hz, 1 H), 4.66 (d,J = 16.6 Hz, 1 H), 3.50 (t,J = 11.7 Hz, 1H), 2.97-3.03 (m, 1H), 2.83 (s, 3H), 2.65-2.94 (m, 4H), 1.78-1.87 (m, 4H).

< Example  32> N- (1- (4- (2- Chloropyridine Yl) phenyl) -2- ( Pyrrolidine Yl) ethyl) -2 - ((cyanomethyl) (3,4-dichlorophenyl) amino) -N-methylacetamide

Figure 112015032633366-pat00086

Was obtained in the same manner as in Example 31, except that 2 - [(cyanomethyl) (3,4-dichlorophenyl) amino] acetic acid obtained in Preparation Example 1 (72 mg, 0.28 mmol) To give the desired compound in a yield of 36% (44 mg, 0.08 mmol).

Rf = 0.45 (dichloromethane and methanol, 10/1, v / v)

One&Lt; 1 &gt; H NMR (500 MHz, CD3OD)δ8.42 (d,J= 5.3 Hz, 1H), 8.77-8.80 (m, 3H), 8.67-8.70 (m,J= 8.4 Hz, 2H), 7.37 (d,J= 8.3 Hz, 1 H), 7.01 (d,J(M, 2H), 3.57 (t, 2H), 4.40-4.48 (m, 2H)J= 11.5 Hz, 1H), 2.82-2.89 (m, 6H), 2.68-2.72 (m, 2H), 1.89-1.96 (m, 4H).

 < Example  33 > 2 - [( methyl ) (3,4- Dichlorophenyl ) Amino] -N- methyl -N- [1- [4- (2- Chloropyridine Yl) phenyl] -2- (pyrrolidin-1-yl) ethyl] acetamide

Figure 112015032633366-pat00087

The procedure of Example 31 was repeated except for using 2 - [(3,4-dichlorophenyl) (methyl) amino] acetic acid (27 mg, 0.12 mmol) 36 mg, 0.06 mmol).

Rf = 0.45 (dichloromethane and methanol, 9/1, v / v)

One&Lt; 1 &gt; H NMR (500 MHz, CD3OD)δ 8.42 (d,J= 5.8 Hz, 1H), 7.76-7.79 (m, 3H), 7.65-7.68 (m,J= 8.1 Hz, 2H), 7.25 (d,J= 9.3 Hz, 1 H), 6.81 (d,J= 2.5 Hz, 1H), 6.61-6.65 (m, 1H), 6.03-6.05 (m, 1H), 4.27-4.37 (m, 2H), 3.46J= 11.6 Hz, 1H), 3.06 (s, 3H), 2.78-2.87 (m, 6H), 2.61-2.65 (m, 2H), 1.85-1.88 (m, 4H).

 < Example  34 > 2 - [(2- Methoxyethyl ) (3,4- Dichlorophenyl ) Amino] -N- methyl Phenyl] -2- (pyrrolidin-1-yl) ethyl] acetamide To a solution of 2-

Figure 112015032633366-pat00088

2- (pyrrolidin-1-yl) ethanamine obtained in Preparation Example 5 and 2 - [(2-methoxyphenyl) Ethyl) (3,4-dichlorophenyl) amino] acetic acid (39 mg, 0.14 mmol) was used to obtain the desired compound in 47% yield (33 mg , 0.05 mmol).

Rf = 0.24 (dichloromethane and methanol, 19/1, v / v)

One&Lt; 1 &gt; H NMR (500 MHz, CD3OD)δ 8.42 (d,J= 5.2 Hz, 1 H), 7.76-7.81 (m, 3 H), 7.68 (dd,J= 1.4, 5.2 Hz, IH), 7.50 (d,J= 8.1 Hz, 2H), 7.23 (d,J= 9.0 Hz, 1 H), 6.80 (d,J= 2.9 Hz, 1 H), 6.64 (dd,J2H), 3.58-3.64 (m, 4H), 3.48 (t, 2H)J= 12.0 Hz, 1 H), 3.37 (s, 3H), 2.88 (s, 3H), 2.80-2.84 (m, 3H), 2.63-2.67 (m, 2H), 1.85-1.88

< Example  35> 2 - [( Methanesulfonyl ) (3,4- Dichlorophenyl ) Amino] -N- methyl Phenyl] -2- (pyrrolidin-1-yl) ethyl] acetamide To a solution of 2-

The procedure of Example 31 was repeated except for using 2 - [(methanesulfonyl) (3,4-dichlorophenyl) amino] acetic acid (47 mg, 0.16 mmol) % Yield (53 mg, 0.09 mmol).

Rf = 0.28 (5% MeOH in MC)

One&Lt; 1 &gt; H NMR (500 MHz, CD3OD) [delta] 8.42 (d,J= 4.9 Hz, 1 H), 7.74-7.79 (m, 4 H), 7.68 (d,J= 4.3 Hz, 1 H), 7.53-7.58 (m, 2H), 7.44 (d,J= 8.0 Hz, 2H), 6.03-6.05 (m, 1H), 4.64-4.84 (m, 2H), 3.40J= 12.3 Hz, 1H), 3.17 (s, 3H), 2.78-2.87 (m, 6H), 2.61-2.65 (m, 2H), 1.80-1.85 (m, 4H).

< Example  36 > 2 - [( Phenylsulfonyl ) (3,4- Dichlorophenyl ) Amino] -N- methyl Phenyl] -2- (pyrrolidin-1-yl) ethyl] acetamide To a solution of 2-

Figure 112015032633366-pat00090

The objective compound was prepared by the same procedure as in Example 31, except for using 2 - [(phenylsulfonyl) (3,4-dichlorophenyl) amino] acetic acid (41 mg, 0.12 mmol) % Yield (30 mg, 0.05 mmol).

Rf = 0.25 (5% MeOH in MC)

One&Lt; 1 &gt; H NMR (500 MHz, CD3OD) [delta] 8.42 (d,J2H), 7.44 (m, 2H), 7.34 (d, 2H)J= 8.1 Hz, 2H), 7.14 (dd,J= 2.2, 8.1 Hz, 1H), 5.90-5.94 (m, 1H), 4.78-4.81 (m, 2H), 3.36J2H), 1.70 ~ 1.77 (m, 4H), 2.75 (s, 3H).

< Example  37 > 2 - [( benzyl ) (3,4- Dichlorophenyl ) Amino] -N- methyl -N- [1- [4- (2- Chloropyridine Yl) phenyl] -2- (pyrrolidin-1-yl) ethyl] acetamide

Figure 112015032633366-pat00091

(38 mg, 0.12 mmol) was used in place of 2 - [(benzyl) (3,4-dichlorophenyl) amino] acetic acid Yield (13 mg, 0.02 mmol).

Rf = 0.25 (5% MeOH in MC)

One&Lt; 1 &gt; H NMR (500 MHz, CD3OD) [delta] 8.42 (d,J= 5.0 Hz, 1 H), 7.78-7.81 (m, 2H), 7.68 (d,J= 3.3 Hz, 1 H), 7.50 (d,J= 8.3 Hz, 2H), 7.21-7.36 (m, 7H), 6.79 (d,J= 3.3 Hz, 1 H), 6.61 (dd,J(M, 2H), 3.50 (t, 2H), 4.65 (s, 2H)J= 11.6 Hz, 1H), 2.80-2.85 (m, 6H), 2.64-2.68 (m, 2H), 1.85-1.90 (m, 4H).

< Example  38 > 2 - [( Cyanomethyl ) (3,4- Dichlorophenyl ) Amino] -N- methyl -N- [2- Morpolino -1- [4- (2-chloropyridin-4-yl) phenyl] ethyl] acetamide

Figure 112015032633366-pat00092

(45 mg, 0.136 mmol) obtained in Preparation Example 1 and 2 - [(cyanomethyl) pyridin-3-yl] ) (3,4-dichlorophenyl) amino] acetic acid (1.2 eq.), The title compound was prepared in 37% yield (27 mg, 0.05 mmol) .

Rf = 0.35 (dichloromethane and methanol, 20 / v / v)

One&Lt; 1 &gt; H NMR (500 MHz, CDCl33)δ 8.45 (d,J = 5.4 Hz, 1 H), 7.60 (d,J = 8.4 Hz, 2H), 7.53 (s, IH), 7.42 (d,J = 5.4 Hz, 1 H), 7.40 (d,J = 8.4 Hz, 2H), 7.35 (d,J = 8.4 Hz, 1 H), 6.84 (s, 1 H), 6.67 (d,J = 8.4 Hz, 1 H), 6.13 (dd,J = 11.5, 4.6 Hz, 1 H), 4.35 (s, 2H), 4.22 (d,J = 17.7 Hz, 1 H), 4.20 (d,J = 17.7 Hz, 1H), 3.68-3.70 (m, 4H), 2.98 (dd,J = 12.3, 11.5 Hz, 1H), 2.82 (s, 3H), 2.78 (dd,J = 12.3, 4.6 Hz, 1H), 2.7-2.76 (m, 2H), 2.42-2.45 (m, 2H).

< Example  39> 2 - [( methyl ) (3,4- Dichlorophenyl ) Amino] -N- methyl -N- [2- Morpolino -1- [4- (2-chloropyridin-4-yl) phenyl] ethyl] acetamide

Figure 112015032633366-pat00093

(51 mg, 0.154 mmol) and 2 - [(3,4-dichlorophenyl) (2-chloropyridin- Methyl) amino] acetic acid (1.2 eq.) Was used in place of the compound obtained in Example 31, the objective compound was obtained in a yield of 16% (14 mg, 0.026 mmol).

Rf = 0.35 (dichloromethane and methanol, 100/3, v / v)

One&Lt; 1 &gt; H NMR (500 MHz, CDCl33)δ 8.45 (d,J = 5.8 Hz, 1 H), 7.58 (d,J = 8.1 Hz, 2H), 7.53 (s, 1 H), 7.42 (d,J = 5.8 Hz, 1 H), 7.39 (d,J = 8.1 Hz, 2H), 7.22 (d,J = 8.9 Hz, 1 H), 6.73 (s, 1 H), 6.52 (d,J = 8.9 Hz, 1 H), 6.17 (dd,J = 10.8, 4.5 Hz, 1 H), 4.15 (d,J = 17.4 Hz, 1 H), 4.13 (d,J = 17.4 Hz, 1H), 3.69-3.72 (m, 4H), 3.12 (dd,J = 12.2, 10.8 Hz, IH), 3.06 (s, 3H), 2.84 (dd,J = 12.2, 4.5 Hz, 1H), 2.77-2.79 (m, 2H), 2.75 (s, 3H), 2.52-2.54 (m, 2H).

The chemical structures of the compounds prepared in Examples 1-39 are summarized in Table 1 below.

Example constitutional formula Example constitutional formula Example constitutional formula


One

Figure 112015032633366-pat00094



2
Figure 112015032633366-pat00095


3
Figure 112015032633366-pat00096


4
Figure 112015032633366-pat00097


5
Figure 112015032633366-pat00098


6
Figure 112015032633366-pat00099


7
Figure 112015032633366-pat00100


8
Figure 112015032633366-pat00101


9
Figure 112015032633366-pat00102


10
Figure 112015032633366-pat00103


11
Figure 112015032633366-pat00104


12
Figure 112015032633366-pat00105


13
Figure 112015032633366-pat00106


14
Figure 112015032633366-pat00107


15
Figure 112015032633366-pat00108


16
Figure 112015032633366-pat00109


17
Figure 112015032633366-pat00110


18
Figure 112015032633366-pat00111


19
Figure 112015032633366-pat00112


20
Figure 112015032633366-pat00113


21
Figure 112015032633366-pat00114


22
Figure 112015032633366-pat00115


23
Figure 112015032633366-pat00116


24
Figure 112015032633366-pat00117


25
Figure 112015032633366-pat00118


26
Figure 112015032633366-pat00119


27
Figure 112015032633366-pat00120


28
Figure 112015032633366-pat00121


29
Figure 112015032633366-pat00122


30
Figure 112015032633366-pat00123


31
Figure 112015032633366-pat00124


32
Figure 112015032633366-pat00125


33
Figure 112015032633366-pat00126


34
Figure 112015032633366-pat00127


35
Figure 112015032633366-pat00128


36
Figure 112015032633366-pat00129


37
Figure 112015032633366-pat00130


38
Figure 112015032633366-pat00131


39
Figure 112015032633366-pat00132

< Experimental Example  1> 3,4- A dichlorophenyl group  Included Acetamide  Derivative Euro Tensin -II receptor binding inhibition activity measurement

In order to confirm the binding inhibition activity of the acetamide derivative containing 3,4-dichlorophenyl group according to the present invention to the urotensin-II receptor, a filtration-based time-resolved fluorescence assay The following experiment was carried out.

Two buffer solutions were prepared: washing solution (25 mM HEPES pH 7.4, 5 mM MgCl 2 , 1 mM CaCl 2 ) and experimental solution (added to BSA 0.5% in wash solution) and labeled with 1 μM europium (Eurotensin-II, # 070-47, Sigma-Aldrich, St. Louis, Mo.) and 1 mM eutectin concentrate (Europent-labeled Urotensin-Ⅱ, Eu-UII, PerkinElmer, Turku, Finland) , USA) at 4 &lt; 0 &gt; C. 1 μM of Eu-UII and 1 mM of urotensin-II were diluted to 8 nM (final reaction concentration: 2 nM) and 4 μM (final reaction concentration: 1 μM), respectively. The buffer solution used in all dilutions and preparations was the experimental solution, and the wash solution was used only to wash the plate at the end. The preparation of the urotensin-II receptor cell membrane for the binding assay was performed using HEK293 UT cell line overexpressing the urotensin-II receptor, which was cultured in a 100 cm 2 flask. If the cells were 90% or more, the medium was removed and washed twice with PBS buffer, followed by addition of 2 ml of 1 mM EDTA-PBS buffer, followed by reaction at 37 ° C for 5 minutes to harvest the cells. The harvested cells were washed twice with PBS buffer, suspended in lysis buffer (10 mM Tris pH 7.4, 5 mM Na-EDTA) supplemented with a 0.5% protease inhibitor cocktail, and pulverized with an ultrasonic mill . Cell debris was removed by centrifugation at 300 g for 5 min and supernatant was centrifuged at 47000 g for 20 min to obtain a precipitate containing cell membrane fraction. The cell membrane fraction precipitate was dissolved in storage buffer (50 mM Tris-HCl pH 7.4, 0.5 mM EDTA, 5 mM MgCl 2 , 10% sucrose) and the concentration was measured by the Bradford method.

50 μl of the urotensin-II receptor (30 mg / ml) was diluted in 5 ml of the test solution and homogenized. Microplates (filter paper-attached microplates, PN5020, Pall Co. Ann Arbor MI, USA) The urotensin-II receptor was dispensed in a volume of 50 μl per well using a channel pipet (multi 8-channel, Eppendorf, Hamburg, Germany). 25 μl of Eu-UII and 25 μl of urotensin-II were used as the non-specific binding control. As a total binding control, 25 μl of 10% DMSO solution and 25 μl of Eu-UII Were used. As the experimental group, 25 μl of the compounds of Examples 1 to 39 according to the present invention and 25 μl of Eu-UII were used. Each test compound, Eu-UII and urotensin-II, accounted for 25% of the total volume during the reaction. After that, it was shaken for 15 seconds and reacted at room temperature for 90 minutes. At the end of the reaction, the plate was filtered and washed by applying pressure to a partially modified, self-fabricated microplate filtration washer (EMBLA, Molecular Devices). 300 μl per well of the washing solution was filtered three times to remove the remaining Eu-UII. Bottom water was wiped off and added with a dissolution solution (DELFIA Enhancement solution, PerkinElmer, Turku, Finland) to 150 μl per well. Time-resolved fluorescence (TRF) values were measured using a multilabel counter (Victor2, PerkinElmer, Turku, Finland) after emulsification for 15 minutes at room temperature (emission wavelength: 615 nm, Wavelength: 340 nm), and the differential fluorescence inhibition rate was calculated by the following equation (1).

Figure 112015032633366-pat00133

After measuring the differential fluorescence inhibition rate, IC 50 values were calculated for test substances inhibited by 50% or more, and the results are shown in Table 2 below.

Example IC 50 ([mu] M) Example IC 50 ([mu] M) One 0.003 21 3.020 2 0.020 22 7.010 3 0.030 23 2.570 4 16% a 24 42% a 5 0.014 25 29% a 6 0.070 26 29% a 7 47% a 27 4.060 8 9.710 28 0.610 9 0.300 29 2.920 10 0.170 30 0.380 11 0.020 31 45% a 12 0.280 32 0.012 13 0.060 33 0.150 14 1.130 34 0.140 15 0.030 35 1.720 16 0.270 36 38% a 17 1.040 37 0.470 18 1.730 38 0.600 19 0.080 39 2.880 20 0.600 - -

a : the retardation of the differential molding light at a concentration of 10 [mu] M

As shown in Table 2 above, the compounds of Examples of the present invention were tested for inhibitory activity against urotensin-II receptor, and as a result, the compounds of Examples 1, 2, 3, 5, 6, 11, 13 and 15 , 19 and 32 antagonistic to the urotensin-II receptor at an IC 50 value of 0.1 μM or less, in particular, the compound of Example 1 has an IC 50 value of 0.005 μM or less, Lt; / RTI &gt; receptors.

Therefore, the compounds according to the present invention act as antagonists to the urotensin-II receptor and thus can be used as antagonists to the urotensin-II receptor, thereby providing a medicament for the treatment of congestive heart failure, cardiac ischemia, myocardial infarction, cardiac hypertrophy and fibrosis, coronary artery disease, arteriosclerosis, hypertension, Inflammatory diseases, neurodegenerative diseases, stroke, pain, depression, psychosis, cancer, and the like.

&Lt; Formulation Example 1 > Preparation of powders

2 g of the compound represented by the general formula (1)

Lactose 1g

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

&Lt; Formulation Example 2 > Preparation of tablet

100 mg of the compound represented by the formula (1)

Corn starch 100 mg

Lactose 100 mg

2 mg of magnesium stearate

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

&Lt; Formulation Example 3 > Preparation of capsules

100 mg of the compound represented by the formula (1)

Corn starch 100 mg

Lactose 100 mg

2 mg of magnesium stearate

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

&Lt; Formulation Example 4 > Preparation of injection

100 mg of the compound represented by the formula (1)

180 mg mannitol

Na 2 HPO 4 .2H 2 O 26 mg

2974 mg of distilled water

According to the conventional method for preparing an injectable preparation, an injectable preparation was prepared by incorporating the aforementioned components in the amounts indicated.

&Lt; Formulation Example 5 > Preparation of health food

The compound represented by the formula (1)

Vitamin mixture quantity

Vitamin A acetate 70 mg

Vitamin E 1.0mg

0.13mg of vitamin

0.15 mg of vitamin B2

Vitamin B6 0.5mg

Vitamin B12 0.2mg

Vitamin C 10mg

Biotin 10mg

Nicotinic acid amide 1.7 mg

Folic acid 50mg

Calcium pantothenate 0.5mg

Mineral mixture quantity

1.75 mg ferrous sulfate

0.82 mg of zinc oxide

Magnesium carbonate 25.3 mg

15 mg of potassium phosphate monobasic

Calcium phosphate diphosphate 55 mg

Potassium citrate 90mg

Calcium carbonate 100 mg

24.8 mg of magnesium chloride

Although the composition ratio of the above-mentioned vitamin and mineral mixture is comparatively mixed with a composition suitable for health food as a preferred embodiment, the compounding ratio may be arbitrarily modified, and the above ingredients are mixed according to a conventional method for producing healthy foods , Granules can be prepared and used in the manufacture of health food compositions according to conventional methods.

&Lt; Formulation Example 6 > Preparation of health drink

The compound represented by the formula (1)

Citric acid 1000mg

Oligosaccharide 100 g

Plum concentrate 2g

Taurine 1g

Purified water was added to the entire 900 ml

The above components were mixed according to a conventional health drink manufacturing method, and the mixture was stirred and heated at 85 DEG C for about 1 hour. The resulting solution was filtered to obtain a sterilized container, which was sealed and sterilized, And used for manufacturing.

Although the composition ratio is relatively mixed with the ingredient suitable for the favorite drink, it is also possible to arbitrarily modify the blending ratio according to the regional or national preference such as the demand class, demand country, use purpose, and the like.

Claims (12)

Claims 1. A compound represented by the following formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]
Figure 112016065279628-pat00134

(In the formula 1,
R 1 is a 5 or 6-membered heteroaryl which is unsubstituted or is substituted by one or more halogens containing at least one heteroatom selected from the group consisting of N, O and S;
R 2 and R 3 together with the N atom to which they are attached may form a 5 or 6 membered heterocycloalkyl wherein the heterocycloalkyl may further comprise an O atom; And
A is O, S or -NR 4 -, wherein R 4 is - (CH 2 ) n R 5 , N is an integer from 0 to 5, R 5 is hydrogen, -CN, C 1-5 linear or branched alkoxy, phenyl,
Figure 112016065279628-pat00135
or
Figure 112016065279628-pat00136
, R &lt; 6 &gt; is -OH, C1-5 straight or branched alkyl, C1-5 straight or branched alkoxy, phenyl or
Figure 112016065279628-pat00137
And R 7 and R 8 are each independently hydrogen or C 1-5 straight chain alkyl).
The method according to claim 1,
Wherein R &lt; 1 &gt; is one or more substituted 5 or 6-membered heteroaryl selected from the group consisting of chloro, fluoro and bromo including at least one heteroatom selected from the group consisting of N, O and S ;
R 2 and R 3 together with the N atom to which they are attached
Figure 112016065279628-pat00138
or
Figure 112016065279628-pat00141
Lt; / RTI &gt;
A is O, S or -NR 4 -, wherein R 4 is - (CH 2 ) n R 5 , N is an integer from 0 to 3, R 5 is hydrogen, -CN, C 1-3 linear or branched alkoxy, phenyl,
Figure 112016065279628-pat00144
or
Figure 112016065279628-pat00145
, R &lt; 6 &gt; is -OH, C1-5 straight or branched alkyl, C1-5 straight or branched alkoxy, phenyl or
Figure 112016065279628-pat00146
And R 7 and R 8 are each independently hydrogen or C 1-3 straight chain alkyl, an optical isomer thereof or a pharmaceutically acceptable salt thereof.
The method according to claim 1,
Wherein R &lt; 1 &
Figure 112015032633366-pat00147
,
Figure 112015032633366-pat00148
,
Figure 112015032633366-pat00149
or
Figure 112015032633366-pat00150
ego;
R 2 and R 3 together with the N atom to which they are attached
Figure 112015032633366-pat00151
or
Figure 112015032633366-pat00152
Lt; / RTI &gt; And
A is O, S or -NR &lt; 4 &gt;-; Wherein R &lt; 4 &gt; is hydrogen, methyl,
Figure 112015032633366-pat00153
,
Figure 112015032633366-pat00154
,
Figure 112015032633366-pat00155
,
Figure 112015032633366-pat00156
,
Figure 112015032633366-pat00157
,
Figure 112015032633366-pat00158
,
Figure 112015032633366-pat00159
,
Figure 112015032633366-pat00160
,
Figure 112015032633366-pat00161
,
Figure 112015032633366-pat00162
,
Figure 112015032633366-pat00163
or
Figure 112015032633366-pat00164
&Lt; / RTI &gt; or an &lt; RTI ID = 0.0 &gt; pharmaceutically &lt; / RTI &gt; acceptable salt thereof.
The method according to claim 1,
The compound represented by the formula (1) is any one selected from the group consisting of the following compounds, an optical isomer thereof or a pharmaceutically acceptable salt thereof:
(1) Synthesis of 2 - [(cyanomethyl) (3,4-dichlorophenyl) amino] -N-methyl-N- [1- [4- (pyridin- 1-yl) ethyl] acetamide;
(2) Synthesis of 2 - [(methyl) (3,4-dichlorophenyl) amino] -N-methyl-N- [1- [4- (pyridin- 1-yl) ethyl] acetamide;
(3) Synthesis of 2 - [(2-methoxyethyl) (3,4-dichlorophenyl) amino] Pyrrolidin-1-yl) ethyl] acetamide;
(4) Synthesis of 2 - [(acetyl) (3,4-dichlorophenyl) amino] -N-methyl-N- [1- [4- (pyridin- 1-yl) ethyl] acetamide;
(5) Synthesis of 2 - [(methanesulfonyl) (3,4-dichlorophenyl) amino] -N-methyl-N- [1- [4- (pyridin- 1-yl) ethyl] acetamide;
(6) Synthesis of 2 - [(benzyl) (3,4-dichlorophenyl) amino] -N-methyl-N- [1- [4- (pyridin- 1-yl) ethyl] acetamide;
(7) Synthesis of 2 - [(phenylsulfonyl) (3,4-dichlorophenyl) amino] -N-methyl-N- [1- [4- (pyridin- 1-yl) ethyl] acetamide;
(8) Synthesis of 2 - [(benzoyl) (3,4-dichlorophenyl) amino] -N-methyl-N- [1- [4- (pyridin- 1-yl) ethyl] acetamide;
(9) Synthesis of 2 - [[(t-butoxycarbonyl) methyl] (3,4-dichlorophenyl) amino] -2- (pyrrolidin-1-yl) ethyl] acetamide;
(10) Synthesis of 2 - [(carboxymethyl) (3,4-dichlorophenyl) amino] -N-methyl-N- [1- [4- (pyridin- -1-yl) ethyl] acetamide;
(11) 2- [(2-Amino-2-oxoethyl) (3,4-dichlorophenyl) amino] 2- (pyrrolidin-1-yl) ethyl] acetamide;
(12) Synthesis of 2 - [(3,4-dichlorophenyl) amino] -N-methyl-N- [1- [4- (pyridin- ) Ethyl] acetamide;
(13) Synthesis of 2- (3,4-dichlorophenoxy) -N-methyl-N- [1- [4- (pyridin- ] Acetamide;
(14) Synthesis of 2 - [(3,4-dichlorophenyl) [2- (dimethylamino) -2-oxoethyl] ) Phenyl] -2- (pyrrolidin-1-yl) ethyl] acetamide;
(15) Synthesis of 2 - [(3,4-dichlorophenyl) [2- (methylamino) -2-oxoethyl] Phenyl] -2- (pyrrolidin-1-yl) ethyl] acetamide;
(16) 2- [(3,4-dichlorophenyl) thio] -N-methyl-N- [1- [4- (pyridin- Yl) ethyl] acetamide;
(17) Synthesis of 2 - [(methyl) (3,4-dichlorophenyl) amino] -N- Acetamide;
(18) Synthesis of 2 - [(benzyl) (3,4-dichlorophenyl) amino] -N- Acetamide;
(19) Synthesis of 2 - [(cyanomethyl) (3,4-dichlorophenyl) amino] -N-methyl-N- [1- [4- (thiophen- Lt; / RTI &gt; yl) ethyl] acetamide;
(20) 2- [(methyl) (3,4-dichlorophenyl) amino] -N-methyl-N- [1- [4- (thiophen- -1-yl) ethyl] acetamide;
(21) Synthesis of 2 - [(3,4-dichlorophenyl) (2-methoxyethyl) amino] -N-methyl-N- [1- [4- (thiophen- (Pyrrolidin-1-yl) ethyl] acetamide;
(22) Synthesis of 2 - [(acetyl) (3,4-dichlorophenyl) amino] -N-methyl-N- [1- [4- (thiophen- -1-yl) ethyl] acetamide;
(23) Synthesis of 2 - [(methanesulfonyl) (3,4-dichlorophenyl) amino] -N-methyl-N- [1- [4- (thiophen- Lt; / RTI &gt; yl) ethyl] acetamide;
(24) Synthesis of 2 - [(benzyl) (3,4-dichlorophenyl) amino] -N-methyl-N- [1- [4- (thiophen- -1-yl) ethyl] acetamide;
(25) Synthesis of 2 - [(phenylsulfonyl) (3,4-dichlorophenyl) amino] -N-methyl-N- [1- [4- (thiophen- Lt; / RTI &gt; yl) ethyl] acetamide;
(26) Synthesis of 2 - [(benzoyl) (3,4-dichlorophenyl) amino] -N-methyl-N- [1- [4- (thiophen- -1-yl) ethyl] acetamide;
(27) Synthesis of 2 - [[(t-butoxycarbonyl) methyl] (3,4-dichlorophenyl) amino] -N- ] -2- (pyrrolidin-1-yl) ethyl] acetamide;
(28) Synthesis of 2 - [(carboxymethyl) (3,4-dichlorophenyl) amino] -N-methyl-N- [1- [4- (thiophen- 1-yl) ethyl] acetamide;
(29) Synthesis of 2 - [(cyanomethyl) (3,4-dichlorophenyl) amino] -N-methyl-N- [2-morpholino- ] Ethyl] acetamide;
(30) Synthesis of 2 - [(2-amino-2-oxoethyl) (3,4-dichlorophenyl) amino] -2- (pyrrolidin-1-yl) ethyl] acetamide;
(31) 2- [(benzoyl) (3,4-dichlorophenyl) amino] -N-methyl-N- [1- [4- (2- chloropyridin- Lt; / RTI &gt; yl) ethyl] acetamide;
(32) Synthesis of 2 - [(cyanomethyl) (3,4-dichlorophenyl) amino] -N-methyl-N- [1- [4- (2- chloropyridin- (Pyrrolidin-1-yl) ethyl] acetamide;
(33) Synthesis of 2 - [(methyl) (3,4-dichlorophenyl) amino] -N-methyl-N- [1- [4- (2-chloropyridin- Lt; / RTI &gt; yl) ethyl] acetamide;
(34) Synthesis of 2 - [(2-methoxyethyl) (3,4-dichlorophenyl) amino] 2- (pyrrolidin-1-yl) ethyl] acetamide;
(35) Synthesis of 2 - [(methanesulfonyl) (3,4-dichlorophenyl) amino] -N-methyl-N- [1- [4- (2- chloropyridin- (Pyrrolidin-1-yl) ethyl] acetamide;
(36) Synthesis of 2 - [(phenylsulfonyl) (3,4-dichlorophenyl) amino] -N-methyl-N- [1- [4- (2- chloropyridin- (Pyrrolidin-1-yl) ethyl] acetamide;
(37) Synthesis of 2 - [(benzyl) (3,4-dichlorophenyl) amino] -N-methyl-N- [1- [4- (2-chloropyridin- Lt; / RTI &gt; yl) ethyl] acetamide;
(38) Synthesis of 2 - [(cyanomethyl) (3,4-dichlorophenyl) amino] -N- ) Phenyl] ethyl] acetamide; And
(39) Synthesis of 2 - [(methyl) (3,4-dichlorophenyl) amino] -N-methyl-N- [2-morpholino- ] Ethyl] acetamide.
As shown in Scheme 1 below,
A process for producing a compound represented by the general formula (1) as set forth in claim 1, comprising the step of reacting a compound represented by the general formula (2) and a compound represented by the general formula (3) in the presence of a condensing agent and a base to prepare a compound represented by the general formula
[Reaction Scheme 1]
Figure 112015032633366-pat00165

(In the above Reaction Scheme 1, R 1 , R 2 , R &lt; 3 &gt; and A are the same as defined in formula (1) of claim 1).
6. The method of claim 5,
The base may be selected from the group consisting of N, N-dimethylaminopyridine (DMAP), pyridine, triethylamine, N, N-diisopropylethylamine (DIPEA), 1,8-diazabicyclo [5.4.0] (DBU), sodium bicarbonate, sodium hydroxide, and potassium hydroxide, either singly or in combination.
6. The method of claim 5,
The condensing agent may be selected from the group consisting of bis (2-oxo-3-oxazolidinyl) phosphinic chloride (BOP-Cl), benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (DIC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC), diphenylphosphonyl azide (DPPA), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide ), N, N-carbonyldiimidazole and O- benzotriazole-N, N, N ', N'-tetramethyl-uronium-hexafluorophosphate (HBTU) Wherein the compound of formula (1) is used alone or in combination of one or more compounds selected from the group consisting of compounds of formula (1).
A pharmaceutical composition comprising a compound represented by the general formula (1) of claim 1, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient for the treatment of hemolytic heart failure, cardiac ischemia, myocardial infarction, cardiac hypertrophy, cardiac fibrosis, coronary artery disease, Wherein the pharmaceutical composition is any one selected from the group consisting of asthma, renal failure, diabetes, vascular inflammation, neurodegenerative diseases, stroke, pain, depression and psychosis.
delete 9. The method of claim 8,
Wherein the compound represented by the formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof acts as an antagonist to the urotensin-II receptor.
A pharmaceutical composition comprising the compound represented by the general formula (1) of claim 1, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an effective ingredient for the treatment of acute heart failure, cardiac ischemia, myocardial infarction, cardiac hypertrophy, cardiac fibrosis, coronary artery disease, Wherein the composition is any one selected from the group consisting of diabetic nephropathy, renal failure, diabetes, vascular inflammation, neurodegenerative diseases, stroke, pain, depression and psychosis. delete
KR1020150047056A 2015-04-02 2015-04-02 34- - Novel acetamide derivatives containing 34-dichlorophenyl group or pharmaceutically acceptable salts thereof preparation method therof and pharmaceutical composition for use in preventing or treating Urotensin- receptor activity related diseases containing the same as an active ingredient KR101664281B1 (en)

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