JP2020050656A - Pharmaceutical composed of 2,6-di-substituted pyridine derivative - Google Patents

Abstract

To provide a novel therapeutic agent of anxiety-related disorder symptoms having agonist activities on both of 5-HTreceptor and Dreceptor.SOLUTION: A pharmaceutical composition contains a pyridine derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof. [Ris an optionally substituted Calkyl, an optionally substituted Ccycloalkyl, or an optionally substituted 5-10 membered saturated or partially unsaturated heterocycle group; Ris a halogen atom, a cyano, a Calkyl optionally substituted with homogeneous or heterologous 1-3 halogen atoms, a Calkoxy optionally substituted with homogeneous or heterologous 1-3 halogen atoms, or an amino optionally substituted with homogeneous or heterologous 1-2 Calkyls; a bond containing a dashed line is a single bond or double bond].SELECTED DRAWING: None

Description

The present invention relates to a pharmaceutical composition comprising a 2,6-disubstituted pyridine derivative having an agonistic activity on both serotonin 5-HT _1A receptor and dopamine D ₄ receptor or a pharmaceutically acceptable salt thereof, and The present invention relates to a therapeutic agent for anxiety-related disorders, which comprises the derivative as an active ingredient.

Serotonin (5-hydroxytryptamine: 5-HT), which is known as one of the major neurotransmitters in the central nervous system, is known to be involved in various brain functions such as emotional reactions and cognitive functions. Serotonin 5-HT _1A receptor (hereinafter, 5-HT _1A receptor), which is one of the subtypes of 5-HT receptor, is highly expressed in cerebral cortex, hippocampus, raphe nucleus, amygdala, and the like. It is thought that overactivity of the amygdala is involved in the formation of anxiety and fear memory, and the 5-HT _1A agonist suppresses the activity of the amygdala by stimulating the 5-HT _1A receptor. It is considered that a neural circuit relating to fear is controlled in a suppressive manner (Non-Patent Document 1).

On the other hand, dopamine D ₄ receptor, which is one of subtypes of the dopamine receptor (hereinafter, D ₄ receptor) are also known to control the neural Anxiety-Fear formation. That, D ₄ receptors are highly expressed in medial prefrontal cortex, which is part of the cerebral cortex, while a mutual neural connections and amygdala also medial prefrontal cortex is the responsibility site of anxiety formed above since you are the activity of the amygdala is suppressed controlled by stimulating D ₄ receptor, that acts to control anxiety, fear has been suggested (non-Patent Document 2).

From the above pharmacological point of view, by simultaneously stimulating the 5-HT _1A receptor and the D ₄ receptor simultaneously and controlling the neural circuit functions involved in anxiety from multiple directions, it is stronger than existing 5-HT _1A agonists. It is expected to create drugs with a wide range of anxiolytic effects. However, drugs that selectively exhibit agonist activity at both of these two receptors are not specifically known.

Patent Document 1, pyridylpiperidine derivatives having agonistic against D ₄ receptor have been disclosed. Patent Document 2 discloses a pyridylpiperazine derivative useful as an anxiolytic, and the like.

International Publication No. WO 2014/192868 JP-A-59-29665

Psychopharmacology 2014, 231 (4), 623-36 Showa University Pharmaceutical Journal Vol.1 No.1 2010, pp.17-28

An object of the present invention has both agonist activity to both 5-HT _1A receptor and D ₄ receptors is to provide novel compounds useful as a symptom of a therapeutic agent for anxiety-related disorders.

The present inventors have conducted intensive studies to achieve the above object, and as a result, have found that a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof (hereinafter abbreviated as “the compound of the present invention” as necessary) sometimes.) is found that both the agonistic activity to both 5-HT _1A receptor and D ₄ receptors, and have completed the present invention.

［式中、Ｒ^１は、置換されていてもよいＣ_１−６アルキル、置換されていてもよいＣ_３−１０シクロアルキル、または置換されていてもよい５員〜１０員の飽和または部分不飽和のヘテロ環基を表し；
Ｒ^２は、ハロゲン原子、シアノ、同種または異種の１〜３個のハロゲン原子で置換されていてもよいＣ_１−６アルキル、同種または異種の１〜３個のハロゲン原子で置換されていてもよいＣ_１−６アルコキシ、または同種または異種の１〜２個のＣ_１−６アルキルで置換されていてもよいアミノを表し；
破線を含む結合は、単結合または二重結合を表す]で表される化合物またはその製薬学的に許容される塩を含有する医薬組成物。 That is, the present invention is as follows.
[Item 1] Equation (1):

[Wherein, R ¹ represents an optionally substituted C _1-6 alkyl, an optionally substituted C _3-10 cycloalkyl, or an optionally substituted 5- to 10-membered saturated or partially unsubstituted alkyl group. Represents a saturated heterocyclic group;
R ² is a halogen atom, cyano, a C _1-6 alkyl optionally substituted with the same or different 1 to 3 halogen atoms, or a C _1-6 alkyl optionally substituted with the same or different 1 to 3 halogen atoms. _{Represents a} good C _1-6 alkoxy, or amino optionally substituted by 1 to 2 same or different C _1-6 alkyl;
The bond containing a broken line represents a single bond or a double bond], or a pharmaceutically acceptable salt thereof.

[Item 2] R ¹ is
(1) a halogen atom, _{hydroxy, C 3-7} cycloalkyl, and _{C 1-6} 1 to 3 amino _{C 1-6} alkyl optionally substituted with a group of same or different selected from the group consisting of alkoxy ,
(2) a halogen atom, hydroxy, cyano, 1 to 3 halogen atoms or _{C 1-6} alkoxy optionally substituted by _{C 1-6} alkyl the same or different, the same or C1-6 alkyl heterologous is selected from the group consisting of amino which may optionally be substituted with one to two C _1-6 alkyl also a C _1-6 alkoxy, and same or different optionally substituted with atoms or C _1-6 alkoxy C _3-10 cycloalkyl which may be substituted with the same or different 1 to 4 groups, or (3) a halogen atom, hydroxy, cyano, 1 to 3 same or different halogen atoms or C _{1- 6} alkoxy optionally substituted by _{C 1-6} alkyl, optionally substituted with 1 to 3 halogen atoms or _{C 1-6} alkoxy the same or different _{C 1- 6} alkoxy and the same or different 1 to 4 groups selected from the group consisting of the same or different amino optionally substituted with 1 to 2 C _1-6 alkyl may be substituted. Item 4. The pharmaceutical composition according to item 1, which is a 5- to 10-membered saturated or partially unsaturated heterocyclic group.

[Claim 3] R ¹ is
(1) a halogen atom, and 1 to 4 same or different are selected from the group consisting of C _1-6 alkyl optionally substituted with 1-3 halogen atoms or C _1-6 alkoxy same or different _3-7 cycloalkyl optionally substituted with 3 groups, or (2) a halogen atom, and 1 to 3 identical or different halogen atoms or C _1-6 alkoxy optionally substituted with C _1-6 alkoxy Item 1 or 2 which is a 5- or 6-membered saturated or partially unsaturated heterocyclic group optionally substituted with 1 to 4 same or different groups selected from the group consisting of _1-6 alkyl A pharmaceutical composition according to claim 1.

[Item 4] R ¹ is C _3-7 cycloalkyl optionally substituted with 1 to 4 fluorines, or 5- or 6-membered saturated or unsubstituted 1 to 4 fluorines. Item 4. The pharmaceutical composition according to any one of Items 1 to 3, which is a partially unsaturated heterocyclic group.

[Item 5] Any one of Items ¹ to 4, wherein R ¹ is cyclohexyl optionally substituted with ¹ to 4 fluorines, or tetrahydropyranyl, tetrahydrofuryl, dihydropyranyl, or dihydrofuryl. A pharmaceutical composition according to claim 1.

[Item 6] The pharmaceutical composition according to any one of Items 1 to 5, wherein R ¹ is difluorocyclohexyl or tetrahydropyranyl.

[Item 7] The item according to any one of Items 1 to 6, wherein R ² is a halogen atom or C _1-6 alkyl optionally substituted with the same or different 1 to 3 halogen atoms. Pharmaceutical composition.

[Item 8] The pharmaceutical composition according to any one of Items 1 to 7, wherein R ² is C _1-4 alkyl _optionally substituted with 1 to 3 fluorines.

[Item 9] The pharmaceutical composition according to any one of Items 1 to 8, wherein the bond containing the broken line is a single bond.

[Item 10] The pharmaceutical composition according to item 1, wherein the compound represented by the formula (1) is selected from the following compounds:
4,4-difluoro-N- (2- {4- [6- (trifluoromethyl) pyridin-2-yl] piperidin-1-yl} ethyl) cyclohexanecarboxamide (Example 1);
N- {2- [4- (6-methylpyridin-2-yl) piperidin-1-yl] ethyl} -tetrahydro-2H-pyran-4-carboxamide (Example 8);
2,2-dimethyl-N- (2- {4- [6- (trifluoromethyl) pyridin-2-yl] piperidin-1-yl} ethyl) propanamide (Example 9), and N- (2- {4- [6- (Trifluoromethyl) pyridin-2-yl] piperidin-1-yl} ethyl) -tetrahydro-2H-pyran-4-carboxamide (Example 11).

[Item 11] The pharmaceutical composition according to item 1, wherein the compound represented by the formula (1) is selected from the following compounds:
4,4-difluoro-N- (2- {4- [6- (trifluoromethyl) pyridin-2-yl] piperidin-1-yl} ethyl) cyclohexanecarboxamide (Example 1);
N- {2- [4- (6-methylpyridin-2-yl) piperidin-1-yl] ethyl} -tetrahydro-2H-pyran-4-carboxamide (Example 8); and N- (2- {4 -[6- (Trifluoromethyl) pyridin-2-yl] piperidin-1-yl @ ethyl) -tetrahydro-2H-pyran-4-carboxamide (Example 11).

[Item 12] The pharmaceutical composition according to item 1, wherein the compound represented by the formula (1) is the following compound:
4,4-Difluoro-N- (2- {4- [6- (trifluoromethyl) pyridin-2-yl] piperidin-1-yl} ethyl) cyclohexanecarboxamide (Example 1).

[Item 13] The pharmaceutical composition according to item 1, wherein the compound represented by the formula (1) is the following compound:
N- {2- [4- (6-Methylpyridin-2-yl) piperidin-1-yl] ethyl} -tetrahydro-2H-pyran-4-carboxamide (Example 8).

[Item 14] The pharmaceutical composition according to item 1, wherein the compound represented by the formula (1) is the following compound:
2,2-Dimethyl-N- (2- {4- [6- (trifluoromethyl) pyridin-2-yl] piperidin-1-yl} ethyl) propanamide (Example 9).

[Item 15] The pharmaceutical composition according to item 1, wherein the compound represented by the formula (1) is the following compound:
N- (2- {4- [6- (trifluoromethyl) pyridin-2-yl] piperidin-1-yl} ethyl) -tetrahydro-2H-pyran-4-carboxamide (Example 11).

[Item 16] A drug containing the pharmaceutical composition according to any one of Items 1 to 15.

[Claim 17] A general anxiety disorder, major depression, obsessive-compulsive disorder, Parkinson's disease, Rett syndrome, attention-deficit / hyperactivity disorder, comprising the pharmaceutical composition according to any one of claims 1 to 15. A therapeutic agent for autism spectrum disorder or dementia.

[Item 18] General anxiety disorder, major depression, obsessive-compulsiveness, which comprises administering to a patient in need of treatment a therapeutically effective amount of the pharmaceutical composition according to any one of Items 1 to 15. A method for treating a disorder, Parkinson's disease, Rett syndrome, attention deficit hyperactivity disorder, autism spectrum disorder, or dementia.

[Item 19] Item 1 for producing a therapeutic agent for generalized anxiety disorder, major depression, obsessive-compulsive disorder, Parkinson's disease, Rett syndrome, attention deficit hyperactivity disorder, autism spectrum disorder, or dementia Use of the pharmaceutical composition according to any one of claims 15 to 15.

[Claim 20] For use in treating general anxiety disorder, major depression, obsessive-compulsive disorder, Parkinson's disease, Rett syndrome, attention deficit hyperactivity disorder, autism spectrum disorder, or dementia, The pharmaceutical composition according to any one of claims 15 to 15.

[Item 21] A combination of the pharmaceutical composition according to any one of Items 1 to 15 with at least one or more other drugs selected from drugs classified as anxiolytics or antidepressants. Pharmaceutical composition.

[Item 22] General anxiety disorder, major depression, obsessive-compulsive disorder, Parkinson's disease, Rett syndrome in combination with at least one or more other drugs selected from drugs classified as anxiolytics or antidepressants Item 16. The pharmaceutical composition according to any one of Items 1 to 15, for treating attention deficit hyperactivity disorder, autism spectrum disorder, or dementia.

[Item 23] The pharmaceutical composition according to item 21 or 22, wherein the anxiolytic is a selective serotonin reuptake inhibitor.

[Item 24] Item 23, wherein the selective serotonin reuptake inhibitor is at least one or more selected from the group consisting of sertraline, escitalopram, fluvoxamine, floxetine, paroxetine, and pharmaceutically acceptable salts thereof. A pharmaceutical composition according to claim 1.

[Item 25] The pharmaceutical composition according to any one of Items 21 to 24, wherein the antidepressant is a serotonin reuptake inhibitor.

[Claim 26] The serotonin reuptake inhibitor is at least selected from the group consisting of milnacipran, duloxetine, venlafaxine, amoxapine, clomipramine, nortriptyline, imipramine, vortioxetine, and a pharmaceutically acceptable salt thereof. Item 29. The pharmaceutical composition according to Item 25, which is one or more.

The present invention compounds have an agonistic activity to both _{5-HT 1A} receptor and _{D 4} receptors. Further, in a preferred embodiment, the metabolic stability is excellent, the elimination half-life (T1 / 2) in humans is long, and dopamine D ₂ receptor (hereinafter referred to as D ₂ receptor), which is another GPCR, and hERG channel. Weak inhibitory effect. Therefore, preferred compounds of the present invention are useful as therapeutic agents for anxiety-related disorders which have a long duration in humans and are highly safe.

FIG. 3 is a view showing the results of a contextual fear conditioning test (Test Example 6) of the compounds of Examples 1, 8 and 11. It is a figure which shows the result of the marble cover test (Test Example 7) of the compounds of Examples 1 and 11. It is a figure which shows the result of the marble cover test (Test Example 7) when the compound of Example 1 and escitalopram and the compound of Example 11 and escitalopram are used together. It is a figure which shows the result of the forced swimming test (Test Example 8) of the compound of Example 1 and 11. It is a figure which shows the result of the microdialysis test (Test example 9) of a compound in the case of using Example 11 and the compound of Example 11 and sertraline in combination.

Hereinafter, the present invention will be described in more detail. In this specification, the number of carbons in the definition of “substituent” may be described as, for example, “C _1-6 ”. Specifically, the notation “C _1-6 alkyl” has the same meaning as an alkyl group having 1 to 6 carbon atoms.

  "Halogen atoms" include fluorine, chlorine, bromine and iodine.

“C _1-6 alkyl” means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. Preferably, it is “C _1-4 alkyl”. Specific examples of “C _1-6 alkyl” include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, Examples thereof include 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl.

“C _3-10 cycloalkyl” means a 3- to 10-membered monocyclic or polycyclic cyclic saturated or partially unsaturated hydrocarbon group. Note that partially unsaturated refers to a state in which some of the bonds have become unsaturated bonds, and refers to a state in which a partially unsaturated aromatic ring has not been reached (hereinafter, "partially unsaturated" is synonymous). Preferably, a _{"C 3-7} cycloalkyl". Specific examples of “C _3-10 cycloalkyl” include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl and the like.

The “C _1-6 alkyl” portion of “C _1-6 alkoxy” has the same _{meaning as} the above “C _1-6 alkyl”. Preferably, it is " _C1-4 alkoxy". Specific examples of “C _1-6 alkoxy” include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.

（式中において環を横切る結合手は、「基」が該環における置換可能な位置で結合することを意味する）
更に好ましくは、式（１１）で表される基が挙げられる。 As the "5- to 10-membered saturated or partially unsaturated heterocyclic group", for example, a 5- to 10-membered member having 1 to 3 same or different atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom And monocyclic or polycyclic saturated or partially unsaturated heterocyclic groups. Specific examples include dihydropyranyl, tetrahydropyranyl, dihydrofuryl, tetrahydrofuryl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, azepanyl, morpholinyl, thiomorpholinyl and the like. The bond of the group may be on a carbon atom or a nitrogen atom constituting the ring.
Preferably, a 5- or 6-membered saturated heterocyclic group is used. More preferably, groups represented by the following formulas (11), (12), (13), and (14) can be mentioned.

(In the formula, a bond crossing a ring means that the “group” is bonded at a substitutable position in the ring.)
More preferably, a group represented by the formula (11) is exemplified.

Examples of the substituent in the “optionally substituted C _1-6 alkyl” include a halogen atom, hydroxy, C _3-7 cycloalkyl, and C _1-6 alkoxy, and preferably a fluorine atom. Can be

Examples of the substituent in the “optionally substituted C _3-10 cycloalkyl” and the “optionally substituted 5- to 10-membered saturated or partially unsaturated heterocyclic group” include, for example,
(A) a halogen atom,
(B) hydroxy,
(C) cyano,
(D) the same or 1 to 3 halogen atoms or _{C 1-6 C 1-6} alkyl optionally substituted by alkoxy heterologous
(E) the same or different 1 to 3 halogen atoms or _{C 1-6} alkoxy optionally substituted _{C 1-6} alkoxy, and one or two of (f) same or different _{C 1-6} Amino which may be substituted with alkyl is exemplified.
Preferably, a halogen atom, and the like, or 1 to 3 halogen atoms or C _1-6 C _1-6 alkyl optionally substituted by alkoxy heterogeneous; preferably, fluorine.

Among the compounds of the present invention represented by the formula (1), preferred examples of the bond containing a broken line, R ¹ and R ² are as follows, but the technical scope of the present invention is limited to the scope of the compounds listed below. It is not something to be done.

  The bond including the broken line is preferably a single bond.

Preferably, R ¹ is
(1) a halogen atom, and 1 to 4 same or different are selected from the group consisting of C _1-6 alkyl optionally substituted with 1-3 halogen atoms or C _1-6 alkoxy same or different _3-7 cycloalkyl optionally substituted with 3 groups, and (2) a halogen atom, and 1 to 3 halogen atoms of the same or different kind or a C _1-6 alkoxy optionally substituted with C _1-6 alkoxy _Examples thereof include a 5- or 6-membered saturated or partially unsaturated heterocyclic group which may be substituted with the same or different 1 to 4 groups selected from the group consisting of _1-6 alkyl.

More preferably, R ¹ is C _3-7 cycloalkyl optionally substituted with 1 to 4 fluorines, and 5 or 6-membered saturated or partial optionally substituted with 1 to 4 fluorines. And unsaturated heterocyclic groups. More preferably, cyclohexyl, tetrahydropyranyl, tetrahydrofuryl, dihydropyranyl, and dihydrofuryl which may be substituted with 1 to 4 fluorines are exemplified. More preferably, difluorocyclohexyl and tetrahydropyranyl are mentioned. More preferably, 4,4-difluorocyclohexyl and 4-tetrahydropyranyl are mentioned.

Preferred examples of R ² include a halogen atom and C _1-6 alkyl which may be substituted with the same or different one to three halogen atoms. More preferably, it is C _1-4 alkyl optionally substituted with 1 to 3 fluorines; still more preferably, methyl which may be substituted with 1 to 3 fluorines.

  The compound represented by the formula (1) may exist as a tautomer. Therefore, the compound of the present invention also includes tautomers of the compound represented by the formula (1).

  The compound represented by the formula (1) may have at least one asymmetric carbon atom. Therefore, the compounds of the present invention include not only racemic forms of the compound represented by the formula (1) but also optically active forms of these compounds. When the compound represented by the formula (1) has two or more asymmetric carbon atoms, stereoisomers may occur. Accordingly, the compounds of the present invention also include stereoisomers of these compounds and mixtures thereof.

Further, a deuterium conversion product obtained by converting one or two or more ¹ H of the compound represented by the formula (1) into ² H (D) is also included in the compound represented by the formula (1). .

Since the compound represented by the formula (1) and a pharmaceutically acceptable salt thereof may exist in the form of a hydrate and / or a solvate, these hydrates or ethanol solvates may be used. And the like are also included in the compounds of the present invention. Further, the compound of the present invention includes all forms of crystalline forms.
As the pharmaceutically acceptable salt, when the compound represented by the formula (1) has an acidic group, for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth salts such as calcium salt and magnesium salt Metal salts; inorganic metal salts such as zinc salts; and organic base salts such as triethylamine, triethanolamine, trihydroxymethylaminomethane, and amino acids.
When the compound represented by the formula (1) has a basic group, for example, inorganic salts such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate; and acetate, propionate Organic such as succinate, lactate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate, benzenesulfonate, ascorbate, etc. Acid salts and the like.

  Hereinafter, the production method of the compound of the present invention will be described with reference to examples, but the present invention is not limited to these.

Production Method The compound of the present invention is synthesized by a combination of the following production methods and known synthesis methods.
Each of the compounds in the reaction formulas may form a salt, and examples of the salt include those similar to the salt of the compound of the formula (1) exemplified in the present specification. These reactions are merely examples, and the compounds of the present invention can be produced by other methods as appropriate based on the knowledge of those skilled in organic synthesis.

  In each of the production methods described below, even when the use of a protective group is not specifically specified, if a functional group requiring protection is present, the functional group is protected as necessary, After completion of the reaction or after performing a series of reactions, the desired product may be obtained by deprotection.

Examples of the protecting group include those described in the literature (TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 3rd Ed., John Wiley and Sons, Inc., New York, etc., 99, etc.). The protecting group for the amino group includes, for example, benzyloxycarbonyl, tert-butoxycarbonyl, acetyl, benzyl and the like. Can be, for example, trialkylsilyl, acetyl, benzyl and the like, respectively.
The introduction and elimination of the protecting group may be carried out by a method commonly used in organic synthetic chemistry (for example, TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 3rd Ed., John Wiley and Sunderland). , Inc., New York (1999)) or a method analogous thereto.

（式中、Ｒ^１およびＲ^２は、前記項１と同義であり；破線を含む結合は、単結合または二重結合を表し；ＬＧは脱離基（例えば、ヨウ素原子、臭素原子、塩素原子、置換スルホニル（例えば、メタンスルホニル、ｐ-トルエンスルホニル等）等）を表し；Ｐｒｏはアミノ基の保護基を表す。） Manufacturing method 1
The compound represented by the formula (1) is produced, for example, by the following method.

(Wherein R ¹ and R ² are as defined in the above item 1; a bond containing a broken line represents a single bond or a double bond; LG is a leaving group (for example, an iodine atom, a bromine atom, a chlorine atom , Substituted sulfonyl (eg, methanesulfonyl, p-toluenesulfonyl, etc.); Pro represents a protecting group for an amino group.)

Step 1-1: Step of producing compound (1-3) Compound (1-3) is prepared by compound (1-1) and compound (1-2) in a suitable inert solvent in the presence or absence of a base. And is produced by reacting This step may be performed in the presence of a base, if necessary, or in the presence of a phase transfer catalyst, if necessary. Reaction temperatures are usually in the range from about -20 ° C to the boiling point of the solvent used. The reaction time varies depending on the conditions such as the reaction temperature, the condensing agent used, the raw materials, and the solvent, but is usually from 10 minutes to 48 hours.
As the compound (1-1), a commercially available compound or a compound produced by a known method (for example, International Publication WO 2014/192868) can be used.
As the compound (1-2), a commercially available compound or a compound produced by a known method (for example, J. Org. Chem. 1988, 53, 2226-2232) can be used.

Examples of the base include organic bases such as triethylamine, diisopropylethylamine and pyridine; potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium phosphate, phosphorus Inorganic bases such as sodium dihydrogen acid, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide and sodium hydride; and metal alkoxides such as sodium methoxide and potassium tert-butoxide.
Examples of the phase transfer catalyst include tetrabutylammonium hydrogen sulfate.
Examples of the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF) and 1,4-dioxane; methanol and ethanol And lower alcohols such as 2-propanol; aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2-pyrrolidinone, and dimethyl sulfoxide; and mixed solvents thereof.

Step 1-2: Production Step of Compound (1-4) Compound (1-4) is prepared by converting the amino-protecting group Pro of compound (1-3) by a known method (for example, Protective Group in Organic Synthesis No. 3). (Theodora W. Green, Peter GM Wuts, published by John Wiley & Sons Inc., 1999).

Step 1-3: Step of producing compound (1) Compound (1) is prepared by reacting compound (1-4) with a carboxylic acid represented by formula (1-5) in an inert solvent in the presence of a condensing agent. It is produced by reacting. The reaction may be further performed in the presence of a base. Reaction temperatures are usually in the range from about -20 ° C to the boiling point of the solvent used. The reaction time varies depending on the conditions such as the reaction temperature, the condensing agent used, the raw materials, and the solvent, but is usually from 10 minutes to 48 hours.
Compound (1) is also produced by reacting compound (1-4) with an acid halide or acid anhydride derived from compound (1-5) in an inert solvent in the presence of a base. You. Reaction temperatures are usually in the range from about -20 ° C to the boiling point of the solvent used. The reaction time varies depending on the conditions such as the reaction temperature, the condensing agent used, the raw materials, and the solvent, but is usually from 10 minutes to 48 hours.

Specific examples of the condensing agent include, for example, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide (WSC), benzotriazol-1-yl-tris ( Dimethylamino) phosphonium hexafluorophosphide salt (BOP), diphenylphosphonyl azide (DPPA), N, N-carbonyldiimidazole (CDI), benzotriazol-1-yl-N, N, N ', N'- Tetramethyluronium hexafluorophosphide (HBTU) and the like.
If necessary, for example, N-hydroxysuccinimide (HOSu), 1-hydroxybenzotriazole (HOBt), 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOOBt) and the like May be added.

  Examples of the base include organic bases such as triethylamine, diisopropylethylamine and pyridine; potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium phosphate, phosphorus Inorganic bases such as sodium dihydrogen acid, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide and sodium hydride; and metal alkoxides such as sodium methoxide and potassium tert-butoxide.

  Examples of the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF) and 1,4-dioxane; acetonitrile, acetone; Aprotic polar solvents such as methyl ethyl ketone, dimethylformamide, N-methyl-2-pyrrolidinone, and dimethyl sulfoxide; basic solvents such as pyridine; and mixed solvents thereof.

（式中、Ｒ^２は、前記項１と同義である。） Manufacturing method 2
The compound represented by the formula (1-1b) is produced from the compound represented by the formula (1-1a) by the following method.

(In the formula, R ² has the same meaning as in the above item 1.)

Step 2: Step of producing compound (1-1b) Compound (1-1b) is produced by subjecting compound (1-1a) to catalytic reduction in a suitable inert solvent under normal pressure or a hydrogen atmosphere under pressure. . Specific examples of the catalyst used for the reduction reaction include a palladium-based catalyst such as palladium-carbon, a rhodium-based catalyst such as rhodium-carbon, a platinum-based catalyst such as platinum-carbon, and a ruthenium-based catalyst such as ruthenium-carbon. . The reaction temperature is usually in the range of 0 ° C to 50 ° C. The reaction time varies depending on the conditions such as the reaction temperature, the catalyst used, the starting materials, and the solvent, but is usually from 10 minutes to 48 hours.

Specific examples of the inert solvent include, for example, ester solvents such as ethyl acetate; aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane. Solvents: alcoholic solvents such as methanol, ethanol, and 2-propanol; aprotic polar solvents such as dimethylformamide, N-methyl-2-pyrrolidinone, and dimethylsulfoxide; and mixed solvents thereof.
Other compounds represented by the formula (1-1) are commercially available, or can be produced by a known production method or a production method analogous thereto.

（式中、Ｒ^２は、前記項１と同義であり；Ｐｒｏはアミノ基の保護基を表す。） Manufacturing method 3
The compound represented by the formula (1-3b) is produced from the compound represented by the formula (1-3a) by the following method.

(Wherein, R ² has the same meaning as in the above item 1; Pro represents an amino-protecting group.)

Step 3: Production Step of Compound (1-3b) Compound (1-3b) is produced by catalytic reduction of compound (1-3a) in a suitable inert solvent under atmospheric pressure or a hydrogen atmosphere under pressure. . Specific examples of the catalyst used for the reduction reaction include a palladium-based catalyst such as palladium-carbon, a rhodium-based catalyst such as rhodium-carbon, a platinum-based catalyst such as platinum-carbon, and a ruthenium-based catalyst such as ruthenium-carbon. . The reaction temperature is usually in the range of 0 ° C to 50 ° C. The reaction time varies depending on the conditions such as the reaction temperature, the catalyst used, the starting materials, and the solvent, but is usually from 10 minutes to 48 hours.

  Specific examples of the inert solvent include, for example, ester solvents such as ethyl acetate; aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane. Solvents: alcoholic solvents such as methanol, ethanol and 2-propanol; aprotic polar solvents such as dimethylformamide, N-methyl-2-pyrrolidinone and dimethylsulfoxide; and mixed solvents thereof.

  The compound of the present invention having a desired substituent at a desired position can be obtained by appropriately combining the above-mentioned production methods. Isolation and purification of intermediates and products in the above production method can be performed by appropriately combining methods used in ordinary organic synthesis, for example, filtration, extraction, washing, drying, concentration, crystallization, various types of chromatography, and the like. it can. In addition, the intermediate can be subjected to the next reaction without particular purification.

  Depending on the reaction conditions and the like, some of the starting compounds or intermediates in the above-mentioned production methods may exist in the form of a salt such as a hydrochloride, but they can be used as they are or in a free form. When the raw material compound or intermediate is obtained in the form of a salt and the raw material compound or intermediate is to be used or obtained in free form, these are dissolved or suspended in a suitable solvent, and a base such as an aqueous solution of sodium hydrogen carbonate is used. It can be converted to a free form by neutralizing with, for example.

Some of the compounds represented by the formula (1) or pharmaceutically acceptable salts thereof include tautomers such as keto enols, isomers such as positional isomers, geometric isomers and optical isomers. May exist, but all possible isomers, including these, and mixtures of the isomers in any ratio are included in the present invention.
In addition, the optical isomer can be separated by performing a known separation step such as a method using an optically active column or a fractional crystallization method in an appropriate step of the above-mentioned production method. Further, an optically active substance can be used as a starting material.

  When it is desired to obtain a salt of the compound represented by the formula (1), when a salt of the compound represented by the formula (1) is obtained, the compound may be purified as it is. When it is obtained in a free form, the compound represented by the formula (1) may be dissolved or suspended in a suitable solvent, and an acid or a base may be added to form a salt. The compound (1) or a pharmaceutically acceptable salt thereof may exist in the form of a solvate with water or various solvents, and such solvates are also included in the present invention.

The 5-HT _1A receptor is highly expressed in the cerebral cortex, hippocampus, raphe nucleus, amygdala and the like. It is thought that overactivity of the amygdala is involved in the formation of anxiety and fear memory, and the 5-HT _1A agonist suppresses the activity of the amygdala by stimulating the 5-HT _1A receptor. It is considered that a neural circuit relating to fear is controlled in a suppressive manner (Non-Patent Document 1). For example, the 5-HT _1A agonists buspirone and tandospirone are used as therapeutics for generalized anxiety disorder (GAD). In addition, a 5-HT _1A agonist is expected to be a therapeutic agent for central nervous diseases different from GAD, for example, major depression, obsessive-compulsive disorder, Parkinson's disease, Rett syndrome, dementia, and the like.

As a treatment for GAD, it is particularly suitably used for improving mental and / or physical symptoms in GAD.
As a treatment for major depression, it is particularly suitably used for improving mental and / or physical symptoms in major depression.
As a treatment for obsessive-compulsive disorder, it is particularly preferably used for improving obsessive-compulsive behavior and / or obsession in obsessive-compulsive disorder.
As a treatment for Parkinson's disease, it is particularly suitably used for ameliorating L-DOPA-induced dyskinesia in Parkinson's disease.
As a treatment for Rett's syndrome, it is particularly suitably used for improving apnea symptoms in Rett's syndrome.
Specific examples of dementia include, for example, Alzheimer's dementia and Lewy body dementia, and are particularly suitable for treating peripheral symptoms (eg, behavioral disorders associated with Alzheimer's dementia) in these dementias. Used.

D ₄ receptors are known to control the neural Anxiety-Fear formation. By stimulating the D ₄ receptor with high expression in medial prefrontal cortex, the activity of the amygdala since it is expected that it is possible to control suppression manner, D ₄ agonists, 5-HT _1A agonists Similarly, anxiolytic It can be expected to show action.
From the above pharmacological point of view, by simultaneously stimulating the 5-HT _1A receptor and the D ₄ receptor simultaneously and controlling the neural circuit functions involved in anxiety from multiple directions, it is stronger than the existing 5-HT _1A agonist. It is expected to create drugs with a wide range of anxiolytic effects.

Further, the present invention compounds have an agonistic against _{D 4} receptor, attention deficit hyperactivity disorder (ADHD: met ADHD in the diagnosis of mental disorders and Statistical Manual Fifth Edition (DSM-5) Therefore, in the conventional DSM-IV, a diagnosis name classified as attention deficit hyperactivity disorder), and a central nervous disease showing symptoms similar to ADHD, for example, autism spectrum disorder (diagnosis and diagnosis of mental disorders) Autism spectrum disorders in the Statistical Guidebook, 5th Edition (DSM-5), classified as Autism, Asperger's Syndrome, Atypical Pervasive Developmental Disorder, and Pediatric Disintegrative Disorder in conventional DSM-IV Is expected to be a therapeutic drug for schizophrenia, mood disorder, cognitive dysfunction, etc. showing ADHD-like symptoms.

As a treatment for ADHD, in particular, it is suitably used for ADHD in which the main symptoms are attention deficit (inattention), hyperactivity (hyperactivity), and impulsivity (impulsivity).
Treatment of autism spectrum disorders includes, among other things, persistent deficits in social communication and interaction, and autism spectrum disorders whose main symptoms are limited repetitive behaviors, interests, and activities. It is preferably used for obstacles.

The present invention compounds have an agonistic activity against _{5-HT 1A} receptor and _{D 4} receptors. Specifically, the present invention compounds exhibit Emax value representing the maximum agonist activity to _{5-HT 1A} receptor and _{D 4} receptor than 50%, or _{The EC 50} values representing the agonist activity of not more than 100 nmol / L (Test Example 1).

The present invention compounds exhibit strong binding affinity for _{5-HT 1A} receptor and _{D 4} receptor (Test Example 2). In a preferred embodiment of the present invention, 5-HT _1A binding affinity to the receptor and D ₄ receptor, a strong 100-fold or more compared to the binding affinity of the D ₂ receptors, due to D ₂ antagonism then in blood levels of side effects such as extrapyramidal symptoms and hyperprolactinemia is not expressed contemplated, it can exhibit the pharmacological action based on the 5-HT _1A and D ₄ receptor agonist properties.

  In a preferred embodiment of the compound of the present invention, the concentration of hERG channel inhibition, which is an index of arrhythmia caused by QT prolongation, and the expected concentration of pharmacological action are different (Test Example 5). The effect can be expected to be small.

The elimination half-life (T1 / 2) of a drug is a factor that determines the number of doses to maintain its effect. Multiple doses per day associated with a short T1 / 2 may lead to forgetful or leftover doses and hinder proper drug treatment. In addition, there is a concern that an increase in the number of times of administration may increase the incidence of side effects, or reduce tolerability due to restriction to high-dose administration. In view of the above, it is expected that achievement of a long T1 / 2 will lead to the creation of a long-acting drug of low concern, which will lead to a reduced burden on patients taking the drug.
In a preferred embodiment of the compound of the present invention, since the predicted human elimination half-life (T1 / 2) is as long as 8 hours or more (Test Example 4), the drug effect has a long lasting effect in a human body, and Is expected to improve drug adherence and be highly tolerated when administered.

  The compound of the present invention can be administered orally or parenterally. When administered orally, it can be administered in a commonly used dosage form. Parenterally, it can be administered in the form of topical administration, injection, transdermal, nasal, and the like. Examples of the oral preparation or rectal preparation include capsules, tablets, pills, powders, cachets, suppositories, and liquid preparations. Injections include, for example, sterile solutions or suspensions. Examples of the topical administration agent include creams, ointments, lotions, and transdermal agents (ordinary patches and matrixes).

The above dosage forms are formulated in a conventional manner together with pharmaceutically acceptable excipients and additives. Pharmaceutically acceptable excipients, additives include carriers, binders, flavors, buffers, thickeners, coloring agents, stabilizers, emulsifiers, dispersants, suspending agents, preservatives, and the like. Can be
Pharmaceutically acceptable carriers include, for example, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter And the like. Capsules can be formulated by incorporating a compound of the present invention together with a pharmaceutically acceptable carrier. The compounds of the present invention can be mixed with pharmaceutically acceptable excipients or placed in a capsule without excipients. Cachets can be prepared in a similar manner.

  Solutions for injection include solutions, suspensions, emulsions and the like. For example, an aqueous solution, a water-propylene glycol solution and the like can be mentioned. Solutions can also be prepared in the form of a solution of polyethylene glycol or / and propylene glycol, which may contain water. A liquid preparation suitable for oral administration can be produced by adding the compound of the present invention to water and adding a coloring agent, a flavor, a stabilizer, a sweetener, a solubilizer, a thickener and the like as necessary. Also, liquid preparations suitable for oral administration can be prepared by adding the compound of the present invention to water together with a dispersant to make it viscous. Examples of the thickener include a pharmaceutically acceptable natural or synthetic gum, resin, methylcellulose, sodium carboxymethylcellulose, or a known suspending agent.

  The dose varies depending on the individual compound and on the disease, age, weight, sex, symptom, administration route and the like of the patient. Usually, the compound of the present invention is administered to an adult (body weight 50 kg) in an amount of 0.1 to 1000 mg. / Day, preferably 0.1-300 mg / day, once or twice or three times a day. It can also be administered once every several days to several weeks.

The compound of the present invention can be used in combination with other drugs for the purpose of enhancing its effects and / or reducing side effects. For example, it can be used in combination with an anxiolytic such as a selective serotonin reuptake inhibitor. Further, for example, it can be used in combination with an antidepressant such as a serotonin reuptake inhibitor.
Examples of the selective serotonin reuptake inhibitor include sertraline, escitalopram, fluvoxamine, floxetine, paroxetine and the like. Serotonin reuptake inhibitors include, for example, milnacipran, duloxetine, venlafaxine, amoxapine, clomipramine, nortriptyline, imipramine, vortioxetine and the like. Hereinafter, drugs that can be used in combination with the compound of the present invention are abbreviated as concomitant drugs.

  The administration period of the compound of the present invention and the concomitant drug is not limited, and they may be administered to a subject at the same time or may be administered at a time interval. Further, the compound of the present invention and a concomitant drug may be used as a mixture. The dose of the concomitant drug can be appropriately determined based on the clinically used dose. The compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, the concomitant drug may be used in an amount of 0.01 to 100 parts by weight per 1 part by weight of the compound of the present invention. In addition, for the purpose of suppressing the side effects, it can be used in combination with a drug (concomitant drug) such as an antiemetic, a sleep inducer, and an anticonvulsant.

Hereinafter, the present invention will be described more specifically with reference examples, examples, and test examples, but the present invention is not limited to the examples. The compound names shown in the following Reference Examples and Examples do not always follow IUPAC nomenclature. Abbreviations may be used for simplification of the description, but these abbreviations have the same meanings as described above.
The following abbreviations may be used in this specification.
The following abbreviations are used in the NMR data of Reference Examples and Examples.
Me: methyl DMF: N, N-dimethylformamide THF: tetrahydrofuran
tert: tertiary CDCl _3: deuterated chloroform DMSO-d _6: deuterated dimethyl sulfoxide

  The proton nuclear magnetic resonance spectrum was measured using an FT-NMR measuring device (300 MHz or 400 MHz) manufactured by JEOL. Chemical shift values are described in terms of δ values (ppm). As symbols used for NMR, s is a singlet, d is a doublet, dd is a doublet, dt is a doublet, t is a triplet, q is a quadruple, and m is a multiplet. The line, br means broad, brs means wide singlet, and J means coupling constant.

参考例４の化合物（６００ｍｇ）、トリエチルアミン（１．３１ｍＬ）、４，４−ジフルオロシクロヘキサンカルボン酸（２５７ｍｇ）およびＤＭＦ（５．０ｍＬ）の混合物にＯ−（ベンゾトリアゾール−1−イル）−Ｎ，Ｎ，Ｎ’，Ｎ’−テトラメチルウロニウムヘキサフルオロホスファート（６５４ｍｇ）を加えた。室温で８時間撹拌後、反応混合物に水を加え、酢酸エチルで抽出した。有機層を硫酸ナトリウムで乾燥、ろ過後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）にて精製し、表題化合物（４０６ｍｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 1.48-2.06 (10H, m), 2.09-2.30 (5H, m), 2.54 (2H, t, J = 6.0 Hz), 2.77-2.88 (1H, m), 2.97-3.08 (2H, m), 3.38 (2H, dt, J = 5.5, 5.5 Hz), 6.22 (1H, brs), 7.37 (1H, d, J = 7.8 Hz), 7.52 (1H, d, J = 7.8 Hz), 7.80 (1H, dd, J = 7.8, 7.8 Hz). Example 1
4,4-difluoro-N- (2- {4- [6- (trifluoromethyl) pyridin-2-yl] piperidin-1-yl} ethyl) cyclohexanecarboxamide

A mixture of the compound of Reference Example 4 (600 mg), triethylamine (1.31 mL), 4,4-difluorocyclohexanecarboxylic acid (257 mg) and DMF (5.0 mL) was added to a mixture of O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (654 mg) was added. After stirring at room temperature for 8 hours, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (406 mg).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.48-2.06 (10H, m), 2.09-2.30 (5H, m), 2.54 (2H, t, J = 6.0 Hz), 2.77-2.88 (1H, m ), 2.97-3.08 (2H, m), 3.38 (2H, dt, J = 5.5, 5.5 Hz), 6.22 (1H, brs), 7.37 (1H, d, J = 7.8 Hz), 7.52 (1H, d, J = 7.8 Hz), 7.80 (1H, dd, J = 7.8, 7.8 Hz).

Examples 2 to 7
According to the method described in Example 1, the compounds of Examples 2 to 7 were obtained from the corresponding compounds of Reference Examples.

参考例６の化合物（５００ｍｇ）、トリエチルアミン（１．２７ｍＬ）およびジクロロメタン（５．０ｍＬ）の混合物に、氷冷下テトラヒドロ−２Ｈ−ピラン−４−カルボニルクロライド（０．２０７ｍＬ）を加えた。室温で１２時間撹拌後、反応混合物に水を加え、クロロホルムで抽出した。有機層を硫酸ナトリウムで乾燥、ろ過後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）にて精製し、表題化合物（４５１ｍｇ）を得た。
¹H-NMR (300 MHz, CDCl₃) δ: 1.71-1.90 (6H, m), 1.91-2.01 (2H, m), 2.08-2.19 (2H, m), 2.31-2.43 (1H, m), 2.51 (2H, t, J = 6.4 Hz), 2.54 (3H, s), 2.63-2.76 (1H, m), 2.95-3.04 (2H, m), 3.33-3.50 (4H, m), 3.99-4.07 (2H, m), 6.20 (1H, brs), 6.98 (1H, d, J = 7.7 Hz), 6.99 (1H, d, J = 7.7 Hz), 7.52 (1H, dd, J = 7.7, 7.7 Hz). Example 8
N- {2- [4- (6-methylpyridin-2-yl) piperidin-1-yl] ethyl} -tetrahydro-2H-pyran-4-carboxamide

To a mixture of the compound of Reference Example 6 (500 mg), triethylamine (1.27 mL) and dichloromethane (5.0 mL), tetrahydro-2H-pyran-4-carbonyl chloride (0.207 mL) was added under ice-cooling. After stirring at room temperature for 12 hours, water was added to the reaction mixture, and extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (451 mg).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.71-1.90 (6H, m), 1.91-2.01 (2H, m), 2.08-2.19 (2H, m), 2.31-2.43 (1H, m), 2.51 (2H, t, J = 6.4 Hz), 2.54 (3H, s), 2.63-2.76 (1H, m), 2.95-3.04 (2H, m), 3.33-3.50 (4H, m), 3.99-4.07 (2H , m), 6.20 (1H, brs), 6.98 (1H, d, J = 7.7 Hz), 6.99 (1H, d, J = 7.7 Hz), 7.52 (1H, dd, J = 7.7, 7.7 Hz).

Examples 9 to 10
According to the method described in Example 8, the compounds of Examples 9 to 10 were obtained from the corresponding compounds of Reference Examples.

参考例４の化合物（３５０ｍｇ）、トリエチルアミン（０．７６５ｍＬ）およびジクロロメタン（３．０ｍＬ）の混合物に、氷冷下テトラヒドロ−２Ｈ−ピラン−４−カルボニルクロライド（０．１２４ｍＬ）を加えた。室温で１２時間撹拌後、反応混合物に水を加え、クロロホルムで抽出した。有機層を硫酸ナトリウムで乾燥、ろ過後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）にて精製し、表題化合物（２３２ｍｇ）を得た。
¹H-NMR (300 MHz, CDCl₃) δ: 1.71-2.02 (8H, m), 2.08-2.21 (2H, m), 2.32-2.44 (1H, m), 2.52 (2H, t, J = 6.0 Hz), 2.75-2.88 (1H, m), 2.95-3.05 (2H, m), 3.33-3.50 (4H, m), 3.99-4.08 (2H, m), 6.15 (1H, brs), 7.37 (1H, d, J = 8.1 Hz), 7.52 (1H, d, J = 7.7 Hz), 7.79 (1H, dd, J = 7.9, 7.9 Hz). Example 11
N- (2- {4- [6- (trifluoromethyl) pyridin-2-yl] piperidin-1-yl} ethyl) -tetrahydro-2H-pyran-4-carboxamide

Tetrahydro-2H-pyran-4-carbonyl chloride (0.124 mL) was added to a mixture of the compound of Reference Example 4 (350 mg), triethylamine (0.765 mL), and dichloromethane (3.0 mL) under ice-cooling. After stirring at room temperature for 12 hours, water was added to the reaction mixture, and extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (232 mg).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.71-2.02 (8H, m), 2.08-2.21 (2H, m), 2.32-2.44 (1H, m), 2.52 (2H, t, J = 6.0 Hz ), 2.75-2.88 (1H, m), 2.95-3.05 (2H, m), 3.33-3.50 (4H, m), 3.99-4.08 (2H, m), 6.15 (1H, brs), 7.37 (1H, d , J = 8.1 Hz), 7.52 (1H, d, J = 7.7 Hz), 7.79 (1H, dd, J = 7.9, 7.9 Hz).

４，４−ジフルオロシクロヘキサン−１−カルボキシリックアシッド（４２．０ ｍｇ）、トリエチルアミン（０．１７８ ｍＬ）、１−［ビス（ジメチルアミノ）メチレン］−１Ｈ−ベンゾトリアゾリウム−３−オキシド ヘキサフルオロホスファート（８９．０ ｍｇ）とＮ，Ｎ−ジメチルホルムアミド（１．０ ｍＬ）の混合物を室温で２０分間攪拌した後、参考例７の化合物（８１．２ ｍｇ）を加えた。室温で２４時間攪拌後、反応混合物に水（３０ ｍＬ）を加え、酢酸エチル（３０ ｍＬ×２回）で抽出し、１ ｍｏｌ/Ｌ水酸化ナトリウム水溶液（１０ ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥しろ過して濃縮した。残渣を分取薄層カラムクロマトグラフィー（ジクロロメタン／メタノール）で分離精製し、表題化合物（４０ ｍｇ）を得た。
¹H-NMR (300 MHz, DMSO-d₆) δ: 1.50-1.90 (6H, m), 2.01 (2H, t, J = 11.3 Hz), 2.18-2.34 (2H, m), 2.50-2.58 (3H, m), 2.66 (2H, t, J = 5.6 Hz), 3.15-3.27 (4H, m), 6.81 (1H, s), 7.73 (1H, d, J = 7.6 Hz), 7.79 (1H, t, J = 5.6 Hz), 7.85 (1H, d, J = 8.1 Hz), 8.04 (1H, dd, J = 7.9, 7.9 Hz). Example 12
4,4-difluoro-N- {2- [6- (trifluoromethyl) -3 ', 6'-dihydro [2,4'-bipyridine] -1'(2'H) -yl] ethyl} -cyclohexane -1-carboxamide

4,4-difluorocyclohexane-1-carboxylic acid (42.0 mg), triethylamine (0.178 mL), 1- [bis (dimethylamino) methylene] -1H-benzotriazolium-3-oxide hexafluoro After a mixture of phosphate (89.0 mg) and N, N-dimethylformamide (1.0 mL) was stirred at room temperature for 20 minutes, the compound of Reference Example 7 (81.2 mg) was added. After stirring at room temperature for 24 hours, water (30 mL) was added to the reaction mixture, extracted with ethyl acetate (30 mL x 2), washed with a 1 mol / L aqueous sodium hydroxide solution (10 mL), and dried over anhydrous magnesium sulfate. , Filtered and concentrated. The residue was separated and purified by preparative thin-layer column chromatography (dichloromethane / methanol) to obtain the title compound (40 mg).
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.50-1.90 (6H, m), 2.01 (2H, t, J = 11.3 Hz), 2.18-2.34 (2H, m), 2.50-2.58 (3H , m), 2.66 (2H, t, J = 5.6 Hz), 3.15-3.27 (4H, m), 6.81 (1H, s), 7.73 (1H, d, J = 7.6 Hz), 7.79 (1H, t, J = 5.6 Hz), 7.85 (1H, d, J = 8.1 Hz), 8.04 (1H, dd, J = 7.9, 7.9 Hz).

Examples 13 to 15
According to the method described in Example 12, the compounds of Examples 13 to 15 were obtained from the corresponding compounds of Reference Examples.

オキサン−３−カルボキシリックアシッド（４１．０ ｍｇ）、トリエチルアミン（０．２６３ ｍＬ）とアセトニトリル（２．０ ｍＬ）の混合物に５０％プロピルホスホン酸無水物−アセトニトリル溶液（３０１ ｍｇ）を滴下し、室温で１０分間攪拌した。その後、参考例７の化合物（１４４ ｍｇ）を加え、室温で２４時間攪拌した。反応混合物から溶媒を留去後、残渣に水（３０ ｍＬ）を加え、酢酸エチル（３０ ｍＬ×２回）で抽出し、飽和炭酸水素ナトリウム水溶液（３０ ｍＬ）で洗浄後、無水硫酸ナトリウムで乾燥しろ過して濃縮した。残渣を分取薄層カラムクロマトグラフィー（ジクロロメタン／メタノール）で分離精製し、表題化合物（２２．０ ｍｇ）を得た。
¹H-NMR (300 MHz, CDCl₃) δ: 1.44-1.78 (4H, m), 1.81-2.00 (2H, m), 2.37-2.49 (1H, m), 2.63-2.83 (4H, m), 3.28 (2H, q, J = 2.9 Hz), 3.39-3.50 (2H, m), 3.55 (1H, ddd, J = 11.3, 9.1, 3.3 Hz), 3.68 (1H, dd, J = 11.5, 8.2 Hz), 3.80 (1H, td, J = 11.4, 4.4 Hz), 3.92 (1H, dd, J = 11.7, 3.8 Hz), 6.47 (1H, s), 6.80 (1H, tt, J = 3.6, 1.5 Hz), 7.45-7.62 (2H, m), 7.76-7.89 (1H, m). Example 16
N- {2- [6- (trifluoromethyl) -3 ', 6'-dihydro [2,4'-bipyridine] -1'(2'H) -yl] ethyl} -tetrahydro-2H-pyran-3 -Carboxamide

A 50% propylphosphonic anhydride-acetonitrile solution (301 mg) was added dropwise to a mixture of oxane-3-carboxylic acid (41.0 mg), triethylamine (0.263 mL) and acetonitrile (2.0 mL), Stirred at room temperature for 10 minutes. Thereafter, the compound of Reference Example 7 (144 mg) was added, and the mixture was stirred at room temperature for 24 hours. After evaporating the solvent from the reaction mixture, water (30 mL) was added to the residue, extracted with ethyl acetate (30 mL x 2), washed with a saturated aqueous solution of sodium hydrogen carbonate (30 mL), and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated. The residue was separated and purified by preparative thin-layer column chromatography (dichloromethane / methanol) to obtain the title compound (22.0 mg).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.44-1.78 (4H, m), 1.81-2.00 (2H, m), 2.37-2.49 (1H, m), 2.63-2.83 (4H, m), 3.28 (2H, q, J = 2.9 Hz), 3.39-3.50 (2H, m), 3.55 (1H, ddd, J = 11.3, 9.1, 3.3 Hz), 3.68 (1H, dd, J = 11.5, 8.2 Hz), 3.80 (1H, td, J = 11.4, 4.4 Hz), 3.92 (1H, dd, J = 11.7, 3.8 Hz), 6.47 (1H, s), 6.80 (1H, tt, J = 3.6, 1.5 Hz), 7.45 -7.62 (2H, m), 7.76-7.89 (1H, m).

Examples 17 to 28
According to the method described in Example 16, the compounds of Examples 17 to 28 were obtained from the corresponding compounds of Reference Examples.

参考例８の化合物（１５０ ｍｇ）、炭酸水素ナトリウム（２３１ ｍｇ）とジクロロメタン（５．０ ｍＬ）の混合物に氷冷下、テトラヒドロ−２Ｈ−ピラン−４−カルボニルクロライド（８１．８ ｍｇ）をゆっくりと加えた。室温で２０時間攪拌後、反応混合物へ１０％炭酸カリウム水溶液（３０ ｍＬ）を加え、１５分間室温で攪拌した。その後、有機層を分注し、飽和塩化ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥し、ろ過して濃縮した。残渣を分取薄層カラムクロマトグラフィー（クロロホルム／３ ｍｏｌ/Ｌアンモニア-メタノール溶液）で分離精製し、表題化合物（９９．０ ｍｇ）を得た。
¹H-NMR (300 MHz, CDCl₃) δ: 1.71-1.90 (4H, m), 2.30-2.43 (1H, m), 2.57 (3H, s), 2.64-2.75 (4H, m), 2.75-2.83 (2H, m), 3.23-3.31 (2H, m), 3.37-3.52 (4H, m), 3.98-4.08 (2H, m), 6.27 (1H, s), 6.63-6.71 (1H, m), 7.04 (1H, d, J = 7.6 Hz), 7.17 (1H, d, J = 7.8 Hz), 7.56 (1H, dd, J = 7.7, 7.7 Hz). Example 29
N- [2- (6-methyl-3 ', 6'-dihydro [2,4'-bipyridine] -1'(2'H) -yl) ethyl] -tetrahydro-2H-pyran-4-carboxamide

Tetrahydro-2H-pyran-4-carbonyl chloride (81.8 mg) was slowly added to a mixture of the compound of Reference Example 8 (150 mg), sodium hydrogencarbonate (231 mg) and dichloromethane (5.0 mL) under ice-cooling. And added. After stirring at room temperature for 20 hours, a 10% aqueous potassium carbonate solution (30 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. Thereafter, the organic layer was dispensed, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was separated and purified by preparative thin-layer column chromatography (chloroform / 3 mol / L ammonia-methanol solution) to obtain the title compound (99.0 mg).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.71-1.90 (4H, m), 2.30-2.43 (1H, m), 2.57 (3H, s), 2.64-2.75 (4H, m), 2.75-2.83 (2H, m), 3.23-3.31 (2H, m), 3.37-3.52 (4H, m), 3.98-4.08 (2H, m), 6.27 (1H, s), 6.63-6.71 (1H, m), 7.04 (1H, d, J = 7.6 Hz), 7.17 (1H, d, J = 7.8 Hz), 7.56 (1H, dd, J = 7.7, 7.7 Hz).

参考例８の化合物（１５０ ｍｇ）から実施例２９と同様の手法により、表題化合物（４８ ｍｇ）を得た。
¹H-NMR (300 MHz, DMSO-d₆) δ: 1.08 (9H, s), 2.45 (3H, s), 2.47-2.54 (4H, m), 2.65 (2H, t, J = 5.6 Hz), 3.13-3.18 (2H, m), 3.19-3.26 (2H, m), 6.58-6.72 (1H, m), 7.09 (1H, d, J = 7.6 Hz), 7.29 (1H, d, J = 7.9 Hz), 7.38 (1H, dd, J = 5.6, 5.6 Hz), 7.63 (1H, dd, J = 7.7, 7.7 Hz). Example 30
2,2-dimethyl-N- [2- (6-methyl-3 ′, 6′-dihydro [2,4′-bipyridine] -1 ′ (2′H) -yl) ethyl] propanamide

The title compound (48 mg) was obtained from the compound of Reference Example 8 (150 mg) in the same manner as in Example 29.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.08 (9H, s), 2.45 (3H, s), 2.47-2.54 (4H, m), 2.65 (2H, t, J = 5.6 Hz), 3.13-3.18 (2H, m), 3.19-3.26 (2H, m), 6.58-6.72 (1H, m), 7.09 (1H, d, J = 7.6 Hz), 7.29 (1H, d, J = 7.9 Hz) , 7.38 (1H, dd, J = 5.6, 5.6 Hz), 7.63 (1H, dd, J = 7.7, 7.7 Hz).

参考例７の化合物（１６０ ｍｇ）、トリエチルアミン（０．３１９ ｍＬ）とジクロロメタン（２．０ ｍＬ）の混合物にピバロイルクロライド（４６．０ ｍｇ）をゆっくりと加え、室温で２０時間攪拌した。その後、反応混合物に水（３０ ｍＬ）を加え、酢酸エチル（３０ ｍＬ×２回）で抽出し飽和食塩水（３０ ｍＬ）で洗浄し、無水硫酸ナトリウムで乾燥後、ろ過して濃縮した。残渣を分取ＨＰＬＣで分離精製し、表題化合物（２３ ｍｇ）をギ酸塩として得た。
¹H-NMR (300 MHz, CDCl₃) δ: 1.23 (9H, s), 2.84-2.97 (2H, m), 3.05-3.13 (2H, m), 3.18 (2H, t, J = 5.7 Hz), 3.58-3.64 (2H, m), 3.66-3.70 (2H, m), 6.75 (1H, s), 6.92 (1H, s), 7.61 (2H, dd, J = 10.5, 7.8 Hz), 7.88 (1H, dd, J = 7.9, 7.9 Hz). Example 31
2,2-dimethyl-N- {2- [6- (trifluoromethyl) -3 ', 6'-dihydro [2,4'-bipyridine] -1'(2'H) -yl] ethyl} propanamide

To a mixture of the compound of Reference Example 7 (160 mg), triethylamine (0.319 mL) and dichloromethane (2.0 mL), pivaloyl chloride (46.0 mg) was slowly added, and the mixture was stirred at room temperature for 20 hours. Thereafter, water (30 mL) was added to the reaction mixture, extracted with ethyl acetate (30 mL × 2), washed with saturated saline (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated and purified by preparative HPLC to give the title compound (23 mg) as formate.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.23 (9H, s), 2.84-2.97 (2H, m), 3.05-3.13 (2H, m), 3.18 (2H, t, J = 5.7 Hz), 3.58-3.64 (2H, m), 3.66-3.70 (2H, m), 6.75 (1H, s), 6.92 (1H, s), 7.61 (2H, dd, J = 10.5, 7.8 Hz), 7.88 (1H, dd, J = 7.9, 7.9 Hz).

Examples 32 to 34
According to the method described in Example 31, the compounds of Examples 32-34 were obtained from the corresponding compounds of Reference Examples.

実施例３２の化合物（１８０ ｍｇ）、シアン化ナトリウム（５００ ｍｇ）とジメチルスルホキシド（１０ ｍＬ）の混合物を１５０℃で７２時間攪拌した。その後、反応混合物に水（１００ ｍＬ）を加え酢酸エチル（１００ ｍＬ×２回）で抽出し、飽和炭酸水素ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥後、ろ過して濃縮した。残渣を分取薄層カラムクロマトグラフィー（ジクロロメタン／３ ｍｏｌ/Ｌ アンモニア−メタノール溶液）で分離精製し、表題化合物（１１．０ ｍｇ）を得た。
¹H-NMR (300 MHz, DMSO-d₆) δ: 1.52-1.60 (4H, m), 1.62-1.87 (4H, m), 1.94-2.17 (2H, m), 2.25-2.43 (3H, m), 2.66-2.80 (1H, m), 2.96 (2H, d, J = 10.9 Hz), 3.09-3.31 (4H, m), 3.85 (2H, td, J = 11.2, 3.4 Hz), 7.67 (2H, dd, J = 8.0, 1.1 Hz), 7.87 (1H, dd, J = 7.7, 1.1 Hz), 7.98 (1H, dd, J = 7.8, 7.8 Hz). Example 35
N- {2- [4- (6-cyanopyridin-2-yl) piperidin-1-yl] ethyl} -tetrahydro-2H-pyran-4-carboxamide

A mixture of the compound of Example 32 (180 mg), sodium cyanide (500 mg), and dimethyl sulfoxide (10 mL) was stirred at 150 ° C. for 72 hours. Thereafter, water (100 mL) was added to the reaction mixture, extracted with ethyl acetate (100 mL × 2), washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was separated and purified by preparative thin-layer column chromatography (dichloromethane / 3 mol / L ammonia-methanol solution) to obtain the title compound (11.0 mg).
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.52-1.60 (4H, m), 1.62-1.87 (4H, m), 1.94-2.17 (2H, m), 2.25-2.43 (3H, m) , 2.66-2.80 (1H, m), 2.96 (2H, d, J = 10.9 Hz), 3.09-3.31 (4H, m), 3.85 (2H, td, J = 11.2, 3.4 Hz), 7.67 (2H, dd , J = 8.0, 1.1 Hz), 7.87 (1H, dd, J = 7.7, 1.1 Hz), 7.98 (1H, dd, J = 7.8, 7.8 Hz).

参考例１５の化合物（２７０ ｍｇ）、５０％ラネーニッケル−水懸濁液（０．２ ｍＬ）とメタノール（５．０ ｍＬ）の混合物を水素雰囲気下、室温で２４時間攪拌した。その後、反応混合物をセライトろ過し、メタノール（１０ ｍＬ×２回）で洗浄し、ろ液を濃縮した。残渣をジクロロメタンとジエチルエーテルとの混合溶媒でトリチュレーションすることで、表題化合物（２２ ｍｇ）を得た。
¹H-NMR (300 MHz, DMSO-d₆) δ: 1.49-1.61 (4H, m), 1.62-1.77 (4H, m), 1.99 (2H, td, J = 11.3, 3.0 Hz), 2.25-2.42 (4H, m), 2.87-2.98 (2H, m), 3.17 (2H, q, J = 6.5 Hz), 3.23-3.32 (2H, m), 3.85 (2H, td, J = 11.2, 3.4 Hz), 5.72 (2H, s), 6.25 (1H, d, J = 8.1 Hz), 6.34 (1H, d, J = 7.3 Hz), 7.27 (1H, dd, J = 7.7, 7.7 Hz), 7.68 (1H, J = 5.6, 5.6 Hz). Example 36
N- {2- [4- (6-aminopyridin-2-yl) piperidin-1-yl] ethyl} -tetrahydro-2H-pyran-4-carboxamide

A mixture of the compound of Reference Example 15 (270 mg), 50% Raney nickel-water suspension (0.2 mL) and methanol (5.0 mL) was stirred at room temperature for 24 hours under a hydrogen atmosphere. Thereafter, the reaction mixture was filtered through celite, washed with methanol (10 mL × 2), and the filtrate was concentrated. The residue was triturated with a mixed solvent of dichloromethane and diethyl ether to give the title compound (22 mg).
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.49-1.61 (4H, m), 1.62-1.77 (4H, m), 1.99 (2H, td, J = 11.3, 3.0 Hz), 2.25-2.42 (4H, m), 2.87-2.98 (2H, m), 3.17 (2H, q, J = 6.5 Hz), 3.23-3.32 (2H, m), 3.85 (2H, td, J = 11.2, 3.4 Hz), 5.72 (2H, s), 6.25 (1H, d, J = 8.1 Hz), 6.34 (1H, d, J = 7.3 Hz), 7.27 (1H, dd, J = 7.7, 7.7 Hz), 7.68 (1H, J = 5.6, 5.6 Hz).

実施例３６の化合物（１００ ｍｇ）のメタノール溶液（１．０ ｍＬ）にパラホルムアルデヒド（３６．０ ｍｇ）とナトリウムメトキシド（８１．０ ｍｇ）を加えた。２時間加熱還流後、反応混合物に氷冷下、水素化ホウ素ナトリウム（４６．０ ｍｇ）を加え、２時間加熱還流した。その後、反応混合物に飽和炭酸水素ナトリウム水溶液（５．０ ｍＬ）を加え、酢酸エチル（３０ ｍＬ×２回）で抽出し、無水硫酸マグネシウムで乾燥後、ろ過して濃縮した。残渣を分取薄層カラムクロマトグラフィー（ジクロロメタン／３ ｍｏｌ/Ｌ アンモニア-メタノール溶液）で分離精製し、表題化合物（３６．０ ｍｇ）を得た。
¹H-NMR (300 MHz, CDCl₃) δ: 1.68-1.89 (6H, m), 1.89-2.01 (2H, m), 2.04-2.22 (2H, m), 2.39 (1H, tt, J = 10.4, 5.3 Hz), 2.46-2.60 (3H, m), 2.92 (3H, d, J - 5.1 Hz), 2.95-3.07 (2H, m), 3.29-3.54 (4H, m), 4.05 (2H, td, J = 11.5, 3.6 Hz), 4.36-4.62 (1H, m), 6.25 (2H, d, J = 8.2 Hz), 6.49 (1H, d, J = 7.3 Hz), 7.43 (1H, dd, J = 8.2, 7.4 Hz). Example 37
N- (2- {4- [6- (methylamino) pyridin-2-yl] piperidin-1-yl} ethyl) -tetrahydro-2H-pyran-4-carboxamide

To a methanol solution (1.0 mL) of the compound of Example 36 (100 mg) was added paraformaldehyde (36.0 mg) and sodium methoxide (81.0 mg). After heating under reflux for 2 hours, sodium borohydride (46.0 mg) was added to the reaction mixture under ice cooling, and the mixture was heated under reflux for 2 hours. Thereafter, a saturated aqueous sodium hydrogen carbonate solution (5.0 mL) was added to the reaction mixture, extracted with ethyl acetate (30 mL × 2), dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was separated and purified by preparative thin-layer column chromatography (dichloromethane / 3 mol / L ammonia-methanol solution) to obtain the title compound (36.0 mg).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.68-1.89 (6H, m), 1.89-2.01 (2H, m), 2.04-2.22 (2H, m), 2.39 (1H, tt, J = 10.4, 5.3 Hz), 2.46-2.60 (3H, m), 2.92 (3H, d, J-5.1 Hz), 2.95-3.07 (2H, m), 3.29-3.54 (4H, m), 4.05 (2H, td, J = 11.5, 3.6 Hz), 4.36-4.62 (1H, m), 6.25 (2H, d, J = 8.2 Hz), 6.49 (1H, d, J = 7.3 Hz), 7.43 (1H, dd, J = 8.2, 7.4 Hz).

実施例３６の化合物（５０．０ ｍｇ）のジクロロエタン溶液（１．５ ｍＬ）にパラホルムアルデヒド（１８．０ ｍｇ）を加え、室温で１時間攪拌した。水素化シアノホウ素ナトリウム（２３．９ ｍｇ）を加え、室温で２４時間攪拌した。その後、反応混合物にジクロロメタン（３０ ｍＬ）を加え、飽和炭酸水素ナトリウム水溶液（１０ ｍＬ×２回）で洗浄し、無水硫酸ナトリウムで乾燥後、ろ過して濃縮した。残渣を分取薄層カラムクロマトグラフィー（ジクロロメタン／３ ｍｏｌ/Ｌ アンモニア−メタノール溶液）で分離精製し、表題化合物（３６．０ ｍｇ）を得た。
¹H-NMR (300 MHz, CDCl₃) δ: 1.75-2.02 (8H, m), 2.15 (2H, t, J = 11.5 Hz), 2.32-2.46 (1H, m), 2.48-2.64 (3H, m), 3.00 (2H, d, J = 11.3 Hz), 3.10 (6H, s), 3.33-3.53 (4H, m), 4.04 (2H, td, J = 11.4, 3.4 Hz), 6.28 (1H, s), 6.37 (1H, d, J = 8.6 Hz), 6.44 (1H, d, J = 7.3 Hz), 7.40 (1H, dd, J = 8.4, 7.3 Hz). Example 38
N- (2- {4- [6- (dimethylamino) pyridin-2-yl] piperidin-1-yl} ethyl) -tetrahydro-2H-pyran-4-carboxamide

Paraformaldehyde (18.0 mg) was added to a dichloroethane solution (1.5 mL) of the compound of Example 36 (50.0 mg), and the mixture was stirred at room temperature for 1 hour. Sodium cyanoborohydride (23.9 mg) was added, and the mixture was stirred at room temperature for 24 hours. Thereafter, dichloromethane (30 mL) was added to the reaction mixture, and the mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by preparative thin-layer column chromatography (dichloromethane / 3 mol / L ammonia-methanol solution) to give the title compound (36.0 mg).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.75-2.02 (8H, m), 2.15 (2H, t, J = 11.5 Hz), 2.32-2.46 (1H, m), 2.48-2.64 (3H, m ), 3.00 (2H, d, J = 11.3 Hz), 3.10 (6H, s), 3.33-3.53 (4H, m), 4.04 (2H, td, J = 11.4, 3.4 Hz), 6.28 (1H, s) , 6.37 (1H, d, J = 8.6 Hz), 6.44 (1H, d, J = 7.3 Hz), 7.40 (1H, dd, J = 8.4, 7.3 Hz).

Ｎ−Ｂｏｃ−１，２，３，６−テトラヒドロ−４−（４，４，５，５−テトラメチル−[１，３，２]−ジオキサボロラン−２−イル）−ピリジン（４１．０ｇ）、ジメトキシエタン（２２１ｍＬ）および水（１１１ｍＬ）の混合物に、２−ブロモ−６−（トリフルオロメチル）ピリジン（３０．０ｇ）、炭酸ナトリウム（７０．３ｇ）とテトラキス（トリフェニルホスフィン）パラジウム（０）（７．６７ｇ）を加えた。８０℃で１５時間撹拌後、反応混合物に濃塩酸（３００ｍＬ）をゆっくりと滴下した。室温で１時間撹拌後、反応混合物をセライトろ過し、ろ液をクロロホルムで洗浄した。水層に２０％水酸化ナトリウム水溶液（３７５ｍＬ）を加え、クロロホルムで抽出した。有機層を硫酸ナトリウムで乾燥、ろ過後、減圧濃縮し、表題化合物（２６．９ｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 2.53-2.59 (2H, m), 3.11 (2H, t, J = 5.7 Hz), 3.59 (2H, q, J = 3.0 Hz), 6.81-6.84 (1H, m), 7.48 (1H, d, J = 7.8 Hz), 7.51 (1H, d, J = 8.0 Hz), 7.78 (1H, dd, J = 7.9, 7.9 Hz). Reference Example 1
6- (trifluoromethyl) -1 ′, 2 ′, 3 ′, 6′-tetrahydro-2,4′-bipyridine

N-Boc-1,2,3,6-tetrahydro-4- (4,4,5,5-tetramethyl- [1,3,2] -dioxaborolan-2-yl) -pyridine (41.0 g), In a mixture of dimethoxyethane (221 mL) and water (111 mL), 2-bromo-6- (trifluoromethyl) pyridine (30.0 g), sodium carbonate (70.3 g) and tetrakis (triphenylphosphine) palladium (0) (7.67 g) was added. After stirring at 80 ° C. for 15 hours, concentrated hydrochloric acid (300 mL) was slowly added dropwise to the reaction mixture. After stirring at room temperature for 1 hour, the reaction mixture was filtered through celite, and the filtrate was washed with chloroform. A 20% aqueous sodium hydroxide solution (375 mL) was added to the aqueous layer, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (26.9 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.53-2.59 (2H, m), 3.11 (2H, t, J = 5.7 Hz), 3.59 (2H, q, J = 3.0 Hz), 6.81-6.84 ( 1H, m), 7.48 (1H, d, J = 7.8 Hz), 7.51 (1H, d, J = 8.0 Hz), 7.78 (1H, dd, J = 7.9, 7.9 Hz).

参考例１の化合物（５３．８ｇ）のメタノール溶液（２３６ｍＬ）に１０％パラジウム／炭素（１２．５ｇ）を加え、水素雰囲気下、室温で１５時間撹拌した。その後、セライトろ過し、溶媒を減圧濃縮し、表題化合物（５４．１ｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 1.73-1.85 (2H, m), 1.95-2.02 (2H, m), 2.76-2.85 (2H, m), 2.90-2.99 (1H, m), 3.23-3.30 (2H, m), 7.36 (1H, d, J = 7.8 Hz), 7.49 (1H, d, J = 7.8 Hz), 7.78 (1H, dd, J = 7.8, 7.8 Hz). Reference example 2
2- (piperidin-4-yl) -6- (trifluoromethyl) pyridine

10% palladium / carbon (12.5 g) was added to a methanol solution (236 mL) of the compound of Reference Example 1 (53.8 g), and the mixture was stirred at room temperature for 15 hours under a hydrogen atmosphere. Then, the mixture was filtered through celite, and the solvent was concentrated under reduced pressure to obtain the title compound (54.1 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.73-1.85 (2H, m), 1.95-2.02 (2H, m), 2.76-2.85 (2H, m), 2.90-2.99 (1H, m), 3.23 -3.30 (2H, m), 7.36 (1H, d, J = 7.8 Hz), 7.49 (1H, d, J = 7.8 Hz), 7.78 (1H, dd, J = 7.8, 7.8 Hz).

参考例２の化合物（９．６２ｇ）、テトラブチルアンモニウムブロマイド（１．３５ｇ）、５０％炭酸カリウム水溶液（５７．７ｇ）およびＴＨＦ（８４ｍL）の混合物にｔｅｒｔ−ブチル（２−ブロモエチル）カルバメート（９．８３ｇ）を加えた。７０℃で１５時間撹拌後、反応混合物に水を加え、酢酸エチルで抽出した。有機層を硫酸ナトリウムで乾燥、ろ過後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）にて精製し、表題化合物（１１．０ｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 1.44 (9H, s), 1.76-1.97 (4H, m), 2.05-2.14 (2H, m), 2.47 (2H, t, J = 6.0 Hz), 2.73-2.84 (1H, m), 2.95-3.03 (2H, m), 3.17-3.28 (2H, m), 5.01 (1H, brs), 7.35 (1H, d, J = 7.8 Hz), 7.49 (1H, d, J = 7.8 Hz), 7.77 (1H, dd, J = 7.8, 7.8 Hz). Reference Example 3
tert-butyl (2- {4- [6- (trifluoromethyl) pyridin-2-yl] piperidin-1-yl} ethyl) carbamate

To a mixture of the compound of Reference Example 2 (9.62 g), tetrabutylammonium bromide (1.35 g), a 50% aqueous potassium carbonate solution (57.7 g) and THF (84 mL), tert-butyl (2-bromoethyl) carbamate (9 .83 g) was added. After stirring at 70 ° C. for 15 hours, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (11.0 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.44 (9H, s), 1.76-1.97 (4H, m), 2.05-2.14 (2H, m), 2.47 (2H, t, J = 6.0 Hz), 2.73-2.84 (1H, m), 2.95-3.03 (2H, m), 3.17-3.28 (2H, m), 5.01 (1H, brs), 7.35 (1H, d, J = 7.8 Hz), 7.49 (1H, d, J = 7.8 Hz), 7.77 (1H, dd, J = 7.8, 7.8 Hz).

参考例３の化合物（１．５７ｇ）のジクロロメタン溶液（８．４ｍＬ）に４ｍｏｌ／Ｌ塩酸 酢酸エチル溶液（１０．５ｍＬ）を加えた。室温で４時間撹拌後、溶媒を留去し、残渣をジエチルエーテル中で撹拌後ろ取することで、表題化合物（１．３７ｇ）を得た。
¹H-NMR (400 MHz, DMSO-D₆) δ: 2.06-2.17 (4H, m), 3.07-3.22 (3H, m), 3.27-3.45 (4H, m), 3.63-3.71 (2H, m), 7.65 (1H, d, J = 7.8 Hz), 7.78 (1H, d, J = 7.8 Hz), 8.08 (1H, dd, J = 7.8, 7.8 Hz), 8.43 (3H, brs). Reference example 4
2- {4- [6- (trifluoromethyl) pyridin-2-yl] piperidin-1-yl} ethylamine trihydrochloride

To a dichloromethane solution (8.4 mL) of the compound of Reference Example 3 (1.57 g) was added a 4 mol / L hydrochloric acid ethyl acetate solution (10.5 mL). After stirring at room temperature for 4 hours, the solvent was distilled off, and the residue was stirred in diethyl ether to give the title compound (1.37 g).
¹ H-NMR (400 MHz, DMSO-D ₆ ) δ: 2.06-2.17 (4H, m), 3.07-3.22 (3H, m), 3.27-3.45 (4H, m), 3.63-3.71 (2H, m) , 7.65 (1H, d, J = 7.8 Hz), 7.78 (1H, d, J = 7.8 Hz), 8.08 (1H, dd, J = 7.8, 7.8 Hz), 8.43 (3H, brs).

２−ブロモ−６−メチルピリジン（５．１１ｇ）、ジメトキシエタン（７９ｍＬ）および水（２０ｍＬ）の混合物に、Ｎ−Ｂｏｃ−１，２，３，６−テトラヒドロ−４−（４，４，５，５−テトラメチル−[１，３，２]−ジオキサボロラン−２−イル）−ピリジン（１１．０ｇ）、炭酸カリウム（８．２１ｇ）とテトラキス（トリフェニルホスフィン）パラジウム（０）（３．４３ｇ）を加えた。８０℃で４時間撹拌後、反応混合物に水を加え、酢酸エチルで抽出した。有機層を硫酸ナトリウムで乾燥、ろ過後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）で精製した。
得られた精製物の酢酸エチル溶液（２０ｍＬ）に４ｍｏｌ／Ｌ塩酸 酢酸エチル溶液（２０ｍＬ）を加えた。室温で２４時間撹拌後、反応混合物を濃縮した。残渣に飽和炭酸水素ナトリウム水溶液を加え、クロロホルム／メタノール溶液で抽出した。有機層を硫酸ナトリウムで乾燥、ろ過後、減圧濃縮した。残渣をアミノシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール）で精製し、表題化合物（４．８８ｇ）を得た。
¹H-NMR (400 MHz, CDCl₃) δ: 2.51-2.57 (5H, m), 3.12 (2H, t, J = 5.7 Hz), 3.58 (2H, q, J = 3.1 Hz), 6.70-6.74 (1H, m), 7.00 (1H, d, J = 7.8 Hz), 7.13 (1H, d, J = 7.8 Hz), 7.53 (1H, dd, J = 7.8, 7.8 Hz). Reference Example 5
6-methyl-1 ', 2', 3 ', 6'-tetrahydro-2,4'-bipyridine

To a mixture of 2-bromo-6-methylpyridine (5.11 g), dimethoxyethane (79 mL) and water (20 mL) was added N-Boc-1,2,3,6-tetrahydro-4- (4,4,5 , 5-Tetramethyl- [1,3,2] -dioxaborolan-2-yl) -pyridine (11.0 g), potassium carbonate (8.21 g) and tetrakis (triphenylphosphine) palladium (0) (3.43 g) ) Was added. After stirring at 80 ° C. for 4 hours, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate).
A 4 mol / L hydrochloric acid ethyl acetate solution (20 mL) was added to an ethyl acetate solution (20 mL) of the obtained purified product. After stirring at room temperature for 24 hours, the reaction mixture was concentrated. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with a chloroform / methanol solution. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (chloroform / methanol) to obtain the title compound (4.88 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.51-2.57 (5H, m), 3.12 (2H, t, J = 5.7 Hz), 3.58 (2H, q, J = 3.1 Hz), 6.70-6.74 ( 1H, m), 7.00 (1H, d, J = 7.8 Hz), 7.13 (1H, d, J = 7.8 Hz), 7.53 (1H, dd, J = 7.8, 7.8 Hz).

参考例２〜４と同様の手法により、参考例５の化合物から表題化合物を得た。
¹H-NMR (300 MHz, DMSO-D₆) δ: 2.11-2.35 (4H, m), 2.78 (3H, s), 3.13-3.29 (2H, m), 3.31-3.46 (4H, m), 3.47-3.61 (1H, m), 3.66-3.78 (2H, m), 7.65 (1H, d, J = 8.1 Hz), 7.77 (1H, d, J = 7.5 Hz), 8.41 (1H, dd, J = 7.8, 7.8 Hz), 8.47 (3H, brs), 11.30 (1H, brs). Reference Example 6
2- [4- (6-methylpyridin-2-yl) piperidin-1-yl] ethylamine trihydrochloride

The title compound was obtained from the compound of Reference Example 5 in the same manner as in Reference Examples 2 to 4.
¹ H-NMR (300 MHz, DMSO-D ₆ ) δ: 2.11-2.35 (4H, m), 2.78 (3H, s), 3.13-3.29 (2H, m), 3.31-3.46 (4H, m), 3.47 -3.61 (1H, m), 3.66-3.78 (2H, m), 7.65 (1H, d, J = 8.1 Hz), 7.77 (1H, d, J = 7.5 Hz), 8.41 (1H, dd, J = 7.8 , 7.8 Hz), 8.47 (3H, brs), 11.30 (1H, brs).

参考例３〜４と同様の手法により、参考例１の化合物から表題化合物を得た。
¹H-NMR (300 MHz, D₂O) δ: 2.84-3.02 (2H, m), 3.44-3.55 (2H, m), 3.56-3.69 (4H, m), 3.99-4.10 (2H, m), 6.50-6.59 (1H, m), 7.72 (1H, d, J = 3.7 Hz), 7.75 (1H, d, J = 3.3 Hz), 8.00 (1H, dd, J = 7.9, 7.9 Hz). Reference Example 7
2- [6- (trifluoromethyl) -3 ′, 6′-dihydro [2,4′-bipyridine] -1 ′ (2′H) -yl] ethylamine trihydrochloride

The title compound was obtained from the compound of Reference Example 1 in the same manner as in Reference Examples 3 and 4.
¹ H-NMR (300 MHz, D ₂ O) δ: 2.84-3.02 (2H, m), 3.44-3.55 (2H, m), 3.56-3.69 (4H, m), 3.99-4.10 (2H, m), 6.50-6.59 (1H, m), 7.72 (1H, d, J = 3.7 Hz), 7.75 (1H, d, J = 3.3 Hz), 8.00 (1H, dd, J = 7.9, 7.9 Hz).

参考例３〜４と同様の手法により、参考例５の化合物から表題化合物を得た。
¹H-NMR (300 MHz, DMSO-d₆) δ: 2.68 (3H, s), 2.95-3.07 (2H, m), 3.33-3.45 (3H, m),3.48-3.56 (2H, m), 3.70-3.84 (1H, m), 3.94-4.07 (1H, m), 4.12-4.27 (1H, m), 6.83 (1H, d, J = 3.9 Hz), 7.55 (1H, d, J = 7.8 Hz), 7.69 (1H, d, J = 8.0 Hz), 8.12 (1H, dd, J = 8.2, 8.2 Hz), 8.60 (3H, s), 11.64 (1H, s). Reference Example 8
2- (6-methyl-3 ', 6'-dihydro [2,4'-bipyridine] -1'(2'H) -yl) ethylamine trihydrochloride

The title compound was obtained from the compound of Reference Example 5 in the same manner as in Reference Examples 3 and 4.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.68 (3H, s), 2.95-3.07 (2H, m), 3.33-3.45 (3H, m), 3.48-3.56 (2H, m), 3.70 -3.84 (1H, m), 3.94-4.07 (1H, m), 4.12-4.27 (1H, m), 6.83 (1H, d, J = 3.9 Hz), 7.55 (1H, d, J = 7.8 Hz), 7.69 (1H, d, J = 8.0 Hz), 8.12 (1H, dd, J = 8.2, 8.2 Hz), 8.60 (3H, s), 11.64 (1H, s).

参考例１および３と同様の手法により、２−クロロ−６−トリフルオロメトキシピリジンから表題化合物を得た。
¹H-NMR (300 MHz, CDCl₃) δ: 1.47 (9H, s), 2.58-2.70 (4H, m), 2.71-2.79 (2H, m), 3.20-3.28 (2H, m), 3.28-3.36 (2H, m), 6.73-6.82 (1H, m), 6.85 (1H, d, J = 8.0 Hz), 7.23-7.30 (1H, m), 7.74 (1H, dd, J = 7.9, 7.9 Hz). Reference Example 9
tert-butyl {2- [6- (trifluoromethoxy) -3 ', 6'-dihydro [2,4'-bipyridine] -1'(2'H) -yl] ethyl} carbamate

In the same manner as in Reference Examples 1 and 3, the title compound was obtained from 2-chloro-6-trifluoromethoxypyridine.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.47 (9H, s), 2.58-2.70 (4H, m), 2.71-2.79 (2H, m), 3.20-3.28 (2H, m), 3.28-3.36 (2H, m), 6.73-6.82 (1H, m), 6.85 (1H, d, J = 8.0 Hz), 7.23-7.30 (1H, m), 7.74 (1H, dd, J = 7.9, 7.9 Hz).

参考例２と同様の手法により、参考例９の化合物から表題化合物を得た。
¹H-NMR (300 MHz, CDCl₃) δ: 1.47 (9H, s), 1.82-2.07 (4H, m), 2.18-2.30 (2H, m), 2.49-2.62 (2H, m), 2.66-2.79 (1H, m), 3.10 (2H, d, J = 11.2 Hz), 3.24-3.40 (2H, m), 6.87 (1H, d, J = 8.1 Hz), 7.11 (1H, d, J = 7.5 Hz), 7.73 (1H, dd, J = 7.8, 7.8 Hz). Reference example 10
tert-butyl (2- {4- [6- (trifluoromethoxy) pyridin-2-yl] piperidin-1-yl} ethyl) carbamate

The title compound was obtained from the compound of Reference Example 9 in the same manner as in Reference Example 2.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.47 (9H, s), 1.82-2.07 (4H, m), 2.18-2.30 (2H, m), 2.49-2.62 (2H, m), 2.66-2.79 (1H, m), 3.10 (2H, d, J = 11.2 Hz), 3.24-3.40 (2H, m), 6.87 (1H, d, J = 8.1 Hz), 7.11 (1H, d, J = 7.5 Hz) , 7.73 (1H, dd, J = 7.8, 7.8 Hz).

参考例４と同様の手法により、参考例１０の化合物から表題化合物を得た。
¹H-NMR (300 MHz, D₂O) δ: 1.93-2.14 (2H, m), 2.15-2.26 (2H, m), 3.04-3.13 (1H, m), 3.16-3.33 (2H, m), 3.38-3.54 (4H, m), 3.62-3.77 (2H, m), 7.13 (1H, d, J = 8.2 Hz), 7.31 (1H, d, J = 7.6 Hz), 7.91 (1H, dd, J = 7.9, 7.9 Hz). Reference Example 11
2- {4- [6- (trifluoromethoxy) pyridin-2-yl] piperidin-1-yl} ethylamine trihydrochloride

The title compound was obtained from the compound of Reference Example 10 in the same manner as in Reference Example 4.
¹ H-NMR (300 MHz, D ₂ O) δ: 1.93-2.14 (2H, m), 2.15-2.26 (2H, m), 3.04-3.13 (1H, m), 3.16-3.33 (2H, m), 3.38-3.54 (4H, m), 3.62-3.77 (2H, m), 7.13 (1H, d, J = 8.2 Hz), 7.31 (1H, d, J = 7.6 Hz), 7.91 (1H, dd, J = (7.9, 7.9 Hz).

参考例９〜１１と同様の手法により、２−ブロモ−６−フルオロピリジンから表題化合物を得た。
¹H-NMR (400 MHz, DMSO-d₆) δ: 2.02-2.19 (4H, m), 2.91-3.06 (1H, m), 3.11-3.21 (2H, m), 3.31-3.44 (4H, m), 3.66 (2H, d, J = 12.2 Hz), 7.05 (1H, dd, J = 8.1, 2.7 Hz), 7.27 (1H, dd, J = 7.4, 2.6 Hz), 7.97 (1H, dd, J = 8.1, 8.1 Hz), 8.54 (3H, s), 11.04 (1H, s). Reference Example 12
2- [4- (6-fluoropyridin-2-yl) piperidin-1-yl] ethylamine trihydrochloride

The title compound was obtained from 2-bromo-6-fluoropyridine in the same manner as in Reference Examples 9 to 11.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.02-2.19 (4H, m), 2.91-3.06 (1H, m), 3.11-3.21 (2H, m), 3.31-3.44 (4H, m) , 3.66 (2H, d, J = 12.2 Hz), 7.05 (1H, dd, J = 8.1, 2.7 Hz), 7.27 (1H, dd, J = 7.4, 2.6 Hz), 7.97 (1H, dd, J = 8.1 , 8.1 Hz), 8.54 (3H, s), 11.04 (1H, s).

参考例９〜１１と同様の手法により、２−ブロモ−６−メトキシピリジンから表題化合物を得た。
¹H-NMR (300 MHz, D₂O) δ: 1.93-2.14 (2H, m), 2.19-2.33 (2H, m), 3.05-3.33 (3H, m), 3.39-3.55 (4H, m), 3.69-3.80 (2H, m), 4.02 (3H, s), 7.16 (2H, dd, J = 15.3, 8.2 Hz), 8.13 (1H, d, J = 8.7, 7.6 Hz). Reference Example 13
2- [4- (6-methoxypyridin-2-yl) piperidin-1-yl] ethylamine trihydrochloride

The title compound was obtained from 2-bromo-6-methoxypyridine in the same manner as in Reference Examples 9 to 11.
¹ H-NMR (300 MHz, D ₂ O) δ: 1.93-2.14 (2H, m), 2.19-2.33 (2H, m), 3.05-3.33 (3H, m), 3.39-3.55 (4H, m), 3.69-3.80 (2H, m), 4.02 (3H, s), 7.16 (2H, dd, J = 15.3, 8.2 Hz), 8.13 (1H, d, J = 8.7, 7.6 Hz).

参考例９〜１１と同様の手法により、２−ブロモ−６−ジフルオロメチルピリジンから表題化合物を得た。
¹H-NMR (300 MHz, D₂O) δ: 1.78-1.92 (2H, m), 1.91-2.10 (2H, m), 2.63 (2H, t, J = 12.1 Hz), 2.83-3.02 (3H, m), 3.09-3.33 (4H, m), 6.71 (1H, t, J = 55.0 Hz), 7.41-7.50 (1H, m), 7.53 (1H, d, J = 7.6 Hz), 7.86-7.96 (1H, m). Reference Example 14
2- {4- [6- (difluoromethyl) pyridin-2-yl] piperidin-1-yl} ethylamine trihydrochloride

The title compound was obtained from 2-bromo-6-difluoromethylpyridine in the same manner as in Reference Examples 9 to 11.
¹ H-NMR (300 MHz, D ₂ O) δ: 1.78-1.92 (2H, m), 1.91-2.10 (2H, m), 2.63 (2H, t, J = 12.1 Hz), 2.83-3.02 (3H, m), 3.09-3.33 (4H, m), 6.71 (1H, t, J = 55.0 Hz), 7.41-7.50 (1H, m), 7.53 (1H, d, J = 7.6 Hz), 7.86-7.96 (1H , m).

実施例３２の化合物（３００ ｍｇ）の１，４−ジオキサン溶液（２．０ ｍＬ）に、５０−６０％ヒドラジン水溶液（２．９ ｍＬ）を加え、１００℃で２４時間攪拌した。反応混合物を濃縮し、ジクロロメタン（１０ ｍＬ）を加え、飽和食塩水（１０ ｍＬ×２回）で洗浄後、濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ジクロロメタン／メタノール）で分離精製し、表題化合物（２７０ ｍｇ）を得た。
¹H-NMR (300 MHz, CDCl₃) δ: 1.63-1.90 (6H, m), 1.90-2.00 (2H, m), 2.14 (2H, td, J =11.7, 2.6 Hz), 2.39 (1H, tt, J = 10.4, 5.3 Hz), 2.47-2.65 (3H, m), 2.91-3.06 (2H, m), 3.28-3.52 (4H, m), 4.05 (2H, td, J = 11.5, 3.6 Hz), 5.74 (1H, s), 6.22 (1H, s), 6.52-6.62 (2H, m), 7.46 (1H, dd, J = 8.2, 7.4 Hz). Reference Example 15
N- (2- {4-[(6E) -6-hydrazinylidene-1,6-dihydropyridin-2-yl] piperidin-1-yl} ethyl) -tetrahydro-2H-pyran-4-carboxamide

To a 1,4-dioxane solution (2.0 mL) of the compound of Example 32 (300 mg) was added a 50-60% aqueous hydrazine solution (2.9 mL), and the mixture was stirred at 100 ° C for 24 hours. The reaction mixture was concentrated, dichloromethane (10 mL) was added, and the mixture was washed with saturated saline (10 mL x 2) and then concentrated. The residue was separated and purified by silica gel column chromatography (dichloromethane / methanol) to obtain the title compound (270 mg).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.63-1.90 (6H, m), 1.90-2.00 (2H, m), 2.14 (2H, td, J = 11.7, 2.6 Hz), 2.39 (1H, tt , J = 10.4, 5.3 Hz), 2.47-2.65 (3H, m), 2.91-3.06 (2H, m), 3.28-3.52 (4H, m), 4.05 (2H, td, J = 11.5, 3.6 Hz), 5.74 (1H, s), 6.22 (1H, s), 6.52-6.62 (2H, m), 7.46 (1H, dd, J = 8.2, 7.4 Hz).

Test Example 1: was expressed in human _{5-HT 1A} receptor and agonist activity evaluation aequorin against human _{D 4} receptor, Gal6 protein, transiently CHO-K1 cells each receptor (Chinese hamster ovary) Thereafter, the seeds were placed in a 384-well plate and cultured at 37 ° C. for 24 hours in a CO ₂ incubator. Various compounds dissolved in DMSO were added, and the change in the amount of luminescence was measured by an FDSS / μCELL drug discovery screening support system (Hamamatsu Photonics). Regarding the agonist activity, the maximum activity (Emax) of each compound was calculated, assuming that the luminescence amount of the well to which no compound was added was 0% and the luminescence amount of the well to which 10 μmol / L endogenous ligand was added was 100%. The results are shown in the table below.

Test Example 2: Evaluation of binding activity to human 5-HT _1A receptor, human D ₄ receptor, and human D ₂ receptor Human 5-HT _1A receptor and human D ₄ receptor of the compound of the present invention and a binding affinity for human D ₂ receptors was measured by the following method.
Human 5-HT _1A receptor, human D ₄ receptor, and CHO cell membrane fraction was expressed human D ₂ receptors was purchased from Perkin Elmer. In binding evaluation test, test compound, dissolved in DMSO, various receptor membrane preparation was diluted with buffer, and for _{5-HT 1A} receptor [3H] 8-OH-DPAT , the _{D 4} receptor [ 3H] Dopamine, for _{D 2} receptors [3H] spiperone (above all from Perkin Elmer) were mixed, respectively and incubated for 30 minutes or 60 minutes at room temperature. Non-specific binding to the receptor was determined by a competitive binding test in the presence of 10 μmol / L 8-OH-DPAT, 10 μmol / L Dopamine, and 10 μmol / L Siperone, respectively. After measuring the radioactivity bound to the receptor using a liquid scintillation counter (Perkin Elmer), the 50% inhibitory concentration was calculated, and the Ki value was evaluated from the dissociation constant calculated from the saturation binding test and the substrate concentration. , Used as binding affinity. The results are shown in the table below.

Test Example 3-1 Human liver microsome metabolic stability test The human liver microsome metabolic stability of the compound of the present invention was evaluated by the following method. Human liver microsomes used were manufactured by Xenontech. Human liver microsomes, NADPH, and a test substance were mixed in a 25 mmol / L phosphate buffer (pH 7.4) to the following concentrations, and incubated at 37 ° C. for 30 minutes.
・ Human liver microsomes: 0.1 mg / mL
NAPDH: 3.2 mmol / L
-Test substance: 0.1 μmol / L
After 30 minutes, the residual ratio of the test substance in the sample was measured by LC-MS, and the metabolic stability of human liver microsomes was calculated from the following equation.
Human liver microsome metabolic stability (mL / min / mg protein) = -LN (residual rate) / reaction time / human liver microsome concentration The results are shown in the table below.

Test Example 3-2: Human liver microsomal metabolic stability test In order to more accurately evaluate human liver microsomal metabolic stability, the human liver microsomal metabolic stability of the compound of the present invention at an appropriate human liver microsomal concentration was determined by the following method. Was evaluated. Human liver microsomes used were manufactured by Xenontech. Human liver microsomes, NADPH, and a test substance were mixed in a 25 mmol / L phosphate buffer (pH 7.4) to the following concentrations, and incubated at 37 ° C. for 30 minutes.
・ Human liver microsome: 0.5 or 1.0 mg / mL
NAPDH: 3.2 mmol / L
-Test substance: 0.1 μmol / L
After 30 minutes, the residual ratio of the test substance in the sample was measured by LC-MS, and the metabolic stability of human liver microsomes was calculated from the following equation.
Human liver microsome metabolic stability (mL / min / mg protein) = -LN (residual rate) / reaction time / human liver microsome concentration The results are shown in the table below.

Test Example 4-1: Human half-life prediction test The elimination half-life of the compound of the present invention in humans was predicted by the following method.
The compound of the present invention was intravenously administered to a cynomolgus monkey with a 0.01 mol / L aqueous hydrochloric acid solution, and blood was collected at 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours and 24 hours after administration. Collected. Plasma was obtained from the collected blood, the drug concentration in plasma was measured by LC-MS, and the monkey distribution volume was calculated from the change in the concentration.
The unbound fraction of the compound of the present invention in human and monkey serum was measured using the equilibrium dialysis method.
The half-life in humans was calculated by applying the following formula to the monkey distribution volume, unbound fraction in human and monkey serum, and the results of human liver microsomal metabolic stability obtained in Test Example 3-1.
・ Human distribution volume = Monkey distribution volume × Unbound fraction in human serum / Unbound fraction in monkey serum ・ Human liver clearance =
(Human hepatic blood flow x unbound fraction in human serum x 56.7 x human liver microsomal metabolic stability) / (human hepatic blood flow + unbound fraction in human serum x 56.7 x human hepatic mylosome metabolic stability)
-Human half-life = 0.693 x human distribution volume / human liver clearance The results are shown in the table below.

Test Example 4-2: Human half-life prediction test In order to more accurately estimate the elimination half-life of the compound of the present invention in humans, the following method was used using the results of human liver microsomal metabolic stability obtained in Test Example 3-2. Predicted by
The compound of the present invention was intravenously administered to a cynomolgus monkey with a 0.01 mol / L aqueous hydrochloric acid solution, and blood was collected at 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours and 24 hours after administration. Collected. Plasma was obtained from the collected blood, the drug concentration in plasma was measured by LC-MS, and the monkey distribution volume was calculated from the change in the concentration.
The unbound fraction of the compound of the present invention in human and monkey serum was measured using the equilibrium dialysis method.
The half-life in humans was calculated by applying the following formula to the monkey distribution volume, the unbound fraction in human and monkey serum, and the results of human liver microsomal metabolic stability obtained in Test Example 3-2.
・ Human distribution volume = Monkey distribution volume × Unbound fraction in human serum / Unbound fraction in monkey serum ・ Human liver clearance =
(Human hepatic blood flow x unbound fraction in human serum x 56.7 x human liver microsomal metabolic stability) / (human hepatic blood flow + unbound fraction in human serum x 56.7 x human hepatic mylosome metabolic stability)
-Human half-life = 0.693 x human distribution volume / human liver clearance The results are shown in the table below.

Test Example 5-1: Evaluation of hERG channel inhibitory activity The hERG channel inhibitory activity of the compound of the present invention was evaluated using a CHO cell in which a hERG channel involved in a human rapid-acting delayed rectifier potassium current (I _Kr ) was forcibly expressed. It was measured by the whole cell patch clamp method using a patch clamp system.
(Preparation of cell suspension)
HERG-CHO cells purchased from ChanTest were cultured at 37 ° C. in a CO ₂ incubator, and immediately before measurement of hERG current, detached from the flask using trypsin to prepare a cell suspension.
(Solution preparation)
An extracellular solution and an intracellular solution used for the measurement were prepared as follows.
Extracellular solution: 2 mmol / L CaCl ₂ , 1 mmol / L MgCl ₂ , 10 mmol / L HEPES, 4 mmol / L KCl, 145 mmol / L NaCl, 10 mmol / L Glucose
Intracellular solution: 5.4 mmol / L CaCl ₂ , 1.8 mmol / L MgCl ₂ , 10 mmol / L HEPES, 31 mmol / L KOH, 10 mmol / L EGTA, 120 mmol / L KCl, 4 mmol / L Na ₂ -ATP
Test substance solution: The test substance was dissolved in DMSO to a concentration of 2 mmol / L or 20 mmol / L to prepare a test substance solution. Further, the test substance solution was diluted 200-fold with the extracellular solution, and serially diluted with the extracellular solution to prepare test substance solutions at various concentrations necessary for calculating the hERG inhibition IC ₅₀ value, and applied.
(Current value measurement and data analysis)
A cell suspension, an extracellular solution, an intracellular solution, and a measurement plate were set in an auto-patch clamp system, and hERG current measurement was performed by the whole-cell patch clamp method. The voltage protocol was such that the holding potential was -80 mV, a depolarizing pulse was applied from -50 mV to +20 mV for 5 seconds, and then a repolarizing pulse was applied at -50 mV for 5 seconds to return to the holding potential. Each pulse interval was 15 seconds. Assay software for Qpatch system (Biolin Scientific) was used for data analysis. Four concentrations were gradually applied to each test substance, and the average value of the maximum outward current (Peak tail current) obtained by the last three stimulations at each applied concentration was used as evaluation data. In addition, the IC ₅₀ value was calculated from the inhibition rate of the current at each concentration of each test substance with respect to the value before application by the Hill equation using the software.
The results are shown in the table below.

Test Example 5-2: Evaluation of hERG channel inhibitory activity The hERG channel inhibitory activity of the compound of the present invention was determined by using a CHO cell in which a hERG channel involved in a human rapidly activated delayed rectifier potassium current (I _Kr ) was forcibly expressed. It was measured by the whole cell patch clamp method using a patch clamp system.
(Preparation of cell suspension)
HERG-CHO cells purchased from ChanTest were cultured at 37 ° C. in a CO ₂ incubator, and immediately before measurement of hERG current, detached from the flask using trypsin to prepare a cell suspension.
(Solution preparation)
An extracellular solution and an intracellular solution used for the measurement were prepared as follows.
Extracellular solution: 2 mmol / L CaCl ₂ , 1 mmol / L MgCl ₂ , 10 mmol / L HEPES, 4 mmol / L KCl, 145 mmol / L NaCl, 10 mmol / L Glucose
Intracellular solution: 10 mmol / L HEPES, 10 mmol / L EGTA, 20 mmol / L KCl, 130 mmol / L KF
Test substance solution: The test substance was dissolved in DMSO to a concentration of 2 mmol / L or 20 mmol / L to prepare a test substance solution. Further, the test substance solution was diluted 200-fold with the extracellular solution, and serially diluted with the extracellular solution to prepare test substance solutions at various concentrations necessary for calculating the hERG inhibition IC ₅₀ value, and applied.
(Current value measurement and data analysis)
A cell suspension, an extracellular solution, an intracellular solution, and a measurement plate were set in an auto-patch clamp system, and hERG current measurement was performed by the whole-cell patch clamp method. The voltage protocol was such that the holding potential was -80 mV, a depolarizing pulse was applied from -50 mV to +20 mV for 5 seconds, and then a repolarizing pulse was applied at -50 mV for 5 seconds to return to the holding potential. Each pulse interval was 15 seconds. For the data analysis, analysis software for Qube (manufactured by Sophion Scientific) was used. Four concentrations were gradually applied to each test substance, and the average value of the maximum outward current (Peak tail current) obtained by the last three stimulations at each applied concentration was used as evaluation data. In addition, the IC ₅₀ value was calculated from the inhibition rate of the current at each concentration of each test substance with respect to the value before application by the Hill equation using the software.
The results are shown in the table below.

Test Example 6: Contextual fear conditioning test The anxiolytic effect of the compound of the present invention was evaluated by the following method.
The evaluation was performed by a fear conditioning experiment apparatus (Ohara Medical Industry Co., Ltd.) using 8-week-old SD male rats in a test schedule of 2 days. On the first day of the test, a 0.5 mA electric shock was presented as a non-conditional stimulus five times in 6 minutes to learn the relationship between the context presented as the condition stimulus (illuminance in cage 200 lx) and the fear stimulus. On the second day of the test, the compound of the present invention was subcutaneously administered to a rat in a physiological saline solution or orally in a methylcellulose suspension solution. Rats were gently placed under non-display conditions. The freezing reaction time and the ratio of the freezing reaction exhibited by the rat during the 5-minute free movement were measured, and the freezing reaction rates in the vehicle administration group and the compound of the present invention administration group were compared, and statistical processing was performed. The groups to which the compounds of Example 1 (administration of 15 mg / kg), Example 8 (administration of 10 mg / kg), and Example 11 (administration of 30 mg / kg) were administered each accounted for 82.5% in comparison with the vehicle administration group. , 41.0%, 65.5% freezing reaction rate decreased (see FIG. 1).

Test Example 7: Marble burying test The effect of the compound of the present invention on obsessive-compulsive disorder-like behavior was evaluated by the following method.
In a plastic cage (floor area: 778 cm ² ), 450 to 500 g of paper bedding was spread, and 20 glass marbles were arranged at equal intervals on the bedding. The compound of the present invention was intraperitoneally administered to a 5-week-old ICR male mouse with a physiological saline solution. Fifteen minutes after the administration, the mouse was gently placed in the corner of the cage, allowed to freely move in the cage for 15 minutes, and then removed from the cage. The number of marbles buried in the bedding was measured, and the number was compared between the vehicle-administered group and the compound-administered group, and statistical processing was performed. The compound administration groups of Example 1 (0.5 mg / kg administration) and Example 11 (2 mg / kg administration) were buried in 44.8% and 64.8% bedding respectively with respect to the solvent administration group. The number of marbles was reduced (see FIG. 2).
The compounds of Example 1 (0.3 mg / kg administration) and Example 11 (1 mg / kg administration) were compared with the case where only escitalopram, a typical selective serotonin uptake inhibitor, was administered alone. When combined was administered, significant enhancement was observed in the effect of reducing the number of buried marbles (43.8%, 42.9%) (see FIG. 3).

Test Example 8: Forced swimming test The antidepressant action of the compound of the present invention was evaluated by the following method.
The test was performed on a 4-day test schedule using 8-week-old Wistar male rats. On the first day of the test, as a swim training, rats were placed in a transparent plastic water tank filled with 5.8 L of tap water at a water temperature of 25 ° C. and allowed to swim for 15 minutes. After the swimming training, the water droplets attached to the animal were immediately wiped off and returned to the home cage, and 15 minutes after the training, the compound of the present invention or the positive control compound was orally administered in a methylcellulose suspension. The compound of the present invention or a positive control compound was orally administered once a day in a methylcellulose suspension solution once a day after the training and two days after the training, and a swimming test was performed on the fourth day. On the day of the swimming test, the compound of the present invention or a positive control compound was orally administered in a methylcellulose suspension solution one hour before the start of the test, and swimming was performed for 5 minutes in the above-mentioned water tank. The swimming behavior of each individual was videotaped from the side of the aquarium, and the immobility time was measured with a stopwatch. It should be noted that “immobile” means that the animal is floating without moving the forelimbs and torso in the aquarium, and it is determined that the animal also includes a slight movement required to maintain the floating posture. The cumulative value of the time indicating immobility was defined as the immobility time of the individual. The immobility time between the vehicle administration group and the compound administration group was compared, and statistical processing was performed. The compound administration groups of Example 1 (5 mg / kg administration) and Example 11 (10 mg / kg administration) showed 74.7% and 59.2% reduction in immobility time, respectively, as compared with the solvent administration group ( (See FIG. 4).

Test Example 9: Microdialysis test The amount of monoamine released in the brain of the compound of the present invention was evaluated by the following method.
Eight-week-old Wistar male rats were used and fixed to a stereotaxic apparatus under anesthesia. The scalp is incised to remove the subcutaneous tissue, the position of the bregma is measured, and the position of the guide cannula (the position of the orbital frontal cortex (2.0 mm to the right of the bregma, 4.2 mm forward) according to the brain record of Paxinos & Watson. )) Was calculated. A hole was drilled at the guide cannula installation position with a dental drill, and an anchor screw was installed about 1 cm rearward. After placing a guide cannula and fixing with dental cement, the scalp was sutured, the animal was removed from the stereotaxic apparatus, and returned to the rearing cage. At the time of measurement, the rat was placed in an acrylic observation cage, a dialysis probe was inserted along a guide cannula, and connected to a free moving tube. The Ringer's solution was perfused at a rate of 2 μL / min using an infusion pump, and the dialysate was collected every 20 minutes. After the collection was started, three samples were collected, and the compound of the present invention was orally administered in a methylcellulose suspension, and dialysate was collected up to 180 minutes (9 samples) after the administration. The collected dialysate was measured for norepinephrine (NE), dopamine (DA) and serotonin (5-HT) content using an HPLC-ECD system. In the compound-administered group of Example 11 (10 mg / kg administration), the serotonin content in the dialysate was reduced (20.6%) and the norepinephrine and dopamine contents were increased (18.3%, 12. 4%). In addition, when Example 11 (10 mg / kg administration) was administered in combination, a significant increase in the norepinephrine and dopamine content in the dialysate (100%, 119%) was observed as compared with the case where sertraline was administered alone. (See FIG. 5).
It is known that serotonin 5-HT1A agonist reduces serotonin content by a single administration. On the other hand, it is thought that the suppression of serotonin release is released by reducing the sensitivity of the autoreceptor by repeated administration and exerts an antidepressant effect (Neuroscience. 1999, 93 (4): 1251-1262, Neurochem Int. 2002, 40 (4): 355-360). Example 11 did not decrease serotonin even in a single administration in combination with sertraline. This point is significantly different from other serotonin 5-HT1A agonists, and it is expected that the combined use with sertraline will enhance the antidepressant action from an early stage.

The compound of the present invention exhibits agonistic activity on both serotonin 5-HT _1A receptor and dopamine D ₄ receptor, and is therefore useful as a therapeutic agent for symptoms of anxiety-related disorders.

Claims (26)

Equation (1):

[Wherein, R ¹ represents an optionally substituted C _1-6 alkyl, an optionally substituted C _3-10 cycloalkyl, or an optionally substituted 5- to 10-membered saturated or partially unsubstituted alkyl group. Represents a saturated heterocyclic group;
R ² is a halogen atom, cyano, a C _1-6 alkyl optionally substituted with the same or different 1 to 3 halogen atoms, or a C _1-6 alkyl optionally substituted with the same or different 1 to 3 halogen atoms. _{Represents a} good C _1-6 alkoxy, or amino optionally substituted by 1 to 2 same or different C _1-6 alkyl;
The bond containing a broken line represents a single bond or a double bond], or a pharmaceutically acceptable salt thereof. R ¹ is
(1) a halogen atom, _{hydroxy, C 3-7} cycloalkyl, and _{C 1-6} 1 to 3 amino _{C 1-6} alkyl optionally substituted with a group of same or different selected from the group consisting of alkoxy ,
(2) a halogen atom, hydroxy, cyano, 1 to 3 halogen atoms or _{C 1-6} alkoxy optionally substituted by _{C 1-6} alkyl the same or different, the same or C1-6 alkyl heterologous is selected from the group consisting of amino which may optionally be substituted with one to two C _1-6 alkyl also a C _1-6 alkoxy, and same or different optionally substituted with atoms or C _1-6 alkoxy C _3-10 cycloalkyl which may be substituted with the same or different 1 to 4 groups, or (3) a halogen atom, hydroxy, cyano, 1 to 3 same or different halogen atoms or C _{1- 6} alkoxy optionally substituted by _{C 1-6} alkyl, optionally substituted with 1 to 3 halogen atoms or _{C 1-6} alkoxy the same or different _{C 1- 6} alkoxy and the same or different 1 to 4 groups selected from the group consisting of the same or different amino optionally substituted with 1 to 2 C _1-6 alkyl may be substituted. The pharmaceutical composition according to claim 1, which is a 5- to 10-membered saturated or partially unsaturated heterocyclic group. R ¹ is
(1) a halogen atom, and 1 to 4 same or different are selected from the group consisting of C _1-6 alkyl optionally substituted with 1-3 halogen atoms or C _1-6 alkoxy same or different number of good C _3-7 cycloalkyl optionally substituted with a group or (2) a halogen atom, and one to three same or different halogen atoms or C _1-6 optionally substituted alkoxy C 5 or 6 membered saturated or partially unsaturated heterocyclic group which may be substituted by the same or different 1 to 4 groups selected from the group consisting of _1-6 alkyl. 3. The pharmaceutical composition according to 2. R ¹ is C _3-7 cycloalkyl optionally substituted with 1 to 4 fluorines, or 5 or 6 membered saturated or partially unsaturated, optionally substituted with 1 to 4 fluorines The pharmaceutical composition according to any one of claims 1 to 3, which is a heterocyclic group. The method according to any one of claims 1 to 4, wherein R ¹ is cyclohexyl optionally substituted with ¹ to 4 fluorines, or tetrahydropyranyl, tetrahydrofuryl, dihydropyranyl, or dihydrofuryl. Pharmaceutical composition. The pharmaceutical composition according to any one of claims 1 to 5, wherein R ¹ is difluorocyclohexyl or tetrahydropyranyl. The pharmaceutical composition according to any one of claims 1 to 6, wherein R ² is a halogen atom or C _1-6 alkyl optionally substituted with the same or different 1 to 3 halogen atoms. . R ² is 1-3 optionally C _1-4 alkyl optionally substituted by fluorine, pharmaceutical composition according to any one of claims 1 to 7.   The pharmaceutical composition according to any one of claims 1 to 8, wherein the bond containing a broken line is a single bond. The pharmaceutical composition according to claim 1, wherein the compound represented by formula (1) is selected from the following compounds:
4,4-difluoro-N- (2- {4- [6- (trifluoromethyl) pyridin-2-yl] piperidin-1-yl} ethyl) cyclohexanecarboxamide,
N- {2- [4- (6-methylpyridin-2-yl) piperidin-1-yl] ethyl} -tetrahydro-2H-pyran-4-carboxamide;
2,2-dimethyl-N- (2- {4- [6- (trifluoromethyl) pyridin-2-yl] piperidin-1-yl} ethyl) propanamide, and N- (2- {4- [6 -(Trifluoromethyl) pyridin-2-yl] piperidin-1-yl {ethyl) -tetrahydro-2H-pyran-4-carboxamide. The pharmaceutical composition according to claim 1, wherein the compound represented by formula (1) is selected from the following compounds:
4,4-difluoro-N- (2- {4- [6- (trifluoromethyl) pyridin-2-yl] piperidin-1-yl} ethyl) cyclohexanecarboxamide,
N- {2- [4- (6-methylpyridin-2-yl) piperidin-1-yl] ethyl} -tetrahydro-2H-pyran-4-carboxamide; and N- (2- {4- [6- ( Trifluoromethyl) pyridin-2-yl] piperidin-1-yl {ethyl) -tetrahydro-2H-pyran-4-carboxamide. The pharmaceutical composition according to claim 1, wherein the compound represented by the formula (1) is the following compound:
4,4-difluoro-N- (2- {4- [6- (trifluoromethyl) pyridin-2-yl] piperidin-1-yl} ethyl) cyclohexanecarboxamide. The pharmaceutical composition according to claim 1, wherein the compound represented by the formula (1) is the following compound:
N- {2- [4- (6-Methylpyridin-2-yl) piperidin-1-yl] ethyl} -tetrahydro-2H-pyran-4-carboxamide. The pharmaceutical composition according to claim 1, wherein the compound represented by the formula (1) is the following compound:
2,2-dimethyl-N- (2- {4- [6- (trifluoromethyl) pyridin-2-yl] piperidin-1-yl} ethyl) propanamide. The pharmaceutical composition according to claim 1, wherein the compound represented by the formula (1) is the following compound:
N- (2- {4- [6- (trifluoromethyl) pyridin-2-yl] piperidin-1-yl} ethyl) -tetrahydro-2H-pyran-4-carboxamide.   A medicament containing the pharmaceutical composition according to claim 1.   A generalized anxiety disorder, major depression, obsessive-compulsive disorder, Parkinson's disease, Rett syndrome, attention deficit hyperactivity disorder, autism spectrum containing the pharmaceutical composition according to any one of claims 1 to 15. A therapeutic agent for a disorder or dementia.   A generalized anxiety disorder, major depression, obsessive-compulsive disorder, Parkinson comprising administering to a patient in need of treatment a therapeutically effective amount of a pharmaceutical composition according to any one of claims 1 to 15. A method for treating disease, Rett syndrome, attention deficit hyperactivity disorder, autism spectrum disorder, or dementia.   For manufacturing a therapeutic agent for generalized anxiety disorder, major depression, obsessive-compulsive disorder, Parkinson's disease, Rett syndrome, attention deficit hyperactivity disorder, autism spectrum disorder, or dementia, the method of claim 1 to 15, Use of a pharmaceutical composition according to any one of the preceding claims.   16. Any of claims 1 to 15, for use in treating general anxiety disorder, major depression, obsessive-compulsive disorder, Parkinson's disease, Rett syndrome, attention deficit hyperactivity disorder, autism spectrum disorder, or dementia. The pharmaceutical composition according to claim 1.   A pharmaceutical composition comprising a combination of the pharmaceutical composition according to any one of claims 1 to 15 and at least one or more other drugs selected from drugs classified as anxiolytics or antidepressants. .   General anxiety disorder, major depression, obsessive-compulsive disorder, Parkinson's disease, Rett syndrome, attention deficit in combination with at least one or more other drugs selected from drugs classified as anxiolytics or antidepressants The pharmaceutical composition according to any one of claims 1 to 15, for treating kinetic disorder, autism spectrum disorder, or dementia.   23. The pharmaceutical composition according to claim 21 or 22, wherein the anxiolytic is a selective serotonin reuptake inhibitor.   The selective serotonin reuptake inhibitor is at least one selected from the group consisting of sertraline, escitalopram, fluvoxamine, floxetine, paroxetine, and pharmaceutically acceptable salts thereof, according to claim 23. Pharmaceutical composition.   The pharmaceutical composition according to any one of claims 21 to 24, wherein the antidepressant is a serotonin reuptake inhibitor.   The serotonin reuptake inhibitor is at least one or more selected from the group consisting of milnacipran, duloxetine, venlafaxine, amoxapine, clomipramine, nortriptyline, imipramine, vortioxetine, and pharmaceutically acceptable salts thereof. 26. The pharmaceutical composition according to claim 25.

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