JP2004131501A - Cyclic amine compound, method for producing the same and use of the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a compound exhibiting excellent CCR5 antagonistic action and useful as a prophylactic/remedy for a human peripheral blood monocytic infection with HIV, especially AIDS. <P>SOLUTION: A pharmaceutical contains the compound expressed by formula (I) (Q<SP>1</SP>and Q<SP>2</SP>are each a 1-3C alkyl; Q<SP>3</SP>is a halogen; and X is CH<SB>2</SB>or SO<SB>2</SB>, and R is -SO<SB>2</SB>NR<SP>1</SP>R<SP>2</SP>or the like when X is CH<SB>2</SB>, or R is a 1-8C alkyl or the like when X is SO<SB>2</SB>) or its salt. <P>COPYRIGHT: (C)2004,JPO

Description

(4) The present invention relates to a cyclic amine compound useful for treating acquired immunodeficiency syndrome, its production method and use.

In recent years, HIV (Human Immunodeficiency Virus) protease inhibitors have been developed as treatments for AIDS (Acquired Immunodeficiency Syndrome), and the treatment of AIDS is achieved by combining with two conventionally used HIV reverse transcriptase inhibitors. Has progressed remarkably, but it is still not enough for eradication of AIDS, and the development of a new anti-AIDS drug based on another mechanism of action is desired.
CD4 has long been known as a receptor when HIV enters target cells. Recently, a seven-transmembrane G protein-coupled chemokine receptor called CCR5 has been known as a second receptor for macrophage-tropic HIV. It has been found that this chemokine receptor plays an essential role in the establishment and transmission of HIV infection. In fact, it has been reported that humans who exhibited resistance to HIV infection despite repeated exposure had a mutation in which the CCR5 gene was homozygously deleted. Therefore, CCR5 antagonists are expected to be new anti-HIV drugs.
Currently, as chemokine receptor antagonists, piperidine derivatives (for example, see Patent Literature 1, Patent Literature 2, Patent Literature 3, Patent Literature 4, and Patent Literature 5), pyrrolidine derivatives (for example, see Patent Literature 6), cyclopentane derivatives ( For example, see Patent Document 7), a triazaspiro [5,5] undecane derivative (for example, see Patent Document 8), a cyclic amide derivative (for example, see Patent Document 9), a cyclic amine derivative (for example, see Patent Document 10), urea Derivatives (for example, see Patent Document 11) and the like are known, but there is no example in which a CCR5 antagonist has been marketed as a therapeutic agent for AIDS to date.
: International Publication No. 99/04794 pamphlet : International Publication No. 99/38514 pamphlet : WO 00/39125 pamphlet : WO 00/66558 pamphlet : International Publication No. 00/66559 pamphlet : International Publication No. 00/51607 pamphlet : International Publication No. 00/76511 pamphlet : International Publication No. 01/40227 pamphlet : International Publication No. 00/66551 pamphlet : International Publication No. 01/25200 pamphlet : International Publication No. 01/25199 pamphlet

In order to search for an anti-AIDS drug based on CCR5 antagonism, the CCR5 gene is cloned from a human tissue-derived cDNA library, ligated to an animal cell expression vector, and introduced into animal cells to obtain a CCR5 expression cell line. There is a need to. This transformed cell line must then be used to screen for compounds that strongly inhibit the binding of the natural ligand CC chemokine RANTES to CCR5.

［式中、Ｑ^１およびＱ^２はそれぞれ同一または異なってＣ_１−３アルキル基を、Ｑ^３はハロゲン原子を、ＸはＣＨ_２またはＳＯ_２を示し、ＲはＸがＣＨ_２のとき、(i)−ＳＯ_２ＮＲ^１Ｒ^２（ただし、Ｒ^１およびＲ^２は同一または異なってそれぞれ水素原子または置換基として水酸基、Ｃ_１−４アルキル基、オキソ基、カルボキシル基、Ｃ_１−４アルコキシ基、ヒドロキシイミノ基、Ｃ_１−４アルコキシイミノ基、Ｃ_１−４アルコキシカルボニル基、Ｃ_１−４アルキルカルボニル基またはＣ_３−８シクロアルキル基を有していてもよいＣ_１−８アルキル基を示すか、またはＲ^１とＲ^２が結合してNと共に含窒素複素環を形成していてもよく、該含窒素複素環は置換基としてＣ_１−４アルキル基、水酸基、オキソ基、カルボキシル基、Ｃ_１−４アルコキシ基、ヒドロキシイミノ基、Ｃ_１−４アルコキシイミノ基、Ｃ_１−４アルコキシカルボニル基、Ｃ_１−４アルキルカルボニル基またはＣ_３−８シクロアルキル基を有していてもよい。）、(ii)−Ｙ^１−Ｗ−Ｚ^１{ただし、Y^１は単結合、Ｏ、Ｓ、ＳＯ、ＳＯ_２、Ｎ(ＳＯ_２Ｒ^３)（R^３はＣ_１−４アルキル基を示す。）、N(ＣＯＯＲ^３) （Ｒ^３ は前記と同意義を示す。）またはＣ(=Ｎ-ＯＲ^４) （R^４は水素原子またはＣ_１−４アルキル基を示す。）を、ＷはＣ_１−４アルキルで置換されていてもよいＣ_１−４アルキレンを、Z^１は水酸基、カルボキシル基、カルバモイル基、Ｃ_１−４アルコキシカルボニル基またはシアノ基を示す。}、(iii)−Ｙ^２−Ｒ^６{式中、Ｙ^２は-ＣＯ-、ＳＯ、ＳＯ_２、-Ｃ(=Ｎ-ＯＲ^４)- （Ｒ^４は前記と同意義を示す。）、-ＮＲ^４-ＳＯ_２-（Ｒ^４は前記と同意義を示す。）、-ＮＲ^４-ＣＯ_２-（Ｒ^４は前記と同意義を示す。）、-ＮＲ^４-ＣＯ-ＮＲ⁵-（Ｒ^４は前記と同意義を、R^５は水素原子またはＣ_１−４アルキル基を示す。）または-ＮＲ^４-ＣＯ-ＮＲ⁵-Ｏ-（Ｒ^４およびR^５は前記と同意義を示す。）を、Ｒ^６はＣ_１−８アルキルを示す。}、(iv)ＮＲ^１Ｒ^２（ただし、Ｒ^１およびＲ^２はそれぞれ前記と同意義を示す。）、(v)-ＮＲ^４-ＣＯ-ＮＨ_２（Ｒ^４は前記と同意義を示す。）、(vi)置換基としてＣ_１−４アルキル基またはオキソ基を有していてもよい複素環基、(vii)置換基としてシアノ基、カルボキシル基またはカルバモイル基を有するフェニル基または(viii)置換基としてシアノ基、カルボキシル基またはカルバモイル基を有するフェニルオキシ基を示し、ＸがＳＯ_２のとき、(i)Ｃ_１−８アルキル基、(ii)ハロゲン原子、(iii)ＮＲ^１Ｒ^２（ただし、Ｒ^１およびＲ^２はそれぞれ前記と同意義を示す。）、(iv)−Ｗ−Ｚ^２（ただし、Ｗは前記と同意義を、Ｚ²はカルボキシル基、カルバモイル基、Ｃ_１−４アルコキシカルボニル基またはシアノ基を示す。）、(v)−ＣＨ＝ＣＨ−Ｚ^２（ただし、Ｚ^２は前記と同意義を示す。）、(vi)−Ｃ≡Ｃ−Ｚ^２（ただし、Ｚ^２は前記と同意義を示す。）、(vii)−Ｙ^３−Ｒ^６{ただし、Ｙ^３は−ＣＯ−、−Ｃ(ＯＨ)Ｒ^４−（Ｒ^４は前記と同意義を示す。）、−Ｃ(＝Ｎ−ＯＲ^４) （Ｒ^４は前記と同意義を示す。）、−ＮＲ^４−ＳＯ_２−(Ｒ^４は前記と同意義を示す。)、-ＮＲ^４-ＣＯ_２-（Ｒ^４は前記と同意義を示す。）、-ＮＲ^４-ＣＯ-ＮＲ⁵-（Ｒ^４およびＲ⁵は前記と同意義を示す。）または-ＮＲ^４-ＣＯ-ＮＲ⁵-Ｏ-（Ｒ^４およびＲ⁵は前記と同意義を示す。）を、Ｒ^６は前記と同意義を示す。}または(viii)置換基としてカルボキシル基、Ｃ_１−４アルコキシカルボニル基またはカルバモイル基を有するフェニル基を示す。］で表される化合物またはその塩、
（２）Ｑ^１がメチル基、Ｑ^２がメチル基でＱ^３が塩素原子である上記（１）記載の化合物、
（３）Ｒとベンゼン環との結合位置が該ベンゼン環とＸとの結合位置に対してパラ位である上記（１）記載の化合物、
（４）ＸがＣＨ_２である上記（１）記載の化合物、
（５）ＸがＳＯ_２で、かつＲがＮＲ^１Ｒ^２（ただし、Ｒ^１およびＲ^２は同一または異なってそれぞれ水素原子または置換基として水酸基、Ｃ_１−４アルキル基、オキソ基、カルボキシル基、Ｃ_１−４アルコキシ基、ヒドロキシイミノ基、Ｃ_１−４アルコキシイミノ基、Ｃ_１−４アルコキシカルボニル基、Ｃ_１−４アルキルカルボニル基またはＣ_３−８シクロアルキル基を有していてもよいＣ_１−８アルキル基を示すか、またはＲ^１とＲ^２が結合してNと共に含窒素複素環を形成していてもよく、該含窒素複素環は置換基としてＣ_１−４アルキル基、水酸基、オキソ基、カルボキシル基、Ｃ_１−４アルコキシ基、ヒドロキシイミノ基、Ｃ_１−４アルコキシイミノ基、Ｃ_１−４アルコキシカルボニル基、Ｃ_１−４アルキルカルボニル基またはＣ_３−８シクロアルキル基を有していてもよい。）である上記（１）記載の化合物、
（６）ＸがＣＨ_２で、かつＲがＳＯ_２ＮＲ^１Ｒ^２（ただし、Ｒ^１およびＲ^２は同一または異なってそれぞれ水素原子または置換基として水酸基、Ｃ_１−４アルキル基、オキソ基、カルボキシル基、Ｃ_１−４アルコキシ基、ヒドロキシイミノ基、Ｃ_１−４アルコキシイミノ基、Ｃ_１−４アルコキシカルボニル基、Ｃ_１−４アルキルカルボニル基またはＣ_３−８シクロアルキル基を有していてもよいＣ_１−８アルキル基を示すか、またはＲ^１とＲ^２が結合してNと共に含窒素複素環を形成していてもよく、該含窒素複素環は置換基としてＣ_１−４アルキル基、水酸基、オキソ基、カルボキシル基、Ｃ_１−４アルコキシ基、ヒドロキシイミノ基、Ｃ_１−４アルコキシイミノ基、Ｃ_１−４アルコキシカルボニル基、Ｃ_１−４アルキルカルボニル基またはＣ_３−８シクロアルキル基を有していてもよい。）である上記（１）記載の化合物、
（７）1-アセチル-N-(3-{4-[(4-アミノフェニル)スルホニル]-1-ピペリジニル}プロピル)-N-(3-クロロ-4-メチルフェニル)-4-ピペリジンカルボキサミド、1-アセチル-N-(3-クロロ-4-メチルフェニル)-N-{3-[4-({4-[(3-メトキシプロピル)アミノ]フェニル}スルホニル)-1-ピペリジニル]プロピル}-4-ピペリジンカルボキサミド、1-アセチル-N-(3-クロロ-4-メチルフェニル)-N-[3-(4-{4-[(4-ヒドロキシ-1-ピペリジニル)スルホニル]ベンジル}-1-ピペリジニル)プロピル]-4-ピペリジンカルボキサミド、1-アセチル-N-(3-クロロ-4-メチルフェニル)-N-{3-[4-(4-{[(2-ヒドロキシエチル)アミノ]スルホニル}ベンジル)-1-ピペリジニル]プロピル}-4-ピペリジンカルボキサミド、1-アセチル-N-(3-クロロ-4-メチルフェニル)-N-[3-(4-{4-[(2-ヒドロキシエチル)チオ]ベンジル}-1-ピペリジニル)プロピル]-4-ピペリジンカルボキサミドまたはそれらの塩である上記（１）記載の化合物、
（８）上記（１）記載の化合物のプロドラッグ、
（９）式：

（式中、Ｑ^１、Ｑ^２およびＱ^３は前記と同意義であり、Ｚは脱離基を示す。）で表される化合物またはその塩と式：

［式中、ＸおよびＲは前記と同意義である。］で表される化合物またはその塩とを反応させることを特徴とする式（Ｉ）で表される化合物またはその塩の製造法、
（１０）上記（１）記載の化合物またはそのプロドラッグからなる医薬、
（１１）ＣＣケモカイン受容体拮抗剤である上記（１０）記載の医薬、
（１２）ＣＣＲ５拮抗剤である上記（１０）記載の医薬、
（１３）ＨＩＶ感染症治療剤である上記（１０）記載の医薬、
（１４）ＡＩＤＳの予防・治療剤である上記（１０）記載の医薬、
（１５）ＡＩＤＳの病態進行抑制剤である上記（１０）記載の医薬、
（１６）輸血用血液または血液製剤である上記（１０）記載の医薬、および
（１７）臓器または骨髄移植時における移植片対宿主病および／または拒絶反応の予防・治療剤である上記（１０）記載の医薬、
（１８）慢性関節リウマチ、自己免疫疾患、アレルギー性疾患、虚血性脳細胞障害、心筋梗塞、腎炎、腎症または動脈硬化の予防・治療剤である上記（１０）記載の医薬、
（１９）ＣＣケモカイン受容体拮抗剤の製造のための上記（１）記載の化合物またはそのプロドラッグの使用、
（２０）ＨＩＶ感染症治療剤、ＡＩＤＳの予防・治療剤、ＡＩＤＳの病態進行抑制剤、臓器または骨髄移植時における移植片対宿主病および／または拒絶反応の予防・治療剤、あるいは慢性関節リウマチ、自己免疫疾患、アレルギー性疾患、虚血性脳細胞障害、心筋梗塞、腎炎、腎症または動脈硬化の予防・治療剤の製造のための上記（１）記載の化合物またはそのプロドラッグの使用、および
（２１）ＨＩＶ感染症の治療、ＡＩＤＳの予防・治療、ＡＩＤＳの病態進行抑制、臓器または骨髄移植時における移植片対宿主病および／または拒絶反応の予防・治療、あるいは慢性関節リウマチ、自己免疫疾患、アレルギー性疾患、虚血性脳細胞障害、心筋梗塞、腎炎、腎症または動脈硬化の予防・治療の方法であって、それらを必要とするヒトに上記（１）記載の化合物またはそのプロドラッグの有効量を投与することを含んでなる方法に関する。 The present inventors have conducted intensive studies on compounds having a CCR5 antagonistic activity, particularly the cyclic amine derivatives and their structural analogs described in WO 01/25200. As a result, the compounds represented by the following general formula (I) or salts thereof are extremely excellent. It has been shown that it has a CCR5 antagonistic effect, is useful as a preventive / therapeutic agent for HIV infection of human peripheral blood mononuclear cells, particularly AIDS, and has excellent oral absorption. Thus, the present invention has been completed.
That is, the present invention
Equation (1):

[In the formula, Q ¹ and Q ² are the same or different and each represents a C _1-3 alkyl group, Q ³ represents a halogen atom, X represents CH ₂ or SO ₂ , and R represents, when X is CH ₂ , i) —SO ₂ NR ¹ R ² (where R ¹ and R ² are the same or different and are each a hydrogen atom or a hydroxyl group, a C _1-4 alkyl group, an oxo group, a carboxyl group, a C _1-4 alkoxy group as a hydrogen atom or a substituent) A _C1-8 alkyl group optionally having a hydroxyimino group, a _C1-4 alkoxyimino group, a _C1-4 alkoxycarbonyl group, a _C1-4 alkylcarbonyl group or a _C3-8 cycloalkyl group. indicating either, or R ¹ and R ² may bond together to form a nitrogen-containing heterocyclic ring together with N, nitrogen-containing heterocycle C _1-4 alkyl group as a substituent, a hydroxyl group, an oxo group, a carboxyl , _{C 1-4} alkoxy groups, hydroxyimino _{groups, C 1-4} alkoxyimino _{group, C 1-4} alkoxycarbonyl group _may have a _{C 1-4} alkyl group or _{C 3-8} cycloalkyl group ), (Ii) -Y ¹ -WZ ¹ [where Y ¹ is a single bond, O, S, SO, SO ₂ , N (SO ₂ R ³ ) (R ³ is a C _1-4 alkyl group. ), N (COOR ³ ) (R ³ has the same meaning as described above) or C (= N-OR ⁴ ) (R ⁴ represents a hydrogen atom or a C _1-4 alkyl group). _{Represents a} C _1-4 alkylene which may be substituted with a C _1-4 alkyl, and Z ¹ represents a hydroxyl group, a carboxyl group, a carbamoyl group, a C _1-4 alkoxycarbonyl group or a cyano group. ^{}, (Iii) -Y 2 -R} 6 { wherein, ^{Y 2} is _{-CO-, SO, SO 2, -C} (= N-OR 4) -, (R 4 is as defined above.) -NR ⁴ -SO _2- (R ⁴ has the same meaning as described above), -NR ⁴ -CO _2- (R ⁴ has the same meaning as described above), -NR ⁴ -CO-NR ^5- ( R ⁴ has the same meaning as described above, and R ⁵ represents a hydrogen atom or a C _1-4 alkyl group.) Or —NR ⁴ —CO—NR ⁵ —O— (R ⁴ and R ⁵ have the same meanings as above. ) And R ⁶ represents C _1-8 alkyl. }, (Iv) NR ¹ R ² (wherein R ¹ and R ² each have the same meaning as described above), (v) -NR ⁴ —CO—NH ₂ (R ⁴ has the same meaning as described above.) ), (Vi) a heterocyclic group optionally having a C _1-4 alkyl group or an oxo group as a substituent, (vii) a phenyl group having a cyano group, a carboxyl group or a carbamoyl group as a substituent, or (viii) A phenyloxy group having a cyano group, a carboxyl group, or a carbamoyl group as a substituent, and when X is SO ₂ , (i) a C _1-8 alkyl group, (ii) a halogen atom, (iii) NR ¹ R ² ( Provided that R ¹ and R ² have the same meanings as above, respectively, and (iv) -WZ ² (where W is the same as above; Z ² is a carboxyl group, a carbamoyl group, C _1-4) Represents an alkoxycarbonyl group or a cyano group), (v) -CH = C H-Z ² (where Z ² has the same meaning as described above), (vi) -C≡C-Z ² (where Z ² has the same meaning as above), (vii) -Y ³ —R ⁶ {where, Y ³ is —CO—, —C (OH) R ⁴ — (R ⁴ has the same meaning as described above), —C (＝ N—OR ⁴ ) (R ⁴ is as defined above. shows the _{^{significance), -. NR 4 -SO 2}} - (R 4 is as defined _{^{above), -. NR 4 -CO 2}} - (R 4 is as defined above), -. NR ⁴ - CO-NR ^5- (R ⁴ and R ⁵ have the same meaning as described above) or -NR ⁴ -CO-NR ⁵ -O- (R ⁴ and R ⁵ have the same meanings as described above); ⁶ has the same meaning as described above. } Or (viii) a phenyl group having a carboxyl group, a _C1-4 alkoxycarbonyl group or a carbamoyl group as a substituent. Or a salt thereof,
(2) The compound according to the above (1), wherein Q ¹ is a methyl group, Q ² is a methyl group, and Q ³ is a chlorine atom.
(3) The compound according to the above (1), wherein the bonding position between R and the benzene ring is para to the bonding position between the benzene ring and X.
(4) The compound according to the above (1), wherein X is CH ₂ ,
(5) X is SO ₂ and R is NR ¹ R ² (provided that R ¹ and R ² are the same or different and each represents a hydrogen atom or a hydroxyl group, a C _1-4 alkyl group, an oxo group, a carboxyl group as a substituent. , A C _1-4 alkoxy group, a hydroxyimino group, a C _1-4 alkoxyimino group, a C _1-4 alkoxycarbonyl group, a C _1-4 alkylcarbonyl group or a C _3-8 cycloalkyl group. It may represent a C _1-8 alkyl group, or R ¹ and R ² may combine with each other to form a nitrogen-containing heterocyclic ring with N, and the nitrogen-containing heterocyclic ring may be a C _1-4 alkyl group, Hydroxyl group, oxo group, carboxyl group, C _1-4 alkoxy group, hydroxyimino group, C _1-4 alkoxyimino group, C _1-4 alkoxycarbonyl group, C _1-4 alkylcarbonyl A compound or a C _3-8 cycloalkyl group).
(6) X is CH ₂ and R is SO ₂ NR ¹ R ² (provided that R ¹ and R ² are the same or different and are each a hydrogen atom or a C _1-4 alkyl group, an oxo group, Having a carboxyl group, a _C1-4 alkoxy group, a hydroxyimino group, a _C1-4 alkoxyimino group, a _C1-4 alkoxycarbonyl group, a _C1-4 alkylcarbonyl group or a _C3-8 cycloalkyl group. _May represent a C _1-8 alkyl group, or R ¹ and R ² may combine with each other to form a nitrogen-containing heterocyclic ring with N, and the nitrogen-containing heterocyclic ring may be a C _1-4 alkyl group as a substituent. group, hydroxyl group, oxo group, carboxyl _{group, C 1-4} alkoxy groups, hydroxyimino _{groups, C 1-4} alkoxyimino _{group, C 1-4} alkoxycarbonyl _{group, C 1-4} Arukiruka Boniru group or C _3-8 which may have a cycloalkyl group.) A above (1) compounds described,
(7) 1-acetyl-N- (3- {4-[(4-aminophenyl) sulfonyl] -1-piperidinyl} propyl) -N- (3-chloro-4-methylphenyl) -4-piperidinecarboxamide; 1-acetyl-N- (3-chloro-4-methylphenyl) -N- {3- [4-({4-[(3-methoxypropyl) amino] phenyl} sulfonyl) -1-piperidinyl] propyl}- 4-piperidinecarboxamide, 1-acetyl-N- (3-chloro-4-methylphenyl) -N- [3- (4- {4-[(4-hydroxy-1-piperidinyl) sulfonyl] benzyl} -1- Piperidinyl) propyl] -4-piperidinecarboxamide, 1-acetyl-N- (3-chloro-4-methylphenyl) -N- {3- [4- (4-{[(2-hydroxyethyl) amino] sulfonyl} Benzyl) -1-piperidinyl] propyl} -4-piperidinecarboxamide, 1-acetyl-N- (3-chloro-4-methylphenyl) -N- [3- (4- {4-[(2-hydroxyethyl) Thio] benzyl} -1-piperidinyl) propyl] -4-piperidine Bokisamido or compounds of the above (1), wherein a salt thereof,
(8) a prodrug of the compound according to (1),
Equation (9):

(Wherein Q ¹ , Q ² and Q ³ are as defined above, and Z represents a leaving group) or a salt thereof and a compound represented by the formula:

[Wherein, X and R are as defined above. A method for producing a compound represented by the formula (I) or a salt thereof, characterized by reacting the compound represented by the formula (I) or a salt thereof:
(10) a medicament comprising the compound according to (1) or a prodrug thereof,
(11) the medicament according to the above (10), which is a CC chemokine receptor antagonist;
(12) the medicament according to the above (10), which is a CCR5 antagonist;
(13) the medicament according to the above (10), which is a therapeutic agent for HIV infection;
(14) the medicament according to the above (10), which is an agent for preventing or treating AIDS;
(15) the medicament according to the above (10), which is an AIDS disease progression inhibitor;
(16) The medicament according to (10), which is a blood or a blood product for blood transfusion, and (17) the agent (10), which is a prophylactic or therapeutic agent for graft-versus-host disease and / or rejection during organ or bone marrow transplantation. The medicament described,
(18) The medicament according to the above (10), which is a preventive / therapeutic agent for rheumatoid arthritis, autoimmune disease, allergic disease, ischemic brain cell injury, myocardial infarction, nephritis, nephropathy or arteriosclerosis.
(19) Use of the compound according to (1) or a prodrug thereof for the production of a CC chemokine receptor antagonist,
(20) an agent for treating HIV infection, an agent for preventing or treating AIDS, an agent for suppressing the progression of AIDS, an agent for preventing or treating graft-versus-host disease and / or rejection during organ or bone marrow transplantation, or rheumatoid arthritis; Use of the compound according to the above (1) or a prodrug thereof for the manufacture of a prophylactic / therapeutic agent for an autoimmune disease, an allergic disease, ischemic brain cell injury, myocardial infarction, nephritis, nephropathy or arteriosclerosis, and ( 21) treatment of HIV infection, prevention and treatment of AIDS, suppression of progression of AIDS, prevention and treatment of graft-versus-host disease and / or rejection during organ or bone marrow transplantation, or rheumatoid arthritis, autoimmune disease, A method of preventing or treating allergic disease, ischemic brain cell injury, myocardial infarction, nephritis, nephropathy or arteriosclerosis, and in need thereof Relates to a method comprising administering the compound of formula (1) wherein an effective amount of a prodrug thereof.

化合物 Since the compound represented by the formula (I) of the present invention or a salt thereof has a strong CCR5 antagonistic effect, it can be advantageously used for prevention and treatment of various HIV infections in humans, for example, AIDS.

In the above formula, examples of the C _1-3 alkyl group represented by Q ¹ and Q ² include methyl, ethyl, n-propyl and i-propyl. Examples of the halogen atom represented by Q ³ include fluorine, chlorine, Bromine and iodine.
As the substituents represented by R ¹ and R ² , a hydroxyl group, a C _1-4 alkyl group, a hydroxyl group, an oxo group, a carboxyl group, a C _1-4 alkoxy group, a hydroxyimino group, a C _1-4 alkoxyimino group, a C _{1 -4} alkoxycarbonyl _group, as the _{"C 1-8} alkyl group" in _{C 1-4} alkyl group or _{C 3-8} cycloalkyl group optionally _{C 1-8} alkyl group which may have a ", for example methyl, Examples thereof include ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl and n-octyl, and among them, those having 1 to 4 carbon atoms such as methyl, ethyl and propyl are preferable.
Examples of the C _1-4 alkyl group as a substituent of the alkyl group include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and the like. Examples of the C _1-4 alkoxy group include methoxy, Ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy and the like, and the C _1-4 alkoxyimino group includes, for example, methoxyimino, ethoxyimino, n-propoxyimino, i-propoxyimino, n-butoxy. imino, such as i- Butokishiimino _is, as the _{C 1-4} alkoxycarbonyl group, for example methoxycarbonyl, ethoxycarbonyl, n- propoxycarbonyl, i- propoxycarbonyl, n- butoxycarbonyl, etc. i- butoxycarbonyl, _{C 1 -4} the alkyl group Mechiruka Boniru, ethylcarbonyl, n- propylcarbonyl, i- propyl carbonyl, n- butylcarbonyl, etc. i- butyl carbonyl. Examples of _{the C 3-8} cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. And these substituents may be substituted at any position of the C _1-8 alkyl group by 1 to 5, preferably 1 to 2 substituents. When R ¹ and R ² combine to form a nitrogen-containing heterocyclic group together with N, examples of the nitrogen-containing heterocyclic group include azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, heptamethyleneimino, morpholinyl, thiomorpholinyl, piperazinyl, homopiperazinyl And 3-8 membered (preferably 5 to 6 membered) saturated or unsaturated (preferably saturated) non-aromatic heterocyclic groups (aliphatic heterocyclic groups), among which pyrrolidinyl, piperidinyl, morpholinyl and the like. And piperazinyl are preferred. The nitrogen-containing heterocycle may be a C _1-4 alkyl group (eg, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, etc.), a hydroxyl group, an oxo group, a carboxyl group, _1-4 alkoxy group (eg, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, etc.), hydroxyimino group, C _1-4 alkoxyimino group (eg, methoxyimino, ethoxyimino, n-propoxyimino, i-propoxyimino, n-butoxyimino, i-butoxyimino, etc., C _1-4 alkoxycarbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl, n- butoxycarbonyl, etc. i- _{butoxycarbonyl), C 1-4} alkylcarbonyl (Eg, methylcarbonyl, ethylcarbonyl, n- propylcarbonyl, i- propyl carbonyl, n- butylcarbonyl, i- butyl carbonyl, etc.) or _{C 3-8} cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Cycloheptyl and the like).
Examples of the C _1-4 alkyl group represented by R ³ and R ⁴ include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and the like.

As the C _1-4 alkylene of the “C _1-4 alkylene optionally substituted by a C _1-4 alkyl group” for W, one or two or four methylenes connected in series, that is, methylene , 1,2-ethylene, 1,3-propylene, and 1,4-butylene, and the C _1-4 alkyl group as a substituent thereof includes, for example, methyl, ethyl, n-propyl, i-propyl, n -Butyl, i-butyl and the like.
The _{C 1-4} alkoxycarbonyl group represented by Z ^1, for example a methoxycarbonyl, ethoxycarbonyl, n- propoxycarbonyl, i- propoxycarbonyl, n- butoxycarbonyl, etc. i- butoxycarbonyl.
Examples of the C _1-4 alkyl group represented by R ⁵ include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and the like.
Examples of the C _1-8 alkyl group represented by R ⁶ include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl and i-pentyl. , T-pentyl, neopentyl, n-hexyl, i-hexyl, n-heptyl, n-octyl and the like.
The “heterocyclic group in the heterocyclic group optionally having a C _1-4 alkyl group or an oxo group as a substituent” represented by R is, for example, an oxygen atom as an atom (ring atom) constituting a ring system. Aromatic heterocyclic ring containing at least one (preferably 1 to 4, more preferably 1 to 2) of 1 to 3 (preferably 1 to 2) heteroatoms selected from, sulfur and nitrogen atoms Group, saturated or unsaturated non-aromatic heterocyclic group (aliphatic heterocyclic group), and the like. As the “aromatic heterocyclic group”, an aromatic monocyclic heterocyclic group (for example, furyl, thienyl, Pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, fura Zanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, 5- or 6-membered aromatic monocyclic heterocyclic groups such as pyrazinyl and triazinyl) and fused aromatic heterocyclic groups [eg benzofuranyl, isobenzofuranyl, benzothienyl, indolyl, isoindolyl, 1H-indazolyl, benzindazolyl Benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, benzopyranyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, Purinyl, buteridinyl, carba Zolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl, phenathridinyl, phenatrolinyl, indolizinyl, pyrrolo [1,2- b ] pyridazinyl, pyrazolo [1, 5- a ] pyridyl, imidazo [1,2- a ] pyridyl, imidazo [1,5- a ] pyridyl, imidazo [1,2- b ] pyridazinyl, imidazo [1,2- a ] pyrimidinyl, 1,2, An 8- to 12-membered aromatic condensed heterocyclic group such as 4-triazolo [4,3- a ] pyridyl, 1,2,4-triazolo [4,3- b ] pyridazinyl (preferably the 5- to 6-membered A heterocyclic ring in which an aromatic monocyclic heterocyclic group is condensed with a benzene ring or the 5- or 6-membered aromatic monocyclic heterocyclic group described above. A heterocyclic ring in which two identical or different heterocyclic rings having the same or different ring groups are condensed)] and the like. , Piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, dihydro-1,2,4-oxadiazolyl, etc. having 3 to 8 members (preferably 5 to 6 members) saturated or unsaturated (preferably saturated) non-aromatic And a heterocyclic group (aliphatic heterocyclic group). Examples of the C _1-4 alkyl group as a substituent of the heterocyclic group include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and the like.

In the “phenyl group having a cyano group, a carboxyl group or a carbamoyl group as a substituent” represented by R, one or two phenyl substituents may be substituted at any substitutable position on the benzene ring.
In the "phenyloxy group having a cyano group, a carboxyl group or a carbamoyl group as a substituent" represented by R, the substituent of the phenyloxy group may be substituted at one or two positions which can be substituted on the benzene ring. Good.
Examples of the C _1-8 alkyl group represented by R include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, Examples include t-pentyl, neopentyl, n-hexyl, i-hexyl, n-heptyl and n-octyl.
Examples of the halogen atom represented by R include fluorine, chlorine, bromine, and iodine.
Examples of the C _1-4 alkoxycarbonyl group represented by Z ² include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl, n-butoxycarbonyl, i-butoxycarbonyl and the like.
One to three substituents in the “phenyl group having a carboxyl group, a C _1-4 alkoxycarbonyl group or a carbamoyl group as a substituent” represented by R may be substituted at any position. Examples of the C _1-4 alkoxycarbonyl group include, for example, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl, n-butoxycarbonyl, i-butoxycarbonyl and the like.
In the formula (II), examples of the leaving group represented by Z include a halogen atom (eg, chlorine atom, bromine atom, iodine atom, etc.), an alkyl or arylsulfonyloxy group (eg, methanesulfonyloxy, ethanesulfonyl Oxy, benzenesulfonyloxy, p-toluenesulfonyloxy, etc.).
As the compound represented by the formula (I), the following compounds are preferable.
1-acetyl-N- (3- {4-[(4-aminophenyl) sulfonyl] -1-piperidinyl} propyl) -N- (3-chloro-4-methylphenyl) -4-piperidinecarboxamide,
1-acetyl-N- (3-chloro-4-methylphenyl) -N- {3- [4-({4-[(3-methoxypropyl) amino] phenyl} sulfonyl) -1-piperidinyl] propyl}- 4-piperidinecarboxamide,
1-acetyl-N- (3-chloro-4-methylphenyl) -N- [3- (4- {4-[(4-hydroxy-1-piperidinyl) sulfonyl] benzyl} -1-piperidinyl) propyl]- 4-piperidinecarboxamide,
1-acetyl-N- (3-chloro-4-methylphenyl) -N- {3- [4- (4-{[(2-hydroxyethyl) amino] sulfonyl} benzyl) -1-piperidinyl] propyl}- 4-piperidinecarboxamide,
1-acetyl-N- (3-chloro-4-methylphenyl) -N- [3- (4- {4-[(2-hydroxyethyl) thio] benzyl} -1-piperidinyl) propyl] -4-piperidine Carboxamide or a salt thereof.

As the salt of the compound represented by the formula (I) of the present invention, a pharmacologically acceptable salt is preferable, for example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, and a salt with an organic acid. And salts with basic or acidic amino acids. Preferable examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and aluminum salt and ammonium salt. Preferable examples of the salt with an organic base include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N'-dibenzylethylenediamine and the like. Preferable examples of the salt with an inorganic acid include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Suitable examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p -Salts with toluenesulfonic acid and the like. Preferable examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, ornithine, and preferable examples of the salt with an acidic amino acid include, for example, salts with aspartic acid, glutamic acid, and the like. Can be The compound represented by the formula (I) of the present invention may be a hydrate or a non-hydrate.
Compound (I) may be labeled with an isotope (eg, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.). When the compound represented by the formula (I) of the present invention exists as a configurational isomer (configuration isomer), a diastereomer, a conformer, or the like, if necessary, separation and separation known per se may be performed. Each can be isolated by purification means. Compound (I) may have one or more asymmetric carbon atoms in the molecule, and when these compounds are in a racemic form, the (S) form, ( R) and can be separated into optical isomers and racemic forms.

化合物 The compound represented by formula (I) or a salt thereof used in the present invention [hereinafter may be referred to as compound (I). Are converted into the compound (I) by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, that is, the compound is converted into the compound (I) by enzymatic oxidation, reduction, hydrolysis, or the like. The compound is a compound which undergoes hydrolysis or the like by stomach acid or the like to change to compound (I). As a prodrug of the compound (I), a compound in which the amino group of the compound (I) is acylated, alkylated, and phosphorylated (eg, the amino group of the compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated) , (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compounds, etc.); Compounds in which the hydroxyl group of compound (I) is acylated, alkylated, phosphorylated, or borated (eg, the hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanyl) Compound, dimethylaminomethylcarbonylated compound etc.); carboxyl group of compound (I) is an ester Amidated compounds (eg, carboxyl group of compound (I) is ethyl-esterified, phenyl-esterified, carboxymethyl-esterified, dimethylaminomethyl-esterified, pivaloyloxymethyl-esterified, ethoxycarbonyloxyethyl-esterified) Phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidated compound, etc.). These compounds can be produced from compound (I) by a method known per se.

The prodrug of compound (I) is a compound that changes to compound (I) under physiological conditions as described in Hirokawa Shoten, 1990, “Development of Pharmaceuticals,” Vol. 7, pp. 163-198, Molecular Design. It may be.
The prodrug of compound (I) may be itself or a pharmacologically acceptable salt. Such salts include, when the prodrug of compound (I) has an acidic group such as a carboxyl group, an inorganic base (eg, an alkali metal such as sodium or potassium, an alkaline earth metal such as calcium or magnesium, zinc, Transition metals such as iron and copper), organic bases (eg, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, organic amines such as N, N'-dibenzylethylenediamine, arginine) , Lysine, or basic amino acids such as ornithine, etc.).
When the prodrug of compound (I) has a basic group such as an amino group, an inorganic acid or an organic acid (eg, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, carbonic acid, bicarbonic acid, formic acid, acetic acid, propionic acid, trifluoroacetic acid) , Fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.), and salts with acidic amino acids such as aspartic acid and glutamic acid. No.
Further, the prodrug of compound (I) may be either a hydrate or a non-hydrate.
In the compound represented by the formula (III), a compound having a basic group or an acidic group can form an acid addition salt or a salt with a base, respectively. Examples of the acid addition salt and the salt with a base include those similar to the salts of the compound represented by the formula (I).

Compound (I) can be produced, for example, by the method shown below.
The compound used in each of the following production methods may form a salt similar to the compound (I) as long as the reaction is not hindered.
In each of the following reactions, when the starting compound has an amino group, a carboxyl group, or a hydroxyl group as a substituent, a protecting group generally used in peptide chemistry or the like is introduced into these groups. Alternatively, the target compound can be obtained by removing the protecting group as necessary after the reaction.
Examples of the amino-protecting group include C _1-6 alkylcarbonyl (eg, acetyl, propionyl and the like) which may have a substituent, formyl, phenylcarbonyl, C _1-6 alkyloxycarbonyl (eg, methoxycarbonyl) , Ethoxycarbonyl, t-butoxycarbonyl, etc.), phenyloxycarbonyl (eg, benzyloxycarbonyl), _C7-10 aralkyloxycarbonyl (eg, benzyloxycarbonyl), trityl, phthaloyl and the like. As these substituents, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkylcarbonyl (eg, acetyl, propionyl, butyryl, etc.), a nitro group and the like are used. Is about one to three.
As the protecting group for the carboxyl group, for example, C _1-6 alkyl _optionally having a substituent (for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, trityl, silyl and the like are used. Can be As these substituents, halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkylcarbonyl (eg, acetyl, propionyl, butyryl, etc.), formyl, nitro group and the like are used. Is about one to three.

Examples of the protecting group for the hydroxy group include C _1-6 alkyl _optionally having a substituent (for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, C _7-10 aralkyl ( For example, benzyl, _{etc.), C 1-6} alkylcarbonyl (e.g., acetyl, propionyl, etc.), formyl, _{phenyloxycarbonyl, C 7-10} aralkyloxycarbonyl (e.g., benzyloxycarbonyl), pyranyl, furanyl, silyl and the like Used. As these substituents, halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkyl, phenyl, C _7-10 aralkyl, nitro group and the like are used, and the number of substituents is 1 to There are about four.
As a method for introducing and removing the protecting group, a method known per se or a method analogous thereto (for example, a method described in Protective Groups in Organic Chemistry (JFWMcOmie et al., Plenum Press)) is used, As a removal method, for example, a method of treating with an acid, a base, reduction, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate or the like is used.
In the following description, the compounds represented by the formulas (III), (IV), (V), (VII), (VIII), (XI), (XII) and (XIII) each include their salts. It may be simply referred to as compound (III), compound (IV), compound (V), compound (VII), compound (VIII), compound (XI), compound (XII) and compound (XIII). Further, the compounds represented by formulas (II), (VI), (IX) and (X) may be simply referred to as compound (II), compound (VI), compound (IX) and compound (X), respectively.

（式中、Ｒ^７はカルボキシル基またはその反応性誘導体を示し、他の各記号は前記と同意義である。）
　この反応は、通常反応に不活性な溶媒中で行われる。該溶媒としては、たとえばエーテル系溶媒（例、エチルエーテル、ジイソプロピルエーテル、ジメトキシエタン、テトラヒドロフラン、ジオキサンなど）、ハロゲン系溶媒（例、ジクロロメタン、ジクロロエタン、クロロホルムなど）、芳香族系溶媒（例、トルエン、クロロベンゼン、キシレンなど）、アセトニトリル、Ｎ，Ｎ−ジメチルホルムアミド（ＤＭＦ）、アセトン、メチルエチルケトン、ジメチルスルホキシド（ＤＭＳＯ）、水などを単独あるいはそれらを混合して用いることができる。中でもアセトニトリル、ジクロロメタン、クロロホルムなどが好ましい。この反応は通常化合物（Ｖ）に対し、化合物（ＩＶ）１ないし５当量、好ましくは１ないし３当量反応させることにより行われる。反応温度は−２０℃から５０℃、好ましくは０℃ないし室温であり、反応時間は通常５分間から１００時間である。またこの反応においては塩基を共存させることにより、反応がより円滑に進行する場合もある。該塩基としては、無機塩基、有機塩基ともに有効である。無機塩基の例としては、アルカリ金属やアルカリ土類金属の水酸化物、水素化物、炭酸塩、炭酸水素塩などがあげられ、中でも炭酸カリウム、炭酸ナトリウム、水酸化ナトリウム、水酸化カリウム、炭酸水素ナトリウム、炭酸水素カリウムが好ましい。有機塩基としてはトリエチルアミンなどの３級アミン類が好ましい。該反応性誘導体には酸無水物、酸ハライド（例えば酸クロリド、酸ブロミド）、活性エステル、などがあげられ、中でも酸ハライドが好ましい。該塩基の使用量は、化合物（Ｖ）に対し、通常１ないし１０当量、好ましくは１ないし３当量である。
　カルボン酸からアシル化する場合には、不活性溶媒中（例えば、ハロゲン系溶媒、アセトニトリル）、化合物（Ｖ）とこれ１当量に対し１ないし１．５当量のカルボン酸とを１ないし１．５当量のジシクロヘキシルカルボジイミド（ＤＣＣ）などの脱水縮合剤存在下反応させることにより行われる。この反応は通常室温下に行われ、反応時間は０．５ないし２４時間である。 Manufacturing method 1
As shown in the following formula, compound (I) can be produced by reacting compound (V) with compound (IV).

(Wherein, R ⁷ represents a carboxyl group or a reactive derivative thereof, and other symbols are as defined above.)
This reaction is usually performed in a solvent inert to the reaction. Examples of the solvent include ether solvents (eg, ethyl ether, diisopropyl ether, dimethoxyethane, tetrahydrofuran, dioxane, etc.), halogen solvents (eg, dichloromethane, dichloroethane, chloroform, etc.), and aromatic solvents (eg, toluene, Chlorobenzene, xylene, etc.), acetonitrile, N, N-dimethylformamide (DMF), acetone, methyl ethyl ketone, dimethyl sulfoxide (DMSO), water and the like can be used alone or as a mixture thereof. Among them, acetonitrile, dichloromethane, chloroform and the like are preferable. This reaction is carried out usually by reacting compound (V) with 1 to 5 equivalents, preferably 1 to 3 equivalents of compound (IV). The reaction temperature is from -20 ° C to 50 ° C, preferably from 0 ° C to room temperature, and the reaction time is usually from 5 minutes to 100 hours. In addition, in this reaction, the presence of a base may allow the reaction to proceed more smoothly. As the base, both inorganic bases and organic bases are effective. Examples of inorganic bases include hydroxides, hydrides, carbonates, hydrogencarbonates of alkali metals and alkaline earth metals, among which potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, hydrogencarbonate Sodium and potassium bicarbonate are preferred. Tertiary amines such as triethylamine are preferred as the organic base. Examples of the reactive derivative include an acid anhydride, an acid halide (for example, acid chloride and acid bromide), an active ester, and the like. Among them, an acid halide is preferable. The amount of the base to be used is generally 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to compound (V).
In the case of acylation from a carboxylic acid, the compound (V) and 1 to 1.5 equivalents of carboxylic acid are added to 1 to 1.5 equivalents to 1 equivalent of the compound (V) in an inert solvent (for example, a halogen solvent or acetonitrile). The reaction is carried out in the presence of an equivalent amount of a dehydrating condensing agent such as dicyclohexylcarbodiimide (DCC). This reaction is usually performed at room temperature, and the reaction time is 0.5 to 24 hours.

（式中、各記号は前記と同意義である。）
　アクロレイン（ＶＩ）と化合物（III）を反応させ、ついで生成物に還元条件下アニリン（VIII）を反応させることにより化合物（Ｖ）を得ることができる。化合物（ＶＩ）と化合物（III）の反応は通常反応に不活性な溶媒中塩基の存在下に行われる。該塩基としては１）強塩基例えば、アルカリ金属またはアルカリ土類金属の水素化物（例、水素化リチウム、水素化ナトリウム、水素化カリウム、水素化カルシウムなど）、アルカリ金属またはアルカリ土類金属のアミド類（例、リチウムアミド、ナトリウムアミド、リチウムジイソプロピルアミド、リチウムジシクロヘキシルアミド、リチウムヘキサメチルジシラジド、ナトリウムヘキサメチルジシラジド、カリウムヘキサメチルジシラジドなど）、アルカリ金属またはアルカリ土類金属の低級アルコキシド（例、ナトリウムメトキシド、ナトリウムエトキシド、カリウム　ｔ−ブトキシドなど）など、2）無機塩基例えば、アルカリ金属またはアルカリ土類金属の水酸化物（例、水酸化ナトリウム、水酸化カリウム、水酸化リチウム、水酸化バリウムなど）、アルカリ金属またはアルカリ土類金属の炭酸塩（例、炭酸ナトリウム、炭酸カリウム、炭酸セシウムなど）、アルカリ金属またはアルカリ土類金属の炭酸水素塩（例、炭酸水素ナトリウム、炭酸水素カリウムなど）など、3）有機塩基等例えば、トリエチルアミン、ジイソプロピルエチルアミン、Ｎ−メチルモルホリン、ジメチルアミノピリジン、ＤＢＵ（１,８−ジアザビシクロ〔５.４.０〕−７−ウンデセン）、ＤＢＮ（１,５−ジアザビシクロ〔４.３.０〕ノン−５−エン）などのアミン類あるいはピリジン、イミダゾール、２,６−ルチジンなどの塩基性複素環化合物などが挙げられる。該溶媒としては、前記化合物（Ｖ）と化合物（ＩＶ）との反応において述べた溶媒が挙げられ、これらを単独または混合して用いることができる。この反応において化合物（VII）が得られる。
　化合物（VII）と化合物（VIII）との反応における還元法としては還元剤を使用するかあるいは接触還元法を用いることができる。この還元剤としては、例えば水素化ホウ素ナトリウム，水素化ホウ素リチウム，シアノ水素化ホウ素ナトリウム、トリアセトキシ水素化ホウ素ナトリウムなどが挙げられる。これらの還元剤の使用量は化合物（VII）に対し通常１〜１０当量、好ましくは１〜４当量である。反応温度は−２０〜５０℃、好ましくは０℃〜室温であり、反応時間は０.５〜２４時間である。
　接触還元法は触媒量のラネーニッケル、酸化白金、金属パラジウム、パラジウム−炭素などの金属触媒と不活性溶媒中（例えば、メタノール、エタノール、イソプロパノール、ｔ−ブタノール等のアルコール性溶媒）、室温ないし１００℃、水素圧が１気圧から１００気圧において、１ないし４８時間反応させることにより得られる。
　この方法において用いられる化合物（ＩＶ）および（III）は公知の一般的方法により合成することができる。 Compound (V) used in this method can be produced, for example, by the method described in Synthetic Comm., 1991, 20, 3167-3180. That is, it can be produced by the following method utilizing an addition reaction of an amine to an unsaturated bond.

(In the formula, each symbol is as defined above.)
Compound (V) can be obtained by reacting acrolein (VI) with compound (III) and then reacting the product with aniline (VIII) under reducing conditions. The reaction between compound (VI) and compound (III) is usually performed in a solvent inert to the reaction in the presence of a base. Examples of the base include: 1) a strong base such as a hydride of an alkali metal or an alkaline earth metal (eg, lithium hydride, sodium hydride, potassium hydride, calcium hydride, etc.), an amide of an alkali metal or an alkaline earth metal (Eg, lithium amide, sodium amide, lithium diisopropylamide, lithium dicyclohexylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, etc.), and lower alkali metal or alkaline earth metal Alkoxides (eg, sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.), 2) inorganic bases such as hydroxides of alkali metals or alkaline earth metals (eg, sodium hydroxide, potassium hydroxide, hydroxide) Lithium, hydroxyl Alkali metal or alkaline earth metal carbonate (eg, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkali metal or alkaline earth metal bicarbonate (eg, sodium bicarbonate, potassium bicarbonate, etc.) ), 3) organic bases and the like, for example, triethylamine, diisopropylethylamine, N-methylmorpholine, dimethylaminopyridine, DBU (1,8-diazabicyclo [5.4.0] -7-undecene), DBN (1,5- Examples thereof include amines such as diazabicyclo [4.3.0] non-5-ene) and basic heterocyclic compounds such as pyridine, imidazole and 2,6-lutidine. Examples of the solvent include the solvents described in the reaction of the compound (V) with the compound (IV), and these can be used alone or as a mixture. In this reaction, compound (VII) is obtained.
As a reduction method in the reaction between compound (VII) and compound (VIII), a reducing agent or a catalytic reduction method can be used. Examples of the reducing agent include sodium borohydride, lithium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and the like. The amount of these reducing agents to be used is generally 1 to 10 equivalents, preferably 1 to 4 equivalents, relative to compound (VII). The reaction temperature is -20 to 50C, preferably 0C to room temperature, and the reaction time is 0.5 to 24 hours.
In the catalytic reduction method, a catalytic amount of a metal catalyst such as Raney nickel, platinum oxide, metallic palladium or palladium-carbon and an inert solvent (for example, an alcoholic solvent such as methanol, ethanol, isopropanol or t-butanol) are used at room temperature to 100 ° C. At a hydrogen pressure of 1 to 100 atm for 1 to 48 hours.
Compounds (IV) and (III) used in this method can be synthesized by a known general method.

（式中、各記号は前記と同意義である。）
　この反応は例えば、オーガニックファンクショナルグループプレパレーションズ（ORGANIC FUNCTIONAL GROUP PREPARATIONS） 第２版、アカデミックプレス社（ACADEMIC PRESS，INC．）記載の方法に準じて行うことができる。
　この反応は通常反応に不活性な溶媒中で行われる。該性溶媒としてアルコール系溶媒、エーテル系溶媒、ハロゲン系溶媒、芳香族系溶媒、アセトニトリル、Ｎ,Ｎ−ジメチルホルムアミド（DMF）、アセトン、メチルエチルケトン、ジメチルスルホキシド（DMSO）などを単独あるいはそれらを混合して用いることができる。中でもアセトニトリル、ジメチルホルムアミド、アセトン、エタノールなどが好ましい。反応温度は通常室温ないし１００℃、好ましくは５０℃ないし８０℃であり反応時間は通常０.５ないし１日である。この反応は通常は化合物（ＩＩ）に対し１ないし３当量の塩基を加えるが、必ずしも必須ではない。該塩基としては、上記化合物（Ｖ）と化合物（ＩＶ）との反応に用いた塩基を用いることができる。
　この反応において原料として用いられる化合物（ＩＩ）は化合物（ＩＶ）を原料にして公知の一般的方法により合成することができる。 Manufacturing method 2
As shown in the following formula, compound (I) can be produced by reacting compound (II) with compound (III).

(In the formula, each symbol is as defined above.)
This reaction can be performed, for example, according to the method described in ORGANIC FUNCTIONAL GROUP PREPARATIONS, 2nd edition, Academic Press (INC.).
This reaction is usually performed in a solvent inert to the reaction. As such a solvent, an alcohol solvent, an ether solvent, a halogen solvent, an aromatic solvent, acetonitrile, N, N-dimethylformamide (DMF), acetone, methyl ethyl ketone, dimethyl sulfoxide (DMSO) or the like may be used alone or in combination. Can be used. Among them, acetonitrile, dimethylformamide, acetone, ethanol and the like are preferable. The reaction temperature is usually from room temperature to 100 ° C, preferably from 50 ° C to 80 ° C, and the reaction time is usually from 0.5 to 1 day. In this reaction, usually 1 to 3 equivalents of a base are added to compound (II), but this is not always necessary. As the base, the base used in the reaction between compound (V) and compound (IV) can be used.
Compound (II) used as a starting material in this reaction can be synthesized from compound (IV) by a known general method.

（式中、各記号は前記と同意義である。）
　この反応は化合物（ＩＸ）と化合物（III）とを通常適当な溶媒（例、水，アルコール系，エーテル系，ハロゲン系，アセトニトリル、これらの２種以上の混合溶媒等）中、必要により、酢酸，トリフルオロ酢酸等の酸性物質を添加し、１〜５当量、好ましくは１〜１.５当量の還元剤の存在下に行われる。該還元剤およびその他の条件は製造法１記載の方法が利用できる。
　この反応において原料として用いられる化合物（ＩＸ）は化合物（ＩＶ）を原料にして公知の一般的方法で製造することができる。 Manufacturing method 3
As shown in the following formula, compound (I) can be produced by reacting compound (IX) with compound (III) under reducing conditions.

(In the formula, each symbol is as defined above.)
In this reaction, compound (IX) and compound (III) are usually added to a suitable solvent (eg, water, alcohol, ether, halogen, acetonitrile, a mixed solvent of two or more of these, etc.) and, if necessary, acetic acid. The reaction is carried out in the presence of 1 to 5 equivalents, preferably 1 to 1.5 equivalents, of a reducing agent. As the reducing agent and other conditions, the method described in Production Method 1 can be used.
Compound (IX) used as a raw material in this reaction can be produced by a known general method using compound (IV) as a raw material.

（式中、Ｚ^３は脱離基を示し、他の記号は前記と同意義である。）
　Ｚ³で示される脱離基としては、Ｚで示される脱離基として述べたものが挙げられる。
　この反応は製造法２の方法に準じて行うことができる。
　この反応において原料として用いられる化合物（ＸＩ）は化合物（III）から公知の一般的方法を用いて製造することができる。
　この反応において原料として用いられる化合物（Ｘ）は化合物（ＩＶ）とアニリン（VIII）とを製造法１の方法に準じて反応させることにより製造することができる。 Manufacturing method 4
As shown in the following formula, compound (I) can be produced by reacting compound (X) with compound (XI).

(In the formula, Z ³ represents a leaving group, and other symbols are as defined above.)
Examples of the leaving group represented by Z ³ include those described as the leaving group represented by Z.
This reaction can be carried out according to the method of Production Method 2.
Compound (XI) used as a starting material in this reaction can be produced from compound (III) by a known general method.
Compound (X) used as a starting material in this reaction can be produced by reacting compound (IV) with aniline (VIII) according to the method of Production Method 1.

（式中、-ＣＯ-Ｒ^８はカルボキシル基またはその反応性誘導体を示し、他の記号は前記と同意義である。）
　化合物（XIII）におけるカルボキシル基の反応性誘導体としては、酸無水物、酸ハライド（例えば酸クロリド、酸ブロミド）、活性エステルなどが挙げられる。この反応は製造法１の方法に準じて行うことができる。
　なお、化合物（I）の置換基Ｒの種類によっては、上記製造法１〜５によって製造された化合物を原料として、その置換基変換によって化合物（I）を製造することができる。置換基変換は公知の一般的方法が用いられるが、例えばエステルの加水分解によるカルボキシル基への変換、カルボキシル基のアミド化によるカルバモイル基への変換、カルボキシル基の還元によるヒドロキシメチル基への変換、カルボニル基の還元やアルキル化によるアルコール体への変換、カルボニル基のオキシム化、シアノ基の1,2,4-オキサジアゾール-3-イル基への変換などがあげられる。 Manufacturing method 5
As shown in the following formula, compound (I) can be produced by reacting compound (XII) with compound (XIII).

(In the formula, -CO-R ⁸ represents a carboxyl group or a reactive derivative thereof, and other symbols are as defined above.)
Examples of the reactive derivative of the carboxyl group in the compound (XIII) include an acid anhydride, an acid halide (eg, acid chloride, acid bromide), an active ester, and the like. This reaction can be carried out according to the method of Production Method 1.
In addition, depending on the type of the substituent R of the compound (I), the compound (I) can be produced by using a compound produced by the above production methods 1 to 5 as a raw material and converting the substituent. For the substituent conversion, known general methods are used, for example, conversion to a carboxyl group by hydrolysis of an ester, conversion to a carbamoyl group by amidation of a carboxyl group, conversion to a hydroxymethyl group by reduction of a carboxyl group, Examples thereof include conversion of a carbonyl group into an alcohol by reduction or alkylation, oximation of a carbonyl group, and conversion of a cyano group to a 1,2,4-oxadiazol-3-yl group.

The compound (I) of the present invention has an excellent CCR antagonistic activity, particularly a strong CCR5 antagonistic activity. Can be used as a prophylactic and therapeutic agent for diseases of The compound (I) of the present invention has low toxicity and can be used safely.
The compound (I) may be used alone or in combination with a pharmaceutically acceptable carrier in a pharmaceutical composition, for example, a solid preparation such as a tablet, a capsule, a granule or a powder; or a liquid preparation such as a syrup or an injection. Can be administered orally or parenterally.
Parenteral administration forms include injections, infusions, suppositories, vaginal suppositories, etc., and vaginal suppositories are particularly useful for prevention of HIV infection.
Pharmaceutically acceptable carriers include various organic or inorganic carrier materials commonly used as pharmaceutical materials, such as excipients, lubricants, binders, and disintegrants in solid preparations; solvents and dissolution aids in liquid preparations. , A suspending agent, an isotonic agent, a buffer, a soothing agent and the like. In addition, if necessary, pharmaceutical additives such as preservatives, antioxidants, coloring agents, sweeteners and the like can be used. Preferred examples of the excipient include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid, and the like. Preferred examples of the lubricant include, for example, magnesium stearate, calcium stearate, talc, colloidal silica and the like. Preferable examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and the like. Preferable examples of the disintegrant include starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, sodium carboxymethyl starch and the like. Preferable examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like. Preferable examples of the solubilizing agent include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Preferred examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; for example, polyvinyl alcohol And hydrophilic polymers such as polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose and hydroxypropylcellulose. Suitable examples of the tonicity agent include, for example, sodium chloride, glycerin, D-mannitol and the like. Preferred examples of the buffer include buffers such as phosphate, acetate, carbonate, and citrate. Preferred examples of the soothing agent include benzyl alcohol and the like. Preferable examples of the preservative include, for example, paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Suitable examples of the antioxidant include, for example, sulfite, ascorbic acid and the like.

The pharmaceutical composition containing the compound (I) of the present invention can be used as a CCR5 antagonist, for example, a prophylactic or therapeutic agent for AIDS and an agent for suppressing the progression of AIDS pathology.
The compound (I) of the present invention may be used in combination with another preventive / therapeutic agent for HIV infection (particularly, a preventive / therapeutic agent for AIDS). In this case, these drugs are separately or simultaneously mixed with pharmacologically acceptable carriers, excipients, binders, diluents and the like to be formulated and used for the prevention and treatment of HIV infection. It can be administered orally or parenterally as a pharmaceutical composition. When the drugs are separately formulated, they can be administered separately by mixing them with a diluent at the time of use.However, the separately formulated individual drugs can be administered simultaneously or with a time lag. And may be separately administered to the same subject. A kit product for administering separately formulated products using a diluent or the like at the time of use (for example, mixing and dissolving an ampule containing a powdered individual drug and two or more drugs at the time of use) Kit products for administering the same subject simultaneously or separately at different times, such as injection kits containing a diluent for the injection, etc. Tablet kit containing tablets containing the same in the same or separate bags and, if necessary, a column for describing the time for administering the drug, for administering two or more tablets simultaneously or separately with a time lag. And the like are also included in the pharmaceutical composition of the present invention.
Specific examples of the prophylactic / therapeutic agents for other HIV infections used in combination with the compound (I) of the present invention include zidovudine, didanosine, zalcitabine, lamivudine. ), Stavudine, abacavir, adefovir, adefovir, adefovir dipivoxil, fozivudine tidoxil, tenofovir (tenofovir), and the like; nevirapine; Antioxidants such as non-nucleic acid reverse transcriptase inhibitors (immunocal, oltipraz) such as delavirdine, efavirenz, loviride, immunocal, immunotipaz (oltipraz) Drugs that have an action); saquinavir (saquina vir), ritonavir (ritonavir), indinavir (indinavir), nelfinavir (nelfinavir), amprenavir (amprenavir), parinavir (palinavir), lacinavir (lasinavir), lopinavir (lopinavir) and the like; and the like.
As a nucleic acid reverse transcriptase inhibitor, zidovudine (zidovudine), didanosine (didanosine), zalcitabine (zalcitabine), lamivudine (lamivudine), stavudine (stavudine) and the like are preferable, and a non-nucleic acid reverse transcriptase inhibitor is nevirapine. (Nevirapine), delavirdine, efavirenz, and the like are preferable. As the protease inhibitor, saquinavir, ritonavir, ritonavir, indinavir, nelfinavir, and the like are preferable.
The compound (I) of the present invention may be, for example, an antagonist of CXCR4 which is a second receptor for T cell-directed HIV-1 (eg, AMD-3100), in addition to the above-mentioned protease inhibitor, nucleic acid reverse transcriptase inhibitor and the like. Etc.), and antibodies against HIV-1 surface antigens or HIV-1 vaccines.

The daily dose of the compound (I) varies depending on the condition and weight of the patient and the method of administration. In the case of oral administration, about 5 to 1000 mg of the active ingredient [compound (I)] per adult (body weight 50 kg) per person, It is preferably about 10 to 600 mg, more preferably about 10 to 300 mg, particularly preferably about 15 to 150 mg, and is administered once or twice to three times a day.
When compound (I) is used in combination with a reverse transcriptase inhibitor or / and a protease inhibitor, the dose of the reverse transcriptase inhibitor or the protease inhibitor is, for example, about 1/200 to the normal dose. It is appropriately selected within a range of not less than 1/2 and not more than about 2 to 3 times. In addition, when two or more drugs are used in combination, when one drug affects the metabolism of another drug, the dose of each drug is appropriately adjusted. The dose at the time of single drug administration is used.
Typical dosages of typical reverse transcriptase inhibitors and protease inhibitors are, for example, as follows.
Zidovudine: 100mg
Didanosine: 125-200 mg
Zalcitabine: 0.75mg
Lamivudine: 150mg
Stavudine: 30-40mg
Saquinavir: 600mg
Ritonavir: 600mg
Indinavir: 800mg
Nelfinavir: 750mg
Specific embodiments in the case of using the compound (I) in combination with a reverse transcriptase inhibitor and / or a protease inhibitor will be described below.
(i) About 10 to 300 mg of compound (I) is administered to the same subject in combination with about 50 to 200 mg of zidovudine per adult (body weight: 50 kg). The individual drugs may be administered at the same time, or may be administered with a time difference of 12 hours or less.
(ii) About 10 to 300 mg of compound (I) is administered to the same subject in combination with about 300 to 1200 mg of saquinavir per adult (body weight: 50 kg). The individual drugs may be administered at the same time, or may be administered with a time difference of 12 hours or less.
In addition, the pharmaceutical composition containing the compound (I) of the present invention is a prophylactic / therapeutic agent for graft-versus-host disease and / or rejection, rheumatoid arthritis, autoimmune disease, allergic disease, ischemic brain cell disorder, It can be used as a prophylactic / therapeutic agent for various diseases as a prophylactic / therapeutic agent for myocardial infarction, chronic nephritis and arteriosclerosis.

Examples of the disease targeted by the preventive / therapeutic agent of the present invention include graft rejection (rejection after transplantation, polycythemia / hypertension / organ disorder / vascular hypertrophy after transplantation, graft-versus-host disease, etc.) Bone disease such as rheumatoid arthritis, rheumatoid arthritis, rheumatoid myelitis, osteoporosis, abnormal proliferation of cells, fracture, refracture, osteomalacia, bone Petchet disease, rigid spinal cord Inflammation, destruction of joint tissue in knee osteoarthritis and similar diseases, etc.), autoimmune diseases (collagen disease, systemic lupus erythematosus, scleroderma, polyarteritis, myasthenia gravis, multiple sclerosis, etc.) ), Allergic diseases (allergic rhinitis, conjunctivitis, gastrointestinal allergy, hay fever, anaphylaxis, atopic dermatitis, bronchial asthma, etc.), inflammatory bowel diseases (ulcerative colitis, Crohn's disease, gastritis) Gastric ulcer, gastric cancer, gastric surgery disorder, dyspepsia, esophageal ulcer, pancreatitis, colorectal polyp, cholelithiasis, hemorrhoidal disease, peptic ulcer, localized ileitis, etc.), inflammatory disease (retinopathy, after surgery / trauma) Inflammation, remission of swelling, pharyngitis, cystitis, meningitis, inflammatory eye disease, etc., respiratory diseases (cold syndrome, pneumonia, asthma, pulmonary hypertension, pulmonary thrombosis / pulmonary embolism, pulmonary sarcoidosis, pulmonary tuberculosis , Interstitial pneumonia, silicosis, adult respiratory distress syndrome, chronic obstructive pulmonary disease, etc.), infectious diseases (cytomegal virus, influenza virus, herpes virus and other viral infections, rickettsial infections, bacterial infections, Sexually transmitted disease, carinii pneumonia, Helicobacter pylori infection, systemic fungal infection, tuberculosis, invasive staphylococcal infection, acute viral encephalitis, acute bacterial meningitis, AIDS encephalopathy, sepsis, sepsis Severe sepsis, septic shock, endotoxin shock, toxin shock syndrome, etc., cancer and associated cachexia, metastasis of the cancer (bladder cancer, breast cancer, cervical cancer, ovarian cancer, chronic lymphocytic leukemia, chronic bone marrow) Leukemia, colorectal cancer, rectal cancer, colon cancer, multiple myeloma, malignant myeloma, prostate cancer, lung cancer, gastric cancer, Hodgkin's disease, malignant melanoma, malignant lymphoma, etc.), non-Hodgkin's lymphoma, non-small Cell lung cancer, malignant melanoma, neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's chorea, diabetic neuropathy, Creutzfeldt-Jakob disease, etc.), mental disorders (depression) Disease, epilepsy, alcoholism, etc.), schizophrenia, venous insufficiency, central nervous system disorders (disorders such as cerebral hemorrhage and cerebral infarction and their sequelae Complications, head trauma, spinal cord injury, cerebral edema, sensory dysfunction, sensory dysfunction, autonomic nervous dysfunction, autonomic nervous dysfunction, etc., central injury (head trauma, spinal cord injury, whiplash, etc.), vascularity Dementia (multiple infarct dementia, Binswanger's disease, etc.), cerebrovascular disorder (asymptomatic cerebrovascular disorder, transient cerebral ischemic attack, stroke, cerebrovascular dementia, hypertensive encephalopathy, etc.), cerebrovascular disorder Recurrence and sequelae (neurological symptoms, psychiatric symptoms, subjective symptoms, impaired activities of daily living, etc.), cerebral vascular dementia, central dysfunction after cerebral vascular occlusion, cerebral circulation, impaired or abnormal renal circulation autoregulation, cerebral blood Barrier disorders, anxiety symptoms, acute coronary syndromes such as unstable angina, discomfort mental states, amnesia, trigeminal neuralgia, otolaryngolaryngological disorders (Mennell syndrome, tinnitus, taste disorder, dizziness, imbalance, swallowing disorders, etc.) Migraine, chronic pain, skin Diseases (keloids, hemangiomas, psoriasis, etc.), obstructive arteriosclerosis, obstructive thrombotic vasculitis, peripheral arterial occlusion, post-ischemic reperfusion injury, Raynaud's disease, Burger's disease, myocarditis, myocardial ischemia, myocardium Infarction, progression of heart failure after myocardial infarction, cardiomyopathy, cardiac hypertrophy, chronic heart failure including acute heart failure and congestion, angina, arrhythmia, tachycardia, abnormal circadian blood pressure, abnormal properties of blood and blood cells (platelet aggregation Hypertension, abnormal erythrocyte deformability, increased leukocyte adhesion, increased blood viscosity, erythrocytosis, vascular purpura, autoimmune hemolytic anemia, disseminated intravascular coagulation, multiple myelopathy, etc.), atherogenic (Including aneurysm, coronary atherosclerosis, cerebral atherosclerosis, peripheral arteriosclerosis, etc.), revascularization / restenosis after bypass surgery, intervention (percutaneous coronary angioplasty, stent placement, coronary artery) Introspection Blood vessel thickening or obstruction and organ damage after intravascular ultrasound, coronary injection thrombolytic therapy, etc., production and hyperactivity of vasoactive substances and thrombogenic substances (endothelin, thromboxane A2, etc.), angiogenesis (porgy) Including abnormal angiogenesis in abnormal capillary network formation in the outer membrane of atherosclerotic lesions), thrombosis, promotion of fat deposition, eye diseases (glaucoma, ocular hypertension, etc.), hypertension, hypertensive tinnitus, dialysis hypotension, Endothelial cells and organ disorders, endocrine disorders (Addison's disease, Cushing's syndrome, brown cell types, primary aldosteronism, etc.), nephritis, kidney diseases (nephritis, glomerulonephritis, glomerulosclerosis, renal failure, thrombotic microangiopathy) , Dialysis complications, radiation-induced organ disorders including nephropathy, diabetic nephropathy, etc.), diabetic diseases (insulin-dependent diabetes, diabetic complications, diabetic retinopathy, diabetes) Microangiopathy, diabetic neuropathy, etc.), impaired glucose tolerance, liver disease (hepatitis including chronic, cirrhosis, etc.), interstitial liver disease, chronic pancreatitis, portal hypertension, obesity, male infertility, women Family diseases (menopause, pregnancy toxin, endometriosis, uterine fibroids, ovarian disease, mammary gland disease, etc.), edema, chronic fatigue syndrome, benign prostatic hyperplasia, Behcet's disease, Hodgkin's disease, racne infarction, impaired consciousness, psoriasis, Diseases caused by environmental or occupational factors (radiation damage, damage caused by ultraviolet rays, infrared rays, laser beams, altitude sickness, etc.), intermittent claudication, and the like.
The dose of the pharmaceutical composition of the present invention can be appropriately selected depending on the administration subject, age and weight of the administration subject, symptoms, administration time, administration method, dosage form, and the like.
The dosage for a particular patient may depend on age, weight, general health, gender, diet, time of administration, mode of administration, rate of excretion, and the extent of the condition the patient is treating at the time, or other Is determined in consideration of the following factors.

The pharmaceutical composition containing the compound (I) of the present invention varies depending on the type of the target disease, but may be used in combination with another drug. Examples of the other drugs include HDL increasing agents [squalene synthase inhibitors, CETP inhibitors, LPL activators, etc.], NMG-CoA reductase inhibitors: cerivastatin, atorvastatin, pravastatin, simvastatin, itavastatin, Lovastatin, Fluvastatin, (+)-3R, 5S-7- [4- (4-Fluorophenyl) -6-isopropyl-2- (N-methyl-N-methanesulfonylamino) pyrimidin-5-yl] -3 , 5-dihydroxy-6 (E) -heptenoic acid, etc., therapeutic agents for atopic dermatitis [such as sodium cromoglycate], allergic rhinitis [sodium cromoglycate, chlorpheniramine maleate, alimemazine tartrate, clemastine fumarate, Homochlorcyclidine hydrochloride, terfenadine, mexican Gin, etc.], imipenem cilastatin sodium, endotoxin antagonist or antibody, oxidosqualene-lanosterol cyclase [eg, decalin derivative, azadecalin derivative and indane derivative], calcium antagonist (eg, diltiazem), glycerol, cholinesterase inhibitor (eg, Aricept (donepezil) etc.), compounds that inhibit cholesterol absorption [eg, sitosterol and neomycin], compounds that inhibit cholesterol biosynthesis [eg, HMG-CoA reductase inhibitors such as lovastatin, simvastatin, pravastatin], cyclooxygenase inhibition Agent [(Cox-I, Cox-II inhibitor) For example, salicylic acid derivatives such as celecoxib, rofecoxib, aspirin, diclofenac, indomethacin Loxoprofen etc.], signal transduction inhibitors, squalene epoxidase inhibitors [eg, NB-598 and related compounds etc.], steroids [dexamethasone, hexestrol, methimazole, betamethasone, triamcinolone, triamcinolone acetonide, fluocinonide, fluocinolone Acetonide, prednisolone, methylprednisolone, cortisone acetate, hydrocortisone, fluorometholone, beclomethasone propionate, estriol and the like], diaserine, nicotinic acid, derivatives and analogs thereof (eg, acipimox and proplicol), nicelogolin, nephrotic syndrome therapeutic agent: Prednisolone (prednin), prednisolone sodium succinate (prednin), methylprednisolone sodium succinate (soldene)・ Medrol), betamethasone (Rinderone), dipyridamole (versantin), dilazeb hydrochloride (comerian), ticlopidine, clopidogrel, FXa inhibitor, and other antiplatelet drugs and anticoagulants, valpital anticonvulsants or anesthetics (phenobarbital, mefoline) Barbital, metal bital, etc.), therapeutic drugs for Parkinson's disease (eg, L-dopa drug), histamine receptor blockers (cimetidine, famotidine, etc.), hydantoin anticonvulsants (phenytoin, mephenytoin, etotoin, etc.), piroxicam, fibrate [Eg, clofibrate, benzafibrate, gemfiprodil, etc.], prostaglandins, megestrol acetic acid, gastric / duodenal ulcer therapeutic agent therapeutic agent: antacid [eg, histamine H2 antagonist (cimetidine) Etc.), Proton Po Inhibitors (such as lansoprazole)], inflammatory mediator action inhibitors, coronary vasodilators: nifedipine, diltiazem, nicorazil, nit nitrate, etc., therapeutic agents for infectious diseases: [eg, antibiotics (cefatiam hydrochloride, cefozopran hydrochloride) Hepatic disease drugs such as chemotherapeutic drugs (sulfur drugs, synthetic antibacterial drugs, antiviral drugs, etc.), biological drugs (vaccines, blood products such as immunoglobulins), etc. , Strong minophagen, etc.], liver hydrolyzate, SH compounds [eg, glutathione, etc.], special amino acid preparations [eg, aminolevans, etc.], phospholipids [eg, polyenephosphatidylcholine, etc.], vitamins [eg, vitamin B] ₁ , B ₂ , B ₆ , B ₁₂ , C, etc.], corticosteroids [eg, dexamethasone, betamethasone, etc.], interferons [eg, interferon α, β, etc.], drugs for treating hepatic encephalopathy [eg, lactulose, etc.], esophagus, hemostasis used when gastric varices rupture Agents (eg, vasopressin, somatostatin, etc.), anti-arthritic drugs, muscle relaxants (pridinol, tubocurarine, pancuronium, tolperisone hydrochloride, chlorphenesin carbamate, baclofen, chlormezanone, mefenesin, clozoxazone, eperisone, tizanidine, etc.), vasodilation Drugs [oxyfedrine, diltiazem, trazoline, hexobendine, bamethane, clonidine, methyldopa, guanabenz, etc.], vasoconstrictors [dopamine, doptamine denopamine, etc.], platelet aggregation inhibitor (ozagrel, etc.), thrombus formation prevention Therapeutic agents: anticoagulants [eg, heparin sodium, heparin calcium, warfarin calcium (warfarin), Xa inhibitors], thrombolytics [eg, tPA, urokinase], antiplatelet drugs [eg, aspirin, sulfinpyrazone ( Antulan), dipyridamole (persantin), ticlopidine (panaldine), cilostazol (pletar), GPIIb / IIIa antagonist (leopro)], antidepressant [imipramine, clomipramine, noxeptiline, phenelzine, amitriptyline hydrochloride, nortriptyline hydrochloride, amoxapine hydrochloride, amoxapine hydrochloride, amoxapine hydrochloride , Maprotiline hydrochloride, sulpiride, alboxamine maleate, trazodone hydrochloride, etc.), antiepileptic drugs [gabapentin, phenytoin, ethosuximide, acetazolamide, chlordia) Zepoxide, trimetadione, carbamazepine, phenovalpital, primidone, sultiam, sodium parbroate, clonazepam, diazepam, nitrazepam, etc.], antiallergic drugs [diphenhydramine, chlorpheniramine, triperenamine, methdilamine, clemizole, diphenylpyramine, methoxyphenamine, Sodium cromoglycate, tranilast, repirinast, amlexanox, ibudilast, ketotifen, terfenadine, mequitazine, acelastin, epinastine, ozagrel hydrochloride, pranlukast hydrate, seratrodast, fexofenadine, ebastine, bucillamine, oxatomide, strong neominophane sorghum Acid, ketotifen fumarate, etc.], anticholinergic agents (eg, ipra bromide) Lopium, flutropium bromide, oxitropium bromide, etc., antiparkinson drugs (dopamine, levodopa, etc.), antirheumatic drugs, anti-inflammatory drugs (eg, aspirin, acetaminophen, diclofenac sodium, ibuprofen, indomethacin, loxoprofen sodium, Dexamethasone), anticoagulants and antiplatelet agents [sodium citrate, activated protein C, tissue factor pathway inhibitor, antithrombin III, dalteparin sodium, argatroban, gabexate, ozacrel sodium, ethyl icosapentate, beraprost sodium , Alprostadil, pentoxifylline, tisokinase, streptokinase, heparin, etc.), anticoagulant [dipyridamole (versantin), dilazep hydrochloride (comerian) Ticlopidine, clovidogrel, Xa inhibitor], antibacterial agent [(i) sulfa drug [sulfamethizole, sulfisoxazole, sulfamonomethoxine, sulfamethizole, salazosulfapyridine, silver sulfadiazine, etc.], (ii) quinoline antibacterial drugs [such as nalidixic acid, pipemidic acid trihydrate, enoxacin, norfloxacin, ofloxacin, tosfloxacin tosylate, ciprofloxacin hydrochloride, lomefloxacin hydrochloride, sparfloxacin, fleroxacin, etc.], and (iii) antituberculosis drugs [ Isoniazid, utambutol (ethambutol hydrochloride), para-aminosalicylic acid (calcium para-aminosalicylate), pyrazinamide, ethionamide, prothionamide, rifampicin, streptomycin sulfate, kanamycin sulfate, cycloserine, etc.], (iv ) Anti-mycobacterials (diaphenylsulfone, rifampicillin, etc.), (v) antivirals [idoxuridine, acyclovir, vitarabine, ganciclovir, etc.], (vi) anti-HIV drugs [zidovudine, didanosine, zalcitabine, indinavir ethanol sulfate] Adducts, ritonavir, etc.), (vii) anti-spirochetes, (viii) antibiotics [tetracycline hydrochloride, ampicillin, piperacillin, gentamicin, dibekacin, canendomycin, lividomycin, tobramycin, amikacin, fradiomycin, sisomicin, tetracycline, oxy Tetracycline, lolitetracycline, doxycycline, ampicillin, piperacillin, ticarcillin, cephalotin, cephapirin, cephaloridine, cefaclor, cephalexin, cefloxazine, Cefadroxil, Cefamandol, Cefotiam, Cefuroxime, Cefotiam, Cefotiam hexetil, Cefuroxime Axetil, Cefdinir, Cefditoren pivoxil, Ceftazidime, Cefpyramide, Cefsulodin, Cefmenoxime, Cefpodoxime proxepisom , Cefmetazole, cefminox, cefoxitin, cefupelazone, latamoxef, flomoxef, cefazolin, cefotaxime, cefoperazone, ceftizoxime, moxalactam, thienamycin, sulfazecin, aztreonam or salts thereof, griseofulvin antibiotics, griseofulcin antibiotics , 38, 877-885 (1985)] Ixime, levofloxacin], antithrombotics (argatroban, etc.), antiprotozoal drugs [metronidazole, tinidazole, diethylcarbamazine citrate, quinine hydrochloride, quinine sulfate, etc.], antitumor drugs [6-O- (N-chloroacetylcarbamoyl) fumagillol Bleomycin, methotrexate, actinomycin D, mitomycin C, daunorubicin, adriamycin, neocarzinostatin, cytosine arabinoside, fluorouracil, tetrahydrofuryl-5-fluorouracil, picibanil, lentinan, levamisole, bestatin, azimexone, glycyrrhizin, doxorubicin hydrochloride Aclarubicin hydrochloride, bleomycin hydrochloride, peplomycin sulfate, vincristine sulfate, vinplastin sulfate, irinotecan hydrochloride, Lofosfamide, melphalan, busulfan, thiotepa, procarbazine hydrochloride, cisplatin, azathioprine, mercaptopurine, tegafur, carmofur, cytarabine, methyltestosterone, testosterone propionate, testosterone enanthate, mepithiostane, phosphestrol, chlormadinone acetate, leuprine acetate, Buserelin acetate, etc.], antifungals [(i) polyethylene antibiotics (eg, amphotericin B, nystatin, tricomycin), (ii) griseofulvin, pyrrolnitrin, and (iii) cytosine antimetabolites (eg, flucytosine, ( iv) imidazole derivatives (eg, econazole, clotrimazole, miconazole nitrate, bifonazole, croconazole), (v) triazole derivatives (eg, fluconazole, itra Conazole and azole compounds [2-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) ) Propyl] -4- [4- (2,2,3,3-tetrafluoropropoxy) phenyl-3- (2H, 4H) -1,2,4-triazolone], (vi) thiocarbamic acid derivatives (eg , Trinaphthol), (vii) echinocandin derivatives (eg, caspofungin, FK-463, V-echinocandin), etc., antipsychotics [chlorpromazine hydrochloride, prochlorperazine, trifloperazine, thioridazine hydrochloride, perphenazine maleate] , Fluphenazine enanthate, prochlorperazine maleate, levomepromazine maleate, promethazine hydrochloride, haloperidol, pro Peridoru, spiperone, reserpine, hydrochloric chloro coupler Min, sulpiride, zotepine and the like], antiulcer [methacrolein pro bromide, hydrochloric His
Thitidine, lansoprazole, metoclopramide, pirenzepine, cimetidine, ranitidine, famotidine, urogastrin, oxesazein, proglumide, omeprazole, sucralfate, sulpiride, setraxate, gefarnate, aldioxa, teprenone, prostaglandin, etc. Nafglinide, voglibose, acarbose, etc.), anti-obesity drugs (eg, mazindol), anti-rheumatic drugs, etc., anxiolytics [diazepam, lorazepam, oxazepam, chlordiazepoxide, medazepam, oxazolam, cloxazolam, clotiazepam, promazepam, fluzozepam, flizazem, flizazem, flizazem, flizazem And antiarrhythmic drugs: disopyramide, lidocaine, quinidine sulfate, flecaini acetate , Mexiletine hydrochloride, amiodarone hydrochloride, and beta-blockers, Ca antagonists, and other anti-asthmatics [isoprenaline hydrochloride, salbutamol sulfate, procaterol hydrochloride, terbutaline sulfate, trimethoxynol hydrochloride, tulobuterol hydrochloride, orciprenaline sulfate, fenoterol hydrobromide, Ephedrine hydrochloride, iprotropium bromide, oxitropium bromide, flutropium bromide, theophylline, aminophylline, sodium cromoglycate, tranilast, repirinast, amlexanox, ibudilast, ketotifen, terfenadine, mequitazine, azelastine, epinastine, ozastrel water Japanese, seratrodast, dexamethasone, prednisolone, hydrocortisone, beclopetazone propionate, flupropionate full Ticazone, beclomethasone propionate, procaterol, etc.), hypothyroid drug [dry thyroid (thyreoid), levothyroxine sodium (thyrazine S), liothyronidine sodium (thyronine, thyronine); nephrotic syndrome drug: prednisolone (predninone) ), Prednisolone sodium succinate (prednin), methylprednisolone sodium succinate (sol medrol), betamethasone (lindelone)], antihypertensive drugs [(i) sympathomimetic drugs [α2 stimulants [eg, clonidine, guanabenz, guanfacine] , Methyldopa, etc.), ganglionic blockers (eg, hexamethonium, trimetaphane, etc.), presynaptic blockers (eg, arteroxylone, dimethylaminoreserpine, rescinamine, reserpine, shiroshi) Gopin), neuron blockers (eg, betanidine, guanethidine, etc.), α1 blockers (eg, bunazosin, doxazosin, prazosin, terazosin, urapidil, etc.), β blockers (eg, propranolol, nadolol, timolol, nipradilol, bunitrolol, (Ii) vasodilators [calcium channel antagonists (eg, manidipine, nicardipine, nilvadipine, nisoldipine, etc.) such as indenolol, penbutolol, carteolol, carvedilol, pindolol, acebutolol, atenolol, pisoprolol, metoprolol, labetalol, amosulalol, and arotinolol. Nitrendipine, benidipine, amlodipine, alanidipine, etc.), phthalazine derivatives (eg, budralazine, cadralazine, ecarazine, hydra) Gin, todralazine, etc.), (iii) ACE inhibitors [Alacepril, captopril, cilazapril, delapril, enalapril, lisinopril, temocapril, trandolapril, quinapril, imidapril, benazepril, bernidopril, etc.], (iv) AII antagonist [iv] Losartan, candesartan, valsartan, telmisartan, irbesartan, forasartan, etc.), (v) diuretics (such as the above diuretics)], antihypertensive drugs: diuretics [eg, furosemide (lasix), bumetanide (Lunetron), azosemide (Diaart)], antihypertensive drugs [eg, ACE inhibitors, (enalapril maleate, etc.) and Ca antagonists (manidipine, amlodipine, etc.), α or β receptor blockers, etc.], therapeutic drugs for hyperlipidemia [HMG-CoA reduction Element inhibitors (eg, fluvastatin, cerivastatin, atorvastatin, etc.), fibrate drugs (eg, simfibrate, clofibrate aluminum, clinofibrate, fenofibrate, etc.), anion exchange resins (eg, cholestyramide, etc.), nicotinic acid preparations (Eg, nicomol, niceritrol, tocopherol nicotinate), polyunsaturated fatty acid derivatives (eg, ethyl icosapentate, polyenphosphatidylcholine, melinamide, etc.), plant sterols (eg, gamma-oryzanol, soysterol, etc.), Elastase, dextran sulfate sodium, squalene synthase inhibitor, CETP inhibitor, ethyl 2-chloro-3 [4- (2-methyl-2-phenylpropoxy) phenyl] propionate [Chemical & Pharmaceutical Bulletin (.. Chem Pharm Bull), 38,2792-2796 (1990)], etc.], bone diseases by: calcium preparations (e.g., calcium carbonate, etc.), calcitonin preparations, active vitamin D ₃ Preparations (eg, alphacalcidol (alphalol), calcitriol (locartrol), etc.), sex hormones (eg, estrogen, estranediol, etc.), hormone preparations (eg, conjugated estrogen (premarin), etc.), Ibriflavone preparation (such as osten), vitamin K ₂ , Vitamin K ₂ Formulations [eg, menatetrenone (Gracade) etc.], bisphosphonic acid-based formulations (eg etidronate), prostaglandin E2, fluorine compounds (eg, sodium fluoride etc.), osteogenic protein (BMP), fibroblast growth factor (FGF) ), Platelet-derived growth factor (PDGF), transforming growth factor (TGF-β), insulin-like growth factors-1 and 2 (IGF-1, -2), parathyroid hormone (PTH), European application publication EP-A1 -376197, EP-A1-460488 and EP-A1-719772 (eg, (2R, 4S)-(-)-N- [4- (diethoxyphosphorylmethyl) phenyl]- 1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzo Epin 2-carboxamide, or the like), fat-soluble vitamins drugs [(i) vitamin A: vitamin A ₁ , Vitamin A ₂ And retinol palmitate, (ii) Vitamin Ds: Vitamin D ₁ , D ₂ , D ₃ , D ₄ And D ₅ (Iii) Vitamin Es: α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, dl-α-tocopherol nicotinate, (iv) Vitamin Ks: Vitamin K ₁ , K ₂ , K ₃ And K ₄ , (V) folic acid (vitamin M) etc.], vitamin derivatives [various derivatives of vitamins such as 5,6-trans-cholecalciferol, 2,5-hydroxycholecalciferol, 1-α-hydroxycholecalciferol, etc. Vitamin D ₃ Vitamin D such as derivatives, 5,6-trans-ergocalciferol ₂ Derivatives and the like], disease-modifying antirheumatic drugs and immunosuppressive drugs [e.g., methotrexate, leflunomide, prograf, sulfasalazine, D-penicillamine, oral gold drug], vasopressors [dopamine, dobutamine, denopamine, digitoxin, digoxin, methyldigoxin, Lanatoside C, G-strophantin, etc.], cardioprotective drugs: cardiac ATP-K openers, Na-H exchange inhibitors, endothelin antagonists, urotensin antagonists, etc., therapeutic agents for heart failure [inotropic drugs (eg, digitoxin, Digoxin, methyl digoxin, lanatoside C, prossilaridine, etc., α, β stimulants (eg, epinephrine, norepinephrine, isoproterenol, dopamine, docarpamine, dobutamine, denopamine), phosphodiesterase inhibitors (eg, amrinone, milrinone) , Olprinone hydrochloride, etc.) Calcium channel sensitivity enhancers (eg, pimoventan, etc.), nitrates (eg, nitroglycerin, isosorbide dinitrate, etc.), ACE inhibitors (eg, ACE inhibitors described above), diuretics (eg, diuresis described above) Drug, etc.), carperitide, ubidecarenone, vesnarinone, aminophylline, etc.), neurotrophic factor, renal failure, renal disease therapeutic agent, biological agent [for example, monoclonal antibody (eg, anti-TNF-α antibody, anti-IL-12 antibody, anti-IL-12 antibody, IL-6 antibody, anti-ICAM-I antibody, anti-CD4 antibody, etc.), soluble receptor (eg, soluble TNF-α receptor, etc.), proteinaceous ligand (IL-I receptor antagonist, etc.)], bile acid binding resin [eg, Cholestyramine, colestipol, etc.], drugs for treating biliary tract diseases: bile drugs [eg, dehydrocholic acid, etc.], Central nervous system drugs, such as sedatives (eg, magnesium sulfate): Antitussives, including anxiolytics, hypnotics, anesthetics, analgesics, autonomic drugs, antiparkinson drugs, and other psychotropic drugs・ Septic drugs [ephedrine hydrochloride, noscapine hydrochloride, codeine phosphate, dihydrocodeine phosphate, isoproterenol hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride, allochloramide, cloferanol, picoperidamine, cloperastine, protochlorol, isoproterenol, salbutamol , Terbutaline, oxymethebanol, morphine hydrochloride, dextromethorphan hydrobromide, oxycodone hydrochloride, dimemorphan phosphate, tipepidine hibenzate, pentoxiverine citrate, clofedanol hydrochloride, benzonate, guaifenesin, bromide hydrochloride Toxin, ambroxol hydrochloride, acetylcysteine, ethyl cysteine hydrochloride, carbocysteine, etc.), sedatives [chlorpromazine hydrochloride, atropine sulfate, phenobarbital, barbital, amobarbital, pentobarbital, sodium thiopental, thiamylal sodium, nitrazepam, estazolam, Flurazapam, haloxazolam, triazolam, flunitrazepam, bromvalerylurea, chloral hydrate, triclofos sodium, etc., analgesics and anti-inflammatory agents [eg, central analgesics (eg, morphine, codeine, pentazocine, etc.), steroids (eg, prednisolone) , Dexamethasone, betamethasone, etc.), anti-inflammatory enzymes (eg, bromelain, lysozyme, proctase, etc.)], antidiabetic drugs [sulfonylurea] (Eg, tolbutamide, chlorpropamide, glyclopyramide, acetohexamide, tolazamide, glibenclamide, glibusol, etc.), biguanides (eg, metformin hydrochloride, pformin hydrochloride, etc.), α-glucosidase inhibitors (eg, voglibose, acarbose, etc.) ), Insulin sensitizers (eg, pioglitazone, troglitazone, etc.), insulin, glucagon, drugs for treating diabetic complications (eg, epalrestat, thioctic acid, etc.), actos, rosiglitazone, kinedak, benfil, hemalin, oigurcon, Glimicron, daoneil, novolin, monotard, insulins, glucoby, dimerin, rustinone, basilcon, deamelin S, isodilic acid, etc.], brain function activators (eg, idebenone, vinpocetine, etc.) , Drugs for the treatment of urogenital and male genital disorders: [eg, drugs for the treatment of prostatic hypertrophy (eg, tamsulosin hydrochloride, prazosin hydrochloride, chrommadinone acetate), drugs for treating prostate cancer (eg, leuprorelin acetate, goserelin acetate, chlormadinone acetate)], etc. Non-steroidal anti-inflammatory drugs [acetaminophen, phenacetin, etensamide, sulpyrine, antipyrine, migrenine, aspirin, mefenamic acid, flufenamic acid, diclofenac sodium, loxoprofen sodium, phenylbutazone, indomethacin, ibuprofen, ketoprofen, ketoprofen, naproxen, oxaprozin , Flurpiprofen, fenbufen, pranoprofen, floctafenin, epilizol, tiaramid hydrochloride, zaltoprofen, gabexate mesilate Camostat mesilate, ulinastatin, colchicine, Purobenejido, sulfinpyrazone, benz pro malonic, allopurinol, sodium gold thiomalate, sodium hyaluronate, sodium salicylate, morphine hydrochloride, salicylic acid, atropine, scopolamine, morphine, pethidine, levorphanol
Finol, ketoprofen, naproxen, oxymorphone or a salt thereof], treatment for pollakiuria / incontinence [flavoxate hydrochloride, etc.], unstable plaque stabilizer [MMP inhibitor, chymase inhibitor, etc.], arrhythmia treatment [sodium Channel blockers (eg, quinidine, procainamide, disopyramide, azimaline, cibenzoline, lidocaine, diphenylhydantoin, mexiletine, propafenone, flecainide, pilsicainide, phenytoin, etc.), β-blockers (eg, propranolol, alprenolol, pfetrol, octolide) Suprenolol, athenol, aseptol, metoprolol, pisoprolol, pindolol, carteolol, allotylol, etc., potassium channel blockers (eg, amiodarone), cal Umchenel blockers (eg, verapamil, diltiazem, etc.), gynecological disorders: [eg, menopause drugs (conjugated estrogens, estradiol, testosterone enanthate, estradiol valerate, etc.), drugs for breast cancer (quen Anesthetics such as tamoxifen acid), drugs for treating endometriosis and uterine fibroids (such as leuprorelin acetate and danazol), etc. [a. Local anesthetics [cocaine hydrochloride, procaine hydrochloride, lidocaine, dibucaine hydrochloride, tetracaine hydrochloride, Mepivacaine hydrochloride, bupivacaine hydrochloride, oxybuprocaine hydrochloride, ethyl aminobenzoate, oxesazein], b. General anesthetic [(i) inhalation anesthetic (eg, ether, halothane, nitrous oxide, influrane, enflurane), (ii) intravenous anesthetics (eg, ketamine hydrochloride, droperidol Thiopental sodium, thiamylal sodium, pentobarbital, etc.]], anesthetic antagonists [levalorphan, nalorphine, naloxone or a salt thereof], chronic heart failure drugs: inotropic drugs [eg, cardiac glycosides (digoxin, etc.), β receptor Stimulants (catecholamine preparations such as denopamine and dobutamine) and PDE inhibitors etc.), diuretics [eg, furosemide (Lasix), spironolactone (aldactone), bumeamide (Lunetron), azosemide (Diart) etc.], ACE inhibitors, [Eg, enalapril maleate (eg, Lenibase)], Ca antagonists [eg, amlodipine, manidipine, etc.] and immunomodulators [cyclosporine, tacrolimus, gusperimus, azathioprine, anti-lymph serum, dried sulfo, etc. Immunoglobulin, erythropoietin, colony stimulating factor, interleukin, interferon, etc.), diuretics [thiazide diuretics (bentilhydrochlorothiazide, cyclobenziazide, ethiazide, hydrochlorothiazide, hydroflumethiazide, methiclothiazide, penfluthiazide, polythiazide) , Trichlormethiazide, etc.), loop diuretics (chlorthalidone, clofenamide, indapamide, mefluzide, methicran, sotrazone, tribamide, quinetazone, metrazone, furosemide, mefluside, etc.), potassium-sparing diuretics (spironolactone, triamterene, etc.)], erectile dysfunction Drugs (viagra, apomorphine, etc.) and the like.

These drugs can be formulated separately or simultaneously and mixed with a pharmacologically acceptable carrier, excipient, binder, diluent and the like, and administered orally or parenterally. When the drugs are separately formulated, they can be administered separately by mixing them with a diluent at the time of use.However, the separately formulated individual drugs can be administered simultaneously or with a time lag. And may be separately administered to the same subject. A kit product for administering separately formulated products using a diluent or the like at the time of use (for example, mixing and dissolving an ampule containing a powdered individual drug and two or more drugs at the time of use) Kit products for administering the same subject simultaneously or separately at different times, such as injection kits containing a diluent for the injection, etc. Tablet kit containing tablets containing the same in the same or separate bags and, if necessary, a column for describing the time for administering the drug, for administering two or more tablets simultaneously or separately with a time lag. And the like are also included in the pharmaceutical composition of the present invention.
When the pharmaceutical composition containing the compound (I) of the present invention is used as a prophylactic / therapeutic agent for graft-versus-host disease and / or rejection when transplanting an organ such as heart, kidney, liver or bone marrow, Is administered from 3 days before and continuously after transplantation. The daily dose of the pharmaceutical composition of the present invention varies depending on the condition and weight of the patient, and the method of administration. In the case of oral administration, the amount of the active ingredient [compound (I)] per adult (body weight 50 kg) is about It is 5 to 1000 mg, preferably about 10 to 600 mg, more preferably about 10 to 300 mg, particularly preferably about 15 to 150 mg, and is administered once or twice or three times a day. In this case, it may be used in combination with an inhibitor for graft-versus-host disease and / or rejection during other organ transplantation. Specific examples of the agent for suppressing graft-versus-host disease and / or rejection at the time of organ transplantation used in combination with the above compound (I) include cyclosporine, tacrolimus, rapamycin, steroid, azathioprine, mycophenolate mofetil And mizoribine. When these drugs are used in combination, when one drug affects the metabolism of another drug, the dose of each drug is appropriately adjusted, but generally, when a single drug is administered for each drug. Is used.
When the pharmaceutical composition containing the compound (I) of the present invention is used for a target disease other than a preventive / therapeutic agent for AIDS, a progression inhibitor for AIDS, graft-versus-host disease at the time of organ transplantation and / or a suppressor for rejection reaction. The daily dose varies depending on the type of the target disease, the condition and weight of the patient, and the method of administration. In the case of oral administration, about 5 to 1000 mg of the active ingredient [compound (I)] per adult (weight 50 kg) per person It is preferably about 10 to 600 mg, more preferably about 10 to 300 mg, particularly preferably about 15 to 150 mg, and is administered once or twice to three times a day. When used in combination with another drug, the dose of the other drug is appropriately selected, for example, in the range of about 1/200 to 1/2 or more, and about 2 to 3 times or less the usual dose. In addition, when two or more drugs are used in combination, when one drug affects the metabolism of another drug, the dose of each drug is appropriately adjusted. The dose at the time of single drug administration is used.

Further, the compound (I) of the present invention can be contained in blood transfusions or blood products or used in combination. Transfusion blood or blood products are usually produced by mixing blood taken from multiple people, which may contain cells infected with HIV virus and cells not infected. Yes, in this case, there is a risk of infecting uninfected cells. By incorporating the compound (I) of the present invention, infection and proliferation of these viruses can be prevented or suppressed. In particular, it is effective to mix the compound (I) when storing a blood product in order to prevent or suppress viral infection and proliferation. In addition, when blood or blood products for transfusion contaminated with the HIV virus are administered, compound (I) can be added to the blood or blood products to allow the body to receive blood or blood products for transfusion. HIV can be prevented from transmitting and multiplying. For example, when orally administered to an adult (body weight about 60 kg) as a prophylaxis of HIV infection at the time of blood transfusion and use of blood products, the dose is usually about 0.02 to 50 mg / kg, preferably about 0 to 50 mg / kg as a CCR antagonist as a single dose. The dose is about 0.05 to 30 mg / kg, more preferably about 0.1 to 10 mg / kg, and it is desirable to administer these doses about once to three times a day. Of course, these dosage ranges can be adjusted on a unit basis as necessary to divide up the daily dose; however, as noted above, doses can vary depending on the nature and extent of the disease, age of the patient, weight, general health, Gender, diet, administration time, administration method, excretion rate, and other factors are determined. In this case, the administration method can also be appropriately selected, and the above-described agent for preventing HIV infection of the present invention may be directly added to blood or a blood product to be transfused before blood transfusion or before use of the blood product. In that case, it is desirable to mix immediately before to 24 hours, preferably immediately before to 12 hours, more preferably immediately before to 6 hours.
When the preventive agent for HIV infection of the present invention is administered separately from blood or blood products to be transfused at the time of blood transfusion or use of blood products, it is desirable to administer it 1 hour before or simultaneously with the use of blood transfusion or blood products, and more preferably 1 It is desirable to continue dosing one to three times a day for four weeks.

Hereinafter, the present invention will be described in more detail with reference to Examples, Reference Examples, Experimental Examples, and Formulation Examples. However, these are merely examples and do not limit the present invention in any way.
The genetic manipulation method described below followed the method described in a companion book (Maniatis et al., Molecular Cloning, Cold Spring Harbor Laboratory, 1989) or the protocol described in the protocol attached to the reagent.
In the following Reference Examples and Examples, silica gel 60 (70-230 or 230-400 mesh) or Fuji Silysia Chemical NH silica gel (100-200 mesh) was used as a filler for column chromatography. ¹ H NMR spectra were measured using Varian Gemini-200 (200 MHz) or Varian Mercury (300 MHz) with tetramethylsilane as an internal standard.

Example 1
1-acetyl-N- (3- {4-[(4-aminophenyl) sulfonyl] -1-piperidinyl} propyl) -N- (3-chloro-4-methylphenyl) -4-piperidinecarboxamide 1-acetyl- N- (3-chloro-4-methylphenyl) -N- (3-chloropropyl) -4-piperidinecarboxamide (474 mg, 1.28 mmol) and the compound synthesized in Reference Example 1-4 (400 mg, 1.28 mmol) and iodine A mixture of potassium chloride (212 mg, 1.28 mmol) and potassium carbonate (442 mg, 3.20 mmol) in acetonitrile (15 mL) was stirred at 70 ° C. for 13 hours. After evaporating the solvent, water and ethyl acetate were added to the residue, and the separated organic layer was washed with saturated saline. After drying over anhydrous magnesium sulfate, the residue was purified by column chromatography (ethyl acetate / methanol = 1/0 → 3/1) to give the title compound (262 mg, 36%) as a colorless amorphous.
¹ H NMR (CDCl ₃ ) δ 1.50-2.04, (13H, m), 2.04 (3H, s), 2.21-2.40 (4H, m), 2.42 (3H, s), 2.70-3.00 (3H, m), 3.50-3.83 (3H, m), 4.17-4.23 (2H, m), 4.44-4.59 (1H, m), 6.70 (2H, d, J = 8.8Hz), 6.95 (1H, dd, J = 2.2, 8.0 Hz), 7.15 (1H, d, J = 2.2Hz), 7.29 (1H, d, J = 8.0Hz), 7.59 (2H, d, J = 8.8Hz).
Example 2
1-acetyl-N- (3-chloro-4-methylphenyl) -N- [3- (4-{[4- (isopropylamino) phenyl] sulfonyl} -1-piperidinyl) propyl] -4-piperidinecarboxamide The title compound was synthesized in the same manner as in Example 1 using the compound obtained in Reference Example 2-3. Yield 52%.
¹ H NMR (CDCl ₃ ) δ 1.24 (6H, d, J = 6.2 Hz), 1.45-2.04 (14H, m), 2.04 (3H, s), 2.20-2.40 (4H, m), 2.42 (3H, s ), 2.70-2.98 (3H, m), 3.55-3.82 (3H, m), 4.06-4.14 (1H, m), 4.45-4.57 (1H, m), 6.56 (2H, d, J = 8.6Hz), 6.95 (1H, dd, J = 2.2, 8.0Hz), 7.15 (1H, d, J = 2.2Hz), 7.29 (1H, d, J = 8.0Hz), 7.57 (2H, d, J = 8.6Hz).
Example 3
1-acetyl-N- (3-chloro-4-methylphenyl) -N- [3- (4-{[4- (dimethylamino) phenyl] sulfonyl} -1-piperidinyl) propyl] -4-piperidinecarboxamide < The title compound was synthesized in the same manner as in Example 1 using the compound obtained in Reference Example 3-3. Yield 38%.
¹ H NMR (CDCl ₃ ) δ 1.50-2.05 (13H, m), 2.05 (3H, s), 2.20-2.40 (4H, m), 2.42 (3H, s,), 2.71-2.98 (3H, m), 3.06 (6H, s), 3.55-3.66 (2H, m), 3.69-3.83 (1H, m), 4.44-4.58 (1H, m), 6.69 (2H, d, J = 9.0Hz), 6.94 (1H, dd, J = 1.8, 8.0Hz), 7.15 (1H, d, J = 1.8Hz), 7.29 (1H, d, J = 8.0Hz), 7.63 (2H, d, J = 9.0Hz).
Example 4
1-acetyl-N- (3- {4-[(3-aminophenyl) sulfonyl] -1-piperidinyl} propyl) -N- (3-chloro-4-methylphenyl) -4-piperidinecarboxamide dihydrochloride Using the compound obtained in Reference Example 4-3, 1-acetyl-N- (3- {4-[(3-aminophenyl) sulfonyl] -1-piperidinyl} in the same manner as in Example 1. (Propyl) -N- (3-chloro-4-methylphenyl) -4-piperidinecarboxamide was synthesized. Yield 41%.
¹ H NMR (CDCl ₃ ) δ 1.53-2.01 (13H, m), 2.05 (3H, s), 2.23-2.45 (4H, m), 2.42 (3H, s), 2.79-2.98 (3H, m), 3.58 -3.65 (2H, m), 3.71-3.81 (1H, m), 3.64 (2H, s), 4.46-4.57 (1H, m), 6.90 (1H, ddd, J = 0.9, 2.4, 7.8Hz), 6.95 (1H, dd, J = 2.1, 8.1Hz), 7.10 (1H, dd, J = 1.8, 2.1Hz), 7.16 (1H, d, J = 2.1Hz), 7.16-7.21 (1H, m), 7.27 ( 1H, d, J = 1.8Hz), 7.32 (1H, d, J = 7.8Hz).
1-acetyl-N- (3- {4-[(3-aminophenyl) sulfonyl] -1-piperidinyl} propyl) -N- (3-chloro-4-methylphenyl) -4-piperidinecarboxamide (233 mg, 0.405 (mmol) was dissolved in ethyl acetate (10 mL), 4N hydrochloric acid / ethyl acetate solution (0.5 mL) was added, and the mixture was stirred for 1 hour. The precipitate was collected by filtration to give the title compound (211 mg, 84%).

Example 5
1-acetyl-N- (3-chloro-4-methylphenyl) -N- [3- (4-{[3- (methylamino) phenyl] sulfonyl} -1-piperidinyl) propyl] -4-piperidinecarboxamide Hydrochloride The title compound was synthesized in the same manner as in Example 4 using the compound obtained in Reference Example 5-3. Yield 52%.
¹ H NMR (CDCl ₃ ) δ1.51-2.05 (13H, m), 2.05 (3H, s), 2.22-2.42 (4H, m), 2.42 (3H, s), 2.78-2.98 (3H, m), 2.88 (3H, d, J = 5.1Hz), 3.62 (2H, dd, J = 7.8, 7.2Hz), 3.70-3.81 (1H, m), 4.02-4.10 (1H, m), 4.47-4.56 (1H, m), 6.78-6.83 (1H, m), 6.92-7.01 (2H, m), 7.10-7.17 (2H, m), 7.26-7.36 (2H, m).
Example 6
1-acetyl-N- (3-chloro-4-methylphenyl) -N- [3- (4-{[4- (4-morpholinyl) phenyl] sulfonyl} -1-piperidinyl) propyl] -4-piperidinecarboxamide The title compound was synthesized in the same manner as in Example 1 using the compound obtained in Reference Example 6-4. 55% yield.
¹ H NMR (CDCl ₃ ) δ1.50-2.05 (13H, m), 2.05 (3H, s), 2.20-2.42 (4H, m), 2.42 (3H, s), 2.72-2.98 (3H, m), 3.27-3.36 (4H, m), 3.55-3.66 (2H, m), 3.68-3.91 (5H, m), 4.44-4.58 (1H, m), 6.87-6.97 (3H, m), 7.15 (1H, d , J = 2.2Hz), 7.29 (1H, d, J = 7.4Hz), 7.68 (2H, d, J = 8.8Hz).
Example 7
1-acetyl-N- (3-chloro-4-methylphenyl) -N- (3- {4-[(4-isopropylphenyl) sulfonyl] -1-piperidinyl} propyl) -4-piperidinecarboxamide The title compound was synthesized in the same manner as in Example 1 using the compound obtained in Reference Example 7-3. Yield 57%.
¹ H NMR (CDCl ₃ ) δ1.28 (6H, d, J = 6.6 Hz), 1.51-1.90 (10H, m), 1.95-2.08 (2H, m), 2.04 (3H, s), 2.24-2.40 ( 4H, m), 2.42 (3H, s), 2.78-3.05 (5H, m), 3.57-3.65 (2H, m), 3.71-3.81 (1H, m), 4.46-4.57 (1H, m), 6.94 ( 1H, dd, J = 8.1, 2.4Hz), 7.15 (1H, d, J = 2.4Hz), 7.28 (1H, d, J = 8.1Hz), 7.39 (2H, d, J = 8.3Hz), 7.75 ( (2H, d, J = 8.3Hz).
Example 8
1-acetyl-N- (3-chloro-4-methylphenyl) -N- (3- {4-[(4-chlorophenyl) sulfonyl] -1-piperidinyl} propyl) -4-piperidinecarboxamide Reference The title compound was synthesized in the same manner as in Example 1 using the compound obtained in Example 8-3. Yield 66%.
¹ H NMR (CDCl ₃ ) δ1.50-2.08 (12H, m), 2.04 (3H, s), 2.21-2.45 (4H, m), 2.42 (3H, s), 2.75-3.00 (4H, m), 3.55-3.67 (2H, m), 3.69-3.84 (1H, m), 4.44-4.58 (1H, m), 6.94 (1H, dd, J = 8.0, 2.2Hz), 7.15 (1H, d, J = 2.2 Hz), 7.29 (1H, d, J = 8.0Hz), 7.50-7.58 (2H, m), 7.75-7.83 (2H, m).
Example 9
1-acetyl-N- (3-chloro-4-methylphenyl) -N- (3- {4-[(4-methylphenyl) sulfonyl] -1-piperidinyl} propyl) -4-piperidinecarboxamide hydrochloride The title compound was synthesized in the same manner as in Example 4 using the compound obtained in Reference Example 9-3. Yield 44%.
¹ H NMR (CDCl ₃ ) δ1.52-1.90 (10H, m), 1.92-2.03 (2H, m), 2.04 (3H, s), 2.23-2.40 (4H, m), 2.42 (3H, s), 2.45 (3H, s), 2.77-2.97 (4H, m), 3.57-3.65 (2H, m), 3.70-3.81 (1H, m), 4.46-4.56 (1H, m), 6.94 (1H, dd, J = 7.8, 2.1Hz), 7.15 (1H, d, J = 2.1Hz), 7.28 (1H, d, J = 7.8Hz), 7.32-7.38 (2H, m), 7.70-7.76 (2H, m).
Example 10
1-acetyl-N- (3-chloro-4-methylphenyl) -N- {3- [4-({4-[(2-ethoxyethyl) amino] phenyl} sulfonyl) -1-piperidinyl] propyl}- 4-Piperidinecarboxamide hydrochloride The title compound was synthesized in the same manner as in Example 4 using the compound obtained in Reference Example 10-2. Yield 42%.
¹ H NMR (CDCl ₃ ) δ1.24 (3H, t, J = 6.9 Hz), 1.52-1.90 (10H, m), 1.94-2.03 (2H, m), 2.04 (3H, s), 2.26 (2H, t, J = 7.5Hz), 2.26-2.41 (2H, m), 2.42 (3H, s), 2.72-2.96 (4H, m), 3.34 (2H, dt, J = 5.4, 5.4Hz), 3.55 (2H , q, J = 6.9H), 3.57-3.66 (2H, m), 3.66 (2H, t, J = 5.4Hz), 3.71-3.81 (1H, m), 4.47-4.56 (1H, m), 4.65 ( 1H, brt, J = 5.4Hz), 6.60-6.66 (2H, m), 6.94 (1H, dd, J = 7.8, 2.1Hz), 7.15 (1H, d, J = 2.1Hz), 7.29 (1H, d, J = 7.8Hz), 7.56-7.62 (2H, m).

Example 11
1-acetyl-N- (3-chloro-4-methylphenyl) -N- {3- [4-({4-[(3-methoxypropyl) amino] phenyl} sulfonyl) -1-piperidinyl] propyl}- 4-Piperidinecarboxamide The title compound was synthesized in the same manner as in Example 1 using the compound obtained in Reference Example 11-2. Yield 42%.
¹ H NMR (CDCl ₃ ) δ1.51-2.05 (14H, m), 2.05 (3H, s), 2.20-2.44 (4H, m), 2.42 (3H, s), 2.70-2.99 (4H, m), 3.29 (2H, dt, J = 5.4, 5.2Hz), 3.37 (3H, s), 3.53 (2H, t, J = 3.8Hz), 3.54-3.66 (2H, m), 3.68-3.84 (1H, m) , 4.44-4.59 (1H, m), 4.75 (1H, brt, J = 5.2Hz), 6.56-6.62 (2H, m), 6.94 (1H, dd, J = 7.8, 1.8Hz), 7.15 (1H, d, J = 1.8Hz), 7.28 (1H, d, J = 7.8Hz), 7.54-7.62 (2H, m).
Example 12
1-acetyl-N- (3-chloro-4-methylphenyl) -N- {3- [4-({4-[(2-hydroxyethyl) amino] phenyl} sulfonyl) -1-piperidinyl] propyl}- 4-Piperidinecarboxamide The title compound was synthesized in the same manner as in Example 1 using the compound obtained in Reference Example 12-2. Yield 33%.
¹ H NMR (CDCl ₃ ) δ1.50-1.90 (10H, m), 1.92-2.07 (2H, m), 2.04 (3H, s), 2.20-2.45 (4H, m), 2.42 (3H, s), 2.73-2.97 (4H, m), 3.25 (2H, dt, J = 5.4, 5.1Hz), 3.56-3.66 (2H, m), 3.70-3.81 (1H, m), 3.87 (2H, t, J = 5.1 Hz), 4.45-4.56 (1H, m), 4.73 (1H, t, J = 5.4Hz), 6.60-6.68 (2H, m), 6.94 (1H, dd, J = 9.6, 1.8Hz), 7.15 (1H , d, J = 1.8Hz), 7.29 (1H, d, J = 9.6Hz), 7.56-7.62 (2H, m).
Example 13
1-acetyl-N- (3-chloro-4-methylphenyl) -N- [3- (4-{[4- (4-oxo-1-piperidinyl) phenyl] sulfonyl} -1-piperidinyl) propyl]- 4-Piperidinecarboxamide A 4N hydrochloric acid / ethyl acetate solution (2.1 mL) was added to a methanol (10 mL) solution of the compound (697 mg, 1.68 mmol) obtained in Reference Example 13-1, and the mixture was stirred for 18 hours. The colorless powder obtained by distilling off the solvent was washed with diisopropyl ether. Acetonitrile (8 mL) and N, N-dimethylformamide (4 mL) were dissolved, and 1-acetyl-N- (3-chloro-4-methylphenyl) -N- (3-chloropropyl) -4-piperidinecarboxamide (589 mg) , 1.59 mmol), potassium iodide (264 mg, 1.59 mmol) and potassium carbonate (680 mg, 4.93 mmol), and the mixture was stirred at 75 degrees for 9 hours. A coupling product (733 mg) was obtained in the same manner as in Example 1. Compounds methanol and the ketal exchange from ¹ H NMR was produced, but was used in the subsequent reaction remains mixture.
A mixed solution of the obtained coupling compound (207 mg, 0.295 mmol) and oxalic acid (664 mg, 7.38 mmol) in water / tetrahydrofuran (1 mL / 1 mL) was heated under reflux for 2 hours. At 0 ° C., an 8N aqueous sodium hydroxide solution (2.5 mL) was added, and the precipitate was filtered. The filtrate was extracted with ethyl acetate and washed with saturated saline. After drying over anhydrous magnesium sulfate and evaporation under reduced pressure, the residue was purified by column chromatography (ethyl acetate / methanol = 3/1) to obtain the title compound (122 mg) as a colorless amorphous.
¹ H NMR (CDCl ₃ ) δ1.50-1.90 (10H, m), 1.95-2.06 (2H, m), 2.04 (3H, s), 2.20-2.43 (4H, m), 2.42 (3H, s), 2.57-2.64 (4H, m), 2.76-2.99 (4H, m), 3.55-3.66 (2H, m), 3.70-3.81 (5H, m), 4.45-4.57 (1H, m), 6.91-6.98 (3H , m), 7.15 (1H, d, J = 2.1Hz), 7.29 (1H, d, J = 9.0Hz), 7.68-7.74 (2H, m).

Example 14
1-acetyl-N- (3-chloro-4-methylphenyl) -N- [3- (4-{[4- (4-hydroxy-1-piperidinyl) phenyl] sulfonyl} -1-piperidinyl) propyl]- 4-Piperidinecarboxamide To a solution of the compound obtained in Example 13 (168 mg, 0.256 mmol) in methanol (4 mL) was added sodium borohydride (11.5 mg, 0.307 mmol) at 0 ° and at room temperature. Stir for 10 minutes. At 0 ° C, 0.5N hydrochloric acid (2 mL) was added, and the mixture was stirred for 10 minutes, 1N aqueous sodium hydroxide solution (2 mL) was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline. After drying over anhydrous magnesium sulfate, the residue was evaporated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / methanol = 10/1) to give the title compound (161 mg, 95%) as a colorless amorphous.
¹ H NMR (CDCl ₃ ) δ1.50-1.90 (14H, m), 1.94-2.07 (2H, m), 2.04 (3H, s), 2.22-2.44 (4H, m), 2.42 (3H, s), 2.73-2.97 (4H, m), 3.15 (2H, ddd, J = 12.6, 9.3, 3.3Hz), 3.55-3.65 (2H, m), 3.67-3.81 (3H, m), 3.90-4.03 (1H, m ), 4.46-4.56 (1H, m), 6.88-6.98 (3H, m), 7.15 (1H, d, J = 2.1Hz), 7.29 (1H, d, J = 9.3Hz), 7.61-7.68 (2H, m).
Example 15
1-acetyl-N- [3- (4-{[4- (4-acetyl-1-piperazinyl) phenyl] sulfonyl} -1-piperidinyl) propyl] -N- (3-chloro-4-methylphenyl)- 4-Piperidinecarboxamide The title compound was synthesized in the same manner as in Example 1 using the compound obtained in Reference Example 14-2. Yield 47%.
¹ H NMR (CDCl ₃ ) δ1.48-2.08 (13H, m), 2.04 (3H, s), 2.16 (3H, s), 2.20-2.44 (4H, m), 2.42 (3H, s), 2.72- 2.99 (4H, m), 3.32-3.46 (4H, m), 3.54-3.85 (6H, m), 4.43-4.60 (1H, m), 6.86-6.98 (3H, m), 7.15 (1H, d, J = 2.2Hz), 7.29 (1H, d, J = 7.8Hz), 7.65-7.74 (2H, m).
Example 16
1-acetyl-N- (3-chloro-4-methylphenyl) -N- {3- [4-({4-[(2-methoxyethyl) amino] phenyl} sulfonyl) -1-piperidinyl] propyl}- 4-Piperidinecarboxamide The title compound was synthesized in the same manner as in Example 1 using the compound obtained in Reference Example 15-2. Yield 58%.
¹ H NMR (CDCl ₃ ) δ1.50-1.90 (10H, m), 1.92-2.08 (2H, m), 2.04 (3H, s), 2.21-2.45 (4H, m), 2.42 (3H, s), 2.73-2.97 (4H, m), 3.34 (1H, dt, J = 5.4, 5.4Hz), 3.41 (3H, s), 3.56-3.65 (4H, m), 3.70-3.81 (1H, m), 4.45- 4.56 (1H, m), 4.62 (1H, t, J = 5.4Hz), 6.60-6.66 (2H, m), 6.94 (1H, dd, J = 8.1, 2.1Hz), 7.15 (1H, d, J = 2.1Hz), 7.28 (1H, d, J = 8.1Hz), 7.56-7.62 (2H, m).
Example 17
1-acetyl-N- (3- {4-[(4-acetylphenyl) sulfonyl] -1-piperidinyl} propyl) -N- (3-chloro-4-methylphenyl) -4-piperidinecarboxamide The title compound was synthesized in the same manner as in Example 1 using the compound obtained in Reference Example 16-6. Yield 59%.
¹ H NMR (CDCl ₃ ) δ1.52-2.04 (12H, m), 2.04 (3H, s), 2.23-2.44 (4H, m), 2.42 (3H, s), 2.68 (3H, s), 2.77- 2.99 (4H, m), 3.54-3.66 (2H, m), 3.70-3.81 (1H, m), 4.46-4.57 (1H, m), 6.94 (1H, dd, J = 7.8, 2.4Hz), 7.15 ( 1H, d, J = 2.4Hz), 7.29 (1H, d, J = 7.8Hz), 7.94-8.00 (2H, m), 8.09-8.14 (2H, m).

Example 18
1-acetyl-N- (3-chloro-4-methylphenyl) -N- [3- (4-{[4- (N-ethoxyethanimidoyl) phenyl] sulfonyl} -1-piperidinyl) propyl] -4 - the compound obtained in piperidinecarboxamide <br/> example 17 (341mg, 0.556mmol) and O- ethyl hydroxylamine hydrochloride (276 mg, 2.83 mmol) and sodium acetate (232 mg, 2.83 mmol) in 2-propanol (5mL ) The mixture was stirred for 17 hours. After evaporating the solvent, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline. After drying over anhydrous magnesium sulfate, the residue was evaporated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate) to obtain the title compound (358 mg, 98%) as a colorless amorphous.
¹ H NMR (CDCl ₃ ) δ1.35 (3H, t, J = 7.0 Hz), 1.52-2.06 (12H, m), 2.04 (3H, s), 2.20-2.45 (4H, m), 2.26 (3H, s), 2.42 (3H, s), 2.73-3.00 (4H, m), 3.54-3.83 (3H, m), 4.29 (2H, q, J = 7.0Hz), 4.44-4.60 (1H, m), 6.94 (1H, dd, J = 8.0, 2.2Hz), 7.15 (1H, d, J = 2.2Hz), 7.28 (1H, d, J = 8.0Hz), 7.82-7.84 (4H, m).
Example 19
1-acetyl-N- (3-chloro-4-methylphenyl) -N- [3- (4-{[4- (N-isobutoxyethaneimidoyl) phenyl] sulfonyl} -1-piperidinyl) propyl]- 4-piperidinecarboxamide
The title compound was synthesized in the same manner as in Example 18 using O-isobutylhydroxylamine hydrochloride. Yield 87%.
¹ H NMR (CDCl ₃ ) δ 0.98 (6H, d, J = 6.3 Hz), 1.50-2.04 (16H, m), 2.20-2.42 (4H, m), 2.27 (3H, s), 2.42 (3H, s), 2.77-2.99 (4H, m), 3.56-3.65 (2H, m), 3.70-3.81 (1H, m), 4.02 (2H, d, J = 6.9Hz), 4.46-4.56 (1H, m) , 6.94 (1H, dd, J = 7.8, 2.4Hz), 7.15 (1H, d, J = 2.4Hz), 7.28 (1H, d, J = 7.8Hz), 7.80-7.86 (4H, m).
Example 20
1-acetyl-N- (3-chloro-4-methylphenyl) -N- [3- (4-{[4- (1-hydroxyethyl) phenyl] sulfonyl} -1-piperidinyl) propyl] -4-piperidine Carboxamide Using the compound obtained in Example 17, the title compound was synthesized in the same manner as in Example 14. 90% yield.
¹ H NMR (CDCl ₃ ) δ1.45-2.13 (13H, m), 1.53 (3H, d, J = 6.2Hz), 2.04 (3H, s), 2.20-2.44 (4H, m), 2.42 (3H, s), 2.72-3.00 (4H, m), 3.51-3.84 (3H, m), 4.39-4.60 (1H, m), 4.91-5.07 (1H, m), 6.94 (1H, dd, J = 8.2, 2.2 Hz), 7.15 (1H, d, J = 2.2Hz), 7.28 (1H, d, J = 8.2Hz), 7.53-7.61 (2H, m), 7.76-7.86 (2h, m).
Example 21
1-acetyl-N- (3-chloro-4-methylphenyl) -N- [3- (4-{[4- (N-methoxyethaneimidoyl) phenyl] sulfonyl} -1-piperidinyl) propyl] -4 -Piperidinecarboxamide
The title compound was synthesized in the same manner as in Example 18 using O-methylhydroxylamine hydrochloride. 85% yield.
¹ H NMR (CDCl ₃ ) δ1.50-1.87 (10H, m), 1.91-2.03 (2H, m), 2.04 (3H, s), 2.19-2.42 (4H, m), 2.25 (3H, s), 2.42 (3H, s), 2.77-2.97 (4H, m), 3.55-3.65 (2H, m), 3.70-3.81 (1H, m), 4.04 (3H, s), 4.46-4.56 (1H, m), 6.94 (1H, dd, J = 8.1, 2.4Hz), 7.15 (1H, d, J = 2.4Hz), 7.29 (1H, d, J = 8.1Hz), 7.81-7.87 (4H, m).

Example 22
1-acetyl-N- (3-chloro-4-methylphenyl) -N- [3- (4-{[4- (N-hydroxyethanimidoyl) phenyl] sulfonyl} -1-piperidinyl) propyl] -4 -Piperidinecarboxamide The title compound was synthesized as in Example 18 using hydroxylamine hydrochloride. 90% yield.
¹ H NMR (CDCl ₃ ) δ1.15-1.82 (8H, m), 1.86-1.98 (2H, m), 2.01-2.13 (2H, m), 2.05 (3H, s), 2.19 (3H, s), 2.24-2.44 (4H, m), 2.39 (3H, s), 2.75-3.05 (4H, m), 3.54-3.86 (3H, m), 4.45-4.58 (1H, m), 6.91 (1H, dd, J = 8.4, 2.1Hz), 7.12 (1H, d, J = 2.1Hz), 7.24 (1H, d, J = 8.4Hz), 7.69-7.75 (2H, m), 7.79-7.85 (2H, m), 9.60 (1H, br s).
Example 23
1- (4-{[1- (3-{[(1-acetyl-4-piperidinyl) carbonyl] [3-chloro-4-methylphenyl] amino} propyl) -4-piperidinyl] sulfonyl} phenyl) -4 -Ethyl piperidinecarboxylate The title compound was synthesized in the same manner as in Example 1 using the compound obtained in Reference Example 17-2. Yield 48%.
_{^{1 H NMR (CDCl 3) δ1.28}} (3H, t, J = 7.0Hz), 1.49-2.13 (16H, m), 2.04 (3H, s), 2.20-2.63 (5H, m), 2.42 (3H, s), 2.71-3.10 (6H, m), 3.54-3.91 (5H, m), 4.17 (2H, q, J = 7.0Hz), 4.40-4.59 (1H, m), 6.86-6.99 (3H, m) , 7.15 (1H, d, J = 2.2Hz), 7.28 (1H, d, J = 7.6Hz), 7.60-7.70 (2H, m).
Example 24
1- (4-{[1- (3-{[(1-acetyl-4-piperidinyl) carbonyl] [3-chloro-4-methylphenyl] amino} propyl) -4-piperidinyl] sulfonyl} phenyl) -4 - the compound obtained in piperidinecarboxylic acid <br/> example 23 (310mg, 0.434mmol) was stirred for 3 hours was added methanol (4 mL) 1N sodium hydroxide solution (0.87 mL) of. At 0 ° C., 1N hydrochloric acid (0.87 mL) was added dropwise, water (2 mL) was added, and the mixture was extracted twice with dichloromethane. The combined organic layers were dried over anhydrous magnesium sulfate and evaporated under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol = 5/1) to give the title compound (186 mg, 62%) as a colorless amorphous.
¹ H NMR (CD ₃ OD) δ1.46-1.79 (11H, m), 1.92-2.06 (3H, m), 2.04 (3H, s), 2.14-2.27 (2H, m), 2.30-2.55 (5H, m), 2.41 (3H, s), 2.80-2.92 (1H, m), 2.93-3.18 (5H, m), 3.62-3.70 (2H, m), 3.79-3.98 (3H, m), 4.36-4.46 ( 1H, m), 7.02-7.09 (2H, m), 7.15 (1H, dd, J = 8.0, 2.0Hz9, 7.38-7.43 (2H, m), 7.58-7.65 (2H, m).
Example 25
(2E) -3- (4-{[1- (3-{[(1-acetyl-4-piperidinyl) carbonyl] [3-chloro-4-methylphenyl] amino} propyl) -4-piperidinyl] sulfonyl} Ethyl phenyl) acrylate The title compound was synthesized as in Example 1 using the compound obtained in Reference Example 18-2. Yield 57%.
¹ H NMR (CDCl ₃ ) δ1.36 (3H, t, J = 6.9 Hz), 1.51-2.06 (12H, m), 2.04 (3H, s), 2.23-2.43 (4H, m), 2.42 (3H, s), 2.77-2.99 (4H, m), 3.56-3.65 (2H, m), 3.70-3.80 (1H, m), 4.30 (2H, q, J = 6.9Hz), 4.46-4.56 (1H, m) , 6.55 (1H, d, J = 15.9Hz), 6.94 (1H, dd, J = 8.1, 2.1Hz), 7.15 (1H, d, J = 2.1Hz), 7.29 (1H, d, J = 8.1Hz) , 7.65-7.72 (2H, m), 7.70 (1H, d, J = 15.9Hz), 7.84-7.90 (2H, m).

Example 26
(2E) -3- (4-{[1- (3-{[(1-acetyl-4-piperidinyl) carbonyl] [3-chloro-4-methylphenyl] amino} propyl) -4-piperidinyl] sulfonyl} Phenyl) acrylic acid The title compound was synthesized in the same manner as in Example 24, using the compound obtained in Example 25. Yield 87%.
¹ H NMR (CD ₃ OD) δ1.48-1.81 (8H, m), 2.03 (3H, s), 2.13-2.58 (8H, m), 2.27 (3H, s), 2.74-2.87 (1H, m) , 3.04-3.36 (3H, m), 3.53-3.65 (2H, m), 3.67-3.78 (1H, m), 4.43-4.56 (1H, m), 6.20 (1H, d, J = 16.2Hz), 6.87 (1H, dd, J = 7.8, 2.4Hz), 7.07 (1H, d, J = 2.4Hz), 7.16 (1H, d, J = 7.8Hz), 7.18 (1H, d, J = 16.2Hz), 7.54 -7.62 (2H, m), 7.76-7.85 (2H, m).
Example 27
4 '-{[1- (3-{[(1-acetyl-4-piperidinyl) carbonyl] [3-chloro-4-methylphenyl] amino} propyl) -4-piperidinyl] sulfonyl} -1,1'- Methyl biphenyl-4-carboxylate Using the compound obtained in Reference Example 19-2, the title compound was synthesized in the same manner as in Example 1. Yield 46%.
¹ H NMR (CDCl ₃ ) δ1.52-1.93 (10H, m), 1.97-2.09 (2H, m), 2.04 (3H, s), 2.23-2.43 (4H, m), 2.41 (3H, s), 2.77-3.01 (4H, m), 3.55-3.66 (2H, m), 3.69-3.81 (1H, m), 3.96 (3H, s), 4.44-4.56 (1H, m), 6.92 (1H, dd, J = 8.1, 2.1Hz), 7.14 (1H, d, J = 2.1Hz), 7.27 (1H, d, J = 8.1Hz), 7.64-7.70 (2H, m), 7.74-7.81 (2H, m), 7.90 -7.96 (2H, m), 8.12-8.18 (2H, m).
Example 28
4 '-{[1- (3-{[(1-acetyl-4-piperidinyl) carbonyl] [3-chloro-4-methylphenyl] amino} propyl) -4-piperidinyl] sulfonyl} -1,1'- Biphenyl-4-carboxylic acid The title compound was synthesized in the same manner as in Example 24, using the compound obtained in Example 27. Yield 91%.
¹ H NMR (CDCl ₃ ) δ1.42-1.95 (10H, m), 2.02 (3H, s), 2.15-2.48 (3H, m), 2.27 (3H, s), 2.51-2.66 (2H, m), 2.71-2.89 (3H, m), 3.33-3.46 (2H, m), 3.62-3.73 (2H, m), 3.76-3.86 (1H, m), 4.32-4.44 (1H, m), 7.06-7.13 (1H , m), 7.17-7.23 (1H, m), 7.33-7.37 (1H, m), 7.47-7.54 (2H, m), 7.80-7.93 (6H, m).
Example 29
1-acetyl-N- {3- [4-({4-[(1E) -3-amino-3-oxo-1-propenyl] phenyl} sulfonyl) -1-piperidinyl] propyl} -N- (3- Chloro-4-methylphenyl) -4-piperidinecarboxamide The title compound was synthesized in the same manner as in Example 1 using the compound obtained in Reference Example 20-2. Yield 43%.
¹ H NMR (CDCl ₃ ) δ1.49-2.08 (12H, m), 2.04 (3H, s), 2.20-2.44 (4H, m), 2.42 (3H, s), 2.75-3.01 (4H, m), 3.52-3.84 (3H, m), 4.42-4.58 (1H, m), 5.55-5.95 (2H, m), 6.59 (1H, d, J = 15.8Hz), 6.93 (1H, dd, J = 8.2, 2.2 Hz), 7.14 (1H, d, J = 2.2Hz), 7.29 (1H, d, J = 8.2Hz), 7.62-7.72 (2H, m), 7.68 (1H, d, J = 15.8Hz), 7.80- 7.90 (2H, m).
Example 30
1-acetyl-N- [3- (4-{[4- (3-amino-3-oxopropyl) phenyl] sulfonyl} -1-piperidinyl) propyl] -N- (3-chloro-4-methylphenyl) -4-piperidinecarboxamide The title compound was synthesized in the same manner as in Example 1 using the compound obtained in Reference Example 21-2. Yield 47%.
¹ H NMR (CDCl ₃ ) δ1.51-1.90 (10H, m), 1.92-2.02 (2H, m), 2.04 (3H, s), 2.22-2.41 (4H, m), 2.42 (3H, s), 2.56 (2H, d, J = 7.5Hz), 2.76-2.97 (4H, m), 3.07 (2H, t, J = 7.5Hz), 3.54-3.66 (2H, m), 3.69-3.83 (1H, m) , 4.44-4.56 (1H, m), 5.25-5.55 (2H, m), 6.93 (1H, dd, J = 8.1, 2.1Hz), 7.13 (1H, d, J = 2.1Hz), 7.27 (1H, d , J = 8.1Hz), 7.36-7.42 (2H, m), 7.72-7.78 (2H, m).

Example 31
1-acetyl-N- (3-chloro-4-methylphenyl) -N- {3- [4-({4-[(E) -2-cyanovinyl] phenyl} sulfonyl) -1-piperidinyl] propyl}- 4-Piperidinecarboxamide The title compound was synthesized in the same manner as in Example 1 using the compound obtained in Reference Example 22-2. Yield 49%.
¹ H NMR (CDCl ₃ ) δ1.52-2.05 (12H, m), 2.04 (3H, s), 2.22-2.42 (4H, m), 2.42 (3H, s), 2.78-2.99 (4H, m), 3.54-3.67 (2H, m), 3.70-3.81 (1H, m), 4.50-4.55 (1H, m), 6.04 (1H, d, J = 16.8Hz), 6.94 (1H, dd, J = 8.1, 2.1 Hz), 7.14 (1H, d, J = 2.1Hz), 7.29 (1H, d, J = 8.1Hz), 7.46 (1H, d, J = 16.8Hz), 7.60-7.66 (2H, m), 7.87- 7.93 (2H, m).
Example 32
1-acetyl-N- (3-chloro-4-methylphenyl) -N- [3- (4- {3-[(methylsulfonyl) amino] benzyl} -1-piperidinyl) propyl] -4-piperidinecarboxamide < The title compound was synthesized in the same manner as in Example 1 using the compound obtained in Reference Example 23-4. Yield 36%.
¹ H NMR (CDCl ₃ ) δ1.15-1.31 (2H, m), 1.40-1.88 (11H, m), 2.05 (3H, s), 2.22-2.45 (4H, m), 2.42 (3H, s), 2.51 (2H, d, J = 6.9Hz), 2.78-2.90 (3H, m), 3.00 (3H, s), 3.60- 3.68 (2H, m), 3.71-3.81 (1H, m), 4.47-4.56 ( 1H, m), 6.93-7.01 (3H, m), 7.02-7.07 (1H, m), 7.18 (1H, d, J = 2.4Hz), 7.22-7.31 (2H, m).
Example 33
1-acetyl-N- (3-chloro-4-methylphenyl) -N- [3- (4- {4-[(4-hydroxy-1-piperidinyl) sulfonyl] benzyl} -1-piperidinyl) propyl]- 4-Piperidinecarboxamide The title compound was synthesized in the same manner as in Example 1 using the compound obtained in Reference Example 24-2. Yield 81%.
¹ H NMR (CDCl ₃ ) δ 1.18-1.35 (2H, m), 1.45-2.00 (17H, m), 2.05 (3H, s), 2.24-2.41 (4H, m), 2.42 (3H, s), 2.58 (2H, d, J = 6.6Hz), 2.78-2.93 (4H, m), 3.27-3.38 (2H, m), 3.58-3.68 (2H, m), 3.71-3.82 (2H, m), 4.46- 4.56 (1H, m), 6.95 (1H, dd, J = 8.1, 2.1Hz), 7.17 (1H, d, J = 2.1Hz), 7.25-7.31 (3H, m), 7.63-7.68 (2H, m) .
Example 34
1-acetyl-N- (3-chloro-4-methylphenyl) -N- {3- [4- (4-{[(2-hydroxyethyl) amino] sulfonyl} benzyl) -1-piperidinyl] propyl}- 4-Piperidinecarboxamide hydrochloride The title compound was synthesized in the same manner as in Example 4 using the compound obtained in Reference Example 25-2. Yield 34%.
¹ H NMR (CDCl ₃ ) δ1.15-1.35 (2H, m), 1.45-1.90 (11H, m), 2.05 (3H, s), 2.22-2.44 (4H, m), 2.42 (3H, s), 2.59 (2H, d, J = 6.3Hz), 2.78-2.90 (3H, m), 3.10 (2H, t, J = 5.1Hz), 3.59-3.81 (5H, m), 4.45-4.55 (1H, m) , 5.05-5.35 (1H, m), 6.96 (1H, dd, J = 8.1, 2.1Hz), 7.18 (1H, d, J = 2.1Hz), 7.24-7.31 (3H, m), 7.74-7.79 (2H , m).

Example 35
1-acetyl-N- {3- [4- (4-acetylbenzyl) -1-piperidinyl] propyl} -N- (3-chloro-4-methylphenyl) -4-piperidinecarboxamide
1-acetyl-N- (3-chloro-4-methylphenyl) -N- (3-chloropropyl) piperidine-4-carboxamide (7.43 g, 20.0 mmol), the compound obtained in Reference Example 26-2 (6.15 g), potassium iodide (3.32 g, 20.0 mmol), potassium carbonate (11.06 g, 80.0 mmol), acetonitrile (40 mL), and N, N-dimethylformamide (40 mL) were stirred at 100 ° C. for 6 hours. After the reaction mixture was concentrated under reduced pressure, ethyl acetate (60 mL) was added, and the mixture was washed with water (30 mL), a 1N aqueous sodium hydroxide solution (10 mL × 2), and a saturated saline solution (10 mL). The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel 200 g, ethyl acetate / methanol = 1/0 → 4/1) to give the title compound (8.90 g, 16.1 mmol, yield 81%) as a pale solid. Obtained as a yellow amorphous.
¹ H NMR (CDCl ₃ ) δ 1.1-1.95 (13H, m), 2.04 (3H, s), 2.2-2.45 (2H, m), 2.28 (2H, t, J = 7.5Hz), 2.42 (3H, s ), 2.58 (3H, s), 2.57 (2H, d, J = 6.2Hz), 2.7-2.95 (3H, m), 3.64 (2H, t, J = 7.5Hz), 3.76 (1H, br d, J = 14.0Hz), 4.51 (1H, br d, J = 12.8Hz), 6.96 (1H, dd, J = 2.2, 8.0Hz), 7.18 (1H, d, J = 2.2Hz), 7.22 (2H, d, J = 8.4Hz), 7.28 (1H, d, J = 8.0Hz), 7.87 (2H, d, J = 8.4Hz).
Example 36
1-acetyl-N- (3-chloro-4-methylphenyl) -N- [3- (4- {4-[(1E) -N-hydroxyethanimidoyl] benzyl} -1-piperidinyl) propyl]- 4-Piperidinecarboxamide To a solution of the compound obtained in Example 35 (1104 mg, 2.00 mmol) in ethanol (10 mL) was added hydroxylamine hydrochloride (695 mg, 10.0 mmol) and sodium acetate (820 mg, 10.0 mmol). The mixture was stirred under reflux for 1 hour. After the reaction mixture was concentrated under reduced pressure, ethyl acetate (40 mL) was added, and the mixture was washed with a 1N aqueous sodium hydroxide solution (15.5 mL) and a saturated saline solution (5 mL). After the organic layer was concentrated under reduced pressure, the residue was subjected to column chromatography (NH silica gel 50 g, hexane / ethyl acetate = 2/1 → 0/1). After the target fraction was concentrated under reduced pressure, the residue was recrystallized from ethyl acetate to give the title compound (878 mg, 1.55 mmol, yield 77%) as a white solid.
¹ H NMR (CDCl ₃ ) δ 1.1-1.95 (13H, m), 2.04 (3H, s), 2.15-2.45 (4H, m), 2.26 (3H, s), 2.41 (3H, s), 2.52 (2H , d, J = 6.0Hz), 2.7-2.95 (3H, m), 3.64 (2H, t, J = 7.5Hz), 3.75 (1H, br d, J = 13.6Hz), 4.51 (1H, br d, J = 12.8Hz), 6.95 (1H, dd, J = 2.0, 8.0Hz), 7.12 (2H, d, J = 8.4Hz), 7.17 (1H, d, J = 2.0Hz), 7.26 (1H, d, J = 8.0Hz), 7.53 (2H, d, J = 8.4Hz), 8.62 (1H, br s, O H ).
Example 37
1-acetyl-N- (3-chloro-4-methylphenyl) -N- [3- (4- {4-[(1E) -N-methoxyethaneimidoyl] benzyl} -1-piperidinyl) propyl]- 4-piperidinecarboxamide
The title compound was synthesized in the same manner as in Example 36 using O-methylhydroxylamine hydrochloride. 95% yield.
¹ H NMR (CDCl ₃ ) δ 1.1-1.9 (13H, m), 2.04 (3H, s), 2.15-2.45 (4H, m), 2.21 (3H, s), 2.42 (3H, s), 2.51 (2H , d, J = 6.2Hz), 2.7-2.95 (3H, m), 3.64 (2H, t, J = 7.7Hz), 3.75 (1H, br d, J = 12.6Hz), 3.98 (3H, s), 4.51 (1H, br d, J = 13.2Hz), 6.95 (1H, dd, J = 2.1, 7.8Hz), 7.12 (2H, d, J = 8.2Hz), 7.17 (1H, d, J = 2.1Hz) , 7.28 (1H, d, J = 7.8Hz), 7.54 (2H, d, J = 8.2Hz).

Example 38
1-acetyl-N- (3-chloro-4-methylphenyl) -N- [3- (4- {4-[(1E) -N-ethoxyethanimidoyl] benzyl} -1-piperidinyl) propyl]- The title compound was synthesized in the same manner as in Example 36 using 4-piperidinecarboxamide O-ethylhydroxylamine hydrochloride. Yield 92%.
¹ H NMR (CDCl ₃ ) δ 1.1-1.9 (13H, m), 1.32 (3H, t, J = 7.2Hz), 2.04 (3H, s), 2.15-2.45 (4H, m), 2.21 (3H, s ), 2.42 (3H, s), 2.51 (2H, d, J = 6.6Hz), 2.7-2.95 (3H, m), 3.64 (2H, t, J = 7.5Hz), 3.76 (1H, br d, J = 12.8Hz), 4.23 (2H, q, J = 7.2Hz), 4.51 (1H, br d, J = 13.2Hz), 6.95 (1H, dd, J = 2.2, 7.6Hz), 7.11 (2H, d, J = 8.2Hz), 7.17 (1H, d, J = 2.2Hz), 7.28 (1H, d, J = 7.6Hz), 7.54 (2H, d, J = 8.2Hz).
Example 39
1-acetyl-N- (3-chloro-4-methylphenyl) -N- (3- {4- [4- (1-hydroxy-1-methylethyl) benzyl] -1-piperidinyl} propyl) -4- To a dichloromethane (20 mL) solution of the compound (552 mg, 1.00 mmol) of piperidinecarboxamide obtained in Example 35 was added trimethylaluminum (2 M hexane solution, 5 mL) under ice-cooling and stirring, and the mixture was stirred at room temperature for 1 hour. Under ice cooling, trimethylaluminum (2 M hexane solution, 5 mL) was added, and the mixture was stirred at room temperature for 1 hour. Under ice cooling, water (40 mL) and a 1N aqueous sodium hydroxide solution (20 mL) were sequentially added, and the mixture was extracted with dichloromethane (20 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel 80 g, hexane / ethyl acetate = 2/1 → 0/1) to give the title compound (206 mg, 0.36 mmol, yield 36%) as a colorless amorphous.
¹ H NMR (CDCl ₃ ) δ 1.1-1.95 (13H, m), 1.57 (6H, s), 2.05 (3H, s), 2.2-2.45 (2H, m), 2.26 (2H, t, J = 7.5Hz ), 2.42 (3H, s), 2.50 (2H, d, J = 6.6Hz), 2.7-2.95 (3H, m), 3.64 (2H, t, J = 7.7Hz), 3.76 (1H, br d, J = 14.2Hz), 4.51 (1H, br d, J = 12.8Hz), 6.95 (1H, dd, J = 2.1, 8.0Hz), 7.09 (2H, d, J = 8.5Hz), 7.18 (1H, d, J = 2.1Hz), 7.28 (1H, d, J = 8.0Hz), 7.38 (2H, d, J = 8.5Hz).
Example 40
1-acetyl-N- (3-chloro-4-methylphenyl) -N- {3- [4- (4-{[(cis) -2,6-dimethyl-4-morpholinyl] sulfonyl} benzyl) -1 -Piperidinyl] propyl} -4-piperidinecarboxamide hydrochloride The title compound was synthesized in the same manner as in Example 1 using the compound obtained in Reference Example 27-2. Yield 54%.
¹ H NMR (CDCl ₃ ) δ 1.14 (6H, d, J = 6.3 Hz), 1.16-1.29 (2H, m), 1.35-2.00 (13H, m), 2.05 (3H, s), 2.25-2.42 ( 4H, m), 2.42 (3H, s), 2.60 (2H, d, J = 6.3Hz), 2.78-2.90 (3H, m), 3.53-3.80 (7H, m), 4.46-4.56 (1H, m) , 6.96 (1H, dd, J = 8.1, 2.1Hz), 7.18 (1H, d, J = 2.1Hz), 7.26-7.32 (3H, m), 7.62-7.66 (2H, m).

Example 41
1-Acetyl-N- (3-chloro-4-methylphenyl) -N- (3- {4- [4- (1-hydroxyethyl) benzyl] -1-piperidinyl} propyl) -4-piperidinecarboxamide To a solution of the compound (442 mg, 0.80 mmol) obtained in 35 in ethanol (8 mL) was added sodium borohydride (45 mg, 1.2 mmol) under ice cooling and stirring, and the mixture was stirred at room temperature for 2 hours. Under ice-cooling, 1N hydrochloric acid (2.4 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. Under ice-cooling, a 1N sodium hydroxide solution (4.8 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Ethyl acetate (40 mL) was added to the residue, and the mixture was washed with water (10 mL) and saturated saline (10 mL). After concentrating the organic layer under reduced pressure, the residue was purified by column chromatography (50 g of NH silica gel, hexane / ethyl acetate = 2/1 → 0/1) to obtain the title compound (396 mg, 0.54 mmol, yield 89%). Was.
¹ H NMR (CDCl ₃ ) δ 1.1-2.1 (13H, m), 1.48 (3H, d, J = 6.6 Hz), 2.04 (3H, s), 2.15-2.55 (2H, m), 2.26 (2H, t , J = 7.5Hz), 2.42 (3H, s), 2.50 (2H, d, J = 6.6Hz), 2.7-2.95 (3H, m), 3.63 (2H, t, J = 7.7Hz), 3.76 (1H , br d, J = 13.2Hz), 4.50 (1H, br d, J = 13.6Hz), 4.86 (1H, q, J = 6.6Hz), 6.96 (1H, dd, J = 2.0, 8.2Hz), 7.10 (2H, d, J = 8.0Hz), 7.17 (1H, d, J = 2.0Hz), 7.28 (2H, d, J = 8.0Hz), 7.28 (1H, d, J = 8.2Hz).
Example 42
1-acetyl-N- (3-chloro-4-methylphenyl) -N- [3- (4- {4-[(4-oxo-1-piperidinyl) sulfonyl] benzyl} -1-piperidinyl) propyl]- 4-piperidinecarboxamide A coupling product was synthesized in the same manner as in Example 1 using the compound obtained in Reference Example 28-2. Yield 70%.
The obtained coupling product was subjected to deprotection of the carbonyl group in the same manner as in Example 13 to synthesize the title compound. Yield 60%.
¹ H NMR (CDCl ₃ ) δ1.20-1.40 (2H, m), 1.45-1.93 (13H, m), 2.05 (3H, s), 2.22-2.44 (4H, m), 2.42 (3H, s), 2.54 (2H, d, J = 6.0Hz), 2.59 (2H, t, J = 6.0Hz), 2.78-2.92 (3H, m), 3.13-3.20 (1H, m), 3.36-3.43 (3H, m) , 3.58-3.69 (2H, m), 3.70-3.81 (1H, m), 4.46-4.56 (1H, m), 6.92-7.01 (1H, m), 7.17 (1H, d, J-1.8Hz), 7.24 -7.33 (3H, m), 7.66-7.72 (2H, m).
Example 43
2- (4-{[1- (3-{[(1-acetyl-4-piperidinyl) carbonyl] [3-chloro-4-methylphenyl] amino} propyl) -4-piperidinyl] methyl} phenyl) -2 -Ethyl methylpropanoate The title compound was synthesized in the same manner as in Example 1, using the compound obtained in Reference Example 29-5. 73% yield.
¹ H NMR (CDCl ₃ ) δ 1.1-1.9 (13H, m), 1.19 (3H, t, J = 7.2Hz), 1.55 (6H, s), 2.05 (3H, s), 2.2-2.5 (2H, m ), 2.26 (2H, t, J = 7.5Hz), 2.42 (3H, s), 2.48 (2H, d, J = 6.6Hz), 2.7-2.95 (3H, m), 3.64 (2H, t, J = 7.7Hz), 3.76 (1H, br d, J = 13.8Hz), 4.12 (2H, q, J = 7.2Hz), 4.51 (1H, br d, J = 13.2Hz), 6.95 (1H, dd, J = 2.2, 8.0Hz), 7.06 (2H, d, J = 8.2Hz), 7.17 (1H, d, J = 2.2Hz), 7.23 (2H, d, J = 8.2Hz), 7.28 (1H, d, J = 8.0Hz).

Example 44
1-acetyl-N- (3-chloro-4-methylphenyl) -N- {3- [4- (4-{[(2-hydroxyethyl) (methyl) amino] sulfonyl} benzyl) -1-piperidinyl] Propyl} -4-piperidinecarboxamide The title compound was synthesized in the same manner as in Example 1 using the compound obtained in Reference Example 30-2. Yield 69%.
¹ H NMR (CDCl ₃ ) δ 1.18-1.37 (2H, m), 1.45-1.89 (11H, m), 2.05 (3H, s), 2.23-2.44 (4H, m), 2.42 (3H, s), 2.59 (2H, d, J = 6.6Hz), 2.78-2.92 (3H, m), 2.84 (3H, s), 3.17 (2H, t, J = 5.4Hz), 3.58-3.68 (2H, m), 3.72 -3.82 (1H, m), 3.77 (2H, t, J = 5.4Hz), 4.46-4.57 (1H, m), 6.96 (1H, dd, J = 8.1, 2.1Hz), 7.18 (1H, d, J = 2.1Hz), 7.25-7.33 (3H, m), 7.68-7.73 (2H, m).
Example 45
1-acetyl-N- (3- {4- [4- (2-amino-1,1-dimethyl-2-oxoethyl) benzyl] -1-piperidinyl} propyl) -N- (3-chloro-4-methyl (Phenyl) -4-piperidinecarboxamide 1-acetyl-N- (3-chloro-4-methylphenyl) -N- (3-chloropropyl) piperidine-4-carboxamide (371 mg, 1.00 mmol), in Reference Example 31-3. A mixture of the obtained compound (260 mg, 1.00 mmol), potassium iodide (166 mg, 1.00 mmol), potassium carbonate (553 mg, 4.00 mmol), acetonitrile (5 mL), N, N-dimethylformamide (5 mL) was added at 100 ° C. Stirred for 6 hours. After the reaction mixture was concentrated under reduced pressure, ethyl acetate (40 mL) was added, and the mixture was washed with water (10 mL), a 1N aqueous sodium hydroxide solution (5 mL × 2), and a saturated saline solution (5 mL). The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel 15 g, ethyl acetate / methanol = 1/0 → 4/1) to give the title compound (355 mg, 0.60 mmol, yield 60%) as a colorless amorphous As obtained.
¹ H NMR (CDCl ₃ ) δ 1.1-2.1 (13H, m), 1.57 (6H, s), 2.04 (3H, s), 2.2-2.45 (2H, m), 2.28 (2H, t, J = 7.7Hz ), 2.42 (3H, s), 2.50 (2H, d, J = 6.2Hz), 2.75-2.95 (3H, m), 3.64 (2H, t, J = 7.5Hz), 3.76 (1H, br d, J = 13.6Hz), 4.51 (1H, br d, J = 14.4Hz), 5.18 (1H, br s), 5.26 (1H, br s), 6.96 (1H, dd, J = 2.1, 8.2Hz), 7.11 ( 2H, d, J = 8.2Hz), 7.18 (1H, d, J = 2.1Hz), 7.28 (1H, d, J = 8.2Hz), 7.30 (2H, d, J = 8.2Hz).
Example 46
1-acetyl-N- (3-chloro-4-methylphenyl) -N- {3- [4- (4-{[(3-methoxypropyl) amino] sulfonyl} benzyl) -1-piperidinyl] propyl}- 4-Piperidinecarboxamide The title compound was synthesized in the same manner as in Example 1 using the compound obtained in Reference Example 32-2. Yield 65%.
¹ H NMR (CDCl ₃ ) δ1.17-1.35 (2H, m), 1.45-4.89 (13H, m), 2.05 (3H, s), 2.23-2.45 (4H, m), 2.42 (3H, s), 2.58 (2H, d, J = 6.6Hz), 2.78-2.90 (3H, m), 3.08 (2H, dt, J = 6.0, 5.7Hz), 3.29 (3H, s), 3.41 (2H, t, J = 5.7Hz), 3.57-3.82 (3H, m), 4.45-4.57 (1H, m), 5.04 (1H, t, J = 5.7Hz), 6.96 (1H, dd, J = 8.1, 1.8Hz), 7.17 ( 1H, d, J = 1.8Hz), 7.23-7.32 (3H, m), 7.72-7.78 (2H, m).
Example 47
1-acetyl-N- (3-chloro-4-methylphenyl) -N- [3- (4- {4-[(4-methoxy-1-piperidinyl) sulfonyl] benzyl} -1-piperidinyl) propyl]- 4-Piperidinecarboxamide hydrochloride The title compound was synthesized in the same manner as in Example 4 using the compound obtained in Reference Example 33-2. Yield 78%.
¹ H NMR (CDCl ₃ ) δ1.15-1.40 (2H, m), 1.45-2.02 (15H, m), 2.05 (3H, s), 2.21-2.44 (4H, m), 2.42 (3H, s), 2.59 (2H, d, J = 6.2Hz), 2.74-3.03 (5H, m), 3.10-3.35 (3H, m), 3.26 (3H, m), 3.59-3.85 (3H, m), 4.42-4.60 ( 1H, m), 6.97 (1H, dd, J = 12.0, 2.0Hz), 7.18 (1H, d, J = 2.0Hz), 7.20-7.35 (3H, m), 7.60-7.71 (2H, m).

Example 48
2- (4-{[1- (3-{[(1-acetyl-4-piperidinyl) carbonyl] [3-chloro-4-methylphenyl] amino} propyl) -4-piperidinyl] methyl} phenyl) -2 -Methylpropanoic acid 1N aqueous sodium hydroxide solution (3.0 mL) was added to a solution of the compound obtained in Example 43 (624 mg, 1.00 mmol) in ethanol (6 mL), and the mixture was stirred at 60 ° C for 17 hours. 1N Hydrochloric acid (3.0 mL) was added to the reaction mixture, followed by concentration under reduced pressure. Water (10 mL) was added to the residue, and the mixture was extracted with dichloromethane (20 mL × 3). The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, dichloromethane / methanol = 1/0 → 4/1) to give the title compound (133 mg, 0.22 mmol, yield 22%) as a pale-yellow amorphous Obtained.
¹ H NMR (CDCl ₃ ) δ 1.45-2.15 (11H, m), 1.54 (6H, s), 2.05 (3H, s), 2.15-2.55 (6H, m), 2.42 (3H, s), 2.7-2.95 (3H, m), 3.35 (2H, br d, J = 9.8Hz), 3.55-3.85 (3H, m), 4.52 (1H, br d, J = 14.0Hz), 7.04 (2H, d, J = 8.0 Hz), 7.14 (1H, dd, J = 1.9, 7.9Hz), 7.22 (1H, d, J = 1.9Hz), 7.33 (1H, d, J = 7.9Hz), 7.34 (2H, d, J = 8.0 Hz).
Example 49
1-acetyl-N- (3-chloro-4-methylphenyl) -N- {3- [4- (4-{[(2-hydroxypropyl) amino] sulfonyl} benzyl) -1-piperidinyl] propyl}- 4-Piperidinecarboxamide The title compound was synthesized in the same manner as in Example 1 using the compound obtained in Reference Example 34-2. Yield 74%.
¹ H NMR (CDCl ₃ ) δ 1.16 (3H, d, J = 6.6 Hz), 1.20-1.35 (2H, m), 1.45-1.90 (12H, m), 2.05 (3H, s), 2.21-2.43 ( 4H, m), 2.42 (3H, s), 2.59 (2H, d, J = 6.6Hz), 2.73-2.94 (3H, m), 3.00-3.12 (1H, m), 3.57-3.97 (4H, m) , 4.45-4.57 (1H, m), 4.92-5.03 (1H, m), 6.96 (1H, dd, J = 8.1, 2.1Hz), 7.18 (1H, d, J = 2.1Hz), 7.24-7.33 (3H , m), 7.72-7.79 (2H, m).
Example 50
1-acetyl-N- (3-chloro-4-methylphenyl) -N- (3- {4- [4-({[(1-hydroxycyclohexyl) methyl] amino} sulfonyl) benzyl] -1-piperidinyl} Propyl) -4-piperidinecarboxamide The title compound was synthesized in the same manner as in Example 1 using the compound obtained in Reference Example 35-2. Yield 68%.
¹ H NMR (CDCl ₃ ) δ 1.10-1.95 (25H, m), 2.05 (3H, s), 2.20-2.45 (4H, m), 2.43 (3H, s), 2.58 (2H, d, J = 6.2 Hz), 2.75-2.95 (4H, m), 3.50-3.87 (3H, m), 4.45-4.60 (1H, m), 4.77-4.93 (1H, m), 6.96 (1H, dd, J = 8.0, 2.2 Hz), 7.18 (1H, dm J = 2.2Hz), 7.22-7.33 (3H, m), 7.70-7.79 (2H, m).
Example 51-1
1-acetyl-N- (3-chloro-4-methylphenyl) -N- {3- [4- (4-cyanobenzyl) piperidin-1-yl] propyl} piperidine-4-carboxamide 1-acetyl-N- (3-Chloro-4-methylphenyl) -N- (3-chloropropyl) piperidine-4-carboxamide (4.46 g, 12.0 mmol), 4- (piperidin-4-ylmethyl) benzonitrile hydrochloride (2.37 g, 10.0 mmol), potassium iodide (1.99 g, 12.0 mmol), potassium carbonate (5.53 g, 40.0 mmol), acetonitrile (50 mL), and N, N-dimethylformamide (50 mL) were stirred at 100 ° C. for 6 hours. After the reaction mixture was concentrated under reduced pressure, ethyl acetate (80 mL) was added, and the mixture was washed with water (20 mL), a 1N aqueous sodium hydroxide solution (10 mL × 2), and a saturated saline solution (10 mL). The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel 100 g, ethyl acetate / methanol = 1/0 → 4/1) to give the title compound (4.00 g, 7.47 mmol, yield 75%) as colorless Obtained as amorphous.
¹ H NMR (CDCl ₃ ) δ 1.1-1.9 (13H, m), 2.05 (3H, s), 2.15-2.45 (2H, m), 2.27 (2H, t, J = 7.4Hz), 2.42 (3H, s ), 2.57 (2H, d, J = 6.6Hz), 2.7-2.95 (3H, m), 3.64 (2H, t, J = 7.5Hz), 3.76 (1H, br d, J = 14.4Hz), 4.52 ( 1H, br d, J = 12.8Hz), 6.95 (1H, dd, J = 2.2, 8.0Hz), 7.17 (1H, d, J = 2.2Hz), 7.22 (2H, d, J = 8.2Hz), 7.29 (1H, d, J = 8.0Hz), 7.56 (2H, d, J = 8.2Hz).

Example 51-2
1-acetyl-N- [3- (4- {4-[(Z) -amino (hydroxyimino) methyl] benzyl} piperidin-1-yl) propyl] -N- (3-chloro-4-methylphenyl) Piperidine-4-carboxamide To a solution of the compound obtained in Example 51-1 (1605 mg, 3.00 mmol) in ethanol (15 mL) was added hydroxylamine hydrochloride (417 mg, 6.00 mmol) and sodium bicarbonate (504 mg, 6.00 mmol) to give 70 Stirred at C for 5 hours. After concentrating the reaction solution under reduced pressure, ethyl acetate (80 mL) was added, and the mixture was washed with a 1N aqueous sodium hydroxide solution (15, 10 mL) and saturated saline (10 mL). The organic layer was concentrated under reduced pressure, and the residue was subjected to column chromatography (NH silica gel 100 g, ethyl acetate / methanol = 1/0 → 9/1). The target fraction was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate-methanol to obtain the title compound (1824 mg) as a white solid.
¹ H NMR (CDCl ₃ ) δ 1.1-1.95 (13H, m), 2.05 (3H, s), 2.2-2.45 (2H, m), 2.27 (2H, t, J = 7.6Hz), 2.41 (3H, s ), 2.53 (2H, d, J = 6.4Hz), 2.7-2.95 (3H, m), 3.64 (2H, t, J = 7.7Hz), 3.75 (1H, br d, J = 13.8Hz), 4.51 ( 1H, br d, J = 12.8Hz), 4.84 (2H, br s, NH ₂ ), 6.96 (1H, dd, J = 2.0, 8.0Hz), 7.15 (2H, d, J = 8.5Hz), 7.17 ( 1H, d, J = 2.0Hz), 7.27 (1H, d, J = 8.0Hz), 7.53 (2H, d, J = 8.5Hz).
Example 51-3
1-acetyl-N- (3-chloro-4-methylphenyl) -N- (3- {4- [4- (5-oxo-2,5-dihydro-1,2,4-oxadiazole-3 -Yl ) benzyl] -1-piperidinyl} propyl) -4-piperidinecarboxamide 1,1′-carbonyldiimidazole (156 mg) in a solution of the compound obtained in Example 51-2 (455 mg, 0.80 mmol) in dioxane (10 mL) , 0.96 mmol) and stirred at 100 ° C. for 3 hours. After the reaction solution was concentrated under reduced pressure, water was added and extracted with dichloromethane (three times). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (50 g of NH silica gel, dichloromethane / methanol = 1/0 → 0/1) to give the title compound (231 mg, 0.39 mmol, yield 49%) as a colorless amorphous.
¹ H NMR (CDCl ₃ ) δ 0.8-2.9 (20H, m), 1.93 (3H, s), 2.39 (3H, s), 3.3-4.1 (5H, m), 4.3-4.5 (1H, m), 6.65 -6.95 (2H, m), 6.92 (1H, d, J = 6.6Hz), 7.15 (1H, s), 7.23 (1H, d, J = 8.4Hz), 7.4-7.7 (2H, m).
Example 52
1-acetyl-N- (3-chloro-4-methylphenyl) -N- (3- {4- [4- (5-methyl-1,2,4-oxadiazol-3-yl) benzyl]- 1-Piperidinyl} propyl) -4-piperidinecarboxamide A mixture of the compound obtained in Example 51-2 (341 mg, 0.60 mmol) and acetic anhydride (5 mL) was stirred at 100 ° C for 1 hour and at 150 ° C for 2 hours. After the reaction solution was concentrated under reduced pressure, ethyl acetate (40 mL) was added, and the mixture was washed with a 1N aqueous sodium hydroxide solution (10, 5 mL) and saturated saline (5 mL). The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography (NH silica gel 40 g, hexane / ethyl acetate = 3/1 → 1/3) to elute the title compound (123 mg, 0.21 mmol, yield 35%). Obtained as a yellow oil.
¹ H NMR (CDCl ₃ ) δ 1.1-2.1 (13H, m), 2.04 (3H, s), 2.2-2.5 (2H, m), 2.28 (2H, t, J = 7.7Hz), 2.42 (3H, s ), 2.57 (2H, d, J = 6.2Hz), 2.65 (3H, s), 2.7-2.95 (3H, m), 3.64 (2H, t, J = 7.5Hz), 3.76 (1H, br d, J = 13.0Hz), 4.51 (1H, br d, J = 13.0Hz), 6.96 (1H, dd, J = 2.2, 8.2Hz), 7.18 (1H, d, J = 2.2Hz), 7.23 (2H, d, J = 8.3Hz), 7.28 (1H, d, J = 8.2Hz), 7.96 (2H, d, J = 8.3Hz).

Example 53
1-acetyl-N- (3-chloro-4-methylphenyl) -N- [3- (4- {4-[(3-hydroxy-1-pyrrolidinyl) sulfonyl] benzyl} -1-piperidinyl) propyl]- 4-Piperidinecarboxamide The title compound was synthesized in the same manner as in Example 1 using the compound obtained in Reference Example 36-2. Yield 78%.
¹ H NMR (CDCl ₃ ) δ1.13-2.03 (15H, m), 2.04 (3H, s), 2.18-2.43 (4H, m), 2.42 (3H, s), 2.59 (2H, d, J = 5.8 Hz), 2.63-2.97 (3H, m), 3.17-3.50 (4H, m), 3.55-3.84 (3H, m), 4.32-4.42 (1H, m), 4.43-4.60 (1H, m), 6.96 ( 1H, dd, J = 8.0, 1.8Hz), 7.17 (1H, d, J = 1.8Hz), 7.23-7.33 (3h, m), 7.70-7.80 (2H, m).
Example 54
1-acetyl-N- (3-chloro-4-methylphenyl) -N- [3- (4- {4-[(4-hydroxy-4-methyl-1-piperidinyl) sulfonyl] benzyl} -1-piperidinyl ) Propyl] -4-piperidinecarboxamide The title compound was synthesized in the same manner as in Example 1 using the compound obtained in Reference Example 37-2. Yield 74%.
¹ H NMR (CDCl ₃ ) δ1.01 (1H, br s), 1.18-1.36 (2H, m), 1.23 (3H, s), 1.53-1.88 (15H, m), 2.05 (3H, s), 2.21 -2.44 (4H, m), 2.42 (3H, s), 2.58 (2H, d, J = 6.3Hz), 2.65-2.76 (2H, m), 2.78-2.90 (3H, m), 3.45-3.56 (2H , m), 3.58-3.68 (2H, m), 3.70-3.81 (1H, m), 4.46-4.57 (1H, m), 6.96 (1H, dd, J = 8.1, 2.1Hz), 7.18 (1H, d , J = 2.1Hz), 7.24-7.31 (3H, m), 7.63-7.69 (2H, m).
Example 55
1-acetyl-N- (3-chloro-4-methylphenyl) -N- {3- [4- (4-{[(2-hydroxy-1,1-dimethylethyl) amino] sulfonyl} benzyl) -1 -Piperidinyl] propyl} -4-piperidinecarboxamide The title compound was synthesized in the same manner as in Example 1 using the compound obtained in Reference Example 38-2. Yield 61%.
¹ H NMR (CDCl ₃ ) δ 1.14 (6H, s), 1.18-1.35 (2H, m), 1.44-1.89 (11H, m), 2.05 (3H, s), 2.22-2.44 (4H, m), 2.42 (3H, s), 2.58 (2H, d, J = 6.6Hz), 2.77-2.95 (3H, m), 3.46 (2H, s), 3.58-3.82 (3H, m), 4.46-4.57 (1H, m), 4.80 (1H, s), 6.95 (1H, dd, J = 8.1, 1.8Hz), 7.17 (1H, d, J = 1.8Hz), 7.22-7.32 (3H, m), 7.77-7.83 (2H , m).
Example 56
1-acetyl-N- (3-chloro-4-methylphenyl) -N- {3- [4- (4-{[ethyl (2-hydroxyethyl) amino] sulfonyl} benzyl) -1-piperidinyl] propyl} -4-piperidinecarboxamide The title compound was synthesized in the same manner as in Example 1 using the compound obtained in Reference Example 39-2. Yield 100%.
¹ H NMR (CDCl ₃ ) δ 1.10-1.38 (2H, m), 1.15 (3H, t, J = 7.2Hz), 1.40-1.90 (12H, m), 2.05 (3H, s), 2.19-2.46 ( 4H, m), 2.42 (3H, s), 2.58 (2H, d, J = 6.2Hz), 2.75-2.94 (3H, m), 3.21-3.44 (4H, m), 3.55-3.83 (5H, m) , 4.42-4.60 (1H, m), 6.96 (1H, dd, J = 8.0, 2.2Hz), 7.18 (1H, d, J = 2.2Hz), 7.22-7.32 (3H, m), 7.68-7.76 (2H , m).

Example 57
1-acetyl-N- (3-chloro-4-methylphenyl) -N- {3- [4- (4-{[(2-hydroxy-2-methylpropyl) amino] sulfonyl} benzyl) -1-piperidinyl ] Propyl} -4-piperidinecarboxamide The title compound was synthesized in the same manner as in Example 1 using the compound obtained in Reference Example 40-2. 83% yield.
¹ H NMR (CDCl ₃ ) δ 1.18-1.33 (2H, m), 1.24 (6H, s), 1.44-1.89 (12H, m), 2.05 (3H, s), 2.23-2.45 (4H, m), 2.42 (3H, s), 2.58 (2H, d, J = 6.3Hz), 2.78-2.92 (2H, m), 2.89 (2H, d, J = 6.3Hz), 3.56-3.88 (3H, m), 4.46 -4.58 (1H, m), 4.88 (1H, t, J = 6.3Hz), 6.96 (1H, dd, J = 8.1, 2.1Hz), 7.17 (1H, d, J = 2.1Hz), 7.24-7.74 ( 3H, m), 7.72-7.78 (2H, m).
Example 58
1-acetyl-N- (3-chloro-4-methylphenyl) -N- {3- [4- (4-{[4- (methoxyimino) -1-piperidinyl] sulfonyl} benzyl) -1-piperidinyl] Propyl} -4-piperidinecarboxamide The title compound was synthesized in the same manner as in Example 1 using the compound obtained in Reference Example 41-3. Yield 66%.
¹ H NMR (CDCl ₃ ) δ1.16-1.35 (2H, m), 1.44-1.88 (14H, m), 2.05 (3H, s), 2.23-2.45 (4H, m), 2.42 (3H, s), 2.58 (2H, d, J = 6.6Hz), 2.67 (2H, t, J = 6.0Hz), 2.77-2.90 (3H, m), 3.12 (2H, t, J = 6.0Hz), 3.19 (2H, t , J = 6.0Hz), 3.59-3.69 (2H, m), 3.70-3.81 (1H, m), 3.78 (3H, s), 6.95 (1H, dd, J = 8.1, 1.8Hz), 7.18 (1H, d, J = 1.8Hz), 7.24-7.32 (3H, m), 7.62-7.68 (2H, m).
Example 59-1
4 '-[(1- {3-[[(1-acetylpiperidin-4-yl) carbonyl] (3-chloro-4-methylphenyl) amino] propyl} piperidin-4-yl) methyl] -1,1 Methyl '-biphenyl-4-carboxylate 1-acetyl-N- (3-chloro-4-methylphenyl) -N- (3-chloropropyl) piperidine-4-carboxamide (1114 mg, 3.00 mmol), Reference Example 42- A mixture of the compound obtained in 2 (774 mg, 2.50 mmol), potassium iodide (498 mg, 3.00 mmol), potassium carbonate (1382 mg, 10.0 mmol), acetonitrile (12.5 mL), N, N-dimethylformamide (12.5 mL) Was stirred at 100 ° C. for 6 hours. After the reaction mixture was concentrated under reduced pressure, ethyl acetate (40 mL) was added, and the mixture was washed with water (10 mL) and saturated saline (5 mL × 2). The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel 30 g, ethyl acetate / methanol = 1/0 → 4/1) to give the title compound (1143 mg, 1.77 mmol, yield 71%) as a pale yellow color Obtained as amorphous.
¹ H NMR (CDCl ₃ ) δ 1.1-2.1 (13H, m), 2.04 (3H, s), 2.2-2.45 (2H, m), 2.29 (2H, t, J = 7.5Hz), 2.42 (3H, s ), 2.57 (2H, d, J = 6.6Hz), 2.7-2.95 (3H, m), 3.64 (2H, t, J = 7.5Hz), 3.76 (1H, br d, J = 12.8Hz), 3.94 ( 3H, s), 4.51 (1H, br d, J = 12.0Hz), 6.96 (1H, dd, J = 2.0, 8.0Hz), 7.18 (1H, d, J = 2.0Hz), 7.22 (2H, d, J = 8.2Hz), 7.28 (1H, d, J = 8.0Hz), 7.54 (2H, d, J = 8.2Hz), 7.64 (2H, d, J = 8.4Hz), 8.09 (2H, d, J = 8.4Hz).
Example 59-2
4 '-{[1- (3-{[(1-acetyl-4-piperidinyl) carbonyl] [3-chloro-4-methylphenyl] amino} propyl) -4-piperidinyl] methyl} -1,1'- Biphenyl-4-carboxylic acid To a solution of the compound (322 mg, 0.50 mmol) obtained in Example 59-1 in methanol (5 mL) was added a 1N aqueous sodium hydroxide solution (1.00 mL), and the mixture was stirred at 60 ° C for 5 hours. 1N Hydrochloric acid (1.00 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Water (15 mL) was added to the residue, and the mixture was extracted with dichloromethane (30 mL, 15 mL × 2). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane / methanol = 1/0 → 2/1) to give the title compound (312 mg, 0.50 mmol, yield 99%) as a colorless amorphous.
¹ H NMR (CDCl ₃ ) δ 1.5-2.1 (11H, m), 2.03 (3H, s), 2.15-2.5 (4H, m), 2.26 (3H, s), 2.6-2.95 (5H, m), 3.3 -3.85 (5H, m), 4.51 (1H, br d, J = 13.6Hz), 6.95-7.25 (5H, m), 7.34 (2H, d, J = 8.4Hz), 7.42 (2H, d, J = 8.0Hz), 7.80 (2H, d, J = 8.4Hz).

Example 60
1-acetyl-N- (3-chloro-4-methylphenyl) -N- (3- {4- [4- (4-morpholinylsulfonyl) benzyl] -1-piperidinyl} propyl) -4-piperidinecarboxamide The title compound was synthesized as in Example 45 using the compound obtained in Reference Example 43-2. Yield 71%.
¹ H NMR (CDCl ₃ ) δ 1.1-2.1 (13H, m), 2.05 (3H, s), 2.2-2.45 (2H, m), 2.29 (2H, t, J = 7.6Hz), 2.42 (3H, s ), 2.60 (2H, d, J = 6.2Hz), 2.7-3.05 (7H, m), 3.55-3.85 (5H, m), 3.64 (2H, t, J = 7.7Hz), 4.51 (1H, br d , J = 13.6Hz), 6.96 (1H, dd, J = 2.1, 8.0Hz), 7.18 (1H, d, J = 2.1Hz), 7.29 (1H, d, J = 8.0Hz), 7.30 (2H, d , J = 8.4Hz), 7.65 (2H, d, J = 8.4Hz).
Example 61
1-acetyl-N- (3- {4- [4- (3-amino-3-oxopropyl) benzyl] -1-piperidinyl} propyl) -N- (3-chloro-4-methylphenyl) -4- Piperidinecarboxamide The title compound was synthesized in the same manner as in Example 1 using the compound obtained in Reference Example 44-3. Yield 61%.
¹ H NMR (CDCl ₃ ) δ1.16-1.86 (13H, m), 2.04 (3H, s), 2.21-2.44 (4H, m), 2.41 (3H, s), 2.47 (2H, d, J = 6.9 Hz), 2.51 (2H, t, J = 7.8Hz), 2.76-2.89 (3H, m), 2.94 (2H, t, J = 7.8Hz), 3.58-3.67 (2H, m), 3.70-3.80 (1H , m), 4.45-4.57 (1H, m), 5.15-5.40 (2H, m), 6.94 (1H, dd, J = 8.1, 2.4Hz), 7.01-7.14 (4H, m), 7.16 (1H, d , J = 2.4Hz), 7.27 (1H, d, J = 8.1Hz).
Example 62
1-acetyl-N- (3-chloro-4-methylphenyl) -N- (3- {4- [4- (3-pyridinyl) benzyl] -1-piperidinyl} propyl) -4-piperidinecarboxamide <br / > The title compound was synthesized in the same manner as in Example 1 using the compound obtained in Reference Example 45-2. 73% yield.
¹ H NMR (CDCl ₃ ) δ 1.20-1.35 (2H, m), 1.45-1.89 (11H, m), 2.04 (3H, s), 2.23-2.43 (4H, m), 2.42 (3H, s), 2.57 (2H, d, J = 6.6Hz), 2.77-2.90 (3H, m), 3.59-3.68 (2H, m), 3.70-3.80 (1H, m), 4.45-4.56 (1H, m), 6.95 ( 1H, dd, J = 8.1, 2.1Hz), 7.17 (1H, d, J = 2.1Hz), 7.22-7.26 (2H, m), 7.27 (1H, d, J = 8.1Hz), 7.34 (1H, ddd , J = 8.1, 4.8, 0.6Hz), 7.45-7.51 (2H, m), 7.84 (1H, ddd, J = 8.1, 2.4, 1.8Hz), 8.56 (1H, dd, J = 4.8, 1.8Hz), 8.82 (1H, dd, J = 2.4, 0.6Hz).
Example 63
3- (4-{[1- (3-{[(1-acetyl-4-piperidinyl) carbonyl] [3-chloro-4-methylphenyl] amino} propyl) -4-piperidinyl] methyl} phenyl) propanoic acid Ethyl The title compound was synthesized in the same manner as in Example 1 using the compound obtained in Reference Example 46-2. 75% yield.
_{^{1 H NMR (CDCl 3) δ1.12-1.90}} (13H, m), 1.23 (3H, t, J = 7.0Hz), 2.04 (3H, s), 2.20-2.45 (4H, m), 2.42 (3H, s), 2.48 (2H, d, J = 6.2Hz), 2.59 (2H, t, J = 8.0Hz), 2.75-2.93 (3H, m), 2.91 (2H, t, J = 8.0Hz), 3.56- 3.83 (3H, m), 4.13 (2H, q, J = 7.0Hz), 4.44-4.58 (1H, m), 6.96 (1H, dd, J = 8.2, 2.2Hz), 7.00-7.14 (4H, m) , 7.17 (1H, d, J = 2.2Hz), 7.28 (1H, d, J = 8.2Hz).

Example 64
3- (4-{[1- (3-{[(1-acetyl-4-piperidinyl) carbonyl] [3-chloro-4-methylphenyl] amino} propyl) -4-piperidinyl] methyl} phenyl) propanoic acid Using the compound obtained in Example 63, the title compound was synthesized in the same manner as in Example 24. Yield 19%.
¹ H NMR (CD ₃ OD) δ1.40-2.00 (11H, m), 2.05 (3H, s), 2.38-2.52 (2H, m), 2.42 (3H, s), 2.53 (2H, t, J = 7.5Hz), 2.59 (2h, d, J = 6.6Hz), 2.83-2.96 (3H, m), 2.87 (2H, t, J = 7.5Hz), 3.02-3.10 (2H, m), 3.43-3.54 ( 2H, m), 3.65-3.90 (3H, m), 4.38-4.47 (1H, m), 7.07-7.12 (2H, m), 7.14-7.19 (2H, m), 7.22 (1H, dd, J = 8.1 , 2.4Hz), 7.45 (1H, d, J = 8.1Hz), 7.46 (1H, d, J = 2.4Hz).
Example 65
1-acetyl-N- (3-chloro-4-methylphenyl) -N- (3- {4- [4- (2-pyridinyl) benzyl] -1-piperidinyl} propyl) -4-piperidinecarboxamide <br / > The title compound was synthesized in the same manner as in Example 1 using the compound obtained in Reference Example 47-2. Yield 76%.
¹ H NMR (CDCl ₃ ) δ1.16-1.91 (13H, m), 2.04 (3H, s), 2.20-2.45 (4H, m), 2.42 (3H, s), 2.57 (2H, d, J = 6.6 Hz), 2.74-2.93 (3H, m), 3.55-3.83 (3H, m), 4.40-4.58 (1H, m), 6.95 (1H, dd, J = 8.0, 2.2Hz), 7.18 (1H, d, J = 2.2Hz), 7.18-7.31 (4H, m), 7.69-7.75 (2H, m), 7.85-7.93 (2H, m), 8.64-8.70 (1H, m).
Example 66-1
1-acetyl-N- (3- {4- [4- (4-amino-4-oxobutanoyl) benzyl] -1-piperidinyl} propyl) -N- (3-chloro-4-methylphenyl) -4 - using the compound obtained in piperidinecarboxamide <br/> reference example 48-3, the title compound was synthesized in the same manner as in example 1. Yield 18%.
¹ H NMR (CDCl ₃ ) δ 1.10-1.91 (13H, m), 2.04 (3H, s), 2.20-2.46 (4H, m), 2.41 (3H, s), 2.57 (2H, d, J = 6.0 Hz), 2.66 (2H, t, J = 6.6Hz), 2.73-2.93 (3H, m), 3.35 (2H, t, J = 6.6Hz), 3.55-3.85 (3H, m), 4.42-4.60 (1H , m), 5.25-5.90 (2H, m), 6.96 (1H, dd, J = 8.0, 2.2Hz), 7.10-7.30 (4H, m), 7.84-7.94 (2H, m).
Example 66-2
1-acetyl-N- [3- (4- {4-[(1E) -4-amino-N-ethoxy-4-oxobutanimidoyl] benzyl} -1-piperidinyl) propyl] -N- (3- Chloro-4-methylphenyl) -4-piperidinecarboxamide The title compound was synthesized in the same manner as in Example 18 using the compound obtained in Example 66-1. Yield 74%.
_{^{1 H NMR (CDCl 3) δ1.17-1.90}} (13H, m), 1.32 (3H, t, J = 7.2Hz), 2.04 (3H, s), 2.19-2.56 (8H, m), 2.42 (3H, s), 2.73-2.93 (3H, m), 3.00-3.12 (2H, m), 3.56-3.84 (3H, m), 4.24 (2H, q, J = 7.2Hz), 4.44-4.58 (1H, m) , 5.15-5.33 (1H, m), 5.52-5.74 (1H, m), 6.96 (1H, dd, J = 8.0, 2.2Hz), 7.08-7.17 (2H, m), 7.17 (1H, d, J = 2.2Hz), 7.28 (1H, d, J = 8.0Hz), 7.51-7.59 (2H, m).

Example 67
1-acetyl-N- (3- {4- [4- (4-amino-N-hydroxy-4-oxobutanimidyl) benzyl] -1-piperidinyl} propyl) -N- (3-chloro-4- (Methylphenyl) -4-piperidinecarboxamide The title compound was synthesized in the same manner as in Example 22 using the compound obtained in Example 66-1. Yield 34%.
¹ H NMR (CDCl ₃ ) δ 1.20-1.93 (13H, m), 2.04 (3H, s), 2.24-2.44 (4H, m), 2.41 (3H, s), 2.48-2.58 (4H, m), 2.77-2.90 (3H, m), 3.10 (3H, t, J = 7.5Hz), 3.58-3.67 (2H, m), 3.69-3.80 (1H, m), 4.45-4.56 (1H, m), 5.44- 5.57 (1H, m), 5.95-6.10 (1H, m), 6.94 (1H, dd, J = 8.1, 2.1Hz), 7.08-7.15 (2H, m), 7.16 (1H, d, J = 2.1Hz) , 7.26 (1H, d, J = 8.1Hz), 7.49-7.55 (2H, m).
Example 68-1
4 '-[(1- {3-[[(1-acetylpiperidin-4-yl) carbonyl] (3-chloro-4-methylphenyl) amino] propyl} piperidin-4-yl) methyl] -1,1 The title compound was synthesized in the same manner as in Example 59-1 using the compound obtained in Reference Example 49-2 of methyl '-biphenyl-3-carboxylate . Yield 67%.
¹ H NMR (CDCl ₃ ) δ 1.1-2.0 (13H, m), 2.04 (3H, s), 2.2-2.45 (2H, m), 2.29 (2H, t, J = 7.7Hz), 2.42 (3H, s ), 2.56 (2H, d, J = 6.2Hz), 2.7-2.95 (3H, m), 3.64 (2H, t, J = 7.9Hz), 3.76 (1H, br d, J = 14.6Hz), 3.95 ( 3H, s), 4.51 (1H, br d, J = 14.0Hz), 6.96 (1H, dd, J = 2.2, 8.0Hz), 7.18 (1H, d, J = 2.2Hz), 7.22 (2H, d, J = 8.4Hz), 7.28 (1H, d, J = 8.0Hz), 7.49 (1H, t, J = 7.9Hz), 7.53 (2H, d, J = 8.4Hz), 7.77 (1H, m), 7.99 (1H, m), 8.26 (1H, m).
Example 68-2
4 '-{[1- (3-{[(1-acetyl-4-piperidinyl) carbonyl] [3-chloro-4-methylphenyl] amino} propyl) -4-piperidinyl] methyl} -1,1'- Biphenyl-3-carboxylic acid The title compound was synthesized as in Example 59-2 using the compound obtained in Example 68-1. 73% yield.
¹ H NMR (CDCl ₃ ) δ 1.45-2.1 (11H, m), 2.01 (3H, s), 2.15-2.95 (9H, m), 2.24 (3H, s), 3.35-3.85 (5H, m), 4.49 (1H, br d, J = 14.2Hz), 6.9-7.1 (2H, m), 7.1-7.25 (3H, m), 7.45 (1H, t, J = 7.8Hz), 7.58 (2H, d, J = 8.0Hz), 7.67 (1H, d, J = 7.8Hz), 8.01 (1H, d, J = 7.8Hz), 8.29 (1H, s).
Example 69
1-acetyl-N- (3- {4- [4- (2-amino-2-oxoethoxy) benzyl] -1-piperidinyl} propyl) -N- (3-chloro-4-methylphenyl) -4- Piperidinecarboxamide The title compound was synthesized in the same manner as in Example 1 using the compound obtained in Reference Example 50-4. Yield 56%.
¹ H NMR (CDCl ₃ ) δ1.14-1.30 (2H, m), 1.36-1.86 (11H, m), 2.04 (3H, s), 2.21-2.44 (4H, m), 2.42 (3H, s), 2.46 (2H, d, J = 6.9Hz), 2.76-2.90 (3H, m), 3.56-3.67 (2H, m), 3.70-3.81 (1H, m), 4.44-4.56 (1H, m), 4.47 ( 2H, s), 5.48-5.68 (1H, m), 6.44-6.62 (1H, m), 6.79-6.85 (2H, m), 6.94 (1H, dd, J = 7.8, 2.4Hz), 7.03-7.09 ( 2H, m), 7.16 (1H, d, J = 2.4Hz), 7.27 (1H, d, J = 7.8z).

Example 70
1-acetyl-N- [3- (4- {4-[(4-acetyl-1-piperazinyl) sulfonyl] benzyl} -1-piperidinyl) propyl] -N- (3-chloro-4-methylphenyl)- 4-Piperidinecarboxamide To a solution of the compound obtained in Reference Example 51 (635 mg, 1.38 mmol) in methanol (10 mL) was added a 1 M potassium carbonate solution (3 mL), and the mixture was stirred overnight. After adding saturated saline (10 mL) and distilling off methanol, the aqueous layer was extracted five times with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 1-acetyl-4-({4-[(piperidin-4-yl) methyl] phenyl} sulfonyl) piperazine (317 mg). Using this compound, the title compound was obtained as a colorless amorphous in the same manner as in Example 1. Yield 39% (2 steps).
¹ H NMR (CDCl ₃ ) δ 1.18-1.36 (2H, m), 1.45-1.98 (11H, m), 2.04 (6H, s), 2.23-2.40 (4H, m), 2.42 (3H, s), 2.59 (2H, d, J = 6.3Hz), 2.78-2.90 (3H, m), 2.95-3.03 (4H, m), 3.55 (2H, t, J = 5.1Hz), 3.63 (2H, t, J = (7.8Hz), 3.70 (2H, t, J = 5.1Hz), 3.70-3.81 (1H, m), 4.47-4.58 (1H, m), 6.95 (1H, dd, J = 8.0, 2.0Hz), 7.16 ( 1H, d, J = 2.0Hz), 7.25-7.33 (3H, m), 7.62 (2H, d, J = 8.0Hz).
Example 71
1-acetyl-N- [3- (4-{[4 '-(aminocarbonyl) -1,1'-biphenyl-4-yl] methyl} -1-piperidinyl) propyl] -N- (3-chloro- 4-Methylphenyl) -4-piperidinecarboxamide N-N-dimethylformamide (5 mL) solution of the compound obtained in Example 59-2 (200 mg, 0.32 mmol) and 1-hydroxybenzotriazole (43 mg, 0.32 mmol) Under ice-cooling and stirring, ammonium chloride (25 mg, 0.47 mmol), triethylamine (0.066 mL, 0.47 mmol), and 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (91 mg, 0.47 mmol) were added in this order. And stirred at room temperature for 18 hours. After the reaction mixture was concentrated under reduced pressure, ethyl acetate (40 mL) was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate (10 mL × 3) and saturated saline (10 mL). The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography (NH silica gel, ethyl acetate / methanol = 1/0 → 9/1) to give the title compound (179 mg, 0.28 mmol, yield 90%) as a colorless amorphous As obtained.
¹ H NMR (CDCl ₃ ) δ 1.1-1.95 (13H, m), 2.04 (3H, s), 2.15-2.45 (2H, m), 2.28 (2H, t, J = 7.5Hz), 2.42 (3H, s ), 2.57 (2H, d, J = 6.6Hz), 2.7-2.95 (3H, m), 3.64 (2H, t, J = 7.5Hz), 3.76 (1H, br d, J = 13.0Hz), 4.51 ( 1H, br d, J = 13.2Hz), 5.4-6.4 (2H, br, CON H ₂ ), 6.96 (1H, dd, J = 2.2, 8.2Hz), 7.18 (1H, d, J = 2.2Hz), 7.22 (2H, d, J = 8.1Hz), 7.28 (1H, d, J = 8.2Hz), 7.53 (2H, d, J = 8.1Hz), 7.66 (2H, d, J = 8.2Hz), 7.88 ( (2H, d, J = 8.2Hz).
Example 72
1-acetyl-N- (3-chloro-4-methylphenyl) -N- (3- {4- [4- (2-hydroxyethoxy) benzyl] -1-piperidinyl} propyl) -4-piperidinecarboxamide The title compound was synthesized in the same manner as in Example 1 using the compound obtained in Reference Example 52-2. Yield 56%.
¹ H NMR (CDCl ₃ ) δ 1.10-1.88 (13H, m), 2.05 (3H, s), 2.18-2.49 (6H, m), 2.42 (3H, s), 2.75-2.83 (3H, m), 3.56-3.84 (3H, m), 2.89-4.00 (2H, m), 4.01-4.11 (2H, m), 4.43-4.66 (1H, m), 6.78-6.87 (2H, m), 6.96 (1H, dd , J = 8.0, 2.2Hz), 7.00-7.09 (2H, m), 7.17 (1H, d, J = 2.2Hz), 7.28 (1H, d, J = 8.0Hz).

Example 73
1-acetyl-N- (3-chloro-4-methylphenyl) -N- (3- {4- [4- (N-ethoxy-3-hydroxypropanimidoyl) benzyl] -1-piperidinyl} propyl)- 4-piperidinecarboxamide Using the compound obtained in Reference Example 53-3, the title compound was synthesized in the same manner as in Example 70. Yield 62%.
¹ H NMR (CDCl ₃ ) δ1.16-1.36 (2H, m), 1.32 (3H, t, J = 6.9Hz), 1.39-1.93 (11H, m), 2.04 (3H, s), 2.20-2.44 ( 4H, m), 2.41 (3H, s), 2.51 (2H, d, J = 6.6Hz), 2.77-2.90 (3H, m), 3.06 (2H, t, J = 6.6Hz), 3.58-3.68 (2H , m), 3.70-3.81 (1H, m), 3.86 (2H, t, J = 6.6Hz), 4.24 (2H, q, J = 6.9Hz), 4.45-4.56 (1H, m), 6.95 (1H, dd, J = 8.1, 1.8Hz), 7.08-7.15 (2H, m), 7.16 (1H, d, J = 1.8Hz), 7.27 (1H, d, J = 8.1Hz), 7.52-7.61 (2H, m ).
Example 74
1-acetyl-N- (3-chloro-4-methylphenyl) -N- [3- (4- {4-[(2-hydroxyethyl) thio] benzyl} -1-piperidinyl) propyl] -4-piperidine The title compound was synthesized in the same manner as in Example 45, using the compound obtained in Carboxamide Reference Example 54-2. 75% yield.
¹ H NMR (CDCl ₃ ) δ 1.1-1.9 (13H, m), 2.05 (3H, s), 2.2-2.5 (2H, m), 2.27 (2H, t, J = 7.7Hz), 2.42 (3H, s ), 2.48 (2H, d, J = 6.6Hz), 2.7-2.95 (3H, m), 3.08 (2H, t, J = 5.9Hz), 3.64 (2H, t, J = 7.7Hz), 3.72 (2H , t, J = 5.9Hz), 3.65-3.85 (1H, m), 4.52 (1H, br d, J = 13.2Hz), 6.96 (1H, dd, J = 2.2, 8.1Hz), 7.06 (2H, d , J = 8.2Hz), 7.18 (1H, d, J = 2.2Hz), 7.29 (1H, d, J = 8.1Hz), 7.31 (2H, d, J = 8.2Hz).
Example 75-1
Methyl 4-[(1- {3-[[(1-acetylpiperidin-4-yl) carbonyl] (3-chloro-4-methylphenyl) amino] propyl} piperidin-4-yl) methyl] methyl benzoate Using the compound obtained in 55, the title compound was synthesized in the same manner as in Example 45. Yield 77%.
¹ H NMR (CDCl ₃ ) δ 1.1-2.1 (13H, m), 2.04 (3H, s), 2.2-2.45 (2H, m), 2.28 (2H, t, J = 7.5Hz), 2.42 (3H, s ), 2.57 (2H, d, J = 6.4Hz), 2.7-2.95 (3H, m), 3.64 (2H, t, J = 7.5Hz), 3.75 (1H, br d, J = 13.8Hz), 3.90 ( 3H, s), 4.51 (1H, br d, J = 14.0Hz), 6.96 (1H, dd, J = 2.1, 8.1Hz), 7.17 (1H, d, J = 2.1Hz), 7.19 (2H, d, J = 8.3Hz), 7.28 (1H, d, J = 8.1Hz), 7.94 (2H, d, J = 8.3Hz).
Example 75-2
4-[(1- {3-[[(1-acetylpiperidin-4-yl) carbonyl] (3-chloro-4-methylphenyl) amino] propyl} piperidin-4-yl) methyl] benzoic acid Example 75 Using the compound obtained in -1, the title compound was synthesized in the same manner as in Example 59-2. Yield 67%.
¹ H NMR (CDCl ₃ ) δ 1.4-2.1 (11H, m), 2.03 (3H, s), 2.1-2.45 (4H, m), 2.27 (3H, s), 2.5-2.9 (5H, m), 3.2 -3.45 (2H, m), 3.45-3.8 (3H, m), 4.49 (1H, br d, J = 13.4Hz), 6.96 (1H, dd, J = 2.1, 8.1Hz), 7.03 (1H, d, J = 8.1Hz), 7.08 (2H, d, J = 8.0Hz), 7.12 (1H, d, J = 2.1Hz), 7.80 (2H, d, J = 8.0Hz).

Example 75-3
1-acetyl-N- (3-chloro-4-methylphenyl) -N- (3- {4- [4- (hydroxymethyl) benzyl] -1-piperidinyl} propyl) -4-piperidinecarboxamide Example 75- To a solution of the compound obtained in 2 (443 mg, 0.80 mmol) in N, N-dimethylformamide (5 mL) was added 1,1′-carbonyldiimidazole (389 mg, 2.40 mmol), and the mixture was stirred at room temperature for 18 hours. The reaction solution was added to an aqueous solution (5 mL) of sodium borohydride (151 mg, 3.99 mmol) and stirred at room temperature for 1 hour. Under ice-cooling, 1N hydrochloric acid (12.0 mL) was added, and the mixture was stirred at room temperature for 30 minutes. Under ice cooling, a 1N sodium hydroxide solution (12.0 mL) was added, and the mixture was concentrated under reduced pressure. Ethyl acetate (40 mL) was added to the residue, and the mixture was washed with water (10 mL) and saturated saline (10 mL). After concentrating the organic layer under reduced pressure, the residue was purified by column chromatography (NH silica gel, hexane / ethyl acetate = 1/1 → 0/1), and further column chromatography (silica gel, ethyl acetate / methanol = 1/0 → 1). / 1) to give the title compound (292 mg, 0.54 mmol, yield 68%).
¹ H NMR (CDCl ₃ ) δ 1.1-2.0 (13H, m), 2.05 (3H, s), 2.2-2.45 (2H, m), 2.27 (2H, t, J = 7.5Hz), 2.42 (3H, s ), 2.51 (2H, d, J = 6.6Hz), 2.7-2.95 (3H, m), 3.63 (2H, t, J = 7.5Hz), 3.76 (1H, br d, J = 12.8Hz), 4.52 ( 1H, br d, J = 13.4Hz), 4.66 (2H, s), 6.96 (1H, dd, J = 2.2, 8.1Hz), 7.12 (2H, d, J = 8.1Hz), 7.18 (1H, d, J = 2.2Hz), 7.28 (1H, d, J = 8.1Hz), 7.28 (2H, d, J = 8.1Hz).
Example 76
1-acetyl-N- (3-chloro-4-methylphenyl) -N- [3- (4- {4-[(2-hydroxyethyl) sulfonyl] benzyl} -1-piperidinyl) propyl] -4-piperidine To a solution of the compound (586 mg, 1.00 mmol) obtained in Example 74 in methanol (10 mL) was added an aqueous solution (5 mL) of oxone (922 mg) under ice cooling and stirring, and the mixture was stirred at room temperature for 6 hours. To the reaction mixture were added a 5% aqueous sodium thiosulfate solution (5 mL) and a saturated aqueous sodium bicarbonate solution (20 mL) under ice-cooling, and the organic solvent was distilled off under reduced pressure, followed by extraction with dichloromethane (20 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, ethyl acetate / methanol = 1/0 → 9/1) to give the title compound (477 mg, 0.77 mmol, yield 77%) as a colorless amorphous.
¹ H NMR (CDCl ₃ ) δ 1.1-2.0 (13H, m), 2.05 (3H, s), 2.2-2.45 (2H, m), 2.27 (2H, t, J = 7.5Hz), 2.42 (3H, s ), 2.62 (2H, d, J = 6.4Hz), 2.7-2.95 (3H, m), 3.35 (2H, t, J = 5.3Hz), 3.64 (2H, t, J = 7.7Hz), 3.76 (1H , br d, J = 13.6Hz), 4.00 (2H, t, J = 5.3Hz), 4.51 (1H, br d, J = 12.8Hz), 6.96 (1H, dd, J = 2.2, 7.8Hz), 7.17 (1H, d, J = 2.2Hz), 7.29 (1H, d, J = 7.8Hz), 7.34 (2H, d, J = 8.5Hz), 7.83 (2H, d, J = 8.5Hz).
Example 77
1-acetyl-N- (3-chloro-4-methylphenyl) -N- {3- [4- (4-{[(3-hydroxypropyl) amino] sulfonyl} benzyl) -1-piperidinyl] propyl}- 4-Piperidinecarboxamide Using the compound obtained in Reference Example 56, the title compound was obtained as a colorless amorphous in the same manner as in Example 70. Yield 43% (2 steps).
¹ H NMR (CDCl ₃ ) δ 1.18-1.35 (2H, m), 1.48-1.95 (13H, m), 2.05 (3H, s), 2.22-2.43 (4H, m), 2.42 (3H, s), 2.59 (2H, d, J = 6.6Hz), 2.78-2.90 (3H, m), 3.11 (2H, q, J = 6.0Hz), 3.63 (2H, t, J = 7.4Hz), 3.70 (2H, t , J = 5.7Hz), 3.70-3.82 (1H, m), 4.45-4.55 (1H, m), 5.10 (1H, m), 6.95 (1H, dd, J = 8.1, 1.9Hz), 7.16 (1H, d, J = 1.9Hz), 7.20-7.30 (3H, m), 7.75 (2H, d, J = 8.1Hz).

Example 78
1-acetyl-N- (3-chloro-4-methylphenyl) -N- [3- (4- {4-[(2-hydroxyethyl) (methylsulfonyl) amino] benzyl} -1-piperidinyl) propyl] -4-Piperidinecarboxamide A 4N hydrochloric acid / ethyl acetate solution (1 mL) was added to a solution of the compound (248 mg, 0.60 mmol) obtained in Reference Example 57-2 in methanol (10 mL), and the mixture was stirred overnight. The solvent was distilled off to obtain 4- {4-[(2-hydroxyethyl) (methylsulfonyl) amino] benzyl} piperidine hydrochloride. Using this compound, the title compound was obtained as a colorless amorphous in the same manner as in Example 1. Yield 63% (2 steps).
_{^{1 H NMR (CDCl 3) δ1.18-1.33}} (2H, m), 1.45-1.95 (11H, m), 2.01 (3H, s), 2.23-2.40 (4H, m), 2.42 (3H, s), 2.51 (2H, d, J = 6.6Hz), 2.78-2.90 (3H, m), 2.97 (3H, s), 3.58-3.70 (4H, m), 3.70-3.83 (1H, m), 3.81 (2H, t, J = 5.3Hz), 4.47-4.56 (1H, m), 6.95 (1H, dd, J = 8.1, 1.8Hz), 7.13-7.18 (3H, m), 7.23-7.32 (3H, m).
Example 79
[(4-{[1- (3-{[(1-acetyl-4-piperidinyl) carbonyl] [3-chloro-4-methylphenyl] amino} propyl) -4-piperidinyl] methyl} phenyl) thio] acetic acid Ethyl 1-acetyl-N- (3-chloro-4-methylphenyl) -N- (3-chloropropyl) piperidine-4-carboxamide (2.23 g, 6.0 mmol), the compound obtained in Reference Example 58-2 ( A mixture of 1.25 g), potassium iodide (1.00 g, 6.0 mmol), sodium hydrogen carbonate (2.02 g, 24.0 mmol), and acetonitrile (30 mL) was stirred at 100 ° C for 18 hours. After the reaction mixture was concentrated under reduced pressure, ethyl acetate (160 mL) was added, and the mixture was washed with water (40 mL) and saturated saline (20 mL). The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, ethyl acetate / methanol = 100/0 → 50/50), followed by column chromatography (NH silica gel, hexane / ethyl acetate = 80/20 → 0/100) to give the title compound (1.52 g, 2.4 mmol, yield 61%) as a colorless oil.
¹ H NMR (CDCl ₃ ) δ 1.05-1.9 (13H, m), 1.22 (3H, t, J = 7.2Hz), 2.05 (3H, s), 2.2-2.5 (2H, m), 2.26 (2H, t , J = 7.5Hz), 2.42 (3H, s), 2.48 (2H, d, J = 6.2Hz), 2.7-2.95 (3H, m), 3.60 (2H, s), 3.63 (2H, t, J = 7.5Hz), 3.76 (1H, br d, J = 14.4Hz), 4.16 (2H, q, J = 7.2Hz), 4.52 (1H, br d, J = 12.8Hz), 6.95 (1H, dd, J = 2.1, 7.9Hz), 7.06 (2H, d, J = 8.2Hz), 7.17 (1H, d, J = 2.1Hz), 7.29 (1H, d, J = 7.9Hz), 7.33 (2H, d, J = 8.6Hz).
Example 80
[(4-{[1- (3-{[(1-acetyl-4-piperidinyl) carbonyl] [3-chloro-4-methylphenyl] amino} propyl) -4-piperidinyl] methyl} phenyl) thio] acetic acid To a solution of the compound obtained in Example 79 (1385 mg, 2.20 mmol) in methanol (10 mL) was added a 1N aqueous sodium hydroxide solution (4.40 mL), and the mixture was stirred at 50 ° C for 1 hour. 1N Hydrochloric acid (4.40 mL) was added to the reaction mixture, followed by concentration under reduced pressure. Water (15 mL) was added to the residue, and the mixture was extracted with dichloromethane (30 mL × 3). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane / methanol = 1/0 → 2/1) to give the title compound (1273 mg, 2.12 mmol, yield 96%) as a colorless amorphous.
¹ H NMR (CDCl ₃ ) δ 1.4-2.1 (11H, m), 2.04 (3H, s), 2.15-2.6 (6H, m), 2.42 (3H, s), 2.65-3.0 (3H, m), 3.3 -3.85 (5H, m), 3.58 (2H, s), 4.52 (1H, br d, J = 13.4Hz), 6.98 (2H, d, J = 8.2Hz), 7.06 (1H, dd, J = 2.1, 8.0Hz), 7.23 (1H, d, J = 2.1Hz), 7.30 (1H, d, J = 8.0Hz), 7.30 (2H, d, J = 8.2Hz).

Example 81
1-acetyl-N- [3- (4- {4-[(2-amino-2-oxoethyl) thio] benzyl} -1-piperidinyl) propyl] -N- (3-chloro-4-methylphenyl)- 4-Piperidinecarboxamide A solution of the compound obtained in Example 80 (420 mg, 0.70 mmol) and 1-hydroxybenzotriazole (95 mg, 0.70 mmol) in N, N-dimethylformamide (5 mL) was stirred under ice-cooling with ammonium chloride ( 56 mg, 1.05 mmol), triethylamine (0.146 mL, 1.05 mmol), and 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (201 mg, 1.05 mmol) were added in that order, and the mixture was stirred at room temperature for 18 hours. After the reaction mixture was concentrated under reduced pressure, ethyl acetate (40 mL) was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate (10 mL × 3) and saturated saline (10 mL). The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography (NH silica gel, ethyl acetate / methanol = 1/0 → 9/1) to give the title compound (348 mg, 0.58 mmol, yield 83%) as a colorless amorphous As obtained.
¹ H NMR (CDCl ₃ ) δ 1.05-1.9 (13H, m), 2.04 (3H, s), 2.15-2.55 (2H, m), 2.26 (2H, t, J = 7.5Hz), 2.42 (3H, s ), 2.47 (2H, d, J = 6.6Hz), 2.7-2.95 (3H, m), 3.58 (2H, s), 3.63 (2H, t, J = 7.6Hz), 3.76 (1H, br d, J = 13.2Hz), 4.50 (1H, br d, J = 13.2Hz), 5.84 (1H, br s), 6.73 (1H, br s), 6.96 (1H, dd, J = 2.1, 8.0Hz), 7.07 ( 2H, d, J = 8.2Hz), 7.18 (1H, d, J = 2.1Hz), 7.24 (2H, d, J = 8.2Hz), 7.28 (1H, d, J = 8.0Hz).
Example 82
Ethyl 4-{[1- (3-{[(1-acetyl-4-piperidinyl) carbonyl] (3-chloro-4-methylphenyl) amino} propyl) -4-piperidinyl] methyl} phenylcarbamate hydrochloride A 4N hydrochloric acid / ethyl acetate solution (3 mL) was added to a solution of the compound (538 mg, 1.48 mmol) obtained in Reference Example 59 in ethanol (10 mL), and the mixture was stirred overnight. The solvent was distilled off to obtain 414 mg of 4- {4-[(ethoxycarbonyl) amino] benzyl} piperidine hydrochloride. 94% yield. Using this compound, the title compound was obtained as a colorless amorphous in the same manner as in Example 4. Yield 41%.
Free base: ¹ H NMR (CDCl ₃ ) δ 1.30 (3H, t, J = 7.4 Hz), 1.20-1.95 (13H, m), 2.05 (3H, s), 2.23-2.40 (4H, m), 2.42 (3H, s), 2.47 (2H, d, J = 6.4Hz), 2.80-2.95 (3H, m), 3.58-3.84 (3H, m), 4.22 (2H, q, J = 7.4Hz), 4.45- 4.60 (1H, m), 6.59 (1H, brs), 6.95-7.10 (3H, m), 7.16-7.34 (4H, m).
Example 83
Methyl 4-{[1- (3-{[(1-acetyl-4-piperidinyl) carbonyl] (3-chloro-4-methylphenyl) amino} propyl) -4-piperidinyl] methyl} phenylcarbamate hydrochloride Using the compound obtained in Reference Example 60, the title compound was obtained as a colorless amorphous in the same manner as in Example 82. Yield 66%.
Free base: ¹ H NMR (CDCl ₃ ) δ1.25-2.00 (13H, m), 2.05 (3H, s), 2.17-2.40 (4H, m), 2.42 (3H, s), 2.48 (2H, d, J = 5.4Hz), 2.74-3.05 (3H, m), 3.58-3.75 (3H, m), 3.77 (3H, s), 4.45-4.60 (1H, m), 6.63 (1H, brs), 6.98-7.10 (3H, m), 7.15-7.35 (4H, m).
Example 84
1-acetyl-N- (3-chloro-4-methylphenyl) -N- {3- [4- (4-{[(ethylamino) carbonyl] amino} benzyl) -1-piperidinyl] propyl} -4- Piperidinecarboxamide hydrochloride Using the compound obtained in Reference Example 61, the title compound was obtained as a colorless amorphous in the same manner as in Example 82. Yield 58%.
Free base: ¹ H NMR (CDCl ₃ ) δ1.11 (3H, t, J = 7.2 Hz), 1.20-2.03 (13H, m), 2.05 (3H, s), 2.24-2.53 (6H, m), 2.42 (3H, s), 2.78-2.97 (3H, m), 3.24 (2H, quin, J = 7.2Hz), 3.65 (2H, t, J = 7.4Hz), 3.66-3.83 (1H, m), 4.45- 4.60 (1H, m), 5.44 (1H, br), 6.95-7.05 (3H, m), 7.15-7.40 (5H, m).

Example 85
1-acetyl-N- (3-chloro-4-methylphenyl) -N- {3- [4- (4-{[(methylamino) carbonyl] amino} benzyl l) -1-piperidinyl] propyl} -4 -Piperidinecarboxamide hydrochloride The title compound was obtained as a colorless amorphous in the same manner as in Example 82 using the compound obtained in Reference Example 62. Yield 33%.
Free base: ¹ H NMR (CDCl ₃ ) δ1.05-1.40 (2H, m), 1.40-2.00 (11H, m), 2.05 (3H, s), 2.20-2.40 (4H, m), 2.42 (3H, s), 2.65 (2H, d, J = 6.6Hz), 2.81 (3H, d, J = 4.8Hz), 2.75-2.92 (3H, m), 3.64 (2H, t, J = 7.4Hz), 3.65- 3.84 (1H, m), 4.45-4.60 (1H, m), 4.91 (1H, m), 6.59 (1H, brs), 6.93-7.10 (3H, m), 7.13-7.23 (4H, m).
Example 86
1-acetyl-N- [3- (4- {4-[(aminocarbonyl) amino] benzyl} -1-piperidinyl) propyl] -N- (3-chloro-4-methylphenyl) -4-piperidinecarboxamide < The title compound was obtained as a colorless amorphous in the same manner as in Example 78 using the compound obtained in Reference Example 63. Yield 16%.
¹ H NMR (CDCl ₃ ) δ1.15-1.35 (2H, m), 1.40-1.92 (11H, m), 2.05 (3H, s), 2.20-2.37 (4H, m), 2.42 (3H, s), 2.47 (2H, d, J = 6.6Hz), 2.75-2.95 (3H, m), 3.64 (2H, t, J = 7.6Hz), 3.65-3.83 (1H, m), 4.42-4.58 (1H, m) , 4.71 (2H, brs), 6.64 (1H, brs), 6.92-7.13 (3H, m), 7.16-7.33 (4H, m).
Example 87
1-acetyl-N- (3-chloro-4-methylphenyl) -N- {3- [4- (4-{[(methoxyamino) carbonyl] amino} benzyl) -1-piperidinyl] propyl} -4- Piperidinecarboxamide hydrochloride Using the compound obtained in Reference Example 64, the title compound was obtained as a colorless amorphous in the same manner as in Example 82. Yield 45%.
Free base: ¹ H NMR (CDCl ₃ ) δ 1.18-1.45 (2H, m), 1.45-2.00 (11H, m), 2.04 (3H, s), 2.24-2.44 (4H, m), 2.41 (3H, m s), 2.48 (2H, d, J = 6.6Hz), 2.73-2.95 (3H, m), 3.53-3.70 (3H, m), 3.79 (3H, s), 4.43-4.60 (1H, m), 6.93 -7.20 (4H, m), 7.30-7.58 (5H, m).
Example 88
1-acetyl-N- (3-chloro-4-methylphenyl) -N- {3- [4- (4-{[(ethoxyamino) carbonyl] amino} benzyl) -1-piperidinyl] propyl} -4- Piperidinecarboxamide Using the compound obtained in Reference Example 65, the title compound was obtained as a colorless amorphous in the same manner as in Example 78. Yield 74%.
_{^{1 H NMR (CDCl 3) δ1.15-1.45}} (2H, m), 1.33 (3H, t, J = 6.8Hz), 1.45-1.90 (11H, m), 2.05 (3H, s), 2.22-2.40 ( 4H, m), 2.42 (3H, s), 2.47 (2H, d, J = 6.2Hz), 2.73-2.95 (3H, m), 3.64 (2H, t, J = 8.0Hz), 3.67-3.83 (1H , m), 3.98 (2H, q, J = 6.8Hz), 4.43-4.60 (1H, m), 6.92-7.20 (5H, m), 7.30-7.42 (3H, m), 7.52 (1H, brs).
Example 89
1-acetyl-N- (3-chloro-4-methylphenyl) -N- {3- [4- (4-{[(isobutoxyamino) carbonyl] amino} benzyl) -1-piperidinyl] propyl l}- 4-Piperidinecarboxamide Using the compound obtained in Reference Example 66, the title compound was obtained as a colorless amorphous in the same manner as in Example 78. Yield 51%.
¹ H NMR (CDCl ₃ ) δ1.01 (6H, d, J = 7.6 Hz), 1.10-1.45 (3H, m), 1.45-2.00 (11H, m), 2.05 (3H, s), 2.20-2.38 ( 4H, m), 2.42 (3H, s), 2.48 (2H, d, J = 6.2Hz), 2.73-2.93 (3H, m), 3.57-3.84 (3H, m), 3.70 (2H, d, J = 6.6Hz), 4.43-4.63 (1H, m), 6.93-7.22 (5H, m), 7.25-7.42 (3H, m), 7.54 (1H, brs).

Example 90
1-acetyl-N- (3-chloro-4-methylphenyl) -N- (3- {4- [4- (4-morpholinyl) benzyl] -1-piperidinyl} propyl) -4-piperidinecarboxamide dihydrochloride The title compound was obtained as a colorless amorphous in the same manner as in Example 4 using the compound obtained in Reference Example 67. Yield 40%.
Free base: ¹ H NMR (CDCl ₃ ) δ 1.10-1.45 (2H, m), 1.45-1.97 (11H, m), 2.07 (3H, s), 2.22-2.50 (6H, m), 2.44 (3H, s), 2.76-2.95 (3H, m), 3.14 (4H, t, J = 4.8Hz), 3.66 (2H, t, J = 7.6Hz), 3.70-3.85 (1H, m), 3.88 (4H, t , J = 4.8Hz), 4.47-4.63 (1H, m), 6.85 (2H, d, J = 8.8Hz), 6.94-7.10 (3H, m), 7.15-7.35 (2H, m).
Example 91
1-acetyl-N- (3-chloro-4-methylphenyl) -N- (3- {4- [4- (dimethylamino) benzyl] -1-piperidinyl l} propyl) -4-piperidinecarboxamide dihydrochloride The title compound was obtained as a colorless amorphous in the same manner as in Example 82 using the compound obtained in Reference Example 68. Yield 43%.
Free base: ¹ H NMR (CDCl ₃ ) δ 1.18-1.45 (2H, m), 1.50-1.97 (11H, m), 2.05 (3H, s), 2.25-2.47 (6H, m), 2.42 (3H, s), 2.75-2.96 (3H, m), 2.91 (6H, s), 3.57-3.84 (3H, m), 4.45-4.60 (1H, m), 6.68 (2H, d, J = 8.8Hz), 6.95 -7.05 (3H, m), 7.15-7.35 (2H, m).
Example 92
1-acetyl-N- (3-chloro-4-methylphenyl) -N- (3- {4- [3- (4-morpholinyl) benzyl] -1-piperidinyl} propyl) -4-piperidinecarboxamide <br / > The title compound was synthesized in the same manner as in Example 1 using the compound obtained in Reference Example 69-2. Yield 68%.
¹ H NMR (CDCl ₃ ) δ1.15-1.33 (2H, m), 1.40-1.86 (11H, m), 2.05 (3H, s), 2.21-2.41 (4H, m), 2.42 (3H, s), 2.47 (2H, d, J = 6.9Hz), 2.77-2.90 (3H, m), 3.12-3.18 (4H, m), 3.60-3.67 (2H, m), 3.70-3.80 (1H, m), 3.83- 3.89 (4H, m), 4.47-4.56 (1H, m), 6.64-6.70 (2H, m), 6.72-6.77 (1H, m), 6.96 (1H, dd, J = 8.1, 2.1Hz), 7.15- 7.21 (2H, m), 7.29 (1H, br s).
Example 93
1-acetyl-N- (3-chloro-4-methylphenyl) -N- (3- {4- [3- (methylamino) benzyl] -1-piperidinyl} propyl) -4-piperidinecarboxamide The title compound was synthesized in the same manner as in Example 1 using the compound obtained in Reference Example 70-2. Yield 62%.
¹ H NMR (CDCl ₃ ) δ 1.16-1.31 (2H, m), 1.40-1.87 (11H, m), 2.05 (3H, s), 2.23-2.45 (6H, m), 2.42 (3H, s), 2.75 -2.90 (3H, m), 2.83 (3H, s), 3.59-3.68 (2H, m), 3.71-3.80 (1H, m), 4.46-4.56 (1H, m), 6.37-6.40 (1H, m) , 6.42-6.51 (2H, m), 6.96 (1H, dd, J = 8.1, 2.1Hz), 7.09 (1H, t, J = 7.5Hz), 7.18 (1H, d, J = 2.1Hz), 7.30 ( 1H, br s).
Example 94
1-acetyl-N- (3- (4- (3-aminobenzyl) -1-piperidinyl) propyl) -N- (3-chloro-4-methylphenyl) -4-piperidinecarboxamide obtained in Reference Example 71. Using the compound, the title compound was synthesized in the same manner as in Example 1. Yield 77%.
¹ H NMR (CDCl ₃ ) δ 1.10-1.30 (2H, m), 1.40-1.85 (12H, m), 2.04 (3H, s), 2.20-2.41 (6H, m), 2.42 (3H, s), 2.77-2.90 (3H, m), 3.53-3.68 (4H, m), 3.71-3.80 (1H, m), 6.46-6.48 (1H, m), 6.49-6.56 (2H, m), 6.96 (1H, dd , J = 7.8, 1.8Hz), 7.05 (1H, t, J = 7.8Hz), 7.18 (1H, d, J = 1.8Hz), 7.29 (1H, br s).

Example 95
1-acetyl-N- (3-chloro-4-methylphenyl) -N-3- (4- (4- (4-cyanophenoxy) benzyl) -1-piperidinyl) propyl) -4-piperidinecarboxamide > A solution of the compound obtained in Reference Example 72 (1.21 g, 3.09 mmol) and trifluoroacetic acid (10 mL) in dichloromethane (15 mL) was stirred for 10 minutes. A colorless powder obtained by evaporating the solvent was dissolved in acetonitrile (20 mL) and N, N-dimethylformamide (10 mL), and 1-acetyl-N- (3-chloro-4-methylphenyl) -N- (3 -Chloropropyl) -4-piperidinecarboxamide (1.15 g, 3.09 mmol), potassium iodide (513 mg, 3.09 mmol) and potassium carbonate (938 mg, 6.80 mmol) were added, and the mixture was stirred for 21 hours. Thereafter, the title compound (1.18 g, 61%) was synthesized in the same manner as in Example 1.
¹ H NMR (CDCl ₃ ) δ 1.20-1.90 (13H, m), 2.05 (3H, s), 2.20-2.60 (4H, m), 2.42 (3H, s), 2.56 (2H, d, J = 6.0 Hz), 2.70-3.20 (3H, m), 3.54-3.86 (3H, m), 4.44-4.60 (1H, m), 6.93-7.04 (4H, m), 7.11-7.21 (3H, m), 7.28- 7.34 (2H, m), 7.55-7.64 (2H, m).
Example 96
Ethyl 4-{[1- (3-{[(1-acetyl-4-piperidinyl) carbonyl] -3-chloro-4-methylanilino} propyl) -4-piperidinyl] sulfonyl} phenylcarbamate Reference Example The title compound was synthesized in the same manner as in Example 1 using the compound obtained in 73-3. Yield 51%.
¹ H NMR (CDCl ₃ ) δ 1.33 (3H, t, J = 7.2Hz), 1.50-2.05 (14H, m), 2.05 (3H, s), 2.20-2.45 (3H, m), 2.42 (3H, s ), 2.74-2.98 (3H, m), 3.55-3.86 (3H, m), 4.26 (2H, q, J = 7.2Hz), 4.45-4.58 (1H, m), 6.94 (1H, dd, J = 2.2 , 7.8Hz), 7.12-7.18 (2H, m), 7.29 (1H, d, J = 7.8Hz), 7.59 (2H, d, J = 8.8Hz), 7.77 (2H, d, J = 8.8Hz).
Example 97
1-acetyl-N- (3-chloro-4-methylphenyl) -N- (3- (4-((3- (dimethylamino) phenyl) sulfonyl) -1-piperidinyl) propyl) -4-piperidinecarboxamide The title compound was synthesized in the same manner as in Example 1 using the compound obtained in Reference Example 74-3. Yield 51%.
¹ H NMR (CDCl ₃ ) δ1.50-2.02 (13H, m), 2.05 (3H, s), 2.24-2.40 (4H, m), 2.42 (3H, s), 2.78-2.99 (3H, m), 3.02 (6H, s), 3.57-3.66 (2H, m), 3.71-3.81 (1H, m), 4.47-4.56 (1H, m), 6.88-6.97 (2H, m), 7.07-7.17 (3H, m ), 7.25-7.31 (1H, m), 7.36 (1H, dd, J = 5.4, 5.2Hz).

Reference Example 1-1
tertbutyl 4-[(4-nitrophenyl) sulfanyl] piperidine-1-carboxylate
N, N- of tertbutyl 4-[(methylsulfonyl) oxy] piperidine-1-carboxylate (23.4 g, 83.9 mmol), 4-nitrothiophenol (19.5 g, 101 mmol) and potassium carbonate (17.4 g, 126 mmol) The mixture of dimethylformamide (400 mL) was stirred at 60 ° C. for 13 hours. Water (400 mL) was added to the residue obtained by evaporating the solvent, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium bicarbonate and saturated saline. After drying over anhydrous magnesium sulfate, the residue was evaporated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / hexane = 1/5 → 1/4) to give the title compound (25.9 g, 91%) as yellow powdery crystals. .
¹ H NMR (CDCl ₃ ) δ1.46 (9H, s), 1.50-1.73 (2H, m), 1.96-2.10 (2H, m), 3.05 (2H, ddd, J = 13.6, 10.7, 3.2Hz), 3.42-3.57 (1H, m), 3.90-4.10 (2H, m), 7.35-7.43 (2H, m), 8.11-8.20 (2H, m).
Reference Example 1-2
tertbutyl 4-[(4-aminophenyl) sulfanyl] piperidine-1-carboxylate The compound obtained in Reference Example 1-1 (25.9 g, 76.6 mmol), hydrazine monohydrate (15 mL, 306 mmol) and trichloride A mixed solution of iron hexahydrate (2.07 g, 7.66 mmol) and activated carbon (4.9 g) in tetrahydrofuran (400 mL) was heated under reflux for 20 hours. The insolubles were filtered through celite and washed with ethyl acetate. The filtrate was evaporated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / hexane = 1/2 → 2/3) to give the title compound (21.1 g, 89%) as yellow powdery crystals.
¹ H NMR (CDCl ₃ ) δ1.34-1.65 (2H, m), 1.44 (9H, s), 1.78-1.93 (2H, m), 2.73-3.01 (3H, m), 3.75 (2H, br s) , 3.90-4.05 (2H, m), 6.58-6.66 (2H, m), 7.21-7.30 (2H, m).
Reference Example 1-3
tertbutyl 4-[(4-aminophenyl) sulfonyl] piperidine-1-carboxylate A solution of the compound obtained in Reference Example 1-2 (6.62 g, 21.5 mmol) in dichloromethane (200 mL) at 0 ° C. with 4-chloro Perbenzoic acid (11.2 g, 45.2 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Dichloromethane (100 mL) was added to the reaction solution, and the mixture was washed with a 5% aqueous sodium thiosulfate solution + saturated sodium hydrogen carbonate (80 + 80 mL), saturated sodium hydrogen carbonate (180 mL × 2), and saturated saline (180 mL). After drying over anhydrous magnesium sulfate and evaporation under reduced pressure, the residue was washed with diisopropyl ether and a small amount of ethyl acetate to obtain the title compound (7.14 g, 98%) as pale yellow powdery crystals.
¹ H NMR (CDCl ₃ ) δ1.43 (9H, s), 1.48-1.70 (2H, m), 1.93-2.06 (2H, m), 2.55-2.75 (2H, m), 2.96 (1H, tt, J = 12.0, 3.9Hz), 4.03-4.30 (4H, m), 6.70-6.75 (2H, m), 7.58-7.63 (2H, m).
Reference Example 1-4
4-[(4-aminophenyl) sulfonyl] piperidine dihydrochloride In a methanol / tetrahydrofuran (40 mL / 20 mL) solution of the compound (2.24 g, 6.59 mmol) obtained in Reference Example 1-3, a 4N hydrochloric acid / ethyl acetate solution ( 20 mL) and stirred for 14 hours. The powder obtained by distilling off the solvent was washed with diisopropyl ether to give the title compound (2.11 g, quant.) As pale yellow powdery crystals.
¹ H NMR (CD ₃ OD) δ 1.80-1.98 (2H, m), 2.14-2.25 (2H, m), 2.94-3.07 (2H, m), 3.40-3.55 (3H, m), 7.14-7.20 ( 2H, m), 7.75-7.81 (2H, m).

Reference Example 2-1
tertbutyl 4-{[4- (isopropylamino) phenyl] sulfanyl} piperidine-1-carboxylate 1 of the compound (2.00 g, 6.49 mmol) obtained in Reference Example 1-2 and acetone (0.57 mL, 7.79 mmol) To a solution of 2,2-dichloroethane (40 mL) was added sodium triacetoxyborohydride (2.03 g, 9.09 mmol), and the mixture was stirred for 18 hours. Saturated sodium hydrogen carbonate (30 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane, and the extract was washed with saturated saline. After drying over anhydrous magnesium sulfate, the residue was evaporated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / hexane = 1/6) to give the title compound (2.00 g, 88%) as a yellow oil.
_{^{1 H NMR (CDCl 3) δ1.22}} (6H, d, J = 5.8Hz), 1.25-1.57 (2H, m), 1.44 (9H, s), 1.79-1.94 (2H, m), 2.73-3.00 ( 2H, m), 3.53-3.70 (2H, m), 3.90-4.05 (2H, m), 6.45-6.54 (2H, m), 7.20-7.30 (2H, m).
Reference Example 2-2
tertbutyl 4-{[4- (isopropylamino) phenyl] sulfonyl} piperidine-1-carboxylate The title compound was obtained in the same manner as in Reference Example 1-3 using the compound obtained in Reference Example 2-1. Compounds were synthesized. Yield 71%.
¹ H NMR (CDCl ₃ ) δ1.26 (6H, d, J = 6.2 Hz), 1.43 (9H, s), 1.45-1.69 (2H, m), 1.94-2.06 (2H, m), 2.55-2.74 ( 2H, m), 2.95 (1H, dt, J = 12.0, 3.6Hz), 3.60-3.78 (1H, m), 4.14-4.30 (3H, m), 6.53-6.62 (2H, m), 7.54-7.63 ( 2H, m).
Reference Example 2-3
4-{[4- (isopropylamino) phenyl] sulfonyl} piperidine dihydrochloride Using the compound obtained in Reference Example 2-2, the title compound was synthesized in the same manner as in Reference Example 1-4. . 97% yield.
¹ H NMR (CD ₃ OD) δ 1.27 (6H, d, J = 6.4Hz), 1.73-1.99 (2H, m), 2.12-2.28 (2H, m), 2.90-3.09 (2H, m), 3.32 -3.56 (3H, m), 3.69-3.84 (1H, m), 6.98-7.08 (2H, m), 7.68-7.78 (2H, m).
Reference Example 3-1
tertbutyl 4-{[4- (dimethylamino) phenyl] sulfanyl} piperidine-1-carboxylate Using the compound obtained in Reference Example 1-2 and formalin, proceed in the same manner as in Reference Example 2-1. To synthesize the title compound. Yield 67%.
¹ H NMR (CDCl ₃ ) δ1.35-1.55 (2H, m), 1.44 (9H, s), 1.79-1.93 (2H, m), 2.73-3.00 (3H, m), 2.96 (6H, s), 3.90-4.10 (2H, m), 6.60-6.70 (2H, m), 7.29-7.40 (2H, m).
Reference Example 3-2
tertbutyl 4-{[4- (dimethylamino) phenyl] sulfonyl} piperidine-1-carboxylate The title compound was obtained in the same manner as in Reference Example 1-3 using the compound obtained in Reference Example 3-1. Compounds were synthesized. Yield 58%.
¹ H NMR (CDCl ₃ ) δ 1.43 (9H, s), 1.45-1.70 (2H, m), 1.94-2.07 (2H, m), 2.55-2.76 (2H, m), 2.85-3.05 (1H, m) , 3.08 (6H, s), 4.14-4.30 (2H, m), 6.66-6.75 (2H, m), 7.60-7.70 (2H, m).
Reference Example 3-3
4-{[4- (dimethylamino) phenyl] sulfonyl} piperidine dihydrochloride Using the compound obtained in Reference Example 3-2, the title compound was synthesized in the same manner as in Reference Example 1-4. . 79% yield.
¹ H NMR (CD ₃ OD) δ 1.72-2.02 (2H, m), 2.10-2.28 (2H, m), 2.90-3.13 (2H, m), 3.11 (6H, s), 3.30-3.55 (3H, m ), 6.93-7.01 (2H, m), 7.68-7.75 (2H, m).

Reference Example 4-1
tertbutyl 4-[(3-aminophenyl) sulfanyl] piperidine-1-carboxylate
The title compound was synthesized in the same manner as in Reference Example 1-1 using 3-aminothiophenol. 82% yield.
¹ H NMR (CDCl ₃ ) δ1.40-1.64 (2H, m), 1.45 (9H, s), 1.87-2.00 (2H, m), 3.92 (2H, ddd, J = 10.8, 10.8, 3.2Hz), 3.20 (1H, tt, J = 10.2, 3.8Hz), 3.69 (2H, br s), 3.86-4.05 (2H, m), 6.58 (1H, ddd, J = 8.0, 2.2, 1.0Hz), 6.73-6.84 (2H, m), 7.08 (1H, t, J = 8.0Hz).
Reference example 4-2
tertbutyl 4-[(3-aminophenyl) sulfonyl] piperidine-1-carboxylate The title compound is synthesized in the same manner as in Reference Example 1-3 using the compound obtained in Reference Example 4-1. did. Yield 81%.
¹ H NMR (CDCl ₃ ) δ1.44 (9H, s), 1.50-1.75 (2H, m), 1.90-2.05 (2H, m), 2.50-2.80 (2H, m), 3.02 (1H, tt, J = 8.0, 3.7Hz), 4.00 (2H, br s), 4.10-4.33 (2H, m), 6.92 (1H, ddd, J = 7.6, 2.4, 1.0Hz), 7.12 (1H, dd, J = 2.4, 1.8Hz), 7.19 (1H, ddd, J = 8.0, 1.8, 1.0Hz), 7.33 (1H, dd, J = 8.0, 7.6Hz).
Reference Example 4-3
4-[(3-Aminophenyl) sulfonyl] piperidine dihydrochloride The title compound was synthesized in the same manner as in Reference Example 1-4, using the compound obtained in Reference Example 4-2. Yield 81%.
¹ H NMR (CD ₃ OD) δ1.60-2.15 (4H, m), 2.73-2.98 (2H, m), 3.22-3.65 (3H, m), 7.05-7.23 (3H, m), 7.42 (1H, t, J = 7.9Hz), 8.55-8.84 (1H, m), 9.20-9.40 (1H, m).
Reference Example 5-1
tertbutyl 4-{[3- (methylamino) phenyl] sulfanyl} piperidine-1-carboxylate The compound (1.63 g, 5.29 mmol) obtained in Reference Example 4-1 and benzotriazole (693 mg, 5.82) (mmol) in ethanol (15 mL) was added with 37% formalin (0.471 mL), and the mixture was stirred for 24.5 hours. Tetrahydrofuran (15 mL) was added to the residue obtained by evaporating the solvent, then sodium borohydride (600 mg, 15.9 mmol) was added, and the mixture was stirred for 21 hours. After adding crushed ice and stirring for 20 minutes, the mixture was extracted with ethyl acetate, and the extract was washed with saturated saline. After drying over anhydrous magnesium sulfate and evaporation under reduced pressure, the residue was purified by column chromatography (ethyl acetate / hexane = 1/4) to give the title compound (1.66 g, 97%) as a colorless oil.
¹ H NMR (CDCl ₃ ) δ1.40-1.60 (2H, m), 1.45 (9H, s), 1.87-1.98 (2H, m), 2.83 (3H, s), 2.85-2.98 (2H, m), 3.21 (1H, tt, J = 10.2, 3.9Hz), 3.76 (1H, br s), 3.87-4.05 (2H, m), 6.50 (1H, ddd, J = 7.8, 2.4, 0.9Hz), 6.66 (1H , dd, J = 2.4, 1.8Hz), 6.75 (1H, ddd, J = 7.8, 1.8, 0.9Hz), 7.14 (1H, t, J = 7.8Hz).
Reference example 5-2
tertbutyl 4-{[3- (methylamino) phenyl] sulfonyl} piperidine-1-carboxylate Using the compound obtained in Reference Example 5-1 in the same manner as in Reference Example 1-3, Compounds were synthesized. Yield 13%.
¹ H NMR (CDCl ₃ ) δ1.44 (9H, s), 1.50-1.77 (2H, m), 1.90-2.05 (2H, m), 2.50-2.80 (2H, m), 2.89 (3H, d, J = 4.8Hz), 3.02 (1H, tt, J = 12.2, 3.6Hz), 4.04-4.35 (3H, m), 6.83 (1H, ddd, J = 8.0, 2.4, 1.0Hz), 7.00 (1, dd, J = 2.8, 1.0Hz), 7.14 (1H, ddd, J = 7.8, 2.8, 1.0Hz), 7.34 (1H, dd, J = 8.0, 7.8Hz).
Reference Example 5-3
4-{[3- (methylamino) phenyl] sulfonyl} piperidine dihydrochloride Using the compound obtained in Reference Example 5-2, the title compound was synthesized in the same manner as in Reference Example 1-4. . Yield 92%.
¹ H NMR (CD ₃ OD) δ1.80-2.05 (2H, m), 2.14-2.28 (2H, m), 2.90-3.12 (2H, m), 3.02 (3H, s), 3.45-3.70 (3H, m), 7.45-7.54 (1H, m), 7.59-7.70 (3H, m).

Reference Example 6-1
tertbutyl 4-[(4-bromophenyl) sulfanyl] piperidine-1-carboxylate
The title compound was synthesized in the same manner as in Reference Example 1-1 using 4-bromothiophenol. 94% yield.
¹ H NMR (CDCl ₃ ) δ 1.40-1.64 (2H, m), 1.45 (9H, s), 1.84-1.99 (2H, m), 2.91 (2H, ddd, J = 10.6, 3.0, 3.0Hz), 3.18 (1H, tt, J = 10.4, 3.6Hz), 1.86-4.04 (2H, m), 7.22-7.30 (2H, m), 7.37-7.46 (2H, m).
Reference Example 6-2
tertbutyl 4-[(4-bromophenyl) sulfonyl] piperidine-1-carboxylate The title compound is synthesized in the same manner as in Reference Example 1-3 using the compound obtained in Reference Example 6-1. did. 94% yield.
¹ H NMR (CDCl ₃ ) δ 1.43 (9H, s), 1.46-1.70 (2H, m), 1.90-2.05 (2H, m), 2.53-2.77 (2H, m), 3.03 (1H, tt, J = 8.0, 3.6Hz), 4.10-4.35 (2H, m), 7.73 (4H, s).
Reference Example 6-3
tertbutyl 4-{[4- (4-morpholinyl) phenyl] sulfonyl} piperidine-1-carboxylate The compound (1.31 g, 3.24 mmol) obtained in Reference Example 6-2 and morpholine (0.339 mL, A suspension of toluene (15 mL) of 3.89 mmol), palladium acetate (7.3 mg, 0.0324 mmol), (+)-BINAP (30.3 mg, 0.0486 mmol) and cesium carbonate (1.48 g, 4.54 mmol) at 100 ° C. 18 Stirred for hours. The insolubles were filtered through celite and washed with ether. The filtrate was evaporated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / hexane = 1/1 → 2/1) to give the title compound (418 mg, 31%) as a yellow amorphous.
¹ H NMR (CDCl ₃ ) δ1.43 (9H, s), 1.48-1.65 (2H, m), 1.93-2.06 (2H, m), 2.55-2.73 (2H, m), 2.97 (1H, tt, J = 5.6, 2.4Hz), 3.30-3.36 (4H, m), 3.84-3.90 (4H, m), 4.10-4.32 (2H, m), 6.90-6.97 (2H, m), 7.63-7.73 (2H, m ).
Reference Example 6-4
4-{[4- (4-morpholinyl) phenyl] sulfonyl} piperidine dihydrochloride The title compound is synthesized in the same manner as in Reference Example 1-4, using the compound obtained in Reference Example 6-3. did. Yield 77%.
¹ H NMR (CD ₃ OD) δ1.74-2.02 (2H, m), 2.11-2.27 (2H, m), 2.90-3.08 (2H, m), 3.15-3.56 (7H, m), 3.79-3.86 ( 4H, m), 7.06-7.15 (2H, m), 7.65-7.75 (2H, m).

Reference example 7-1
tertbutyl 4-[(4-isopropylphenyl) sulfanyl] piperidine-1-carboxylate
The title compound was synthesized in the same manner as in Reference Example 1-1 using 4-isopropylthiophenol. Yield 53%.
¹ H NMR (CDCl ₃ ) δ1.25 (6H, d, J = 6.8 Hz), 1.40-1.65 (2H, m), 1.44 (9H, s), 1.83-1.99 (2H, m), 2.81-2.98 ( 3H, m), 3.14 (1H, tt, J = 10.2, 4.0Hz), 3.84-4.05 (2H, m), 7.12-7.22 (2H, m), 7.31-7.40 (2H, m).
Reference Example 7-2
tertbutyl 4-[(4-isopropylphenyl) sulfonyl] piperidine-1-carboxylate Using the compound obtained in Reference Example 7-1, synthesize the title compound in the same manner as in Reference Example 1-3. did. 89% yield.
_{^{1 H NMR (CDCl 3) δ1.29}} (6H, d, J = 7.0Hz), 1.43 (9H, s), 1.48-1.72 (2H, m), 1.90-2.08 (2H, m), 2.54-2.78 ( 2H, m), 2.93-3.02 (2H, m), 4.12-4.34 (2H, m), 7.38-7.46 (2H, m), 7.74-7.82 (2H, m).
Reference Example 7-3
4-[(4-isopropylphenyl) sulfonyl] piperidine hydrochloride The title compound was synthesized in the same manner as in Reference Example 1-4, using the compound obtained in Reference Example 7-2. Yield 81%.
_{^{1 H NMR (CD 3 OD)}} δ1.29 (6H, d, J = 7.2Hz), 1.80-1.96 (2H, m), 2.14-2.25 (2H, m), 2.94-3.10 (3H, m), 3.43 -3.55 (3H, m), 7.54-7.59 (2H, m), 7.81-7.86 (2H, m).
Reference Example 8-1
tertbutyl 4-[(4-chlorophenyl) sulfanyl] piperidine-1-carboxylate
The title compound was synthesized in the same manner as in Reference Example 1-1 using 4-chlorothiophenol. Yield 92%.
¹ H NMR (CDCl ₃ ) δ1.39-1.61 (2H, m), 1.45 (9H, s), 1.82-1.99 (2H, m), 2.91 (2H, ddd, J = 13.6, 10.6, 4.2Hz), 3.17 (1H, tt, J = 10.6, 3.8Hz), 3.84-4.07 (2H, m), 7.24-7.38 (4H, m).
Reference Example 8-2
tertbutyl 4-[(4-chlorophenyl) sulfonyl] piperidine-1-carboxylate Using the compound obtained in Reference Example 8-1, the title compound was synthesized in the same manner as in Reference Example 1-3. . 78% yield.
¹ H NMR (CDCl ₃ ) δ1.43 (9H, s), 1.45-1.71 (2H, m), 1.90-2.05 (2H, m), 2.53-2.78 (2H, m), 3.03 (1H, tt, J = 12.0, 3.6Hz), 4.12-4.36 (2H, m), 7.52-7.60 (2H, m), 7.77-7.85 (2H, m).
Reference Example 8-3
4-[(4-chlorophenyl) sulfonyl] piperidine hydrochloride The title compound was synthesized in the same manner as in Reference Example 1-4, using the compound obtained in Reference Example 8-2. 94% yield.
¹ H NMR (CD ₃ OD) δ1.77-2.01 (2H, m), 2.09-2.28 (2H, m), 3.00 (2H, dt, J = 12.8, 3.2Hz), 3.43-3.63 (3H, m) , 7.67-7.75 (2H, m), 7.87-7.95 (2H, m).

Reference Example 9-1
tertbutyl 4-[(4-methylphenyl) sulfanyl] piperidine-1-carboxylate
The title compound was synthesized in the same manner as in Reference Example 1-1 using 4-methylthiophenol. 97% yield.
¹ H NMR (CDCl ₃ ) δ1.42-1.57 (2H, m), 1.44 (9H, s), 1.83-1.95 (2H, m), 2.34 (3H, s), 2.81-2.95 (2H, m), 3.12 (1H, tt, J = 6.8, 2.6Hz), 3.85-4.07 (2H, m), 7.09-7.15 (2H, m), 7.31-7.36 (2H, m).
Reference Example 9-2
tertbutyl 4-[(4-methylphenyl) sulfonyl] piperidine-1-carboxylate Using the compound obtained in Reference Example 9-1, synthesize the title compound in the same manner as in Reference Example 1-3. did. Yield 84%.
¹ H NMR (CDCl ₃ ) δ1.43 (9H, s), 1.45-1.70 (2H, m), 1.90-2.06 (2H, m), 2.46 (3H, s), 2.52-2.76 (2H, m), 3.01 (1H, tt, J = 12.0, 3.6Hz), 4.13-4.32 (2H, m), 7.34-7.41 (2H, m), 7.70-7.78 (2H, m).
Reference Example 9-3
4-[(4-methylphenyl) sulfonyl] piperidine hydrochloride The title compound was synthesized in the same manner as in Reference Example 1-4, using the compound obtained in Reference Example 9-2. 89% yield.
¹ H NMR (CD ₃ OD) δ1.75-2.00 (2H, m), 2.10-2.25 (2H, m), 2.47 (3H, s), 2.99 (2H, dt, J = 12.8, 3.2Hz), 3.39 -3.56 (3H, m), 7.45-7.56 (2H, m), 7.75-7.82 (2H, m).
Reference Example 10-1
tertbutyl 4-({4-[(2-ethoxyethyl) amino] phenyl} sulfonyl) piperidine-1-carboxylate The compound (886 mg, 2.19 mmol) obtained in Reference Example 6-2 and 2- ethoxyethyl amine (0.276 mL, 2.63 mmol) and _{Pd 2 (dba) 3 · CHCl} 3 (40.1mg, 0.0438mmol) and (+) - BINAP (54.6mg, 0.0876mmol) and sodium t- butoxide (285 mg, 3.07 mmol) Of toluene (20 mL) was stirred at 70 ° C. for 5 hours. The insolubles were filtered through celite and washed with ether. The filtrate was evaporated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / hexane = 1/1) to give the title compound (758 mg, 84%) as a yellow amorphous.
_{^{1 H NMR (CDCl 3) δ1.24}} (3H, t, J = 7.0Hz), 1.43 (9H, s), 1.43-1.67 (2H, m), 1.91-2.07 (2H, m), 2.50-2.76 ( 2H, m), 2.95 (1H, tt, J = 12.2, 3.6Hz), 3.35 (2H, dt, J = 5.2, 5.2Hz), 3.55 (2H, q, J = 7.0Hz), 3.67 (2H, t , J = 5.2HZ), 4.10-4.31 (2H, m), 4.68 (1H, t, J = 5.2Hz), 6.60-6.69 (2H, m), 7.56-7.65 (2H, m).
Reference Example 10-2
4-({4-[(2-ethoxyethyl) amino] phenyl} sulfonyl) piperidine dihydrochloride Using the compound obtained in Reference Example 10-1, in the same manner as in Reference Example 1-4 The title compound was synthesized. 94% yield.
_{^{1 H NMR (CD 3 OD)}} δ1.20 (3H, t, J = 6.9Hz), 1.76-1.93 (2H, m), 2.14-2.25 (2H, m), 2.93-3.06 (2H, m), 3.30 -3.42 (1H, m), 3.37 (2H, t, J = 5.7Hz), 3.44-3.52 (2H, m), 3.54 (2H, q, J = 6.9Hz), 3.63 (2H, t, J = 5.7 Hz), 6.81-6.86 (2H, m), 7.58-7.63 (2H, m).
Reference Example 11-1
tertbutyl 4-({4-[(3-methoxypropyl) amino] phenyl} sulfonyl) piperidine-1-carboxylate
The title compound was synthesized in the same manner as in Reference Example 10-1 using 3-methoxypropylamine. 97% yield.
¹ H NMR (CDCl ₃ ) δ1.43 (9H, s), 1.47-1.65 (2H, m), 1.85-2.06 (4H, m), 2.53-2.75 (2H, m), 2.95 (1H, tt, J = 12.0, 3.6Hz), 3.29 (2H, dt, J = 6.0, 5.4Hz), 3.37 (3H, s), 3.53 (2H, t, J = 5.7Hz), 4.08-4.34 (2H, m), 4.81 (1H, t, J = 5.4Hz), 6.58-6.64 (2H, m), 7.56-7.62 (2H, m).
Reference Example 11-2
4-({4-[(3-methoxypropyl) amino] phenyl} sulfonyl) piperidine dihydrochloride Using the compound obtained in Reference Example 11-1, in the same manner as in Reference Example 1-4 The title compound was synthesized. Yield 93%.
¹ H NMR (CD ₃ OD) δ1.77-1.92 (4H, m), 2.30-2.45 (2H, m), 2.93-3.06 (2H, m), 3.29 (2H, t, J = 6.9Hz), 3.31 -3.52 (3H, m), 3.35 (3H, s), 3.50 (2H, t, J = 6.0Hz), 6.83-6.88 (2H, m), 7.60-7.65 (2H, m).

Reference Example 12-1
tertbutyl 4-({4-[(2-hydroxyethyl) amino] phenyl} sulfonyl) piperidine-1-carboxylate The compound (749 mg, 1.85 mmol) obtained in Reference Example 6-2 and 2- (t-butyldiphenylsilyloxy) ethylamine (665 mg, 2.22 mmol) and _{Pd 2 (dba) 3 · CHCl} 3 (33.9mg, 0.0370mmol) and (+) - BINAP (46.1mg, 0.0740mmol) and sodium t-butoxide (249 mg, 2.59 mmol) in toluene (15 mL) was stirred at 75 ° C. for 5 hours. The insolubles were filtered through celite and washed with ether. The filtrate was evaporated under reduced pressure, the residue was dissolved in tetrahydrofuran (15 mL), and a 1 M tetrabutylammonium fluoride / tetrahydrofuran solution (3 mL) was added, followed by stirring for 25 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure.The residue was purified by column chromatography (ethyl acetate / hexane = 1/1 → 1/0) to give the title compound (502 mg, 71 %) As colorless powdery crystals.
¹ H NMR (CDCl ₃ ) δ1.43 (9H, s), 1.46-1.82 (3H, m), 1.90-2.06 (2H, m), 2.52-2.74 (2H, m), 2.95 (1H, tt, J = 12.0, 3.8Hz), 3.36 (2H, dt, J = 5.6, 5.2Hz), 3.89 (2H, t, J = 5.2Hz), 4.12-4.29 (2H, m), 6.60-6.70 (2H, m) , 7.55-7.65 (2H, m).
Reference Example 12-2
4-({4-[(2-hydroxyethyl) amino] phenyl} sulfonyl) piperidine dihydrochloride Using the compound obtained in Reference Example 11-1, similar to Reference Example 1-4 The title compound was synthesized. Yield 93%.
¹ H NMR (CD ₃ OD) δ1.73-1.98 (2H, m), 2.11-2.27 (2H, m), 2.91-3.10 (2H, m), 3.28-3.55 (5H, m), 3.73 (2H, t, J = 5.8Hz), 6.87-6.96 (2H, m), 7.60-7.69 (2H, m).
Reference Example 13-1
tertbutyl 4-{[4- (1,4-dioxa-8-azaspiro [4.5] dec-8-yl) phenyl] sulfonyl} piperidine-1-carboxylate
The title compound was synthesized in the same manner as in Reference Example 10-1 using 1,4-dioxa-8-azaspiro [4.5] decane. 86% yield.
¹ H NMR (CDCl ₃ ) δ1.43 (9H, s), 1.55-1.69 (2H, m), 1.76-1.86 (4H, m), 1.91-2.07 (2H, m), 2.51-2.76 (2H, m ), 2.96 (1H, tt, J = 12.2, 3.8Hz), 3.47-3.58 (4H, m), 4.01 (4H, s), 4.12-4.31 (2H, m), 6.88-6.98 (2H, m), 7.60-7.70 (2H, m).
Reference Example 14-1
tertbutyl 4-{[4- (4-acetyl-1-piperazinyl) phenyl] sulfonyl} piperidine-1-carboxylate
The title compound was synthesized in the same manner as in Reference Example 10-1 using 1-acetylpiperazine. Yield 78%.
¹ H NMR (CDCl ₃ ) δ1.43 (9H, s), 1.43-1.67 (2H, m), 1.91-2.07 (2H, m), 2.16 (3H, s), 2.55-2.74 (2H, m), 2.98 (1H, tt, J = 12.0, 3.6Hz), 3.33-3.46 (4H, m), 3.61-3.71 (2H, m), 3.74-3.84 (2H, m), 4.12-4.32 (2H, m), 6.88-6.98 (2H, m), 7.66-7.75 (2H, m).
Reference Example 14-2
4-{[4- (4-acetyl-1-piperazinyl) phenyl] sulfonyl} piperidine dihydrochloride Using the compound obtained in Reference Example 14-1, in the same manner as in Reference Example 1-4 The title compound was synthesized. 97% yield.
¹ H NMR (CD ₃ OD) δ 1.78-1.95 (2H, m), 2.13-2.24 (2H, m), 2.17 (3H, s), 2.94-3.07 (2H, m), 3.35-3.53 (7H, m), 3.69-3.77 (2H, m), 7.10-7.17 (2H, m), 7.69-7.76 (2H, m).

Reference Example 15-1
The title compound was synthesized in the same manner as in Reference Example 10-1 using tertbutyl 4-({4-[(2-methoxyethyl) amino] phenyl} sulfonyl) piperidine-1-carboxylate 2-methoxyethylamine. 93% yield.
¹ H NMR (CDCl ₃ ) δ1.43 (9H, s), 1.47-1.63 (2H, m), 1.93-2.04 (2H, m), 2.50-2.75 (2H, m), 2.95 (1H, tt, J = 12.3, 3.3Hz), 3.35 (2H, dt, J = 5.7, 5.4Hz), 3.41 (3H, s), 3.63 (2H, t, J = 5.4Hz), 4.11-4.30 (2H, m), 4.66 (1H, t, J = 5.7Hz), 6.61-6.67 (2H, m), 7.58-7.63 (2H, m).
Reference Example 15-2
4-({4-[(2-methoxyethyl) amino] phenyl} sulfonyl) piperidine dihydrochloride Using the compound obtained in Reference Example 15-1, in the same manner as in Reference Example 1-4 The title compound was synthesized. 96% yield.
¹ H NMR (CD ₃ OD) δ 0.78-1.07 (2H, m), 1.77-1.93 (2H, m), 2.14-2.25 (2H, m), 2.94-3.06 (2H, m), 3.32-3.43 ( 1H, m), 3.38 (3H, s), 3.38 (2H, t, J = 5.7Hz), 3.59 (2H, t, J = 5.7Hz), 3.83-6.88 (2H, m), 7.59-7.65 (2H , m).
Reference Example 16-1
tertbutyl 4- (phenylsulfanyl) piperidine-1-carboxylate The title compound was synthesized in the same manner as in Reference Example 1-1 using thiophenol. Yield 100%.
¹ H NMR (CDCl ₃ ) δ1.45 (9H, s), 1.48-1.63 (2H, m), 1.84-2.00 (2H, m), 2.83-3.00 (2H, m), 3.21 (1H, tt, J = 8.2, 4.0Hz), 3.85-4.04 (2H, m), 7.24-7.36 (3H, m), 7.38-7.45 (2H, m).
Reference Example 16-2
4- (Phenylsulfanyl) piperidine hydrochloride The title compound was synthesized in the same manner as in Reference Example 1-4, using the compound obtained in Reference Example 16-1. 82% yield.
¹ H NMR (CD ₃ OD) δ1.70-1.87 (2H, m), 2.03-2.27 (2H, m), 2.97-3.15 (2H, m), 3.25-3.53 (3H, m), 7.25-7.53 ( 5H, m).
Reference Example 16-3
4- (phenylsulfanyl) -1- (trifluoroacetyl) piperidine <br/> compound obtained in Reference Example _{16-2 (14.1g, 61.3mmol) H 2} O (50mL) was added 8N aqueous sodium hydroxide solution (8 mL) was added dropwise. The aqueous solution was extracted with dichloromethane (100 mL + 50 mL), and the extract was dried over potassium carbonate. The solvent was distilled off to obtain a colorless oil (14.2 g).
To a solution of the above oil and triethylamine (17.2 mL, 123 mmol) in dichloromethane (200 mL) was added trifluoroacetic anhydride (13.0 mL, 92.0 mmol) at 0 ° C., and the mixture was stirred at room temperature for 30 minutes. Water (200 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (100 mL). The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / hexane = 1/3) to give the title compound (17.4 g, 98%) as a colorless oil.
¹ H NMR (CDCl ₃ ) δ1.53-1.75 (2H, m), 1.97-2.12 (2H, m), 3.10-3.42 (3H, m), 3.85-4.01 (1H, m), 4.15-4.30 (1H , m), 7.25-7.47 (5H, m).
Reference Example 16-4
1- (4-{[1- (trifluoroacetyl) -4-piperidinyl] sulfanyl} phenyl) ethanone The compound (4.81 g, 16.6 mmol) obtained in Reference Example 16-3 and acetyl chloride (1.53 Aluminum chloride (5.52 g, 41.5 mmol) was added to a dichloromethane (50 mL) solution of the solution (1 mL, 21.6 mmol) under ice-cooling, and the mixture was stirred for 1 hour. After pouring into ice water (50 mL) and stirring for 1 hour, the separated aqueous layer was extracted with dichloromethane. The combined organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and then dried over anhydrous magnesium sulfate. The solid obtained by evaporating the solvent was washed with diisopropyl ether to obtain the title compound (4.59 g, 84%).
¹ H NMR (CDCl ₃ ) δ1.60-1.82 (2H, m), 2.03-2.20 (2H, m), 2.59 (3H, s), 3.21-3.47 (2H, m), 3.57 (1H, tt, J = 9.2, 4.0Hz), 3.86-4.03 (1H, m), 4.13-4.29 (1H, m), 7.38-7.46 (2H, m), 7.86-7.94 (2H, m).
Reference Example 16-5
1- (4-{[1- (trifluoroacetyl) -4-piperidinyl] sulfonyl} phenyl) ethanone The compound obtained in Reference Example 16-4 was used in the same manner as in Reference Example 1-3. To synthesize the title compound. 96% yield.
¹ H NMR (CDCl ₃ ) δ1.66-1.85 (2H, m), 2.05-2.21 (2H, m), 2.69 (3H, s), 2.74-2.86 (1H, m), 3.08-3.27 (2H, m ), 4.08-4.19 (1H, m), 4.58-4.68 (1H, m), 7.98-8.02 (2H, m), 8.13-8.18 (2H, m).
Reference Example 16-6
1- [4-{(4-Piperidinyl) sulfonyl} phenyl] ethanone 1M was added to a mixed solution of the compound (3.33 g, 9.17 mmol) obtained in Reference Example 16-5 in methanol / tetrahydrofuran (80 mL / 40 mL). An aqueous potassium carbonate solution (18.3 mL) was added dropwise, and the mixture was stirred for 45 minutes. Water was added to the residue obtained by evaporating the solvent, and the mixture was extracted with dichloromethane. The aqueous layer was extracted with dichloromethane, and the combined organic layer was dried over potassium carbonate. The solvent was distilled off to obtain the title compound (2.45 g, 100%).
¹ H NMR (CDCl ₃ ) δ1.45-1.69 (2H, m), 1.92-2.08 (2H, m), 2.48-2.65 (2H, m), 2.68 (3H, s), 3.06 (1H, tt, J = 12.2, 3.8Hz), 3.12-3.26 (2H, m), 7.94-8.02 (2H, m), 8.09-8.16 (2H, m).

Reference Example 17-1
tertbutyl 4-({4- [4- (ethoxycarbonyl) -1-piperidinyl] phenyl} sulfonyl) piperidine-1-carboxylate The compound obtained in Reference Example 6-2 (518 mg, 1.28 mmol) and ethyl isonipecotate (0.276 mL, 1.79 mmol) and _{Pd 2 (dba) 3 · CHCl} 3 (46.9mg, 0.0512mmol) and (+) - BINAP (63.8mg, 0.102mmol) and cesium carbonate (626 mg, 1.92 mmol) Was stirred in a sealed tube at 100 ° C. for 24 hours. The insolubles were filtered through celite and washed with ether. The filtrate was evaporated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / hexane = 2/3 → 1/1) to obtain the title compound (486 mg, 79%) as a pale yellow amorphous.
¹ H NMR (CDCl ₃ ) δ 1.27 (3H, t, J = 7.0 Hz), 1.43 (9H, s), 1.45-1.68 (2H, m), 1.72-2.12 (6H, m), 2.46-2.75 ( 3H, m), 2.85-3.10 (3H, m), 3.76-3.92 (2H, m), 4.11-4.30 (2H, m), 4.17 (2H, q, J = 7.0Hz), 6.86-6.98 (2H, m), 7.60-7.71 (2H, m).
Reference Example 17-2
4-({4- [4- (ethoxycarbonyl) -1-piperidinyl] phenyl} sulfonyl) piperidine dihydrochloride Using the compound obtained in Reference Example 17-1, Reference Examples 1-4 and The title compound was synthesized in the same manner. Yield 93%.
_{^{1 H NMR (CD 3 OD)}} δ1.26 (3H, t, J = 7.2Hz), 1.78-2.50 (8H, m), 2.66-2.84 (1H, m), 2.92-3.11 (2H, m), 3.17 -3.58 (5H, m), 3.82-4.01 (2H, m), 4.15 (2H, q, J = 7.2Hz), 7.27-7.38 (2H, m), 7.73-7.90 (2H, m).

Reference Example 18-1
tertbutyl 4-({4-[(E) -3-ethoxy-3-oxo-1-propenyl] phenyl} sulfonyl) piperidine-1-carboxylate The compound obtained in Reference Example 6-2 ( 610 mg, 1.51 mmol), ethyl acrylate (0.327 mL, 3.02 mmol), palladium acetate (34.0 mg, 0.151 mmol), tri (2-methylphenyl) phosphine (91.8 mg, 0.302 mmol), and triethylamine (0.442 mL, 3.02 mmol) )) In acetonitrile (5 mL) was stirred at 80 ° C. for 14 hours in a sealed tube. The insolubles were filtered through celite and washed with ether. The filtrate was evaporated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / hexane = 1/3 → 1/2) to give the title compound (666 mg, 100%) as a pale yellow solid.
_{^{1 H NMR (CDCl 3) δ1.35}} (3H, t, J = 7.2Hz), 1.43 (9H, s), 1.53-1.70 (2H, m), 1.92-2.04 (2H, m), 2.55-2.75 ( 2H, m), 3.04 (1H, tt, J = 12.0, 3.6Hz), 4.16-4.31 (2H, m), 4.29 (2H, q, J = 7.2Hz), 6.55 (1H, d, J = 16.2Hz) ), 7.66-7.72 (2H, m), 7.70 (1H, d, J = 46.2Hz), 7.84-7.90 (2H, m).
Reference Example 18-2
4-({4-[(E) -3-ethoxy-3-oxo-1-propenyl] phenyl} sulfonyl) piperidine hydrochloride Using the compound obtained in Reference Example 18-1, Reference Example The title compound was synthesized in the same manner as in 1-4. 82% yield.
¹ H NMR (CD ₃ OD) δ1.33 (3H, t, J = 7.2Hz), 1.82-1.99 (2H, m), 2.14-2.25 (2H, m), 3.00 (2H, dt, J = 12.9, 3.3Hz), 3.44-3.61 (3H, m), 4.27 (2H, q, J = 7.2Hz), 6.72 (1H, d, J = 16.2Hz), 7.75 (1H, d, J = 16.2Hz), 7.88 -7.96 (4H, m).
Reference Example 19-1
tertbutyl 4-{[4 '-(methoxycarbonyl) -1,1'-biphenyl-4-yl] sulfonyl} piperidine-1-carboxylate The compound obtained in Reference Example 6-2 (1.72 g , 4.26 mmol), 4-methoxycarbonylphenylboronic acid (921 mg, 5.11 mmol), tetrakistriphenylphosphine palladium (246 mg, 0.213 mmol), 2M aqueous sodium carbonate solution (4.5 mL) and methanol (4 mL) in toluene (35 mL). The suspension was stirred at 80 ° C. for 26 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium bicarbonate (twice) and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / hexane = 1/3 → 1/2 → 2/3) to obtain the title compound (1.25 g, 64%) as a colorless solid.
¹ H NMR (CDCl ₃ ) δ1.43 (9H, s), 1.56-1.72 (2H, m), 1.94-2.09 (2H, m), 2.56-2.77 (2H, m), 3.07 (1H, tt, J = 12.0, 3.6Hz), 3.96 (3H, s), 4.15-4.34 (2H, m), 7.64-7.70 (2H, m), 7.77-7.83 (2, m), 7.92-7.97 (2H, m), 8.12-8.18 (2H, m).
Reference Example 19-2
Methyl 4 '-(piperidin-4-ylsulfonyl) -1,1'-biphenyl-4-carboxylate hydrochloride Using the compound obtained in Reference Example 19-1, Reference Examples 1-4 The title compound was synthesized in the same manner. Yield 92%.
¹ H NMR (CD ₃ OD) δ1.82-1.99 (2H, m), 2.18-2.28 (2H, m), 2.93-3.05 (2H, m), 3.43-3.51 (3H, m), 3.94 (3H, s), 7.82-7.87 (2H, m), 7.98-8.05 (4H, m), 8.13-8.18 (2H, m).

Reference Example 20-1
tertbutyl 4-({4-[(1E) -3-amino-3-oxo-1-propenyl] phenyl} sulfonyl) piperidine-1-carboxylate Reference Example 18- The title compound was synthesized in the same manner as in 1. Yield 100%.
¹ H NMR (CDCl ₃ ) δ1.43 (9H, s), 1.53-1.68 (2H, m), 1.91-2.06 (2H, m), 2.54-2.76 (2H, m), 3.05 (1H, tt, J = 12.3, 3.6Hz), 4.12-4.33 (2H, m), 5.67 (2H, br s), 6.58 (1H, d, J = 15.9Hz), 7.64-7.71 (2H, m), 7.68 (1H, d) , J = 15.9Hz), 7.83-7.89 (2H, m).
Reference Example 20-2
4-({4-[(1E) -3-amino-3-oxo-1-propenyl] phenyl} sulfonyl) piperidine trifluoroacetate The compound obtained in Reference Example 20-1 (502 mg , 1.27 mmol) in dichloromethane (10 mL) was added with trifluoroacetic acid (5 mL) and stirred for 15 hours. The solid obtained by evaporating the solvent was washed with diisopropyl ether and ethyl acetate to obtain the title compound (479 mg, 92%).
¹ H NMR (CD ₃ OD) δ1.82-1.98 (2H, m), 2.15-2.25 (2H, m), 3.00 (2H, dt, J = 12.9, 3.3Hz), 3.45-3.59 (3H, m) , 6.83 (1H, d, J = 15.9Hz), 7.62 (1H, d, J = 15.9Hz), 7.84-7.89 (2H, m), 7.92-7.97 (2H, m).
Reference Example 21-1
tertbutyl 4-{[4- (3-amino-3-oxopropyl) phenyl] sulfonyl} piperidine-1-carboxylate Ethanol of the compound obtained in Reference Example 20-1 (895 mg, 2.27 mmol) 10% palladium carbon (about 20 mg) was added to a mixed solution of 5% / 5mL / 2mL in ethyl acetate / ethyl acetate / tetrahydrofuran, and the mixture was stirred under a hydrogen stream for 5 days. . The insolubles were filtered through celite and washed with ether. The colorless solid obtained by evaporating the filtrate under reduced pressure was washed with ethyl acetate to obtain the title compound (499 mg, 55%).
¹ H NMR (CDCl ₃ ) δ1.43 (9H, s), 1.50-1.69 (2H, m), 1.92-2.06 (2H, m), 2.55-2.74 (2H, m), 2.57 (2H, t, J = 7.5Hz), 2.95-3.11 (1H, m), 3.08 (2H, t, J = 7.5Hz), 4.10-4.31 (2H, m), 5.22-5.46 (2H, m), 7.39-7.46 (2H, m), 7.74-7.81 (2H, m).
Reference Example 21-2
4-{[4- (3-amino-3-oxopropyl) phenyl] sulfonyl} piperidine trifluoroacetate As in Reference Example 20-2, using the compound obtained in Reference Example 21-1. To synthesize the title compound. Yield 92%.
¹ H NMR (CD ₃ OD) δ1.79-1.96 (2H, m), 2.12-2.24 (2H, m), 2.56 (2H, t, J = 7.5Hz), 2.92-3.05 (2H, m), 3.04 (2H, t, J = 7.5Hz), 3.41-3.54 (3H, m), 7.51-7.57 (2H, m), 7.79-8.04 (2H, m).

Reference Example 22-1
tertbutyl 4-({4-[(E) -2-cyanoethenyl] phenyl} sulfonyl) piperidine-1-carboxylate Using acrylonitrile, the title compound was synthesized in the same manner as in Reference Example 18-1. . Yield 54%.
¹ H NMR (CDCl ₃ ) δ1.43 (9H, s), 1.52-1.69 (2H, m), 1.91-2.04 (2H, m), 2.54-2.75 (2H, m), 3.05 (1H, tt, J = 11.7, 3.6Hz), 4.14-4.33 (2H, m), 6.04 (1H, d, J = 16.5Hz), 7.45 (1H, d, J = 16.5Hz), 7.62-7.67 (2H, m), 7.88 -7.93 (2H, m).
Reference Example 22-2
4-({4-[(E) -2-cyanoethenyl] phenyl} sulfonyl) piperidine trifluoroacetate The compound obtained in Reference Example 22-1 was used in the same manner as in Reference Example 20-2. To synthesize the title compound. 95% yield.
¹ H NMR (CD ₃ OD) δ1.82-1.99 (2H, m), 2.13-2.26 (2H, m), 3.00 (2H, dt, J = 12.9, 3.0Hz), 3.44-3.61 (3H, m) , 6.46 (1H, d, J = 16.8Hz), 7.64 (1H, d, J = 16.8Hz), 7.84-7.98 (4H, m).
Reference Example 23-1
tertbutyl 4- (3-nitrobenzylidene) piperidine-1-carboxylateA solution of 3-nitrobenzyl bromide (9.98 g, 46.2 mmol) and triethyl phosphite (9.6 mL) in acetonitrile (50 mL) was added. Heated to reflux for hours. After evaporating the solvent, N, N-dimethylformamide (50 mL), 1-tertbutyloxycarbonyl-4-piperidone (10.1 g, 50.8 mmol) and potassium tert-butoxide (7.24 g, 64.7 mmol) were added under ice cooling, The mixture was stirred at room temperature for 15 hours. After evaporating the solvent, ethyl acetate and methanol were added, and unnecessary substances were filtered. The filtrate was concentrated, dissolved in ethyl acetate, and washed twice with a saturated saline solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / hexane = 1/5) to obtain the title compound (7.56 g, 51%) as a yellow solid.
¹ H NMR (CDCl ₃ ) δ1.48 (9H, s), 2.32-2.50 (4H, m), 3.37-3.59 (4H, m), 6.39 (1H, br s), 7.44-7.54 (2H, m) , 8.02-8.10 (2H, m).
Reference Example 23-2
tertbutyl 4- (3-aminobenzyl) piperidine-1-carboxylate Using the compound obtained in Reference Example 23-1, the title compound was synthesized in the same manner as in Reference Example 21-1. 89% yield.
¹ H NMR (CDCl ₃ ) δ1.09-1.25 (2H, m), 1.45 (9H, s), 1.52-1.77 (3H, m), 2.43 (2H, d, J = 7.0Hz), 2.53-2.74 ( 2H, m), 3.62 (2H, br s), 3.94-4.17 (2H, m), 6.45-6.58 (3H, m), 7.06 (1H, t, J = 7.6Hz).
Reference Example 23-3
tertbutyl 4- {3-[(methylsulfonyl) amino] benzyl} piperidine-1-carboxylate The compound (2.23 g, 7.69 mmol) obtained in Reference Example 23-2 and methanesulfonyl chloride (0.627 mL) , 8.07 mmol) in a solution of tetrahydrofuran (40 mL) was added dropwise with triethylamine (1.08 mL, 7.69 mmol) under ice cooling, and the mixture was stirred at the same temperature for 15 minutes and at room temperature for 20 minutes. Under ice cooling, 0.1N hydrochloric acid (50 mL) was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure.The residue was purified by column chromatography (ethyl acetate / hexane = 1/2) to give the title compound (2.62 g, 93%). Obtained as a colorless amorphous.
¹ H NMR (CDCl ₃ ) δ1.06-1.24 (2H, m), 1.45 (9H, s), 1.55-1.75 (3H, m), 2.53 (2H, d, J = 6.9Hz), 2.55-2.71 ( 2H, m), 3.02 (3H, s), 3.95-4.20 (2H, m), 6.63 (1H, br s), 6.95-7.08 (3H, m), 7.24-7.30 (1H, m).
Reference Example 23-4
N- [3- (piperidin-4-ylmethyl) phenyl] methanesulfonamide hydrochloride The title compound is synthesized in the same manner as in Reference Example 1-4, using the compound obtained in Reference Example 23-3. did. 94% yield.
¹ H NMR (CD ₃ OD) δ1.30-1.56 (2H, m), 1.78-2.02 (3H, m), 2.61 (2H, d, J = 6.6Hz), 2.84-3.04 (3H, m), 2.94 (3H, s), 3.28-3.43 (2H, m), 6.95-7.13 (3H, m), 7.27 (1H, t, J = 7.6Hz).

Reference Example 24-1
1-[(4-{[1- (trifluoroacetyl) piperidin-4-yl] methyl} phenyl) sulfonyl] piperidin-4-ol
In a solution of 4-{[1- (trifluoroacetyl) piperidin-4-yl] methyl} benzenesulfonyl chloride (1.70 g, 4.59 mmol) in tetrahydrofuran (40 mL), 4-hydroxypiperidine (0.696 mL, 6.89 mmol) and triethylamine ( 1.16 mL, 8.26 mmol) and stirred for 30 minutes. Water (40 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure.The residue was purified by column chromatography (ethyl acetate / hexane = 5/1) to give the title compound (1.85 g, 93%). Obtained as a colorless amorphous.
¹ H NMR (CDCl ₃ ) δ1.19-1.35 (2H, m), 1.42 (1H, d, J = 3.6Hz), 1.57-2.00 (7H, m), 2.60-2.78 (3H, m), 2.87- 2.98 (2H, m), 3.01-3.13 (1H, m), 3.24-3.35 (2H, m), 3.73-3.86 (1H, m), 3.93-4.06 (1H, m), 4.48-4.60 (1H, m ), 7.26-7.32 (2H, m), 7.67-7.76 (2H, m).
Reference Example 24-2
1-{[4- (piperidin-4-ylmethyl) phenyl] sulfonyl} piperidin-4-ol To a solution of the compound (5.40 g, 12.4 mmol) obtained in Reference Example 24-1 in methanol (50 mL) A 1 M potassium carbonate solution (20 mL) was added, and the mixture was stirred for 2 hours. Saturated saline (20 mL) was added, methanol was distilled off, and the aqueous layer was extracted four times with dichloromethane. The combined organic layers were dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give the title compound (3.80 g, 90%) as a colorless solid.
¹ H NMR (CDCl ₃ ) δ1.04-1.28 (2H, m), 1.53-1.80 (5H, m), 1.85-2.02 (2H, m), 2.46-2.65 (4H, m), 2.79-2.95 (2H , m), 2.97-3.12 (2H, m), 3.24-3.40 (2H, m), 3.69-3.83 (1H, m), 7.23-7.33 (2H, m), 7.62-7.71 (2H, m).
Reference Example 25-1
N- (2-hydroxyethyl) -4-{[1- (trifluoroacetyl) piperidin-4-yl] methyl} benzenesulfonylamide
The title compound was synthesized in the same manner as in Reference Example 24-1 using 2-aminoethanol. Yield 84%.
¹ H NMR (CDCl ₃ ) δ1.15-1.40 (2H, m), 1.50-2.00 (3H, m), 2.63-2.81 (1H, m), 2.65 (2H, d, J = 7.0Hz), 2.903. 18 (3H, m), 3.72 (2H, t, J = 5.0Hz), 3.90-4.10 (1H, m), 4.45-4.60 (1H, m), 5.23 (1H, t, J = 6.2Hz), 7.25 -7.35 (2H, m), 7.77-7.86 (2H, m).
Reference Example 25-2
N- (2-hydroxyethyl) -4- (piperidin-4-ylmethyl) benzenesulfonylamide Using the compound obtained in Reference Example 25-1, the title compound in the same manner as in Reference Example 24-2 Was synthesized. Yield 84%.
¹ H NMR (CDCl ₃ ) δ1.02-1.28 (2H, m), 1.50-1.76 (3H, m), 2.45-2.64 (4H, m), 2.90-3.30 (7H, m), 3.61-3.70 (2H , m), 7.20-7.33 (2H, m), 7.73-7.82 (2H, m).

Reference Example 26-1
1- (4-{[1- (trifluoroacetyl) piperidin-4-yl] methyl} phenyl) ethanone 4-benzyl-1- (trifluoroacetyl) piperidine (13.56 g, 50.0 mmol) and acetyl chloride (4.62 mL , 65.0 mmol) in dichloromethane (150 mL) was added with aluminum chloride (16.67 g, 125 mmol) under ice cooling and stirring, and the mixture was stirred under ice cooling for 3 hours. The reaction mixture was poured into ice water (150 g), stirred for 30 minutes, and extracted with dichloromethane (150, 50 mL). The organic layer was washed with saturated aqueous sodium hydrogen carbonate (50 mL) and saturated saline (50 mL), and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 250 g, hexane / ethyl acetate = 9/1 → 3/2) to give the title compound (14.92 g, 47.6 mmol, yield 95%) as a pale-yellow oil.
¹ H NMR (CDCl ₃ ) δ 1.1-1.4 (2H, m), 1.65-2.05 (3H, m), 2.60 (3H, s), 2.63 (2H, d, J = 7.0Hz), 2.6-2.8 (1H , m), 2.95-3.15 (1H, m), 3.9-4.1 (1H, m), 4.45-4.65 (1H, m), 7.24 (2H, d, J = 8.4Hz), 7.90 (2H, d, J = 8.4Hz).
Reference Example 26-2
1- [4- (Piperidin-4-ylmethyl) phenyl] ethanone An aqueous solution of potassium carbonate (10.37 g, 75.0 mmol) in a solution of the compound obtained in Reference Example 26-1 (7.83 g, 25.0 mmol) in methanol (100 mL) (50 mL) and the mixture was stirred at room temperature for 3 days. After evaporating the organic solvent under reduced pressure, water (30 mL) was added, and the mixture was extracted with dichloromethane (80 mL, 40 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound (6.15 g).
¹ H NMR (CDCl ₃ ) δ 1.05-1.3 (2H, m), 1.5-1.85 (3H, m), 2.4-2.65 (2H, m), 2.59 (3H, s), 2.59 (2H, d, J = 6.6Hz), 2.95-3.15 (2H, m), 7.24 (2H, d, J = 8.4Hz), 7.88 (2H, d, J = 8.4Hz).
Reference Example 27-1
Cis 2,6-dimethyl-4-[(4-{[1- (trifluoroacetyl) piperidin-4-yl] methyl} phenyl) sulfonyl] morpholine Using cis 2,6-dimethyl morpholine, The title compound was synthesized in the same manner as in Reference Example 24-1. 86% yield.
_{^{1 H NMR (CDCl 3) δ1.15}} (6H, d, J = 6.2Hz), 1.15-1.40 (2H, m), 1.68-2.02 (5H, m), 2.59-2.81 (1H, m), 2.65 ( 2H, d, J = 7.0Hz), 2.97-3.16 (1H, m), 3.51-3.81 (4H, m), 3.92-4.11 (1H, m), 4.45-4.63 (1H, m), 7.27-7.36 ( 2H, m), 7.64-7.72 (2H, m).
Reference Example 27-2
Cis 2,6-dimethyl-4-{[4- (piperidin-4-ylmethyl) phenyl] sulfonyl} morpholine Same as Reference Example 24-2 using the compound obtained in Reference Example 27-1. To synthesize the title compound. Yield 100%.
¹ H NMR (CDCl ₃ ) δ 1.10-1.25 (2H, m), 1.15 (6H, d, J = 6.3 Hz), 1.56-1.74 (3H, m), 1.95 (2H, dd, J = 11.7, 10.5 Hz), 2.51-2.63 (2H, m), 2.61 (2H, d, J = 6.9Hz), 3.02-3.11 (2H, m), 3.53-3.60 (2H, m), 3.66-3.78 (2H, m) , 7.29-7.34 (2H, m), 7.63-7.67 (2H, m).

Reference Example 28-1
8-[(4-{[1- (trifluoroacetyl) piperidin-4-yl] methyl} phenyl) sulfonyl] -1,4-dioxa-8-azaspiro {4.5} decane
The title compound was synthesized in the same manner as in Reference Example 24-1 using 1,4-dioxa-8-azaspiro {4.5} decane. 83% yield.
¹ H NMR (CDCl ₃ ) δ1.14-1.39 (2H, m), 1.69-2.00 (7H, m), 2.60-2.80 (1H, m), 2.64 (2H, d, J = 7.0Hz), 2.99- 3.23 (5H, m), 3.91 (4H, s), 3.93-4.09 (1H, m), 4.48-4.62 (1H, m), 7.25-7.33 (2H, m), 7.65-7.73 (2H, m).
Reference Example 28-2
8-{[4- (piperidin-4-ylmethyl) phenyl] sulfonyl} -1,4-dioxa-8-azaspiro {4.5} decane Using the compound obtained in Reference Example 28-1, reference was made. The title compound was synthesized in the same manner as in Example 24-2. Yield 100%.
¹ H NMR (CDCl ₃ ) δ1.05-1.30 (2H, m), 1.54-1.84 (7H, m), 2.46-2.65 (2H, m), 2.59 (2H, d, J = 6.6Hz), 2.99- 3.22 (6H, m), 3.90 (4H, s), 7.25-7.32 (2H, m), 7.63-7.70 (2H, m).
Reference Example 29-1
2-Methyl-2- (4-methylphenyl) propanoate 60% sodium hydride (16.83 g, 421 mmol) in tetrahydrofuran (400 mL) suspension at room temperature under stirring, (4-methylphenyl) ethyl acetate (25.00 g , 140 mmol) in tetrahydrofuran (100 mL) was added dropwise. Subsequently, methyl iodide (21.0 mL, 337 mmol) was added dropwise, and the mixture was stirred at room temperature for 18 hours. After the reaction mixture was poured into 1N hydrochloric acid (500 mL) under ice-cooling and stirring, ethyl acetate (500 mL) was added, and the organic layer was separated. The organic layer was washed with a 5% aqueous sodium thiosulfate solution (150 mL × 2), a saturated aqueous sodium bicarbonate solution (150 mL × 2), and a saturated saline solution (150 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by distillation under reduced pressure (108-110 ° C / 3.5 torr) to give the title compound (22.64 g, 110 mmol, yield 78%) as a pale-yellow oil.
¹ H NMR (CDCl ₃ ) δ 1.18 (3H, t, J = 7.2 Hz), 1.56 (6H, s), 2.32 (3H, s), 4.11 (2H, q, J = 7.2 Hz), 7.13 (2H, d, J = 8.0Hz), 7.24 (2H, d, J = 8.0Hz).
Reference Example 29-2
Ethyl 2- [4- (bromomethyl) phenyl] -2-methylpropanoate The compound obtained in Reference Example 29-1 (18.38 g, 89.1 mmol), 1,3-dibromo-5,5-dimethylhydantoin (15.29 g , 53.5 mmol) and 2,2′-azobisisobutyronitrile (293 mg) were added to a mixture of ethyl acetate (220 mL), and the mixture was stirred under reflux with heating (external temperature 100 ° C.) for 6 hours. After cooling the reaction mixture to room temperature, it was washed with saturated aqueous sodium hydrogen carbonate (200 mL, 50 mL × 2) and saturated brine (50 mL), and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 500 g, hexane / ethyl acetate = 1/0 → 19/1) to give the title compound (25.15 g, 88.2 mmol, yield 99%) as a pale-yellow oil.
¹ H NMR (CDCl ₃ ) δ 1.19 (3H, t, J = 7.2 Hz), 1.56 (6H, s), 4.12 (2H, q, J = 7.2 Hz), 4.48 (2H, s), 7.2-7.5 ( 4H, m).
Reference Example 29-3
Ethyl 2- {4-[(diethoxyphosphoryl) methyl] phenyl} -2-methylpropanoate A mixture of the compound obtained in Reference Example 29-2 (30.00 g, 105 mmol) and triethyl phosphite (21.6 mL) was prepared. Stirred at 140 ° C. for 15 hours. The reaction mixture was purified by column chromatography (silica gel 500 g, hexane / ethyl acetate = 1/1 → 0/1) to give the title compound (30.50 g, 89.1 mmol, yield 85%) as a pale yellow oil.
¹ H NMR (CDCl ₃ ) δ 1.1-1.3 (9H, m), 1.55 (6H, s), 3.12 (2H, d, J = 21.6Hz), 3.9-4.2 (6H, m), 7.2-7.35 (4H , m).
Reference Example 29-4
Ethyl 2- {4-[(1-benzylpiperidin-4-ylidene) methyl] phenyl} -2-methylpropanoate obtained in Reference Example 29-3 with 1-benzyl-4-piperidone (1.29 g, 6.82 mmol) To a solution of the compound (2.34 g, 6.83 mmol) in N, N-dimethylformamide (7 mL) was added potassium t-butoxide (1.07 g) under ice-cooling and stirring, and the mixture was stirred at room temperature for 1 hour. Under ice cooling and stirring, water (35 mL) was added, and the mixture was extracted with ethyl acetate (35 mL, 20 mL × 2). The organic layer was washed with water (10 mL × 2) and saturated saline (10 mL), and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 80 g, hexane / ethyl acetate = 9/1 → 2/1) to give the title compound (1.18 g, 3.13 mmol, yield 46%).
¹ H NMR (CDCl ₃ ) δ 1.18 (3H, t, J = 7.2 Hz), 1.56 (6H, s), 2.3-2.6 (8H, m), 3.52 (2H, s), 4.12 (2H, q, J = 7.2Hz), 6.23 (1H, s), 7.14 (2H, d, J = 8.6Hz), 7.2-7.4 (7H, m).
Reference Example 29-5
Ethyl 2-methyl-2- [4- (piperidin-4-ylmethyl) phenyl] propanoate 20% palladium hydroxide carbon on a solution of the compound (1166 mg, 3.09 mmol) obtained in Reference Example 29-4 in ethanol (15 mL) (50% hydrous product, 466 mg) and hydrogenated at 50 ° C. for 18 hours. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (878 mg, 3.03 mmol, yield 98%) as a colorless oil.
¹ H NMR (CDCl ₃ ) δ 1.0-1.3 (2H, m), 1.19 (3H, t, J = 7.2Hz), 1.5-1.75 (3H, m), 1.56 (6H, s), 2.45-2.65 (2H , m), 2.50 (2H, d, J = 6.6Hz), 2.95-3.15 (2H, m), 4.12 (2H, q, J = 7.2Hz), 7.09 (2H, d, J = 8.4Hz), 7.24 (2H, d, J = 8.4Hz).

Reference Example 30-1
N- (2-hydroxyethyl) -N-methyl-4-{[1- (trifluoroacetyl) piperidin-4-yl] methyl} benzenesulfonylamide
The title compound was synthesized in the same manner as in Reference Example 24-1 using 2-methylaminoethanol. Yield 100%.
¹ H NMR (CDCl ₃ ) δ1.19-1.36 (2H, m), 1.70-1.96 (3H, m), 2.62-2.78 (3H, m), 2.85 (3H, s), 3.00-3.14 (1H, m ), 3.18 (2H, t, J = 5.1Hz), 3.78 (2H, t, J = 5.1Hz), 3.95-4.06 (1H, m), 4.48-4.59 (1H, m), 7.29-7.34 (2H, m), 7.72-7.77 (2H, m).
Reference Example 30-2
N- (2-hydroxyethyl) -N-methyl-4- (piperidin-4-ylmethyl) benzenesulfonylamide Using the compound obtained in Reference Example 30-1, similar to Reference Example 24-2 To synthesize the title compound. Yield 100%.
¹ H NMR (CDCl ₃ ) δ1.05-1.30 (2H, m), 1.52-1.90 (3H, m), 2.48-2.65 (4H, m), 2.84 (3H, s), 3.00-3.12 (2H, m ), 3.17 (2H, t, J = 5.2Hz), 3.77 (2H, t, J = 5.2Hz), 7.26-7.35 (2H, m), 7.67-7.75 (2H, m).

Reference Example 31-1
2- {4-[(1-benzylpiperidine-4-ylidene) methyl] phenyl} -2-methylpropanoic acid To a solution of the compound (14.72 g, 39.0 mmol) obtained in Reference Example 29-4 in ethanol (120 mL) A 2N aqueous sodium hydroxide solution (120 mL) was added, and the mixture was stirred at 80 ° C for 20 hours. After 2N hydrochloric acid (120 mL) was added to the reaction mixture under ice-cooling and stirring, the organic solvent was distilled off under reduced pressure, and the mixture was extracted with dichloromethane (300 mL, 150 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Acetone was added to the residue, and the precipitate was collected by filtration and dried under reduced pressure to give the title compound (10.80 g, 30.9 mmol, yield 79%) as a white solid.
¹ H NMR (CDCl ₃ ) δ 1.59 (6H, s), 2.3-2.75 (8H, m), 3.77 (2H, s), 6.20 (1H, s), 7.05 (2H, d, J = 8.4Hz), 7.31 (5H, s), 7.38 (2H, d, J = 8.4Hz), 8.17 (1H, br s, CO ₂ H).
Reference Example 31-2
2- {4-[(1-benzylpiperidin-4-ylidene) methyl] phenyl} -2-methylpropanamide The compound obtained in Reference Example 31-1 (1747 mg, 5.00 mmol) and 1-hydroxybenzotriazole (676 mg , 5.00 mmol) in N, N-dimethylformamide (10 mL) solution under ice-cooling and stirring, ammonium chloride (401 mg, 7.50 mmol), triethylamine (1.045 mL, 7.50 mmol), 1- [3- (dimethylamino) propyl] -3-Ethylcarbodiimide hydrochloride (1438 mg, 7.50 mmol) was added in that order, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, aqueous sodium bicarbonate was added, and the mixture was extracted with a mixed solvent of ethyl acetate-tetrahydrofuran (1/1). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the precipitate was collected by filtration and dried under reduced pressure to give the title compound (1520 mg, 4.36 mmol, yield 87%) as a white solid.
¹ H NMR (CDCl ₃ ) δ 1.58 (6H, s), 2.3-2.6 (8H, m), 3.53 (2H, s), 5.19 (1H, br s), 5.29 (1H, br s), 6.24 (1H , s), 7.19 (2H, d, J = 8.0Hz), 7.2-7.4 (7H, m).
Reference Example 31-3
2-Methyl-2- [4- (piperidin-4-ylmethyl) phenyl] propanamide 20% in a solution of the compound obtained in Reference Example 31-2 (1394 mg, 4.00 mmol) in methanol (30 mL) -tetrahydrofuran (30 mL) Palladium hydroxide carbon (50% water content, 558 mg) was added, and hydrogenation was performed at 50 ° C. for 20 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the precipitate was collected by filtration and dried under reduced pressure to give the title compound (962 mg, 3.69 mmol, yield 92%) as a white solid.
¹ H NMR (CDCl ₃ ) δ 1.0-1.3 (2H, m), 1.45-1.8 (3H, m), 1.58 (6H, s), 2.4-2.65 (2H, m), 2.51 (2H, d, J = 6.6Hz), 2.95-3.15 (2H, m), 5.19 (1H, br s), 5.34 (1H, br s), 7.13 (2H, d, J = 8.4Hz), 7.31 (2H, d, J = 8.4) Hz).
Reference Example 32-1
N- (3-methoxypropyl) -4-{[1- (trifluoroacetyl) piperidin-4-yl] methyl} benzenesulfonylamide
The title compound was synthesized in the same manner as in Reference Example 24-1 using 3-methoxypropylamine. 95% yield.
¹ H NMR (CDCl ₃ ) δ1.19-1.36 (2H, m), 1.68-1.95 (5H, m), 2.64 (2H, d, J = 6.6 Hz), 2.64-2.77 (1H, m), 3.05- 3.13 (3H, m), 3.30 (3H, s), 3.42 (2H, t, J = 5.7Hz), 3.94-4.06 (1H, m), 4.49-4.59 (1H, m), 5.10 (1H, t, J = 5.7Hz), 7.26-7.31 (2H, m), 7.77-7.82 (2H, m).
Reference Example 32-2
N- (3-methoxypropyl) -4- (piperidin-4-ylmethyl) benzenesulfonylamide Using the compound obtained in Reference Example 32-1, the title compound in the same manner as in Reference Example 24-2 Was synthesized. 97% yield.
¹ H NMR (CDCl ₃ ) δ1.08-1.28 (2H, m), 1.50-1.78 (5H, m), 2.49-2.63 (4H, m), 3.01-3.13 (3H, m), 3.29 (3H, s ), 3.41 (2H, t, J = 5.4Hz), 4.95-5.10 (1H, m), 7.24-7.34 (2H, m), 7.63-7.80 (2H, m).

Reference Example 33-1
4-methoxy-1-[(4-{[1- (trifluoroacetyl) piperidin-4-yl] methyl} phenyl) sulfonyl] piperidine
The title compound was synthesized in the same manner as in Reference Example 24-1 using 4-methoxypiperidine. Yield 88%.
¹ H NMR (CDCl ₃ ) δ1.19-1.35 (2H, m), 1.67-1.95 (7H, m), 2.61-2.78 (3H, m), 2.96-3.20 (5H, m), 3.25-3.34 (1H , m), 3.26 (3H, s), 3.95-4.06 (1H, m), 4.49-4.60 (1H, m), 7.26-7.32 (2H, m), 7.66-7.71 (2H, m).
Reference Example 33-2
4-methoxy-1-{[4- (piperidin-4-ylmethyl) phenyl] sulfonyl} piperidine The title compound was obtained in the same manner as in Reference Example 24-2 using the compound obtained in Reference Example 33-1. Compounds were synthesized. Yield 100%.
¹ H NMR (CDCl ₃ ) δ1.06-1.31 (2H, m), 1.52-1.98 (7H, m), 2.47-2.64 (4H, m), 2.99-3.34 (7H, m), 3.26 (3H, s ), 7.26-7.33 (2H, m), 7.62-7.70 (2H, m).
Reference Example 34-1
N- (2-hydroxypropyl) -4-{[1- (trifluoroacetyl) piperidin-4-yl] methyl} benzenesulfonylamide
The title compound was synthesized in the same manner as in Reference Example 24-1 using 1-amino-2-propanol. Yield 92%.
¹ H NMR (CDCl ₃ ) δ1.11-1.39 (2H, m), 1.18 (3H, d, J = 6.2Hz), 1.68-1.95 (3H, m), 1.93 (1H, d, J = 4.4Hz) , 2.63-2.87 (2H, m), 2.65 (2H, d, J = 7.0Hz), 2.98-3.16 (2H, m), 3.84-4.18 (3H, m), 4.45-4.62 (1H, m), 7.25 -7.34 (2H, m), 7.76-7.84 (2H, m).
Reference Example 34-2
N- (2-hydroxypropyl) -4- (piperidin-4-ylmethyl) benzenesulfonylamide Using the compound obtained in Reference Example 34-1, the title compound in the same manner as in Reference Example 24-2 Was synthesized. 79% yield.
¹ H NMR (CDCl ₃ ) δ1.02-1.30 (2H, m), 1.16 (3H, d, J = 6.6Hz), 1.53-1.74 (3H, m), 2.45-2.84 (8H, m), 2.98- 3.12 (3H, m), 3.80-3.98 (1H, m), 7.23-7.38 (2H, m), 7.72-7.82 (2H, m).

Reference Example 35-1
N-[(1-hydroxycyclohexyl) methyl] -4-{[1- (trifluoroacetyl) piperidin-4-yl] methyl} benzenesulfonylamide
The title compound was synthesized in the same manner as in Reference Example 24-1 using 1- (aminomethyl) cyclohexanol. Yield 80%.
¹ H NMR (CDCl ₃ ) δ1.19-1.62 (12H, m), 1.70-1.95 (3H, m), 1.97 (1H, s), 2.64 (2H, d, J = 7.2Hz), 2.64-2.77 ( 1H, m), 2.91 (2H, d, J = 6.3Hz), 3.00-3.13 (1H, m), 3.93-4.05 (1H, m), 4.47-4.58 (1H, m), 5.15 (1H, t, J = 6.3Hz), 7.25-7.32 (2H, m), 7.76-7.83 (2H, m).
Reference Example 35-2
N-[(1-hydroxycyclohexyl) methyl] -4- (piperidin-4-ylmethyl) benzenesulfonylamide Using the compound obtained in Reference Example 35-1, the same procedure as in Reference Example 24-2 was carried out. To synthesize the title compound. 79% yield.
¹ H NMR (CDCl ₃ ) δ 1.10-1.82 (15H, m), 2.48-2.62 (4H, m), 2.91 (2H, s), 3.01-3.09 (2H, m), 7.26-7.32 (2H, m ), 7.73-7.79 (2H, m).

Reference Example 36-1
1-[(4-{[1- (trifluoroacetyl) piperidin-4-yl] methyl} phenyl) sulfonyl] pyrrolidin-3-ol
The title compound was synthesized in the same manner as in Reference Example 24-1 using 3-hydroxypyrrolidine. 75% yield.
¹ H NMR (CDCl ₃ ) δ1.17-1.36 (2H, m), 1.52-1.62 (1H, m), 1.66-2.00 (4H, m), 2.58-2.77 (3H, m), 3.00-3.12 (1H , m), 3.20-3.52 (5H, m), 3.92-4.06 (1H, m), 4.35-4.44 (1H, m), 4.47-4.58 (1H, m), 7.26-7.33 (2H, m), 7.74 -7.82 (2H, m).
Reference Example 36-2
1-{[4- (piperidin-4-ylmethyl) phenyl] sulfonyl} pyrrolidin-3-ol The title compound was obtained in the same manner as in Reference Example 24-2, using the compound obtained in Reference Example 36-1. Compounds were synthesized. 79% yield.
¹ H NMR (CDCl ₃ ) δ 1.10-1.30 (2H, m), 1.53-2.02 (5H, m), 2.50-2.63 (4H, m), 3.03-3.13 (2H, m), 3.20-3.26 (1H , m), 3.34-3.48 (4H, m), 4.34-4.41 (1H, m), 7.21-7.34 (2H, m), 7.73-7.78 (2H, m).

Reference Example 37-1
4-methyl-1-[(4-{[1- (trifluoroacetyl) piperidin-4-yl] methyl} phenyl) sulfonyl] piperidin-4-ol
The title compound was synthesized in the same manner as in Reference Example 24-1 using 4-hydroxy-4-methylpiperidine. Yield 100%.
¹ H NMR (CDCl ₃ ) δ1.16-1.35 (2H, m), 1.25 (3H, s), 1.49-1.94 (7H, m), 2.60-2.78 (5H, m), 3.00-3.13 (1H, m ), 3.46-3.59 (2H, m), 3.93-4.06 (1H, m), 4.49-4.60 (1H, m), 7.25-7.33 (2H, m), 7.67-7.74 (2H, m).
Reference Example 37-2
4-methyl-1-{[4- (piperidin-4-ylmethyl) phenyl] sulfonyl} piperidin-4-ol Using the compound obtained in Reference Example 37-1, Reference Example 24-2 was used. The title compound was synthesized in the same manner. 86% yield.
¹ H NMR (CDCl ₃ ) δ1.11-1.26 (2H, m), 1.24 (3H, s), 1.56-1.80 (7H, m), 2.50-2.62 (4H, m), 2.71 (2H, dt, J = 11.7, 3.0Hz), 3.02-3.10 (2H, m), 3.46-3.56 (2H, m), 7.26-7.31 (2H, m), 7.64-7.70 (2, m).

Reference Example 38-1
N- (2-hydroxy-1,1-dimethylethyl) -4-{[1- (trifluoroacetyl) piperidin-4-yl] methyl} benzenesulfonylamide
The title compound was synthesized in the same manner as in Reference Example 24-1 using 2-amino-2-methylpropanol. Yield 92%.
_{^{1 H NMR (CDCl 3) δ1.15}} (6H, s), 1.15-1.35 (2H, m), 1.63-1.95 (3H, m), 2.29 (1H, t, J = 6.3Hz), 2.56-2.77 ( 3H, m), 3.00-3.12 (1H, m), 3.48 (2H, d, J = 6.3Hz), 3.94-4.06 (1H, m), 4.46-4.59 (1H, m), 4.89 (1H, s) , 7.24-7.32 (2H, m), 7.80-7.87 (2H, m).
Reference Example 38-2
N- (2-hydroxy-1,1-dimethylethyl) -4- (piperidin-4-ylmethyl) benzenesulfonylamide Using the compound obtained in Reference Example 38-1, Reference Example 24-2 The title compound was synthesized as described above. Yield 84%.
¹ H NMR (CDCl ₃ ) δ1.04-1.27 (2H, m), 1.14 (6H, s), 1.52-2.08 (5H, m), 2.46-2.64 (4H, m), 2.98-3.11 (2H, m ), 3.46 (2H, s), 7.26-7.31 (2H, m), 7.77-7.85 (2H, m).

Reference Example 39-1
N-ethyl-N- (2-hydroxyethyl) -4-{[1- (trifluoroacetyl) piperidin-4-yl] methyl} benzenesulfonylamide
The title compound was synthesized in the same manner as in Reference Example 24-1 using 2-ethylaminoethanol. 97% yield.
¹ H NMR (CDCl ₃ ) δ1.11-1.38 (2H, m), 1.16 (3H, t, J = 7.0Hz), 1.67-1.96 (3H, m), 2.21 (1H, t, J = 5.4HZ) , 2.26-2.80 (1H, m), 2.65 (2H, d, J = 6.6Hz), 2.98-3.15 (1H, m), 3.23-3.36 (4H, m), 3.79 (2H, dt, J = 5.4, 5.4Hz), 3.92-4.09 (1H, m), 4.47-4.62 (1H, m), 7.24-7.33 (2H, m), 7.73-7.81 (2H, m).
Reference Example 39-2
N-ethyl-N- (2-hydroxyethyl) -4- (piperidin-4-ylmethyl) benzenesulfonylamide Using the compound obtained in Reference Example 39-1, similar to Reference Example 24-2 To synthesize the title compound. Yield 100%.
¹ H NMR (CDCl ₃ ) δ1.09-1.25 (2H, m), 1.16 (3H, t, J = 7.2Hz), 1.55-2.00 (4H, m), 2.49-2.62 (2H, m), 2.60 ( 2H, d, J = 6.9Hz), 3.01-3.09 (2H, m), 3.23-3.33 (4H, m), 3.77 (2H, t, J = 5.4Hz), 7.26-7.31 (2H, m), 7.71 -7.76 (2H, m).

Reference Example 40-1
N- (2-hydroxy-2,2-dimethylethyl) -4-{[1- (trifluoroacetyl) piperidin-4-yl] methyl} benzenesulfonylamide acetone cyanohydrin (90%) (0.989 mL , 9.75 mmol) in tetrahydrofuran (50 mL) was added with a borane dimethylsulfide complex (1.20 mL, 12.7 mmol), and the mixture was heated under reflux for 3.5 hours. After cooling to room temperature, methanol (15 mL) was added, and the mixture was stirred for 5 minutes, and then the solvent was distilled off to synthesize 1-amino-2-methyl-2-propanol. Dissolved in a solution of tetrahydrofuran (15 mL), added dropwise to a solution of 4-{[1- (trifluoroacetyl) piperidin-4-yl] methyl} benzenesulfonyl chloride (720 mg, 1.95 mmol) in tetrahydrofuran (15 mL), and triethylamine (1.40 mL, 9.75 mmol) was added. After stirring for 2 hours, water was added to the reaction solution, extracted with ethyl acetate, and the extract was washed with saturated saline. After drying over anhydrous magnesium sulfate, the residue was purified by column chromatography (ethyl acetate / hexane = 3/1) to give the title compound (739 mg, 90%) as a colorless oil.
¹ H NMR (CDCl ₃ ) δ 1.18-1.34 (2H, m), 1.25 (6H, s), 1.70-1.95 (3H, m), 2.64-2.77 (1H, m), 2.65 (2H, d, J = 7.2Hz), 2.90 (2H, d, J = 6.6Hz), 3.01-3.12 (1H, m), 3.95-4.06 (1H, m), 4.50-4.59 (1H, m), 4.79 (1H, t, J = 6.6Hz), 7.26-7.33 (2H, m), 7.77-7.82 (2H, m).
Reference Example 40-2
N- (2-hydroxy-2,2-dimethylethyl) -4- (piperidin-4-ylmethyl) benzenesulfonylamide Using the compound obtained in Reference Example 40-1, Reference Example 24-2 The title compound was synthesized as described above. 90% yield.
¹ H NMR (CDCl ₃ ) δ1.09-1.25 (2H, m), 1.24 (6H, s), 1.55-1.74 (3H, m), 2.49-2.62 (2H, m), 2.60 (2H, d, J = 6.9Hz), 2.89 (2H, s), 3.00-3.09 (2H, m), 7.26-7.32 (2H, m), 7.74-7.79 (2H, m).

Reference Example 41-1
1-[(4-{[1- (trifluoroacetyl) piperidin-4-yl] methyl} phenyl) sulfonyl] piperidin-4-one Reference Example 24-1 using piperidin-4-one The title compound was synthesized in the same manner as described above. Yield 88%.
¹ H NMR (CDCl ₃ ) δ1.15-1.39 (2H, m), 1.67-2.00 (3H, m), 2.55 (4H, t, J = 6.2Hz), 2.61-2.80 (3H, m), 2.97- 3.16 (1H, m), 3.40 (4H, t, J = 6.2Hz), 3.92-4.09 (1H, m), 5.46-5.62 (1H, m), 7.29-7.38 (2H, m), 7.69-7.78 ( 2H, m).
Reference Example 41-2
1-[(4-{[1- (trifluoroacetyl) piperidin-4-yl] methyl} phenyl) sulfonyl] piperidin-4-one O-methyloxime The compound obtained in Reference Example 41-1 O-Methylhydroxylamine hydrochloride (359 mg, 4.29 mmol) and sodium acetate (352 mg, 4.29 mmol) were added to a 2-propanol solution (10 mL) of (317 mg, 0.859 mmol), and the mixture was stirred for 2.5 days. After the solvent was distilled off, ethyl acetate was added to the residue, and the mixture was washed with saturated sodium hydrogen carbonate and saturated saline. After drying over anhydrous magnesium sulfate and evaporation under reduced pressure, the residue was purified by column chromatography (ethyl acetate / hexane = 1/2) to give the title compound (313 mg, 79%) as colorless powdery crystals.
¹ H NMR (CDCl ₃ ) δ1.14-1.39 (2H, m), 1.67-1.98 (3H, m), 2.43 (2H, dd, J = 6.4, 5.4Hz), 2.60-2.80 (5H, m), 2.98-3.24 (5H, m), 3.78 (3H, s), 3.93-4.09 (1H, m), 4.47-4.61 (1H, m), 7.26-7.34 (2H, m), 7.65-7.73 (2H, m ).
Reference Example 41-3
1-{[4- (piperidin-4-ylmethyl) phenyl] sulfonyl} piperidin-4-one O-methyloxime Using the compound obtained in Reference Example 41-2, Reference Example 24-2 The title compound was synthesized in the same manner. Yield 100%.
¹ H NMR (CDCl ₃ ) δ 1.10-1.26 (2H, m), 1.53-1.75 (3H, m), 2.42 (2H, t, J = 6.0Hz), 2.49-2.62 (4H, m), 2.67 ( 2H, t, J = 6.0Hz), 3.01-3.11 (2H, m), 3.13 (2H, t, J = 6.0Hz), 3.19 (2H, t, J = 6.0Hz), 3.78 (3H, s), 7.26-7.32 (2H, m), 7.64-7.69 (2H, m).

Reference Example 42-1
Methyl 4 '-(pyridin-4-ylmethyl) -1,1'-biphenyl-4-carboxylate (4-methoxycarbonylphenyl) boronic acid (1188 mg, 6.60 mmol) under an argon stream, potassium fluoride (1394 mg, 24.0 mmol), a mixture of tris (dibenzylideneacetone) dipalladium (549 mg, 0.60 mmol), 4- (4-chlorobenzyl) pyridine (1222 mg, 6.00 mmol) dioxane (18 mL) solution and tert-butyl A solution of phosphine (364 mg, 1.80 mmol) in dioxane (6 mL) was added, and the mixture was stirred at 100 ° C. for 24 hours. After the reaction mixture was concentrated under reduced pressure, the residue was subjected to column chromatography (NH silica gel 100 g, hexane / ethyl acetate = 9/1 → 4/1). After the target fraction was concentrated under reduced pressure, diisopropyl ether was added to the residue, and the precipitate was collected by filtration and dried under reduced pressure to give the title compound (947 mg, 3.12 mmol, yield 52%) as a white solid.
_{^{1 H NMR (CDCl 3) δ}} 3.94 (3H, s), 4.03 (2H, s), 7.16 (2H, d, J = 5.8Hz), 7.28 (2H, d, J = 8.3Hz), 7.59 (2H, d, J = 8.3Hz), 7.65 (2H, d, J = 8.4Hz), 8.10 (2H, d, J = 8.4Hz), 8.53 (2H, d, J = 5.8Hz).
Reference Example 42-2
Methyl 4 '-(piperidin-4-ylmethyl) -1,1'-biphenyl-4-carboxylate Platinum oxide (96 mg) in a solution of the compound obtained in Reference Example 42-1 (1002 mg, 3.30 mmol) in acetic acid (11 mL) ) Was added and the mixture was stirred at room temperature for 6 hours under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Aqueous sodium bicarbonate was added to the residue, and the mixture was extracted with dichloromethane (three times). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Diisopropyl ether was added to the residue, and the precipitate was collected by filtration and dried under reduced pressure to give the title compound (850 mg, 2.75 mmol, yield 83%) as a white solid.
¹ H NMR (CDCl ₃ ) δ 1.05-1.35 (2H, m), 1.55-1.8 (3H, m), 2.45-2.65 (4H, m), 2.95-3.15 (2H, m), 3.94 (3H, s) , 7.24 (2H, d, J = 8.4Hz), 7.55 (2H, d, J = 8.4Hz), 7.65 (2H, d, J = 8.8Hz), 8.09 (2H, d, J = 8.8Hz).

Reference Example 43-1
4-[(4-{[1- (trifluoroacetyl) piperidin-4-yl] methyl} phenyl) sulfonyl] morpholine Using morpholine, the title compound is synthesized in the same manner as in Reference Example 24-1. did. Yield 91%.
¹ H NMR (CDCl ₃ ) δ 1.17-1.38 (2H, m), 1.73-1.94 (3H, m), 2.66 (2H, d, J = 7.0Hz), 2.68-2.78 (1H, m), 3.00 (4H , t, J = 4.8Hz), 3.01-3.15 (1H, m), 3.76 (4H, t, J = 4.8Hz), 3.98-4.10 (1H, m), 4.53-4.60 (1H, m), 7.33 ( 2H, d, J = 8.4Hz), 7.69 (2H, d, J = 8.4Hz).
Reference Example 43-2
4-{[4- (piperidin-4-ylmethyl) phenyl] sulfonyl} morpholine The title compound was synthesized in the same manner as in Reference Example 24-2, using the compound obtained in Reference Example 43-1. . Yield 100%.
¹ H NMR (CDCl ₃ ) δ 1.21-1.82 (5H, m), 2.60-2.71 (4H, m), 3.00 (4H, t, J = 4.8 Hz), 3.19-3.26 (2H, m), 3.75 (4H , t, J = 4.8Hz), 5.08 (1H, br s), 7.32 (2H, d, J = 8.4Hz), 7.67 (2H, d, J = 8.4Hz).

Reference Example 44-1
1-benzyl-4- (4-bromobenzylidene) piperidine
The title compound was synthesized in the same manner as in Reference Example 23-1 using 4-bromobenzyl bromide and N-benzylpiperidin-4-one. 97% yield.
¹ H NMR (CDCl ₃ ) δ 2.35-2.57 (8H, m), 3.52 (2H, s), 6.18 (1H, br s), 7.00-7.08 (2H, m), 7.20-7.45 (7H, m) .
Reference Example 44-2
(2E) -3- {4-[(1-benzylpiperidine-4-ylidene) methyl] phenyl} -2-propenamide The compound obtained in Reference Example 44-1 (1.64 g, 4.80 mmol) And acrylamide (718 mg, 9.60 mmol), palladium acetate (108 mg, 0.480 mmol), tri (2-methylphenyl) phosphine (292 mg, 0.960 mmol) and triethylamine (1.34 mL, 9.60 mmol) in a mixture of acetonitrile (30 mL). Stirred at 8 ° C. for 8 hours. The solvent was distilled off under reduced pressure, and the residue was washed with ethyl acetate to obtain the title compound (773 mg, 49%) as a solid.
¹ H NMR (CDCl ₃ ) δ2.36-2.62 (8H, m), 3.53 (2H, s), 5.38-5.58 (2H, m), 6.25 (1H, br s), 6.42 (1H, d, J = 15.6Hz), 7.17-7.38 (7H, m), 7.42-7.50 (2H, m), 7.62 (1H, d, J = 15.6Hz).
Reference Example 44-3
3- [4- (piperidin-4-ylmethyl) phenyl] propanamide 20% water was added to a solution of the compound (647 mg, 1.95 mmol) obtained in Reference Example 44-2 in tetrahydrofuran / methanol (10 mL / 10 mL). Palladium oxide carbon (about 3 mg) was added and the mixture was stirred under a hydrogen stream for 15 hours. The insolubles were filtered through celite and washed with ether. The residue obtained by evaporating the filtrate under reduced pressure was purified by column chromatography (ethyl acetate / methanol = 20/1 → 5/1) to obtain the title compound (451 mg, 94%) as a colorless solid.
¹ H NMR (CDCl ₃ ) δ1.05-1.22 (2H, m), 1.42-1.69 (3H, m), 2.45-2.58 (6H, m), 2.94 (2H, t, J = 8.1Hz), 5.25- 5.50 (2H, m), 7.02-7.14 (4H, m).

Reference Example 45-1
3- {4-[(1-benzylpiperidin-4-ylidene) methyl] phenyl} pyridine The compound (939 mg, 2.75 mmol) obtained in Reference Example 44-1 and diethyl (3-pyridyl) borane ( A mixture of 484 mg (3.29 mmol), tetrakistriphenylphosphine palladium (318 mg, 0.275 mmol) and potassium carbonate (607 mg, 4.40 mmol) in tetrahydrofuran / water (25 mL / 25 mL) was heated under reflux for 18 hours. After cooling to room temperature, the mixture was extracted with dichloromethane, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure.The residue was purified by column chromatography (ethyl acetate / hexane = 1/5) to give the title compound (798 mg, 85%) as a colorless powder Obtained as crystals.
¹ H NMR (CDCl ₃ ) δ2.38-2.61 (8H, m), 3.54 (2H, s), 6.31 (1H, br s), 7.23-7.39 (8H, m), 7.50-7.57 (2H, m) , 7.87 (1H, ddd, J = 8.1, 2.4, 1.8Hz), 8.57 (1H, dd, J = 5.1, 1.8Hz), 8.83-8.87 (1H, m).
Reference Example 45-2
3- [4- (Piperidin-4-ylmethyl) phenyl] pyridine Using the compound obtained in Reference Example 45-1, the title compound was synthesized in the same manner as in Reference Example 44-3. 79% yield.
¹ H NMR (CDCl ₃ ) δ 1.10-1.27 (2H, m), 1.58-1.74 (3H, m), 2.50-2.61 (4H, m), 3.00-3.10 (2H, m), 7.22-7.28 (2H , m), 7.34 (1H, ddd, J = 8.1, 4.8, 0.9Hz), 7.46-7.52 (2H, m), 7.85 (1H, ddd, 8.1, 2.4, 1.8Hz), 8.56 (1H, dd, J = 4.8, 1.8Hz), 8.83 (1H, dd, J = 2.4, 0.9Hz).

Reference Example 46-1
(2E) -3- {4-[(1-benzylpiperidin-4-ylidene) methyl] phenyl} -2-propenoate ethyl As in reference example 44-2 using ethyl acrylate. The title compound was synthesized. 86% yield.
¹ H NMR (CDCl ₃ ) δ1.34 (3H, t, J = 7.2Hz), 2.35-2.59 (8H, m), 3.53 (2H, s), 4.26 (2H, q, J = 7.2Hz), 6.26 (1H, br s), 6.39 (1H, d, J = 16.0Hz), 7.17-7.37 (7H, m), 7.41-7.50 (2H, m), 7.66 (1H, d, J = 16.0Hz).
Reference Example 46-2
Ethyl 3- [4- (piperidin-4-ylmethyl) phenyl] propanoate The title compound is synthesized in the same manner as in Reference Example 44-3 using the compound obtained in Reference Example 46-1 and ethanol. did. Yield 87%.
¹ H NMR (CDCl ₃ ) δ1.01-1.28 (2H, m), 1.23 (3H, t, J = 7.4 Hz), 1.48-1.69 (3H, m), 2.44-2.65 (6H, m), 2.92 ( 2H, t, J = 8.2Hz), 2.97-3.09 (2H, m), 4.13 (2H, q, J = 7.4Hz), 7.02-7.15 (4H, m).

Reference Example 47-1
2- {4-[(1-benzylpiperidine-4-ylidene) methyl] phenyl} pyridine The compound obtained in Reference Example 44-1 (929 mg, 2.72 mmol) and 2-tributylstannylpyridine (1.00 g, 2.72 mmol) and a suspension of tetrakistriphenylphosphinepalladium (157 mg, 0.136 mmol) in tetrahydrofuran (15 mL) were heated under reflux for 22 hours. After cooling to room temperature, the mixture was diluted with ether and washed with 10% aqueous ammonia and saturated saline. After drying over anhydrous magnesium sulfate and evaporation under reduced pressure, the residue was purified by column chromatography (ethyl acetate / hexane = 1/10) to give the title compound (316 mg, 34%) as a pale yellow oil.
¹ H NMR (CDCl ₃ ) δ2.38-2.63 (8H, m), 3.55 (2H, s), 6.32 (1H, br s), 7.17-7.37 (8H, m), 7.70-7.76 (2H, m) , 7.90-7.98 (2H, m), 8.65-8.71 (1H, m).
Reference Example 47-2
2- [4- (Piperidin-4-ylmethyl) phenyl] pyridine Using the compound obtained in Reference Example 47-1, the title compound was synthesized in the same manner as in Reference Example 44-3. Yield 88%.
¹ H NMR (CDCl ₃ ) δ1.02-1.30 (2H, m), 1.45-1.77 (3H, m), 2.44-2.64 (4H, m), 2.97-3.12 (2H, m), 7.16-7.31 (3H , m), 7.68-7.76 (2H, m), 7.86-7.96 (2H, m), 8.64-8.71 (1H, m).

Reference Example 48-1
4-oxo-4- (4-{[1- (trifluoroacetyl) piperidin-4-yl] methyl} phenyl) butanoic acid
The title compound was synthesized in the same manner as in Reference Example 16-4 using 4-benzyl-1- (trifluoroacetyl) piperidine and succinic anhydride. 86% yield.
¹ H NMR (CDCl ₃ ) δ1.11-1.38 (2H, m), 1.67-1.96 (3H, m), 2.50-2.86 (1H, m), 2.64 (2H, d, J = 6.6Hz), 2.82 ( 2H, t, J = 6.6Hz), 2.96-3.15 (1H, m), 3.30 (2H, t, J = 6.6Hz), 3.90-4.08 (1H, m), 4.44-4.60 (1H, m), 7.20 -7.30 (2H, m), 7.88-7.98 (2H, m).
Reference Example 48-2
4-oxo-4- (4-{[1- (trifluoroacetyl) piperidin-4-yl] methyl} phenyl) butanamide Using the compound obtained in Reference Example 48-1, Reference Example 31 The title compound was synthesized in the same manner as in -2. 86% yield.
¹ H NMR (CDCl ₃ ) δ1.13-1.39 (2H, m), 1.67-1.99 (3H, m), 2.58-2.89 (5H, m), 2.96-3.12 (1H, m), 3.36 (2H, t , J = 6.6Hz), 3.90-4.07 (1H, m), 4.46-4.60 (1H, m), 5.30-5.90 (2H, m), 7.20-7.28 (2H, m), 7.88-7.97 (2H, m ).
Reference Example 48-3
4-oxo-4- [4- (piperidin-4-ylmethyl) phenyl] butanamide Using the compound obtained in Reference Example 48-2, synthesize the title compound in the same manner as in Reference Example 24-2. did. Yield 100%.
¹ H NMR (CDCl ₃ ) δ1.08-1.25 (2H, m), 1.55-1.80 (3H, m), 2.48-2.60 (2H, m), 2.58 (2H, d, J = 6.9Hz), 2.66 ( 2H, t, J = 6.6Hz), 3.00-3.09 (2H, m), 3.35 (2H, t, J = 6.6Hz), 5.35-5.55 (1H, m), 5.70-5.90 (1H, m), 7.20 -7.26 (2H, m), 7.86-7.94 (2H, m).

Reference Example 49-1
4 '-[(1-Benzylpiperidin-4-ylidene) methyl] -1,1'-biphenyl-3-carboxylate 1-benzyl-4- (4-bromobenzylidene) piperidine (2054 mg, 6.00 mmol), (3-methoxycarbonylphenyl) boronic acid (1296 mg, 7.20 mmol), sodium carbonate (1272 mg, 12.0 mmol), tetrakis (triphenylphosphine) palladium (693 mg, 0.60 mmol), dimethoxyethane (24 mL), distilled water (12 mL) was stirred at 80 ° C. for 12 hours. Ethyl acetate (120 mL) was added to the reaction mixture, and insolubles were filtered off. The filtrate was washed with water (40 mL) and saturated saline (40 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 100 g, hexane / ethyl acetate = 4/1 → 2/1), and further purified by column chromatography (NH silica gel 100 g, hexane / ethyl acetate = 19/1 → 9/1). Repurification gave the title compound (2.07 g, 5.21 mmol, 87% yield) as a pale yellow oil.
¹ H NMR (CDCl ₃ ) δ 2.4-2.65 (8H, m), 3.54 (2H, s), 3.94 (3H, s), 6.30 (1H, s), 7.2-7.4 (5H, m), 7.29 (2H , d, J = 8.2Hz), 7.50 (1H, t, J = 7.7Hz), 7.57 (2H, d, J = 8.2Hz), 7.78 (1H, m), 8.00 (1H, m), 8.28 (1H , m).
Reference Example 49-2
4 '-(piperidin-4-ylmethyl) -1,1'-biphenyl-3-carboxylate Methanol (10 mL) of compound (2.00 g, 5.03 mmol) obtained in Reference Example 49-1-tetrahydrofuran (10 mL) To the solution was added 20% palladium hydroxide (0.80 g), and the mixture was stirred at 50 ° C for 14 hours under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (1.50 g, 4.84 mmol, yield 96%) as a pale-yellow oil.
¹ H NMR (CDCl ₃ ) δ 1.1-1.4 (2H, m), 1.55-1.8 (3H, m), 2.45-2.7 (4H, m), 3.0-3.2 (2H, m), 3.94 (3H, s) , 7.22 (2H, d, J = 8.2Hz), 7.49 (1H, t, J = 7.7Hz), 7.54 (2H, d, J = 8.2Hz), 7.77 (1H, m), 8.00 (1H, m) , 8.27 (1H, m).

Reference Example 50-1
tertbutyl 4- [4- (benzyloxy) benzylidene] piperidine-1-carboxylate
The title compound was synthesized in the same manner as in Reference Example 23-1 using 4-benzyloxybenzyl chloride. Yield 64%.
¹ H NMR (CDCl ₃ ) δ1.47 (9H, s), 2.26-2.35 (2H, m), 2.40-2.49 (2H, m), 3.34-3.53 (4H, m), 5.05 (2H, s), 6.28 (1H, br s), 6.89-6.95 (2H, m), 7.08-7.14 (2H, m), 7.28-7.45 (5H, m).
Reference Example 50-2
tertbutyl 4- (4-hydroxybenzyl) piperidine-1-carboxylate The title compound was synthesized in the same manner as in Reference Example 21-1, using the compound obtained in Reference Example 50-1. Yield 100%.
¹ H NMR (CDCl ₃ ) δ1.02-1.19 (2H, m), 1.45 (9H, s), 1.51-1.67 (3H, m), 2.45 (2H, d, J = 6.6Hz), 2.52-2.72 ( 2H, m), 3.93-4.20 (2H, m), 4.32-4.56 (1H, m), 6.72-6.78 (2H, m), 6.94-7.00 (2H, m).
Reference Example 50-3
tertbutyl 4- [4- (2-amino-2-oxoethoxy) benzyl] piperidine-1-carboxylate The compound (978 mg, 3.36 mmol) obtained in Reference Example 50-2 and 1-bromoacetamide (510 mg, 3.70 mmol) and a suspension of cesium carbonate (1.31 g, 4.03 mmol) in N, N-dimethylacetamide (7 mL) were stirred at 100 ° C. for 18 hours. Add water, extract three times with dichloromethane, evaporate the extract under reduced pressure, and purify the residue by column chromatography (ethyl acetate / hexane = 1/1 → 1/0) to give the title compound (483 mg, 41%) as colorless Obtained as a solid.
¹ H NMR (CDCl ₃ ) δ1.03-1.21 (2H, m), 1.45 (9H, s), 1.54-1.70 (3H, m), 2.49 (2H, d, J = 6.9Hz), 2.54-2.71 ( 2H, m), 3.98-4.16 (2H, m), 4.47 (2H, s), 5.55-5.83 (1H, m), 6.46-6.66 (1H, m), 6.81-6.87 (2H, m), 7.04- 7.11 (2H, m).
Reference Example 50-4
2- [4- (piperidin-4-ylmethyl) phenoxy] acetamidotrifluoroacetate The title compound is synthesized in the same manner as in Reference Example 20-2 using the compound obtained in Reference Example 50-3. did. Yield 100%.
¹ H NMR (DMSO) δ1.12-1.40 (2H, m), 1.59-1.86 (3H, m), 2.42-2.54 (2H, m), 2.76-2.91 (2H, m), 3.15-3.31 (2H, m), 4.38 (2H, s), 6.83-6.92 (2H, m), 7.05-7.15 (2H, m), 7.35-7.59 (2H, m).

Reference Example 51
1-acetyl-4-[(4-{[1- (trifluoroacetyl) piperidin-4-yl] methyl} phenyl) sulfonyl] piperazine
The title compound was synthesized in the same manner as in Reference Example 24-1 using N-acetylpiperazine. Yield 87%.
¹ H NMR (CDCl ₃ ) δ1.17-1.40 (2H, m), 1.65-1.95 (3H, m), 2.04 (3H, s), 2.65 (2H, d, J = 6.2Hz), 2.70-2.82 ( 1H, m), 2.93-3.17 (5H, m), 3.56 (2H, t, J = 5.0Hz), 3.71 (2H, t, J = 5.0Hz), 3.95-4.08 (1H, m), 4.50-4.64 (1H, m), 7.32 (2H, d, J = 8.5Hz), 7.67 (2H, d, J = 8.5Hz).

Reference Example 52-1
tertbutyl 4- [4- (2-hydroxyethoxy) benzyl] piperidine-1-carboxylate The compound obtained in Reference Example 50-2 (1.02 g, 3.51 mmol) and 2-iodoethanol (0.327 mL) , 4.21 mmol) and 60% sodium hydride (211 mg, 5.27 mmol) in N, N-dimethylacetamide (20 mL) was stirred at 100 ° C. for 26 hours. After evaporating the solvent, water and ethyl acetate were added, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / hexane = 1/3 → 3/1) to obtain the title compound (867 mg, 74%) as a colorless oil.
¹ H NMR (CDCl ₃ ) δ1.02-1.20 (2H, m), 1.45 (9H, s), 1.52-1.67 (3H, m), 2.04 (1H, t, J = 6.0Hz), 2.48 (2H, d, J = 6.6Hz), 2.54-2.70 (2H, s), 3.92-3.98 (2H, m), 4.03-4.09 (4H, m), 6.81-6.87 (2H, m), 7.02-7.07 (2H, m).
Reference Example 52-2
2- [4- (Piperidin-4-ylmethyl) phenoxy] ethanol hydrochloride The title compound was synthesized in the same manner as in Reference Example 1-4, using the compound obtained in Reference Example 52-1. Yield 100%.
¹ H NMR (CD ₃ OD) δ1.32-1.49 (2H, m), 1.75-1.91 (3H, m), 2.54 (2H, d, J = 6.9Hz), 2.84-2.99 (2H, m), 3.29 -3.40 (2H, m), 3.82-3.87 (2H, m), 3.97-4.02 (2H, m), 6.84-6.90 (2H, m), 7.05-7.11 (2H, m).

Reference Example 53-1
3-hydroxy-1- (4-{[1- (trifluoroacetyl) piperidin-4-yl] methyl} phenyl) -1-propanone O-ethyloxime
Using 4-benzyl-1- (trifluoroacetyl) piperidine and propiolactone, the title compound was synthesized together with difficult-to-separate impurities in the same manner as in Reference Example 16-4. Using the above compound and O-ethylhydroxylamine hydrochloride, the title compound was synthesized in the same manner as in Reference Example 41-2. Yield 7%.
¹ H NMR (CDCl ₃ ) δ1.12-1.38 (2H, m), 1.33 (3H, t, J = 7.0Hz), 1.55-2.03 (3H, m), 2.58 (2H, d, J = 7.0Hz) , 2.60-2.79 (1H, m), 2.92-3.11 (1H, m), 3.07 (2H, t, J = 6.2Hz), 3.82-4.06 (3H, m), 4.26 (2H, q, J = 7.0Hz ), 4.44-4.60 (1H, m), 7.11-7.20 (2H, m), 7.57-7.65 (2H, m).
Reference Example 53-2
3-Hydroxy-1- [4- (piperidin-4-ylmethyl) phenyl] -1-propanone O-ethyloxime Using the compound obtained in Reference Example 53-2, Reference Example 24-2 was used. The title compound was synthesized in the same manner.
¹ H NMR (CDCl ₃ ) δ 1.10-1.30 (2H, m), 1.33 (3H, t, J = 7.4Hz), 1.50-1.86 (3H, m), 2.43-2.60 (4H, m), 3.96- 3.10 (2H, m), 3.07 (2H, t, J = 6.6Hz), 3.87 (2H, t, J = 6.6Hz), 4.24 (2H, q, J = 7.4Hz), 7.10-7.20 (2H, m ), 7.53-7.62 (2H, m).

Reference Example 54-1
2-[(4-{[1- (trifluoroacetyl) piperidin-4-yl] methyl} phenyl) sulfanyl] ethanol was added to a mixture of concentrated sulfuric acid (7 mL) and distilled water (35 mL) under ice-cooling and stirring. {[1- (Trifluoroacetyl) piperidin-4-yl] methyl} benzenesulfonyl chloride (3.70 g, 10.0 mmol) in dichloromethane (10 mL) solution and zinc powder (6.54 g) are added in this order, and the mixture is added at 60 ° C. for 6 hours. Stirred. The insoluble material was separated by filtration and washed with dichloromethane. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (twice). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain crude 4-{[1- (trifluoroacetyl) piperidin-4-yl] methyl} benzenethiol (3.17 g) as a colorless oil. To a solution of the obtained oil (3.17 g) in acetonitrile (20 mL) under ice-cooling and stirring, 2-iodoethanol (0.936 mL, 12.0 mmol) and triethylamine (2.79 mL, 20.0 mmol) were sequentially added, and the mixture was added at room temperature for 1 hour. Stirred. The reaction mixture was concentrated under reduced pressure, ethyl acetate (80 mL) was added, and the mixture was washed with water (20 mL), 1N hydrochloric acid (20 mL × 2), and saturated saline (20 mL). The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane / ethyl acetate = 4/1 → 2/3) to give the title compound (2.56 g, 7.37 mmol, yield 74%) as a colorless oil Obtained as a product.
¹ H NMR (CDCl ₃ ) δ 1.1-1.35 (2H, m), 1.65-1.95 (3H, m), 2.05 (1H, t, J = 6.2Hz), 2.54 (2H, d, J = 7.0Hz), 2.6-2.8 (1H, m), 2.95-3.15 (1H, m), 3.10 (2H, t, J = 5.8Hz), 3.73 (2H, dt, J = 6.2, 5.8Hz), 3.9-4.1 (1H, m m), 4.45-4.6 (1H, m), 7.07 (2H, d, J = 8.2Hz), 7.34 (2H, d, J = 8.2Hz).
Reference Example 54-2
2-{[4- (piperidin-4-ylmethyl) phenyl] sulfanyl} ethanol Potassium carbonate (3.01 g, 21.8 mmol) was added to a methanol solution (30 mL) of the compound (2.52 g, 7.25 mmol) obtained in Reference Example 54-1. ) Was added and stirred at room temperature for 8 hours. The reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate (three times). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound (1.88 g) as a white solid.
¹ H NMR (CDCl ₃ ) δ 1.0-1.3 (2H, m), 1.5-1.75 (3H, m), 2.4-2.65 (4H, m), 2.95-3.15 (2H, m), 3.08 (2H, t, J = 6.1Hz), 3.72 (2H, t, J = 6.1Hz), 7.07 (2H, d, J = 8.2Hz), 7.32 (2H, d, J = 8.2Hz).
Reference Example 55
Methyl 4- (piperidin-4 -ylmethyl) benzoate 4- (piperidin-4-ylmethyl) benzamide (2.18 g, 10.0 mmol), methanol (20 mL), and a mixture of concentrated sulfuric acid (1.1 mL) is heated under reflux for 20 hours. Stirred. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate (100 mL) was added, and the mixture was extracted with dichloromethane (40 mL, 20 mL × 4). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (2.28 g, 9.8 mmol, 98%) as a colorless oil.
¹ H NMR (CDCl ₃ ) δ 1.1-1.35 (2H, m), 1.55-1.8 (3H, m), 2.45-2.7 (4H, m), 2.95-3.2 (2H, m), 3.90 (3H, s) , 7.21 (2H, d, J = 8.5Hz), 7.95 (2H, d, J = 8.5Hz).
Reference Example 56
N- (3-hydroxypropyl) -4-{[1- (trifluoroacetyl) piperidin-4-yl] methyl} benzenesulfonamide
The title compound was synthesized in the same manner as in Reference Example 24-1 using 3-aminopropanol. Yield 81%.
¹ H NMR (CDCl ₃ ) δ 1.18-1.37 (2H, m), 1.62-1.80 (4H, m), 1.80-2.03 (1H, m), 2.65 (2H, d, J = 6.9Hz), 2.70- 2.78 (1H, m), 3.00-3.07 (1H, m), 3.12 (2H, dd, J = 12.3, 6.3Hz), 3.75 (2H, t, J = 5.4Hz), 4.00 (1H, m), 4.53 (1H, m), 5.11 (1H, t, J = 5.7Hz), 7.28 (2H, d, J = 8.1Hz), 7.78 (2H, d, J = 8.1Hz).

Reference Example 57-1
tert-butyl 4- {4-[[2- (benzoyloxy) ethyl] (methylsulfonyl) amino] benzyl} piperidine-1-carboxylate
tert-Butyl 4- [4- (methylsulfonylamino) benzyl] piperidine-1-carboxylate (386 mg, 1.05 mmol) and 2-iodoethyl benzoate (430 mg, 1.56 mmol) were added to N, N-dimethylformamide (8 mL). After dissolution, 60% sodium hydride (62 mg, 1.56 mmol) was added, and the mixture was stirred at 60 ° C. for 2 hours. Water was added to the reaction solution, and extracted three times with ethyl acetate. The combined organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / hexane = 1/2) to obtain the title compound (524 mg, 97%) as a colorless solid.
¹ H NMR (CDCl ₃ ) δ1.05-1.20 (2H, m), 1.45 (9H, s), 1.50-1.68 (3H, m), 2.51 (2H, d, J = 6.9Hz), 2.53-2.68 ( 2H, m), 2.93 (3H, s), 3.95-4.15 (4H, m), 4.40 (2H, t, J = 5.4Hz), 7.14 (2H, d, J = 8.4Hz), 7.24-7.30 (2H , m), 7.42 (2H, t, J = 1.8Hz), 7.52-7.58 (1H, m), 7.90-7.95 (2H, m).
Reference Example 57-2
tert-butyl 4- {4-[(2-hydroxyethyl) (methylsulfonyl) amino] benzyl} piperidine-1-carboxylate Of the compound (634 mg, 1.23 mmol) obtained in Reference Example 57-1 A 1 M sodium hydroxide solution (1.5 mL) was added to a methanol (25 mL) solution, and the mixture was stirred at room temperature for 2 hours. After evaporating the solvent, water and ethyl acetate were added, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate to obtain the title compound (439 mg, 86%).
¹ H NMR (CDCl ₃ ) δ1.02-1.28 (2H, m), 1.45 (9H, s), 1.50-1.80 (3H, m), 2.54 (2H, d, J = 6.8Hz), 2.60-2.73 ( 2H, m), 2.98 (3H, s), 3.68 (2H, q, J = 5.4Hz), 3.82 (2H, t, J = 5.4Hz), 4.00-4.18 (2H, m), 7.18 (2H, d , J = 8.2Hz), 7.29 (2H, d, J = 8.2Hz).

Reference Example 58-1
A mixture of [(4-{[1- (trifluoroacetyl) piperidin-4-yl] methyl} phenyl) sulfanyl] ethyl acetate concentrated sulfuric acid (10 mL) and distilled water (50 mL) was stirred under ice-cooling with 4- { A solution of [1- (trifluoroacetyl) piperidin-4-yl] methyl} benzenesulfonyl chloride (5.55 g, 15.0 mmol) in dichloromethane (15 mL) and zinc powder (9.81 g) are sequentially added, and the mixture is stirred at 60 ° C. for 6 hours. did. The insoluble material was separated by filtration and washed with dichloromethane. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (twice). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain crude 4-{[1- (trifluoroacetyl) piperidin-4-yl] methyl} benzenethiol (4.94 g) as a colorless oil. To a solution of the obtained oil (4.94 g) in acetonitrile (30 mL) was added, in ice, and stirred, ethyl bromoacetate (2.16 mL, 19.5 mmol) and triethylamine (4.18 mL, 30.0 mmol) in that order, and the mixture was stirred at room temperature for 18 hours. did. The reaction mixture was concentrated under reduced pressure, ethyl acetate (40 mL) was added, and the mixture was washed with water (10 mL), 1N hydrochloric acid (10 mL × 2), and saturated saline (10 mL). After concentration of the organic layer under reduced pressure, the residue was purified by column chromatography (150 g of NH silica gel, hexane / ethyl acetate = 1/0 → 9/1) to give the title compound (2.98 g, 7.65 mmol, yield 51%). Obtained as a colorless oil.
¹ H NMR (CDCl ₃ ) δ 1.1-1.35 (2H, m), 1.23 (3H, t, J = 7.2Hz), 1.65-1.95 (3H, m), 2.54 (2H, d, J = 7.0Hz), 2.6-2.8 (1H, m), 2.95-3.15 (1H, m), 3.61 (2H, s), 3.9-4.1 (1H, m), 4.17 (2H, q, J = 7.2Hz), 4.45-4.6 ( 1H, m), 7.07 (2H, d, J = 8.1Hz), 7.35 (2H, d, J = 8.1Hz).
Reference Example 58-2
Ethyl {[4- (piperidin-4-ylmethyl) phenyl] sulfanyl} acetate To a solution of the compound (1.56 g, 4.0 mmol) obtained in Reference Example 58-1 in ethanol (10 mL) -tetrahydrofuran (10 mL) Under ice cooling and stirring, sodium borohydride (303 mg, 8.0 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was added dropwise to 1N hydrochloric acid (16 mL) under ice-cooling and stirring. The obtained mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate (40 mL) was added, and the mixture was extracted with dichloromethane (30 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound (1.25 g) as a colorless oil.
¹ H NMR (CDCl ₃ ) δ 1.0-1.3 (2H, m), 1.22 (3H, t, J = 7.2Hz), 1.45-1.7 (3H, m), 2.4-2.65 (2H, m), 2.49 (2H , d, J = 6.6Hz), 2.95-3.15 (2H, m), 3.60 (2H, s), 4.16 (2H, q, J = 7.2Hz), 7.08 (2H, d, J = 8.4Hz), 7.34 (2H, d, J = 8.4Hz).
Reference Example 59
tert-butyl 4- {4-[(ethoxycarbonyl) amino] benzyl} piperidine-1-carboxylate
tert-Butyl 4- (4-aminobenzyl) piperidine-1-carboxylate (500 mg, 1.72 mmol) and triethylamine (209 mg, 2.06 mmol) were dissolved in tetrahydrofuran (10 mL), and ethyl chloroformate (206 mg, 1.89 mmol) was added and stirred for 1 hour. Water was added to the reaction solution, and extracted three times with ethyl acetate. The combined organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / hexane = 1/3) to obtain the title compound (598 mg, 96%) as a colorless oil.
¹ H NMR (CDCl ₃ ) δ1.00-1.25 (2H, m), 1.30 (3H, t, J = 7.2Hz), 1.45 (9H, s), 1.50-1.68 (3H, m), 2.48 (2H, d, J = 7.0Hz), 2.62 (2H, t, J = 12.4Hz), 3.95-4.18 (2H, m), 4.22 (2H, q, J = 7.2Hz), 6.54 (1H, brs), 7.06 ( 2H, d, J = 8.6Hz), 7.29 (2H, d, J = 8.6Hz).
Reference Example 60
tert-butyl 4- {4-[(methoxycarbonyl) amino] benzyl} piperidine-1-carboxylate The title compound was synthesized in the same manner as in Reference Example 59 using methyl chloroformate. Yield 84%.
¹ H NMR (CDCl ₃ ) δ1.00-1.23 (2H, m), 1.45 (9H, s), 1.50-1.67 (3H, m), 2.50 (2H, d, J = 7.0Hz), 2.62 (2H, t, J = 11.6Hz), 3.77 (3H, s), 3.95-4.14 (2H, m), 6.61 (1H, brs), 7.07 (2H, d, J = 8.8Hz), 7.29 (2H, d, J = 8.8Hz).
Reference Example 61
tert-butyl 4- (4-{[(ethylamino) carbonyl] amino} benzyl) piperidine-1-carboxylate
Tert-butyl 4- (4-aminobenzyl) piperidine-1-carboxylate (1.00 g, 2.44 mmol) was dissolved in dichloromethane (10 mL), and ethyl isocyanate (294 mg, 3.13 mmol) was added, followed by stirring for 8 hours. Water was added to the reaction solution, and extracted three times with ethyl acetate. The combined organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate / ethyl ether / hexane to obtain the title compound (1.154 g, 93%).
_{^{1 H NMR (CDCl 3) δ1.00-1.27}} (2H, m), 1.14 (3H, t, J = 7.4Hz), 1.45 (9H, s), 1.50-1.68 (3H, m), 2.49 (2H, d, J = 6.2Hz), 2.63 (2H, t, J = 12.0Hz), 3.28 (2H, q, J = 7.4Hz), 3.97-4.14 (2H, m), 4.80 (1H, br), 6.45 ( 1H, br), 7.06 (2H, d, J = 7.6Hz), 7.20 (2H, d, J = 7.6Hz).

Reference Example 62
The title compound was synthesized in the same manner as in Reference Example 61 using tert-butyl 4- (4-{[(methylamino) carbonyl] amino} benzyl) piperidine-1-carboxylate methyl isocyanate. Yield 91%.
¹ H NMR (CDCl ₃ ) δ1.00-1.28 (2H, m), 1.45 (9H, s), 1.50-1.70 (3H, m), 2.49 (2H, d, J = 6.2Hz), 2.63 (2H, t, J = 12.0Hz), 2.82 (3H, s), 3.97-4.15 (2H, m), 4.92 (1H, br), 6.60 (1H, br), 7.06 (2H, d, J = 8.0Hz), 7.20 (2H, d, J = 8.0Hz).
Reference Example 63
tert-butyl 4- {4-[(aminocarbonyl) amino] benzyl} piperidine-1-carboxylate
Tert-butyl 4- (4-aminobenzyl) piperidine-1-carboxylate (820 mg, 2.82 mmol) and triethylamine (592 μl, 4.24 mmol) were dissolved in tetrahydrofuran (10 mL), and trimethylsilyl isocyanate (573 μl, 4.24 mmol) was added. In addition, the mixture was heated under reflux for 8 hours. A saturated aqueous sodium hydrogen carbonate solution (50 mL) was added to the reaction solution, and the mixture was stirred for 1 day. The reaction solution was extracted twice with ethyl acetate, and the combined organic layers were dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate), and recrystallized from ethyl acetate / ethyl ether / hexane to give the title compound (376 mg, 40%) as a colorless oil.
¹ H NMR (CDCl ₃ ) δ1.00-1.22 (2H, m), 1.45 (9H, s), 1.50-1.68 (3H, m), 2.47 (2H, d, J = 6.2Hz), 2.62 (2H, d, J = 12.0Hz), 3.95-4.15 (2H, m), 5.03 (2H, br), 7.02 (2H, d, J = 8.2Hz), 7.23 (2H, d, J = 8.2Hz) 7.53 (1H , br).
Reference Example 64
tert-butyl 4- (4-{[(methoxyamino) carbonyl] amino} benzyl) piperidine-1-carboxylate
tert-Butyl 4- (4-aminobenzyl) piperidine-1-carboxylate (500 mg, 1.72 mmol) was dissolved in N, N-dimethylformamide (6 mL) and N, N'-carbonyldiimidazole (558 mg) under ice cooling. , 3.44 mmol) and then triethylamine (209 mg, 2.06 mmol) and stirred for 30 minutes. O-Methylhydroxylamine hydrochloride (431 mg, 5.16 mmol) and then triethylamine (1.04 g, 10.3 mmol) were added to the reaction solution at room temperature, and the mixture was stirred overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / hexane = 1/1) and recrystallized from ethyl acetate / ethyl ether / hexane to obtain the title compound (551 mg, 88%). .
¹ H NMR (CDCl ₃ ) δ1.00-1.27 (2H, m), 1.45 (9H, s), 1.53-1.67 (3H, m), 2.50 (2H, d, J = 7.0Hz), 2.62 (2H, t, J = 11.8Hz), 3.80 (3H, s), 3.97-4.15 (2H, m), 7.09 (2H, d, J = 8.0Hz), 7.15 (1H, brs), 7.39 (2H, d, J = 8.0Hz), 7.50 (1H, brs).
Reference Example 65
tert-butyl 4- (4-{[(ethoxyamino) carbonyl] amino} benzyl) piperidine-1-carboxylate
The title compound was synthesized in the same manner as in Reference Example 64 using O-ethylhydroxylamine hydrochloride. 94% yield.
¹ H NMR (CDCl ₃ ) δ1.00-1.25 (2H, m), 1.33 (3H, t, J = 7.2Hz), 1.45 (9H, s), 1.50-1.83 (3H, m), 2.50 (2H, m d, J = 6.4Hz), 2.63 (2H, t, J = 12.4Hz), 3.98 (2H, q, J = 7.2Hz), 3.95-4.18 (2H, m), 7.10 (2H, d, J = 8.4 Hz), 7.11 (1H, brs), 7.38 (2H, d, J = 8.4Hz), 7.52 (1H, brs).

Reference Example 66
tert-butyl 4- (4-{[(isobutoxyamino) carbonyl] amino} benzyl) piperidine-1-carboxylate
The title compound was synthesized in the same manner as in Reference Example 64 using O-isobutylhydroxylamine hydrochloride.
_{^{1 H NMR (CDCl 3) δ0.95}} (6H, d, J = 7.0Hz), 1.06-1.25 (2H, m), 1.45 (9H, s), 1.50-1.73 (3H, m), 1.90-2.10 ( 1H, m), 2.50 (2H, d, J = 6.8Hz), 2.63 (2H, t, J = 12.8Hz), 3.65 (2H, d, J = 7.0Hz), 3.98-4.15 (2H, m), 7.09 (2H, d, J = 8.6Hz), 7.38 (2H, d, J = 8.6Hz), 7.54 (1H, brs), 7.67 (1H, brs).
Reference Example 67
4- [4- (4-morpholinyl) benzyl] piperidine hydrochloride
Dissolve tert-butyl 4- (4-aminobenzyl) piperidine-1-carboxylate (1 g, 3.45 mmol) in 1-butanol (20 mL), bis (2-chloroethyl) ether (490 mg, 3.45 mmol) and potassium carbonate (1 g, 7.23 mmol) was added and the mixture was heated under reflux for 30 hours. After cooling, the reaction solution was poured into water (50 mL) and extracted with ethyl acetate. The extract was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (hexane / ethyl acetate = 3/1) to give tert-butyl 4- [4- (4-morpholinyl) benzyl] piperidine-1. -Carboxylate (869 mg) was obtained as a colorless oil.
This compound (859 mg, 2.39 mmol) was dissolved in ethyl acetate (10 mL), 4N-ethyl acetate solution of hydrogen chloride (5 mL) was added thereto, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure to obtain the title compound (562 mg) as a colorless powder.
¹ H NMR (DMSO-d ₆ ) δ 1.36-1.88 (5H, m), 2.52-2.80 (4H, m), 3.17-3.22 (2H, m), 3.42 (4H, m), 4.00 (4H, m) , 7.25-7.30 (2H, m), 7.53-7.60 (2H, m), 8.89 (1H, m), 9.12 (1H, m)
Reference Example 68
tert-butyl 4- [4- (dimethylamino) benzyl] piperidine-1-carboxylate
tert-Butyl 4- (4-aminobenzyl) piperidine-1-carboxylate (510 mg, 1.76 mmol) was dissolved in dichloroethane (10 mL), 37% formalin (464 mg, 5.72 mmol), and then sodium triacetoxyborohydride ( 1.30 g, 6.13 mmol) was added and stirred for 4 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / hexane = 1/5) to give the title compound (461 mg, 82%) as a colorless oil.
_{^{1 H NMR (CDCl 3) δ1.00-1.27}} (2H, m), 1.45 (9H, s), 1.52-1.70 (3H, m), 2.44 (2H, d, J = 6.6Hz), 2.50-2.72 ( 2H, m), 2.92 (6H, s), 3.95-4.18 (2H, br), 6.68 (2H, d, J = 8.6Hz), 7.02 (2H, d, J = 8.6Hz).

Reference Example 69-1
tert-butyl 4- [3- (4-morpholinyl) benzyl] piperidine-1-carboxylate Compound (1.13 g, 3.90 mmol) obtained in Reference Example 23-2 and bis (2-chloroethyl) ether (0.457 mL, 3.90 mmol) and 1-butanol (20 mL) of potassium carbonate (1.13 g, 8.19 mmol) were heated under reflux for 27 hours. The reaction solution was poured into water, extracted with ethyl acetate, and the extract was washed with water and saturated saline. The solvent was dried and evaporated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / hexane = 1/5) to give the title compound (329 mg, 23%) as a colorless oil.
¹ H NMR (CDCl ₃ ) δ1.05-1.22 (2H, m), 1.45 (9H, s), 1.55-1.72 (3H, m), 2.50 (2H, d, J = 6.9Hz), 2.55-2.71 ( 2H, m), 3.13-3.20 (4H, m), 3.83-3.90 (4H, m), 3.98-4.16 (2H, m), 6.65-6.79 (3H, m), 7.19 (1H, t, J = 7.8 Hz).
Reference Example 69-2
4- [3- (4-Piperidinylmethyl) phenyl] morpholine dihydrochloride Using the compound obtained in Reference Example 69-1, the title compound was synthesized in the same manner as in Reference Example 1-4. Yield 100%.
¹ H NMR (CD ₃ OD) δ1.40-1.58 (2H, m), 1.80-2.07 (3H, m), 2.74 (2H, d, J = 7.2Hz), 2.89-3.02 (2H, m), 3.33 -3.42 (2H, m), 3.69-3.77 (4H, m), 4.12-4.18 (4H, m), 7.40-7.45 (1H, m), 7.52-7.65 (2H, m), 7.67-7.71 (1H, m).

Reference Example 70-1
tert-Butyl 4- [3- (methylamino) benzyl] piperidine-1-carboxylate Using the compound obtained in Reference Example 23-2, the title compound was synthesized in the same manner as in Reference Example 5-1. 95% yield.
¹ H NMR (CDCl ₃ ) δ1.00-1.23 (2H, m), 1.45 (9H, s), 1.54-1.72 (2H, m), 2.46 (2H, d, J = 7.0Hz), 2.53-2.73 ( 2H, m), 2.83 (3H, s), 3.67 (1H, br s), 3.92-4.20 (2H, m), 6.37-6.53 (3H, m), 7.10 (1H, t, J = 7.8Hz).
Reference Example 70-2
N-methyl-3- (4-piperidinylmethyl) aniline dihydrochloride Using the compound obtained in Reference Example 70-1, the title compound was synthesized in the same manner as in Reference Example 1-4. 95% yield.
¹ H NMR (CD ₃ OD) δ1.40-1.56 (2H, m), 1.82-2.06 (3H, m), 2.72 (2H, d, J = 7.2Hz), 2.89-3.04 (2H, m), 3.08 (3H, s), 3.29-3.43 (2H, m), 7.34-7.42 (3H, m), 7.52 (1H, t, J = 8.1Hz).

Reference Example 71
3- (4-Piperidinylmethyl) aniline dihydrochloride Using the compound obtained in Reference Example 23-2, the title compound was synthesized in the same manner as in Reference Example 1-4. Yield 92%.
¹ H NMR (CD ₃ OD) δ1.39-1.55 (2H, m), 1.80-2.01 (3H, m), 2.70 (2H, d, J = 7.2Hz), 2.88-3.01 (2H, m), 3.33 -3.42 (2H, m), 7.23-7.28 (2H, m), 7.33-7.38 (1H, m), 7.45-7.51 (1H, m).
Reference Example 72
tert-butyl 4- [4- (4-cyanophenoxy) benzyl] piperidine-1-carboxylate The compound (1.51 g, 5.19 mmol) obtained in Reference Example 50-2 and 4-fluorobenzonitrile (761 mg, 6.23 mmol) ) And 60% sodium hydride (311 mg, 7.79 mmol) in N, N-dimethylformamide (40 mL) was stirred at 100 ° C for 17 hours. Water was added at 0 ° C and the mixture was extracted with ethyl acetate, and the extract was washed with saturated saline. The solvent was dried and evaporated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / hexane = 1/1) to give the title compound (2.08 g, 100%) as a colorless oil.
¹ H NMR (CDCl ₃ ) δ1.07-1.25 (2H, m), 1.45 (9H, s), 1.55-1.70 (3H, m), 2.55 (2H, d, J = 6.9Hz), 2.57-2.72 ( 2H, m), 4.00-4.18 (2H, m), 6.94-7.01 (4H, m), 7.13-7.19 (2H, m), 7.55-7.61 (2H, m).

Reference Example 73-1
tert-Butyl 4-({4-[(ethoxycarbonyl) amino] phenyl} sulfanyl) piperidine-1-carboxylate Using the compound obtained in Reference Example 1-2, the title compound was obtained in the same manner as in Reference Example 59. Synthesized. Yield 80%.
¹ H NMR (CDCl ₃ ) δ 1.35 (3H, t, J = 6.8 Hz), 1.40-1.60 (2H, m), 1.44 (9H, s), 1.80-1.95 (2H, m), 2.78-2.94 (2H , m), 3.08 (1H, tt, J = 3.6, 11.8Hz), 3.84-4.03 (2H, m), 4.23 (2H, q, J = 6.8Hz), 6.63 (1H, br s), 7.30-7.42 (4H, m).
Reference Example 73-2
tert-butyl 4-({4-[(ethoxycarbonyl) amino] phenyl} sulfonyl) piperidine-1-carboxylate The title compound was obtained in the same manner as in Reference Example 1-3 using the compound obtained in Reference Example 73-1. Compounds were synthesized. Yield 88%.
¹ H NMR (CDCl ₃ ) δ 1.33 (3H, t, J = 7.2Hz), 1.43 (9H, s), 1.45-1.70 (2H, m), 1.90-2.05 (2H, m), 2.55-2.75 (2H , m), 3.00 (1H, tt, J = 3.6, 12.0Hz), 4.14-4.27 (2H, m), 4.27 (2H, q, J = 7.2Hz), 7.00 (1H, br s), 7.57-7.65 (2H, m), 7.75-7.84 (2H, m).
Reference Example 73-3
Ethyl 4- (4-piperidinesulfonyl) phenylcarbamate hydrochloride Using the compound obtained in Reference Example 73-2, the title compound was synthesized in the same manner as in Reference Example 1-4. 95% yield.
¹ H NMR (CD ₃ OD) δ 1.31 (3H, t, J = 7.2 Hz), 1.72-1.98 (2H, m), 2.10-2.25 (2H, m), 2.87-3.06 (2H, m), 3.35- 3.55 (3H, m), 4.21 (2H, q, J = 7.2Hz), 7.67-7.85 (4H, m).

Reference Example 74-1
tert-Butyl 4-{[3- (dimethylamino) phenyl] sulfanyl} piperidine-1-carboxylate Using the compound obtained in Reference Example 4-1, synthesize the title compound in the same manner as in Reference Example 3-1. did. Yield 54%.
¹ H NMR (CDCl ₃ ) δ1.40-1.66 (2H, m), 1.45 (9H, s), 1.85-2.01 (2H, m), 2.82-3.01 (2H, m), 2.95 (6H, s), 3.21 (1H, tt, J = 10.0, 3.6Hz), 3.88-4.06 (2H, m), 6.59-6.67 (1H, m), 6.74-6.81 (2H, m), 7.12-7.22 (1H, m).
Reference Example 74-2
tert-Butyl 4-{[3- (dimethylamino) phenyl] sulfonyl} piperidine-1-carboxylate Oxone (commercially available) (Name) (2.19 g, 7.14 mmol) and water (2 mL) were added and stirred for 3.5 hours. The insoluble material was separated by filtration and washed with acetone. After the filtrate was concentrated to about 5 mL, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure.The residue was purified by column chromatography (ethyl acetate / hexane = 1/1) to give the title compound (522 mg, 40%) as colorless Obtained as an oil.
¹ H NMR (CDCl ₃ ) δ1.44 (9H, s), 1.56-1.72 (2H, m), 1.92-2.04 (2H, m), 2.54-2.75 (2H, m), 2.95-3.08 (1H, m ), 3.03 (6H, s), 4.08-4.33 (2H, m), 6.92 (1H, ddd, J = 8.4, 5.7, 0.9Hz), 7.08-7.16 (2H, m), 7.38 (1H, dd, J = 8.4, 7.8Hz).
Reference Example 74-3
N, N-Dimethyl-3- (4-piperidinylsulfonyl) aniline Using the compound obtained in Reference Example 74-2, the title compound was synthesized in the same manner as in Reference Example 1-4. 96% yield.
¹ H NMR (CD ₃ OD) δ1.86-2.02 (2H, m), 2.16-2.26 (2H, m), 2.96-3.09 (2H, m), 3.20 (6H, s), 3.46-3.67 (3H, m), 7.55-7.63 (2H, m), 7.65-7.72 (2H, m).

Experimental example 1
(Measurement of RANTES binding inhibitory action)
(1) Cloning of human CCR5 chemokine receptor The CCR5 gene was cloned from human spleen cDNA by PCR. A primer set prepared by using 0.5 ng of spleen cDNA (TOYOBO, QUICK-Clone cDNA) as a template and referring to the CCR5 gene base sequence reported by Samson et al. (Biochemistry 35 (11), 3362-3367 (1996)).
SEQ ID NO: 1 described in Experimental Example (1) of WO99 / 32100 [Sequence length: 34; Sequence type: Nucleic acid; Number of strands: Single strand; Topology: Linear; SEQ ID NO: 2 [Sequence length: 34; Sequence type: nucleic acid; Number of strands: single-stranded; Topology: linear; Of other nucleic acid synthetic DNA] was added to each, and a PCR reaction was carried out using DNA thermal cycler 480 (Perkin Elmer) using TaKaRa EX Taq (Takara Shuzo) (reaction conditions: 95 ° C. for 1 hour). 30 cycles of 1 minute at 60 ° C. and 5 minutes at 75 ° C.). The PCR product was subjected to agarose gel electrophoresis, and a DNA fragment of about 1.0 kb was recovered. Then, the CCR5 gene was cloned using Original TA Cloning Kit (Funakoshi).
(2) Preparation of plasmid for expression of human CCR5 The plasmid obtained above was digested with restriction enzymes XbaI (Takara Shuzo) and BamHI (Takara Shuzo), and then subjected to agarose gel electrophoresis to recover a DNA fragment of about 1.0 kb. The DNA fragment was mixed with an expression plasmid pcDNA3.1 (Funakoshi) for animal cells digested with XbaI and BamHI, and DNA Ligation Kit Ver. 2 (Takara Shuzo) and transformed into competent cells of Escherichia coli JM109 (Takara Shuzo) to obtain plasmid pCKR5.
(3) Introduction and Expression of Human CCR5 Expression Plasmid into CHO-K1 Cells Grow in 750 ml tissue culture flask (Becton Dickinson) using Ham F12 medium (Nippon Pharmaceutical) containing 10% fetal bovine serum (Lifetech Oriental). The detached CHO-K1 cells were detached with 0.5 g / L trypsin-0.2 g / L EDTA (Lifetech Oriental), washed with PBS (Lifetech Oriental), and centrifuged (1000 rpm, 5 minutes). Suspended in PBS. Next, DNA was introduced into the cells using Gene Pulser (Bio-Rad) under the following conditions. That is, 8 × 10 ⁶ cells and 10 μg of the human CCR5 expression plasmid pCKR5 were added to a 0.4 cm gap cuvette, and electroporation was performed under a voltage of 0.25 kV and a capacitance of 960 μF. Thereafter, the cells were transferred to a Ham F12 medium containing 10% fetal bovine serum, cultured for 24 hours, the cells were again detached and centrifuged, and Geneticin (Lifetech Oriental) was added to a concentration of 500 μg / ml. The cells were suspended in a ham F12 medium containing 10% fetal bovine serum, diluted to 10 ⁴ cells / ml, and seeded on a 96-well plate (Becton Dickinson) to obtain a geneticin-resistant strain.
Next, after the obtained geneticin-resistant strain was cultured in a 96-well plate (Becton Dickinson), CCR5-expressing cells were selected from the resistant strains. That is, a ham F12 medium containing 200 pM [ ¹²⁵ I] -RANTES (Amersham) as a ligand was added in an assay buffer (ham F12 medium containing 0.5% BSA, 20 mM HEPES (Wako Pure Chemicals, pH 7.2)) at room temperature for 40 minutes. After binding reaction, the cells were washed with ice-cold PBS, 1M NaOH was added at 50 μl / well, and the mixture was stirred. The radioactivity was measured with a γ-counter, whereby the cells to which ligands specifically bound, CCR5 / The CHO strain was selected.

(4) Evaluation of compound based on CCR5 antagonistic activity CCR5 / CHO strain was seeded at 5 × 10 ⁴ cells / well in a 96-well microplate, cultured for 24 hours, aspirated off the medium, and contained a test compound (1 μM). Assay buffer was added to each well, and [ ¹²⁵ I] -RANTES (Amersham) as a ligand was added to 100 pM, followed by reaction at room temperature for 40 minutes. Next, the assay buffer was removed by suction and then washed twice with cooled PBS. Next, 200 μl of Microscint-20 (Packard) was added to each well, and the radioactivity was measured with a top count (Packard).
According to the method described above, the CCR5 binding inhibition rate of the test compound was measured. The results are shown in the table below.
Example number Inhibition rate at 1.0 μM (%)
399
8 96
11 99
28 99
34 100
37 98
39 100
45 100
52 97
61 96
67 100
70 100
76 90

Experimental example 2
Growth inhibitory effect on HIV infection (measurement of anti-HIV-1 activity of test compound using MOLT-4 / CCR5 cells)
(1) Cells and Medium As human CCR5-expressing cells, MOLT-4 / CCR5 cells (AIDS Res. Hum. Retrovir. 16, 935-941 (2000)) which are human lymphocyte-derived cell lines reported by Baba et al. . An RPMI 1640 medium (Nikken Institute of Biomedical Research) containing 10% fetal bovine serum (FBS, GIBCO) and 1 mg / mL Geneticin (Lifetech Oriental) was used as a medium.
(2) Test compound The test compound was dissolved in dimethylsulfoxide (DMSO) and diluted to 200 nM in RPMI 1640 medium containing 10% FBS, 1 mg / mL Geneticin (Lifetech Oriental).
(3) Ba-L strain, a laboratory strain of virus R5 HIV-1, was used.
(4) Infected MOLT-4 / CCR5 cells (4 × 10 ⁶ cells / 1 mL) were inoculated with R5 HIV-1 Ba-L strain at 1,000 CCID ₅₀ / mL and incubated at 37 ° C. for 6 hours. After the incubation, the infected cells from which the virus not adsorbed to the cells were washed away were suspended in 2 mL of a medium, and the infected cells and 100 μL of the test compound were dispensed into a 96-well microplate at 37 ° C. in the presence of 5% CO _2. Cultured for 3 days. The concentration of the test compound was 100 nM. Three days after infection, the cells were diluted 5-fold with a medium containing the same concentration of the test compound, and cultured for another 2 days. The amount of p24 in the supernatant after the culture was measured using a commercially available ELISA kit (ZeptoMetrix). The infection inhibition rate was calculated as the p24 amount of the test compound administration group relative to the p24 amount of the control group.
The results of measuring the infection inhibition rate of the test compound are shown in the table below.

Example No. Inhibition rate at 100 nM (%)
6 100
17 100
22 100
26 99
28 100
57 100
58 100
59 100
60 100
Formulation Example 1 Capsule (1) 1-acetyl-N- (3- {4-[(4-aminophenyl) sulfonyl] -1-piperidinyl} propyl) -N- (3-chloro-4-methylphenyl)- 4-piperidinecarboxamide 40mg
(2) Lactose 61mg
(3) Microcrystalline cellulose 18mg
(4) 1 mg of magnesium stearate
1 capsule (contents) 120mg
After mixing (1), (2), (3) and (4), the mixture is sealed in a gelatin capsule.
Formulation Example 2 Capsule (1) 1-acetyl-N- (3-chloro-4-methylphenyl) -N- {3- [4-({4-[(3-methoxypropyl) amino] phenyl} sulfonyl) 1-piperidinyl] propyl} -4-piperidinecarboxamide 40 mg
(2) Lactose 61mg
(3) Microcrystalline cellulose 18mg
(4) 1 mg of magnesium stearate
1 capsule (contents) 120mg
After mixing (1), (2), (3) and (4), the mixture is sealed in a gelatin capsule.

Formulation Example 3 Capsule (1) 1-acetyl-N- (3-chloro-4-methylphenyl) -N- [3- (4- {4-[(4-hydroxy-1-piperidinyl) sulfonyl] benzyl} benzyl} 1-piperidinyl) propyl] -4-piperidinecarboxamide 40 mg
(2) Lactose 61mg
(3) Microcrystalline cellulose 18mg
(4) 1 mg of magnesium stearate
1 capsule (contents) 120mg
After mixing (1), (2), (3) and (4), the mixture is sealed in a gelatin capsule.
Formulation Example 4 Tablet (1) 1-acetyl-N- (3-chloro-4-methylphenyl) -N- {3- [4- (4-{[(2-hydroxyethyl) amino] sulfonyl} benzyl)- 1-piperidinyl] propyl} -4-piperidinecarboxamide 40 mg
(2) mannitol 51.2mg
(3) Microcrystalline cellulose 18mg
(4) 3.6 mg of hydroxypropyl cellulose
(5) Croscarmellose sodium 6mg
(6) 1.2 mg of magnesium stearate
1 tablet 120mg
Mix (1), (2), (3) and (4) and granulate. (5) and (6) are added to the granules and pressed into tablets.
Formulation Example 5 Tablet (1) 1-acetyl-N- (3-chloro-4-methylphenyl) -N- [3- (4- {4-[(2-hydroxyethyl) thio] benzyl} -1-piperidinyl ) Propyl] -4-piperidinecarboxamide 40mg
(2) Mannitol 51.2mg
(3) Microcrystalline cellulose 18mg
(4) 3.6 mg of hydroxypropyl cellulose
(5) Croscarmellose sodium 6mg
(6) 1.2 mg of magnesium stearate
1 tablet 120mg
Mix (1), (2), (3) and (4) and granulate. (5) and (6) are added to the granules and pressed into tablets.

Claims (21)

formula:

[In the formula, Q ¹ and Q ² are the same or different and each represents a C _1-3 alkyl group, Q ³ represents a halogen atom, X represents CH ₂ or SO ₂ , and R represents, when X is CH ₂ , i) —SO ₂ NR ¹ R ² (where R ¹ and R ² are the same or different and are each a hydrogen atom or a hydroxyl group, a C _1-4 alkyl group, an oxo group, a carboxyl group, a C _1-4 alkoxy group as a hydrogen atom or a substituent) A _C1-8 alkyl group optionally having a hydroxyimino group, a _C1-4 alkoxyimino group, a _C1-4 alkoxycarbonyl group, a _C1-4 alkylcarbonyl group or a _C3-8 cycloalkyl group. indicating either, or R ¹ and R ² may bond together to form a nitrogen-containing heterocyclic ring together with N, nitrogen-containing heterocycle C _1-4 alkyl group as a substituent, a hydroxyl group, an oxo group, a carboxyl , _{C 1-4} alkoxy groups, hydroxyimino _{groups, C 1-4} alkoxyimino _{group, C 1-4} alkoxycarbonyl group _may have a _{C 1-4} alkyl group or _{C 3-8} cycloalkyl group ), (Ii) -Y ¹ -WZ ¹ [where Y ¹ is a single bond, O, S, SO, SO ₂ , N (SO ₂ R ³ ) (R ³ is a C _1-4 alkyl group. ), N (COOR ³ ) (R ³ has the same meaning as described above) or C (= N-OR ⁴ ) (R ⁴ represents a hydrogen atom or a C _1-4 alkyl group). _{Represents a} C _1-4 alkylene which may be substituted with a C _1-4 alkyl, and Z ¹ represents a hydroxyl group, a carboxyl group, a carbamoyl group, a C _1-4 alkoxycarbonyl group or a cyano group. ^{}, (Iii) -Y 2 -R} 6 { wherein, ^{Y 2} is _{-CO-, SO, SO 2, -C} (= N-OR 4) -, (R 4 is as defined above.) -NR ⁴ -SO _2- (R ⁴ has the same meaning as described above), -NR ⁴ -CO _2- (R ⁴ has the same meaning as described above), -NR ⁴ -CO-NR ^5- ( R ⁴ has the same meaning as described above, and R ⁵ represents a hydrogen atom or a C _1-4 alkyl group.) Or —NR ⁴ —CO—NR ⁵ —O— (R ⁴ and R ⁵ have the same meanings as above. ) And R ⁶ represents C _1-8 alkyl. }, (Iv) NR ¹ R ² (wherein R ¹ and R ² each have the same meaning as described above), (v) -NR ⁴ —CO—NH ₂ (R ⁴ has the same meaning as described above.) ), (Vi) a heterocyclic group optionally having a C _1-4 alkyl group or an oxo group as a substituent, (vii) a phenyl group having a cyano group, a carboxyl group or a carbamoyl group as a substituent, or (viii) A phenyloxy group having a cyano group, a carboxyl group, or a carbamoyl group as a substituent, and when X is SO ₂ , (i) a C _1-8 alkyl group, (ii) a halogen atom, (iii) NR ¹ R ² ( Provided that R ¹ and R ² have the same meanings as above, respectively, and (iv) -WZ ² (where W is the same as above; Z ² is a carboxyl group, a carbamoyl group, C _1-4) Represents an alkoxycarbonyl group or a cyano group), (v) -CH = C H-Z ² (where Z ² has the same meaning as described above), (vi) -C≡C-Z ² (where Z ² has the same meaning as above), (vii) -Y ³ —R ⁶ {where, Y ³ is —CO—, —C (OH) R ⁴ — (R ⁴ has the same meaning as described above), —C (＝ N—OR ⁴ ) (R ⁴ is as defined above. shows the _{^{significance), -. NR 4 -SO 2}} - (R 4 is as defined _{^{above), -. NR 4 -CO 2}} - (R 4 is as defined above), -. NR ⁴ - CO-NR ^5- (R ⁴ and R ⁵ have the same meaning as described above) or -NR ⁴ -CO-NR ⁵ -O- (R ⁴ and R ⁵ have the same meanings as described above); ⁶ has the same meaning as described above. } Or (viii) a phenyl group having a carboxyl group, a _C1-4 alkoxycarbonyl group or a carbamoyl group as a substituent. Or a salt thereof. The compound according to claim 1, wherein Q ¹ is a methyl group, Q ² is a methyl group, and Q ³ is a chlorine atom. The compound according to claim 1, wherein the bonding position between R and the benzene ring is para to the bonding position between the benzene ring and X. The compound of claim 1 wherein X is is CH _2. X is SO ₂ and R is NR ¹ R ² (provided that R ¹ and R ² are the same or different and each represents a hydrogen atom or a substituent as a hydroxyl group, a C _1-4 alkyl group, an oxo group, a carboxyl group, a C _{1 -4} alkoxy groups, hydroxyimino _{groups, C 1-4} alkoxyimino _{group, C 1-4} alkoxycarbonyl group which _may have a _{C 1-4} alkyl group or _{C 3-8} cycloalkyl group _{C 1- It} may represent an _8- alkyl group, or R ¹ and R ² may combine with each other to form a nitrogen-containing heterocyclic ring together with N, and the nitrogen-containing heterocyclic ring may be a C _1-4 alkyl group, a hydroxyl group, an oxo group, Group, carboxyl group, C _1-4 alkoxy group, hydroxyimino group, C _1-4 alkoxyimino group, C _1-4 alkoxycarbonyl group, C _1-4 alkylcarbonyl group or _May have a C _3-8 cycloalkyl group.). X is CH ₂ , and R is SO ₂ NR ¹ R ² (where R ¹ and R ² are the same or different and are each a hydrogen atom or a hydroxyl group, a C _1-4 alkyl group, an oxo group, a carboxyl group, A C _1-4 optionally having a C _1-4 alkoxy group, a hydroxyimino group, a C _1-4 alkoxyimino group, a C _1-4 alkoxycarbonyl group, a C _1-4 alkylcarbonyl group or a C _3-8 cycloalkyl group; _It may represent a _1-8 alkyl group, or R ¹ and R ² may combine to form a nitrogen-containing heterocycle together with N, and the nitrogen-containing heterocycle may be a C _1-4 alkyl group or a hydroxyl group as a substituent. , oxo group, carboxyl _{group, C 1-4} alkoxy groups, hydroxyimino _{groups, C 1-4} alkoxyimino _{group, C 1-4} alkoxycarbonyl _{group, C 1-4} alkyl carbonylation May have a group or C _3-8 cycloalkyl group.) A which is a compound according to claim 1. 1-acetyl-N- (3- {4-[(4-aminophenyl) sulfonyl] -1-piperidinyl} propyl) -N- (3-chloro-4-methylphenyl) -4-piperidinecarboxamide, 1-acetyl -N- (3-chloro-4-methylphenyl) -N- {3- [4-({4-[(3-methoxypropyl) amino] phenyl} sulfonyl) -1-piperidinyl] propyl} -4-piperidine Carboxamide, 1-acetyl-N- (3-chloro-4-methylphenyl) -N- [3- (4- {4-[(4-hydroxy-1-piperidinyl) sulfonyl] benzyl} -1-piperidinyl) propyl ] -4-Piperidinecarboxamide, 1-acetyl-N- (3-chloro-4-methylphenyl) -N- {3- [4- (4-{[(2-hydroxyethyl) amino] sulfonyl} benzyl)- 1-piperidinyl] propyl} -4-piperidinecarboxamide, 1-acetyl-N- (3-chloro-4-methylphenyl) -N- [3- (4- {4-[(2-hydroxyethyl) thio] benzyl } -1-piperidinyl) propyl] -4-piperidinecarboxy Bromide or compound according to claim 1 a salt thereof. A prodrug of the compound of claim 1. formula:

(Wherein Q ¹ and Q ² are the same or different and each represents a C _1-3 alkyl group, Q ³ represents a halogen atom, and Z represents a leaving group) or a salt thereof and a formula:

[Wherein, X represents CH ₂ or SO ₂ , and R represents, when X is CH ₂ , (i) —SO ₂ NR ¹ R ² (where R ¹ and R ² are the same or different and are each a hydrogen atom or As a substituent, a hydroxyl group, a C _1-4 alkyl group, an oxo group, a carboxyl group, a C _1-4 alkoxy group, a hydroxyimino group, a C _1-4 alkoxyimino group, a C _1-4 alkoxycarbonyl group, a C _1-4 alkyl A C _1-8 alkyl group which may have a carbonyl group or a C _3-8 cycloalkyl group, or R ¹ and R ² may be combined with each other to form a nitrogen-containing heterocyclic ring with N; And the nitrogen-containing heterocyclic ring has a C _1-4 alkyl group, a hydroxyl group, an oxo group, a carboxyl group, a C _1-4 alkoxy group, a hydroxyimino group, a C _1-4 alkoxyimino group, a C _1-4 alcohol as a substituent. Alkoxycarbonyl group _may have a _{C 1-4} alkyl group or _{C 3-8} cycloalkyl ^{group.), (Ii) -Y 1} -W-Z 1 { However, Y ¹ is a single bond, O _{, S, SO, SO 2,} N (SO 2 R 3) (R 3 represents a _{C 1-4} alkyl group.) or N (COOR ³⁾ (indicating the ^{R 3} are as defined above.) or C ( ^{= N-oR 4) (R} 4 is a hydrogen atom or a _{C 1-4} alkyl group a.), W is a good _{C 1-4} alkylene optionally substituted by _{C 1-4} alkyl, Z ¹ is a hydroxyl group , A carboxyl group, a carbamoyl group, a _C1-4 alkoxycarbonyl group or a cyano group. ^{}, (Iii) -Y 2 -R} 6 { wherein, ^{Y 2} is _{-CO-, SO, SO 2, -C} (= N-OR 4) -, (R 4 is as defined above.) -NR ⁴ -SO _2- (R ⁴ has the same meaning as described above), -NR ⁴ -CO _2- (R ⁴ has the same meaning as described above), -NR ⁴ -CO-NR ^5- ( R ⁴ has the same meaning as described above, and R ⁵ represents a hydrogen atom or a C _1-4 alkyl group.) Or —NR ⁴ —CO—NR ⁵ —O— (R ⁴ and R ⁵ have the same meanings as above. ), And R ⁶ represents C _1-8 alkyl. }, (Iv) NR ¹ R ² (wherein R ¹ and R ² each have the same meaning as described above), (v) -NR ⁴ —CO—NH ₂ (R ⁴ has the same meaning as described above.) ), (Vi) a heterocyclic group optionally having a C _1-4 alkyl group or an oxo group as a substituent, (vii) a phenyl group having a cyano group, a carboxyl group or a carbamoyl group as a substituent, or (viii) A phenyloxy group having a cyano group, a carboxyl group, or a carbamoyl group as a substituent, and when X is SO ₂ , (i) a C _1-8 alkyl group, (ii) a halogen atom, (iii) NR ¹ R ² ( Provided that R ¹ and R ² have the same meanings as above, respectively, and (iv) -WZ ² (where W is the same as above; Z ² is a carboxyl group, a carbamoyl group, C _1-4) Represents an alkoxycarbonyl group or a cyano group), (v) -CH = C H-Z ² (where Z ² has the same meaning as described above), (vi) -C≡C-Z ² (where Z ² has the same meaning as above), (vii) -Y ³ —R ⁶ {where, Y ³ is —CO—, —C (OH) R ⁴ — (R ⁴ has the same meaning as described above), —C (＝ N—OR ⁴ ) (R ⁴ is as defined above. shows the _{^{significance), -. NR 4 -SO 2}} - (R 4 is as defined _{^{above), -. NR 4 -CO 2}} - (R 4 is as defined above), -. NR ⁴ - CO-NR ^5- (R ⁴ and R ⁵ have the same meaning as described above) or -NR ⁴ -CO-NR ⁵ -O- (R ⁴ and R ⁵ have the same meanings as described above); ⁶ has the same meaning as described above. } Or (viii) a phenyl group having a carboxyl group, a _C1-4 alkoxycarbonyl group or a carbamoyl group as a substituent. A compound represented by the formula or a salt thereof:

(Wherein each symbol is as defined above) or a method for producing a salt thereof. A medicament comprising the compound according to claim 1 or a prodrug thereof. The medicament according to claim 10, which is a CC chemokine receptor antagonist. The medicament according to claim 10, which is a CCR5 antagonist. The medicament according to claim 10, which is a therapeutic agent for HIV infection. The medicament according to claim 10, which is a prophylactic / therapeutic agent for AIDS. The medicament according to claim 10, which is an AIDS disease progression inhibitor. The medicament according to claim 10, which is a blood or a blood product for transfusion. The medicament according to claim 10, which is an agent for preventing or treating graft-versus-host disease and / or rejection during organ or bone marrow transplantation. The medicament according to claim 10, which is an agent for preventing or treating rheumatoid arthritis, autoimmune disease, allergic disease, ischemic brain cell injury, myocardial infarction, nephritis, nephropathy or arteriosclerosis. Use of the compound according to claim 1 or a prodrug thereof for the production of a CC chemokine receptor antagonist. An agent for treating HIV infection, an agent for preventing or treating AIDS, an agent for suppressing the progression of AIDS, an agent for preventing or treating graft-versus-host disease and / or rejection during organ or bone marrow transplantation, or rheumatoid arthritis, autoimmune disease Use of the compound according to claim 1 or a prodrug thereof for the manufacture of a prophylactic or therapeutic agent for an allergic disease, ischemic brain cell injury, myocardial infarction, nephritis, nephropathy or arteriosclerosis. Treatment of HIV infection, prevention and treatment of AIDS, suppression of AIDS pathogenesis, prevention and treatment of graft-versus-host disease and / or rejection during organ or bone marrow transplantation, or rheumatoid arthritis, autoimmune disease, allergic disease A method for preventing or treating diseases, ischemic brain cell injury, myocardial infarction, nephritis, nephropathy or arteriosclerosis, and administering an effective amount of the compound according to claim 1 or a prodrug thereof to a human in need thereof. A method comprising: