HK1159622B

HK1159622B - 7-piperidinoalkyl-3,4-dihydroquinolone derivative

Info

Publication number: HK1159622B
Application number: HK12100046.0A
Authority: HK
Inventors: 鹿沼幸佑; 宫腰直树; 川村円; 柴田刚
Original assignee: 大正制药株式会社
Priority date: 2008-10-02
Filing date: 2009-09-30
Publication date: 2015-06-26

Description

7-piperidinoalkyl-3, 4-dihydroquinolone derivatives

Technical Field

The present invention relates to a compound having a melanin concentrating hormone receptor antagonistic action, a pharmaceutically acceptable salt or hydrate thereof.

Background

Depression and anxiety disorders constitute major psychiatric disorders. The prevalence of depression and anxiety disorders has increased during life in recent years. To date, tricyclic antidepressants based on the monoamine hypothesis (TCA), selective 5-hydroxytryptamine reuptake inhibitors (SSRI), 5-hydroxytryptamine and norepinephrine reuptake inhibitors (SNRI), and the like have been developed as antidepressants. Using benzodiazepines based on the gamma-aminobutyric acid mechanism (GABA)They are used as anxiolytic. In recent years, SSRI and SNRI have been demonstrated for benzodiazepines such as panic disorder and obsessive compulsive disorderAnxiety disorders in which the drug-like agent is ineffective are also effective and thus are also the first line treatment for anxiety disorders. However, SSRI and SNRI are not effective in patients with treatment-resistant depression, and require, for example, several weeks for the onset of antidepressant and anxiolytic effects, which is disadvantageous. Therefore, it is desirable to develop antidepressant and anxiolytic drugs with different mechanisms of action from existing drugs.

Melanin-concentrating hormone (MCH), a neuropeptide consisting of 19 amino acids, is biosynthesized and widely distributed in the limbic system and the like in the brain. Melanin concentrating hormone-type 1 receptor (MCH1R) and melanin concentrating hormone-type 2 receptor (MCH2R) are currently known as two MCH receptor subtypes. MCH2R is not expressed in rodents and its physiological function is not yet clear; it is clear that MCH1R is closely related to feeding behavior and energy metabolism. More specifically, it was reported that food intake was increased by injecting MCH into rats. In addition, it has been reported that weight loss and metabolic increase are observed in MCH-gene-deleted modified mice (MCH-defective gene-modified mice) (see non-patent document 1). Thus, MCH1R antagonists may be useful as prophylactic or therapeutic agents for obesity, eating disorders, appetite disorders, hyperphagia, bulimia, anorexia phobia, and the like.

On the other hand, it has been reported that MCH1R is also closely related to stress response and mood regulation. Activation of the hypothalamus-pituitary-adrenal (HPA) axis by MCH is antagonized by MCH1R antagonists and neutralizing antibodies to Corticotropin Releasing Factor (CRF). MCH is presumed to activate the HPA system by promoting the release of CRF from the hypothalamus. MCH1R is primarily distributed among kernels with motivation and reward (reward) associated therewith. When MCH was injected into this site, depressive-like symptoms were found in the forced swim test, whereas MCH knockout mice had antidepressant-like symptoms. Studies with MCH1R knockout mice indicate that MCH1R negatively modulates the activity of reward-associated dopaminergic neurons in the nucleus accumbens. In addition, ATC0175 (a non-peptide MCH1R antagonist) showed antidepressant-like and anxiolytic-like effects in experimental animal models (non-patent document 2). From the above facts, MCH1R is not only involved in the control of feeding behavior and energy metabolism, but also in the onset of depression and anxiety, and thus it is predicted that MCH receptor antagonists (particularly MCH1R antagonists) may become antidepressants and anxiolytics having mechanisms different from the conventional mechanisms of action.

Recently, MCH receptor antagonists having a naphthalene skeleton and a 1, 3-benzodioxole structure have been disclosed in patent document 1 and non-patent documents 3,4,5 and 6. However, these documents neither disclose nor teach the structure of the compounds of the present invention.

Patent document 1: U.S. patent application publication No. 2005/209274

Non-patent document 1: trends Endocrinol Metab, Vol 11, p 299-303 (2000)

Non-patent document 2: drug Development Research 65, 278 and 290 (2005)

Non-patent document 3: 224th The American Chemical Society MEDI-343(2002) (224 th American Chemical Society MEDI-343(2002))

Non-patent document 4: bioorganic & Medicinal Chemistry Letters, Vol.16, 5445-5450 (2006)

Non-patent document 5: bioorganic & Medicinal Chemistry Letters 15, 3412, 3416 (2005)

Non-patent document 6: bioorganic & Medicinal Chemistry Letters 17, 874-878 (2007)

DISCLOSURE OF THE INVENTION

Problems to be solved by the invention

It is an object of the present invention to provide a novel compound, a pharmaceutically acceptable salt or hydrate thereof, which is useful for the prevention or treatment of: depression, anxiety disorders (such as generalized anxiety disorder, post-traumatic stress disorder, panic disorder, obsessive-compulsive disorder, or social anxiety disorder), attention deficit disorder, mania, manic depression, schizophrenia, mood disorder, stress, sleep disorder, aggression, memory impairment, cognitive impairment, dementia, amnesia, delirium, obesity, eating disorder, appetite disorder, hyperphagia, bulimia, anorexia phobia, diabetes, cardiovascular disease, hypertension, dyslipidemia, myocardial infarction, movement disorder (such as parkinson's disease, epilepsy, convulsion, or tremor), drug abuse, drug addiction, or sexual dysfunction.

Means for solving the problems

As a result of intensive studies, the present inventors have found that a 7-piperidinoalkyl-3, 4-dihydroquinolone compound represented by the following formula (I) has an excellent MCH receptor antagonistic action. The present invention has been completed based on this finding.

More specifically, the present invention provides a method for producing,

1) a compound represented by formula (I), a pharmaceutically acceptable salt or hydrate thereof:

wherein, in the formula (I)

R is a hydrogen atom or C_1-6An alkyl group;

A¹、A²and A³Which may be the same or different, are each a hydrogen atom, a halogen atom, C_1-6Alkyl or C_1-6An alkoxy group;

x is C_1-6An alkylene group;

y is a bond or C_1-6An alkylene group;

z is a bond or C_1-6Alkylene, wherein the C_1-6The alkylene group may be substituted with an aryl group;

w is a bond or an oxygen atom; and

cy is an aryl or heteroaryl group, wherein the aryl or heteroaryl group may have 1 to 3 substituents which may be the same or different, selected from halogen atoms, cyano, C_1-6Alkyl radical, C_1-6Alkoxy and C_2-6Alkanoyl radical, wherein said C_1-6Alkyl or C_1-6Alkoxy groups may be substituted with 1 to 3 halogen atoms;

2) a compound according to the above 1), a pharmaceutically acceptable salt or hydrate thereof, wherein in the formula (I)

R is a hydrogen atom;

A¹、A²and A³Each is a hydrogen atom;

x is C_1-6An alkylene group;

y is a bond;

w is a bond or an oxygen atom; and

cy is phenyl or pyridyl, wherein the phenyl or pyridyl group may have 1 to 3 substituents which may be the same or different, the substituents being selected from the group consisting of a halogen atom, cyano, C_1-6Alkyl radical, C_1-6Alkoxy and C_2-6Alkanoyl radical, wherein said C_1-6Alkyl or C_1-6Alkoxy groups may be substituted with 1 to 3 halogen atoms;

3) the compound according to the above 1), a pharmaceutically acceptable salt or hydrate thereof, wherein in the formula (I),

r is a hydrogen atom;

A¹、A²and A³Each is a hydrogen atom;

x is methylene, wherein the methylene may be substituted by methyl;

y is a bond;

z is a bond or methylene;

w is a bond or an oxygen atom; and

cy is a phenyl group, wherein the phenyl group may have 1 to 3 substituents which may be the same or different, selected from a halogen atom, C_1-6Alkyl radical, C_1-6Alkoxy and C_2-6An alkanoyl group;

4) the compound according to the above 1), pharmaceutically acceptable salt or hydrate thereof, wherein the compound represented by the formula (I) is

3-methoxy-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl ] piperidin-4-yl } benzamide

2.3-fluoro-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl ] piperidin-4-yl } benzamide

3, 5-difluoro-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl ] piperidin-4-yl } benzamide

3, 4-difluoro-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl ] piperidin-4-yl } benzamide

4-fluoro-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl ] piperidin-4-yl } benzamide

3-chloro-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl ] piperidin-4-yl } benzamide

3-methyl-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl ] piperidin-4-yl } benzamide

3, 5-dichloro-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl ] piperidin-4-yl } benzamide

3, 4-dichloro-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl ] piperidin-4-yl } benzamide

4-fluoro-3-methyl-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl ] piperidin-4-yl } benzamide

4-fluoro-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl ] piperidin-4-yl } -3- (trifluoromethyl) benzamide

3-fluoro-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl ] piperidin-4-yl } -5- (trifluoromethyl) benzamide

3, 5-dimethoxy-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl ] piperidin-4-yl } benzamide

N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl ] piperidin-4-yl } benzamide

N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl ] piperidin-4-yl } -2, 2-diphenylacetamide

4-chloro-3-fluoro-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl ] piperidin-4-yl } benzamide

17.3-bromo-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl ] piperidin-4-yl } benzamide

18.3-fluoro-5-methoxy-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl ] piperidin-4-yl } benzamide

3-chloro-4-fluoro-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl ] piperidin-4-yl } benzamide

20.3-acetyl-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl ] piperidin-4-yl } benzamide

3,4, 5-trifluoro-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl ] piperidin-4-yl } benzamide

4-fluoro-3-methoxy-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl ] piperidin-4-yl } benzamide

3-chloro-5-fluoro-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl ] piperidin-4-yl } benzamide

24.3-cyano-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl ] piperidin-4-yl } benzamide

25.5-chloro-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl ] piperidin-4-yl } pyridine-3-carboxamide

26.3-chloro-5-methoxy-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl ] piperidin-4-yl } benzamide

27.4-chloro-3-methyl-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl ] piperidin-4-yl } benzamide

28.2- (3-chloro-4-fluorophenoxy) -N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl ] piperidin-4-yl } acetamide

29.2- (3-chlorophenoxy) -N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl ] piperidin-4-yl } acetamide

3-chloro-4-fluoro-N- {1- [1- (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) ethyl ] piperidin-4-yl } benzamide, or

N- {1- [ (6-fluoro-2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl ] piperidin-4-yl } -3-methoxybenzamide;

5) a pharmaceutical composition containing the compound of any one of the above 1) to 4), a pharmaceutically acceptable salt or hydrate thereof as an active ingredient;

6) the pharmaceutical composition of the above 5), which is a melanin concentrating hormone receptor antagonist; and is

7) A prophylactic or therapeutic agent for a compound of any one of 1) to 4), a pharmaceutically acceptable salt or hydrate thereof as an active ingredient for the following diseases: depression, anxiety disorder (generalized anxiety disorder, post-traumatic stress disorder, panic disorder, obsessive-compulsive disorder, or social anxiety disorder), attention deficit disorder, mania, manic depression, schizophrenia, mood disorder, stress, sleep disorder, attack, memory impairment, cognitive impairment, dementia, amnesia, delirium, obesity, eating disorder, appetite disorder, hyperphagia, bulimia, anorexia phobia, diabetes, cardiovascular disease, hypertension, dyslipidemia, myocardial infarction, movement disorder (parkinson's disease, epilepsy, spasm, or tremor), drug abuse, drug addiction, or sexual dysfunction.

Advantages of the invention

The compounds of the invention were found to have MCH receptor antagonistic activity. Based on MCH receptor antagonism, medicaments containing the compounds of the invention are useful as therapeutic or prophylactic agents for the following diseases: depression, anxiety disorders (such as generalized anxiety disorder, post-traumatic stress disorder, panic disorder, obsessive-compulsive disorder, or social anxiety disorder), attention deficit disorder, mania, manic depression, schizophrenia, mood disorder, stress, sleep disorder, aggression, memory impairment, cognitive impairment, dementia, amnesia, delirium, obesity, eating disorder, appetite disorder, hyperphagia, bulimia, anorexia phobia, diabetes, cardiovascular disease, hypertension, dyslipidemia, myocardial infarction, movement disorder (such as parkinson's disease, epilepsy, convulsion, or tremor), drug abuse, drug addiction, or sexual dysfunction.

Best mode for carrying out the invention

The terms used in the present specification are defined as follows.

"halogen atom" represents a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

“C_1-6Alkyl' stands forA straight chain alkyl group having 1 to 6 carbon atoms or a branched chain alkyl group having 3 to 6 carbon atoms. Straight-chain alkyl represents methyl, ethyl, propyl, butyl, pentyl and hexyl. Branched alkyl radicals represent, for example, isopropyl, isobutyl, tert-butyl, isopentyl, 1-ethylpropyl and isohexyl.

“C_1-6The alkoxy group "represents a linear alkoxy group having 1 to 6 carbon atoms or a branched alkoxy group having 3 to 6 carbon atoms. The linear alkoxy groups represent methoxy, ethoxy, propoxy, butoxy, pentoxy and hexoxy. Branched alkoxy represents, for example, isopropoxy, isobutoxy, tert-butoxy, isopentoxy, 1-ethylpropoxy and isohexoxy.

“C_1-6The alkylene group "represents a linear alkylene group having 1 to 6 carbon atoms or a branched alkylene group having 3 to 6 carbon atoms, and includes, for example, methylene, ethylene, propylene, butylene, pentylene, hexylene, isopropylene, isobutylene, t-butylene, isopentylene, 1-ethylpropylene and isohexylene.

″C_2-6Alkanoyl "represents a compound having C_1-5Carbonyl of alkyl. Examples thereof include methylcarbonyl, ethylcarbonyl, propylcarbonyl, butylcarbonyl, pentylcarbonyl, hexylcarbonyl, isopropylcarbonyl, isobutylcarbonyl, tert-butylcarbonyl, isopentylcarbonyl, 1-ethylpropylcarbonyl and isohexylcarbonyl.

"aryl" represents a monocyclic to tetracyclic aromatic carbocyclic group formed from 6 to 18 carbon atoms. Examples thereof include phenyl, naphthyl, anthracenyl, 9H-fluorenyl.

The "heteroaromatic ring" represents a monocyclic to bicyclic aromatic heterocyclic group of 5 to 10 atoms including 1 to 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms. Examples thereof include pyrrolyl, pyrazolyl, imidazolyl, furyl,Azolyl radical, isoOxazolyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoAzolyl, benzothiazolyl, benzopyrazolyl, benzisoxazoOxazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, cinnolinyl, and 9H-xanthenyl.

One aspect of the compound of the present invention relates to a 7-piperidinoalkyl-3, 4-dihydrocarbostyril compound represented by formula (I):

{ wherein (in formula (I)), R, X, Y, Z, W, A¹、A²、A³And Cy is as defined above }.

Preferred aspects of the compounds of the invention are as follows. In the formula (I), R is a hydrogen atom, A¹、A²And A³Each represents a hydrogen atom, X is C_1-6Alkylene, Y is a bond, Z is a bond or C_1-6Alkylene (wherein said C_1-6Alkylene group may be substituted with aryl group), W is a bond or an oxygen atom, and Cy is phenyl or pyridyl (wherein the phenyl or pyridyl group may have 1 to 3 substituents which may be the same or different, selected from a halogen atom, cyano group, C_1-6Alkyl radical, C_1-6Alkoxy and C_2-6Alkanoyl radical, wherein said C_1-6Alkyl or C_1-6Alkoxy groups may be substituted with 1 to 3 halogen atoms).

Another preferred aspect of the compounds of the present invention is as follows. In the formula (I), R is a hydrogen atom, A¹、A²And A³Each is a hydrogen atom, X is a methylene group (wherein the methylene group may be substituted by a methyl group), Y is a bond, Z is a bond or a methylene group, W is a bond or an oxygen atom, and Cy is a phenyl group (wherein the phenyl group may have 1 to 3 substituents which may be the same or different, the substituents being selected from a halogen atom, C_1-6Alkyl radical, C_1-6Alkoxy and C_2-6Alkanoyl) group. The above phenyl group is preferably an unsubstituted phenyl group or a substituted phenyl group represented by any one of formulae (IIa) to (IId):

{ where R^A、R^BAnd R^CWhich may be the same or different, each represents a halogen atom, C_1-6Alkyl radical, C_1-6Alkoxy or C_2-6Alkanoyl }.

Preferred specific compounds of the invention are

N- {1- [ (6-fluoro-2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl ] piperidin-4-yl } -3-methoxybenzamide.

A pharmaceutically acceptable salt or hydrate thereof.

One aspect of the compound of the present invention is a pharmaceutical (medicinal drug) containing at least one compound described in the present specification or a pharmaceutically acceptable salt thereof as an active ingredient.

One aspect of the compounds of the present invention is a medicament as an MCH receptor antagonist containing as active ingredient at least one compound described in the specification or a pharmaceutically acceptable salt thereof.

One aspect of the compound of the present invention is a pharmaceutical agent for preventing or treating a disease selected from the group consisting of: depression, anxiety disorders (such as generalized anxiety disorder, post-traumatic stress disorder, panic disorder, obsessive-compulsive disorder, or social anxiety disorder), attention deficit disorder, mania, manic depression, schizophrenia, mood disorder, stress, sleep disorder, aggression, memory impairment, cognitive impairment, dementia, amnesia, delirium, obesity, eating disorder, appetite disorder, hyperphagia, bulimia, anorexia phobia, diabetes, cardiovascular disease, hypertension, dyslipidemia, myocardial infarction, movement disorder (such as parkinson's disease, epilepsy, convulsion, or tremor), drug abuse, drug addiction, or sexual dysfunction. A preferred aspect is a prophylactic or therapeutic drug for depression and anxiety, which contains at least one compound described in the present specification, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient. As another preferred aspect are preventive or therapeutic drugs for obesity, eating disorders, appetite disorders, hyperphagia, bulimia and anorexia phobia, which contain at least one compound described in the present specification, a pharmaceutically acceptable salt or hydrate thereof, as an active ingredient.

Preferred compounds of the invention have excellent MCH receptor antagonism; but has low binding affinity to the hERG channel. Compounds with strong binding affinity for the hERG channel may be at risk of causing side effects on the cardiovascular system. Therefore, a compound having the above action is expected to exhibit excellent pharmaceutical effectiveness and to have high safety.

The compound (I) of the present invention, a pharmaceutically acceptable salt or hydrate thereof can be synthesized by various organic synthesis methods known to those skilled in the art. Examples thereof include the following production methods, but the present invention is not limited thereto. In addition, in the following reaction scheme, R, X, Y, Z, W, A¹、A²、A³And Cy is as defined above.

"inert solvent" represents, for example, aromatic solvents such as benzene, toluene, xylene and pyridine; hydrocarbon solvents such as hexane, pentane, cyclohexane; halogenated hydrocarbon solvents such as dichloromethane, chloroform, 1, 2-dichloroethane and carbon tetrachloride; ether solvents such as tetrahydrofuran, diethyl ether, 1, 2-dimethoxyethane and 1, 4-bisAn alkane; ester solvents such as ethyl acetate and ethyl formate; alcohol solvents such as methanol, ethanol, isopropanol, t-butanol and ethylene glycol; ketone solvents such as acetone and methyl ethyl ketone; amide solvents such as N, N-dimethylformamide, N-methylpyrrolidone and N, N-dimethylacetamide; sulfoxide solvents such as dimethyl sulfoxide; nitrile solvents such as acetonitrile and propionitrile; water; as well as homogeneous and heterogeneous mixtures of these solvents. These inert solvents are appropriately selected according to various reaction conditions known to those skilled in the art.

"base" represents, for example, hydrides of alkali metals or alkaline earth metals such as lithium hydride, sodium hydride, potassium hydride and calcium hydride; alkali metal or alkaline earth metal amides such as lithium amide, sodium amide, lithium diisopropylamide, lithium dicyclohexylamide, lithium hexamethyldisilylamide, sodium hexamethyldisilylamide and potassium hexamethyldisilylamide; lower alkoxides of alkali metals or alkaline earth metals such as sodium methoxide, sodium ethoxide, and potassium tert-butoxide; alkyl lithium such as butyl lithium, sec-butyl lithium, tert-butyl lithium and methyl lithium; hydroxides of alkali metals or alkaline earth metals such as sodium hydroxide, potassium hydroxide, lithium hydroxide and barium hydroxide; carbonates of alkali metals or alkaline earth metals such as sodium carbonate, potassium carbonate and cesium carbonate; alkali metal or alkaline earth metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; amines such as triethylamine, N-methylmorpholine, N-diisopropylethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1, 5-diazabicyclo [4.3.0] non-5-ene (DBN), and N, N-dimethylaniline; basic heterocyclic compounds such as pyridine, imidazole and 2, 6-lutidine. These bases are appropriately selected according to various reaction conditions known to those skilled in the art.

"acid" represents, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; and organic acids such as p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, formic acid and acetic acid. These acids may be appropriately selected according to various reaction conditions known to those skilled in the art.

[ production method 1]

The compounds (I) of the present invention can be prepared by the methods shown in scheme 1.

(procedure 1)

Wherein X¹Represents a bond or C_1-5An alkylene group;

X²represents a bond or C_1-4An alkylene group;

X^arepresents a halogen atom or a hydroxyl group;

R¹represents C_1-5An alkyl group;

provided that X is²And R¹The total number of carbon atoms of (a) is 1 to 5; and is

P¹A protecting group which represents a hydrogen atom or an amino group, such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, acetyl or benzyl (see protecting Groups in Organic Synthesis), third edition,John Wiley & Sons，INC.)。

step 1: the carbonyl compound (1) or (2) and the amine compound (3) are subjected to reductive amination reaction using a reducing agent in an inert solvent and in the presence or absence of an acid. As a result, compound (4) can be obtained. (see Organic Transformations, 1989, VCH Publishers, INC.). The carbonyl compound (1) or (2) used herein is a commercially available compound or a known compound. Further, the carbonyl compound (1) or (2) can be synthesized from a commercially available compound or a known compound using various organic synthesis methods known to those skilled in the art. The reducing agent used here is, for example, sodium triacetoxyborohydride, sodium cyanoborohydride and sodium borohydride.

Step 2: removal of the protecting group P of the amino group of the compound (4) by various organic synthesis methods known to those skilled in the art¹(see Protective Groups in Organic Synthesis), third edition, John Wiley&Sons, INC.). As a result, the amine compound (5) can be obtained. In addition, also at P¹In the case of the compound (3) which is a hydrogen atom, the amine compound (5) can be directly obtained by performing the same reductive amination reaction as in step 1.

And step 3: in an inert solvent and in the presence or absence of a base, an amine compound (5) and wherein X^aAn acid halide compound (6) which is a halogen atom or wherein X^aThe carboxylic acid compound (6) which is a hydroxyl group is subjected to amidation reaction. As a result, the compound (I) of the present invention can be obtained. The acid halide compound (6) or the carboxylic acid compound (6) is obtained as a commercially available compound or a known compound. Further, the acid halide compound (6) or the carboxylic acid compound (6) can be synthesized from a commercially available compound or a known compound by various synthetic methods known to those skilled in the art. The amidation reaction as used herein means an amidation reaction using a condensing agent such as N, N' -dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, diphenylphosphoryl azide or carbonyldiimidazole in an inert solvent and in the presence or absence of a base, or using ethyl chlorocarbonateIsobutyl chlorocarbonate, pivaloyl chloride, etc. (see basic and experimental of Peptide Synthesis, 1985, Maruzen co., Ltd.). In the amidation reaction using the condensing agent herein, an additive such as 1-hydroxybenzotriazole may be used, if necessary.

Further, the carbonyl compound, which is the starting material in scheme 1, can be prepared as compound (11) or (13) by the method shown in scheme 2.

(procedure 2)

Wherein R is²Represents C_1-6An alkyl group.

And 4, step 4: the carboxylic acid compound (7) is subjected to Friedel-Crafts reaction in the presence of an acid catalyst. As a result, the carbonyl compound (8) can be obtained. The acid catalysts used here are aluminum trichloride, chlorosulphate and polyphosphoric acid (see Tetrahedron, 2007, volume 63, pp 389-395).

And 5: the carbonyl compound (8) is subjected to Schmidt reaction using sodium azide or the like in the presence of an acid catalyst such as methanesulfonic acid, sulfuric acid, polyphosphoric acid, and titanium tetrachloride (see Stretic Applications of Named Reactions in Organic Synthesis, the strategy of applying the trade name reaction in Organic vehicles), 2005, Elsevier, INC., or U.S. Pat. No. 2006/0063799). As a result, the amide compound (9) was obtained.

Step 6: the compound (9) is reacted with zinc cyanide, copper cyanide, potassium cyanide, or the like in the presence or absence of a palladium catalyst. As a result, the nitrile compound (10) can be obtained (see Tetrahedron, 2006, vol. 62, p. 4705-4708).

And 7: the nitrile compound (10) is reduced in an inert solvent and in the presence of a metal catalyst. As a result, the carbonyl compound (11) can be obtained (see Comprehensive Organic Transformations, 1989, VCH Publishers, INC., or International publication WO 1996/20180). As the metal catalyst, raney nickel, tin dichloride, and the like are used.

And 8: the nitrile compound (10) can be converted into the nitrile compound (12) by various alkylation reactions known to those skilled in the art (see Organic Transformations, 1989, VCH Publishers, INC.).

And step 9: the nitrile compound (12) can be converted into the carbonyl compound (13) by the same method as in step 7.

Further, the carbonyl compound (1) which is the starting material in scheme 1 can be produced in the form of carbonyl compound (17) by the method shown in scheme 3.

(procedure 3)

Wherein X³Represents a bond or C_1-4An alkylene group;

X^brepresentative for Wittig reagents or Horner-Emmons reagents (e.g., as in WittigSalts or diesters of phosphorous acid, etc.); and

R³represents C_1-6An alkyl group.

Step 10: the carbonyl compounds (14) are reacted with Wittig reagent or Horner-Emmons reagent (15) in an inert solvent and in the presence of a base (see Organic Transformations: Comprehensive Organic Transformations, 1989, VCH Publishers, INC.). As a result, the olefin compound (16) can be obtained.

Step 11: the olefinic compound (16) can be converted into the carbonyl compound (17) by various hydrolysis reactions known to those skilled in the art (see Protective Groups in Organic Synthesis, third edition, John Wiley & Sons, INC.).

Further, the carbonyl compound (1) which is the starting material in scheme 1 can be produced as the carbonyl compound (19) by the method shown in scheme 4.

(procedure 4)

Wherein X³Same as defined above;

R⁴represents C_1-5An alkyl group;

provided that X is³And R⁴The total number of carbon atoms of (a) is 1 to 5; and is

M represents a metal used in the alkylation reaction. The metal used herein represents, for example, halides of metals such as lithium and magnesium, and the like.

Step 12: in an inert solvent, use is made of⁴The organometallic reagent represented by-M is used for the alkylation of the carbonyl compound (14) (see Organic Transformations, 1989, VCH Publishers, INC.). As a result, an alcohol compound (18) was obtained.

Step 13: the alcohol compound (18) can be converted into the carbonyl compound (19) by an oxidation reaction known to those skilled in the art in an inert solvent (see oxidation in Organic Chemistry, 1990, American Chemical Society). The oxidation reaction known to the person skilled in the art is, for example, the use of pyridine dichromateOr pyridinium chlorochromateEtc., a chromic acid oxidation reaction, a manganese oxidation reaction using manganese dioxide or the like, a dimethyl sulfoxide oxidation reaction using oxalyl chloride (Swern oxidation) or dicyclohexylcarbodiimide (Moffatt oxidation) or the like as an activator, a 2,2, 6, 6-tetramethyl-1-piperidinyloxy oxidation reaction using a co-oxidant such as sodium hypochlorite (TEMPO oxidation), or an oxidation reaction using Dess-Martin reagent.

Further, a compound (24), which is a carbonyl compound (1) used as a starting material in scheme 1, wherein A¹、A²And A³At least one of which is a halogen atom, can be prepared by the method shown in scheme 5.

(procedure 5)

Wherein A is⁴、A⁵And A⁶Which may be the same or different, each represents a hydrogen atom or a halogen atom;

with the proviso that A⁴、A⁵And A⁶At least one of them represents a halogen atom;

P²protecting Groups representing hydroxy Groups such as tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tetrahydropyranyl, methoxymethyl, acetyl, benzoyl or benzyl (see protecting Groups in Organic Synthesis, third edition, John Wiley& Sons，INC.)。

Step 14: the hydroxyl group of the alcohol compound (20) is protected with a protecting group such as t-butyldimethylsilyl group, t-butyldiphenylsilyl group, tetrahydropyranyl group, methoxymethyl group, acetyl group, benzoyl group or benzyl group (see Protective Groups in Organic Synthesis, third edition, John Wiley & Sons, INC.). As a result, compound (21) was obtained.

Step 15: compound (21) is converted to compound (22) having a halogen substituent on the aromatic ring by various halogenation reactions known to those skilled in the art (see Organic Transformations, 1989, VCH Publishers, INC., or Tetrahedron Letters 1999, Vol.40, p. 2673-2676).

Step 16: protecting group P of Compound (22) by Using various organic Synthesis methods known to those skilled in the art²(see Protective Groups in Organic Synthesis), third edition, John Wiley&Sons, INC.). As a result, the alcohol compound (23) can be obtained.

And step 17: the alcohol compound (23) can be converted into the carbonyl compound (24) by the same method as in step 13.

[ production method 2]

The compounds (I) of the present invention can be prepared by the methods shown in scheme 6.

(procedure 6)

Wherein X¹、X²、X^a、R¹And P¹As defined above.

Step 18: compound (25) can be converted to compound (26) using the same procedure as in step 3 of scheme 1.

Step 19: compound (26) can be converted to compound (27) using the same method as in step 2 of scheme 1. Furthermore, also in which P¹In the case of the compound (25) which is a hydrogen atom, the same amidation reaction as in step 3 of scheme 1 is carried out. As a result, it can be directly obtainedCompound (27).

Step 20: the carbonyl compound (1) or (2) is subjected to reductive amination with the amine compound (27) by the same method as in step 1 of scheme 1. As a result, the compound (I) of the present invention can be obtained.

Further, the nitrile compound (10) in scheme 2 can be prepared from the phenol compound (28) by the method shown in scheme 7.

(procedure 7)

Wherein L represents a leaving group such as a halogen atom, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a p-toluenesulfonyloxy group or the like.

Step 21: the phenol compound (28) used herein is available as a commercially available compound or a known compound. Further, the phenol compound (28) can be synthesized from commercially available compounds or known compounds by using various organic synthesis methods known to those skilled in the art. When L represents a halogen atom, compound (29) can be obtained by halogenating the hydroxyl group of compound (28) with a halogenating agent such as bromine or oxalyl chloride in the presence of trimethylphosphine, tributylphosphine, triphenylphosphine, or the like in an inert solvent, or with a halogenating agent such as thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, phosphorus pentabromide, or phosphorus oxychloride in the presence or absence of a base in an inert solvent or in the absence of a solvent. Alternatively, when L represents a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group or a p-toluenesulfonyloxy group, for example, the hydroxyl group of compound (28) is reacted with methanesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, N-phenyl-bis (trifluoromethanesulfonimide) or p-toluenesulfonyl chloride in an inert solvent in the presence or absence of a base to give compound (29) [ see Organic Transformations of large (Comprehensive Organic Transformations, 1989, VCH Publishers, Inc. ].

Step 22: compound (29) can be converted into the nitrile compound (10) by the same method as in step 6 of scheme 2.

When the compound (I) of the present invention forms a salt and is used as a medicament, the salt is preferably a pharmaceutically acceptable salt. As the pharmaceutically acceptable salts, for example, salts with various inorganic acids such as hydrochloride, sulfate, hydrobromide, nitrate and phosphate; or salts with organic acids such as acetate, oxalate, lactate, citrate, malate, tartrate, maleate, fumarate, succinate, methanesulfonate, ethanesulfonate, benzenesulfonate and p-toluenesulfonate; however, the pharmaceutically acceptable salt is not limited thereto.

In addition, as pharmaceutically acceptable salts, alkali metal salts (e.g., sodium salt, potassium salt), alkaline earth metal salts (e.g., calcium salt, magnesium salt, barium salt), salts with inorganic bases such as aluminum salt or ammonium salt; or a salt with an organic base such as trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine or N, N-dibenzylethylenediamine.

When the compound (I) of the present invention includes optical isomers, stereoisomers, regioisomers, rotamers, single compounds and mixtures thereof, are included in the compound of the present invention. In addition, when the compound (I) of the present invention forms a hydrate or solvate, they are also included in the scope of the present invention. Furthermore, the compound (I) of the present invention may be isotopically substituted (for example, D, B, C, D, C,³H、¹³C、¹⁴C、¹⁵N、³⁵S、¹²⁵I, etc.) a marker.

The MCH receptor antagonists and drugs of the present invention are each prepared by formulating the compound (I), a pharmaceutically acceptable salt or hydrate thereof, alone or together with a pharmaceutically acceptable carrier, according to well-known methods. As pharmaceutically acceptable carriers, there may be mentioned various organic or inorganic carrier substances which are commonly used as raw materials for preparations. Mention may be made, for example, of: excipients used in solid formulations (e.g., lactose, white sugar, D-mannitol, starch, corn starch, microcrystalline cellulose, light silicon dioxide), lubricants (e.g., magnesium stearate, calcium stearate, talc, colloidal silicon dioxide), binders (e.g., microcrystalline cellulose, white sugar, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methyl cellulose, sodium carboxymethyl cellulose), disintegrants (e.g., sucrose, carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose), or solvents used in liquid formulations (e.g., water for injection, alcohols, propylene glycol, polyethylene glycol, sesame oil, corn oil), solubilizers (e.g., polyethylene glycol, propylene glycol, sodium lauryl sulfate, and sodium lauryl sulfate), and the like, D-mannitol, benzyl benzoate, ethanol, triaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate), suspending agents (e.g., surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionate, lecithin, benzalkonium chloride, benzethonium chloride, glycerol monostearate, and the like; or hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose and hydroxypropylcellulose), isotonic agents (e.g., glucose, D-sorbitol, sodium chloride, glycerol, D-mannitol), buffers (e.g., phosphates, acetates, carbonates, citrates) or placebo (e.g., benzyl alcohol), and the like. In addition, in the preparation of the formulation, preservatives (e.g., parabens, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid), antioxidants (e.g., sulfite, ascorbic acid), colorants, sweeteners, adsorbents, wetting agents, and the like may also be used as needed.

The MCH receptor antagonists and agents of the invention may be administered orally or parenterally (e.g., intravenous, topical, rectal injection). Examples of the dosage form include tablets (including sugar-coated tablets and film-coated tablets), powders, granules, powders, lozenges, capsules (including soft capsules), liquid preparations, injections (e.g., subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections), external preparations (e.g., nasal administration, transdermal preparations, ointments, creams), suppositories (e.g., rectal suppositories, vaginal suppositories), sustained-release agents (e.g., sustained-release microcapsules), pills and drops. These can be prepared by a commonly used formulation technique (for example, the method described in the 15 th revised Japanese pharmacopoeia).

The dose of the MCH receptor antagonist and the drug of the present invention may be appropriately selected depending on the subject of administration, the route of administration, the disease, the age, weight and symptoms of the patient. For example, when treating an adult patient, the amount administered is 1-2000mg per day. The amount may be administered once daily or in several divided doses.

When the MCH receptor antagonist is used as an active ingredient of a medicament, it is noted that it can be used not only for humans but also for other mammals. For example, in accordance with recent advances in the field of animal health care, the MCH receptor antagonists may be used in the treatment of obesity in domestic animals (e.g., cats, dogs), and the MCH receptor antagonists may also be used in other domestic animals whose disease or disorder is not yet clear (e.g., edible animals such as cattle, chickens, fish).

Examples

The present invention is illustrated in more detail by the following examples; these examples should not be construed as limiting the invention and these examples may be varied within the scope of the invention.

The "room temperature" mentioned in the examples means 0 ℃ to 40 ℃. "silica gel 60N" and "Chromatorrex NH" used in purification by column chromatography were purchased from Kanto Chemical Co., Inc. and Fuji Silysia, respectively.

In the examples, the data measured by the apparatus were measured by the following measuring apparatus.

MS spectrum: shimadzu LCMS-2010EV or micromass Platform LC

NMR spectra: 600MHz (JNM-ECA600, JEOL Ltd.) or 200MHz (GEMINI2000/200, Warrian corporation)

The compounds in the examples are named according to ACD/Name (ACD/Labs 8.00, Advanced Chemistry Development Inc.).

Abbreviations used in the examples are as follows:

Ac₂o (acetic anhydride), AcOH (acetic acid), APCI (atmospheric pressure chemical ionization), brs (broad peak), DCl₃(deuterated chloroform), CHCl₃(chloroform), CH₃CN (acetonitrile), d (doublet), dd (doublet), ddd (doublet), DMAP (N, N-dimethyl-4-aminopyridine), DMF (N, N-dimethylformamide), DMSO-d₆(deuterated dimethyl sulfoxide), dt (double triplet), EDC [ 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide]EI (Electron ionization), ESI (electrospray ionization), Et₃N (triethylamine), Et₂O (diethyl ether), EtOAc (ethyl acetate), EtOH (ethanol), H (proton), HCl (hydrochloric acid or hydrochloric acid), H₂O (water), HOBt (1-hydroxybenzotriazole), Hz (Hertz), IPA (isopropanol), IPE (isopropyl ether), J (coupling constant), K₂CO₃(Potassium carbonate), m (multiplet), MeI (methyl iodide), MeMgBr (methyl magnesium bromide), MeOH (methanol), MeOH-d₄(deuterated methanol), MgSO₄(magnesium sulfate), MnO₂(manganese dioxide), MS (Mass Spectrometry), NaBH₄(sodium borohydride), NaH (sodium hydride), NaHCO₃(sodium bicarbonate), Na₂SO₄(sodium sulfate), NH₄Cl (ammonium chloride), NMR (nuclear magnetic resonance Spectroscopy), NaBH (OAc)₃Sodium triacetoxyborohydride, NaNH₂Sodium amide, NaOH (sodium hydroxide), Pd₂(dba)₃[ Tris (dibenzylideneacetone) dipalladium]、Ph₃PCH₂OMe Br [ bromo (methoxymethyl) triphenyl)]、iPr₂Net (diisopropylethylamine), q (quartet), s (singlet)) T (triplet), td (triplet), THF (tetrahydrofuran), TMEDA (tetramethylethylenediamine), v/v (volume/volume), Xantphos [4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene]。

Example 1: synthesis of 3-methoxy-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl ] piperidin-4-yl } benzamide

Step 1-1: to chlorosulfuric acid (1.19L) was added 3- (4-bromophenyl) propionic acid (91.1g) under ice-cooling, and the mixture was stirred for 2 hours. To H under ice cooling₂O (2.00L) was added slowly to the reaction mixture with CHCl₃The extraction was carried out 6 times. The combined organic layers were washed with saturated NaHCO₃Washing with aqueous solution over Na₂SO₄Dried and concentrated under reduced pressure. To the resulting residue MeOH was added and the mixture was heated to reflux for 30 min. A solid material was obtained by filtration to obtain solid a. The filtrate was concentrated under reduced pressure to obtain solid B in the same manner. After that, the filtrate was concentrated again under reduced pressure to obtain solid C in the same manner. Solids A, B and C were combined to give 6-bromo-2, 3-dihydro-1H-inden-1-one (59.3g, light yellow solid).

¹H NMR(600MHz，CDCl₃，δ)：2.66-2.75(m，2H)，3.04-3.12(m，2H)，7.36(d，J＝8.3Hz，1H)，7.67(dd，J＝8.0，2.1Hz，1H)，7.86(d，J ＝1.8Hz，1H)；

ESI/APCI MS m/z 210[M+H]⁺.

Step 1-2: CHCl of the Compound (39.5g) obtained in step 1-1 under ice-cooling₃Sodium azide (36.5g) was added portionwise to the solution (560mL) and methanesulfonic acid (122mL), and the mixture was then heated to reflux for 2.5 hours. The reaction mixture was added to H under ice-cooling₂In O (400mL), the pH was adjusted to 9 with 28% ammonia and CHCl₃Extraction was carried out three times. The combined organic layers were washed with Na₂SO₄Dried and concentrated under reduced pressure. Thereafter, the residue was purified by column chromatography (silica gel 60N, mobile phase: EtOAc/hexane)Alkyl 50/50 to 75/25; v/v). The resulting solid material was suspended in EtOAc/hexane solution (1/1; v/v) and the mixture was stirred at room temperature for 1 hour. Solid material was obtained by filtration to give 7-bromo-3, 4-dihydroquinolin-2 (1H) -one (15.5g, light yellow solid).

¹H NMR(200MHz，CDCl₃，δ)：2.59-2.68(m，2H)，2.88-2.97(m，2H)，6.91-7.16(m，3H)，8.27(brs，1H)；

ESI/APCI MS m/z 226[M+H]⁺.

Step 1-3: to a DMF solution (14.5mL) of the compound (3.00g) obtained in step 1-2 was added zinc cyanide (1.04g) and Pd₂(dba)₃(122mg), Xantphos (154mg) and TMEDA (590. mu.L) and the mixture was stirred under microwave irradiation (180 ℃ C.) for 5 minutes. To the reaction mixture was added CHCl₃The mixture was filtered through Celite and washed with DMF. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 60N, mobile phase: EtOAc/hexanes 50/50 to 100/0; v/v). To the resulting solid material was added EtOAc at room temperature and the mixture was stirred for 30 min. Solid material was obtained by filtration and washed with EtOAc to give 2-oxo-1, 2,3, 4-tetrahydroquinoline-7-carbonitrile (15.5g, a pale yellow solid).

¹H NMR(600MHz，CDCl₃，δ)：2.64-2.68(m，2H)，3.00-3.04(m，2H)，7.04(s，1H)，7.23-7.29(m，2H)，8.46(brs，1H)；ESI/APCI MS m/z 173[M+H]⁺.

Step 1-4: to a solution of the compound (32.6g) obtained in step 1-3 in formic acid (250mL) was added Raney nickel catalyst (50.0g) and the mixture was stirred at 50 ℃ for 2 hours. After the reaction mixture was filtered through Celite, the filtrate was concentrated under reduced pressure. To the residue was added saturated NaHCO₃Aqueous solution, the mixture was adjusted to pH6 and filtered to give solid a. Filtrate with CHCl₃Extracting three times, and passing combined organic layers through Na₂SO₄Dried and concentrated under reduced pressure. Mixing the residue withSolid A was combined and suspended in EtOAc/CHCl₃In a solution mixture of/acetone (10/10/1; v/v/v) and the mixture was stirred at room temperature for 1 hour and filtered to give 2-oxo-1, 2,3, 4-tetrahydroquinoline-7-carbaldehyde (19.8g, light yellow solid).

¹H NMR(200MHz，CDCl₃，δ)：2.65-2.76(m，2H)，3.02-3.13(m，2H)，7.31-7.38(m，2H)，7.49-7.55(m，1H)，9.13(brs，1H)，9.95(s，1H)；ESI/APCI MS m/z 176[M+H]⁺.

Step 1-5: the compound obtained in steps 1-4 (19.8g) was reacted with tert-butyl piperidin-4-ylcarbamate (24.8g) in CHCl at 70 deg.C₃The solution in (450mL) was stirred for 1.5 hours and allowed to cool to room temperature. Thereafter, NaBH (OAc) was added to the mixture under ice cooling₃(35.9g) and the mixture was stirred at room temperature for 12 hours. To the reaction mixture was added saturated NaHCO₃Aqueous solution, followed by separation of the aqueous and organic layers. Aqueous layer with CHCl₃Extraction was carried out three times. The combined organic layers were washed with Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 60N, mobile phase: MeOH/CHCl)₃33/66 to 100/0, v/v) to yield {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl]Piperidin-4-yl } carbamic acid tert-butyl ester (37.8g, colorless solid).

¹H NMR(600MHz，CDCl₃，δ)：1.35-1.51(m，11H)，1.82-1.96(m，2H)，2.07(t，J＝10.5Hz，2H)，2.49-2.66(m，2H)，2.78(brs，2H)，2.93(t，J ＝7.6Hz，2H)，3.29-3.55(m，3H)，4.48(brs，1H)，6.76(s，1H)，6.90(d，J＝7.3Hz，1H)，7.08(d，J＝7.8Hz，1H)，8.37(brs，1H)；ESI/APCI MS m/z 360[M+H]⁺.

Step 1-6: to a solution of the compound obtained in steps 1-5 (37.8g) in EtOAc (130mL) was added a 4M HCl/EtOAc solution (263mL) under ice-cooling and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was suspended in EtOAc (200mL) and filtered to give a solidAnd (3) a body. To the solid was added CHCl₃(200mL) and H₂O (200mL) and the mixture was stirred for 15 min. After separation of the aqueous and organic layers, the aqueous layer was washed with CHCl₃And washing twice. The aqueous layer was adjusted to pH10 by the addition of 2M aqueous NaOH solution, and the solution was then treated with CHCl₃The extraction is carried out for 30 times. The combined organic layers were washed with Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by column chromatography (Chromatorex NH, mobile phase: MeOH/CHCl₃1/4; v/v) to give 7- [ (4-aminopiperidin-1-yl) methyl]-3, 4-dihydroquinolin-2 (1H) -one (17.9g, colorless solid).

¹H NMR(600MHz，CDCl₃，δ)：1.32-1.49(m，2H)，1.74-1.88(m，2H)，1.93-2.09(m，2H)，2.54-2.70(m，3H)，2.80(d，J＝11.9Hz，2H)，2.93(t，J＝7.6Hz，2H)，3.41(s，2H)，6.74(s，1H)，6.90(d，J ＝9.2Hz，1H)，7.07(d，J＝7.3Hz，1H)，8.28(brs，1H)；ESI/APCI MS m/z 260[M+H]⁺.

Step 1-7: to the compound obtained in steps 1-6 (250mg) in CHCl₃To the solution (5.00mL) was added iPr₂NEt (370. mu.L) and 3-methoxybenzoyl chloride (180mg) and the mixture was stirred at room temperature for 3 days. To the reaction mixture was added saturated NaHCO₃Aqueous solution of CHCl₃The extraction was carried out 4 times. The combined organic layers were washed with Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by column chromatography [ successively (silica gel 60N, mobile phase: MeOH/CHCl)₃0/100 to 10/90; v/v) and (Chromatorex NH, mobile phase: CHCl₃)]To obtain a solid. To the resulting solid was added IPA at room temperature and the mixture was stirred for 1 hour, filtered and washed with IPA and hexane to give the title compound (159mg, colorless solid).

¹H NMR(600MHz，CDCl₃，δ)：1.48-1.62(m，2H)，1.94-2.06(m，2H)，2.10-2.21(m，2H)，2.57-2.67(m，2H)，2.78-2.87(m，2H)，2.90-2.99(m，2H)，3.44(s，2H)，3.85(s，3H)，3.94-4.05(m，1H)，6.01(d，J ＝7.8Hz，1H)，6.74(s，1H)，6.91(d，J＝7.3Hz，1H)，7.02(dd，J＝7.6，2.1Hz，1H)，7.09(d，J＝7.8Hz，1H)，7.21-7.27(m，1H)，7.29-7.35(m，2H)，7.85(s，1H)；ESI/APCI MS m/z 394[M+H]⁺.

Example 2: synthesis of 3-methoxy-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl ] piperidin-4-yl } benzamide monohydrochloride monohydrate

To the suspension of the compound obtained in steps 1-7 (167mg) in EtOAc (1.70mL) was added 4M HCl/EtOAc solution (140 μ L) and the mixture was stirred at room temperature for 1.5 h and filtered to give the title compound (160mg, colorless solid).

¹H NMR(600MHz，MeOH-d₄，δ)：1.98(brs，2H)，2.18(brs，2H)，2.53-2.62(m，2H)，2.98(t，J＝7.6Hz，2H)，3.03-3.19(m，2H)，3.50(brs，2H)，3.81(s，3H)，4.11(brs，1H)，4.23(brs，2H)，6.98(s，1H)，7.05-7.15(m，2H)，7.27-7.39(m，4H)；ESI/APCI MS m/z 394[M(free)+H]⁺

The compounds of example 3 to example 30 were obtained in the same manner as in example 1.

TABLE 1

Example 31: synthesis of 3-chloro-4-fluoro-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl ] piperidin-4-yl } benzamide

To a solution of the compound obtained in steps 1-6 (250mg) in DMF (2.50mL) was added 3-chloro-4-fluorobenzoic acid (191mg), Et₃N(320μL)、HOBt·H₂O (222mg) and EDC. HCl (222mg) and the mixture was stirred at room temperature for three days. To the reaction mixture was added saturated NaHCO₃Aqueous solution of CHCl₃And extracting for four times. The combined organic layers were washed with Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by column chromatography [ successively (silica gel 60N, mobile phase: MeOH/CHCl)₃0/100 to 10/90; v/v) and (Chromatorex NH, mobile phase: CHCl₃)]. IPA was added to the residue at room temperature and the mixture was stirred for 1 hour. The precipitate was obtained by filtration and washed with IPA and hexane to give the title compound (263mg, colorless solid).

¹H NMR(600MHz，CDCl₃，δ)：1.53-1.64(m，2H)，1.96-2.04(m，2H)，2.10-2.20(m，2H)，2.58-2.67(m，2H)，2.80-2.90(m，2H)，2.94(t，J＝7.6Hz，2H)，3.45(s，2H)，3.93-4.04(m，1H)，6.18(brs，1H)，6.77(s，1H)，6.90(d，J＝7.3Hz，1H)，7.10(d，J ＝7.8Hz，1H)，7.18(t，J＝8.7Hz，1H)，7.67(ddd，J＝8.6，4.5，2.1Hz，1H)，7.83-7.95(m，2H)；ESI/APCI MS m/z 416[M+H]⁺.

The compounds of examples 32 to 47 were obtained in the same manner as in example 31.

TABLE 2

Example 48: synthesis of 3-chloro-4-fluoro-N- {1- [ (1-methyl-2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl ] piperidin-4-yl } benzamide

Step 48-1: to a solution of the compound (1.25g) obtained in step 1-3 in DMF (20mL) was added NaH (0.29g) under ice-cooling and the mixture was stirred for 30 minutes. To the mixture was added MeI (1.12g) and the mixture was stirred at room temperature for 12 hours. After addition of water, the reaction mixture was extracted three times with EtOAc. The combined organic layers were washed with water and brine, over MgSO₄Dried and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 60N, mobile phase: EtOAc/hexanes: 30/70 to 50/50; v/v) to give 1-methyl-2-oxo-1, 2,3, 4-tetrahydroquinoline-7-carbonitrile (0.94g, colorless solid).

¹H NMR(600MHz，CDCl₃，δ)：2.64-2.73(m，2H)，2.92-3.04(m，2H)，3.37(s，3H)，7.21-7.23(m，1H)，7.26-7.29(m，1H)，7.31-7.34(m，1H)；EI MS m/z 186[M]⁺.

Step 48-2: from the compound (0.92g) obtained in step 48-1, 1-methyl-2-oxo-1, 2,3, 4-tetrahydroquinoline-7-carbaldehyde (0.93g, pale yellow solid) was obtained in the same manner as in step 1-4.

¹H NMR(600MHz，CDCl₃，δ)：2.69-2.75(m，2H)，3.00-3.06(m，2H)，3.45(s，3H)，7.35-7.40(m，1H)，7.51-7.53(m，1H)，7.54-7.57(m，1H)，10.02(s，1H)；EI MS m/z 189[M]⁺.

Step 48-3: the compound obtained in step 48-2 (0.93g), tert-butyl piperidin-4-ylcarbamate (0.82g) and AcOH (0.27g) in CHCl at room temperature₃Adding NaBH (OAc) into the solution₃(1.30g) and the mixture was stirred at room temperature for 12 hours. After adding saturated NaHCO₃After the aqueous solution, the aqueous and organic layers were separated. Aqueous layer with CHCl₃Extraction was carried out three times. The combined organic layers were washed with Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by column chromatography (Chromatorex NH, mobile phase: EtOAc/hexane: 50/50; v/v) to give {1- [ (1-methyl-2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl]Piperidin-4-yl } carbamic acid tert-butyl ester (0.78g, colorless amorphous).

¹H NMR(600MHz，CDCl₃，δ)：1.37-1.44(m，2H)，1.45(s，9H)，1.84-1.97(m，2H)，2.07-2.13(m，2H)，2.60-2.68(m，2H)，2.75-2.84(m，2H)，2.85-2.91(m，2H)，3.36(s，3H)，3.42-3.55(m，3H)，4.44(brs，1H)，6.91-6.98(m，2H)，7.09(d，J ＝7.3Hz，1H)；ESI/APCI MS m/z 374[M+H]⁺.

Step 48-4: the same procedures used in step 1-6 were repeated except for using the compound obtained in step 48-3 (0.77g) to give 7- [ (4-aminopiperidin-1-yl) methyl ] -1-methyl-3, 4-dihydroquinolin-2 (1H) -one (0.57g, as a colorless solid).

¹H NMR(600MHz，CDCl₃，δ)：1.33-1.45(m，2H)，1.76-1.82(m，2H)，2.00-2.07(m，2H)，2.58-2.67(m，2H)，2.66-2.71(m，1H)，2.79-2.85(m，2H)，2.86-2.90(m，2H)，3.37(s，3H)，3.48(s，2H)，6.95(d，J＝7.8Hz，1H)，6.98(s，1H)，7.09(d，J＝7.3Hz，1H)；ESI/APCI MS m/z 274[M+H]⁺.

Step 48-5: the title compound (183mg, colorless solid) was obtained from the compound obtained in step 48-4 (200mg) and 3-chloro-4-fluorobenzoic acid (141mg) by the same method as in example 31.

¹H NMR(600MHz，CDCl₃，δ)：1.51-1.58(m，2H)，1.98-2.05(m，2H)，2.18(t，J ＝10.8Hz，2H)，2.60-2.68(m，2H)，2.83-2.91(m，4H)，3.36(s，3H)，3.50(s，2H)，3.94-4.02(m，1H)，5.89(d，J ＝7.8Hz，1H)，6.95(d，J＝7.3Hz，1H)，6.96-6.99(m，1H)，7.09(d，J＝7.3Hz，1H)，7.18(t，J＝8.7Hz，1H)，7.63(ddd，J ＝8.6，4.5，2.1Hz，1H)，7.81(dd，J＝6.9，2.3Hz，1H)；ESI/APCI MS m/z 430[M+H]⁺.

Example 49: synthesis of 3-chloro-4-fluoro-N- ({1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl ] piperidin-4-yl } methyl) benzamide

Step 49-1: the same procedure as in step 48-3 was carried out using the compound obtained in step 1-4 (0.87g) and tert-butyl (piperidin-4-ylmethyl) carbamate (0.88g) to give tert-butyl ({1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl ] piperidin-4-yl } methyl) carbamate (0.68g, as a colorless solid).

¹H NMR(600MHz，CDCl₃，δ)：1.20-1.31(m，2H)，1.43(s，9H)，1.43-1.45(m，1H)，1.61-1.67(m，2H)，1.88-1.98(m，2H)，2.60-2.67(m，2H)，2.83-2.90(m，2H)，2.90-2.98(m，2H)，2.99-3.05(m，2H)，3.42(s，2H)，4.56-4.63(m，1H)，6.73(s，1H)，6.91(d，J＝7.8Hz，1H)，7.09(d，J＝7.3Hz，1H)，7.86(s，1H)；ESI/APCI MS m/z 374[M+H]⁺.

Step 49-2: using the same procedure as in step 1-6, from the compound obtained in step 49-1 (0.66g), 7- { [4- (aminomethyl) piperidin-1-yl ] methyl } -3, 4-dihydroquinolin-2 (1H) -one (0.35g, colorless amorphous substance) was obtained.

¹H NMR(600MHz，CDCl₃，δ)：1.17-1.30(m，2H)，1.27-1.33(m，1H)，1.66-1.73(m，2H)，1.90-1.97(m，2H)，2.56-2.60(m，2H)，2.61-2.66(m，2H)，2.85-2.92(m，2H)，2.92-2.97(m，2H)，3.42(s，2H)，6.76(s，1H)，6.92(d，J＝7.3Hz，1H)，7.09(d，J＝7.8Hz，1H)，8.16(brs，1H)；ESI/APCI MS m/z 274[M+H]⁺.

Step 49-3: the title compound (120mg, colorless solid) was obtained from the compound obtained in step 49-2 (211mg) and 3-chloro-4-fluorobenzoic acid (145mg) by the same method as in example 31.

¹H NMR(600MHz，CDCl₃，δ)：1.29-1.40(m，2H)，1.59-1.67(m，1H)，1.68-1.74(m，2H)，1.92-2.00(m，2H)，2.58-2.65(m，2H)，2.86-2.91(m，2H)，2.91-2.96(m，2H)，3.30-3.37(m，2H)，3.42(s，2H)，6.07-6.13(m，1H)，6.70(s，1H)，6.90(d，J＝7.3Hz，1H)，7.08(d，J＝7.3Hz，1H)，7.18(t，J＝8.7Hz，1H)，7.45(brs，1H)，7.64(ddd，J＝8.4，4.5，2.3Hz，1H)，7.82(dd，J＝7.1，2.1Hz，1H)；ESI/APCI MS m/z 430[M+H]⁺.

Example 50: synthesis of 3-methoxy-N- {1- [2- (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) ethyl ] piperidin-4-yl } benzamide

Step 50-1: adding NaNH under ice cooling₂Ph of₃PCH₂A mixture of OMe & Br (4.97g) in THF (20mL) was stirred for 10 min. To the mixture was slowly added dropwise a solution of the compound (1.00g) obtained in steps 1 to 4 in THF (80 mL). After completion of the dropwise addition, the mixture was stirred at room temperature for 4 hours. To the reaction mixture was added saturated NaHCO₃Aqueous solution, extracted once with EtOAc and with CHCl₃The extraction was performed twice. The combined organic layers were washed with brine, over MgSO₄Dried and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 60N, mobile phase: EtOAc/hexanes: 20/80 to 40/60; v/v) to give 7- (2-methoxyvinyl) -3, 4-dihydroquinolin-2 (1H) -one (0.60g, colorless solid).

¹H NMR(600MHz，CDCl₃，δ)：2.48-2.76(m，2H)，2.79-3.07(m，2H)，3.59-3.84(m，3H)，5.10-7.18(m，5H)，8.17-8.76(m，1H)；ESI/APCI MS m/z 204[M+H]⁺.

Step 50-2: to a solution of the compound (590mg) obtained in step 50-1 in THF (11.8mL) was added concentrated HCl (8.9mL) under ice-cooling and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added saturated K₂CO₃The solution is prepared from CHCl₃And (4) extracting. The organic layer was MgSO₄Dried and concentrated under reduced pressure to give (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) acetaldehyde (0.51g, colorless amorphous).

¹H NMR(600MHz，CDCl₃，δ)：2.60-2.70(m，2H)，2.91-3.01(m，2H)，3.57-3.76(m，2H)，6.58-7.20(m，3H)，9.72-9.77(m，1H)；EI MS m/z 189[M]⁺.

Step 50-3: to a suspension of tert-butyl 4-aminopiperidine-1-carboxylate (78.0g) and 3-methoxybenzoic acid (65.2g) in DMF (780mL) was added Et₃N(130mL)、HOBt·H₂O (71.7g) and EDC & HCl (82.8g) and the mixture was stirred at room temperature for 12 hours. Addition of H₂O (1.56L) and the mixture was stirred in a water bath for 1.5 hours. The precipitate was filtered to give 4- [ (3-methoxybenzoyl) amino group]Tert-butyl piperidine-1-carboxylate (126g, colorless solid). To a suspension of the compound obtained in the above procedure in EtOAc (900mL) was added 4M HCl/EtOAc solution (900mL) and the mixture was stirred at room temperature for 4 h. The reaction solution was concentrated under reduced pressure, and CHCl was then added to the residue₃(2.00L) and 2M aqueous NaOH (1.00L) and the mixture was stirred for 15 minutes. The aqueous layer was separated from the organic layer, followed by CHCl₃Extracted twice (800 mL). The combined organic layers were washed with Na₂SO₄Dried and concentrated under reduced pressure to give 3-methoxy-N-piperidin-4-ylbenzamide (87.8g, a pale yellow solid).

¹H NMR(200MHz，CDCl₃，δ)：1.30-1.52(m，2H)，1.97-2.12(m，2H)，2.75(dt，J＝12.0，2.4Hz，2H)，3.11(dt，J＝12.8，3.5Hz，2H)，3.85(s，3H)，3.96-4.18(m，1H)，6.00(d，J＝7.9Hz，1H)，6.98-7.07(m，1H)，7.21-7.38(m，3H)；ESI MS m/z 235，[M+H]⁺.

Step 50-4: the title compound (0.22g, colorless solid) was obtained from the compound obtained in step 50-2 (0.51g) and the compound obtained in step 50-3 (0.57g) by the same method as in step 48-3.

¹H NMR(600MHz，CDCl₃，δ)：1.50-1.62(m，2H)，2.00-2.11(m，2H)，2.19-2.27(m，2H)，2.54-2.65(m，4H)，2.72-2.78(m，2H)，2.88-2.99(m，4H)，3.84(s，3H)，3.96-4.06(m，1H)，5.96(d，J＝7.8Hz，1H)，6.59(s，1H)，6.79-6.86(m，1H)，7.02(dd，J＝8.3，1.8Hz，1H)，7.07(d，J＝7.8Hz，1H)，7.22-7.28(m，1H)，7.29-7.36(m，2H)，7.80(s，1H)；ESI/APCI MS m/z 408[M+H]⁺.

Example 51: synthesis of 3-chloro-4-fluoro-N- {1- [1- (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) ethyl ] piperidin-4-yl } benzamide

Step 51-1: to a solution of the compound obtained in steps 1-4 (1.25g) in THF (150mL) was added 3M MeMgBr Et₂O solution and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added saturated NH₄Aqueous Cl and the mixture was stirred for 1 hour, after which the organic layer was separated. Aqueous layer with CHCl₃Extraction was carried out three times. The combined organic layers were over MgSO₄Dried and concentrated under reduced pressure. Thereafter, IPE was added to the residue and the mixture was stirred for 10 minutes. The precipitate was filtered to give 7- (1-hydroxyethyl) -3, 4-dihydroquinolin-2 (1H) -one (1.02g, light yellow solid).

¹H NMR(600MHz，CDCl₃，δ)：1.48(d，J＝6.4Hz，3H)，2.59-2.67(m，2H)，2.91-3.01(m，2H)，4.81-4.91(m，1H)，6.76-6.79(m，1H)，6.96-7.00(m，1H)，7.13-7.16(m，1H)，7.57(brs，1H)；ESI/APCI MS m/z 192[M+H]⁺.

Step 51-2: compound obtained in step 51-1 (1.00g) in CHCl₃(120mL) solution was added MnO₂(13.6g) and the mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 60N, mobile phase MeOH/CHCl)₃0/100 to 10/90; v/v) to give 7-acetyl-3, 4-dihydroquinolin-2 (1H) -one (0.58g, as a colorless solid).

¹H NMR(600MHz，CDCl₃，δ)：2.56-2.62(m，3H)，2.62-2.72(m，2H)，2.99-3.09(m，2H)，7.18-7.32(m，1H)，7.34-7.40(m，1H)，7.51-7.65(m，1H)，8.18(brs，1H)；ESI/APCI MS m/z 190[M+H]⁺.

Step 51-3: to tert-butyl 4-aminopiperidine-1-carboxylate (35.0g) in CHCl under ice-cooling₃Et was added to the solution (350mL)₃N (122mL) and 3-chloro-4-fluorobenzoyl chloride (37.1g) and the mixture was stirred at the same temperature for 1.5 hours. To the reaction mixture was added saturated NaHCO₃Aqueous solution of CHCl₃Extraction was carried out three times. The combined organic layers were over MgSO₄Drying and concentrating under reduced pressure to give 4- [ (3-chloro-4-fluorobenzoyl) amino]Piperidine-1-carboxylic acid tert-butyl ester (62.0 g). To a suspension of the resulting compound in EtOAc (300mL) was added 4M HCl/EtOAc solution (300mL) and the mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure and to the residue was added 1M aqueous NaOH (300mL) and the solution was taken up in CHCl₃Extraction was carried out three times. The combined organic layers were over MgSO₄Dried and concentrated under reduced pressure. The residue was suspended in EtOAc/hexanes (200mL, 1/1; v/v) and the mixture was stirred for 1 h. The precipitate was filtered to give 3-chloro-4-fluoro-N-piperidin-4-ylbenzamide (37.7g, colorless solid).

¹H NMR(200MHz，CDCl₃，δ)：1.30-1.53(m，2H)，1.94-2.12(m，2H)，2.75(td，J＝12.0，2.4Hz，2H)，3.10-3.14(m，2H)，3.93-4.17(m，1H)，5.87-6.09(m，1H)，7.19(t，J ＝8.6Hz，1H)，7.59-7.70(m，1H)，7.83(dd，J＝7.0，2.2Hz，1H)；ESI MS m/z 257，[M+H]⁺.

Step 51-4: to a solution of the compound obtained in step 51-2 (206mg), the compound obtained in step 51-3 (560mg), and AcOH (327mg) in MeOH (15mL) at room temperature was added NaBH₃CN (274mg), the mixture was refluxed for 12 hours. After the reaction mixture was cooled to room temperature, NaBH was added₃CN (274mg) and the mixture was refluxed for 72 hours. After adding saturated NaHCO₃After the aqueous solution, the aqueous and organic layers were separated. Aqueous layer with CHCl₃Extraction was carried out three times. The combined organic layers were over MgSO₄Dried and concentrated under reduced pressure. The residue was purified by column chromatography [ sequentially (silica gel 60N, mobile phase: MeOH/CHCl)₃0/100 to 20/80; v/v) and (Chromatorex NH, mobile phase MeOH/CHCl₃0/100 to 10/90; v/v)]To give the title compound (7mg, colorless solid).

¹H NMR(600MHz，CDCl₃，δ)：1.30-1.37(m，3H)，1.44-1.64(m，2H)，1.89-2.20(m，4H)，2.60-2.67(m，2H)，2.72-3.07(m，2H)，2.90-2.97(m，2H)，3.30-3.37(m，1H)，3.88-3.98(m，1H)，6.10(d，J＝7.3Hz，1H)，6.73(s，1H)，6.87-6.92(m，1H)，7.09(d，J＝7.8Hz，1H)，7.18(t，J＝8.5Hz，1H)，7.66(ddd，J＝8.7，4.6，2.3Hz，1H)，7.79(brs，1H)，7.85(dd，J＝6.9，2.3Hz，1H)；ESI/APCI MS m/z 430[M+H]⁺.

Example 52: synthesis of N- {1- [ (8-fluoro-2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl ] piperidin-4-yl } -3-methoxybenzamide

Step 52-1: to a solution of the compound (1.00g) obtained in steps 1 to 4 in MeOH (10.0mL) was added NaBH under ice-cooling₄(216mg) And the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added saturated NaHCO₃The aqueous solution was concentrated under reduced pressure. Thereafter, H was added to the residue₂O, the solution is taken up in CHCl₃Extraction was carried out three times. The combined organic layers were washed with brine, over Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 60N, mobile phase: MeOH/CHCl)₃0/100 to 10/90; v/v) to give 7- (hydroxymethyl) -3, 4-dihydroquinolin-2 (1H) -one (550mg, colorless solid).

¹H NMR(600MHz，CDCl₃，δ)：2.56-2.61(m，2H)，2.92(t，J＝7.6Hz，2H)，4.62(d，J＝6.0Hz，2H)，6.76(s，1H)，6.94(d，J＝7.8Hz，1H)，7.11(d，J＝7.3Hz，1H)，7.90(brs，1H)；ESI/APCI MS m/z 178[M+H]⁺.

Step 52-2: CHCl of the Compound (670mg) obtained in step 52-1 under ice-cooling₃(30.0mL) of the solution was added Ac₂O (536. mu.L), DMAP (20.0mg) and Et₃N (1.05mL) and the mixture was stirred at room temperature for 45 min. To the reaction mixture was added saturated NaHCO₃Aqueous solution of CHCl₃Extraction was carried out three times. The combined organic layers were washed with Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 60N, mobile phase: MeOH/CHCl)₃0/100 to 10/90; v/v) to give acetic acid (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl ester (767mg, pale yellow solid).

¹H NMR(600MHz，CDCl₃，δ)：2.09(s，3H)，2.61-2.65(m，2H)，2.96(t，J＝7.6Hz，2H)，5.04(s，2H)，6.74(s，1H)，6.96-6.99(m，1H)，7.15(d，J＝7.3Hz，1H)，7.72(brs，1H)；ESI/APCI MS m/z 220[M+H]⁺.

Step 52-3: to the compound (958mg) obtained in step 52-2 in CH₃CN (22.0mL) solution was added 1-fluoro-4-hydroxy-1, 4-diaza-cationic heterobicyclic (diazoniabicyclo) [2.2 ] bis tetrafluoroborate.2]Octane (1.91g) and the mixture was stirred at room temperature for three days. After concentrating the reaction mixture under reduced pressure, the residue was purified by column chromatography (silica gel 60N, mobile phase: MeOH/CHCl)₃0/100 to 10/90; v/v) to give solid A and solid B. To a solution of solid A in MeOH (2.00mL) was added K₂CO₃(69.0mg) and the mixture was stirred at room temperature for 2 hours. Adding H to the reaction mixture₂O, the mixture was concentrated under reduced pressure and taken up in CHCl₃Extraction was carried out three times. The combined organic layers were washed with brine, over Na₂SO₄Dried and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 60N, mobile phase: MeOH/CHCl)₃0/00 to 15/85; v/v) to give 8-fluoro-7- (hydroxymethyl) -3, 4-dihydroquinolin-2 (1H) -one (37.0mg, as a colorless solid).

¹H NMR(600MHz，CDCl₃，δ)：2.63-2.66(m，2H)，2.98-3.01(m，2H)，4.74(s，2H)，6.95(d，J＝7.8Hz，1H)，7.02(t，J＝7.6Hz，1H)，7.53(brs，1H)；ESI/APCI MS m/z 196[M+H]⁺.

In the same manner, 6-fluoro-7- (hydroxymethyl) -3, 4-dihydroquinolin-2 (1H) -one (76.0mg, colorless solid substance) was obtained from solid B.

¹H NMR(600MHz，CDCl₃，δ)：2.60-2.62(m，2H)，2.94(t，J＝7.6Hz，2H)，4.72(s，2H)，6.79(d，J＝6.4Hz，1H)，6.88(d，J＝10.1Hz，1H)，7.38(brs，1H)；ESI/APCI MS m/z 196[M+H]⁺.

Step 52-4: 8-fluoro-7- (hydroxymethyl) -3, 4-dihydroquinolin-2 (1H) -one obtained in step 52-3 (39.0mg) in CHCl₃MnO was added to a solution of (6.00mL) and acetone (6.00mL)₂(152mg) and the mixture was stirred at room temperature for 2 days. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to give 8-fluoro-2-oxo-1, 2,3, 4-tetrahydroquinoline-7-carbaldehyde (40.0mg, colorless solid).

¹H NMR(600MHz，CDCl₃，δ)：2.68-2.71(m，2H)，3.06-3.09(m，2H)，7.09(d，J＝7.8Hz，1H)，7.47(d，J＝7.8Hz，1H)，7.60(brs，1H)，10.29(s，1H)；ESI/APCI MS m/z 194[M+H]⁺.

Step 52-5: from the compound obtained in step 52-4 (40.0mg) and 3-methoxy-N- (piperidin-4-yl) benzamide (73.0mg), a solid was obtained in the same manner as in step 1-5. To the resulting solid was added IPA at room temperature and the mixture was stirred for 1 hour. The precipitate was filtered and washed with IPA and hexanes to give the title compound (8.0mg, colorless solid).

¹H NMR(600MHz，CDCl₃，δ)：1.47-1.60(m，2H)，2.00-2.05(m，2H)，2.20-2.31(m，2H)，2.63-2.67(m，2H)，2.87(brs，2H)，2.99(t，J＝7.6Hz，2H)，3.57(brs，2H)，3.84(s，3H)，3.99(brs，1H)，5.91(brs，1H)，6.90-6.98(m，2H)，7.02(dd，J＝8.3，1.8Hz，1H)，7.22-7.25(m，1H)，7.30-7.33(m，2H)，7.51(brs，1H)；ESI/APCI MS m/z 412[M+H]⁺.

Example 53: synthesis of N- {1- [ (6-fluoro-2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl ] piperidin-4-yl } -3-methoxybenzamide

Step 53-1: from 6-fluoro-7- (hydroxymethyl) -3, 4-dihydroquinolin-2 (1H) -one (76.0mg) obtained in step 52-3, 6-fluoro-2-oxo-1, 2,3, 4-tetrahydroquinolin-e-7-carbaldehyde (32.0mg, colorless solid) was obtained in the same manner as in step 52-4.

¹H NMR(600MHz，CDCl₃，δ)：2.63-2.66(m，2H)，3.02-3.05(m，2H)，7.03(d，J＝9.6Hz，1H)，7.18(d，J＝5.5Hz，1H)，7.54(brs，1H)，10.30(s，1H)；ESI/APCI MS m/z 194[M+H]⁺.

Step 53-2: the title compound (38.0mg, colorless solid) was obtained from the compound obtained in step 53-1 (32.0mg) and 3-methoxy-N- (piperidin-4-yl) benzamide (58.0mg) by the same method as in step 52-5.

¹H NMR(600MHz，CDCl₃，δ)：1.51-1.62(m，2H)，2.00-2.05(m，2H)，2.21-2.28(m，2H)，2.59-2.63(m，2H)，2.81-2.88(m，2H)，2.93(t，J＝7.6Hz，2H)，3.52(brs，2H)，3.84(s，3H)，4.00(brs，1H)，5.97(brs，1H)，6.76(d，J＝5.5Hz，1H)，6.86(d，J＝9.6Hz，1H)，7.02(dd，J＝8.7，2.3Hz，1H)，7.22-7.26(m，1H)，7.30-7.34(m，2H)，7.42-7.46(m，1H)；ESI/APCI MS m/z412[M+H]⁺.

Reference 1: synthesis of 3-methoxy-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl ] piperidin-4-yl } benzamide

Step R1-1: to 7-hydroxy-3, 4-dihydroquinolin-2 (1H) -one (200g) in CHCl at room temperature over 10 minutes₃To the suspension in (2.0L) was added pyridine (212 g). To this mixture was added Tf over 35 minutes₂O (344g), keeping the temperature below 10 ℃. After allowing the mixture to warm to 15 ℃ over 1 hour, the reaction mixture was allowed to cool to 0 ℃ and quenched by the addition of water (2.0L). Separating the organic layer with saturated KHSO₄The aqueous solution and water were washed twice with Na₂SO₄Drying and concentration gave 2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl trifluoromethanesulfonate as a pale yellow solid (346 g).

¹H NMR(200MHz，CDCl₃，δ)：2.63-2.72(m，2H)，2.96-3.05(m，2H)，6.75(d，J＝2.2Hz，1H)，6.90(dd，J＝8.4，2.2Hz，1H)，7.20-7.26(m，1H)，8.83(brs，1H)；ESI/APCI MS m/z 294[M-H]^-.

Step R1-2: trifluoromethanesulfonic acid 2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl ester (338g), Zn (CN) at 100 ℃₂(134g) And Pd (PPh)₃)₄A mixture of (33.5g) in DMF (3.0L) was heated for 4 hours and cooled to room temperature. Adding Zn (CN) to the mixture₂(134g) And Pd (PPh)₃)₄(12.7g) and the mixture was stirred at 100 deg.CFor 2 hours. After cooling to 60 ℃, the reaction mixture was filtered through a pad of Celite. The filtrate was concentrated to give a solid. The solid was washed twice with EtOAc to give 2-oxo-1, 2,3, 4-tetrahydroquinoline-7-carbonitrile as a pale yellow solid (165 g).

¹H NMR(600MHz，DMSO-d₆，δ)：2.43-2.45(m，2H)，2.90-2.97(m，2H)，7.12(s，1H)，7.31-7.37(m，2H)，10.29(s，1H)；ESI/APCI MS m/z 171[M-H]^-.

Step R1-3: to 2-oxo-1, 2,3, 4-tetrahydroquinoline-7-carbonitrile (160g) in HCO over 30 min at room temperature₂To the suspension in H (1.6L) was added Raney nickel catalyst (slurry in water, 160 g). The mixture was heated at 100 ℃ for 2 hours. After cooling to room temperature, the reaction mixture was filtered through a pad of Celite and washed with HCO₂And H, washing. The filtrate was concentrated to give a solid. The solid was stirred with water (1.3L) and filtered to give 2-oxo-1, 2,3, 4-tetrahydroquinoline-7-carbaldehyde as a beige solid (156 g).

¹H NMR(600MHz，DMSO-d₆，δ)：2.43-2.45(m，2H)，2.94(t，J＝7.6Hz，2H)，7.30(s，1H)，7.38(d，J＝7.3Hz，1H)，7.44-7.49(m，1H)，9.87(s，1H)，10.29(s，1H)；ESI/APCI MSm/z 176[M+H]⁺.

Step R1-4: to tert-butyl 4-aminopiperidine-1-carboxylate (150g) and Et over 40 minutes under ice-cooling₃To a solution of N (209mL) in IPA (1.0L) was added 3-methoxybenzoyl chloride (102 mL). The mixture was stirred at room temperature for 2 hours. After cooling to 0 ℃, 12M aqueous HCl (0.5L) was added to the mixture over 30 minutes and the mixture was stirred at 50 ℃ for 1 hour. After cooling to 0 ℃, 12M aqueous NaOH (0.5L) and water (0.4L) were added to the reaction mixture over 40 minutes. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, over MgSO₄Drying and concentration gave 3-methoxy-N- (piperidin-4-yl) benzamide as a light brown solid (160 g).

¹H NMR(600MHz，DMSO-d₆，δ)：1.52-1.61(m，2H)，1.78-1.86(m，2H)，2.71(td，J＝12.3，2.5Hz，2H)，3.06-3.15(m，2H)，3.79(s，3H)，3.84-4.02(m，1H)，7.07(ddd，J ＝8.0，2.5，0.92Hz，1H)，7.33-7.46(m，3H)，8.32(d，J＝7.8Hz，1H)；ESI/APCI MS m/z 235[M+H]⁺.

Step R1-5: to 2-oxo-1, 2,3, 4-tetrahydroquinoline-7-carbaldehyde (135g) in CHCl at room temperature₃(1.4L) to the suspension was added 3-methoxy-N- (piperidin-4-yl) benzamide (190g) and AcOH (45 mL). The mixture was stirred at room temperature for 2 hours. After cooling to 0 ℃ NaBH (OAc) is added in portions₃. The mixture was stirred at room temperature for 19 hours. After cooling to 0 ℃, 8M aqueous NaOH (0.5L) and water (0.5L) were added to the reaction mixture. The organic layer was separated, washed with water and brine, over MgSO₄Dried and concentrated to give a colorless solid. The solid was suspended in EtOAc (3.0L), the mixture refluxed for 1 hour and cooled to room temperature. The precipitate was filtered to give a colorless solid. The solid was resuspended in EtOAc (2.4L), and the mixture was refluxed for 1 hour and cooled to room temperature. The precipitate was filtered to give the title compound as a colourless solid (229 g).

¹H NMR(600MHz，CDCl₃，δ)：1.48-1.62(m，2H)，1.94-2.06(m，2H)，2.10-2.21(m，2H)，2.57-2.67(m，2H)，2.78-2.87(m，2H)，2.90-2.99(m，2H)，3.44(s，2H)，3.85(s，3H)，3.94-4.05(m，1H)，6.01(d，J＝7.8Hz，1H)，6.77(s，1H)，6.91(d，J ＝7.3Hz，1H)，7.02(dd，J＝7.6，2.1Hz，1H)，7.09(d，J＝7.8Hz，1H)，7.21-7.27(m，1H)，7.29-7.35(m，2H)，8.00(s，1H)；ESI/APCI MS m/z 394[M+H]⁺.

TABLE 3

Example 54 (calcium evaluation test of MCH1R)

FDSS assays measure intracellular calcium concentration, which is used as an index to assess Gq-coupled receptor activity. For example: the assay can determine whether the analyte is an antagonist, inverse agonist or agonist of the Gq-coupled receptor. FDSS6000^TMThe system (Hamamatsu Photonics K.K.) was designed to be evaluated based on functions such as measuring intracellular calcium for high throughput screening. Intracellular calcium released by activation of Gq-coupled receptors can be measured fluorometrically by incorporating calcium indicators, such as Fluo4, into the cells. On the other hand, this assay cannot measure the activation of Gi-and Go-coupled receptors, since this activation is not associated with the calcium signal transduction pathway.

Using a fluorescence imaging plate reader system in a 96-well microplate orIntracellular fluorescence can be measured rapidly and continuously in 384-well microplates. FDSS6000^TMFluorescence can be measured simultaneously in all wells sensitively and accurately in seconds. This system is ideal for functional assays in cells such as monitoring intracellular calcium flux generated within seconds after activation of Gq-coupled receptors.

Test method

Cells stably expressing non-endogenously active MCH1R were plated at 3X 10 the day before the assay⁴Cells/well were seeded into 96-well microplates. mu.L of Medium (Dulbecco's Modified Eagle Medium, pH 7.4) containing 10% fetal bovine serum, 2mM glutamine, 1mM sodium pyruvate, and 0.5mg/mL G418 per well was used for the culture. On the day of the assay, the medium was removed and 100 μ L per well of assay buffer { Hank's balanced salt solution containing 20mM HEPES, 0.5mM probenecid, 0.05mg/mL amaranth, and 0.2% Bovine Serum Albumin (BSA), pH 7.4} containing 2 μ M Fluo4-AM and 0.04% Pluronic F127 was added followed by 5% CO₂Was incubated at 37 ℃ for 30 minutes. Assay buffer containing each concentration of MCH was added at 50. mu.L per well using FDSS6000^TMTransient changes in intracellular calcium concentration caused by MCH were monitored at Ex.488nm and Em.530nm for 180 seconds. MCH was added to a final concentration of 50nM in testing for analyte antagonistic activity. Various concentrations of analyte were used for inhibition curves, and the concentration of analyte that inhibited 50% of the increase in intracellular calcium upon addition of 50nM MCH (IC) was calculated using data analysis software Origin Ver.6₅₀Value).

Among the compounds of the present invention, IC₅₀Compounds with values of 50nM or less are shown below:

example numbers 1,2,3,4, 5, 6, 7, 8, 10, 12, 14, 15, 18, 19, 23, 27, 28, 29, 30, 31, 32, 33, 35, 36, 37, 38, 39, 43, 46, 47, 51 and 53.

In addition, some compounds of the present invention are shown in Table 4IC₅₀The value is obtained.

TABLE 4

Industrial applicability

The compounds of the present invention have MCH receptor antagonistic action and are useful as preventive or therapeutic agents for MCH-related diseases, more specifically, as preventive or therapeutic agents for the following diseases: depression, anxiety disorders (such as generalized anxiety disorder, post-traumatic stress disorder, panic disorder, obsessive-compulsive disorder, or social anxiety disorder), attention deficit disorder, mania, manic depression, schizophrenia, mood disorder, stress, sleep disorder, aggression, memory impairment, cognitive impairment, dementia, amnesia, delirium, obesity, eating disorder, appetite disorder, hyperphagia, bulimia, anorexia phobia, diabetes, cardiovascular disease, hypertension, dyslipidemia, myocardial infarction, movement disorder (such as parkinson's disease, epilepsy, convulsion, or tremor), drug abuse, drug addiction, or sexual dysfunction.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof:

wherein, in the formula (I)

R is a hydrogen atom or C_1-6An alkyl group;

A¹、A²and A³Which may be the same or different, are each a hydrogen atom, a halogenAtom, C_1-6Alkyl or C_1-6An alkoxy group;

x is C_1-6An alkylene group;

y is a bond or C_1-6An alkylene group;

z is a bond or C_1-6Alkylene, wherein said C_1-6Alkylene groups may be substituted with phenyl groups;

w is a bond or an oxygen atom; and

cy is phenyl or pyridyl, wherein the phenyl or pyridyl group may have 1 to 3 substituents which may be the same or different, the substituents being selected from the group consisting of a halogen atom, cyano, C_1-6Alkyl radical, C_1-6Alkoxy and C_2-6Alkanoyl radical, wherein said C_1-6Alkyl or C_1-6The alkoxy group may be substituted with 1 to 3 halogen atoms.

2. The compound of claim 1, wherein, in formula (I),

r is a hydrogen atom;

A¹、A²and A³Each is a hydrogen atom;

x is C_1-6An alkylene group;

y is a bond;

w is a bond or an oxygen atom; and

3. The compound of claim 1, wherein, in formula (I),

r is a hydrogen atom;

A¹、A²and A³Each is a hydrogen atom;

x is methylene, wherein the methylene may be substituted by methyl;

y is a bond;

z is a bond or methylene;

w is a bond or an oxygen atom; and

cy is a phenyl group, wherein the phenyl group may have 1 to 3 substituents which may be the same or different, selected from a halogen atom, C_1-6Alkyl radical, C_1-6Alkoxy and C_2-6An alkanoyl group.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (I) is

3-fluoro-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl]Piperidin-4-yl benzamide 3, 5-difluoro-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl]Piperidin-4-yl benzamide 3, 4-difluoro-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl]Piperidin-4-yl benzamide 4-fluoro-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl]Piperidin-4-yl benzamide 3-chloro-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl]Piperidin-4-yl benzamide 3-methyl-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl]Piperidin-4-yl benzamide 3, 5-dichloro-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl]Piperidin-4-yl benzamide 3, 4-dichloro-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl]Piperidin-4-yl benzamide 4-fluoro-3-methyl-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl]Piperidin-4-yl benzamide 4-fluoro-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl]Piperidin-4-yl } -3- (trifluoromethyl) benzamides 3-fluoro-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl]Piperidin-4-yl } -5- (trifluoromethyl) benzamides 3, 5-dimethoxy-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl group]Piperidin-4-yl benzamide N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl]Piperidin-4-yl benzamide N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl)) Methyl radical]Piperidin-4-yl } -2, 2-diphenylacetamide 4-chloro-3-fluoro-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl]Piperidin-4-yl benzamide 3-bromo-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl]Piperidin-4-yl benzamide 3-fluoro-5-methoxy-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl]Piperidin-4-yl benzamide 3-chloro-4-fluoro-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl]Piperidin-4-yl benzamide 3-acetyl-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl]Piperidin-4-yl benzamide 3,4, 5-trifluoro-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl]Piperidin-4-yl benzamide 4-fluoro-3-methoxy-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl]Piperidin-4-yl benzamide 3-chloro-5-fluoro-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl]Piperidin-4-yl benzamide 3-cyano-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl]Piperidin-4-yl benzamide 5-chloro-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl]Piperidin-4-yl } pyridine-3-carboxamides 3-chloro-5-methoxy-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl]Piperidin-4-yl benzamide 4-chloro-3-methyl-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl]Piperidin-4-yl benzamide 2- (3-chloro-4-fluorophenoxy) -N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl]Piperidin-4-yl } acetamides 2- (3-chlorophenoxy) -N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl]Piperidin-4-yl } acetamides 3-chloro-4-fluoro-N- {1- [1- (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) ethyl]Piperidin-4-yl } benzamide, or N- {1- [ (6-fluoro-2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl]Piperidin-4-yl } -3-methoxybenzamide

。

5. The compound of claim 1, wherein the compound represented by formula (I) is 3-methoxy-N- {1- [ (2-oxo-1, 2,3, 4-tetrahydroquinolin-7-yl) methyl ] piperidin-4-yl } benzamide, or a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition comprising the compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof as an active ingredient.

7. A pharmaceutical composition comprising the compound of claim 5 or a pharmaceutically acceptable salt thereof as an active ingredient.

8. The pharmaceutical composition of claim 6 or 7, which is a melanin concentrating hormone receptor antagonist.

9. A prophylactic or therapeutic agent for the following diseases, which comprises a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof as an active ingredient: depression, anxiety disorders, attention deficit disorder, mania, schizophrenia, mood disorders, stress, sleep disorders, aggression, memory impairment, cognitive impairment, dementia, amnesia, delirium, obesity, eating disorders, appetite disorders, hyperphagia, bulimia, anorexia phobia, diabetes, cardiovascular disease, dyslipidemia, movement disorders, drug abuse, drug addiction, or sexual dysfunction.

10. A prophylactic or therapeutic agent for the following diseases, which comprises the compound of claim 5 or a pharmaceutically acceptable salt thereof as an active ingredient: depression, anxiety disorders, attention deficit disorder, mania, schizophrenia, mood disorders, stress, sleep disorders, aggression, memory impairment, cognitive impairment, dementia, amnesia, delirium, obesity, eating disorders, appetite disorders, hyperphagia, bulimia, anorexia phobia, diabetes, cardiovascular disease, dyslipidemia, movement disorders, drug abuse, drug addiction, or sexual dysfunction.

11. The medicament of claim 9 or 10, wherein the anxiety disorder is selected from the group consisting of generalized anxiety disorder, post traumatic stress disorder, panic disorder, obsessive compulsive disorder, and social anxiety disorder.

12. A medicament as claimed in claim 9 or 10, wherein said movement disorder is selected from parkinson's disease, epilepsy, spasticity and tremor.

13. The medicament of claim 9 or 10, wherein the mania is selected from manic depression.

14. The medicament of claim 9 or 10, wherein the cardiovascular disease is selected from hypertension and myocardial infarction.