KR101468207B1 - Novel thieno[3,2-b]pyridinyl urea derivatives or pharmaceutically acceptable salts thereof, preparation method therof and pharmaceutical composition for use in preventing or treating Urotensin-Ⅱ receptor activity related diseases containing the same as an active ingredient - Google Patents

Abstract

The present invention relates to novel thieno [3,2-b] pyridylurea derivatives and their therapeutic uses for U-Ⅱ receptor activity related diseases. The thieno [3,2-b] pyridylurea derivative according to the present invention acts as an antagonist to the U-Ⅱ receptor and thus can be used for the treatment of congestive heart failure, cardiac ischemia, myocardial infarction, cardiac hypertrophy and fibrosis, coronary artery disease, II receptor activity-related diseases such as hypertension, renal failure, diabetes, vascular inflammation, neurodegenerative diseases, stroke, pain, depression, psychosis and cancer.

Description

A novel thieno [3,2-b] pyridylurea derivative or a pharmaceutically acceptable salt thereof, a process for the production thereof, and a pharmaceutical for the prophylactic or therapeutic treatment of a disease associated with the activity of urotensin-II receptor comprising the same as an active ingredient [0001] The present invention relates to novel compounds of formula (I) or their pharmaceutically acceptable salts and their use as active ingredients,

The present invention relates to a novel thieno [3,2-b] pyridylurea derivative or a pharmaceutically acceptable salt thereof, a process for the preparation thereof, and a process for the prevention or the treatment of a disease associated with the activity of a urotensin- ≪ / RTI >

(Hereinafter referred to as "U-II") is a cysteine-linked cyclic peptide, and is known to be one of the most potent vasoconstrictors known to date to be 10 times or more stronger than endothelin-1 (see Non-Patent Document 1 ). U-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).

U-II has been reported to induce myocardial cell hypertrophy and smooth muscle cell proliferation, indicating that it is involved in chronic vascular diseases such as heart failure and atherosclerosis (Non-Patent Document 3). In addition, U-II has been reported to increase the peripheral vascular tone characteristic of chronic heart failure (Non-Patent Document 4). U-Ⅱ is highly expressed in the plasma of patients with renal dysfunction (Non-Patent Document 5). U-Ⅱ has also been reported to be associated with diabetes (Non-Patent Document 6). U-II has also been reported to be associated with central nervous system disorders (Non-Patent Document 7). Overexpressing U-Ⅱ receptors in certain tumor cell lines (Non-Patent Document 8).

U-Ⅱ physiological activity is mediated through the activation of the U-Ⅱ receptor (UT). Previously, the orphan receptor GPR14, a G-protein-coupled-receptor (GPCR) as a seven-domain transmembrane receptor, has been identified as a U-II receptor (Non-Patent Document 9). U-Ⅱ receptors are expressed in various tissues such as blood vessels, heart, liver, kidney, muscle and lung (Non-Patent Document 10).

U-Ⅱ receptor antagonists 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. U-II receptor antagonists may also be useful in the treatment of central nervous system disorders, such as neurodegenerative diseases, stroke, pain, depression and psychosis, and may be useful in the treatment of certain cancers.

Research into the development of U-Ⅱ receptor antagonists is underway to derive low molecular weight synthetic compounds with various chemical skeletons from peptidomimetics studies based on Urandtide.

Accordingly, the present inventors have made efforts to develop a compound having an antagonistic effect on the U-Ⅱ receptor, and have found that a specific structure of the thieno [3,2-b] pyridylurea derivative acts as an antagonist of the U- , And U-Ⅱ receptor activity-related diseases.

 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 a novel thieno [3,2-b] pyridylurea derivative or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a process for preparing the novel thieno [3,2-b] pyridylurea derivatives.

Another object of the present invention is to provide a method for the prevention or treatment of U-Ⅱ receptor activity-related diseases containing the novel thieno [3,2-b] pyridylurea derivative or a pharmaceutically acceptable salt thereof as an active ingredient To provide a pharmaceutical composition.

In order to achieve the above object, the present invention provides a novel thieno [3,2-b] pyridylurea derivative represented by the following general formula (I): or a pharmaceutically acceptable salt thereof:

[Chemical Formula 1]

(X, R ¹ , R ² , R ³ , R ^{4 in the} above formula (1) And n are as defined herein.

The present invention also provides a process for preparing a novel thieno [3,2-b] pyridylurea derivative represented by the above formula (1).

Further, the present invention relates to a method for the prevention of U-Ⅱ receptor activity-related diseases containing the novel thieno [3,2-b] pyridylurea derivative represented by the above formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient Or a pharmaceutical composition for therapeutic use.

The novel thieno [3,2-b] pyridylurea derivative according to the present invention acts as an antagonist to the U-Ⅱ receptor and is useful for the treatment of congestive heart failure, cardiac ischemia, myocardial infarction, cardiac hypertrophy, II receptor activity-related diseases such as atherosclerosis, hypertension, asthma, renal failure, diabetes, vascular inflammation, neurodegenerative diseases, stroke, pain, depression, psychosis and cancer.

Hereinafter, the present invention will be described in detail.

The present invention provides a novel thieno [3,2-b] pyridylurea derivative represented by the following general formula (1) and a pharmaceutically acceptable salt thereof.

In Formula 1,

X is oxygen (O) or sulfur (S);

R ¹ is hydrogen, C ₁ -C ₆ linear or branched alkyl or phenyl;

R ² is hydrogen, halogen, C ₁ -C ₆ linear or branched alkyl;

R ³ is hydrogen, halogen, C ₁ -C ₆ linear or branched alkyl or phenyl;

R ⁴ is hydrogen, halogen, C ₁ -C ₆ straight or branched chain alkyl; And

n is an integer of 0 to 6;

Preferably, in the above formula (1)

X is oxygen (O) or sulfur (S);

R ¹ is hydrogen, C ₁ -C ₄ linear or branched alkyl or phenyl;

R ² is hydrogen, halogen, C ₁ -C ₄ linear or branched alkyl;

R ³ is hydrogen, halogen, C ₁ -C ₄ linear or branched alkyl or phenyl;

R ⁴ is hydrogen, halogen, C ₁ -C ₄ linear or branched alkyl; And

n is an integer of 0 to 5;

More preferably, in Formula 1,

X is oxygen (O) or sulfur (S);

R < ¹ > is hydrogen, methyl, ethyl or phenyl;

R ² is hydrogen, fluoro, chloro, bromo, methyl or ethyl;

R < ³ > is hydrogen, fluoro, chloro, bromo, methyl, ethyl or phenyl;

R < ⁴ > is hydrogen, fluoro, chloro, bromo, methyl or ethyl; And

n is an integer of 0 to 4;

Even more preferably, the thieno [3,2-b] pyridylurea derivative represented by Formula 1 is any one selected from the following group of compounds:

(1) Synthesis of 1- [2- (4-benzyl-4-hydroxypiperidin- 1 -yl) ethyl] -3- (2-methylthieno [3,2- b] pyridin- Urea;

(2) Synthesis of 1- [2- (4-benzyl-4-hydroxypiperidin-1-yl) ethyl] -3- (2-phenylthieno [3,2- b] pyridin- Urea;

(3) Synthesis of 1- [2- (4-benzyl-4-hydroxypiperidin-1-yl) ethyl] -3- (3-bromothiouno [3,2- b] pyridin- ) Urea;

(4) Synthesis of 1- [2- (4-benzyl-4-hydroxypiperidin-1-yl) ethyl] -3- (3-methylthieno [3,2- b] pyridin- Urea;

(5) Synthesis of 1- [2- (4-benzyl-4-hydroxypiperidin- 1 -yl) ethyl] -3- (5- methylthieno [3,2- b] pyridin- Urea;

(6) Synthesis of 1- [2- (4-benzyl-4-hydroxypiperidin-1-yl) ethyl] -3- Urea;

(7) Synthesis of 1- [2- (4-benzyl-4-hydroxypiperidin-1-yl) ethyl] -3- (5- chlorothieno [3,2- b] pyridin- Urea;

(8) Synthesis of 1- [2- (4-benzyl-4-hydroxypiperidin- 1 -yl) ethyl] -3- (5- phenylthieno [3,2- b] pyridin- Urea;

(9) 1- [2- [4- (2-Bromobenzyl) -4-hydroxypiperidin- 1 -yl] ethyl] -3- (thieno [3,2- b] pyridin- - yl) urea;

(10) 1- [2- [4- (3-Bromobenzyl) -4-hydroxypiperidin- 1 -yl] ethyl] -3- (thieno [3,2- b] pyridin- - yl) urea;

(11) 1- [2- [4- (2-Methylbenzyl) -4-hydroxypiperidin- 1 -yl] ethyl] -3- (thieno [3,2- b] pyridin- Yl) urea;

(12) 1- [2- [4- (3-Methylbenzyl) -4-hydroxypiperidin- 1 -yl] ethyl] -3- (thieno [3,2- b] pyridin- Yl) urea;

(13) 1- [2- [4- (4-methylbenzyl) -4-hydroxypiperidin- 1 -yl] ethyl] -3- (thieno [3,2- b] pyridin- Yl) urea;

(14) 1- [2- [4- (4-Fluorobenzyl) -4-hydroxypiperidin- 1 -yl] ethyl] -3- (thieno [3,2- b] pyridin- - yl) urea;

(15) 4-Benzyl-4-hydroxy-N- (thieno [3,2-b] pyridin-7-yl) piperidine-1-carboxamide;

(16) 1- [3- (4-Benzyl-4-hydroxypiperidin-1-yl) propyl] -3- (thieno [3,2-b] pyridin-7-yl) urea;

(17) 1- [4- (4-Benzyl-4-hydroxypiperidin-1-yl) butyl] -3- (thieno [3,2-b] pyridin-7-yl) urea;

(18) 1- [2- (4-Benzyl-4-hydroxypiperidin-1-yl) ethyl] -3- (thieno [3,2-b] pyridin-7-yl) urea; And

(19) Synthesis of 1- [2- (4-benzyl-4-hydroxypiperidin-1-yl) ethyl] -3- (thieno [3,2- b] pyridin- .

The structures of the novel thieno [3,2-b] pyridylurea derivatives represented by Formula 1 according to the present invention are shown in Table 1 below.

Example constitutional formula Example constitutional formula

One

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

_

_

The derivatives of formula (I) of the present invention can be used in the form of pharmaceutically acceptable salts, and as salts, acid addition salts formed by pharmaceutically acceptable free acids are 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, hydroxyalkanoates, Citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid and the like, which are non-toxic organic acids such as hydrochloric acid, hydrobromic acid, Examples of such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, But are not limited to, at least one selected from the group consisting of hydrides, hydrides, hydrides, hydrides, hydrides, hydrides, hydrides, , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluene sulfonate, chlorobenzene Propionate, naphthalene-1, < / RTI > < RTI ID = 0.0 & -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 a derivative of the formula (1) in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile and the like, Followed by filtration and drying. Alternatively, 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).

Further, the present invention relates to novel thieno [3,2-b] pyridylurea derivatives represented by the above formula (1) and pharmaceutically acceptable salts thereof, as well as solvates, hydrates and the like which can be prepared therefrom All included.

The present invention also provides a process for preparing a thieno [3,2-b] pyridylurea derivative represented by the above formula (1).

Recipe 1  :

The method for producing the thieno [3,2-b] pyridylurea derivative represented by the formula (1) according to the present invention can be carried out,

A step of hydrolyzing a compound represented by the formula (2) under base or acid conditions to obtain a compound represented by the formula (3) (step 1);

(Step 2) of obtaining a compound represented by the formula (4) by subjecting a compound represented by the formula (3) obtained in the step 1) to an azidation reaction with an azidating reagent under a base condition; And

The compound represented by the general formula (5), which is obtained through the intramolecular rearrangement reaction of the compound represented by the general formula (4) obtained in the above step 2, is reacted with the compound represented by the general formula (6) under basic conditions to obtain the cyano , 2-b] pyridylurea derivative compound (step 3).

[Reaction Scheme 1]

(In the above Reaction Scheme 1, R ¹ , R ² , R ³ , R ⁴ And n is as defined in Formula 1 above; The compound of formula (5) is a compound produced through an intramolecular shift reaction of the compound of formula (4); The compound of formula (Ia) is included in the compound of formula (1).

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

First, step 1 according to the present invention is a step of hydrolyzing a nitrile group compound represented by formula (2) under base or acid conditions to obtain a carboxylic acid compound represented by formula (3).

In step 1, the base may be an inorganic base such as sodium carbonate, potassium carbonate, potassium hydroxide, sodium hydroxide, cesium carbonate, barium hydroxide, etc. The acid may be hydrochloric acid, sulfuric acid or methanesulfonic acid.

In the step 1, the solvent may be an ether solvent such as tetrahydrofuran, dioxane, dichloromethane, 1,2-dimethoxyethane and the like; Aromatic hydrocarbon solvents such as benzene, toluene, xylene and the like; Lower alcohols such as methanol, ethanol, propanol, butanol and the like; Dimethylformamide (DMF); Dimethyl sulfoxide (DMSO); Acetonitrile and the like can be used alone or in combination.

Further, the reaction of step 1 above may be carried out at 0 ° C to the boiling point of the solvent or lower.

Next, in the step 2 according to the present invention, the carboxylic acid compound represented by the formula (3) obtained in the above step 1 is subjected to azidation reaction with an azidation reagent under a base condition to obtain a carboxylic azide compound represented by the formula (4) .

In step 2, the base is an organic base such as pyridine, triethylamine, N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene An inorganic base such as sodium carbonate, sodium carbonate, potassium carbonate, cesium carbonate and the like can be used in an equivalent amount or in an excess amount.

In step 2, the carboxylic acid compound is subjected to an azidation reaction with an azidating reagent such as diphenylphosphoryl azide (DPPA) or azido dimethylimidazolinium (ADMC) (SOCl ₂ ), phosphorus oxychloride (POCl ₃ ), N-halosuccinimide / triphenylphosphine, bistrichloromethyl carbonate, trichlorophosphate, dihydroxy (3,4,5-trifluorophenyl) borane, 1-propanephosphoric acid cyclic unhadride, and the like, followed by substitution reaction using sodium azide to produce a carboxy halide indirectly Carboxyl azide may also be prepared.

Further, in the step 2, the solvent may be an ether-based solvent such as tetrahydrofuran, dioxane, dichloromethane, 1,2-dimethoxyethane and the like; Aromatic hydrocarbon solvents such as benzene, toluene, xylene and the like; Dichloromethane, dichloroethane, chloroform, etc. may be used alone or in combination. The reaction of Step 2 can be carried out at a temperature ranging from room temperature to a boiling point of the solvent or less.

Next, the step 3 according to the present invention is characterized in that an isocyanate compound represented by the general formula (5), which is obtained through the intramolecular rearrangement reaction of the carboxylic azide compound represented by the general formula (4) obtained in the above step 2, To obtain a thieno [3,2-b] pyridylurea compound represented by the general formula (Ia).

In step 3, the base is an organic base such as pyridine, triethylamine, N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) An inorganic base such as sodium carbonate, sodium carbonate, potassium carbonate, cesium carbonate and the like can be used in an equivalent amount or in an excess amount.

In the step 3, the solvent may be an ether solvent such as tetrahydrofuran, dioxane, dichloromethane, 1,2-dimethoxyethane and the like; Aromatic hydrocarbon solvents such as benzene, toluene, xylene and the like; Dichloromethane, dichloroethane, chloroform, etc. may be used alone or in combination.

Further, the reaction of Step 3 can be carried out at a temperature ranging from room temperature to a boiling point of the solvent or lower.

Preparation of starting material 1:

The compound of Formula 2, which is the starting material of Reaction Scheme ^1, Can be manufactured and used in two ways.

Specifically, the substituent R < ^{1 >} Lt; / RTI > is hydrogen,

A step of chlorinating a compound represented by the formula (7) with a chlorination reagent to obtain a compound represented by the formula (8) (step 1); And

A step of cyanating a compound represented by the formula (8) obtained in the step 1 with a cyanation reagent under a transition metal catalyst to obtain a compound represented by the formula (2a) (step 2-a).

Also, when the substituent R < ¹ > is a compound of formula (2b) wherein an alkyl or phenyl group is introduced,

A step of chlorinating a compound represented by the formula (7) with a chlorination reagent to obtain a compound represented by the formula (8) (step 1);

A step of alkylating or halogenating the compound represented by the formula 8 obtained in the above step 1 under basic conditions and Suzuki coupling reaction under a base and a transition metal catalyst to obtain a compound represented by the formula 9 -b); And

And a step of cyanating a compound represented by the formula (9) obtained in the above step 2-b with a cyanation reagent under a metal catalyst to obtain a compound represented by the formula (2b) (step 3-b) .

[Reaction Scheme 2]

(In the above Reaction Scheme 2, R ¹ is as defined in the above formula (1); and the compound of the formula (2) is contained in the compound of the formula (2).

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

First, substituent R < ^{1 >} In the case of the compound of formula (2a) in which hydrogen is introduced,

Step 1 according to the present invention is a step of chlorinating a hydroxy compound represented by the formula (7) with a chlorination reagent to obtain a chloro compound represented by the formula (8).

In step 1, the chlorination reagent may be phosphorous oxychloride (POCl ₃ ) or phosphorous trichloride (PCl ₃ ), and the solvent may be selected from the group consisting of tetrahydrofuran, dioxane, 1,2-dimethoxyethane and the like Ether solvents; Aromatic hydrocarbon solvents such as benzene, toluene, xylene and the like; Dichloromethane, dichloroethane, chloroform, etc. may be used alone or in combination.

In addition, the reaction of Step 1 can be carried out at a temperature ranging from room temperature to a boiling point of the solvent or lower.

Next, the step 2-a according to the present invention is a step of reacting the chloro compound represented by the formula 8 obtained in the step 1 with a metal cyanide under a transition metal catalyst condition to obtain a nitrile compound represented by the formula 2a.

In step 2-a, the metal cyanide reagent may be zinc cyanide, potassium cyanide, iron cyanide, copper cyanide, or the like.

In the step 2-a, the transition metal catalyst may be tetrakistriphenylphosphine palladium (Pd (PPh ₃ ) ₄ ), palladium charcoal (Pd-C), bistriphenylpalladium dichloride (PdCl ₂ (PPh ₃ ) ₂ ), tris dibenzylidene acetone palladium (Pd ₂ (dba) ₃ ), 1,1-bis (diphenylphosphinoferrocene) dichloropalladium (PdCl ₂ (dppf)), aryl palladium chloride dimer ] ₂ ), diacetate palladium (Pd (OAc) ₂ ), palladium dichloride (PdCl ₂ ) and the like can be used.

Further, in the step 2-a, the solvent may be an ether solvent such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane and the like; Aromatic hydrocarbon solvents such as benzene, toluene, xylene and the like; Lower alcohols such as methanol, ethanol, propanol, butanol and the like; Dimethylformamide (DMF); Dimethyl sulfoxide (DMSO); Acetonitrile, water, etc. may be used alone or in combination,

Furthermore, the reaction of step 1 above can be carried out at 0 ° C to the boiling point of the solvent.

The substituent R < ^{1 >} Is a compound of formula (2b) wherein an alkyl or phenyl group is introduced,

Step 1 according to the present invention is a step of chloroforming a compound represented by the formula (7) with a chlorination reagent to obtain a compound represented by the formula (8).

The specific preparation method of the step 1 is a step of reacting the substituent R ¹ This compound is the same as the preparation method of Step 1 in the case of the compound of Formula 2a in which hydrogen is introduced.

Next, the step 2-b according to the present invention can be carried out by alkylating or halogenating the compound represented by the formula 8 obtained in the above step 1 under basic conditions, then reacting the boronic acid compound with Suzuki ) Coupling reaction to obtain a compound represented by the formula (9).

In the step 2-b, the base of the alkylation reaction or the halogenation reaction may be an equivalent or an excess amount of lithium diisopropylamide (LDA), n-butyllithium, s-butyllithium, t-butyllithium, , And as the solvent, ether solvents such as tetrahydrofuran, dioxane, dichloromethane, 1,2-dimethoxyethane and the like can be used.

In the step 2-b, the base of the Suzuki coupling reaction may be an equivalent amount or an excess amount of inorganic bases such as sodium carbonate, potassium carbonate, potassium hydroxide, sodium hydroxide, cesium carbonate, barium hydroxide and the like.

Further, in the step 2-b, the boronic acid compound can be used by using commercially available compounds or by preparing from the corresponding halide compound by a known method.

Moreover, in the transition metal catalyst in step 2-b is a transition metal catalyst, tetrakis (triphenylphosphine) palladium _{(Pd (PPh 3) 4)} , palladium charcoal (Pd-C), bis-triphenyl palladium dichloride (PdCl ₂ (PPh ₃ ) ₂ ), trisdibenzylidene acetone palladium (Pd ₂ (dba) ₃ ), 1,1-bis (diphenylphosphinoferrocene) dichloropalladium (PdCl ₂ (dppf)), aryl palladium chloride dimer Palladium catalysts such as [PdCl (allyl)] ₂ ), diacetate palladium (Pd (OAc) ₂ ), palladium dichloride (PdCl ₂ ) and the like can be used.

Further, triphenylphosphine (PPh ₃ ), triosoctolylphosphine (P- (O-tolyl) ₃ ), tributylphosphine (PBu ₃ ), and the like may be used in the step 2- Or a salt such as lithium chloride, lithium bromide, lithium iodide, or the like can be used as an adduct.

Further, in the step 2-b, the solvent of the Suzuki coupling reaction may be an ether solvent such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane and the like; Aromatic hydrocarbon solvents such as benzene, toluene and xylene; Lower alcohols such as methanol, ethanol, propanol, butanol and the like; Dimethylformamide (DMF); Dimethyl sulfoxide (DMSO); Acetonitrile, water, etc., may be used alone or in combination.

Further, the reaction of step 2-b can be carried out at 0 ° C to the boiling point of the solvent or lower.

Next, Step 3-b according to the present invention is a process for producing a nitrile compound of Formula 2b by coupling reaction of a chloro compound represented by Formula 9 obtained in Step 2-b with a metal cyanide under a transition metal catalyst condition to be.

The specific production method in the step 3-b is the same as the production method of the step 2-a.

Preparation of starting material 2:

As to the starting material is a compound of Formula 2 of Scheme 1 shown in Scheme 3, the substituents R ² And R < ³ >.

Specifically, in the case of the compound of the formula (2c) wherein the substituent R ² is introduced,

Brominating a compound represented by the formula (10) with a brominating reagent to obtain a compound represented by the formula (11) (step 1-c); And

(Step 2-c) comprising subjecting a compound represented by the formula 11 obtained in the above step 1-c to a Suzuki coupling reaction with a boronic acid compound under basic and transition metal catalyst conditions ≪ / RTI >

Further, in the case of the compound of the formula (2d) wherein the substituent R ³ is introduced,

Oxidizing a compound represented by the formula (10) with an oxidizing agent to obtain a compound represented by the formula (12) (step 1-d);

(Step 2-d) of obtaining a compound represented by the formula (13) by subjecting the compound represented by the formula (12) obtained in the step 1-d to chlorination reaction with a chloro reagent; And

(Step 3-d) of coupling a compound represented by the formula 13 obtained in the above step 2-d with an alkyl metal compound or a phenylboronic acid compound under a transition metal catalyst condition to obtain a compound represented by the formula 2d And can be produced by a production method.

[Reaction Scheme 3]

(Wherein R ¹ , R ² and R ³ are as defined in the above formula (1), and the compounds of the formulas (2c) and (2d) are included in the compound of the formula (2).

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

First, in the case of the compound of the formula (2c) wherein the substituent R ² is introduced,

Step 1-c according to the present invention is a step of brominating a compound represented by the formula (10) with a brominating reagent to obtain a bromo compound represented by the formula (11).

In step 1-c, the bromination reagent may be N-bromosuccinimide (NBS), bromine, styrene-4-vinyl (N-alkylpyridinium bromide), etc. The solvent may be hydrochloric acid, Acid solvents such as methanesulfonic acid and the like; Dichloromethane, dichloroethane, chloroform, etc. may be used alone or in combination.

In addition, the reaction of step 1-c can be carried out at room temperature or below the boiling point of the solvent.

Next, Step 2-c according to the present invention is a process for producing a compound of the formula (2c) by reacting a compound represented by the formula (11) obtained in the above step 1-c with Suzuki coupling reaction with a boronic acid compound under basic and transition metal catalyst conditions .

In the above Step 2-c, the boronic acid compound can be used by using commercially available compounds or by preparing from the corresponding halide compound by a known method.

In the step 2-c, the transition metal catalyst may be palladium, nickel or a platinum derivative, but it is preferable to use a palladium catalyst. The palladium catalyst may be at least one selected from the group consisting of tetrakistriphenylphosphine palladium (Pd (PPh ₃ ) ₄ ), palladium charcoal (Pd-C), bistriphenylpalladium dichloride (PdCl ₂ (PPh ₃ ) ₂ ), trisdibenzylidene acetone palladium Pd ₂ (dba) ₃ ), 1,1-bis (diphenylphosphinoferrocene) dichloropalladium (PdCl ₂ (dppf)), arylpalladium chloride dimer ([PdCl (allyl)] ₂ ), diacetate palladium OAc) ₂ ), palladium dichloride (PdCl ₂ ), and the like.

Further, triphenylphosphine (PPh ₃ ), triosoctolylphosphine (P- (O-tolyl) ₃ ), tributylphosphine (PBu ₃ ), and the like were added in the step 2- Or a salt such as lithium chloride, lithium bromide, lithium iodide, or the like can be used as an adduct.

Further, in step 2-c, the solvent may be an ether solvent such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane and the like, an aromatic hydrocarbon solvent such as benzene, toluene, xylene, methanol, ethanol, Lower alcohols such as butanol; Dimethylformamide (DMF); Dimethyl sulfoxide (DMSO); Acetonitrile, water, etc., may be used alone or in combination.

In step 2-c, an inorganic base such as sodium carbonate, potassium carbonate, potassium hydroxide, sodium hydroxide, cesium carbonate, barium hydroxide or the like may be used in an equivalent amount or an excess amount.

Further, the reaction of step 2-c may be carried out at 0 ° C to a boiling point of the solvent or lower.

Also, in the case of the compound of formula (2d) wherein the substituent R ³ is introduced,

The step 1-d according to the present invention is a step of obtaining an N-oxide compound represented by the formula (12) by an oxidation reaction of a compound represented by the formula (10) with an oxidizing agent.

In step 1-d, the oxidizing agent may be m-chloroperbenzoic acid (MCPBA), perbenzoic acid, peracetic acid, trifluoroperacetic acid, hydrogen peroxide (H ₂ O ₂ ), dioxirane,

In the above step 1-d, the solvent may be an ether solvent such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane and the like; Dichloromethane, dichloroethane, chloroform, water, etc., may be used alone or in combination.

Further, the reaction of the above step 1-d can be carried out at room temperature or below the boiling point of the solvent.

Next, the step 2-d according to the present invention is a step for obtaining a compound represented by the formula (13) by subjecting the compound represented by the formula (12) obtained in the step 1-d to a chlorination reaction with a chloro reagent.

In step 2-d, phosphorus oxychloride (POCl ₃ ) or phosphorous trichloride (PCl ₃ ) may be used as the chlorination reagent.

In addition, in step 2-d, the solvent may be an ether-based solvent such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane and the like; Aromatic hydrocarbon solvents such as benzene, toluene, xylene and the like; Dichloromethane, dichloroethane, chloroform, etc. may be used alone or in combination.

Further, the reaction of step 2-d may be carried out at a temperature ranging from room temperature to a boiling point of the solvent.

Next, the above step 3-d according to the present invention can be carried out by coupling a chloro compound represented by the formula 13 obtained in the above step 2-d with an alkyl metal compound or a boronic acid compound under a base or transition metal catalyst condition, To obtain the compound to be displayed.

In the above step 3-d, the alkyl metal compound may be alkyl aluminum, zinc, magnesium, etc., and the boronic acid compound may be a commercially available compound, and the alkyl metal compound may be alkyl aluminum.

In the step 3-d, the transition metal catalyst may be palladium, nickel, iron, platinum or the like, and it is preferable to use a palladium catalyst. The palladium catalyst may be at least one selected from the group consisting of tetrakistriphenylphosphine palladium (Pd (PPh ₃ ) ₄ ), palladium charcoal (Pd-C), bistriphenylpalladium dichloride (PdCl ₂ (PPh ₃ ) ₂ ), trisdibenzylidene acetone palladium Pd ₂ (dba) ₃ ), 1,1-bis (diphenylphosphinoferrocene) dichloropalladium (PdCl ₂ (dppf)), arylpalladium chloride dimer ([PdCl (allyl)] ₂ ), diacetate palladium OAc) ₂ ), palladium dichloride (PdCl ₂ ), and the like.

Further, when boronic acid is used in step 3-d, the reaction is carried out in the presence of a base. The base may be an inorganic base such as sodium carbonate, potassium carbonate, potassium hydroxide, sodium hydroxide, cesium carbonate, barium hydroxide and the like.

(PPh ₃ ), triosoctolylphosphine (P- (O-tolyl) ₃ ), tributylphosphine (PBu ₃ ), and the like were used in the above step 3-d to promote the reaction and increase the yield. ) And the like, or salts such as lithium chloride, lithium bromide, lithium iodide and the like can be used as adducts.

In the step 3-d, the solvent may be an ether solvent such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane and the like; Aromatic hydrocarbon solvents such as benzene, toluene, xylene and the like; Lower alcohols such as methanol, ethanol, propanol, butanol and the like; Dimethylformamide (DMF); Dimethyl sulfoxide (DMSO); Acetonitrile, water and the like can be used alone or in combination, and the reaction of Step 2 can be carried out at 0 ° C to a boiling point of the solvent or lower.

Recipe 2:

Another method for producing a thieno [3,2-b] pyridylurea derivative represented by the formula (1) according to the present invention is a method for producing a thieno [3,2-

A step of subjecting a compound represented by the formula (14) to an azide substitution reaction with an azide reagent to obtain a compound represented by the formula (15) (step 1);

A step (step 2) of reducing the compound represented by the formula (15) obtained in the above step 1 under hydrogenation reaction conditions to obtain the compound represented by the formula (16);

Reacting a compound represented by the formula (16) obtained in the above step 2 with a compound represented by the formula (17) to obtain a compound represented by the formula (18) (step 3); And

To obtain a thieno [3,2-b] pyridylurea compound represented by the formula (Ib) by alkylation with a compound represented by the formula (19) in the presence of a base in the step 3 ). ≪ / RTI >

[Reaction Scheme 4]

(In the above Reaction Scheme 4, R ¹ , R ² , R ³ , R ⁴ And n are the same as defined in Formula 1, and the compound of Formula (Ib) is included in the compound of Formula (1).

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

Step 1 according to the present invention is a step for azide substitution reaction of the chloro compound represented by the formula (14) to obtain the azide compound represented by the formula (15).

In the step 1, the azide reagent may be sodium azide, and the solvent may be an ether solvent such as tetrahydrofuran, dioxane, dichloromethane, 1,2-dimethoxyethane and the like; Dimethylformamide (DMF); Dimethyl sulfoxide (DMSO); Acetonitrile and the like can be used alone or in combination.

In addition, the reaction of Step 1 can be carried out at a temperature ranging from room temperature to a boiling point of the solvent or lower.

Next, in the step 2 according to the present invention, the azide compound represented by the formula (15) obtained in the step (1) is subjected to a reduction reaction using a transition metal catalyst under hydrogenation conditions to obtain an amine compound represented by the formula (16).

In the step 2, the transition metal catalyst may be nickel, palladium, platinum or the like,

In the step 2, the solvent may be a lower alcohol such as methanol, ethanol, propanol, butanol and the like; Ether solvents such as tetrahydrofuran, dioxane, dichloromethane, 1,2-dimethoxyethane, etc. may be used alone or in combination.

Further, the reaction of Step 2 can be carried out at a temperature ranging from room temperature to a boiling point of the solvent.

Next, the step 3 of the present invention is a step of reacting the amine compound represented by the formula (16) obtained in the above step 2 with an isocyanate compound represented by the formula (17) to obtain the compound represented by the formula (18).

In the step 3, the solvent is an ether solvent such as tetrahydrofuran, dioxane, dimethoxyethane, 1,2-dimethoxyethane and the like; Dimethylformamide (DMF); Dimethyl sulfoxide (DMSO); Acetonitrile and the like can be used alone or in combination.

In addition, 3 can be carried out at room temperature or below the boiling point of the solvent.

Next, in the step 4 according to the present invention, the compound represented by the formula 18 obtained in the above step 3 is subjected to alkylation reaction with the compound represented by the formula 19 under basic conditions to obtain cyano [3,2-b ] Pyridyl urea compound.

In the step 4, the base may be an equivalent of an inorganic base such as a tertiary amine organic base such as triethylamine, isopropylethylamine or the like or an inorganic base such as sodium carbonate, potassium carbonate, potassium hydroxide, sodium hydroxide, cesium carbonate, barium hydroxide and the like .

In addition, in the step 4, the solvent may be an ether solvent including tetrahydrofuran, dioxane, dimethoxyethane, 1,2-dimethoxyethane and the like; Dimethylformamide (DMF); Dimethyl sulfoxide (DMSO); Acetonitrile and the like can be used alone or in combination.

Further, the reaction of Step 4 can be carried out at a temperature ranging from room temperature to a boiling point of the solvent.

Method 3:

Another method for preparing a thieno [3,2-b] pyridylurea derivative represented by the formula (1) according to the present invention is a method for producing a thieno [3,2-

Reacting a compound represented by the formula (20) with a thiocarbonyl reagent under basic conditions to obtain an isothiocyanate compound represented by the formula (21) (step 1); And

(Step 2) of reacting the compound represented by the formula 21 obtained in the above step 1 with a compound represented by the formula 6 under a base condition to obtain a cyano [3,2-b] pyridylurea compound represented by the formula 1c, . ≪ / RTI >

[Reaction Scheme 5]

(In the above Reaction Scheme 5, R ¹ , R ² , R ³ , R ⁴ And n are the same as defined in Formula 1, and the compound of Formula 1c is included in the compound of Formula 1.

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

Step 1 according to the present invention is a step of reacting an amine compound represented by the general formula (20) with a thiocarbonyl reagent under a basic condition to obtain an isothiocyanate compound represented by the general formula (21).

In the above step 1, the thiocarbonyl reagent may be at least one compound selected from the group consisting of carbon disulfide, thiophosgene, thyourea, dipyridyl thionocarbonate (DPT), 1,1'-thiocarbonyldiimidazole, Thiocarbonyl-1,2,4-triazole or 1,1'-thiocarbonyl-2,2'-pyridone.

In the step 1, the base may be an organic base such as pyridine, triethylamine, N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene Inorganic bases such as sodium carbonate, potassium carbonate, potassium hydroxide, sodium hydroxide, cesium carbonate, barium hydroxide and the like can be used in an equivalent amount or in an excess amount.

Further, in the step 1, the solvent may be an ether solvent such as tetrahydrofuran, dioxane, dimethoxyethane, 1,2-dimethoxyethane and the like; Aromatic hydrocarbon solvents such as benzene, toluene, xylene and the like; Dichloromethane, dichloroethane, chloroform, etc. may be used alone or in combination.

Further, the reaction of Step 1 can be carried out at a temperature ranging from room temperature to a boiling point of the solvent or lower.

Next, in the step 2 according to the present invention, the isothiocyanate compound represented by the formula (21) obtained in the above step 1 is reacted with the amine compound represented by the formula (6) under basic conditions to obtain cyano [3 , 2-b] pyridylurea compound.

In step 2, the base is an organic base such as pyridine, triethylamine, N , N -diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) An inorganic base such as sodium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, barium hydroxide and the like can be used in an equivalent amount or an excess amount.

In the step 2, the solvent may be an ether solvent such as tetrahydrofuran, dioxane, dimethoxyethane or 1,2-dimethoxyethane; Aromatic hydrocarbon solvents such as benzene, toluene, xylene and the like; Dichloromethane, dichloroethane, chloroform, etc. may be used alone or in combination.

Further, the reaction of Step 2 can be carried out at a temperature ranging from room temperature to a boiling point of the solvent.

The present invention also relates to a method for the prophylactic or therapeutic treatment of U-Ⅱ receptor activity-related diseases containing the thieno [3,2-b] pyridylurea derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient A pharmaceutical composition is provided.

The U-Ⅱ receptor activity-related diseases include, but are not limited to, congestive heart failure, cardiac ischemia, myocardial infarction, cardiac hypertrophy, cardiac fibrosis, coronary artery disease, arteriosclerosis, hypertension, asthma, renal failure, diabetes, vascular inflammation, Pain, depression, mental illness, and cancer.

The thieno [3,2-b] pyridylurea derivatives represented by the above formula (1) according to the present invention were tested for their U-Ⅱ receptor binding inhibitory activity, , Compounds of 10, 11, 14, and 18 were found to antagonize the superior U-Ⅱ receptor at IC ₅₀ values of less than 100 nM. In particular, the compounds of Examples 5, 11, The IC ₅₀ value was 30 nM or less, indicating an effect of antagonizing the U-Ⅱ receptor, which is excellent (see Experimental Example 1).

Therefore, the thieno [3,2-b] pyridylurea derivative represented by the formula (1) according to the present invention acts as an antagonist to the U-Ⅱ receptor and thus can be used for the treatment of congestive heart failure, cardiac ischemia, myocardial infarction, Is useful for the prevention or treatment of diseases related to U-Ⅱ receptor activity such as fibrosis, coronary artery disease, arteriosclerosis, hypertension, asthma, renal failure, diabetes, vascular inflammation, neurodegenerative diseases, stroke, pain, depression, psychosis and cancer .

When the composition of the present invention is used as a medicine, the pharmaceutical composition containing the derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient may be administered orally or parenterally May be formulated and administered, but the present invention is not limited thereto.

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 containing the derivative represented by Formula 1 as an active ingredient may be administered parenterally, and parenteral administration may be performed by subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.

In order to formulate the formulation for parenteral administration, the thieno [3,2-b] pyridylurea derivative of Formula 1 or a pharmaceutically acceptable salt thereof is mixed with water together with a stabilizer or a buffer to prepare a solution or suspension , Which can be prepared in an ampoule or vial unit dosage form. 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 dosage of the pharmaceutical composition containing the derivative of Formula 1 as an active ingredient may be varied depending on the age, body weight, sex, dosage form, health condition and disease severity of the patient, and preferably 0.01 to 200 mg / Kg / day, depending on the judgment of the physician or pharmacist, may be administered by oral or parenteral route by dividing the time interval by several times a day, preferably once or three times a day.

Hereinafter, the present invention will be described in detail by way of examples,

It should be noted, however, that the following examples are illustrative of the present invention and are not intended to limit the scope of the present invention.

< Manufacturing example  1> Thieno [3,2-b] pyridine -7- Carbonitrile  Produce

Step 1: 7- Of 3-chloro-thieno [3,2-b] pyridine  Produce

A no [3,2-b] pyridin-7-ol (1.0 g, 6.61 mmol) in Im phosphorus oxychloride (POCl _3, 10 ml), and the mixture was stirred at 90 占 폚 for 4 hours. The reaction was terminated at 0 &lt; 0 &gt; C using ice water, and saturated sodium hydroxide was slowly added until pH 9 at the same temperature. Saturated sodium hydrogencarbonate (100 ml) was further added, extracted with dichloromethane (200 ml), dried over anhydrous magnesium sulfate (MgSO ₄ ) and concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (dichloromethane and methanol, 20/1, v / v) to give the title compound (5.3 g, 31.2 mmol, 98%, yellow oil).

Rf = 0.36 (n-hexane and ethyl acetate, 3/1, v / v);

^{1 H NMR (300 MHz, CDCl} 3) δ 8.60 (d, J = 5.0 Hz, 1H), 7.80 (d, J = 5.5 Hz, 1H), 7.59 (d, J = 5.5 Hz, 1H), 7.28 (d , &Lt; / RTI &gt; J = 5.0 Hz, 1H).

Step 2: Thieno [3,2-b] pyridine -7- Carbonitrile  Produce

7-Chlorothieno [3,2-b] pyridine (110 mg, 0.65 mmol) obtained in the above step 1 was dissolved in N, N-dimethylacetamide (5 ml) _{2, 76 mg, 0.65 mmol)} , tris (dibenzylideneacetone) dipalladium _{(Pd (dba) 3, 27} mg, 0.03 mmol), 1,1- bis (diphenylphosphino) ferrocene (dppf, 17mg, 0.03 mmol) and zinc (4.2 mg, 0.07 mmol) were added, followed by microwave reaction at 180 ° C for 15 minutes. Water (30 ml) was added to terminate the reaction, followed by filtration through celite. The mixture was extracted with ethyl acetate (30 ml), dried over anhydrous magnesium sulfate (MgSO ₄ ) and concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (n-hexane and ethyl acetate, 3/1, v / v) to give the title compound (73 mg, 70%, pale yellow solid).

Rf = 0.20 (n-hexane and ethyl acetate, 3/1, v / v)

^{1 H NMR (300 MHz, CDCl} 3) δ 8.84 (d, J = 4.7 Hz, 1H), 7.93 (d, J = 5.5 Hz, 1H), 7.66 (d, J = 5.5 Hz, 1H), 7.53 (d , &Lt; / RTI &gt; J = 4.7 Hz, 1H).

< Manufacturing example  2> 2- Methylthieno [3,2-b] pyridine -7- Carbonitrile  Produce

Step 1: 7- Chloro -2- Methylthieno [3,2-b] pyridine  Produce

7-Chlorothi eno [3,2-b] pyridine (200 mg, 1.18 mmol) obtained in Preparation Example 1 was dissolved in tetrahydrofuran (10 ml) and cooled to 0 ° C. butyllithium ( n- BuLi, 2.5 M, 710 μl, 1.77 mmol) was added and stirred for 10 minutes. Methyl iodide (220 μl, 3.54 mmol) was further added at the same temperature and slowly warmed to room temperature Lt; / RTI &gt; The reaction was terminated by adding water (60 ml), followed by extraction with acetone (60 ml), drying over anhydrous magnesium sulfate (MgSO ₄ ) and concentration under reduced pressure. The filtrate was purified by silica gel column chromatography (n-hexane and ethyl acetate, 3/1, v / v) to obtain the title compound (120 mg, 0.65 mmol, 55%, pale yellow crystals).

Rf = 0.36 (n-hexane and ethyl acetate, 3/1, v / v);

¹ H NMR (300 MHz, CDCl ₃ ) ? 8.49 (d, J = 5.1 Hz, IH), 7.23 (s, IH), 7.17 (d, J = 5.1 Hz, IH), 2.65 (s, 3H).

Step 2: 2- Methylthieno [3,2-b] pyridine -7- Carbonitrile  Produce

Was obtained in the same manner as in Step 2 of Preparation Example 1, except that 7-chloro-2-methylthieno [3,2-b] pyridine (120 mg, 0.65 mmol) The compound (110 mg, 97%, pale yellow solid) was obtained.

Rf = 0.16 (n-hexane and ethyl acetate, 5/1, v / v);

¹ H NMR (300 MHz, CD ₃ OD) ? 8.73 (d, J = 4.8 Hz, 1H), 7.41 (d, J = 4.8 1H), 7.30 (s, 1H), 2.71

< Manufacturing example  3> 7- Chloro -2- Phenylthieno [3,2-b] pyridine  Produce

Step 1: 7- Chloro -2- Iodo-thieno [3,2-b] pyridine  Produce

7-Chlorothi eno [3,2-b] pyridine (182 mg, 1.07 mmol) obtained in the above Step 1 of Preparation Example 1 was dissolved in tetrahydrofuran (5 ml), and lithium di (LDA, 2M, 810 [mu] l, 1.61 mmol) was added and stirred for 10 minutes. Iodine (680 [mu] l, 2.68 mmol) was further added, slowly warmed to room temperature and stirred for one hour. Water (30 ml) was added to terminate the reaction. The reaction mixture was extracted with ethyl acetate (30 ml), dried over anhydrous magnesium sulfate (MgSO ₄ ) and concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (n-hexane and ethyl acetate, 50/1, v / v) to give the title compound (245 mg, 0.83 mmol, 78%, pale yellow solid).

Rf = 0.38 (n-hexane and ethyl acetate, 10/1, v / v);

¹ H NMR (300 MHz, CDCl ₃ ) ? 8.51 (d, J = 5.1 Hz, 1H), 7.80 (s, 1H), 7.21 (d, J = 5.1 Hz, 1H).

Step 2: 7- Chloro -2- Phenylthieno [3,2-b] pyridine  Produce

The compound (240 mg, 0.81 mmol) obtained in the above Step 1 was dissolved in 1,2-dimethoxyethane (5 ml), tetrakis triphenylphosphine palladium (Pd (PPh ₃ ) ₄ , 46 mg, 0.04 mmol ), Phenylboronic acid (149 mg, 1.22 mmol) and saturated sodium hydrogencarbonate (8 ml) were added and the mixture was refluxed for 3 hours. The reaction was terminated by addition of water (30 ml), followed by extraction with ethyl acetate (30 ml), drying over anhydrous magnesium sulfate (MgSO ₄ ) and concentration under reduced pressure. The filtrate was purified by silica gel column chromatography (n-hexane and ethyl acetate, 50/1, v / v) to obtain the title compound (166 mg, 0.68 mmol, 84%, yellow solid).

Rf = 0.26 (n-hexane and ethyl acetate, 10/1, v / v);

^{1 H NMR (300 MHz, CDCl} 3) δ 8.55 (d, J = 4.6 Hz, 1H), 7.76 (s, 1H), 7.74 (m, 2H), 7.45 (m, 3H), 7.23 (d, J = 4.6 Hz, 1H).

Step 3: 2- Phenylthieno [3,2-b] pyridine -7- Carbonitrile  Produce

       2-phenylthieno [3,2-b] pyridine (160 mg, 0.65 mmol) obtained in the above Step 2, the title compound (148 mg, 97%, yellow solid).

Rf = 0.18 (n-hexane and ethyl acetate, 5/1, v / v)

^{1 H NMR (300 MHz, CDCl} 3) δ 8.79 (d, J = 4.8 Hz, 1H), 7.83 (s, 1H), 7.77 (m, 2H), 7.48 (m, 4H).

< Manufacturing example  4> 3- Bromo-thieno [3,2-b] pyridine -7- Carbonitrile  Produce

The solution of thieno [3,2-b] pyridine-7-carbonitrile (50 mg, 0.31 mmol) obtained in Preparation Example 1 was dissolved in a mixed solvent of chloroform and acetic acid (5/1, 2 ml) Was added N-bromosuccinimide (NBS, 110 mg, 0.62 mmol), and the mixture was refluxed for 20 hours. The reaction was terminated by adding water (30 ml), extracted with dichloromethane (30 ml), dried over anhydrous magnesium sulfate (MgSO ₄ ) and concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (n-hexane and ethyl acetate, 50/1, v / v) to give the title compound (15 mg, 0.06 mmol, 19%, white solid).

Rf = 0.34 (n-hexane and ethyl acetate, 5/1, v / v);

^{1 H NMR (300 MHz, CDCl} 3) δ 8.97 (d, J = 4.7 Hz, 1H), 7.97 (s, 1H), 7.64 (d, J = 4.7 Hz, 1H).

< Manufacturing example  5> 3- Methylthieno [3,2-b] pyridine -7- Carbonitrile  Produce

3-Bromo-thieno [3,2-b] pyridine-7-carbonitrile (94 mg, 0.39 mmol) obtained in Preparation Example 4 was dissolved in dioxane (5 ml), and methylboronic acid , 0.43 mmol), bis-triphenyl palladium dichloride _{(Pd (PPh 3) 2 Cl} 2 , 14 mg, 0.02 mmol) and cesium carbonate (Cs ₂ CO ₃ , 319 mg, 0.98 mmol) were added and the mixture was stirred at 120 ° C for 2.5 hours under microwave conditions. 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 (n-hexane and ethyl acetate, 10/1, v / v) to give the title compound (39 mg, 0.22 mmol, 56%, white solid).

Rf = 0.30 (n-hexane and ethyl acetate, 10/1, v / v);

¹ H NMR (300 MHz, CDCl ₃ ) ? 8.84 (d, J = 4.6 Hz, 1H), 7.56 (s, 1H), 7.52 (d, J = 4.6 Hz,

< Manufacturing example  6> 5- Chlorothieno [3,2-b] pyridine -7- Carbonitrile  Produce

Step 1: 7- Cyanothi eno [3,2-b] pyridine  4- Oxide , 3- Chlorobenzoate  Produce

The thieno [3,2-b] pyridine-7-carbonitrile (170 mg, 1.06 mmol) obtained in Preparation Example 1 was dissolved in dichloromethane (5 ml), and then methacrolephoperbenzoic acid (mCPBA) , 1.27 mmol), and the mixture was stirred at room temperature for 20 hours. The solvent was concentrated under reduced pressure to give the title compound (73 mg, 0.22 mmol, 21%).

Rf = 0.30 (dichloromethane and methanol, 20/1, v / v);

^{1 H NMR (300 MHz, CDCl} 3) δ 11.1 (br, s, 1H), 8.46 (d, J = 6.1 Hz, 1H), 8.08 (s, 1H), 7.98 (d, J = 8.3 Hz, 1H) , 7.91 (d, J = 5.3 Hz, 1H), 7.87 (m, 1H), 7.58 (m, 2H), 7.43 (m, 1H).

Step 2: 5- Chlorothieno [3,2-b] pyridine -7- Carbonitrile  Produce

3-chlorobenzoate (352 mg, 1.06 mmol) obtained in the above step 1 was slowly added to phosphorus oxychloride (POCl ₃ , 3 ml) And the mixture was stirred at 90 DEG C for 20 hours. The reaction was terminated at 0 &lt; 0 &gt; C using ice water, and saturated sodium hydroxide was slowly added until pH 9 at the same temperature. After completion of the reaction, the reaction mixture was extracted with dichloromethane (200 ml) and washed with a saturated aqueous solution of sodium hydrogencarbonate (100 ml). The organic layer was dried over anhydrous magnesium sulfate (MgSO ₄ ) and concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (dichloromethane and methanol, 20/1, v / v) to give the title compound (43 mg, 0.02 mmol, 2%, yellow solid).

Rf = 0.38 (n-hexane and ethyl acetate, 10/1, v / v);

^{1 H NMR (300 MHz, CDCl} 3) δ 7.99 (d, J = 5.5 Hz, 1H), 7.60 (d, J = 5.5 1H), 7.58 (s, 1H).

< Manufacturing example  7> 5- Methylthieno [3,2-b] pyridine -7- Carbonitrile  Produce

5-Chlorothi eno [3,2-b] pyridine-7-carbonitrile (40 mg, 0.21 mmol) obtained in Preparative Example 6 was dissolved in dioxane (2 ml), tetrakis ) palladium _{(Pd (PPh 3) 4,} 23 mg, 0.02 mmol) and trimethyl aluminum (2M in Hexane, 525 μl, 1.05 mmol) and then the mixture was refluxed for 2 hours. The mixture was stirred for 5 minutes, extracted with ethyl acetate (20 ml), further basified with 10 N NaOH, and extracted with ethyl acetate (20 ml). After drying with anhydrous magnesium sulfate (MgSO ₄₎ to give the after concentration under reduced pressure, the filtrate was purified by silica gel column chromatography (n-hexane and ethyl acetate, 5/1, v / v) The title compound (28 mg, 0.16 mmol, 76 %, Pale white solid).

Rf = 0.09 (n-hexane and ethyl acetate, 10/1, v / v);

^{1 H NMR (300 MHz, CDCl} 3) δ 7.88 (d, J = 5.5 Hz, 1H), 7.57 (d, J = 5.5 Hz, 1H), 7.42 (s, 1H), 2.75 (s, 3H).

< Manufacturing example  8> 5- Ethylthieno [3,2-b] pyridine -7- Carbonitrile  Produce

Except that 5-chloro-thieno [3,2-b] pyridine-7-carbonitrile (100 mg, 0.51 mmol) obtained in Preparation Example 6 and triethylaluminum (1 M, 2.3 ml) , The title compound (50 mg, 52%) was obtained.

Rf = 0.48 (n-hexane and ethyl acetate, 10/1, v / v);

^{1 H NMR (300 MHz, CDCl} 3) δ 7.89 (d, J = 6.0 Hz, 1H), 7.61 (d, J = 6.0 Hz, 1H), 7.43 (s, 1H), 3.02 (m, 2H), 1.39 (t, 3 H).

< Manufacturing example  9> 5- Phenylthieno [3,2-b] pyridine -7- Carbonitrile  Produce

5-Chlorothi eno [3,2-b] pyridine-7-carbonitrile (50 mg, 0.25 mmol) obtained in Preparative Example 6 was dissolved in dioxane (3 ml), and phenylboronic acid (32 mg) , Cesium carbonate (209 mg), and bistriphenylphosphine palladium dichloride (9 mg) were added, and the mixture was stirred at 120 ° C for 1 hour under microwave conditions. The reaction was terminated, filtered through celite, extracted twice with ethyl acetate (20 ml), and washed twice with water. After drying with anhydrous sodium sulfate (Na ₂ SO ₄₎ and the filtrate was concentrated under reduced pressure, purified by silica gel column chromatography (n-hexane and ethyl acetate, 10/1, v / v) The title compound (50 mg, 0.21 mmol, 83 % ).

Rf = 0.65 (n-hexane and ethyl acetate, 10/1, v / v);

^One&Lt; 1 &gt; H NMR (300 MHz, CDCl3₃) [delta] 8.07 (d,J = 6.7 Hz, 2H), 7.97 (s, 1H), 7.95 (d,J = 5.5 Hz, 1 H), 7.72 (d,J = 5.5 Hz, IH), 7.57-7. 49 (m, 3H).

< Example  1 > 1- [2- (4-Benzyl- Hydroxypiperidine Yl) ethyl] -3- (2- Methylthieno [3,2-b] pyridine -7 days) Urea  Produce

Step 1: 2- Methylthieno [3,2-b] pyridine -7- Carboxylic  Produce

2-Methylthieno [3,2-b] pyridine-7-carbonitrile (110 mg, 0.63 mmol) obtained in Preparation Example 2 was dissolved in ethanol (5 ml), sodium hydroxide (10 N, 3.15 mmol) was added and refluxed for 20 hours. The reaction mixture was neutralized with sulfuric acid, extracted with ethyl acetate (30 ml) and dried over anhydrous magnesium sulfate (MgSO ₄ ). The solvent was concentrated under reduced pressure to give the title compound (120 mg, 0.63 mmol, 99 %, Yellow oil).

¹ H NMR (300 MHz, CD ₃ OD) ? 8.68 (d, J = 5.0 Hz, 1H), 7.84 (d, J = 5.0 Hz, 1H), 7.27 (s, 1H), 2.69

Step 2: 2- Methylthieno [3,2-b] pyridine -7- Carbonyl Azaid  Produce

2-methylthieno [3,2-b] pyridine-7-carboxylic acid (120 mg, 0.63 mmol) obtained in the above Step 1 was dissolved in N, N-dimethylformamide (5 ml) 176 [mu] l, 1.26 mmol) and diphenylphosphoryl azide (205 [mu] l, 0.95 mmol) were added and stirred at room temperature for 2 hours. The reaction was terminated with water (30 ml), extracted with dichloromethane (30 ml), dried over anhydrous magnesium sulfate (MgSO ₄ ) and concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (n-hexane and ethyl acetate, 3/1, v / v) to give the title compound (122 mg, 0.56 mmol, 89%, yellow solid).

Rf = 0.19 (n-hexane and ethyl acetate, 5/1, v / v);

¹ H NMR (300 MHz, CDCl ₃ ) ? 8.70 (d, J = 4.9 Hz, 1H), 7.62 (d, J = 4.9 Hz, 1H), 7.24 (s,

Step 3: l- [2- (4-Benzyl-4- Hydroxypiperidine Yl) ethyl] -3- (2- Methylthieno [3,2-b] pyridine -7 days) Urea  Produce

The compound (122 mg, 0.56 mmol) obtained in the above Step 2 was dissolved in toluene (5 ml), and the mixture was heated under reflux for one hour. After cooling to room temperature, 1- (2-aminoethyl) -4-benzylpiperidin-4-ol hydrochloride (182 mg, 0.67 mmol) and triethylamine (234 μl, 1.68 mmol) were dissolved in dichloromethane ml), and the mixture was stirred at room temperature for 2 hours. The reaction was terminated with water (10 ml), extracted twice with dichloromethane (10 ml) and washed with saturated sodium chloride solution (5 ml). The organic layer was dried over anhydrous magnesium sulfate (MgSO ₄ ) and concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (methanol: dichloromethane = 1: 10) to obtain the title compound (129 mg, 54%, yellow solid).

Rf = 0.11 (dichloromethane and methanol, 5/1, v / v);

_{^{H 1 -NMR (500MHz, CD 3}} OD) δ 8.31 (d, J = 5.7 Hz, 1H), 7.92 (d, J = 5.7 Hz, 1H), 7.27 (m, 2H), 7.21 (m, 3H), 7.12 (s, 1H), 3.47 (t, J = 6.3 Hz, 2H), 2.94 (m, 2H), 2.78 (s, 2H), 2.76 (t, J = 6.3 Hz, 2H), 2.69 (m, 2H ), 2.62 (s, 3H), 1.77 (m, 2H), 1.61 (m, 2H).

< Example  2 > 1- [2- (4-Benzyl- Hydroxypiperidine Yl) ethyl] -3- (2- Phenylthieno [3,2-b] pyridine -7 days) Urea  Produce

 2-phenylthieno [3,2-b] pyridine-7-carbonyl azide (133 mg, 0.25 mmol) obtained by reacting the compound obtained in Preparative Example 3 in the same manner as in Step 1 and Step 2 of Example 1, 0.47 mmol) was reacted in the same manner as in step 3 of Example 1 to obtain the title compound (14 mg, 6%, pale yellow solid).

Rf = 0.2 (dichloromethane and methanol, 5/1, v / v);

_{^{H 1 -NMR (500MHz, CD 3}} OD) δ 8.40 (d, J = 5.5 Hz, 1H), 7.97 (d, J = 5.5 Hz, 1H), 7.80 (m, 2H), 7.71 (s, 1H), J = 6.1 Hz, 2H), 2.96 (d, J = 10.1 Hz, 2H), 7.50 (m, 2H), 7.44 ), 2.80 (s, 2H), 2.79 (m, 2H), 2.70 (t, J = 6.1 Hz, 2H), 1.80 (m, 2H), 1.62 (m, 2H).

< Example 3 RTI ID = 0.0 > 1- [2- (4-benzyl- Hydroxypiperidine Yl) ethyl] -3- (3- Bromo-thieno [3,2-b] pyridine -7 days) Urea  Produce

The compound obtained in Preparation Example 4 was reacted in the same manner as in Step 1 and Step 2 of Example 1 to give 3-bromothieno [3,2-b] pyridine-7-carbonyl azide (27 mg , 0.10 mmol) was reacted in the same manner as Step 3 of Example 1 to obtain the title compound (12 mg, 20%, pale yellow solid).

Rf = 0.11 (dichloromethane and methanol, 10/1, v / v);

H ¹ _{NMR (500MHz, CD 3 OD)} δ 8.48 (d, J = 5.5 Hz, 1H), 8.05 (d, J = 5.5 Hz, 1H), 8.00 (s, 1H), 7.29-7.22 (m, 2H), 7.21 -7.17 (m, 3H), 3.48 (t, J = 6.0 Hz, 2H), 3.02 (d, J = 9.7 Hz, 2H), 2.83 (t, J = 6.0 Hz, 2H), 2.77 (s, 2H) , 2.80-2.71 (m, 2H), 1.81-1.74 (m, 2H), 1.61 (d, J = 13.5 Hz, 2H).

< Example  4> 1- [2- (4-Benzyl-4- Hydroxypiperidine Yl) ethyl] -3- (3- Methylthieno [3,2-b] pyridine -7 days) Urea  Produce

The compound obtained in Preparation Example 5 was reacted with 3-methylthieno [3,2-b] pyridine-7-carbonyl azide (14.8 mg, 0.07 mmol), the title compound (20 mg, 71%, pale yellow solid) was obtained.

Rf = 0.29 (dichloromethane and methanol, 10/1, v / v)

_{^{H 1 -NMR (500MHz, CD 3}} OD) δ 8.45 (d, J = 5.5 Hz, 1H), 8.03 (d, J = 5.5 Hz, 1H), 7.55 (s, 1H), 7.33-7.20 (m, 5H ), 3.59 (t, J = 6.0 Hz, 2H), 3.38-3.31 (m, 2H), 3.10 (t, J = 6.0 Hz, 2H), 3.12-3.0 (m, 2H), 2.83 (s, 2H) , 2.47 (s, 3H), 1.97-1.83 (m, 2H), 1.72 (d, J = 14.0 Hz, 2H).

< Example  5> 1- [2- (4-Benzyl-4- Hydroxypiperidine Yl) ethyl] -3- (5- Methylthieno [3,2-b] pyridine -7 days) Urea  Produce

 The compound obtained in Preparative Example 7 was reacted with 5-methylthieno [3,2-b] pyridine-7-carbonyl azide (60 mg, 0.36 mmol) to give the title compound (12 mg, 8.3%, pale yellow solid) by the same procedure as in step 3 of Example 1 above.

Rf = 0.09 (dichloromethane and methanol, 5/1, v / v)

_{^{H 1 -NMR (500MHz, CD 3}} OD) δ 7.91 (s, 1H), 7.90 (d, J = 5.6 Hz, 1H), 7.41 (d, J = 5.6 Hz, 1H), 7.30 (m, 2H), J = 6.0 Hz, 2H), 3.36 (m, 2H), 3.12 (t, J = 6.0 Hz, 2H), 3.09 (t, J = 2.85 (s, 2H), 2.62 (s, 3H), 2.04 (m, 2H), 1.91 (m, 2H).

< Example  6 > 1- [2- (4-Benzyl- Hydroxypiperidine Yl) ethyl] -3- (5- Ethylthieno [3,2-b] pyridine -7 days) Urea  Produce

 Ethyl-thieno [3,2-b] pyridine-7-carbonyl azide (50 mg, 0.25 mmol) obtained by reacting the compound obtained in Preparative Example 8 in the same manner as in Step 1 and Step 2 of Example 1, 0.24 mmol) was reacted in the same manner as Step 3 of Example 1 to obtain the title compound (20 mg, 20%).

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

^One&Lt; 1 &gt; H NMR (500 MHz, CD₃OD) [delta] 7.52 (s, IH), 7.24-7.15 (m, 6H), 6.92 (d,J2H), 1.55 (m, 2H), 2.60 (m, 2H), 2.50 (m, 2H) .

< Example  7 > 1- [2- (4-Benzyl- Hydroxy -Piperidin-l-yl) -ethyl] -3- (5- Chloro - Cyeno [ 3,2-b] pyridine -7 days)- Urea  Produce

Chloro-thieno [3,2-b] pyridine-7-carbonyl azide (20 mg, 0.25 mmol) obtained by reacting the compound obtained in Preparation Example 6 in the same manner as in Step 1 and 2 of Example 1, 0.083 mmol) was reacted in the same manner as in step 3 of Example 1 to obtain the title compound (14 mg, 38%, pale yellow solid).

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

^One&Lt; 1 &gt; H NMR (500 MHz, CD₃OD) [delta] 7.52 (s, IH), 7.24-7.15 (m, 6H), 6.92 (d,J2H), 1.55 (m, 2H), 2.60 (m, 2H), 2.50 (m, 2H) .

< Example  8 > 1- [2- (4-Benzyl- Hydroxypiperidine Yl) ethyl] -3- (5- Phenylthieno [3,2-b] pyridine -7 days) Urea  Produce

The compound obtained in Preparative Example 9 was reacted with 5-phenylthieno [3,2-b] pyridine-7-carbonyl azide (22 mg, 0.078 mmol) was reacted in the same manner as in step 3 of Example 1 to obtain the title compound (14 mg, 37%, pale yellow solid).

Rf = 0.42 (dichloromethane and methanol, 10/1, v / v);

^One&Lt; 1 &gt; H NMR (500 MHz, CD₃OD)δ 8.47 (s, 1 H), 7.97 (d,J = 7.6 Hz, 2H), 7.93 (d,J = 5.5 Hz, 1 H), 7.55 (d,J 2H), 2.66 (t, 2H), 2.55 (m, 3H) m, 2 H), 1.75 (m, 2 H), 1.59 (m, 2 H).

< Example  9> 1- [2- [4- (2- Bromobenzyl )-4- Hydroxypiperidine -1-yl] ethyl] -3- ( Thieno [3,2-b] pyridine -7 days) Urea  Produce

The compound obtained in Preparation Example 1 was reacted with thieno [3,2-b] pyridine-7-carbonyl azide (48 mg, 0.24 mmol) obtained in the same manner as in Step 1 and Step 2 of Example 1, The procedure of Step 3 of Example 1 was repeated except for using 1- (2-aminoethyl) -4- (2-bromobenzyl) piperidin-4-ol (107 mg, 0.31 mmol) To obtain the title compound (31 mg, 26%, pale yellow solid).

Rf = 0.12 (dichloromethane and methanol, 9/1, v / v);

^One&Lt; 1 &gt; H NMR (500 MHz, CD₃OD)δ 8.41 (d,J= 4.5 Hz, 1 H), 8.02 (d,J= 4.5 Hz, 1 H), 7.90 (d,J= 5.6 Hz, 1 H), 7.54 (d,J= 7.5 Hz, 1 H), 7.45 (d,J= 5.6 Hz, 1 H), 7.38-7.39 (m, 1 H), 7.23 (t,J= 7.0 Hz, 1 H), 7.09 (t,J(M, 2H), 2.50-2.55 (m, 2H), 2.36-2.43 (m, 2H) 1.78-1.87 (m, 2H), 1.57-1.61 (m, 2H).

< Example  10 > 1- [2- [4- (3- Bromobenzyl )-4- Hydroxypiperidine -1-yl] ethyl] -3- (tert &Lt; RTI ID = 0.0 &gt; [3,2-b] pyridine -7 days) Urea  Produce

The compound obtained in Preparation Example 1 was reacted with thieno [3,2-b] pyridine-7-carbonyl azide (107 mg, 0.31 mmol) obtained in the same manner as in Step 1 and Step 2 of Example 1, The procedure of Step 3 of Example 1 was repeated except that 1- (2-aminoethyl) -4- (3-bromobenzyl) piperidin-4-ol (107 mg, 0.31 mmol) To obtain the title compound (63 mg, 53%).

Rf = 0.17 (dichloromethane and methanol, 9/1, v / v);

^One&Lt; 1 &gt; H NMR (500 MHz, CD₃OD)δ 8.40 (d,J= 5.9 Hz, 1 H), 8.01 (d,J= 5.9 Hz, 1 H), 7.90 (d,J= 5.2 Hz, 1 H), 7.45 (d,J= 5.2 Hz, 1H), 7.40 (s, 1H), 7.33- .35 (m, 1H), 7.16-7.18 (m, 2H), 3.38J= 6.5 Hz, 1H), 2.72 (s, 2H), 2.68-2.70 (m, 2H), 2.54J= 6.5 Hz, 1H), 2.39-2.44 (m, 2H), 1.65-1.70 (m, 2H), 1.50-1.53 (m, 2H).

< Example  11 > 1- [2- [4- (2- Methylbenzyl )-4- Hydroxypiperidine -1-yl] ethyl] -3- ( Thieno [3,2-b] pyridine -7 days) Urea  Produce

The compound obtained in Preparation Example 1 was reacted with thieno [3,2-b] pyridine-7-carbonyl azide (50 mg, 0.24 mmol) obtained in the same manner as in Step 1 and Step 2 of Example 1, The procedure of Step 3 of Example 1 was repeated except that 1- (2-aminoethyl) -4- (2-methylbenzyl) piperidin-4-ol (82 mg, 0.29 mmol) To give the title compound (40 mg, 39%, pale yellow solid).

Rf = 0.18 (dichloromethane and methanol, 9/1, v / v);

^One&Lt; 1 &gt; H NMR (500 MHz, CD₃OD)δ 8.39 (d,J= 5.5 Hz, 1 H), 8.00 (d,J= 5.5 Hz, 1 H), 7.88 (d,J= 4.8 Hz, 1 H), 7.44 (d,J2H), 2.80-2. 70 (m, 2H), 2.50-2. 51 (m, 2H) 2.28-2.41 (m, 5H), 1.71-1.76 (m, 2H), 1.56-1.59 (m, 2H).

< Example  12> 1- [2- [4- (3- Methylbenzyl )-4- Hydroxypiperidine -1-yl] ethyl] -3- ( Thieno [3,2-b] pyridine -7 days) Urea  Produce

The compound obtained in Preparation Example 1 was reacted with thieno [3,2-b] pyridine-7-carbonyl azide (50 mg, 0.24 mmol) obtained in the same manner as in Step 1 and Step 2 of Example 1, The procedure of Step 3 of Example 1 was repeated except that 1- (2-aminoethyl) -4- (3-methylbenzyl) piperidin-4-ol (131 mg, 0.46 mmol) To give the title compound (30 mg, 29%, pale yellow solid).

Rf = 0.24 (dichloromethane and methanol, 9/1, v / v);

^One&Lt; 1 &gt; H NMR (500 MHz, CD₃OD)δ 8.37 (d,J= 5.9 Hz, 1 H), 7.99 (d,J= 5.9 Hz, 1 H), 7.86 (d,J= 5.2 Hz, 1 H), 7.42 (d,J= 5.2 Hz, 1 H), 7.09-7.10 (m, 1 H), 6.95-6.98 (m, 3H), 3.28-3.32 (m, 2H), 2.66-2.68 ), 2.38-2.40 (m, 2H), 2.26 (s, 3H), 1.65-1.67 (m, 2H), 1.49-1.51 (m, 2H).

< Example  13 > 1- [2- [4- (4- Methylbenzyl )-4- Hydroxypiperidine -1-yl] ethyl] -3- ( Thieno [3,2-b] pyridine -7 days) Urea  Produce

The compound obtained in Preparation Example 1 was reacted with thieno [3,2-b] pyridine-7-carbonyl azide (50 mg, 0.24 mmol) obtained in the same manner as in Step 1 and Step 2 of Example 1, The procedure of Step 3 of Example 1 was repeated except that 1- (2-aminoethyl) -4- (4-methylbenzyl) piperidin-4-ol (82 mg, 0.29 mmol) To give the title compound (10 mg, 10%, pale yellow solid).

Rf = 0.18 (dichloromethane and methanol, 9/1, v / v);

^One&Lt; 1 &gt; H NMR (500 MHz, CD₃OD)δ 8.40 (d,J= 5.6 Hz, 1 H), 8.01 (d,J= 5.6 Hz, 1 H), 7.90 (d,J= 5.5 Hz, 1 H), 7.44 (d,J= 5.5 Hz, 1 H), 7.04-7.08 (m, 4 H), 3.37 (t,J= 6.1 Hz, 2H), 2.67- .69 (m, 4H), 2.52 (t,J= 6.1 Hz, 2H), 2.39-43 (m, 2H), 2.27 (s, 3H), 1.65-1.71 (m, 2H), 1.50-1.53 (m, 2H).

< Example  14 > 1- [2- [4- (4- Fluorobenzyl )-4- Hydroxypiperidine -1-yl] ethyl] -3- (tert &Lt; RTI ID = 0.0 &gt; [3,2-b] pyridine -7 days) Urea  Produce

The compound obtained in Preparation Example 1 was reacted with thieno [3,2-b] pyridine-7-carbonyl azide (42 mg, 0.21 mmol) obtained in the same manner as in Step 1 and Step 2 of Example 1, The procedure of Step 3 of Example 1 was repeated except for using 1- (2-aminoethyl) -4- (4-fluorobenzyl) piperidin-4-ol (72 mg, 0.50 mmol) To obtain the title compound (35 mg, 39%, pale yellow solid).

Rf = 0.16 (dichloromethane and methanol, 9/1, v / v);

^One&Lt; 1 &gt; H NMR (500 MHz, CD₃OD)δ 8.41 (d,J= 5.6 Hz, 1 H), 8.03 (d,J= 5.6 Hz, 1 H), 7.90 (d,J= 5.1 Hz, 1 H), 7.45 (d,J= 5.1 Hz, 1H), 7.18-7.22 (m, 2H), 6.95-7.00 (m, 2H), 3.39J= 6.5 Hz, 2H), 2.66-2.72 (m, 4H), 2.53 (t,J= 6.5 Hz, 2H), 2.40-2.46 (m, 2H), 1.62-1.72 (m, 2H), 1.48-1.54 (m, 2H).

< Example  15> 4-Benzyl-4- Hydroxy -N- ( Thieno [3,2-b] pyridine -7-yl) piperidin-1-car Copymade Manufacturing

The compound obtained in Preparation Example 1 was reacted with thieno [3,2-b] pyridine-7-carbonyl azide (43 mg, 0.21 mmol) obtained in the same manner as in Step 1 and Step 2 of Example 1, The title compound (2.5 mg, 3%) was obtained as a pale yellow solid by the same procedure as in the step 3 of Example 1 except that 4-benzyl-piperidin-4-ol (71 mg, 0.31 mmol) ).

Rf = 0.34 (1-dichloromethane and methanol, 10/1, v / v);

^One&Lt; 1 &gt; H NMR (300 MHz, CDCl3₃) [delta] 8.44 (d,J = 5.4 Hz, 1 H), 7.92 (dJ = 5.4 Hz, 1 H), 7.44 (d,J = 5.4 Hz, 1 H), 7.31 (d,J 2H), 2.81 (s, 2H), 2.03-2.01 (m, 2H), 1.72-1.69 (m, 2H) 1.60-1.57 (m, 2H).

< Example  16> 1- [3- (4-Benzyl-4- Hydroxypiperidine Yl) propyl] -3- ( Thieno [3,2-b] pyridine -7 days) Urea  Produce

The compound obtained in Preparative Example 1 was reacted with thieno [3,2-b] pyridine-7-carbonyl azide (46 mg, 0.22 mmol) obtained in the same manner as in Step 1 and Step 2 of Example 1, The procedure of step 3 of Example 1 was repeated except for using 1- (3-aminopropyl) -4-benzyl-piperidin-4-ol (83 mg, 0.33 mmol) 13 mg, 13%, pale yellow solid).

R _f = 0.28 (dichloromethane and methanol, 10/1, v / v);

^One&Lt; 1 &gt; H NMR (300 MHz, CD₃OD) [delta] 8.43 (d,J = 5.6 Hz, 1 H), 8.02 (d,J = 5.6 Hz, 1 H), 7.93-7.90 (m, 1 H), 7.47 (d,J 2H), 2.46-2.43 (m, 2H), 2.54-2.73 (m, 2H) ), 1.80-1.77 (m, 2H), 1.73-1.67 (m, 2H), 1.56-1.53 (m, 2H).

< Example  17> 1- [4- (4-Benzyl-4- Hydroxypiperidine Yl) butyl] -3- ( Thieno [3,2-b] pyridine -7 days) Urea  Produce

The compound obtained in Preparative Example 1 was reacted with thieno [3,2-b] pyridine-7-carbonyl azide (37 mg, 0.18 mmol) obtained in the same manner as in Step 1 and Step 2 of Example 1, The procedure of Step 3 of Example 1 was repeated except for using 1- (4-aminobutyl) -4-benzyl-piperidin-4-ol (106 mg, 0.40 mmol) 7 mg, 9%, pale yellow solid).

H ¹ _{NMR (300MHz, CD 3 OD)} δ 8.43 (d, J = 5.3 Hz, 1H), 8.01 (d, J = 6.0 Hz, 1H), 7.94 (d, J = 5.3 Hz, 1H), 7.47 (d, J = 6.0 Hz, 1H), 7.30-7.21 (m, 5H), 3.39-3.37 (m, 2H), 3.32-3.30 (m, 2H), 3.24-3.19 ), 2.82 (s, 2H), 1.92-1.86 (m, 2H), 1.81-1.78 (m, 2H), 1.77-1.72 (m, 2H), 1.65-1.61 (m, 2H).

< Example  18> 1- [2- (4-Benzyl-4- Hydroxypiperidine Yl) ethyl] -3- ( Thieno [3,2-b] pyridine -7 days) Urea  Produce

Step 1: 7- B] pyridine &lt; / RTI &gt;  Produce

7-Chlorothi eno [3,2-b] pyridine (2.0 g, 11.81 mmol) obtained in the above Step 2 of Preparation Example 1 was dissolved in N, N-dimethylformamide (10 ml), sodium azide 3.84 g, 59.05 mmol), and the mixture was stirred at 100 ° C for 20 hours. Water (50 ml) was added to terminate the reaction, and the mixture was extracted with ethyl acetate (50 ml). The organic layer was dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (n-hexane and ethyl acetate, 3/1, v / v) to give the title compound (610 mg, 3.47 mmol, 29%, yellow solid).

Rf = 0.19 (n-hexane and ethyl acetate, 10/1, v / v);

^One&Lt; 1 &gt; H NMR (300 MHz, CDCl3₃) [delta] 8.68 (d,J = 5.1 Hz, 1 H), 7.77 (d,J = 5.4 Hz, 1 H), 7.57 (d,J = 5.4 Hz, 1 H), 7.04 (d,J = 5.1 Hz, 1H).

Step 2: 7- Aminothieno [3,2-b] pyridine  Produce

(600 mg, 3.41 mmol) and Raney nickel (60 mg) were dissolved in methanol (30 ml) and hydrogenated under hydrogen gas at 20 [deg.] C &Lt; / RTI &gt; After completion of the reaction, the filtrate was filtered through celite and the filtrate was concentrated to obtain the title compound (500 mg, 3.33 mmol, 98%, yellow solid).

Rf = 0.22 (dichloromethane and methanol, 10/1, v / v);

^One&Lt; 1 &gt; H NMR (300 MHz, CDCl3₃) [delta] 8.11 (d,J = 5.4 Hz, 1 H), 7.78 (d,J = 5.4 Hz, 1 H), 7.33 (d,J = 5.4 Hz, 1 H), 6.53 (d,J = 5.4 Hz, 1H).

Step 3: 1- (2- Chloroethyl ) -3- ( Thieno [3,2-b] pyridine -7 days) Urea  Produce

The cyano [3,2-b] pyridin-7-amine (118 mg, 0.79 mmol) prepared in the above step 2 was dissolved in tetrahydrofuran (5 ml), and 2-chloroethyl isocyanate (81 [ 0.95 mmol), and the mixture was stirred at 50 DEG C for 6 hours. After completion of the reaction, the mixture was extracted twice with ethyl acetate (25 ml) and washed twice with water and brine. Anhydrous sodium sulfate (Na ₂ SO _4), after drying under reduced pressure to give a concentrated filtrate was purified by silica gel column chromatography (n-hexane and ethyl acetate, 1/1, v / v)) The title compound (78 mg, 0.31 mmol, 39 %).

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

H ¹ _{NMR (300MHz, CD 3 OD)} δ 8.45 (d, J = 5.8 Hz, 1H), 8.07 (d, J = 5.3 Hz, 1H), 7.94 (d, J = 5.3 Hz, 1H), 7.48 (d, J = 5.8 Hz, 1H), 3.72 (t, J = 5.8 Hz, 2H), 3.62 (t, J = 5.8 Hz, 2H).

Step 4: l- [2- (4-Benzyl-4- Hydroxypiperidine Yl) ethyl] -3- ( Thieno [3,2-b] pyridine -7 days) Urea  Produce

(78 mg, 0.31 mmol) prepared in step 3 was dissolved in tetrahydrofuran (7 ml), and the mixture was stirred at &lt; RTI ID = 0.0 & 4-benzyl-piperidin-4-ol (71 mg, 0.37 mmol) and sodium bicarbonate (208 mg, 2.48 mmol) were added and the mixture was stirred at 50 ° C for 7 days. The reaction was terminated by addition of water (25 ml), followed by extraction with dichloromethane (25 ml), drying over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentration under reduced pressure. The filtrate was purified by silica gel column chromatography (5% -> 10% methanol / dichloromethane) to give the title compound (39 mg, 0.095 mmol, 31%, white solid).

Rf = 0.19 (dichloromethane and methanol, 10/1, v / v) * 1.5;

H ¹ _{NMR (300MHz, CD 3 OD)} δ 8.44 (d, J = 5.7 Hz, 1H), 8.05 (d, J = 5.7 Hz, 1H), 7.94 (d, J = 5.7 Hz, 1H), 7.93 (s, 1H ), 7.49 (d, J = 5.7 Hz, 1H), 7.20-7.30 (m, 6H), 3.45 (t, J = 6.6 Hz, 2H), 2.85-2.87 (m, 2H), 2.80 (s, 2H) , 2.68 (t, J = 6.6 Hz, 2H), 2.58 (t, J = 11.1 Hz, 2H), 1.74-1.80 (m, 2H), 1.59-1.62 (m, 2H).

< Example  19> 1- [2- (4-Benzyl-4- Hydroxypiperidine Yl) ethyl] -3- ( Thieno [3,2-b] pyridine -7 days) Thaiorea  Produce

Step 1: Preparation of 7-isothiocyanato-thieno [3,2-b] pyridine

7-Aminothieno [3,2-b] pyridine (50 mg, 0.33 mmol) prepared in Step 2 of Example 18 was dissolved in dichloromethane (5 ml) and di (2-pyridyl) (DPT, 153 mg, 0.66 mmol) and 4-dimethylaminopyridine (DMAP, 4 mg, 0.03 mmol) were added and the mixture was stirred at room temperature for 2 hours. The reaction was terminated by adding water (10 ml), extracted twice with dichloromethane (10 ml), dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (n-hexane and ethyl acetate, 5/1, v / v) to give the title compound (54 mg, 0.28 mmol, 85%, white solid).

Rf = 0.48 (n-hexane and ethyl acetate, 1/1, v / v);

^One&Lt; 1 &gt; H NMR (300 MHz, CDCl3₃)δ8.64 (d,J = 5.0 Hz, 1 H), 7.78 (d,J = 5.5 Hz, 1 H), 7.57 (d,J = 5.5 Hz, 1 H), 7.06 (d,J = 5.0 Hz, 1H).

Step 2: l- [2- (4-Benzyl-4- Hydroxypiperidine Yl) ethyl] -3- ( Thieno [3,2-b] pyridine -7 days) Thaiorea  Produce

The reaction was carried out in the same manner as in step 3 of Example 1, except that 7-isothiocyanato-thieno [3,2-b] pyridine (50 mg, 0.26 mmol) To give the title compound (104 mg, 92%, pale yellow solid).

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

H ¹ NMR (300 MHz, CD ₃ OD)? 8.52 (d, J = 5.4 Hz , 1H), 8.03-7.95 (m, 2H), 7.53 (d, J = 5.6 Hz, 1H), 3.85 (t, J = 5.9 Hz, 2H), 2.92 (d, J = 11.1 Hz, 2H), 2.83 (t, J = 5.9 Hz, 2H), 2.78 (s, 2H), 2.70-2.62 (m, 2H), 1.79-1.68 (m, 2H), 1.59 (d, J = 1.30 Hz, 2H).

< Experimental Example  1> Thieno [3,2-b] pyridyl Urea  Measurement of U-Ⅱ receptor binding inhibition of derivatives

In order to confirm the binding inhibitory activity of the thieno [3,2-b] pyridylurea derivative according to the present invention on the U-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 (U-Ⅱ, # 070-47, Sigma-Aldrich, St. Louis, Mo.) and 1 mM europrotin concentrate (Europium-labeled Urotensin-II, Eu-UII, PerkinElmer, Turku, Finland) USA) at 4 ° C. 1 μM Eu-UII and 1 mM U-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. U-Ⅱ receptor cell membrane preparation for the binding assay was performed using a HEK293 _UT cell line overexpressed with U-Ⅱ receptor in a 100 cm ² flask. If the cells were 90% or more, the medium was removed, washed twice with PBS buffer, and 2 mL of 1 mM EDTA-PBS buffer was added and the cells were harvested by incubation at 37 ° C for 5 minutes. 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 0.5% Protease Inhibitor cocktail, and pulverized with an ultrasonic grinder. 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. Cell membrane fraction precipitates were 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 U-Ⅱ receptor (30 mg / ml) was diluted in 5 ml of the test solution and homogenized. Microplates (Multiwell 96 well filter plates PN5020, Pall Co. Ann Arbor MI, USA) U-Ⅱ receptors were dispensed at 50 ㎕ per well using a pipet (multi 8-channel, Eppendorf, Hamburg, Germany). As a non-specific binding control, 25 μl of Eu-UII and 25 μl of U-II were dispensed. As a total binding control, 25 μl of 10% DMSO solution and 25 μl of Eu-MCH were added Respectively. As experimental groups, 25 μl of the novel compound represented by the above formula according to the present invention and 25 μl of Eu-UII were used. Since each test compound, Eu-UII and U-II, accounted for 25% of the total volume during the reaction, they were prepared at a concentration of 4 times before the addition. 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 [mu] l per well of the washing solution was filtered three times to remove the remaining Eu-UII. Bottom water was wiped off and the solution was added with 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).

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.

compound IC ₅₀ (nM) Example 1 78 Example 2 47.3% ^a Example 3 3,220 Example 4 1,230 Example 5 26 Example 6 60 Example 7 25.6% ^a Example 8 25.4% ^a Example 9 50 Example 10 40 Example 11 20 Example 12 140 Example 13 190 Example 14 10 Example 15 - Example 16 2,620 Example 17 7,480 Example 18 40 Example 19 2,480

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

The compounds of Examples 1, 5, 6, 9, 10, 11, 14 and 18 among the thieno [3,2-b] pyridylurea derivatives according to the present invention have IC ₅₀ values Ⅱ receptor in the concentration of 100 nM or less. In particular, the compounds of Examples 5, 11, and 14 of the present invention have an IC ₅₀ value of 30 nM or less and exhibit excellent U-Ⅱ receptor Lt; RTI ID = 0.0 &gt;

Therefore, the derivative according to the present invention acts as an antagonist to the U-Ⅱ receptor and thus can be used as an antagonist for the U-Ⅱ receptor, thereby being useful as an antagonist for the U-Ⅱ receptor, Ⅱ receptor activity-related diseases such as degenerative diseases, stroke, pain, depression, psychosis, cancer and the like.

Meanwhile, the thieno [3,2-b] pyridylurea derivative represented by Formula 1 according to the present invention can be formulated into various forms depending on the purpose. Hereinafter, some formulation methods in which the compound represented by Formula 1 according to the present invention is contained as an active ingredient are exemplified, and the present invention is not limited thereto.

< Formulation example  1> Sanje  Produce

2 g of the cyano [3,2-b] pyridylurea derivative of the formula (1)

Lactose 1 g

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

< Formulation example  2> Preparation of tablets

100 mg of the thieno [3,2-b] pyridylurea derivative of 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.

< Formulation example  3> Preparation of capsules

100 mg of the thieno [3,2-b] pyridylurea derivative of 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.

< Formulation example  4> Preparation of injection

100 mg of the thieno [3,2-b] pyridylurea derivative of 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.

Claims (9)

A novel thieno [3,2-b] pyridylurea derivative represented by the following formula (1): or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]

(In the formula 1,
X is oxygen (O) or sulfur (S);
R ¹ is hydrogen, C ₁ -C ₆ linear or branched alkyl or phenyl;
R ² is hydrogen, halogen, C ₁ -C ₆ linear or branched alkyl;
R ³ is hydrogen, halogen, C ₁ -C ₆ linear or branched alkyl or phenyl;
R ⁴ is hydrogen, halogen, C ₁ -C ₆ straight or branched chain alkyl; And
and n is an integer of 0 to 6).
The method according to claim 1,
X is oxygen (O) or sulfur (S);
R ¹ is hydrogen, C ₁ -C ₄ linear or branched alkyl or phenyl;
R ² is hydrogen, halogen, C ₁ -C ₄ linear or branched alkyl;
R ³ is hydrogen, halogen, C ₁ -C ₄ linear or branched alkyl or phenyl;
R ⁴ is hydrogen, halogen, C ₁ -C ₄ linear or branched alkyl; And
and n is an integer of 0 to 5, or a pharmaceutically acceptable salt thereof. 2. A thieno [3,2-b] pyridylurea derivative or a pharmaceutically acceptable salt thereof.
The method according to claim 1,
X is oxygen (O) or sulfur (S);
R &lt; ¹ &gt; is hydrogen, methyl, ethyl or phenyl;
R ² is hydrogen, fluoro, chloro, bromo, methyl or ethyl;
R &lt; ³ &gt; is hydrogen, fluoro, chloro, bromo, methyl, ethyl or phenyl;
R &lt; ⁴ &gt; is hydrogen, fluoro, chloro, bromo, methyl or ethyl; And
and n is an integer of 0 to 4. 2. A thieno [3,2-b] pyridylurea derivative or a pharmaceutically acceptable salt thereof.
The method according to claim 1,
The thieno [3,2-b] pyridylurea derivative is a compound represented by the formula
(1) Synthesis of 1- [2- (4-benzyl-4-hydroxypiperidin- 1 -yl) ethyl] -3- (2-methylthieno [3,2- b] pyridin- Urea;
(2) Synthesis of 1- [2- (4-benzyl-4-hydroxypiperidin-1-yl) ethyl] -3- (2-phenylthieno [3,2- b] pyridin- Urea;
(3) Synthesis of 1- [2- (4-benzyl-4-hydroxypiperidin-1-yl) ethyl] -3- (3-bromothiouno [3,2- b] pyridin- ) Urea;
(4) Synthesis of 1- [2- (4-benzyl-4-hydroxypiperidin-1-yl) ethyl] -3- (3-methylthieno [3,2- b] pyridin- Urea;
(5) Synthesis of 1- [2- (4-benzyl-4-hydroxypiperidin- 1 -yl) ethyl] -3- (5- methylthieno [3,2- b] pyridin- Urea;
(6) Synthesis of 1- [2- (4-benzyl-4-hydroxypiperidin-1-yl) ethyl] -3- Urea;
(7) Synthesis of 1- [2- (4-benzyl-4-hydroxypiperidin-1-yl) ethyl] -3- (5- chlorothieno [3,2- b] pyridin- Urea;
(8) Synthesis of 1- [2- (4-benzyl-4-hydroxypiperidin- 1 -yl) ethyl] -3- (5- phenylthieno [3,2- b] pyridin- Urea;
(9) 1- [2- [4- (2-Bromobenzyl) -4-hydroxypiperidin- 1 -yl] ethyl] -3- (thieno [3,2- b] pyridin- - yl) urea;
(10) 1- [2- [4- (3-Bromobenzyl) -4-hydroxypiperidin- 1 -yl] ethyl] -3- (thieno [3,2- b] pyridin- - yl) urea;
(11) 1- [2- [4- (2-Methylbenzyl) -4-hydroxypiperidin- 1 -yl] ethyl] -3- (thieno [3,2- b] pyridin- Yl) urea;
(12) 1- [2- [4- (3-Methylbenzyl) -4-hydroxypiperidin- 1 -yl] ethyl] -3- (thieno [3,2- b] pyridin- Yl) urea;
(13) 1- [2- [4- (4-methylbenzyl) -4-hydroxypiperidin- 1 -yl] ethyl] -3- (thieno [3,2- b] pyridin- Yl) urea;
(14) 1- [2- [4- (4-Fluorobenzyl) -4-hydroxypiperidin- 1 -yl] ethyl] -3- (thieno [3,2- b] pyridin- - yl) urea;
(15) 4-Benzyl-4-hydroxy-N- (thieno [3,2-b] pyridin-7-yl) piperidine-1-carboxamide;
(16) 1- [3- (4-Benzyl-4-hydroxypiperidin-1-yl) propyl] -3- (thieno [3,2-b] pyridin-7-yl) urea;
(17) 1- [4- (4-Benzyl-4-hydroxypiperidin-1-yl) butyl] -3- (thieno [3,2-b] pyridin-7-yl) urea;
(18) 1- [2- (4-Benzyl-4-hydroxypiperidin-1-yl) ethyl] -3- (thieno [3,2-b] pyridin-7-yl) urea; And
(19) Synthesis of 1- [2- (4-benzyl-4-hydroxypiperidin-1-yl) ethyl] -3- (thieno [3,2- b] pyridin- , Or a pharmaceutically acceptable salt thereof, wherein the thieno [3,2-b] pyridylurea derivative or a pharmaceutically acceptable salt thereof is a compound selected from the group consisting of
As shown in Scheme 1 below,
A step of hydrolyzing a compound represented by the formula (2) under base or acid conditions to obtain a compound represented by the formula (3) (step 1);
A step of azide-forming a compound represented by the formula (3) obtained in the step 1 with an azidating reagent to obtain a compound represented by the formula (4) (step 2); And
The compound represented by the formula (5), which is obtained through the intramolecular rearrangement reaction of the compound represented by the formula (4) obtained in the above step 2, is subjected to coupling reaction with the compound represented by the formula (6) 3,2-b] pyridylurea derivative of claim 1, which comprises the step of obtaining a [3,2-b] pyridylurea derivative compound (step 3)
[Reaction Scheme 1]

(In the above Reaction Scheme 1, R ¹ , R ² , R ³ , R ⁴ And n are the same as defined in the above formula (1); The compound of formula (5) is a compound produced through an intramolecular shift reaction of the compound of formula (4); The compound of the formula (Ia) is included in the compound of the formula (1).
As shown in Scheme 4 below,
A step of subjecting a compound represented by the formula (14) to an azide substitution reaction with an azide reagent to obtain a compound represented by the formula (15) (step 1);
A step (step 2) of reducing the compound represented by the formula (15) obtained in the above step 1 under hydrogenation reaction conditions to obtain the compound represented by the formula (16);
Reacting a compound represented by the formula (16) obtained in the above step 2 with a compound represented by the formula (17) to obtain a compound represented by the formula (18) (step 3); And
Alkylation reaction of the compound represented by the formula (18) obtained in the above step 3 with the compound represented by the formula (19) in the presence of a base to obtain a cyano [3,2-b] pyridylurea compound represented by the formula A process for preparing the novel thieno [3,2-b] pyridylurea derivative according to claim 1,
[Reaction Scheme 4]

(In the above Reaction Scheme 4, R ¹ , R ² , R ³ , R ⁴ And n are the same as defined in the above formula (1); The compound of formula (Ib) is included in the compound of formula (1).
As shown in Scheme 5 below,
Reacting a compound represented by the formula (20) with a thiocarbonyl reagent to obtain an isothiocyanate compound represented by the formula (21) (step 1); And
(Step 2) of reacting the compound represented by the formula 21 obtained in the above step 1 with a compound represented by the formula 6 in the presence of a base to obtain a cyano [3,2-b] pyridylurea compound represented by the formula 1c, A process for preparing the novel thieno [3,2-b] pyridylurea derivative according to claim 1,
[Reaction Scheme 5]

(Wherein R ¹ , R ² , R ³ , R ⁴ and n are as defined in the above-mentioned formula (1) and the compound of the formula (1c) is included in the compound of the formula (1).
A pharmaceutical composition for the treatment of congestive heart failure, cardiac ischemia, myocardial infarction, cardiac hypertrophy, cardiac hypertrophy, heart failure, Wherein the compound is at least one selected from the group consisting of fibrosis, coronary artery disease, arteriosclerosis, hypertension, renal failure, diabetes, vascular inflammation, neurodegenerative diseases, stroke, pain, depression, psychosis and cancer A pharmaceutical composition for preventing or treating a related disease. delete