WO2008072703A1 - Biphenylamide derivative - Google Patents

Abstract

Disclosed is a novel biphenylamide derivative represented by the formula (1a) and having an antagonistic effect on a histamine H3 receptor or a pharmaceutically acceptable salt thereof. Also disclosed is a pharmaceutical agent which comprises the derivative or the salt as an active ingredient. The compound or the pharmaceutical agent is effective for the prevention or treatment of a disease such as dementia, Alzheimer's disease, attention deficit hyperactivity disorder, schizophrenia, eating disorder, obesity, diabetes, hyperlipemia, sleep disorder, narcolepsy, sleep apnea syndrome, circadian rhythm disorder, depression or allergic rhinitis.

Description

 Specification

 Biphenylamide derivatives

 Technical field

 [0001] The present invention relates to biphenylamide derivatives having histamine H3 receptor antagonistic activity and pharmaceuticals containing these derivatives as active ingredients, particularly dementia, Alzheimer's disease, attention deficit / hyperactivity disorder, schizophrenia , Epilepsy, central convulsions, eating disorders, obesity, diabetes, hyperlipidemia, sleep disorders, narcolepsy, sleep apnea syndrome, circadian rhythm disorders, depression, or allergic rhinitis preventive or therapeutic agent About.

 Background art

 [0002] Histamine is normally stored in intracellular granules in mast cells, lungs, liver, and gastric mucosa, and released to the outside by external stimuli such as antigen binding to antibody on the cell surface. Is issued. For example, when mast cells are stimulated by an antigen that has entered from the outside, histamine is released from moonlit cells and causes allergic reactions by stimulating histamine HI (HI) receptors present on blood vessels and smooth muscle. . In addition, histamine released from ECL cells (enterochromaffin-like cells) on the gastric mucosa stimulates histamine H2 (H2) receptors on mural cells and promotes gastric acid secretion. Based on these facts, HI receptor antagonists or H2 receptor antagonists have been developed as therapeutic agents for allergic diseases or gastric ulcers, and are now widely used as pharmaceuticals.

[0003] Furthermore, it has been revealed that histamine acts as a neurotransmitter on the histamine H3 (H3) receptor present in the central nerve and peripheral nerve, and exhibits various physiological functions. This receptor was clawed in 1999 and its gene sequence and amino acid sequence were clarified, but the amino acid sequence homology with the HI and H2 receptors was as low as 22% and 21.4%, respectively. (See Non-Patent Document 1). The H3 receptor is present in the presynaptic membrane and has been shown to function as an autoreceptor that controls histamine synthesis and release (see Non-Patent Document 2). It has also been clarified that the H3 receptor controls the release of histamine and the release of other neurotransmitters such as acetylcholine, serotonin, donomin, and noradrenaline (see Non-Patent Document 3). These facts This suggests that antagonists can serve as therapeutic agents for various diseases associated with abnormal neurotransmitter release in the nerve!

 [0004] The results of studies in animal models using synthetic compounds show that H3 receptor antagonists are dementia, Alzheimer's disease (see Non-Patent Documents 4 and 5), attention deficit / hyperactivity disorder (Non-Patent Document 6). ), Schizophrenia (see Non-Patent Document 7), epilepsy, central convulsions and other therapeutic agents.

 [0005] In addition, H3 receptor has been shown to be involved in eating behavior (see Non-Patent Document 8), and as an indication for H3 receptor antagonist or inverse agonist, eating disorders, obesity, diabetes Metabolic diseases such as hyperlipidemia are also envisaged.

 [0006] In addition, histamine has been shown to play a role in regulating the diurnal rhythm in the brain and maintaining a balance between arousal and sleep (see Non-Patent Documents 9 and 10), or an H3 receptor antagonist, Diseases associated with sleep disorders such as sleep disorders, narcolepsy, sleep apnea syndrome, circadian rhythm disorders, and depression are also envisaged as indications for inverse agonists.

 [0007] Furthermore, it has been shown that H3 receptors are present in sympathetic nerves of the nasal mucosa, and it has been reported that combined use of H3 receptor antagonists and HI receptor antagonists significantly improves nasal congestion. (See Non-Patent Document 11). This indicates that the H3 receptor antagonist or inverse agonist may be useful for the treatment of allergic rhinitis or the like alone or in combination with the HI receptor antagonist.

 [0008] H3 receptor antagonists or inverse agonists are summarized in multiple reviews (see Non-Patent Documents 12 to 15), and these can be referred to. Initially, many imidazole compounds with histamine itself as the lead compound were reported, but concerns about the inhibitory action of the drug metabolizing enzyme cytochrome P450 (CYP) have been shown, and it has not been developed as a pharmaceutical product.

 [0009] Recently, many publications and patents on non-imidazole H3 receptor antagonists or inverse agonists have been reported (see Patent Documents;! ~ 9).

[0010] For example, Patent Document 10 reports a H3 receptor antagonist having a biphenyl structure represented by the following formula (A).

[0011] [Chemical 1]

[0012] Further, in Patent Document 11, a beef represented by the following formula (B):

 A body antagonist has been reported!

 [0013] [Chemical 2]

 [0014] Patent Document 12 reports an H3 receptor antagonist having a structure in which a pyrimi: ring represented by the following formula (C): a ring and a benzene ring are bonded.

 [0015] [Chemical 3]

 [0016] However, no reports have been made on the compounds having the structure disclosed in the present invention! / '

 Patent Document 1: WO2005 / 097751 International Publication

 Patent Document 2: WO2005 / 097778 International Publication

 Patent Document 3: WO2005 / 118547 International Publication

 Patent Document 4: WO2006 / 014136 International Publication

 Patent Document 5: WO2006 / 045416 International Publication

Patent Document 6: WO2006 / 046131 International Publication Patent Document 7: WO2006 / 059778 International Publication

Patent Document 8: ¥ 02006/061193 International Publication

Patent Document 9: WO2006 / 107661 International Publication

Patent Document 10: WO2002 / 012190 International Publication

Patent Document 11: WO2002 / 040461 International Publication

Patent Document 12: WO2005 / 007644 International Publication

Non-patent literature l: Lovenberg T.W. et al., Molecular pharmacology, 55, 1101-1107, 1999 Non-patent literature 2: Arrang J-M. Et al., Nature, 302, 832-837, 1983

Non-patent literature 3: Brown RE et al., Progress in Neurobiology, 63, 637-672, 2001 Non-patent literature 4: Huang YW. Et al., Behavioral Brain Research, 151, 287-293, 2004 Non-patent literature 5: Komater ν · Α · Behavioural Brain Research, 159, 295-300, 2005 Non-Patent Document 6: Passani Μ · Β · et al., Neuroscience and Biobehavioral Reviews, 24, 107—11

3, 2000

Non-patent literature 7: Fox GB et al., J. Pharmacol. Exp. Ther., 313, 176-190, 2005 Non-patent literature 8: Hancock Α · Α · et al., Curr. Opin. Investig. Drug, 4, 1190-1197 Non-Patent Document 9: Huang Z_Shira, Prog. Natr. Acad. Sci., 103, 4687-4692, 2006 Non-Patent Document 10: Babier AJ et al., Br. J. Pharmacol., 143, 649-661, 2004

Non-Patent Document ll: McLeod R 丄. Et al., Am. J. Rhinol., 13, 391-399, 1999

Non-patent document 12: Schwartz JC et al., Trends in Pharmacol. Sci., 7, 24-28, 1986 Non-patent document 13: Passani Μ · Β · et al., Trends in Pharmacol. Sci., 25, 618-625, 2004 Patent Document 14: Leurs R. et al., Nature Drug Discovery, 4, 107-122, 2005

Non-Patent Document 15: Leurs R. et al., Drug Discovery Today, 10, 1613-1627, 2005 Disclosure of the Invention

Problems to be solved by the invention

The object of the present invention is a novel biphenyl amide derivative, more specifically, a strong binding inhibitory action on the H3 receptor, and disorders caused by the H3 receptor, such as dementia, Alzheimer's disease, attention deficit Hyperactivity, schizophrenia, epilepsy, central convulsions, eating disorders, fatness, diabetes, hyperlipidemia, sleep disorders, narcolepsy, sleep apnea syndrome, circadian rhythm It is an object of the present invention to provide a novel biphenylamide derivative useful for the prevention and treatment of murine disorders, depression, allergic rhinitis and the like.

 Means for solving the problem

[0018] As a result of intensive studies for the above purpose, the present inventors have found that biphenyl amide derivative power

The present invention was completed by finding that it has potent inhibitory activity against the H3 receptor.

[0019] That is, the present invention provides

 (1) Formula (la)

[0020] [Chemical 4]

R ¹ is C-C alkyl (the C-C alkyl is C-C cyclic alkyl or hydroxy

 1 6 1 6 3 8

 Or C to C cyclic alkyl (the C to C cyclic alkyl is C to C).

 3 8 3 8 1

Can be substituted with C alkyl or hydroxyl! /)

 6

R ² and R ³ are the same or different and each represents a hydrogen atom; C to C alkyl (the C to C alkyl

 1 6 1 6

 Is halogen; C to C cyclic alkyl; hydroxyl; C to C alkoxycarbonyl or

 3 8 2 7

C-c cyclic alkyl (which may be substituted with carboxy) Halogen; may be substituted with C to C alkyl or hydroxyl) or — (CH 2) −

1 6 2 m

A group represented by Ar or

Or R ² and R ³ may be bonded together with adjacent nitrogen atoms, and may contain one or more nitrogen, oxygen, or sulfur atoms in addition to the nitrogen atoms in the ring. Member saturated heterocycles (the saturated heterocycles are halogen; C to C alkyl; C to C alkoxy or hydro

 1 6 1 6

May be substituted with xyl),

 Ar is aryl (the aryl is halogen; C to C alkyl; C to C alkoxy or hydrogen)

 1 6 1 6

Or heteroaryl (wherein the heteroaryl may be substituted with halogen; c-c alkyl; c-c alkoxy or hydroxyl),

1 6 1 6

m represents an integer of 0 to 2,

R ⁴ represents a hydrogen atom or C to C alkyl,

 1 6

R ⁵ is C-C alkyl (wherein the C-C alkyl is halogen; C-C cyclic alkyl; C

 1 6 1 6 3 8 1

-C may be substituted with alkoxy or hydroxyl); C-C cyclic alkyl (the C

 6 3 8 3

-C cyclic alkyl is halogen; c-c alkyl; c-c alkoxy or hydroxy

8 1 6 1 6

Aryl) (wherein the aryl is halogen; alkyl; c to c alcohol)

 1 6 may be substituted with xoxy or hydroxyl) or heteroaryl (wherein the heteroaryl is halogen; alkyl; may be substituted with C to C alkoxy or hydroxyl);

 1 6

R ⁴ and R ⁵ may be bonded together with an adjacent nitrogen atom and carbonyl carbon, and may contain one or more nitrogen, oxygen, or sulfur atoms in addition to the nitrogen atom in the ring. 5- to 7-membered saturated heterocycle (the saturated heterocycle is halogen; C-C alkyl; C-C

 1 6 1 6 Lucoxy; may be substituted with hydroxyl or oxo! /, Or may be formed! /. } Or a pharmaceutically acceptable salt thereof.

 (2) Formula (lb)

[Chemical 5]

In the formula (lb), R ¹ is C to C The C to C anolenoquinole may be substituted with a C to C cyclic alkyl) or C to C cyclic alkyl (the C to C cyclic alkyl is C to C

 3 8 3 8 1 may be substituted with alkyl)

 6

R ² and R ³ are the same or different and each represents a hydrogen atom or C-C alkyl,

 1 6

Or R ² and R ³ may be bonded together with adjacent nitrogen atoms, and may contain one or more nitrogen, oxygen, or sulfur atoms in addition to the nitrogen atoms in the ring. Member saturated heterocycles, which may be substituted with C to C alkyl or hydroxyl

 1 6

Form. }

A biphenylamide derivative represented by: or a pharmaceutically acceptable salt thereof,

 (3) a compound selected from the following group,

1-Cyclopentyl 1 4— {[4'— (Pyrrolidine 1 1-ylcarboninole) Biphenyl 2-4

-Isopropyl 4- 4 {{[4'- (Pyrrolidine-Yellou 4

-Echinolei 4 1 {[4 '(Pyrrolidine-Ninole) Bihue Ninore 4-—Inole] o {[4'— (Pyrrolidine--: Nore

4 ィル）ォキシ]ビフェニル 4 ィル } カルボ- -4—ォーノレ 1 one (2-methylcyclopentyl) 4 {[4, one (pyrrolidine

4-yl) oxy] biphenyl 4-yl} carbo-4-ol

1 1 ({4, 1 [(1 4 yl) oxy] biphenyl 4 yl} Carbonyl) 4-methylpi

4 1 ({4, 1 • 4 yl) oxy] biphenyl 4 yl} carbolinole) morpholine,

1-Cyclobutyl 4 {[4 '— (Pyrrolidine

シクロプチルー 4 {[4' （ジメチルァミノカルボ二ノレ）ビフエ二ルー 4ーィノレ]ォ シクロプチルー 4 { [3 '—(ピロリジン- ェ二ルー 4ーィ

Cyclopetit Lou 4 {[4 '(Dimethylamino Carboninole) Biphenyl 2 Louie] Cyclopetit Lou 4 {[3' — (Pyrrolidine-Zhenru 4

4 1 ({4, 1 [(1-Cyclopentylbiperidine 1-enenole 4-yl) carboninole) morpholine,

 4- ({4 '-[(1-tert-Butylbiperidine 4-inole) oxy] biphenyl-4-recarbonyl) morpholine,

 4 'one [(1 cyclobutylpiperidine 4 yl) oxy] N— (4 fluo: 1) biphenyl 4-carboxamide,

N- (4 Fluorobenzyl) 4 '{[1- (1-methylethyl) piperidine-4-inole] oxy} biphenyl 4 carboxamide,

 1 1 {4 '1 [(1 cyclobutylpiperidine 4 yl) oxy] biphenyl 4 yl} pi-lysine-2-one,

 1 {4 '[(1-Cyclopentylbiperidine 4-ynole) oxy] biphenyl 4-yl} pyrrolidin-2-one,

 1- (4 ′-{[1- (1-methylethyl) piperidine 4-yl] oxy} biphenyl 4-yl) pyrrolidine-2-one,

1- {4 '-[(1-tert-Butylbiperidine 4 Inole) oxy] biphenyl 4- Pyrrolidin-2-one,

 [0022] (4) A medicament comprising as an active ingredient the biphenylamide derivative according to any one of (1) to (3), or a pharmaceutically acceptable salt thereof,

 (5) The pharmaceutical of (4), which is a histamine H3 receptor antagonist, and

 (6) Dementia, Alzheimer's disease, attention deficit / hyperactivity characterized by containing the compound according to any one of (1) to (3) or a pharmaceutically acceptable salt thereof as an active ingredient Disease, schizophrenia, epilepsy, central convulsions, eating disorders, obesity, diabetes, hyperlipidemia, sleep disorders

, Narcolepsy, sleep apnea syndrome, circadian rhythm disorder, depression, or allergic rhinitis.

 The invention's effect

 [0023] It has been found that the compound of the present invention has an excellent histamine H3 receptor antagonistic action.

 BEST MODE FOR CARRYING OUT THE INVENTION

[0024] The terms used in the present specification are as defined below.

In the present invention, the halogen is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

 [0026] "C to C alkyl" refers to a linear or branched alkyl group having 1 to 6 carbon atoms.

 1 6

 And, for example, a group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butinole, tert-butinole, n-pentinole, isopentinole, neopentinole or n-hexyl.

 [0027] "C to C cyclic alkyl" means cyclopropyl, cyclobutyl, cyclopentyl, cyclo

 3 8

 Hexyl, cycloheptyl or cyclooctyl group.

 [0028] "C-C alkoxy" refers to a linear or branched alkoxy group having 6 to 6 carbon atoms;

 1 6

 For example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy or n-hexyloxy, etc. Indicates a group.

[0029] "C-C alkoxycarbonyl" refers to a straight-chain or branched alkyl group having 6 to 6 carbon atoms;

 2 7

It represents a carbonyl group to which a coxy group is bonded, for example, methoxycarbonyl, ethoxycanole boninole, n-propoxycanoleponinore, isopropoxycanoleponinore, n-butoxycanolepoini It represents a group such as nore, isobutoxycarbonyl, sec butoxycarbonyl, tert butoxycarbonyl, n pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl or n-hexyloxycarbonyl.

 [0030] "4-7 membered saturated heterocycle which is bonded together with adjacent nitrogen atoms and may contain one or more nitrogen, oxygen or sulfur atoms in addition to the nitrogen atom" Is a saturated 4- to 7-membered monocyclic heterocycle containing one nitrogen atom and further containing one or more heteroatoms selected from nitrogen, oxygen and sulfur atoms. A cyclic group, for example, a group such as 1-azetidyl, 1-pyrrolidinyl, piperidino, 1-azepanyl, 1-imidazolidinyl, 1-virazolidinyl, 1-piperadil, 3-oxazolidinyl, morpholino or 1-thiomorpholinyl.

 [0031] "It may be bonded together with the adjacent nitrogen atom and carbonyl carbon atom or sulfonyl sulfur atom, and may contain one or more nitrogen, oxygen, or sulfur atoms in addition to the nitrogen atom in the ring." The “˜7-membered saturated heterocyclic ring” includes one nitrogen atom and one carbonyl group, and further includes one or more heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom. A saturated 5- to 7-membered monocyclic heterocyclic group, such as 2-oxo-pyrrolidine 1-yl, 2-oxo-piperidine 1-yl, 2-oxo ase Bread 1-yl, 2-oxo-oxazolidin 3-yl, 2-oxo-imidazolidine 1-yl, 2-oxo-thiazolidine 3-yl or 3-oxo-morpholine 4-yl Etc. are shown.

 [0032] "Aryl" refers to a phenyl group or a naphthyl group.

 [0033] "Heteroaryl" refers to a monocyclic or bicyclic aromatic heterocyclic group such as pyridine, pyridazine, pyrimidine, pyrazine, quinoline, isoquinoline, quinazoline, quinoxaline, pyrrole, furan, thiophene, pyrazole, Groups such as imidazole, tale zonazore, iso tale zonazore, thiazo monole, isothia zonole, triazonole, indanole, benzofuran, benzothiophene, benzoimidazole, indazonore, benzoxazonole, benzothiazonole or benzotriazole Is mentioned.

[0034] In the present invention, pharmaceutically acceptable salts include, for example, salts with inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid. Acid, male Acid, citrate, benzene sulfonic acid, methane sulfonic acid, p toluene sulfonic acid, benzoic acid, camphor sulfonic acid, ethane sulfonic acid, darcoheptonic acid, darconic acid, glutamic acid, glycolic acid, malic acid, malonic acid, mandel Acid, galactaric acid, naphthalene

2-salt with organic acid such as sulfonic acid, salt with one or more metal ions such as lithium ion, sodium ion, potassium ion, calcium ion, magnesium ion, zinc ion, aluminum ion, ammonia, arginine, lysine And salts with amines such as piperazine, choline, jetylamine, 4-phenylcyclohexylamine, 2-aminoethanol, and benzathine.

 [0035] The compounds of the present invention may also exist as various solvates. It may also be a hydrate from the viewpoint of applicability as a medicine.

 [0036] The compounds of the present invention include all enantiomers, diastereomers, equilibrium compounds, mixtures of these in arbitrary proportions, racemates and the like.

 [0037] The compounds of the present invention also include compounds in which one or more hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, sulfur atoms are substituted with radioactive isotopes or stable isotopes. These labeled compounds are useful in, for example, metabolic and pharmacokinetic studies, biological analysis as receptor ligands, and the like.

 [0038] The compound of the present invention can be combined with one or more pharmaceutically acceptable carriers, excipients or diluents to form a pharmaceutical preparation. Examples of the carriers, excipients and diluents include water, lactose, dextrose, fructose, sucrose, sorbitol, mannitol mononole, polyethylene glycolenolate, propylene glycolenolate, starch, gum, gelatin, anoreginate, calcium silicate, Included are various oils such as calcium phosphate, cellulose, water syrup, methyl cellulose, polybulurpyrrolidone, alkyl parahydroxybenzosorbate, talc, magnesium stearate, stearic acid, glycerin, sesame oil, olive oil, soybean oil, etc. .

[0039] Furthermore, additives such as extenders, binders, disintegrants, pH adjusters, and solubilizers that are generally used as necessary are mixed with the above-mentioned carriers, excipients, or diluents, so that usual preparations are mixed. Depending on the technology, it can be prepared as an oral or parenteral pharmaceutical such as tablets, pills, capsules, granules, powders, solutions, emulsions, suspensions, ointments, injections, skin patches, etc. . Compound of the present invention The product can be administered orally or parenterally to adult patients as a single dose of 0.00;! To 500 mg once or several times a day. The dose can be increased or decreased as appropriate depending on the type of disease to be treated, the age, weight, symptoms, etc. of the patient.

Yes

 [0040] Desirable profiles of the compound of the present invention include excellent drug efficacy, excellent pharmacokinetics, excellent physical properties, low toxicity, and the like.

 [0041] The compound of the present invention can be produced by the following method.

 [0042] (Method for producing the compound of the present invention)

 The compound of the present invention can be produced by a known organic chemical method, for example, according to the method according to the following reaction formula.

[0043] In the following reaction formula; ^ ~ Is as defined above. X, Y and Z may be the same or different, and may be a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, a methanesulfonyloxy group, a benzenesulfonyloxy group, a p-toluenesulfonyloxy group, a trifluoromethanesulfonyloxy. Represents a leaving group such as an organic sulfonyloxy group such as an xy group, and W represents a substituent generally used in a coupling reaction (for example, a group containing an element such as boron, tin, zinc or silicon). More preferably, boric acid group, jetylpolyl group, 4, 4, 5, 5-tetramethyl- [1,3,2] dioxabolananyl group, tri-n-butylstannyl group, etc.), R ⁶ and R ⁷ represents a hydrogen atom, an alkyl group or a cycloalkyl group. R ⁶ and R ⁷ together with the adjacent carbon atom may form an unsubstituted force, or a cycloalkyl ring substituted with a ˜C alkyl group.

 1 6

 Hereinafter, a method for producing the compound of the present invention represented by Reaction Scheme 1 will be described. This production process is a process for producing the compound (lb) of the present invention from the compound (2). (Scheme 1)

[0045] [Chemical 6]

)

 [0046] (Process la)

 Step la is a step for obtaining compound (4) by a coupling reaction between compound (2) and compound (3). Compound (2) and Compound (3) are compounds that are known compounds and can be easily synthesized from known compounds. Here, as the coupling reaction, for example, the compound (2) and the compound (3) are combined with an organophosphorus compound such as triphenylphosphine or tributylphosphine and diethyl azodicarboxylate, diisopropyl azodicarboxylate, ditertbutyl azodicarboxylate or the like. Or a reaction carried out in a solvent with a phosphorus ylide reagent such as tributylphosphorane. Examples of the solvent include ethers such as jetyl ether, tetrahydrofuran, and 1,4 dioxane; aromatic hydrocarbons such as toluene and benzene; aliphatic hydrocarbons such as hexane and cyclohexane; And halogenated hydrocarbons such as dichloromethane; amides such as N, N dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone; dimethyl sulfoxide; acetonitrile and mixed solvents thereof.

[0047] (Step 2a)

Step 2a is a step for obtaining the compound (5) by converting the nitrile group of the compound (4) into a carboxylic acid by hydrolysis. The hydrolysis method in step 2a is a general nitrile. For example, hydrolysis reaction under acidic conditions, hydrolysis reaction under basic conditions, and oxidative hydrolysis reaction. These reactions can all be carried out without solvent or in a solvent.

 [0048] Examples of the solvent used in Step 2a include alcohols such as methanol, ethanol, and isopropanol; ethers such as jetyl ether, tetrahydrofuran, and 1,4 dioxane; and aromatic hydrocarbons such as toluene and benzene. Aliphatic hydrocarbons such as hexane and cyclohexane; halogenated hydrocarbons such as black mouth form and dichloromethane; amides such as N 1, N dimethylformamide, N, N dimethylacetamide, and N methyl 2-pyrrolidone Dimethyl sulfoxide; acetonitrile; water or a mixed solvent thereof.

 [0049] (Step 3a)

 Step 3a is a step for condensing compound (5) and compound (6) under the conditions of the amidation reaction to obtain compound (lb) of the present invention. Here, the conditions for amidation reaction indicate the general conditions for amidation of carboxylic acid. For example, after introducing carboxylic acid to carboxylic acid chloride such as carboxylic acid chloride or carboxylic acid bromide, it is reacted with amine. Method, a method in which a mixed acid anhydride obtained from carboxylic acid and chlorocarbonate, etc. is reacted with ammine, and after introducing carboxylic acid to an active ester such as benzotriazolyl ester or succinimidyl ester. And a method of reacting carboxylic acid with amin in the presence of a dehydrating condensing agent. All of these reactions can be carried out in a solvent in the presence or absence of a base.

 [0050] Examples of the dehydrating condensing agent used in Step 3a include 3- (3 dimethylaminopropyl) 1 ethyl carpositimide hydrochloride, dicyclohexyl carpositimide, diphenylphosphoryl azide, carbonyldiimidazole, O (7 Zabenzotriazole-1-1) 1, 1, 3, 3, 3-tetramethyluronium hexafluorophosphate, etc. 1-hydroxybenzotriazole, hydroxy An activator such as succinimide can be used.

[0051] Examples of the base used in Step 3a include organic amines such as pyridine, triethylamine, diisopropylethylamine; potassium carbonate, sodium hydrogen carbonate, sodium hydroxide. And inorganic bases such as

 [0052] Examples of the solvent used in Step 3a include alcohols such as methanol, ethanol, and isopropanol; ethers such as jetyl ether, tetrahydrofuran, and 1,4 dioxane; and aromatic hydrocarbons such as toluene and benzene. Aliphatic hydrocarbons such as hexane and cyclohexane; halogenated hydrocarbons such as black mouth form and dichloromethane; amides such as N 1, N dimethylformamide, N, N dimethylacetamide, and N methyl 2-pyrrolidone Dimethyl sulfoxide; acetonitrile; water or a mixed solvent thereof.

 (Scheme 2)

 [0053] [Chemical 7]

 [0054] Compound (4) can be obtained by a coupling reaction of compound (2) and compound (7). Here, examples of the coupling reaction include a method of reacting the compound (2) and the compound (7) in a solvent in the presence or absence of a base. If necessary, it is possible to add, for example, sodium bromide or potassium iodide.

 [0055] When a base is used in Step 4a, examples of the base include organic amines such as pyridine, triethylamine and diisopropylethylamine; inorganic bases such as potassium carbonate, sodium hydrogencarbonate and sodium hydroxide. Can be mentioned.

[0056] Examples of the solvent used in Step 4a include alcohols such as methanol, ethanol, and isopropanol; ethers such as jetyl ether, tetrahydrofuran, and 1,4 dioxane; and aromatic hydrocarbons such as toluene and benzene. Aliphatic hydrocarbons such as hexane and cyclohexane; halogenated hydrocarbons such as black mouth form and dichloromethane; amides such as N 1, N dimethylformamide, N, N dimethylacetamide, and N methyl 2-pyrrolidone Dimethyl sulfoxide; acetonitrile; water or a mixed solvent thereof. I can get lost.

 (Scheme 3)

 [0057] [Chemical 8]

 [0058] In addition, the compound (lc) of the present invention can be synthesized by converting the compound (4) into force ruberamoyl by hydrolysis. The hydrolysis method in step 5 indicates general nitrile hydrolysis conditions, such as hydrolysis under acidic conditions, hydrolysis under basic conditions, and oxidative hydrolysis. Is mentioned. All of these reactions can be carried out without solvent or in a solvent.

 [0059] Examples of the solvent used in Step 5 include alcohols such as methanol, ethanol, and isopropanol; ethers such as jetyl ether, tetrahydrofuran, and 1,4 dioxane; and aromatic hydrocarbons such as toluene and benzene. Aliphatic hydrocarbons such as hexane and cyclohexane; halogenated hydrocarbons such as black mouth form and dichloromethane; amides such as N 1, N dimethylformamide, N, N dimethylacetamide, and N methyl 2-pyrrolidone Dimethyl sulfoxide; acetonitrile; water or a mixed solvent thereof.

 Hereinafter, a method for producing the compound of the present invention represented by Reaction Scheme 4 will be described. This production process is a process for producing the compound (lb) of the present invention from the compound (8) and the compound (9).

 (Scheme 4)

[0061] [Chemical 9]

[0062] (Step 6)

 Step 6a is a step for condensing compound (8) and compound (9) by a coupling reaction to obtain compound (10). Compound (8) and Compound (9) are compounds that are known compounds and can be easily synthesized from known compounds. Examples of the coupling reaction include general coupling reaction conditions such as Suzuki Miyaura coupling reaction and Stille coupling reaction. For example, (Danishefsky et al., Angew. Chem. Int. Ed., 40, 4544). — 4 568, 2001).

[0063] (process lb)

 Step lb is a step for obtaining the compound (lb) of the present invention by condensing the compound (10) and the compound (3) by a coupling reaction. Here, examples of the coupling reaction include the same reaction as in step la.

 [0064] (Scheme 5)

 [0065] [Chemical 10]

[0066] In addition, compound (10) is obtained by combining known compound (11) and compound (6) under the conditions for the amidation reaction. Can be obtained by condensation. Here, the amidation reaction includes the same reaction as in step 3a.

 (Scheme 6)

[0067] [Chemical 11]

 [0068] Further, the compound (lb) of the present invention can be obtained by a coupling reaction between the compound (10) and the compound (7). Here, examples of the coupling reaction include the same reaction as in step 4a.

[0069] Hereinafter, a method for producing the compound of the present invention represented by Reaction Scheme 7 will be described. This production process is a process for producing the compound (lb) of the present invention from the compound (10) and the compound (12).

 (Scheme 7)

 [0070] [Chemical 12]

(1 b) [0071] (Step 4c)

 Step 4c is a step for obtaining compound (13) by a coupling reaction of compound (10) and compound (12). The compound (12) is a known compound or a compound that can be easily synthesized from a known compound. Here, examples of the coupling reaction include the same reaction as in step 4a.

[Step 7]

 Step 7 is a step for obtaining compound (14) by reacting compound (13) under the conditions for deprotection of the tert-butoxycarbonyl group. Here, the deprotection conditions for the tert-butoxycarbonyl group indicate general deprotection conditions for the tert-butoxycarbonyl group, for example, according to the method described in (TW Greene and PGM Wuts Protective Groups in Organic Synthesis). Can be implemented. All of these reactions can be carried out without solvent or in a solvent.

 [0073] Examples of the solvent used in Step 7 include alcohols such as methanol, ethanol, and isopropanol; ethers such as jetyl ether, tetrahydrofuran, and 1,4 dioxane; and aromatic hydrocarbons such as toluene and benzene. Aliphatic hydrocarbons such as hexane and cyclohexane; halogenated hydrocarbons such as black mouth form and dichloromethane; amides such as N 1, N dimethylformamide, N, N dimethylacetamide, and N methyl 2-pyrrolidone Dimethyl sulfoxide; acetonitrile; water or a mixed solvent thereof.

 [0074] (Process 8)

 Step 8 is a step for obtaining the compound (lb) of the present invention by reacting the compound (14) and the compound (15) under the conditions of the reductive amination reaction. Compound (15) is a known compound or a compound that can be easily synthesized from a known compound. Here, the conditions for the reductive amination reaction indicate the general conditions for the reductive amination reaction in which the amine and the carbonyl compound are condensed in a solvent by adding a reducing agent in the presence or absence of an acid. Examples include conditions using sodium borohydride as a reducing agent, conditions using sodium triacetoxyborohydride, conditions using sodium cyanoborohydride, and the like.

[0075] When an acid is used in Step 8, examples of the acid include organic acids such as acetic acid and formic acid; hydrochloric acid, sulfur Examples thereof include mineral acids such as acid and nitric acid.

 [0076] Examples of the solvent used in Step 8 include alcohols such as methanol, ethanol, and isopropanol; ethers such as jetyl ether, tetrahydrofuran, and 1,4 dioxane; and aromatic hydrocarbons such as toluene and benzene. Aliphatic hydrocarbons such as hexane and cyclohexane; halogenated hydrocarbons such as black mouth form and dichloromethane; amides such as N 1, N dimethylformamide, N, N dimethylacetamide, and N methyl 2-pyrrolidone Dimethyl sulfoxide; acetonitrile; water or a mixed solvent thereof.

 (Reaction Scheme 8)

 [0077] [Chemical 13]

 [0078] Further, the compound (lb) of the present invention can be obtained by a coupling reaction between the compound (14) and the compound (16). Compound (16) is a compound that can be easily synthesized from a known compound and a known compound. Here, examples of the coupling reaction include a method of reacting compound (14) and compound (16) in a solvent in the presence or absence of a base. Moreover, it is possible to add, for example, sodium bromide, potassium iodide, etc. as required.

 [0079] When a base is used in Step 9, examples of the base include organic amines such as pyridine, triethylamine, disopropylethylamine; potassium carbonate, sodium hydrogen carbonate, sodium hydroxide, sodium hydride and the like. Inorganic bases can be mentioned.

[0080] Examples of the solvent used in Step 9 include alcohols such as methanol, ethanol, and isopropanol; ethers such as jetyl ether, tetrahydrofuran, and 1,4 dioxane; and aromatic hydrocarbons such as toluene and benzene. Aliphatic hydrocarbons such as hexane and cyclohexane; halogenated hydrocarbons such as chloroform and dichloromethane; N 2, N dimethylformamide, N, N dimethylacetamide, N methyl 2-pyrrolidone And amides such as dimethyl sulfoxide; acetonitrile; water or a mixed solvent thereof.

 Hereinafter, a method for producing the compound of the present invention represented by Reaction Formula 9 will be described. This production process is a process for producing the compound (lb) of the present invention from the compound (3) and the compound (8).

 (Scheme 9)

 [0082] [Chemical 14]

 (1 b)

 [0083] (Process lc)

 Step lc is a step for obtaining compound (15) by condensing compound (8) and compound (3) by a coupling reaction. Here, examples of the coupling reaction include the same reaction as in step la.

 (Process 6b)

 Step 6b is a step for condensing compound (15) and compound (9) by a coupling reaction to obtain compound (lb) of the present invention. Here, examples of the coupling reaction include the same reaction as in step 6a.

[0084] Hereinafter, a method for producing the compound of the present invention represented by Reaction Scheme 10 will be described. This production process is a process for producing the compound (Id) of the present invention from the compound (15) and the compound (16). (Scheme 10)

 [0085] [Chemical 15]

 ,Five

 [0086] (Process 6c)

 Step 6c is a step for obtaining the compound (Id) of the present invention by condensing the compound (15) and the compound (16) by a coupling reaction. Here, examples of the coupling reaction include the same reaction as in step 6a.

 [0087] The present invention will be specifically described below with reference to Examples and Test Examples, but the present invention is not limited to these.

 Example 1

 [0088]

[0089] (1) Manufacture of 4, 4-ylcarbonyl) bifenole 4 ol

[0090] [Chemical 16]

[0091] 4 (4-Hydroxyphenyl) benzoic acid (5.00 g), 1-{3-} 3 ethyl carpositimide hydrochloride (5.36 g) and 1-hydroxybenzotriazole hydrate (6.31 g ) To N, N dimethylformamide (50 ml) to make a solution. (3.32 g) was added at room temperature and stirred overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the precipitated crystals were collected by filtration to give the title compound (5.25 g) as a colorless solid.

 [0092] (2) 4— {[4, Preparation of mono (pyrrolidine 1-ylcarboninole) biphenyl 4-lysine 1

 [0093] [Chemical 17]

 [0094] 4-L (Methylsulfonyl) oxy "piperidine 1 tert butyl sulfonate (7.84 g), 4, 1 (pyrrolidine 1-ylcarboninole) biphenyl 4 ol (2. 50 g) Then, potassium carbonate (3.88 g) was added to N, N dimethylformamide (50 ml) to form a suspension, and the mixture was stirred at 85 3 C for 6 hours. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 1: 1) to obtain the title compound (3. llg) as a colorless solid.

 [0095] (3) 4— {[4, One (Pyrrolidine 1-ylcarboninole) Bihue nilu 4-

[0096] [Chemical 18]

[0097] 4-{[4 '-(Pyrrolidine mono-1-ylcarboninole) biphenyl mono 4-tert-butyl carboxylate (3.000 g) was added to tetrahydrofuran (30 ml) to form a solution, and 4M hydrochloric acid was added. Ethyl acetate solution was added and stirred overnight at room temperature. Reduce reaction mixture The reaction mixture was concentrated under pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (2.45 g) as a colorless solid.

[0098] (4) 1-Cyclopentyl 4 {[4, 1 (Pyrrolidine 1-ylcarboninole) biphenyl

[0099] [Chemical 19]

 [0100] 4 {[4 '(Pyrrolidine 1-ylcarbonyl) biphenyl 4-yl] oxy} piperidine (0. 500 g), cyclopentanone (0.180 g) and acetic acid (0.257 g) Sodium triacetoxypolohydride (0 · 454 g) was added to 10 ml 1) to prepare a solution, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane: ethyl acetate = 1: 1) to obtain the title compound (0.220 g) as a colorless solid.

 1H NMR (600 MHz, CHLOROFORM— d) δ ppm 1.38-1.47 (m, 2 H), 1.50-1.59 (m, 2 H), 1.65-1.73 (m, 2 H), 1.83-1.92 (m, 6 H ), 1.93-2.00 (m, 2 H), 2.00-2. 07 (m, 2 H), 2.35 (br. S., 2 H), 2.48-2.56 (m, 1 H), 2.82 (br. S) ., 2 H), 3.49 (t, J = 6.6 Hz, 2 H), 3.66 (t, J = 6.9 Hz, 2 H), 4.36 (br. S., 1 H), 6.97 (d, J = 8.7 Hz, 2 H), 7.51 (d, J = 9.2 Hz, 2 H), 7.56 (s, 4 H)

MS (ESI / APCI Dual) (Positive) m / z; 419 (M + H) ⁺

 Example 2

[0101] 1-Isopropyl 4- 4 {{[4 '-(Pyrrolidine 1-ylcarboninole) biphenyl 4- 4-] [0102]

[0103] 4 {[4 '(Pyrrolidine 1-ylcarbonyl) biphenyl 4yl] oxy} piperidine (0 · 500 g), isopropino-reotide (0.363 g) and diisopropylethylamine (0.277 g) ) Was added to N, N dimethylformamide (5 ml) to form a solution, and the mixture was stirred at 80 ° C for 2 hours. Saturated sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: _n- hexane: ethyl acetate = 2: 1) to obtain the title compound (0.214 g) as a colorless solid.

 1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.06 (d, J = 6.4 Hz, 5 H), 1.59 (br. S ·, 4 H), 1.81-1.92 (m, 3 H), 1.93-2.08 ( m, 3 H), 2.36-2.45 (m, 2 H), 2.70-2.8 4 (m, 2 H), 3.49 (t, J = 6.6 Hz, 2 H), 3.66 (t, J = 7.1 Hz, 2 H), 4.31-4.38 (m, 1 H), 6.98 (d, 2 H), 7.51 (d, 2 H), 7.56 (s, 4 H)

MS (ESI / APCI Dual) (Positive) m / z; 393 (M + H) ⁺

 Example 3

 [0104] 1-Ethyl 4— {[4,1 (Pyrrolidine 1-ylcarboninole) biphenyl 4-inole] oxy} Production of piperidine

[0105] [Chemical 21]

[0106] In the same manner as in Example 2, 4 {[4 '(pyrrolidine 1-ylcarbonyl) biphenyl 4-yl] oxy} piperidine (0 · 500 g) and ethylzide (0.333 g) were used as starting materials. As a material, the title compound was obtained as a colorless solid.

 IH NMR (600 MHz, CHLOROFORM— d) δ ppm 1.10 (t, J = 7.3 Hz, 3 H), 1.81-1.9 1 (m, 4 H), 1.92-2.00 (m, 2 H), 2.00-2.07 ( m, 2 H), 2.31 (br. s., 2 H), 2.44 (q, 2 H), 2.76 (br. s., 2 H), 3.49 (t, J = 6.6 Hz, 2 H), 3.66 (t, J = 6.9 Hz, 2 H), 4.33-4.40 (m, 1 H), 6.98 (d, J = 8.7 Hz, 2 H), 7.51 (d, 2 H), 7.56 (s, 4 H)

MS (ESI / APCI Dual) (Positive) m / z; 379 (M + H) ⁺

 Example 4

 [0107] 1-Cyclopropylmethyl-4 {[4 '(Pyrrolidine 1-ylcarbonyl) biphenyl [0108] [Chemical 22]

 [0109] By the same method as in Example 2, the title compound was obtained as a colorless solid using 4-{[4 '(pyrrolidine 1-ylcarbonyl) biphenol. 097g) as a starting material.

 IH NMR (600 MHz, CHLOROFORM— d) δ ppm 0.10-0.14 (m, 2 H), 0.51-0.56 (m, 2 H), 0.85-0.93 (m, 1 H), 1.84-2.10 (m, 8 H ), 2.25-2.46 (m, 4 H), 2.86 (br. S., 2 H), 3.50 (t, J = 6.6 Hz, 2 H), 3.67 (t, J = 6.9 Hz, 2 H), 4.38 (br. s., 1 H), 6.99 (d, J = 8.7 Hz, 2 H), 7.52 (d, J = 8.7 Hz, 2 H), 7.55-7.60 (m, 4 H)

MS (ESI / APCI Dual) (Positive) m / z; 405 (M + H) ⁺

 Example 5

 [0110] 1- (2-Methylcyclopentyl) -4 {[4 '(Pyrrolidine 1-ylcarboninole) biphenyl 4-yl] oxy} Preparation of piperidine

[0111] [Chemical 23]

 [0112] In the same manner as in Example 1 (4), 4 {[4 '(pyrrolidine 1-ylcarbonyl) biphenyl 4-inole] oxy} piperidine (0.213 g) and 2 methylcyclopentanone (0.092 g ) As a starting material to give the title compound (0.041 g) as a colorless solid.

 1H NMR (600 MHz, CHLOROFORM— d) δ ppm 0.84 (d, J = 6.9 Hz, 3 H), 1.37-1.5 2 (m, 2 H), 1.68-2.07 (m, 8 H), 2.13-2.34 ( m, 4 H), 2.79 (br. s., 2 H), 3.50 (t, J = 6.6 Hz, 2 H), 3.67 (t, J = 7.1 Hz, 2 H), 4.34 (br. s., 1 H), 6.98 (d, J = 8.7 Hz, 2 H), 7.52 (d, J = 8.7 Hz, 2 H), 7.57 (s, 4 H)

MS (ESI / APCI Dual) (Positive) m / z; 433 (M + H) ⁺

 Example 6

 [0113] Preparation of 1 ({4 '[(1-Cyclobutylpiperidine-4-yl) oxy] biphenyl 4-yl} carbonyl) piperidine 4-ol

[0114] (1) Production of 4 '-[(1-Cyclobutylpiperidine 4-yl) oxy] biphenyl 4-carbotriyl

[0115] [Chemical 24]

[0116] Triphenylphosphine (15.7 g) was added to tetrahydrofuran (100 ml) to form a solution. Under ice-cooling, 40% toluene solution of ditertbutyl azodicarboxylate (26. lg) was added, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture, 1-cyclobutylpiperidin-4-ol (7.76 g) and 4′-hydroxybiphenyl 4-carbonitryl (19.5 g) were added, and the mixture was stirred for 3 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by NH-type silica gel column chromatography (developing solvent: n hexane: ethyl acetate = 1: 1), and further silica gel column chromatography (developing solvent: black mouth form: methanol = 10). : Purification by 1) gave the title compound (6.13 g) as a colorless solid.

 [0117] (2) Production of 4 '-[(1-cyclobutylpiperidine 4-yl) oxy] biphenyl 4-strength rubon hydrochloride

 [0118] [Chemical 25]

 [0119] 4 '[[1 Cyclobutylpiperidine 4 yl] oxy] biphenyl 4 carbolyl (6. 10 g) and potassium hydroxide (10.3 g) mixed with ethanol (30 ml) and water (30 ml) It was added to the combined solution and refluxed for 5 hours. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The obtained residue was acidified with 6M hydrochloric acid, and the precipitated solid was collected by filtration to give the title compound (3.50 g) as a colorless solid.

 [0120] (3) Preparation of 1-({4 '-[(1-cyclobutylpiperidine 4-yl) oxy] biphenyl 4-carbonyl} carbonyl) piperidine 4-ol

 [0121] [Chemical 26]

_ 3—ェチノレ力ノレポジイミド 塩酸塩（0· 545g)、 一ル水和物（0.383g)及びトリェチ ルァミン（0. 144g)を N, N ジメチルホルムアミド（5ml)に加えて溶液とし、 4 ヒド 口キシピペリジン (0. 287g)を加えて室温にて一晩撹拌した。反応混合物に飽和炭 酸水素ナトリウム水溶液を加え、酢酸ェチルで抽出した。有機層を飽和食塩水で洗 浄し、無水硫酸ナトリウムで乾燥し、減圧下濃縮した。得られた残渣を NH型シリカゲ ルカラムクロマトグラフィー（展開溶媒: n へキサン:酢酸ェチル = 1： 1)にて精製し、 無色固体の表題化合物（0. 024g)を得た。 [0122] 4 '-[(1--4-yl) oxy] bifenole 4-carboxylic acid hydrochloride (0 · 500 g),

_ 3-Ethenoleol Norepositimide Hydrochloride (0 · 545g), Monohydrate (0.383g) and Trieti Luamine (0.144 g) was added to N, N dimethylformamide (5 ml) to give a solution, 4-hydroxypropylidine (0.487 g) was added, and the mixture was stirred overnight at room temperature. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by NH-type silica gel column chromatography (developing solvent: n hexane: ethyl acetate = 1: 1) to obtain the title compound (0.024 g) as a colorless solid.

 1H NMR (600 MHz, CHLOROFORM- d) δ ppm 1.51-1.75 (m, 8 H), 1.79-2.20 (m, 8 H), 2.59-2.77 (m, 4 H), 3.22-3.42 (m, 4 H ), 3.95-4.02 (m, 1 H), 4.36 (br. S., 1 H), 6.97 (d, J = 8.7 Hz, 2 H), 7.44 (d, J = 8.3 Hz, 2 H), 7.50 (d, J = 8.7 Hz, 2 H), 7.56 (d, J = 8.3 Hz, 2 H)

MS (ESI / APCI Dual) (Positive) m / z; 435 (M + H) ⁺

 Example Ί

 [0123] 1— ({4, 1 [(1-Cyclobutylpiperidine-4-yl) oxy] biphenyl 4-inole} carbonyl) 4-methylbiperazine

 [0124] [Chemical 27]

 Example 6 In the same manner as in (3), 4 ′ [(1-cyclobutylpiperidine-4-yl) oxy] biphenyl 4 carboxylic acid hydrochloride (0 · 500 g) and 1-methylbiperazine (0 2 61 g) was used as a starting material to give the title compound (0.020 g) as a colorless solid.

 1H NMR (600 MHz, CHLOROFORM— d) δ ppm 1.61-1.94 (m, 10 H), 2.11-2.22

(m, 2 H), 2.32 (s, 3 H), 2.33-2.68 (m, 6 H), 2.69-2.78 (m, 1 H), 3.50 (br. s., 2 H), 3.78 (br. s., 2 H), 4.36 (br. s., 1 H), 6.97 (d, J = 8.7 Hz, 2 H), 7.44 (d, J = 8.3 Hz,

2 H), 7.50 (d, J = 9.2 Hz, 2 H), 7.56 (d, J = 8.3 Hz, 2 H)

MS (ESI / APCI Dual) (Positive) m / z; 434 (M + H) ⁺ Example 8

 [0126] Production of 4-one ({4, 1 [(1-cyclobutylpiperidine-4-yl) oxy] biphenyl 4-monole} carbonyl) morpholine

 [0127] [Chemical 28]

 Example 6 In the same manner as in (3), 4 ′ [(1-cyclobutylpiperidine-4-yl) oxy] biphenyl mono 4 carboxylic acid hydrochloride (0 · 500 g) and monoreforin (0.247 g) As a starting material, the title compound (0.035 g) was obtained as a colorless solid.

 1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.62-2.25 (m, 11 H), 2.56-2.82 (m, 4 H), 3.41-3.88 (m, 8 H), 4.33-4.41 (m, 1 H ), 6.97 (d, J = 8.7 Hz, 2 H), 7.45 (d, J = 8.3 Hz, 2 H), 7.50 (d, J = 8.7 Hz, 2 H), 7.57 (d, J = 8.3 Hz, 2 H)

MS (ESI / APCI Dual) (Positive) m / z; 421 (M + H) ⁺

 Example 9

[0129] 1-Cyclobutyl 1 4-— {[4 '-(Pyrrolidine 1-ylcarbonyl) Biphenyl 1 4

 [0130] (1) Manufacture of 4, 1, (Pyrrolidine-1-ylcarbonyl) biphenyl 4-ol

[0131] [Chemical 29]

[0132] 4 Bromophenol (0 · 415 g), (4 pyrrolidylcarboylphenyl) boric acid (0 · 44 Og), tetrakis (triphenylphosphine) palladium (0) (0.116 g), 2M sodium carbonate Aqueous aqueous solution ((55mmll)) and etanolanol ((55mmll)) are added to toluluenen ((55mmll)) to form a suspended suspension. The atmosphere was stirred and stirred at 110000 ° CC for 22 hours. . The reaction mixture was allowed to cool while standing at room temperature, and extracted with ethyl acetate acetate. . The organic / organic layer is washed and washed with saturated Japanese saline solution, dried and dried with anhydrous magnesium sulfate sulfate, and concentrated under reduced pressure under reduced pressure. I did. . The resulting residue residue is refined and refined on a shirari-kagegerulkakararamuku chloromamatogurafurafi ((development and development solvent medium: ethytille acetate acetate)) The title compound ((00 .. 221100gg)) was obtained as a colorless solid solid product. .

[[00113333]] ((22)) 11——Cyclochlorobutbutyryl roux 44 {{[[44 ,, ichi ((Pipirololizidine 11-Iruluka Carbobo Ninorele)) Bibihue 22 Lulu 44

 [[00113344]] [[Chemical 3300]]

 Example 6 In the same manner as in (1), 1-cyclobutylpiperidine-4-ol (0.139 g) and 4,-(pyrrolidine-1-ylcarbonyl) biphenyl 4-ol (0.200 g) ) As a starting material to give the title compound (0.080 g) as a colorless solid.

 1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.61-2.25 (m, 14 H), 2.57-2.82 (m, 4 H), 3.50 (t, J = 6.7 Hz, 2 H), 3.66 (t, J = 6.9 Hz, 2 H), 4.35-4.41 (m, 1 H), 6.9 9 (d, J = 8.5 Hz, 2 H), 7.51 (d, J = 8.5 Hz, 2 H), 7.57 (s, 4 H)

MS (ESI / APCI Dual) (Positive) m / z; 405 (M + H) ⁺

 Example 10

 [0136] Preparation of 4 '[(1-cyclobutylpiperidine-4-yl) oxy] biphenyl 4-carboxamide

[0137] [Chemical 31]

[0138] 4，一 [ (1ーシクロブチルピペリジンー4 ィル）ォキシ]ビフエ二ルー 4 カルボ二トリ ノレ（0· 125g)及び水酸ィ匕カリウム（0· 100g)を tert ブチノレアノレコーノレ（2ml)にカロ えて懸濁液とし、 100°Cにて 2時間撹拌した。反応混合物に水を加え、酢酸ェチルで 抽出し、有機層を飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥し、減 圧下濃縮した。得られた残渣を NH型シリカゲルカラムクロマトグラフィー（展開溶媒： 酢酸ェチル）にて精製し、無色固体の表題化合物（0. 064g)を得た。

[0138] 4, 1 [(1-Cyclobutylpiperidine-4-yl) oxy] biphenyl 4-carbon trinore (0 · 125 g) and potassium hydroxide (0 · 100 g) were added to tert-butylenoreno The suspension was added to a slurry (2 ml) and stirred at 100 ° C for 2 hours. Water was added to the reaction mixture, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by NH-type silica gel column chromatography (developing solvent: ethyl acetate) to obtain the title compound (0.064 g) as a colorless solid.

 1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.60-2.30 (m, 10 H), 2.55-2.85 (m, 4 H), 4.35-4.45 (m, 1 H), 5.45 5.65 (m, 1 H) , 6.05 6.15 (m, 1 H), 6.99 (d, J = 8.7 Hz, 2 H), 7.54 (d, J = 8.3 Hz, 2 H), 7.63 (d, J = 8.7 Hz, 2 H), 7.86 (d, J = 8.3 Hz, 2 H)

MS (ESI / APCI Dual) (Positive) m / z; 351 (M + H) ⁺

 Example 11

 [0139] 1-Cyclobutyl-4 {[4 '(Dimethylaminocarbolinole) biphenyl 4-inole] oxy} Production of piperidine

[0140] (1) Production of 1-cyclobutylpiperidine-4-ol

[0141] [Chemical 32]

[0142] 4-Hydroxypiperidine (13 · 12 g), cyclobutanone (10 g) and acetic acid (9 · 35 g) were added to black form (300 ml) to form a suspension and stirred at room temperature for 30 minutes. Sodium triacetoxypolohydride (32.99 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 16 hours. Water (10 ml) was added to the reaction mixture, and the residue obtained by concentration under reduced pressure was purified by NH-type silica gel column chromatography (developing solvent: n hexane: ethyl acetate = 4: 1). The resulting colorless oil was diluted with black mouthform and washed with 2M aqueous sodium hydroxide. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (10.75 g) as a brown oil. [0143] (2) 1--4 one

[0144] [Chemical 33]

25g)、 4 ョードフエノーノレ（7. 09g)及 びトリフエニルホスフィン（8. 87g)をテトラヒドロフラン（60ml)に加えて溶液とし、ァゾ ジカルボン酸ジ tert ブチル（5. 25g)を加え、室温で 16時間撹拌した。反応混合 物に 2M塩酸酢酸溶液（2ml)を加え、室温で 1時間撹拌した後、水を加え、酢酸ェ チルで洗浄した。水層を 6M水酸化ナトリウム水溶液で中和し、クロ口ホルムで抽出し た。有機層を無水硫酸マグネシウムで乾燥し、減圧下濃縮した。得られた残渣を NH 型シリカゲルカラムクロマトグラフィー（展開溶媒: n へキサン:酢酸ェチル = 1： 1)に て精製し、得られた淡黄色油状物を再結晶（酢酸ェチルー n へキサン）して無色固 体の表題化合物（1. 66g)を得た。 [0145]

25 g), 4 chlorophenol (7.09 g) and triphenylphosphine (8.87 g) in tetrahydrofuran (60 ml) to make a solution, add di tert butyl azodicarboxylate (5.25 g), Stir at room temperature for 16 hours. To the reaction mixture was added 2M hydrochloric acid / acetic acid solution (2 ml), and the mixture was stirred at room temperature for 1 hour. Water was added, and the mixture was washed with ethyl acetate. The aqueous layer was neutralized with 6M aqueous sodium hydroxide and extracted with black mouth form. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by NH-type silica gel column chromatography (developing solvent: n-hexane: ethyl acetate = 1: 1), and the resulting pale yellow oil was recrystallized (ethyl acetate-hexane). The title compound (1.66 g) was obtained as a colorless solid.

 [0146] (3) 1-Cyclobutyl-4 {[4 '(Dimethylaminocarbonyl) biphenyl 4 yl]

[0147] [Chemical 34]

 [0148] -4— (4 phenphenoxy) piperidine (0.100 g), acetic acid

 (0. Ol lg) and tri (2 methino olefin phosphine) phosphine (0.030 g) were added to tolylene (5.7 ml) H to form a suspension, and {4 [(dimethyla

: n へキ サン:酢酸ェチル = 1：1)にて精製して無色固体の表題化合物（0. 016g)を得た。 1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.63 - 2.26 (m， 12 H)， 2.58 - 2.80 (m， 3 H)， 3.01 - 3.16 (m， 6 H)， 4.38 (br. s.， 1 H)， 6.98 (d， J=8.7 Hz, 2 H)， 7.47 (d， J=8.3 Hz, 2 H)， 7.51 (d， J=9.2 Hz, 2 H)， 7.57 (d， J=8.7 Hz, 2 H) Nyl] phenyl} boric acid (0 · 045 g) in methanol (3.8 ml) and 2M aqueous carbonate (2 ml) were added and stirred at 70 ° C. for 4 hours. The reaction mixture is allowed to cool to room temperature and 8M A mixture of aqueous ammonia / saturated aqueous sodium carbonate (1.9 ml / 19 ml) was added, and the mixture was stirred for 5 minutes and extracted with black mouth form. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.

The title compound (0.016 g) was obtained by purification with n: hexane: ethyl acetate = 1: 1). 1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.63-2.26 (m, 12 H), 2.58-2.80 (m, 3 H), 3.01-3.16 (m, 6 H), 4.38 (br. S., 1 H), 6.98 (d, J = 8.7 Hz, 2 H), 7.47 (d, J = 8.3 Hz, 2 H), 7.51 (d, J = 9.2 Hz, 2 H), 7.57 (d, J = 8.7 Hz , 2 H)

MS (ESI / APCI Dual) (Positive) m / z; 379 (M + H) ⁺

 Example 12

 [0149] 1-Cyclobutyl-4 {[4 '(Methylaminocarboninole) biphenyl 4-inole] oxy} piperidine production

[0150] [Chemical 35]

 [0151] In the same manner as in Example 11 (3), 1-cyclobutyl-4- (4-iodophenoxy) piperidine (0 · 100 g) and {4 [(methylamino) carbonyl] phenyl} boric acid (0 · The title compound (0.059 g) was obtained as a colorless solid starting from 30 g).

 1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.52-2.25 (m, 12 H), 2.57-2.81

(m, 3 H), 3.04 (d, J = 5.0 Hz, 3 H), 4.38 (br. s., 1 H), 6.11-6.16 (m, 1 H), 6.99 (d, J = 9.2 Hz, 2 H), 7.53 (d, J = 8.7 Hz, 2 H), 7.61 (d, J = 8.7 Hz, 2 H), 7.80 (d, J = 8.3 Hz,

2 H)

MS (ESI / APCI Dual) (Positive) m / z; 365 (M + H) ⁺

 Example 13

[0152] 1-Cyclobutyl 1 4-— {[3, 1 (Pyrrolidine 1-ylcarboninole) Biphenyl 2-4 [0153] [Chemical 36]

 Example 11 In the same manner as in (3), 1-cyclobutyl-4 (4-iodophenoxy) piperidine (0 · 200 g) and (3 pyrrolidylcarboxylphenyl) borate (0 · 151 g) As a starting material, the title compound (0.074 g) was obtained as a colorless solid.

 IH NMR (600 MHz, CHLOROFORM-d) δ ppm 1.61-2.23 (m, 16 H), 2.57-2.79 (m, 3 H), 3.45 (t, J = 6.9 Hz, 2 H), 3.66 (t, J = 6.9 Hz, 2 H), 4.28-4.39 (m, 1 H), 6.9 6 (d, J = 8.7 Hz, 2 H), 7.40-7.43 (m, 2 H), 7.50 (d, J = 9.2 Hz , 2 H), 7.55-7.61 (m, 1 H), 7.68 (s, 1 H)

MS (ESI / APCI Dual) (Positive) m / z; 405 (M + H) ⁺

 Example 14

 [0155] 4 1 ({4 '[(1-Cyclopentylbiperidine-4-ynole) oxy] biphenyl 4 4-il

} Carbonyl) morpholine production

[0156] [Chemical 37]

実施例 11 (3)と同様の方法により、 1—シクロブチル— 4— (4—ョードフエノキシ）ピ ペリジンの代わりに 1ーシクロプロピルー4一（4ーョードフエノキシ）ピぺリジンを、 （3 ピロリジルカルボユルフェニル）ほう酸の代わりに 4 （モルホリン— 4 カルボニル )フエニルほう酸をそれぞれ用いて表題化合物を得た。

Example 11 In the same manner as in (3), instead of 1-cyclobutyl-4- (4-iodophenoxy) piperidine, 1-cyclopropyl-4-one (4-iodophenoxy) piperidine was The title compound was obtained by using 4 (morpholine-4-carbonyl) phenyl boric acid instead of 3 pyrrolidylcarboylphenyl) boric acid, respectively.

IH NMR (600 MHz, CHLOROFORM-d) δ ppm 0.39-0.49 (m, 4 H), 1.59-1.65 (m , 1 H), 1.75-1.84 (m, 2 H), 1.94-2.02 (m, 2 H), 2.49 (br.s, 2 H), 2.91 (br.s, 2 H), 3.42-3.90 (m , 8 H), 4.37 (br.s, 1 H), 6.98 (d, J = 9.2 Hz, 2 H), 7.45 (d, J = 8.3 Hz, 2 H), 7.50 (d, J = 9.2 Hz, 2 H), 7.58 (d, J = 8.3 Hz, 2 H)

MS (ESI / APCI Dual) (Positive) m / z; 407 (M + H) ⁺

 Example 15

 [0158] Preparation of 4-({4 '— [(l-tert-butylbiperidine-4-ynole) oxy] biphenyl 4-carbonyl} carbonyl) morpholine

[0159] [Chemical 38]

Example 11 According to the same method as in (3), instead of 1-cyclobutyl-4 mono (4-phenoxy) piperidine, l-tert-butyl 4-di (4-phenoxy) piperidine The title compound was obtained using lysine in place of (3-pyrrolidylcarboylphenyl) borate instead of 4 (morpholine-l-4-carbonole) phenylborate.

 1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.10 (s, 9 H), 1.79-1.88 (m, 2 H), 1.99-2.07 (m, 2 H), 2.44 (t, J = 8.7 Hz, 2 H), 2.84-2.93 (m, 2 H), 3.73 (br. S., 8 H), 4.33 (br.s, 1 H), 6.99 (d, J = 8.7 Hz, 2 H), 7.46 (d , J = 8.3 Hz, 2 H), 7.51 (d, J = 8.7 Hz, 2 H), 7.59 (d, J = 8.3 Hz, 2 H)

MS (ESI / APCI Dual) (Positive) m / z; 423 (M + H) ⁺

 Example 16

 [0161] 4 '[(1-Cyclobutylpiperidine 4-yl) oxy] N— (4 Fluorobenzyl

) Bifu Nieru 4 Manufacture of carboxamide

[0162] [Chemical 39]

Example 6 In the same manner as in (3), the title compound was obtained using 4-2-4-funole benzoylamine.

 IH NMR (600 MHz, CHLOROFORM- d) δ ppm 1.63-1.76 (m, 2 H), 1.80-1.94 (m, 4 H), 1.97-2.08 (m, 4 H), 2.16 (br. S., 2 H), 2.63 (br. S., 2 H), 2.70-2.77 (m, 1 H), 4.37 (br. S., 1 H), 4.63 (d, J = 6.0 Hz, 2 H), 6.36- 6.44 (m, 1 H), 6.95-7.00 (m, 2 H), 7.01-7.07 (m, 2 H), 7.31-7.36 (m, 2 H), 7.50-7.54 (m, 2 H), 7.58- 7. 63 (m, 2 H), 7.80-7.85 (m, 2 H)

MS (ESI / APCI Dual) (Positive) m / z; 459 (M + H) ⁺

 Example 17

 [0164] Production of N- (4 Fluorobenzyl) -4, {[1 (1-Methyl-4-yl I oxy) biphenyl 4 Carboxamide

 [0165] [Chemical 40]

[0166] In the same manner as in Example 6 (3), replace 4-2 4-funole benzoylamine with 4 '[(1--4 inole) oxy] bifeninore 4 monostrength rubonic acid hydrochloride In addition, 4 -4-yl) oxy] biphenyl 4 monostrength rubonic acid hydrochloride was used to obtain the title compound. IH NMR (600 MHz, CHLOROFORM- d) δ ppm 1.06 (d, J = 6.4 Hz, 6 H), 1.79-1.8 9 (m, 2 H), 1.99-2.08 (m, 2 H), 2.36-2.46 ( m, 2 H), 2.70-2.84 (m, 3 H), 4.30- 4.39 (m, 1 H), 4.63 (d, J = 5.5 Hz, 2 H), 6.37-6.43 (m, 1 H), 6.96-7.01 (m, 2 H), 7.01-7.07 (m, 2 H) 7.31-7.38 (m, 2 H), 7.48-7.56 (m, 2 H), 7.58-7.66 (m, 2 H), 7.79-7.87 (m, 2 H)

MS (ESI / APCI Dual) (Positive) m / z; 447 (M + H) ⁺

 Example 18

 [0167] 1-{4 '-[(1-Cyclobutylpiperidine 4 yl) oxy] biphenyl 4 yl

[0168] [Chemical 41]

Example 11 The title compound was obtained in the same manner as in (3), except that 1- (4 laurylphenyl) pyrrolidin-2-one was used instead of (3-pyrrolidylcarboylphenyl) boric acid. 1H NMR (600 MHz, CHLOROFORM- d) δ ppm 1.62-1.75 (m, 2 H), 1.79-1.93 (m, 4 H), 1.97-2.08 (m, 4 H), 2.10-2.22 (m, 4 H ), 2.58-2.67 (m, 4 H), 2.70-2.78 (m, 1 H), 3.89 (t, J = 6.9 Hz, 2 H), 4.34 (br. S., 1 H), 6.93- 6.97 (m, 2 H), 7.45-7.50 (m, 2 H), 7.52-7.56 (m, 2 H), 7.62-7.67 (m, 2 H)

MS (ESI / APCI Dual) (Positive) m / z; 391 (M + H) ⁺

 Example 19

 [0170] 1-{4 '-[(1-Cyclopentylbiperidine 4-ynole) oxy] biphenyl 4-yl} Production of pyrrolidine 2-year-old

[0171] [Chemical 42]

 Example 11 In the same manner as in (3), instead of (3-pyrrolidylcarboxylphenyl) boric acid, 1 4 boragerufen pyrrolidin-2-one was added to 1-cyclobutyl-4 4 thiophenoxy) pipette. The title compound was obtained using 1-cyclopentyl-4- (4-phenoloxy) piperidine instead of lysine.

 1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.37-1.46 (m, 2 H), 1.50-1.60 (m, 2 H), 1.64-1.74 (m, 2 H), 1.82-1.91 (m, 4 H ), 1.99-2.07 (m, 2 H), 2.14-2.21 (m, 2 H), 2.34 (br. S., 2 H), 2.48-2.55 (m, 1 H), 2.63 (t, J = 8.0 Hz, 2 H), 2.81 (br. S., 2 H), 3.89 (t, J = 6.9 Hz, 2 H), 4.34 (br. S., 1 H), 6.94-6.98 (m, 2 H), 7.45-7.50 (m, 2 H), 7.51-7.56 (m, 2 H), 7.62-7.67 (m, 2 H)

MS (ESI / APCI Dual) (Positive) m / z; 405 (M + H) ⁺

 Example 20

 [0173] 1-(4 '-{[1-(1-Methylethyl) piperidine 4-yl] oxy} biphenyl 4-yl) pyrrolidin-2-one production

[0174] [Chemical 43]

実施例 11 (3)と同様の方法により、（3—ピロリジルカルボユルフェニル）ほう酸の代 わりに 1 4 ボラユルフェ二 ピロリジンー2 オンを、 1ーシクロブチルー 4 4 ーョードフエノキシ）ピぺリジンの代わりに 1 イソプロピルー4 4 ョードフエノキシ )ピペリジンをそれぞれ用いて表題化合物を得た。 IH NMR (600 MHz, CHLOROFORM- d) δ ppm 1.06 (d， J=6.4 Hz, 6 H)， 1.78 - 1.8 8 (m， 2 H)， 1.99 - 2.07 (m， 2 H)， 2.14 - 2.21 (m， 2 H)， 2.39 (t， J=8.7 Hz, 2 H)， 2.63 (t， J=8.0 Hz, 2 H)， 2.71 - 2.83 (m， 3 H)， 3.89 (t， J=7.1 Hz, 2 H)， 4.28 - 4.36 (m， 1 H)， 6.94 - 6.98 (m， 2 H)， 7.46 - 7.50 (m， 2 H)， 7.52 - 7.56 (m， 2 H)， 7.63 - 7.67 (m ， 2 H)

Example 11 In the same manner as in (3), instead of (3-pyrrolidylcarboylphenyl) boric acid, instead of 14 The title compound was obtained using 1 isopropyl-4 4 odophenoxy) piperidine. IH NMR (600 MHz, CHLOROFORM- d) δ ppm 1.06 (d, J = 6.4 Hz, 6 H), 1.78-1.8 8 (m, 2 H), 1.99-2.07 (m, 2 H), 2.14-2.21 ( m, 2 H), 2.39 (t, J = 8.7 Hz, 2 H), 2.63 (t, J = 8.0 Hz, 2 H), 2.71-2.83 (m, 3 H), 3.89 (t, J = 7.1 Hz , 2 H), 4.28-4.36 (m, 1 H), 6.94-6.98 (m, 2 H), 7.46-7.50 (m, 2 H), 7.52-7.56 (m, 2 H), 7.63-7.67 (m , 2 H)

MS (ESI / APCI Dual) (Positive) m / z; 379 (M + H) ⁺

 Example 21

 [0176] 1-{4 '-[(1 -tert-Butylbiperidine 4-inole) oxy] biphenyl 4-vinyl} Pyrrolidine 2--Manufacturing

[0177] [Chemical 44]

[0178] In the same manner as in Example 11 (3), instead of (3 pyrrolidylcarboylphenyl) boric acid, 1- (4 volatileylphenol) pyrrolidine-2-one was added to 1-cyclobutyl-4 1- (4-iodophenoxy). The title compound was obtained using 1-tertbutyl 4- (4-phodophenoxy) piperidine instead of piperidine.

 IH NMR (600 MHz, CHLOROFORM-d) δ ppm 1.10 (s, 9 H), 1.79-1.88 (m, 2 H), 1.99-2.07 (m, 2 H), 2.14-2.23 (m, 2 H), 2.39-2.48 (m, 2 H), 2.63 (t, J = 8.3 Hz, 2 H), 2.84-2.93 (m, 2 H), 3.90 (t, J = 6.9 Hz, 2 H), 4.29-4.36 ( m, 1 H), 6.97 (d, J = 8.7 Hz, 2 H), 7.49 (d, J = 8.7 Hz, 2 H), 7.55 (d, J = 8.7 Hz, 2 H), 7.65 (d, J = 8.7 Hz,

2 H)

MS (ESI / APCI Dual) (Positive) m / z; 393 (M + H) ⁺

 Test Example 1: H3 receptor binding test

[0179] Human-type H3 receptor expression CHO—K1 cell membrane preparation (Euroscreen, ES-392— 1), R (-)-α-methyl [ ³ H] histamine (Amersham, TRK-1017, specific activity 1.74 TBq / mmol, 2 nM), and test drug The mixture was reacted at room temperature for 1 hour. After completion of the reaction, the reaction mixture was suction filtered through a glass filter (GF / C) treated with 0.3% polyethyleneimine, and the glass filter was filtered with 50 mM Tris— containing 0.1% BSA and 5 mM magnesium chloride. Washed 5 times with HC1 washing solution (pH 7.4). After washing, the glass filter was dried, a scintillator was added, and the radioactivity on the filter was measured with a liquid scintillation counter.

[0180] ΙΟ ^ Μ R () 1 a R (—) 1 a Methyl [3H] histamine binding amount when the reaction was carried out in the presence of methyl histamine, and the total R () 1 a the difference between the methyl ^[3 H] histamine binding of nonspecific binding of specific R (-) - and the a- methyl ^[3 H] histamine binding degree. Inhibition curves were obtained by reacting various concentrations of each test drug with a constant concentration (2 nM) of R () 1 a methyl [ ³ H] histamine under the conditions described above. From the inhibition curve, the test drug concentration (IC) at which the binding of R (—)-a-methyl [ ³ H] histamine was inhibited by 50% was determined. The results are shown in Table 1.

 50

 [0181] [Table 1]

H3 receptor

 Example 钻 会 ≡ ¾! ¾

IC ₅₀ (n! VI)

 1 2.3

 2 3.2

 8 1.7

 9 2.2

 10 3.4

 12 2.0

 13 3.0 Test Example 2: [35S] GTP-γ S binding test

Human type H3 receptor membrane preparation (protein 7.5 H g / 100 1), 30 M GDP, 100 MR (−) a methylhistamine, and a test compound were reacted at room temperature for 30 minutes. After the reaction was completed, [ ³ ¾] GTP-γ-S (0.2 nM) was further added, and the reaction was continued for 30 minutes. After completion of the reaction, the reaction mixture is suction filtered through a glass filter (GF / C), The glass filter was washed 3 times with 20 mM HEPES washing solution (pH 7.4) containing lOOmM sodium chloride and ImM magnesium chloride. After washing, the glass filter was dried, a scintillator was added, and the radioactivity on the filter was measured with a liquid scintillation counter.

[0183] R (-)-In the absence of α-methylhistamine, [ ³ ] GTP-γ- S binding amount is defined as non-specific binding, and R (-)-α-methylhistamine is present. The difference from the total binding obtained was defined as the specific [ ³ ] GTP-γ-S binding degree. Inhibition of constant concentrations of [ ³ ] GTP-γ-S (0.2nM) and R (—)-one α-methylhistamine (100 Μ) by reacting various concentrations of each test drug under the conditions described above A curve was obtained. From the inhibition curve, the test drug concentration (IC) at which [ ³⁵ S] GTP-γ-S binding was inhibited by 50% was determined. The results are shown in Table 2.

 50

 did.

[0184] [Table 2]

[ ³⁵ S] GTP S

 Example

Concealment G ₅₀ (nM)

 1 1.5

 2 0.9

 9 2.2

 10 0.8

[0185] Test Example 3: Social Recognition Test

SD male rats were used for the test. Adult rats were placed in a Perspex test box and acclimated for 30 minutes. Then, young rats were placed in the same test box, and the exploratory action time that mature rats showed to the juvenile rat for 5 minutes was measured (first exploratory action time). S niffing, grooming and closely following were measured as exploratory behavior. After a 5-minute search, mature and young rats were removed from the test box and returned to their home cages. After 90 minutes, adult rats were placed in the same test box as the first exploratory behavior and acclimated for 30 minutes. Then, the same young rats as in the first time were placed in the test box, and the exploratory behavior time that the adult rats showed to the young rats in 5 minutes was measured (second exploratory behavior time). 2 for the first search action time The ratio of the second search action time (second search time / first search action time) was used as an indicator of social recognition. The compound of the present invention was orally administered to adult rats immediately after the first exploratory behavior. The compounds of the present invention were dissolved in 0.03N hydrochloric acid solution and examined at 0.1, 0.3 and lmg / kg. As a result, the compound of Example 2 significantly decreased the second search time / first search action time at 0.3 and 1 mg / kg as compared with the solvent group, and showed a social cognitive enhancing action.

Industrial applicability

 According to the present invention, it has an H3 receptor antagonism and a disorder caused by the H3 receptor, such as dementia, Alzheimer's disease, attention deficit / hyperactivity disorder, schizophrenia, epilepsy, central convulsions, feeding A novel bihue useful for the prevention and treatment of disorders such as disability, obesity, diabetes, hyperlipidemia, sleep disorders, narcolepsy, sleep apnea syndrome, circadian rhythm disorders, depression, or allergic rhinitis It became possible to provide dill derivatives.

Claims

Claim Formula (la)  [Chemical 1]

{In formula (la) R ¹ is C-C alkyl (the C-C alkyl is C-C cyclic alkyl or hydroxy  1 6 1 6 3 8 Or C to C cyclic alkyl (the C to C cyclic alkyl is C to C).  3 8 3 8 1 Can be substituted with C alkyl or hydroxyl! /)  6 R represents a group represented by the following structural formula (I) or (Π), and R4 R ⁵  ,

N ¹ h  (I) (I ") R ² and R ³ are the same or different and each represents a hydrogen atom; C to C alkyl (the C to C alkyl  1 6 1 6 Is halogen; C to C cyclic alkyl; hydroxyl; C to C alkoxycarbonyl or  3 8 2 7 C-c cyclic alkyl (which may be substituted with carboxy)  3 8 3 8 Halogen; may be substituted with C to C alkyl or hydroxyl) or mono (CH)- 1 6 2 m A group represented by Ar or Or R ² and R ³ may be bonded together with adjacent nitrogen atoms, and may contain one or more nitrogen, oxygen, or sulfur atoms in addition to the nitrogen atoms in the ring. Member saturated heterocycles (the saturated heterocycles are halogen; C to C alkyl; C to C alkoxy or hydro  1 6 1 6 May be substituted with xyl), Ar is aryl (the aryl is halogen; C to C alkyl; C to C alkoxy or hydrogen)  1 6 1 6  Or heteroaryl (wherein the heteroaryl may be substituted with halogen; c-c alkyl; c-c alkoxy or hydroxyl), 1 6 1 6  m represents an integer of 0 to 2, R ⁴ represents a hydrogen atom or C to C alkyl,  1 6 R ⁵ is C-C alkyl (wherein the C-C alkyl is halogen; C-C cyclic alkyl; C  1 6 1 6 3 8 1 -C may be substituted with alkoxy or hydroxyl); C-C cyclic alkyl (the C  6 3 8 3 -C cyclic alkyl is halogen; c-c alkyl; c-c alkoxy or hydroxy 8 1 6 1 6  Aryl) (wherein the aryl is halogen; alkyl; c to c alcohol)  1 6 may be substituted with xoxy or hydroxyl) or heteroaryl (wherein the heteroaryl is halogen; alkyl; may be substituted with C to C alkoxy or hydroxyl);  1 6 R ⁴ and R ⁵ may be bonded together with an adjacent nitrogen atom and carbonyl carbon, and may contain one or more nitrogen, oxygen, or sulfur atoms in addition to the nitrogen atom in the ring. 5- to 7-membered saturated heterocycle (the saturated heterocycle is halogen; C-C alkyl; C-C  1 6 1 6 Lucoxy; may be substituted with hydroxyl or oxo! /, Or may be formed! /. } A biphenylamide derivative represented by the formula: or a pharmaceutically acceptable salt thereof.  [2] Formula (lb)  [Chemical 2]

In the formula (lb), R ¹ is C to C The C to C canorequinole may be substituted with a C to C cyclic alkyl, or C to C cyclic alkyl (the C to C cyclic alkyl is C to C  3 8 3 8 1 may be substituted with alkyl)  6 R ² and R ³ are the same or different and each represents a hydrogen atom or C-C alkyl,  1 6 Alternatively, R ² and R ³ are bonded together with an adjacent nitrogen atom, and the nitrogen is In addition to the elementary atom, it may contain one or more nitrogen, oxygen, or sulfur atoms. 4 7-membered saturated heterocycle (the saturated heterocycle may be substituted with CC alkyl or hydroxyl).  1 6  Form. }  Or a pharmaceutically acceptable salt thereof.  [3] The compound according to claim 1, selected from the following group.  1-Cyclopentyl- 4— {[4 '-(Pyrrolidine 1-ylcarboninole) Biphenyl 2-4 -Isopropyl 4- 4 {{[4'- (Pyrrolidine-Yellou 4 -Echinolei 4 1 {[4 '(Pyrrolidine-Ninole) Bihue Ninore 4-—Inole] o {[4'— (Pyrrolidine--: Nore

 1— (2 Methylcyclopentyl) 4— {[4 '-(Pyrrolidine mono-l-l ({4'-[(1-cyclobutylpiperidine- 1 4-yl) oxy] biphenyl- 1-4-yl} carbonyl) Piperidine-4 oar,  1 1 ({4 '1 [(1 cyclobutylpiperidine 4 yl) oxy] biphenyl 4 yl} carbonyl) 4-methylpiperazine,  4 1 ({4 '1 [(1 cyclobutylpiperidine 4 yl) oxy] biphenyl 4 yl} carboninole) morpholine,  1-Cyclobutyl 4- {{4 '-(Pyrrolidine 1-ylcarboninole) Biphenyl 2-4 4 '-[(1-4-inore) oxy] bihuenolei 4  1 Cyclobutyl 4 1 {[4 (Methylaminenore 4- -Cyclobutyl 4- {[4 '(Dimethylamino Carboninole) Bifuenil 4-Ginole] o Xi} piperidine,  1-cyclobutyl 1 4-— {[3, 1 (pyrrolidine 1-ylcarboninole) biphenyl 2-4 4— ({4 '[(1-Cyclopentylbiperidine 4-ynole) oxy] biphenyl 4-carbon} carbolinole) morpholine,  4- ({4 '-[(1-tert-butylbiperidine 4-inole) oxy] biphenyl 4-carbon} carbonole) morpholine,  4 ′ [(1-cyclobutylpiperidine 4-yl) oxy] N— (4 fluorobenzyl) biphenyl 4-carboxamide,  N- (4 Fluorobenzyl) 1 4 '1 {[1 1 (1-Methylethyl) piperidine-4 yl] oxy} biphenyl 4 carboxamide,  1 1 {4 '1 [(1 cyclobutylpiperidine 4 yl) oxy] biphenyl 4 yl} pi-lysine-2-one,  1 {4 '[(1-Cyclopentylbiperidine 4-ynole) oxy] biphenyl 4-yl} pyrrolidin-2-one,  1- (4 ′-{[1- (1-methylethyl) piperidine 4-yl] oxy} biphenyl 4-yl) pyrrolidine-2-one,  1- {4 '-[(1-tert-Butylbiperidine 4-inole) oxy] biphenyl 4-yl} pyrrolidin-2-one.  [4] A pharmaceutical comprising the biphenylamide derivative according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient. [5] The medicament of claim 4, which is a histamine H3 receptor antagonist.  [6] Dementia, Alzheimer's disease, attention deficit 'hyperactivity disorder, characterized in that it contains the biphenylamide derivative according to claim 1, 2 or 3 or a pharmaceutically acceptable salt thereof as an active ingredient. Schizophrenia, epilepsy, central convulsions, eating disorders, obesity, diabetes, hyperlipidemia, sleep disorders, narcolepsy, sleep apnea syndrome, circadian rhythm disorders, depression, or allergic rhinitis Preventive or therapeutic agent.