JP2008260693A

JP2008260693A - Pharmaceutical composition containing thienopyridine-2-carboxamide derivative

Info

Publication number: JP2008260693A
Application number: JP2007102676A
Authority: JP
Inventors: Satoru Naito; 覚内藤; Akira Nakao; 彰中尾; Takeshi Shinozuka; 剛篠塚; Keiji Saito; 啓志斎藤; Kiyoshi Oizumi; 喜代志大泉
Original assignee: Daiichi Sankyo Co Ltd
Current assignee: Daiichi Sankyo Co Ltd
Priority date: 2007-04-10
Filing date: 2007-04-10
Publication date: 2008-10-30

Abstract

<P>PROBLEM TO BE SOLVED: To provide a pharmaceutical composition promoting osteogenesis. <P>SOLUTION: The pharmaceutical composition comprises a compound represented by general formula (I) [wherein R<SP>1</SP>is a hydrogen atom or a 1-6C alkyl group; and R<SP>2</SP>is a substituted cyclic amino] or its physiologically acceptable salt. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

本発明は骨形成を促進する化合物又はその薬理上許容される塩を含有する医薬組成物に関する。 The present invention relates to a pharmaceutical composition containing a compound that promotes bone formation or a pharmacologically acceptable salt thereof.

チエノピリジン誘導体がＩκＢ kinase complex阻害作用を有することは知られている。（特許文献１参照）また、３−アミノ−４−（ジメチルアミノ）チエノ［２，３−ｂ］ピリジン−２−カルボキサミドおよび３−アミノ−４−アニリノチエノ［２，３−ｂ］ピリジン−２−カルボキサミドが公知化合物として知られている。（非特許文献１参照）しかし、それらの化合物が骨に及ぼす影響は報告されていない。
国際公開第０３／１０３６６１号明細書 Pharm.Chem.J.(Engl.Transl.),26,870-874,(1992) It is known that thienopyridine derivatives have an IκB kinase complex inhibitory action. (See Patent Document 1) In addition, 3-amino-4- (dimethylamino) thieno [2,3-b] pyridine-2-carboxamide and 3-amino-4-anilinothieno [2,3-b] pyridine-2- Carboxamide is known as a known compound. However, the influence which those compounds have on bone has not been reported.
International Publication No. 03/103661 Specification Pharm.Chem.J. (Engl.Transl.), 26,870-874, (1992)

本発明者らは、骨形成を促進する化合物について鋭意研究を行った結果、チエノピリジン−２−カルボキサミド誘導体が優れた薬理効果を有することを見出して本発明を完成した。 As a result of intensive studies on compounds that promote bone formation, the present inventors have found that thienopyridine-2-carboxamide derivatives have excellent pharmacological effects and have completed the present invention.

本発明は、
（１）下記一般式（Ｉ） The present invention
(1) The following general formula (I)

［式中、
Ｒ^１は、水素原子、シクロプロピル基又はＣ_１−Ｃ_６アルキル基を示し、
Ｒ^２は、下記一般式（Ｒ^２ａ）又は一般式（Ｒ^２ｂ） [Where:
R ¹ represents a hydrogen atom, a cyclopropyl group or a C ₁ -C ₆ alkyl group,
R ² represents the following general formula (R ² a) or general formula (R ² b)

（式中、ｍは０又は１を示し；ｎは０、１、２又は３を示し；ｋは１又は２を示し；Ｒ^３は水素原子又はＣ_１−Ｃ_６アルキル基を示し；Ｗは酸素原子又は硫黄原子を示し；Ｘ^１は置換基群αから選択される１乃至３個の基で置換されていてもよいシクロプロピル基、置換基群αから選択される１乃至４個の基で置換されていてもよい５又は６員ヘテロシクリル基、又は、置換基群αから選択される１乃至４個の基で置換されていてもよい５又は６員ヘテロアリール基を示し；Ｘ^２は置換基群αから選択される１乃至４個の基で置換されていてもよい５又は６員ヘテロシクリル基、又は、置換基群αから選択される１乃至４個の基で置換されていてもよい５又は６員ヘテロアリール基を示し；ＹはＣＨ又はＮを示し；置換基群αは、ハロゲン原子、オキソ基、Ｃ_１−Ｃ_６アルキル基、Ｃ_１−Ｃ_６ハロゲン化アルキル基、Ｃ_１−Ｃ_３アルコキシ−Ｃ_１−Ｃ_６アルキル基、Ｃ₃−Ｃ₆シクロアルキル基及びＣ_１−Ｃ_３アルコキシ基からなる群を示す。）で表される基を示す。
但し、Ｘ^１が置換基群αから選択される１乃至３個の基で置換されていてもよいシクロプロピル基である場合は、ｎは１、２又は３であり、
Ｘ^１又はＸ^２が置換基群αから選択される１乃至４個の基で置換されていてもよい５又は６員ヘテロシクリル基であり、且つ当該基が飽和ヘテロシクリル基である場合は、当該基は少なくとも１つのオキソ基で置換されている基である。］
を有する化合物又はその薬理上許容される塩を有効成分として含有する医薬組成物
である。 (Wherein m represents 0 or 1, n represents 0, 1, 2 or 3; k represents 1 or 2; R ³ represents a hydrogen atom or a C ₁ -C ₆ alkyl group; W represents Represents an oxygen atom or a sulfur atom; X ¹ represents a cyclopropyl group which may be substituted with 1 to 3 groups selected from substituent group α, and 1 to 4 groups selected from substituent group α in optionally substituted 5 or 6 membered heterocyclyl group, or represents a 1 to 4 may be substituted with a group 5 or 6 membered heteroaryl group selected from substituent group alpha; X ² is A 5- or 6-membered heterocyclyl group optionally substituted with 1 to 4 groups selected from the substituent group α, or a 1 to 4 group selected from substituent group α A good 5- or 6-membered heteroaryl group; Y represents CH or N; , Oxo _group, C 1 -C ₆ _alkyl, C 1 -C ₆ halogenated alkyl _groups, C 1 -C ₃ alkoxy _-C 1 -C ₆ alkyl group, C ₃ -C ₆ cycloalkyl group and a _C 1 -C Represents a group consisting of ₃ alkoxy groups.).
However, when X ¹ is a cyclopropyl group optionally substituted with 1 to 3 groups selected from the substituent group α, n is 1, 2 or 3.
When X ¹ or X ² is a 5- or 6-membered heterocyclyl group optionally substituted with 1 to 4 groups selected from the substituent group α, and the group is a saturated heterocyclyl group, the group Is a group substituted with at least one oxo group. ]
Or a pharmacologically acceptable salt thereof as an active ingredient.

上記のうち、好適な医薬組成物は、
（２）Ｒ^１が、水素原子、シクロプロピル基又はＣ_１−Ｃ_４アルキル基である、（１）に記載された医薬組成物、
（３）Ｒ^１が、水素原子、メチル基、エチル基、プロピル基又はシクロプロピル基である、（１）に記載された医薬組成物、
（４）Ｒ^１が、水素原子又はメチル基である、（１）に記載された医薬組成物、
（５）Ｒ^２が、下記一般式（Ｒ^２ａ）、一般式（Ｒ^２ｂ−１）又は一般式（Ｒ^２ｂ−２） Among the above, preferred pharmaceutical compositions are:
(2) The pharmaceutical composition according to (1), wherein R ¹ is a hydrogen atom, a cyclopropyl group, or a C ₁ -C ₄ alkyl group,
(3) The pharmaceutical composition according to (1), wherein R ¹ is a hydrogen atom, a methyl group, an ethyl group, a propyl group, or a cyclopropyl group,
(4) The pharmaceutical composition according to (1), wherein R ¹ is a hydrogen atom or a methyl group,
(5) R ² is represented by the following general formula (R ² a), general formula (R ² b-1) or general formula (R ² b-2)

（式中、ｍ、ｎ、ｋ、Ｒ^３、Ｗ、Ｘ^１、Ｘ^２及びＹは前記と同意義を示す。）である、（１）乃至（４）から選択されるいずれか１項に記載された医薬組成物、
（６）Ｒ³が、水素原子又はメチル基である、（１）乃至（５）から選択されるいずれか１項に記載された医薬組成物、
（７）Ｒ³が、水素原子である、（１）乃至（５）から選択されるいずれか１項に記載された医薬組成物、
（８）Ｘ^１が置換基群αから選択される１乃至４個の基で置換されていてもよい５又は６員ヘテロシクリル基、又は、置換基群αから選択される１乃至４個の基で置換されていてもよい５又は６員ヘテロアリール基であり、ｎが１、２又は３である、（１）乃至（７）から選択されるいずれか１項に記載された医薬組成物、
（９）Ｘ^２が置換基群αから選択される１乃至４個の基で置換されていてもよい５又は６員ヘテロシクリル基、又は、置換基群αから選択される１乃至４個の基で置換されていてもよい５又は６員ヘテロアリール基であり、ｋが２である、（１）乃至（７）から選択されるいずれか１項に記載された医薬組成物、
（１０）Ｘ^１又はＸ^２が、下記から選択されるいずれか１つの一般式で表される基 (Wherein m, n, k, R ³ , W, X ¹ , X ² and Y are as defined above), any one of (1) to (4) The described pharmaceutical composition,
(6) The pharmaceutical composition according to any one of (1) to (5), wherein R ³ is a hydrogen atom or a methyl group,
(7) The pharmaceutical composition according to any one of (1) to (5), wherein R ³ is a hydrogen atom.
(8) X ¹ is a 5- or 6-membered heterocyclyl group optionally substituted with 1 to 4 groups selected from substituent group α, or 1 to 4 groups selected from substituent group α A pharmaceutical composition according to any one of (1) to (7), which is a 5- or 6-membered heteroaryl group optionally substituted with n, and n is 1, 2 or 3.
(9) 5 or 6-membered heterocyclyl group, which X ² may be substituted with 1 to 4 groups selected from substituent group α, or 1 to 4 groups selected from substituent group α A pharmaceutical composition according to any one of (1) to (7), which is a 5- or 6-membered heteroaryl group optionally substituted with
(10) X ¹ or X ² is a group represented by any one general formula selected from

（式中、Ｒ^４a、Ｒ^４b、Ｒ^４c及びＲ^４ｄは、同一又は異なって、水素原子又は置換基群αの定義におけるハロゲン原子、Ｃ_１−Ｃ_６アルキル基、Ｃ_１−Ｃ_６ハロゲン化アルキル基、Ｃ_１−Ｃ_３アルコキシ−Ｃ_１−Ｃ_６アルキル基、Ｃ₃−Ｃ₆シクロアルキル基若しくはＣ_１−Ｃ_３アルコキシ基を示す。）である、（１）乃至（７）から選択されるいずれか１項に記載された医薬組成物、
（１１）Ｘ^１又はＸ^２が、下記から選択されるいずれか１つの一般式で表される基 (Wherein R ^4a , R ^4b , R ^4c and R ^4d are the same or different and are a hydrogen atom or a halogen atom in the definition of substituent group α, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ halogenated group). An alkyl group, a C ₁ -C ₃ alkoxy-C ₁ -C ₆ alkyl group, a C ₃ -C ₆ cycloalkyl group or a C ₁ -C ₃ alkoxy group.) Selected from (1) to (7) Any one of the above-mentioned pharmaceutical compositions,
(11) X ¹ or X ² is a group represented by any one general formula selected from the following

（式中、Ｒ^４a、Ｒ^４b、Ｒ^４c及びＲ^４ｄは、同一又は異なって、水素原子又は置換基群αの定義におけるハロゲン原子、Ｃ_１−Ｃ_６アルキル基、Ｃ_１−Ｃ_６ハロゲン化アルキル基、Ｃ_１−Ｃ_３アルコキシ−Ｃ_１−Ｃ_６アルキル基、Ｃ₃−Ｃ₆シクロアルキル基若しくはＣ_１−Ｃ_３アルコキシ基を示す。）である、（１）乃至（７）から選択されるいずれか１項に記載された医薬組成物、
（１２）Ｒ^４a、Ｒ^４b、Ｒ^４c及びＲ^４ｄは、同一又は異なって、水素原子、Ｃ_１−Ｃ_６アルキル基、Ｃ₃−Ｃ₆シクロアルキル基又はＣ_１−Ｃ_３アルコキシ−Ｃ_１−Ｃ_６アルキル基である、（１１）に記載された医薬組成物、
（１３）Ｒ^４a、Ｒ^４b、Ｒ^４c及びＲ^４ｄは、同一又は異なって、水素原子、メチル基、エチル基、プロピル基、イソプロピル基、シクロプロピル基又は２−メトキシエチル基である、（１１）に記載された医薬組成物、
（１４）Ｘ^１又はＸ^２が、下記から選択されるいずれか１つの式で表される基である、（１）乃至（７）から選択されるいずれか１項に記載された医薬組成物； (Wherein R ^4a , R ^4b , R ^4c and R ^4d are the same or different and are a hydrogen atom or a halogen atom in the definition of substituent group α, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ halogenated group). An alkyl group, a C ₁ -C ₃ alkoxy-C ₁ -C ₆ alkyl group, a C ₃ -C ₆ cycloalkyl group or a C ₁ -C ₃ alkoxy group.) Selected from (1) to (7) Any one of the above-mentioned pharmaceutical compositions,
(12) R ^4a , R ^4b , R ^4c and R ^4d are the same or different and are a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₃ -C ₆ cycloalkyl group or a C ₁ -C ₃ alkoxy-C _1. -C a _alkyl group, a pharmaceutical composition described in (11),
(13) R ^4a , R ^4b , R ^4c and R ^4d are the same or different and each is a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group or a 2-methoxyethyl group. ) The pharmaceutical composition described in
(14) The pharmaceutical composition according to any one of (1) to (7), wherein X ¹ or X ² is a group represented by any one formula selected from the following: ;

、
（１５）Ｒ^２が一般式（Ｒ^２ａ）で表される基であり、Ｘ^１がシクロプロピル基であり、ｎが１である、（１）乃至（７）から選択されるいずれか１項に記載された医薬組成物であり、
特に好適な医薬組成物は、
（１６）下記から選択される1つの化合物又はその薬理上許容される塩を有効成分として含有する医薬組成物：
３−アミノ−４−｛４−［４−（２−メチル−２Ｈ−テトラゾール−５−イル）フェニル］−１，４−ジアゼパン−１−イル｝チエノ［２，３−ｂ］ピリジン−２−カルボキサミド、
３−アミノ−４−｛４−［４−（１−メチル−１Ｈ−テトラゾール−５−イル）フェニル］−１，４−ジアゼパン−１−イル｝チエノ［２，３−ｂ］ピリジン−２−カルボキサミド、
３−アミノ−４−｛４−［４−（２−オキソピロリジン−１−イル）フェニル］−１，４−ジアゼパン−１−イル｝チエノ［２，３−ｂ］ピリジン−２−カルボキサミド、
３−アミノ−４−｛４−［４−（５−メチル−１，２，４−オキサジアゾール−３−イル）フェニル］−１，４−ジアゼパン−１−イル｝チエノ［２，３−ｂ］ピリジン−２−カルボキサミド、
３−アミノ−４−｛４−［４−（３−メチル−１，２，４−オキサジアゾール−５−イル）フェニル］−１，４−ジアゼパン−１−イル｝チエノ［２，３−ｂ］ピリジン−２−カルボキサミド、
３−アミノ−４−{４−[４−(２−オキソ−１，３−オキサゾリジン−３−イル)フェニル]−１，４−ジアゼパン-1-イル}チエノ[２，３−ｂ]ピリジン−２−カルボキサミド、
３−アミノ−４−{４−[４−(５−メチル−１，３，４−オキサジアゾール−２−イル)フェニル]−１，４−ジアゼパン−１−イル}チエノ[２，３−ｂ]ピリジン−２−カルボキサミド、
３−アミノ−４−（（３Ｓ）−３−{[（３−メチル−１,２,４−オキサジアゾール−５−イル）メトキシ]メチル}ピペリジン−１−イル）チエノ[２,３−ｂ]ピリジン−２−カルボキサミド、
３−アミノ−４−（（３Ｓ）−３−{［２−（２−メチル−２Ｈ−テトラゾール−５−イル）エトキシ］メチル}ピペリジン−１−イル）チエノ[２，３−ｂ]ピリジン−２−カルボキサミド、
３−アミノ−４−（３−｛〔（２−メチル−２Ｈ−テトラゾール−５−イル）メトキシ〕メチル｝ピペリジン−１−イル）チエノ〔２,３−ｂ〕ピリジン−２−カルボキサミド、
３−アミノ−４−｛（３Ｓ）−３−［（シクロプロピルメトキシ）メチル］ピペリジン−１−イル｝−６−メチルチエノ［２，３−ｂ］ピリジン−２−カルボキサミド、
３−アミノ−４−{（３Ｓ）−３−[（シクロプロピルメトキシ）メチル]ピペリジン−１−イル}チエノ[２，３−ｂ]ピリジン−２−カルボキサミド、
３−アミノ−６−メチル−４−（（３Ｓ）−３−｛［２−（２−メチル−２Ｈ−テトラゾール−５−イル）エトキシ］メチル｝ピペリジン−１−イル）チエノ［２，３−ｂ］ピリジン−２−カルボキサミド、
３−アミノ−４−（３−｛［２−（２−オキソ−１，３−オキサゾリジン−３−イル）エトキシ］メチル｝ピペリジン−１−イル）チエノ［２，３−ｂ］ピリジン−２−カルボキサミド、
３−アミノ−４−｛（３Ｓ）−３−［（ピリジン−２−イルメトキシ）メチル］ピペリジン−１−イル｝チエノ［２，３−ｂ］ピリジン−２−カルボキサミド、及び
３−アミノ−４−((３Ｓ)−３−{[２−(２Ｈ−テトラゾール−２−イル)エトキシ]メチル}ピペリジン−１−イル)チエノ[２，３−ｂ]ピリジン−２−カルボキサミド
又は
（１７）下記から選択される1つの化合物又はその薬理上許容される塩を有効成分として含有する医薬組成物：
３−アミノ−６−メチル−４−（（３Ｓ）−３−｛［（３−メチル−１，２，４−オキサジアゾール−５−イル）メトキシ］メチル｝ピペリジン−１−イル）チエノ［２，３−ｂ］ピリジン−２−カルボキサミド、
３−アミノ−４−（（３Ｓ）−3−｛［（5−メチル−１，２，４−オキサジアゾール−３−イル）メトキシ］メチル｝ピペリジン−１−イル）チエノ［２，３−ｂ］ピリジン−２−カルボキサミド、
３−アミノ−６−メチル−４−（（３Ｓ）−３−｛［（５−メチル−１，２，４−オキサジアゾール−３−イル）メトキシ］メチル｝ピペリジン−１−イル）チエノ［２，３−ｂ］ピリジン−２−カルボキサミド、
３−アミノ−４−｛（３Ｓ）−3−［（ピリジン−３−イルメトキシ）メチル］ピペリジン−１−イル）チエノ［２，３−ｂ］ピリジン−２−カルボキサミド、
３−アミノ−６−メチル−４−｛（３Ｓ）−3−［（ピリジン−３−イルメトキシ）メチル］ピペリジン−１−イル）チエノ［２，３−ｂ］ピリジン−２−カルボキサミド、
３−アミノ−６−メチル−４−（（３Ｓ）−３−｛［（１−メチル−１Ｈ−イミダゾール−５−イル）メトキシ］メチル｝ピペリジン−１−イル）チエノ［２，３−ｂ］ピリジン−２−カルボキサミド、
３−アミノ−４−((３Ｓ)−３−{[(１−メチル−１Ｈ−イミダゾール−２−イル)メトキシ]メチル}ピペリジン−１−イル)チエノ[２，３−ｂ]ピリジン−２−カルボキサミド、
３−アミノ−４−((３Ｓ)−３−｛［（１−エチル−１Ｈ−イミダゾール−５−イル)メトキシ]メチル}ピペリジン−１−イル) −６−メチルチエノ[２，３−ｂ]ピリジン−２−カルボキサミド、
３−アミノ−４−((３Ｓ)−３−{[２−(１Ｈ−イミダゾール−１−イル)エトキシ]メチル}ピペリジン−１−イル)チエノ[２，３−ｂ]ピリジン−２−カルボキサミド、
３−アミノ−４−((３Ｓ)−３−{[２−(１Ｈ−イミダゾール−１−イル)エトキシ]メチル}ピペリジン−１−イル) −６−メチルチエノ[２，３−ｂ]ピリジン−２−カルボキサミド、
３−アミノ−４−（（３Ｓ）−３−｛［２−（１Ｈ−１，２，３−トリアゾール−１−イル）エトキシ］メチル｝ピペリジン−１−イル）チエノ［２，３−ｂ］ピリジン−２−カルボキサミド、
３−アミノ−４−((３Ｓ)−３−{[２−(１Ｈ−１，２，４−トリアゾール−１−イル)エトキシ]メチル}ピペリジン−１−イル)チエノ[２，３−ｂ]ピリジン−２−カルボキサミド、
３−アミノ−６−メチルー４−（（３Ｓ）−｛［２−（１Ｈ−１，２，４−トリアゾール−１−イル）エトキシ］メチル｝ピペリジン−１−イル）チエノ［２，３−ｂ］ピリジン−２−カルボキサミド、
３−アミノ−６−メチル−４−((３Ｓ)−３−{[２−(２Ｈ−テトラゾール−２−イル)エトキシ]メチル}ピペリジン−１−イル)チエノ[２，３−ｂ]ピリジン−２−カルボキサミド、
３−アミノ−４−((３Ｓ)−３−{[２−(１Ｈ−テトラゾール−１−イル)エトキシ]メチル}ピペリジン−１−イル)チエノ[２，３−ｂ]ピリジン−２−カルボキサミド、
３−アミノ−６−メチル−４−((３Ｓ)−３−{[２−(１Ｈ−テトラゾール−１−イル)エトキシ]メチル}ピペリジン−１−イル)チエノ[２，３−ｂ]ピリジン−２−カルボキサミド、
３−アミノ−４−((３Ｓ)−３−{[２−(５−メチル−１Ｈ−テトラゾール−１−イル)エトキシ]メチル}ピペリジン−１−イル)チエノ[２，３−ｂ]ピリジン−２−カルボキサミド、
３−アミノ−６−メチル−４−((３Ｓ)−３−{[２−(５−メチル−１Ｈ−テトラゾール−１−イル)エトキシ]メチル}ピペリジン−１−イル)チエノ[２，３−ｂ]ピリジン−２−カルボキサミド、
３−アミノ−６−メチル−４−((３Ｓ)−３−{[３−(１Ｈ−テトラゾール−１−イル)プロポキシ]メチル}ピペリジン−１−イル)チエノ[２，３−ｂ]ピリジン−２−カルボキサミド、
３−アミノ−４−((３Ｓ)−３−{[３−(２Ｈ−テトラゾール−２−イル)プロポキシ]メチル}ピペリジン−１−イル)チエノ[２，３−ｂ]ピリジン−２−カルボキサミド、
３−アミノ−６−メチル−４−((３Ｓ)−３−{[３−(２Ｈ−テトラゾール−２−イル)プロポキシ]メチル}ピペリジン−１−イル)チエノ[２，３−ｂ]ピリジン−２−カルボキサミド、
３−アミノ−４−（（３Ｓ）−３−｛［２−（１−エチル−１Ｈ−テトラゾール−５−イル）エトキシ］メチル｝ピペリジン−１−イル）チエノ［２，３−ｂ］ピリジン−２−カルボキサミド、
３−アミノ−４−（（３Ｓ）−３−｛［２−（１−エチル−１Ｈ−テトラゾール−５−イル）エトキシ］メチル｝ピペリジン−１−イル）−６−メチルチエノ［２，３−ｂ］ピリジン−２−カルボキサミド、
３−アミノ−６−メチル−４−（（３Ｓ）−３−｛［２−（１−プロピル−１Ｈ−テトラゾール−５−イル）エトキシ］メチル｝ピペリジン−１−イル）チエノ［２，３−ｂ］ピリジン−２−カルボキサミド、
３−アミノ−４−((３Ｓ)−３−{[２−(１−イソプロピル−１Ｈ−テトラゾール−５−イル)エトキシ]メチル}ピペリジン−１−イル) −６−メチルチエノ[２，３−ｂ]ピリジン−２−カルボキサミド、
３−アミノ−４−((３Ｓ)−３−{[２−(１−シクロプロピル−１Ｈ−テトラゾール−５−イル)エトキシ]メチル}ピペリジン−１−イル) −６−メチルチエノ[２，３−ｂ]ピリジン−２−カルボキサミド、及び
３−アミノ−４−［（３Ｓ）−３−（｛２−［１−（２−メトキシエチル）−１Ｈ−テトラゾール−５−イル］エトキシ｝メチル）ピペリジン−１−イル］−６−メチルチエノ［２，３−ｂ］ピリジン−２−カルボキサミド
である。 ,
(15) Any one selected from (1) to (7), wherein R ² is a group represented by the general formula (R ² a), X ¹ is a cyclopropyl group, and n is 1. The pharmaceutical composition described in the paragraph,
Particularly preferred pharmaceutical compositions are
(16) A pharmaceutical composition comprising as an active ingredient one compound selected from the following or a pharmacologically acceptable salt thereof:
3-Amino-4- {4- [4- (2-methyl-2H-tetrazol-5-yl) phenyl] -1,4-diazepan-1-yl} thieno [2,3-b] pyridine-2- Carboxamide,
3-Amino-4- {4- [4- (1-methyl-1H-tetrazol-5-yl) phenyl] -1,4-diazepan-1-yl} thieno [2,3-b] pyridine-2- Carboxamide,
3-amino-4- {4- [4- (2-oxopyrrolidin-1-yl) phenyl] -1,4-diazepan-1-yl} thieno [2,3-b] pyridine-2-carboxamide;
3-Amino-4- {4- [4- (5-methyl-1,2,4-oxadiazol-3-yl) phenyl] -1,4-diazepan-1-yl} thieno [2,3- b] pyridine-2-carboxamide,
3-Amino-4- {4- [4- (3-methyl-1,2,4-oxadiazol-5-yl) phenyl] -1,4-diazepan-1-yl} thieno [2,3- b] pyridine-2-carboxamide,
3-Amino-4- {4- [4- (2-oxo-1,3-oxazolidine-3-yl) phenyl] -1,4-diazepan-1-yl} thieno [2,3-b] pyridine- 2-carboxamide,
3-Amino-4- {4- [4- (5-methyl-1,3,4-oxadiazol-2-yl) phenyl] -1,4-diazepan-1-yl} thieno [2,3- b] pyridine-2-carboxamide,
3-Amino-4-((3S) -3-{[(3-methyl-1,2,4-oxadiazol-5-yl) methoxy] methyl} piperidin-1-yl) thieno [2,3- b] pyridine-2-carboxamide,
3-Amino-4-((3S) -3-{[2- (2-methyl-2H-tetrazol-5-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine- 2-carboxamide,
3-amino-4- (3-{[(2-methyl-2H-tetrazol-5-yl) methoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide;
3-amino-4-{(3S) -3-[(cyclopropylmethoxy) methyl] piperidin-1-yl} -6-methylthieno [2,3-b] pyridine-2-carboxamide,
3-amino-4-{(3S) -3-[(cyclopropylmethoxy) methyl] piperidin-1-yl} thieno [2,3-b] pyridine-2-carboxamide,
3-Amino-6-methyl-4-((3S) -3-{[2- (2-methyl-2H-tetrazol-5-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3- b] pyridine-2-carboxamide,
3-Amino-4- (3-{[2- (2-oxo-1,3-oxazolidine-3-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine-2- Carboxamide,
3-amino-4-{(3S) -3-[(pyridin-2-ylmethoxy) methyl] piperidin-1-yl} thieno [2,3-b] pyridine-2-carboxamide, and 3-amino-4- ((3S) -3-{[2- (2H-tetrazol-2-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide or (17) selected from A pharmaceutical composition comprising one active compound or a pharmacologically acceptable salt thereof as an active ingredient:
3-Amino-6-methyl-4-((3S) -3-{[(3-methyl-1,2,4-oxadiazol-5-yl) methoxy] methyl} piperidin-1-yl) thieno [ 2,3-b] pyridine-2-carboxamide,
3-Amino-4-((3S) -3-{[(5-methyl-1,2,4-oxadiazol-3-yl) methoxy] methyl} piperidin-1-yl) thieno [2,3- b] pyridine-2-carboxamide,
3-amino-6-methyl-4-((3S) -3-{[(5-methyl-1,2,4-oxadiazol-3-yl) methoxy] methyl} piperidin-1-yl) thieno [ 2,3-b] pyridine-2-carboxamide,
3-amino-4-{(3S) -3-[(pyridin-3-ylmethoxy) methyl] piperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide;
3-amino-6-methyl-4-{(3S) -3-[(pyridin-3-ylmethoxy) methyl] piperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide;
3-Amino-6-methyl-4-((3S) -3-{[(1-methyl-1H-imidazol-5-yl) methoxy] methyl} piperidin-1-yl) thieno [2,3-b] Pyridine-2-carboxamide,
3-Amino-4-((3S) -3-{[(1-methyl-1H-imidazol-2-yl) methoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine-2- Carboxamide,
3-Amino-4-((3S) -3-{[(1-ethyl-1H-imidazol-5-yl) methoxy] methyl} piperidin-1-yl) -6-methylthieno [2,3-b] pyridine -2-carboxamide,
3-amino-4-((3S) -3-{[2- (1H-imidazol-1-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide;
3-Amino-4-((3S) -3-{[2- (1H-imidazol-1-yl) ethoxy] methyl} piperidin-1-yl) -6-methylthieno [2,3-b] pyridine-2 -Carboxamide,
3-Amino-4-((3S) -3-{[2- (1H-1,2,3-triazol-1-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b] Pyridine-2-carboxamide,
3-Amino-4-((3S) -3-{[2- (1H-1,2,4-triazol-1-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b] Pyridine-2-carboxamide,
3-Amino-6-methyl-4-((3S)-{[2- (1H-1,2,4-triazol-1-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b ] Pyridine-2-carboxamide,
3-Amino-6-methyl-4-((3S) -3-{[2- (2H-tetrazol-2-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine- 2-carboxamide,
3-amino-4-((3S) -3-{[2- (1H-tetrazol-1-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide;
3-Amino-6-methyl-4-((3S) -3-{[2- (1H-tetrazol-1-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine- 2-carboxamide,
3-Amino-4-((3S) -3-{[2- (5-methyl-1H-tetrazol-1-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine- 2-carboxamide,
3-Amino-6-methyl-4-((3S) -3-{[2- (5-methyl-1H-tetrazol-1-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3- b] pyridine-2-carboxamide,
3-Amino-6-methyl-4-((3S) -3-{[3- (1H-tetrazol-1-yl) propoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine- 2-carboxamide,
3-amino-4-((3S) -3-{[3- (2H-tetrazol-2-yl) propoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide;
3-Amino-6-methyl-4-((3S) -3-{[3- (2H-tetrazol-2-yl) propoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine- 2-carboxamide,
3-Amino-4-((3S) -3-{[2- (1-ethyl-1H-tetrazol-5-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine- 2-carboxamide,
3-Amino-4-((3S) -3-{[2- (1-ethyl-1H-tetrazol-5-yl) ethoxy] methyl} piperidin-1-yl) -6-methylthieno [2,3-b ] Pyridine-2-carboxamide,
3-Amino-6-methyl-4-((3S) -3-{[2- (1-propyl-1H-tetrazol-5-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3- b] pyridine-2-carboxamide,
3-Amino-4-((3S) -3-{[2- (1-isopropyl-1H-tetrazol-5-yl) ethoxy] methyl} piperidin-1-yl) -6-methylthieno [2,3-b ] Pyridine-2-carboxamide,
3-amino-4-((3S) -3-{[2- (1-cyclopropyl-1H-tetrazol-5-yl) ethoxy] methyl} piperidin-1-yl) -6-methylthieno [2,3- b] Pyridin-2-carboxamide and 3-amino-4-[(3S) -3-({2- [1- (2-methoxyethyl) -1H-tetrazol-5-yl] ethoxy} methyl) piperidine- 1-yl] -6-methylthieno [2,3-b] pyridine-2-carboxamide.

本発明は、更に、
（１８）骨疾患又は変形性関節症の予防若しくは治療のための、（１）乃至（１７）から選択されるいずれか１項に記載された医薬組成物、
（１９）骨疾患が、骨粗鬆症、関節リウマチに伴う骨減少症若しくは骨破壊、骨ページェット病、骨折、又は小人症に起因する骨形成不全である、（１８）に記載された医薬組成物、及び、
（２０）骨粗鬆症が、閉経後骨粗鬆症、老人性骨粗鬆症又はステロイドや免疫抑制剤の使用による続発性骨粗鬆症である、（１９）に記載された医薬組成物
に関する。 The present invention further provides:
(18) The pharmaceutical composition according to any one of (1) to (17) for prevention or treatment of bone disease or osteoarthritis,
(19) The pharmaceutical composition according to (18), wherein the bone disease is osteogenesis due to osteoporosis, osteopenia or bone destruction associated with rheumatoid arthritis, Paget's disease, fracture, or dwarfism. ,as well as,
(20) The pharmaceutical composition according to (19), wherein the osteoporosis is postmenopausal osteoporosis, senile osteoporosis, or secondary osteoporosis due to use of a steroid or an immunosuppressant.

上記一般式（Ｉ）において、
Ｒ^１、Ｒ^３、Ｒ^４a、Ｒ^４b、Ｒ^４c、Ｒ^４ｄ及び置換基群αの定義における「Ｃ_１−Ｃ_６アルキル基」；並びに置換基群αの定義における「Ｃ_１−Ｃ_３アルコキシ−Ｃ_１−Ｃ_６アルキル基」のＣ_１−Ｃ_６アルキル部分は、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓ−ブチル、tert−ブチル、ペンチル、イソペンチル、２−メチルブチル、ネオペンチル、１−エチルプロピル、ヘキシル、イソヘキシル、４−メチルペンチル、３−メチルペンチル、２−メチルペンチル、１−メチルペンチル、３，３−ジメチルブチル、２，２−ジメチルブチル、１，１−ジメチルブチル、１，２−ジメチルブチル、１，３−ジメチルブチル、２，３−ジメチルブチル又は２−エチルブチル基のような直鎖若しくは分枝鎖アルキル基であり得る。Ｒ^１の「Ｃ_１−Ｃ_６アルキル基」としては、好適には、Ｃ_１−Ｃ_４直鎖若しくは分枝鎖アルキル基であり、最も好適には、メチル基である。Ｒ^３の「Ｃ_１−Ｃ_６アルキル基」としては、好適には、Ｃ_１−Ｃ_４直鎖若しくは分枝鎖アルキル基であり、更に好適には、Ｃ_１−Ｃ_２直鎖若しくは分枝鎖アルキル基であり、最も好適には、メチル基である。Ｒ^４a、Ｒ^４b、Ｒ^４c、Ｒ^４ｄ及び置換基群αの「Ｃ_１−Ｃ_６アルキル基」としては、好適にはＣ_１−Ｃ_４直鎖若しくは分枝鎖アルキル基であり、最も好適には、メチル、エチル、プロピル又はイソプロピル基である。 In the general formula (I),
R ¹ , R ³ , R ^4a , R ^4b , R ^4c , R ^4d and “C ₁ -C ₆ alkyl group” in the definition of substituent group α; and “C ₁ -C ₃ alkoxy in the definition of substituent group α _C 1 -C ₆ alkyl moiety of the -C ₁ -C ₆ alkyl group "include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s- butyl, tert- butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1 -Ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1 , 2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl or 2-ethylbutyl groups, It can be an alkyl group. The “C ₁ -C ₆ alkyl group” for R ¹ is preferably a C ₁ -C ₄ linear or branched alkyl group, and most preferably a methyl group. The “C ₁ -C ₆ alkyl group” for R ³ is preferably a C ₁ -C ₄ linear or branched alkyl group, more preferably a C ₁ -C ₂ linear or branched group. A chain alkyl group, and most preferably a methyl group. R ^4a , R ^4b , R ^4c , R ^4d and the “C ₁ -C ₆ alkyl group” of the substituent group α are preferably C ₁ -C ₄ linear or branched alkyl groups, most preferably Is a methyl, ethyl, propyl or isopropyl group.

Ｘ^１及びＸ^２の定義における「置換基群αから選択される１乃至４個の基で置換されていてもよい５又は６員ヘテロシクリル基」の５又は６員ヘテロシクリル基とは、硫黄原子、酸素原子及び／若しくは窒素原子を１乃至３個含む５又は６員飽和ヘテロシクリル基若しくは部分飽和ヘテロシクリル基を意味し、例えば、ピロリジニル、ジヒドロピロリル、イミダゾリジニル、ジヒドロイミダゾリル、ピラゾリジニル、ジヒドロピラゾリル、オキサゾリジニル、チアゾリジニル、ジヒドロオキサジアゾリル、オキサジアゾリジニル、ジヒドロチアゾリル、ジヒドロイソキサゾリル、ピペリジル、ジヒドロピリジニル、テトラヒドロピリジニル、ジヒドロピリミジニル、テトラヒドロピリミジニル、ヘキサヒドロピリミジニル、１，３−オキサジナニル、ピラニル、ジヒドロピラニル、テトラヒドロピラニル、テトラヒドロフラニル、ジヒドロフラニル、ピペラジニル、モルホリニル又はチオモルホリニルであり得、好適には、窒素原子を１個含み、更に、硫黄原子、酸素原子及び／又は窒素原子を１又は２個含んでもよい５又は６員ヘテロシクリル基であり、最も好適には、ピロリジニル、イミダゾリジニル、ジヒドロイミダゾリル、ジヒドロオキサジアゾリル、ジヒドロオキサゾリル、ジヒドロチアゾリル、ジヒドロイソキサゾリル、ピペリジル、ヘキサヒドロピリミジニル、1，3−オキサジナニル又はオキサゾリジニルである。 The 5- or 6-membered heterocyclyl group in the “5- or 6-membered heterocyclyl group optionally substituted with 1 to 4 groups selected from the substituent group α” in the definition of X ¹ and X ² is a sulfur atom, Means a 5- or 6-membered saturated or partially saturated heterocyclyl group containing 1 to 3 oxygen and / or nitrogen atoms, such as pyrrolidinyl, dihydropyrrolyl, imidazolidinyl, dihydroimidazolyl, pyrazolidinyl, dihydropyrazolyl, oxazolidinyl, thiazolidinyl , Dihydrooxadiazolyl, oxadiazolidinyl, dihydrothiazolyl, dihydroisoxazolyl, piperidyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, hexahydropyrimidinyl, 1,3-oxadi Nanyl, pyranyl, dihydropyranyl, tetrahydropyranyl, tetrahydrofuranyl, dihydrofuranyl, piperazinyl, morpholinyl or thiomorpholinyl, preferably containing one nitrogen atom, and further comprising a sulfur atom, oxygen atom and / or nitrogen 5- or 6-membered heterocyclyl groups which may contain 1 or 2 atoms, most preferably pyrrolidinyl, imidazolidinyl, dihydroimidazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydrothiazolyl, dihydroisoxazolyl , Piperidyl, hexahydropyrimidinyl, 1,3-oxadinanyl or oxazolidinyl.

尚、Ｘ^１又はＸ^２が置換基群αから選択される１乃至４個の基で置換されていてもよい５又は６員飽和ヘテロシクリル基である場合は、当該基は少なくとも１つのオキソ基で置換されている基である。 When X ¹ or X ² is a 5- or 6-membered saturated heterocyclyl group optionally substituted with 1 to 4 groups selected from the substituent group α, the group is at least one oxo group. A group that is substituted.

Ｘ^１及びＸ^２の定義における「置換基群αから選択される１乃至４個の基で置換されていてもよい５又は６員ヘテロアリール基」の５又は６員ヘテロアリール基は、硫黄原子、酸素原子及び／若しくは窒素原子を１乃至４個含む５又は６員ヘテロアリール基を意味し、例えば、フリル、チエニル、ピロリル、ピラゾリル、イミダゾリル、オキサゾリル、イソキサゾリル、チアゾリル、イソチアゾリル、トリアゾリル、オキサジアゾリル、チアジアゾリル、テトラゾリル、ピリジル、ピリダジニル、ピリミジニル又はピラジニルであり得、好適には、ピラゾリル、イミダゾリル、オキサゾリル、イソキサゾリル、チアゾリル、イソチアゾリル、トリアゾリル、オキサジアゾリル、チアジアゾリル、テトラゾリル、ピリジル、ピリダジニル、ピリミジニル又はピラジニルであり得、特に好適には、イミダゾリル、トリアゾリル、オキサジアゾリル、テトラゾリル又はピリジルである。 The 5- or 6-membered heteroaryl group of the “5- or 6-membered heteroaryl group optionally substituted with 1 to 4 groups selected from the substituent group α” in the definition of X ¹ and X ² is a sulfur atom Represents a 5- or 6-membered heteroaryl group containing 1 to 4 oxygen atoms and / or nitrogen atoms, for example, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl , Tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl, preferably pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyr It can be midinyl or pyrazinyl, particularly preferably imidazolyl, triazolyl, oxadiazolyl, tetrazolyl or pyridyl.

Ｘ^１及びＸ^２の定義における「置換基群αから選択される１乃至４個の基で置換されていてもよい５又は６員ヘテロシクリル基」及び「置換基群αから選択される１乃至４個の基で置換されていてもよい５又は６員ヘテロアリール基」としては、好適には、下記から選択されるいずれか１つの一般式で表される基 “5 or 6-membered heterocyclyl group optionally substituted with 1 to 4 groups selected from substituent group α” and “1 to 4 selected from substituent group α” in the definition of X ¹ and X ² As the “5- or 6-membered heteroaryl group optionally substituted with one group”, preferably, a group represented by any one general formula selected from the following:

（式中、Ｒ^４a、Ｒ^４b、Ｒ^４c及びＲ^４ｄは、同一又は異なって、水素原子又は置換基群αの定義におけるハロゲン原子、Ｃ_１−Ｃ_６アルキル基、Ｃ_１−Ｃ_６ハロゲン化アルキル基、Ｃ_１−Ｃ_３アルコキシ−Ｃ_１−Ｃ_６アルキル基、Ｃ₃−Ｃ₆シクロアルキル基若しくはＣ_１−Ｃ_３アルコキシ基を示す。）であり、更に好適には、下記から選択されるいずれか１つの一般式で表される基 (Wherein R ^4a , R ^4b , R ^4c and R ^4d are the same or different and are a hydrogen atom or a halogen atom in the definition of substituent group α, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ halogenated group). An alkyl group, a C ₁ -C ₃ alkoxy-C ₁ -C ₆ alkyl group, a C ₃ -C ₆ cycloalkyl group or a C ₁ -C ₃ alkoxy group), and more preferably selected from the following: A group represented by any one general formula

（式中、Ｒ^４a、Ｒ^４b、Ｒ^４c及びＲ^４ｄは、同一又は異なって、水素原子又は置換基群αの定義におけるハロゲン原子、Ｃ_１−Ｃ_６アルキル基、Ｃ_１−Ｃ_６ハロゲン化アルキル基、Ｃ_１−Ｃ_３アルコキシ−Ｃ_１−Ｃ_６アルキル基、Ｃ₃−Ｃ₆シクロアルキル基若しくはＣ_１−Ｃ_３アルコキシ基を示し、好適には、同一又は異なって、水素原子、Ｃ_１−Ｃ_６アルキル基、Ｃ₃−Ｃ₆シクロアルキル基又はＣ_１−Ｃ_３アルコキシ−Ｃ_１−Ｃ_６アルキル基であり、最も好適には、同一又は異なって、水素原子、メチル基、エチル基、プロピル基、イソプロピル基、シクロプロピル基又は２−メトキシエチル基である）であり、最も好適には、下記から選択されるいずれか１つの一般式で表される基 (Wherein R ^4a , R ^4b , R ^4c and R ^4d are the same or different and are a hydrogen atom or a halogen atom in the definition of substituent group α, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ halogenated group). An alkyl group, a C ₁ -C ₃ alkoxy-C ₁ -C ₆ alkyl group, a C ₃ -C ₆ cycloalkyl group or a C ₁ -C ₃ alkoxy group, preferably the same or different, a hydrogen atom, ₁ -C ₆ alkyl group, a C ₃ -C ₆ cycloalkyl group or a _C 1 -C ₃ alkoxy _-C 1 -C ₆ alkyl group, and most preferably are the same or different, a hydrogen atom, a methyl group, ethyl Group, propyl group, isopropyl group, cyclopropyl group or 2-methoxyethyl group), and most preferably a group represented by any one general formula selected from the following:

、
である。 ,
It is.

Ｘ^１の定義における「置換基群αから選択される１乃至３個の基で置換されていてもよいシクロプロピル基」は、好適には、シクロプロピル又は２−メチルシクロプロピルであり、最も好適には、シクロプロピルである。 The “cyclopropyl group optionally substituted with 1 to 3 groups selected from substituent group α” in the definition of X ¹ is preferably cyclopropyl or 2-methylcyclopropyl, most preferably Is cyclopropyl.

Ｒ^４a、Ｒ^４b、Ｒ^４c、Ｒ^４ｄ及び置換基群αの定義における「ハロゲン原子」は、フッ素原子、塩素原子、臭素原子又はヨウ素原子であり、好適には、フッ素原子又は塩素原子である。 “Halogen atom” in the definition of R ^4a , R ^4b , R ^4c , R ^4d and substituent group α is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom or a chlorine atom. .

Ｒ^４a、Ｒ^４b、Ｒ^４c、Ｒ^４ｄ及び置換基群αの定義における「Ｃ_１−Ｃ_６ハロゲン化アルキル基」は、前記「Ｃ_１−Ｃ_６アルキル基」の１個若しくは２個以上の水素原子が上記「ハロゲン原子」で置換された基であり、好適には、Ｃ_１−Ｃ_４ハロゲン化アルキル基であり、更に好適にはトリフルオロメチル、トリクロロメチル、ジフルオロメチル、ジクロロメチル、ジブロモメチル、フルオロメチル、２，２，２−トリクロロエチル、２，２，２−トリフルオロエチル、２−ブロモエチル、２−クロロエチル、２−フルオロエチル又は２，２−ジブロモエチル基であり、より更に好適には、トリフルオロメチル、トリクロロメチル、ジフルオロメチル又はフルオロメチル基であり、最も好適には、トリフルオロメチル基である。 “C ₁ -C ₆ halogenated alkyl group” in the definition of R ^4a , R ^4b , R ^4c , R ^4d and substituent group α is one or more of the above “C ₁ -C ₆ alkyl group” A hydrogen atom is a group substituted by the above “halogen atom”, preferably a C ₁ -C ₄ halogenated alkyl group, and more preferably trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromo Methyl, fluoromethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl or 2,2-dibromoethyl group, and more preferred Is a trifluoromethyl, trichloromethyl, difluoromethyl or fluoromethyl group, most preferably a trifluoromethyl group.

置換基群αの定義における「Ｃ_１−Ｃ_３アルコキシ基」；及び置換基群αの定義における「Ｃ_１−Ｃ_３アルコキシ−Ｃ_１−Ｃ_６アルキル基」のアルコキシ部分は、例えば、メトキシ、エトキシ、プロポキシ又はイソプロポキシであり得、好適には、メトキシ、エトキシ又はプロポキシ基であり、更に好適には、メトキシ又はエトキシ基であり、最も好適には、メトキシ基である。 The alkoxy moiety of “C ₁ -C ₃ alkoxy group” in the definition of substituent group α; and “C ₁ -C ₃ alkoxy-C ₁ -C ₆ alkyl group” in the definition of substituent group α is, for example, methoxy, It can be ethoxy, propoxy or isopropoxy, preferably a methoxy, ethoxy or propoxy group, more preferably a methoxy or ethoxy group, and most preferably a methoxy group.

Ｒ^４a、Ｒ^４b、Ｒ^４c、Ｒ^４ｄ及び置換基群αの定義における「Ｃ_３−Ｃ_６シクロアルキル基」は、シクロプロピル、シクロブチル、シクロペンチル又はシクロヘキシル基のような炭素数３乃至６の飽和環状炭化水素基であり、好適にはシクロプロピル基である。 “C ₃ -C ₆ cycloalkyl group” in the definition of R ^4a , R ^4b , R ^4c , R ^4d and substituent group α is a C 3-6 saturation such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group. A cyclic hydrocarbon group, preferably a cyclopropyl group.

Ｒ^４a、Ｒ^４b、Ｒ^４c、Ｒ^４ｄ及び置換基群αの定義における「Ｃ_１−Ｃ_３アルコキシ−Ｃ_１−Ｃ_６アルキル基」は、前記「Ｃ_１−Ｃ_６アルキル基」が前記「Ｃ_１−Ｃ_３アルコキシ基」で置換された基であり、好適には、メトキシメチル、１−メトキシエチル、２−メトキシエチル、３−メトキシプロピル、エトキシメチル、１−エトキシエチル、２−エトキシエチル又はプロポキシメチル基であり、更に好適には、２−メトキシエチル、３−メトキシプロピル又は２−エトキシエチル基であり、最も好適には、２−メトキシエチル基である。 In the definition of R ^4a , R ^4b , R ^4c , R ^4d and substituent group α, the “C ₁ -C ₃ alkoxy-C ₁ -C ₆ alkyl group” is the same as the above “C ₁ -C ₆ alkyl group”. A group substituted with a “C ₁ -C ₃ alkoxy group”, preferably methoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 3-methoxypropyl, ethoxymethyl, 1-ethoxyethyl, 2-ethoxyethyl Or a propoxymethyl group, more preferably a 2-methoxyethyl, 3-methoxypropyl or 2-ethoxyethyl group, and most preferably a 2-methoxyethyl group.

「その薬理上許容される塩」とは、本発明の化合物（Ｉ）は、酸又は塩基と反応させることにより、塩にすることができるので、その塩を示す。 The “pharmacologically acceptable salt” indicates the salt of the compound (I) of the present invention because it can be converted into a salt by reacting with an acid or a base.

塩基性の官能基に基づく塩は、例えば、塩酸塩、臭化水素酸塩若しくは沃化水素酸塩のようなハロゲン化水素酸塩、硝酸塩、過塩素酸塩、硫酸塩又は燐酸塩等の無機酸塩；メタンスルホン酸塩、トリフルオロメタンスルホン酸塩若しくはエタンスルホン酸塩のような低級アルカンスルホン酸塩、ベンゼンスルホン酸塩若しくはｐ−トルエンスルホン酸塩のようなアリールスルホン酸塩又は酢酸塩、りんご酸塩、フマール酸塩、コハク酸塩、クエン酸塩、アスコルビン酸塩、酒石酸塩、蓚酸塩若しくはマレイン酸塩のようなカルボン酸塩等の有機酸塩；或いは、グリシン塩、リジン塩、アルギニン塩、オルニチン塩、グルタミン酸塩又はアスパラギン酸塩のようなアミノ酸塩であり得る。 Salts based on basic functional groups are inorganic, such as hydrohalides such as hydrochloride, hydrobromide or hydroiodide, nitrates, perchlorates, sulfates or phosphates. Acid salt; lower alkane sulfonate such as methane sulfonate, trifluoromethane sulfonate or ethane sulfonate, aryl sulfonate such as benzene sulfonate or p-toluene sulfonate or acetate, apple Acid salt, fumarate salt, succinate salt, citrate salt, ascorbate salt, tartrate salt, carboxylic acid salt such as succinate salt or maleate salt; or glycine salt, lysine salt, arginine salt Or an amino acid salt such as ornithine, glutamate or aspartate.

酸性の官能基に基づく塩は、例えば、ナトリウム塩、カリウム塩若しくはリチウム塩のようなアルカリ金属塩、カルシウム塩若しくはマグネシウム塩のようなアルカリ土類金属塩、アルミニウム塩、又は鉄塩等の金属塩；アンモニウム塩；ｔ−オクチルアミン塩、ジベンジルアミン塩、モルホリン塩、グルコサミン塩、フェニルグリシンアルキルエステル塩、エチレンジアミン塩、Ｎ−メチルグルカミン塩、グアニジン塩、ジエチルアミン塩、トリエチルアミン塩、ジシクロヘキシルアミン塩、Ｎ，Ｎ’−ジベンジルエチレンジアミン塩、クロロプロカイン塩、プロカイン塩、ジエタノールアミン塩、Ｎ−ベンジルフェネチルアミン塩、ピペラジン塩、テトラメチルアンモニウム塩又はトリス（ヒドロキシメチル）アミノメタン塩のような有機アミン塩；或いは、グリシン塩、リジン塩、アルギニン塩、オルニチン塩、グルタミン酸塩又はアスパラギン酸塩のようなアミノ酸塩であり得る。 Salts based on acidic functional groups include, for example, alkali metal salts such as sodium salt, potassium salt or lithium salt, alkaline earth metal salts such as calcium salt or magnesium salt, aluminum salts, or metal salts such as iron salts. Ammonium salt; t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, Presence such as N, N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt or tris (hydroxymethyl) aminomethane salt Amine salts; or glycine salts, lysine salts, arginine salts, ornithine salts, amino acid salts such as glutamate or aspartate.

本発明にかかる一般式（Ｉ）を有する化合物又はその薬理上許容される塩は、大気中に放置したり、又は、再結晶をすることにより、水分を吸収し、吸着水が付いたり、水和物となる場合があり、そのような水和物も本発明に包含される。 The compound having the general formula (I) or a pharmacologically acceptable salt thereof according to the present invention absorbs moisture by being left in the atmosphere or recrystallized, and adsorbed water is attached. Such hydrates are also included in the present invention.

本発明にかかる一般式（Ｉ）を有する化合物には、分子内の不斉中心に基づく光学異性体が存在する場合がある。本発明にかかる化合物においては、これらの異性体およびこれらの異性体の混合物がすべて単一の式、即ち一般式（Ｉ）で示されている。従って、本発明はこれらの異性体およびこれらの異性体の任意の割合の混合物をもすべて含む。 The compound having the general formula (I) according to the present invention may have an optical isomer based on an asymmetric center in the molecule. In the compounds according to the present invention, these isomers and mixtures of these isomers are all represented by a single formula, that is, the general formula (I). Accordingly, the present invention includes all of these isomers and mixtures of these isomers in any proportion.

本発明にかかる一般式（Ｉ）を有する化合物又はその薬理上許容される塩は、骨形成を促進する作用、骨吸収を抑制する作用及び／又は骨密度を改善する作用を有するので、本発明にかかる一般式（Ｉ）を有する化合物又はその薬理上許容される塩を有効成分として含有する組成物は、医薬｛特に、骨疾患［例えば、骨粗鬆症（例えば、閉経後骨粗鬆症、老人性骨粗鬆症又はステロイドや免疫抑制剤の使用による続発性骨粗鬆症）、関節リウマチに伴う骨減少症若しくは骨破壊、骨ページェット病、骨折、又は小人症に起因する骨形成不全］又は変形性関節症の予防若しくは治療のための医薬｝として有用である。 The compound having the general formula (I) according to the present invention or a pharmacologically acceptable salt thereof has an action of promoting bone formation, an action of suppressing bone resorption, and / or an action of improving bone density. The composition containing the compound having the general formula (I) or the pharmacologically acceptable salt thereof as an active ingredient is a pharmaceutical {especially bone disease [for example, osteoporosis (for example, postmenopausal osteoporosis, senile osteoporosis or steroids). Or secondary osteoporosis due to the use of immunosuppressive agents), osteopenia or bone destruction associated with rheumatoid arthritis, Paget's disease, bone fracture, or osteogenesis due to dwarfism] or prevention or treatment of osteoarthritis It is useful as a pharmaceutical for

本発明にかかる一般式（Ｉ）を有する化合物は、以下に記載する方法によって製造することができる。
＜Ａ法＞
一般式（Ｉ）において、Ｒ^１が水素原子である化合物は、Ａ法に従って製造することができる。 The compound having the general formula (I) according to the present invention can be produced by the method described below.
<Method A>
In general formula (I), a compound in which R ¹ is a hydrogen atom can be produced according to Method A.

［式中、Ｒ^２は、前記と同意義を示し、
Ｒ^５は、メチル又はエチルを示し、
Ｒ^６、Ｒ^７、Ｒ^８及びＲ^９は、それぞれ、Ｃ_１−Ｃ_６アルキル基（好適には、メチル、エチル又はイソプロピル、特に好適には、メチル）を示し、
Ｒ^１０は、ハロゲン原子（好適には、塩素原子又は臭素原子、特に好適には、塩素原子）を示す。］
第１工程は、化合物（１）とアミン化合物（２）とを、不活性溶媒中で反応させ、化合物（３）を製造する工程であり、Ｊ．Ｏｒｇ．Ｃｈｅｍ，（１９６２）２７，２４３３−２４３９に記載された方法に準じて実施することができる。 [Wherein R ² represents the same meaning as described above,
R ⁵ represents methyl or ethyl,
R ⁶ , R ⁷ , R ⁸ and R ⁹ each represent a C ₁ -C ₆ alkyl group (preferably methyl, ethyl or isopropyl, particularly preferably methyl);
R ¹⁰ represents a halogen atom (preferably a chlorine atom or a bromine atom, particularly preferably a chlorine atom). ]
The first step is a step of producing compound (3) by reacting compound (1) and amine compound (2) in an inert solvent. Org. Chem, (1962) 27, 2433-2439.

使用される不活性溶媒は、例えば、メタノール、エタノール、プロパノール、２−プロパノール又はブタノールのようなアルコール類；ベンゼン、トルエン又はキシレンのような芳香族炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン又は１，２−ジメトキシエタンのようなエーテル類；Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、Ｎ−メチル−２−ピロリドン、Ｎ−メチルピロリジノン又はヘキサメチルホスホロトリアミドのようなアミド類；或いは、メチレンクロリド、クロロホルム、四塩化炭素、ジクロロエタン、クロロベンゼン、ｏ−ジクロロベンゼン、ｍ−ジクロロベンゼン、フルオロベンゼン、トリクロロメチルベンゼン又はトリフルオロメチルベンゼンのようなハロゲン化炭化水素類であり得、好適には、メタノール、エタノール又はＮ，Ｎ−ジメチルホルムアミドである。 Inert solvents used are, for example, alcohols such as methanol, ethanol, propanol, 2-propanol or butanol; aromatic hydrocarbons such as benzene, toluene or xylene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane Or ethers such as 1,2-dimethoxyethane; amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphorotriamide Or, like methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene, fluorobenzene, trichloromethylbenzene or trifluoromethylbenzene; It obtained a halogenated hydrocarbon, preferably, methanol, ethanol or N, N- dimethylformamide.

反応温度は、原料化合物又は使用される溶媒によって変化するが、通常、０℃ 乃至反応混合物の還流温度であり、好適には、室温乃至反応混合物の還流温度である。 The reaction temperature varies depending on the raw material compound or the solvent used, but is usually 0 ° C. to the reflux temperature of the reaction mixture, preferably room temperature to the reflux temperature of the reaction mixture.

反応時間は、原料化合物、使用される溶媒又は反応温度によって異なるが、通常、３０分間乃至９６時間であり、好適には、３０分間乃至２４時間である。 While the reaction time varies depending on the raw material compound, the solvent used and the reaction temperature, it is generally 30 minutes to 96 hours, preferably 30 minutes to 24 hours.

反応終了後、反応液を濾過して得られる析出物、又は溶媒を留去して得られる残留物を、特に精製することなく、次の工程（第２工程）で使用することができる。また、不活性溶媒としてアミド類を用いた場合には、反応溶液をそのまま次の工程で使用することができる。 After completion of the reaction, the precipitate obtained by filtering the reaction solution or the residue obtained by distilling off the solvent can be used in the next step (second step) without any particular purification. When amides are used as the inert solvent, the reaction solution can be used as it is in the next step.

第２工程は、化合物（３）とＮ，Ｎ−ジアルキルホルムアミドジアルキルアセタール（４）とを不活性溶媒中で反応させ、アミジン誘導体（５）を製造する工程である。 The second step is a step for producing the amidine derivative (5) by reacting the compound (3) with N, N-dialkylformamide dialkylacetal (4) in an inert solvent.

反応に用いられるＮ，Ｎ−ジアルキルホルムアミドジアルキルアセタール（４）の量は、好適には、１当量の化合物（３）に対して、１乃至２当量である。 The amount of N, N-dialkylformamide dialkylacetal (4) used in the reaction is preferably 1 to 2 equivalents relative to 1 equivalent of compound (3).

反応温度は、原料化合物又は使用される溶媒によって変化するが、通常、０℃ 乃至反応混合物の還流温度であり、好適には、室温である。 The reaction temperature varies depending on the raw material compound or the solvent used, but is usually from 0 ° C. to the reflux temperature of the reaction mixture, preferably room temperature.

反応終了後、反応液を濾過して得られる析出物、又は溶媒を留去して得られる残留物を、特に精製することなく、次の工程（第３工程）で使用することができる。また、不活性溶媒としてアミド類を用いた場合には、反応溶液をそのまま次の工程で使用することができる。 After completion of the reaction, the precipitate obtained by filtering the reaction solution or the residue obtained by distilling off the solvent can be used in the next step (third step) without any particular purification. When amides are used as the inert solvent, the reaction solution can be used as it is in the next step.

第３工程は、不活性溶媒中でアミジン誘導体（５）を処理することによりチオピリドン誘導体（６）を製造する工程である。 The third step is a step of producing the thiopyridone derivative (6) by treating the amidine derivative (5) in an inert solvent.

使用される不活性溶媒は、例えば、メタノール、エタノール、プロパノール、２−プロパノール又はブタノールのようなアルコール類；ベンゼン、トルエン又はキシレンのような芳香族炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン又は１，２−ジメトキシエタンのようなエーテル類；Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、Ｎ−メチル−２−ピロリドン、Ｎ−メチルピロリジノン又はヘキサメチルホスホロトリアミドのようなアミド類；或いは、メチレンクロリド、クロロホルム、四塩化炭素、ジクロロエタン、クロロベンゼン、ｏ−ジクロロベンゼン、ｍ−ジクロロベンゼン、フルオロベンゼン、トリクロロメチルベンゼン又はトリフルオロメチルベンゼンのようなハロゲン化炭化水素類であり得、好適には、エタノール又はＮ，Ｎ−ジメチルホルムアミドであり、特に好適には、Ｎ，Ｎ−ジメチルホルムアミドである。 Inert solvents used are, for example, alcohols such as methanol, ethanol, propanol, 2-propanol or butanol; aromatic hydrocarbons such as benzene, toluene or xylene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane Or ethers such as 1,2-dimethoxyethane; amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphorotriamide Or, like methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene, fluorobenzene, trichloromethylbenzene or trifluoromethylbenzene; Obtained a halogenated hydrocarbon, preferably, ethanol or N, a N- dimethylformamide, particularly preferably, N, it is N- dimethylformamide.

反応温度は、原料化合物又は使用される溶媒によって変化するが、通常、室温乃至反応混合物の還流温度であり、好適には、５０℃乃至１２０℃である。 While the reaction temperature varies depending on the raw material compound or the solvent used, it is generally room temperature to the reflux temperature of the reaction mixture, preferably 50 ° C. to 120 ° C.

反応時間は、原料化合物、使用される溶媒又は反応温度によって異なるが、通常、１０分間乃至６時間であり、好適には、１０分間乃至２時間である。 While the reaction time varies depending on the raw material compound, the solvent used or the reaction temperature, it is generally 10 minutes to 6 hours, preferably 10 minutes to 2 hours.

反応終了後、必要により、目的化合物は常法（抽出、カラムクロマトグラフィー、濾過及び濃縮）に従って、反応混合物から採取される。また、不活性溶媒としてアミド類を用いた場合には、反応溶液をそのまま次の工程（第４工程）で使用することができる。 After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method (extraction, column chromatography, filtration and concentration) as necessary. When amides are used as the inert solvent, the reaction solution can be used as it is in the next step (fourth step).

第４工程は、チオピリドン誘導体（６）とα−ハロアセトアミド（７）とを不活性溶媒中、塩基の存在下で反応させ、チエノピリジン誘導体（Ｉａ）を製造する工程である。 The fourth step is a step of producing a thienopyridine derivative (Ia) by reacting the thiopyridone derivative (6) with α-haloacetamide (7) in an inert solvent in the presence of a base.

使用される不活性溶媒は、例えば、メタノール、エタノール、プロパノール、２−プロパノール又はブタノールのようなアルコール類；或いは、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、Ｎ−メチル−２−ピロリドン、Ｎ−メチルピロリジノン又はヘキサメチルホスホロトリアミドのようなアミド類であり得、好適には、エタノール又はＮ，Ｎ−ジメチルホルムアミドである。 Inert solvents used are, for example, alcohols such as methanol, ethanol, propanol, 2-propanol or butanol; or N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone , N-methylpyrrolidinone or amides such as hexamethylphosphorotriamide, preferably ethanol or N, N-dimethylformamide.

使用される塩基は、例えば、ナトリウムメトキシド、ナトリウムエトキシド、カリウムtert−ブトキシド又はリチウムメトキシドのようなアルカリ金属アルコキシド類；水酸化ナトリウム、水酸化カリウム又は水酸化リチウムのようなアルカリ金属水酸化物類；或いは、上記アルカリ金属水酸化物の水溶液であり得、好適には、ナトリウムエトキシド又は水酸化ナトリウム水溶液である。 Bases used are, for example, alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide or lithium methoxide; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide. Or an aqueous solution of the above alkali metal hydroxide, preferably sodium ethoxide or aqueous sodium hydroxide.

反応温度は、原料化合物、使用される溶媒又は塩基によって変化するが、通常、０℃ 乃至反応混合物の還流温度であり、好適には、室温乃至反応混合物の還流温度である。 The reaction temperature varies depending on the raw material compound, the solvent or base used, and is usually 0 ° C. to the reflux temperature of the reaction mixture, preferably room temperature to the reflux temperature of the reaction mixture.

反応時間は、原料化合物、使用される溶媒、塩基又は反応温度によって異なるが、通常、１０分間乃至６時間であり、好適には、３０分間乃至２時間である。 While the reaction time varies depending on the raw material compound, the solvent used, the base, or the reaction temperature, it is generally 10 minutes to 6 hours, and preferably 30 minutes to 2 hours.

反応終了後、必要により、目的化合物は常法に従って、反応混合物から採取される。 After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method if necessary.

例えば、反応混合物に水を加えて析出する目的化合物を濾過する；又は、反応混合物を適宜中和し、また、不溶物が存在する場合にはろ過により除去した後、水を加え、酢酸エチル又はトルエンのような水に混和しない有機溶剤で抽出し、水等で洗浄し、抽出液を無水硫酸マグネシウム等で乾燥した後、溶剤を留去することによって得られる。 For example, water is added to the reaction mixture and the target compound precipitated is filtered; or the reaction mixture is appropriately neutralized, and if any insoluble matter is present, it is removed by filtration, water is added, and ethyl acetate or Extraction is performed with an organic solvent that is not miscible with water, such as toluene, washing with water or the like, drying the extract with anhydrous magnesium sulfate or the like, and then distilling off the solvent.

得られた化合物は必要ならば、常法、例えばシリカゲルカラムクロマトグラフィーで分離、精製することができる。 If necessary, the obtained compound can be separated and purified by a conventional method such as silica gel column chromatography.

第５工程は、化合物（３）とＮ，Ｎ−ジアルキルホルムアミドジアルキルアセタール（４）とを不活性溶媒中で反応させ、アミジン誘導体（８）を製造する工程である。 The fifth step is a step for producing the amidine derivative (8) by reacting the compound (3) with N, N-dialkylformamide dialkylacetal (4) in an inert solvent.

使用される不活性溶媒は、例えば、メタノール、エタノール、プロパノール、２−プロパノール又はブタノールのようなアルコール類；ベンゼン、トルエン又はキシレンのような芳香族炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン又は１，２−ジメトキシエタンのようなエーテル類；Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、Ｎ−メチル−２−ピロリドン、Ｎ−メチルピロリジノン又はヘキサメチルホスホロトリアミドのようなアミド類；或いは、メチレンクロリド、クロロホルム、四塩化炭素、ジクロロエタン、クロロベンゼン、ｏ−ジクロロベンゼン、ｍ−ジクロロベンゼン、フルオロベンゼン、トリクロロメチルベンゼン又はトリフルオロメチルベンゼンのようなハロゲン化炭化水素類であり得、好適には、芳香族炭化水素類であり、特に好適には、トルエンである。 Inert solvents used are, for example, alcohols such as methanol, ethanol, propanol, 2-propanol or butanol; aromatic hydrocarbons such as benzene, toluene or xylene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane Or ethers such as 1,2-dimethoxyethane; amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphorotriamide Or, like methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene, fluorobenzene, trichloromethylbenzene or trifluoromethylbenzene; It obtained a halogenated hydrocarbon, preferably, an aromatic hydrocarbon, particularly preferably toluene.

反応に用いられるＮ，Ｎ−ジアルキルホルムアミドジアルキルアセタール（４）の量は、好適には、１当量の化合物（３）に対して、２乃至３当量である。 The amount of N, N-dialkylformamide dialkylacetal (4) used in the reaction is preferably 2 to 3 equivalents relative to 1 equivalent of compound (3).

反応温度は、原料化合物又は使用される溶媒によって変化するが、通常、０℃乃至反応混合物の還流温度であり、好適には、室温乃至反応混合物の還流温度である。 The reaction temperature varies depending on the raw material compound or the solvent used, but is usually 0 ° C. to the reflux temperature of the reaction mixture, preferably room temperature to the reflux temperature of the reaction mixture.

反応時間は、原料化合物、使用される溶媒又は反応温度によって異なるが、通常、３分間乃至６時間であり、好適には、３分間乃至２時間である。 While the reaction time varies depending on the raw material compound, the solvent used or the reaction temperature, it is generally 3 minutes to 6 hours, preferably 3 minutes to 2 hours.

反応終了後、溶媒を減圧下で留去して得られる残留物を、特に精製することなく、次の工程（第６工程）で使用することができる。 After completion of the reaction, the residue obtained by distilling off the solvent under reduced pressure can be used in the next step (sixth step) without any particular purification.

第６工程は、アミジン誘導体（８）をアルカリ性水溶液で処理することによりチオピリドン誘導体（６）を製造する工程である。 The sixth step is a step of producing the thiopyridone derivative (6) by treating the amidine derivative (8) with an alkaline aqueous solution.

使用されるアルカリ性水溶液は、例えば、アルカリ金属水酸化物（例えば、水酸化ナトリウム、水酸化カリウム又は水酸化リチウム）の水溶液であり得、好適には、水酸化ナトリウム水溶液である。 The alkaline aqueous solution used can be, for example, an aqueous solution of an alkali metal hydroxide (for example, sodium hydroxide, potassium hydroxide or lithium hydroxide), and preferably an aqueous sodium hydroxide solution.

反応温度は、原料化合物又は使用される溶媒によって変化するが、通常、室温乃至反応混合物の還流温度であり、好適には、反応混合物の還流温度である。 The reaction temperature varies depending on the raw material compound or the solvent used, but is usually room temperature to the reflux temperature of the reaction mixture, and preferably the reflux temperature of the reaction mixture.

反応時間は、原料化合物、使用される溶媒又は反応温度によって異なるが、通常、１０分間乃至２時間であり、好適には、３０分間乃至１時間である。 While the reaction time varies depending on the raw material compound, the solvent used or the reaction temperature, it is generally 10 minutes to 2 hours, preferably 30 minutes to 1 hour.

反応終了後、必要により、目的化合物は常法（抽出、カラムクロマトグラフィー、濾過及び濃縮）に従って、反応混合物から採取される。
＜Ｂ法＞
一般式（Ｉ）において、Ｒ^１がＣ_１−Ｃ_６アルキル基である化合物は、Ｂ法に従って製造することができる。 After completion of the reaction, if necessary, the target compound is collected from the reaction mixture according to a conventional method (extraction, column chromatography, filtration and concentration).
<Method B>
In general formula (I), a compound in which R ¹ is a C ₁ -C ₆ alkyl group can be produced according to Method B.

（式中、Ｒ^２、Ｒ^５、Ｒ^６、Ｒ^７、Ｒ^８、Ｒ^９、及びＲ^１０は、前記と同意義を示し、Ｒ^１’は、Ｒ^１の定義におけるＣ_１−Ｃ_６アルキル基を示し、Ｒ^１１は、ＣＯＮＨ_２又はＣＮを示す。）
第７工程は、化合物（９）とアミン化合物（２）とを、不活性溶媒中で反応させ、化合物（１０）を製造する工程であり、第１工程に記載された方法と同様の方法で実施される。 Wherein R ² , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are as defined above, and R ^{1 ′} is C ₁ -C ₆ alkyl in the definition of R ¹ And R ¹¹ represents CONH ₂ or CN.)
The seventh step is a step of producing compound (10) by reacting compound (9) and amine compound (2) in an inert solvent, and is the same method as described in the first step. To be implemented.

第８工程は、Ｒ^１１がＣＯＮＨ_２である化合物（１０）と（Ｎ，Ｎ−ジアルキル）アルキルアミドジアルキルアセタール（１１）とを不活性溶媒中で反応させ、ピリドン誘導体（１２）を製造する工程であり、Ｐｈａｒｍ．Ｃｈｅｍ．Ｊ．（Ｅｎｇｌ．Ｔｒａｎｓｌ．）２５，（１９９１），６２３−６２８に記載された方法に準じて実施することができる。
The eighth step is a step of producing a pyridone derivative (12) by reacting a compound (10) in which R ¹¹ is CONH ₂ with (N, N-dialkyl) alkylamide dialkylacetal (11) in an inert solvent. Pharm. Chem. J. et al. (Engl. Transl.) 25, (1991), 623-628.

使用される不活性溶媒は、例えば、ベンゼン、トルエン又はキシレンのような芳香族炭化水素類；或いは、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、Ｎ−メチル−２−ピロリドン、Ｎ−メチルピロリジノン又はヘキサメチルホスホロトリアミドのようなアミド類であり得、好適には、アミド類であり、特に好適には、Ｎ，Ｎ−ジメチルホルムアミドである。 Inert solvents used are, for example, aromatic hydrocarbons such as benzene, toluene or xylene; or N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N- Amides such as methylpyrrolidinone or hexamethylphosphorotriamide may be used, preferably amides, and particularly preferably N, N-dimethylformamide.

反応温度は、原料化合物又は使用される溶媒によって変化するが、通常、室温乃至反応混合物の還流温度であり、好適には、５０℃乃至反応混合物の還流温度である。 While the reaction temperature varies depending on the raw material compound or the solvent used, it is generally room temperature to the reflux temperature of the reaction mixture, preferably 50 ° C. to the reflux temperature of the reaction mixture.

反応時間は、原料化合物、使用される溶媒又は反応温度によって異なるが、通常、1時間乃至２４時間であり、好適には、１時間乃至５時間である。 The reaction time varies depending on the raw material compound, the solvent used, or the reaction temperature, but is usually 1 hour to 24 hours, and preferably 1 hour to 5 hours.

例えば、反応混合物を適宜中和し、また、不溶物が存在する場合にはろ過により除去した後、水を加え、酢酸エチル又はトルエンのような水に混和しない有機溶剤で抽出し、水等で洗浄し、抽出液を無水硫酸マグネシウム等で乾燥した後、溶剤を留去することによって得られる。 For example, the reaction mixture is appropriately neutralized, and if insoluble matter is present, it is removed by filtration, water is added, and the mixture is extracted with an organic solvent that is not miscible with water, such as ethyl acetate or toluene. After washing and drying the extract with anhydrous magnesium sulfate or the like, it is obtained by distilling off the solvent.

第９工程は、ピリドン誘導体（１２）を、塩基の存在下又は非存在下、ハロゲン化剤を用いてハロゲン化することにより、クロロピリジン誘導体（１３）を製造する工程である。 The ninth step is a step of producing the chloropyridine derivative (13) by halogenating the pyridone derivative (12) with a halogenating agent in the presence or absence of a base.

不活性溶媒中で反応をおこなう場合、溶媒としては、例えば、ベンゼン、トルエン又はキシレンのような芳香族炭化水素類；或いは、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン又は１，２−ジメトキシエタンのようなエーテル類が用いられ、好適には、トルエン又はジオキサンが用いられる。 When the reaction is carried out in an inert solvent, examples of the solvent include aromatic hydrocarbons such as benzene, toluene or xylene; or diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane or 1,2-dimethoxyethane. Ethers are used, and preferably toluene or dioxane is used.

使用される塩基は、例えば、トリエチルアミン、トリブチルアミン、ジイソプロピルエチルアミン、Ｎ−メチルモルホリン、ピリジン、４−（Ｎ，Ｎ−ジメチルアミノ）ピリジン、Ｎ，Ｎ−ジメチルアニリン、Ｎ，Ｎ−ジエチルアニリン、１，５−ジアザビシクロ［４．３．０］ノナ−５−エン、１，４−ジアザビシクロ［２．２．２］オクタン（ＤＡＢＣＯ）又は１，８−ジアザビシクロ［５．４．０］−７−ウンデセン（ＤＢＵ）のような有機アミン類であり得、特に好適には、Ｎ，Ｎ−ジメチルアニリンである。 Examples of the base used include triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1 , 5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO) or 1,8-diazabicyclo [5.4.0] -7-undecene Organic amines such as (DBU) can be used, and N, N-dimethylaniline is particularly preferable.

使用されるハロゲン化剤は、例えば、三塩化リン、五塩化リン又はオキシ塩化リンのような塩化リン類；或いは、塩化チオニルであり得、好適には、五塩化リン、オキシ塩化リン又は塩化チオニルである。 The halogenating agent used can be, for example, phosphorus chlorides such as phosphorus trichloride, phosphorus pentachloride or phosphorus oxychloride; or thionyl chloride, preferably phosphorus pentachloride, phosphorus oxychloride or thionyl chloride It is.

反応温度は、原料化合物、溶媒、塩基又はハロゲン化剤によって変化するが、通常、室温乃至反応混合物の還流温度であり、好適には、５０℃乃至反応混合物の還流温度である。 The reaction temperature varies depending on the raw material compound, solvent, base or halogenating agent, and is usually room temperature to the reflux temperature of the reaction mixture, preferably 50 ° C. to the reflux temperature of the reaction mixture.

反応時間は、原料化合物、溶媒、塩基、ハロゲン化剤又は反応温度によって異なるが、通常、１時間乃至２４時間であり、好適には、1時間乃至８時間である。 While the reaction time varies depending on the raw material compound, solvent, base, halogenating agent or reaction temperature, it is generally 1 hour to 24 hours, preferably 1 hour to 8 hours.

第１０工程は、クロロピリジン誘導体（１３）と２−メルカプトアセトアミド（１４）とを、不活性溶媒中、塩基の存在下で反応させて、チエノピリジン誘導体（Ｉｂ）を製造する工程である。 The tenth step is a step of producing a thienopyridine derivative (Ib) by reacting the chloropyridine derivative (13) and 2-mercaptoacetamide (14) in an inert solvent in the presence of a base.

使用される不活性溶媒は、例えば、メタノール、エタノール、プロパノール、２−プロパノール又はブタノールのようなアルコール類；ベンゼン、トルエン又はキシレンのような芳香族炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン又は１，２−ジメトキシエタンのようなエーテル類；或いは、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、Ｎ−メチル−２−ピロリドン、Ｎ−メチルピロリジノン又はヘキサメチルホスホロトリアミドのようなアミド類であり得、好適には、アルコール類又はアミド類であり、更に好適には、エタノール又はＮ，Ｎ−ジメチルホルムアミドである。 Inert solvents used are, for example, alcohols such as methanol, ethanol, propanol, 2-propanol or butanol; aromatic hydrocarbons such as benzene, toluene or xylene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane Or ethers such as 1,2-dimethoxyethane; or N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphorotriamide It may be an amide, preferably an alcohol or amide, more preferably ethanol or N, N-dimethylformamide.

反応温度は、原料化合物、使用される溶媒又は塩基によって変化するが、通常、室温乃至反応混合物の還流温度である。 The reaction temperature varies depending on the raw material compound, the solvent or base used, and is usually room temperature to the reflux temperature of the reaction mixture.

反応時間は、原料化合物、使用される溶媒、塩基又は反応温度によって異なるが、通常、１時間乃至２４時間であり、好適には、１時間乃至２時間である。 While the reaction time varies depending on the raw material compound, the solvent used, the base, or the reaction temperature, it is generally 1 hour to 24 hours, preferably 1 hour to 2 hours.

第１１工程は、Ｒ^１１がＣＮである化合物（１０）と（Ｎ，Ｎ−ジアルキル）アルキルアミドジアルキルアセタール（１１）とを不活性溶媒中又は無溶媒中で反応させ、エナミン誘導体（１５）を製造する工程である。 In the eleventh step, the compound (10) in which R ¹¹ is CN and (N, N-dialkyl) alkylamide dialkylacetal (11) are reacted in an inert solvent or in the absence of a solvent to give the enamine derivative (15). It is a manufacturing process.

不活性溶媒中で反応を行なう場合、使用される不活性溶媒は、例えば、メタノール、エタノール、プロパノール、２−プロパノール又はブタノールのようなアルコール類；ベンゼン、トルエン又はキシレンのような芳香族炭化水素類；或いは、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、Ｎ−メチル−２−ピロリドン、Ｎ−メチルピロリジノン又はヘキサメチルホスホロトリアミドのようなアミド類であり得、好適には、アルコール類、芳香族炭化水素類又はアミド類であり、特に好適には、メタノール、エタノール、キシレン又はＮ，Ｎ−ジメチルホルムアミドである。 When the reaction is carried out in an inert solvent, the inert solvent used is, for example, an alcohol such as methanol, ethanol, propanol, 2-propanol or butanol; an aromatic hydrocarbon such as benzene, toluene or xylene. Or amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphorotriamide, preferably alcohols , Aromatic hydrocarbons or amides, particularly preferably methanol, ethanol, xylene or N, N-dimethylformamide.

反応時間は、原料化合物、使用される溶媒又は反応温度によって異なるが、通常、1時間乃至２４時間であり、好適には、１時間乃至８時間である。 While the reaction time varies depending on the raw material compound, the solvent used, or the reaction temperature, it is generally 1 hour to 24 hours, preferably 1 hour to 8 hours.

第１２工程は、エナミン誘導体（１５）を酸で処理して、ピリドン誘導体（１２）を製造する工程である。 The twelfth step is a step of producing the pyridone derivative (12) by treating the enamine derivative (15) with an acid.

使用される酸は、例えば、塩酸などの無機酸；或は、ギ酸、酢酸、トリフルオロ酢酸又はポリリン酸などの有機酸であり得、好適には、塩酸、酢酸又はポリリン酸である。 The acid used can be, for example, an inorganic acid such as hydrochloric acid; or an organic acid such as formic acid, acetic acid, trifluoroacetic acid or polyphosphoric acid, preferably hydrochloric acid, acetic acid or polyphosphoric acid.

反応を不活性溶媒中でおこなう場合、溶媒としては、例えば、ベンゼン、トルエン又はキシレンのような芳香族炭化水素類；Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、Ｎ−メチル−２−ピロリドン、Ｎ−メチルピロリジノン又はヘキサメチルホスホロトリアミドのようなアミド類；メタノール又はエタノールのようなアルコール類；或いは、水又は水と上記溶媒との混合溶媒であり得、特に好適には、水である。 When the reaction is carried out in an inert solvent, examples of the solvent include aromatic hydrocarbons such as benzene, toluene or xylene; N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2- Amides such as pyrrolidone, N-methylpyrrolidinone or hexamethylphosphorotriamide; alcohols such as methanol or ethanol; or water or a mixed solvent of water and the above solvent, particularly preferably water is there.

反応温度は、原料化合物又は使用される酸によって変化するが、通常、室温乃至反応混合物の還流温度であり、好適には、５０℃乃至反応混合物の還流温度である。 The reaction temperature varies depending on the starting compound or the acid used, but is usually room temperature to the reflux temperature of the reaction mixture, preferably 50 ° C. to the reflux temperature of the reaction mixture.

反応時間は、原料化合物、使用される酸又は反応温度によって異なるが、通常、1時間乃至２４時間であり、好適には、１時間乃至８時間である。 While the reaction time varies depending on the raw material compound, the acid used, or the reaction temperature, it is generally 1 hour to 24 hours, preferably 1 hour to 8 hours.

第１２Ｂ工程は、エナミン誘導体（１５）にハロゲン化剤を反応させて、クロロピリジン誘導体（１３）を製造する工程である。 Step 12B is a step for producing a chloropyridine derivative (13) by reacting an enamine derivative (15) with a halogenating agent.

不活性溶媒中で反応を行う場合、溶媒としては、例えば、ベンゼン、トルエン又はキシレンのような芳香族炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン又は１，２−ジメトキシエタンのようなエーテル類；或いはメタノール、エタノール、プロパノール、２−プロパノール又はブタノールのようなアルコール類が用いられ、好適には、ジオキサン、メタノール又はエタノールが用いられる。 When the reaction is carried out in an inert solvent, examples of the solvent include aromatic hydrocarbons such as benzene, toluene or xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane or 1,2-dimethoxyethane. Or alcohols such as methanol, ethanol, propanol, 2-propanol or butanol, preferably dioxane, methanol or ethanol.

使用されるハロゲン化剤は、例えば、三塩化リン、五塩化リン又はオキシ塩化リンのような塩化リン類；塩化チオニルのような塩化スルホン類；塩化トリメチルシラン、塩化ｔ−ブチルジメチルシランのようなクロロシラン類；塩化オキサリルのような酸クロリド類；或いは塩化水素又は臭化水素のような無機酸類であり得、好適にはメタノール又はエタノール溶媒と塩化チオニル、塩化トリメチルシラン又は塩化オキサリルの組み合わせ；或は、メタノール、エタノール、ジオキサン溶媒又はメタノールとジオキサンとの混合溶媒と塩化水素との組み合わせである。 The halogenating agents used are, for example, phosphorus chlorides such as phosphorus trichloride, phosphorus pentachloride or phosphorus oxychloride; sulfones such as thionyl chloride; trimethylsilane chloride, t-butyldimethylsilane chloride Chlorosilanes; acid chlorides such as oxalyl chloride; or inorganic acids such as hydrogen chloride or hydrogen bromide, preferably a combination of methanol or ethanol solvent and thionyl chloride, trimethylsilane chloride or oxalyl chloride; or , Methanol, ethanol, dioxane solvent or a mixed solvent of methanol and dioxane and a combination of hydrogen chloride.

ただし、臭化水素酸を用いた場合には、ブロモピリジン誘導体が得られる。 However, when hydrobromic acid is used, a bromopyridine derivative is obtained.

反応温度は、原料化合物、溶媒又はハロゲン化剤によって変化するが、通常、０℃乃至反応混合物の還流温度であり、好適には室温乃至反応混合物の還流温度である。 The reaction temperature varies depending on the raw material compound, the solvent or the halogenating agent, but is usually 0 ° C. to the reflux temperature of the reaction mixture, preferably room temperature to the reflux temperature of the reaction mixture.

反応時間は、原料化合物、溶媒又はハロゲン化剤によって異なるが、通常、１０分間乃至２４時間であり、好適には３０分間乃至１２時間である。 While the reaction time varies depending on the raw material compound, the solvent or the halogenating agent, it is generally 10 minutes to 24 hours, preferably 30 minutes to 12 hours.

例えば、反応混合物を適宜中和し、また、不溶物が存在する場合にはろ過により除去した後、水を加え、酢酸エチル又はトルエンのような水に混和しない有機溶媒で抽出し、水等で洗浄し、抽出液を無水硫酸マグネシウム等で乾燥した後、溶剤を除去することによって得られる。 For example, the reaction mixture is appropriately neutralized, and if insoluble matter is present, it is removed by filtration, water is added, and the mixture is extracted with an organic solvent that is not miscible with water, such as ethyl acetate or toluene. After washing and drying the extract with anhydrous magnesium sulfate or the like, it is obtained by removing the solvent.

第１３工程は、クロロピリジン誘導体（１３）とチオ尿素又はナトリウムスルフィド（好適には、チオ尿素）を不活性溶媒中で反応させて、チオピリドン誘導体（１６）を製造する工程である。 The thirteenth step is a step of producing the thiopyridone derivative (16) by reacting the chloropyridine derivative (13) with thiourea or sodium sulfide (preferably thiourea) in an inert solvent.

使用される不活性溶媒は、例えば、メタノール、エタノール、プロパノール、２−プロパノール又はブタノールのようなアルコール類；ベンゼン、トルエン又はキシレンのような芳香族炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、ジオキサン又は１，２−ジメトキシエタンのようなエーテル類；或いは上記溶媒の混合物であり得、好適には、アルコール類、芳香族炭化水素類又はアルコール類と芳香族炭化水素類の混合物であり、更に好適には、エタノール、トルエン又はエタノールとトルエンの混合物である。 Inert solvents used are, for example, alcohols such as methanol, ethanol, propanol, 2-propanol or butanol; aromatic hydrocarbons such as benzene, toluene or xylene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane Or ethers such as 1,2-dimethoxyethane; or a mixture of the above solvents, preferably alcohols, aromatic hydrocarbons or a mixture of alcohols and aromatic hydrocarbons, and more preferably Is ethanol, toluene or a mixture of ethanol and toluene.

触媒量の塩化水素を加えることにより反応時間を短縮することができる。 The reaction time can be shortened by adding a catalytic amount of hydrogen chloride.

反応時間は、原料化合物、使用される溶媒又は反応温度によって異なるが、通常、１０分間乃至４８時間であり、好適には、３０分間乃至２４時間である。 While the reaction time varies depending on the raw material compound, the solvent used or the reaction temperature, it is usually 10 minutes to 48 hours, preferably 30 minutes to 24 hours.

第１４工程は、チオピリドン誘導体（１６）とα−ハロアセトアミド（７）とを不活性溶媒中、塩基の存在下で反応させ、チエノピリジン誘導体（Ｉｂ）を製造する工程であり、第４工程に記載された方法と同様の方法で実施される。 The fourteenth step is a step of producing a thienopyridine derivative (Ib) by reacting the thiopyridone derivative (16) with α-haloacetamide (7) in the presence of a base in an inert solvent, which is described in the fourth step. It is carried out in a manner similar to that described.

本Ｂ法において、化合物（１１）に代えてＡ法で使用した化合物（４）を用いれば、一般式（Ｉ）において、Ｒ^１が水素原子である化合物を製造することができる。 In this method B, if compound (4) used in method A is used instead of compound (11), a compound in which R ¹ is a hydrogen atom in general formula (I) can be produced.

上記Ａ法及びＢ法において出発原料となる化合物（２）（＝Ｒ^２−Ｈ）のうち、その部分構造（即ち「Ｘ^１」又は「Ｘ^２」に該当する構造）としてヘテロシクリル又はヘテロアリールを有するものは、公知の化合物から、後述する参考例又は公知の方法（例えば、以下に列挙する文献）にしたがって、容易に製造することができる。
Ｔｅｔｒａｈｅｄｒｏｎ．Ｌｅｔｔ．，２００１，４２，１４４１−１４４４；
Ｊ．Ｐｒａｋｔ．Ｃｈｅｍ．，１９７３，３１５，１０５７−１０６６；
Ｊ．Ｈｅｔｅｒｏｃｙｃｌｅ．Ｃｈｅｍ．，１９８３，２０，１４３１−１４３３；
Ｓｙｎｔｈ．Ｃｏｍｍｕｎ．，２００２，３２，２４２７−２４３２；
Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９９２，３５，１４７２−１４８４；
Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９６７，１０，９８６；
Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９９６，３９，９５７−９６７；
Ｏｒｇ．Ｌｅｔｔ．，２００２，１８，３１２７−２１３０；
Ｓｙｎｔｈｅｓｉｓ，１９９６，１２，１４２８−１４３０；
Ｊ．Ｏｒｇ．Ｃｈｅｍ．，１９８０，４５，３７５０−３７５３；
Ｈｅｔｅｒｏｃｙｃｌｅｓ，１９９３，３６，４５５−４７２；
Ｊ．Ｏｒｇ．Ｃｈｅｍ．，２００３，６８，７３１６−７３２１；
Ｊ．Ｏｒｇ．Ｃｈｅｍ．，１９９５，６０，１０９０−１０９２；
Ｊ．Ｍｅｄ．Ｃｈｅｍ．，２００２，４５，２９４２−２９５２；
Ｊ．Ｏｒｇ．Ｃｈｅｍ．ＵＳＳＲ（ｅｎｇｌ．Ｔｒａｎｓｌ．）．，１９９４，２０，３５７−３６２；
Ｊ．Ｍｅｄ．Ｃｈｅｍ．，２００４，１２，２９９５−３００８；
ＷＯ９５２７６９２；
ＷＯ２００３０４２１８８；
ＷＯ２００２０７６９７８；
Ｊ，Ｏｒｇ．Ｃｈｅｍ．，１９９９，６４，２９４１−２９４３；
Ｃｈｅｍ．Ｐｈａｒｍ．Ｂｕｌｌ．，２０００，４８，１９３５−１９４６；
Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．，１９２３，４５，７８５−７９０；
ＵＳ３８６２１７２；
Ｊ．Ｐｒａｋｔ．Ｃｈｅｍ．，１９５４，４，５７−７５；
Ｊ．Ｍｅｄ．Ｃｈｅｍ．，２００３，４６，２８４−３０２；及び
Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９９８，１３，２３９０−２４１０。 Of the compound (2) (= R ² —H) which is the starting material in the above methods A and B, heterocyclyl or heteroaryl is selected as a partial structure thereof (ie, a structure corresponding to “X ¹ ” or “X ² ”). What has can be easily manufactured from a well-known compound according to the reference example mentioned later or a well-known method (for example, literature enumerated below).
Tetrahedron. Lett. , 2001, 42, 1441-1444;
J. et al. Prakt. Chem. 1973, 315, 1057-1066;
J. et al. Heterocycle. Chem. , 1983, 20, 1431-1433;
Synth. Commun. , 2002, 32, 2427-2432;
J. et al. Med. Chem. 1992, 35, 1472-1484;
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J. et al. Org. Chem. , 1980, 45, 3750-3753;
Heterocycles, 1993, 36, 455-472;
J. et al. Org. Chem. , 2003, 68, 7316-7321;
J. et al. Org. Chem. 1995, 60, 1090-1092;
J. et al. Med. Chem. , 2002, 45, 2942-2952;
J. et al. Org. Chem. USSR (engl. Transl.). 1994, 20, 357-362;
J. et al. Med. Chem. , 2004, 12, 2995-3008;
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WO 2003042188;
WO 2002076978;
J, Org. Chem. 1999, 64, 2941-2943;
Chem. Pharm. Bull. 2000, 48, 1935-1946;
J. et al. Am. Chem. Soc. , 1923, 45, 785-790;
US 3862172;
J. et al. Prakt. Chem. 1954, 4, 57-75;
J. et al. Med. Chem. , 2003, 46, 284-302; Med. Chem. 1998, 13, 2390-2410.

本発明にかかる一般式（Ｉ）を有する化合物又はその薬理上許容される塩は、骨形成を促進する作用、骨吸収を抑制する作用及び／又は骨密度を改善する作用を有するので、本発明にかかる一般式（Ｉ）を有する化合物又はその薬理上許容される塩を有効成分として含有する組成物は、医薬｛特に、骨疾患［例えば、骨粗鬆症（例えば、閉経後骨粗鬆症、老人性骨粗鬆症又はステロイドや免疫抑制剤の使用による続発性骨粗鬆症）、関節リウマチに伴う骨減少症若しくは骨破壊、骨ページェット病、骨折、又は小人症に起因する骨形成不全］又は変形性関節症の予防若しくは治療のための医薬｝として有用であり、哺乳動物（例えば、ヒト、ウマ、ウシ又はブタ、好適には、ヒト）若しくは鳥類（好適には、ニワトリ、更に好適には雌性ニワトリ）に投与することができる。その投与形態は、例えば、錠剤、カプセル剤、顆粒剤、散剤又はシロップ剤等による経口投与、或いは、注射剤又は座剤等による非経口投与であり得、そのための製剤は賦形剤、滑沢剤、結合剤、崩壊剤、安定剤、矯味矯臭剤、希釈剤などの添加剤を用いて周知の方法で製造される。 The compound having the general formula (I) according to the present invention or a pharmacologically acceptable salt thereof has an action of promoting bone formation, an action of suppressing bone resorption, and / or an action of improving bone density. The composition containing the compound having the general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient is a pharmaceutical {particularly a bone disease [for example, osteoporosis (for example, postmenopausal osteoporosis, senile osteoporosis or steroid Or secondary osteoporosis due to the use of immunosuppressive agents), osteopenia or bone destruction associated with rheumatoid arthritis, Paget's disease, bone fracture, or osteogenesis due to dwarfism] or prevention or treatment of osteoarthritis For use in mammals (eg, humans, horses, cows or pigs, preferably humans) or birds (preferably chickens, more preferably female chickens). It can be administered to re). The dosage form may be, for example, oral administration using tablets, capsules, granules, powders or syrups, or parenteral administration such as injections or suppositories. It is produced by a well-known method using additives such as an agent, a binder, a disintegrant, a stabilizer, a flavoring agent, and a diluent.

賦形剤は、例えば、乳糖、白糖、ぶどう糖、マンニット若しくはソルビットのような糖誘導体、トウモロコシデンプン、バレイショデンプン、α−デンプン、デキストリン若しくはカルボキシメチルデンプンのような澱粉誘導体、結晶セルロース、低置換度ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム若しくは内部架橋カルボキシメチルセルロースナトリウムのようなセルロース誘導体、アラビアゴム、デキストラン、又は、プルラン等の有機系賦形剤；或いは、軽質無水珪酸、合成珪酸アルミニウム若しくはメタ珪酸アルミン酸マグネシウムのような珪酸塩誘導体、燐酸カルシウムのような燐酸塩、炭酸カルシウムのような炭酸塩、又は、硫酸カルシウムのような硫酸塩等の無機系賦形剤であり得る。 Excipients include, for example, sugar derivatives such as lactose, sucrose, glucose, mannitol or sorbit, starch derivatives such as corn starch, potato starch, α-starch, dextrin or carboxymethyl starch, crystalline cellulose, low degree of substitution Organic excipients such as hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium or internally cross-linked sodium carboxymethylcellulose sodium, gum arabic, dextran, or pullulan; or light anhydrous silicic acid, synthetic silicic acid Silicate derivatives such as aluminum or magnesium metasilicate aluminate, phosphates such as calcium phosphate, carbonates such as calcium carbonate, or It may be inorganic excipients such as sulfuric acid salts, such as calcium.

滑沢剤は、例えば、ステアリン酸、ステアリン酸カルシウム若しくはステアリン酸マグネシウムのようなステアリン酸金属塩；タルク；コロイドシリカ；ビーガム若しくはゲイ蝋のようなワックス類；硼酸；アジピン酸；硫酸ナトリウムのような硫酸塩；グリコール；フマル酸；安息香酸ナトリウム；ＤＬ−ロイシン；脂肪酸ナトリウム塩；ラウリル硫酸ナトリウム若しくはラウリル硫酸マグネシウムのようなラウリル硫酸塩；無水珪酸若しくは珪酸水和物のような珪酸類；又は、上記澱粉誘導体であり得る。 Lubricants include, for example, stearic acid metal salts such as stearic acid, calcium stearate or magnesium stearate; talc; colloidal silica; waxes such as bee gum or gay wax; boric acid; adipic acid; sulfuric acid such as sodium sulfate Salt; glycol; fumaric acid; sodium benzoate; DL-leucine; fatty acid sodium salt; lauryl sulfate such as sodium lauryl sulfate or magnesium lauryl sulfate; silicic acid such as anhydrous silicic acid or silicic acid hydrate; or the above starch It can be a derivative.

結合剤は、例えば、ポリビニルピロリドン若しくはマクロゴール、或いは、前記賦形剤と同様の化合物であり得る。 The binder may be, for example, polyvinyl pyrrolidone or macrogol, or a compound similar to the excipient.

崩壊剤は、例えば、前記賦形剤と同様の化合物、又は、クロスカルメロースナトリウム、カルボキシメチルスターチナトリウム若しくは架橋ポリビニルピロリドンのような化学修飾されたデンプン・セルロース類であり得る。 The disintegrant may be, for example, the same compound as the excipient, or a chemically modified starch / cellulose such as croscarmellose sodium, carboxymethyl starch sodium or crosslinked polyvinylpyrrolidone.

安定剤は、例えば、メチルパラベン若しくはプロピルパラベンのようなパラオキシ安息香酸エステル類；クロロブタノール、ベンジルアルコール若しくはフェニルエチルアルコールのようなアルコール類；塩化ベンザルコニウム；フェノール若しくはクレゾールのようなフェエノール類；チメロサール；デヒドロ酢酸；又は、ソルビン酸であり得る。 Stabilizers include, for example, paraoxybenzoates such as methyl paraben or propyl paraben; alcohols such as chlorobutanol, benzyl alcohol or phenylethyl alcohol; benzalkonium chloride; phenols such as phenol or cresol; thimerosal; Dehydroacetic acid; or sorbic acid.

矯味矯臭剤は、通常使用される甘味料、酸味料若しくは香料等であり得る。 The flavoring agent can be a commonly used sweetener, acidulant, fragrance or the like.

本発明にかかる一般式（Ｉ）を有する化合物又はその薬理上許容される塩の使用量は症状、年齢、投与方法等によって異なるが、例えば経口投与の場合には、１日あたり、下限として０．００１ｍｇ／ｋｇ（好ましくは０．０１ｍｇ／ｋｇ）、上限として、１００ｍｇ／ｋｇ（好ましくは１０ｍｇ／ｋｇ）を１回または数回に分けて、症状に応じて投与することが望ましい。静脈内投与の場合には、成人に対して１日当たり、下限として０．０００１ｍｇ／ｋｇ（好ましくは０．００１ｍｇ／ｋｇ）、上限として、１ｍｇ／ｋｇ（好ましくは０．１ｍｇ／ｋｇ）を１回または数回に分けて、症状に応じて投与することが望ましい。 The amount of the compound having the general formula (I) according to the present invention or a pharmacologically acceptable salt thereof varies depending on symptoms, age, administration method, etc. It is desirable to administer 0.001 mg / kg (preferably 0.01 mg / kg) and, as an upper limit, 100 mg / kg (preferably 10 mg / kg) once or several times according to the symptoms. In the case of intravenous administration, it is 0.0001 mg / kg (preferably 0.001 mg / kg) as the lower limit and 1 mg / kg (preferably 0.1 mg / kg) as the upper limit once a day for adults. Or it is desirable to divide into several times according to the symptoms.

以下に、参考例、実施例、製剤例及び試験例を挙げて本発明をより具体的に説明するが、本発明はこれらに限定されるものではない。
［参考例］
［参考例１］１−［４−（２−メチル−２Ｈ−テトラゾール−５−イル）フェニル］−１，４−ジアゼパン
（１ａ）ベンジル４−［４−（２−メチル−２Ｈ−テトラゾール−５−イル）フェニル］−１，４−ジアゼパン−１−カルボキシラート
５−（４−ブロモフェニル）−２−メチル−２Ｈ−テトラゾール（Ｊ．Ｏｒｇ．Ｃｈｅｍ．ＵＳＳＲ（ｅｎｇｌ．Ｔｒａｎｓｌ．），１９８４，２０，３５７−３６２）（１．９９ｇ，８．３２ｍｍｏｌ）、ベンジル１，４−ジアゼパン−１−カルボキシラート（２．３４ｇ，９．９８ｍｍｏｌ）、ナトリウムｔｅｒｔ−ブトキシド（１．１２ｇ，１１．７ｍｍｏｌ）、トリス（ジベンジルデンアセトン）ジパラジウム（０）（３８ｍｇ，０．０４ｍｍｏｌ）および２−（ジシクロヘキシルホスフィノ）−２’−（Ｎ，Ｎ−ジメチルアミノ）ビフェニル（６５ｍｇ，０．１７ｍｍｏｌ）をｔｅｒｔ−ブタノール（８．３ｍＬ）と１，４−ジオキサン（１６．６ｍＬ）の混合溶媒に懸濁し、還流下で５時間攪拌した。反応混合物を室温に冷却したのち，ジエチルエーテル（５０ｍＬ）を加え、不溶物をセライトにより除去した。溶媒を減圧下に留去して得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝２:１）により精製し、２．５０ｇ（収率７７％）の標記目的化合物を得た。 Hereinafter, the present invention will be described more specifically with reference to Reference Examples, Examples, Formulation Examples, and Test Examples, but the present invention is not limited thereto.
[Reference example]
[Reference Example 1] 1- [4- (2-Methyl-2H-tetrazol-5-yl) phenyl] -1,4-diazepane (1a) benzyl 4- [4- (2-methyl-2H-tetrazole-5) -Yl) phenyl] -1,4-diazepan-1-carboxylate 5- (4-bromophenyl) -2-methyl-2H-tetrazole (J. Org. Chem. USSR (engl. Transl.), 1984, 20 357-362) (1.99 g, 8.32 mmol), benzyl 1,4-diazepane-1-carboxylate (2.34 g, 9.98 mmol), sodium tert-butoxide (1.12 g, 11.7 mmol), Tris (dibenzyldenacetone) dipalladium (0) (38 mg, 0.04 mmol) and 2- (dicyclohexylphosphine) Ino) -2 ′-(N, N-dimethylamino) biphenyl (65 mg, 0.17 mmol) was suspended in a mixed solvent of tert-butanol (8.3 mL) and 1,4-dioxane (16.6 mL), Stir at reflux for 5 hours. The reaction mixture was cooled to room temperature, diethyl ether (50 mL) was added, and the insoluble material was removed with celite. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate = 2: 1) to obtain 2.50 g (yield 77%) of the title compound.

淡橙色油状物;
IR (film) ν_max 2952, 1699, 1617, 1469, 1232 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.94-2.08 (2H, m), 3.29-3.35 (1H, m), 3.37-3.43 (1H, m), 3.57-3.70 (6H, m), 4.34 (3H, s), 5.06 (1H, s), 5.12 (1H, s), 6.71-6.78 (2H, m), 7.24-7.36 (5H, m), 7.92-7.97 (2H, m);
MS (FAB) m/z: 393 [M+H]⁺, 364, 325, 274。
Pale orange oil;
IR (film) ν _max 2952, 1699, 1617, 1469, 1232 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.94-2.08 (2H, m), 3.29-3.35 (1H, m), 3.37-3.43 (1H, m), 3.57-3.70 (6H, m), 4.34 (3H , s), 5.06 (1H, s), 5.12 (1H, s), 6.71-6.78 (2H, m), 7.24-7.36 (5H, m), 7.92-7.97 (2H, m);
MS (FAB) m / z: 393 [M + H] ⁺ , 364, 325, 274.

（１ｂ）１−［４−（２−メチル−２Ｈ−テトラゾール−５−イル）フェニル］−１，４−ジアゼパン
参考例１（１ａ）で製造したベンジル４−［４−（２−メチル−２Ｈ−テトラゾール−５−イル）フェニル］−１，４−ジアゼパン−１−カルボキシラート（２．５０ｇ，６．３７ｍｍｏｌ）をエタノール（２５ｍＬ）に溶解し、１０％パラジウム−炭素（５３ｗｔ％，２．５０ｇ，１．２５ｍｍｏｌ）の存在下に、常圧水素雰囲気下で水添した。反応液を５時間攪拌したのち、触媒を除去し、溶媒を減圧下で留去すると、１．６０ｇ（収率９７％）の標記目的化合物が得られた。
(1b) 1- [4- (2-Methyl-2H-tetrazol-5-yl) phenyl] -1,4-diazepan benzyl 4- [4- (2-methyl-2H) prepared in Reference Example 1 (1a) -Tetrazol-5-yl) phenyl] -1,4-diazepan-1-carboxylate (2.50 g, 6.37 mmol) was dissolved in ethanol (25 mL) and 10% palladium-carbon (53 wt%, 2.50 g). , 1.25 mmol) in the presence of atmospheric pressure hydrogen atmosphere. After stirring the reaction solution for 5 hours, the catalyst was removed, and the solvent was distilled off under reduced pressure to obtain 1.60 g (yield 97%) of the title object compound.

黄色油状物;
IR (film) ν_max 3335, 2933, 1616, 1467, 1197 cm^-1;
¹H NMR(CDCl₃, 500 MHz) δ 1.92 (2H, quint, J = 5.9 Hz), 2.84 (2H, t, J = 5.9 Hz), 3.06 (2H, t, J = 5.4 Hz), 3.61 (2H, t, J = 5.4 Hz), 3.65 (2H, t, J = 5.9 Hz), 4.35 (3H, s), 6.77 (2H, d, J = 8.8 Hz), 7.96 (2H, d, J = 8.8 Hz);
MS (EI) m/z: 258 [M^+・], 230, 174。
Yellow oil;
IR (film) ν _max 3335, 2933, 1616, 1467, 1197 cm ^-1 ;
¹ H NMR (CDCl ₃ , 500 MHz) δ 1.92 (2H, quint, J = 5.9 Hz), 2.84 (2H, t, J = 5.9 Hz), 3.06 (2H, t, J = 5.4 Hz), 3.61 (2H , t, J = 5.4 Hz), 3.65 (2H, t, J = 5.9 Hz), 4.35 (3H, s), 6.77 (2H, d, J = 8.8 Hz), 7.96 (2H, d, J = 8.8 Hz) );
MS (EI) m / z: 258 [M ⁺ .], 230, 174.

［参考例２］１−［４−（１−メチル−１Ｈ−テトラゾール−５−イル）フェニル］−１，４−ジアゼパン
（２ａ）ベンジル４−［４−（１−メチル−１Ｈ−テトラゾール−５−イル）フェニル］−１，４−ジアゼパン−１−カルボキシラート
５−（４−ブロモフェニル）−１−メチル−１Ｈ−テトラゾール（Ｊ．Ｏｒｇ．Ｃｈｅｍ．ＵＳＳＲ（ｅｎｇｌ．Ｔｒａｎｓｌ．），１９８４，２０，３５７−３６２）を用いて参考例１（１ａ）と同様に反応を行い、標記目的化合物を得た。
黄色油状物;
IR (film) ν_max 3498, 2958, 1699, 1613, 1493, 1422 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.93-2.08 (2H, m), 3.31-3.38 (1H, m), 3.38-3.45 (1H, m), 3.53-3.72 (6H, m), 4.13 (1.5H, s), 4.14 (1.5H, s), 5.07 (1H, s), 5.12 (1H, s), 6.74-6.82 (2H, m), 7.23-7.35 (5H, m), 7.56-7.64 (2H, m);
MS (FAB) m/z: 393 [M+H]⁺, 257, 242。
[Reference Example 2] 1- [4- (1-Methyl-1H-tetrazol-5-yl) phenyl] -1,4-diazepane (2a) benzyl 4- [4- (1-methyl-1H-tetrazole-5) -Yl) phenyl] -1,4-diazepan-1-carboxylate 5- (4-bromophenyl) -1-methyl-1H-tetrazole (J. Org. Chem. USSR (engl. Transl.), 1984, 20 , 357-362) in the same manner as in Reference Example 1 (1a) to give the title object compound.
Yellow oil;
IR (film) ν _max 3498, 2958, 1699, 1613, 1493, 1422 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.93-2.08 (2H, m), 3.31-3.38 (1H, m), 3.38-3.45 (1H, m), 3.53-3.72 (6H, m), 4.13 (1.5 H, s), 4.14 (1.5H, s), 5.07 (1H, s), 5.12 (1H, s), 6.74-6.82 (2H, m), 7.23-7.35 (5H, m), 7.56-7.64 (2H , m);
MS (FAB) m / z: 393 [M + H] ⁺ , 257, 242.

（２ｂ）１−［４−（１−メチル−１Ｈ−テトラゾール−５−イル）フェニル］−１，４−ジアゼパン
参考例２（２ａ）で製造したベンジル４−［４−（１−メチル−１Ｈ−テトラゾール−５−イル）フェニル］−１，４−ジアゼパン−１−カルボキシラートを用いて参考例１（１ｂ）と同様に反応を行い、標記目的化合物を得た。
白色粉末;
Mp 100-101 ℃;
IR (KBr) ν_max 3331, 3208, 2939, 2834, 1613, 1494, 1448, 1196 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.93 (2H, quint, J = 5.9 Hz), 2.85 (2H, t, J = 5.9 Hz), 3.03-3.09 (2H, m), 3.53-3.68 (4H, m), 4.15 (3H, s), 6.78 (2H, d, J = 9.0 Hz), 7.60 (2H, d, J = 9.0 Hz);
MS (EI) m/z: 258 [M^+・], 216, 202, 188。
(2b) 1- [4- (1-Methyl-1H-tetrazol-5-yl) phenyl] -1,4-diazepan benzyl 4- [4- (1-methyl-1H) prepared in Reference Example 2 (2a) -Tetrazol-5-yl) phenyl] -1,4-diazepan-1-carboxylate was used in the same manner as in Reference Example 1 (1b) to give the title object compound.
White powder;
Mp 100-101 ° C;
IR (KBr) ν _max 3331, 3208, 2939, 2834, 1613, 1494, 1448, 1196 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.93 (2H, quint, J = 5.9 Hz), 2.85 (2H, t, J = 5.9 Hz), 3.03-3.09 (2H, m), 3.53-3.68 (4H, m), 4.15 (3H, s), 6.78 (2H, d, J = 9.0 Hz), 7.60 (2H, d, J = 9.0 Hz);
MS (EI) m / z: 258 [M ^+. ], 216, 202, 188.

［参考例３］１−［４−（２−エチル−２Ｈ−テトラゾール−５−イル）フェニル］−１，４−ジアゼパン
（３ａ）ベンジル４−［４−（２−エチル−２Ｈ−テトラゾール−５−イル）フェニル］−１，４−ジアゼパン−１−カルボキシラート
５−（４−ブロモフェニル）−２−エチル−２Ｈ−テトラゾール（ＷＯ２００２０７６９７８）を用いて参考例１（１ａ）と同様に反応を行い、標記目的化合物を得た。
淡褐色油状物;
IR (film) ν_max 3509, 2946, 2212, 1699, 1616, 1470, 1423 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.67 (3H, t, J = 7.4 Hz), 1.93-2.09 (2H, m), 3.30-3.36 (1H, m), 3.37-3.44 (1H, m), 3.55-3.72 (6H, m), 4.67 (2H, q, J = 7.4 Hz), 5.08 (1H, s), 5.14 (1H, s), 6.73-6.78 (2H, m), 7.24-7.39 (5H, m), 7.98 (2H, d, J = 8.6 Hz);
MS (FAB) m/z: 407 [M+H]⁺, 406, 378, 335。
[Reference Example 3] 1- [4- (2-Ethyl-2H-tetrazol-5-yl) phenyl] -1,4-diazepane (3a) benzyl 4- [4- (2-ethyl-2H-tetrazole-5) -Il) phenyl] -1,4-diazepan-1-carboxylate The reaction is carried out in the same manner as in Reference Example 1 (1a) using 5- (4-bromophenyl) -2-ethyl-2H-tetrazole (WO2002077698). To give the title compound.
Light brown oil;
IR (film) ν _max 3509, 2946, 2212, 1699, 1616, 1470, 1423 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.67 (3H, t, J = 7.4 Hz), 1.93-2.09 (2H, m), 3.30-3.36 (1H, m), 3.37-3.44 (1H, m), 3.55-3.72 (6H, m), 4.67 (2H, q, J = 7.4 Hz), 5.08 (1H, s), 5.14 (1H, s), 6.73-6.78 (2H, m), 7.24-7.39 (5H, m), 7.98 (2H, d, J = 8.6 Hz);
MS (FAB) m / z: 407 [M + H] ⁺ , 406, 378, 335.

（３ｂ）１−［４−（２−エチル−２Ｈ−テトラゾール−５−イル）フェニル］−１，４−ジアゼパン
参考例３（３ａ）で製造したベンジル４−［４−（２−エチル−２Ｈ−テトラゾール−５−イル）フェニル］−１，４−ジアゼパン−１−カルボキシラートを用いて参考例１（１ｂ）と同様に反応を行い、標記目的化合物を得た。
白色粉末;
Mp 87-90 ℃;
IR (KBr) ν_max 3349, 2940, 2833, 2210, 1614, 1468 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.66 (3H, t, J = 7.4 Hz), 1.92 (2H, quint, J = 5.9 Hz), 2.80-2.87 (2H, m), 3.01-3.09 (2H, m), 3.57-3.69 (4H, m), 4.66 (2H, q, J = 7.4 Hz), 6.77 (2H, d, J = 9.0 Hz), 7.98 (2H, d, J = 9.0 Hz);
MS (EI) m/z: 272 [M^+・], 244, 201, 188。
(3b) 1- [4- (2-Ethyl-2H-tetrazol-5-yl) phenyl] -1,4-diazepane benzyl 4- [4- (2-ethyl-2H) prepared in Reference Example 3 (3a) -Tetrazol-5-yl) phenyl] -1,4-diazepan-1-carboxylate was used in the same manner as in Reference Example 1 (1b) to give the title object compound.
White powder;
Mp 87-90 ° C;
IR (KBr) ν _max 3349, 2940, 2833, 2210, 1614, 1468 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.66 (3H, t, J = 7.4 Hz), 1.92 (2H, quint, J = 5.9 Hz), 2.80-2.87 (2H, m), 3.01-3.09 (2H, m), 3.57-3.69 (4H, m), 4.66 (2H, q, J = 7.4 Hz), 6.77 (2H, d, J = 9.0 Hz), 7.98 (2H, d, J = 9.0 Hz);
MS (EI) m / z: 272 [M ^+. ], 244, 201, 188.

［参考例４］１−｛４−［（２−メチル−２Ｈ−テトラゾール−５−イル）メチル］フェニル｝−１，４−ジアゼパン
（４ａ）５−（４−ブロモベンジル）−２−メチル−２Ｈ−テトラゾール及び５−（４−ブロモベンジル）−１−メチル−１Ｈ−テトラゾール
氷冷下５−（４−ブロモベンジル）−２Ｈ−テトラゾール（Ｊ．Ｍｅｄ．Ｃｈｅｍ．，１９９１，３４，１１２５−１１３６）（２．３９ｇ，１０ｍｍｏｌ）と炭酸カリウム（２．０７ｇ，１５ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（６０ｍＬ）懸濁液に、ヨードメタン（３．１１ｍＬ，５０ｍｍｏｌ）を加え、氷冷下で１時間、室温で２０時間攪拌した。反応液に水（１００ｍＬ）を加え、酢酸エチル（１００ｍＬ×３）で抽出した。有機層を合せ、水（１００ｍＬ）、飽和食塩水（１００ｍＬ）で順じ洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。残渣をカラムクロマトグラフィー（溶出液：ヘキサン／酢酸エチル＝５／１〜１／１）にて精製し、１．１８ｇの標記目的化合物５−（４−ブロモベンジル）−２−メチル−２Ｈ−テトラゾール（収率４７％）と１．３０ｇの５−（４−ブロモベンジル）−１−メチル−１Ｈ−テトラゾール（収率５１％）を得た。
[Reference Example 4] 1- {4-[(2-Methyl-2H-tetrazol-5-yl) methyl] phenyl} -1,4-diazepane (4a) 5- (4-bromobenzyl) -2-methyl- 2H-tetrazole and 5- (4-bromobenzyl) -1-methyl-1H-tetrazole 5- (4-bromobenzyl) -2H-tetrazole (J. Med. Chem., 1991, 34, 1125-1136 under ice cooling. ) (2.39 g, 10 mmol) and potassium carbonate (2.07 g, 15 mmol) in a suspension of N, N-dimethylformamide (60 mL) was added iodomethane (3.11 mL, 50 mmol), and the mixture was cooled with ice for 1 hour. And stirred at room temperature for 20 hours. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic layers were combined, washed successively with water (100 mL) and saturated brine (100 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (eluent: hexane / ethyl acetate = 5/1 to 1/1) and 1.18 g of the title compound 5- (4-bromobenzyl) -2-methyl-2H-tetrazole (Yield 47%) and 1.30 g of 5- (4-bromobenzyl) -1-methyl-1H-tetrazole (51% yield) were obtained.

５−（４−ブロモベンジル）−２−メチル−２Ｈ−テトラゾール
黄色プリズム晶;
Mp 49-50 ℃;
IR (film) ν_max 3030, 2957, 1592, 1489 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 4.18 (2H, s), 4.30 (3H, s), 7.20 (2H, d, J = 8.2 Hz), 7.44 (2H, d, J = 8.2 Hz);
MS (EI) m/z: 252 [M^+・], 224, 169。
5- (4-bromobenzyl) -2-methyl-2H-tetrazole yellow prism crystals;
Mp 49-50 ° C;
IR (film) ν _max 3030, 2957, 1592, 1489 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 4.18 (2H, s), 4.30 (3H, s), 7.20 (2H, d, J = 8.2 Hz), 7.44 (2H, d, J = 8.2 Hz);
MS (EI) m / z: 252 [M ⁺ .], 224, 169.

５−（４−ブロモベンジル）−１−メチル−１Ｈ−テトラゾール
黄色プリズム晶;
Mp 94-96 ℃;
IR (KBr) ν_max 2955, 1921, 1595, 1515, 1491, 1459, 1421 cm^-1;
¹H NMR(CDCl₃, 500 MHz) δ 3.87 (3H, s), 4.25 (2H, s), 7.08 (2H, d, J = 8.5 Hz), 7.48 (2H, d, J = 8.5 Hz);
MS (EI) m/z: 252 [M^+・], 196, 169。
5- (4-bromobenzyl) -1-methyl-1H-tetrazole yellow prism crystals;
Mp 94-96 ° C;
IR (KBr) ν _max 2955, 1921, 1595, 1515, 1491, 1459, 1421 cm ^-1 ;
¹ H NMR (CDCl ₃ , 500 MHz) δ 3.87 (3H, s), 4.25 (2H, s), 7.08 (2H, d, J = 8.5 Hz), 7.48 (2H, d, J = 8.5 Hz);
MS (EI) m / z: 252 [M ⁺ .], 196, 169.

（４ｂ）ベンジル４−｛４−［（２−メチル−２Ｈ−テトラゾール−５−イル）メチル］フェニル｝−１，４−ジアゼパン−１−カルボキシラート
参考例４（４ａ）で製造した５−（４−ブロモベンジル）−１−メチル−１Ｈ−テトラゾールを用いて参考例１（１ａ）と同様に反応を行い、標記目的化合物を得た。
黄色油状物;
IR (film) ν_max 3509, 2953, 1698, 1520, 1229 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.88-2.02 (2H, m), 3.25-3.31 (1H, m), 3.32-3.38 (1H, m), 3.48-3.57 (4H, m), 3.58-3.65 (2H, m), 4.10 (2H, s), 4.25 (1.5H, s), 4.26 (1.5H, s), 5.05 (1H, s), 5.11 (1H, s), 6.61 (2H, d, J = 8.6 Hz), 7.14 (2H, d, J = 8.6 Hz), 7.24-7.36 (5H, m);
MS (FAB) m/z: 406 [M^+・], 405, 377, 323。
(4b) Benzyl 4- {4-[(2-methyl-2H-tetrazol-5-yl) methyl] phenyl} -1,4-diazepan-1-carboxylate 5- (5) prepared in Reference Example 4 (4a) 4-Bromobenzyl) -1-methyl-1H-tetrazole was used to carry out the reaction in the same manner as in Reference Example 1 (1a) to obtain the title compound.
Yellow oil;
IR (film) ν _max 3509, 2953, 1698, 1520, 1229 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.88-2.02 (2H, m), 3.25-3.31 (1H, m), 3.32-3.38 (1H, m), 3.48-3.57 (4H, m), 3.58-3.65 (2H, m), 4.10 (2H, s), 4.25 (1.5H, s), 4.26 (1.5H, s), 5.05 (1H, s), 5.11 (1H, s), 6.61 (2H, d, J = 8.6 Hz), 7.14 (2H, d, J = 8.6 Hz), 7.24-7.36 (5H, m);
MS (FAB) m / z: 406 [M ^+. ], 405, 377, 323.

（４ｃ）１−｛４−［（２−メチル−２Ｈ−テトラゾール−５−イル）メチル］フェニル｝−１，４−ジアゼパン
参考例４（４ｂ）で製造したベンジル４−｛４−［（２−メチル−２Ｈ−テトラゾール−５−イル）メチル］フェニル｝−１，４−ジアゼパン−１−カルボキシラートを用いて参考例１（１ｂ）と同様に反応を行い、標記目的化合物を得た。
黄色油状物;
IR (film) ν_max 3333, 2930, 1734, 1615, 1521, 1394, 1364 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.87 (2H, quint, J = 5.9 Hz), 2.77-2.84 (2H, m), 2.96-3.04 (2H, m), 3.48-3.57 (4H, m), 4.11 (2H, s), 4.28 (3H, s), 6.64 (2H, d, J = 9.0 Hz), 7.16 (2H, d, J = 9.0 Hz);
MS (EI) m/z: 272 [M^+・], 230, 216, 189。
(4c) 1- {4-[(2-Methyl-2H-tetrazol-5-yl) methyl] phenyl} -1,4-diazepane benzyl 4- {4-[(2 -Methyl-2H-tetrazol-5-yl) methyl] phenyl} -1,4-diazepan-1-carboxylate was reacted in the same manner as in Reference Example 1 (1b) to give the title object compound.
Yellow oil;
IR (film) ν _max 3333, 2930, 1734, 1615, 1521, 1394, 1364 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.87 (2H, quint, J = 5.9 Hz), 2.77-2.84 (2H, m), 2.96-3.04 (2H, m), 3.48-3.57 (4H, m), 4.11 (2H, s), 4.28 (3H, s), 6.64 (2H, d, J = 9.0 Hz), 7.16 (2H, d, J = 9.0 Hz);
MS (EI) m / z: 272 [M ^+. ], 230, 216, 189.

［参考例５］１−｛４−［（１−メチル−１Ｈ−テトラゾール−５−イル）メチル］フェニル｝−１，４−ジアゼパン
（５ａ）ベンジル４−｛４−［（１−メチル−１Ｈ−テトラゾール−５−イル）メチル］フェニル｝−１，４−ジアゼパン−１−カルボキシラート
参考例４（４ａ）で製造した５−（４−ブロモベンジル）−１−メチル−１Ｈ−テトラゾールを用いて参考例１（１ａ）と同様に反応を行い、標記目的化合物を得た。
黄色油状物;
IR (film) ν_max 3494, 2951, 1698, 1615, 1521, 1471, 1423 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.88-2.03 (2H, m), 3.27-3.33 (1H, m), 3.34-3.39 (1H, m), 3.48-3.66 (4H, m), 3.81 (3H, s), 4.16 (2H, s), 5.06 (1H, s), 5.10 (1H, s), 6.57-6.64 (2H, m), 6.96-7.02 (2H, m), 7.24-7.35 (5H, m);
MS (FAB) m/z: 407 [M+H]⁺, 379, 353, 329。
[Reference Example 5] 1- {4-[(1-methyl-1H-tetrazol-5-yl) methyl] phenyl} -1,4-diazepane (5a) benzyl 4- {4-[(1-methyl-1H -Tetrazol-5-yl) methyl] phenyl} -1,4-diazepan-1-carboxylate Using 5- (4-bromobenzyl) -1-methyl-1H-tetrazole prepared in Reference Example 4 (4a) The reaction was carried out in the same manner as in Reference Example 1 (1a) to obtain the title target compound.
Yellow oil;
IR (film) ν _max 3494, 2951, 1698, 1615, 1521, 1471, 1423 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.88-2.03 (2H, m), 3.27-3.33 (1H, m), 3.34-3.39 (1H, m), 3.48-3.66 (4H, m), 3.81 (3H , s), 4.16 (2H, s), 5.06 (1H, s), 5.10 (1H, s), 6.57-6.64 (2H, m), 6.96-7.02 (2H, m), 7.24-7.35 (5H, m );
MS (FAB) m / z: 407 [M + H] ⁺ , 379, 353, 329.

（５ｂ）１−｛４−［（１−メチル−１Ｈ−テトラゾール−５−イル）メチル］フェニル｝−１，４−ジアゼパン
参考例５（５ａ）で製造したベンジル４−｛４−［（１−メチル−１Ｈ−テトラゾール−５−イル）メチル］フェニル｝−１，４−ジアゼパン−１−カルボキシラートを用いて参考例１（１ｂ）と同様に反応を行い、標記目的化合物を得た。
黄色油状物;
IR (film) ν_max 3413, 3327, 2934, 1615, 1521 cm^-1;
¹H NMR(CDCl₃, 500 MHz) δ 1.87 (2H, quint, J = 5.9 Hz), 2.81 (2H, t, J = 5.9 Hz), 3.01 (2H, t, J = 5.4 Hz), 3.51 (2H, t, J = 5.4 Hz), 3.55 (2H, t, J = 5.9 Hz), 3.83 (3H, s), 4.18 (2H, s), 6.63 (2H, d, J = 8.8 Hz), 7.00 (2H, d, J = 8.8 Hz);
MS (EI) m/z: 272 [M^+・], 230, 216, 189。
(5b) 1- {4-[(1-Methyl-1H-tetrazol-5-yl) methyl] phenyl} -1,4-diazepane benzyl 4- {4-[(1 -Methyl-1H-tetrazol-5-yl) methyl] phenyl} -1,4-diazepan-1-carboxylate was reacted in the same manner as in Reference Example 1 (1b) to give the title object compound.
Yellow oil;
IR (film) ν _max 3413, 3327, 2934, 1615, 1521 cm ^-1 ;
¹ H NMR (CDCl ₃ , 500 MHz) δ 1.87 (2H, quint, J = 5.9 Hz), 2.81 (2H, t, J = 5.9 Hz), 3.01 (2H, t, J = 5.4 Hz), 3.51 (2H , t, J = 5.4 Hz), 3.55 (2H, t, J = 5.9 Hz), 3.83 (3H, s), 4.18 (2H, s), 6.63 (2H, d, J = 8.8 Hz), 7.00 (2H , d, J = 8.8 Hz);
MS (EI) m / z: 272 [M ^+. ], 230, 216, 189.

［参考例６］１−［４−（１−エチル−１Ｈ−テトラゾール−５−イル）フェニル］−１，４−ジアゼパン
（６ａ）５−（４−ブロモフェニル）−１−エチル−１Ｈ−テトラゾール
氷冷下、４−ブロモ−Ｎ−エチルベンザミド（Ｊ，Ｏｒｇ．Ｃｈｅｍ．，２００１，６６，３２９１−３２９８）（２．１７ｇ，９．５１ｍｍｏｌ）と２，６−ルチジン（１６７０μＬ，１４．３ｍｍｏｌ）の塩化メチレン（１９ｍＬ）溶液に、塩化オキザリル（９５０μＬ，１０．５ｍｍｏｌ）をゆっくりと滴下し、氷冷下で１５分攪拌し、イミノクロライドの塩化メチレン溶液を作成した。
Reference Example 6 1- [4- (1-Ethyl-1H-tetrazol-5-yl) phenyl] -1,4-diazepane (6a) 5- (4-bromophenyl) -1-ethyl-1H-tetrazole Under cooling with ice, 4-bromo-N-ethylbenzamide (J, Org. Chem., 2001, 66, 3291-3298) (2.17 g, 9.51 mmol) and 2,6-lutidine (1670 μL, 14.3 mmol) Oxalyl chloride (950 μL, 10.5 mmol) was slowly added dropwise to a methylene chloride solution (19 mL) and stirred for 15 minutes under ice cooling to prepare a methylene chloride solution of iminochloride.

次いで、アジ化ナトリウム（９３０ｍｇ，１４，３ｍｍｏｌ）、２，３，５−トリフェニル−２Ｈ−テトラゾリウムクロライド（１５９ｍｇ，０．４８ｍｍｏｌ）の塩化メチレン（１９ｍＬ）と水（３８ｍＬ）の二層系溶液に、先のイミノクロライドの塩化メチレン溶液を滴下し、室温で１時間攪拌した。反応液を分液し、水層を塩化メチレン（２０ｍＬ×２）で抽出した後、有機層を合せ、無水硫酸ナトリウムで乾燥後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー（溶出液：ヘキサン／酢酸エチル＝２／１）にて精製し、２．２８ｇ（収率９５％）の標記目的化合物を得た。
無色プリズム晶;
Mp 104-105 ℃;
IR (KBr) ν_max 2976, 1599, 1466, 1428 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.59 (3H, t, J = 7.4 Hz), 4.46 (2H, q, J = 7.4 Hz), 7.55 (2H, d, J = 8.6 Hz), 7.70 (2H, d, J = 8.6 Hz);
MS (EI) m/z: 252 [M^+・], 211, 196, 182;
Anal. Calcd for C₉H₉BrN₄: C, 42.71; H, 3.58; N, 22.14. Found: C, 42.71; H, 3.59; N, 21.95。 Then, into a bilayer solution of sodium azide (930 mg, 14, 3 mmol), 2,3,5-triphenyl-2H-tetrazolium chloride (159 mg, 0.48 mmol) in methylene chloride (19 mL) and water (38 mL). The previous iminochloride in methylene chloride was added dropwise and stirred at room temperature for 1 hour. The reaction solution was separated, the aqueous layer was extracted with methylene chloride (20 mL × 2), the organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 2/1) to obtain 2.28 g (yield 95%) of the title compound.
Colorless prisms;
Mp 104-105 ° C;
IR (KBr) ν _max 2976, 1599, 1466, 1428 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.59 (3H, t, J = 7.4 Hz), 4.46 (2H, q, J = 7.4 Hz), 7.55 (2H, d, J = 8.6 Hz), 7.70 (2H , d, J = 8.6 Hz);
MS (EI) m / z: 252 [M ^{+ ・} ], 211, 196, 182;
Anal. Calcd for C ₉ H ₉ BrN ₄ : C, 42.71; H, 3.58; N, 22.14. Found: C, 42.71; H, 3.59; N, 21.95.

（６ｂ）ベンジル４−［４−（１−エチル−１Ｈ−テトラゾール−５−イル）フェニル］−１，４−ジアゼパン−１−カルボキシラート
参考例６（６ａ）で製造した５−（４−ブロモフェニル）−１−エチル−１Ｈ−テトラゾールを用いて参考例１（１ａ）と同様に反応を行い、標記目的化合物を得た。
黄色油状物;
IR (film) ν_max 3503, 2945, 1699, 1613, 1486 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.54-1.61 (3H, m), 1.93-2.08 (2H, m), 3.32-3.37 (1H, m), 3.39-3.44 (1H, m), 3.58-3.71 (6H, m), 4.41-4.50 (2H, m), 5.07 (1H, s), 5.12 (1H, s), 6.74-6.81 (2H, m), 7.24-7.35 (5H, m), 7.51-7.58 (2H, m);
MS (FAB) m/z: 407 [M+H]⁺, 406, 379, 353。
(6b) Benzyl 4- [4- (1-ethyl-1H-tetrazol-5-yl) phenyl] -1,4-diazepan-1-carboxylate 5- (4-Bromo prepared in Reference Example 6 (6a) The reaction was conducted in the same manner as in Reference Example 1 (1a) using (phenyl) -1-ethyl-1H-tetrazole to obtain the title compound.
Yellow oil;
IR (film) ν _max 3503, 2945, 1699, 1613, 1486 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.54-1.61 (3H, m), 1.93-2.08 (2H, m), 3.32-3.37 (1H, m), 3.39-3.44 (1H, m), 3.58-3.71 (6H, m), 4.41-4.50 (2H, m), 5.07 (1H, s), 5.12 (1H, s), 6.74-6.81 (2H, m), 7.24-7.35 (5H, m), 7.51-7.58 (2H, m);
MS (FAB) m / z: 407 [M + H] ⁺ , 406, 379, 353.

（６ｃ）１−［４−（１−エチル−１Ｈ−テトラゾール−５−イル）フェニル］−１，４−ジアゼパン
参考例６（６ｂ）で製造したベンジル４−［４−（１−エチル−１Ｈ−テトラゾール−５−イル）フェニル］−１，４−ジアゼパン−１−カルボキシラートを用いて参考例１（１ｂ）と同様に反応を行い、標記目的化合物を得た。
黄色油状物;
IR (film) ν_max 3445, 3319, 2931, 1635, 1520 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.59 (3H, t, J = 7.4 Hz), 1.92 (2H, t, J = 5.9 Hz), 2.82-2.88 (2H, m), 3.03-3.09 (2H, m), 3.58-3.68 (4H, m), 4.48 (2H, q, J = 7.4 Hz), 6.80 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz);
MS (FAB) m/z: 273 [M+H]⁺, 257, 246。
(6c) 1- [4- (1-Ethyl-1H-tetrazol-5-yl) phenyl] -1,4-diazepane benzyl 4- [4- (1-ethyl-1H) prepared in Reference Example 6 (6b) -Tetrazol-5-yl) phenyl] -1,4-diazepan-1-carboxylate was used in the same manner as in Reference Example 1 (1b) to give the title object compound.
Yellow oil;
IR (film) ν _max 3445, 3319, 2931, 1635, 1520 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.59 (3H, t, J = 7.4 Hz), 1.92 (2H, t, J = 5.9 Hz), 2.82-2.88 (2H, m), 3.03-3.09 (2H, m), 3.58-3.68 (4H, m), 4.48 (2H, q, J = 7.4 Hz), 6.80 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz);
MS (FAB) m / z: 273 [M + H] ⁺ , 257, 246.

［参考例７］１−｛４−［２−（２−メトキシエチル）−２Ｈ−テトラゾール−５−イル］フェニル｝−１，４−ジアゼパン
（７ａ）５−（４−ブロモフェニル）−２−（２−メトキシエチル）−２Ｈ−テトラゾール
ヨードメタンの代わりに１−ブロモ−２−メトキシエタンを用いて、参考例４（４ａ）と同様に反応を行い、標記目的化合物を得た。
白色粉末;
Mp 69-71 ℃;
IR (KBr) ν_max 3012, 2985, 2940, 2892, 2864, 2831, 1604, 1451, 1417 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 3.37 (3H, s), 3.98 (2H, t, J = 5.5 Hz), 4.82 (2H, t, J = 5.5 Hz), 7.62 (2H, d, J = 8.2 Hz), 8.02 (2H, d, J = 8.2 Hz);
MS (EI) m/z: 282 [M^+・], 254, 211, 209, 182;
Anal. Calcd for C₁₀H₁₁BrN₄O: C, 42.42; H, 3.92; N, 19.79. Found: C, 42.61; H, 4.07; N, 19.98。
[Reference Example 7] 1- {4- [2- (2-methoxyethyl) -2H-tetrazol-5-yl] phenyl} -1,4-diazepane (7a) 5- (4-bromophenyl) -2- (2-Methoxyethyl) -2H-tetrazole The reaction was carried out in the same manner as in Reference Example 4 (4a) using 1-bromo-2-methoxyethane instead of iodomethane to obtain the title compound.
White powder;
Mp 69-71 ° C;
IR (KBr) ν _max 3012, 2985, 2940, 2892, 2864, 2831, 1604, 1451, 1417 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 3.37 (3H, s), 3.98 (2H, t, J = 5.5 Hz), 4.82 (2H, t, J = 5.5 Hz), 7.62 (2H, d, J = 8.2 Hz), 8.02 (2H, d, J = 8.2 Hz);
MS (EI) m / z: 282 [M ^{+ ・} ], 254, 211, 209, 182;
Anal. Calcd for C ₁₀ H ₁₁ BrN ₄ O: C, 42.42; H, 3.92; N, 19.79. Found: C, 42.61; H, 4.07; N, 19.98.

（７ｂ）ベンジル４−｛４−［２−（２−メトキシエチル）−２Ｈ−テトラゾール−５−イル］フェニル｝−１，４−ジアゼパン−１−カルボキシラート
参考例７（７ａ）で製造した５−（４−ブロモフェニル）−２−（２−メトキシエチル）−２Ｈ−テトラゾールを用いて参考例１（１ａ）と同様に反応を行い、標記目的化合物を得た。
黄色油状物;
IR (film) ν_max 2943, 1699, 1616, 1470, 1423 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.92-2.08 (2H, s), 3.26-3.44 (2H, m), 3.36 (3H, s), 3.56-3.72 (6H, m), 3.96 (2H, t, J = 5.5 Hz), 4.79 (2H, t, J = 5.5 Hz), 5.08 (1H, s), 5.14 (1H, s), 6.72-6.79 (2H, m), 7.23-7.25 (5H, m), 7.95-8.02 (2H, m);
MS (FAB) m/z: 437 [M+H]⁺, 408, 335, 273。
(7b) Benzyl 4- {4- [2- (2-methoxyethyl) -2H-tetrazol-5-yl] phenyl} -1,4-diazepan-1-carboxylate 5 prepared in Reference Example 7 (7a) The reaction was performed in the same manner as in Reference Example 1 (1a) using-(4-bromophenyl) -2- (2-methoxyethyl) -2H-tetrazole to obtain the title object compound.
Yellow oil;
IR (film) ν _max 2943, 1699, 1616, 1470, 1423 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.92-2.08 (2H, s), 3.26-3.44 (2H, m), 3.36 (3H, s), 3.56-3.72 (6H, m), 3.96 (2H, t , J = 5.5 Hz), 4.79 (2H, t, J = 5.5 Hz), 5.08 (1H, s), 5.14 (1H, s), 6.72-6.79 (2H, m), 7.23-7.25 (5H, m) , 7.95-8.02 (2H, m);
MS (FAB) m / z: 437 [M + H] ⁺ , 408, 335, 273.

（７ｃ）１−｛４−［２−（２−メトキシエチル）−２Ｈ−テトラゾール−５−イル］フェニル｝−１，４−ジアゼパン
参考例７（７ｂ）で製造したベンジル４−｛４−［２−（２−メトキシエチル）−２Ｈ−テトラゾール−５−イル］フェニル｝−１，４−ジアゼパン−１−カルボキシラートを用いて参考例１（１ｂ）と同様に反応を行い、標記目的化合物を得た。
黄色油状物;
IR (film) ν_max 3445, 3336, 2932, 1615, 1469 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.92 (2H, quint, J = 5.9 Hz), 2.80-2.86 (2H, m), 3.04 (2H, t, J = 5.5 Hz), 3.35 (3H, s), 3.59 (2H, t, J = 5.5 Hz), 3.64 (2H, t, J = 6.3 Hz), 3.95 (2H, t, J = 5.5 Hz), 4.77 (2H, t, J = 5.5 Hz), 6.75 (2H, d, J = 9.0 Hz), 7.96 (2H, d, J = 9.0 Hz);
MS (FAB) m/z: 303 [M+H]⁺, 272, 230。
(7c) 1- {4- [2- (2-methoxyethyl) -2H-tetrazol-5-yl] phenyl} -1,4-diazepane benzyl 4- {4- [prepared in Reference Example 7 (7b) 2- (2-Methoxyethyl) -2H-tetrazol-5-yl] phenyl} -1,4-diazepane-1-carboxylate is reacted in the same manner as in Reference Example 1 (1b) to give the title compound. Obtained.
Yellow oil;
IR (film) ν _max 3445, 3336, 2932, 1615, 1469 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.92 (2H, quint, J = 5.9 Hz), 2.80-2.86 (2H, m), 3.04 (2H, t, J = 5.5 Hz), 3.35 (3H, s) , 3.59 (2H, t, J = 5.5 Hz), 3.64 (2H, t, J = 6.3 Hz), 3.95 (2H, t, J = 5.5 Hz), 4.77 (2H, t, J = 5.5 Hz), 6.75 (2H, d, J = 9.0 Hz), 7.96 (2H, d, J = 9.0 Hz);
MS (FAB) m / z: 303 [M + H] ⁺ , 272, 230.

［参考例８］１−｛４−［１−（２−メトキシエチル）−１Ｈ−テトラゾール−５−イル］フェニル｝−１，４−ジアゼパン
（８ａ）ベンジル４−［４−（トリフルオロアセチル）フェニル］−１，４−ジアゼパン−１−カルボキシラート
２，２，２，４'−テトラフルオロアセトフェノン（３．８４ｇ、２０ｍｍｏｌ）、ベンジル１，４−ジアゼパン−１−カルボキシラート（４．６９ｇ、２０ｍｍｏｌ）およびトリエチルアミン（３．０７ｍＬ，２２ｍｍｏｌ）をジメチルスルフォキシド（４０ｍＬ）に溶解し、１００℃で１時間撹拌した。反応液に酢酸エチル（１００ｍＬ）及び水（１００ｍＬ）を加え分液後、有機層を水（５０ｍＬ×２）、食塩水（５０ｍＬ）で洗浄し、無水硫酸ナトリウムで乾燥し、溶媒を減圧下に留去した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝３：１）で精製し、８．１３ｇ（定量的）の標記目的化合物を得た。
微橙色油状物
IR (film) ν_max2959, 1697, 1595, 1528, 1423, 1166 cm^-1;
¹H NMR(CDCl₃, 500 MHz) δ 1.93-2.06 (2H, m), 3.33-3.38 (1H, m), 3.40-3.46 (1H, m), 3.60-3.74 (6H, m), 5.07 (1H, s), 5.13 (1H, s), 6.67-6.74 (2H, m), 7.25-7.37 (5H, m), 7.91-7.98 (2H, m);
MS (FAB) m/z: 407 [M+H]⁺, 406, 315, 289。
[Reference Example 8] 1- {4- [1- (2-methoxyethyl) -1H-tetrazol-5-yl] phenyl} -1,4-diazepane (8a) benzyl 4- [4- (trifluoroacetyl) Phenyl] -1,4-diazepane-1-carboxylate 2,2,2,4′-tetrafluoroacetophenone (3.84 g, 20 mmol), benzyl 1,4-diazepane-1-carboxylate (4.69 g, 20 mmol) ) And triethylamine (3.07 mL, 22 mmol) were dissolved in dimethyl sulfoxide (40 mL) and stirred at 100 ° C. for 1 hour. Ethyl acetate (100 mL) and water (100 mL) were added to the reaction solution and the layers were separated. The organic layer was washed with water (50 mL × 2) and brine (50 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Distilled off. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3: 1) to obtain 8.13 g (quantitative) of the title compound.
Slight orange oil
IR (film) ν _max 2959, 1697, 1595, 1528, 1423, 1166 cm ^-1 ;
¹ H NMR (CDCl ₃ , 500 MHz) δ 1.93-2.06 (2H, m), 3.33-3.38 (1H, m), 3.40-3.46 (1H, m), 3.60-3.74 (6H, m), 5.07 (1H , s), 5.13 (1H, s), 6.67-6.74 (2H, m), 7.25-7.37 (5H, m), 7.91-7.98 (2H, m);
MS (FAB) m / z: 407 [M + H] ⁺ , 406, 315, 289.

（８ｂ）４−｛４−［（ベンジルオキシ）カルボニル］−１，４−ジアゼパン−１−イル｝安息香酸
参考例８（８ａ）で製造したベンジル４−［４−（トリフルオロアセチル）フェニル］−１，４−ジアゼパン−１−カルボキシラート（７．１８ｇ，１７．７ｍｍｏｌ）をＮ，Ｎ−ジメチルホルムアミド（３５．４ｍＬ）に溶解し、８Ｎ水酸化ナトリウム水溶液（４．４２ｍＬ，３５．３ｍｍｏｌ）を加え、８０℃で１時間加熱攪拌した。反応液を冷却し、水（７０ｍＬ）で希釈したのち、酢酸エチル（７０ｍＬ）で洗浄した。水層を１Ｎ塩化水素水溶液にて酸性とし、酢酸エチルで（５０ｍＬ×３）抽出した後、有機層を合わせ無水硫酸マグネシウムで乾燥し、溶媒を減圧下に留去した。残渣にエーテル（５０ｍＬ）を加え結晶化した後、濾取し、エーテルで洗浄後乾燥し、５．８２ｇ（収率６９％）の標記目的化合物を得た。
無色プリズム晶
Mp 135-137 ℃;
IR (KBr) ν_max3063, 2947, 2667, 2562, 1699, 1667, 1600, 1417 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.92-2.07 (2H, m), 3.30-3.36 (1H, m), 3.41 (1H, t, J = 5.9 Hz), 3.58-3.71 (6H, m), 5.08 (1H, s), 5.14 (1H, s), 6.63-6.72 (2H, m), 7.24-7.38 (5H, m), 7.91-7.99 (2H, m);
MS (EI) m/z: 354 [M^+・], 263, 202。
(8b) 4- {4-[(Benzyloxy) carbonyl] -1,4-diazepan-1-yl} benzoic acid Benzyl 4- [4- (trifluoroacetyl) phenyl] prepared in Reference Example 8 (8a) -1,4-diazepan-1-carboxylate (7.18 g, 17.7 mmol) was dissolved in N, N-dimethylformamide (35.4 mL) and 8N aqueous sodium hydroxide solution (4.42 mL, 35.3 mmol) was dissolved. And heated and stirred at 80 ° C. for 1 hour. The reaction mixture was cooled, diluted with water (70 mL), and washed with ethyl acetate (70 mL). The aqueous layer was acidified with 1N aqueous hydrogen chloride solution and extracted with ethyl acetate (50 mL × 3). The organic layers were combined and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was crystallized by adding ether (50 mL), collected by filtration, washed with ether and dried to give 5.82 g (yield 69%) of the title compound.
Colorless prism crystal
Mp 135-137 ° C;
IR (KBr) ν _max 3063, 2947, 2667, 2562, 1699, 1667, 1600, 1417 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.92-2.07 (2H, m), 3.30-3.36 (1H, m), 3.41 (1H, t, J = 5.9 Hz), 3.58-3.71 (6H, m), 5.08 (1H, s), 5.14 (1H, s), 6.63-6.72 (2H, m), 7.24-7.38 (5H, m), 7.91-7.99 (2H, m);
MS (EI) m / z: 354 [M ⁺ .], 263, 202.

（８ｃ）ベンジル４−（４−｛［（２−メトキシエチル）アミノ］カルボニル｝フェニル）−１，４−ジアゼパン−１−カルボキシラート
氷冷下、参考例８（８ｂ）で製造した４−｛４−［（ベンジルオキシ）カルボニル］−１，４−ジアゼパン−１−イル｝安息香酸（３．５４ｇ，１０ｍｍｏｌ）のテトラヒドロフラン（４０ｍＬ）溶液に１，１’−カルボニルジイミダゾール（１．９５ｇ，１２ｍｍｏｌ）を加え３０分攪拌した。反応液を室温まで昇温した後、１−ブロモ−２−メトキシエタン（１．３０ｍＬ，１５ｍｍｏｌ）を加え３０分攪拌した。反応液に飽和炭酸水素ナトリウム水溶液（４０ｍＬ）を加え、酢酸エチル（４０ｍＬ×３）で抽出した。有機層を合せ、飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧下に留去した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル）にて精製し、３．８５ｇ（収率８４％）の標記目的化合物を得た。
黄色油状物;
IR (film) ν_max 2943, 1699, 1616, 1470, 1423 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.92-2.06 (2H, m), 3.29-3.33 (1H, m), 3.36-3.41 (1H, m), 3.39 (3H, s), 3.53-3.69 (10H, m), 5.08 (1H, s), 5.13 (1H, s), 6.35 (1H, br.s), 6.64-6.70 (2H, m), 7.26-7.37 (5H, m), 7.64-7.70 (2H, m);
MS (FAB) m/z: 437 [M+H]⁺, 408, 335, 273。
(8c) Benzyl 4- (4-{[(2-methoxyethyl) amino] carbonyl} phenyl) -1,4-diazepan-1-carboxylate 4- {prepared in Reference Example 8 (8b) under ice cooling To a solution of 4-[(benzyloxy) carbonyl] -1,4-diazepan-1-yl} benzoic acid (3.54 g, 10 mmol) in tetrahydrofuran (40 mL), 1,1′-carbonyldiimidazole (1.95 g, 12 mmol). ) Was added and stirred for 30 minutes. After raising the temperature of the reaction solution to room temperature, 1-bromo-2-methoxyethane (1.30 mL, 15 mmol) was added and stirred for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution (40 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (40 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain 3.85 g (yield 84%) of the title compound.
Yellow oil;
IR (film) ν _max 2943, 1699, 1616, 1470, 1423 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.92-2.06 (2H, m), 3.29-3.33 (1H, m), 3.36-3.41 (1H, m), 3.39 (3H, s), 3.53-3.69 (10H , m), 5.08 (1H, s), 5.13 (1H, s), 6.35 (1H, br.s), 6.64-6.70 (2H, m), 7.26-7.37 (5H, m), 7.64-7.70 (2H , m);
MS (FAB) m / z: 437 [M + H] ⁺ , 408, 335, 273.

（８ｄ）ベンジル４−｛４−［１−（２−メトキシエチル）−１Ｈ−テトラゾール−５−イル］フェニル｝−１，４−ジアゼパン−１−カルボキシラート
参考例８（８ｃ）で製造したベンジル４−（４−｛［（２−メトキシエチル）アミノ］カルボニル｝フェニル）−１，４−ジアゼパン−１−カルボキシラートを用いて参考例６（６ａ）と同様に反応を行い、標記目的化合物を得た。
黄色油状物;
IR (film) ν_max 3496, 2941, 1698, 1612, 1487 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.92-2.09 (2H, m), 3.29-3.38 (4H, m), 3.39-3.45 (1H, m), 3.57-3.73 (6H, m), 3.91-3.98 (2H, m), 4.49-4.57 (2H, m), 5.09 (1H, s), 5.14 (1H, s), 6.75-6.83 (2H, m), 7.25-7.39 (5H, m), 7.66-7.44 (2H, m);
MS (FAB) m/z: 437 [M+H]⁺, 436, 394, 337。
(8d) Benzyl 4- {4- [1- (2-methoxyethyl) -1H-tetrazol-5-yl] phenyl} -1,4-diazepan-1-carboxylate Benzyl prepared in Reference Example 8 (8c) 4- (4-{[(2-Methoxyethyl) amino] carbonyl} phenyl) -1,4-diazepane-1-carboxylate was reacted in the same manner as in Reference Example 6 (6a) to give the title compound. Obtained.
Yellow oil;
IR (film) ν _max 3496, 2941, 1698, 1612, 1487 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.92-2.09 (2H, m), 3.29-3.38 (4H, m), 3.39-3.45 (1H, m), 3.57-3.73 (6H, m), 3.91-3.98 (2H, m), 4.49-4.57 (2H, m), 5.09 (1H, s), 5.14 (1H, s), 6.75-6.83 (2H, m), 7.25-7.39 (5H, m), 7.66-7.44 (2H, m);
MS (FAB) m / z: 437 [M + H] ⁺ , 436, 394, 337.

（８ｅ）１−｛４−［１−（２−メトキシエチル）−１Ｈ−テトラゾール−５−イル］フェニル｝−１，４−ジアゼパン
参考例８（８ｄ）で製造したベンジル４−｛４−［１−（２−メトキシエチル）−１Ｈ−テトラゾール−５−イル］フェニル｝−１，４−ジアゼパン−１−カルボキシラートを用いて参考例１（１ｂ）と同様に反応を行い、標記目的化合物を得た。
黄色油状物;
IR (film) ν_max 3329, 2933, 1611, 1488, 1402 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.92 (2H, quint, J = 5.9 Hz), 2.81-2.88 (2H, m), 3.06 (2H, t, J = 5.5 Hz), 3.33 (3H, s), 3.57-3.69 (4H, m), 3.94 (2H, t, J = 5.1 Hz), 4.54 (2H, t, J = 5.4 Hz), 6.79 (2H, d, J = 9.0 Hz), 7.68 (2H, d, J = 9.0 Hz);
MS (EI) m/z: 302 [M^+・], 277, 260, 234。
(8e) 1- {4- [1- (2-methoxyethyl) -1H-tetrazol-5-yl] phenyl} -1,4-diazepane benzyl 4- {4- [prepared in Reference Example 8 (8d) 1- (2-Methoxyethyl) -1H-tetrazol-5-yl] phenyl} -1,4-diazepane-1-carboxylate is reacted in the same manner as in Reference Example 1 (1b) to give the title compound. Obtained.
Yellow oil;
IR (film) ν _max 3329, 2933, 1611, 1488, 1402 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.92 (2H, quint, J = 5.9 Hz), 2.81-2.88 (2H, m), 3.06 (2H, t, J = 5.5 Hz), 3.33 (3H, s) , 3.57-3.69 (4H, m), 3.94 (2H, t, J = 5.1 Hz), 4.54 (2H, t, J = 5.4 Hz), 6.79 (2H, d, J = 9.0 Hz), 7.68 (2H, d, J = 9.0 Hz);
MS (EI) m / z: 302 [M ^+. ], 277, 260, 234.

［参考例９］１−［３−（１−メチル−１Ｈ−テトラゾール−５−イル）フェニル］ピペラジン
（９ａ）ｔｅｒｔ−ブチル４−［３−（１−メチル−１Ｈ−テトラゾール−５−イル）フェニル］ピペラジン−１−カルボキシラート
５−（３−ブロモフェニル）−１−メチルー１Ｈ−テトラゾール（ＷＯ９５２７６９２）及びｔｅｒｔ−ブチルピペラジン−１−カルボキシラートを用いて参考例１（１ａ）と同様に反応を行い、標記目的化合物を得た。
淡黄色プリズム晶;
Mp 82-84 ℃;
IR (film) ν_max 3370, 2980, 2858, 1702, 1687, 1424 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.49 (9H, s), 3.19-3.24 (4H, m), 3.56-3.61 (4H, m), 4.16 (3H, s), 7.06-7.11 (2H, m), 7.26-7.29 (1H, m), 7.40-7.45 (1H, m);
MS (FAB) m/z: 345 [M^+・], 289, 243, 230。
[Reference Example 9] 1- [3- (1-Methyl-1H-tetrazol-5-yl) phenyl] piperazine (9a) tert-butyl 4- [3- (1-methyl-1H-tetrazol-5-yl) Phenyl] piperazine-1-carboxylate 5- (3-Bromophenyl) -1-methyl-1H-tetrazole (WO9527692) and tert-butyl piperazine-1-carboxylate were used in the same manner as in Reference Example 1 (1a). The title compound was obtained.
Pale yellow prisms;
Mp 82-84 ° C;
IR (film) ν _max 3370, 2980, 2858, 1702, 1687, 1424 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.49 (9H, s), 3.19-3.24 (4H, m), 3.56-3.61 (4H, m), 4.16 (3H, s), 7.06-7.11 (2H, m ), 7.26-7.29 (1H, m), 7.40-7.45 (1H, m);
MS (FAB) m / z: 345 [M ^+. ], 289, 243, 230.

（９ｂ）１−［３−（１−メチル−１Ｈ−テトラゾール−５−イル）フェニル］ピペラジン
参考例９（９ａ）で製造したｔｅｒｔ−ブチル４−［３−（１−メチル−１Ｈ−テトラゾール−５−イル）フェニル］ピペラジン−１−カルボキシラート（２．６０ｇ，７．５５ｍｍｏｌ）をメタノール（３８ｍＬ）に溶解し、４N塩化水素−１，４−ジオキサン溶液（９．５ｍＬ）を加えた。混合物を室温で２時間攪拌した後、減圧下に濃縮した。残渣に１N水酸化ナトリウム水溶液（５０ｍＬ）を加え、水層を塩化メチレン（３×５０ｍＬ）で抽出した。抽出液を無水硫酸ナトリウムで乾燥後、溶媒を減圧下留去して、１．８４ｇ（定量的）の標記目的化合物を得た。
微黄色油状物;
IR (film) ν_max 3314, 2951, 2830, 1607, 1586, 1490, 1453, cm^-1;
¹H NMR(CDCl₃, 500 MHz) δ 3.05-3.09 (4H, m), 3.23-3.28 (4H, m), 4.17 (3H, s), 7.07-7.14 (2H, m), 7.28-7.30 (1H, m), 7.41-7.46 (1H, m);
MS (EI) m/z: 244 [M^+・], 202, 145。
(9b) 1- [3- (1-Methyl-1H-tetrazol-5-yl) phenyl] piperazine tert-Butyl 4- [3- (1-methyl-1H-tetrazol-) prepared in Reference Example 9 (9a) 5-yl) phenyl] piperazine-1-carboxylate (2.60 g, 7.55 mmol) was dissolved in methanol (38 mL) and 4N hydrogen chloride-1,4-dioxane solution (9.5 mL) was added. The mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. To the residue was added 1N aqueous sodium hydroxide solution (50 mL), and the aqueous layer was extracted with methylene chloride (3 × 50 mL). The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 1.84 g (quantitative) of the title compound.
A slightly yellow oil;
IR (film) ν _max 3314, 2951, 2830, 1607, 1586, 1490, 1453, cm ^-1 ;
¹ H NMR (CDCl ₃ , 500 MHz) δ 3.05-3.09 (4H, m), 3.23-3.28 (4H, m), 4.17 (3H, s), 7.07-7.14 (2H, m), 7.28-7.30 (1H , m), 7.41-7.46 (1H, m);
MS (EI) m / z: 244 [M ⁺ .], 202, 145.

［参考例１０］１−［４−（１，４−ジアゼパン−１−イル）フェニル］ピペリジン−２−オン
（１０ａ）ベンジル４−［４−（２−オキソピペリジン−１−イル）フェニル］−１，４−ジアゼパン−１−カルボキシラート
１−（４−ブロモフェニル）ピペリジン−２−オン（ＵＳ３８６２１７２）を用いて参考例１（１ａ）と同様に反応を行い、標記目的化合物を得た。
黄色油状物;
IR (film) ν_max 3458, 2945, 1698, 1650, 1518 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.86-2.05 (6H, m), 2.50-2.56 (2H, m), 3.32 (1H, t, J = 6.3 Hz), 3.39 (1H, t, J = 6.3 Hz), 3.49-3.66 (8H, m), 5.09 (1H, s), 5.13 (1H, s), 6.62-6.68 (2H, m), 7.02-7.07 (2H, m), 7.26-7.36 (5H, m);
MS (FAB) m/z: 408 [M+H]⁺, 407, 326, 272。
[Reference Example 10] 1- [4- (1,4-diazepan-1-yl) phenyl] piperidin-2-one (10a) benzyl 4- [4- (2-oxopiperidin-1-yl) phenyl]- 1,4-Diazepan-1-carboxylate 1- (4-Bromophenyl) piperidin-2-one (US3862172) was used in the same manner as in Reference Example 1 (1a) to give the title object compound.
Yellow oil;
IR (film) ν _max 3458, 2945, 1698, 1650, 1518 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.86-2.05 (6H, m), 2.50-2.56 (2H, m), 3.32 (1H, t, J = 6.3 Hz), 3.39 (1H, t, J = 6.3 Hz), 3.49-3.66 (8H, m), 5.09 (1H, s), 5.13 (1H, s), 6.62-6.68 (2H, m), 7.02-7.07 (2H, m), 7.26-7.36 (5H, m);
MS (FAB) m / z: 408 [M + H] ⁺ , 407, 326, 272.

（１０ｂ）１−［４−（１，４−ジアゼパン−１−イル）フェニル］ピペリジン−２−オン
参考例１０（１０ａ）で製造したベンジル４−［４−（２−オキソピペリジン−１−イル）フェニル］−１，４−ジアゼパン−１−カルボキシラートを用いて参考例１（１ｂ）と同様に反応を行い、標記目的化合物を得た。
白色粉末;
Mp 117-119 ℃;
IR (KBr) ν_max 3324, 2939, 1649, 1518 cm^-1;
¹H NMR(DMSO-d₆, 400 MHz) δ 1.84-1.95 (6H, m), 2.49-2.56 (2H, m), 2.80-2.86 (2H, m), 2.98-3.04 (2H, m), 3.49-3.60 (6H, m), 6.65 (2H, d, J = 9.0 Hz), 7.03 (2H, d, J = 9.0 Hz);
MS (EI) m/z: 273 [M^+・], 231, 217;
Anal. Calcd for C₁₆H₂₃N₃O・0.46EtOH: C, 68.99; H, 8.81; N, 14.26. Found: C, 68.70; H, 8.51; N, 14.42。
(10b) 1- [4- (1,4-diazepan-1-yl) phenyl] piperidin-2-one benzyl 4- [4- (2-oxopiperidin-1-yl) prepared in Reference Example 10 (10a) ) Phenyl] -1,4-diazepane-1-carboxylate was used in the same manner as in Reference Example 1 (1b) to obtain the title compound.
White powder;
Mp 117-119 ° C;
IR (KBr) ν _max 3324, 2939, 1649, 1518 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.84-1.95 (6H, m), 2.49-2.56 (2H, m), 2.80-2.86 (2H, m), 2.98-3.04 (2H, m), 3.49 -3.60 (6H, m), 6.65 (2H, d, J = 9.0 Hz), 7.03 (2H, d, J = 9.0 Hz);
MS (EI) m / z: 273 [M ^{+ ・} ], 231, 217;
_{_{. Anal Calcd for C 16 H 23}} N 3 O · 0.46EtOH:. C, 68.99; H, 8.81; N, 14.26 Found: C, 68.70; H, 8.51; N, 14.42.

［参考例１１］１−[４−（４，５−ジヒドロイソキサゾール−３−イル）フェニル]−１，４−ジアゼパン
（１１ａ）３−(４−ブロモフェニル)−４，５−ジヒドロイソキサゾール
１−（４−ブロモフェニル）−３−クロロプロパン−１−オン（１９．５４ｇ，７８．９ｍｍｏｌ）のエタノール（１５０ｍＬ）溶液に、ヒドロキシルアミン塩酸塩（１０．９７ｇ，１５７．８ｍｍｏｌ）及び水酸化カリウム（１３．２８ｇ，１５７．８ｍｍｏｌ）を加え１０時間撹拌した。生成した固体を除去し、残渣を濃縮した。残渣に水（５０ｍＬ）を加え、酢酸エチル（１００ｍＬ）で２回抽出し、無水硫酸ナトリウムで乾燥後，溶媒を減圧下留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル，３：１）を用いて精製し，２．１１ｇ（収率１２％）の標記目的化合物を得た。
[Reference Example 11] 1- [4- (4,5-Dihydroisoxazol-3-yl) phenyl] -1,4-diazepane (11a) 3- (4-bromophenyl) -4,5-dihydroiso To a solution of xazole 1- (4-bromophenyl) -3-chloropropan-1-one (19.54 g, 78.9 mmol) in ethanol (150 mL), hydroxylamine hydrochloride (10.97 g, 157.8 mmol) and water Potassium oxide (13.28 g, 157.8 mmol) was added and stirred for 10 hours. The formed solid was removed and the residue was concentrated. Water (50 mL) was added to the residue, extracted twice with ethyl acetate (100 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified using silica gel column chromatography (hexane / ethyl acetate, 3: 1) to obtain 2.11 g (yield 12%) of the title compound.

¹H NMR(DMSO-d₆, 400 MHz) δ 3.32 (2H, t, J = 9.3 Hz), 4.40 (2H, t, J = 9.3 Hz), 7.63 (2H, d, J = 8.6 Hz), 7.67 (2H, t, J = 8.6 Hz);
MS (EI) m/z: 228 [M+H]⁺, 208, 181, 147, 118, 102。

（１１ｂ）ｔｅｒｔ−ブチル４−[４−（４，５−ジヒドロイソキサゾール−３−イル）フェニル]−１，４−ジアゼパン−１−カルボキシラート
参考例１１（１１ａ）で製造した３−(４−ブロモフェニル)−４，５−ジヒドロイソキサゾールを用いて参考例１（１ａ）と同様に反応を行い、標記目的化合物を得た。
白色固体
Mp 90-91 ℃;
IR (KBr) ν_max 2973, 1686, 1607, 1522, 1413, 1360, 1236, 1170, 929, 878, 824 cm^-1;
¹H NMR(CDCl₃, 500 MHz) δ 1.37 (4.5H, s), 1.43 (4.5H, s), 1.94-1.99 (2H, m), 3.22 (1H, t, J = 6.4 Hz), 3.20 (2H, t, J = 9.8 Hz), 3.30-3.33 (1H, m), 3.59-3.61 (6H, m), 4.41 (2H, t, J = 9.8 Hz), 6.70 (2H, d, J = 7.8 Hz), 7.54 (2H, t, J = 8.8 Hz);
MS (FAB) m/z: 345 [M+H]⁺, 290, 244, 242, 167, 19.
Anal. Calcd for C₁₉H₂₇N₃O₃: C, 66.06; H, 7.88; N, 12.16. Found: C, 66.05; H, 7.81; N, 12.01。
¹ H NMR (DMSO-d ₆ , 400 MHz) δ 3.32 (2H, t, J = 9.3 Hz), 4.40 (2H, t, J = 9.3 Hz), 7.63 (2H, d, J = 8.6 Hz), 7.67 (2H, t, J = 8.6 Hz);
MS (EI) m / z: 228 [M + H] ⁺ , 208, 181, 147, 118, 102.

(11b) tert-butyl 4- [4- (4,5-dihydroisoxazol-3-yl) phenyl] -1,4-diazepan-1-carboxylate 3- (prepared in Reference Example 11 (11a) 4-Bromophenyl) -4,5-dihydroisoxazole was used in the same manner as in Reference Example 1 (1a) to obtain the title compound.
White solid
Mp 90-91 ° C;
IR (KBr) ν _max 2973, 1686, 1607, 1522, 1413, 1360, 1236, 1170, 929, 878, 824 cm ^-1 ;
¹ H NMR (CDCl ₃ , 500 MHz) δ 1.37 (4.5H, s), 1.43 (4.5H, s), 1.94-1.99 (2H, m), 3.22 (1H, t, J = 6.4 Hz), 3.20 ( 2H, t, J = 9.8 Hz), 3.30-3.33 (1H, m), 3.59-3.61 (6H, m), 4.41 (2H, t, J = 9.8 Hz), 6.70 (2H, d, J = 7.8 Hz) ), 7.54 (2H, t, J = 8.8 Hz);
MS (FAB) m / z: 345 [M + H] ⁺ , 290, 244, 242, 167, 19.
Anal. Calcd for C ₁₉ H ₂₇ N ₃ O ₃ : C, 66.06; H, 7.88; N, 12.16. Found: C, 66.05; H, 7.81; N, 12.01.

（１１ｃ）１−[４−（４，５−ジヒドロイソキサゾール−３−イル）フェニル]−１，４−ジアゼパン
参考例１１（１１ｂ）で製造したｔｅｒｔ−ブチル４−[４−（４，５−ジヒドロイソキサゾール−３−イル）フェニル]−１，４−ジアゼパン−１−カルボキシラートを用いて参考例９（９ｂ）と同様に反応を行い、標記目的化合物を得た。
淡黄色固体
Mp 104-105 ℃;
IR (KBr) ν_max 3358, 2923, 1606, 1525, 1404, 1360, 1198, 931, 875, 818 cm^-1;
¹H NMR(CDCl₃, 500 MHz) δ 1.90 (2H, quint, J = 5.9 Hz), 2.83 (2H, t, J = 5.9 Hz), 3.04 (2H, t, J = 5.4 Hz), 3.29 (2H, t, J = 10.3 Hz), 3.58 (2H, t, J = 5.4 Hz), 3.62 (2H, t, J = 6.4 Hz), 4.41 (2H, t, J = 10.3 Hz), 6.69 (2H, d, J = 8.8 Hz), 7.54 (2H, d, J = 8.8 Hz);
MS (EI) m/z: 245 [M⁺], 215, 203, 189, 175, 161, 145, 116, 102, 89, 70, 56, 43.
Anal. Calcd for C₁₄H₁₉N₃O・0.16H₂O: C, 67.75; H, 7.85; N, 16.13. Found: C, 67.83; H, 7.84; N, 16.95。
(11c) 1- [4- (4,5-dihydroisoxazol-3-yl) phenyl] -1,4-diazepan tert-butyl 4- [4- (4,4) prepared in Reference Example 11 (11b) 5-Dihydroisoxazol-3-yl) phenyl] -1,4-diazepane-1-carboxylate was used in the same manner as in Reference Example 9 (9b) to give the title object compound.
Pale yellow solid
Mp 104-105 ° C;
IR (KBr) ν _max 3358, 2923, 1606, 1525, 1404, 1360, 1198, 931, 875, 818 cm ^-1 ;
¹ H NMR (CDCl ₃ , 500 MHz) δ 1.90 (2H, quint, J = 5.9 Hz), 2.83 (2H, t, J = 5.9 Hz), 3.04 (2H, t, J = 5.4 Hz), 3.29 (2H , t, J = 10.3 Hz), 3.58 (2H, t, J = 5.4 Hz), 3.62 (2H, t, J = 6.4 Hz), 4.41 (2H, t, J = 10.3 Hz), 6.69 (2H, d , J = 8.8 Hz), 7.54 (2H, d, J = 8.8 Hz);
MS (EI) m / z: 245 [M ⁺ ], 215, 203, 189, 175, 161, 145, 116, 102, 89, 70, 56, 43.
_{_{. Anal Calcd for C 14 H 19}} N 3 O · 0.16H 2 O:. C, 67.75; H, 7.85; N, 16.13 Found: C, 67.83; H, 7.84; N, 16.95.

［参考例１２］１−[４−（５−メチルイソキサゾール−３−イル）フェニル]−１，４−ジアゼパン
（１２ａ）３−（４−ブロモフェニル）−５−メチルイソキサゾール
窒素雰囲気下、４−ブロモ−Ｎ−ヒドロキシルベンゼンカルボキシイミドイルクロリド（Ｊ．Ｍｅｄ．Ｃｈｅｍ．，２００３，４６，２８４−３０２）（３．５８ｇ，１５．３ｍｍｏｌ）及び酢酸イソプロペニル（３．３３ｍＬ，３０．６ｍｍｏｌ）のエーテル（５０ｍＬ）溶液に、０℃にてトリエチルアミン（４．２７ｍＬ，３０．６ｍｍｏｌ）のエーテル（１０ｍＬ）溶液を２時間かけて滴下し、室温で１２時間撹拌した。反応液を濃縮し、ジイソプロピルエーテルにより固化した固体を取り除き、シリカゲルカラムクロマトグラフィー（ヘキサン／エーテル，２０：１）を用いて精製し，０．４５ｇ（収率１２％）の標記目的化合物を得た。
[Reference Example 12] 1- [4- (5-Methylisoxazol-3-yl) phenyl] -1,4-diazepane (12a) 3- (4-bromophenyl) -5-methylisoxazole Nitrogen atmosphere Below, 4-bromo-N-hydroxylbenzenecarboximidoyl chloride (J. Med. Chem., 2003, 46, 284-302) (3.58 g, 15.3 mmol) and isopropenyl acetate (3.33 mL, 30. To a solution of 6 mmol) in ether (50 mL), a solution of triethylamine (4.27 mL, 30.6 mmol) in ether (10 mL) was added dropwise at 0 ° C. over 2 hours and stirred at room temperature for 12 hours. The reaction solution was concentrated, the solid solidified with diisopropyl ether was removed, and purified using silica gel column chromatography (hexane / ether, 20: 1) to obtain 0.45 g (yield 12%) of the title compound. .

淡黄色固体
Mp 89-90 ℃;
IR (KBr) ν_max 1611, 1444, 1423, 1263, 1110, 1072, 1009, 905, 829, 788, 507 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 2.49 (3H, s), 6.26 (1H, s), 7.57 (2H, d, J = 8.2 Hz), 7.65 (2H, d, J = 8.2 Hz);
MS (EI) m/z: 237 [M⁺], 224, 222, 194, 183, 157, 155, 116, 102, 88, 75, 74, 43, 40。
Pale yellow solid
Mp 89-90 ° C;
IR (KBr) ν _max 1611, 1444, 1423, 1263, 1110, 1072, 1009, 905, 829, 788, 507 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 2.49 (3H, s), 6.26 (1H, s), 7.57 (2H, d, J = 8.2 Hz), 7.65 (2H, d, J = 8.2 Hz);
MS (EI) m / z: 237 [M ⁺ ], 224, 222, 194, 183, 157, 155, 116, 102, 88, 75, 74, 43, 40.

（１２ｂ）ベンジル４−[４−（５−メチルイソキサゾール−３−イル）フェニル]−１，４−ジアゼパン−１−カルボキシラート
参考例１２（１２ａ）で製造した３−（４−ブロモフェニル）−５−メチルイソキサゾールを用いて参考例１（１ａ）と同様に反応を行い、標記目的化合物を得た。
褐色ペースト状物質;
IR (film) ν_max 2948, 1699, 1613, 1537, 1424, 1230, 755 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.96-2.05 (2H, m), 2.44 (3H, s), 3.32 (1H, t, J = 6.3 Hz), 3.39 (1H, t, J = 5.9 Hz), 3.57-3.66 (6H, m), 5.07 (1H, s), 5.13 (1H, s), 6.18 (1H, s), 6.69-6.73 (2H, m), 7.28-7.33 (5H, m), 7.62 (2H, dd, J = 2.4, 9.0 Hz);
MS (FAB) m/z: 392 [M+H]⁺, 391, 256, 213, 201, 165, 39, 31。
(12b) Benzyl 4- [4- (5-methylisoxazol-3-yl) phenyl] -1,4-diazepan-1-carboxylate 3- (4-Bromophenyl) prepared in Reference Example 12 (12a) ) -5-Methylisoxazole was used in the same manner as in Reference Example 1 (1a) to obtain the title compound.
Brown pasty substance;
IR (film) ν _max 2948, 1699, 1613, 1537, 1424, 1230, 755 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.96-2.05 (2H, m), 2.44 (3H, s), 3.32 (1H, t, J = 6.3 Hz), 3.39 (1H, t, J = 5.9 Hz) , 3.57-3.66 (6H, m), 5.07 (1H, s), 5.13 (1H, s), 6.18 (1H, s), 6.69-6.73 (2H, m), 7.28-7.33 (5H, m), 7.62 (2H, dd, J = 2.4, 9.0 Hz);
MS (FAB) m / z: 392 [M + H] ⁺ , 391, 256, 213, 201, 165, 39, 31.

（１２ｃ）１−[４−（５−メチルイソキサゾール−３−イル）フェニル]−１，４−ジアゼパン
参考例１２（１２ｂ）で製造したベンジル４−[４−（５−メチルイソキサゾール−３−イル）フェニル]−１，４−ジアゼパン−１−カルボキシラートを用いて参考例１（１ｂ）と同様に反応を行い、標記目的化合物を得た。
淡黄色固体
Mp 54-61 ℃;
IR (KBr) ν_max 2929, 1610, 1537, 1498, 1438, 1400, 1198, 894, 821 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.91 (2H, quint, J = 5.9 Hz), 2.43 (3H, s), 2.81-2.84 (2H, m), 3.01-3.05 (2H, m), 3.58 (2H, t, J = 5.5 Hz), 3.62 (2H, t, J = 6.3 Hz), 6.18 (1H, s), 6.71 (2H, d, J = 9.0 Hz), 7.61 (2H, d, J = 9.0 Hz);
MS (FAB) m/z: 258 [M+H]⁺, 242, 215, 165, 65。
(12c) 1- [4- (5-Methylisoxazol-3-yl) phenyl] -1,4-diazepan benzyl 4- [4- (5-methylisoxazole) prepared in Reference Example 12 (12b) The reaction was conducted in the same manner as in Reference Example 1 (1b) using -3-yl) phenyl] -1,4-diazepan-1-carboxylate to obtain the title compound.
Pale yellow solid
Mp 54-61 ° C;
IR (KBr) ν _max 2929, 1610, 1537, 1498, 1438, 1400, 1198, 894, 821 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.91 (2H, quint, J = 5.9 Hz), 2.43 (3H, s), 2.81-2.84 (2H, m), 3.01-3.05 (2H, m), 3.58 ( 2H, t, J = 5.5 Hz), 3.62 (2H, t, J = 6.3 Hz), 6.18 (1H, s), 6.71 (2H, d, J = 9.0 Hz), 7.61 (2H, d, J = 9.0 Hz);
MS (FAB) m / z: 258 [M + H] ⁺ , 242, 215, 165, 65.

［参考例１３］１−[４−（３−メチル−１，２，４−チアジアゾール−５−イル）フェニル]−１，４−ジアゼパン
（１３ａ）４−ブロモベンズアミド
アンモニア水溶液（２８％，３．６５ｇ，６０ｍｍｏｌ）に０℃にて４−ブロモベンゾイルクロリド（４．３９ｇ，２０ｍｍｏｌ）のエ−テル（２０ｍＬ）溶液を滴下し、１０分間撹拌した。生成した沈殿を水／エタノール（５：１）にて洗浄し、４．００ｇ（収率９９％）の標記目的化合物を得た。
白色固体
Mp 191-192 ℃;
¹H NMR(CDCl₃, 400 MHz) δ 7.60 (2H, d, J = 9.0 Hz), 7.69 (2H, d, J = 9.0 Hz)。
[Reference Example 13] 1- [4- (3-Methyl-1,2,4-thiadiazol-5-yl) phenyl] -1,4-diazepane (13a) 4-bromobenzamide Aqueous ammonia solution (28%, 3. 65 g, 60 mmol) was added dropwise an ether (20 mL) solution of 4-bromobenzoyl chloride (4.39 g, 20 mmol) at 0 ° C. and stirred for 10 minutes. The resulting precipitate was washed with water / ethanol (5: 1) to obtain 4.00 g (yield 99%) of the title compound.
White solid
Mp 191-192 ° C;
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.60 (2H, d, J = 9.0 Hz), 7.69 (2H, d, J = 9.0 Hz).

（１３ｂ）４−ブロモベンゼンカルボチオアミド
参考例１３（１３ａ）で製造した４−ブロモベンズアミド（４．００ｇ，２０ｍｍｏｌ）のトルエン（５０ｍＬ）溶液に、ローソン試薬（４．８５ｇ，１２ｍｍｏｌ）を加え、１２時間加熱還流した。反応液をデカント、濃縮し、３．９９ｇ（収率９２％）の粗製の標記目的化合物を得た。
褐色固体
¹H NMR(CDCl₃, 400 MHz) δ 7.53 (2H, d, J = 9.0 Hz), 7.73 (2H, d, J = 9.0 Hz)。

（１３ｃ）５−（４−ブロモフェニル）−３−メチル−１，２，４−チアジアゾール
窒素雰囲気下、参考例１３（１３ｂ）で製造した粗製の４−ブロモベンゼンカルボチオアミド（３．９９ｇ，１８．５ｍｍｏｌ）にＮ，Ｎ−ジメチルホルムアミドジメチルアセタール（８ｍＬ）を加え、３０分間撹拌した。反応液を濃縮し、得られた残留物をエタノール（５０ｍＬ）に溶解し、ピリジン（３．０ｍＬ，３９ｍｍｏｌ）及びヒドロキシルアミン−Ｏ−スルホン酸（２．３０ｇ，２０．４ｍｍｏｌ）を加え、１２時間撹拌した。反応液を濃縮し、得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル，１０：１）にて精製し，０．８２ｇ（収率１７％）の標記目的化合物を得た。
(13b) 4-Bromobenzenecarbothioamide To a solution of 4-bromobenzamide (4.00 g, 20 mmol) prepared in Reference Example 13 (13a) in toluene (50 mL) was added Lawesson's reagent (4.85 g, 12 mmol). Heated to reflux for hours. The reaction solution was decanted and concentrated to obtain 3.99 g (yield 92%) of the crude title compound.
Brown solid
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.53 (2H, d, J = 9.0 Hz), 7.73 (2H, d, J = 9.0 Hz).

(13c) 5- (4-Bromophenyl) -3-methyl-1,2,4-thiadiazole Crude 4-bromobenzenecarbothioamide (3.99 g, 18) prepared in Reference Example 13 (13b) under a nitrogen atmosphere. 0.5 mmol), N, N-dimethylformamide dimethyl acetal (8 mL) was added and stirred for 30 minutes. The reaction mixture was concentrated, and the resulting residue was dissolved in ethanol (50 mL). Pyridine (3.0 mL, 39 mmol) and hydroxylamine-O-sulfonic acid (2.30 g, 20.4 mmol) were added for 12 hours. Stir. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate, 10: 1) to obtain 0.82 g (yield 17%) of the title compound.

白色固体
Mp 72-74 ℃;
IR (KBr) ν_max 1589, 1480, 1396, 1314, 1070, 1011, 825, 670, 479 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 2.73 (3H, s), 7.62 (2H, d, J = 8.2 Hz), 7.80 (2H, d, J = 8.2 Hz);
MS (EI) m/z: 254 [M⁺], 215, 213, 183, 181, 155, 134, 120, 102, 90, 73, 72。
White solid
Mp 72-74 ° C;
IR (KBr) ν _max 1589, 1480, 1396, 1314, 1070, 1011, 825, 670, 479 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 2.73 (3H, s), 7.62 (2H, d, J = 8.2 Hz), 7.80 (2H, d, J = 8.2 Hz);
MS (EI) m / z: 254 [M ⁺ ], 215, 213, 183, 181, 155, 134, 120, 102, 90, 73, 72.

（１３ｄ）ｔｅｒｔ−ブチル４−[４−（３−メチル−１，２，４−チアジアゾール−５−イル）フェニル]−１，４−ジアゼパン−１−カルボキシラート
参考例１３（１３ｃ）で製造した５−（４−ブロモフェニル）−３−メチル−１，２，４−チアジアゾールを用いて参考例１（１ａ）と同様に反応を行い、標記目的化合物を得た。
黄色泡状物質;
IR (film) ν_max 2974, 1693, 1607, 1484, 1417, 1366, 1240, 1189, 929, 818, 671 cm^-1;
¹H NMR(CDCl₃, 500 MHz) δ 1.37 (4.5H, s), 1.43 (4.5 H, s), 1.97-2.01 (2H, m), 2.67 (3H, s), 3.24 (1H, t, J = 5.9 Hz), 3.34 (1H, t, J = 5.9 Hz), 3.61-3.64 (6H, m), 6.73 (2H, d, J = 8.8 Hz), 7.79 (2H, d, J = 8.8 Hz);
MS (FAB) m/z: 375 [M+H]⁺, 374, 335, 319, 273, 257, 244, 230, 219。
(13d) tert-butyl 4- [4- (3-methyl-1,2,4-thiadiazol-5-yl) phenyl] -1,4-diazepan-1-carboxylate prepared in Reference Example 13 (13c) The reaction was performed in the same manner as in Reference Example 1 (1a) using 5- (4-bromophenyl) -3-methyl-1,2,4-thiadiazole to obtain the title object compound.
Yellow foam;
IR (film) ν _max 2974, 1693, 1607, 1484, 1417, 1366, 1240, 1189, 929, 818, 671 cm ^-1 ;
¹ H NMR (CDCl ₃ , 500 MHz) δ 1.37 (4.5H, s), 1.43 (4.5 H, s), 1.97-2.01 (2H, m), 2.67 (3H, s), 3.24 (1H, t, J = 5.9 Hz), 3.34 (1H, t, J = 5.9 Hz), 3.61-3.64 (6H, m), 6.73 (2H, d, J = 8.8 Hz), 7.79 (2H, d, J = 8.8 Hz);
MS (FAB) m / z: 375 [M + H] ⁺ , 374, 335, 319, 273, 257, 244, 230, 219.

（１３ｅ）１−[４−（３−メチル−１，２，４−チアジアゾール−５−イル）フェニル]−１，４−ジアゼパン
参考例１３（１３ｄ）で製造したｔｅｒｔ−ブチル４−[４−（３−メチル−１，２，４−チアジアゾール−５−イル）フェニル]−１，４−ジアゼパン−１−カルボキシラートを用いて参考例９（９ｂ）と同様に反応を行い、標記目的化合物を得た。
褐色固体
Mp 91-93 ℃;
IR (KBr) ν_max 2930, 1605, 1482, 1428, 1320, 1186, 811 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.91 (2H, quint, J = 5.9 Hz), 2.66 (3H, s), 2.83 (2H, t, J = 5.9 Hz), 3.04 (2H, t, J = 5.1 Hz), 3.60 (2H, t, J = 5.5 Hz), 3.65 (2H, t, J = 6.3 Hz), 6.70 (2H, d, J = 9.0 Hz), 7.76 (2H, d, J = 9.0 Hz);
MS (FAB) m/z: 275 [M+H]⁺, 242, 226, 165, 65;。
(13e) 1- [4- (3-Methyl-1,2,4-thiadiazol-5-yl) phenyl] -1,4-diazepan tert-butyl 4- [4- prepared in Reference Example 13 (13d) (3-Methyl-1,2,4-thiadiazol-5-yl) phenyl] -1,4-diazepane-1-carboxylate was reacted in the same manner as in Reference Example 9 (9b) to give the title compound. Obtained.
Brown solid
Mp 91-93 ° C;
IR (KBr) ν _max 2930, 1605, 1482, 1428, 1320, 1186, 811 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.91 (2H, quint, J = 5.9 Hz), 2.66 (3H, s), 2.83 (2H, t, J = 5.9 Hz), 3.04 (2H, t, J = 5.1 Hz), 3.60 (2H, t, J = 5.5 Hz), 3.65 (2H, t, J = 6.3 Hz), 6.70 (2H, d, J = 9.0 Hz), 7.76 (2H, d, J = 9.0 Hz) );
MS (FAB) m / z: 275 [M + H] ⁺ , 242, 226, 165, 65 ;.

［参考例１４］１−[４−（４，５−ジメチル−４Ｈ−１，２，４−トリアゾール−３−イル）フェニル]−１，４−ジアゼパン
（１４ａ）４−ブロモ−Ｎ−メチルベンズアミド
４−ブロモ安息香酸とメチルアミン水溶液を用いて参考例８（８ｃ）と同様に反応を行い、標記目的化合物を得た。
白色固体
Mp 162-164 ℃;
IR (KBr) ν_max 3344, 1638, 1594, 1553, 1483, 1407, 1323, 1165, 1071, 840, 751 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 3.02 (3H ,d, J = 4.3 Hz), 6.08 (1H, br.s), 7.55 (2H, d, J = 8.2 Hz), 7.61 (2H, d, J = 8.2 Hz).
MS (EI) m/z: 213 [M⁺], 212, 183, 155, 134, 131, 104, 93, 75, 74, 50, 40。
[Reference Example 14] 1- [4- (4,5-Dimethyl-4H-1,2,4-triazol-3-yl) phenyl] -1,4-diazepane (14a) 4-bromo-N-methylbenzamide The title target compound was obtained by reacting in the same manner as in Reference Example 8 (8c) using 4-bromobenzoic acid and an aqueous methylamine solution.
White solid
Mp 162-164 ° C;
IR (KBr) ν _max 3344, 1638, 1594, 1553, 1483, 1407, 1323, 1165, 1071, 840, 751 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 3.02 (3H, d, J = 4.3 Hz), 6.08 (1H, br.s), 7.55 (2H, d, J = 8.2 Hz), 7.61 (2H, d, J = 8.2 Hz).
MS (EI) m / z: 213 [M ⁺ ], 212, 183, 155, 134, 131, 104, 93, 75, 74, 50, 40.

（１４ｂ）４−ブロモ−Ｎ−メチルベンゼンカルボチオアミド
参考例１４（１４ａ）で製造した４−ブロモ−Ｎ−メチルベンズアミドを用いて参考例１３（１３ｂ）と同様に反応を行い、標記目的化合物を得た。
淡黄色固体
Mp 129-132 ℃;
IR (KBr) ν_max 3335, 1539, 1483, 1394, 1359, 1255, 1043, 943, 829, 720, 626 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 3.37 (3H ,d, J = 4.7 Hz), 7.53 (2H, d, J = 8.6 Hz), 7.63 (2H, d, J = 8.6 Hz);
MS (EI) m/z: 229 [M⁺], 201, 199, 183, 155, 135, 120, 117, 102, 75, 74, 64, 50, 44, 40;
Anal. Calcd for C₈H₈BrNS: C, 41.75; H, 3.50; N, 6.09; S, 13.93. Found: C, 41.73; H, 3.67; N, 5.80; S, 13.74。
(14b) 4-Bromo-N-methylbenzenecarbothioamide Using 4-bromo-N-methylbenzamide prepared in Reference Example 14 (14a), the reaction was carried out in the same manner as in Reference Example 13 (13b) to obtain the title compound. Obtained.
Pale yellow solid
Mp 129-132 ° C;
IR (KBr) ν _max 3335, 1539, 1483, 1394, 1359, 1255, 1043, 943, 829, 720, 626 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 3.37 (3H, d, J = 4.7 Hz), 7.53 (2H, d, J = 8.6 Hz), 7.63 (2H, d, J = 8.6 Hz);
MS (EI) m / z: 229 [M ⁺ ], 201, 199, 183, 155, 135, 120, 117, 102, 75, 74, 64, 50, 44, 40;
Anal. Calcd for C ₈ H ₈ BrNS: C, 41.75; H, 3.50; N, 6.09; S, 13.93. Found: C, 41.73; H, 3.67; N, 5.80; S, 13.74.

（１４ｃ）メチル４−ブロモ−Ｎ−メチルベンゼンカルボイミドチオエートハイドロヨーダイド
参考例（１４ｂ）で製造した４−ブロモ−Ｎ−メチルベンゼンカルボチオアミド（３．０３ｇ，１３．２ｍｍｏｌ）のテトラヒドロフラン（１０ｍＬ）溶液に、ヨウ化メチル（８．２ｍＬ，１３２ｍｍｏｌ）を加え、１２時間撹拌した。生成した固体を濾取し、テトラヒドロフランにて洗浄し、４．４７ｇ（収率９１％）の標記目的化合物を（Ｅ）、（Ｚ）体混合物として得た。
淡黄色固体
Mp 156-158 ℃;
IR (KBr) ν_max 2970, 1614, 1489, 1423, 1396, 1228, 1152, 1066, 1012, 956, 834, 801 cm^-1;
¹H NMR(CD₃OD, 400 MHz) δ 2.51 (1H, s), 2.82 (2H, s), 3.30 (2H, s), 3.34 (1H, s), 7.51-7.59 (2H, m), 7.82-7.85 (2H, m);
MS (FAB) m/z: 244 [M+H]⁺, 196, 165, 65, 51, 39, 27;
Anal. Calcd for C₉H₁₁BrINS: C, 29.05; H, 2.98; N, 3.76. Found: C, 28.93; H, 2.97; N, 3.62。
(14c) Methyl 4-bromo-N-methylbenzenecarbomidothioate hydroiodide 4-bromo-N-methylbenzenecarbothioamide (3.03 g, 13.2 mmol) prepared in Reference Example (14b) in tetrahydrofuran (10 mL) ) Methyl iodide (8.2 mL, 132 mmol) was added to the solution and stirred for 12 hours. The produced solid was collected by filtration and washed with tetrahydrofuran to obtain 4.47 g (yield 91%) of the title object compound as a mixture of (E) and (Z).
Pale yellow solid
Mp 156-158 ° C;
IR (KBr) ν _max 2970, 1614, 1489, 1423, 1396, 1228, 1152, 1066, 1012, 956, 834, 801 cm ^-1 ;
¹ H NMR (CD ₃ OD, 400 MHz) δ 2.51 (1H, s), 2.82 (2H, s), 3.30 (2H, s), 3.34 (1H, s), 7.51-7.59 (2H, m), 7.82 -7.85 (2H, m);
MS (FAB) m / z: 244 [M + H] ⁺ , 196, 165, 65, 51, 39, 27;
Anal. Calcd for C ₉ H ₁₁ BrINS: C, 29.05; H, 2.98; N, 3.76. Found: C, 28.93; H, 2.97; N, 3.62.

（１４ｄ）４−ブロモ−Ｎ’’−メチルベンゼンカルボキシイミドヒドラジドハイドロヨーダイド
参考例１４（１４ｃ）で製造したメチル４−ブロモ−Ｎ−メチルベンゼンカルボイミドチオエートハイドロヨーダイド（４．４７ｇ，１２．０ｍｍｏｌ）のメタノール（２０ｍＬ）溶液に、ヒドラジンハイドラート（０．５８ｍＬ，１２．０ｍｍｏｌ）を加え、１０分間撹拌した。反応液を濃縮し、エーテルで結晶化、濾取し、エーテルにて洗浄し、４．００ｇ（収率９４％）の標記目的化合物を得た。
(14d) 4-Bromo-N ″ -methylbenzenecarboximide hydrazide hydroiodide Methyl 4-bromo-N-methylbenzenecarbomidothioate hydroiodide (4.47 g, 12) prepared in Reference Example 14 (14c) 0.0 mmol) in methanol (20 mL) was added hydrazine hydrate (0.58 mL, 12.0 mmol) and stirred for 10 minutes. The reaction mixture was concentrated, crystallized with ether, collected by filtration, and washed with ether to give 4.00 g (yield 94%) of the title compound.

白色固体
Mp 172-175 ℃;
IR (KBr) ν_max 3034, 1667, 1599, 1487, 1363, 1072, 947, 841, 773 cm^-1;
¹H NMR(CD₃OD, 400 MHz) δ 2.94 (3H, s), 7.51 (2H, d, J = 8.6 Hz), 7.80 (2H, d, J = 8.6 Hz);
MS (FAB) m/z: 228 [M⁺], 198, 196, 155, 65, 63, 51, 39, 31。
White solid
Mp 172-175 ° C;
IR (KBr) ν _max 3034, 1667, 1599, 1487, 1363, 1072, 947, 841, 773 cm ^-1 ;
¹ H NMR (CD ₃ OD, 400 MHz) δ 2.94 (3H, s), 7.51 (2H, d, J = 8.6 Hz), 7.80 (2H, d, J = 8.6 Hz);
MS (FAB) m / z: 228 [M ⁺ ], 198, 196, 155, 65, 63, 51, 39, 31.

（１４ｅ）３−（４−ブロモフェニル）−４，５−ジメチル−４Ｈ−１，２，４−トリアゾール
参考例１４（１４ｄ）で製造した４−ブロモ−Ｎ''−メチルベンゼンカルボキシイミドヒドラジドハイドロヨーダイド（７．１５ｇ，２０．１ｍｍｏｌ）のエタノール（３０ｍＬ）溶液に、オルト酢酸トリエチル（５．５ｍＬ）を加え、３０分間加熱還流した。反応液に４Ｍ炭酸カリウム水溶液（５０ｍＬ）を加え、塩化メチレン（１００ｍＬ）にて２回抽出、無水硫酸ナトリウムで乾燥後，溶媒を減圧下留去した。得られた固体をエーテルにて洗浄し、３．１８ｇ（収率６３％）の標記目的化合物を得た。
白色固体
Mp 182-186 ℃;
IR (KBr) ν_max 3051, 1517, 1489, 1461, 1416, 1077, 1008, 841, 731, 550 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 2.51 (3H, s), 3.58 (3H, s), 7.49 (2H, d, J = 8.6 Hz), 7.63 (2H, d, J = 8.6 Hz);
MS (EI) m/z: 252 [M⁺], 251, 250, 196, 182, 172, 155, 143, 131, 104, 102, 76, 75, 56, 50, 42。
(14e) 4- (4-Bromophenyl) -4,5-dimethyl-4H-1,2,4-triazole 4-Bromo-N ″ -methylbenzenecarboximide hydrazide hydrolyzed in Reference Example 14 (14d) Triethyl orthoacetate (5.5 mL) was added to an ethanol (30 mL) solution of iodide (7.15 g, 20.1 mmol), and the mixture was heated to reflux for 30 minutes. To the reaction solution was added 4M aqueous potassium carbonate solution (50 mL), extracted twice with methylene chloride (100 mL), and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained solid was washed with ether to obtain 3.18 g (yield 63%) of the title compound.
White solid
Mp 182-186 ° C;
IR (KBr) ν _max 3051, 1517, 1489, 1461, 1416, 1077, 1008, 841, 731, 550 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 2.51 (3H, s), 3.58 (3H, s), 7.49 (2H, d, J = 8.6 Hz), 7.63 (2H, d, J = 8.6 Hz);
MS (EI) m / z: 252 [M ⁺ ], 251, 250, 196, 182, 172, 155, 143, 131, 104, 102, 76, 75, 56, 50, 42.

（１４ｆ）ベンジル４−[４−（４，５−ジメチル−４Ｈ−１，２，４−トリアゾール−３−イル）フェニル]−１，４−ジアゼパン−１−カルボキシラート
参考例１４（１４ｅ）で製造した３−（４−ブロモフェニル）−４，５−ジメチル−４Ｈ−１，２，４−トリアゾールを用いて参考例１（１ａ）と同様に反応を行い、標記目的化合物を得た。
黄色ペースト状物質;
IR (film) ν_max 3387, 2952, 1697, 1614, 1530, 1473, 1423, 1333, 1182, 1120, 928, 823, 738 cm^-1;
¹H NMR(CDCl₃, 500 MHz) δ 1.96-2.06 (2H, m), 2.48 (3H, s), 3.34 (1H, t, J = 6.4 Hz), 3.41 (1H, t, J = 6.4 Hz), 3.57 (3H, s), 3.56-3.68 (6H, m), 5.10 (1H, s), 5.14 (1H, s), 6.75-6.87 (2H, m), 7.30-7.39 (5H, m), 7.48 (2H, d, J = 8.8 Hz);
MS (FAB) m/z: 406 [M+H]⁺, 372, 353, 317, 273, 242。
(14f) Benzyl 4- [4- (4,5-dimethyl-4H-1,2,4-triazol-3-yl) phenyl] -1,4-diazepan-1-carboxylate in Reference Example 14 (14e) Using the produced 3- (4-bromophenyl) -4,5-dimethyl-4H-1,2,4-triazole, the reaction was carried out in the same manner as in Reference Example 1 (1a) to obtain the title object compound.
Yellow pasty substance;
IR (film) ν _max 3387, 2952, 1697, 1614, 1530, 1473, 1423, 1333, 1182, 1120, 928, 823, 738 cm ^-1 ;
¹ H NMR (CDCl ₃ , 500 MHz) δ 1.96-2.06 (2H, m), 2.48 (3H, s), 3.34 (1H, t, J = 6.4 Hz), 3.41 (1H, t, J = 6.4 Hz) , 3.57 (3H, s), 3.56-3.68 (6H, m), 5.10 (1H, s), 5.14 (1H, s), 6.75-6.87 (2H, m), 7.30-7.39 (5H, m), 7.48 (2H, d, J = 8.8 Hz);
MS (FAB) m / z: 406 [M + H] ⁺ , 372, 353, 317, 273, 242.

（１４ｇ）１−[４−（４，５−ジメチル−４Ｈ−１，２，４−トリアゾール−３−イル）フェニル]−１，４−ジアゼパン
参考例１４（１４ｆ）で製造したベンジル４−[４−（４，５−ジメチル−４Ｈ−１，２，４−トリアゾール−３−イル）フェニル]−１，４−ジアゼパン−１−カルボキシラートを用いて参考例１（１ｂ）と同様に反応を行い、標記目的化合物を得た。
褐色液体
IR (film) ν_max 3308, 2933, 1687, 1614, 1532, 1493, 1364, 1183, 1038, 822 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.92 (2H, quint, J = 5.5 Hz), 2.49 (3H, s), 2.84 (2H, t, J = 5.9 Hz), 3.05 (2H, t, J = 5.1 Hz), 3.58 (3H, s), 3.57-3.65 (4H, m), 6.76 (2H, d, J = 8.8 Hz), 7.45 (2H, d, J = 8.8 Hz);
MS (EI) m/z: 271 [M⁺], 270, 229, 215, 201, 187, 186, 173, 145, 116, 114, 56, 44。
(14 g) 1- [4- (4,5-Dimethyl-4H-1,2,4-triazol-3-yl) phenyl] -1,4-diazepane benzyl 4- [produced in Reference Example 14 (14f) 4- (4,5-Dimethyl-4H-1,2,4-triazol-3-yl) phenyl] -1,4-diazepane-1-carboxylate is reacted in the same manner as in Reference Example 1 (1b). The title compound was obtained.
Brown liquid
IR (film) ν _max 3308, 2933, 1687, 1614, 1532, 1493, 1364, 1183, 1038, 822 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.92 (2H, quint, J = 5.5 Hz), 2.49 (3H, s), 2.84 (2H, t, J = 5.9 Hz), 3.05 (2H, t, J = 5.1 Hz), 3.58 (3H, s), 3.57-3.65 (4H, m), 6.76 (2H, d, J = 8.8 Hz), 7.45 (2H, d, J = 8.8 Hz);
MS (EI) m / z: 271 [M ⁺ ], 270, 229, 215, 201, 187, 186, 173, 145, 116, 114, 56, 44.

［参考例１５］１−[４−（４，５−ジメチル−４Ｈ−１，２，４−トリアゾール−３−イル）−３−メチルフェニル]−１，４−ジアゼパン
（１５ａ）４−ブロモ−Ｎ，２−ジメチルベンズアミド
４−ブロモ−２−メチル安息香酸とメチルアミン水溶液を用いて参考例８（８ｃ）と同様に反応を行い、標記目的化合物を得た。
白色固体
Mp 112-113 ℃;
IR (KBr) ν_max 3287, 1638, 1546, 1414, 1312, 868 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 2.43 (3H, s), 3.00 (3H ,d, J = 5.1 Hz), 5.71 (1H, br.s), 7.22 (1H, d, J = 8.2 Hz), 7.34 (1H, d, J = 8.2 Hz), 7.39 (1H, s);
MS (EI) m/z: 227 [M⁺], 197, 196, 171, 169, 90, 89;
Anal. Calcd for C₉H₁₀BrNO: C, 47.39; H, 4.42; N, 6.14; Br, 35.03. Found: C, 47.15; H, 4.38; N, 6.27; Br, 35.23。
[Reference Example 15] 1- [4- (4,5-Dimethyl-4H-1,2,4-triazol-3-yl) -3-methylphenyl] -1,4-diazepane (15a) 4-bromo- N, 2-Dimethylbenzamide 4-Bromo-2-methylbenzoic acid and a methylamine aqueous solution were used in the same manner as in Reference Example 8 (8c) to give the title object compound.
White solid
Mp 112-113 ° C;
IR (KBr) ν _max 3287, 1638, 1546, 1414, 1312, 868 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 2.43 (3H, s), 3.00 (3H, d, J = 5.1 Hz), 5.71 (1H, br.s), 7.22 (1H, d, J = 8.2 Hz) , 7.34 (1H, d, J = 8.2 Hz), 7.39 (1H, s);
MS (EI) m / z: 227 [M ⁺ ], 197, 196, 171, 169, 90, 89;
Anal. Calcd for C ₉ H ₁₀ BrNO: C, 47.39; H, 4.42; N, 6.14; Br, 35.03. Found: C, 47.15; H, 4.38; N, 6.27; Br, 35.23.

（１５ｂ）４−ブロモ−Ｎ，２−ジメチルベンゼンカルボチオアミド
参考例１５（１５ａ）で製造した４−ブロモ−Ｎ，２−ジメチルベンズアミドを用いて参考例１４（１４ａ）と同様に反応を行い、標記目的化合物を得た。
白色固体
Mp 117-118 ℃;
IR (KBr) ν_max 3178, 3056, 2977, 1552, 1440, 1365, 1276, 1256, 1047, 944, 815, 626 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 2.33 (3H, s), 3.31 (3H ,d, J = 4.7 Hz), 7.10 (1H, d, J = 8.2 Hz), 7.30 (1H, d, J = 8.2 Hz), 7.32 (1H, s), 7.36 (1H, br.s);
MS (EI) m/z: 243 [M⁺], 242, 212, 210, 169, 134, 131, 102, 89, 74, 69, 51, 50;
Anal. Calcd for C₉H₁₀BrNS: C, 44.27; H, 4.13; N, 5.74; Br, 32.73; S, 13.13. Found: C, 44.19; H, 3.91; N, 5.71; Br, 32.63; S, 13.04。

（１５ｃ）メチル４−ブロモ−Ｎ，２−ジメチルベンゼンカルボイミドチオエートハイドロヨーダイド
参考例１５（１５ｂ）で製造した４−ブロモ−Ｎ，２−ジメチルベンゼンカルボチオアミドを用いて参考例１４（１４ｃ）と同様に反応を行い、標記目的化合物を得た。
淡黄色固体
Mp 155-157 ℃;
IR (KBr) ν_max 2926, 2819, 1587, 1431, 1255, 1023, 927, 836, 586 cm^-1;
¹H NMR(CD₃OD, 500 MHz) δ 2.35 (3H, s), 2.36 (3H, s), 3.46 (3H, s), 7.33 (1H, d, J = 8.3 Hz), 7.67 (1H, d, J = 8.3 Hz), 7.73 (1H ,s);
MS (FAB) m/z: 258 [M+H]⁺, 244, 212, 210, 196, 179, 63, 39, 31, 27;
Anal. Calcd for C₁₀H₁₃BrINS: C, 31.11; H, 3.39; N, 3.63; Br, 20.70; S, 8.31. Found: C, 30.72; H, 3.33; N, 3.57; Br, 20.78; S, 8.28。

（１５ｄ）４−ブロモ−Ｎ''，２−ジメチルベンゼンカルボキシイミドヒドラジドハイドロヨーダイド
参考例１５（１５ｃ）で製造したメチル４−ブロモ−Ｎ，２−ジメチルベンゼンカルボイミドチオエートハイドロヨーダイドを用いて参考例１４（１４ｄ）と同様に反応を行い、標記目的化合物を得た。
白色固体
Mp 162-172 ℃(dec.);
IR (KBr) ν_max 2142, 3156, 3056, 1671, 1606, 1485, 1083, 956, 842, 661 cm^-1;
¹H NMR(CD₃OD, 400 MHz) δ 2.33 (3H, s), 2.79 (3H, s), 7.29 (1H, d, J = 8.2 Hz), 7.58 (1H, d, J = 8.2 Hz), 7.66 (1H, s);
MS (EI) m/z: 241 [M⁺], 227, 212, 169, 128, 127, 89。
(15b) 4-Bromo-N, 2-dimethylbenzenecarbothioamide The same reaction as in Reference Example 14 (14a) was performed using 4-bromo-N, 2-dimethylbenzamide prepared in Reference Example 15 (15a). The title object compound was obtained.
White solid
Mp 117-118 ° C;
IR (KBr) ν _max 3178, 3056, 2977, 1552, 1440, 1365, 1276, 1256, 1047, 944, 815, 626 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 2.33 (3H, s), 3.31 (3H, d, J = 4.7 Hz), 7.10 (1H, d, J = 8.2 Hz), 7.30 (1H, d, J = 8.2 Hz), 7.32 (1H, s), 7.36 (1H, br.s);
MS (EI) m / z: 243 [M ⁺ ], 242, 212, 210, 169, 134, 131, 102, 89, 74, 69, 51, 50;
Anal.Calcd for C ₉ H ₁₀ BrNS: C, 44.27; H, 4.13; N, 5.74; Br, 32.73; S, 13.13.Found: C, 44.19; H, 3.91; N, 5.71; Br, 32.63; S, 13.04.

(15c) Methyl 4-bromo-N, 2-dimethylbenzenecarboimidethioate hydroiodide Reference Example 14 (14c) using 4-bromo-N, 2-dimethylbenzenecarbothioamide prepared in Reference Example 15 (15b) ) To give the title object compound.
Pale yellow solid
Mp 155-157 ° C;
IR (KBr) ν _max 2926, 2819, 1587, 1431, 1255, 1023, 927, 836, 586 cm ^-1 ;
¹ H NMR (CD ₃ OD, 500 MHz) δ 2.35 (3H, s), 2.36 (3H, s), 3.46 (3H, s), 7.33 (1H, d, J = 8.3 Hz), 7.67 (1H, d , J = 8.3 Hz), 7.73 (1H, s);
MS (FAB) m / z: 258 [M + H] ⁺ , 244, 212, 210, 196, 179, 63, 39, 31, 27;
Anal.Calcd for C ₁₀ H ₁₃ BrINS: C, 31.11; H, 3.39; N, 3.63; Br, 20.70; S, 8.31.Found: C, 30.72; H, 3.33; N, 3.57; Br, 20.78; S, 8.28.

(15d) 4-Bromo-N ″, 2-dimethylbenzenecarboximide hydrazide hydroiodide Using methyl 4-bromo-N, 2-dimethylbenzenecarbomidothioate hydroiodide prepared in Reference Example 15 (15c) In the same manner as in Reference Example 14 (14d), the title target compound was obtained.
White solid
Mp 162-172 ° C (dec.);
IR (KBr) ν _max 2142, 3156, 3056, 1671, 1606, 1485, 1083, 956, 842, 661 cm ^-1 ;
¹ H NMR (CD ₃ OD, 400 MHz) δ 2.33 (3H, s), 2.79 (3H, s), 7.29 (1H, d, J = 8.2 Hz), 7.58 (1H, d, J = 8.2 Hz), 7.66 (1H, s);
MS (EI) m / z: 241 [M ⁺ ], 227, 212, 169, 128, 127, 89.

（１５ｅ）３−（４−ブロモ−２−メチルフェニル）−４，５−ジメチル−４Ｈ−１，２，４−トリアゾール
参考例１５（１５ｄ）で製造した４−ブロモ−Ｎ’’，２−ジメチルベンゼンカルボキシイミドヒドラジドハイドロヨーダイドを用いて参考例１４（１４ｅ）と同様に反応を行い、標記目的化合物を得た。
白色固体
Mp 129-131 ℃;
IR (KBr) ν_max 2960, 1598, 1531, 1494, 1456, 1095, 856, 826, 742, 654, 566 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 2.33 (3H, s), 2.52 (3H, s), 3.36 (3H, s), 7.14 (1H, d, J = 7.8 Hz), 7.43 (1H, dd, J = 2.0, 7.8 Hz), 7.49 (1H, d, J = 2.0 Hz);
MS (EI) m/z: 265 [M⁺], 264, 252, 223, 209, 196, 186, 171, 144, 130, 116, 115, 89, 76, 56, 40.
Anal. Calcd for C₁₁H₁₂BrN₃: C, 49.64; H, 4.54; N, 15.79; Br, 30.02. Found: C, 49.50; H, 4.57; N, 15.89; Br, 29.82。
(15e) 4-Bromo-N ″, 2-prepared in 3- (4-bromo-2-methylphenyl) -4,5-dimethyl-4H-1,2,4-triazole Reference Example 15 (15d) Dimethylbenzenecarboximide hydrazide Hydroiodide was used in the same manner as in Reference Example 14 (14e) to obtain the title compound.
White solid
Mp 129-131 ° C;
IR (KBr) ν _max 2960, 1598, 1531, 1494, 1456, 1095, 856, 826, 742, 654, 566 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 2.33 (3H, s), 2.52 (3H, s), 3.36 (3H, s), 7.14 (1H, d, J = 7.8 Hz), 7.43 (1H, dd, J = 2.0, 7.8 Hz), 7.49 (1H, d, J = 2.0 Hz);
MS (EI) m / z: 265 [M ⁺ ], 264, 252, 223, 209, 196, 186, 171, 144, 130, 116, 115, 89, 76, 56, 40.
Anal. Calcd for C ₁₁ H ₁₂ BrN ₃ : C, 49.64; H, 4.54; N, 15.79; Br, 30.02. Found: C, 49.50; H, 4.57; N, 15.89; Br, 29.82.

（１５ｆ）ベンジル４−[４−（４，５−ジメチル−４Ｈ−１，２，４−トリアゾール−３−イル）−３−メチルフェニル]−１，４−ジアゼパン−１−カルボキシラート
参考例１５（１５ｅ）で製造した３−（４−ブロモ−２−メチルフェニル）−４，５−ジメチル−４Ｈ−１，２，４−トリアゾールを用いて参考例１（１ａ）と同様に反応を行い、標記目的化合物を得た。
白色泡状物質
IR (KBr) ν_max 2950, 1697, 1610, 1474, 1422, 1235, 1120, 928 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.86-2.02 (2H, m), 2.19 (3H, s), 2.50 (3H, s), 3.35 (1.5 H, s), 3.36 (1.5H, s), 3.32-3.42 (2H, m), 3.57-3.68 (6H, m), 5.11 (1H, s), 5.14 (1H, s), 6.55-6.59 (2H, m), 7.09-7.11 (1H, m), 7.30-7.33 (5H, m);
MS (FAB) m/z: 420 [M+H]⁺, 419, 330, 255, 241, 215, 188, 63, 39, 31。
(15f) Benzyl 4- [4- (4,5-dimethyl-4H-1,2,4-triazol-3-yl) -3-methylphenyl] -1,4-diazepan-1-carboxylate Reference Example 15 Using 3- (4-bromo-2-methylphenyl) -4,5-dimethyl-4H-1,2,4-triazole prepared in (15e), the reaction was carried out in the same manner as in Reference Example 1 (1a), The title object compound was obtained.
White foam
IR (KBr) ν _max 2950, 1697, 1610, 1474, 1422, 1235, 1120, 928 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.86-2.02 (2H, m), 2.19 (3H, s), 2.50 (3H, s), 3.35 (1.5 H, s), 3.36 (1.5H, s), 3.32-3.42 (2H, m), 3.57-3.68 (6H, m), 5.11 (1H, s), 5.14 (1H, s), 6.55-6.59 (2H, m), 7.09-7.11 (1H, m), 7.30-7.33 (5H, m);
MS (FAB) m / z: 420 [M + H] ⁺ , 419, 330, 255, 241, 215, 188, 63, 39, 31.

（１５ｇ）１−[４−（４，５−ジメチル−４Ｈ−１，２，４−トリアゾール−３−イル）−３−メチルフェニル]−１，４−ジアゼパン
参考例１５（１５ｆ）で製造したベンジル４−[４−（４，５−ジメチル−４Ｈ−１，２，４−トリアゾール−３−イル）−３−メチルフェニル]−１，４−ジアゼパン−１−カルボキシラートを用いて参考例１（１ｂ）と同様に反応を行い、標記目的化合物を得た。
褐色液体
IR (film) ν_max 3334, 2933, 1611, 1486, 1240, 750 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.90 (2H, quint, J = 5.9 Hz), 2.18 (3H, s), 2.48 (3H, s), 2.84 (2H, t, J = 5.9 Hz), 3.04 (2H, t, J = 5.5 Hz), 3.36 (3H, s), 3.55-3.62 (4H, m), 6.55-6.58 (2H, m), 7.08 (1H, d, J = 9.4 Hz);
MS (EI) m/z: 285 [M⁺], 284, 243, 229, 215, 187, 186, 172, 115, 103, 91, 56, 43。
(15 g) 1- [4- (4,5-Dimethyl-4H-1,2,4-triazol-3-yl) -3-methylphenyl] -1,4-diazepan Prepared in Reference Example 15 (15f). Reference Example 1 using benzyl 4- [4- (4,5-dimethyl-4H-1,2,4-triazol-3-yl) -3-methylphenyl] -1,4-diazepane-1-carboxylate The reaction was carried out in the same manner as (1b) to obtain the title object compound.
Brown liquid
IR (film) ν _max 3334, 2933, 1611, 1486, 1240, 750 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.90 (2H, quint, J = 5.9 Hz), 2.18 (3H, s), 2.48 (3H, s), 2.84 (2H, t, J = 5.9 Hz), 3.04 (2H, t, J = 5.5 Hz), 3.36 (3H, s), 3.55-3.62 (4H, m), 6.55-6.58 (2H, m), 7.08 (1H, d, J = 9.4 Hz);
MS (EI) m / z: 285 [M ⁺ ], 284, 243, 229, 215, 187, 186, 172, 115, 103, 91, 56, 43.

［参考例１６］ベンジル４−[４−（１−メチル−１Ｈ−ピラゾール−５−イル）フェニル]−１，４−ジアゼパン−１−カルボキシラート
（１６ａ）ベンジル４−（４−アセチルフェニル）−１，４−ジアゼパン−１−カルボキシラート
１−（４−フルオロフェニル）エタノンを用いて参考例８（８ａ）と同様に反応を行い、標記目的化合物を得た。
黄色液体
IR (film) ν_max 2949, 1699, 1596, 1424, 1360, 1285, 1232, 1192, 1120, 928, 821, 593 cm^-1;
¹H NMR(CDCl₃, 500 MHz) δ 1.95-2.04 (2H, m), 2.50 (3H, s), 3.33 (1H, t, J = 6.4 Hz), 3.40 (1H, t, J = 5.9 Hz), 3.60-3.67 (6H, m), 5.07 (1H, s), 5.13 (1H, s), 6.65-6.68 (2H, m), 6.27-7.35 (5H, m), 7.84-7.87 (2H, m);
MS (FAB) m/z: 353 [M+H]⁺, 352, 337, 311, 265, 261, 217, 200, 174, 91。
[Reference Example 16] Benzyl 4- [4- (1-methyl-1H-pyrazol-5-yl) phenyl] -1,4-diazepan-1-carboxylate (16a) Benzyl 4- (4-acetylphenyl)- 1,4-diazepan-1-carboxylate 1- (4-Fluorophenyl) ethanone was used for the reaction in the same manner as in Reference Example 8 (8a) to obtain the title object compound.
Yellow liquid
IR (film) ν _max 2949, 1699, 1596, 1424, 1360, 1285, 1232, 1192, 1120, 928, 821, 593 cm ^-1 ;
¹ H NMR (CDCl ₃ , 500 MHz) δ 1.95-2.04 (2H, m), 2.50 (3H, s), 3.33 (1H, t, J = 6.4 Hz), 3.40 (1H, t, J = 5.9 Hz) , 3.60-3.67 (6H, m), 5.07 (1H, s), 5.13 (1H, s), 6.65-6.68 (2H, m), 6.27-7.35 (5H, m), 7.84-7.87 (2H, m) ;
MS (FAB) m / z: 353 [M + H] ⁺ , 352, 337, 311, 265, 261, 217, 200, 174, 91.

（１６ｂ）ベンジル４−｛４−[（２Ｅ）−３−（ジメチルアミノ）プロペ−２−ノイル]フェニル｝−１，４−ジアゼパン−１−カルボキシラート
実施例１６（１６ａ）で製造したベンジル４−（４−アセチルフェニル）−１，４−ジアゼパン−１−カルボキシラート（３．６８ｇ，１０．４ｍｍｏｌ）のトルエン（３０ｍＬ）溶液に、ジメチルホルムアミドジメチルアセタール（１４ｍＬ）を加え５日間加熱還流した。反応液に酢酸エチル（５０ｍＬ）を加え、水（５０ｍＬ）にて２回洗浄し、無水硫酸ナトリウムで乾燥後，溶媒を減圧下留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル）を用いて精製し，標記目的化合物（２．８８ｇ，収率６８％）を得た。
(16b) Benzyl 4- {4-[(2E) -3- (dimethylamino) prop-2-noyl] phenyl} -1,4-diazepan-1-carboxylate Benzyl 4 prepared in Example 16 (16a) Dimethylformamide dimethyl acetal (14 mL) was added to a toluene (30 mL) solution of-(4-acetylphenyl) -1,4-diazepan-1-carboxylate (3.68 g, 10.4 mmol), and the mixture was heated to reflux for 5 days. Ethyl acetate (50 mL) was added to the reaction mixture, washed twice with water (50 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title object compound (2.88 g, yield 68%).

黄色泡状物質
IR (film) ν_max 2946, 1698, 1641, 1599, 1568, 1422, 1357, 1187, 1117, 1053, 753 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.95-2.04 (2H, m), 3.01 (6H, brs), 3.30 (1H, t, J = 6.3 Hz), 3.38 (1H, t, J = 6.3 Hz), 3.58-3.66 (6H, m), 5.07 (1H, s), 5.13 (1H, s), 5.71 (1H, d, J = 12.1 Hz), 6.64-6.67 (2H, m), 7.24-7.33 (5H, m), 7.75 (1H, d, J = 12.1 Hz), 7.85 (2H, d, J = 8.6 Hz);
MS (FAB) m/z: 408 [M+H]⁺, 337, 273, 246, 229, 165, 93。

（１６ｃ）ベンジル４−[４−（１−メチル−１Ｈ−ピラゾール−５−イル）フェニル]−１，４−ジアゼパン−１−カルボキシラート
参考例１６（１６ｂ）で製造したベンジル４−｛４−[（２Ｅ）−３−（ジメチルアミノ）プロペ−２−ノイル]フェニル｝−１，４−ジアゼパン−１−カルボキシラート（９１７ｍｇ，２．３ｍｍｏｌ）のエタノール（５ｍＬ）溶液に、Ｎ−メチルヒドラジン（０．１４ｍＬ，２．７ｍｍｏｌ）を加え、１日撹拌した。反応液を濃縮し、得られた残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル）を用いて精製し，６００ｍｇ（収率６８％）の標記目的化合物を得た。
無色液体
IR (film) ν_max 2947, 1699, 1615, 1500, 1423, 1235, 928, 770 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.97-2.05 (2H, m), 3.36 (1H, t, J = 5.9 Hz), 3.43 (1H, t, J = 5.9 Hz), 3.58-3.69 (6H, m), 3.87 (1.5H, s), 3.88 (1.5H, s), 5.09 (1H, s), 5.14 (1H, s), 6.22 (1H, s), 6.73-6.76 (2H, m), 7.25-7.33 (7H, m), 7.48 (0.5H, s), 7.48 (0.5H, s);
MS (FAB) m/z: 391 [M+H]⁺, 376, 353, 273, 246, 242。
Yellow foam
IR (film) ν _max 2946, 1698, 1641, 1599, 1568, 1422, 1357, 1187, 1117, 1053, 753 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.95-2.04 (2H, m), 3.01 (6H, brs), 3.30 (1H, t, J = 6.3 Hz), 3.38 (1H, t, J = 6.3 Hz) , 3.58-3.66 (6H, m), 5.07 (1H, s), 5.13 (1H, s), 5.71 (1H, d, J = 12.1 Hz), 6.64-6.67 (2H, m), 7.24-7.33 (5H , m), 7.75 (1H, d, J = 12.1 Hz), 7.85 (2H, d, J = 8.6 Hz);
MS (FAB) m / z: 408 [M + H] ⁺ , 337, 273, 246, 229, 165, 93.

(16c) Benzyl 4- [4- (1-methyl-1H-pyrazol-5-yl) phenyl] -1,4-diazepan-1-carboxylate Benzyl 4- {4- prepared in Reference Example 16 (16b) To a solution of [(2E) -3- (dimethylamino) prop-2-noyl] phenyl} -1,4-diazepane-1-carboxylate (917 mg, 2.3 mmol) in ethanol (5 mL) was added N-methylhydrazine ( 0.14 mL, 2.7 mmol) was added and stirred for 1 day. The reaction mixture was concentrated, and the resulting residue was purified using silica gel column chromatography (ethyl acetate) to obtain 600 mg (yield 68%) of the title compound.
Colorless liquid
IR (film) ν _max 2947, 1699, 1615, 1500, 1423, 1235, 928, 770 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.97-2.05 (2H, m), 3.36 (1H, t, J = 5.9 Hz), 3.43 (1H, t, J = 5.9 Hz), 3.58-3.69 (6H, m), 3.87 (1.5H, s), 3.88 (1.5H, s), 5.09 (1H, s), 5.14 (1H, s), 6.22 (1H, s), 6.73-6.76 (2H, m), 7.25 -7.33 (7H, m), 7.48 (0.5H, s), 7.48 (0.5H, s);
MS (FAB) m / z: 391 [M + H] ⁺ , 376, 353, 273, 246, 242.

（１６ｄ）１−[４−メチル−１Ｈ−ピラゾール−５−イル]フェニル]−１，４−ジアゼパン
参考例１６（１６ｃ）で製造したベンジル４−[４−（１−メチル−１Ｈ−ピラゾール−５−イル）フェニル]−１，４−ジアゼパン−１−カルボキシラートを用いて参考例１（１ｂ）と同様に反応を行い、標記目的化合物を得た。
褐色液体
IR (film) ν_max 3317, 2936, 1614, 1500, 1197, 820, 758 cm^-1;
¹H NMR(CDCl₃, 500 MHz) δ 1.92 (2H, quint, J = 5.9 Hz), 2.86 (2H, t, J = 5.9 Hz), 3.06 (2H, t, J = 4.9 Hz), 3.59 (2H, t, J = 5.4 Hz), 3.62 (2H, t, J = 6.4 Hz), 3.88 (3H, s), 6.22 (1H, d, J = 2.0 Hz), 6.75 (2H, d, J = 8.8 Hz), 7.26 (2H, d, J = 8.8 Hz), 7.48 (1H, d, J = 2.0 Hz);
MS (EI) m/z: 256 [M⁺], 226, 214, 200, 186, 171, 157, 142, 130, 116, 103, 89, 77, 70, 56, 43。
(16d) 1- [4-Methyl-1H-pyrazol-5-yl] phenyl] -1,4-diazepan benzyl 4- [4- (1-methyl-1H-pyrazole-) prepared in Reference Example 16 (16c) 5-yl) phenyl] -1,4-diazepane-1-carboxylate was used in the same manner as in Reference Example 1 (1b) to give the title object compound.
Brown liquid
IR (film) ν _max 3317, 2936, 1614, 1500, 1197, 820, 758 cm ^-1 ;
¹ H NMR (CDCl ₃ , 500 MHz) δ 1.92 (2H, quint, J = 5.9 Hz), 2.86 (2H, t, J = 5.9 Hz), 3.06 (2H, t, J = 4.9 Hz), 3.59 (2H , t, J = 5.4 Hz), 3.62 (2H, t, J = 6.4 Hz), 3.88 (3H, s), 6.22 (1H, d, J = 2.0 Hz), 6.75 (2H, d, J = 8.8 Hz ), 7.26 (2H, d, J = 8.8 Hz), 7.48 (1H, d, J = 2.0 Hz);
MS (EI) m / z: 256 [M ⁺ ], 226, 214, 200, 186, 171, 157, 142, 130, 116, 103, 89, 77, 70, 56, 43.

［参考例１７］１−[４−（１，３−ジメチル−１Ｈ−１，２，４−トリアゾール−５−イル）フェニル]−１，４−ジアゼパン
（１７ａ）ベンジル４−[４−（１，３−ジメチル−１Ｈ−１，２，４−トリアゾール−５−イル）フェニル]−１，４−ジアゼパン−１−カルボキシラート
３−（４−ブロモフェニル）−４，５−ジメチル−４Ｈ−１，２，４−トリアゾール（Ｊ．Ｈｅｔｅｒｏｃｙｃｌｉｃ．Ｃｈｅｍ．，１９８３，２０，３０１−３０４．）を用いて参考例１（１ａ）と同様に反応を行い、標記目的化合物を得た。
黄色液体
IR (film) ν_max 2944, 1699, 1614, 1487, 1422, 1235, 1120, 823, 756, 700 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.96-2.04 (2H, m), 2.39 (3H, s), 3.32 (1H, t, J = 5.9 Hz), 3.39 (1H, t, J = 5.9 Hz), 3.58-3.66 (6H, m), 3.88 (1.5H, s), 3.89 (1.5H, s), 5.08 (1H, s), 5.12 (1H, s), 6.72-6.75 (2H, m), 7.27-7.32 (5H, m), 7.49-7.52 (2H, m);
MS (FAB) m/z: 406 [M+H]⁺, 326, 273, 246, 220。
[Reference Example 17] 1- [4- (1,3-Dimethyl-1H-1,2,4-triazol-5-yl) phenyl] -1,4-diazepane (17a) Benzyl 4- [4- (1 , 3-Dimethyl-1H-1,2,4-triazol-5-yl) phenyl] -1,4-diazepan-1-carboxylate 3- (4-Bromophenyl) -4,5-dimethyl-4H-1 , 2,4-triazole (J. Heterocyclic. Chem., 1983, 20, 301-304) was used in the same manner as in Reference Example 1 (1a) to obtain the title compound.
Yellow liquid
IR (film) ν _max 2944, 1699, 1614, 1487, 1422, 1235, 1120, 823, 756, 700 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.96-2.04 (2H, m), 2.39 (3H, s), 3.32 (1H, t, J = 5.9 Hz), 3.39 (1H, t, J = 5.9 Hz) , 3.58-3.66 (6H, m), 3.88 (1.5H, s), 3.89 (1.5H, s), 5.08 (1H, s), 5.12 (1H, s), 6.72-6.75 (2H, m), 7.27 -7.32 (5H, m), 7.49-7.52 (2H, m);
MS (FAB) m / z: 406 [M + H] ⁺ , 326, 273, 246, 220.

（１７ｂ）１−[４−（１，３−ジメチル−１Ｈ−１，２，４−トリアゾール−５−イル）フェニル]−１，４−ジアゼパン
参考例１７（１７ａ）で製造したベンジル４−[４−（１，３−ジメチル−１Ｈ−１，２，４−トリアゾール−５−イル）フェニル]−１，４−ジアゼパン−１−カルボキシラートを用いて参考例１（１ｂ）と同様に反応を行い、標記目的化合物を得た。
褐色液体
IR (film) ν_max 3319, 2932, 1613, 1489, 1400, 1195, 822, 747 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.91 (2H, quint, J = 6.3 Hz), 2.39 (3H, s), 2.83 (2H, t, J = 5.9 Hz), 3.04 (2H, t, J = 5.1 Hz), 3.59 (2H, t, J = 5.5 Hz), 3.63 (2H, t, J = 5.9 Hz), 3.90 (3H, s), 6.74 (2H, d, J = 8.6 Hz), 7.50 (2H, d, J = 8.6 Hz);
MS (EI) m/z: 271 [M⁺], 270, 241, 229, 215, 201, 187, 173, 131, 116, 108, 102, 70。
(17b) 1- [4- (1,3-Dimethyl-1H-1,2,4-triazol-5-yl) phenyl] -1,4-diazepane benzyl 4- [produced in Reference Example 17 (17a) 4- (1,3-Dimethyl-1H-1,2,4-triazol-5-yl) phenyl] -1,4-diazepane-1-carboxylate is reacted in the same manner as in Reference Example 1 (1b). The title compound was obtained.
Brown liquid
IR (film) ν _max 3319, 2932, 1613, 1489, 1400, 1195, 822, 747 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.91 (2H, quint, J = 6.3 Hz), 2.39 (3H, s), 2.83 (2H, t, J = 5.9 Hz), 3.04 (2H, t, J = 5.1 Hz), 3.59 (2H, t, J = 5.5 Hz), 3.63 (2H, t, J = 5.9 Hz), 3.90 (3H, s), 6.74 (2H, d, J = 8.6 Hz), 7.50 (2H , d, J = 8.6 Hz);
MS (EI) m / z: 271 [M ⁺ ], 270, 241, 229, 215, 201, 187, 173, 131, 116, 108, 102, 70.

［参考例１８］１−[４−（４−メチル−４Ｈ−１，２，４−トリアゾール−３−イル）フェニル]−１，４−ジアゼパン
（１８ａ）ベンジル４−｛４−[（メチルアミノ）カルボニル]フェニル｝−１，４−ジアゼパン−１−カルボキシラート
１−ブロモ−２−メトキシエタンの代わりにメチルアミン水溶液を用いて参考例８（８ａ）と同様に反応を行い、標記目的化合物を得た。
無色ペースト状物質;
IR (film) ν_max 2943, 1693, 1608, 1514, 1425, 1233, 928, 830, 767 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.94-2.03 (2H, m), 1.99 (3H, d, J = 5.0 Hz), 3.31 (1H, t, J = 5.9 Hz), 3.39 (1H, t, J = 6.3 Hz), 3.57-3.66 (6H, m), 5.07 (1H, s), 5.13 (1H, s), 5.96 (1H, brs), 6.65-6.68 (2H, m), 7.27-7.36 (5H, m), 7.62-7.66 (2H, m);
MS (FAB) m/z: 368 [M+H]⁺, 337, 273, 257, 246, 235。
Reference Example 18 1- [4- (4-Methyl-4H-1,2,4-triazol-3-yl) phenyl] -1,4-diazepane (18a) benzyl 4- {4-[(methylamino )] Carbonyl] phenyl} -1,4-diazepan-1-carboxylate The reaction was carried out in the same manner as in Reference Example 8 (8a) using methylamine aqueous solution instead of 1-bromo-2-methoxyethane, and the title compound was obtained. Obtained.
Colorless paste-like substance;
IR (film) ν _max 2943, 1693, 1608, 1514, 1425, 1233, 928, 830, 767 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.94-2.03 (2H, m), 1.99 (3H, d, J = 5.0 Hz), 3.31 (1H, t, J = 5.9 Hz), 3.39 (1H, t, J = 6.3 Hz), 3.57-3.66 (6H, m), 5.07 (1H, s), 5.13 (1H, s), 5.96 (1H, brs), 6.65-6.68 (2H, m), 7.27-7.36 (5H , m), 7.62-7.66 (2H, m);
MS (FAB) m / z: 368 [M + H] ⁺ , 337, 273, 257, 246, 235.

（１８ｂ）ベンジル４−｛４−[（メチルアミノ）カルボノチオイル]フェニル｝−１，４−ジアゼパン−１−カルボキシラート
参考例１８（１８ａ）で製造したベンジル４−｛４−[（メチルアミノ）カルボニル]フェニル｝−１，４−ジアゼパン−１−カルボキシラートを用いて参考例１４（１４ｂ）と同様に反応を行い、標記目的化合物を得た。
褐色泡状物質;
IR (KBr) ν_max 3311, 2947, 1696, 1603, 1512, 1423, 1194, 1120, 1040 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.94-2.03 (2H, m), 3.30 (1H, t, J = 6.7 Hz), 3.37 (3H, d, J = 5.1 Hz), 3.37-3.39 (1H, m), 3.57-3.65 (6H, m), 5.08 (1H, s), 5.13 (1H, s), 6.62-6.65 (2H, m), 7.29-7.35 (5H, m), 7.50 (1H, br.s), 7.72-7.76 (2H, m);
MS (FAB) m/z: 384 [M+H]⁺, 350, 273, 246, 182, 165。
(18b) benzyl 4- {4-[(methylamino) carbonothioyl] phenyl} -1,4-diazepan-1-carboxylate benzyl 4- {4-[(methylamino) prepared in Reference Example 18 (18a) ) Carbonyl] phenyl} -1,4-diazepane-1-carboxylate was used in the same manner as in Reference Example 14 (14b) to obtain the title compound.
Brown foam;
IR (KBr) ν _max 3311, 2947, 1696, 1603, 1512, 1423, 1194, 1120, 1040 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.94-2.03 (2H, m), 3.30 (1H, t, J = 6.7 Hz), 3.37 (3H, d, J = 5.1 Hz), 3.37-3.39 (1H, m), 3.57-3.65 (6H, m), 5.08 (1H, s), 5.13 (1H, s), 6.62-6.65 (2H, m), 7.29-7.35 (5H, m), 7.50 (1H, br. s), 7.72-7.76 (2H, m);
MS (FAB) m / z: 384 [M + H] ⁺ , 350, 273, 246, 182, 165.

（１８ｃ）ベンジル４−[４−（４−メチル−４Ｈ−１，２，４−トリアゾール−３−イル）フェニル]−１，４−ジアゼパン−１−カルボキシラート
実施例１８（１８ｂ）で製造したベンジル４−｛４−[（メチルアミノ）カルボノチオイル]フェニル｝−１，４−ジアゼパン−１−カルボキシラート（２．３０ｇ，６．０ｍｍｏｌ）のテトラヒドロフラン（２０ｍＬ）溶液に、ヨウ化メチル（７．４ｍＬ，６０ｍｍｏｌ）を加え、１２時間撹拌した。反応液を濃縮しメタノール（２０ｍＬ）に溶解し、Ｎ−ホルミルヒドラジン（０．７２ｇ，１２．０ｍｍｏｌ）を加え、１日間加熱還流した。反応液を濃縮し、得られた残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル／メタノール＝５：１）を用いて精製し，２．０９ｇ（収率８９％）の標記目的化合物を得た。
(18c) Benzyl 4- [4- (4-methyl-4H-1,2,4-triazol-3-yl) phenyl] -1,4-diazepan-1-carboxylate Prepared in Example 18 (18b) To a solution of benzyl 4- {4-[(methylamino) carbonothioyl] phenyl} -1,4-diazepane-1-carboxylate (2.30 g, 6.0 mmol) in tetrahydrofuran (20 mL) was added methyl iodide (7 4 mL, 60 mmol) was added and stirred for 12 hours. The reaction mixture was concentrated, dissolved in methanol (20 mL), N-formylhydrazine (0.72 g, 12.0 mmol) was added, and the mixture was heated to reflux for 1 day. The reaction mixture was concentrated, and the resulting residue was purified using silica gel column chromatography (ethyl acetate / methanol = 5: 1) to obtain 2.09 g (yield 89%) of the title compound.

黄色液体
IR (film) ν_max 3328, 1694, 1614, 1486, 1232, 1120, 754 cm^-1;
¹H NMR(CDCl₃, 500 MHz) δ 1.97-2.05 (2H, m), 3.34 (1H, t, J = 5.9 Hz), 3.41 (1H, t, J = 5.9 Hz), 3.60-3.69 (6H, m), 3.74 (3H, d, J = 5.4 Hz), 5.10 (1H, s), 5.14 (1H, s), 6.76-6.79 (2H, m), 7.31-7.35 (5H, m), 7.53-7.55 (2H, m), 8.13 (1H, s);
MS (FAB) m/z: 392 [M+H]⁺, 273, 246, 219, 165。
Yellow liquid
IR (film) ν _max 3328, 1694, 1614, 1486, 1232, 1120, 754 cm ^-1 ;
¹ H NMR (CDCl ₃ , 500 MHz) δ 1.97-2.05 (2H, m), 3.34 (1H, t, J = 5.9 Hz), 3.41 (1H, t, J = 5.9 Hz), 3.60-3.69 (6H, m), 3.74 (3H, d, J = 5.4 Hz), 5.10 (1H, s), 5.14 (1H, s), 6.76-6.79 (2H, m), 7.31-7.35 (5H, m), 7.53-7.55 (2H, m), 8.13 (1H, s);
MS (FAB) m / z: 392 [M + H] ⁺ , 273, 246, 219, 165.

（１８ｄ）１−[４−（４−メチル−４Ｈ−１，２，４−トリアゾール−３−イル）フェニル]−１，４−ジアゼパン
参考例１８（１８ｃ）で製造したベンジル４−[４−（４−メチル−４Ｈ−１，２，４−トリアゾール−３−イル）フェニル]−１，４−ジアゼパン−１−カルボキシラートを用いて参考例１（１ｂ）と同様に反応を行い、標記目的化合物を得た。
無色液体
IR (CHCl₃ solution) ν_max 3322, 1613, 1488, 1199, 822, 742 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.92 (2H, quint, J = 5.1 Hz), 2.85 (2H, t, J = 5.5 Hz), 3.06 (2H, t, J = 5.9 Hz), 3.60 (2H, t, J = 5.1 Hz), 3.64 (2H, t, J = 5.9 Hz), 3.75 (3H, s), 6.78 (2H, d, J = 8.6 Hz), 7.54 (2H, d, J = 8.6 Hz), 8.13 (1H, s);
MS (EI) m/z: 257 [M⁺], 256, 227, 215, 201, 187, 173, 172, 159, 131, 116, 104, 102, 70, 56, 43, 42。
(18d) 1- [4- (4-Methyl-4H-1,2,4-triazol-3-yl) phenyl] -1,4-diazepane benzyl 4- [4- prepared in Reference Example 18 (18c) (4-Methyl-4H-1,2,4-triazol-3-yl) phenyl] -1,4-diazepane-1-carboxylate was reacted in the same manner as in Reference Example 1 (1b) to give the title A compound was obtained.
Colorless liquid
IR (CHCl ₃ solution) ν _max 3322, 1613, 1488, 1199, 822, 742 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.92 (2H, quint, J = 5.1 Hz), 2.85 (2H, t, J = 5.5 Hz), 3.06 (2H, t, J = 5.9 Hz), 3.60 (2H , t, J = 5.1 Hz), 3.64 (2H, t, J = 5.9 Hz), 3.75 (3H, s), 6.78 (2H, d, J = 8.6 Hz), 7.54 (2H, d, J = 8.6 Hz) ), 8.13 (1H, s);
MS (EI) m / z: 257 [M ⁺ ], 256, 227, 215, 201, 187, 173, 172, 159, 131, 116, 104, 102, 70, 56, 43, 42.

［参考例１９］１−［４−（１，４−ジアゼパン−１−イル）フェニル］ピロリジン−２−オン
（１９ａ）ｔｅｒｔ−ブチル４−［４−（２−オキソピロリジン−１−イル）フェニル］
−１，４−ジアゼパン−１−カルボキシラート
１−（４-ブロモフェニル）−２−ピロリジノンを用いて参考例１（１ａ）と同様に反応を行い、標記目的化合物を得た。
淡黄色粉末；
Mp 107-110 ℃;
IR (KBr) ν_max 1702, 1688, 1672, 1519, 1235, 1174, 929, 811 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 1.40 (4.5H, s), 1.45 (4.5H, s), 1.93-2.01 (2H, m), 2.10-2.17 (2H, m), 2.58 (2H, t, J = 8.0 Hz), 3.17-3.31 (2H, m), 3.48-3.59 (6H, m), 3.80 (2H, t, J = 7.0 Hz), 6.68 (2H, d, J = 9.0 Hz), 7.39 (2H, d, J = 9.0 Hz);
MS (FAB) m/z: 359 [M+H]⁺;
Anal. Calcd for C₂₀H₂₉N₃O₃: C, 66.83; H, 8.13; N, 11.69. Found: C, 66.78; H, 7.90; N, 11.66。
[Reference Example 19] 1- [4- (1,4-diazepan-1-yl) phenyl] pyrrolidin-2-one
(19a) tert-butyl 4- [4- (2-oxopyrrolidin-1-yl) phenyl]
-1,4-diazepane-1-carboxylate
The reaction was conducted in the same manner as in Reference Example 1 (1a) using 1- (4-bromophenyl) -2-pyrrolidinone to obtain the title object compound.
Pale yellow powder;
Mp 107-110 ° C;
IR (KBr) ν_max 1702, 1688, 1672, 1519, 1235, 1174, 929, 811 cm^-1;
¹H NMR (CDCl_Three, 400MHz) δ 1.40 (4.5H, s), 1.45 (4.5H, s), 1.93-2.01 (2H, m), 2.10-2.17 (2H, m), 2.58 (2H, t, J = 8.0 Hz), 3.17-3.31 (2H, m), 3.48-3.59 (6H, m), 3.80 (2H, t, J = 7.0 Hz), 6.68 (2H, d, J = 9.0 Hz), 7.39 (2H, d, J = 9.0 Hz);
MS (FAB) m / z: 359 [M + H]⁺;
Anal. Calcd for C₂₀H₂₉N_ThreeO_Three: C, 66.83; H, 8.13; N, 11.69. Found: C, 66.78; H, 7.90; N, 11.66.

（１９ｂ）１−［４−（１，４−ジアゼパン−１−イル）フェニル］ピロリジン−２−オン
参考例１９（１９ａ）で製造したｔｅｒｔ−ブチル４−［４−（２−オキソピロリジン−１−イル）フェニル］−１，４−ジアゼパン−１−カルボキシラートを用いて参考例８（８ｂ）と同様に反応を行い、標記目的化合物を得た。
アモルファス粉末;
IR (KBr) ν_max 1685, 1518, 818 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 1.86-1.92 (2H, m), 2.10-2.17 (2H, m), 2.58 (2H, t, J = 8.2 Hz), 2.80-2.83 (2H, m), 3.01-3.03 (2H, m), 3.53-3.59 (4H, m), 3.81 (2H, t, J = 7.0 Hz), 6.68 (2H, d, J = 9.0 Hz), 7.38 (2H, d, J = 9.0 Hz);
MS (EI) m/z: 259 [M⁺], 217, 203;
Anal. Calcd for C₁₅H₂₁N₃O・0.2 H₂O: C, 68.52; H, 8.20; N, 15.98. Found: C, 68.53; H, 8.22; N, 15.68。
(19b) 1- [4- (1,4-diazepan-1-yl) phenyl] pyrrolidin-2-one tert-butyl 4- [4- (2-oxopyrrolidine-1) prepared in Reference Example 19 (19a) -Il) phenyl] -1,4-diazepan-1-carboxylate was used in the same manner as in Reference Example 8 (8b) to give the title object compound.
Amorphous powder;
IR (KBr) ν _max 1685, 1518, 818 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400MHz) δ 1.86-1.92 (2H, m), 2.10-2.17 (2H, m), 2.58 (2H, t, J = 8.2 Hz), 2.80-2.83 (2H, m), 3.01 -3.03 (2H, m), 3.53-3.59 (4H, m), 3.81 (2H, t, J = 7.0 Hz), 6.68 (2H, d, J = 9.0 Hz), 7.38 (2H, d, J = 9.0 Hz);
MS (EI) m / z: 259 [M ⁺ ], 217, 203;
_{_{. Anal Calcd for C 15 H 21}} N 3 O · 0.2 H 2 O:. C, 68.52; H, 8.20; N, 15.98 Found: C, 68.53; H, 8.22; N, 15.68.

［参考例２０］１−［４−（５−メチル−１，２，４−オキサジアゾール−３−イル）フェニル］−１，４−ジアゼパン
（２０ａ）ｔｅｒｔ−ブチル４−（４−シアノフェニル）−１，４−ジアゼパン−１−カルボキシラート
４−フルオロベンゾニトリルとｔｅｒｔ−ブチル１，４−ジアゼパン−１−カルボキシラートを用いて参考例８（８ａ）と同様に反応を行い、標記目的化合物を得た。
無色油状物
IR (film) ν_max 2975, 2214, 1691, 1606, 1521, 1417, 1365, 1240, 1178, 929, 819, 544 cm^-1;
¹H NMR(DMSO-d₆, 400 MHz) δ 1.16 (4.5H, s), 1.28 (4.5H, s), 1.68-1.85 (2H, m), 3.17 (1H, t, J = 5.9 Hz), 3.25 (1H, t, J = 5.5 Hz), 3.44-3.68 (6H, m), 6.81 (2H, d, J = 9.4 Hz), 7.48 (2H, dd, J = 3.5, 9.4 Hz);
HRMS m/z calcd for C₁₇H₂₃N₃O₂ 301.1790, found 301.1784;
MS (FAB) m/z: 302 [M+H]⁺, 301, 246, 228, 200, 120。
[Reference Example 20] 1- [4- (5-Methyl-1,2,4-oxadiazol-3-yl) phenyl] -1,4-diazepane (20a) tert-butyl 4- (4-cyanophenyl) ) -1,4-diazepan-1-carboxylate Using 4-fluorobenzonitrile and tert-butyl 1,4-diazepan-1-carboxylate, the reaction was carried out in the same manner as in Reference Example 8 (8a) to give the title target compound. Got.
Colorless oil
IR (film) ν _max 2975, 2214, 1691, 1606, 1521, 1417, 1365, 1240, 1178, 929, 819, 544 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.16 (4.5H, s), 1.28 (4.5H, s), 1.68-1.85 (2H, m), 3.17 (1H, t, J = 5.9 Hz), 3.25 (1H, t, J = 5.5 Hz), 3.44-3.68 (6H, m), 6.81 (2H, d, J = 9.4 Hz), 7.48 (2H, dd, J = 3.5, 9.4 Hz);
HRMS m / z calcd for C ₁₇ H ₂₃ N ₃ O ₂ 301.1790, found 301.1784;
MS (FAB) m / z: 302 [M + H] ⁺ , 301, 246, 228, 200, 120.

（２０ｂ）ｔｅｒｔ−ブチル４−｛４−［（Ｚ）−アミノ（ヒドロキシイミノ）メチル］フェニル｝−１，４−ジアゼパン−１−カルボキシラート
参考例２０（２０ａ）で製造したｔｅｒｔ−ブチル４−（４−シアノフェニル）−１，４−ジアゼパン−１−カルボキシラート（１．４７ｇ，４．９ｍｍｏｌ）および５０％ヒドロキシルアミン水溶液（０．５ｍＬ，８．２ｍｍｏｌ）のエタノール（５ｍＬ）溶液を、加熱還流下に８時間攪拌した。溶媒を減圧下留去して得られた残留物に、水（３０ｍＬ）を加え、水層を酢酸エチル（２ｘ５０ｍＬ）で抽出した。抽出液を無水硫酸ナトリウムで乾燥後、溶媒を減圧下留去した。得られた粗結晶をジエチルエーテルで洗浄し、１．４０ｇ（収率８６％）の標記目的化合物を得た。
(20b) tert-butyl 4- {4-[(Z) -amino (hydroxyimino) methyl] phenyl} -1,4-diazepan-1-carboxylate tert-butyl 4-prepared in Reference Example 20 (20a) 4- A solution of (4-cyanophenyl) -1,4-diazepane-1-carboxylate (1.47 g, 4.9 mmol) and 50% aqueous hydroxylamine (0.5 mL, 8.2 mmol) in ethanol (5 mL) was heated. Stir for 8 hours under reflux. Water (30 mL) was added to the residue obtained by evaporating the solvent under reduced pressure, and the aqueous layer was extracted with ethyl acetate (2 × 50 mL). The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude crystals were washed with diethyl ether to obtain 1.40 g (yield 86%) of the title compound.

淡黄色粉末
Mp 141-145 ℃ and 180-185 ℃ (dec);
IR (KBr) ν_max 1688, 1674, 1613, 1528, 1417, 1168, 929, 819 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 1.37 (4.5H, s), 1.43 (4.5H, s), 1.93-2.00 (2H, m), 3.17-3.31 (2H, m), 3.53-3.62 (6H, m), 4.77 (2H, br), 6.66 (2H, d, J = 9.0 Hz), 7.45 (2H, d, J = 9.0 Hz);
MS (FAB) m/z: 335 [M+H]⁺;
Anal. Calcd for C₁₇H₂₆N₄O₃・0.1EtOAc:C,60.89; H, 7.87; N, 16.32. Found: C, 60.99; H, 7.82; N, 16.31。
Pale yellow powder
Mp 141-145 ° C and 180-185 ° C (dec);
IR (KBr) ν _max 1688, 1674, 1613, 1528, 1417, 1168, 929, 819 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400MHz) δ 1.37 (4.5H, s), 1.43 (4.5H, s), 1.93-2.00 (2H, m), 3.17-3.31 (2H, m), 3.53-3.62 (6H, m), 4.77 (2H, br), 6.66 (2H, d, J = 9.0 Hz), 7.45 (2H, d, J = 9.0 Hz);
MS (FAB) m / z: 335 [M + H] ⁺ ;
_{_{. Anal Calcd for C 17 H 26}} N 4 O 3 · 0.1EtOAc:. C, 60.89; H, 7.87; N, 16.32 Found: C, 60.99; H, 7.82; N, 16.31.

（２０ｃ）ｔｅｒｔ−ブチル４−［４−（５−メチル−１，２，４−オキサジアゾール−３−イル）フェニル］−１，４−ジアゼパン−１−カルボキシラート
参考例２０（２０ｂ）で製造したｔｅｒｔ−ブチル４−｛４−［（Ｚ）−アミノ（ヒドロキシイミノ）メチル］フェニル｝−１，４−ジアゼパン−１−カルボキシラート（９８０ｍｇ，２．９ｍｍｏｌ）の塩化メチレン（１０ｍＬ）溶液に、トリエチルアミン（３５６ｍｇ，０．４９ｍＬ，３．５ｍｍｏｌ）および無水酢酸（３２９ｍｇ，０．３ｍＬ，３．２ｍｍｏｌ）を加え、室温にて２時間攪拌した。反応混合物に酢酸エチル（５０ｍＬ）を加え、有機層を水（５０ｍＬ）と飽和重曹水（５０ｍＬ）で順次洗浄した。有機層を無水硫酸ナトリウムで乾燥したのち、減圧下で溶媒を留去した。得られた残留物をテトラヒドロフラン（１０ｍＬ）に溶解し、１Ｍフッ化テトラブチルアンモニウム−テトラヒドロフラン溶液（３ｍＬ）を加えた。反応混合物を室温にて５時間攪拌したのち、酢酸エチル（１００ｍＬ）と飽和食塩水（５０ｍＬ）で分液した。有機層を無水硫酸ナトリウムで乾燥した後、溶媒を減圧下留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝２：１）にて精製し、１０１１ｍｇ（収率９６％）の標記目的化合物を得た。
(20c) tert-butyl 4- [4- (5-methyl-1,2,4-oxadiazol-3-yl) phenyl] -1,4-diazepan-1-carboxylate In Reference Example 20 (20b) Prepared tert-butyl 4- {4-[(Z) -amino (hydroxyimino) methyl] phenyl} -1,4-diazepane-1-carboxylate (980 mg, 2.9 mmol) in methylene chloride (10 mL) solution. , Triethylamine (356 mg, 0.49 mL, 3.5 mmol) and acetic anhydride (329 mg, 0.3 mL, 3.2 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Ethyl acetate (50 mL) was added to the reaction mixture, and the organic layer was washed successively with water (50 mL) and saturated aqueous sodium hydrogen carbonate (50 mL). After drying the organic layer with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (10 mL), and 1M tetrabutylammonium fluoride-tetrahydrofuran solution (3 mL) was added. The reaction mixture was stirred at room temperature for 5 hours, and then partitioned between ethyl acetate (100 mL) and saturated brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2: 1) to obtain 1011 mg (yield 96%) of the title object compound.

淡黄色粉末
Mp 118-119 ℃;
IR (KBr) ν_max 1693, 1613, 1486, 1173, 927, 817, 753 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 1.36 (4.5H, s), 1.43 (4.5H, s), 1.95-2.02 (2H, m), 2.61 (3H, s), 3.20-3.34 (2H, m), 3.57-3.64 (6H, m), 6.73 (2H, d, J = 8.6 Hz), 7.87 (2H, d, J = 8.6 Hz);
MS (FAB) m/z: 358 [M⁺];
Anal. Calcd for C₁₉H₂₆N₄O₃: C, 63.67; H, 7.31; N, 15.63. Found: C, 63.51; H, 7.11; N, 15.69。
Pale yellow powder
Mp 118-119 ° C;
IR (KBr) ν _max 1693, 1613, 1486, 1173, 927, 817, 753 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400MHz) δ 1.36 (4.5H, s), 1.43 (4.5H, s), 1.95-2.02 (2H, m), 2.61 (3H, s), 3.20-3.34 (2H, m) , 3.57-3.64 (6H, m), 6.73 (2H, d, J = 8.6 Hz), 7.87 (2H, d, J = 8.6 Hz);
MS (FAB) m / z: 358 [M ⁺ ];
Anal. Calcd for C ₁₉ H ₂₆ N ₄ O ₃ : C, 63.67; H, 7.31; N, 15.63. Found: C, 63.51; H, 7.11; N, 15.69.

（２０ｄ）１−［４−（５−メチル−１，２，４−オキサジアゾール−３−イル）フェニル］−１，４−ジアゼパン
参考例２０（２０ｃ）で製造したｔｅｒｔ−ブチル４−［４−（５−メチル−１，２，４−オキサジアゾール−３−イル）フェニル］−１，４−ジアゼパン−１−カルボキシラートを用いて参考例９（９ｂ）と同様に反応を行い、標記目的化合物を得た。
淡黄色粉末
Mp 80-84 ℃;
IR (KBr) ν_max 3281, 1615, 1590, 1487, 1193, 898, 821, 754 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 1.85-1.91 (2H, m), 2.06 (1H, br), 2.58 (3H, s), 2.78-2.81 (2H, m), 2.99-3.02 (2H, m), 3.55-3.62 (4H, m), 6.71 (2H, d, J = 9.0 Hz), 7.86 (2H, d, J = 9.0 Hz);
MS (EI) m/z: 258 [M⁺], 216, 202。

［参考例２１］１−［４−（３−メチル−１，２，４−オキサジアゾール−５−イル）フェニル］−１，４−ジアゼパン
（２１ａ）ｔｅｒｔ−ブチル４−[４−（トリフルオロアセチル）フェニル]−１，４−ジアゼパン−１−カルボキシラート
ベンジル１，４−ジアゼパン−１−カルボキシラートの代わりにｔｅｒｔ−ブチル１，４−ジアゼパン−１−カルボキシラートを用いて参考例８（８ａ）と同様に反応を行い、標記目的化合物を得た。
黄色粉末
Mp 91-92 ℃;
IR (KBr) ν_max 2977, 1688, 1596, 1529, 1416, 1166 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 1.34 (4.5H, s), 1.42 (4.5H, s), 1.93-2.03 (2H, m), 3.22-3.29 (1H, m), 3.33-3.39 (1H, m), 3.57-3.72 (6H, m), 6.72 (2H, d, J = 9.0 Hz), 7.95 (2H, d, J = 9.0 Hz);
MS (EI) m/z: 372 [M^+・], 317, 273。
(20d) 1- [4- (5-Methyl-1,2,4-oxadiazol-3-yl) phenyl] -1,4-diazepan tert-butyl 4- [prepared in Reference Example 20 (20c) 4- (5-Methyl-1,2,4-oxadiazol-3-yl) phenyl] -1,4-diazepan-1-carboxylate is used in the same manner as in Reference Example 9 (9b), The title object compound was obtained.
Pale yellow powder
Mp 80-84 ° C;
IR (KBr) ν _max 3281, 1615, 1590, 1487, 1193, 898, 821, 754 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400MHz) δ 1.85-1.91 (2H, m), 2.06 (1H, br), 2.58 (3H, s), 2.78-2.81 (2H, m), 2.99-3.02 (2H, m) , 3.55-3.62 (4H, m), 6.71 (2H, d, J = 9.0 Hz), 7.86 (2H, d, J = 9.0 Hz);
MS (EI) m / z: 258 [M ⁺ ], 216, 202.

[Reference Example 21] 1- [4- (3-Methyl-1,2,4-oxadiazol-5-yl) phenyl] -1,4-diazepane (21a) tert-butyl 4- [4- (tri Fluoroacetyl) phenyl] -1,4-diazepane-1-carboxylate Reference Example 8 using tert-butyl 1,4-diazepan-1-carboxylate instead of benzyl 1,4-diazepane-1-carboxylate The reaction was carried out in the same manner as in 8a) to obtain the title object compound.
Yellow powder
Mp 91-92 ° C;
IR (KBr) ν _max 2977, 1688, 1596, 1529, 1416, 1166 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.34 (4.5H, s), 1.42 (4.5H, s), 1.93-2.03 (2H, m), 3.22-3.29 (1H, m), 3.33-3.39 (1H, m), 3.57-3.72 (6H, m), 6.72 (2H, d, J = 9.0 Hz), 7.95 (2H, d, J = 9.0 Hz);
MS (EI) m / z: 372 [M ⁺ .], 317, 273.

（２１ｂ）４−［４−（ｔｅｒｔ−ブトキシカルボニル）−１，４−ジアゼパン−１−イル］安息香酸
参考例２１（２１ａ）で製造したｔｅｒｔ−ブチル４−[４−（トリフルオロアセチル）フェニル]−１，４−ジアゼパン−１−カルボキシラートを用いて参考例８（８ｂ）と同様に反応を行い、標記目的化合物を得た。
白色粉末;
Mp 211-214 ^oC.
IR (KBr): 2974, 1692, 1602, 1525, 1417, 1296, 1237, 1186, 929, 773 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 7.93 (2H, d, J = 9.0 Hz), 7.25-7.24 (5H, m), 6.68 (2H, d, J = 8.2 Hz), 3.66-3.57 (6H, m), 3.34-3.32 (1H, m), 3.24-3.21(1H, m), 2.00-1.97 (2H, m), 1.44 (4.5H, s), 1.37 (4.5H, s);
¹³C NMR(CDCl₃, 125 MHz) δ 172.1, 155.3, 154.9, 151.4, 151.3, 132.5, 132.4, 116.4, 110.6, 110.5, 79.8, 50.7, 50.3, 48.8, 48.1, 46.5, 46.3, 46.1, 45.7, 28.4, 28.3, 24.8, 24.6;
MS (EI): m/z: 321 [M+H⁺], 221;
HRMS-EI: m/z [M+H]⁺ calcd for C₁₇H₂₅N₂O₄: 321.1814; found: 321.1829;
Anal. Calcd for C₁₇H₂₄N₂O₄: C, 63.73; H, 7.55; N, 8.74. Found: C, 63.56; H, 7.48; N, 8.74。
(21b) 4- [4- (tert-Butoxycarbonyl) -1,4-diazepan-1-yl] benzoic acid tert-Butyl 4- [4- (trifluoroacetyl) phenyl prepared in Reference Example 21 (21a) ] -1,4-Diazepan-1-carboxylate was used in the same manner as in Reference Example 8 (8b) to give the title object compound.
White powder;
Mp 211-214 ^o C.
IR (KBr): 2974, 1692, 1602, 1525, 1417, 1296, 1237, 1186, 929, 773 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.93 (2H, d, J = 9.0 Hz), 7.25-7.24 (5H, m), 6.68 (2H, d, J = 8.2 Hz), 3.66-3.57 (6H, m), 3.34-3.32 (1H, m), 3.24-3.21 (1H, m), 2.00-1.97 (2H, m), 1.44 (4.5H, s), 1.37 (4.5H, s);
¹³ C NMR (CDCl ₃ , 125 MHz) δ 172.1, 155.3, 154.9, 151.4, 151.3, 132.5, 132.4, 116.4, 110.6, 110.5, 79.8, 50.7, 50.3, 48.8, 48.1, 46.5, 46.3, 46.1, 45.7, 28.4 , 28.3, 24.8, 24.6;
MS (EI): m / z: 321 [M + H ⁺ ], 221;
HRMS-EI: m / z [M + H] ⁺ calcd for C ₁₇ H ₂₅ N ₂ O ₄ : 321.1814; found: 321.1829;
_{_{. Anal Calcd for C 17 H 24}} N 2 O 4:. C, 63.73; H, 7.55; N, 8.74 Found: C, 63.56; H, 7.48; N, 8.74.

（２１ｃ）ｔｅｒｔ−ブチル４−［４−（３−メチル−１，２，４−オキサジアゾール−５−イル）フェニル］−１，４−ジアゼパン−１−カルボキシラート
参考例２１（２１ｂ）で製造した４−［４−（ｔｅｒｔ−ブトキシカルボニル）−１，４−ジアゼパン−１−イル］安息香酸（３．２０ｇ，１０ｍｍｏｌ）と１−ヒドロキシベンゾトリアゾール水和物（１．８４ｇ，１２ｍｍｏｌ）の塩化メチレン（５０ｍＬ）溶液に、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（ＷＳＣ・ＨＣｌ）（２．３０ｇ，１２ｍｍｏｌ）を加えた。反応混合物を室温にて３０分間攪拌したのち、アセトアミドオキシム（０．８９ｇ，１２ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（１０ｍＬ）溶液を加えた。１２時間室温にて攪拌したのち、反応液を酢酸エチル（１００ｍＬ）と飽和食塩水（１００ｍＬ）で分液した。有機層を飽和重曹水（２ｘ５０ｍＬ）で洗浄し、無水硫酸ナトリウムで乾燥後、溶媒を減圧下に留去した。得られた残留物をテトラヒドロフラン（２０ｍＬ）に溶解し、１Ｍフッ化テトラブチルアンモニウム−テトラヒドロフラン溶液（１３ｍＬ，１３ｍｍｏｌ）を加えた。混合物を加熱還流下に１時間攪拌したのち、溶媒を減圧下で留去した。残留物を水（１００ｍＬ）と酢酸エチル（１００ｍＬ）で分液し、有機層を無水硫酸ナトリウムで乾燥後、溶媒を減圧下で留去した。得られた粗結晶をエタノール（８ｍＬ）から再結晶し、２．４６ｇ（収率６９％）の標記目的化合物を得た。
(21c) tert-butyl 4- [4- (3-methyl-1,2,4-oxadiazol-5-yl) phenyl] -1,4-diazepan-1-carboxylate In Reference Example 21 (21b) 4- [4- (tert-Butoxycarbonyl) -1,4-diazepan-1-yl] benzoic acid (3.20 g, 10 mmol) and 1-hydroxybenzotriazole hydrate (1.84 g, 12 mmol) prepared To a methylene chloride (50 mL) solution, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC.HCl) (2.30 g, 12 mmol) was added. After the reaction mixture was stirred at room temperature for 30 minutes, a solution of acetamide oxime (0.89 g, 12 mmol) in N, N-dimethylformamide (10 mL) was added. After stirring for 12 hours at room temperature, the reaction mixture was partitioned between ethyl acetate (100 mL) and saturated brine (100 mL). The organic layer was washed with saturated aqueous sodium hydrogen carbonate (2 × 50 mL) and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (20 mL), and 1M tetrabutylammonium fluoride-tetrahydrofuran solution (13 mL, 13 mmol) was added. The mixture was stirred with heating under reflux for 1 hour, and then the solvent was distilled off under reduced pressure. The residue was partitioned between water (100 mL) and ethyl acetate (100 mL), the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude crystals were recrystallized from ethanol (8 mL) to obtain 2.46 g (yield 69%) of the title object compound.

淡黄色粉末
Mp 130-131 ℃;
IR (KBr) ν_max 1695, 1610, 1499, 1173, 927, 818, 757 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 1.35 (4.5H, s), 1.42 (4.5H, s), 1.95-2.02 (2H, m), 2.42 (3H, s), 3.22-3.35 (2H, m), 3.58-3.67 (6H, m), 6.74 (2H, d, J = 9.0 Hz), 7.91 (2H, d, J = 9.0 Hz);
MS (FAB) m/z: 359 [M+H]⁺;
Anal. Calcd for C₁₉H₂₆N₄O₃: C, 63.67; H, 7.31; N, 15.63. Found: C, 63.60; H, 7.26; N, 15.56。
Pale yellow powder
Mp 130-131 ° C;
IR (KBr) ν _max 1695, 1610, 1499, 1173, 927, 818, 757 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400MHz) δ 1.35 (4.5H, s), 1.42 (4.5H, s), 1.95-2.02 (2H, m), 2.42 (3H, s), 3.22-3.35 (2H, m) , 3.58-3.67 (6H, m), 6.74 (2H, d, J = 9.0 Hz), 7.91 (2H, d, J = 9.0 Hz);
MS (FAB) m / z: 359 [M + H] ⁺ ;
Anal. Calcd for C ₁₉ H ₂₆ N ₄ O ₃ : C, 63.67; H, 7.31; N, 15.63. Found: C, 63.60; H, 7.26; N, 15.56.

（２１ｄ）１−［４−（３−メチル−１，２，４−オキサジアゾール−５−イル）フェニル］−１，４−ジアゼパン
参考例２１（２１ｃ）で製造したｔｅｒｔ−ブチル４−［４−（３−メチル−１，２，４−オキサジアゾール−５−イル）フェニル］−１，４−ジアゼパン−１−カルボキシラートを用いて参考例９（９ｂ）と同様に反応を行い、標記目的化合物を得た。
淡黄色粉末
Mp 86-88 ℃;
IR (KBr) ν_max 1612, 1503, 1193, 820, 757 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 1.89-1.95 (2H, m), 2.42 (3H, s), 2.82-2.85 (2H, m), 3.03-3.06 (2H, m), 3.59-3.67 (4H, m), 6.73 (2H, d, J = 9.0 Hz), 7.91 (2H, d, J = 9.0 Hz);
MS (EI) m/z: 258 [M⁺], 216, 202;
Anal. Calcd for C₁₄H₁₈N₄O・0.1 H₂O: C, 64.64; H, 7.05; N, 21.54. Found: C, 64.85; H, 7.06; N, 21.22。
(21d) 1- [4- (3-Methyl-1,2,4-oxadiazol-5-yl) phenyl] -1,4-diazepan tert-butyl 4- [prepared in Reference Example 21 (21c) 4- (3-Methyl-1,2,4-oxadiazol-5-yl) phenyl] -1,4-diazepan-1-carboxylate is used for the reaction as in Reference Example 9 (9b), The title object compound was obtained.
Pale yellow powder
Mp 86-88 ° C;
IR (KBr) ν _max 1612, 1503, 1193, 820, 757 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.89-1.95 (2H, m), 2.42 (3H, s), 2.82-2.85 (2H, m), 3.03-3.06 (2H, m), 3.59-3.67 (4H, m), 6.73 (2H, d, J = 9.0 Hz), 7.91 (2H, d, J = 9.0 Hz);
MS (EI) m / z: 258 [M ⁺ ], 216, 202;
Anal. Calcd for C ₁₄ H ₁₈ N ₄ O · 0.1 H ₂ O: C, 64.64; H, 7.05; N, 21.54. Found: C, 64.85; H, 7.06; N, 21.22.

［参考例２２］１−［４−（１，４−ジアゼパン−１−イル）フェニル］−３−メチルイミダゾリジン−２−オン
（２２ａ）Ｎ'−（４−ブロモフェニル）−Ｎ−（２−ヒドロキシエチル）−Ｎ−メチルウレア
４−ブロモフェニルイソシアナート（１．９８ｇ，１０ｍｍｏｌ）のテトラヒドロフラン（２０ｍＬ）溶液に、２−（メチルアミノ）エタノール（０．７５ｇ，１０ｍｍｏｌ）のテトラヒドロフラン（１０ｍＬ）溶液を滴下した。反応混合物を終夜攪拌したのち、ジエチルエーテル（５０ｍＬ）を加えた。結晶を濾別し、さらにジエチルエーテルで洗浄することで、２．３７ｇ（収率８７％）の標記目的化合物を得た。
[Reference Example 22] 1- [4- (1,4-diazepan-1-yl) phenyl] -3-methylimidazolidin-2-one (22a) N ′-(4-bromophenyl) -N- (2 -Hydroxyethyl) -N-methylurea 4-bromophenyl isocyanate (1.98 g, 10 mmol) in tetrahydrofuran (20 mL) was added 2- (methylamino) ethanol (0.75 g, 10 mmol) in tetrahydrofuran (10 mL). It was dripped. The reaction mixture was stirred overnight and then diethyl ether (50 mL) was added. The crystals were filtered off and washed with diethyl ether to obtain 2.37 g (yield 87%) of the title compound.

淡黄色粉末
Mp 165-166 ℃;
IR (KBr) ν_max 3259, 1643, 1536, 1400, 813 cm^-1;
¹H NMR (DMSO-d₆, 400MHz) δ 2.96 (3H, s), 3.37 (2H, t, J = 5.6 Hz), 3.54-3.57 (2H, m), 4.97 (2H, br.t, J = 5.0 Hz), 7.39 (2H, d, J = 9.0 Hz), 7.42 (2H, d, J = 9.4 Hz), 8.45 (1H, br.s);
MS (EI) m/z: 272 [M⁺], 199, 171。
Pale yellow powder
Mp 165-166 ° C;
IR (KBr) ν _max 3259, 1643, 1536, 1400, 813 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.96 (3H, s), 3.37 (2H, t, J = 5.6 Hz), 3.54-3.57 (2H, m), 4.97 (2H, br.t, J = 5.0 Hz), 7.39 (2H, d, J = 9.0 Hz), 7.42 (2H, d, J = 9.4 Hz), 8.45 (1H, br.s);
MS (EI) m / z: 272 [M ⁺ ], 199, 171.

（２２ｂ）１−（４−ブロモフェニル）−３−メチルイミダゾリジン−２−オン
参考例２２（２２ａ）で製造したＮ'−（４−ブロモフェニル）−Ｎ−（２−ヒドロキシエチル）−Ｎ−メチルウレア（２．３７ｇ，８．７ｍｍｏｌ）とカリウムｔｅｒｔ−ブトキシド（２．３４ｇ，２０．８ｍｍｏｌ）のテトラヒドロフラン（１２０ｍＬ）懸濁液を氷冷し、ｐ−トルエンスルホニルクロリド（１．９９ｇ，１０．４ｍｍｏｌ）のテトラヒドロフラン（３０ｍＬ）溶液を滴下した。１０分間攪拌したのち、反応混合物に水（１００ｍＬ）と酢酸エチル（２００ｍＬ）を加えて分液した。有機層を飽和食塩水（１００ｍＬ）で洗浄したのち無水硫酸ナトリウムで乾燥し、溶媒を減圧下に留去した。得られた粗結晶をエタノールから再結晶し、１．８７ｇ（収率８４％）で標記目的化合物が得られた。
(22b) 1- (4-Bromophenyl) -3-methylimidazolidin-2-one N ′-(4-bromophenyl) -N- (2-hydroxyethyl) -N prepared in Reference Example 22 (22a) -A suspension of methylurea (2.37 g, 8.7 mmol) and potassium tert-butoxide (2.34 g, 20.8 mmol) in tetrahydrofuran (120 mL) was ice-cooled and p-toluenesulfonyl chloride (1.99 g, 10. 4 mmol) in tetrahydrofuran (30 mL) was added dropwise. After stirring for 10 minutes, water (100 mL) and ethyl acetate (200 mL) were added to the reaction mixture for liquid separation. The organic layer was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude crystals were recrystallized from ethanol to obtain the title compound in 1.87 g (yield 84%).

淡黄色粉末
Mp 154-157 ℃;
IR (KBr) ν_max 1697, 1497, 1274, 824, 758, 747 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 2.88 (3H, s), 3.45-3.49 (2H, m), 3.74-3.78 (2H, m), 7.39 (2H, d, J = 9.4 Hz), 7.43 (2H, d, J = 9.4 Hz);
MS (EI) m/z: 254 [M⁺];
Anal. Calcd for C₁₀H₁₁N₂OBr: C, 47.08; H, 4.35; N, 10.98; Br, 31.32. Found: C, 46.89; H, 4.14; N, 10.93; Br, 31.60。
Pale yellow powder
Mp 154-157 ° C;
IR (KBr) ν _max 1697, 1497, 1274, 824, 758, 747 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400MHz) δ 2.88 (3H, s), 3.45-3.49 (2H, m), 3.74-3.78 (2H, m), 7.39 (2H, d, J = 9.4 Hz), 7.43 (2H , d, J = 9.4 Hz);
MS (EI) m / z: 254 [M ⁺ ];
_{_{. Anal Calcd for C 10 H 11}} N 2 OBr:. C, 47.08; H, 4.35; N, 10.98; Br, 31.32 Found: C, 46.89; H, 4.14; N, 10.93; Br, 31.60.

（２２ｃ）ｔｅｒｔ−ブチル４−［４−（３−メチル−２−オキソイミダゾリジン−１−イル）フェニル］−１，４−ジアゼパン−１−カルボキシラート
参考例２２（２２ｂ）で製造した１−（４−ブロモフェニル）−３−メチルイミダゾリジン−２−オンを用いて参考例１（１ａ）と同様に反応を行い、標記目的化合物を得た。
淡黄色粉末
Mp 120-122 ℃;
IR (KBr) ν_max 1702, 1684, 1523, 1174, 930, 811 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 1.40 (4.5H, s), 1.45 (4.5H, s), 1.94-2.01 (2H, m), 2.87 (3H, s), 3.17-3.31 (2H, m), 3.40-3.44 (2H, m), 3.50-3.57 (6H, m), 3.72-3.76 (2H, m), 6.68 (2H, d, J = 9.0 Hz), 7.35 (2H, d, J = 9.0 Hz);
MS (FAB) m/z: 374 [M⁺];
Anal. Calcd for C₂₀H₃₀N₄O₃: C, 64.15; H, 8.07; N, 14.96. Found: C, 64.10; H, 8.01; N, 14.91。
(22c) tert-butyl 4- [4- (3-methyl-2-oxoimidazolidin-1-yl) phenyl] -1,4-diazepan-1-carboxylate 1-produced in Reference Example 22 (22b) The reaction was carried out in the same manner as in Reference Example 1 (1a) using (4-bromophenyl) -3-methylimidazolidin-2-one to obtain the title compound.
Pale yellow powder
Mp 120-122 ° C;
IR (KBr) ν _max 1702, 1684, 1523, 1174, 930, 811 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400MHz) δ 1.40 (4.5H, s), 1.45 (4.5H, s), 1.94-2.01 (2H, m), 2.87 (3H, s), 3.17-3.31 (2H, m) , 3.40-3.44 (2H, m), 3.50-3.57 (6H, m), 3.72-3.76 (2H, m), 6.68 (2H, d, J = 9.0 Hz), 7.35 (2H, d, J = 9.0 Hz );
MS (FAB) m / z: 374 [M ⁺ ];
_{_{. Anal Calcd for C 20 H 30}} N 4 O 3:. C, 64.15; H, 8.07; N, 14.96 Found: C, 64.10; H, 8.01; N, 14.91.

（２２ｄ）１−［４−（１，４−ジアゼパン−１−イル）フェニル］−３−メチルイミダゾリジン−２−オン
参考例２２（２２ｃ）で製造したｔｅｒｔ−ブチル４−［４−（３−メチル−２−オキソイミダゾリジン−１−イル）フェニル］−１，４−ジアゼパン−１−カルボキシラートを用いて参考例９（９ｂ）と同様に反応を行い、標記目的化合物を得た。
淡黄色粉末
Mp 124-127 ℃;
IR (KBr) ν_max 3314, 1696, 1683, 1518, 1271, 1113, 814, 747 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 1.54 (1H, br), 1.85-1.91 (2H, m), 2.79-2.82 (2H, m), 2.86 (3H, s), 3.00-3.02 (2H, m), 3.39-3.43 (2H, m), 3.50-3.57 (4H, m), 3.71-3.75 (2H, m), 6.66 (2H, d, J = 9.4 Hz), 7.32 (2H, d, J = 9.4 Hz);
MS (EI) m/z: 274 [M⁺], 232, 218;
Anal. Calcd for C₁₅H₂₂N₄O: C, 65.67; H, 8.08; N, 20.42. Found: C, 65.35; H, 8.00; N, 20.28。
(22d) 1- [4- (1,4-diazepan-1-yl) phenyl] -3-methylimidazolidin-2-one tert-butyl 4- [4- (3) prepared in Reference Example 22 (22c) Using -methyl-2-oxoimidazolidin-1-yl) phenyl] -1,4-diazepan-1-carboxylate, the reaction was carried out in the same manner as in Reference Example 9 (9b) to obtain the title object compound.
Pale yellow powder
Mp 124-127 ° C;
IR (KBr) ν _max 3314, 1696, 1683, 1518, 1271, 1113, 814, 747 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400MHz) δ 1.54 (1H, br), 1.85-1.91 (2H, m), 2.79-2.82 (2H, m), 2.86 (3H, s), 3.00-3.02 (2H, m) , 3.39-3.43 (2H, m), 3.50-3.57 (4H, m), 3.71-3.75 (2H, m), 6.66 (2H, d, J = 9.4 Hz), 7.32 (2H, d, J = 9.4 Hz );
MS (EI) m / z: 274 [M ⁺ ], 232, 218;
_{_{. Anal Calcd for C 15 H 22}} N 4 O:. C, 65.67; H, 8.08; N, 20.42 Found: C, 65.35; H, 8.00; N, 20.28.

［参考例２３］１−［４−（１，４−ジアゼパン−１−イル）フェニル］−３−メチル−１，３−ジヒドロ−２Ｈ−イミダゾール−２−オン
（２３ａ）１−（４−ブロモフェニル）−１，３−ジヒドロ−２Ｈ−イミダゾール−２−オン
４−ブロモフェニルイソシアナート（０．９９ｇ，５ｍｍｏｌ）のテトラヒドロフラン（１０ｍＬ）溶液に、２，２−ジメトキシエチルアミン（０．５３ｇ，５ｍｍｏｌ）のテトラヒドロフラン（５ｍＬ）溶液を滴下した。反応混合物を３時間攪拌したのち、減圧下濃縮した。得られた残留物をメタノール（２５ｍＬ）に溶解し、０．２５Ｎ塩化水素水溶液（２４ｍＬ）を加えた。さらに、テトラヒドロフラン（１０ｍＬ）を加えて析出した固体を溶解したのち、室温にて５日間攪拌した。反応混合物を減圧下に濃縮して得られた粗結晶をエタノール（１０ｍＬ）から再結晶することで、０．９８ｇ（収率８２％）の標記目的化合物を得た。
[Reference Example 23] 1- [4- (1,4-diazepan-1-yl) phenyl] -3-methyl-1,3-dihydro-2H-imidazol-2-one (23a) 1- (4-bromo Phenyl) -1,3-dihydro-2H-imidazol-2-one 4-bromophenyl isocyanate (0.99 g, 5 mmol) in tetrahydrofuran (10 mL) was added to 2,2-dimethoxyethylamine (0.53 g, 5 mmol). Of tetrahydrofuran (5 mL) was added dropwise. The reaction mixture was stirred for 3 hours and then concentrated under reduced pressure. The obtained residue was dissolved in methanol (25 mL), and 0.25N aqueous hydrogen chloride solution (24 mL) was added. Further, tetrahydrofuran (10 mL) was added to dissolve the precipitated solid, and the mixture was stirred at room temperature for 5 days. The crude crystals obtained by concentrating the reaction mixture under reduced pressure were recrystallized from ethanol (10 mL) to obtain 0.98 g (yield 82%) of the title compound.

淡黄色粉末
Mp 174-176 ℃;
IR (KBr) ν_max 3580, 1694, 1494, 899, 820 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 6.42 (1H, t, J = 2.4 Hz), 6.52 (1H, t, J = 2.4 Hz), 7.48 (2H, d, J = 9.0 Hz), 7.54 (2H, d, J = 9.0 Hz), 9.33 (1H, br.s);
MS (EI) m/z: 238 [M⁺]。
Pale yellow powder
Mp 174-176 ° C;
IR (KBr) ν _max 3580, 1694, 1494, 899, 820 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 6.42 (1H, t, J = 2.4 Hz), 6.52 (1H, t, J = 2.4 Hz), 7.48 (2H, d, J = 9.0 Hz), 7.54 (2H, d, J = 9.0 Hz), 9.33 (1H, br.s);
MS (EI) m / z: 238 [M ⁺ ].

（２３ｂ）１−（４−ブロモフェニル）−３−メチル−１，３−ジヒドロ−２Ｈ−イミダゾール−２−オン
参考例２３（２３ａ）で製造した１−（４−ブロモフェニル）−１，３−ジヒドロ−２Ｈ−イミダゾール−２−オン（７１７ｍｇ，３．０ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（６ｍＬ）溶液を、水素化ナトリウム（５５％油性，１４４ｍｇ，３．３ｍｍｏｌ）のテトラヒドロフラン懸濁液へ、氷冷下で滴下した。同温度で３０分間攪拌したのち、ヨウ化メチル（５５３ｍｇ，０．２４ｍＬ，３．９ｍｍｏｌ）を加えた。反応温度を昇温し、さらに室温で２時間攪拌した後、反応混合物を水（１００ｍＬ）と酢酸エチル（１００ｍＬ）で分液し、有機層を無水硫酸ナトリウムで乾燥後、減圧下に溶媒を留去した。得られた粗結晶をジイソプロピルエーテルで洗浄し、６３４ｍｇ（収率８３％）の標記目的化合物を得た。
(23b) 1- (4-Bromophenyl) -1,3 produced in Reference Example 23 (23a) 1- (4-Bromophenyl) -3-methyl-1,3-dihydro-2H-imidazol-2-one -A solution of dihydro-2H-imidazol-2-one (717 mg, 3.0 mmol) in N, N-dimethylformamide (6 mL) to a tetrahydrofuran suspension of sodium hydride (55% oily, 144 mg, 3.3 mmol). The solution was added dropwise under ice cooling. After stirring at the same temperature for 30 minutes, methyl iodide (553 mg, 0.24 mL, 3.9 mmol) was added. The reaction temperature was raised, and the mixture was further stirred at room temperature for 2 hours. The reaction mixture was partitioned between water (100 mL) and ethyl acetate (100 mL), the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Left. The obtained crude crystals were washed with diisopropyl ether to obtain 634 mg (yield 83%) of the title compound.

淡黄色粉末
Mp 141-143 ℃;
IR (KBr) ν_max 1682, 1493, 1270 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 3.32 (3H, s), 6.34 (1H, d, J = 3.0 Hz), 6.54 (1H, d, J = 3.0 Hz), 7.50-7.55 (4H, m);
MS (EI) m/z: 252 [M⁺];
Anal. Calcd for C₁₀H₉N₂OBr: C, 47.46; H, 3.58; N, 11.07; Br, 31.57. Found: C, 47.49; H, 3.93; N, 11.00; Br, 31.16。
Pale yellow powder
Mp 141-143 ° C;
IR (KBr) ν _max 1682, 1493, 1270 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 3.32 (3H, s), 6.34 (1H, d, J = 3.0 Hz), 6.54 (1H, d, J = 3.0 Hz), 7.50-7.55 (4H, m);
MS (EI) m / z: 252 [M ⁺ ];
_{_{. Anal Calcd for C 10 H 9}} N 2 OBr:. C, 47.46; H, 3.58; N, 11.07; Br, 31.57 Found: C, 47.49; H, 3.93; N, 11.00; Br, 31.16.

（２３ｃ）ベンジル４−［４−（３−メチル−２−オキソ−２，３−ジヒドロ−１Ｈ−イミダゾール−１−イル）フェニル］−１，４−ジアゼパン−１−カルボキシラート
参考例２３（２３ｂ）で製造した１−（４−ブロモフェニル）−３−メチル−１，３−ジヒドロ−２Ｈ−イミダゾール−２−オンを用いて参考例１（１ａ）と同様に反応を行い、標記目的化合物を得た。
淡黄色粉末
Mp 114-116 ℃;
IR (KBr) ν_max 1695, 1686, 1522, 1225, 1121 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 1.93-2.05 (2H, m), 3.31 (3H, s), 3.29-3.67 (8H, m), 5.10 (1H, s), 5.14 (1H, s), 6.26-6.27 (1H, m), 6.43-6.45 (1H, m), 6.69-6.71 (2H, m), 7.31-7.37 (7H, m);
MS (FAB) m/z: 406 [M⁺];
Anal. Calcd for C₂₃H₂₆N₄O₃: C, 67.96; H, 6.45; N, 13.78. Found: C, 68.25; H, 6.74; N, 13.70。
(23c) Benzyl 4- [4- (3-methyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl) phenyl] -1,4-diazepan-1-carboxylate Reference Example 23 (23b 1)-(4-bromophenyl) -3-methyl-1,3-dihydro-2H-imidazol-2-one prepared in the same manner as in Reference Example 1 (1a) to give the title compound. Obtained.
Pale yellow powder
Mp 114-116 ° C;
IR (KBr) ν _max 1695, 1686, 1522, 1225, 1121 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.93-2.05 (2H, m), 3.31 (3H, s), 3.29-3.67 (8H, m), 5.10 (1H, s), 5.14 (1H, s), 6.26 -6.27 (1H, m), 6.43-6.45 (1H, m), 6.69-6.71 (2H, m), 7.31-7.37 (7H, m);
MS (FAB) m / z: 406 [M ⁺ ];
_{_{. Anal Calcd for C 23 H 26}} N 4 O 3:. C, 67.96; H, 6.45; N, 13.78 Found: C, 68.25; H, 6.74; N, 13.70.

（２３ｄ）１−［４−（１，４−ジアゼパン−１−イル）フェニル］−３−メチル−１，３−ジヒドロ−２Ｈ−イミダゾール−２−オン
参考例２３（２３ｃ）で製造したベンジル４−［４−（３−メチル−２−オキソ−２，３−ジヒドロ−１Ｈ−イミダゾール−１−イル）フェニル］−１，４−ジアゼパン−１−カルボキシラートを用いて参考例１（１ｂ）と同様に反応を行い、標記目的化合物を得た。
淡黄色粉末
Mp 142-146 ℃;
IR (KBr) ν_max 3314, 1676, 1522, 1265, 817, 799 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 1.73 (1H, br), 1.87-1.93 (2H, m), 2.81-2.84 (2H, m), 3.01-3.04 (2H, m), 3.30 (3H, s), 3.53-3.60 (4H, m), 6.24 (1H, d, J = 3.0 Hz), 6.42 (1H, d, J = 3.0 Hz), 6.69 (2H, d, J = 9.4 Hz), 7.32 (2H, d, J = 9.4 Hz);
MS (EI) m/z: 272 [M⁺], 230, 216;
Anal. Calcd for C₁₅H₂₀N₄O・0.2 H₂O: C, 65.29; H, 7.45; N, 20.30. Found: C, 65.40; H, 7.38; N, 19.96。
(23d) 1- [4- (1,4-Diazepan-1-yl) phenyl] -3-methyl-1,3-dihydro-2H-imidazol-2-one benzyl 4 prepared in Reference Example 23 (23c) -[4- (3-Methyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl) phenyl] -1,4-diazepane-1-carboxylate with Reference Example 1 (1b) The reaction was conducted in the same manner to obtain the title target compound.
Pale yellow powder
Mp 142-146 ° C;
IR (KBr) ν _max 3314, 1676, 1522, 1265, 817, 799 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400MHz) δ 1.73 (1H, br), 1.87-1.93 (2H, m), 2.81-2.84 (2H, m), 3.01-3.04 (2H, m), 3.30 (3H, s) , 3.53-3.60 (4H, m), 6.24 (1H, d, J = 3.0 Hz), 6.42 (1H, d, J = 3.0 Hz), 6.69 (2H, d, J = 9.4 Hz), 7.32 (2H, d, J = 9.4 Hz);
MS (EI) m / z: 272 [M ⁺ ], 230, 216;
_{_{. Anal Calcd for C 15 H 20}} N 4 O · 0.2 H 2 O:. C, 65.29; H, 7.45; N, 20.30 Found: C, 65.40; H, 7.38; N, 19.96.

［参考例２４］１−[４−(４，５−ジヒドロ−１，３−オキサゾール−２−イル)フェニル]−１，４−ジアゼパン
（２４ａ）４−ブロモ−Ｎ−（２−クロロエチル）ベンズアミド
４−ブロモ安息香酸（４．０２ｇ、２０．０ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（２０ｍＬ）溶液に、２−クロロエチルアミン塩酸塩（２．５５ｇ、２２．０ｍｍｏｌ）、トリエチルアミン（３．５ｍＬ、２５．０ｍｍｏｌ）、ＷＳＣ・ＨＣｌ（４．２０ｇ、２２．０ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール（３．００ｇ、２２．０ｍｍｏｌ）を順次加え、室温で２４時間撹拌した。反応液に水（１００ｍＬ）を加え、酢酸エチル（１００ｍＬ）で３回抽出した。有機層を合せ、水（１００ｍＬ）および飽和塩化ナトリウム水溶液（１００ｍＬ）で順次洗浄し、無水硫酸ナトリウムで乾燥後，溶媒を減圧下留去し、１．８３ｇ（収率９０％）の標記目的化合物を得た。
[Reference Example 24] 1- [4- (4,5-Dihydro-1,3-oxazol-2-yl) phenyl] -1,4-diazepane (24a) 4-bromo-N- (2-chloroethyl) benzamide To a solution of 4-bromobenzoic acid (4.02 g, 20.0 mmol) in N, N-dimethylformamide (20 mL) was added 2-chloroethylamine hydrochloride (2.55 g, 22.0 mmol), triethylamine (3.5 mL, 25 mL). 0.0 mmol), WSC · HCl (4.20 g, 22.0 mmol) and 1-hydroxybenzotriazole (3.00 g, 22.0 mmol) were sequentially added, and the mixture was stirred at room temperature for 24 hours. Water (100 mL) was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate (100 mL). The organic layers were combined, washed successively with water (100 mL) and saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 1.83 g (yield 90%) of the title compound. Got.

白色粉末；
¹H NMR(DMSO-d₆, 500 MHz) δ 3.69-3.84 (4H, m), 6.51 (1H, brs), 7.59 (2H, d, J = 8.6 Hz), 7.66 (2H, d, J = 8.6 Hz)。

（２４ｂ）２−(４−ブロモフェニル)−４，５−ジヒドロ−１，３−オキサゾール
参考例２４（２４ａ）で製造した４−ブロモ−Ｎ−（２−クロロエチル）ベンズアミド（１．８３ｇ，７．０ｍｍｏｌ）のメタノール（２０ｍＬ）溶液に、２８％ナトリウムメトキシドメタノール溶液（１０ｍＬ）を加え、室温で２時間撹拌した。反応液を濃縮し、得られた残渣に水（３０ｍＬ）を加え、塩化メチレン（５０ｍＬ）で３回抽出した。有機層を合わせて、飽和塩化ナトリウム水溶液（５０ｍＬ）で洗浄し、無水硫酸ナトリウムで乾燥後，溶媒を減圧下留去し、１．４２ｇ（収率９７％）の標記目的化合物を得た。
White powder;
¹ H NMR (DMSO-d ₆ , 500 MHz) δ 3.69-3.84 (4H, m), 6.51 (1H, brs), 7.59 (2H, d, J = 8.6 Hz), 7.66 (2H, d, J = 8.6 Hz).

(24b) 2- (4-Bromophenyl) -4,5-dihydro-1,3-oxazole 4-bromo-N- (2-chloroethyl) benzamide (1.83 g, 7) prepared in Reference Example 24 (24a) 0.0 mmol) in methanol (20 mL) was added 28% sodium methoxide methanol solution (10 mL) and stirred at room temperature for 2 hours. The reaction mixture was concentrated, water (30 mL) was added to the obtained residue, and the mixture was extracted 3 times with methylene chloride (50 mL). The organic layers were combined, washed with a saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 1.42 g (yield 97%) of the title compound.

白色粉末
Mp 96-98 ℃;
IR (KBr) ν_max 2939, 1645, 1591, 1483, 1397, 1355, 1260, 1076, 1010, 942, 835, 726, 667 cm^-1;
¹H NMR(CDCl₃, 500 MHz) δ 4.05 (2H, t, J = 9.4 Hz), 4.43 (2H, t, J = 9.4 Hz), 7.54 (2H, d, J = 8.6 Hz), 7.80 (2H, d, J = 8.6 Hz);
MS (EI) m/z: 225 [M⁺], 197, 195, 183, 155, 116, 89, 75;
Anal. Calcd for C₉H₈BrNO: C, 47.82; H, 3.57; N, 6.20. Found: C, 47.66; H, 3.37; N, 6.17。
White powder
Mp 96-98 ° C;
IR (KBr) ν _max 2939, 1645, 1591, 1483, 1397, 1355, 1260, 1076, 1010, 942, 835, 726, 667 cm ^-1 ;
¹ H NMR (CDCl ₃ , 500 MHz) δ 4.05 (2H, t, J = 9.4 Hz), 4.43 (2H, t, J = 9.4 Hz), 7.54 (2H, d, J = 8.6 Hz), 7.80 (2H , d, J = 8.6 Hz);
MS (EI) m / z: 225 [M ⁺ ], 197, 195, 183, 155, 116, 89, 75;
Anal. Calcd for C ₉ H ₈ BrNO: C, 47.82; H, 3.57; N, 6.20. Found: C, 47.66; H, 3.37; N, 6.17.

（２４ｃ）ｔｅｒｔ−ブチル４−[４−(４，５−ジヒドロ−１，３−オキサゾール−２−イル)フェニル]−１，４−ジアゼパン−１−カルボキシラート
参考例２４（２４ｂ）で製造した２−(４−ブロモフェニル)−４，５−ジヒドロ−１，３−オキサゾールを用いて参考例１（１ａ）と同様に反応を行い、標記目的化合物を得た。
白色粉末
Mp 148-153 ℃;
IR (KBr) ν_max 2975, 1690, 1639, 1609, 1470, 1416, 1359, 1238, 1167, 1067, 930, 815, 675 cm^-1;
¹H NMR(CDCl₃, 500 MHz) δ 1.37 (4.5H, s), 1.44 (4.5H, s), 1.95-2.02 (2H, m), 3.20 (1H, t, J = 5.9 Hz), 3.31 (1H, t, J = 5.9 Hz), 3.55-3.65 (6H, m), 4.01 (2H, t, J = 9.3 Hz), 4.37 (2H, t, J = 9.3 Hz), 6.68 (2H, d, J = 8.8 Hz), 7.79 (2H, d, J = 8.8 Hz);
MS (FAB) m/z: 346 [M+H⁺], 290, 244, 175, 93, 57;
Anal. Calcd for C₁₉H₂₇N₃O₃: C, 66.06; H, 7.88; N, 12.16. Found: C, 65.91; H, 8.06; N, 12.04。
(24c) tert-butyl 4- [4- (4,5-dihydro-1,3-oxazol-2-yl) phenyl] -1,4-diazepan-1-carboxylate prepared in Reference Example 24 (24b) The reaction was carried out in the same manner as in Reference Example 1 (1a) using 2- (4-bromophenyl) -4,5-dihydro-1,3-oxazole to obtain the title compound.
White powder
Mp 148-153 ° C;
IR (KBr) ν _max 2975, 1690, 1639, 1609, 1470, 1416, 1359, 1238, 1167, 1067, 930, 815, 675 cm ^-1 ;
¹ H NMR (CDCl ₃ , 500 MHz) δ 1.37 (4.5H, s), 1.44 (4.5H, s), 1.95-2.02 (2H, m), 3.20 (1H, t, J = 5.9 Hz), 3.31 ( 1H, t, J = 5.9 Hz), 3.55-3.65 (6H, m), 4.01 (2H, t, J = 9.3 Hz), 4.37 (2H, t, J = 9.3 Hz), 6.68 (2H, d, J = 8.8 Hz), 7.79 (2H, d, J = 8.8 Hz);
MS (FAB) m / z: 346 [M + H ⁺ ], 290, 244, 175, 93, 57;
Anal. Calcd for C ₁₉ H ₂₇ N ₃ O ₃ : C, 66.06; H, 7.88; N, 12.16. Found: C, 65.91; H, 8.06; N, 12.04.

（２４ｄ）１−[４−(４，５−ジヒドロ−１，３−オキサゾール−２−イル)フェニル]−１，４−ジアゼパン
参考例２４（２４ｃ）で製造したｔｅｒｔ−ブチル４−[４−(４，５−ジヒドロ−１，３−オキサゾール−２−イル)フェニル]−１，４−ジアゼパン−１−カルボキシラートを用いて参考例９（９ｂ）と同様に反応を行い、標記目的化合物を得た。
淡黄色粉末
Mp 112-115 ℃;
IR (KBr) ν_max 2938, 1639, 1609, 1523, 1466, 1400, 1358, 1186, 1072, 944, 821, 676 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.80-1.95 (2H, m), 2.81 (2H, t, J = 5.5 Hz), 3.02 (2H, t, J = 5.5 Hz), 3.57 (2H, t, J = 5.5 Hz), 3.62 (2H, t, J = 6.3 Hz), 4.00 (2H, t, J = 9.4 Hz), 4.36 (2H, t, J = 9.4 Hz), 6.67 (2H, d, J = 9.4 Hz), 7.77 (2H, d, J = 9.4 Hz);
MS (EI) m/z: 245 [M⁺], 215, 203, 189, 160, 144, 43;
Anal. Calcd for C₁₄H₁₉N₃O・0.14H₂O: C, 67.83; H, 7.84; N, 16.95. Found: C, 68.01; H, 8.10; N, 16.71。
(24d) 1- [4- (4,5-dihydro-1,3-oxazol-2-yl) phenyl] -1,4-diazepan tert-butyl 4- [4- prepared in Reference Example 24 (24c) Using (4,5-dihydro-1,3-oxazol-2-yl) phenyl] -1,4-diazepane-1-carboxylate, the reaction was conducted in the same manner as in Reference Example 9 (9b) to give the title compound. Obtained.
Pale yellow powder
Mp 112-115 ° C;
IR (KBr) ν _max 2938, 1639, 1609, 1523, 1466, 1400, 1358, 1186, 1072, 944, 821, 676 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.80-1.95 (2H, m), 2.81 (2H, t, J = 5.5 Hz), 3.02 (2H, t, J = 5.5 Hz), 3.57 (2H, t, J = 5.5 Hz), 3.62 (2H, t, J = 6.3 Hz), 4.00 (2H, t, J = 9.4 Hz), 4.36 (2H, t, J = 9.4 Hz), 6.67 (2H, d, J = 9.4 Hz), 7.77 (2H, d, J = 9.4 Hz);
MS (EI) m / z: 245 [M ⁺ ], 215, 203, 189, 160, 144, 43;
Anal. Calcd for C ₁₄ H ₁₉ N ₃ O.0.14H ₂ O: C, 67.83; H, 7.84; N, 16.95. Found: C, 68.01; H, 8.10; N, 16.71.

［参考例２５］１−[３−(４，５−ジヒドロ−１，３−オキサゾール−２−イル)フェニル]−１，４−ジアゼパン
（２５ａ）３−ブロモ−Ｎ−(２−クロロエチル)ベンズアミド
３−ブロモ安息香酸を用いて参考例２４（２４ａ）と同様に反応を行い、標記目的化合物を得た。
白色粉末；
¹H NMR(CDCl₃, 400 MHz) δ 3.69-3.84 (4H, m), 6.49 (1H, br.s), 7.31 (1H, t, J = 7.8 Hz), 7.61-7.65 (1H, m), 7.66-7.71 (1H, m), 7.91 (1H, t, J = 2.0 Hz)。
[Reference Example 25] 1- [3- (4,5-Dihydro-1,3-oxazol-2-yl) phenyl] -1,4-diazepane (25a) 3-Bromo-N- (2-chloroethyl) benzamide The reaction was performed in the same manner as in Reference Example 24 (24a) using 3-bromobenzoic acid to obtain the title object compound.
White powder;
¹ H NMR (CDCl ₃ , 400 MHz) δ 3.69-3.84 (4H, m), 6.49 (1H, br.s), 7.31 (1H, t, J = 7.8 Hz), 7.61-7.65 (1H, m), 7.66-7.71 (1H, m), 7.91 (1H, t, J = 2.0 Hz).

（２５ｂ）２−(３−ブロモフェニル)−４，５−ジヒドロ−１，３−オキサゾール
参考例２５（２５ａ）で製造した３−ブロモ−Ｎ−(２−クロロエチル)ベンズアミドを用いて参考例２４（２４ｂ）と同様に反応を行い、標記目的化合物を得た。
白色粉末
Mp 34 ℃;
IR (KBr) ν_max 2967, 1649, 1566, 1472, 1357, 1251, 1064, 947, 792, 703 cm^-1;
¹H NMR(CDCl₃, 500 MHz) δ 4.06 (2H, t, J = 9.8 Hz), 4.44 (2H, t, J = 9.8 Hz), 7.28 (1H, t, J = 7.8 Hz), 7.60 (1H, d, J = 7.8 Hz), 7.87 (1H, d, J = 7.8 Hz), 8.10 (1H, s);
MS (EI) m/z: 225 [M⁺], 197, 195, 185, 183, 157, 155, 116, 89;
Anal. Calcd for C₉H₈BrNO: C, 47.82; H, 3.57; N, 6.20. Found: C, 47.47; H, 3.35; N, 6.22。
(25b) 2- (3-Bromophenyl) -4,5-dihydro-1,3-oxazole Reference Example 24 using 3-bromo-N- (2-chloroethyl) benzamide prepared in Reference Example 25 (25a) The reaction was carried out in the same manner as (24b) to obtain the title object compound.
White powder
Mp 34 ° C;
IR (KBr) ν _max 2967, 1649, 1566, 1472, 1357, 1251, 1064, 947, 792, 703 cm ^-1 ;
¹ H NMR (CDCl ₃ , 500 MHz) δ 4.06 (2H, t, J = 9.8 Hz), 4.44 (2H, t, J = 9.8 Hz), 7.28 (1H, t, J = 7.8 Hz), 7.60 (1H , d, J = 7.8 Hz), 7.87 (1H, d, J = 7.8 Hz), 8.10 (1H, s);
MS (EI) m / z: 225 [M ⁺ ], 197, 195, 185, 183, 157, 155, 116, 89;
Anal. Calcd for C ₉ H ₈ BrNO: C, 47.82; H, 3.57; N, 6.20. Found: C, 47.47; H, 3.35; N, 6.22.

（２５ｃ）ｔｅｒｔ−ブチル４−[３−(４，５−ジヒドロ−１，３−オキサゾール−２−イル)フェニル]−１，４−ジアゼパン−１−カルボキシラート
参考例２５（２５ｂ）で製造した２−(３−ブロモフェニル)−４，５−ジヒドロ−１，３−オキサゾールを用いて参考例１（１ａ）と同様に反応を行い、標記目的化合物を得た。
淡黄色粉末
Mp 98-103 ℃;
IR (KBr) ν_max 2971, 1701, 1649, 1605, 1497, 1410, 1363, 1237, 1175, 932, 783, 712 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.35 (4.5H, s), 1.43 (4.5H, s), 1.92-2.03 (2H, m), 3.18 (1H, t, J = 5.9 Hz), 3.29 (1H, t, J = 5.9 Hz), 3.49-3.63 (6H, m), 4.04 (2H, t, J = 9.8 Hz), 4.40 (2H, t, J = 9.8 Hz), 6.78-6.82 (1H, m), 7.17-7.80 (3H, m);
MS (FAB) m/z: 346 [M+H⁺], 290, 244, 203, 175, 57;
Anal. Calcd for C₁₉H₂₇N₃O₃: C, 66.06; H, 7.88; N, 12.16. Found: C, 65.86; H, 7.91; N, 11.86。

（２５ｄ）１−[３−(４，５−ジヒドロ−１，３−オキサゾール−２−イル)フェニル]−１，４−ジアゼパン
参考例２５（２５ｃ）で製造したｔｅｒｔ−ブチル４−[３−(４，５−ジヒドロ−１，３−オキサゾール−２−イル)フェニル]−１，４−ジアゼパン−１−カルボキシラートを用いて参考例９（９ｂ）と同様に反応を行い、標記目的化合物を得た。
淡黄色液体。

［参考例２６］１−[４−(１，３−オキサゾール−２−イル)フェニル]−１，４−ジアゼパン
（２６ａ）４−ブロモ−Ｎ−（２，２−ジメトキシ）ベンズアミド
４−ブロモ安息香酸と２−アミノアセトアルデヒドジメチルアセタールを用いて参考例２４（２４ａ）と同様に反応を行い、標記目的化合物を得た。
白色粉末;
IR (KBr) ν_max 3267, 2943, 1633, 1552, 1334, 1123, 1062, 855 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 3.43 (6H, s), 3.59 (2H, dd, J = 5.1, 5.9 Hz), 4.47 (1H, t, J = 5.1 Hz), 6.27 (1H, br.s), 7.56 (2H, d, J = 9.0 Hz), 7.63 (2H, d, J = 9.0 Hz);
MS (FAB) m/z: 288 [M+H⁺], 258, 256, 185, 183, 75;
Anal. Calcd for C₁₁H₁₄BrNO₃: C, 45.85; H, 4.90; N, 4.86. Found: C, 45.67; H, 4.93; N, 4.93。
(25c) tert-butyl 4- [3- (4,5-dihydro-1,3-oxazol-2-yl) phenyl] -1,4-diazepan-1-carboxylate prepared in Reference Example 25 (25b) 2- (3-Bromophenyl) -4,5-dihydro-1,3-oxazole was used in the same manner as in Reference Example 1 (1a) to give the title object compound.
Pale yellow powder
Mp 98-103 ° C;
IR (KBr) ν _max 2971, 1701, 1649, 1605, 1497, 1410, 1363, 1237, 1175, 932, 783, 712 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.35 (4.5H, s), 1.43 (4.5H, s), 1.92-2.03 (2H, m), 3.18 (1H, t, J = 5.9 Hz), 3.29 ( 1H, t, J = 5.9 Hz), 3.49-3.63 (6H, m), 4.04 (2H, t, J = 9.8 Hz), 4.40 (2H, t, J = 9.8 Hz), 6.78-6.82 (1H, m ), 7.17-7.80 (3H, m);
MS (FAB) m / z: 346 [M + H ⁺ ], 290, 244, 203, 175, 57;
Anal. Calcd for C ₁₉ H ₂₇ N ₃ O ₃ : C, 66.06; H, 7.88; N, 12.16. Found: C, 65.86; H, 7.91; N, 11.86.

(25d) 1- [3- (4,5-Dihydro-1,3-oxazol-2-yl) phenyl] -1,4-diazepan tert-butyl 4- [3- produced in Reference Example 25 (25c) Using (4,5-dihydro-1,3-oxazol-2-yl) phenyl] -1,4-diazepane-1-carboxylate, the reaction was conducted in the same manner as in Reference Example 9 (9b) to give the title compound. Obtained.
Pale yellow liquid.

[Reference Example 26] 1- [4- (1,3-oxazol-2-yl) phenyl] -1,4-diazepane (26a) 4-bromo-N- (2,2-dimethoxy) benzamide 4-bromobenzoic acid The reaction was performed in the same manner as in Reference Example 24 (24a) using acid and 2-aminoacetaldehyde dimethyl acetal to obtain the title compound.
White powder;
IR (KBr) ν _max 3267, 2943, 1633, 1552, 1334, 1123, 1062, 855 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 3.43 (6H, s), 3.59 (2H, dd, J = 5.1, 5.9 Hz), 4.47 (1H, t, J = 5.1 Hz), 6.27 (1H, br. s), 7.56 (2H, d, J = 9.0 Hz), 7.63 (2H, d, J = 9.0 Hz);
MS (FAB) m / z: 288 [M + H ⁺ ], 258, 256, 185, 183, 75;
Anal. Calcd for C ₁₁ H ₁₄ BrNO ₃ : C, 45.85; H, 4.90; N, 4.86. Found: C, 45.67; H, 4.93; N, 4.93.

（２６ｂ）２−(４−ブロモフェニル)−１，３−オキサゾール
五酸化二りんにメタンスルホン酸を加え、室温で３時間撹拌した。続いて、反応液に参考例２６（２６ａ）で製造した４−ブロモ−Ｎ−（２，２−ジメトキシ）ベンズアミドを加え、１５０℃で７時間撹拌した。反応液を０℃に冷却し、氷（２００ｇ）を加え、炭酸カリウムで液性を中性にし、酢酸エチル（２００ｍＬ）で３回抽出した。有機層を合わせて、水（２００ｍＬ）および飽和食塩水（２００ｍＬ）で順次洗浄し、無水硫酸ナトリウムで乾燥後，溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル，５：１）を用いて精製し、３．５０ｇ（収率９７％）の標記目的化合物を得た。
(26b) 2- (4-Bromophenyl) -1,3-oxazole Methanesulfonic acid was added to diphosphorus pentoxide, and the mixture was stirred at room temperature for 3 hours. Subsequently, 4-bromo-N- (2,2-dimethoxy) benzamide produced in Reference Example 26 (26a) was added to the reaction solution, and the mixture was stirred at 150 ° C. for 7 hours. The reaction solution was cooled to 0 ° C., ice (200 g) was added, the solution was neutralized with potassium carbonate, and extracted three times with ethyl acetate (200 mL). The organic layers were combined, washed successively with water (200 mL) and saturated brine (200 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified using silica gel column chromatography (hexane / ethyl acetate, 5: 1) to obtain 3.50 g (yield 97%) of the title compound.

白色粉末
Mp 84 ℃;
IR (KBr) ν_max 3115, 1602, 1477, 1401, 1261, 919, 827, 729 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 7.23 (1H, s), 7.59 (2H, d, J = 8.2 Hz), 7.71 (1H, s), 7.91 (2H, d, J = 8.2 Hz);
MS (EI) m/z: 223 [M⁺], 197, 195, 170, 169, 168, 167, 116, 89;
Anal. Calcd for C₉H₆BrNO: C, 48.25; H, 2.70; N, 6.25. Found: C, 48.02; H, 2.74; N, 6.20。
White powder
Mp 84 ° C;
IR (KBr) ν _max 3115, 1602, 1477, 1401, 1261, 919, 827, 729 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 7.23 (1H, s), 7.59 (2H, d, J = 8.2 Hz), 7.71 (1H, s), 7.91 (2H, d, J = 8.2 Hz);
MS (EI) m / z: 223 [M ⁺ ], 197, 195, 170, 169, 168, 167, 116, 89;
Anal. Calcd for C ₉ H ₆ BrNO: C, 48.25; H, 2.70; N, 6.25. Found: C, 48.02; H, 2.74; N, 6.20.

（２６ｃ）ｔｅｒｔ−ブチル４−[４−(１，３−オキサゾール−２−イル)フェニル] −１，４−ジアゼパン−１−カルボキシラート
参考例２６（２６ｂ）で製造した２−(４−ブロモフェニル)−１，３−オキサゾールを用いて参考例１（１ａ）と同様に反応を行い、標記目的化合物を得た。
黄色液体
IR (film) ν_max 2974, 1691, 1613, 1500, 1416, 1364, 1237, 1168, 918, 736 cm^-1;
¹H NMR(CDCl₃, 500 MHz) δ 1.37 (4.5H, s), 1.44 (4.5H, s), 1.95-2.04 (2H, m), 3.22 (1H, t, J = 5.9 Hz), 3.33 (1H, t, J = 5.9 Hz), 3.56-3.66 (6H, m), 6.74 (2H, d, J = 8.7 Hz), 7.15 (1H, s), 7.62 (1H, s), 7.89 (2H, d, J = 8.7 Hz);
MS (FAB) m/z: 343 [M⁺], 288, 242, 199, 173, 57。
(26c) tert-butyl 4- [4- (1,3-oxazol-2-yl) phenyl] -1,4-diazepan-1-carboxylate 2- (4-bromo prepared in Reference Example 26 (26b) The reaction was conducted in the same manner as in Reference Example 1 (1a) using (phenyl) -1,3-oxazole to obtain the title compound.
Yellow liquid
IR (film) ν _max 2974, 1691, 1613, 1500, 1416, 1364, 1237, 1168, 918, 736 cm ^-1 ;
¹ H NMR (CDCl ₃ , 500 MHz) δ 1.37 (4.5H, s), 1.44 (4.5H, s), 1.95-2.04 (2H, m), 3.22 (1H, t, J = 5.9 Hz), 3.33 ( 1H, t, J = 5.9 Hz), 3.56-3.66 (6H, m), 6.74 (2H, d, J = 8.7 Hz), 7.15 (1H, s), 7.62 (1H, s), 7.89 (2H, d , J = 8.7 Hz);
MS (FAB) m / z: 343 [M ⁺ ], 288, 242, 199, 173, 57.

（２６ｄ）１−[４−(１，３−オキサゾール−２−イル)フェニル]−１，４−ジアゼパン
参考例２６（２６ｃ）で製造したｔｅｒｔ−ブチル４−[４−(１，３−オキサゾール−２−イル)フェニル] −１，４−ジアゼパン−１−カルボキシラートを用いて参考例９（９ｂ）と同様に反応を行い、標記目的化合物を得た。
淡黄色液体
IR (film) ν_max 3331, 2923, 1612, 1500, 1360, 1190, 818, 724 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.80-1.97 (2H, m), 2.84 (2H, t, J = 5.9 Hz), 3.05 (2H, t, J = 5.4 Hz), 3.60 (2H, t, J = 5.4 Hz), 3.64 (2H, t, J = 5.9 Hz), 6.74 (2H, d, J = 9.0 Hz), 7.15 (1H, s), 7.61 (1H, s), 7.88 (2H, d, J = 9.0 Hz);
MS (EI) m/z: 243 [M⁺], 213, 201, 187, 173, 158, 144, 117, 89, 70;
Anal. Calcd for C₁₄H₁₇N₃O: C, 69.11; H, 7.04; N, 17.27. Found: C, 69.11; H, 7.10; N, 17.14。
(26d) 1- [4- (1,3-oxazol-2-yl) phenyl] -1,4-diazepan tert-butyl 4- [4- (1,3-oxazole) prepared in Reference Example 26 (26c) -2-yl) phenyl] -1,4-diazepane-1-carboxylate was used in the same manner as in Reference Example 9 (9b) to give the title object compound.
Pale yellow liquid
IR (film) ν _max 3331, 2923, 1612, 1500, 1360, 1190, 818, 724 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.80-1.97 (2H, m), 2.84 (2H, t, J = 5.9 Hz), 3.05 (2H, t, J = 5.4 Hz), 3.60 (2H, t, J = 5.4 Hz), 3.64 (2H, t, J = 5.9 Hz), 6.74 (2H, d, J = 9.0 Hz), 7.15 (1H, s), 7.61 (1H, s), 7.88 (2H, d, J = 9.0 Hz);
MS (EI) m / z: 243 [M ⁺ ], 213, 201, 187, 173, 158, 144, 117, 89, 70;
Anal. Calcd for C ₁₄ H ₁₇ N ₃ O: C, 69.11; H, 7.04; N, 17.27. Found: C, 69.11; H, 7.10; N, 17.14.

［参考例２７］１−[４−(４，５−ジヒドロ−１，３−チアゾール−２−イル)フェニル]−１，４−ジアゼパン
（２７ａ）２−(４−ブロモフェニル)−４，５−ジヒドロ−１，３−チアゾール
４−ブロモ安息香酸（４．０２ｇ、２０．０ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（４０ｍＬ）溶液に、２−アミノエタノール（１．２０ｍＬ、２０．０ｍｍｏｌ）、ＷＳＣ・ＨＣｌ（４．２０ｇ、２２．０ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール（３．００ｇ、２２．０ｍｍｏｌ）を順次加え、室温で２４時間撹拌した。反応液に水（６０ｍＬ）を加え、酢酸エチル（１００ｍＬ）で３回抽出した。有機層を合わせて、無水硫酸ナトリウムで乾燥後、溶媒を減圧下留去した。得られた残渣をトルエン（８０ｍＬ）に溶解し、ローソン試薬（３．９８ｇ、９．６ｍｍｏｌ）を加え、１２０℃で３時間撹拌した。反応液をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル，３：１）を用いて精製し、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル，１０：１→５：１→２：１）を用いてさらに精製し、１．８４ｇ（収率４６％）標記目的化合物を得た。
[Reference Example 27] 1- [4- (4,5-dihydro-1,3-thiazol-2-yl) phenyl] -1,4-diazepane (27a) 2- (4-bromophenyl) -4,5 -Dihydro-1,3-thiazole 4-bromobenzoic acid (4.02 g, 20.0 mmol) in N, N-dimethylformamide (40 mL) solution, 2-aminoethanol (1.20 mL, 20.0 mmol), WSC -HCl (4.20 g, 22.0 mmol) and 1-hydroxybenzotriazole (3.00 g, 22.0 mmol) were sequentially added, and the mixture was stirred at room temperature for 24 hours. Water (60 mL) was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate (100 mL). The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in toluene (80 mL), Lawesson's reagent (3.98 g, 9.6 mmol) was added, and the mixture was stirred at 120 ° C. for 3 hr. The reaction solution was purified using silica gel column chromatography (hexane / ethyl acetate, 3: 1), and the solvent was distilled off under reduced pressure. The resulting residue was further purified using silica gel column chromatography (hexane / ethyl acetate, 10: 1 → 5: 1 → 2: 1) to obtain 1.84 g (yield 46%) of the title object compound.

淡黄色粉末
Mp 82-84 ℃;
IR (KBr) ν_max 2942,1600, 1479, 1393, 1316, 1241, 1065, 1001, 927, 818, 597 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 3.43 (2H, t, J = 8.6 Hz), 4.45 (2H, t, J = 8.6 Hz), 7.55 (2H, d, J = 8.6 Hz), 7.70 (2H, d, J = 8.6 Hz);
MS (EI) m/z: 241 [M⁺], 197, 195, 184, 183, 182, 181, 157, 155, 102, 60;
Anal. Calcd for C₉H₈BrNS: C, 44.64; H, 3.33; N, 5.78. Found: C, 44.61; H, 3.30; N, 5.76。
Pale yellow powder
Mp 82-84 ° C;
IR (KBr) ν _max 2942,1600, 1479, 1393, 1316, 1241, 1065, 1001, 927, 818, 597 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 3.43 (2H, t, J = 8.6 Hz), 4.45 (2H, t, J = 8.6 Hz), 7.55 (2H, d, J = 8.6 Hz), 7.70 (2H , d, J = 8.6 Hz);
MS (EI) m / z: 241 [M ⁺ ], 197, 195, 184, 183, 182, 181, 157, 155, 102, 60;
Anal. Calcd for C ₉ H ₈ BrNS: C, 44.64; H, 3.33; N, 5.78. Found: C, 44.61; H, 3.30; N, 5.76.

（２７ｂ）ベンジル４−[４−(４，５−ジヒドロ−１，３−チアゾール−２−イル)フェニル]−１，４−ジアゼパン−１−カルボキシラート
参考例２７（２７ａ）で製造した２−(４−ブロモフェニル)−４，５−ジヒドロ−１，３−チアゾールを用いて参考例１（１ａ）と同様に反応を行い、標記目的化合物を得た。
黄色液体;
IR (film) ν_max 2942, 1698, 1605, 1519, 1422, 1228, 1186, 1002, 927, 820 cm^-1;
¹H NMR(CDCl₃, 500 MHz) δ 1.93-2.04 (2H, m), 3.30 (1H, t, J = 5.9 Hz), 3.33 -3.41 (3H, m), 3.56-3.68 (6H, m), 4.37-4.43 (2H, m), 5.08 (1H, s), 5.13 (1H, s), 6.64-6.67 (2H, m), 7.26-7.37 (5H, m), 7.67-7.72 (2H, m);
MS (FAB) m/z: 396 [M+H⁺], 338, 246, 93。
(27b) Benzyl 4- [4- (4,5-dihydro-1,3-thiazol-2-yl) phenyl] -1,4-diazepan-1-carboxylate 2-prepared in Reference Example 27 (27a) The reaction was performed in the same manner as in Reference Example 1 (1a) using (4-bromophenyl) -4,5-dihydro-1,3-thiazole to obtain the title object compound.
Yellow liquid;
IR (film) ν _max 2942, 1698, 1605, 1519, 1422, 1228, 1186, 1002, 927, 820 cm ^-1 ;
¹ H NMR (CDCl ₃ , 500 MHz) δ 1.93-2.04 (2H, m), 3.30 (1H, t, J = 5.9 Hz), 3.33 -3.41 (3H, m), 3.56-3.68 (6H, m), 4.37-4.43 (2H, m), 5.08 (1H, s), 5.13 (1H, s), 6.64-6.67 (2H, m), 7.26-7.37 (5H, m), 7.67-7.72 (2H, m);
MS (FAB) m / z: 396 [M + H ⁺ ], 338, 246, 93.

（２７ｃ）１−[４−(４，５−ジヒドロ−１，３−チアゾール−２−イル)フェニル]−１，４−ジアゼパン
参考例２７（２７ｂ）で製造したベンジル４−[４−(４，５−ジヒドロ−１，３−チアゾール−２−イル)フェニル]−１，４−ジアゼパン−１−カルボキシラート（１．０８ｇ，２．７３ｍｍｏｌ）の酢酸（１０ｍＬ）溶液に、２５％臭化水素−酢酸溶液（１０ｍＬ）を加え、室温で３０分間撹拌した。反応液に水（１００ｍＬ）を加え、塩化メチレン（５０ｍＬ）で洗浄した。炭酸カリウムで液性を塩基性とし、塩化メチレン／２−プロパノール（（４：１）、１００ｍＬ）で３回抽出し、無水硫酸ナトリウムで乾燥後，溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（塩化メチレン／メタノール，４０：１）を用いて精製し、６００ｍｇ（収率８４％）標記目的化合物を得た。
(27c) 1- [4- (4,5-Dihydro-1,3-thiazol-2-yl) phenyl] -1,4-diazepane benzyl 4- [4- (4) prepared in Reference Example 27 (27b) , 5-Dihydro-1,3-thiazol-2-yl) phenyl] -1,4-diazepane-1-carboxylate (1.08 g, 2.73 mmol) in acetic acid (10 mL) was added 25% hydrogen bromide. -Acetic acid solution (10 mL) was added and stirred at room temperature for 30 minutes. Water (100 mL) was added to the reaction mixture, and the mixture was washed with methylene chloride (50 mL). The solution was made basic with potassium carbonate, extracted three times with methylene chloride / 2-propanol ((4: 1), 100 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride / methanol, 40: 1) to obtain 600 mg (yield 84%) of the title object compound.

褐色粉末
Mp 107-112 ℃;
IR (KBr) ν_max 3302, 2935, 1606, 1518, 1395, 1315, 1253, 1185, 1002, 813 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.85-1.94 (2H, m), 2.82 (2H, t, J = 5.9 Hz), 3.03 (2H, t, J = 5.5 Hz), 3.35 (2H, t, J = 8.2 Hz), 3.58 (2H, t, J = 5.5 Hz), 3.63 (2H, t, J = 5.9 Hz), 4.39 (2H, t, J = 8.2 Hz), 6.67 (2H, d, J = 8.2 Hz), 7.69 (2H, d, J = 8.2 Hz);
MS (EI) m/z: 261 [M⁺], 219, 205, 177, 145, 130, 116, 103, 84, 70。
Brown powder
Mp 107-112 ° C;
IR (KBr) ν _max 3302, 2935, 1606, 1518, 1395, 1315, 1253, 1185, 1002, 813 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.85-1.94 (2H, m), 2.82 (2H, t, J = 5.9 Hz), 3.03 (2H, t, J = 5.5 Hz), 3.35 (2H, t, J = 8.2 Hz), 3.58 (2H, t, J = 5.5 Hz), 3.63 (2H, t, J = 5.9 Hz), 4.39 (2H, t, J = 8.2 Hz), 6.67 (2H, d, J = 8.2 Hz), 7.69 (2H, d, J = 8.2 Hz);
MS (EI) m / z: 261 [M ⁺ ], 219, 205, 177, 145, 130, 116, 103, 84, 70.

［参考例２８］３−[４−(１，４−ジアゼパン−１−イル)フェニル]−１，３−オキサゾリジン−２−オン
（２８ａ）３−(４−ブロモフェニル)−１，３−オキサゾリジン−２−オン
４−ブロモアニリン（２９．５ｇ、１７２ｍｍｏｌ）のテトラヒドロフラン（５００ｍＬ）溶液を０℃に冷却し、トリエチルアミン（７０ｍＬ、５００ｍｍｏｌ）、クロロギ酸２−クロロエチルエステル（１８．１ｍＬ、１７４ｍｍｏｌ）を順次加え、室温で２時間撹拌した。続いて、反応液に８Ｍ水酸化ナトリウム水溶液（１８０ｍＬ）を加え、７０℃で３時間撹拌した。
反応液を濃縮し、得られた残渣に水（１００ｍＬ）を加え、酢酸エチル（２００ｍＬ）で３回抽出した。有機層を合わせて、水（１００ｍＬ）および飽和塩化ナトリウム水溶液（１００ｍＬ）で洗浄し、無水硫酸ナトリウムで乾燥後，溶媒を減圧下留去した。得られた残渣をエーテルで粉末化し、３４．０ｇ（収率８２％）の標記目的化合物を得た。
[Reference Example 28] 3- [4- (1,4-diazepan-1-yl) phenyl] -1,3-oxazolidine-2-one (28a) 3- (4-bromophenyl) -1,3-oxazolidine A solution of 2-one 4-bromoaniline (29.5 g, 172 mmol) in tetrahydrofuran (500 mL) was cooled to 0 ° C. and triethylamine (70 mL, 500 mmol), chloroformic acid 2-chloroethyl ester (18.1 mL, 174 mmol) was added. Sequentially added and stirred at room temperature for 2 hours. Then, 8M sodium hydroxide aqueous solution (180 mL) was added to the reaction liquid, and it stirred at 70 degreeC for 3 hours.
The reaction mixture was concentrated, water (100 mL) was added to the obtained residue, and the mixture was extracted 3 times with ethyl acetate (200 mL). The organic layers were combined, washed with water (100 mL) and saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was triturated with ether to obtain 34.0 g (yield 82%) of the title object compound.

白色粉末
Mp 132-135 ℃;
IR (KBr) ν_max 1740, 1490, 1402, 1314, 1224, 1131, 999, 828 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 4.04 (2H, t, J = 8.6 Hz), 4.50 (2H, t, J = 8.6 Hz), 7.41-7.52 (4H, m);
MS (EI) m/z: 241 [M⁺], 198, 184, 182, 171, 169, 157, 155, 117, 90, 52;
Anal. Calcd for C₉H₈BrNO₂: C, 44.66; H, 3.33; N, 5.79. Found: C, 44.57; H, 3.23; N, 5.74。
White powder
Mp 132-135 ° C;
IR (KBr) ν _max 1740, 1490, 1402, 1314, 1224, 1131, 999, 828 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 4.04 (2H, t, J = 8.6 Hz), 4.50 (2H, t, J = 8.6 Hz), 7.41-7.52 (4H, m);
MS (EI) m / z: 241 [M ⁺ ], 198, 184, 182, 171, 169, 157, 155, 117, 90, 52;
Anal. Calcd for C ₉ H ₈ BrNO ₂ : C, 44.66; H, 3.33; N, 5.79. Found: C, 44.57; H, 3.23; N, 5.74.

（２８ｂ）ベンジル４−[４−(２−オキソ−１，３−オキサゾリジン−３−イル)フェニル]−１，４−ジアゼパン−１−カルボキシラート
参考例２８（２８ａ）で製造した３−(４−ブロモフェニル)−１，３−オキサゾリジン−２−オンを用いて参考例１（１ａ）と同様に反応を行い、標記目的化合物を得た。
褐色液体;
IR (film) ν_max 3498, 2948, 1745, 1696, 1520, 1417, 1223, 1122, 1038, 753 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.88-2.07 (2H, m), 3.30 (1H, t, J = 5.9 Hz), 3.37 (1H, t, J = 5.9 Hz), 3.48-3.69 (6H, m), 3.95-4.04 (2H, m), 4.42-4.48 (2H, m), 5.09 (1H, s), 5.13 (1H, s), 6.64-6.72 (2H, m), 7.25-7.40 (7H, m);
MS (FAB) m/z: 395 [M⁺], 273, 260, 246, 220, 165, 93, 65。
(28b) Benzyl 4- [4- (2-oxo-1,3-oxazolidin-3-yl) phenyl] -1,4-diazepan-1-carboxylate 3- (4 prepared in Reference Example 28 (28a) -Bromophenyl) -1,3-oxazolidine-2-one was used in the same manner as in Reference Example 1 (1a) to obtain the title object compound.
Brown liquid;
IR (film) ν _max 3498, 2948, 1745, 1696, 1520, 1417, 1223, 1122, 1038, 753 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.88-2.07 (2H, m), 3.30 (1H, t, J = 5.9 Hz), 3.37 (1H, t, J = 5.9 Hz), 3.48-3.69 (6H, m), 3.95-4.04 (2H, m), 4.42-4.48 (2H, m), 5.09 (1H, s), 5.13 (1H, s), 6.64-6.72 (2H, m), 7.25-7.40 (7H, m);
MS (FAB) m / z: 395 [M ⁺ ], 273, 260, 246, 220, 165, 93, 65.

（２８ｃ）３−[４−(１，４−ジアゼパン−１−イル)フェニル]−１，３−オキサゾリジン−２−オン
参考例２８（２８ｂ）で製造したベンジル４−[４−(２−オキソ−１，３−オキサゾリジン−３−イル)フェニル]−１，４−ジアゼパン−１−カルボキシラートを用いて参考例１（１ｂ）と同様に反応を行い、標記目的化合物を得た。
褐色液体;
IR (film) ν_max 3486, 2938, 1725, 1617, 1522, 1311, 1227, 1129, 1051, 751 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.84-1.95 (2H, m), 2.81 (2H, t, J = 6.3 Hz), 3.02 (2H, t, J = 5.5 Hz), 3.54 (2H, t, J = 5.5 Hz), 3.57 (2H, t, J = 6.3 Hz), 4.00 (2H, t, J = 8.2 Hz), 4.45 (2H, t, J = 8.2 Hz), 6.69 (2H, d, J = 9.0 Hz), 7.33 (2H, d, J = 9.0 Hz);
MS (FAB) m/z: 261 [M⁺], 219, 205, 105, 70, 56。
(28c) 3- [4- (1,4-diazepan-1-yl) phenyl] -1,3-oxazolidine-2-one benzyl 4- [4- (2-oxo) prepared in Reference Example 28 (28b) Reaction was carried out in the same manner as in Reference Example 1 (1b) using -1,3-oxazolidine-3-yl) phenyl] -1,4-diazepan-1-carboxylate to obtain the title compound.
Brown liquid;
IR (film) ν _max 3486, 2938, 1725, 1617, 1522, 1311, 1227, 1129, 1051, 751 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.84-1.95 (2H, m), 2.81 (2H, t, J = 6.3 Hz), 3.02 (2H, t, J = 5.5 Hz), 3.54 (2H, t, J = 5.5 Hz), 3.57 (2H, t, J = 6.3 Hz), 4.00 (2H, t, J = 8.2 Hz), 4.45 (2H, t, J = 8.2 Hz), 6.69 (2H, d, J = 9.0 Hz), 7.33 (2H, d, J = 9.0 Hz);
MS (FAB) m / z: 261 [M ⁺ ], 219, 205, 105, 70, 56.

［参考例２９］１−［５−（４，５−ジヒドロ−１，３−オキサゾール−２−イル）ピリジン−２−イル］−１，４−ジアゼパン
（２９ａ）２−クロロ−５−(４，５−ジヒドロ−１，３−オキサゾール−２−イル)ピリジン
６−クロロニコチン酸（３．１６ｇ、２０．０ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（４０ｍＬ）溶液に、２−クロロエチルアミン塩酸塩（２．５５ｇ、２２．０ｍｍｏｌ）、トリエチルアミン（３．５ｍＬ、２５．０ｍｍｏｌ）、ＷＳＣ・ＨＣｌ（４．２０ｇ、２２．０ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール（３．００ｇ、２２．０ｍｍｏｌ）を順次加え、室温で２４時間撹拌した。続いて、反応液に８Ｍ水酸化ナトリウム水溶液（２０ｍＬ）を加え、室温で１時間撹拌した。反応液に水（１００ｍＬ）を加え、酢酸エチル（１００ｍＬ）で３回抽出した。有機層を合せ、水（１００ｍＬ）および飽和塩化ナトリウム水溶液（１００ｍＬ）で洗浄し、無水硫酸ナトリウムで乾燥後，溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル，１：１→１：２）を用いて精製し、２．９７ｇ（収率８２％）の標記目的化合物を得た。
[Reference Example 29] 1- [5- (4,5-Dihydro-1,3-oxazol-2-yl) pyridin-2-yl] -1,4-diazepane (29a) 2-chloro-5- (4 , 5-Dihydro-1,3-oxazol-2-yl) pyridine 6-chloronicotinic acid (3.16 g, 20.0 mmol) in N, N-dimethylformamide (40 mL) was added 2-chloroethylamine hydrochloride ( 2.55 g, 22.0 mmol), triethylamine (3.5 mL, 25.0 mmol), WSC · HCl (4.20 g, 22.0 mmol), 1-hydroxybenzotriazole (3.00 g, 22.0 mmol) were sequentially added. And stirred at room temperature for 24 hours. Subsequently, 8M aqueous sodium hydroxide solution (20 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. Water (100 mL) was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate (100 mL). The organic layers were combined, washed with water (100 mL) and saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified using silica gel column chromatography (hexane / ethyl acetate, 1: 1 → 1: 2) to obtain 2.97 g (yield 82%) of the title compound.

白色粉末
Mp 106-108 ℃;
IR (KBr) ν_max 1655, 1589, 1458, 1347, 1258, 1117, 1017, 935, 742 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 4.07 (2H, t, J = 9.4 Hz), 4.46 (2H, t, J = 9.4 Hz), 7.37 (1H, d, J = 8.6 Hz), 8.15 (1H, dd, J = 2.4, 8.6 Hz), 8.89 (1H, d, J = 2.4 Hz);
MS (EI) m/z: 182 [M⁺], 152, 140, 126, 112, 90, 76;
Anal. Calcd for C₈H₇ClN₂O: C, 52.62; H, 3.86; N, 15.34. Found: C, 52.43; H, 3.75; N, 15.31。
White powder
Mp 106-108 ° C;
IR (KBr) ν _max 1655, 1589, 1458, 1347, 1258, 1117, 1017, 935, 742 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 4.07 (2H, t, J = 9.4 Hz), 4.46 (2H, t, J = 9.4 Hz), 7.37 (1H, d, J = 8.6 Hz), 8.15 (1H , dd, J = 2.4, 8.6 Hz), 8.89 (1H, d, J = 2.4 Hz);
MS (EI) m / z: 182 [M ⁺ ], 152, 140, 126, 112, 90, 76;
Anal. Calcd for C ₈ H ₇ ClN ₂ O: C, 52.62; H, 3.86; N, 15.34. Found: C, 52.43; H, 3.75; N, 15.31.

（２９ｂ）ベンジル４−[５−(４，５−ジヒドロ−１，３−オキサゾール−２−イル)ピリジン−２−イル]−１，４−ジアゼパン−１−カルボキシラート
参考例２９（２９ａ）で製造した２−クロロ−５−(４，５−ジヒドロ−１，３−オキサゾール−２−イル)ピリジンを用いて参考例１（１ａ）と同様に反応を行い、標記目的化合物を得た。
褐色液体;
IR (film) ν_max 3395, 2950, 1698, 1606, 1509, 1422, 1362, 1235, 1121, 942 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.90-2.04 (2H, m), 3.33 (1H, t, J = 5.9 Hz), 3.48 (1H, t, J = 5.9 Hz), 3.60-3.71 (4H, m), 3.78-3.88 (2H, m), 4.00 (2H, t, J = 9.4 Hz), 4.37 (2H, t, J = 9.4 Hz), 5.08 (1H, s), 5.12 (1H, s), 6.47 (1H, d, J = 8.6 Hz), 7.26-7.37 (5H, m), 7.93 (1H, d, J = 8.6 Hz), 8.63 (1H, s);
MS (FAB) m/z: 381 [M+H⁺], 338, 273, 242, 165,。
(29b) Benzyl 4- [5- (4,5-dihydro-1,3-oxazol-2-yl) pyridin-2-yl] -1,4-diazepan-1-carboxylate In Reference Example 29 (29a) Using the produced 2-chloro-5- (4,5-dihydro-1,3-oxazol-2-yl) pyridine, a reaction was carried out in the same manner as in Reference Example 1 (1a) to obtain the title object compound.
Brown liquid;
IR (film) ν _max 3395, 2950, 1698, 1606, 1509, 1422, 1362, 1235, 1121, 942 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.90-2.04 (2H, m), 3.33 (1H, t, J = 5.9 Hz), 3.48 (1H, t, J = 5.9 Hz), 3.60-3.71 (4H, m), 3.78-3.88 (2H, m), 4.00 (2H, t, J = 9.4 Hz), 4.37 (2H, t, J = 9.4 Hz), 5.08 (1H, s), 5.12 (1H, s), 6.47 (1H, d, J = 8.6 Hz), 7.26-7.37 (5H, m), 7.93 (1H, d, J = 8.6 Hz), 8.63 (1H, s);
MS (FAB) m / z: 381 [M + H ^<+ >], 338, 273, 242, 165 ,.

（２９ｃ）１−［５−（４，５−ジヒドロ−１，３−オキサゾール−２−イル）ピリジン−２−イル］−１，４−ジアゼパン
参考例２９（２９ｂ）で製造したベンジル４−[５−(４，５−ジヒドロ−１，３−オキサゾール−２−イル)ピリジン−２−イル]−１，４−ジアゼパン−１−カルボキシラートを用いて参考例１（１ｂ）と同様に反応を行い、標記目的化合物を得た。
黄色液体;
IR (film) ν_max 3388, 2940, 1606, 1510, 1420, 1362, 1091, 941cm^-1;
¹H NMR(CDCl₃, 500 MHz) δ 1.83-1.94 (2H, m), 2.84 (2H, t, J = 5.9 Hz), 3.03 (2H, t, J = 5.9 Hz), 3.73-3.81 (4H, m), 4.00 (2H, t, J = 9.4 Hz), 4.38 (2H, t, J = 9.4 Hz), 6.49 (1H, d, J = 9.0 Hz), 7.94 (1H, dd, J = 2.4, 9.0 Hz), 8.66 (1H, d, J = 2.4 Hz);
MS (FAB) m/z: 247 [M+H⁺], 190, 65。
(29c) 1- [5- (4,5-Dihydro-1,3-oxazol-2-yl) pyridin-2-yl] -1,4-diazepane benzyl 4- [produced in Reference Example 29 (29b) 5- (4,5-Dihydro-1,3-oxazol-2-yl) pyridin-2-yl] -1,4-diazepan-1-carboxylate is used for the reaction as in Reference Example 1 (1b). The title compound was obtained.
Yellow liquid;
IR (film) ν _max 3388, 2940, 1606, 1510, 1420, 1362, 1091, 941 cm ^-1 ;
¹ H NMR (CDCl ₃ , 500 MHz) δ 1.83-1.94 (2H, m), 2.84 (2H, t, J = 5.9 Hz), 3.03 (2H, t, J = 5.9 Hz), 3.73-3.81 (4H, m), 4.00 (2H, t, J = 9.4 Hz), 4.38 (2H, t, J = 9.4 Hz), 6.49 (1H, d, J = 9.0 Hz), 7.94 (1H, dd, J = 2.4, 9.0 Hz), 8.66 (1H, d, J = 2.4 Hz);
MS (FAB) m / z: 247 [M + H ^<+ >], 190, 65.

［参考例３０］１−[４−(４，５−ジヒドロ−１，３−オキサゾール−２−イルメチル)フェニル]−１，４−ジアゼパン
（３０ａ）２−(４−ブロモベンジル)−４，５−ジヒドロ−１，３−オキサゾール
４−ブロモフェニル酢酸を用いて参考例２９（２９ａ）と同様に反応を行い、標記目的化合物を得た。
黄色液体;
IR (film) ν_max 3313, 1666, 1554, 1489, 1362, 1243, 1164, 1012, 803 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 3.56 (2H, s), 3.84 (2H, t, J = 9.4 Hz), 4.24 (2H, t, J = 9.4 Hz), 7.18 (2H, d, J = 8.2 Hz), 7.44 (2H, d, J = 8.2 Hz);
MS (EI) m/z: 239 [M⁺], 211, 196, 184, 171, 169, 159, 132, 116, 90, 89, 65, 51。
[Reference Example 30] 1- [4- (4,5-dihydro-1,3-oxazol-2-ylmethyl) phenyl] -1,4-diazepane (30a) 2- (4-bromobenzyl) -4,5 -Dihydro-1,3-oxazole The reaction was carried out in the same manner as in Reference Example 29 (29a) using 4-bromophenylacetic acid to obtain the title compound.
Yellow liquid;
IR (film) ν _max 3313, 1666, 1554, 1489, 1362, 1243, 1164, 1012, 803 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 3.56 (2H, s), 3.84 (2H, t, J = 9.4 Hz), 4.24 (2H, t, J = 9.4 Hz), 7.18 (2H, d, J = 8.2 Hz), 7.44 (2H, d, J = 8.2 Hz);
MS (EI) m / z: 239 [M ⁺ ], 211, 196, 184, 171, 169, 159, 132, 116, 90, 89, 65, 51.

（３０ｂ）ベンジル４−[４−(４，５−ジヒドロ−１，３−オキサゾール−２-イルメチル)フェニル]−１，４−ジアゼパン−１−カルボキシラート
参考例３０（３０ａ）で製造した２−(４−ブロモベンジル)−４，５−ジヒドロ−１，３−オキサゾールを用いて参考例１（１ａ）と同様に反応を行い、標記目的化合物を得た。
黄色液体;
IR (film) ν_max 3385, 2942, 1697, 1520, 1422, 1228, 985, 699 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.89-2.04 (2H, m), 3.30 (1H, t, J = 6.3 Hz), 3.37 (1H, t, J = 5.5 Hz), 3.47-3.59 (6H, m), 3.60-3.68 (2H, m), 3.77-3.85 (2H, m), 4.15-4.25 (2H, m), 5.06 (1H, s), 5.12 (1H, s), 6.62 (2H, d, J = 8.6 Hz), 7.12 (2H, d, J = 8.6 Hz), 7.26-7.35 (5H, m);
MS (FAB) m/z: 394 [M+H⁺], 359, 323, 258, 215, 189, 91, 63。
(30b) Benzyl 4- [4- (4,5-dihydro-1,3-oxazol-2-ylmethyl) phenyl] -1,4-diazepan-1-carboxylate 2-prepared in Reference Example 30 (30a) The reaction was performed in the same manner as in Reference Example 1 (1a) using (4-bromobenzyl) -4,5-dihydro-1,3-oxazole to obtain the title object compound.
Yellow liquid;
IR (film) ν _max 3385, 2942, 1697, 1520, 1422, 1228, 985, 699 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.89-2.04 (2H, m), 3.30 (1H, t, J = 6.3 Hz), 3.37 (1H, t, J = 5.5 Hz), 3.47-3.59 (6H, m), 3.60-3.68 (2H, m), 3.77-3.85 (2H, m), 4.15-4.25 (2H, m), 5.06 (1H, s), 5.12 (1H, s), 6.62 (2H, d, J = 8.6 Hz), 7.12 (2H, d, J = 8.6 Hz), 7.26-7.35 (5H, m);
MS (FAB) m / z: 394 [M + H ⁺ ], 359, 323, 258, 215, 189, 91, 63.

（３０ｃ）１−[４−(４，５−ジヒドロ−１，３−オキサゾール−２−イルメチル)フェニル]−１，４−ジアゼパン
参考例３０（３０ｂ）で製造したベンジル４−[４−(４，５−ジヒドロ−１，３−オキサゾール−２-イルメチル)フェニル]−１，４−ジアゼパン−１−カルボキシラートを用いて参考例１（１ａ）と同様に反応を行い、標記目的化合物を得た。
淡黄色液体;
IR (film) ν_max 3313, 2934, 1664, 1520, 1362, 1189, 986, 807 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.83-1.94 (2H, m), 2.83 (2H, t, J = 5.9 Hz), 3.01 (2H, t, J = 5.9 Hz), 3.43-3.61 (6H, m), 3.83 (2H, t, J = 9.4 Hz), 4.23 (2H, t, J = 9.4 Hz), 6.65 (2H, d, J = 8.6 Hz), 7.14 (2H, d, J = 8.6 Hz);
MS (EI) m/z: 259 [M⁺], 229, 217, 203, 189, 174, 159, 146, 133, 118, 91, 70, 56。
(30c) 1- [4- (4,5-dihydro-1,3-oxazol-2-ylmethyl) phenyl] -1,4-diazepane benzyl 4- [4- (4) prepared in Reference Example 30 (30b) , 5-Dihydro-1,3-oxazol-2-ylmethyl) phenyl] -1,4-diazepane-1-carboxylate was reacted in the same manner as in Reference Example 1 (1a) to obtain the title compound. .
A pale yellow liquid;
IR (film) ν _max 3313, 2934, 1664, 1520, 1362, 1189, 986, 807 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.83-1.94 (2H, m), 2.83 (2H, t, J = 5.9 Hz), 3.01 (2H, t, J = 5.9 Hz), 3.43-3.61 (6H, m), 3.83 (2H, t, J = 9.4 Hz), 4.23 (2H, t, J = 9.4 Hz), 6.65 (2H, d, J = 8.6 Hz), 7.14 (2H, d, J = 8.6 Hz) ;
MS (EI) m / z: 259 [M ⁺ ], 229, 217, 203, 189, 174, 159, 146, 133, 118, 91, 70, 56.

［参考例３１］１−[４−(１−メチル−１Ｈ−イミダゾール−２−イル)フェニル]−１，４−ジアゼパン
（３１ａ）エチル 4-ブロモベンゼンカルボキシイミドアート塩酸塩
４−ブロモベンゾニトリル（３．６４ｇ、２０．０ｍｍｏｌ）のエタノール（２００ｍＬ）溶液を０℃に冷却し、塩化水素ガスを飽和するまで吹き込み、室温で２４時間撹拌した。反応液を濃縮し、得られた残渣をエーテルで粉末化し、４．６７ｇ（収率８８％）の標記目的化合物を得た。
[Reference Example 31] 1- [4- (1-Methyl-1H-imidazol-2-yl) phenyl] -1,4-diazepane (31a) ethyl 4-bromobenzenecarboximidoate hydrochloride 4-bromobenzonitrile ( A solution of 3.64 g, 20.0 mmol) in ethanol (200 mL) was cooled to 0 ° C., and hydrogen chloride gas was blown in until saturated, followed by stirring at room temperature for 24 hours. The reaction mixture was concentrated, and the resulting residue was triturated with ether to give 4.67 g (yield 88%) of the title compound.

白色粉末
Mp 193-194 ℃;
IR (KBr) ν_max 2933, 1709, 1635, 1602, 1458, 1403, 1069, 808 cm^-1;
¹H NMR(DMSO-d₆, 400 MHz) δ 1.48 (3H, t, J = 7.0 Hz), 4.01 (2H, q, J = 7.0 Hz), 7.89 (2H, d, J = 8.6 Hz), 8.04 (2H, d, J = 8.6 Hz);
MS (FAB) m/z: 228 [M⁺], 200, 183, 63;
Anal. Calcd for C₉H₁₀BrNO・1.00HCl・0.75H₂O: C, 38.88; H, 4.53; N, 5.04. Found: C, 38.82; H, 4.11; N, 5.77。
White powder
Mp 193-194 ° C;
IR (KBr) ν _max 2933, 1709, 1635, 1602, 1458, 1403, 1069, 808 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.48 (3H, t, J = 7.0 Hz), 4.01 (2H, q, J = 7.0 Hz), 7.89 (2H, d, J = 8.6 Hz), 8.04 (2H, d, J = 8.6 Hz);
MS (FAB) m / z: 228 [M ⁺ ], 200, 183, 63;
Anal. Calcd for C ₉ H ₁₀ BrNO · 1.00HCl · 0.75H ₂ O: C, 38.88; H, 4.53; N, 5.04. Found: C, 38.82; H, 4.11; N, 5.77.

（３１ｂ）４−ブロモ−Ｎ−（２，２−ジメトキシエチル）ベンゼンカルボキシイミドアミド塩酸塩
参考例３１（３１ａ）で製造したエチル４−ブロモベンゼンカルボキシイミドアート（４．６４ｇ，１７．５ｍｍｏｌ）のエタノール（４０ｍＬ）溶液にアミノアセトアルデヒドジメチルアセタール（１．８９ｍＬ、１７．６ｍｍｏｌ）を加え、室温で６４時間撹拌した。反応液を濃縮し、５．６４ｇ（定量的）の粗生な標記目的化合物を得た。
(31b) 4-Bromo-N- (2,2-dimethoxyethyl) benzenecarboximido hydrochloride Hydrochloride of ethyl 4-bromobenzenecarboximide ate (4.64 g, 17.5 mmol) prepared in Reference Example 31 (31a) Aminoacetaldehyde dimethyl acetal (1.89 mL, 17.6 mmol) was added to an ethanol (40 mL) solution, and the mixture was stirred at room temperature for 64 hours. The reaction solution was concentrated to obtain 5.64 g (quantitative) of the crude title object compound.

淡黄色液体;
¹H NMR(DMSO-d₆ 400 MHz) δ 3.39 (3H, s), 3.46 (3H, s), 3.81 (2H, brd, J = 4.3 Hz), 4.62 (1H, t, J = 4.3 Hz), 7.58 (2H, d, J = 8.6 Hz), 7.84 (2H, d, J = 8.6 Hz)。
A pale yellow liquid;
¹ H NMR (DMSO-d ₆ 400 MHz) δ 3.39 (3H, s), 3.46 (3H, s), 3.81 (2H, brd, J = 4.3 Hz), 4.62 (1H, t, J = 4.3 Hz), 7.58 (2H, d, J = 8.6 Hz), 7.84 (2H, d, J = 8.6 Hz).

（３１ｃ）２−(４−ブロモフェニル)−１Ｈ−イミダゾール
参考例３１（３１ｂ）で製造した４−ブロモ−Ｎ−（２，２−ジメトキシエチル）ベンゼンカルボキシイミドアミド（５．６４ｇ）にトリフルオロ酢酸（３５ｍＬ）を加え、８０℃で４時間撹拌した。反応液に水（２００ｍＬ）を加え、炭酸カリウムで液性を塩基性とし、塩化メチレン／２−プロパノール（（４：１）、２００ｍＬ）で２回抽出し、無水硫酸ナトリウムで乾燥後，溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（塩化メチレン／メタノール，９：１）を用いて精製し、２．０８ｇ（収率５５％）の標記目的化合物を得た。
(31c) 2- (4-Bromophenyl) -1H-imidazole To 4-bromo-N- (2,2-dimethoxyethyl) benzenecarboximidamide (5.64 g) prepared in Reference Example 31 (31b), trifluoro Acetic acid (35 mL) was added and stirred at 80 ° C. for 4 hours. Water (200 mL) was added to the reaction solution, the solution was made basic with potassium carbonate, extracted twice with methylene chloride / 2-propanol ((4: 1), 200 mL), dried over anhydrous sodium sulfate, and the solvent was removed. Distilled off under reduced pressure. The resulting residue was purified using silica gel column chromatography (methylene chloride / methanol, 9: 1) to obtain 2.08 g (yield 55%) of the title compound.

淡黄色粉末
Mp 278-281 ℃;
IR (KBr) ν_max 2814, 1494, 1446, 1106, 949, 824, 724 cm^-1;
¹H NMR(DMSO-d₆ 400 MHz) δ 7.04 (1H, br.s), 7.27 (1H, br.s), 7.65 (2H, d, J = 8.6 Hz), 7.88 (2H, d, J = 8.6 Hz);
MS (EI) m/z: 222 [M⁺], 197, 195, 169, 143, 116, 102, 89, 75, 40;
Anal. Calcd for C₉H₇BrN₂・0.25H₂O: C, 47.50; H, 3.32; N, 12.31. Found: C, 47.55; H, 3.13; N, 12.18。
Pale yellow powder
Mp 278-281 ° C;
IR (KBr) ν _max 2814, 1494, 1446, 1106, 949, 824, 724 cm ^-1 ;
¹ H NMR (DMSO-d ₆ 400 MHz) δ 7.04 (1H, br.s), 7.27 (1H, br.s), 7.65 (2H, d, J = 8.6 Hz), 7.88 (2H, d, J = 8.6 Hz);
MS (EI) m / z: 222 [M ⁺ ], 197, 195, 169, 143, 116, 102, 89, 75, 40;
_{_{. Anal Calcd for C 9 H 7}} BrN 2 · 0.25H 2 O:. C, 47.50; H, 3.32; N, 12.31 Found: C, 47.55; H, 3.13; N, 12.18.

（３１ｄ）２−(４−ブロモフェニル)−１−メチル−１Ｈ−イミダゾール
参考例３１（３１ｃ）で製造した２−(４−ブロモフェニル)−１Ｈ−イミダゾール（２．００ｇ，８．９７ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（２０ｍＬ）溶液を０℃に冷却し、水素化ナトリウム（３９３ｍｇ、８．９７ｍｍｏｌ）を加え、０℃で１５分間撹拌した。続いて、ヨウ化メチル（０．５６ｍＬ、９．０６ｍｍｏｌ）を加え、室温で１８時間撹拌した。反応液に水（１００ｍＬ）を加え、塩化メチレン（１００ｍＬ）で３回抽出した。有機層を合わせて、水（１００ｍＬ）および飽和塩化ナトリウム水溶液（１００ｍＬ）で洗浄し、無水硫酸ナトリウムで乾燥後，溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル，１：２→１：５→０：１）を用いて精製し、１．６８ｇ（収率８０％）の標記目的化合物を得た。
(31d) 2- (4-Bromophenyl) -1-methyl-1H-imidazole of 2- (4-bromophenyl) -1H-imidazole (2.00 g, 8.97 mmol) prepared in Reference Example 31 (31c) The N, N-dimethylformamide (20 mL) solution was cooled to 0 ° C., sodium hydride (393 mg, 8.97 mmol) was added, and the mixture was stirred at 0 ° C. for 15 min. Subsequently, methyl iodide (0.56 mL, 9.06 mmol) was added, and the mixture was stirred at room temperature for 18 hours. Water (100 mL) was added to the reaction mixture, and the mixture was extracted 3 times with methylene chloride (100 mL). The organic layers were combined, washed with water (100 mL) and saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified using silica gel column chromatography (hexane / ethyl acetate, 1: 2 → 1: 5 → 0: 1) to obtain 1.68 g (yield 80%) of the title compound.

黄色液体;
IR (film) ν_max 3369, 1631, 1472, 1282, 1076, 1008, 832, 726 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 3.75 (3H, s), 6.98 (1H, brs), 7.12 (1H, brs), 7.52 (2H, d, J = 8.6 Hz), 7.60 (2H, d, J = 8.6 Hz);
MS (EI) m/z: 236 [M⁺], 185, 183, 156, 129, 116, 102, 89, 75, 54。
Yellow liquid;
IR (film) ν _max 3369, 1631, 1472, 1282, 1076, 1008, 832, 726 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 3.75 (3H, s), 6.98 (1H, brs), 7.12 (1H, brs), 7.52 (2H, d, J = 8.6 Hz), 7.60 (2H, d, J = 8.6 Hz);
MS (EI) m / z: 236 [M ⁺ ], 185, 183, 156, 129, 116, 102, 89, 75, 54.

（３１ｅ）ベンジル４−[４−(１−メチル−１Ｈ−イミダゾール−２−イル)フェニル]−１，４−ジアゼパン−１−カルボキシラート
参考例３１（３１ｄ）で製造した２−(４−ブロモフェニル)−１−メチル−１Ｈ−イミダゾールを用いて参考例１（１ａ）と同様に反応を行い、標記目的化合物を得た。
黄色液体;
IR (film) ν_max 2946, 1695, 1613, 1475, 1227, 1120, 927, 753 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.94-2.07 (2H, m), 3.31 (1H, t, J = 5.9 Hz), 3.39 (1H, t, J = 5.9 Hz), 3.55-3.74 (9H, m), 5.09 (1H, s), 5.13 (1H, s), 6.69-6.76 (2H, m), 6.89 (1H, brs), 7.05 (1H, brs), 7.26-7.35 (5H, m), 7.44-7.49 (2H, m);
MS (FAB) m/z: 391 [M+H⁺], 357, 301, 283, 255, 226, 186, 91。
(31e) Benzyl 4- [4- (1-methyl-1H-imidazol-2-yl) phenyl] -1,4-diazepan-1-carboxylate 2- (4-Bromo prepared in Reference Example 31 (31d) The reaction was conducted in the same manner as in Reference Example 1 (1a) using (phenyl) -1-methyl-1H-imidazole to obtain the title object compound.
Yellow liquid;
IR (film) ν _max 2946, 1695, 1613, 1475, 1227, 1120, 927, 753 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.94-2.07 (2H, m), 3.31 (1H, t, J = 5.9 Hz), 3.39 (1H, t, J = 5.9 Hz), 3.55-3.74 (9H, m), 5.09 (1H, s), 5.13 (1H, s), 6.69-6.76 (2H, m), 6.89 (1H, brs), 7.05 (1H, brs), 7.26-7.35 (5H, m), 7.44 -7.49 (2H, m);
MS (FAB) m / z: 391 [M + H ⁺ ], 357, 301, 283, 255, 226, 186, 91.

（３１ｆ）１−[４−(１−メチル−１Ｈ−イミダゾール−２−イル)フェニル]−１，４−ジアゼパン
参考例３１（３１ｅ）で製造したベンジル４−[４−(１−メチル−１Ｈ−イミダゾール−２−イル)フェニル]−１，４−ジアゼパン−１−カルボキシラートを用いて参考例１（１ｂ）と同様に反応を行い、標記目的化合物を得た。
淡黄色液体;
IR (film) ν_max 3320, 2935, 1613, 1513, 1474, 1195, 819, 753 cm^-1;
¹H NMR(CDCl₃, 500 MHz) δ 1.89-1.96 (2H, m), 2.85 (2H, t, J = 5.9 Hz), 3.05 (2H, t, J = 5.4 Hz), 3.60 (2H, t, J = 5.4 Hz), 3.63 (2H, t, J = 5.9 Hz), 3.72 (3H, s), 6.75 (2H, d, J = 8.8 Hz), 6.91 (1H, s), 7.07 (1H, s), 7.48 (2H, d, J = 8.8 Hz);
MS (FAB) m/z: 257 [M⁺], 239, 200, 186。
(31f) 1- [4- (1-Methyl-1H-imidazol-2-yl) phenyl] -1,4-diazepan benzyl 4- [4- (1-methyl-1H) prepared in Reference Example 31 (31e) -Imidazole-2-yl) phenyl] -1,4-diazepane-1-carboxylate was used in the same manner as in Reference Example 1 (1b) to give the title object compound.
A pale yellow liquid;
IR (film) ν _max 3320, 2935, 1613, 1513, 1474, 1195, 819, 753 cm ^-1 ;
¹ H NMR (CDCl ₃ , 500 MHz) δ 1.89-1.96 (2H, m), 2.85 (2H, t, J = 5.9 Hz), 3.05 (2H, t, J = 5.4 Hz), 3.60 (2H, t, J = 5.4 Hz), 3.63 (2H, t, J = 5.9 Hz), 3.72 (3H, s), 6.75 (2H, d, J = 8.8 Hz), 6.91 (1H, s), 7.07 (1H, s) , 7.48 (2H, d, J = 8.8 Hz);
MS (FAB) m / z: 257 [M ⁺ ], 239, 200, 186.

［参考例３２］１−[４−(５−メチル−１，３，４−オキサジアゾール−２−イル)フェニル]−１，４−ジアゼパン
（３２ａ）２−(４−ブロモフェニル)−５−メチル−１，３，４−オキサジアゾール
４−ブロモベンゾイルヒドラジン（２．１５ｇ、１０．０ｍｍｏｌ）にオルト酢酸トリエチルを加え、加熱還流下１５時間撹拌した。反応液を濃縮し、２．３７ｇ（収率９９％）標記目的化合物を得た。
白色粉末
Mp 111-115 ℃;
IR (KBr) ν_max 3067, 1586, 1478, 1404, 1247, 1086, 1008, 731 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 2.61 (3H, s), 7.63 (2H, d, J = 8.6 Hz), 7.88 (2H, d, J = 8.6 Hz);
MS (EI) m/z: 238 [M⁺], 198, 183, 155, 119, 103, 89, 75, 43;
Anal. Calcd for C₉H₇BrN₂O: C, 45.22; H, 2.95; N, 11.72. Found: C, 45.19; H, 3.21; N, 11.59。
[Reference Example 32] 1- [4- (5-Methyl-1,3,4-oxadiazol-2-yl) phenyl] -1,4-diazepane (32a) 2- (4-bromophenyl) -5 -Methyl-1,3,4-oxadiazole To 4-bromobenzoylhydrazine (2.15 g, 10.0 mmol) was added triethyl orthoacetate, and the mixture was stirred with heating under reflux for 15 hours. The reaction solution was concentrated to obtain 2.37 g (yield 99%) of the title target compound.
White powder
Mp 111-115 ° C;
IR (KBr) ν _max 3067, 1586, 1478, 1404, 1247, 1086, 1008, 731 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 2.61 (3H, s), 7.63 (2H, d, J = 8.6 Hz), 7.88 (2H, d, J = 8.6 Hz);
MS (EI) m / z: 238 [M +], 198, 183, 155, 119, 103, 89, 75, 43;
Anal. Calcd for C ₉ H ₇ BrN ₂ O: C, 45.22; H, 2.95; N, 11.72. Found: C, 45.19; H, 3.21; N, 11.59.

（３２ｂ）ベンジル４−[４−(５−メチル−１，３，４−オキサジアゾール−２−イル)フェニル]−１，４−ジアゼパン−１−カルボキシラート
参考例３２（３２ａ）で製造した２−(４−ブロモフェニル)−５−メチル−１，３，４−オキサジアゾールを用いて参考例１（１ａ）と同様に反応を行い、標記目的化合物を得た。
淡黄色液体;
IR (film) ν_max 2946, 1698, 1613, 1504, 1422, 1230, 1119, 926, 739 cm^-1;
¹H NMR(CDCl₃, 500 MHz) δ 1.93-2.08 (2H, m), 2.57 (3H, s), 3.34 (1H, t, J = 5.9 Hz), 3.41 (1H, t, J = 5.9 Hz), 3.56-3.74 (6H, m), 5.07 (1H, s), 5.13 (1H, s), 6.70-6.78 (2H, m), 7.25-7.38 (5H, m), 7.81-7.89 (2H, m);
MS (FAB) m/z: 393 [M+H⁺], 273, 257, 242, 219, 176, 165, 65。
(32b) Benzyl 4- [4- (5-methyl-1,3,4-oxadiazol-2-yl) phenyl] -1,4-diazepan-1-carboxylate Prepared in Reference Example 32 (32a) The reaction was carried out in the same manner as in Reference Example 1 (1a) using 2- (4-bromophenyl) -5-methyl-1,3,4-oxadiazole to obtain the title compound.
A pale yellow liquid;
IR (film) ν _max 2946, 1698, 1613, 1504, 1422, 1230, 1119, 926, 739 cm ^-1 ;
¹ H NMR (CDCl ₃ , 500 MHz) δ 1.93-2.08 (2H, m), 2.57 (3H, s), 3.34 (1H, t, J = 5.9 Hz), 3.41 (1H, t, J = 5.9 Hz) , 3.56-3.74 (6H, m), 5.07 (1H, s), 5.13 (1H, s), 6.70-6.78 (2H, m), 7.25-7.38 (5H, m), 7.81-7.89 (2H, m) ;
MS (FAB) m / z: 393 [M + H ⁺ ], 273, 257, 242, 219, 176, 165, 65.

（３２ｃ）１−[４−(５−メチル−１，３，４−オキサジアゾール−２−イル)フェニル]−１，４−ジアゼパン
参考例３２（３２ｂ）で製造したベンジル４−[４−(５−メチル−１，３，４−オキサジアゾール−２−イル)フェニル]−１，４−ジアゼパン−１−カルボキシラートを用いて参考例１（１ｂ）と同様に反応を行い、標記目的化合物を得た。
淡黄色液体;
IR (film) ν_max 3426, 2933, 1614, 1507, 1402, 1291, 1192, 815 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.87-1.95 (2H, m), 2.56 (3H, s), 2.83 (2H, t, J = 5.9 Hz), 3.04 (2H, t, J = 5.5 Hz), 3.59 (2H, t, J = 5.5 Hz), 3.64 (2H, t, J = 5.9 Hz), 6.72 (2H, d, J = 9.0 Hz), 7.82 (2H, d, J = 9.0 Hz);
MS (EI) m/z: 258 [M⁺], 228, 216, 202, 190, 160, 146, 132, 119, 90, 70, 44。
(32c) 1- [4- (5-Methyl-1,3,4-oxadiazol-2-yl) phenyl] -1,4-diazepane Benzyl 4- [4- prepared in Reference Example 32 (32b) (5-Methyl-1,3,4-oxadiazol-2-yl) phenyl] -1,4-diazepane-1-carboxylate was reacted in the same manner as in Reference Example 1 (1b) to give A compound was obtained.
A pale yellow liquid;
IR (film) ν _max 3426, 2933, 1614, 1507, 1402, 1291, 1192, 815 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.87-1.95 (2H, m), 2.56 (3H, s), 2.83 (2H, t, J = 5.9 Hz), 3.04 (2H, t, J = 5.5 Hz) , 3.59 (2H, t, J = 5.5 Hz), 3.64 (2H, t, J = 5.9 Hz), 6.72 (2H, d, J = 9.0 Hz), 7.82 (2H, d, J = 9.0 Hz);
MS (EI) m / z: 258 [M ⁺ ], 228, 216, 202, 190, 160, 146, 132, 119, 90, 70, 44.

［参考例３３］１−[４−(１−{[２−(トリメチルシリル)エトキシ]メチル}−１Ｈ−イミダゾール−２−イル)フェニル]−１，４−ジアゼパン
（３３ａ）２−(４−ブロモフェニル)−１−{[２−(トリメチルシリル)エトキシ]メチル}−１Ｈ−イミダゾール
ヨウ化メチルの代わりに２−（トリメチルシリル）エトキシメチルクロリドを用いて参考例３１（３１ｄ）と同様に反応を行い、標記目的化合物を得た。
黄色液体;
IR (film) ν_max 2953, 1496, 1373, 1250, 1082, 834 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 0.01 (9H, s), 0.95 (2H, t, J = 8.2 Hz), 3.61 (2H, t, J = 8.2 Hz), 5.26 (2H, s), 7.12 (1H, d, J = 1.2 Hz), 7.15 (1H, d, J = 1.2 Hz), 7.56 (2H, d, J = 8.2 Hz), 7.71 (2H, d, J = 8.2 Hz);
MS (EI) m/z: 354, 352 [M⁺], 311, 294, 236, 222, 200, 156, 103, 73。
[Reference Example 33] 1- [4- (1-{[2- (Trimethylsilyl) ethoxy] methyl} -1H-imidazol-2-yl) phenyl] -1,4-diazepane (33a) 2- (4-bromo Phenyl) -1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-imidazole Reaction was performed in the same manner as in Reference Example 31 (31d) using 2- (trimethylsilyl) ethoxymethyl chloride instead of methyl iodide. The title object compound was obtained.
Yellow liquid;
IR (film) ν _max 2953, 1496, 1373, 1250, 1082, 834 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 0.01 (9H, s), 0.95 (2H, t, J = 8.2 Hz), 3.61 (2H, t, J = 8.2 Hz), 5.26 (2H, s), 7.12 (1H, d, J = 1.2 Hz), 7.15 (1H, d, J = 1.2 Hz), 7.56 (2H, d, J = 8.2 Hz), 7.71 (2H, d, J = 8.2 Hz);
MS (EI) m / z: 354, 352 [M ⁺ ], 311, 294, 236, 222, 200, 156, 103, 73.

（３３ｂ）ベンジル４−[４−(１−{[２−(トリメチルシリル)エトキシ]メチル}−１Ｈ−イミダゾール−２−イル)フェニル]−１，４−ジアゼパン−１−カルボキシラート
参考例３３（３３ａ）で製造した２−(４−ブロモフェニル)−１−{[２−(トリメチルシリル)エトキシ]メチル}−１Ｈ−イミダゾールを用いて参考例１（１ａ）と同様に反応を行い、標記目的化合物を得た。
黄色液体;
IR (film) ν_max 2952, 1699, 1613, 1473, 1231, 1081, 927, 836 cm^-1;
¹H NMR(CDCl₃, 500 MHz) δ 0.00 (9H, s), 0.94 (2H, t, J = 8.2 Hz), 1.92-2.09 (2H, m), 3.32 (1H, t, J = 5.9 Hz), 3.39 (1H, t, J = 5.9 Hz), 3.51-3.71 (8H, m), 5.11 (1H, s), 5.15 (1H, s), 5.23-5.28 (2H, m), 6.71-6.79 (2H, m), 7.06 (1H, brs), 7.10 (1H, brs), 7.28-7.39 (5H, m), 7.66 (2H, d, J = 9.0 Hz);
MS (FAB) m/z: 507 [M+H⁺], 449, 389, 377, 258, 244, 226, 200, 186。
(33b) Benzyl 4- [4- (1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-imidazol-2-yl) phenyl] -1,4-diazepan-1-carboxylate Reference Example 33 (33a The reaction was conducted in the same manner as in Reference Example 1 (1a) using 2- (4-bromophenyl) -1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-imidazole prepared in Obtained.
Yellow liquid;
IR (film) ν _max 2952, 1699, 1613, 1473, 1231, 1081, 927, 836 cm ^-1 ;
¹ H NMR (CDCl ₃ , 500 MHz) δ 0.00 (9H, s), 0.94 (2H, t, J = 8.2 Hz), 1.92-2.09 (2H, m), 3.32 (1H, t, J = 5.9 Hz) , 3.39 (1H, t, J = 5.9 Hz), 3.51-3.71 (8H, m), 5.11 (1H, s), 5.15 (1H, s), 5.23-5.28 (2H, m), 6.71-6.79 (2H , m), 7.06 (1H, brs), 7.10 (1H, brs), 7.28-7.39 (5H, m), 7.66 (2H, d, J = 9.0 Hz);
MS (FAB) m / z: 507 [M + H ⁺ ], 449, 389, 377, 258, 244, 226, 200, 186.

（３３ｃ）１−[４−(１−{[２−(トリメチルシリル)エトキシ]メチル}−１Ｈ−イミダゾール−２−イル)フェニル]−１，４−ジアゼパン
参考例３３（３３ｂ）で製造したベンジル４−[４−(１−{[２−(トリメチルシリル)エトキシ]メチル}−１Ｈ−イミダゾール−２−イル)フェニル]−１，４−ジアゼパン−１−カルボキシラートを用いて参考例１（１ｂ）と同様に反応を行い、標記目的化合物を得た。
黄色液体;
IR (film) ν_max 2950, 1612, 1470, 1361, 1250, 1081, 836 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 0.00 (9H, s), 0.94 (2H, t, J = 8.2 Hz), 1.88-1.96 (2H, m), 2.84 (2H, t, J = 5.9 Hz), 3.05 (2H, t, J = 4.7 Hz), 3.53-3.67 (7H, m), 5.27 (2H, s), 6.75 (2H, d, J = 9.0 Hz), 7.06 (1H, brs), 7.09 (1H, brs), 7.64 (2H, d, J = 9.0 Hz);
MS (EI) m/z: 372 [M⁺], 330, 316, 300, 272, 258, 241, 212, 198, 186, 170, 156, 144, 103, 73。
(33c) 1- [4- (1-{[2- (Trimethylsilyl) ethoxy] methyl} -1H-imidazol-2-yl) phenyl] -1,4-diazepan benzyl 4 prepared in Reference Example 33 (33b) Reference Example 1 (1b) with-[4- (1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-imidazol-2-yl) phenyl] -1,4-diazepane-1-carboxylate The reaction was carried out in the same manner to obtain the title target compound.
Yellow liquid;
IR (film) ν _max 2950, 1612, 1470, 1361, 1250, 1081, 836 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 0.00 (9H, s), 0.94 (2H, t, J = 8.2 Hz), 1.88-1.96 (2H, m), 2.84 (2H, t, J = 5.9 Hz) , 3.05 (2H, t, J = 4.7 Hz), 3.53-3.67 (7H, m), 5.27 (2H, s), 6.75 (2H, d, J = 9.0 Hz), 7.06 (1H, brs), 7.09 ( 1H, brs), 7.64 (2H, d, J = 9.0 Hz);
MS (EI) m / z: 372 [M ⁺ ], 330, 316, 300, 272, 258, 241, 212, 198, 186, 170, 156, 144, 103, 73.

［参考例３４］ｔａｒｔ−ブチル４−[４−(５−オキソ−４，５−ジヒドロ−１，２，４−オキサジアゾール−３−イル)フェニル]−１，４−ジアゼパン−１−カルボキシラート
（３４ａ）ｔｅｒｔ−ブチル４−[４−(５−オキソ−４，５−ジヒドロ−１，２，４−オキサジアゾール−３−イル)フェニル]−１，４−ジアゼパン−１−カルボキシラート
参考例２０（２０ｂ）で製造したｔｅｒｔ−ブチル４−{４−[(Ｚ)−アミノ(ヒドロキシイミノ)メチル]フェニル}−１，４−ジアゼパン−１−カルボキシラート（２４．５ｇ，７３．４ｍｍｏｌ）の１，４−ジオキサン（３００ｍＬ）溶液に、１，８−ジアザビシクロ[５，４，０]−７−ウンデセン（１３．１ｍＬ、８７．８ｍｍｏｌ）、１，１’−カルボニルジイミダゾール（１４．３ｇ、８７．８ｍｍｏｌ）を順次加え、１００℃で１４時間撹拌した。反応液を濃縮し、水（１００ｍＬ）および１Ｍ水酸化ナトリウム水溶液（１００ｍＬ）を加え、酢酸エチル（１００ｍＬ）で洗浄した。続いて１Ｍ塩化水素水溶液（１５０ｍＬ）を加え、塩化メチレン（３００ｍＬ）で３回抽出した。有機層を合わせて、水（１００ｍＬ）および飽和塩化ナトリウム水溶液（１００ｍＬ）で洗浄し、無水硫酸ナトリウムで乾燥後，溶媒を減圧下留去した。得られた残渣を塩化メチレンで粉末化し、１０．７ｇ（収率４０％）の標記目的化合物を得た。
[Reference Example 34] tart-butyl 4- [4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) phenyl] -1,4-diazepan-1-carboxy Lato (34a) tert-butyl 4- [4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) phenyl] -1,4-diazepan-1-carboxylate Tert-Butyl 4- {4-[(Z) -amino (hydroxyimino) methyl] phenyl} -1,4-diazepan-1-carboxylate prepared in Reference Example 20 (20b) (24.5 g, 73.4 mmol) ) In 1,4-dioxane (300 mL), 1,8-diazabicyclo [5,4,0] -7-undecene (13.1 mL, 87.8 mmol), 1,1′-carbonyldiimidazole (14. 3g, 8 .8Mmol), and the mixture was stirred at 100 ° C. 14 hours. The reaction mixture was concentrated, water (100 mL) and 1M aqueous sodium hydroxide solution (100 mL) were added, and the mixture was washed with ethyl acetate (100 mL). Subsequently, 1M aqueous hydrogen chloride solution (150 mL) was added, and the mixture was extracted 3 times with methylene chloride (300 mL). The organic layers were combined, washed with water (100 mL) and saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was triturated with methylene chloride to obtain 10.7 g (yield 40%) of the title object compound.

白色粉末
Mp 232-235 ℃；
IR (KBr) ν_max 2974, 1749, 1682, 1612, 1478, 1364, 1171, 929, 753 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.35 (4.5H, s), 1.42 (4.5H, s), 1.91-2.01 (2H, m), 3.24 (1H, t, J = 5.9 Hz), 3.35 (1H, t, J = 5.9 Hz), 3.55-3.67 (6H, m), 6.74 (2H, d, J = 8.6 Hz), 7.59 (2H, d, J = 8.6 Hz);
MS (FAB) m/z: 360 [M⁺], 305, 261, 246, 219, 182, 93, 57;
Anal. Calcd for C₁₈H₂₄N₄O₄: C, 59.99; H, 6.71; N, 15.55. Found: C, 59.96; H, 6.85; N, 15.38。
White powder
Mp 232-235 ° C;
IR (KBr) ν _max 2974, 1749, 1682, 1612, 1478, 1364, 1171, 929, 753 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.35 (4.5H, s), 1.42 (4.5H, s), 1.91-2.01 (2H, m), 3.24 (1H, t, J = 5.9 Hz), 3.35 ( 1H, t, J = 5.9 Hz), 3.55-3.67 (6H, m), 6.74 (2H, d, J = 8.6 Hz), 7.59 (2H, d, J = 8.6 Hz);
MS (FAB) m / z: 360 [M ⁺ ], 305, 261, 246, 219, 182, 93, 57;
_{_{. Anal Calcd for C 18 H 24}} N 4 O 4:. C, 59.99; H, 6.71; N, 15.55 Found: C, 59.96; H, 6.85; N, 15.38.

（３４ｂ）ｔｅｒｔ−ブチル４−[４−(４−メチル−５−オキソ−４，５−ジヒドロ−１，２，４−オキサジアゾール−３−イル)フェニル]−１，４−ジアゼパン−１−カルボキシラート
参考例３４（３４ａ）で製造したｔｅｒｔ−ブチル４−[４−(５−オキソ−４，５−ジヒドロ−１，２，４−オキサジアゾール−３−イル)フェニル]−１，４−ジアゼパン−１−カルボキシラート（９２０ｍｇ，２．５６ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（１０ｍＬ）溶液を０℃に冷却し、水素化ナトリウム（１６８ｍｇ、３．８５ｍｍｏｌ）、ヨウ化メチル（０．３２ｍＬ、５．１７ｍｍｏｌ）を順次加え、室温で３時間撹拌した。反応液に水（１００ｍＬ）を加え、酢酸エチル（１００ｍＬ）で３回抽出した。有機層を合わせて、水（１００ｍＬ）および飽和塩化ナトリウム水溶液（１００ｍＬ）で洗浄し、無水硫酸ナトリウムで乾燥後，溶媒を減圧下留去した。得られた残渣をエーテルで粉末化し、８７２ｍｇ（収率９１％）の標記目的化合物を得た。
(34b) tert-butyl 4- [4- (4-methyl-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) phenyl] -1,4-diazepan-1 -Carboxylate tert-Butyl 4- [4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) phenyl] -1, prepared in Reference Example 34 (34a) A solution of 4-diazepan-1-carboxylate (920 mg, 2.56 mmol) in N, N-dimethylformamide (10 mL) was cooled to 0 ° C., sodium hydride (168 mg, 3.85 mmol), methyl iodide (0. (32 mL, 5.17 mmol) was sequentially added, and the mixture was stirred at room temperature for 3 hours. Water (100 mL) was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate (100 mL). The organic layers were combined, washed with water (100 mL) and saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was triturated with ether to obtain 872 mg (yield 91%) of the title object compound.

淡黄色粉末
Mp 166-168 ℃；
IR (KBr) ν_max 2972, 1775, 1689, 1609, 1456, 1194, 761 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.36 (4.5H, s), 1.42 (4.5H, s), 1.91-2.06 (2H, m), 3.21-3.40 (5H, m), 3.51-3.70 (6H, m), 6.79 (2H, d, J = 9.0 Hz), 7.46 (2H, d, J = 9.0 Hz);
MS (FAB) m/z: 374 [M+H⁺], 319, 301, 275, 260, 244, 219, 182, 93, 57;
Anal. Calcd for C₁₉H₂₆N₄O₄: C, 60.95; H, 7.00; N, 14.96. Found: C, 60.70; H, 6.82; N, 14.85。
Pale yellow powder
Mp 166-168 ° C;
IR (KBr) ν _max 2972, 1775, 1689, 1609, 1456, 1194, 761 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.36 (4.5H, s), 1.42 (4.5H, s), 1.91-2.06 (2H, m), 3.21-3.40 (5H, m), 3.51-3.70 (6H , m), 6.79 (2H, d, J = 9.0 Hz), 7.46 (2H, d, J = 9.0 Hz);
MS (FAB) m / z: 374 [M + H ⁺ ], 319, 301, 275, 260, 244, 219, 182, 93, 57;
Anal. Calcd for C ₁₉ H ₂₆ N ₄ O ₄ : C, 60.95; H, 7.00; N, 14.96. Found: C, 60.70; H, 6.82; N, 14.85.

（３４ｃ）３−[４−(１，４−ジアゼパン−１−イル)フェニル]−４−メチル−１，２，４−オキサジアゾール−５(４Ｈ)−オン
参考例３４（３４ｂ）で製造したｔｅｒｔ−ブチル４−[４−(４−メチル−５−オキソ−４，５−ジヒドロ−１，２，４−オキサジアゾール−３−イル)フェニル]−１，４−ジアゼパン−１−カルボキシラートを用いて参考例９（９ｂ）と同様に反応を行い、標記目的化合物を得た。
淡黄色粉末
Mp 130-132 ℃；
IR (KBr) ν_max 2935, 1778, 1610, 1524, 1455, 1196, 971, 758 cm^-1;
¹H NMR(CDCl₃, 500 MHz) δ 1.88-1.95 (2H, m), 2.85 (2H, t, J = 5.9 Hz), 3.05 (2H, t, J = 5.4 Hz), 3.34 (3H, s), 3.60 (2H, t, J = 5.4 Hz), 3.65 (2H, t, J = 5.4 Hz), 6.78 (2H, d, J = 9.3 Hz), 7.45 (2H, d, J = 9.3 Hz);
MS (EI) m/z: 274 [M⁺], 252, 232, 218, 204, 189, 174, 159, 145, 131, 102, 90, 69, 43;
Anal. Calcd for C₁₄H₁₈N₄O₂: C, 61.30; H, 6.61; N, 20.42. Found: C, 61.33; H, 6.67; N, 20.31。
(34c) 3- [4- (1,4-Diazepan-1-yl) phenyl] -4-methyl-1,2,4-oxadiazol-5 (4H) -one Prepared in Reference Example 34 (34b) Tert-butyl 4- [4- (4-methyl-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) phenyl] -1,4-diazepan-1-carboxy The reaction was carried out in the same manner as in Reference Example 9 (9b) using lath to obtain the title object compound.
Pale yellow powder
Mp 130-132 ° C;
IR (KBr) ν _max 2935, 1778, 1610, 1524, 1455, 1196, 971, 758 cm ^-1 ;
¹ H NMR (CDCl ₃ , 500 MHz) δ 1.88-1.95 (2H, m), 2.85 (2H, t, J = 5.9 Hz), 3.05 (2H, t, J = 5.4 Hz), 3.34 (3H, s) , 3.60 (2H, t, J = 5.4 Hz), 3.65 (2H, t, J = 5.4 Hz), 6.78 (2H, d, J = 9.3 Hz), 7.45 (2H, d, J = 9.3 Hz);
MS (EI) m / z: 274 [M ⁺ ], 252, 232, 218, 204, 189, 174, 159, 145, 131, 102, 90, 69, 43;
Anal. Calcd for C ₁₄ H ₁₈ N ₄ O ₂ : C, 61.30; H, 6.61; N, 20.42. Found: C, 61.33; H, 6.67; N, 20.31.

［参考例３５］１−[４−(１，２−ジメチル−１Ｈ−イミダゾール−４−イル)フェニル]−１，４−ジアゼパン
（３５ａ）Ｎ−[２−(４−ブロモフェニル)−２−オキソエチル]アセトアミド
２−アミノ−１−（４−ブロモフェニル）エタン−１−オン塩酸塩（４．５０ｇ，１８．０ｍｍｏｌ）のテトラヒドロフラン（１００ｍＬ）溶液を０℃に冷却し、トリエチルアミン（１０ｍＬ、７２．０ｍｍｏｌ）、塩化アセチル（１．５４ｍＬ、２１．７ｍｍｏｌ）を加え、室温で５時間撹拌した。反応液を濃縮し、水（１００ｍＬ）を加え、塩化メチレン（１００ｍＬ）で３回抽出した。有機層を合わせて、水（１００ｍＬ）および飽和塩化ナトリウム水溶液（１００ｍＬ）で洗浄し、無水硫酸ナトリウムで乾燥後，溶媒を減圧下留去した。得られた残渣をエーテルで粉末化し、３．９３ｇ（収率８５％）の標記目的化合物を得た。
[Reference Example 35] 1- [4- (1,2-dimethyl-1H-imidazol-4-yl) phenyl] -1,4-diazepane (35a) N- [2- (4-bromophenyl) -2- Oxoethyl] acetamido 2-amino-1- (4-bromophenyl) ethan-1-one Hydrochloride (4.50 g, 18.0 mmol) in tetrahydrofuran (100 mL) was cooled to 0 ° C. and triethylamine (10 mL, 72.72). 0 mmol) and acetyl chloride (1.54 mL, 21.7 mmol) were added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated, water (100 mL) was added, and the mixture was extracted 3 times with methylene chloride (100 mL). The organic layers were combined, washed with water (100 mL) and saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was triturated with ether to give 3.93 g (yield 85%) of the title object compound.

白色粉末
Mp 179-181 ℃;
IR (KBr) ν_max 3314, 1683, 1646, 1587, 1372, 1235, 1006, 821 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 2.10 (3H, s), 4.71 (2H, brs), 6.48 (1H, brs), 7.64 (2H, d, J = 8.6 Hz), 7.82 (2H, d, J = 8.6 Hz);
MS (EI) m/z: 255 [M⁺], 252, 227, 183, 155, 72, 43;
Anal. Calcd for C₁₀H₁₀BrNO₂: C, 46.90; H, 3.94; N, 5.47. Found: C, 46.86; H, 3.98; N, 5.42。
White powder
Mp 179-181 ° C;
IR (KBr) ν _max 3314, 1683, 1646, 1587, 1372, 1235, 1006, 821 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 2.10 (3H, s), 4.71 (2H, brs), 6.48 (1H, brs), 7.64 (2H, d, J = 8.6 Hz), 7.82 (2H, d, J = 8.6 Hz);
MS (EI) m / z: 255 [M ⁺ ], 252, 227, 183, 155, 72, 43;
Anal. Calcd for C ₁₀ H ₁₀ BrNO ₂ : C, 46.90; H, 3.94; N, 5.47. Found: C, 46.86; H, 3.98; N, 5.42.

（３５ｂ）４−(４−ブロモフェニル)−２−メチル−１Ｈ−イミダゾール
参考例３５（３５ａ）で製造したＮ−[２−(４−ブロモフェニル)−２−オキソエチル]アセトアミド（３．９０ｇ，１５．２ｍｍｏｌ）の酢酸（３０ｍＬ）溶液に、酢酸アンモニウム（１１．７０ｇ、１５２ｍｍｏｌ）を加え、１２０℃で９時間撹拌した。反応液に水（２００ｍＬ）を加え、炭酸カリウムで液性を塩基性にし、塩化メチレン／２−プロパノール（（４：１）、５０ｍＬ）で３回抽出した。有機層を合わせて、無水硫酸ナトリウムで乾燥後，溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル，１：５→１：１０）を用いて精製し、３．０３ｇ（収率８４％）の標記目的化合物を得た。
(35b) 4- (4-Bromophenyl) -2-methyl-1H-imidazole N- [2- (4-Bromophenyl) -2-oxoethyl] acetamide (3.90 g, prepared in Reference Example 35 (35a)) Ammonium acetate (11.70 g, 152 mmol) was added to a solution of 15.2 mmol) in acetic acid (30 mL), and the mixture was stirred at 120 ° C. for 9 hours. Water (200 mL) was added to the reaction solution, the solution was made basic with potassium carbonate, and extracted three times with methylene chloride / 2-propanol ((4: 1), 50 mL). The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified using silica gel column chromatography (hexane / ethyl acetate, 1: 5 → 1: 10) to obtain 3.03 g (yield 84%) of the title compound.

黄色粉末
Mp 201-203 ℃
IR (KBr) ν_max 2765, 1808, 1610, 1519, 1416, 1288, 1159, 1025, 804 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 2.46 (3H, s), 7.17 (1H, s), 7.45 (2H, d, J = 8.6 Hz), 7.55 (2H, brd);
MS (EI) m/z: 236 [M⁺], 208, 197, 195, 183, 157, 130, 116, 89, 79;
Anal. Calcd for C₁₀H₉BrN₂: C, 50.66; H, 3.83; N, 11.82. Found: C, 50.47; H, 3.97; N, 11.65。
Yellow powder
Mp 201-203 ℃
IR (KBr) ν _max 2765, 1808, 1610, 1519, 1416, 1288, 1159, 1025, 804 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 2.46 (3H, s), 7.17 (1H, s), 7.45 (2H, d, J = 8.6 Hz), 7.55 (2H, brd);
MS (EI) m / z: 236 [M ⁺ ], 208, 197, 195, 183, 157, 130, 116, 89, 79;
Anal. Calcd for C ₁₀ H ₉ BrN ₂ : C, 50.66; H, 3.83; N, 11.82. Found: C, 50.47; H, 3.97; N, 11.65.

（３５ｃ）４−(４−ブロモフェニル)−１，２−ジメチル−１Ｈ−イミダゾール
参考例３５（３５ｂ）で製造した４−(４−ブロモフェニル)−２−メチル−１Ｈ−イミダゾール（３．００，１２．７ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（６０ｍＬ）溶液を０℃に冷却し、水素化ナトリウム（８３０ｍｇ、１９．０ｍｍｏｌ）、ヨウ化メチル（０．９５ｍＬ、１５．４ｍｍｏｌ）を順次加え、室温で５時間撹拌した。反応液に水（１５０ｍＬ）を加え、酢酸エチル（１５０ｍＬ）で３回抽出した。有機層を合わせて、水（１５０ｍＬ）および飽和塩化ナトリウム水溶液（１５０ｍＬ）で洗浄し、無水硫酸ナトリウムで乾燥後，溶媒を減圧下留去した。得られた残渣をヘキサン／酢酸エチル（１：１）で粉末化し、２．２７ｇ（収率７１％）標記目的化合物を得た。
(35c) 4- (4-Bromophenyl) -1,2-dimethyl-1H-imidazole 4- (4-bromophenyl) -2-methyl-1H-imidazole prepared in Reference Example 35 (35b) (3.00) , 12.7 mmol) in N, N-dimethylformamide (60 mL) was cooled to 0 ° C., and sodium hydride (830 mg, 19.0 mmol) and methyl iodide (0.95 mL, 15.4 mmol) were sequentially added. Stir at room temperature for 5 hours. Water (150 mL) was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate (150 mL). The organic layers were combined, washed with water (150 mL) and saturated aqueous sodium chloride solution (150 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was pulverized with hexane / ethyl acetate (1: 1) to obtain 2.27 g (yield 71%) of the title object compound.

白色粉末
Mp 156-157 ℃;
IR (KBr) ν_max 2910, 1554, 1408, 1213, 944, 758 cm^-1;
¹H NMR(CDCl₃, 500 MHz) δ 2.42 (3H, s), 2.36 (3H, s), 7.08 (1H, s), 7.46 (2H, d, J = 8.6 Hz), 7.59 (2H, d, J = 8.6 Hz);
MS (EI) m/z: 250 [M⁺], 210, 194, 171, 130, 115, 102, 86;
Anal. Calcd for C₁₁H₁₁BrN₂: C, 52.61; H, 4.42; N, 11.16. Found: C, 52.47; H, 4.34; N, 11.12。
White powder
Mp 156-157 ° C;
IR (KBr) ν _max 2910, 1554, 1408, 1213, 944, 758 cm ^-1 ;
¹ H NMR (CDCl ₃ , 500 MHz) δ 2.42 (3H, s), 2.36 (3H, s), 7.08 (1H, s), 7.46 (2H, d, J = 8.6 Hz), 7.59 (2H, d, J = 8.6 Hz);
MS (EI) m / z: 250 [M ⁺ ], 210, 194, 171, 130, 115, 102, 86;
Anal. Calcd for C ₁₁ H ₁₁ BrN ₂ : C, 52.61; H, 4.42; N, 11.16. Found: C, 52.47; H, 4.34; N, 11.12.

（３５ｄ）ベンジル４−[４−(１，２−ジメチル−１Ｈ−イミダゾール−４−イル)フェニル]−１，４−ジアゼパン−１−カルボキシラート
参考例３５（３５ｃ）で製造した４−(４−ブロモフェニル)−１，２−ジメチル−１Ｈ−イミダゾールを用いて参考例１（１ａ）と同様に反応を行い、標記目的化合物を得た。
黄色液体;
IR (film) ν_max 2944, 1696, 1422, 1226, 1119, 927, 753 cm^-1;
¹H NMR(CDCl₃, 500 MHz) δ 1.93-2.06 (2H, m), 2.40 (3H, s), 3.29 (1H, t, J = 5.9 Hz), 3.37 (1H, t, J = 5.9 Hz), 3.51-3.69 (9H, m), 5.08 (1H, s), 5.12 (1H, s), 6.64-6.70 (2H, m), 6.91 (1H, s), 7.26-7.36 (5H, m), 7.55 (2H, d, J = 8.6 Hz);
MS (FAB) m/z: 405 [M+H⁺], 326, 273, 242, 214, 165, 91, 65。
(35d) Benzyl 4- [4- (1,2-dimethyl-1H-imidazol-4-yl) phenyl] -1,4-diazepane-1-carboxylate 4- (4 prepared in Reference Example 35 (35c) -Bromophenyl) -1,2-dimethyl-1H-imidazole was used in the same manner as in Reference Example 1 (1a) to obtain the title compound.
Yellow liquid;
IR (film) ν _max 2944, 1696, 1422, 1226, 1119, 927, 753 cm ^-1 ;
¹ H NMR (CDCl ₃ , 500 MHz) δ 1.93-2.06 (2H, m), 2.40 (3H, s), 3.29 (1H, t, J = 5.9 Hz), 3.37 (1H, t, J = 5.9 Hz) , 3.51-3.69 (9H, m), 5.08 (1H, s), 5.12 (1H, s), 6.64-6.70 (2H, m), 6.91 (1H, s), 7.26-7.36 (5H, m), 7.55 (2H, d, J = 8.6 Hz);
MS (FAB) m / z: 405 [M + H ⁺ ], 326, 273, 242, 214, 165, 91, 65.

（３５ｅ）１−[４−(１，２−ジメチル−１Ｈ−イミダゾール−４−イル)フェニル]−１，４−ジアゼパン
参考例３５（３５ｄ）で製造したベンジル４−[４−(１，２−ジメチル−１Ｈ−イミダゾール−４−イル)フェニル]−１，４−ジアゼパン−１−カルボキシラートを用いて参考例１（１ｂ）と同様に反応を行い、標記目的化合物を得た。
白色粉末
Mp 159-162 ℃;
IR (film) ν_max 3339, 2925, 1616, 1508, 1405, 1227, 1014, 818, 747 cm^-1;
¹H NMR(CDCl₃, 500 MHz) δ 1.86-1.94 (2H, m), 2.41 (3H, s), 2.83 (2H, t, J = 5.9 Hz), 3.03 (2H, t, J = 5.4 Hz), 3.53-3.63 (7H, m), 6.70 (1H, d, J = 8.8 Hz), 6.92 (1H, s), 7.57 (1H, d, J = 8.8 Hz);
MS (EI) m/z: 270 [M⁺], 240, 214, 200, 185, 171, 143, 130, 108, 42。
(35e) 1- [4- (1,2-Dimethyl-1H-imidazol-4-yl) phenyl] -1,4-diazepane benzyl 4- [4- (1,2) prepared in Reference Example 35 (35d) -Dimethyl-1H-imidazol-4-yl) phenyl] -1,4-diazepan-1-carboxylate was used in the same manner as in Reference Example 1 (1b) to give the title object compound.
White powder
Mp 159-162 ° C;
IR (film) ν _max 3339, 2925, 1616, 1508, 1405, 1227, 1014, 818, 747 cm ^-1 ;
¹ H NMR (CDCl ₃ , 500 MHz) δ 1.86-1.94 (2H, m), 2.41 (3H, s), 2.83 (2H, t, J = 5.9 Hz), 3.03 (2H, t, J = 5.4 Hz) , 3.53-3.63 (7H, m), 6.70 (1H, d, J = 8.8 Hz), 6.92 (1H, s), 7.57 (1H, d, J = 8.8 Hz);
MS (EI) m / z: 270 [M ⁺ ], 240, 214, 200, 185, 171, 143, 130, 108, 42.

［参考例３６］１−メチル−３−[２−(ピペリジン−３−イルメトキシ)エチル]イミダゾリジン−２，４−ジオン
（３６ａ）ベンジル３−[（２−ｔｅｒｔ−ブトキシ−２−オキソエトキシ）メチル]ピペリジン−１−カルボキシラート
ベンジル３−（ヒドロキシメチル）ピペリジン−１−カルボキシラート（Ａｒｃｈ．Ｐｈａｒｍ．（ＷｅｉｎｈｅｉｍＧｅｒ．），３２３,１９９０，９−１２）（１１．９７ｇ，４８．０１ｍｍｏｌ）、ブロモ酢酸ｔｅｒｔ−ブチル（１６．３ｍＬ，１１０ｍｍｏｌ）及びテトラ−ｎ−ブチルアンモニウム硫酸水素塩（３．８ｇ，１１ｍｍｏｌ）のベンゼン（１８ｍＬ）懸濁液に、氷冷下、５０％水酸化ナトリウム水溶液（１８ｍＬ）を数回に分けて加えた。０℃で１５分撹拌し、更に室温で終夜撹拌したのち、反応混合物に酢酸エチル（３０ｍＬ）を加え分液した。有機層を飽和食塩水（３ｘ６０ｍＬ）で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下に溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（へキサン：酢酸エチル＝５：１〜４：１）により精製し、標記目的化合物（１６．８８ｇ，収率９６％）を得た。
[Reference Example 36] 1-methyl-3- [2- (piperidin-3-ylmethoxy) ethyl] imidazolidine-2,4-dione (36a) benzyl 3-[(2-tert-butoxy-2-oxoethoxy) Methyl] piperidine-1-carboxylate benzyl 3- (hydroxymethyl) piperidine-1-carboxylate (Arch. Pharm. (Weinheim Ger.), 323, 1990, 9-12) (11.97 g, 48.01 mmol), To a suspension of tert-butyl bromoacetate (16.3 mL, 110 mmol) and tetra-n-butylammonium hydrogensulfate (3.8 g, 11 mmol) in benzene (18 mL) under ice-cooling, a 50% aqueous sodium hydroxide solution ( 18 mL) was added in several portions. After stirring at 0 ° C. for 15 minutes and further overnight at room temperature, ethyl acetate (30 mL) was added to the reaction mixture to separate the layers. The organic layer was washed with saturated brine (3 × 60 mL), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1-4: 1) to give the title object compound (16.88 g, yield 96%).

無色液体
IR (film) ν_max3033, 2935, 2858, 1747, 1701, 1431, 1368, 1260, 1232, 1138, 979, 850, 734, 699 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.28 (1H, br s), 1.47 (10H, s), 1.67 (1H, br s), 1.84 (2H, br s), 2.76 (1H, br s), 2.88 (1H, t, J = 10.3 Hz), 3.30-3.44 (2H, br m), 3.92 (2H, s), 3.98 (1H, br s), 4.10 (1H, br s), 5.13 (2H, s), 7.27-7.39 (5H, m);
HRMS m/z: found [M+H]⁺ 364.2111, calcd for C₂₀H₃₀NO₅ [M+H]⁺ 364.2124。
Colorless liquid
IR (film) ν _max 3033, 2935, 2858, 1747, 1701, 1431, 1368, 1260, 1232, 1138, 979, 850, 734, 699 cm ^-1 ;
^{_{1 H NMR (CDCl 3, 400}} MHz) δ 1.28 (1H, br s), 1.47 (10H, s), 1.67 (1H, br s), 1.84 (2H, br s), 2.76 (1H, br s), 2.88 (1H, t, J = 10.3 Hz), 3.30-3.44 (2H, br m), 3.92 (2H, s), 3.98 (1H, br s), 4.10 (1H, br s), 5.13 (2H, s ), 7.27-7.39 (5H, m);
HRMS m / z: found [M + H] ⁺ 364.2111, calcd for C ₂₀ H ₃₀ NO ₅ [M + H] ⁺ 364.2124.

（３６ｂ）（{１−[（ベンジルオキシ）カルボニル]ピペリジン−３−イル}メトキシ）酢酸
参考例３６（３６ａ）で製造したベンジル３−[（２−ｔｅｒｔ−ブトキシ−２−オキソエトキシ）メチル]ピペリジン−１−カルボキシラート（５．０４ｇ，１３．９ｍｍｏｌ）の塩化メチレン溶液（３０ｍＬ）を氷冷し、トリフルオロ酢酸（１０ｍＬ）を加えた。反応混合物を０℃で１５分撹拌し、更に室温で終夜撹拌したのち減圧下に溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（へキサン：酢酸エチル＝６：４〜１：５）により精製し、標記目的化合物（３．８６ｇ，収率９１％）を得た。
(36b) ({1-[(Benzyloxy) carbonyl] piperidin-3-yl} methoxy) acetic acid Benzyl 3-[(2-tert-butoxy-2-oxoethoxy) methyl] prepared in Reference Example 36 (36a) Piperidine-1-carboxylate (5.04 g, 13.9 mmol) in methylene chloride (30 mL) was ice-cooled, and trifluoroacetic acid (10 mL) was added. The reaction mixture was stirred at 0 ° C. for 15 minutes, further stirred overnight at room temperature, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 4 to 1: 5) to give the title object compound (3.86 g, yield 91%).

無色液体
IR (film) ν_max3065, 2937, 1698, 1441, 1263, 1139, 977, 699 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.24-1.40 (1H, m), 1.41-1.56 (1H, m), 1.57-1.72 (1H, m), 1.73-2.00 (2H, m), 2.78-3.30 (2H, m), 3.31-3.48 (2H, m), 3.57-4.15 (4H, m), 5.13 (2H, br s), 7.27-7.40 (5H, m);
MS (FAB) m/z: 308 [M+H]⁺, 264, 246, 176。
Colorless liquid
IR (film) ν _max 3065, 2937, 1698, 1441, 1263, 1139, 977, 699 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.24-1.40 (1H, m), 1.41-1.56 (1H, m), 1.57-1.72 (1H, m), 1.73-2.00 (2H, m), 2.78-3.30 (2H, m), 3.31-3.48 (2H, m), 3.57-4.15 (4H, m), 5.13 (2H, br s), 7.27-7.40 (5H, m);
MS (FAB) m / z: 308 [M + H] ⁺ , 264, 246, 176.

（３６ｃ）ベンジル３−[(２−ヒドロキシエトキシ)メチル]ピペリジン−１−カルボキシラート
窒素雰囲気下、水素化ホウ素ナトリウム（０．７８５ｇ，２０．８ｍｍｏｌ）のテトラヒドロフラン（２０ｍＬ）懸濁液に、三フッ化ホウ素エーテル錯体（３．５ｍＬ，２７．７ｍｍｏｌ）を氷冷下にゆっくり滴下し、３０分撹拌した。反応混合物に、参考例３６（３６ｂ）で製造した（{１−[（ベンジルオキシ）カルボニル]ピペリジン−３−イル}メトキシ）酢酸（５．３１７ｇ，１７．３ｍｍｏｌ）のテトラヒドロフラン（２２ｍＬ）溶液を滴下し、０℃で３時間撹拌したのち、メタノール（５ｍＬ）を加えた。不溶物をセライトにより除き、酢酸エチル（１００ｍＬ）で洗浄した後、減圧下に溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（へキサン：酢酸エチル＝６：４〜１００％酢酸エチル）を用いて精製し、標記目的化合物（４．５４６ｇ，収率９０％）を得た。
(36c) Benzyl 3-[(2-hydroxyethoxy) methyl] piperidine-1-carboxylate To a suspension of sodium borohydride (0.785 g, 20.8 mmol) in tetrahydrofuran (20 mL) under a nitrogen atmosphere, Boron ether complex (3.5 mL, 27.7 mmol) was slowly added dropwise under ice cooling and stirred for 30 minutes. To the reaction mixture, a solution of ({1-[(benzyloxy) carbonyl] piperidin-3-yl} methoxy) acetic acid (5.317 g, 17.3 mmol) prepared in Reference Example 36 (36b) in tetrahydrofuran (22 mL) was added dropwise. After stirring at 0 ° C. for 3 hours, methanol (5 mL) was added. The insoluble material was removed with celite and washed with ethyl acetate (100 mL). The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 4 to 100% ethyl acetate). To obtain the title compound (4.546 g, yield 90%).

無色液体;
IR (film) ν_max3446, 2933, 1698, 1435, 1261, 1154, 1072, 699 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.20-1.34 (1H, m), 1.40-1.55 (1H, m), 1.57-1.72 (1H, m), 1.74-1.94 (2H, m), 2.75-3.15 (2H, m), 3.29-3.37 (2H, m), 3.42-3.60 (2H, m), 3.64-4.03 (4H, m), 5.12 (2H, brs), 7.25-7.37 (5H, m);
MS (FAB) m/z: 294 [M+H]⁺, 250, 246, 226, 165。
Colorless liquid;
IR (film) ν _max 3446, 2933, 1698, 1435, 1261, 1154, 1072, 699 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.20-1.34 (1H, m), 1.40-1.55 (1H, m), 1.57-1.72 (1H, m), 1.74-1.94 (2H, m), 2.75-3.15 (2H, m), 3.29-3.37 (2H, m), 3.42-3.60 (2H, m), 3.64-4.03 (4H, m), 5.12 (2H, brs), 7.25-7.37 (5H, m);
MS (FAB) m / z: 294 [M + H] ⁺ , 250, 246, 226, 165.

（３６ｄ）１−メチル−３−[２−(ピペリジン−３−イルメトキシ)エチル]イミダゾリジン−２，４−ジオン
参考例３６（３６ｃ）で製造したベンジル３−[(２−ヒドロキシエトキシ)メチル]ピペリジン−１−カルボキシラート（２．０２ｇ，６．９０ｍｍｏｌ）のテトラヒドロフラン（３５ｍＬ）溶液を０℃に冷却し、１−メチルヒダントイン（９６０ｍｇ、８．４５ｍｍｏｌ）、トリフェニルホスフィン（２．２１ｇ、８．４５ｍｍｏｌ）、アゾジカルボン酸ジエチル（３．８５ｍＬ、８．４５ｍｍｏｌ）を順次加え、室温で２日間撹拌した。反応液を濃縮し、得られた残渣を酢酸（３ｍＬ）に溶解し、２５％臭化水素−酢酸溶液（３ｍＬ）を加え、室温で２時間撹拌した。反応液に水（５０ｍＬ）を加え、塩化メチレン（５０ｍＬ）で洗浄した。炭酸カリウムで液性を塩基性にし、塩化メチレン／２−プロパノール（（４：１）、５０ｍＬ）で３回抽出し、無水硫酸ナトリウムで乾燥後、溶媒を減圧下留去し、１．７６ｇ（定量的）の標記目的化合物を得た。
(36d) 1-Methyl-3- [2- (piperidin-3-ylmethoxy) ethyl] imidazolidine-2,4-dione Benzyl 3-[(2-hydroxyethoxy) methyl] prepared in Reference Example 36 (36c) A solution of piperidine-1-carboxylate (2.02 g, 6.90 mmol) in tetrahydrofuran (35 mL) was cooled to 0 ° C., 1-methylhydantoin (960 mg, 8.45 mmol), triphenylphosphine (2.21 g, 8. 45 mmol) and diethyl azodicarboxylate (3.85 mL, 8.45 mmol) were sequentially added, and the mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated, and the resulting residue was dissolved in acetic acid (3 mL). A 25% hydrogen bromide-acetic acid solution (3 mL) was added, and the mixture was stirred at room temperature for 2 hr. Water (50 mL) was added to the reaction mixture, and the mixture was washed with methylene chloride (50 mL). The solution was made basic with potassium carbonate, extracted three times with methylene chloride / 2-propanol ((4: 1), 50 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 1.76 g ( The title compound was obtained quantitatively.

淡黄色液体;
¹H NMR(CDCl₃, 500 MHz) δ 1.09-1.21 (1H, m), 1.45-1.56 (1H, m), 1.64-1.82 (3H, m), 2.40 (1H, dd, J = 9.8, 12.4 Hz), 2.62 (1H, dt, J = 2.9, 11.7 Hz) 3.00 (3H, s), 3.00-3.05 (1H, m), 3.07-3.13 (1H, m), 3.55-3.63 (2H, m), 3.70 (2H, t, J = 5.9 Hz), 3.88 (2H, s);
MS (EI) m/z: 226 [M⁺]。
A pale yellow liquid;
¹ H NMR (CDCl ₃ , 500 MHz) δ 1.09-1.21 (1H, m), 1.45-1.56 (1H, m), 1.64-1.82 (3H, m), 2.40 (1H, dd, J = 9.8, 12.4 Hz ), 2.62 (1H, dt, J = 2.9, 11.7 Hz) 3.00 (3H, s), 3.00-3.05 (1H, m), 3.07-3.13 (1H, m), 3.55-3.63 (2H, m), 3.70 (2H, t, J = 5.9 Hz), 3.88 (2H, s);
MS (EI) m / z: 226 [M ⁺ ].

［参考例３７］１−メチル−３−［２−（ピペリジン−３−イルメトキシ）エチル］イミダゾリジン−２−オン
（３７ａ）ベンジル３−({２−[(メチルスルホニル)オキシ]エトキシ}メチル)ピペリジン−１−カルボキシラート
窒素雰囲気下、トリエチルアミン（１．７０ｍＬ，１２．１ｍｍｏｌ）、メタンスルホニルクロリド（０．８７ｍＬ，１１．２ｍｍｏｌ）と参考例３６（３６ｃ）で製造したベンジル３−[（２−ヒドロキシエトキシ）メチル]ピペリジン−１−カルボキシラート（２．７４ｇ，９．３４ｍｍｏｌ）の塩化メチレン（５０ｍＬ）溶液を終夜撹拌した。反応液に飽和食塩水（１５ｍＬ）を加えたのち抽出操作を行った。抽出液を無水硫酸ナトリウムで乾燥し、ろ過後、溶媒を減圧下に留去して得られた粗生成物をシリカゲルカラムクロマトグラフィー（へキサン：酢酸エチル＝４：１〜２：１）により精製し、標記目的化合物（３．２５ｇ，収率９４％）を得た。
[Reference Example 37] 1-methyl-3- [2- (piperidin-3-ylmethoxy) ethyl] imidazolidin-2-one (37a) benzyl 3-({2-[(methylsulfonyl) oxy] ethoxy} methyl) Piperidine-1-carboxylate Benzyl 3-[(2-) prepared with triethylamine (1.70 mL, 12.1 mmol), methanesulfonyl chloride (0.87 mL, 11.2 mmol) and Reference Example 36 (36c) under nitrogen atmosphere. A solution of (hydroxyethoxy) methyl] piperidine-1-carboxylate (2.74 g, 9.34 mmol) in methylene chloride (50 mL) was stirred overnight. A saturated saline solution (15 mL) was added to the reaction solution, followed by extraction. The extract was dried over anhydrous sodium sulfate, filtered, and then the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 to 2: 1). To give the title object compound (3.25 g, yield 94%).

淡黄色液体;
IR (film) ν_max2937, 1697, 1433, 1354, 1236, 1175, 1019, 922, 807 cm^-1;
¹H NMR(CDCl₃, 500 MHz) δ 1.16-1.28 (1H, m), 1.41-1.55 (1H, m), 1.62-1.73 (1H, m), 1.74-1.87 (2H, m), 2.62-2.82 (1H, m), 2.83-3.13 (4H, m), 3.27-3.41 (2H, m), 3.57-3.72 (2H, m), 3.93-4.17 (2H, m), 4.25-4.40 (2H, m), 5.07-5.18 (2H, m), 7.28-7.41 (5H, m);
MS (FAB) m/z: 372 [M+H]⁺, 330, 264, 236, 226, 204, 165, 91, 63。

（３７ｂ）ベンジル３−[(２−アジドエトキシ)メチル]ピペリジン−１−カルボキシラート
アジ化ナトリウム（７２３ｍｇ，１１．１２ｍｍｏｌ）と参考例３７（３７ａ）で製造したベンジル３−({２−[(メチルスルホニル)オキシ]エトキシ}メチル)ピペリジン−１−カルボキシラート（３．１７８ｇ，８．５６ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（１０ｍＬ）溶液を８０℃で６時間加熱撹拌した。反応混合物に酢酸エチル（５０ｍＬ）と水（２０ｍＬ）を加えて分液した。有機層を飽和食塩水（２ｘ１５ｍＬ）で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過後、減圧下に溶媒を留去して得られた粗生成物をシリカゲルカラムクロマトグラフィー（へキサン：酢酸エチル＝７：３）により精製し、標記目的化合物（２．７２１ｇ，収率１００％）を得た。
A pale yellow liquid;
IR (film) ν _max 2937, 1697, 1433, 1354, 1236, 1175, 1019, 922, 807 cm ^-1 ;
¹ H NMR (CDCl ₃ , 500 MHz) δ 1.16-1.28 (1H, m), 1.41-1.55 (1H, m), 1.62-1.73 (1H, m), 1.74-1.87 (2H, m), 2.62-2.82 (1H, m), 2.83-3.13 (4H, m), 3.27-3.41 (2H, m), 3.57-3.72 (2H, m), 3.93-4.17 (2H, m), 4.25-4.40 (2H, m) , 5.07-5.18 (2H, m), 7.28-7.41 (5H, m);
MS (FAB) m / z: 372 [M + H] ⁺ , 330, 264, 236, 226, 204, 165, 91, 63.

(37b) Benzyl 3-[(2-azidoethoxy) methyl] piperidine-1-carboxylate Benzyl 3-({2-[() prepared with sodium azide (723 mg, 11.12 mmol) and Reference Example 37 (37a) A solution of methylsulfonyl) oxy] ethoxy} methyl) piperidine-1-carboxylate (3.178 g, 8.56 mmol) in N, N-dimethylformamide (10 mL) was heated and stirred at 80 ° C. for 6 hours. Ethyl acetate (50 mL) and water (20 mL) were added to the reaction mixture for liquid separation. The organic layer was washed with saturated brine (2 × 15 mL), dried over anhydrous sodium sulfate, filtered, and then the solvent was distilled off under reduced pressure. The resulting crude product was subjected to silica gel column chromatography (hexane: ethyl acetate = 7: 3) to give the title object compound (2.721 g, yield 100%).

淡黄色液体;
IR (film) ν_max2934, 2103, 1699, 1432, 1235, 1153, 699 cm^-1;
¹H NMR(CDCl₃, 500 MHz) δ 1.22-1.34 (1H, m), 1.40-1.54 (1H, m), 1.62-1.72 (1H, m), 1.74-1.89 (2H, m), 2.64-2.95 (2H, m), 3.26-3.41 (4H, m), 3.53-3.63 (2H, m), 3.94-4.15 (2H, m), 5.07-5.19 (2H, m), 7.28-7.39 (5H, m);
MS (FAB) m/z: 319 [M+H]⁺, 275, 242, 211, 183, 91, 63。
A pale yellow liquid;
IR (film) ν _max 2934, 2103, 1699, 1432, 1235, 1153, 699 cm ^-1 ;
¹ H NMR (CDCl ₃ , 500 MHz) δ 1.22-1.34 (1H, m), 1.40-1.54 (1H, m), 1.62-1.72 (1H, m), 1.74-1.89 (2H, m), 2.64-2.95 (2H, m), 3.26-3.41 (4H, m), 3.53-3.63 (2H, m), 3.94-4.15 (2H, m), 5.07-5.19 (2H, m), 7.28-7.39 (5H, m) ;
MS (FAB) m / z: 319 [M + H] ⁺ , 275, 242, 211, 183, 91, 63.

（３７ｃ）ベンジル３−[(２−アミノエトキシ)メチル]ピペリジン−１−カルボキシラート
参考例３７（３７ｂ）で製造したベンジル３−[(２−アジドエトキシ)メチル]ピペリジン−１−カルボキシラート（２．５０ｇ，７．８５ｍｍｏｌ）のテトラヒドロフラン（６０ｍＬ）溶液にトリフェニルホスフィン（２．４７ｇ、９．４２ｍｍｏｌ）を加え、室温で２１時間撹拌後、水（０．３ｍＬ、１６．７ｍｍｏｌ）を加え、室温で６時間撹拌した。反応液を濃縮し、水（２００ｍＬ）、１Ｍ塩化水素水溶液（２０ｍＬ）を加え、塩化メチレンで洗浄した。続いて、炭酸カリウムを加えて液性を塩基性とし、塩化メチレン／２−プロパノール（（４：１）、２００ｍＬ）で３回抽出した。有機層を合わせて、無水硫酸ナトリウムで乾燥後、溶媒を減圧下留去し、２．２０ｇ（収率９６％）の標記目的化合物を得た。
(37c) Benzyl 3-[(2-aminoethoxy) methyl] piperidine-1-carboxylate benzyl 3-[(2-azidoethoxy) methyl] piperidine-1-carboxylate prepared in Reference Example 37 (37b) (2 Triphenylphosphine (2.47 g, 9.42 mmol) was added to a tetrahydrofuran (60 mL) solution of .50 g, 7.85 mmol), and the mixture was stirred at room temperature for 21 hours, and then water (0.3 mL, 16.7 mmol) was added. For 6 hours. The reaction mixture was concentrated, water (200 mL), 1M aqueous hydrogen chloride solution (20 mL) were added, and the mixture was washed with methylene chloride. Subsequently, potassium carbonate was added to make the liquid basic, and extracted three times with methylene chloride / 2-propanol ((4: 1), 200 mL). The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 2.20 g (yield 96%) of the title compound.

淡黄色液体;
IR (film) ν_max2933, 1698, 1432, 1260, 1153, 699 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.16-1.32 (1H, m), 1.39-1.56 (1H, m), 1.59-1.72 (1H, m), 1.72-1.90 (2H, m), 2.61-2.96 (4H, m), 3.19-3.48 (4H, m), 3.87-4.19 (2H, m), 5.13 (2H, brs), 7.26-7.41 (5H, m);
MS (FAB) m/z: 293 [M+H⁺], 249, 230, 185, 65。
A pale yellow liquid;
IR (film) ν _max 2933, 1698, 1432, 1260, 1153, 699 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.16-1.32 (1H, m), 1.39-1.56 (1H, m), 1.59-1.72 (1H, m), 1.72-1.90 (2H, m), 2.61-2.96 (4H, m), 3.19-3.48 (4H, m), 3.87-4.19 (2H, m), 5.13 (2H, brs), 7.26-7.41 (5H, m);
MS (FAB) m / z: 293 [M + H ⁺ ], 249, 230, 185, 65.

（３７ｄ）ベンジル３−{[２−({[(２−ヒドロキシエチル)(メチル)アミノ]カルボニル}アミノ)エトキシ]メチル}ピペリジン−１−カルボキシラート
参考例３７（３７ｃ）で製造したベンジル３−[(２−アミノエトキシ)メチル]ピペリジン−１−カルボキシラート（２．０５ｇ，７．０２ｍｍｏｌ）のテトラヒドロフラン（７０ｍＬ）溶液に、１，１−カルボジイミダゾール（１．３７ｇ、８．４５ｍｍｏｌ）を加え、室温で２０分間撹拌した後、Ｎ−エタノールアミン（２．８ｍＬ、３５ｍｍｏｌ）を加え、２日間撹拌した。反応液を濃縮し、０．２Ｍ塩化水素水溶液（２５０ｍＬ）を加え、塩化メチレンで３回抽出した。有機層を合わせて、無水硫酸ナトリウムで乾燥後，溶媒を減圧下留去し、２．７６ｇ（定量的）の標記目的化合物を得た。
(37d) Benzyl 3-{[2-({[(2-hydroxyethyl) (methyl) amino] carbonyl} amino) ethoxy] methyl} piperidine-1-carboxylate Benzyl 3- prepared in Reference Example 37 (37c) To a solution of [(2-aminoethoxy) methyl] piperidine-1-carboxylate (2.05 g, 7.02 mmol) in tetrahydrofuran (70 mL) was added 1,1-carbodiimidazole (1.37 g, 8.45 mmol). After stirring at room temperature for 20 minutes, N-ethanolamine (2.8 mL, 35 mmol) was added and stirred for 2 days. The reaction mixture was concentrated, 0.2 M aqueous hydrogen chloride solution (250 mL) was added, and the mixture was extracted 3 times with methylene chloride. The organic layers were combined and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 2.76 g (quantitative) of the title compound.

淡黄色液体;
IR (film) ν_max3368, 2933, 1697, 1632, 1538, 1435, 1261, 1123, 764 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.08-1.25 (1H, m), 1.40-1.55 (1H, m), 1.63-1.77 (1H, m), 1.78-1.91 (2H, m), 2.74 (1H, dd, J = 9.4, 13.3 Hz), 2.80-3.03 (4H, m), 3.15-3.60 (8H, m), 3.70-3.80 (2H, m), 3.82-3.92 (1H, m), 4.01-4.12 (1H, m), 5.10 (2H, brs), 7.26-7.37 (5H, m);
MS (FAB) m/z: 394 [M+H]⁺, 376, 350, 275, 242, 230, 185, 91, 63。
A pale yellow liquid;
IR (film) ν _max 3368, 2933, 1697, 1632, 1538, 1435, 1261, 1123, 764 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.08-1.25 (1H, m), 1.40-1.55 (1H, m), 1.63-1.77 (1H, m), 1.78-1.91 (2H, m), 2.74 (1H , dd, J = 9.4, 13.3 Hz), 2.80-3.03 (4H, m), 3.15-3.60 (8H, m), 3.70-3.80 (2H, m), 3.82-3.92 (1H, m), 4.01-4.12 (1H, m), 5.10 (2H, brs), 7.26-7.37 (5H, m);
MS (FAB) m / z: 394 [M + H] ⁺ , 376, 350, 275, 242, 230, 185, 91, 63.

（３７ｅ）ベンジル３−{[２−(３−メチル−２−オキソイミダゾリジン−１−イル)エトキシ]メチル}ピペリジン−１−カルボキシラート
参考例３７（３７ｄ）で製造したベンジル３−{[２−({[(２−ヒドロキシエチル)(メチル)アミノ]カルボニル}アミノ)エトキシ]メチル}ピペリジン−１−カルボキシラート（２．３６ｇ，６．００ｍｍｏｌ）のテトラヒドロフラン（７５ｍＬ）溶液を０℃に冷却し、カリウムｔｅｒｔ−ブトキシド（１．６２ｇ、１４．４ｍｍｏｌ）を加え、ｐ−トルエンスルホニルクロリド（１．３８ｇ、７．２６ｍｍｏｌ）のテトラヒドロフラン（２５ｍＬ）溶液を滴下し、０℃で２時間撹拌した。反応液に水（２００ｍＬ）を加え、塩化メチレンで３回抽出した。有機層を合わせて、無水硫酸ナトリウムで乾燥後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／メタノール，１：０→１０：１）を用いて精製し、２．１２ｇ（収率９４％）標記目的化合物を得た。
(37e) benzyl 3-{[2- (3-methyl-2-oxoimidazolidin-1-yl) ethoxy] methyl} piperidine-1-carboxylate benzyl 3-{[2 prepared in Reference Example 37 (37d) -A solution of ({[(2-hydroxyethyl) (methyl) amino] carbonyl} amino) ethoxy] methyl} piperidine-1-carboxylate (2.36 g, 6.00 mmol) in tetrahydrofuran (75 mL) was cooled to 0 ° C. , Potassium tert-butoxide (1.62 g, 14.4 mmol) was added, and a tetrahydrofuran (25 mL) solution of p-toluenesulfonyl chloride (1.38 g, 7.26 mmol) was added dropwise, followed by stirring at 0 ° C. for 2 hours. Water (200 mL) was added to the reaction mixture, and the mixture was extracted 3 times with methylene chloride. The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified using silica gel column chromatography (ethyl acetate / methanol, 1: 0 → 10: 1) to obtain 2.12 g (yield 94%) of the title object compound.

無色液体;
IR (film) ν_max2858, 1754, 1698, 1441, 1260, 1152, 762 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.13-1.27 (1H, m), 1.40-1.53 (1H, m), 1.60-1.71 (1H, m), 1.72-1.85 (2H, m), 2.53-2.72 (1H, m), 2.76 (3H, s), 2.78-2.90 (1H, m), 3.09-3.57 (10H, m), 3.93-4.19 (2H, m), 5.11 (2H, s), 7.26-7.37 (5H, m);
MS (FAB) m/z: 376 [M+H⁺], 332, 268, 240, 186, 127, 91, 63。
Colorless liquid;
IR (film) ν _max 2858, 1754, 1698, 1441, 1260, 1152, 762 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.13-1.27 (1H, m), 1.40-1.53 (1H, m), 1.60-1.71 (1H, m), 1.72-1.85 (2H, m), 2.53-2.72 (1H, m), 2.76 (3H, s), 2.78-2.90 (1H, m), 3.09-3.57 (10H, m), 3.93-4.19 (2H, m), 5.11 (2H, s), 7.26-7.37 (5H, m);
MS (FAB) m / z: 376 [M + H ⁺ ], 332, 268, 240, 186, 127, 91, 63.

（３７ｆ）１−メチル−３−［２−（ピペリジン−３−イルメトキシ）エチル］イミダゾリジン−２−オン
参考例３７（３７ｅ）で製造したベンジル３−{[２−(３−メチル−２−オキソイミダゾリジン−１−イル)エトキシ]メチル}ピペリジン−１−カルボキシラートを用いて参考例１（１ｂ）と同様に反応を行い、標記目的化合物を得た。
黄色液体;
IR (film) ν_max3471, 2928, 1693, 1502, 1447, 1277, 1122, 761 cm^-1;
¹H NMR(CDCl₃, 500 MHz) δ 1.05-1.16 (1H, m), 1.40-1.51 (1H, m), 1.62-1.69 (1H, m), 1.70-1.80 (2H, m), 2.34 (1H, dd, J = 9.3, 12.2 Hz), 2.55 (1H, dt, J = 2.9, 12.2 Hz) 2.79 (3H, s), 2.97-3.03 (1H, m), 3.22-3.30 (4H, m), 3.33-3.44 (4H, m), 3.48-3.57 (2H, m);
MS (EI) m/z: 241 [M]⁺, 145, 127, 113, 97, 82, 70, 56。
(37f) 1-Methyl-3- [2- (piperidin-3-ylmethoxy) ethyl] imidazolidin-2-one Benzyl 3-{[2- (3-methyl-2-yl) prepared in Reference Example 37 (37e) Reaction was conducted in the same manner as in Reference Example 1 (1b) using oxoimidazolidin-1-yl) ethoxy] methyl} piperidine-1-carboxylate to obtain the title compound.
Yellow liquid;
IR (film) ν _max 3471, 2928, 1693, 1502, 1447, 1277, 1122, 761 cm ^-1 ;
¹ H NMR (CDCl ₃ , 500 MHz) δ 1.05-1.16 (1H, m), 1.40-1.51 (1H, m), 1.62-1.69 (1H, m), 1.70-1.80 (2H, m), 2.34 (1H , dd, J = 9.3, 12.2 Hz), 2.55 (1H, dt, J = 2.9, 12.2 Hz) 2.79 (3H, s), 2.97-3.03 (1H, m), 3.22-3.30 (4H, m), 3.33 -3.44 (4H, m), 3.48-3.57 (2H, m);
MS (EI) m / z: 241 [M] ⁺ , 145, 127, 113, 97, 82, 70, 56.

［参考例３８］（３Ｓ）−３−{[（５−メチル−１,３,４−オキサジアゾール−２−イル）メトキシ]メチル}ピペリジン
（３８ａ）ｔｅｒｔ-ブチル（３Ｓ）−３−[（２−ｔｅｒｔ−ブトキシ−２−オキソエトキシ）メチル]ピペリジン−１−カルボキシラート
ｔｅｒｔ−ブチル（３Ｓ）−３−（ヒドロキシメチル）ピペリジン−１−カルボキシラートを用いて参考例３６（３６ａ）と同様に反応を行い、標記目的化合物を得た。
無色液体;
IR (film) ν_max2933, 1750, 1695, 1424, 1367, 1266, 1139 cm^-1;
¹H NMR(CDCl₃, 500 MHz) δ 1.21-1.32 (1H, m), 1.37-1.53 (1H, m), 1.45 (9H, m), 1.48 (9H, m), 1.60-1.68 (1H, m), 1.76-1.89 (2H, m), 2.59-2.77 (1H, m), 2.79-2.86 (1H, m), 3.33-3.43 (2H, m), 3.83-4.01 (4H, m);
MS (FAB) m/z: 330 [M+H]⁺, 274, 218, 172。
[Reference Example 38] (3S) -3-{[(5-Methyl-1,3,4-oxadiazol-2-yl) methoxy] methyl} piperidine (38a) tert-butyl (3S) -3- [ (2-tert-Butoxy-2-oxoethoxy) methyl] piperidine-1-carboxylate Similar to Reference Example 36 (36a) using tert-butyl (3S) -3- (hydroxymethyl) piperidine-1-carboxylate The title target compound was obtained.
Colorless liquid;
IR (film) ν _max 2933, 1750, 1695, 1424, 1367, 1266, 1139 cm ^-1 ;
¹ H NMR (CDCl ₃ , 500 MHz) δ 1.21-1.32 (1H, m), 1.37-1.53 (1H, m), 1.45 (9H, m), 1.48 (9H, m), 1.60-1.68 (1H, m ), 1.76-1.89 (2H, m), 2.59-2.77 (1H, m), 2.79-2.86 (1H, m), 3.33-3.43 (2H, m), 3.83-4.01 (4H, m);
MS (FAB) m / z: 330 [M + H] ⁺ , 274, 218, 172.

（３８ｂ）｛［（３Ｓ）−１−（ｔｅｒｔ−ブトキシカルボニル）ピペリジン−３−イル］メトキシ｝酢酸
参考例３８（３８ａ）で製造したｔｅｒｔ-ブチル（３Ｓ）−３−[（２−ｔｅｒｔ−ブトキシ−２−オキソエトキシ）メチル]ピペリジン−１−カルボキシラートを用いて参考例３６（３６ｂ）と同様に反応を行い、標記目的化合物を得た。
淡黄色液体;
IR (film) ν_max3108, 2933, 1760, 1692, 1436, 1153, 858 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.26-1.39 (1H, m), 1.40-1.53 (1H, m), 1.46 (9H, s), 1.58-1.69 (1H, m), 1.74-1.96 (2H, m), 2.72-3.30 (2H, m), 3.38-4.23 (6H, m);
MS (FAB) m/z: 274 [M+H⁺], 240, 218, 172, 142。
(38b) {[(3S) -1- (tert-butoxycarbonyl) piperidin-3-yl] methoxy} acetic acid tert-butyl (3S) -3-[(2-tert-) prepared in Reference Example 38 (38a) Using butoxy-2-oxoethoxy) methyl] piperidine-1-carboxylate, the reaction was conducted in the same manner as in Reference Example 36 (36b) to give the title object compound.
A pale yellow liquid;
IR (film) ν _max 3108, 2933, 1760, 1692, 1436, 1153, 858 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.26-1.39 (1H, m), 1.40-1.53 (1H, m), 1.46 (9H, s), 1.58-1.69 (1H, m), 1.74-1.96 (2H , m), 2.72-3.30 (2H, m), 3.38-4.23 (6H, m);
MS (FAB) m / z: 274 [M + H ⁺ ], 240, 218, 172, 142.

（３８ｃ）ｔｅｒｔ−ブチル（３Ｓ）−３−{[（５−メチル−１,３,４−オキサジアゾール−２−イル）メトキシ]メチル}ピペリジン−１−カルボキシラート
参考例３８（３８ｂ）で製造した{[（３Ｓ）−１−（ｔｅｒｔ−ブトキシカルボニル）ピペリジン−３−イル]メトキシ}酢酸（２．０８ｇ，７．６０ｍｍｏｌ）のテトラヒドロフラン（８０ｍＬ）溶液に、１，１−カルボジイミダゾール（１．３６ｇ、８．３６ｍｍｏｌ）を加え、室温で３０分間撹拌した後、ヒドラジン一水和物（１．３８ｍＬ、２２．８ｍｍｏｌ）を加え、室温で３時間撹拌した。反応液を濃縮し、水（１００ｍＬ）を加え、酢酸エチルで３回抽出した。有機層を合わせて、無水硫酸ナトリウムで乾燥後，溶媒を減圧下留去した。得られた残渣にオルト酢酸トリエチル（５０ｍＬ、２７５ｍｍｏｌ）を加え、加熱還流下３日間撹拌した。反応液を濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル，１：１→１：３）を用いて精製し、９５０ｍｇ（収率４０％）の標記目的化合物を得た。
(38c) tert-butyl (3S) -3-{[(5-methyl-1,3,4-oxadiazol-2-yl) methoxy] methyl} piperidine-1-carboxylate In Reference Example 38 (38b) To a solution of the prepared {[(3S) -1- (tert-butoxycarbonyl) piperidin-3-yl] methoxy} acetic acid (2.08 g, 7.60 mmol) in tetrahydrofuran (80 mL), 1,1-carbodiimidazole ( 1.36 g, 8.36 mmol) was added, and the mixture was stirred at room temperature for 30 minutes, hydrazine monohydrate (1.38 mL, 22.8 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated, water (100 mL) was added, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Triethyl orthoacetate (50 mL, 275 mmol) was added to the resulting residue, and the mixture was stirred for 3 days under reflux with heating. The reaction mixture was concentrated, and the resulting residue was purified using silica gel column chromatography (hexane / ethyl acetate, 1: 1 → 1: 3) to obtain 950 mg (yield 40%) of the title compound.

黄色液体;
IR (film) ν_max3498, 2933, 1690, 1590, 1425, 1268, 1152, 974 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.14-1.31 (1H, m), 1.38-1.51 (1H, m), 1.45 (9H, s), 1.57-1.67 (1H, m), 1.73-1.88 (2H, m), 2.46-2.74 (1H, m), 2.55 (3H, s), 2.76-2.88 (1H, m), 3.36-3.43 (2H, m), 3.80-4.05 (2H, m), 4.62 (2H, s);
MS (FAB) m/z: 312 [M+H⁺], 256, 238, 212。
Yellow liquid;
IR (film) ν _max 3498, 2933, 1690, 1590, 1425, 1268, 1152, 974 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.14-1.31 (1H, m), 1.38-1.51 (1H, m), 1.45 (9H, s), 1.57-1.67 (1H, m), 1.73-1.88 (2H , m), 2.46-2.74 (1H, m), 2.55 (3H, s), 2.76-2.88 (1H, m), 3.36-3.43 (2H, m), 3.80-4.05 (2H, m), 4.62 (2H , s);
MS (FAB) m / z: 312 [M + H ^<+ >], 256, 238, 212.

（３８ｄ）（３Ｓ）−３−{[（５−メチル−１,３,４−オキサジアゾール−２−イル）メトキシ]メチル}ピペリジン
参考例３８（３８ｃ）で製造したｔｅｒｔ−ブチル（３Ｓ）−３−{[（５−メチル−１,３,４−オキサジアゾール−２−イル）メトキシ]メチル}ピペリジン−１−カルボキシラートを用いて参考例９（９ｂ）と同様に反応を行い、標記目的化合物を得た。
黄色液体;
IR (film) ν_max3405, 2930, 1663, 1590, 1445, 1270, 1102, 790 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.04-1.18 (1H, m), 1.38-1.52 (1H, m), 1.57-1.70 (1H, m), 1.72-1.86 (2H, m), 2.34 (1H, dd, J = 10.1, 11.7 Hz), 2.46-2.61 (1H, m), 2.56 (3H, s), 2.99 (1H, brd, J = 12.1 Hz), 3.12 (1H, brd, J = 11.7 Hz), 3.34-3.42 (2H, m), 4.63 (2H, s);
MS (EI) m/z: 211 [M⁺], 155, 114, 98, 84, 56。
(38d) (3S) -3-{[(5-Methyl-1,3,4-oxadiazol-2-yl) methoxy] methyl} piperidine tert-butyl prepared in Reference Example 38 (38c) (3S) -3-{[(5-Methyl-1,3,4-oxadiazol-2-yl) methoxy] methyl} piperidine-1-carboxylate was reacted in the same manner as in Reference Example 9 (9b), The title object compound was obtained.
Yellow liquid;
IR (film) ν _max 3405, 2930, 1663, 1590, 1445, 1270, 1102, 790 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.04-1.18 (1H, m), 1.38-1.52 (1H, m), 1.57-1.70 (1H, m), 1.72-1.86 (2H, m), 2.34 (1H , dd, J = 10.1, 11.7 Hz), 2.46-2.61 (1H, m), 2.56 (3H, s), 2.99 (1H, brd, J = 12.1 Hz), 3.12 (1H, brd, J = 11.7 Hz) , 3.34-3.42 (2H, m), 4.63 (2H, s);
MS (EI) m / z: 211 [M ⁺ ], 155, 114, 98, 84, 56.

［参考例３９］（３Ｓ）−３−｛［（３−メチル−１，２，４−オキサジアゾール−５−イル）メトキシ］メチル｝ピペリジン
（３９ａ）ｔｅｒｔ−ブチル（３Ｓ）−３−{[（３−メチル−１,２,４−オキサジアゾール−５−イル）メトキシ]メチル}ピペリジン−１−カルボキシラート
参考例３８（３８ｂ）で製造した｛［（３Ｓ）−１−（ｔｅｒｔ−ブトキシカルボニル）ピペリジン−３−イル］メトキシ｝酢酸を用いて参考例２１（２１ａ）と同様に反応を行い、標記目的化合物を得た。
無色液体;
IR (film) ν_max2933, 1691, 1586, 1425, 1268, 1153 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.19-1.31 (1H, m), 1.37-1.51 (1H, m), 1.45 (9H, s), 1.57-1.68 (1H, m), 1.74-1.91 (2H, m), 2.42 (3H, s), 2.57-2.76 (1H, m), 2.78-2.99 (1H, m), 3.42-3.50 (2H, m), 3.79-4.03 (2H, m), 4.67 (2H, s);
MS (FAB) m/z: 312 [M+H⁺], 256, 238, 212。
[Reference Example 39] (3S) -3-{[(3-Methyl-1,2,4-oxadiazol-5-yl) methoxy] methyl} piperidine (39a) tert-butyl (3S) -3- { [(3-Methyl-1,2,4-oxadiazol-5-yl) methoxy] methyl} piperidine-1-carboxylate prepared in Reference Example 38 (38b) {[(3S) -1- (tert- Using butoxycarbonyl) piperidin-3-yl] methoxy} acetic acid, the reaction was carried out in the same manner as in Reference Example 21 (21a) to obtain the title compound.
Colorless liquid;
IR (film) ν _max 2933, 1691, 1586, 1425, 1268, 1153 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.19-1.31 (1H, m), 1.37-1.51 (1H, m), 1.45 (9H, s), 1.57-1.68 (1H, m), 1.74-1.91 (2H , m), 2.42 (3H, s), 2.57-2.76 (1H, m), 2.78-2.99 (1H, m), 3.42-3.50 (2H, m), 3.79-4.03 (2H, m), 4.67 (2H , s);
MS (FAB) m / z: 312 [M + H ^<+ >], 256, 238, 212.

（３９ｂ）（３Ｓ）−３−{[（３−メチル−１,２,４−オキサジアゾール−５−イル）メトキシ]メチル}ピペリジン
参考例３９（３９ａ）で製造したベンジル３−{[２−(３−メチル−２−オキソイミダゾリジン−１−イル)エトキシ]メチル}ピペリジン−１−カルボキシラートを用いて参考例１（１ｂ）と同様に反応を行い、標記目的化合物を得た。
淡黄色液体;
IR (film) ν_max3392, 2932, 1586, 1440, 1393, 1340, 1273, 1128, 887 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.08-1.20 (1H, m), 1.40-1.52 (1H, m), 1.60-1.70 (1H, m), 1.75-1.90 (2H, m), 2.37 (1H, dd, J = 10.1, 11.7 Hz), 2.42 (3H, s), 2.55 (1H, dt, J = 3.1, 11.7 Hz), 2.98 (1H, brd, J = 12.1 Hz), 3.13 (1H, brd, J = 12.1 Hz), 3.40-3.45 (2H, m), 4.66 (2H, s);
MS (FAB) m/z: 212 [M+H]⁺, 178, 165, 96。

［参考例４０］（３Ｓ）−３−｛［２−（２−メチル−２Ｈ−テトラゾール−５−イル）エトキシ］メチル｝ピペリジン
（４０ａ）ｔｅｒｔ−ブチル（３Ｓ）−３−［（２−シアノエトキシ）メチル］ピペリジン−１−カルボキシラート
ｔｅｒｔ−ブチル（３Ｓ）−３−（ヒドロキシメチル）ピペリジン−１−カルボキシラート（２．１５ｇ,１０ｍｍｏｌ）、アクリロニトリル（１．３１ｍＬ,２０ｍｍｏｌ）及び水酸化カリウム（１１２ｍｇ,２ｍｍｏｌ）のテトラヒドロフラン（２０ｍＬ）溶液を室温で２４時間撹拌した。反応液に水（５０ｍＬ）及び酢酸エチル（５０ｍＬ）を加え、有機層を分離し、無水硫酸ナトリウムで乾燥後，溶媒を減圧下留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝３：１）を用いて精製し，１．６６ｇ（収率６２％）標記目的化合物を得た。
(39b) (3S) -3-{[(3-Methyl-1,2,4-oxadiazol-5-yl) methoxy] methyl} piperidine benzyl 3-{[2 prepared in Reference Example 39 (39a) The reaction was performed in the same manner as in Reference Example 1 (1b) using-(3-methyl-2-oxoimidazolidin-1-yl) ethoxy] methyl} piperidine-1-carboxylate to obtain the title object compound.
A pale yellow liquid;
IR (film) ν _max 3392, 2932, 1586, 1440, 1393, 1340, 1273, 1128, 887 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.08-1.20 (1H, m), 1.40-1.52 (1H, m), 1.60-1.70 (1H, m), 1.75-1.90 (2H, m), 2.37 (1H , dd, J = 10.1, 11.7 Hz), 2.42 (3H, s), 2.55 (1H, dt, J = 3.1, 11.7 Hz), 2.98 (1H, brd, J = 12.1 Hz), 3.13 (1H, brd, J = 12.1 Hz), 3.40-3.45 (2H, m), 4.66 (2H, s);
MS (FAB) m / z: 212 [M + H] ⁺ , 178, 165, 96.

[Reference Example 40] (3S) -3-{[2- (2-Methyl-2H-tetrazol-5-yl) ethoxy] methyl} piperidine (40a) tert-butyl (3S) -3-[(2-cyano Ethoxy) methyl] piperidine-1-carboxylate tert-butyl (3S) -3- (hydroxymethyl) piperidine-1-carboxylate (2.15 g, 10 mmol), acrylonitrile (1.31 mL, 20 mmol) and potassium hydroxide ( A solution of 112 mg, 2 mmol) in tetrahydrofuran (20 mL) was stirred at room temperature for 24 hours. Water (50 mL) and ethyl acetate (50 mL) were added to the reaction solution, the organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3: 1) to obtain 1.66 g (yield 62%) of the title object compound.

無色液体
IR (film) ν_max2934, 2864, 2252, 1689, 1425, 1366, 1267, 1153, 972, 884, 771 cm^-1;
¹H NMR(CDCl₃, 500 MHz) δ 1.22-1.28 (2H, m), 1.46 (9H, s), 1.63-1.65 (1H, m), 1.66-1.80 (2H, m), 2.59 (2H, t, J = 6.4 Hz), 2.61-2.65 (1H, m), 2.80-2.87 (1H, m), 3.35-3.36 (2H, m), 3.62-3.65 (2H, m), 3.86-3.96 (2H, m);
MS (EI) m/z: 268 [M⁺], 209, 195, 167, 158, 140, 128, 114, 98, 85, 84, 57, 41。
Colorless liquid
IR (film) ν _max 2934, 2864, 2252, 1689, 1425, 1366, 1267, 1153, 972, 884, 771 cm ^-1 ;
¹ H NMR (CDCl ₃ , 500 MHz) δ 1.22-1.28 (2H, m), 1.46 (9H, s), 1.63-1.65 (1H, m), 1.66-1.80 (2H, m), 2.59 (2H, t , J = 6.4 Hz), 2.61-2.65 (1H, m), 2.80-2.87 (1H, m), 3.35-3.36 (2H, m), 3.62-3.65 (2H, m), 3.86-3.96 (2H, m );
MS (EI) m / z: 268 [M ⁺ ], 209, 195, 167, 158, 140, 128, 114, 98, 85, 84, 57, 41.

（４０ｂ）ｔｅｒｔ−ブチル（３Ｓ）−３−{［２−（１Ｈ−テトラゾール−５−イル）エトキシ］メチル}ピペリジン−１−カルボキシラート
参考例４０（４０ａ）で製造したｔｅｒｔ−ブチル（３Ｓ）−３−［（２−シアノエトキシ）メチル］ピペリジン−１−カルボキシラート（１．３２ｇ,４．９ｍｍｏｌ）、アジ化ナトリウム（２．８８ｇ,４４．３ｍｍｏｌ）及びトリエチルアミン塩酸塩（２．０３ｇ,１４．８ｍｍｏｌ）の１，２−ジメトキシエタン（１５ｍＬ）溶液を９０℃で２４時間撹拌した。反応液に水（５０ｍＬ）及び酢酸エチル（５０ｍＬ）を加え、有機層を分離し、無水硫酸ナトリウムで乾燥後，溶媒を減圧下留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル／メタノール＝２０：１）を用いて精製し，０．８９ｇ（収率５８％）の標記目的化合物を得た。
(40b) tert-butyl (3S) -3-{[2- (1H-tetrazol-5-yl) ethoxy] methyl} piperidine-1-carboxylate tert-butyl prepared in Reference Example 40 (40a) (3S) -3-[(2-cyanoethoxy) methyl] piperidine-1-carboxylate (1.32 g, 4.9 mmol), sodium azide (2.88 g, 44.3 mmol) and triethylamine hydrochloride (2.03 g, 14 .8 mmol) in 1,2-dimethoxyethane (15 mL) was stirred at 90 ° C. for 24 hours. Water (50 mL) and ethyl acetate (50 mL) were added to the reaction solution, the organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / methanol = 20: 1) to obtain 0.89 g (yield 58%) of the title compound.

無色液体
IR (film) ν_max2931, 2865, 1690, 1655, 1558, 1479, 1435, 1367, 1271, 1155, 857 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.49 (9H, s), 1.51-1.72 (4H, m), 1.94-1.99 (1H, m), 2.94 (2H, brs), 3.20-3.32 (3H, m), 3.50 (1H, t, J = 8.6 Hz), 3.64-3.69 (1H, m), 3.83-3.96 (2H, m), 4.07-4.10 (1H, m);
MS (FAB) m/z: 312 [M+H⁺], 268, 212, 47, 46, 31。
Colorless liquid
IR (film) ν _max 2931, 2865, 1690, 1655, 1558, 1479, 1435, 1367, 1271, 1155, 857 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.49 (9H, s), 1.51-1.72 (4H, m), 1.94-1.99 (1H, m), 2.94 (2H, brs), 3.20-3.32 (3H, m ), 3.50 (1H, t, J = 8.6 Hz), 3.64-3.69 (1H, m), 3.83-3.96 (2H, m), 4.07-4.10 (1H, m);
MS (FAB) m / z: 312 [M + H ⁺ ], 268, 212, 47, 46, 31.

（４０ｃ）ｔｅｒｔ−ブチル（３Ｓ）−３−{［２−（２−メチル−２Ｈ−テトラゾール−５−イル）エトキシ］メチル}ピペリジン−１−カルボキシラート
参考例４０（４０ｂ）で製造したｔｅｒｔ−ブチル（３Ｓ）−３−{［２−（１Ｈ−テトラゾール−５−イル）エトキシ］メチル}ピペリジン−１−カルボキシラート（０．８９ｇ,２．９ｍｍｏｌ）、ヨウ化メチル（０．９０ｍＬ,１４．５ｍｍｏｌ）及び炭酸カリウム（０．６０ｇ,４．４ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（１０ｍＬ）溶液を２４時間撹拌した。反応液に水（５０ｍＬ）及び酢酸エチル（５０ｍＬ）を加え、有機相を分離し、無水硫酸ナトリウムで乾燥後，溶媒を減圧下留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル）を用いて精製し，０．３２ｇ（収率３４％）標記目的化合物を得た。
(40c) tert-butyl (3S) -3-{[2- (2-methyl-2H-tetrazol-5-yl) ethoxy] methyl} piperidine-1-carboxylate tert- prepared in Reference Example 40 (40b) Butyl (3S) -3-{[2- (1H-tetrazol-5-yl) ethoxy] methyl} piperidine-1-carboxylate (0.89 g, 2.9 mmol), methyl iodide (0.90 mL, 14. 5 mmol) and potassium carbonate (0.60 g, 4.4 mmol) in N, N-dimethylformamide (10 mL) were stirred for 24 hours. Water (50 mL) and ethyl acetate (50 mL) were added to the reaction solution, the organic phase was separated, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified using silica gel column chromatography (ethyl acetate) to obtain 0.32 g (yield 34%) of the title object compound.

淡黄色液体
IR (film) ν_max2976, 2932, 2860, 1692, 1424, 1366, 1267, 1178, 1153, 1119, 770 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.14-1.17 (1H, m), 1.59-1.77 (4H, m), 2.74-2.80 (1H, m), 3.14 (2H, t, J = 6.7 Hz), 3.31 (2H, dd, J = 1.6, 6.3 Hz), 3.78-3.88 (4H, m), 4.30 (3H, s);
MS (FAB) m/z: 326 [M+H⁺], 252, 242, 226, 57, 47, 31, 29, 19。

（４０ｄ）（３Ｓ）−３−｛［２−（２−メチル−２Ｈ−テトラゾール−５−イル）エトキシ］メチル｝ピペリジン
参考例４０（４０ｃ）で製造したｔｅｒｔ−ブチル（３Ｓ）−３−{［２−（２−メチル−２Ｈ−テトラゾール−５−イル）エトキシ］メチル}ピペリジン−１−カルボキシラートを用いて参考例９（９ｂ）と同様に反応を行い、標記目的化合物を得た。
無色液体
IR (film) ν_max3397, 2929, 2858, 1551, 1498, 1414, 1270, 1119, 857, 811, 743, 606 cm^-1;
¹H NMR(CDCl₃, 500 MHz) δ 1.07 (1H dq, J = 3.9, 11.7 Hz), 1.38-1.46 (1H, m), 1.60-1.65 (1H, m), 1.71-1.78 (2H, m), 2.29 (1H, dd, J = 10.3, 12.2 Hz), 2.54 (1H, dt, J = 2.9, 11.7 Hz), 2.98 (1H, d, J = 12.2 Hz), 3.06 (1H, d, J = 12.2 Hz), 3.15 (2H, t, J = 6.8 Hz), 3.26-3.30 (2H, m), 3.77-3.85 (2H, m);
MS (FAB) m/z: 226 [M+H⁺], 219, 198, 178, 169, 69, 55, 41, 39, 30, 23。

［参考例４１］３−〔３−（ピペリジン−３−イルメトキシ）プロピル〕−1,３−オキサゾリン−２−オン
（４１ａ）ベンジル３−〔（２−シアノエトキシ）メチル〕ピペリジン−１−カルボキシラート
ベンジル３−（ヒドロキシメチル）ピペリジン−１−カルボキシラート（Ａｒｃｈ．Ｐｈａｒｍ．（ＷｅｉｎｈｅｉｍＧｅｒ．），３２３,１９９０，９−１２）を用いて参考例４０（４０ａ）と同様に反応を行い、標記目的化合物を得た。
IR (liquid film) ν_max2937, 2863, 2251, 1698, 1471, 1433, 1262, 1236, 1155, 1117 cm^-1;
¹H NMR(CDCl₃, 400MHz) δ 1.22-1.33 (1H, m), 1.40-1.53 (1H, m), 1.62-1.70 (1H, m), 1.76-1.87 (2H, br), 2.55 (2H, br.s), 2.66-2.87 (1H, br), 2.93 (1H, t, J=11.0 Hz), 3.35 (2H, d, J=5.1 Hz), 3.59 (2H, br.s), 3.92 (1H, dt, J=4.2, 13.3 Hz), 4.01 (1H, br s), 5.08-5.17 (2H, m), 7.27-7.35 (5H, m);
MS(EI) m/z: 303 [M+H]⁺。
Pale yellow liquid
IR (film) ν _max 2976, 2932, 2860, 1692, 1424, 1366, 1267, 1178, 1153, 1119, 770 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.14-1.17 (1H, m), 1.59-1.77 (4H, m), 2.74-2.80 (1H, m), 3.14 (2H, t, J = 6.7 Hz), 3.31 (2H, dd, J = 1.6, 6.3 Hz), 3.78-3.88 (4H, m), 4.30 (3H, s);
MS (FAB) m / z: 326 [M + H ⁺ ], 252, 242, 226, 57, 47, 31, 29, 19.

(40d) (3S) -3-{[2- (2-Methyl-2H-tetrazol-5-yl) ethoxy] methyl} piperidine tert-butyl (3S) -3- {prepared in Reference Example 40 (40c) The reaction was carried out in the same manner as in Reference Example 9 (9b) using [2- (2-methyl-2H-tetrazol-5-yl) ethoxy] methyl} piperidine-1-carboxylate to obtain the title compound.
Colorless liquid
IR (film) ν _max 3397, 2929, 2858, 1551, 1498, 1414, 1270, 1119, 857, 811, 743, 606 cm ^-1 ;
¹ H NMR (CDCl ₃ , 500 MHz) δ 1.07 (1H dq, J = 3.9, 11.7 Hz), 1.38-1.46 (1H, m), 1.60-1.65 (1H, m), 1.71-1.78 (2H, m) , 2.29 (1H, dd, J = 10.3, 12.2 Hz), 2.54 (1H, dt, J = 2.9, 11.7 Hz), 2.98 (1H, d, J = 12.2 Hz), 3.06 (1H, d, J = 12.2 Hz), 3.15 (2H, t, J = 6.8 Hz), 3.26-3.30 (2H, m), 3.77-3.85 (2H, m);
MS (FAB) m / z: 226 [M + H ⁺ ], 219, 198, 178, 169, 69, 55, 41, 39, 30, 23.

[Reference Example 41] 3- [3- (Piperidin-3-ylmethoxy) propyl] -1,3-oxazolin-2-one (41a) benzyl 3-[(2-cyanoethoxy) methyl] piperidine-1-carboxylate The reaction was carried out in the same manner as in Reference Example 40 (40a) using benzyl 3- (hydroxymethyl) piperidine-1-carboxylate (Arch. Pharm. (Weinheim Ger.), 323, 1990, 9-12). A compound was obtained.
IR (liquid film) ν _max 2937, 2863, 2251, 1698, 1471, 1433, 1262, 1236, 1155, 1117 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.22-1.33 (1H, m), 1.40-1.53 (1H, m), 1.62-1.70 (1H, m), 1.76-1.87 (2H, br), 2.55 (2H, br.s), 2.66-2.87 (1H, br), 2.93 (1H, t, J = 11.0 Hz), 3.35 (2H, d, J = 5.1 Hz), 3.59 (2H, br.s), 3.92 (1H , dt, J = 4.2, 13.3 Hz), 4.01 (1H, br s), 5.08-5.17 (2H, m), 7.27-7.35 (5H, m);
MS (EI) m / z: 303 [M + H] ^< +>.

（４１ｂ）ベンジル３−〔（３−アミノプロポキシ）メチル〕ピペリジン−１−カルボキシラート
参考例４１（４１ａ）で得られたベンジル３−〔（２−シアノエトキシ）メチル〕ピペリジン−１−カルボキシラート（２．０６ｇ、６．８１ｍｍｏｌ）を、メタノール（３０ｍＬ）に溶解し、コバルト（ＩＩ）クロリド（過剰量）および水素化ホウ素ナトリウム（過剰量）を５−６回に分けて加え、窒素雰囲気下、０℃で３．５時間攪拌した。反応液に水を加え、塩化メチレンを加えて抽出した。得られた有機相を減圧下に溶媒を留去し、残渣を、シリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル，１：１−０：１，Ｖ／Ｖ）を用いて精製し、１．３１ｇ（収率６３％）の標記目的化合物を得た。
(41b) Benzyl 3-[(3-aminopropoxy) methyl] piperidine-1-carboxylate benzyl 3-[(2-cyanoethoxy) methyl] piperidine-1-carboxylate obtained in Reference Example 41 (41a) ( 2.06 g, 6.81 mmol) was dissolved in methanol (30 mL) and cobalt (II) chloride (excess) and sodium borohydride (excess) were added in 5-6 portions under a nitrogen atmosphere. Stir at 0 ° C. for 3.5 hours. Water was added to the reaction mixture, and methylene chloride was added for extraction. The solvent was distilled off from the obtained organic phase under reduced pressure, and the residue was purified using silica gel column chromatography (hexane: ethyl acetate, 1: 1-0: 1, V / V) to obtain 1.31 g ( The title target compound was obtained in a yield of 63%.

無色油状物
IR (liquid film) ν_max2935, 2858, 1699, 1470, 1432, 1261, 1236, 1154, 1116, 699 cm^-1;
¹H NMR(CD₃OD, 400MHz) δ 1.20-1.32 (1H, m), 1.38-1.51 (1H, m), 1.62-1.81 (5H, m), 2.55-2.83 (3H, m), 2.92 (1H, br s), 3.20-3.33 (2H, m), 3.38-3.51 (2H, m), 3.91 (1H, d, J=13.3 Hz), 4.04 (1H, d, J=12.5 Hz), 5.09 (2H, s), 7.26-7.33 (5H, m);
MS(FAB) m/z: 307 [M+H]⁺。
Colorless oil
IR (liquid film) ν _max 2935, 2858, 1699, 1470, 1432, 1261, 1236, 1154, 1116, 699 cm ^-1 ;
¹ H NMR (CD ₃ OD, 400 MHz) δ 1.20-1.32 (1H, m), 1.38-1.51 (1H, m), 1.62-1.81 (5H, m), 2.55-2.83 (3H, m), 2.92 (1H , br s), 3.20-3.33 (2H, m), 3.38-3.51 (2H, m), 3.91 (1H, d, J = 13.3 Hz), 4.04 (1H, d, J = 12.5 Hz), 5.09 (2H , s), 7.26-7.33 (5H, m);
MS (FAB) m / z: 307 [M + H] ^< +>.

（４１ｃ）ベンジル３−｛〔３−（２−オキソ−1,３−オキサゾリン−３−イル）プロポキシ〕メチル｝ピペリジン−１−カルボキシラート
参考例４１（４１ｂ）で得られたベンジル３−〔（３−アミノプロポキシ）メチル〕ピペリジン−１−カルボキシラート（１．２８ｇ、４．１９ｍｍｏｌ）を、塩化メチレン（１０ｍＬ）に溶解し、４−Ｎ，Ｎ−ジメチルアミノピリジン（６６８ｍｇ、５．４７ｍｍｏｌ）、および２−クロロエチルクロロホルメート（０．５７ｍＬ、５．４５ｍｍｏｌ）を加え、窒素雰囲気下、０℃で１時間、室温で１時間攪拌した。反応液に０．１Ｎ塩化水素水を加え、塩化メチレンで抽出した。得られた有機相を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、減圧下に溶媒を留去した。
(41c) Benzyl 3-{[3- (2-oxo-1,3-oxazolin-3-yl) propoxy] methyl} piperidine-1-carboxylate benzyl 3-[(obtained in Reference Example 41 (41b) 3-aminopropoxy) methyl] piperidine-1-carboxylate (1.28 g, 4.19 mmol) was dissolved in methylene chloride (10 mL) and 4-N, N-dimethylaminopyridine (668 mg, 5.47 mmol), And 2-chloroethyl chloroformate (0.57 mL, 5.45 mmol) was added, and the mixture was stirred at 0 ° C. for 1 hour and at room temperature for 1 hour under a nitrogen atmosphere. To the reaction solution was added 0.1N hydrogen chloride water, and the mixture was extracted with methylene chloride. The obtained organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.

得られた残渣（５００ｍｇ）をテトラヒドロフラン（８ｍＬ）に溶解し、氷冷下、水素化ナトリウム（１１７ｍｇ、２．６８ｍｍｏｌ）を加えて、８０℃で１．５時間攪拌した。反応液に水を加えて酢酸エチルで抽出した。得られた有機相を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、減圧下に溶媒を留去した。残渣を、シリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル，１：２−１：３，Ｖ／Ｖ）を用いて精製し、２８７ｍｇ（収率６３％）の標記目的化合物を得た。
油状物
IR (liquid film) ν_max 2932, 2860, 1753, 1698, 1431, 1369, 1262, 1236, 1154, 1117 cm^-1;
¹H NMR(CDCl₃, 400MHz) δ 1.13-1.26 (1H, m), 1.40-1.54 (1H, br), 1.62-1.71 (1H, br), 1.73-1.86 (4H, br), 2.56-2.77 (1H, br), 2.83-2.90 (1H, m), 3.20-3.37 (4H, m), 3.37-3.50 (3H, m), 3.57 (1H, br), 3.95-4.15 (1H, br), 3.98 (1H, d, J = 13.3 Hz), 4.18-4.35 (2H, br), 5.11 (2H, s), 7.26-7.35 (5H, m);
MS(FAB) m/z: 377 [M+H]⁺。 The obtained residue (500 mg) was dissolved in tetrahydrofuran (8 mL), sodium hydride (117 mg, 2.68 mmol) was added under ice cooling, and the mixture was stirred at 80 ° C. for 1.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate, 1: 2-1: 3, V / V) to obtain 287 mg (yield 63%) of the title compound.
Oily material
IR (liquid film) ν _max 2932, 2860, 1753, 1698, 1431, 1369, 1262, 1236, 1154, 1117 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.13-1.26 (1H, m), 1.40-1.54 (1H, br), 1.62-1.71 (1H, br), 1.73-1.86 (4H, br), 2.56-2.77 ( 1H, br), 2.83-2.90 (1H, m), 3.20-3.37 (4H, m), 3.37-3.50 (3H, m), 3.57 (1H, br), 3.95-4.15 (1H, br), 3.98 ( 1H, d, J = 13.3 Hz), 4.18-4.35 (2H, br), 5.11 (2H, s), 7.26-7.35 (5H, m);
MS (FAB) m / z: 377 [M + H] ^< +>.

（４１ｄ）３−〔３−（ピペリジン−３−イルメトキシ）プロピル〕−1,３−オキサゾリン−２−オン
参考例４１（４１ｃ）で製造したベンジル３−｛〔３−（２−オキソ−1,３−オキサゾリン−３−イル）プロポキシ〕メチル｝ピペリジン−１−カルボキシラートを用いて参考例１（１ｂ）と同様に反応を行い、標記目的化合物を得た。
無色油状物
IR (liquid film) ν_max3465, 2929, 2857, 1746, 1486, 1431, 1267, 1122, 1054, 764 cm^-1;
¹H NMR(CD₃OD, 500MHz) δ 1.11-1.19 (1H, m), 1.45-1.54 (1H, m), 1.65-1.70 (1H, m), 1.74-1.83 (4H, m), 2.31 (1H, dd, J = 10.3, 12.2 Hz), 2.51 (1H, dt, J = 2.9, 12.2 Hz), 2.96 (1H, d, J = 12.2 Hz), 3.09 (1H, d, J = 12.2 Hz), 3.21-3.29 (2H, m), 3.32-3.35 (2H, m), 3.41-3.49 (2H, m), 3.65 (2H, t, J = 8.1 Hz), 4.33 (2H, t, J = 8.1 Hz);
MS(EI) m/z: 242 [M⁺]。
(41d) 3- [3- (Piperidin-3-ylmethoxy) propyl] -1,3-oxazolin-2-one Benzyl 3-{[3- (2-oxo-1, 3-oxazolin-3-yl) propoxy] methyl} piperidine-1-carboxylate was reacted in the same manner as in Reference Example 1 (1b) to give the title object compound.
Colorless oil
IR (liquid film) ν _max 3465, 2929, 2857, 1746, 1486, 1431, 1267, 1122, 1054, 764 cm ^-1 ;
¹ H NMR (CD ₃ OD, 500 MHz) δ 1.11-1.19 (1H, m), 1.45-1.54 (1H, m), 1.65-1.70 (1H, m), 1.74-1.83 (4H, m), 2.31 (1H , dd, J = 10.3, 12.2 Hz), 2.51 (1H, dt, J = 2.9, 12.2 Hz), 2.96 (1H, d, J = 12.2 Hz), 3.09 (1H, d, J = 12.2 Hz), 3.21 -3.29 (2H, m), 3.32-3.35 (2H, m), 3.41-3.49 (2H, m), 3.65 (2H, t, J = 8.1 Hz), 4.33 (2H, t, J = 8.1 Hz);
MS (EI) m / z: 242 [M ⁺ ].

［参考例４２］３−｛〔２−（１−メチル−１Ｈ−テトラゾール−５−イル）エトキシ〕メチル｝ピペリジン
（４２ａ）ベンジル３−｛〔２−（１Ｈ−テトラゾール−５−イル）エトキシ〕メチル｝ピペリジン−１−カルボキシラート
参考例４１（４１ａ）で製造したベンジル３−〔（２−シアノエトキシ）メチル〕ピペリジン−１−カルボキシラートを用いて参考例４０（４０ｂ）と同様に反応を行い、標記目的化合物を得た。
無色油状物
IR (liquid film) ν_max: 3136, 2929, 2864, 1698, 1672, 1440, 1264, 1237, 1156, 1116 cm^-1;
¹H NMR(CDCl₃, 400MHz) δ 1.46-1.59 (3H, m), 1.67-1.78 (1H, m), 1.94-2.02 (1H, m), 3.00-3.12 (2H, m), 3.14 (1H, dd, J = 2.7, 5.9 Hz), 3.19 (1H, dd, J = 3.1, 9.0 Hz), 3.26 (1H, dd, J = 3.7, 9.0 Hz), 3.37-3.42 (1H, m), 3.48 (1H, dt, J = 2.0, 9.2 Hz), 3.73-3.80 (1H, m), 3.95-4.08 (2H, m), 5.18 (1H, AB type d’s, J = 12.2 Hz), 5.21 (1H, AB type d’s, J = 12.2 Hz ), 7.27-7.35 (5H, m);
MS(FAB) m/z: 346 [M+H]⁺。
[Reference Example 42] 3-{[2- (1-Methyl-1H-tetrazol-5-yl) ethoxy] methyl} piperidine (42a) benzyl 3-{[2- (1H-tetrazol-5-yl) ethoxy] Methyl} piperidine-1-carboxylate Reaction was carried out in the same manner as in Reference Example 40 (40b) using benzyl 3-[(2-cyanoethoxy) methyl] piperidine-1-carboxylate prepared in Reference Example 41 (41a). To give the title compound.
Colorless oil
IR (liquid film) ν _max : 3136, 2929, 2864, 1698, 1672, 1440, 1264, 1237, 1156, 1116 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.46-1.59 (3H, m), 1.67-1.78 (1H, m), 1.94-2.02 (1H, m), 3.00-3.12 (2H, m), 3.14 (1H, dd, J = 2.7, 5.9 Hz), 3.19 (1H, dd, J = 3.1, 9.0 Hz), 3.26 (1H, dd, J = 3.7, 9.0 Hz), 3.37-3.42 (1H, m), 3.48 (1H , dt, J = 2.0, 9.2 Hz), 3.73-3.80 (1H, m), 3.95-4.08 (2H, m), 5.18 (1H, AB type d's, J = 12.2 Hz), 5.21 (1H, AB type d's , J = 12.2 Hz), 7.27-7.35 (5H, m);
MS (FAB) m / z: 346 [M + H] ^< +>.

（４２ｂ）ベンジル３−｛〔２−（１−メチル−１Ｈ−テトラゾール−５−イル）エトキシ〕メチル｝ピペリジン−１−カルボキシラート
参考例４２（４２ａ）で製造したベンジル３−｛〔２−（１Ｈ−テトラゾール−５−イル）エトキシ〕メチル｝ピペリジン−１−カルボキシラートを用いて参考例４０（４０ｃ）と同様に反応を行い、標記目的化合物を得た。
無色油状物
IR (liquid film) ν_max2936, 2861, 1698, 1470, 1433, 1288, 1261, 1237, 1154, 1116 cm^-1;
¹H NMR(CDCl₃, 400MHz) δ 1.05-1.15 (1H, m), 1.45 (1H, br s), 1.61-1.80 (3H, m), 2.58 (1H, br.s), 2.81-2.88 (1H, m), 3.02-3.16 (2H, m), 3.16-3.29 (2H, m), 3.68-3.83 (3H, br), 3.89-4.12 (4H, m), 5.11 (2H, s ), 7.27-7.37 (5H, m);
MS(FAB) m/z: 360 [M+H]⁺。
(42b) Benzyl 3-{[2- (1-methyl-1H-tetrazol-5-yl) ethoxy] methyl} piperidine-1-carboxylate Benzyl 3-{[2- (2) prepared in Reference Example 42 (42a) 1H-tetrazol-5-yl) ethoxy] methyl} piperidine-1-carboxylate was reacted in the same manner as in Reference Example 40 (40c) to give the title object compound.
Colorless oil
IR (liquid film) ν _max 2936, 2861, 1698, 1470, 1433, 1288, 1261, 1237, 1154, 1116 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.05-1.15 (1H, m), 1.45 (1H, br s), 1.61-1.80 (3H, m), 2.58 (1H, br.s), 2.81-2.88 (1H , m), 3.02-3.16 (2H, m), 3.16-3.29 (2H, m), 3.68-3.83 (3H, br), 3.89-4.12 (4H, m), 5.11 (2H, s), 7.27-7.37 (5H, m);
MS (FAB) m / z: 360 [M + H] ⁺ .

（４２ｃ）３−｛〔２−（１−メチル−１Ｈ−テトラゾール−５−イル）エトキシ〕メチル｝ピペリジン
参考例４２（４２ｂ）で製造したベンジル３−｛〔２−（１−メチル−１Ｈ−テトラゾール−５−イル）エトキシ〕メチル｝ピペリジン−１−カルボキシラートを用いて参考例１（１ｂ）と同様に反応を行い、標記目的化合物を得た。
無色油状物
IR (liquid film) ν_max3396, 2937, 2801, 2524, 1531, 1466, 1372, 1123, 1114, 1037 cm^-1;
¹H NMR (CDCl₃, 500MHz) δ 1.14-1.21 (1H, m), 1.72-1.87 (3H ,m), 2.08-2.17 (1H, m), 2.53 (1H, t, J = 11.5 Hz), 2.73 (1H, dt, J = 4.4, 9.5 Hz), 3.15 (2H, t, J = 5.9 Hz), 3.24-3.31 (2H, m), 3.31 (1H, dd, J = 7.1, 9.5 Hz), 3.38 (1H, dd, J = 4.9, 9.5 Hz), 3.79-3.86 (2H, m), 4.07 (3H, s), 5.12-5.84 (1H, br);
MS(FAB) m/z: 226 [M+H]⁺;

［参考例４３］３−｛〔（２−メチル−２Ｈ−テトラゾール−５−イル）メトキシ〕メチル｝ピペリジン
（４３ａ）ベンジル３−〔（シアノメトキシ）メチル〕ピペリジン−１−カルボキシラート
ベンジル３−（ヒドロキシメチル）ピペリジン−１−カルボキシラート（Ａｒｃｈ．Ｐｈａｒｍ．（ＷｅｉｎｈｅｉｍＧｅｒ．），３２３,１９９０，９−１２）（１．０１ｇ、４．０５ｍｍｏｌ）を、テトラヒドロフラン（１０ｍＬ）に溶解し、氷冷下、水素化ナトリウム（２１６ｍｇ、４．９５ｍｍｏｌ）を加えた後、窒素雰囲気下、室温で３０分攪拌した後、臭化アセトニトリル（０．３８ｍＬ、５．６７ｍｍｏｌ）のテトラヒドロフラン（７ｍＬ）溶液を２時間以上かけて滴下した。室温で２時間攪拌した後、水を加え、酢酸エチルを用いて抽出した。
(42c) 3-{[2- (1-Methyl-1H-tetrazol-5-yl) ethoxy] methyl} piperidine benzyl 3-{[2- (1-methyl-1H--] prepared in Reference Example 42 (42b) Tetrazol-5-yl) ethoxy] methyl} piperidine-1-carboxylate was used in the same manner as in Reference Example 1 (1b) to give the title object compound.
Colorless oil
IR (liquid film) ν _max 3396, 2937, 2801, 2524, 1531, 1466, 1372, 1123, 1114, 1037 cm ^-1 ;
¹ H NMR (CDCl ₃ , 500 MHz) δ 1.14-1.21 (1H, m), 1.72-1.87 (3H, m), 2.08-2.17 (1H, m), 2.53 (1H, t, J = 11.5 Hz), 2.73 (1H, dt, J = 4.4, 9.5 Hz), 3.15 (2H, t, J = 5.9 Hz), 3.24-3.31 (2H, m), 3.31 (1H, dd, J = 7.1, 9.5 Hz), 3.38 ( 1H, dd, J = 4.9, 9.5 Hz), 3.79-3.86 (2H, m), 4.07 (3H, s), 5.12-5.84 (1H, br);
MS (FAB) m / z: 226 [M + H] ⁺ ;

[Reference Example 43] 3-{[(2-Methyl-2H-tetrazol-5-yl) methoxy] methyl} piperidine (43a) benzyl 3-[(cyanomethoxy) methyl] piperidine-1-carboxylate benzyl 3- ( Hydroxymethyl) piperidine-1-carboxylate (Arch. Pharm. (Weinheim Ger.), 323, 1990, 9-12) (1.01 g, 4.05 mmol) was dissolved in tetrahydrofuran (10 mL) and cooled with ice. , Sodium hydride (216 mg, 4.95 mmol) was added, and the mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere. It was dripped over. After stirring at room temperature for 2 hours, water was added and the mixture was extracted with ethyl acetate.

得られた有機相を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、減圧下に溶媒を留去し、残渣を、シリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル，５：１−４：１，Ｖ／Ｖ）を用いて精製し、６５５ｍｇ（収率５６％）標記目的化合物を得た。 The obtained organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate, 5: 1-4: 1, V / V) to obtain 655 mg (56% yield) of the title object compound.

無色油状物
IR (liquid film) ν_max3469, 2939, 2862, 1698, 1471, 1434, 1263, 1236, 1155, 1110 cm^-1;
¹H NMR(CDCl₃, 400MHz) δ 1.23-1.33 (1H, m), 1.41-1.54 (1H, m), 1.62-1.71 (1H, m), 1.75-1.90 (2H, m), 2.90-2.97 (1H, m), 2.69-2.87 (1H, br), 3.38-3.50 (2H, m), 3.94-4.10 (1H, br), 3.93 (1H, dt, J = 4.0, 13.4 Hz), 4.18 (2H, br s), 5.07-5.18 (2H, m), 7.27-7.37 (5H, m);
MS(EI) m/z: 289 [M+H]⁺。

（４３ｂ）ベンジル３−〔（１Ｈ−テトラゾール−５−イルメトキシ）メチル〕ピペリジン−１−カルボキシラート
参考例４３（４３ａ）で得られた化合物を用いて参考例４０（４０ｂ）と同様に反応を行い、標記目的化合物を得た。
無色油状物
IR (liquid film) ν_max2935, 2863, 1698, 1662, 1475, 1442, 1265, 1237, 1156, 1117 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 1.46-1.63 (3H, m), 1.71-1.80 (1H, m), 2.02-2.10 (1H, m), 2.97-3.11 (2H, m), 3.43 (2H, d, J = 7.4 Hz), 4.02 (1H, d, J = 11.5 Hz), 4.27 (1H, d, J = 11.5 Hz), 4.49 (1H, d, J = 14.7 Hz), 5.03 (1H, d, J = 14.7 Hz), 5.19 (1H, AB type d’s, J = 12.3 Hz), 5.22 (1H, AB type d’s, J = 12.3 Hz ), 7.24-7.35 (5H, m);
MS(FAB) m/z: 332 [M+H]⁺。
Colorless oil
IR (liquid film) ν _max 3469, 2939, 2862, 1698, 1471, 1434, 1263, 1236, 1155, 1110 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.23-1.33 (1H, m), 1.41-1.54 (1H, m), 1.62-1.71 (1H, m), 1.75-1.90 (2H, m), 2.90-2.97 ( 1H, m), 2.69-2.87 (1H, br), 3.38-3.50 (2H, m), 3.94-4.10 (1H, br), 3.93 (1H, dt, J = 4.0, 13.4 Hz), 4.18 (2H, br s), 5.07-5.18 (2H, m), 7.27-7.37 (5H, m);
MS (EI) m / z: 289 [M + H] ^< +>.

(43b) Benzyl 3-[(1H-tetrazol-5-ylmethoxy) methyl] piperidine-1-carboxylate The reaction was carried out in the same manner as in Reference Example 40 (40b) using the compound obtained in Reference Example 43 (43a). To give the title compound.
Colorless oil
IR (liquid film) ν _max 2935, 2863, 1698, 1662, 1475, 1442, 1265, 1237, 1156, 1117 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.46-1.63 (3H, m), 1.71-1.80 (1H, m), 2.02-2.10 (1H, m), 2.97-3.11 (2H, m), 3.43 (2H, d, J = 7.4 Hz), 4.02 (1H, d, J = 11.5 Hz), 4.27 (1H, d, J = 11.5 Hz), 4.49 (1H, d, J = 14.7 Hz), 5.03 (1H, d, J = 14.7 Hz), 5.19 (1H, AB type d's, J = 12.3 Hz), 5.22 (1H, AB type d's, J = 12.3 Hz), 7.24-7.35 (5H, m);
MS (FAB) m / z: 332 [M + H] ^< +>.

（４３ｃ）ベンジル３−｛〔（２−メチル−２Ｈ−テトラゾール−５−イル）メトキシ〕メチル｝ピペリジン−１−カルボキシラート及びベンジル３−｛〔（１−メチル−１Ｈ−テトラゾール−５−イル）メトキシ〕メチル｝ピペリジン−１−カルボキシラート
参考例４３（４３ｂ）で得られたベンジル３−〔（１Ｈ−テトラゾール−５−イルメトキシ）メチル〕ピペリジン−１−カルボキシラートを用いて参考例４０（４０ｃ）と同様に反応を行い、標記目的化合物（低極性側、２−Ｍｅ体、と高極性側１−Ｍｅ体）を得た。
(43c) Benzyl 3-{[(2-methyl-2H-tetrazol-5-yl) methoxy] methyl} piperidine-1-carboxylate and benzyl 3-{[(1-methyl-1H-tetrazol-5-yl) Methoxy] methyl} piperidine-1-carboxylate Reference Example 40 (40c) using benzyl 3-[(1H-tetrazol-5-ylmethoxy) methyl] piperidine-1-carboxylate obtained in Reference Example 43 (43b) The title target compound (low polarity side, 2-Me isomer, and high polarity side 1-Me isomer) was obtained.

ベンジル３−｛〔（２−メチル−２Ｈ−テトラゾール−５−イル）メトキシ〕メチル｝ピペリジン−１−カルボキシラート
無色油状物
IR (liquid film) ν_max2935, 2859, 1699, 1471, 1432, 1261, 1235, 1154, 1109, 1074 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 1.20-1.29 (1H, m), 1.45 (1H, br s), 1.61-1.70 (1H, m), 1.75-1.89 (2H, m), 2.60-2.81 (1H, br), 2.84-2.91 (1H, m), 3.43 (2H, d, J = 5.9 Hz), 3.95 (1H, dt, J = 4.0, 13.0 Hz), 4.04 (1H, br s), 4.33 (3H, s), 4.71 (2H, s), 5.07-5.17 (2H, m), 7.24-7.34 (5H, m);
MS(FAB) m/z: 346 [M+H]⁺。
Benzyl 3-{[(2-methyl-2H-tetrazol-5-yl) methoxy] methyl} piperidine-1-carboxylate colorless oil
IR (liquid film) ν _max 2935, 2859, 1699, 1471, 1432, 1261, 1235, 1154, 1109, 1074 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400MHz) δ 1.20-1.29 (1H, m), 1.45 (1H, br s), 1.61-1.70 (1H, m), 1.75-1.89 (2H, m), 2.60-2.81 (1H , br), 2.84-2.91 (1H, m), 3.43 (2H, d, J = 5.9 Hz), 3.95 (1H, dt, J = 4.0, 13.0 Hz), 4.04 (1H, br s), 4.33 (3H , s), 4.71 (2H, s), 5.07-5.17 (2H, m), 7.24-7.34 (5H, m);
MS (FAB) m / z: 346 [M + H] ^< +>.

ベンジル３−｛〔（１−メチル−１Ｈ−テトラゾール−５−イル）メトキシ〕メチル｝ピペリジン−１−カルボキシラート
無色油状物
IR (liquid film) ν_max2937, 2860, 1698, 1473, 1433, 1360, 1262, 1236, 1154, 1107 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 1.17-1.26 (1H, m), 1.48 (1H, br.s), 1.61-1.71 (1H, br), 1.71-1.91 (2H, m), 2.75 (1H, t, J = 11.0 Hz), 2.82-3.03 (1H, br), 3.32-3.41 (2H, m), 3.82-4.07 (4H, m), 4.07-4.22 (1H, br), 4.08 (2H, br.s), 5.11 (1H, AB type d’s, J = 12.5 Hz), 5.12 (1H, AB type d’s, J = 12.5 Hz ), 7.30-7.40 (5H, m);
MS(FAB) m/z: 346 [M+H]⁺。
Benzyl 3-{[(1-methyl-1H-tetrazol-5-yl) methoxy] methyl} piperidine-1-carboxylate colorless oil
IR (liquid film) ν _max 2937, 2860, 1698, 1473, 1433, 1360, 1262, 1236, 1154, 1107 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.17-1.26 (1H, m), 1.48 (1H, br.s), 1.61-1.71 (1H, br), 1.71-1.91 (2H, m), 2.75 (1H, t, J = 11.0 Hz), 2.82-3.03 (1H, br), 3.32-3.41 (2H, m), 3.82-4.07 (4H, m), 4.07-4.22 (1H, br), 4.08 (2H, br. s), 5.11 (1H, AB type d's, J = 12.5 Hz), 5.12 (1H, AB type d's, J = 12.5 Hz), 7.30-7.40 (5H, m);
MS (FAB) m / z: 346 [M + H] ^< +>.

（４３ｄ）３−｛〔（２−メチル−２Ｈ−テトラゾール−５−イル）メトキシ〕メチル｝ピペリジン
参考例４３（４３ｃ）で得られたベンジル３−｛〔（２−メチル−２Ｈ−テトラゾール−５−イル）メトキシ〕メチル｝ピペリジン−１−カルボキシラートを用いて参考例１（１ｂ）と同様に反応を行い、標記目的化合物を得た。
無色油状物
IR (liquid film) ν_max3318, 2928, 2855, 1555, 1447, 1354, 1271, 1104, 1074, 1037 cm^-1;
¹H NMR (CDCl₃, 500MHz) δ 1.08-1.16 (1H, m), 1.40-1.49 (1H, m), 1.61-1.70 (2H ,m), 1.77-1.87 (2H, m), 2.34 (1H, dd, J = 10.3, 12.2 Hz), 2.55 (1H, dt, J = 2.9, 12.2 Hz), 2.99 (1H, dt, J = 3.4, 12.2 Hz), 3.13 (1H, d, J = 11.7 Hz), 3.38-3.44 (2H, m), 4.36 (3H, s), 4.74 (2H, s);
MS(EI) m/z: 211 [M⁺]。
(43d) 3-{[(2-Methyl-2H-tetrazol-5-yl) methoxy] methyl} piperidine benzyl 3-{[(2-methyl-2H-tetrazole-5 obtained in Reference Example 43 (43c) The reaction was performed in the same manner as in Reference Example 1 (1b) using -yl) methoxy] methyl} piperidine-1-carboxylate to obtain the title compound.
Colorless oil
IR (liquid film) ν _max 3318, 2928, 2855, 1555, 1447, 1354, 1271, 1104, 1074, 1037 cm ^-1 ;
¹ H NMR (CDCl ₃ , 500 MHz) δ 1.08-1.16 (1H, m), 1.40-1.49 (1H, m), 1.61-1.70 (2H, m), 1.77-1.87 (2H, m), 2.34 (1H, dd, J = 10.3, 12.2 Hz), 2.55 (1H, dt, J = 2.9, 12.2 Hz), 2.99 (1H, dt, J = 3.4, 12.2 Hz), 3.13 (1H, d, J = 11.7 Hz), 3.38-3.44 (2H, m), 4.36 (3H, s), 4.74 (2H, s);
MS (EI) m / z: 211 [M ^<+ >].

［参考例４４］３−｛〔（１−メチル−１Ｈ−テトラゾール−５−イル）メトキシ〕メチル｝ピペリジン
参考例４３（４３ｃ）で得られたベンジル３−｛〔（２−メチル−２Ｈ−テトラゾール−５−イル）メトキシ〕メチル｝ピペリジン−１−カルボキシラートを用いて参考例１（１ｂ）と同様に反応を行い、標記目的化合物を得た。
無色油状物
IR (liquid film) ν_max3319, 2930, 2856, 1547, 1475, 1450, 1416, 1358, 1283, 1103 cm^-1;
¹H NMR (CDCl₃, 500MHz) δ 1.06-1.14 (1H, m), 1.41-1.50 (1H, m), 1.51-1.62 (1H, br), 1.63-1.68 (1H ,m), 1.72-1.84 (2H, m), 2.33 (1H, t, J = 10.3 Hz), 2.54 (1H, dt, J = 2.7, 11.7 Hz), 2.99 (1H, dt, J = 3.4, 12.2 Hz), 3.09 (1H, d, J = 11.7 Hz), 3.33 (2H, d, J = 6.8 Hz), 4.12 (3H, s), 4.82 (2H, s);
MS(FAB) m/z: 212 [M+H]⁺。
[Reference Example 44] 3-{[(1-Methyl-1H-tetrazol-5-yl) methoxy] methyl} piperidine Benzyl 3-{[(2-methyl-2H-tetrazole) obtained in Reference Example 43 (43c) The reaction was performed in the same manner as in Reference Example 1 (1b) using -5-yl) methoxy] methyl} piperidine-1-carboxylate to obtain the title compound.
Colorless oil
IR (liquid film) ν _max 3319, 2930, 2856, 1547, 1475, 1450, 1416, 1358, 1283, 1103 cm ^-1 ;
¹ H NMR (CDCl ₃ , 500 MHz) δ 1.06-1.14 (1H, m), 1.41-1.50 (1H, m), 1.51-1.62 (1H, br), 1.63-1.68 (1H, m), 1.72-1.84 ( 2H, m), 2.33 (1H, t, J = 10.3 Hz), 2.54 (1H, dt, J = 2.7, 11.7 Hz), 2.99 (1H, dt, J = 3.4, 12.2 Hz), 3.09 (1H, d , J = 11.7 Hz), 3.33 (2H, d, J = 6.8 Hz), 4.12 (3H, s), 4.82 (2H, s);
MS (FAB) m / z: 212 [M + H] ^< +>.

［参考例４５］（３Ｓ）−３−［（シクロプロピルメトキシ）メチル］ピペリジン塩酸塩
（４５ａ）ｔｅｒｔ−ブチル（３Ｓ）−３−［（シクロプロピルメトキシ）メチル］ピペリジン−１−カルボキシラート
窒素雰囲気下、水素化ナトリウム（１．５７ｇ，３６．０ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（６ｍＬ）溶液に、ｔｅｒｔ−ブチル（３Ｓ）−３−（ヒドロキシメチル）ピペリジン−１−カルボキシラート（６．４６ｇ，３０．０ｍｍｏｌ）のテトラヒドロフラン（３０ｍＬ）溶液を０℃にて加えた。１０分後、（ブロモメチル）シクロプロパン（３．８ｍＬ，３９．０ｍｍｏｌ）を加え、室温で１８時間撹拌した。反応液を０℃に冷却し、水（３０ｍＬ）及び酢酸エチル（５０ｍＬ）を加え、水（５０ｍＬ）にて２回有機相を洗浄し、無水硫酸ナトリウムで乾燥後，溶媒を減圧下留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル，５：１）を用いて精製し，標記目的化合物（７．４５ｇ，収率９２％）を得た。
[Reference Example 45] (3S) -3-[(cyclopropylmethoxy) methyl] piperidine hydrochloride (45a) tert-butyl (3S) -3-[(cyclopropylmethoxy) methyl] piperidine-1-carboxylate Nitrogen atmosphere Under a solution of sodium hydride (1.57 g, 36.0 mmol) in N, N-dimethylformamide (6 mL), tert-butyl (3S) -3- (hydroxymethyl) piperidine-1-carboxylate (6.46 g) was added. , 30.0 mmol) in tetrahydrofuran (30 mL) was added at 0 ° C. After 10 minutes, (bromomethyl) cyclopropane (3.8 mL, 39.0 mmol) was added and stirred at room temperature for 18 hours. The reaction solution was cooled to 0 ° C., water (30 mL) and ethyl acetate (50 mL) were added, the organic phase was washed twice with water (50 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. . The obtained residue was purified using silica gel column chromatography (hexane / ethyl acetate, 5: 1) to obtain the title object compound (7.45 g, yield 92%).

無色液体
IR (film) ν_max2976, 2931, 2855, 1695, 1422, 1365, 1266, 1178, 1151, 1112, 971, 886, 769 cm^-1;
¹H NMR(CDCl₃, 500 MHz) δ 0.20 (2H, d, J = 5.4 Hz), 0.52 (2H, d, J = 7.8 Hz), 1.00-1.07 (1H, m), 1.17-1.25 (1H, m), 1.46 (9H, s), 1.56-1.66 (2H, m), 1.76-1.81 (2H, m), 2.57-2.75 (1H, m), 2.83 (1H, t, J = 8.3 Hz), 3.25 (2H, d, J = 6.4 Hz), 3.30 (2H, d, J = 6.4 Hz), 3.87 (1H, dt, J = 3.9, 13.2 Hz), 3.92-4.05 (1H, m);
MS (EI) m/z: 269 [M⁺], 268, 241, 239, 213, 212, 185, 182, 158, 141, 128, 114, 98, 84, 82, 57, 55, 41。
Colorless liquid
IR (film) ν _max 2976, 2931, 2855, 1695, 1422, 1365, 1266, 1178, 1151, 1112, 971, 886, 769 cm ^-1 ;
¹ H NMR (CDCl ₃ , 500 MHz) δ 0.20 (2H, d, J = 5.4 Hz), 0.52 (2H, d, J = 7.8 Hz), 1.00-1.07 (1H, m), 1.17-1.25 (1H, m), 1.46 (9H, s), 1.56-1.66 (2H, m), 1.76-1.81 (2H, m), 2.57-2.75 (1H, m), 2.83 (1H, t, J = 8.3 Hz), 3.25 (2H, d, J = 6.4 Hz), 3.30 (2H, d, J = 6.4 Hz), 3.87 (1H, dt, J = 3.9, 13.2 Hz), 3.92-4.05 (1H, m);
MS (EI) m / z: 269 [M ⁺ ], 268, 241, 239, 213, 212, 185, 182, 158, 141, 128, 114, 98, 84, 82, 57, 55, 41.

（４５ｂ）（３Ｓ）−３−［（シクロプロピルメトキシ）メチル］ピペリジン塩酸塩
参考例４５（４５ａ）で製造したｔｅｒｔ−ブチル（３Ｓ）−３−［（シクロプロピルメトキシ）メチル］ピペリジン−１−カルボキシラート（２．６９ｇ，１０．０ｍｍｏｌ）に４Ｍ塩化水素−１，４−ジオキサン溶液（１３ｍＬ）を加え、室温で１時間撹拌した。反応液を濃縮し、得られた残渣をエーテルにて結晶化し、標記目的化合物（１．７１ｇ、収率８３％）を得た。
(45b) (3S) -3-[(Cyclopropylmethoxy) methyl] piperidine hydrochloride tert-butyl (3S) -3-[(cyclopropylmethoxy) methyl] piperidine-1-prepared in Reference Example 45 (45a) A 4M hydrogen chloride-1,4-dioxane solution (13 mL) was added to carboxylate (2.69 g, 10.0 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the resulting residue was crystallized from ether to give the title object compound (1.71 g, yield 83%).

無色結晶
Mp 97-98 ℃
IR (KBr) ν_max2937, 2795, 2526, 1583, 1454, 1385, 1126, 1092, 1034, 1009, 893, 595 cm^-1;
¹H NMR(DMSO-d₆, 400 MHz) δ 0.14-0.17 (2H, m), 0.43-0.48 (2H, m), 0.93-1.03 (1H, m), 1.16-1.25 (1H, m), 1.59-1.77 (3H, m), 1.98-2.04 (1H, m), 2.57 (1H, t, J = 12.1 Hz), 2.73 (1H, dt, J = 2.7, 12.5 Hz), 3.17-3.33 (6H, m), 8.87 (1H, brs);
MS (EI) m/z: 169 [M⁺], 168, 140, 126, 114, 98, 84, 82, 55, 36.
Anal. Calcd for C₁₀H₁₉NO・0.20H₂O: C, 57.38; H, 9.82; N, 6.69; Cl, 16.94. Found: C, 57.55; H, 9.83; N, 6.67; Cl, 16.68。
Colorless crystals
Mp 97-98 ℃
IR (KBr) ν _max 2937, 2795, 2526, 1583, 1454, 1385, 1126, 1092, 1034, 1009, 893, 595 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 400 MHz) δ 0.14-0.17 (2H, m), 0.43-0.48 (2H, m), 0.93-1.03 (1H, m), 1.16-1.25 (1H, m), 1.59 -1.77 (3H, m), 1.98-2.04 (1H, m), 2.57 (1H, t, J = 12.1 Hz), 2.73 (1H, dt, J = 2.7, 12.5 Hz), 3.17-3.33 (6H, m ), 8.87 (1H, brs);
MS (EI) m / z: 169 [M ⁺ ], 168, 140, 126, 114, 98, 84, 82, 55, 36.
_{_{. Anal Calcd for C 10 H 19}} NO · 0.20H 2 O:. C, 57.38; H, 9.82; N, 6.69; Cl, 16.94 Found: C, 57.55; H, 9.83; N, 6.67; Cl, 16.68.

［参考例４６］ｔｅｒｔ−ブチル２−（ピペリジン−３−イルメトキシ）エチルカルバマート
（４６ａ）ベンジル３−（｛２−[（ｔｅｒｔ−ブトキシカルボニル）アミノ]エトキシ｝メチル）ピペリジン−１−カルボキシラート
トリフェニルホスフィン（２．２８０ｇ，８．６９ｍｍｏｌ）を、参考例３７（３７ｂ）で製造したベンジル３−[（２−アジドエトキシ）メチル]ピペリジン−１−カルボキシラート（２．６３５ｇ，８．２８ｍｍｏｌ）のテトラヒドロフラン（８ｍＬ）溶液に加え、室温にて２０時間撹拌した。反応液に水（０．３ｍＬ）を加え２０時間撹拌した後、ジ−ｔｅｒｔ−ブチルジカーボナート（１．９８７ｇ，９．１０ｍｍｏｌ）を加え、更に４０時間撹拌した。反応混合物を濃縮して得られた粗生成物をシリカゲルカラムクロマトグラフィー（へキサン：酢酸エチル＝８：２）により精製し、標記目的化合物（３．２１８ｇ，収率９９％）を得た。
[Reference Example 46] tert-butyl 2- (piperidin-3-ylmethoxy) ethylcarbamate (46a) benzyl 3-({2-[(tert-butoxycarbonyl) amino] ethoxy} methyl) piperidine-1-carboxylate tri Phenylphosphine (2.280 g, 8.69 mmol) was added to benzyl 3-[(2-azidoethoxy) methyl] piperidine-1-carboxylate (2.635 g, 8.28 mmol) prepared in Reference Example 37 (37b). To the tetrahydrofuran (8 mL) solution was added and stirred at room temperature for 20 hours. Water (0.3 mL) was added to the reaction solution, and the mixture was stirred for 20 hours, di-tert-butyl dicarbonate (1.987 g, 9.10 mmol) was added, and the mixture was further stirred for 40 hours. The crude product obtained by concentrating the reaction mixture was purified by silica gel column chromatography (hexane: ethyl acetate = 8: 2) to obtain the title object compound (3.218 g, yield 99%).

無色油状物
IR (film) ν_max3355, 2933, 2861, 1701, 1520, 1433, 1260, 1237, 1155, 1121, 985, 867, 764, 699 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.17-1.30 (1H, m), 1.44 (10H, s), 1.58-1.70 (1H, m), 1.72-1.83 (1H, m), 2.75 (1H, br s), 2.92 (1H, t, J = 10.9 Hz), 3.28 (4H, d, J = 5.9 Hz), 3.37-3.48 (2H, m), 3.87-4.06 (2H, m), 4.68-5.05 (1H, m), 5.12 (2H, m), 7.25-7.37 (5H, m);
HRMS m/z: found [M+H]⁺ 393.2429, calcd for C₂₁H₂₉N₁₀O₂ [M+H]⁺393.2389。

（４６ｂ）ｔｅｒｔ−ブチル２−（ピペリジン−３−イルメトキシ）エチルカルバマート
窒素雰囲気下、参考例４６（４６ａ）で製造したベンジル３−（｛２−[（ｔｅｒｔ−ブトキシカルボニル）アミノ]エトキシ｝メチル）ピペリジン−１−カルボキシラート（３．１５８ｇ，８．０４ｍｍｏｌ）のエタノール（１４ｍＬ）溶液に、１０％パラジウム−炭素触媒（２５７ｍｇ）を加え、常圧水素雰囲気下、終夜撹拌した。触媒をセライトろ過により除去し、エタノールで洗浄した後、減圧下に溶媒を留去し、得られた粗生成物をシリカゲルカラムクロマトグラフィー（Ｃｈｒｏｍａｔｏｒｅｘ（ＮＨ），ＦｕｊｉＳｉｌｙｓｉａＣｈｅｍｉｃａｌＬＴＤ．）（１００％酢酸エチル）により精製し、標記目的化合物（２．０１８ｇ，収率９７％）を得た。
Colorless oil
IR (film) ν _max 3355, 2933, 2861, 1701, 1520, 1433, 1260, 1237, 1155, 1121, 985, 867, 764, 699 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.17-1.30 (1H, m), 1.44 (10H, s), 1.58-1.70 (1H, m), 1.72-1.83 (1H, m), 2.75 (1H, br s), 2.92 (1H, t, J = 10.9 Hz), 3.28 (4H, d, J = 5.9 Hz), 3.37-3.48 (2H, m), 3.87-4.06 (2H, m), 4.68-5.05 (1H , m), 5.12 (2H, m), 7.25-7.37 (5H, m);
HRMS m / z: found [M + H] ⁺ 393.2429, calcd for C ₂₁ H ₂₉ N ₁₀ O ₂ [M + H] ⁺ 393.2389.

(46b) tert-butyl 2- (piperidin-3-ylmethoxy) ethylcarbamate benzyl 3-({2-[(tert-butoxycarbonyl) amino] ethoxy} methyl prepared in Reference Example 46 (46a) under nitrogen atmosphere ) To a solution of piperidine-1-carboxylate (3.158 g, 8.04 mmol) in ethanol (14 mL) was added 10% palladium-carbon catalyst (257 mg), and the mixture was stirred overnight under a normal pressure hydrogen atmosphere. After removing the catalyst by Celite filtration and washing with ethanol, the solvent was distilled off under reduced pressure, and the resulting crude product was subjected to silica gel column chromatography (Chromatorex (NH), Fuji Silicon Chemical LTD.) (100% acetic acid). To obtain the title compound (2.018 g, yield 97%).

白色固体
IR (film) ν_max3303, 3205, 2978, 2939, 2857, 2804, 1690, 1560, 1367, 1275, 1170, 1126, 979, 949, 869, 777, 608 cm^-1;
¹H NMR (CDCl₃, 400 MHz) δ 1.03-1.16 (1H, m), 1.44 (9H, s), 1.56-1.69 (2H, br s), 1.70-1.81 (2H, br s), 2.32 (1H, t, J = 10.9 Hz), 2.54 (1H, t, J = 10.9 Hz), 2.99 (1H, d, J = 12.2 Hz), 3.10 (1H, d, J = 12.2 Hz), 3.20-3.32 (4H, m), 3.43 (2H, br s), 4.86 (1H, br s);
HRMS m/z: found [M+H]⁺ 259.1998, calcd for C₁₃H₂₇N₂O₃ [M+H]⁺259.2021。

［参考例４７］３−｛［（１−メチル−１Ｈ−テトラゾール−５−イル）チオ］メチル｝ピペリジン
（４７ａ）ベンジル３−（｛［（４−メチルフェニル）スフォニル］オキシ｝メチル）ピペリジン−１−カルボキシラート
氷冷下、ベンジル３−（ヒドロキシメチル）ピペリジン−１−カルボキシラート（Ａｒｃｈ．Ｐｈａｒｍ．（ＷｅｉｎｈｅｉｍＧｅｒ．），３２３,１９９０，９−１２）（９．９７ｇ，４０ｍｍｏｌ）、ｐ−トルエンスルフォニルクロリド（１１．４４ｇ，６０ｍｍｏｌ）の塩化メチレン（４００ｍＬ）溶液に、トリエチルアミン（１１．１５ｍＬ，８０ｍｍｏｌ）を加え、室温で４時間攪拌した。減圧下、塩化メチレンを留去し、水（２００ｍＬ）を加え、酢酸エチルで抽出（２００ｍＬ×３）した。有機層を合せ、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下に溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル，３／１）にて精製し、１４．９３ｇ（収率９３％）の標記目的化合物を得た。
White solid
IR (film) ν _max 3303, 3205, 2978, 2939, 2857, 2804, 1690, 1560, 1367, 1275, 1170, 1126, 979, 949, 869, 777, 608 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.03-1.16 (1H, m), 1.44 (9H, s), 1.56-1.69 (2H, br s), 1.70-1.81 (2H, br s), 2.32 (1H , t, J = 10.9 Hz), 2.54 (1H, t, J = 10.9 Hz), 2.99 (1H, d, J = 12.2 Hz), 3.10 (1H, d, J = 12.2 Hz), 3.20-3.32 (4H , m), 3.43 (2H, br s), 4.86 (1H, br s);
HRMS m / z: found [M + H] ⁺ 259.1998, calcd for C ₁₃ H ₂₇ N ₂ O ₃ [M + H] ⁺ 259.2021.

[Reference Example 47] 3-{[(1-Methyl-1H-tetrazol-5-yl) thio] methyl} piperidine (47a) benzyl 3-({[(4-methylphenyl) sulfonyl] oxy} methyl) piperidine- 1-Carboxylate Under cooling with ice, benzyl 3- (hydroxymethyl) piperidine-1-carboxylate (Arch. Pharm. (Weinheim Ger.), 323, 1990, 9-12) (9.97 g, 40 mmol), p- Triethylamine (11.15 mL, 80 mmol) was added to a solution of toluenesulfonyl chloride (11.44 g, 60 mmol) in methylene chloride (400 mL), and the mixture was stirred at room temperature for 4 hours. Under reduced pressure, methylene chloride was distilled off, water (200 mL) was added, and the mixture was extracted with ethyl acetate (200 mL × 3). The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate, 3/1) to obtain 14.93 g (yield 93%) of the title compound.

淡黄色油状物;
IR (film) ν_max2494, 2861, 1699, 1432, 1361, 1263, 1236, 1177 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.18-1.33 (1H, m), 1.35-1.51 (1H, m), 1.59-1.68 (1H, m), 1.70-1.91 (2H, m), 2.44 (3H, s), 2.54-2.79 (1H, m), 2.80-2.90 (1H, m), 3.81-4.04 (4H, m), 5.09 (2H, s), 7.26-7.37 (7H, m), 7.74 (2H, d, J = 7.8 Hz);
MS (FAB) m/z: 404 [M+H]⁺, 360, 270, 226。
Pale yellow oil;
IR (film) ν _max 2494, 2861, 1699, 1432, 1361, 1263, 1236, 1177 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.18-1.33 (1H, m), 1.35-1.51 (1H, m), 1.59-1.68 (1H, m), 1.70-1.91 (2H, m), 2.44 (3H , s), 2.54-2.79 (1H, m), 2.80-2.90 (1H, m), 3.81-4.04 (4H, m), 5.09 (2H, s), 7.26-7.37 (7H, m), 7.74 (2H , d, J = 7.8 Hz);
MS (FAB) m / z: 404 [M + H] ⁺ , 360, 270, 226.

（４７ｂ）ベンジル３−｛［（１−メチル−１Ｈ−テトラゾール−５−イル）チオ］メチル｝ピペリジン−１−カルボキシラート
参考例４７（４７ａ）で製造したベンジル３−（｛［（４−メチルフェニル）スフォニル］オキシ｝メチル）ピペリジン−１−カルボキシラート（２．０９ｇ，５．１８ｍｍｏｌ）、１−メチル−１Ｈ−テトラゾール−５−チオール（６６２ｍｇ，５．７０ｍｍｏｌ）と炭酸カリウム（８６０ｍｇ，６．２２ｍｍｏｌ）をジメチルスルフォキシド（１０．４ｍＬ）に溶解し、１００℃で３時間加熱攪拌した。反応液を室温まで冷やし、水（２０ｍＬ）を加え、酢酸エチルで抽出（２０ｍＬ×３）した。有機層を合せ、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、減圧下に溶媒を留去した。残渣をシリカゲルクロマトグラフィ−（ヘキサン／酢酸エチル，２／１）にて精製し、１．５８ｇ（収率８８％）の標記目的化合物を得た。
(47b) Benzyl 3-{[(1-methyl-1H-tetrazol-5-yl) thio] methyl} piperidine-1-carboxylate Benzyl 3-({[(4-Methyl) prepared in Reference Example 47 (47a) Phenyl) sulfonyl] oxy} methyl) piperidine-1-carboxylate (2.09 g, 5.18 mmol), 1-methyl-1H-tetrazol-5-thiol (662 mg, 5.70 mmol) and potassium carbonate (860 mg, 6. 22 mmol) was dissolved in dimethyl sulfoxide (10.4 mL), and the mixture was stirred with heating at 100 ° C. for 3 hours. The reaction solution was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate, 2/1) to obtain 1.58 g (yield 88%) of the title compound.

無色油状物;
IR (film) ν_max2938, 2856, 1699, 1433, 1238 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.22-1.60 (2H, m), 1.64-1.76 (1H, m), 1.90-2.04 (2H, m), 2.70-3.49 (4H, m), 3.75-4.23 (5H, m), 5.10 (2H, m), 7.24-7.39 (5H, m);
MS (FAB) m/z: 348 [M+H]⁺, 258, 240。
Colorless oil;
IR (film) ν _max 2938, 2856, 1699, 1433, 1238 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.22-1.60 (2H, m), 1.64-1.76 (1H, m), 1.90-2.04 (2H, m), 2.70-3.49 (4H, m), 3.75-4.23 (5H, m), 5.10 (2H, m), 7.24-7.39 (5H, m);
MS (FAB) m / z: 348 [M + H] ⁺ , 258, 240.

（４７ｃ）３−｛［（１−メチル−１Ｈ−テトラゾール−５−イル）チオ］メチル｝ピペリジン
参考例４７（４７ｃ）で製造したベンジル３−｛［（１−メチル−１Ｈ−テトラゾール−５−イル）チオ］メチル｝ピペリジン−１−カルボキシラートを用いて、参考例２７（２７ｃ）と同様に反応を行い、標記目的化合物を得た。

淡褐色油状物;
IR (film) ν_max3323, 2930, 2851, 1448, 1391, 1279, 1172 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.16-1.29 (1H, m), 1.39-1.52 (1H, m), 1.64-1.74 (1H, m), 1.83-2.02 (2H, m), 2.41 (1H, t, J = 11.3 Hz), 2.58 (1H, dt, J = 11.3, 2.3 Hz), 2.95-3.04 (1H, m), 3.15-3.34 (3H, m), 3.92 (3H, s);
MS (FAB) m/z: 214 [M+H]⁺, 176, 130。
(47c) 3-{[(1-Methyl-1H-tetrazol-5-yl) thio] methyl} piperidine Benzyl 3-{[(1-methyl-1H-tetrazole-5- 5) prepared in Reference Example 47 (47c) Yl) thio] methyl} piperidine-1-carboxylate was used to carry out the reaction in the same manner as in Reference Example 27 (27c) to give the title object compound.

Light brown oil;
IR (film) ν _max 3323, 2930, 2851, 1448, 1391, 1279, 1172 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.16-1.29 (1H, m), 1.39-1.52 (1H, m), 1.64-1.74 (1H, m), 1.83-2.02 (2H, m), 2.41 (1H , t, J = 11.3 Hz), 2.58 (1H, dt, J = 11.3, 2.3 Hz), 2.95-3.04 (1H, m), 3.15-3.34 (3H, m), 3.92 (3H, s);
MS (FAB) m / z: 214 [M + H] ⁺ , 176, 130.

［参考例４８］２−｛［（３Ｓ）−ピペリジン−３−イルメトキシ］メチル｝ピリジン
（４８ａ）ｔｅｒｔ−ブチル（３Ｓ）−３−［（ピリジン−２−イルメトキシ）メチル］ピペリジン−１−カルボキシラート
ｔｅｒｔ−ブチル（３Ｓ）−３−（ヒドロキシメチル）ピペリジン−１−カルボキシラート（１．０５ｇ，４．９ｍｍｏｌ）、２−（クロロメチル）ピリジン塩酸塩（１．２０ｇ，７．３ｍｍｏｌ）およびテトラ−ｎ−ブチルアンモニウム硫酸水素塩（０．３３ｇ，０．９８ｍｍｏｌ）のトルエン（２ｍＬ）懸濁液に、５０％水酸化ナトリウム水溶液（２ｍＬ）を加え、８０℃にて８時間攪拌した。反応混合物に水（１００ｍＬ）を加え、水層をジエチルエーテル（１００ｍＬ）で抽出した。抽出液を無水硫酸ナトリウムで乾燥後、溶媒を減圧下で留去した。得られた残留物を塩化メチレン（１０ｍＬ）に溶解し、無水酢酸（２ｍＬ）と触媒量の４−ジメチルアミノピリジンを加え、未反応のｔｅｒｔ−ブチル（３Ｓ）−３−（ヒドロキシメチル）ピペリジン−１−カルボキシラートをアセチル化した。室温で反応混合物を２時間攪拌したのち、飽和重曹水（５０ｍＬ）と塩化メチレン（５０ｍＬ）で分液した。有機層を無水硫酸ナトリウムで乾燥後、溶媒を減圧下留去して得られた残留物をシリカゲルカラムクロマトグラフィー（塩化メチレン／メタノール＝３０：１）により精製し、０．４３ｇ（収率２９％）の標記目的化合物を得た。
[Reference Example 48] 2-{[(3S) -piperidin-3-ylmethoxy] methyl} pyridine (48a) tert-butyl (3S) -3-[(pyridin-2-ylmethoxy) methyl] piperidine-1-carboxylate tert-Butyl (3S) -3- (hydroxymethyl) piperidine-1-carboxylate (1.05 g, 4.9 mmol), 2- (chloromethyl) pyridine hydrochloride (1.20 g, 7.3 mmol) and tetra- A 50% aqueous sodium hydroxide solution (2 mL) was added to a suspension of n-butylammonium hydrogensulfate (0.33 g, 0.98 mmol) in toluene (2 mL), and the mixture was stirred at 80 ° C. for 8 hours. Water (100 mL) was added to the reaction mixture, and the aqueous layer was extracted with diethyl ether (100 mL). The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in methylene chloride (10 mL), acetic anhydride (2 mL) and a catalytic amount of 4-dimethylaminopyridine were added, and unreacted tert-butyl (3S) -3- (hydroxymethyl) piperidine- 1-carboxylate was acetylated. The reaction mixture was stirred at room temperature for 2 hours and then partitioned between saturated aqueous sodium hydrogen carbonate (50 mL) and methylene chloride (50 mL). After drying the organic layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methylene chloride / methanol = 30: 1) to give 0.43 g (yield 29%). The title compound was obtained.

油状物;
IR (liquid film) ν_max 1692, 1151, 762 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 1.21-1.30 (1H, m), 1.41-1.52 (1H, m), 1.46 (9H, s), 1.61-1.69 (1H, m), 1.80-1.93 (2H, m), 2.65-2.75 (1H, br), 3.39-3.46 (1H, m), 3.39-3.46 (2H, m), 3.90 (1H, brd, J = 12.9 Hz), 3.90-4.30 (1H, br), 4.62 (2H, s), 7.18 (1H, dd, J = 5.1, 7.4 Hz), 7.45 (1H, brd, J = 7.8 Hz), 7.69 (1H, ddd, J = 2.0, 7.4, 7.8 Hz), 8.54 (1H, brd, J = 5.1 Hz);
MS (FAB) m/z: 307 [M+H]⁺, 207。
Oily matter;
IR (liquid film) ν _max 1692, 1151, 762 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.21-1.30 (1H, m), 1.41-1.52 (1H, m), 1.46 (9H, s), 1.61-1.69 (1H, m), 1.80-1.93 (2H, m), 2.65-2.75 (1H, br), 3.39-3.46 (1H, m), 3.39-3.46 (2H, m), 3.90 (1H, brd, J = 12.9 Hz), 3.90-4.30 (1H, br) , 4.62 (2H, s), 7.18 (1H, dd, J = 5.1, 7.4 Hz), 7.45 (1H, brd, J = 7.8 Hz), 7.69 (1H, ddd, J = 2.0, 7.4, 7.8 Hz), 8.54 (1H, brd, J = 5.1 Hz);
MS (FAB) m / z: 307 [M + H] ⁺ , 207.

（４８ｂ）２−｛［（３Ｓ）−ピペリジン−３−イルメトキシ］メチル｝ピリジン
参考例４８（４８ａ）で製造したｔｅｒｔ−ブチル（３Ｓ）−３−［（ピリジン−２−イルメトキシ）メチル］ピペリジン−１−カルボキシラート（０．４３ｇ，１．４ｍｍｏｌ）のメタノール（２ｍＬ）溶液に、４Ｎ塩化水素−１，４−ジオキサン溶液（２ｍＬ）を加え、室温にて２時間攪拌した。反応混合物を減圧下に濃縮して得られた残留物に、１Ｎ水酸化ナトリウム水溶液（１０ｍＬ）を加えたのち、水層を塩化メチレン（３ｘ２０ｍＬ）で抽出した。抽出液を無水硫酸ナトリウムで乾燥後、減圧下で溶媒を留去して、０．２７ｇ（収率９４％）の標記目的化合物を得た。
(48b) 2-{[(3S) -piperidin-3-ylmethoxy] methyl} pyridine tert-butyl (3S) -3-[(pyridin-2-ylmethoxy) methyl] piperidine- prepared in Reference Example 48 (48a) To a solution of 1-carboxylate (0.43 g, 1.4 mmol) in methanol (2 mL) was added 4N hydrogen chloride-1,4-dioxane solution (2 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, 1N aqueous sodium hydroxide solution (10 mL) was added to the resulting residue, and the aqueous layer was extracted with methylene chloride (3 × 20 mL). The extract was dried over anhydrous sodium sulfate and then the solvent was distilled off under reduced pressure to obtain 0.27 g (yield 94%) of the title compound.

油状物;
IR (liquid film) ν_max 3393, 1637, 1593, 1124, 1112, 1088, 764 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 1.12-1.23 (1H, m), 1.43-1.54 (1H, m), 1.65-1.71 (1H, m), 1.81-1.92 (2H, m), 1.91 (1H, brs), 2.40 (1H, dd, J = 10.6, 11.7 Hz), 2.57 (1H, ddd, J = 3.1, 11.7, 12.1 Hz), 3.02 (1H, brd, J = 12.1 Hz), 3.19 (1H, brd, J = 11.7 Hz), 3.36-3.44 (2H, m), 4.61 (2H, s), 7.18 (1H, dd, J = 4.7, 7.4 Hz), 7.43 (1H, brd, J = 7.8 Hz), 7.69 (1H, ddd, J = 2.0, 7.4, 7.8 Hz), 8.53 (1H, brd, J = 4.7 Hz);
MS (FAB) m/z: 207 [M+H]⁺。
Oily matter;
IR (liquid film) ν _max 3393, 1637, 1593, 1124, 1112, 1088, 764 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.12-1.23 (1H, m), 1.43-1.54 (1H, m), 1.65-1.71 (1H, m), 1.81-1.92 (2H, m), 1.91 (1H, brs), 2.40 (1H, dd, J = 10.6, 11.7 Hz), 2.57 (1H, ddd, J = 3.1, 11.7, 12.1 Hz), 3.02 (1H, brd, J = 12.1 Hz), 3.19 (1H, brd , J = 11.7 Hz), 3.36-3.44 (2H, m), 4.61 (2H, s), 7.18 (1H, dd, J = 4.7, 7.4 Hz), 7.43 (1H, brd, J = 7.8 Hz), 7.69 (1H, ddd, J = 2.0, 7.4, 7.8 Hz), 8.53 (1H, brd, J = 4.7 Hz);
MS (FAB) m / z: 207 [M + H] ^< +>.

［参考例４９］(３Ｓ)−３−{[２−(２Ｈ−テトラゾール−２−イル)エトキシ]メチル}ピペリジン塩酸塩
（４９ａ）ｔｅｒｔ−ブチル (３Ｓ)−３−[(２−ヒドロキシエトキシ)メチル]ピペリジン−１−カルボキシラート
参考例３８（３８ａ）で製造したｔｅｒｔ-ブチル（３Ｓ）−３−[（２−ｔｅｒｔ−ブトキシ−２−オキソエトキシ）メチル]ピペリジン−１−カルボキシラート（１３．２ｇ，４０．０ｍｍｏｌ）のテトラヒドロフラン（８０ｍＬ）溶液を、水素化アルミニウムリチウム（１．８２ｇ，４８．０ｍｍｏｌ）のテトラヒドロフラン懸濁液に、０℃にて３０分かけて滴下した後、３時間撹拌した。反応液に、１Ｎ水酸化ナトリウム水溶液９．１ｍＬを加え、室温にて１時間攪拌した。反応液を、セライトを用いてろ過し、溶媒を減圧下に留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル，１：１→１：２）を用いて精製し、標記目的化合物（９．５４ｇ、収率９２％）を得た。
[Reference Example 49] (3S) -3-{[2- (2H-tetrazol-2-yl) ethoxy] methyl} piperidine hydrochloride (49a) tert-butyl (3S) -3-[(2-hydroxyethoxy) Methyl] piperidine-1-carboxylate tert-Butyl (3S) -3-[(2-tert-butoxy-2-oxoethoxy) methyl] piperidine-1-carboxylate prepared in Reference Example 38 (38a) (13. 2 g, 40.0 mmol) in tetrahydrofuran (80 mL) was added dropwise to a tetrahydrofuran suspension of lithium aluminum hydride (1.82 g, 48.0 mmol) at 0 ° C. over 30 minutes, followed by stirring for 3 hours. . To the reaction solution, 9.1 mL of 1N aqueous sodium hydroxide solution was added and stirred at room temperature for 1 hour. The reaction solution was filtered using celite, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate, 1: 1 → 1: 2) to obtain the title object compound (9.54 g, yield 92%).

無色液体;
¹H NMR(CDCl₃, 400 MHz) δ 1.18-1.33 (1H, m), 1.38-1.53 (1H, m), 1.46 (9H, s), 1.57-1.68 (1H, m), 1.72-1.89 (2H, m), 2.72-3.10 (2H, m), 3.32-3.37 (2H, m), 3.45-3.53 (1H, m) ,3.53-3.61 (1H, m), 3.64-3.90 (4H, m)。
Colorless liquid;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.18-1.33 (1H, m), 1.38-1.53 (1H, m), 1.46 (9H, s), 1.57-1.68 (1H, m), 1.72-1.89 (2H m, 2.72-3.10 (2H, m), 3.32-3.37 (2H, m), 3.45-3.53 (1H, m), 3.53-3.61 (1H, m), 3.64-3.90 (4H, m).

（４９ｂ）ｔｅｒｔ−ブチル (３Ｓ)−３−[(２−{[(４−メチルフェニル)スルホニル]オキシ}エトキシ)メチル]ピペリジン−１−カルボキシラート
氷冷下、参考例４９（４９ａ）で製造したｔｅｒｔ−ブチル (３Ｓ)−３−[(２−ヒドロキシエトキシ)メチル]ピペリジン−１−カルボキシラート（９．５４ｇ，３６．９ｍｍｏｌ）の塩化メチレン（７４ｍＬ）溶液に、トリエチルアミン（１５．５ｍＬ，１１１ｍｍｏｌ）、４−ジメチルアミノピリジン（４５２ｍｇ，３．６９ｍｍｏｌ）、ｐ−トルエンスルホニルクロリド（１０．６ｇ，５５．４ｍｍｏｌ）を順次加え、０℃で３時間撹拌した後、室温で１２時間撹拌した。反応液に、飽和炭酸水素ナトリウム水溶液（５０ｍＬ）、水（５０ｍＬ）を加え、酢酸エチルで２回抽出した。有機層を合わせて、水、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥後，溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル，３：１→１：１）を用いて精製し、標記目的化合物（１５．２ｇ、定量的）を得た。
(49b) tert-butyl (3S) -3-[(2-{[(4-methylphenyl) sulfonyl] oxy} ethoxy) methyl] piperidine-1-carboxylate prepared in Reference Example 49 (49a) under ice cooling To a solution of tert-butyl (3S) -3-[(2-hydroxyethoxy) methyl] piperidine-1-carboxylate (9.54 g, 36.9 mmol) in methylene chloride (74 mL) was added triethylamine (15.5 mL, 111 mmol). ), 4-dimethylaminopyridine (452 mg, 3.69 mmol) and p-toluenesulfonyl chloride (10.6 g, 55.4 mmol) were sequentially added, and the mixture was stirred at 0 ° C. for 3 hours and then at room temperature for 12 hours. Saturated aqueous sodium hydrogen carbonate solution (50 mL) and water (50 mL) were added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate, 3: 1 → 1: 1) to obtain the title object compound (15.2 g, quantitative).

黄色液体;
¹H NMR(CDCl₃, 400 MHz) δ 1.08-1.21 (1H, m), 1.33-1.49 (1H, m), 1.45 (9H, s), 1.57-1.76 (3H, m), 2.45 (3H, s), 2.42-2.65 (1H, m), 2.78 (1H, brt, J = 10.9 Hz), 3.26 (2H, brd, J = 5.5 Hz), 3.60 (2H, t, J = 4.7 Hz), 3.82-4.00 (2H, m), 4.15 (2H, t, J = 4.7 Hz), 7.35 (2H, d, J = 8.6 Hz), 7.80 (2H, d, J = 8.6 Hz)。
Yellow liquid;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.08-1.21 (1H, m), 1.33-1.49 (1H, m), 1.45 (9H, s), 1.57-1.76 (3H, m), 2.45 (3H, s ), 2.42-2.65 (1H, m), 2.78 (1H, brt, J = 10.9 Hz), 3.26 (2H, brd, J = 5.5 Hz), 3.60 (2H, t, J = 4.7 Hz), 3.82-4.00 (2H, m), 4.15 (2H, t, J = 4.7 Hz), 7.35 (2H, d, J = 8.6 Hz), 7.80 (2H, d, J = 8.6 Hz).

（４９ｃ）ｔｅｒｔ−ブチル (３Ｓ)−３−{[２−(２Ｈ−テトラゾール−２−イル)エトキシ]メチル}ピペリジン−１−カルボキシラート
参考例４９（４９ｂ）で製造したｔｅｒｔ−ブチル (３Ｓ)−３−[(２−{[(４−メチルフェニル)スルホニル]オキシ}エトキシ)メチル]ピペリジン−１−カルボキシラート（４．１０ｇ，９．９３ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（２０ｍＬ）溶液に、炭酸カリウム（２．７６ｇ，１９．９ｍｍｏｌ）、１Ｈ−テトラゾール（１．４０ｇ，１９．９ｍｍｏｌ）を順次加え、６０℃で１時間撹拌した。反応液に、水（１００ｍＬ）を加え、酢酸エチルで２回抽出した。有機層を合わせて、水、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥後，溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル，１：１→１：３→１：５）を用いて精製し、標記目的化合物（１．６１ｇ、収率５２％）を得た。
(49c) tert-butyl (3S) -3-{[2- (2H-tetrazol-2-yl) ethoxy] methyl} piperidine-1-carboxylate tert-butyl prepared in Reference Example 49 (49b) (3S) To a solution of -3-[(2-{[(4-methylphenyl) sulfonyl] oxy} ethoxy) methyl] piperidine-1-carboxylate (4.10 g, 9.93 mmol) in N, N-dimethylformamide (20 mL). , Potassium carbonate (2.76 g, 19.9 mmol) and 1H-tetrazole (1.40 g, 19.9 mmol) were sequentially added, and the mixture was stirred at 60 ° C. for 1 hour. Water (100 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate, 1: 1 → 1: 3 → 1: 5) to obtain the title object compound (1.61 g, yield 52%).

淡黄色液体;
¹H NMR(CDCl₃, 500 MHz) δ 1.06-1.16 (1H, m), 1.32-1.49 (1H, m), 1.45 (9H, s), 1.54-1.62 (1H, m), 1.62-1.76 (2H, m), 2.44-2.60 (1H, m), 2.73-2.81 (1H, m), 3.28 (2H, d, J = 6.4 Hz), 3.76-3.94 (2H, m), 3.98 (2H, d, J = 5.4 Hz), 4.81 (2H, d, J = 5.4 Hz), 8.52 (1H, s)。
A pale yellow liquid;
¹ H NMR (CDCl ₃ , 500 MHz) δ 1.06-1.16 (1H, m), 1.32-1.49 (1H, m), 1.45 (9H, s), 1.54-1.62 (1H, m), 1.62-1.76 (2H , m), 2.44-2.60 (1H, m), 2.73-2.81 (1H, m), 3.28 (2H, d, J = 6.4 Hz), 3.76-3.94 (2H, m), 3.98 (2H, d, J = 5.4 Hz), 4.81 (2H, d, J = 5.4 Hz), 8.52 (1H, s).

（４９ｄ）（(３Ｓ)−３−{[２−(２Ｈ−テトラゾール−２−イル)エトキシ]メチル}ピペリジン塩酸塩
参考例４９（４９ｃ）で製造したｔｅｒｔ−ブチル (３Ｓ)−３−{[２−(２Ｈ−テトラゾール−２−イル)エトキシ]メチル}ピペリジン−１−カルボキシラートを用いて、参考例４５（４５ｂ）と同様に反応を行い、標記目的化合物を得た。
無色液体;
¹H NMR(CDCl₃, 400 MHz) δ 1.19-1.34 (1H, m), 1.67-1.79 (1H, m), 1.81-1.99 (2H, m), 2.17-2.29 (1H, m), 2.60-2.73 (1H, m), 2.74-2.87 (1H, m), 3.27-3.48 (4H, m), 3.93-4.05 (2H, m), 4.84 (2H, t, J = 5.4 Hz), 8.56 (1H, s), 9.44 (1H, brs)。
(49d) ((3S) -3-{[2- (2H-tetrazol-2-yl) ethoxy] methyl} piperidine hydrochloride tert-butyl (3S) -3-{[prepared in Reference Example 49 (49c) 2- (2H-tetrazol-2-yl) ethoxy] methyl} piperidine-1-carboxylate was used in the same manner as in Reference Example 45 (45b) to give the title object compound.
Colorless liquid;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.19-1.34 (1H, m), 1.67-1.79 (1H, m), 1.81-1.99 (2H, m), 2.17-2.29 (1H, m), 2.60-2.73 (1H, m), 2.74-2.87 (1H, m), 3.27-3.48 (4H, m), 3.93-4.05 (2H, m), 4.84 (2H, t, J = 5.4 Hz), 8.56 (1H, s ), 9.44 (1H, brs).

［参考例５０］（３Ｓ）−３−｛［（５−メチル−１，２，４−オキサジアゾール−３−イル）メトキシ］メチル｝ピペリジン塩酸塩
（５０ａ）ｔｅｒｔ−ブチル（３Ｓ）−３−［（シアノメトキシ）メチル］ピペリジン−１−カルボキシラート
参考例４３（４３ａ）と同様にｔｅｒｔ−ブチル（３Ｓ）−３−（ヒドロキシメチル）ピペリジン−１−カルボキシラートを用いて反応を行い、表記化合物を得た。
無色油状物
¹H NMR(CDCl₃, 400 MHz) δ 1.19-1.31 (1H, m), 1.37-1.52 (1H, m), 1.46 (9H, s), 1.59-1.70 (1H, m), 1.74-1.91 (2H, m), 2.61-2.75 (1H, m), 2.79-2.89 (1H, m), 3.38-3.49 (2H, m), 3.79-4.02 (2H, m), 4.23 (2H, s)。

（５０ｂ）ｔｅｒｔ−ブチル（３Ｓ）−３−（｛［２−アミノ−２−（ヒドロキシイミノ）エチル］オキシ｝メチル）ピペリジン−１−カルボキラート
参考例５０（５０ａ）で合成したｔｅｒｔ−ブチル（３Ｓ）−３−［（シアノメトキシ）メチル］ピペリジン−１−カルボキシラート（１１．７９ｇ，４６．４ｍｍｏｌ）のエタノール（４６ｍＬ）溶液に５０％ヒドロキシルアミン水溶液（５．７ｍＬ）を加え、１００℃で８時間加熱した。反応液を室温まで冷却し、水（１００ｍＬ）を加え、酢酸エチルで２回抽出した。有機層を合わせ飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、溶媒を減圧下に留去した。得られた残渣をシリカゲルクロマトグラフィー（酢酸エチル／メタノール，１００：０→１０：１）にて精製し、表記目的化合物（８．８２ｇ，収率６６％）を得た。
無色油状物
IR (film) ν_max 3482,3349,2975,2930,2858,1670,1588,1428 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.18-1.31 (1H, m), 1.38-1.51 (1H, m), 1.46 (9H, s), 1.55-1.69 (1H, m), 1.72-1.90 (2H, m), 2.70-3.08 (2H, m), 3.31 (2H, d, J = 6.7 Hz), 3.61-4.02 (5H, m), 4.71-4.96 (2H, m);
MS (EI) m/z: 287 [M^+・], 231, 214, 170。

（５０ｃ）ｔｅｒｔ−ブチル（３Ｓ）−３−｛［（５−メチル−１，２，４−オキサジアゾール−３−イル）メトキシ］メチル｝ピペリジン−１−カルボキシラート
参考例５０（５０ｂ）で合成したｔｅｒｔ−ブチル（３Ｓ）−３−（｛［２−アミノ−２−（ヒドロキシイミノ）エチル］オキシ｝メチル）ピペリジン−１−カルボキラート（８．８２ｇ，３０．７ｍｍｏｌ）の塩化メチレン（９２．１ｍＬ）溶液に、無水酢酸（３．１９ｍＬ，３３．８ｍｍｏｌ）、トリエチルアミン（５．１３ｍＬ，３６．８ｍｍｏｌ）を順次加え、室温で２時間撹拌した。反応液を減圧下に濃縮した後、飽和重曹水（１００ｍＬ）を加え、酢酸エチルで３回抽出した。有機層を合わせ、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下に溶媒を留去した。得られた残渣をテトラヒドロフラン（３７ｍＬ）に溶解し、テトラブチルアンモウニウムフルオライドのテトラヒドロフラン１Ｍ溶液（３７ｍＬ，３６．８ｍｍｏｌ）を加え、室温で１時間撹拌した。反応後、水（１００ｍＬ）を加え、酢酸エチルで３回抽出した。有機層を合わせ、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下に溶媒を留去した。得られた残渣をシリカゲルクロマトグラフィー（ヘキサン／酢酸エチル，１：１）にて精製し、表記目的化合物（７．９３ｇ，収率８３％）を得た。
無色油状物
IR (film) ν_max 3508, 2976, 2931, 2858, 1691, 1587, 1424 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.17-1.30 (1H, m), 1.36-1.50 (1H, m), 1.45 (9H, s), 1.55-1.68 (1H, m), 1.74-1.90 (2H, m), 2.59-2.74 (1H, m), 2.60 (3H, s), 2.76-2.88 (1H, m), 3.43 (2H, d, J = 6.3 Hz), 3.80-4.07 (2H, m), 4.57 (2H, d, J = 1.6 Hz);
MS (FAB) m/z: 312 [M+H]⁺, 238, 212。

（５０ｄ）（３Ｓ）−３−｛［（５−メチル−１，２，４−オキサジアゾール−３−イル）メトキシ］メチル｝ピペリジン塩酸塩
参考例５０（５０ｃ）で得られたｔｅｒｔ−ブチル（３Ｓ）−３−｛［（５−メチル−１，２，４−オキサジアゾール−３−イル）メトキシ］メチル｝ピペリジン−１−カルボキシラートを用いて、参考例４５（４５ｂ）と同様に反応を行い、表記目的化合物を得た。
無色油状物
IR (film) ν_max 3402, 2949, 2802, 2558, 2407, 1586 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.33-1.45 (1H, m), 1.80-2.05 (3H, m), 2.08-2.24 (1H, m), 2.27-2.40 (1H, m), 2.62 (3H, s), 2.70-2.86 (2H, m), 3.38-3.59 (3H, m), 4.57 (2H, s), 9.32-9.70 (2H, m);
MS (EI) m/z: 211 [M^+・], 153, 114。

［参考例５１］ (３Ｓ)−３−{[ (３−メチル−１，２，４−チアジアゾール−５−イル)メトキシ]メチル}ピペリジン塩酸塩
（５１ａ）ｔｅｒｔ−ブチル（３Ｓ）−３−[(２−アミノ−２−オキソエトキシ)メチル]ピペリジン−１−カルボキシラート
参考例（３８ｂ）で製造した｛［（３Ｓ）−１−（ｔｅｒｔ−ブトキシカルボニル）ピペリジン−３−イル］メトキシ｝酢酸（５．４７ｇ，２０．０ｍｍｏｌ）のテトラヒドロフラン（６０ｍＬ）溶液に１，１‘−カルボニルジイミダゾール（３．９０ｇ，２４．０ｍｍｏｌ）を加え、室温で３０分間撹拌した。続いて、反応液に濃アンモニア水（６．７０ｍＬ，１００ｍｍｏｌ）を加え、室温で１６時間撹拌した。反応液を濃縮し、得られた残渣に水（１００ｍＬ）を加え、酢酸エチル（１００ｍｌ）で２回抽出した。有機層を合わせて、無水硫酸ナトリウムで乾燥後，溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／メタノール，１：０→２０：１）を用いて精製し、標記目的化合物（５．１４ｇ，収率９４％）を得た。
無色油状物;
¹H NMR(CDCl₃, 400 MHz) δ 1.22-1.34 (1H, m), 1.37-1.53 (1H, m), 1.46 (9H, s), 1.55-1.71 (1H, m), 1.73-1.95 (2H, m), 2.71-3.16 (2H, m), 3.32-3.47 (2H, m), 3.54-4.02 (4H, m), 5.46 (1H, brs), 6.72 (1H, brs);
MS (FAB) m/z: 273 [M+H]⁺, 217, 199, 173.

（５１ｂ）ｔｅｒｔ−ブチル (３Ｓ)−３−[(２−アミノ−２−チオキソエトキシ)メチル]ピペリジン−１−カルボキシラート
窒素雰囲気下、参考例５１（５１ａ）で製造したｔｅｒｔ−ブチル（３Ｓ）−３−[(２−アミノ−２−オキソエトキシ)メチル]ピペリジン−１−カルボキシラート（４．６８ｇ，１７．２ｍｍｏｌ）のテトラヒドロフラン（８６ｍｌ）溶液にローソン試薬（６．９６ｇ，１７．２ｍｍｏｌ）を加え、室温で６時間撹拌した。反応液に、０．５Ｎ水酸化ナトリウム水溶液（２００ｍＬ）を加え、水層を酢酸エチル（２００ｍＬ）で２回抽出した。有機層を合わせて、水 (２００ｍL)および飽和塩化ナトリウム水溶液(２００ｍL)で順次洗浄し、無水硫酸ナトリウムで乾燥後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル，３：１→１：１）を用いて精製し、標記目的化合物（４．１５ｇ，収率８４％）を得た。
無色固体;
Mp 94 ℃；
¹H NMR(CDCl₃, 400 MHz) δ 1.21-1.39 (1H, m), 1.39-1.51 (1H, m), 1.45 (9H, s), 1.52-1.66 (1H, m), 1.70-1.81 (1H, m), 1.83-1.95 (1H, m), 2.61-3.95 (6H, m), 4.18-4.43 (2H, m), 7.52 (1H, brs), 8.43 (1H, brs);
MS (FAB) m/z: 289 [M+H]⁺, 233, 189, 142, 96.

（５１ｃ）ｔｅｒｔ−ブチル (３Ｓ)−３− [(２−｛［（１Ｚ）−１−(ジメチルアミノ)エチリデン］アミノ｝−２−チオキソエトキシ)メチル]ピペリジン−１−カルボキシラート
参考例５１（５１ｂ）で製造したｔｅｒｔ−ブチル (３Ｓ)−３−[(２−アミノ−２−チオキソエトキシ)メチル]ピペリジン−１−カルボキシラート（２．５４ｇ，８．８２ｍｍｏｌ）の塩化メチレン（４４ｍＬ）溶液に、Ｎ，Ｎ−ジメチルアセトアミドジメチルアセタール（３．８７ｍＬ，２６．５ｍｍｏｌ）を加え、室温で１７時間攪拌した。反応液を濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／メタノール，１：０→１０：１）を用いて精製し、標記目的化合物（２．７６ｇ，収率８８％）を得た。
黄色油状物;
¹H NMR(CDCl₃, 400 MHz) δ 1.14-1.29 (1H, m), 1.37-1.52 (1H, m), 1.45 (9H, s), 1.59-1.69 (1H, m), 1.75-1.87 (2H, m), 2.47 (3H, s), 2.50-2.71 (1H, m), 2.78 (1H, t, J = 11.0 Hz), 3.19 (3H, s), 3.24 (3H, s), 3.35-3.48 (2H, m), 3.85-4.10 (2H, m), 4.35 (2H, s) ;
MS (FAB) m/z: 358 [M+H]⁺, 301, 258, 129.

（５１ｄ）ｔｅｒｔ−ブチル (３Ｓ)−３−{[（３−メチル−１，２，４−チアジアゾール−５−イル）メトキシ]メチル}ピペリジン−１−カルボキシラート
ヒドロキシルアミン−Ｏ−スルホン酸（１．２４ｇ，１１．０ｍｍｏｌ）のメタノール（１１ｍＬ）溶液に、ピリジン（３．５２ｍＬ，４４．０ｍｍｏｌ）を加え、参考例５１（５１ｃ）で製造したｔｅｒｔ−ブチル (３Ｓ)−３− [(２−｛［（１Ｚ）−１−(ジメチルアミノ)エチリデン］アミノ｝−２−チオキソエトキシ)メチル]ピペリジン−１−カルボキシラート（２．６０ｇ，７．２７ｍｍｏｌ）のエタノール（３６ｍＬ）溶液を１０分間かけて滴下し、室温で３時間攪拌した。反応液を濃縮し、得られた残渣に水（１００ｍＬ）を加え、酢酸エチル（１００ｍｌ）で２回抽出した。有機層を合わせて、有機層を合わせて、水 (２００ｍL)および飽和塩化ナトリウム水溶液(２００ｍL)で順次洗浄し、無水硫酸ナトリウムで乾燥後，溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル，１：１）を用いて精製し、標記目的化合物（１．８０ｇ，収率７６％）を得た。
淡黄色油状物;
¹H NMR(CDCl₃, 400 MHz) δ 1.21-1.33 (1H, m), 1.40-1.55 (1H, m), 1.46 (9H, s), 1.62-1.71 (1H, m), 1.77-1.95 (2H, m), 2.61-2.76 (1H, m), 2.66 (3H, s), 2.78-2.88 (1H, m), 3.44-3.58 (2H, m), 3.82-3.97 (1H, m), 3.98-4.11 (1H, m), 4.85 (2H, s) ;
MS (FAB) m/z: 328 [M+H]⁺, 272, 228.

（５１ｅ） (３Ｓ)−３−{[ (３−メチル−１，２，４−チアジアゾール−５−イル)メトキシ]メチル}ピペリジン塩酸塩
参考例５１（５１ｄ）で得られたｔｅｒｔ−ブチル (３Ｓ)−３−{[（３−メチル−１，２，４−チアジアゾール−５−イル）メトキシ]メチル}ピペリジン−１−カルボキシラートを用いて、参考例４５（４５ｂ）と同様に反応を行い、表記目的化合物を得た。
¹H NMR(DMSO-d₆ 400 MHz) δ 1.18-1.34 (1H, m), 1.56-1.84 (3H, m), 2.01-2.19 (1H, m), 2.58 (3H, s), 2.60-2.83 (2H, m), 3.14-3.31 (2H, m), 3.48-3.61 (2H, m), 4.94 (2H, s), 9.00 (1H, brs);
MS (EI) m/z: 227 [M]⁺, 197, 171, 114, 99.

ｔｅｒｔ−ブチル（３Ｓ）−３−（ヒドロキシメチル）ピペリジン−１−カルボキシラートと各種ハロゲン化アルキル化合物を出発原料として用いて、参考例４８（４８ａ）と同様に反応を行ったのち、参考例９（９ｂ）或は参考例４５（４５ｂ）に準じた方法で参考例５２乃至５６の化合物を得た。

［参考例５２］３−｛［（３Ｓ）−ピペリジン−３−イルメトキシ］メチル｝ピリジン
出発原料（ハロゲン化アルキル化合物）：３−（クロロメチル）ピリジン塩酸塩
oil;
IR (liquid film) νmax 3393, 1638, 1579, 1093, 795, 714 cm-1;
1H NMR (CDCl3, 400MHz) δ 1.09-1.19 (1H, m), 1.42-1.53 (1H, m), 1.63-1.88 (3H, m), 1.76 (1H, brs), 2.37 (1H, dd, J = 10.7, 11.7 Hz), 2.56 (1H, ddd, J = 2.7, 11.7, 12.1 Hz), 3.00 (1H, brd, J = 12.1 Hz), 3.15 (1H, brd, J = 11.7 Hz), 3.29-3.37 (2H, m), 4.50 (2H, s), 7.28 (1H, dd, J = 4.7, 7.8 Hz), 7.66 (1H, brd, J = 7.8 Hz), 8.53 (1H, brd, J = 4.7 Hz), 8.56 (1H, brs);
MS (EI) m/z: 206 [M+], 114, 108.
Anal. Calcd for C12H18N2O・0.2 H2O: C, 68.67; H, 8.84; N, 13.35. Found: C, 68.65; H, 9.02; N, 13.20.

［参考例５３］４−｛［（３Ｓ）−ピペリジン−３−イルメトキシ］メチル｝ピリジン
出発原料（ハロゲン化アルキル化合物）：４−（クロロメチル）ピリジン塩酸塩
MS (FAB) m/z: 206 [M+H]+,189,158,140
1H NMR(DMSO-d6, 400 MHz) δ1.21-1.36(1H, m), 1.63-1.82(3H, m), 2.14(1H, br), 2.62-2.83(2H, m), 3.21(1H, d, J=11.7Hz), 3.28(1H, d, J=11.7Hz), 3.43-3.52(2H, m), 4.77(2H, s), 7.90(2H, d, J=5.9Hz), 8.85(2H, d, J=5.9Hz)

［参考例５４］（３Ｓ）−３−｛［（２−メチル−１，３−チアゾール−５−イル）メトキシ］メチル｝ピペリジン塩酸塩
出発原料（ハロゲン化アルキル化合物）：５−（クロロメチル）−２−メチル−１，３−チアゾール塩酸塩（参考ＵＳ−２００３−６２５１２１）
淡黄色アモルファス状物質;
IR (film) ν_max 3403, 2947, 2783, 1594, 1454 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.30-1.44 (1H, m), 1.77-2.05 (3H, m), 2.37-2.50 (1H, m), 2.73-2.99 (2H, m), 3.15 (3H, s), 3.31-3.47 (2H, m), 3.51-3.63 (2H, m), 4.70-4.85 (2H, m), 8.19 (1H, s), 9.44-9.58 (1H, m), 9.63-9.74 (1H, m);
MS (FAB) m/z: 227 [M+H]⁺, 186, 112。

［参考例５５］（３Ｓ）−３−｛［（１−メチル−１Ｈ−イミダゾール−４−イル）メトキシ］メチル｝ピペリジン塩酸塩
出発原料（ハロゲン化アルキル化合物）：４−（クロロメチル）−1−メチル−１Ｈ−イミダゾール塩酸塩（参考ＵＳ−２００３−６２５１２１）
褐色油状物;
¹H NMR(CDCl₃, 400 MHz) δ 1.31-1.43 (1H, m), 1.68-1.89 (2H, m), 1.90-1.99 (1H, m), 2.05-2.17 (1H, m), 2.73-2.82 (1H, m), 2.85-2.95 (1H, m), 3.27-3.45 (3H, m), 3.65 (3H, s), 4.57 (2H, s), 7.57 (1H, s), 8.90 (1H, s)。

［参考例５６］（３Ｓ）−３−｛［（１−メチル−１Ｈ−イミダゾール−５−イル）メトキシ］メチル｝ピペリジン２塩酸塩
出発原料（ハロゲン化アルキル化合物）：５−（クロロメチル）−１−メチル−１Ｈ−イミダゾール塩酸塩（参考ＵＳ−２００３−６２５１２１）
微褐色アモルファス状物質;
IR (film) ν_max 3402, 2954, 2786, 259, 2412 cm^-1;
¹H NMR(CD₃OD, 400 MHz) δ 1.31-1.46 (1H, m), 1.61-2.00 (3H, m), 2.04-2.17 (1H, m), 2.78 (1H, t, J = 12.1 Hz), 2.85-2.95 (1H, m), 3.27-3.46 (3H, m), 3.52 (1H, dd, J = 9.4, 5.1 Hz), 3.93 (1H, s), 4.65 (2H, s), 7.59 (1H, s), 8.91 (1H, s);
MS (FAB) m/z: 210 [M+H]⁺, 184, 165。

［参考例５７］（３Ｓ）−３−{[（５−メチル−１,３,４−チアジアゾール−２−イル）メトキシ]メチル}ピペリジン
（５７ａ）ｔｅｒｔ−ブチル（３Ｓ）−３−{[２−（２−アセチルヒドラジノ）−２−オキソエトキシ]メチル}ピペリジン−１−カルボキシラート
参考例３８（３８ｂ）で製造した{[（３Ｓ）−１−（ｔｅｒｔ−ブトキシカルボニル）ピペリジン−３−イル]メトキシ}酢酸（２．１８ｇ，７．９９ｍｍｏｌ）のテトラヒドロフラン（４０ｍＬ）溶液に、１，１‘−カルボニルジイミダゾール（１．５６ｇ，９．５９ｍｍｏｌ）を加え、室温で３０分間撹拌した後、アセトヒドラジド（０．７１ｇ，９．５９ｍｍｏｌ）を加え、室温で１６時間撹拌した。反応液を濃縮し、水（２００ｍＬ）を加え、塩化メチレンで抽出（５ｘ１５０ｍＬ）した。有機層を合わせて、無水硫酸ナトリウムで乾燥後，溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／メタノール，２０：１→１０：１）を用いて精製し、２．２１ｇ（収率８４％）の標記目的化合物を得た。
淡黄色油状物;
¹H NMR(CDCl₃, 500 MHz) δ 1.21-1.32 (1H, m), 1.39-1.52 (1H, m), 1.45 (9H, s), 1.58-1.71 (1H, m), 1.76-1.93 (2H, m), 2.07 (3H, s), 2.75-3.04 (2H, m), 3.37-3.50 (2H, m), 3.66-3.94 (2H, m), 4.04-4.12 (2H, m), 8.10 (1H, brs), 8.78 (1H, brs) ;
MS (FAB) m/z: 330 [M+H]⁺, 274, 230.

（５７ｂ）ｔｅｒｔ−ブチル（３Ｓ）−３−{[（５−メチル−１,３,４−チアジアゾール−２−イル）メトキシ]メチル}ピペリジン−１−カルボキシラート
参考例５７（５７ａ）で製造したｔｅｒｔ−ブチル（３Ｓ）−３−{[２−（２−アセチルヒドラジノ）−２−オキソエトキシ]メチル}ピペリジン−１−カルボキシラート（２．２０ｇ，６．６９ｍｍｏｌ）のテトラヒドロフラン（６７ｍＬ）溶液に、窒素雰囲気下、ローソン試薬（４．０５ｇ，１０．０４ｍｍｏｌ）を加え５時間撹拌した。反応液に０．５Ｎ水酸化ナトリウム水溶液（２００ｍＬ）を加え、水層を酢酸エチル（４００ｍＬ）で抽出した。抽出液を無水硫酸ナトリウムで乾燥後，溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル，１：５）を用いて精製し、１．９５ｇ（収率８９％）の標記目的化合物を得た。
淡黄色油状物;
¹H NMR(CDCl₃, 500 MHz) δ 1.16-1.28 (1H, m), 1.39-1.52 (1H, m), 1.46 (9H, s), 1.59-1.68 (1H, m), 1.74-1.88 (2H, m), 2.52-2.72 (1H, m), 2.74-2.84 (1H, m), 2.78 (3H, s), 3.36-3.47 (2H, m), 3.84-4.11 (2H, m), 4.84 (2H, s);
MS (FAB) m/z: 328 [M+H]⁺, 228.

（５７ｃ）（３Ｓ）−３−{[（５−メチル−１,３,４−チアジアゾール−２−イル）メトキシ]メチル}ピペリジン
参考例５７（５７ｂ）で製造したｔｅｒｔ−ブチル（３Ｓ）−３−{[（５−メチル−１,３,４−チアジアゾール−２−イル）メトキシ]メチル}ピペリジン−１−カルボキシラートを用いて、参考例４５（４５ｂ）と同様に反応を行い、表記目的化合物を得た。
¹H NMR(CDCl₃, 400 MHz) δ 1.30-1.46 (1H, m), 1.78-2.06 (3H, m), 2.30-2.45 (1H, m), 2.67-2.91 (2H, m), 2.88 (3H, s), 3.37-3.61 (4H, m), 4.90 (2H, s), 9.64 (1H, brs);
MS (EI) m/z: 227 [M]⁺, 171, 129, 114, 99.

［参考例５８］４−メチル−３−{[（３Ｓ）−ピペリジン−３−イルメトキシ]メチル}−１,２,４−オキサジアゾール−５（４Ｈ）−オン）
（５８ａ）ｔｅｒｔ−ブチル（３Ｓ）−３−{[（５−オキソ−４，５−ジヒドロ１,２,４−オキサジアゾール−３−イル）メトキシ]メチル}ピペリジン−１−カルボキシラート
参考例５０（５０ｂ）で合成したｔｅｒｔ−ブチル（３Ｓ）−３−（｛［２−アミノ−２−（ヒドロキシイミノ）エチル］オキシ｝メチル）ピペリジン−１−カルボキラート（２．００ｇ，７．０ｍｍｏｌ）の１，４−ジオキサン（２８ｍＬ）溶液に、１，１‘−カルボニルジイミダゾール（１．９４ｇ，１２．０ｍｍｏｌ）を加え、１００℃にて３時間撹拌した。反応液を濃縮した後、水（１００ｍＬ）と塩化メチレン（１００ｍＬ）を加え、さらに１Ｎ塩酸（１５ｍＬ）を加えて分液した。水層を塩化メチレンで抽出（２ｘ１００ｍＬ）し、合わせた有機層を無水硫酸ナトリウムで乾燥後，溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（塩化メチレン／メタノール，３０：１）を用いて精製し、１．４５ｇ（収率６６％）の標記目的化合物を得た。
黄色油状物;
¹H NMR(CDCl₃, 400 MHz) δ 1.31-1.61 (3H, m), 1.45 (9H, s), 1.65-1.80 (1H, m), 1.86-2.05 (1H, m), 2.96-3.16 (2H, m), 3.34-3.42 (1H, m), 3.49-3.59 (1H, m), 3.71-3.83 (1H, m) , 3.87-4.01 (1H, m), 4.12-4.24 (1H, m), 4.48-4.60 (1H, m), 10.87 (1H, brs);
MS (FAB) m/z: 314 [M+H]⁺, 258, 214.

（５８ｂ）ｔｅｒｔ−ブチル（３Ｓ）−３−{[（４−メチル−５−オキソ−４，５−ジヒドロ１,２,４−オキサジアゾール−３−イル）メトキシ]メチル}ピペリジン−１−カルボキシラート
参考例５８（５８ａ）で製造したｔｅｒｔ−ブチル（３Ｓ）−３−{[（５−オキソ−４，５−ジヒドロ１,２,４−オキサジアゾール−３−イル）メトキシ]メチル}ピペリジン−１−カルボキシラート（１．４３ｇ，４．５７ｍｍｏｌ）をＮ，Ｎ−ジメチルホルムアミド（２２ｍＬ）に溶解し、反応容器を窒素置換した。氷冷下、反応溶液に水素化ナトリウム（油性６３％，２６２ｍｇ，６．８８ｍｍｏｌ）を加え、３０分間撹拌し、さらに、ヨウ化メチル（０．５７ｍＬ，９．１４ｍｍｏｌ）を加えた。引き続き反応液を３０分間撹拌したのち、室温にて１２時間撹拌した。反応液を水（２００ｍＬ）と酢酸エチル（４００ｍＬ）で分液して得られた有機層を、水と食塩水で洗浄し、無水硫酸ナトリウムで乾燥後，溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン，１：１）を用いて精製し、１．２９ｇ（収率８６％）の標記目的化合物を得た。
淡黄色固体;
Mp 73-75 ℃；
¹H NMR(CDCl₃, 400 MHz) δ 1.15-1.28 (1H, m), 1.37-1.53 (1H, m), 1.45 (9H, s), 1.58-1.69 (1H, m), 1.70-1.89 (2H, m), 2.67 (1H, dd, J = 9.4, 12.9 Hz), 2.76-2.94 (1H, m), 3.32 (3H, s), 3.34-3.40 (2H, m), 3.74-3.99 (2H, m), 4.42 (1H, s);
MS (FAB) m/z: 328 [M+H]⁺, 272, 228.

（５８ｃ）４−メチル−３−{[（３Ｓ）−ピペリジン−３−イルメトキシ]メチル}−１,２,４−オキサジアゾール−５（４Ｈ）−オン塩酸塩
参考例５８（５８ｂ）で製造したｔｅｒｔ−ブチル（３Ｓ）−３−{[（４−メチル−５−オキソ−４，５−ジヒドロ１,２,４−オキサジアゾール−３−イル）メトキシ]メチル}ピペリジン−１−カルボキシラートを用いて、参考例４５（４５ｂ）と同様に反応を行い、表記目的化合物を得た。
無色固体;
¹H NMR(DMSO-d₆, 400 MHz) δ 1.14-1.29 (1H, m), 1.57-1.80 (3H, m), 1.99-2.12 (1H, m), 2.54-2.79 (2H, m), 3.17 (3H, s), 3.18-3.25 (1H, m), 3.33-3.46 (2H, m), 3.50-3.68 (1H, m), 4.52 (2H, s), 9.05 (1H, brs);
MS (EI) m/z: 228 [M]⁺, 183, 153, 114, 98.

［参考例５９］ (３Ｓ)−３−{[(１−メチル−１Ｈ−イミダゾール−２−イル)メトキシ]メチル}ピペリジン塩酸塩
（５９ａ）ｔｅｒｔ−ブチル (３Ｓ)−３−[（１Ｈ−イミダゾール−２−イルメトキシ）メチル]ピペリジン−１−カルボキシラート
窒素雰囲気下、塩化オキサリル（３．４３ｍＬ，４０．０ｍｍｏｌ）の塩化メチレン（５０ｍＬ）溶液を−７８℃に冷却した。この溶液にジメチルスルホキシド（２．８４ｍＬ，４０．０ｍｍｏｌ）の塩化メチレン（１０ｍＬ）溶液を１０分間かけて滴下し、−７８℃で１５分間攪拌した後、参考例（４９ａ）で製造したｔｅｒｔ−ブチル (３Ｓ)−３−［（２−ヒドロキシエトキシ）メチル］ピペリジン−１−カルボキシラート（５．１８ｇ，２０．０ｍｍｏｌ）の塩化メチレン（３０ｍＬ）溶液を３０分間かけて滴下し、−７８℃で１５分間攪拌した。この反応液にトリエチルアミン（１１．２ｍＬ，８０．０ｍｍｏｌ）の塩化メチレン（１０ｍＬ）溶液を３０分間かけて滴下し、−７８℃で３０分間撹拌後、室温で１時間攪拌した。反応液に、水（１００ｍＬ）および飽和塩化アンモニウム水溶液（１００ｍＬ）を加え分液した後、水層をジエチルエーテル（３００ｍＬ）で１回抽出した。有機層を、水（３００ｍＬ）、飽和塩化ナトリウム水溶液（３００ｍＬ）で順次洗浄し、無水硫酸ナトリウムで乾燥後、溶媒を減圧下留去した。続いて、得られた残渣をメタノール（２００ｍＬ）に溶解し、濃アンモニア水を加え、室温で１０分間攪拌後、４０％グリオキサール水溶液を加え、室温で７２時間攪拌した。反応液を濃縮し、得られた残渣に水（２００ｍＬ）を加え、塩化メチレン（２００ｍＬ）で１回抽出した。有機層を、無水硫酸ナトリウムで乾燥後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／メタノール，２０：１→１０：１）を用いて精製し、標記目的化合物（３．７４ｇ，６３％）を得た。
褐色油状物;
¹H NMR(CDCl₃, 400 MHz) δ 1.35-1.49 (1H, m) , 1.46 (9H, s), 1.54-1.65 (1H, m), 1.69-1.99 (3H, m), 3.16-3.71 (6H, m), 4.43-4.81 (2H, m),7.02 (2H, s) ;
MS (FAB) m/z: 296 [M+H]⁺, 240, 196.

（５９ｂ）ｔｅｒｔ−ブチル (３Ｓ)−３−{[（１−メチル−１Ｈ−イミダゾール−２−イル）メトキシ]メチル}ピペリジン−１−カルボキシラート
窒素雰囲気下、参考例５９（５９ａ）で製造したｔｅｒｔ−ブチル (３Ｓ)−３−[（１Ｈ−イミダゾール−２−イルメトキシ）メチル]ピペリジン−１−カルボキシラート（３．７２ｇ，１２．６ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（５０ｍＬ）溶液を０℃に冷却し、水素化ナトリウム（６３％油性，７３２ｍｇ，１９．２ｍｍｏｌ）を加え、０℃で３０分攪拌した。続いて、ヨウ化メチル（８６４μＬ，１３．９ｍｍｏｌ）を加え、０℃で２時間撹拌した。反応液に水（２００ｍＬ）を加え、酢酸エチル（２００ｍＬ）で２回抽出した。有機層を合わせて、無水硫酸ナトリウムで乾燥後，溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／メタノール，２０：１→１０：１）を用いて精製し、標記目的化合物（３．２３ｇ，８３％）を得た。
淡黄色油状物;
¹H NMR(CDCl₃, 400 MHz) δ 1.09-1.22 (1H, m), 1.45 (9H, s), 1.56-1.67 (2H, m), 1.69-1.82 (2H, m), 2.54 (1H, t, J = 11.7 Hz), 2.75 (1H, t, J = 11.7 Hz), 3.23-3.35 (2H, m), 3.71 (3H, s), 3.81-4.07 (2H, m), 4.56 (2H, s), 6.88 (1H, brs), 6.95 (1H, brs);
MS (FAB) m/z: 310 [M+H]⁺, 254, 210.

（５９ｃ） (３Ｓ)−３−{[(１−メチル−１Ｈ−イミダゾール−２−イル)メトキシ]メチル}ピペリジン塩酸塩
参考例５９（５９ｂ）で製造したｔｅｒｔ−ブチル (３Ｓ)−３−{[（１−メチル−１Ｈ−イミダゾール−２−イル）メトキシ]メチル}ピペリジン−１−カルボキシラートを用いて、参考例４５（４５ｂ）と同様に反応を行い、表記目的化合物を得た。
¹H NMR(DMSO-d₆, 400 MHz) δ 1.15-1.31 (1H, m), 1.61-1.82 (3H, m), 2.06-2.17 (1H, m), 2.57-2.79 (2H, m), 3.13-3.28 (2H, m), 3.38-3.51 (2H, m), 3.82 (3H, s), 4.83 (2H, s), 7.67 (1H, d, J = 2.0 Hz), 7.74 (1H, d, J = 2.0 Hz), 9.29 (1H, brs);
MS (FAB) m/z: 210 [M+H]⁺, 95.

［参考例６０］ (３Ｓ)−３−{[(４−メチル−４Ｈ−１，２，４−トリアゾール−３−イル)メトキシ]メチル}ピペリジン塩酸塩
（６０ａ）ｔｅｒｔ−ブチル（３Ｓ）−３−{[２−(メチルアミノ)−２−オキソエトキシ]メチル}ピペリジン−１−カルボキシラート
参考例３８（３８ｂ）で製造した｛［（３Ｓ）−１−（ｔｅｒｔ−ブトキシカルボニル）ピペリジン−３−イル］メトキシ｝酢酸（４．５３ｇ，１６．６ｍｍｏｌ）のテトラヒドロフラン（５０ｍＬ）溶液に１，１‘−カルボニルジイミダゾール（３．２３ｇ，２０．０ｍｍｏｌ）を加え、室温で３０分間撹拌した。続いて、反応液に４０％メチルアミン水溶液（２．０８ｍＬ，２５．０ｍｍｏｌ）を加え、室温で１７時間撹拌した。反応液を濃縮し、得られた残渣に水（１５０ｍＬ）を加え、酢酸エチル（１５０ｍｌ）で２回抽出した。有機層を合わせて、無水硫酸ナトリウムで乾燥後，溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／メタノール，１：０→２０：１）を用いて精製し、標記目的化合物（４．４２ｇ，収率９３％）を得た。
淡黄色固体;
Mp 58-59 ℃；
¹H NMR(CDCl₃, 400 MHz) δ 1.18-1.31 (1H, m), 1.39-1.52 (1H, m), 1.46 (9H, s), 1.59-1.70 (1H, m), 1.72-1.93 (2H, m), 2.73-3.07 (5H, m), 3.38 (2H, d, J = 6.6 Hz), 3.60-4.01 (4H, m), 6.65 (1H, brs);
MS (FAB) m/z: 287 [M+H]⁺, 231, 187.

（６０ｂ）ｔｅｒｔ−ブチル（３Ｓ）−３−{[２−(メチルアミノ)−２−チオキソエトキシ]メチル}ピペリジン−１−カルボキシラート
窒素雰囲気下、参考例６０（６０ａ）で製造したｔｅｒｔ−ブチル（３Ｓ）−３−{[２−(メチルアミノ)−２−オキソエトキシ]メチル}ピペリジン−１−カルボキシラート（４．４０ｇ，１５．４ｍｍｏｌ）のテトラヒドロフラン（８０ｍｌ）溶液にローソン試薬（６．２３ｇ，１５．４ｍｍｏｌ）を加え、室温で５時間撹拌した。反応液に、０．５Ｎ水酸化ナトリウム水溶液（２００ｍＬ）を加え、水層を酢酸エチル（３００ｍＬ）で１回抽出した。有機層を、水 (１００ｍＬ)および飽和塩化ナトリウム水溶液(１００ｍＬ)で順次洗浄し、無水硫酸ナトリウムで乾燥後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル，３：１→１：１）を用いて精製し、標記目的化合物（４．４２ｇ，収率９５％）を得た。
無色固体;
Mp 103-105 ℃；
¹H NMR(CDCl₃, 400 MHz) δ 1.21-1.37 (1H, m), 1.38-1.52 (1H, m), 1.46 (9H, s), 1.54-1.68 (1H, m), 1.72-1.80 (1H, m), 1.84-1.95 (1H, m), 2.89-3.30 (5H, m), 3.35-3.93 (4H, m), 4.21-4.46 (2H, m), 8.74 (1H, brs);
MS (FAB) m/z: 303 [M+H]⁺, 247, 203.

（６０ｃ）ｔｅｒｔ−ブチル (３Ｓ)−３−{[（４−メチル−４Ｈ−１，２，４−トリアゾール−３−イル）メトキシ]メチル}ピペリジン−１−カルボキシラート
参考例６０（６０ｂ）で製造したｔｅｒｔ−ブチル（３Ｓ）−３−{[２−(メチルアミノ)−２−チオキソエトキシ]メチル}ピペリジン−１−カルボキシラート（１．８２ｇ，６．００ｍｍｏｌ）のテトラヒドロフラン（６ｍＬ）溶液に、ヨウ化メチル（７．４７ｍＬ，１２０ｍｍｏｌ）を加え、室温で３時間攪拌した。反応液を濃縮し、得られた残渣をエタノール（１８ｍＬ）に溶解し、ホルモヒドラジド（１．０８ｍＬ，１８．０ｍｍｏｌ）を加え、加熱還流下１７時間攪拌した。反応液を濃縮し、得られた残渣に水（１００ｍＬ）を加え、塩化メチレン（１００ｍｌ）で２回抽出した。有機層を合わせて、無水硫酸ナトリウムで乾燥後，溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／メタノール，２０：１）を用いて精製し、標記目的化合物（１．３４ｇ，収率７２％）を得た。
淡黄色油状物;
¹H NMR(CDCl₃, 400 MHz) δ 1.10-1.23 (1H, m), 1.33-1.49 (1H, m), 1.45 (9H, s), 1.55-1.66 (1H, m), 1.70-1.82 (2H, m), 2.59 (2H, dd, J = 9.7, 13.3 Hz), 2.73-2.86 (1H, m), 3.26-3.38 (1H, m), 3.75 (3H, s), 3.76-4.02 (2H, m), 4.70 (2H, s), 8.10 (1H, s);
MS (FAB) m/z: 311 [M+H]⁺, 211.

（６０ｄ） (３Ｓ)−３−{[(４−メチル−４Ｈ−１，２，４−トリアゾール−３−イル)メトキシ]メチル}ピペリジン塩酸塩
参考例６０（６０ｃ）で製造したｔｅｒｔ−ブチル (３Ｓ)−３−{[（４−メチル−４Ｈ−１，２，４−トリアゾール−３−イル）メトキシ]メチル}ピペリジン−１−カルボキシラートを用いて、参考例４５（４５ｂ）と同様に反応を行い、表記目的化合物を得た。
¹H NMR(DMSO-d₆, 400 MHz) δ 1.14-1.29 (1H, m), 1.59-1.79 (3H, m), 2.02-2.14 (1H, m), 2.54-2.79 (2H, m), 3.13-3.25 (2H, m), 3.35-3.48 (2H, m), 3.77 (3H, s), 4.77 (2H, s), 9.15 (1H, brs), 9.24 (1H, s);
MS (FAB) m/z: 211 [M+H]⁺, 188.

［参考例６１］ (３Ｓ)−３−{[（１−エチル−１Ｈ−イミダゾール−５−イル)メトキシ]メチル）ピペリジン塩酸塩
（６１ａ）ｔｅｒｔ−ブチル (３Ｓ)−３−{[(１−エチル−１Ｈ−イミダゾール−５−イル)メトキシ]メチル}ピペリジン−１−カルボキシラート
窒素雰囲気下、参考例４９（４９ａ）で製造したｔｅｒｔ−ブチル (３Ｓ)−３−［（２−ヒドロキシエトキシ）メチル］ピペリジン−１−カルボキシラート（２．３０ｇ，８．８８ｍｍｏｌ）の塩化メチレン（８９ｍＬ）溶液を０℃に冷却し、Ｄｅｓｓ−Ｍａｒｔｉｎ試薬（５．６５ｇ，１３．３ｍｍｏｌ）を加え、０℃で１５分間、室温で３時間攪拌した。反応液に飽和チオ硫酸ナトリウム水溶液（５０ｍＬ）および飽和炭酸水素ナトリウム水溶液（５０ｍＬ）を加えて室温で３０分間攪拌した後、酢酸エチル (１００ｍＬ) で３回抽出した。有機層を合わせて、水 (１００ｍＬ)および飽和塩化ナトリウム水溶液(１００ｍＬ)で順次洗浄し、無水硫酸ナトリウムで乾燥後、溶媒を減圧下留去した。続いて、得られた残渣をメタノール（２５ｍＬ）に溶解し、３０〜４０％エチルアミンメタノール溶液を加え、室温にて３０分間攪拌後、ｐ−トルエンスルホニルメチルイソシアニドを加え、室温にて７２時間攪拌した。反応液を濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／メタノール，１０：１）を用いて精製し、標記目的化合物（１．２９ｇ，収率５８％）を得た。
橙色油状物;
¹H NMR(CDCl₃, 400 MHz) δ 1.04-1.24 (1H, m), 1.35-1.50 (13H, m), 1.56-1.68 (1H, m), 1.69-1.82 (2H, m), 2.51-2.64 (1H, m), 2.72-2.82 (1H, m), 3.20-3.29 (2H, m), 3.31-4.05 (4H, m), 4.44 (2H, s), 6.98 (1H, s), 7.51 (1H, s);
MS (FAB) m/z: 324 [M+H]⁺, 268, 242.

（６１ｂ） (３Ｓ)−３−{[（１−エチル−１Ｈ−イミダゾール−５−イル)メトキシ]メチル}ピペリジン塩酸塩
参考例６１（６１ａ）で製造したｔｅｒｔ−ブチル (３Ｓ)−３−{[(１−エチル−１Ｈ−イミダゾール−５−イル)メトキシ]メチル}ピペリジン−１−カルボキシラートを用いて、参考例４５（４５ｂ）と同様に反応を行い、表記目的化合物を得た。
¹H NMR(DMSO-d₆, 400 MHz) δ 1.10-1.29 (1H, m), 1.43 (3H, t, J = 7.4 Hz), 1.59-1.80 (3H, m), 2.01-2.13 (1H, m), 2.53-2.64 (1H, m), 2.65-2.77 (1H, m), 3.10-3.45 (4H, m), 4.14-4.26 (2H, m), 4.59 (2H, s), 7.74 (1H, brs), 9.09 (1H, brs), 9.22 (1H, brs) ;
MS (FAB) m/z: 224 [M+H]⁺, 180, 109, 97.

参考例４９（４９ｂ）で製造したｔｅｒｔ−ブチル (３Ｓ)−３−[(２−{[(４−メチルフェニル)スルホニル]オキシ}エトキシ)メチル]ピペリジン-1-カルボキシラートと各種アミン化合物を出発原料として用いて、参考例４９（４９ｃ）と同様に反応を行ったのち、参考例４５（４５ｂ）に準じた方法で参考例６２乃至７１の化合物を得た。

［参考例６２］ (３Ｓ)−３−{[２−(１Ｈ−ピラゾール−１−イル)エトキシ]メチル}ピペリジン２塩酸塩
出発原料（アミン化合物）：ピラゾール
¹H NMR(DMSO-d₆, 400 MHz) δ 1.06-1.20 (1H, m), 1.56-1.76 (3H, m), 1.91-2.03 (1H, m), 2.42-2.56 (1H, m), 2.63-2.74 (1H, m), 3.05-3.19 (2H, m), 3.21-3.83 (2H, m), 3.65-3.76 (2H, m), 4.27 (2H, t, J = 5.5 Hz), 6.24 (1H, t, J = 1.9 Hz), 7.47 (1H, d, J = 1.9 Hz), 7.73 (1H, d, J = 1.9 Hz), 9.11 (1H, brs);
MS (FAB) m/z: 210 [M+H]⁺, 154, 136, 98.

［参考例６３］ (３Ｓ)−３−{[２−(１Ｈ−イミダゾール−１−イル)エトキシ]メチル}ピペリジン２塩酸塩
出発原料（アミン化合物）：イミダゾール
¹H NMR(DMSO-d₆, 400 MHz) δ 1.07-1.21 (1H, m), 1.55-1.78 (3H, m), 1.93-2.04 (1H, m), 2.44-2.59 (1H, m), 2.64-2.78 (1H, m), 3.06-3.22 (2H, m), 3.26-3.39 (2H, m), 3.70-3.77 (2H, m), 4.35-4.41 (2H, m), 7.70 (1H, dd, J = 1.6, 2.0 Hz), 7.76 (1H, dd, J = 1.6, 2.0 Hz), 9.07 (1H, brs), 9.16 (1H, d, J = 1.6 Hz);
MS (EI) m/z: 209 [M]⁺, 153, 141, 126, 111, 96, 82.

［参考例６４］ (３Ｓ)−３−{[２−(２−メチル−１Ｈ−イミダゾール−１−イル)エトキシ]メチル}ピペリジン２塩酸塩
出発原料（アミン化合物）：２−メチルイミダゾール
¹H NMR(DMSO-d₆, 400 MHz) δ 1.08-1.21 (1H, m), 1.58-1.80 (3H, m), 1.96-2.08 (1H, m), 2.43-2.58 (1H, m), 2.62 (3H, s), 2.60-2.74 (1H, m), 3.06-3.21 (2H, m), 3.25-3.38 (2H, m), 3.70 (2H, t, J = 5.1 Hz), 4.29 (2H, t, J = 5.1 Hz), 7.56 (1H, d, J = 2.0 Hz), 7.62 (1H, d, J = 2.0 Hz), 9.24 (1H, brs);
MS (EI) m/z: 222 [M]⁺, 167, 110, 96, 83.

［参考例６５］（３Ｓ）−３−｛［２−（１Ｈ−１，２，３−トリアゾール−１−イル）エトキシ］メチル｝ピペリジン塩酸塩
出発原料（アミン化合物）：１，２，３−トリアゾール
白色アモルファス状物質;
IR (film) ν_max3404, 2947, 2543, 2413, 1936, 1592, 1541 cm^-1;
¹H NMR(CD₃OD, 400 MHz) δ 1.23-1.37 (1H, m), 1.65-1.82 (2H, m), 1.86-1.95 (1H, m), 1.97-2.10 (1H, m), 2.65-2.75 (1H, m), 2.82-2.93 (1H, m), 3.25-3.41 (3H, m), 3.43-3.50 (1H, m), 3.78-3.98 (2H, m), 4.78-4.84 (2H, m), 8.35 (1H, d, J = 1.2 Hz), 8.50 (1H, d, J = 1.2 Hz);
MS (EI) m/z: 210 [M^+・], 154, 141, 114。

［参考例６６］（（２ｂ）（３Ｓ）−３−｛［２−（２Ｈ−１，２，３−トリアゾール−２−イル）エトキシ］メチル｝ピペリジン塩酸塩
出発原料（アミン化合物）：１，２，３−トリアゾール
白色粉末;
IR (KBr) ν_max2944, 2797, 2772, 2523, 2405, 1582 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.25-1.39 (1H, m), 1.69-1.79 (1H, m), 1.82-2.01 (2H, m), 2.14-2.26 (1H, m), 2.61-2.74 (1H, m), 2.75-2.88 (1H, m), 3.24-3.44 (4H, m), 3.91 (2H, t, J = 5.5 Hz), 4.61 (2H, t, J = 5.5 Hz), 7.65 (2H, s), 9.27-9.42 (1H, m), 9.46-9.65 (1H, m);
MS (EI) m/z: 210 [M^+・], 114。

［参考例６７］ (３Ｓ)−３−{[２−(１Ｈ−１，２，４−トリアゾール−１−イル)エトキシ]メチル}ピペリジン２塩酸塩
出発原料（アミン化合物）：１，２，４−トリアゾール
¹H NMR(DMSO-d₆, 400 MHz) δ 1.06-1.18 (1H, m), 1.57-1.75 (3H, m), 1.91-2.03 (1H, m), 2.44-2.54 (1H, m), 2.62-2.73 (1H, m), 3.04-3.19 (2H, m), 3.23-3.36 (2H, m), 3.66-3.79 (2H, m), 4.40 (2H, t, J = 5.5 Hz), 8.25 (1H, s), 8.89 (1H, s), 9.16 (1H, brs);
MS (EI) m/z: 210 [M]⁺, 154, 141, 114, 97.

［参考例６８］ (３Ｓ)−３−{[２−(４Ｈ−１，２，４−トリアゾール−４−イル)エトキシ]メチル}ピペリジン２塩酸塩
出発原料（アミン化合物）：１，２，４−トリアゾール
¹H NMR(DMSO-d₆, 400 MHz) δ 1.06-1.18 (1H, m), 1.57-1.75 (3H, m), 1.91-2.03 (1H, m), 2.44-2.54 (1H, m), 2.62-2.73 (1H, m), 3.04-3.19 (2H, m), 3.23-3.36 (2H, m), 3.66-3.79 (2H, m), 4.40 (2H, t, J = 5.5 Hz), 8.89 (2H, s), 9.15 (1H, s);
MS (EI) m/z: 210 [M]⁺, 154, 114, 97.

［参考例６９］ (３Ｓ)−３−{[２−(１Ｈ−テトラゾール−１−イル)エトキシ]メチル}ピペリジン塩酸塩
出発原料（アミン化合物）：テトラゾール
IR (film) ν_max 3403, 2951, 1592, 1454, 1126 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.22-1.34 (1H, m), 1.71-1.82 (1H, m), 1.84-2.03 (2H, m), 2.31-2.43 (1H, m), 2.65-2.79 (1H, m), 2.86-2.99 (1H, m), 3.35-3.54 (4H, m), 3.78-3.93 (2H, m) , 4.66-4.76 (2H, m), 9.23 (1H, s), 9.50 (1H, brs) ;
MS (FAB) m/z: 212 [M+H]⁺, 184, 98.

［参考例７０］ (３Ｓ)−３−{[２−(５−メチル−２Ｈ−テトラゾール−２−イル)エトキシ]メチル}ピペリジン塩酸塩
出発原料（アミン化合物）：５−メチルテトラゾール
IR (film) ν_max 3402, 2945, 1595, 1455, 1126 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.22-1.34 (1H, m), 1.70-1.80 (1H, m), 1.82-2.00 (2H, m), 2.19-2.31 (1H, m), 2.56 (3H, s), 2.61-2.73 (1H, m), 2.73-2.86 (1H, m), 3.30-3.46 (4H, m), 3.89-4.01 (2H, m), 4.73 (2H, t, J = 5.5 Hz), 9.45 (1H, brs) ;
MS (FAB) m/z: 225 [M+H]⁺, 196, 169, 141, 114, 98.

［参考例７１］ (３Ｓ)−３−{[２−(５−メチル−１Ｈ−テトラゾール−１−イル)エトキシ]メチル}ピペリジン塩酸塩
出発原料（アミン化合物）：５−メチルテトラゾール
¹H NMR(DMSO-d₆, 400 MHz) δ 1.03-1.16 (1H, m), 1.52-1.65 (2H, m), 1.68-1.78 (1H, m), 1.88-2.00 (1H, m), 2.41-2.51 (1H, m), 2.53 (3H, m), 2.61-2.74 (1H, m), 3.01-3.20 (2H, m), 3.21-3.33 (2H, m), 3.70-3.80 (2H, m), 4.51-4.58 (2H, m), 8.91 (1H, brs);
MS (EI) m/z: 225 [M]⁺, 169, 114, 98.

［参考例７２］（３Ｓ）−３−｛［３−（１Ｈ−イミダゾール−１−イル）プロポキシ］メチル｝ピペリジン２塩酸塩
（７２ａ）ｔｅｒｔ−ブチル（３Ｓ）−３−｛［３−（ベンジルオキシ）プロポキシ］メチル｝ピペリジン−１−カルボキシラート
ｔｅｒｔ−ブチル（３Ｓ）−３−（ヒドロキシメチル）ピペリジン−１−カルボキシラート（４．３０ｇ，２０．０ｍｍｏｌ）、［（３−ブロモプロポキシ）メチル］ベンゼン（７．０６ｍＬ，４０．０ｍｍｏｌ）、及びテトラ−ｎ−ブチルアンモニウム硫酸水素塩（１．３６ｇ，４．０ｍｍｏｌ）のベンゼン（８ｍＬ）溶液に、５０％水酸化ナトリウム水溶液（８ｍＬ）を加え、室温で２４時間攪拌した。反応液を水（２００ｍＬ）とジエチルエーテル（２００ｍＬ）で分液して得られた有機層を、水 (２００ｍＬ)および飽和塩化ナトリウム水溶液(２００ｍＬ)で順次洗浄し、無水硫酸ナトリウムで乾燥後，溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル，１０：１→３：１）を用いて精製し、標記目的化合物（４．４３ｇ，収率６１％）を得た。
無色油状物;
¹H NMR(CDCl₃, 400 MHz) δ 1.11-1.24 (1H, m), 1.37-1.50 (1H, m), 1.45 (9H, s), 1.58-1.68 (1H, m), 1.70-1.82 (2H, m), 1.83-1.92 (2H, m), 2.42-2.70 (1H, m), 2.73-2.84 (1H, m), 3.22-3.29 (2H, m), 3.50 (2H, t, J = 6.3 Hz), 3.56 (2H, t, J = 6.3 Hz), 3.80-4.11 (2H, m), 4.51 (2H, s), 7.27-7.37 (5H, m);
MS (FAB) m/z: 364 [M+H⁺], 308, 264.

（７２ｂ）ｔｅｒｔ−ブチル（３Ｓ）−３−［（３−ヒドロキシプロポキシ）メチル］ピペリジン−１−カルボキシラート
参考例７２（７２ａ）で製造したｔｅｒｔ−ブチル（３Ｓ）−３−｛［３−（ベンジルオキシ）プロポキシ］メチル｝ピペリジン−１−カルボキシラート（４．４２ｇ，１２．２ｍｍｏｌ）のエタノール（１２０ｍＬ）溶液に、１０％パラジウム炭素（４．４２ｇ）を加え、系内を水素雰囲気とし、室温で５時間撹拌した。反応液をセライトでろ過し、溶媒を減圧下留去した。得られた粉末をヘキサンで洗浄し、標記目的化合物（３．０１ｇ，９０％）を得た。
無色固体；
Mp 79-80 ℃；
¹H NMR(CDCl₃, 500 MHz) δ 1.17-1.28 (1H, m), 1.39-1.49 (1H, m), 1.46 (9H, s), 1.58-1.66 (1H, m), 1.73-1.86 (4H, m), 2.62-3.04 (2H, m), 3.28-3.34 (2H, m), 3.54-3.90 (6H, m);
MS (FAB) m/z: 274 [M+H⁺], 218, 174.

（７２ｃ）ｔｅｒｔ−ブチル（３Ｓ）−３−［（３−｛［（４−メチルフェニル）スルホニル］オキシ｝プロポキシ）メチル］ピペリジン−１−カルボキシラート
氷冷下、参考例７２（７２ｂ）で製造したｔｅｒｔ−ブチル（３Ｓ）−３−［（３−ヒドロキシプロポキシ）メチル］ピペリジン−１−カルボキシラート（２．９２ｇ，１０．７ｍｍｏｌ）、トリエチルアミン（４．４８ｍＬ，３２．１ｍｍｏｌ）及び４−ジメチルアミノピリジン（１３０ｍｇ，１．１ｍｍｏｌ）の塩化メチレン（２２ｍＬ）溶液に、ｐ−トルエンスルホニルクロリド（３．０６ｇ，１６．１ｍｍｏｌ）を数回に分けて加えた。氷冷下で１時間攪拌後、室温まで昇温し、室温で１４時間攪拌した。反応液に、飽和炭酸水素ナトリウム水溶液（１００ｍＬ）及び水（１００ｍＬ）を加え、水層を酢酸エチル（２００ｍＬ）で２回抽出した。有機層を合わせて、水 (２００ｍＬ)および飽和塩化ナトリウム水溶液(２００ｍＬ)で順次洗浄し、無水硫酸ナトリウムで乾燥後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル，５：１→３：１→１：１）を用いて精製し、標記目的化合物（４．４０ｇ，収率９６％）を得た。
黄色油状物；
¹H NMR(CDCl₃, 400 MHz) δ 1.03-1.20 (1H, m), 1.34-1.51 (1H, m), 1.45 (9H, s), 1.56-1.77 (3H, m), 1.83-1.93 (2H, m), 2.36-2.62 (1H, m), 2.45 (3H, s), 2.76 (1H, t, J = 11.0 Hz), 3.14-3.21 (2H, m), 3.41 (2H, t, J = 5.9 Hz), 3.81-4.04 (2H, m), 4.13 (2H, t, J = 5.9 Hz), 7.35 (2H, d, J = 8.6 Hz), 7.80 (2H, d, J = 8.6 Hz);
MS (FAB) m/z: 428 [M+H⁺], 372, 328.

（７２ｄ）ｔｅｒｔ−ブチル（３Ｓ）−３−｛［３−(１Ｈ−イミダゾール−１−イル)プロポキシ］メチル｝ピペリジン−１−カルボキシラート
参考例７２（７２ｃ）で製造したｔｅｒｔ−ブチル（３Ｓ）−３−［（３−｛［（４−メチルフェニル）スルホニル］オキシ｝プロポキシ）メチル］ピペリジン−１−カルボキシラート（２．１０ｇ，４．９２ｍｍｏｌ）のＮ，Ｎ‘−ジメチルホルムアミド（９．８ｍＬ）溶液にイミダゾール（１．６８ｇ，２４．６ｍｍｏｌ）を加え、１００℃で１８時間撹拌した。反応液を濃縮し、得られた残渣に水（１００ｍＬ）を加え、塩化メチレン（１５０ｍＬ）で２回抽出した。有機層を合わせて、無水硫酸ナトリウムで乾燥後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（塩化メチレン／メタノール，２０：１）を用いて精製し、標記目的化合物（１．２２ｇ，収率７７％）を得た
無色油状物；
¹H NMR(CDCl₃, 400 MHz) δ 1.13-1.27 (1H, m), 1.38-1.52 (1H, m), 1.46 (9H, s), 1.60-1.69 (1H, m), 1.70-1.86 (2H, m), 1.94-2.05 (2H, m), 2.54-2.69 (1H, m), 2.75-2.86 (1H, m), 3.19-3.38 (4H, m), 3.83-4.13 (4H, m), 6.91 (1H, brs), 7.06 (1H, brs), 7.47 (1H, brs);
MS (FAB) m/z: 324 [M+H]⁺, 268, 224.

（７２ｅ）（３Ｓ）−３−｛［３−（１Ｈ−イミダゾール−１−イル）プロポキシ］メチル｝ピペリジン２塩酸塩
参考例７２（７２ｄ）で製造したｔｅｒｔ−ブチル（３Ｓ）−３−｛［３−(１Ｈ−イミダゾール−１−イル)プロポキシ］メチル｝ピペリジン−１−カルボキシラート（１．２１ｇ，３．７５ｍｍｏｌ）のメタノール（３．８ｍＬ）溶液に４Ｍ塩化水素ジオキサン溶液（３．８ｍＬ）を加え、室温で２時間撹拌した。反応液を濃縮し、標記目的化合物（１．１２ｇ，収率１００％）を得た。
¹H NMR(CDCl₃, 400 MHz) δ 1.19-1.31 (1H, m), 1.67-1.77 (1H, m), 1.86-2.04 (2H, m), 2.11-2.23 (2H, m), 2.26-2.37 (1H, m), 2.56-2.69 (1H, m), 2.90-3.03 (1H, m), 3.29-3.44 (4H, m), 3.53-3.66 (2H, m), 4.38-4.58 (2H, m), 7.24 (1H, s), 7.56 (1H, s), 9.49 (1H, brs), 9.71 (1H, s);
MS (FAB) m/z: 224 [M+H]⁺, 176.

参考例７２（７２ｃ）で製造したｔｅｒｔ−ブチル（３Ｓ）−３−［（３−｛［（４−メチルフェニル）スルホニル］オキシ｝プロポキシ）メチル］ピペリジン−1−カルボキシラートとテトラゾールを出発原料として用いて、参考例７２（７２ｄ）と同様に反応を行い、２種の異性体を分取したのち、参考例７２（７２ｅ）に準じた方法で参考例７３及び参考例７４の化合物を得た。

［参考例７３］ (３Ｓ)−３−{[３−(１Ｈ−テトラゾール−１−イル)プロポキシ]メチル}ピペリジン塩酸塩
出発原料（アミン化合物）：テトラゾール
¹H NMR(DMSO-d₆, 400 MHz) δ 1.25-1.38 (1H, m), 1.66-1.85 (2H, m), 1.89-2.03 (2H, m), 2.15-2.24 (2H, m), 2.69 (1H, t, J = 12.1 Hz), 2.89 (1H, t, J = 12.1 Hz), 3.23-3.38 (4H, m), 3.42-3.51 (2H, m), 4.61 (2H, t, J = 6.7 Hz), 9.19 (1H, s);
MS (FAB) m/z: 226 [M+H]⁺, 198, 165.

［参考例７４］ (３Ｓ)−３−{[３−(２Ｈ−テトラゾール−２−イル)プロポキシ]メチル}ピペリジン塩酸塩
出発原料（アミン化合物）：テトラゾール
¹H NMR(CDCl₃, 400 MHz) δ 1.26-1.41 (1H, m), 1.82-2.07 (3H, m), 2.21-2.36 (3H, m), 2.65-2.86 (2H, m), 3.25-3.52 (6H, m), 4.76 (2H, t, J = 6.7 Hz), 8.54 (1H, s), 9.67 (1H, brs);
MS (EI) m/z: 225 [M]⁺, 196, 142, 114, 98.

［参考例７５］（３Ｓ）−３−{［２−（１−エチル−１Ｈ−テトラゾール−５−イル）エトキシ］メチル}ピペリジン塩酸塩
参考例４０（４０ｂ）で製造したｔｅｒｔ−ブチル（３Ｓ）−３−{［２−（１Ｈ−テトラゾール−５−イル）エトキシ］メチル}ピペリジン−１−カルボキシラートとヨウ化エチルとを用いて、参考例４０（４０ｃ）と同様に反応を行い、参考例４５（４５ｂ）の方法に従って表記目的化合物を得た。
白色粉末;
Mp 108-110 ℃;
IR (KBr) ν_max 2941, 2843, 2797, 2526, 2406, 1596, 1582 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.29-1.43 (1H, m), 1.63 (3H, t, J = 7.4 Hz), 1.76-2.02 (3H, m), 2.19-2.32 (1H, m), 2.65-2.86 (2H, m), 3.13 (2H, t, J = 6.6 Hz), 3.34-3.43 (3H, m), 3.46 (1H, dd, J = 9.4, 4.7 Hz), 3.81 (2H, t, J = 6.6 Hz), 4.65 (2H, t, J = 7.4 Hz), 9.37-9.62 (2H, m);
MS (FAB) m/z: 240 [M+H]⁺, 168, 114。

［参考例７６］（３Ｓ）−３−｛［２−（１−エチル−１Ｈ−テトラゾール−５−イル）エトキシ］メチル｝ピペリジン塩酸塩
（７６ａ）ｔｅｒｔ−ブチル（３Ｓ）−３−｛［（３−ｔｅｒｔ−ブトキシ−３−オキソプロポキシ）メチル］ピペリジン−１−カルボキシラート
参考例４０（４０ａ）と同様の条件下に、ｔｅｒｔ−ブチル（３Ｓ）−３−（ヒドロキシメチル）ピペリジン−１−カルボキシラートとアクリル酸ｔｅｒｔ−ブチルを用いて反応を行い、表記化合物を得た。
無色油状物 98 %;
IR (film) ν_max 2977, 2931, 2860, 1732, 1695 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.13-1.26 (1H, m), 1.37-1.48 81H, m), 1.45 (9H, s), 1.58-1.67 (1H, m), 1.70-1.82 (2H, m), 2.47 (2H, t, J = 6.3 Hz), 2.50-2.69 (1H, m), 2.74-2.83 (1H, m), 3.29 (2H, d, J = 6.3 Hz), 3.64 (2H, t, J = 6.3 Hz), 3.82-4.03 (2H, m);
MS (FAB) m/z: 344 [M+H]⁺, 244, 232, 186。

（７６ｂ）３−｛［（３Ｓ）−１−（ｔｅｒｔ−ブトキシカルボニル）ピペリジン−３−イル］メトキシ｝プロパン酸
参考例７６（７６ａ）で製造した（ｔｅｒｔ−ブチル（３Ｓ）−３−｛［（３−ｔｅｒｔ−ブトキシ−３−オキソプロポキシ）メチル］ピペリジン−１−カルボキシラート（３３．６４ｇ，９８．０ｍｍｏｌ）のエタノール（３００ｍＬ）溶液に、水酸化リチウム・一水和物（１２．３ｇ，２９４ｍｍｏｌ）の水（１５０ｍＬ）溶液を加え、室温で3時間撹拌した。反応後、減圧下に溶媒を留去し後、水（２００ｍＬ）を加え、氷冷下に１Ｎ塩酸水溶液（２９４ｍＬ）を加えた。ついで酢酸エチルで３回抽出した後、有機層を合わせ、無水硫酸マグネシウムで乾燥後、減圧下に溶媒を留去し、表記目的化合物を得た。
白色粉末 91 %
Mp 88-90
IR (film) ν_max 3176, 2976, 2935, 2887, 2867, 1738, 1672 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.12-1.26 (1H, m), 1.35-1.51 (1H, m), 1.45 (9H, s), 1.56-1.67 (1H, m), 1.69-1.84 (2H, m), 2.51-2.70 (3H, m), 2.76-2.86 (1H, m), 3.24-3.36 (2H, m), 3.61-3.74 (2H, m), 3.78-4.07 (2H, m);
MS (FAB) m/z: 288 [M+H]⁺, 260, 232, 188。

（７６ｃ）ｔｅｒｔ−ブチル（３Ｓ）−３−｛［（３−（エチルアミノ）−３−オキソプロポキシ）メチル］ピペリジン−１−カルボキシラート
氷冷下、参考例７６（７６ｂ）で製造した３−｛［（３Ｓ）−１−（ｔｅｒｔ−ブトキシカルボニル）ピペリジン−３−イル］メトキシ｝プロパン酸（２．２７ｇ，７．９０ｍｍｏｌ）のテトラヒドロフラン（１５．８ｍＬ）溶液に、１，１‘−カルボニルジイミダゾール（１．４１ｇ，８．６９ｍｍｏｌ）を加え、氷冷下で３０分、室温で３０分撹拌した。次いで３０〜４０％エチルアミンのメタノール溶液（１．５ｍＬ）を加え、室温で１時間撹拌した。反応後、水（５０ｍＬ）を加え、酢酸エチルで３回抽出した。有機層を合わせ、無水硫酸ナトリウムで乾燥後、減圧下に溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル，１：３→０：１００）にて精製し、表記目的化合物を得た。
無色油状物 94 %;
IR (film) ν_max 3303, 2975, 2932, 2861, 1691, 1670, 1654 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.14 (3H, t, J = 7.4 Hz), 1.19-1.29 (1H, m), 1.39-1.52 (1H, m), 1.46 (9H, s), 1.57-1.68 (1H, m), 1.73-1.85 (2H, m), 2.40-2.46 (2H, m), 2.66-2.76 (1H, m), 2.80-2.98 (1H, m), 3.25-3.35 (4H, m), 3.60-3.94 (4H, m);
MS (FAB) m/z: 315 [M+H]⁺, 273, 215。

（７６ｄ）ｔｅｒｔ−ブチル（３Ｓ）−３−｛［２−（１−エチル−１Ｈ−テトラゾール−５−イル）エトキシ］メチル｝ピペリジン−１−カルボキシラート
氷冷下、参考例７６（７６ｃ）で製造したｔｅｒｔ−ブチル（３Ｓ）−３−｛［（３−（エチルアミノ）−３−オキソプロポキシ）メチル］ピペリジン−１−カルボキシラート（２．８３ｇ，９．００ｍｍｏｌ）と２，６−ルチジン（１．５７ｍＬ，１３．５ｍｍｏｌ）の塩化メチレン（３５ｍＬ）溶液に、塩化オキザリル（８３１μＬ，９．００ｍｍｏｌ）の塩化メチレン（１０ｍＬ）溶液を滴下し、氷冷で１５分撹拌した。この溶液を、アジ化ナトリウム（８７８ｍｇ，１３．５ｍｍｏｌ）、塩化２，３，５−トリフェニル−２Ｈ−テトラゾリウム（１５１ｍｇ，０．４５ｍｍｏｌ）の塩化メチレン（４５ｍＬ）と水（９０ｍＬ）の混合溶液に加え、室温で１時間撹拌した。反応後、反応液を分液し、水層を塩化メチレンで２回抽出した。有機層を合わせ、無水硫酸マグネシウムで乾燥後、減圧下に溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル，１：２→１：３）にて精製し、表記目的化合物を得た。
淡褐色油状物 43 %;
IR (KBr) ν_max 3499, 2977, 2933, 2861, 1688 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.03-1.16 (1H, m), 1.35-1.47 (1H, m), 1.45 (9H, m), 1.51-1.77 (3H, m), 1.56 (2H, t, J = 7.4 Hz), 2.46-2.60 (1H, m), 2.73-2.82 (1H, m), 3.12 (2H, t, J = 5.9 Hz), 3.26 (2H, d, J = 5.9 Hz), 3.73-4.05 (2H, m), 3.80 (2H, t, J = 5.9 Hz), 4.39 (2H, q, J = 7.4 Hz);
MS (FAB) m/z: 340 [M+H]⁺, 273, 240。

（７６ｅ）（３Ｓ）−３−｛［２−（１−エチル−１Ｈ−テトラゾール−５−イル）エトキシ］メチル｝ピペリジン塩酸塩
参考例７６（７６ｄ）で得られたｔｅｒｔ−ブチル（３Ｓ）−３−｛［２−（１−エチル−１Ｈ−テトラゾール−５−イル）エトキシ］メチル｝ピペリジン−１−カルボキシラートを用いて、参考例４５（４５ｂ）と同様に反応を行い、表記目的化合物を得た。
微褐色粉末定量的;
Mp 133-136 ℃;
IR (KBr) ν_max 2941, 2872, 2843, 2795, 2529, 2409, 1658 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.18-1.31 (1H, m), 1.56 (3H, t, J = 7.4 Hz), 1.61-1.82 (2H, m), 1.85-1.99 (2H, m), 2.20-2.35 (1H, m), 2.59-2.72 (1H, m), 2.74-2.87 (1H, m), 3.13 (2H, t, J = 5.9 Hz), 3.31-3.48 (4H, m), 3.80-3.92 (2H, m), 4.40 (2H, q, J = 7.4 Hz), 9.39-9.63 (2H, m);
MS (FAB) m/z: 240 [M+H]⁺, 212, 196, 169。

参考例７６（７６ｂ）で製造した３−｛［（３Ｓ）−１−（ｔｅｒｔ−ブトキシカルボニル）ピペリジン−３−イル］メトキシ｝プロパン酸と各種アミン化合物を出発原料として用いて、参考例７６（７６ｃ）乃至参考例７６（７６ｅ）と同様に反応を行い、参考例７７乃至８０の化合物を得た。

［参考例７７］（３Ｓ）−３−｛［２−（１−プロピル−１Ｈ−テトラゾール−５−イル）エトキシ］メチル｝ピペリジン塩酸塩
微黄色油状物;
IR (film) ν_max 3397, 2937, 2783, 2549, 2517, 2398 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 0.99 (3H, t, J = 7.4 Hz), 1.17-1.31 (1H, m), 1.72-2.02 (5H, m), 2.20-2.34 (1H, m), 2.61-2.73 (1H, m), 2.75-2.87 (1H, m), 3.13 (2H, t, J = 6.3 Hz), 3.31-3.48 (4H, m), 3.81-3.92 (2H, m), 4.25-4.35 (2H, m), 9.32-9.63 (2H, m);
MS (FAB) m/z: 254 [M+H]⁺, 242, 226。

［参考例７８］ (３Ｓ)−３−{[２−(１−イソプロピル−１Ｈ−テトラゾール−５−イル)エトキシ]メチル}ピペリジン塩酸塩
淡黄色固体；
¹H NMR(DMSO-d₆, 400 MHz) δ 1.08-1.20 (1H, m), 1.49 (6H, d, J = 6.7 Hz), 1.57-1.68 (2H, m), 1.69-1.78 (1H, m), 1.92-2.04 (1H, m), 2.45-2.57 (1H, m), 2.63-2.75 (1H, m), 3.06-3.22 (4H, m), 3.24-3.38 (2H, m), 3.70-3.82 (2H, m), 4.78-4.87 (1H, m), 9.01 (1H, brs);
MS (FAB) m/z: 254 [M+H]⁺, 229, 185, 169.

［参考例７９］ (３Ｓ)−３−{[２−(１−シクロプロピル−１Ｈ−テトラゾール−５−イル)エトキシ]メチル}ピペリジン塩酸塩
¹H NMR(CDCl₃, 400 MHz) δ 1.18-1.38 (5H, m), 1.72-2.01 (4H, m), 2.23-2.35 (1H, m), 2.61-2.73 (1H, m), 2.74-2.86 (1H, m), 3.23 (2H, t, J = 6.3 Hz), 3.31-3.50 (3H, m), 3.55-3.63 (1H, m), 3.82-3.94 (2H, m), 9.52 (1H, brs) ;
MS (FAB) m/z: 252 [M+H]⁺, 202, 183.

［参考例８０］（３Ｓ）−３−（｛［２−［１−（２−メトキシエチル）−１Ｈ−テトラゾール−５−イル］エトキシ］メチル｝ピペリジン塩酸塩
微黄色油状物;
IR (KBr) ν_max 3396, 2944, 2555, 2405, 1726 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.19-1.34 (1H, m), 1.72-2.00 (3H, m), 2.21-2.34 (1H, m), 2.61-2.74 (1H, m), 2.75-2.88 (1H, m), 3.21 (2H, t, J = 6.3 Hz), 3.29 (3H, s), 3.31-3.48 (4H, m), 3.73-3.87 (4H, m), 4.52-4.61 (2H, m), 9,32-9.57 (2H, m);
MS (EI) m/z: 270 [M^+・], 213, 173, 114。

［実施例］
［実施例１］
３−アミノ−４−｛４−［４−（２−メチル−２Ｈ−テトラゾール−５−イル）フェニル］−１，４−ジアゼパン−１−イル｝チエノ［２，３−ｂ］ピリジン−２−カルボキサミド
（１ａ）４−｛４−［４−（２−メチル−２Ｈ−テトラゾール−５−イル）フェニル］−１，４−ジアゼパン−１−イル｝−２−チオキソ−１，２−ジヒドロピリジン−３−カルボニトリル
参考例１（１ｂ）で製造した１−［４−（２−メチル−２Ｈ−テトラゾール−５−イル）フェニル］−１，４−ジアゼパン（７８９ｍｇ，３．０５ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（６．１ｍＬ）溶液に、（２Ｚ）−２−シアノ−３−エトキシブテ−２−エンチオアミド（Ｊ．Ｏｒｇ．Ｃｈｅｍ．，１９６２，２７，２４３３−２４３９）（５１９ｍｇ，３．０５ｍｍｏｌ）を加え、１５分室温攪拌した。次いでＮ，Ｎ−ジメチルホルムアミドジメチルアセタール（４４６μＬ，３．３６ｍｍｏｌ）を加え１時間攪拌したのち、８０℃で３０分加熱攪拌した。反応液を室温まで放冷したのち、トルエンを加え共沸（３回）し、残渣をシリカゲルカラムクロマトグラフィー（塩化メチレン／メタノール，１０／１）により精製し、３１０ｍｇ（収率２６％）の標記目的化合物を得た。
[Reference Example 50] (3S) -3-{[(5-Methyl-1,2,4-oxadiazol-3-yl) methoxy] methyl} piperidine hydrochloride
(50a) tert-butyl (3S) -3-[(cyanomethoxy) methyl] piperidine-1-carboxylate
The reaction was conducted using tert-butyl (3S) -3- (hydroxymethyl) piperidine-1-carboxylate in the same manner as in Reference Example 43 (43a) to obtain the title compound.
Colorless oil
¹ H NMR (CDCl _Three , 400 MHz) δ 1.19-1.31 (1H, m), 1.37-1.52 (1H, m), 1.46 (9H, s), 1.59-1.70 (1H, m), 1.74-1.91 (2H, m), 2.61- 2.75 (1H, m), 2.79-2.89 (1H, m), 3.38-3.49 (2H, m), 3.79-4.02 (2H, m), 4.23 (2H, s).

(50b) tert-butyl (3S) -3-({[2-amino-2- (hydroxyimino) ethyl] oxy} methyl) piperidine-1-carboxylate
50% hydroxyl in a solution of tert-butyl (3S) -3-[(cyanomethoxy) methyl] piperidine-1-carboxylate (11.79 g, 46.4 mmol) synthesized in Reference Example 50 (50a) in ethanol (46 mL) An aqueous amine solution (5.7 mL) was added, and the mixture was heated at 100 ° C. for 8 hours. The reaction mixture was cooled to room temperature, water (100 mL) was added, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate / methanol, 100: 0 → 10: 1) to obtain the title compound (8.82 g, yield 66%).
Colorless oil
IR (film) ν _max 3482,3349,2975,2930,2858,1670,1588,1428 cm ^-1 ;
¹ H NMR (CDCl _Three , 400 MHz) δ 1.18-1.31 (1H, m), 1.38-1.51 (1H, m), 1.46 (9H, s), 1.55-1.69 (1H, m), 1.72-1.90 (2H, m), 2.70- 3.08 (2H, m), 3.31 (2H, d, J = 6.7 Hz), 3.61-4.02 (5H, m), 4.71-4.96 (2H, m);
MS (EI) m / z: 287 [M ^{+ ・} ], 231, 214, 170.

(50c) tert-butyl (3S) -3-{[(5-methyl-1,2,4-oxadiazol-3-yl) methoxy] methyl} piperidine-1-carboxylate
Tert-Butyl (3S) -3-({[2-amino-2- (hydroxyimino) ethyl] oxy} methyl) piperidine-1-carboxylate synthesized in Reference Example 50 (50b) (8.82 g, 30. To a solution of 7 mmol) in methylene chloride (92.1 mL), acetic anhydride (3.19 mL, 33.8 mmol) and triethylamine (5.13 mL, 36.8 mmol) were sequentially added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate (100 mL) was added, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (37 mL), a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (37 mL, 36.8 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction, water (100 mL) was added, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane / ethyl acetate, 1: 1) to obtain the title compound (7.93 g, yield 83%).
Colorless oil
IR (film) ν _max 3508, 2976, 2931, 2858, 1691, 1587, 1424 cm ^-1 ;
¹ H NMR (CDCl _Three , 400 MHz) δ 1.17-1.30 (1H, m), 1.36-1.50 (1H, m), 1.45 (9H, s), 1.55-1.68 (1H, m), 1.74-1.90 (2H, m), 2.59- 2.74 (1H, m), 2.60 (3H, s), 2.76-2.88 (1H, m), 3.43 (2H, d, J = 6.3 Hz), 3.80-4.07 (2H, m), 4.57 (2H, d, J = 1.6 Hz);
MS (FAB) m / z: 312 [M + H] ⁺ , 238, 212.

(50d) (3S) -3-{[(5-Methyl-1,2,4-oxadiazol-3-yl) methoxy] methyl} piperidine hydrochloride
Tert-Butyl (3S) -3-{[(5-methyl-1,2,4-oxadiazol-3-yl) methoxy] methyl} piperidine-1-carboxylate obtained in Reference Example 50 (50c) Was used in the same manner as in Reference Example 45 (45b) to give the title object compound.
Colorless oil
IR (film) ν _max 3402, 2949, 2802, 2558, 2407, 1586 cm ^-1 ;
¹ H NMR (CDCl _Three , 400 MHz) δ 1.33-1.45 (1H, m), 1.80-2.05 (3H, m), 2.08-2.24 (1H, m), 2.27-2.40 (1H, m), 2.62 (3H, s), 2.70- 2.86 (2H, m), 3.38-3.59 (3H, m), 4.57 (2H, s), 9.32-9.70 (2H, m);
MS (EI) m / z: 211 [M ^{+ ・} ], 153, 114.

[Reference Example 51] (3S) -3-{[(3-Methyl-1,2,4-thiadiazol-5-yl) methoxy] methyl} piperidine hydrochloride
(51a) tert-butyl (3S) -3-[(2-amino-2-oxoethoxy) methyl] piperidine-1-carboxylate
1,1 was added to a solution of {[(3S) -1- (tert-butoxycarbonyl) piperidin-3-yl] methoxy} acetic acid (5.47 g, 20.0 mmol) prepared in Reference Example (38b) in tetrahydrofuran (60 mL). '-Carbonyldiimidazole (3.90 g, 24.0 mmol) was added and stirred at room temperature for 30 minutes. Subsequently, concentrated aqueous ammonia (6.70 mL, 100 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated, water (100 mL) was added to the resulting residue, and the mixture was extracted twice with ethyl acetate (100 ml). The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / methanol, 1: 0 → 20: 1) to obtain the title object compound (5.14 g, yield 94%).
Colorless oil;
¹ H NMR (CDCl _Three , 400 MHz) δ 1.22-1.34 (1H, m), 1.37-1.53 (1H, m), 1.46 (9H, s), 1.55-1.71 (1H, m), 1.73-1.95 (2H, m), 2.71- 3.16 (2H, m), 3.32-3.47 (2H, m), 3.54-4.02 (4H, m), 5.46 (1H, brs), 6.72 (1H, brs);
MS (FAB) m / z: 273 [M + H] ⁺ , 217, 199, 173.

(51b) tert-Butyl (3S) -3-[(2-amino-2-thioxoethoxy) methyl] piperidine-1-carboxylate
Tert-Butyl (3S) -3-[(2-amino-2-oxoethoxy) methyl] piperidine-1-carboxylate prepared in Reference Example 51 (51a) under nitrogen atmosphere (4.68 g, 17.2 mmol) Lawson's reagent (6.96 g, 17.2 mmol) was added to a tetrahydrofuran (86 ml) solution, and the mixture was stirred at room temperature for 6 hours. To the reaction solution was added 0.5N aqueous sodium hydroxide solution (200 mL), and the aqueous layer was extracted twice with ethyl acetate (200 mL). The organic layers were combined, washed successively with water (200 mL) and saturated aqueous sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate, 3: 1 → 1: 1) to obtain the title object compound (4.15 g, yield 84%).
Colorless solid;
Mp 94 ° C;
¹ H NMR (CDCl _Three , 400 MHz) δ 1.21-1.39 (1H, m), 1.39-1.51 (1H, m), 1.45 (9H, s), 1.52-1.66 (1H, m), 1.70-1.81 (1H, m), 1.83- 1.95 (1H, m), 2.61-3.95 (6H, m), 4.18-4.43 (2H, m), 7.52 (1H, brs), 8.43 (1H, brs);
MS (FAB) m / z: 289 [M + H] ⁺ , 233, 189, 142, 96.

(51c) tert-butyl (3S) -3-[(2-{[(1Z) -1- (dimethylamino) ethylidene] amino} -2-thioxoethoxy) methyl] piperidine-1-carboxylate
Tert-Butyl (3S) -3-[(2-amino-2-thioxoethoxy) methyl] piperidine-1-carboxylate (2.54 g, 8.82 mmol) of methylene chloride prepared in Reference Example 51 (51b) (44 mL) To the solution was added N, N-dimethylacetamide dimethyl acetal (3.87 mL, 26.5 mmol), and the mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated, and the resulting residue was purified using silica gel column chromatography (ethyl acetate / methanol, 1: 0 → 10: 1) to give the title object compound (2.76 g, yield 88%). It was.
Yellow oil;
¹ H NMR (CDCl _Three , 400 MHz) δ 1.14-1.29 (1H, m), 1.37-1.52 (1H, m), 1.45 (9H, s), 1.59-1.69 (1H, m), 1.75-1.87 (2H, m), 2.47 ( 3H, s), 2.50-2.71 (1H, m), 2.78 (1H, t, J = 11.0 Hz), 3.19 (3H, s), 3.24 (3H, s), 3.35-3.48 (2H, m), 3.85 -4.10 (2H, m), 4.35 (2H, s);
MS (FAB) m / z: 358 [M + H] ⁺ , 301, 258, 129.

(51d) tert-butyl (3S) -3-{[(3-methyl-1,2,4-thiadiazol-5-yl) methoxy] methyl} piperidine-1-carboxylate
Pyridine (3.52 mL, 44.0 mmol) was added to a solution of hydroxylamine-O-sulfonic acid (1.24 g, 11.0 mmol) in methanol (11 mL), and tert-butyl prepared in Reference Example 51 (51c) ( Of 3S) -3-[(2-{[(1Z) -1- (dimethylamino) ethylidene] amino} -2-thioxoethoxy) methyl] piperidine-1-carboxylate (2.60 g, 7.27 mmol) Ethanol (36 mL) solution was added dropwise over 10 minutes and stirred at room temperature for 3 hours. The reaction mixture was concentrated, water (100 mL) was added to the resulting residue, and the mixture was extracted twice with ethyl acetate (100 ml). The organic layers were combined, the organic layers were combined, washed successively with water (200 mL) and saturated aqueous sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate, 1: 1) to obtain the title object compound (1.80 g, yield 76%).
Pale yellow oil;
¹ H NMR (CDCl _Three , 400 MHz) δ 1.21-1.33 (1H, m), 1.40-1.55 (1H, m), 1.46 (9H, s), 1.62-1.71 (1H, m), 1.77-1.95 (2H, m), 2.61- 2.76 (1H, m), 2.66 (3H, s), 2.78-2.88 (1H, m), 3.44-3.58 (2H, m), 3.82-3.97 (1H, m), 3.98-4.11 (1H, m), 4.85 (2H, s);
MS (FAB) m / z: 328 [M + H] ⁺ , 272, 228.

(51e) (3S) -3-{[(3-Methyl-1,2,4-thiadiazol-5-yl) methoxy] methyl} piperidine hydrochloride
Using tert-butyl (3S) -3-{[(3-methyl-1,2,4-thiadiazol-5-yl) methoxy] methyl} piperidine-1-carboxylate obtained in Reference Example 51 (51d) In the same manner as in Reference Example 45 (45b), the title object compound was obtained.
¹ H NMR (DMSO-d ₆ 400 MHz) δ 1.18-1.34 (1H, m), 1.56-1.84 (3H, m), 2.01-2.19 (1H, m), 2.58 (3H, s), 2.60-2.83 (2H, m), 3.14-3.31 (2H, m), 3.48-3.61 (2H, m), 4.94 (2H, s), 9.00 (1H, brs);
MS (EI) m / z: 227 [M] ⁺ , 197, 171, 114, 99.

tert-Butyl (3S) -3- (hydroxymethyl) piperidine-1-carboxylate and various alkyl halide compounds were used as starting materials and reacted in the same manner as in Reference Example 48 (48a), then Reference Example 9 (9b) or the compounds of Reference Examples 52 to 56 were obtained by a method according to Reference Example 45 (45b).

[Reference Example 52] 3-{[(3S) -piperidin-3-ylmethoxy] methyl} pyridine
Starting material (alkyl halide compound): 3- (chloromethyl) pyridine hydrochloride
oil;
IR (liquid film) νmax 3393, 1638, 1579, 1093, 795, 714 cm-1;
1H NMR (CDCl3, 400MHz) δ 1.09-1.19 (1H, m), 1.42-1.53 (1H, m), 1.63-1.88 (3H, m), 1.76 (1H, brs), 2.37 (1H, dd, J = 10.7, 11.7 Hz), 2.56 (1H, ddd, J = 2.7, 11.7, 12.1 Hz), 3.00 (1H, brd, J = 12.1 Hz), 3.15 (1H, brd, J = 11.7 Hz), 3.29-3.37 ( 2H, m), 4.50 (2H, s), 7.28 (1H, dd, J = 4.7, 7.8 Hz), 7.66 (1H, brd, J = 7.8 Hz), 8.53 (1H, brd, J = 4.7 Hz), 8.56 (1H, brs);
MS (EI) m / z: 206 [M +], 114, 108.
Anal.Calcd for C12H18N2O ・ 0.2 H2O: C, 68.67; H, 8.84; N, 13.35.Found: C, 68.65; H, 9.02; N, 13.20.

[Reference Example 53] 4-{[(3S) -piperidin-3-ylmethoxy] methyl} pyridine
Starting material (halogenated alkyl compound): 4- (chloromethyl) pyridine hydrochloride
MS (FAB) m / z: 206 [M + H] +, 189,158,140
1H NMR (DMSO-d6, 400 MHz) δ1.21-1.36 (1H, m), 1.63-1.82 (3H, m), 2.14 (1H, br), 2.62-2.83 (2H, m), 3.21 (1H, d, J = 11.7Hz), 3.28 (1H, d, J = 11.7Hz), 3.43-3.52 (2H, m), 4.77 (2H, s), 7.90 (2H, d, J = 5.9Hz), 8.85 ( (2H, d, J = 5.9Hz)

[Reference Example 54] (3S) -3-{[(2-Methyl-1,3-thiazol-5-yl) methoxy] methyl} piperidine hydrochloride
Starting material (halogenated alkyl compound): 5- (chloromethyl) -2-methyl-1,3-thiazole hydrochloride (reference US-2003-625121)
Pale yellow amorphous material;
IR (film) ν _max 3403, 2947, 2783, 1594, 1454 cm ^-1 ;
¹ H NMR (CDCl _Three , 400 MHz) δ 1.30-1.44 (1H, m), 1.77-2.05 (3H, m), 2.37-2.50 (1H, m), 2.73-2.99 (2H, m), 3.15 (3H, s), 3.31- 3.47 (2H, m), 3.51-3.63 (2H, m), 4.70-4.85 (2H, m), 8.19 (1H, s), 9.44-9.58 (1H, m), 9.63-9.74 (1H, m);
MS (FAB) m / z: 227 [M + H] ⁺ , 186, 112.

[Reference Example 55] (3S) -3-{[(1-Methyl-1H-imidazol-4-yl) methoxy] methyl} piperidine hydrochloride
Starting material (halogenated alkyl compound): 4- (chloromethyl) -1-methyl-1H-imidazole hydrochloride (reference US-2003-625121)
Brown oil;
¹ H NMR (CDCl _Three , 400 MHz) δ 1.31-1.43 (1H, m), 1.68-1.89 (2H, m), 1.90-1.99 (1H, m), 2.05-2.17 (1H, m), 2.73-2.82 (1H, m), 2.85-2.95 (1H, m), 3.27-3.45 (3H, m), 3.65 (3H, s), 4.57 (2H, s), 7.57 (1H, s), 8.90 (1H, s).

[Reference Example 56] (3S) -3-{[(1-Methyl-1H-imidazol-5-yl) methoxy] methyl} piperidine dihydrochloride
Starting material (halogenated alkyl compound): 5- (chloromethyl) -1-methyl-1H-imidazole hydrochloride (reference US-2003-625121)
Fine brown amorphous material;
IR (film) ν _max 3402, 2954, 2786, 259, 2412 cm ^-1 ;
¹ H NMR (CD _Three OD, 400 MHz) δ 1.31-1.46 (1H, m), 1.61-2.00 (3H, m), 2.04-2.17 (1H, m), 2.78 (1H, t, J = 12.1 Hz), 2.85-2.95 (1H , m), 3.27-3.46 (3H, m), 3.52 (1H, dd, J = 9.4, 5.1 Hz), 3.93 (1H, s), 4.65 (2H, s), 7.59 (1H, s), 8.91 ( 1H, s);
MS (FAB) m / z: 210 [M + H] ⁺ , 184, 165.

[Reference Example 57] (3S) -3-{[(5-Methyl-1,3,4-thiadiazol-2-yl) methoxy] methyl} piperidine
(57a) tert-butyl (3S) -3-{[2- (2-acetylhydrazino) -2-oxoethoxy] methyl} piperidine-1-carboxylate
To a solution of {[(3S) -1- (tert-butoxycarbonyl) piperidin-3-yl] methoxy} acetic acid (2.18 g, 7.9 mmol) prepared in Reference Example 38 (38b) in tetrahydrofuran (40 mL) was added 1 1,1′-carbonyldiimidazole (1.56 g, 9.59 mmol) was added and stirred at room temperature for 30 minutes, acetohydrazide (0.71 g, 9.59 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction was concentrated, water (200 mL) was added and extracted with methylene chloride (5 × 150 mL). The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified using silica gel column chromatography (ethyl acetate / methanol, 20: 1 → 10: 1) to obtain 2.21 g (yield 84%) of the title compound.
Pale yellow oil;
¹ H NMR (CDCl _Three , 500 MHz) δ 1.21-1.32 (1H, m), 1.39-1.52 (1H, m), 1.45 (9H, s), 1.58-1.71 (1H, m), 1.76-1.93 (2H, m), 2.07 ( 3H, s), 2.75-3.04 (2H, m), 3.37-3.50 (2H, m), 3.66-3.94 (2H, m), 4.04-4.12 (2H, m), 8.10 (1H, brs), 8.78 ( 1H, brs);
MS (FAB) m / z: 330 [M + H] ⁺ , 274, 230.

(57b) tert-butyl (3S) -3-{[(5-methyl-1,3,4-thiadiazol-2-yl) methoxy] methyl} piperidine-1-carboxylate
Tert-Butyl (3S) -3-{[2- (2-acetylhydrazino) -2-oxoethoxy] methyl} piperidine-1-carboxylate prepared in Reference Example 57 (57a) (2.20 g, 6. 69 mmol) in tetrahydrofuran (67 mL) was added Lawesson's reagent (4.05 g, 10.04 mmol) under a nitrogen atmosphere and stirred for 5 hours. To the reaction solution was added 0.5N aqueous sodium hydroxide solution (200 mL), and the aqueous layer was extracted with ethyl acetate (400 mL). The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified using silica gel column chromatography (hexane / ethyl acetate, 1: 5) to obtain 1.95 g (yield 89%) of the title object compound.
Pale yellow oil;
¹ H NMR (CDCl _Three , 500 MHz) δ 1.16-1.28 (1H, m), 1.39-1.52 (1H, m), 1.46 (9H, s), 1.59-1.68 (1H, m), 1.74-1.88 (2H, m), 2.52- 2.72 (1H, m), 2.74-2.84 (1H, m), 2.78 (3H, s), 3.36-3.47 (2H, m), 3.84-4.11 (2H, m), 4.84 (2H, s);
MS (FAB) m / z: 328 [M + H] ⁺ , 228.

(57c) (3S) -3-{[(5-Methyl-1,3,4-thiadiazol-2-yl) methoxy] methyl} piperidine
Using tert-butyl (3S) -3-{[(5-methyl-1,3,4-thiadiazol-2-yl) methoxy] methyl} piperidine-1-carboxylate prepared in Reference Example 57 (57b) In the same manner as in Reference Example 45 (45b), the title object compound was obtained.
¹ H NMR (CDCl _Three , 400 MHz) δ 1.30-1.46 (1H, m), 1.78-2.06 (3H, m), 2.30-2.45 (1H, m), 2.67-2.91 (2H, m), 2.88 (3H, s), 3.37- 3.61 (4H, m), 4.90 (2H, s), 9.64 (1H, brs);
MS (EI) m / z: 227 [M] ⁺ , 171, 129, 114, 99.

Reference Example 58 4-Methyl-3-{[(3S) -piperidin-3-ylmethoxy] methyl} -1,2,4-oxadiazol-5 (4H) -one)
(58a) tert-butyl (3S) -3-{[(5-oxo-4,5-dihydro 1,2,4-oxadiazol-3-yl) methoxy] methyl} piperidine-1-carboxylate
Tert-Butyl (3S) -3-({[2-amino-2- (hydroxyimino) ethyl] oxy} methyl) piperidine-1-carboxylate synthesized in Reference Example 50 (50b) (2.00 g, 7. (0 mmol) in 1,4-dioxane (28 mL) was added 1,1′-carbonyldiimidazole (1.94 g, 12.0 mmol), and the mixture was stirred at 100 ° C. for 3 hours. The reaction mixture was concentrated, water (100 mL) and methylene chloride (100 mL) were added, and 1N hydrochloric acid (15 mL) was further added to separate the layers. The aqueous layer was extracted with methylene chloride (2 × 100 mL), the combined organic layers were dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified using silica gel column chromatography (methylene chloride / methanol, 30: 1) to obtain 1.45 g (yield 66%) of the title object compound.
Yellow oil;
¹ H NMR (CDCl _Three , 400 MHz) δ 1.31-1.61 (3H, m), 1.45 (9H, s), 1.65-1.80 (1H, m), 1.86-2.05 (1H, m), 2.96-3.16 (2H, m), 3.34- 3.42 (1H, m), 3.49-3.59 (1H, m), 3.71-3.83 (1H, m), 3.87-4.01 (1H, m), 4.12-4.24 (1H, m), 4.48-4.60 (1H, m ), 10.87 (1H, brs);
MS (FAB) m / z: 314 [M + H] ⁺ , 258, 214.

(58b) tert-butyl (3S) -3-{[(4-methyl-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) methoxy] methyl} piperidine-1- Carboxylate
Tert-Butyl (3S) -3-{[(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) methoxy] methyl} piperidine- prepared in Reference Example 58 (58a) 1-carboxylate (1.43 g, 4.57 mmol) was dissolved in N, N-dimethylformamide (22 mL), and the reaction vessel was purged with nitrogen. Under ice cooling, sodium hydride (oiliness 63%, 262 mg, 6.88 mmol) was added to the reaction solution, stirred for 30 minutes, and methyl iodide (0.57 mL, 9.14 mmol) was further added. Subsequently, the reaction solution was stirred for 30 minutes and then stirred at room temperature for 12 hours. The organic layer obtained by separating the reaction solution with water (200 mL) and ethyl acetate (400 mL) was washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified using silica gel column chromatography (ethyl acetate / hexane, 1: 1) to obtain 1.29 g (yield 86%) of the title object compound.
A pale yellow solid;
Mp 73-75 ° C;
¹ H NMR (CDCl _Three , 400 MHz) δ 1.15-1.28 (1H, m), 1.37-1.53 (1H, m), 1.45 (9H, s), 1.58-1.69 (1H, m), 1.70-1.89 (2H, m), 2.67 ( 1H, dd, J = 9.4, 12.9 Hz), 2.76-2.94 (1H, m), 3.32 (3H, s), 3.34-3.40 (2H, m), 3.74-3.99 (2H, m), 4.42 (1H, s);
MS (FAB) m / z: 328 [M + H] ⁺ , 272, 228.

(58c) 4-Methyl-3-{[(3S) -piperidin-3-ylmethoxy] methyl} -1,2,4-oxadiazol-5 (4H) -one hydrochloride
Tert-Butyl (3S) -3-{[(4-Methyl-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) methoxy] prepared in Reference Example 58 (58b) Methyl} piperidine-1-carboxylate was used in the same manner as in Reference Example 45 (45b) to give the title object compound.
Colorless solid;
¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.14-1.29 (1H, m), 1.57-1.80 (3H, m), 1.99-2.12 (1H, m), 2.54-2.79 (2H, m), 3.17 (3H, s), 3.18- 3.25 (1H, m), 3.33-3.46 (2H, m), 3.50-3.68 (1H, m), 4.52 (2H, s), 9.05 (1H, brs);
MS (EI) m / z: 228 [M] ⁺ , 183, 153, 114, 98.

[Reference Example 59] (3S) -3-{[(1-Methyl-1H-imidazol-2-yl) methoxy] methyl} piperidine hydrochloride
(59a) tert-Butyl (3S) -3-[(1H-imidazol-2-ylmethoxy) methyl] piperidine-1-carboxylate
Under a nitrogen atmosphere, a solution of oxalyl chloride (3.43 mL, 40.0 mmol) in methylene chloride (50 mL) was cooled to -78 ° C. To this solution was added dropwise a solution of dimethyl sulfoxide (2.84 mL, 40.0 mmol) in methylene chloride (10 mL) over 10 minutes, and the mixture was stirred at −78 ° C. for 15 minutes, and then tert-butyl prepared in Reference Example (49a). A solution of (3S) -3-[(2-hydroxyethoxy) methyl] piperidine-1-carboxylate (5.18 g, 20.0 mmol) in methylene chloride (30 mL) was added dropwise over 30 minutes, and 15 ° C. at −78 ° C. Stir for minutes. To this reaction solution, a solution of triethylamine (11.2 mL, 80.0 mmol) in methylene chloride (10 mL) was added dropwise over 30 minutes, stirred at −78 ° C. for 30 minutes, and then stirred at room temperature for 1 hour. Water (100 mL) and a saturated aqueous ammonium chloride solution (100 mL) were added to the reaction solution, and the mixture was partitioned. The aqueous layer was extracted once with diethyl ether (300 mL). The organic layer was washed successively with water (300 mL) and saturated aqueous sodium chloride solution (300 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Subsequently, the obtained residue was dissolved in methanol (200 mL), concentrated aqueous ammonia was added, and after stirring at room temperature for 10 minutes, 40% glyoxal aqueous solution was added and stirred at room temperature for 72 hours. The reaction mixture was concentrated, water (200 mL) was added to the resulting residue, and the mixture was extracted once with methylene chloride (200 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / methanol, 20: 1 → 10: 1) to obtain the title object compound (3.74 g, 63%).
Brown oil;
¹ H NMR (CDCl _Three , 400 MHz) δ 1.35-1.49 (1H, m), 1.46 (9H, s), 1.54-1.65 (1H, m), 1.69-1.99 (3H, m), 3.16-3.71 (6H, m), 4.43- 4.81 (2H, m), 7.02 (2H, s);
MS (FAB) m / z: 296 [M + H] ⁺ , 240, 196.

(59b) tert-butyl (3S) -3-{[(1-methyl-1H-imidazol-2-yl) methoxy] methyl} piperidine-1-carboxylate
Under a nitrogen atmosphere, tert-butyl (3S) -3-[(1H-imidazol-2-ylmethoxy) methyl] piperidine-1-carboxylate (3.72 g, 12.6 mmol) prepared in Reference Example 59 (59a) was used. The N, N-dimethylformamide (50 mL) solution was cooled to 0 ° C., sodium hydride (63% oily, 732 mg, 19.2 mmol) was added, and the mixture was stirred at 0 ° C. for 30 min. Subsequently, methyl iodide (864 μL, 13.9 mmol) was added, and the mixture was stirred at 0 ° C. for 2 hours. Water (200 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (200 mL). The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / methanol, 20: 1 → 10: 1) to obtain the title object compound (3.23 g, 83%).
Pale yellow oil;
¹ H NMR (CDCl _Three , 400 MHz) δ 1.09-1.22 (1H, m), 1.45 (9H, s), 1.56-1.67 (2H, m), 1.69-1.82 (2H, m), 2.54 (1H, t, J = 11.7 Hz) , 2.75 (1H, t, J = 11.7 Hz), 3.23-3.35 (2H, m), 3.71 (3H, s), 3.81-4.07 (2H, m), 4.56 (2H, s), 6.88 (1H, brs ), 6.95 (1H, brs);
MS (FAB) m / z: 310 [M + H] ⁺ , 254, 210.

(59c) (3S) -3-{[(1-Methyl-1H-imidazol-2-yl) methoxy] methyl} piperidine hydrochloride
Using tert-butyl (3S) -3-{[(1-methyl-1H-imidazol-2-yl) methoxy] methyl} piperidine-1-carboxylate prepared in Reference Example 59 (59b), Reference Example 45 The reaction was carried out in the same manner as (45b) to obtain the title compound.
¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.15-1.31 (1H, m), 1.61-1.82 (3H, m), 2.06-2.17 (1H, m), 2.57-2.79 (2H, m), 3.13-3.28 (2H, m), 3.38-3.51 (2H, m), 3.82 (3H, s), 4.83 (2H, s), 7.67 (1H, d, J = 2.0 Hz), 7.74 (1H, d, J = 2.0 Hz), 9.29 (1H , brs);
MS (FAB) m / z: 210 [M + H] ⁺ , 95.

[Reference Example 60] (3S) -3-{[(4-Methyl-4H-1,2,4-triazol-3-yl) methoxy] methyl} piperidine hydrochloride
(60a) tert-butyl (3S) -3-{[2- (methylamino) -2-oxoethoxy] methyl} piperidine-1-carboxylate
In a tetrahydrofuran (50 mL) solution of {[(3S) -1- (tert-butoxycarbonyl) piperidin-3-yl] methoxy} acetic acid (4.53 g, 16.6 mmol) prepared in Reference Example 38 (38b), 1′-carbonyldiimidazole (3.23 g, 20.0 mmol) was added and stirred at room temperature for 30 minutes. Subsequently, a 40% aqueous methylamine solution (2.08 mL, 25.0 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated, water (150 mL) was added to the obtained residue, and the mixture was extracted twice with ethyl acetate (150 ml). The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / methanol, 1: 0 → 20: 1) to obtain the title object compound (4.42 g, yield 93%).
A pale yellow solid;
Mp 58-59 ° C;
¹ H NMR (CDCl _Three , 400 MHz) δ 1.18-1.31 (1H, m), 1.39-1.52 (1H, m), 1.46 (9H, s), 1.59-1.70 (1H, m), 1.72-1.93 (2H, m), 2.73- 3.07 (5H, m), 3.38 (2H, d, J = 6.6 Hz), 3.60-4.01 (4H, m), 6.65 (1H, brs);
MS (FAB) m / z: 287 [M + H] ⁺ , 231, 187.

(60b) tert-butyl (3S) -3-{[2- (methylamino) -2-thioxoethoxy] methyl} piperidine-1-carboxylate
Tert-Butyl (3S) -3-{[2- (methylamino) -2-oxoethoxy] methyl} piperidine-1-carboxylate (4.40 g, 15) prepared in Reference Example 60 (60a) under a nitrogen atmosphere .4 mmol) in tetrahydrofuran (80 ml) was added Lawesson's reagent (6.23 g, 15.4 mmol) and stirred at room temperature for 5 hours. To the reaction solution was added 0.5N aqueous sodium hydroxide solution (200 mL), and the aqueous layer was extracted once with ethyl acetate (300 mL). The organic layer was washed successively with water (100 mL) and saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate, 3: 1 → 1: 1) to obtain the title object compound (4.42 g, yield 95%).
Colorless solid;
Mp 103-105 ° C;
¹ H NMR (CDCl _Three , 400 MHz) δ 1.21-1.37 (1H, m), 1.38-1.52 (1H, m), 1.46 (9H, s), 1.54-1.68 (1H, m), 1.72-1.80 (1H, m), 1.84- 1.95 (1H, m), 2.89-3.30 (5H, m), 3.35-3.93 (4H, m), 4.21-4.46 (2H, m), 8.74 (1H, brs);
MS (FAB) m / z: 303 [M + H] ⁺ , 247, 203.

(60c) tert-butyl (3S) -3-{[(4-methyl-4H-1,2,4-triazol-3-yl) methoxy] methyl} piperidine-1-carboxylate
Tert-Butyl (3S) -3-{[2- (methylamino) -2-thioxoethoxy] methyl} piperidine-1-carboxylate (1.82 g, 6.00 mmol) prepared in Reference Example 60 (60b) To a tetrahydrofuran (6 mL) solution of methyl iodide (7.47 mL, 120 mmol) was added and stirred at room temperature for 3 hours. The reaction mixture was concentrated, and the resulting residue was dissolved in ethanol (18 mL), formohydrazide (1.08 mL, 18.0 mmol) was added, and the mixture was stirred with heating under reflux for 17 hr. The reaction mixture was concentrated, water (100 mL) was added to the resulting residue, and the mixture was extracted twice with methylene chloride (100 ml). The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / methanol, 20: 1) to obtain the title object compound (1.34 g, yield 72%).
Pale yellow oil;
¹ H NMR (CDCl _Three , 400 MHz) δ 1.10-1.23 (1H, m), 1.33-1.49 (1H, m), 1.45 (9H, s), 1.55-1.66 (1H, m), 1.70-1.82 (2H, m), 2.59 ( 2H, dd, J = 9.7, 13.3 Hz), 2.73-2.86 (1H, m), 3.26-3.38 (1H, m), 3.75 (3H, s), 3.76-4.02 (2H, m), 4.70 (2H, s), 8.10 (1H, s);
MS (FAB) m / z: 311 [M + H] ⁺ , 211.

(60d) (3S) -3-{[(4-Methyl-4H-1,2,4-triazol-3-yl) methoxy] methyl} piperidine hydrochloride
The tert-butyl (3S) -3-{[(4-methyl-4H-1,2,4-triazol-3-yl) methoxy] methyl} piperidine-1-carboxylate prepared in Reference Example 60 (60c) And the reaction was conducted in the same manner as in Reference Example 45 (45b) to give the title object compound.
¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.14-1.29 (1H, m), 1.59-1.79 (3H, m), 2.02-2.14 (1H, m), 2.54-2.79 (2H, m), 3.13-3.25 (2H, m), 3.35-3.48 (2H, m), 3.77 (3H, s), 4.77 (2H, s), 9.15 (1H, brs), 9.24 (1H, s);
MS (FAB) m / z: 211 [M + H] ⁺ , 188.

[Reference Example 61] (3S) -3-{[(1-Ethyl-1H-imidazol-5-yl) methoxy] methyl) piperidine hydrochloride
(61a) tert-butyl (3S) -3-{[(1-ethyl-1H-imidazol-5-yl) methoxy] methyl} piperidine-1-carboxylate
Under a nitrogen atmosphere, tert-butyl (3S) -3-[(2-hydroxyethoxy) methyl] piperidine-1-carboxylate (2.30 g, 8.88 mmol) prepared in Reference Example 49 (49a) in methylene chloride (2. 89 mL) solution was cooled to 0 ° C., Dess-Martin reagent (5.65 g, 13.3 mmol) was added and stirred at 0 ° C. for 15 minutes and at room temperature for 3 hours. Saturated aqueous sodium thiosulfate solution (50 mL) and saturated aqueous sodium hydrogen carbonate solution (50 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 30 min, and extracted three times with ethyl acetate (100 mL). The organic layers were combined, washed successively with water (100 mL) and saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Subsequently, the obtained residue was dissolved in methanol (25 mL), 30-40% ethylamine methanol solution was added, and after stirring at room temperature for 30 minutes, p-toluenesulfonylmethyl isocyanide was added and stirred at room temperature for 72 hours. . The reaction mixture was concentrated, and the resulting residue was purified using silica gel column chromatography (ethyl acetate / methanol, 10: 1) to give the title object compound (1.29 g, yield 58%).
Orange oil;
¹ H NMR (CDCl _Three , 400 MHz) δ 1.04-1.24 (1H, m), 1.35-1.50 (13H, m), 1.56-1.68 (1H, m), 1.69-1.82 (2H, m), 2.51-2.64 (1H, m), 2.72-2.82 (1H, m), 3.20-3.29 (2H, m), 3.31-4.05 (4H, m), 4.44 (2H, s), 6.98 (1H, s), 7.51 (1H, s);
MS (FAB) m / z: 324 [M + H] ⁺ , 268, 242.

(61b) (3S) -3-{[(1-Ethyl-1H-imidazol-5-yl) methoxy] methyl} piperidine hydrochloride
Using tert-butyl (3S) -3-{[(1-ethyl-1H-imidazol-5-yl) methoxy] methyl} piperidine-1-carboxylate prepared in Reference Example 61 (61a), Reference Example 45 The reaction was carried out in the same manner as (45b) to obtain the title compound.
¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.10-1.29 (1H, m), 1.43 (3H, t, J = 7.4 Hz), 1.59-1.80 (3H, m), 2.01-2.13 (1H, m), 2.53-2.64 (1H, m), 2.65-2.77 (1H, m), 3.10-3.45 (4H, m), 4.14-4.26 (2H, m), 4.59 (2H, s), 7.74 (1H, brs), 9.09 (1H, brs) , 9.22 (1H, brs);
MS (FAB) m / z: 224 [M + H] ⁺ , 180, 109, 97.

Starting with tert-butyl (3S) -3-[(2-{[(4-methylphenyl) sulfonyl] oxy} ethoxy) methyl] piperidine-1-carboxylate prepared in Reference Example 49 (49b) and various amine compounds The reaction was carried out in the same manner as in Reference Example 49 (49c) using the starting material, and then the compounds of Reference Examples 62 to 71 were obtained by the method according to Reference Example 45 (45b).

[Reference Example 62] (3S) -3-{[2- (1H-pyrazol-1-yl) ethoxy] methyl} piperidine dihydrochloride
Starting material (amine compound): Pyrazole
¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.06-1.20 (1H, m), 1.56-1.76 (3H, m), 1.91-2.03 (1H, m), 2.42-2.56 (1H, m), 2.63-2.74 (1H, m), 3.05-3.19 (2H, m), 3.21-3.83 (2H, m), 3.65-3.76 (2H, m), 4.27 (2H, t, J = 5.5 Hz), 6.24 (1H, t, J = 1.9 Hz) , 7.47 (1H, d, J = 1.9 Hz), 7.73 (1H, d, J = 1.9 Hz), 9.11 (1H, brs);
MS (FAB) m / z: 210 [M + H] ⁺ , 154, 136, 98.

[Reference Example 63] (3S) -3-{[2- (1H-imidazol-1-yl) ethoxy] methyl} piperidine dihydrochloride
Starting material (amine compound): Imidazole
¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.07-1.21 (1H, m), 1.55-1.78 (3H, m), 1.93-2.04 (1H, m), 2.44-2.59 (1H, m), 2.64-2.78 (1H, m), 3.06-3.22 (2H, m), 3.26-3.39 (2H, m), 3.70-3.77 (2H, m), 4.35-4.41 (2H, m), 7.70 (1H, dd, J = 1.6, 2.0 Hz), 7.76 (1H, dd, J = 1.6, 2.0 Hz), 9.07 (1H, brs), 9.16 (1H, d, J = 1.6 Hz);
MS (EI) m / z: 209 [M] ⁺ , 153, 141, 126, 111, 96, 82.

[Reference Example 64] (3S) -3-{[2- (2-Methyl-1H-imidazol-1-yl) ethoxy] methyl} piperidine dihydrochloride
Starting material (amine compound): 2-methylimidazole
¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.08-1.21 (1H, m), 1.58-1.80 (3H, m), 1.96-2.08 (1H, m), 2.43-2.58 (1H, m), 2.62 (3H, s), 2.60- 2.74 (1H, m), 3.06-3.21 (2H, m), 3.25-3.38 (2H, m), 3.70 (2H, t, J = 5.1 Hz), 4.29 (2H, t, J = 5.1 Hz), 7.56 (1H, d, J = 2.0 Hz), 7.62 (1H, d, J = 2.0 Hz), 9.24 (1H, brs);
MS (EI) m / z: 222 [M] ⁺ , 167, 110, 96, 83.

[Reference Example 65] (3S) -3-{[2- (1H-1,2,3-triazol-1-yl) ethoxy] methyl} piperidine hydrochloride
Starting material (amine compound): 1,2,3-triazole
White amorphous material;
IR (film) ν _max 3404, 2947, 2543, 2413, 1936, 1592, 1541 cm ^-1 ;
¹ H NMR (CD _Three OD, 400 MHz) δ 1.23-1.37 (1H, m), 1.65-1.82 (2H, m), 1.86-1.95 (1H, m), 1.97-2.10 (1H, m), 2.65-2.75 (1H, m) , 2.82-2.93 (1H, m), 3.25-3.41 (3H, m), 3.43-3.50 (1H, m), 3.78-3.98 (2H, m), 4.78-4.84 (2H, m), 8.35 (1H, d, J = 1.2 Hz), 8.50 (1H, d, J = 1.2 Hz);
MS (EI) m / z: 210 [M ^{+ ・} ], 154, 141, 114.

[Reference Example 66] ((2b) (3S) -3-{[2- (2H-1,2,3-triazol-2-yl) ethoxy] methyl} piperidine hydrochloride
Starting material (amine compound): 1,2,3-triazole
White powder;
IR (KBr) ν _max 2944, 2797, 2772, 2523, 2405, 1582 cm ^-1 ;
¹ H NMR (CDCl _Three , 400 MHz) δ 1.25-1.39 (1H, m), 1.69-1.79 (1H, m), 1.82-2.01 (2H, m), 2.14-2.26 (1H, m), 2.61-2.74 (1H, m), 2.75-2.88 (1H, m), 3.24-3.44 (4H, m), 3.91 (2H, t, J = 5.5 Hz), 4.61 (2H, t, J = 5.5 Hz), 7.65 (2H, s), 9.27 -9.42 (1H, m), 9.46-9.65 (1H, m);
MS (EI) m / z: 210 [M ^{+ ・} ], 114.

[Reference Example 67] (3S) -3-{[2- (1H-1,2,4-triazol-1-yl) ethoxy] methyl} piperidine dihydrochloride
Starting material (amine compound): 1,2,4-triazole
¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.06-1.18 (1H, m), 1.57-1.75 (3H, m), 1.91-2.03 (1H, m), 2.44-2.54 (1H, m), 2.62-2.73 (1H, m), 3.04-3.19 (2H, m), 3.23-3.36 (2H, m), 3.66-3.79 (2H, m), 4.40 (2H, t, J = 5.5 Hz), 8.25 (1H, s), 8.89 (1H, s), 9.16 (1H, brs);
MS (EI) m / z: 210 [M] ⁺ , 154, 141, 114, 97.

[Reference Example 68] (3S) -3-{[2- (4H-1,2,4-triazol-4-yl) ethoxy] methyl} piperidine dihydrochloride
Starting material (amine compound): 1,2,4-triazole
¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.06-1.18 (1H, m), 1.57-1.75 (3H, m), 1.91-2.03 (1H, m), 2.44-2.54 (1H, m), 2.62-2.73 (1H, m), 3.04-3.19 (2H, m), 3.23-3.36 (2H, m), 3.66-3.79 (2H, m), 4.40 (2H, t, J = 5.5 Hz), 8.89 (2H, s), 9.15 (1H, s);
MS (EI) m / z: 210 [M] ⁺ , 154, 114, 97.

[Reference Example 69] (3S) -3-{[2- (1H-tetrazol-1-yl) ethoxy] methyl} piperidine hydrochloride
Starting material (amine compound): Tetrazole
IR (film) ν _max 3403, 2951, 1592, 1454, 1126 cm ^-1 ;
¹ H NMR (CDCl _Three , 400 MHz) δ 1.22-1.34 (1H, m), 1.71-1.82 (1H, m), 1.84-2.03 (2H, m), 2.31-2.43 (1H, m), 2.65-2.79 (1H, m), 2.86-2.99 (1H, m), 3.35-3.54 (4H, m), 3.78-3.93 (2H, m), 4.66-4.76 (2H, m), 9.23 (1H, s), 9.50 (1H, brs);
MS (FAB) m / z: 212 [M + H] ⁺ , 184, 98.

[Reference Example 70] (3S) -3-{[2- (5-Methyl-2H-tetrazol-2-yl) ethoxy] methyl} piperidine hydrochloride
Starting material (amine compound): 5-methyltetrazole
IR (film) ν _max 3402, 2945, 1595, 1455, 1126 cm ^-1 ;
¹ H NMR (CDCl _Three , 400 MHz) δ 1.22-1.34 (1H, m), 1.70-1.80 (1H, m), 1.82-2.00 (2H, m), 2.19-2.31 (1H, m), 2.56 (3H, s), 2.61- 2.73 (1H, m), 2.73-2.86 (1H, m), 3.30-3.46 (4H, m), 3.89-4.01 (2H, m), 4.73 (2H, t, J = 5.5 Hz), 9.45 (1H, brs);
MS (FAB) m / z: 225 [M + H] ⁺ , 196, 169, 141, 114, 98.

[Reference Example 71] (3S) -3-{[2- (5-Methyl-1H-tetrazol-1-yl) ethoxy] methyl} piperidine hydrochloride
Starting material (amine compound): 5-methyltetrazole
¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.03-1.16 (1H, m), 1.52-1.65 (2H, m), 1.68-1.78 (1H, m), 1.88-2.00 (1H, m), 2.41-2.51 (1H, m), 2.53 (3H, m), 2.61-2.74 (1H, m), 3.01-3.20 (2H, m), 3.21-3.33 (2H, m), 3.70-3.80 (2H, m), 4.51-4.58 (2H, m ), 8.91 (1H, brs);
MS (EI) m / z: 225 [M] ⁺ , 169, 114, 98.

[Reference Example 72] (3S) -3-{[3- (1H-imidazol-1-yl) propoxy] methyl} piperidine dihydrochloride
(72a) tert-butyl (3S) -3-{[3- (benzyloxy) propoxy] methyl} piperidine-1-carboxylate
tert-butyl (3S) -3- (hydroxymethyl) piperidine-1-carboxylate (4.30 g, 20.0 mmol), [(3-bromopropoxy) methyl] benzene (7.06 mL, 40.0 mmol), and To a solution of tetra-n-butylammonium hydrogensulfate (1.36 g, 4.0 mmol) in benzene (8 mL) was added 50% aqueous sodium hydroxide solution (8 mL), and the mixture was stirred at room temperature for 24 hours. The organic layer obtained by separating the reaction solution with water (200 mL) and diethyl ether (200 mL) was washed successively with water (200 mL) and saturated aqueous sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, solvent Was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate, 10: 1 → 3: 1) to obtain the title object compound (4.43 g, yield 61%).
Colorless oil;
¹ H NMR (CDCl _Three , 400 MHz) δ 1.11-1.24 (1H, m), 1.37-1.50 (1H, m), 1.45 (9H, s), 1.58-1.68 (1H, m), 1.70-1.82 (2H, m), 1.83- 1.92 (2H, m), 2.42-2.70 (1H, m), 2.73-2.84 (1H, m), 3.22-3.29 (2H, m), 3.50 (2H, t, J = 6.3 Hz), 3.56 (2H, t, J = 6.3 Hz), 3.80-4.11 (2H, m), 4.51 (2H, s), 7.27-7.37 (5H, m);
MS (FAB) m / z: 364 [M + H ⁺ ], 308, 264.

(72b) tert-butyl (3S) -3-[(3-hydroxypropoxy) methyl] piperidine-1-carboxylate
Tert-Butyl (3S) -3-{[3- (benzyloxy) propoxy] methyl} piperidine-1-carboxylate (4.42 g, 12.2 mmol) of ethanol (120 mL) prepared in Reference Example 72 (72a) To the solution, 10% palladium carbon (4.42 g) was added, the inside of the system was brought to a hydrogen atmosphere, and the mixture was stirred at room temperature for 5 hours. The reaction solution was filtered through celite, and the solvent was distilled off under reduced pressure. The obtained powder was washed with hexane to obtain the title object compound (3.01 g, 90%).
Colorless solid;
Mp 79-80 ° C;
¹ H NMR (CDCl _Three , 500 MHz) δ 1.17-1.28 (1H, m), 1.39-1.49 (1H, m), 1.46 (9H, s), 1.58-1.66 (1H, m), 1.73-1.86 (4H, m), 2.62- 3.04 (2H, m), 3.28-3.34 (2H, m), 3.54-3.90 (6H, m);
MS (FAB) m / z: 274 [M + H ⁺ ], 218, 174.

(72c) tert-butyl (3S) -3-[(3-{[(4-methylphenyl) sulfonyl] oxy} propoxy) methyl] piperidine-1-carboxylate
Under ice-cooling, tert-butyl (3S) -3-[(3-hydroxypropoxy) methyl] piperidine-1-carboxylate (2.92 g, 10.7 mmol) prepared in Reference Example 72 (72b), triethylamine (4 .48 mL, 32.1 mmol) and 4-dimethylaminopyridine (130 mg, 1.1 mmol) in methylene chloride (22 mL) were added p-toluenesulfonyl chloride (3.06 g, 16.1 mmol) in several portions. It was. After stirring for 1 hour under ice cooling, the mixture was warmed to room temperature and stirred at room temperature for 14 hours. A saturated aqueous sodium hydrogen carbonate solution (100 mL) and water (100 mL) were added to the reaction solution, and the aqueous layer was extracted twice with ethyl acetate (200 mL). The organic layers were combined, washed successively with water (200 mL) and saturated aqueous sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate, 5: 1 → 3: 1 → 1: 1) to obtain the title object compound (4.40 g, yield 96%).
Yellow oil;
¹ H NMR (CDCl _Three , 400 MHz) δ 1.03-1.20 (1H, m), 1.34-1.51 (1H, m), 1.45 (9H, s), 1.56-1.77 (3H, m), 1.83-1.93 (2H, m), 2.36- 2.62 (1H, m), 2.45 (3H, s), 2.76 (1H, t, J = 11.0 Hz), 3.14-3.21 (2H, m), 3.41 (2H, t, J = 5.9 Hz), 3.81-4.04 (2H, m), 4.13 (2H, t, J = 5.9 Hz), 7.35 (2H, d, J = 8.6 Hz), 7.80 (2H, d, J = 8.6 Hz);
MS (FAB) m / z: 428 [M + H ⁺ ], 372, 328.

(72d) tert-butyl (3S) -3-{[3- (1H-imidazol-1-yl) propoxy] methyl} piperidine-1-carboxylate
Tert-Butyl (3S) -3-[(3-{[(4-methylphenyl) sulfonyl] oxy} propoxy) methyl] piperidine-1-carboxylate (2.10 g, 4) prepared in Reference Example 72 (72c) .92 mmol) in N, N′-dimethylformamide (9.8 mL) was added imidazole (1.68 g, 24.6 mmol), and the mixture was stirred at 100 ° C. for 18 hours. The reaction mixture was concentrated, water (100 mL) was added to the obtained residue, and the mixture was extracted twice with methylene chloride (150 mL). The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride / methanol, 20: 1) to obtain the title object compound (1.22 g, yield 77%).
Colorless oil;
¹ H NMR (CDCl _Three , 400 MHz) δ 1.13-1.27 (1H, m), 1.38-1.52 (1H, m), 1.46 (9H, s), 1.60-1.69 (1H, m), 1.70-1.86 (2H, m), 1.94- 2.05 (2H, m), 2.54-2.69 (1H, m), 2.75-2.86 (1H, m), 3.19-3.38 (4H, m), 3.83-4.13 (4H, m), 6.91 (1H, brs), 7.06 (1H, brs), 7.47 (1H, brs);
MS (FAB) m / z: 324 [M + H] ⁺ , 268, 224.

(72e) (3S) -3-{[3- (1H-imidazol-1-yl) propoxy] methyl} piperidine dihydrochloride
Tert-Butyl (3S) -3-{[3- (1H-imidazol-1-yl) propoxy] methyl} piperidine-1-carboxylate (1.21 g, 3.75 mmol) prepared in Reference Example 72 (72d) 4M hydrogen chloride dioxane solution (3.8 mL) was added to a methanol solution (3.8 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give the title object compound (1.12 g, yield 100%).
¹ H NMR (CDCl _Three , 400 MHz) δ 1.19-1.31 (1H, m), 1.67-1.77 (1H, m), 1.86-2.04 (2H, m), 2.11-2.23 (2H, m), 2.26-2.37 (1H, m), 2.56-2.69 (1H, m), 2.90-3.03 (1H, m), 3.29-3.44 (4H, m), 3.53-3.66 (2H, m), 4.38-4.58 (2H, m), 7.24 (1H, s ), 7.56 (1H, s), 9.49 (1H, brs), 9.71 (1H, s);
MS (FAB) m / z: 224 [M + H] ⁺ , 176.

Starting from tert-butyl (3S) -3-[(3-{[(4-methylphenyl) sulfonyl] oxy} propoxy) methyl] piperidine-1-carboxylate and tetrazole prepared in Reference Example 72 (72c) Then, the reaction was carried out in the same manner as in Reference Example 72 (72d), and after separating the two isomers, the compounds of Reference Example 73 and Reference Example 74 were obtained by the method according to Reference Example 72 (72e). .

[Reference Example 73] (3S) -3-{[3- (1H-tetrazol-1-yl) propoxy] methyl} piperidine hydrochloride
Starting material (amine compound): Tetrazole
¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.25-1.38 (1H, m), 1.66-1.85 (2H, m), 1.89-2.03 (2H, m), 2.15-2.24 (2H, m), 2.69 (1H, t, J = 12.1 Hz), 2.89 (1H, t, J = 12.1 Hz), 3.23-3.38 (4H, m), 3.42-3.51 (2H, m), 4.61 (2H, t, J = 6.7 Hz), 9.19 (1H, s );
MS (FAB) m / z: 226 [M + H] ⁺ , 198, 165.

[Reference Example 74] (3S) -3-{[3- (2H-tetrazol-2-yl) propoxy] methyl} piperidine hydrochloride
Starting material (amine compound): Tetrazole
¹ H NMR (CDCl _Three , 400 MHz) δ 1.26-1.41 (1H, m), 1.82-2.07 (3H, m), 2.21-2.36 (3H, m), 2.65-2.86 (2H, m), 3.25-3.52 (6H, m), 4.76 (2H, t, J = 6.7 Hz), 8.54 (1H, s), 9.67 (1H, brs);
MS (EI) m / z: 225 [M] ⁺ , 196, 142, 114, 98.

[Reference Example 75] (3S) -3-{[2- (1-Ethyl-1H-tetrazol-5-yl) ethoxy] methyl} piperidine hydrochloride
Using tert-butyl (3S) -3-{[2- (1H-tetrazol-5-yl) ethoxy] methyl} piperidine-1-carboxylate prepared in Reference Example 40 (40b) and ethyl iodide, The reaction was carried out in the same manner as in Reference Example 40 (40c), and the title compound was obtained according to the method of Reference Example 45 (45b).
White powder;
Mp 108-110 ° C;
IR (KBr) ν _max 2941, 2843, 2797, 2526, 2406, 1596, 1582 cm ^-1 ;
¹ H NMR (CDCl _Three , 400 MHz) δ 1.29-1.43 (1H, m), 1.63 (3H, t, J = 7.4 Hz), 1.76-2.02 (3H, m), 2.19-2.32 (1H, m), 2.65-2.86 (2H, m), 3.13 (2H, t, J = 6.6 Hz), 3.34-3.43 (3H, m), 3.46 (1H, dd, J = 9.4, 4.7 Hz), 3.81 (2H, t, J = 6.6 Hz), 4.65 (2H, t, J = 7.4 Hz), 9.37-9.62 (2H, m);
MS (FAB) m / z: 240 [M + H] ⁺ , 168, 114.

[Reference Example 76] (3S) -3-{[2- (1-Ethyl-1H-tetrazol-5-yl) ethoxy] methyl} piperidine hydrochloride
(76a) tert-butyl (3S) -3-{[(3-tert-butoxy-3-oxopropoxy) methyl] piperidine-1-carboxylate
The reaction was conducted using tert-butyl (3S) -3- (hydroxymethyl) piperidine-1-carboxylate and tert-butyl acrylate under the same conditions as in Reference Example 40 (40a) to obtain the title compound. .
Colorless oil 98%;
IR (film) ν _max 2977, 2931, 2860, 1732, 1695 cm ^-1 ;
¹ H NMR (CDCl _Three , 400 MHz) δ 1.13-1.26 (1H, m), 1.37-1.48 81H, m), 1.45 (9H, s), 1.58-1.67 (1H, m), 1.70-1.82 (2H, m), 2.47 (2H , t, J = 6.3 Hz), 2.50-2.69 (1H, m), 2.74-2.83 (1H, m), 3.29 (2H, d, J = 6.3 Hz), 3.64 (2H, t, J = 6.3 Hz) , 3.82-4.03 (2H, m);
MS (FAB) m / z: 344 [M + H] ⁺ , 244, 232, 186.

(76b) 3-{[(3S) -1- (tert-Butoxycarbonyl) piperidin-3-yl] methoxy} propanoic acid
(Tert-Butyl (3S) -3-{[(3-tert-butoxy-3-oxopropoxy) methyl] piperidine-1-carboxylate (33.64 g, 98.0 mmol) prepared in Reference Example 76 (76a) A solution of lithium hydroxide monohydrate (12.3 g, 294 mmol) in water (150 mL) was added to an ethanol (300 mL) solution, and the mixture was stirred for 3 hours at room temperature. Thereafter, water (200 mL) was added, and a 1N hydrochloric acid aqueous solution (294 mL) was added under ice cooling, followed by extraction three times with ethyl acetate, and the organic layers were combined, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Distill off to obtain the title compound.
91% white powder
Mp 88-90
IR (film) ν _max 3176, 2976, 2935, 2887, 2867, 1738, 1672 cm ^-1 ;
¹ H NMR (CDCl _Three , 400 MHz) δ 1.12-1.26 (1H, m), 1.35-1.51 (1H, m), 1.45 (9H, s), 1.56-1.67 (1H, m), 1.69-1.84 (2H, m), 2.51- 2.70 (3H, m), 2.76-2.86 (1H, m), 3.24-3.36 (2H, m), 3.61-3.74 (2H, m), 3.78-4.07 (2H, m);
MS (FAB) m / z: 288 [M + H] ⁺ , 260, 232, 188.

(76c) tert-butyl (3S) -3-{[(3- (ethylamino) -3-oxopropoxy) methyl] piperidine-1-carboxylate
Tetrahydrofuran of 3-{[(3S) -1- (tert-butoxycarbonyl) piperidin-3-yl] methoxy} propanoic acid (2.27 g, 7.90 mmol) prepared in Reference Example 76 (76b) under ice cooling To the (15.8 mL) solution, 1,1′-carbonyldiimidazole (1.41 g, 8.69 mmol) was added, and the mixture was stirred for 30 minutes under ice cooling and for 30 minutes at room temperature. Subsequently, 30-40% ethylamine methanol solution (1.5 mL) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction, water (50 mL) was added, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate, 1: 3 → 0: 100) to obtain the title compound.
94% colorless oil;
IR (film) ν _max 3303, 2975, 2932, 2861, 1691, 1670, 1654 cm ^-1 ;
¹ H NMR (CDCl _Three , 400 MHz) δ 1.14 (3H, t, J = 7.4 Hz), 1.19-1.29 (1H, m), 1.39-1.52 (1H, m), 1.46 (9H, s), 1.57-1.68 (1H, m) , 1.73-1.85 (2H, m), 2.40-2.46 (2H, m), 2.66-2.76 (1H, m), 2.80-2.98 (1H, m), 3.25-3.35 (4H, m), 3.60-3.94 ( 4H, m);
MS (FAB) m / z: 315 [M + H] ⁺ , 273, 215.

(76d) tert-butyl (3S) -3-{[2- (1-ethyl-1H-tetrazol-5-yl) ethoxy] methyl} piperidine-1-carboxylate
Under ice cooling, tert-butyl (3S) -3-{[(3- (ethylamino) -3-oxopropoxy) methyl] piperidine-1-carboxylate (2.83 g, prepared in Reference Example 76 (76c)) was prepared. To a solution of 9.00 mmol) and 2,6-lutidine (1.57 mL, 13.5 mmol) in methylene chloride (35 mL), a solution of oxalyl chloride (831 μL, 9.00 mmol) in methylene chloride (10 mL) was added dropwise and ice-cooled. For 15 minutes. This solution was added to a mixed solution of sodium azide (878 mg, 13.5 mmol), 2,3,5-triphenyl-2H-tetrazolium chloride (151 mg, 0.45 mmol) in methylene chloride (45 mL) and water (90 mL). The mixture was further stirred at room temperature for 1 hour. After the reaction, the reaction solution was separated, and the aqueous layer was extracted twice with methylene chloride. The organic layers were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate, 1: 2 → 1: 3) to obtain the title compound.
Light brown oil 43%;
IR (KBr) ν _max 3499, 2977, 2933, 2861, 1688 cm ^-1 ;
¹ H NMR (CDCl _Three , 400 MHz) δ 1.03-1.16 (1H, m), 1.35-1.47 (1H, m), 1.45 (9H, m), 1.51-1.77 (3H, m), 1.56 (2H, t, J = 7.4 Hz) , 2.46-2.60 (1H, m), 2.73-2.82 (1H, m), 3.12 (2H, t, J = 5.9 Hz), 3.26 (2H, d, J = 5.9 Hz), 3.73-4.05 (2H, m ), 3.80 (2H, t, J = 5.9 Hz), 4.39 (2H, q, J = 7.4 Hz);
MS (FAB) m / z: 340 [M + H] ⁺ , 273, 240.

(76e) (3S) -3-{[2- (1-Ethyl-1H-tetrazol-5-yl) ethoxy] methyl} piperidine hydrochloride
Using tert-butyl (3S) -3-{[2- (1-ethyl-1H-tetrazol-5-yl) ethoxy] methyl} piperidine-1-carboxylate obtained in Reference Example 76 (76d), The reaction was carried out in the same manner as in Reference Example 45 (45b) to obtain the title object compound.
Fine brown powder quantitative;
Mp 133-136 ° C;
IR (KBr) ν _max 2941, 2872, 2843, 2795, 2529, 2409, 1658 cm ^-1 ;
¹ H NMR (CDCl _Three , 400 MHz) δ 1.18-1.31 (1H, m), 1.56 (3H, t, J = 7.4 Hz), 1.61-1.82 (2H, m), 1.85-1.99 (2H, m), 2.20-2.35 (1H, m), 2.59-2.72 (1H, m), 2.74-2.87 (1H, m), 3.13 (2H, t, J = 5.9 Hz), 3.31-3.48 (4H, m), 3.80-3.92 (2H, m) , 4.40 (2H, q, J = 7.4 Hz), 9.39-9.63 (2H, m);
MS (FAB) m / z: 240 [M + H] ⁺ , 212, 196, 169.

Using Reference Example 76 (76b) 3-{[(3S) -1- (tert-butoxycarbonyl) piperidin-3-yl] methoxy} propanoic acid and various amine compounds as starting materials, Reference Example 76 ( 76c) to Reference Example 76 (76e) were reacted in the same manner to obtain Reference Examples 77 to 80.

[Reference Example 77] (3S) -3-{[2- (1-propyl-1H-tetrazol-5-yl) ethoxy] methyl} piperidine hydrochloride
A slightly yellow oil;
IR (film) ν _max 3397, 2937, 2783, 2549, 2517, 2398 cm ^-1 ;
¹ H NMR (CDCl _Three , 400 MHz) δ 0.99 (3H, t, J = 7.4 Hz), 1.17-1.31 (1H, m), 1.72-2.02 (5H, m), 2.20-2.34 (1H, m), 2.61-2.73 (1H, m), 2.75-2.87 (1H, m), 3.13 (2H, t, J = 6.3 Hz), 3.31-3.48 (4H, m), 3.81-3.92 (2H, m), 4.25-4.35 (2H, m) , 9.32-9.63 (2H, m);
MS (FAB) m / z: 254 [M + H] ⁺ , 242, 226.

[Reference Example 78] (3S) -3-{[2- (1-Isopropyl-1H-tetrazol-5-yl) ethoxy] methyl} piperidine hydrochloride
Pale yellow solid;
¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.08-1.20 (1H, m), 1.49 (6H, d, J = 6.7 Hz), 1.57-1.68 (2H, m), 1.69-1.78 (1H, m), 1.92-2.04 (1H, m), 2.45-2.57 (1H, m), 2.63-2.75 (1H, m), 3.06-3.22 (4H, m), 3.24-3.38 (2H, m), 3.70-3.82 (2H, m), 4.78- 4.87 (1H, m), 9.01 (1H, brs);
MS (FAB) m / z: 254 [M + H] ⁺ , 229, 185, 169.

[Reference Example 79] (3S) -3-{[2- (1-Cyclopropyl-1H-tetrazol-5-yl) ethoxy] methyl} piperidine hydrochloride
¹ H NMR (CDCl _Three , 400 MHz) δ 1.18-1.38 (5H, m), 1.72-2.01 (4H, m), 2.23-2.35 (1H, m), 2.61-2.73 (1H, m), 2.74-2.86 (1H, m), 3.23 (2H, t, J = 6.3 Hz), 3.31-3.50 (3H, m), 3.55-3.63 (1H, m), 3.82-3.94 (2H, m), 9.52 (1H, brs);
MS (FAB) m / z: 252 [M + H] ⁺ , 202, 183.

[Reference Example 80] (3S) -3-({[2- [1- (2-methoxyethyl) -1H-tetrazol-5-yl] ethoxy] methyl} piperidine hydrochloride
A slightly yellow oil;
IR (KBr) ν _max 3396, 2944, 2555, 2405, 1726 cm ^-1 ;
¹ H NMR (CDCl _Three , 400 MHz) δ 1.19-1.34 (1H, m), 1.72-2.00 (3H, m), 2.21-2.34 (1H, m), 2.61-2.74 (1H, m), 2.75-2.88 (1H, m), 3.21 (2H, t, J = 6.3 Hz), 3.29 (3H, s), 3.31-3.48 (4H, m), 3.73-3.87 (4H, m), 4.52-4.61 (2H, m), 9,32- 9.57 (2H, m);
MS (EI) m / z: 270 [M ^{+ ・} ], 213, 173, 114.

[Example]
[Example 1]
3-Amino-4- {4- [4- (2-methyl-2H-tetrazol-5-yl) phenyl] -1,4-diazepan-1-yl} thieno [2,3-b] pyridine-2- Carboxamide
(1a) 4- {4- [4- (2-Methyl-2H-tetrazol-5-yl) phenyl] -1,4-diazepan-1-yl} -2-thioxo-1,2-dihydropyridine-3- Carbonitrile
N, N-dimethylformamide of 1- [4- (2-methyl-2H-tetrazol-5-yl) phenyl] -1,4-diazepane (789 mg, 3.05 mmol) prepared in Reference Example 1 (1b) ( 6.1 mL) solution was added (2Z) -2-cyano-3-ethoxybute-2-enethioamide (J. Org. Chem., 1962, 27, 2433-2439) (519 mg, 3.05 mmol), 15 Stir for minutes at room temperature. Next, N, N-dimethylformamide dimethylacetal (446 μL, 3.36 mmol) was added and stirred for 1 hour, followed by heating and stirring at 80 ° C. for 30 minutes. The reaction mixture was allowed to cool to room temperature, toluene was added and azeotroped (three times), and the residue was purified by silica gel column chromatography (methylene chloride / methanol, 10/1) to give 310 mg (yield 26%) of the title. The target compound was obtained.

褐色粉末;
Mp 263-265 ℃;
IR (KBr) ν_max 3444, 3121, 2953, 2205, 1615, 1521, 1467, 1250 cm^-1;
¹H NMR(DMSO-d₆, 400 MHz) δ 1.92-2.02 (2H, m), 3.56-3.64 (2H, m), 3.71-3.85 (4H, m), 3.95-4.02 (2H, m), 4.34 (3H, s), 6.44 (1H, d, J = 7.8 Hz), 6.91 (2H, d, J = 9.0 Hz), 7.35 (1H, d, J = 7.8 Hz), 7.81 (2H, d, J = 9.0 Hz), 12.52 (1H, br.s);
MS (FAB) m/z: 393 [M+H]⁺, 257, 235;
Anal. Calcd for C₁₉H₂₀N₈S・0.72H₂O: C, 56.28; H, 5.33; N, 27.64; S, 7.91. Found: C, 55.98; H, 5.03; N, 27.40; S, 7.89。
Brown powder;
Mp 263-265 ° C;
IR (KBr) ν _max 3444, 3121, 2953, 2205, 1615, 1521, 1467, 1250 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.92-2.02 (2H, m), 3.56-3.64 (2H, m), 3.71-3.85 (4H, m), 3.95-4.02 (2H, m), 4.34 (3H, s), 6.44 (1H, d, J = 7.8 Hz), 6.91 (2H, d, J = 9.0 Hz), 7.35 (1H, d, J = 7.8 Hz), 7.81 (2H, d, J = 9.0 Hz), 12.52 (1H, br.s);
MS (FAB) m / z: 393 [M + H] ⁺ , 257, 235;
Anal. Calcd for C ₁₉ H ₂₀ N ₈ S ・ 0.72H ₂ O: C, 56.28; H, 5.33; N, 27.64; S, 7.91. Found: C, 55.98; H, 5.03; N, 27.40; S, 7.89 .

（１ｂ）３−アミノ−４−｛４−［４−（２−メチル−２Ｈ−テトラゾール−５−イル）フェニル］−１，４−ジアゼパン−１−イル｝チエノ［２，３−ｂ］ピリジン−２−カルボキサミド
実施例１（１ａ）で製造した４−｛４−［４−（２−メチル−２Ｈ−テトラゾール−５−イル）フェニル］−１，４−ジアゼパン−１−イル｝−２−チオキソ−１，２−ジヒドロピリジン−３−カルボニトリル（３１０ｍｇ，０．７９ｍｍｏｌ）をＮ，Ｎ−ジメチルホルムアミド（１．５８ｍＬ）に溶解し、８Ｎ水酸化ナトリウム水溶液（２９６μＬ，２．３７ｍｍｏｌ）と２−クロロアセトアミド（８９ｍｇ，０．９５ｍｍｏｌ）を加え、室温で１時間攪拌した。反応混合物に水（３．２ｍＬ）、エタノール（１．６ｍＬ）を加え、析出した固体を濾別、水とエタノールで洗浄し２９１ｍｇ（収率８２％）の標記目的化合物を得た。
(1b) 3-Amino-4- {4- [4- (2-methyl-2H-tetrazol-5-yl) phenyl] -1,4-diazepan-1-yl} thieno [2,3-b] pyridine 2-Carboxamide 4- {4- [4- (2-Methyl-2H-tetrazol-5-yl) phenyl] -1,4-diazepan-1-yl} -2-prepared in Example 1 (1a) Thioxo-1,2-dihydropyridine-3-carbonitrile (310 mg, 0.79 mmol) was dissolved in N, N-dimethylformamide (1.58 mL), 8N aqueous sodium hydroxide solution (296 μL, 2.37 mmol) and 2- Chloroacetamide (89 mg, 0.95 mmol) was added and stirred at room temperature for 1 hour. Water (3.2 mL) and ethanol (1.6 mL) were added to the reaction mixture, and the precipitated solid was separated by filtration and washed with water and ethanol to obtain 291 mg (yield 82%) of the title compound.

微褐色粉末
Mp 230-232 ℃;
IR (KBr) ν_max 3443, 3322, 3185, 2953, 2842, 1651, 1614, 1579, 1465 cm^-1;
¹H NMR(DMSO-d₆, 500 MHz) δ 2.15-2.22 (2H, m), 3.18-3.25 (2H, m), 3.29-3.37 (2H, m), 3.63 (2H, t, J = 6.3 Hz), 3.82-3.88 (2H, m), 4.37 (3H, s), 6.93 (2H, d, J = 8.8 Hz), 7.01 (2H, br.s), 7.09 (1H, d, J = 5.4 Hz), 7.10 (2H, br.s), 7.86 (2H, d, J = 8.8 Hz), 8.40 (1H, d, J = 5.4 Hz);
MS (FAB) m/z: 450 [M+H]⁺, 433, 273;
Anal. Calcd for C₂₁H₂₃N₉OS・0.4H₂O: C, 55.22; H, 5.25; N, 27.60; S, 7.02. Found: C, 55.42; H, 5.35; N, 27.40; S, 6.84。
Fine brown powder
Mp 230-232 ° C;
IR (KBr) ν _max 3443, 3322, 3185, 2953, 2842, 1651, 1614, 1579, 1465 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 500 MHz) δ 2.15-2.22 (2H, m), 3.18-3.25 (2H, m), 3.29-3.37 (2H, m), 3.63 (2H, t, J = 6.3 Hz ), 3.82-3.88 (2H, m), 4.37 (3H, s), 6.93 (2H, d, J = 8.8 Hz), 7.01 (2H, br.s), 7.09 (1H, d, J = 5.4 Hz) , 7.10 (2H, br.s), 7.86 (2H, d, J = 8.8 Hz), 8.40 (1H, d, J = 5.4 Hz);
MS (FAB) m / z: 450 [M + H] ⁺ , 433, 273;
Anal.Calcd for C ₂₁ H ₂₃ N ₉ OS0.4H ₂ O: C, 55.22; H, 5.25; N, 27.60; S, 7.02. Found: C, 55.42; H, 5.35; N, 27.40; S, 6.84 .

（２Ｚ）−２−シアノ−３−エトキシブタ−２−エンチオアミドと各種アミン化合物を出発原料として用いて、実施例１［（１ａ）及び（１ｂ）］と同様に反応を行い、実施例２乃至３８の化合物を得た。
Using (2Z) -2-cyano-3-ethoxybut-2-enethioamide and various amine compounds as starting materials, the reaction was carried out in the same manner as in Example 1 [(1a) and (1b)]. 38 compounds were obtained.

［実施例２］
３−アミノ−４−｛４−［４−（１−メチル−１Ｈ−テトラゾール−５−イル）フェニル］−１，４−ジアゼパン−１−イル｝チエノ［２，３−ｂ］ピリジン−２−カルボキサミド
出発原料（アミン化合物）：参考例２の化合物
淡褐色粉末;
Mp 137-138 ℃;
IR (KBr) ν_max 3435, 3322, 3187, 2949, 2852, 1646, 1609, 1579, 1493 cm^-1;
¹H NMR(DMSO-d₆, 500 MHz) δ 2.15-2.23 (2H, m), 3.18-3.27 (2H, m), 3.29-3.36 (2H, m), 3.66 (2H, t, J = 6.3 Hz), 3.86-3.91 (2H, m), 4.17 (3H, s), 6.98 (2H, d, J = 8.8 Hz), 6.99 (2H, br.s), 7.10 (1H, d, J = 5.4 Hz), 7.11 (2H, br.s), 7.70 (2H, d, J = 8.8 Hz), 8.41 (1H, d, J = 5.4 Hz);
MS (FAB) m/z: 450 [M+H]⁺, 449, 433, 329;
Anal. Calcd for C₂₁H₂₃N₉OS・2.34H₂O: C, 51.30; H, 5.67; N, 25.64; S, 6.52. Found: C, 51.19; H, 5.51; N, 25.84; S, 6.41。
[Example 2]
3-Amino-4- {4- [4- (1-methyl-1H-tetrazol-5-yl) phenyl] -1,4-diazepan-1-yl} thieno [2,3-b] pyridine-2- Carboxamide starting material (amine compound): compound of Reference Example 2 light brown powder;
Mp 137-138 ° C;
IR (KBr) ν _max 3435, 3322, 3187, 2949, 2852, 1646, 1609, 1579, 1493 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 500 MHz) δ 2.15-2.23 (2H, m), 3.18-3.27 (2H, m), 3.29-3.36 (2H, m), 3.66 (2H, t, J = 6.3 Hz ), 3.86-3.91 (2H, m), 4.17 (3H, s), 6.98 (2H, d, J = 8.8 Hz), 6.99 (2H, br.s), 7.10 (1H, d, J = 5.4 Hz) , 7.11 (2H, br.s), 7.70 (2H, d, J = 8.8 Hz), 8.41 (1H, d, J = 5.4 Hz);
MS (FAB) m / z: 450 [M + H] ⁺ , 449, 433, 329;
Anal.Calcd for C ₂₁ H ₂₃ N ₉ OS ・ 2.34H ₂ O: C, 51.30; H, 5.67; N, 25.64; S, 6.52.Found: C, 51.19; H, 5.51; N, 25.84; S, 6.41 .

［実施例３］
３−アミノ−４−｛４−［４−（２−エチル−２Ｈ−テトラゾール−５−イル）フェニル］−１，４−ジアゼパン−１−イル｝チエノ［２，３−ｂ］ピリジン−２−カルボキサミド
出発原料（アミン化合物）：参考例３の化合物
微褐色粉末;
Mp 241-242 ℃;
IR (KBr) ν_max 3444, 3322, 3185, 2953, 2844, 1652, 1614, 1580, 1465 cm^-1;
¹H NMR(DMSO-d₆, 400 MHz) δ 1.55 (3H, t, J = 7.4 Hz), 2.13-2.22 (2H, m), 3.17-3.25 (2H, m), 3.28-3.36 (2H, m), 3.62 (2H, t, J = 6.8 Hz), 3.81-3.87 (2H, m), 4.68 (2H, q, J = 7.4 Hz), 6.90 (2H, d, J = 8.8 Hz), 6.99 (2H, br.s), 7.07 (1H, d, J = 5.1 Hz), 7.07 (2H, br.s), 7.84 (2H, d, J = 8.8 Hz), 8.38 (1H, d, J = 5.1 Hz);
MS (FAB) m/z: 464 [M+H]⁺, 447, 399, 338;
Anal. Calcd for C₂₂H₂₅N₉OS・0.4H₂O: C, 56.13; H, 5.52; N, 26.78; S, 6.81. Found: C, 56.18; H, 5.36; N, 26.61; S, 6.65。
[Example 3]
3-Amino-4- {4- [4- (2-ethyl-2H-tetrazol-5-yl) phenyl] -1,4-diazepan-1-yl} thieno [2,3-b] pyridine-2- Carboxamide starting material (amine compound): compound of Reference Example 3 fine brown powder;
Mp 241-242 ° C;
IR (KBr) ν _max 3444, 3322, 3185, 2953, 2844, 1652, 1614, 1580, 1465 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.55 (3H, t, J = 7.4 Hz), 2.13-2.22 (2H, m), 3.17-3.25 (2H, m), 3.28-3.36 (2H, m ), 3.62 (2H, t, J = 6.8 Hz), 3.81-3.87 (2H, m), 4.68 (2H, q, J = 7.4 Hz), 6.90 (2H, d, J = 8.8 Hz), 6.99 (2H , br.s), 7.07 (1H, d, J = 5.1 Hz), 7.07 (2H, br.s), 7.84 (2H, d, J = 8.8 Hz), 8.38 (1H, d, J = 5.1 Hz) ;
MS (FAB) m / z: 464 [M + H] ⁺ , 447, 399, 338;
Anal. Calcd for C ₂₂ H ₂₅ N ₉ OS0.4H ₂ O: C, 56.13; H, 5.52; N, 26.78; S, 6.81. Found: C, 56.18; H, 5.36; N, 26.61; S, 6.65 .

［実施例４］
３−アミノ−４−（４−｛４−［（２−メチル−２Ｈ−テトラゾール−５−イル）メチル］フェニル｝−１，４−ジアゼパン−１−イル）チエノ［２，３−ｂ］ピリジン−２−カルボキサミド
出発原料（アミン化合物）：参考例４の化合物
淡黄色粉末;
Mp 209-211 ℃;
IR (KBr) ν_max 3444, 3330, 3176, 2951, 2838, 1651, 1578, 1520, 1366 cm^-1;
¹H NMR(DMSO-d₆, 500 MHz) δ 2.08-2.17 (2H, m), 3.13-3.22 (2H, m), 3.23-3.32 (2H, m), 3.49-3.55 (2H, m), 3.70-3.78 (2H, m), 4.06 (2H, s), 4.30 (3H, s), 6.71 (2H, d, J = 8.8 Hz), 7.00 (2H, br.s), 7.03-7.13 (5H, m), 8.39 (1H, d, J = 5.4 Hz);
MS (FAB) m/z: 464 [M+H]⁺, 447, 380, 338;
Anal. Calcd for C₂₂H₂₅N₉OS: C, 57.00; H, 5.44; N, 27.19; S, 6.92. Found: C, 56.86; H, 5.48; N, 27.08; S, 6.83。
[Example 4]
3-Amino-4- (4- {4-[(2-methyl-2H-tetrazol-5-yl) methyl] phenyl} -1,4-diazepan-1-yl) thieno [2,3-b] pyridine 2-Carboxamide starting material (amine compound): compound of Reference Example 4 pale yellow powder;
Mp 209-211 ° C;
IR (KBr) ν _max 3444, 3330, 3176, 2951, 2838, 1651, 1578, 1520, 1366 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 500 MHz) δ 2.08-2.17 (2H, m), 3.13-3.22 (2H, m), 3.23-3.32 (2H, m), 3.49-3.55 (2H, m), 3.70 -3.78 (2H, m), 4.06 (2H, s), 4.30 (3H, s), 6.71 (2H, d, J = 8.8 Hz), 7.00 (2H, br.s), 7.03-7.13 (5H, m ), 8.39 (1H, d, J = 5.4 Hz);
MS (FAB) m / z: 464 [M + H] ⁺ , 447, 380, 338;
Anal. Calcd for C ₂₂ H ₂₅ N ₉ OS: C, 57.00; H, 5.44; N, 27.19; S, 6.92. Found: C, 56.86; H, 5.48; N, 27.08; S, 6.83.

［実施例５］
３−アミノ−４−（４−｛４−［（１−メチル−１Ｈ−テトラゾール−５−イル）メチル］フェニル｝−１，４−ジアゼパン−１−イル）チエノ［２，３−ｂ］ピリジン−２−カルボキサミド
出発原料（アミン化合物）：参考例５の化合物
微黄色粉末;
Mp 194-194 ℃;
IR (KBr) ν_max 3439, 3326, 3183, 2950, 2836, 16451579, 1520, 1368 cm^-1;
¹H NMR(DMSO-d₆, 400 MHz) δ 2.07-2.17 (2H, m), 3.13-3.21 (2H, m), 3.23-3.31 (2H, m), 3.48-3.55 (2H, m), 3.71-3.77 (2H, m), 3.93 (3H, s), 4.17 (2H, s), 6.72 (2H, d, J = 8.6 Hz), 6.97 (2H, br.s), 7.01-7.11 (5H, m), 8.36 (1H, d, J = 5.5 Hz);
MS (FAB) m/z: 464 [M+H]⁺, 447, 380, 338;
Anal. Calcd for C₂₂H₂₅N₉OS・0.2EtOH: C, 56.91; H, 5.59; N, 26.66; S, 6.78. Found: C, 59.66; H, 5.41; N, 26.48; S, 6.63。
[Example 5]
3-Amino-4- (4- {4-[(1-methyl-1H-tetrazol-5-yl) methyl] phenyl} -1,4-diazepan-1-yl) thieno [2,3-b] pyridine -2-carboxamide starting material (amine compound): compound of Reference Example 5 slightly yellow powder;
Mp 194-194 ° C;
IR (KBr) ν _max 3439, 3326, 3183, 2950, 2836, 16451579, 1520, 1368 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.07-2.17 (2H, m), 3.13-3.21 (2H, m), 3.23-3.31 (2H, m), 3.48-3.55 (2H, m), 3.71 -3.77 (2H, m), 3.93 (3H, s), 4.17 (2H, s), 6.72 (2H, d, J = 8.6 Hz), 6.97 (2H, br.s), 7.01-7.11 (5H, m ), 8.36 (1H, d, J = 5.5 Hz);
MS (FAB) m / z: 464 [M + H] ⁺ , 447, 380, 338;
Anal. Calcd for C ₂₂ H ₂₅ N ₉ OS 0.2EtOH: C, 56.91; H, 5.59; N, 26.66; S, 6.78. Found: C, 59.66; H, 5.41; N, 26.48;

［実施例６］
３−アミノ−４−｛４−［４−（１−エチル−１Ｈ−テトラゾール−５−イル）フェニル］−１，４−ジアゼパン−１−イル｝チエノ［２，３−ｂ］ピリジン−２−カルボキサミド
出発原料（アミン化合物）：参考例６の化合物
微黄色粉末;
Mp 206-208 ℃;
IR (KBr) ν_max 3442, 3324, 3179, 2941, 2839, 1647, 1610, 1579, 1486 cm^-1;
¹H NMR(DMSO-d₆, 500 MHz) δ 1.46 (3H, t, J = 7.3 Hz), 2.16-2.24 (2H, m), 3.18-3.27 (2H, m), 3.29-3.38 (2H, m), 3.63-3.69 (2H, m), 3.85-3.92 (2H, m), 4.51 (2H, q, J = 7.3 Hz), 6.98 (2H, d, J = 9.3 Hz), 7.00 (2H, br.s), 7.10 (1H, d, J = 5.4 Hz), 7.10 (2H, br.s), 7.63 (2H, d, J = 9.3 Hz), 8.41 (1H, d, J = 5.4 Hz);
MS (FAB) m/z: 464 [M+H]⁺, 463, 447, 379;
Anal. Calcd for C₂₂H₂₅N₉OS・1.1H₂O: C, 54.67; H, 5.67; N, 26.08; S, 6.63. Found: C, 54.53; H, 5.52; N, 26.18; S, 6.59。
[Example 6]
3-Amino-4- {4- [4- (1-ethyl-1H-tetrazol-5-yl) phenyl] -1,4-diazepan-1-yl} thieno [2,3-b] pyridine-2- Carboxamide starting material (amine compound): compound of Reference Example 6 slightly yellow powder;
Mp 206-208 ° C;
IR (KBr) ν _max 3442, 3324, 3179, 2941, 2839, 1647, 1610, 1579, 1486 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 500 MHz) δ 1.46 (3H, t, J = 7.3 Hz), 2.16-2.24 (2H, m), 3.18-3.27 (2H, m), 3.29-3.38 (2H, m ), 3.63-3.69 (2H, m), 3.85-3.92 (2H, m), 4.51 (2H, q, J = 7.3 Hz), 6.98 (2H, d, J = 9.3 Hz), 7.00 (2H, br. s), 7.10 (1H, d, J = 5.4 Hz), 7.10 (2H, br.s), 7.63 (2H, d, J = 9.3 Hz), 8.41 (1H, d, J = 5.4 Hz);
MS (FAB) m / z: 464 [M + H] ⁺ , 463, 447, 379;
Anal. Calcd for C ₂₂ H ₂₅ N ₉ OS 1.1H ₂ O: C, 54.67; H, 5.67; N, 26.08; S, 6.63. Found: C, 54.53; H, 5.52; N, 26.18; S, 6.59 .

［実施例７］
３−アミノ−４−（４−｛４−［２−（２−メトキシエチル）−２Ｈ−テトラゾール−５−イル］フェニル｝−１，４−ジアゼパン−１−イル）チエノ［２，３−ｂ］ピリジン−２−カルボキサミド
出発原料（アミン化合物）：参考例７の化合物
淡褐色粉末;
Mp 250-252 ℃;
IR (KBr) ν_max 3446, 3322, 3185, 2930, 2839, 1650, 1614, 1580, 1466 cm^-1;
¹H NMR(DMSO-d₆, 400 MHz) δ 2.14-2.24 (2H, m), 3.16-3.38 (7H, m), 3.59-3.67 (2H, m), 3.81-3.94 (4H, m), 4.84 (2H, t, J = 5.1 Hz), 6.93 (2H, d, J = 8.6 Hz), 7.02 (2H, br.s), 7.06-7.15 (3H, m), 7.87 (2H, d, J = 8.6 Hz), 8.40 (1H, d, J = 5.4 Hz);
MS (FAB) m/z: 494 [M+H]⁺, 493, 450, 392;
Anal. Calcd for C₂₃H₂₇N₉O₂S・0.5H₂O: C, 54.97; H, 5.62; N, 25.08; S, 6.38. Found: C, 54.94; H, 5.39; N, 25.25; S, 6.35。
[Example 7]
3-Amino-4- (4- {4- [2- (2-methoxyethyl) -2H-tetrazol-5-yl] phenyl} -1,4-diazepan-1-yl) thieno [2,3-b ] Pyridine-2-carboxamide starting material (amine compound): compound of Reference Example 7 light brown powder;
Mp 250-252 ° C;
IR (KBr) ν _max 3446, 3322, 3185, 2930, 2839, 1650, 1614, 1580, 1466 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.14-2.24 (2H, m), 3.16-3.38 (7H, m), 3.59-3.67 (2H, m), 3.81-3.94 (4H, m), 4.84 (2H, t, J = 5.1 Hz), 6.93 (2H, d, J = 8.6 Hz), 7.02 (2H, br.s), 7.06-7.15 (3H, m), 7.87 (2H, d, J = 8.6 Hz), 8.40 (1H, d, J = 5.4 Hz);
MS (FAB) m / z: 494 [M + H] ⁺ , 493, 450, 392;
Anal. Calcd for C ₂₃ H ₂₇ N ₉ O ₂ S ・ 0.5H ₂ O: C, 54.97; H, 5.62; N, 25.08; S, 6.38. Found: C, 54.94; H, 5.39; N, 25.25; S , 6.35.

［実施例８］
３−アミノ−４−（４−｛４−［１−（２−メトキシエチル）−１Ｈ−テトラゾール−５−イル］フェニル｝−１，４−ジアゼパン−１−イル）チエノ［２，３−ｂ］ピリジン−２−カルボキサミド
出発原料（アミン化合物）：参考例８の化合物
微黄色粉末;
Mp 207-209 ℃;
IR (KBr) ν_max 3442, 3327, 3189, 2932, 2836, 1646, 1610, 1579, 1487 cm^-1;
¹H NMR(DMSO-d₆, 500 MHz) δ 2.15-2.24 (2H, m), 3.15-3.27 (2H, m), 3.19 (3H, s), 3.28-3.37 (2H, m), 3.62-3.68 (2H, m), 3.82 (2H, t, J = 5.1 Hz), 3.85-3.91 (2H, m), 4.62 (2H, t, J = 5.1 Hz), 6.97 (2H, d, J = 9.3 Hz), 7.02 (2H, br.s), 7.09 (1H, d, J = 5.4 Hz), 7.11 (2H, br.s), 7.66 (2H, d, J = 9.3 Hz), 8.41 (1H, d, J = 5.4 Hz);
MS (FAB) m/z: 494 [M+H]⁺, 273, 246;
Anal. Calcd for C₂₃H₂₇N₉O₂S・0.6H₂O: C, 54.77; H, 5.64; N, 24.99; S, 6.36. Found: C, 54.56; H, 5.42; N, 25.07; S, 6.28。
[Example 8]
3-Amino-4- (4- {4- [1- (2-methoxyethyl) -1H-tetrazol-5-yl] phenyl} -1,4-diazepan-1-yl) thieno [2,3-b Pyridine-2-carboxamide starting material (amine compound): compound of Reference Example 8 slightly yellow powder;
Mp 207-209 ° C;
IR (KBr) ν _max 3442, 3327, 3189, 2932, 2836, 1646, 1610, 1579, 1487 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 500 MHz) δ 2.15-2.24 (2H, m), 3.15-3.27 (2H, m), 3.19 (3H, s), 3.28-3.37 (2H, m), 3.62-3.68 (2H, m), 3.82 (2H, t, J = 5.1 Hz), 3.85-3.91 (2H, m), 4.62 (2H, t, J = 5.1 Hz), 6.97 (2H, d, J = 9.3 Hz) , 7.02 (2H, br.s), 7.09 (1H, d, J = 5.4 Hz), 7.11 (2H, br.s), 7.66 (2H, d, J = 9.3 Hz), 8.41 (1H, d, J = 5.4 Hz);
MS (FAB) m / z: 494 [M + H] ⁺ , 273, 246;
Anal.Calcd for C ₂₃ H ₂₇ N ₉ O ₂ S ・ 0.6H ₂ O: C, 54.77; H, 5.64; N, 24.99; S, 6.36. Found: C, 54.56; H, 5.42; N, 25.07; S , 6.28.

［実施例９］
３−アミノ−４−｛４−［３−（１−メチル−１Ｈ−テトラゾール−５−イル）フェニル］ピペラジン−１−イル｝チエノ［２，３−ｂ］ピリジン−２−カルボキサミド
出発原料（アミン化合物）：参考例９の化合物
微黄色粉末;
Mp 142-144 ℃;
IR (KBr) ν_max 3436, 3328, 3214, 2835, 1648, 1582, 1493, 1376 cm^-1;
¹H NMR(DMSO-d₆, 400 MHz) δ 2.82-4.01 (8H, m), 4.16 (3H, s), 6.96 (2H, br.s), 7.08 (1H, d, J = 5.1 Hz), 7.13 (2H, br.s), 7.19-7.24 (1H, m), 7.25-7.31 (1H, m), 7.38 (1H, s), 7.43-7.50 (1H, m), 7.46 (1H, d, J = 5.1 Hz);
MS (FAB) m/z: 436 [M+H]⁺, 419, 391, 341;
Anal. Calcd for C₂₀H₂₁N₉OS・1.4H₂O: C, 52.14; H, 5.21; N, 27.36; S, 6.96. Found: C, 52.12; H, 4.97; N, 27.43; S, 6.75。
[Example 9]
3-Amino-4- {4- [3- (1-methyl-1H-tetrazol-5-yl) phenyl] piperazin-1-yl} thieno [2,3-b] pyridine-2-carboxamide starting material (amine Compound): compound of Reference Example 9 slightly yellow powder;
Mp 142-144 ° C;
IR (KBr) ν _max 3436, 3328, 3214, 2835, 1648, 1582, 1493, 1376 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.82-4.01 (8H, m), 4.16 (3H, s), 6.96 (2H, br.s), 7.08 (1H, d, J = 5.1 Hz), 7.13 (2H, br.s), 7.19-7.24 (1H, m), 7.25-7.31 (1H, m), 7.38 (1H, s), 7.43-7.50 (1H, m), 7.46 (1H, d, J = 5.1 Hz);
MS (FAB) m / z: 436 [M + H] ⁺ , 419, 391, 341;
Anal.Calcd for C ₂₀ H ₂₁ N ₉ OS ・ 1.4H ₂ O: C, 52.14; H, 5.21; N, 27.36; S, 6.96. Found: C, 52.12; H, 4.97; N, 27.43; S, 6.75 .

［実施例１０］
３−アミノ−４−｛４−［４−（２−オキソピペリジン−１−イル）フェニル］−１，４−ジアゼパン−１−イル｝チエノ［２，３−ｂ］ピリジン−２−カルボキサミド
出発原料（アミン化合物）：参考例１０の化合物
黄色粉末;
Mp 262-263 ℃;
IR (KBr) ν_max 3439, 3324, 3183, 2944, 2864, 1644, 1579, 1517 cm^-1;
¹H NMR(DMSO-d₆, 400 MHz) δ 1.75-1.88 (4H, m), 2.10-2.19 (2H, m), 2.30-2.37 (2H, m), 3.16-3.24 (2H, m), 3.25-3.33 (2H, m), 3.48-3.57 (4H, m), 3.73-3.80 (2H, m), 6.73 (2H, d, J = 9.0 Hz), 6.97 (2H, br.s), 7.01 (2H, d, J = 9.0 Hz), 7.06 (1H, d, J = 5.4 Hz), 7.07 (2H, br.s), 8.37 (1H, d, J = 5.4 Hz);
MS (FAB) m/z: 465 [M+H]⁺, 464, 448, 379;
Anal. Calcd for C₂₄H₂₈N₆O₂S・0.4H₂O: C, 61.10; H, 6.15; N, 17.81; S, 6.80. Found: C, 61.03; H, 6.09; N, 17.94; S, 6.64。
[Example 10]
3-Amino-4- {4- [4- (2-oxopiperidin-1-yl) phenyl] -1,4-diazepan-1-yl} thieno [2,3-b] pyridine-2-carboxamide starting material (Amine compound): Compound Yellow powder of Reference Example 10;
Mp 262-263 ° C;
IR (KBr) ν _max 3439, 3324, 3183, 2944, 2864, 1644, 1579, 1517 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.75-1.88 (4H, m), 2.10-2.19 (2H, m), 2.30-2.37 (2H, m), 3.16-3.24 (2H, m), 3.25 -3.33 (2H, m), 3.48-3.57 (4H, m), 3.73-3.80 (2H, m), 6.73 (2H, d, J = 9.0 Hz), 6.97 (2H, br.s), 7.01 (2H , d, J = 9.0 Hz), 7.06 (1H, d, J = 5.4 Hz), 7.07 (2H, br.s), 8.37 (1H, d, J = 5.4 Hz);
MS (FAB) m / z: 465 [M + H] ⁺ , 464, 448, 379;
Anal. Calcd for C ₂₄ H ₂₈ N ₆ O ₂ S ・ 0.4H ₂ O: C, 61.10; H, 6.15; N, 17.81; S, 6.80. Found: C, 61.03; H, 6.09; N, 17.94; S , 6.64.

［実施例１１］
３−アミノ−４−｛４−[４−（４，５−ジヒドロイソキサゾール−３−イル）フェニル]−１，４−ジアゼパン−１−イル｝チエノ[２，３−ｂ]ピリジン−２−カルボキサミド
出発原料（アミン化合物）：参考例１１の化合物
淡黄色粉末
Mp 224-226 ℃;
IR (KBr) ν_max 3444, 3329, 3168, 1656, 1605, 1575, 1524, 1365, 1201, 936, 865, 815 cm^-1;
¹H NMR(DMSO-d₆, 400 MHz) δ 2.13-2.17 (2H, m), 3.19 (2H, brs), 3.29-3.31 (4H, m), 3.60 (2H, t, J = 6.3 Hz), 3.82 (2H, t, J = 4.7 Hz), 4.27 (2H, t, J = 9.8 Hz), 6.82 (2H, d, J = 8.6 Hz), 6.98 (2H, brs), 7.06 (1H, d, J = 5.5 Hz), 8.08 (2H, brs), 7.47 (2H, d, J = 8.6 Hz), 8.38 (1H, d, J = 5.5 Hz);
HRMS m/z calcd for C₂₂H₂₅O₂N₆S 437.1760, found 437.1747.
MS (ESI) m/z: 437 [M+H]⁺.
Anal. Calcd for C₂₂H₂₄N₆O₂S・0.5H₂O: C, 59.31; H, 5.66; N, 18.86; S, 7.20. Found: C, 59.14; H, 5.53; N, 18.81, S, 7.19。
[Example 11]
3-Amino-4- {4- [4- (4,5-dihydroisoxazol-3-yl) phenyl] -1,4-diazepan-1-yl} thieno [2,3-b] pyridine-2 Carboxamide starting material (amine compound): compound of Reference Example 11 pale yellow powder
Mp 224-226 ° C;
IR (KBr) ν _max 3444, 3329, 3168, 1656, 1605, 1575, 1524, 1365, 1201, 936, 865, 815 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.13-2.17 (2H, m), 3.19 (2H, brs), 3.29-3.31 (4H, m), 3.60 (2H, t, J = 6.3 Hz), 3.82 (2H, t, J = 4.7 Hz), 4.27 (2H, t, J = 9.8 Hz), 6.82 (2H, d, J = 8.6 Hz), 6.98 (2H, brs), 7.06 (1H, d, J = 5.5 Hz), 8.08 (2H, brs), 7.47 (2H, d, J = 8.6 Hz), 8.38 (1H, d, J = 5.5 Hz);
HRMS m / z calcd for C ₂₂ H ₂₅ O ₂ N ₆ S 437.1760, found 437.1747.
MS (ESI) m / z: 437 [M + H] ⁺ .
Anal.Calcd for C ₂₂ H ₂₄ N ₆ O ₂ S ・ 0.5H ₂ O: C, 59.31; H, 5.66; N, 18.86; S, 7.20. Found: C, 59.14; H, 5.53; N, 18.81, S , 7.19.

［実施例１２］
３−アミノ−４−｛４−［４−（５−メチルイソキサゾール−３−イル）フェニル］−１，４−ジアゼパン−１−イル｝チエノ［２，３−ｂ］ピリジン−２−カルボキサミド
出発原料（アミン化合物）：参考例１２の化合物
淡黄色粉末
Mp 206-209 ℃;
IR (KBr) ν_max 3443, 3326, 1650, 1609, 1499, 1439, 1367, 1201, 938, 822 cm^-1;
¹H NMR(DMSO-d₆, 400 MHz) δ 2.14-2.19 (2H, m), 2.41 (3H, s), 3.19 (2H, brs), 3.29-3.31 (2H, m), 3.61 (2H, q, J = 5.9 Hz), 3.81-3.84 (2H, m), 6.80 (1H, s), 6.84 (2H, d, J = 8.6 Hz), 6.99 (2H, brs), 7.07 (1H, d, J = 5.5 Hz), 7.07 (2H, brs), 7.61 (2H, d, J = 8.6 Hz), 8.38 (1H, d, J = 5.5 Hz);
HRMS m/z calcd for C₂₃H₂₅O₂N₆S 449.1760, found 449.1777.
MS (FAB) m/z: 449 [M+H]⁺, 448, 432, 343, 248, 230, 187, 63;
Anal. Calcd for C₂₃H₂₄N₆O₂S・0.8EtOH: C, 60.87; H, 5.98; N, 17.31; S, 6.61. Found: C, 60.86; H, 5.97; N, 17.45; S, 6.35。

［実施例１３］
３−アミノ−４−{４−[４−（３−メチル−１，２，４−チアジアゾール−５−イル）フェニル]−１，４−ジアゼパン−１−イル}チエノ[２，３−ｂ]ピリジン−２−カルボキサミド
出発原料（アミン化合物）：参考例１３の化合物
淡黄色粉末
Mp 264-265 ℃;
IR (KBr) ν_max 3437, 3322, 1650, 1604, 1426, 1368, 1190, 937, 818 cm^-1;
¹H NMR(DMSO-d₆, 500 MHz) δ 2.16-2.21 (2H, m), 2.57 (3H, s), 3.21 (2H, brs), 3.32 (2H, brs), 3.66 (2H, t, J = 6.4 Hz), 3.88 (2H, t, J = 5.4 Hz), 6.92 (2H, d, J = 8.8 Hz), 7.00 (2H, brs), 7.09 (1H, d, J = 5.4 Hz), 7.09 (2H, brs), 7.80 (2H, d, J = 8.8 Hz), 8.41 (1H, d, J = 5.4 Hz);
HRMS m/z calcd for C₂₂H₂₄ON₇S₂466.1484, found 466.1528.
MS (ESI) m/z: 466 [M+H]⁺;
Anal. Calcd for C₂₂H₂₃N₇OS₂・0.34H₂O: C, 56.02; H, 5.06; N, 20.79; S, 13.59. Found: C, 56.01; H, 5.08; N, 20.78; S, 13.34。
[Example 12]
3-Amino-4- {4- [4- (5-methylisoxazol-3-yl) phenyl] -1,4-diazepan-1-yl} thieno [2,3-b] pyridine-2-carboxamide Starting material (amine compound): compound of Reference Example 12 pale yellow powder
Mp 206-209 ° C;
IR (KBr) ν _max 3443, 3326, 1650, 1609, 1499, 1439, 1367, 1201, 938, 822 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.14-2.19 (2H, m), 2.41 (3H, s), 3.19 (2H, brs), 3.29-3.31 (2H, m), 3.61 (2H, q , J = 5.9 Hz), 3.81-3.84 (2H, m), 6.80 (1H, s), 6.84 (2H, d, J = 8.6 Hz), 6.99 (2H, brs), 7.07 (1H, d, J = 5.5 Hz), 7.07 (2H, brs), 7.61 (2H, d, J = 8.6 Hz), 8.38 (1H, d, J = 5.5 Hz);
HRMS m / z calcd for C ₂₃ H ₂₅ O ₂ N ₆ S 449.1760, found 449.1777.
MS (FAB) m / z: 449 [M + H] ⁺ , 448, 432, 343, 248, 230, 187, 63;
Anal. Calcd for C ₂₃ H ₂₄ N ₆ O ₂ S0.8EtOH: C, 60.87; H, 5.98; N, 17.31; S, 6.61. Found: C, 60.86; H, 5.97; N, 17.45; S, 6.35 .

[Example 13]
3-Amino-4- {4- [4- (3-methyl-1,2,4-thiadiazol-5-yl) phenyl] -1,4-diazepan-1-yl} thieno [2,3-b] Pyridine-2-carboxamide starting material (amine compound): compound of Reference Example 13 pale yellow powder
Mp 264-265 ° C;
IR (KBr) ν _max 3437, 3322, 1650, 1604, 1426, 1368, 1190, 937, 818 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 500 MHz) δ 2.16-2.21 (2H, m), 2.57 (3H, s), 3.21 (2H, brs), 3.32 (2H, brs), 3.66 (2H, t, J = 6.4 Hz), 3.88 (2H, t, J = 5.4 Hz), 6.92 (2H, d, J = 8.8 Hz), 7.00 (2H, brs), 7.09 (1H, d, J = 5.4 Hz), 7.09 ( 2H, brs), 7.80 (2H, d, J = 8.8 Hz), 8.41 (1H, d, J = 5.4 Hz);
HRMS m / z calcd for C ₂₂ H ₂₄ ON ₇ S ₂ 466.1484, found 466.1528.
MS (ESI) m / z: 466 [M + H] ⁺ ;
Anal. Calcd for C ₂₂ H ₂₃ N ₇ OS ₂ , 0.34H ₂ O: C, 56.02; H, 5.06; N, 20.79; S, 13.59. Found: C, 56.01; H, 5.08; N, 20.78; S, 13.34.

［実施例１４］
３−アミノ−４−{４−[４−（４，５−ジメチル−４Ｈ−１，２，４−トリアゾール−３−イル）フェニル]−１，４−ジアゼパン−１−イル}チエノ[２，３−ｂ]ピリジン−２−カルボキサミド
出発原料（アミン化合物）：参考例１４の化合物
黄色粉末
Mp 167-169 ℃;
IR (KBr) ν_max 3444, 3328, 3160, 1653, 1610, 1579, 1496, 1367, 1183, 934, 821 cm^-1;
¹H NMR(DMSO-d₆, 500 MHz) δ 2.18-2.20 (2H, m), 2.37 (3H, s), 3.23 (2H, brs), 3.30-3.33 (2H, m), 3.55 (3H, s), 3.63 (2H, t, J = 6.4 Hz), 3.86 (2H, t, J = 4.9 Hz), 6.91 (2H, d, J = 8.8 Hz), 7.01 (2H, brs), 7.10 (1H, d, J = 5.4 Hz), 7.10 (2H, brs), 7.47 (2H, d, J = 8.8 Hz), 8.42 (1H, d, J = 5.4 Hz);
HRMS m/z calcd for C₂₃H₂₇ON₈S 463.2029, found 463.2055.
MS (ESI) m/z: 463 [M+H]⁺;
Anal. Calcd for C₂₃H₂₆N₈OS・1.24H₂O: C, 56.97; H, 5.92; N, 23.11; S, 6.61. Found: C, 57.33; H, 5.97; N, 23.14; S, 6.22。
[Example 14]
3-amino-4- {4- [4- (4,5-dimethyl-4H-1,2,4-triazol-3-yl) phenyl] -1,4-diazepan-1-yl} thieno [2, 3-b] pyridine-2-carboxamide starting material (amine compound): compound yellow powder of Reference Example 14
Mp 167-169 ° C;
IR (KBr) ν _max 3444, 3328, 3160, 1653, 1610, 1579, 1496, 1367, 1183, 934, 821 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 500 MHz) δ 2.18-2.20 (2H, m), 2.37 (3H, s), 3.23 (2H, brs), 3.30-3.33 (2H, m), 3.55 (3H, s ), 3.63 (2H, t, J = 6.4 Hz), 3.86 (2H, t, J = 4.9 Hz), 6.91 (2H, d, J = 8.8 Hz), 7.01 (2H, brs), 7.10 (1H, d , J = 5.4 Hz), 7.10 (2H, brs), 7.47 (2H, d, J = 8.8 Hz), 8.42 (1H, d, J = 5.4 Hz);
HRMS m / z calcd for C ₂₃ H ₂₇ ON ₈ S 463.2029, found 463.2055.
MS (ESI) m / z: 463 [M + H] ⁺ ;
Anal.Calcd for C ₂₃ H ₂₆ N ₈ OS ・ 1.24H ₂ O: C, 56.97; H, 5.92; N, 23.11; S, 6.61. Found: C, 57.33; H, 5.97; N, 23.14; S, 6.22 .

［実施例１５］
３−アミノ−４−{４−[４−（４，５−ジメチル−４Ｈ−１，２，４−トリアゾール−３−イル）−３−メチルフェニル]−１，４−ジアゼパン−１−イル}チエノ[２，３−ｂ]ピリジン−２−カルボキサミド
出発原料（アミン化合物）：参考例１５の化合物
淡黄色粉末
Mp 258-262 ℃;
IR (KBr) ν_max 3421, 3166, 2953, 1649, 1609, 1498, 1365, 1231, 1135, 941 cm^-1;
¹H NMR(DMSO-d₆, 400 MHz) δ 2.11 (3H, s), 2.16-2.19 (2H, m), 2.37 (3H, s), 3.23 (2H, brs), 3.29-3.32 (2H, m), 3.32 (3H, s), 3.60 (2H, t, J = 6.3 Hz), 3.82-3.84 (2H, m), 6.70 (1H, dd, J = 2.7, 9.0 Hz), 6.75 (1H, s), 6.99 (2H, brs), 7.06-7.09 (4H, m), 8.39 (1H, d, J = 5.5 Hz);
HRMS m/z calcd for C₂₄H₂₉ON₈S 477.2185, found 477.2176.
MS (ESI) m/z: 477 [M+H]⁺, 460, 434;
Anal. Calcd for C₂₄H₂₈N₈OS・0.36H₂O: C, 59.67; H, 5.99; N, 23.20; S, 6.64. Found: C, 59.83; H, 5.95; N, 22.95; S, 6.45。
[Example 15]
3-amino-4- {4- [4- (4,5-dimethyl-4H-1,2,4-triazol-3-yl) -3-methylphenyl] -1,4-diazepan-1-yl} Thieno [2,3-b] pyridine-2-carboxamide starting material (amine compound): compound of Reference Example 15 pale yellow powder
Mp 258-262 ° C;
IR (KBr) ν _max 3421, 3166, 2953, 1649, 1609, 1498, 1365, 1231, 1135, 941 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.11 (3H, s), 2.16-2.19 (2H, m), 2.37 (3H, s), 3.23 (2H, brs), 3.29-3.32 (2H, m ), 3.32 (3H, s), 3.60 (2H, t, J = 6.3 Hz), 3.82-3.84 (2H, m), 6.70 (1H, dd, J = 2.7, 9.0 Hz), 6.75 (1H, s) , 6.99 (2H, brs), 7.06-7.09 (4H, m), 8.39 (1H, d, J = 5.5 Hz);
HRMS m / z calcd for C ₂₄ H ₂₉ ON ₈ S 477.2185, found 477.2176.
MS (ESI) m / z: 477 [M + H] ⁺ , 460, 434;
Anal.Calcd for C ₂₄ H ₂₈ N ₈ OS ・ 0.36H ₂ O: C, 59.67; H, 5.99; N, 23.20; S, 6.64. Found: C, 59.83; H, 5.95; N, 22.95; S, 6.45 .

［実施例１６］
３−アミノ−４−{４−[４−（１−メチル−１Ｈ−ピラゾール−５−イル）フェニル]−１，４−ジアゼパン−１−イル}チエノ[２，３−ｂ]ピリジン−２−カルボキサミド
出発原料（アミン化合物）：参考例１６の化合物
白色粉末
Mp 248-251 ℃;
IR (KBr) ν_max 3435, 3320, 3171, 1650, 1499, 1376, 937, 823, 445 cm^-1;
¹H NMR(DMSO-d₆, 400 MHz) δ 2.14-2.19 (2H, m), 3.23 (2H, brs), 3.29-3.31 (2H, m), 3.60 (2H, t, J = 6.3 Hz), 3.82-3.84 (2H, m), 3.82 (3H, s), 6.25 (1H, d, J = 2.0 Hz), 6.86 (2H, d, J = 8.6 Hz), 6.95 (2H, brs), 7.08 (2H, brs), 7.09 (1H, d, J = 5.1 Hz), 7.31 (2H, d, J = 8.6 Hz), 7.38 (1H, d, J = 2.0 Hz), 8.39 (1H, d, J = 5.1 Hz);
HRMS m/z calcd for C₂₃H₂₆ON₇S 448.1919, found 448.1908.
MS (FAB) m/z: 448 [M+H]⁺, 447, 431, 391, 371, 341, 273, 235, 219, 186;
Anal. Calcd for C₂₃H₂₅N₇OS・0.38H₂O: C, 60.79; H, 5.71; N, 21.58; S, 7.06. Found: C, 60.70; H, 5.70; N, 21.70; S, 7.12。
[Example 16]
3-Amino-4- {4- [4- (1-methyl-1H-pyrazol-5-yl) phenyl] -1,4-diazepan-1-yl} thieno [2,3-b] pyridine-2- Carboxamide starting material (amine compound): Compound white powder of Reference Example 16
Mp 248-251 ° C;
IR (KBr) ν _max 3435, 3320, 3171, 1650, 1499, 1376, 937, 823, 445 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.14-2.19 (2H, m), 3.23 (2H, brs), 3.29-3.31 (2H, m), 3.60 (2H, t, J = 6.3 Hz), 3.82-3.84 (2H, m), 3.82 (3H, s), 6.25 (1H, d, J = 2.0 Hz), 6.86 (2H, d, J = 8.6 Hz), 6.95 (2H, brs), 7.08 (2H , brs), 7.09 (1H, d, J = 5.1 Hz), 7.31 (2H, d, J = 8.6 Hz), 7.38 (1H, d, J = 2.0 Hz), 8.39 (1H, d, J = 5.1 Hz) );
HRMS m / z calcd for C ₂₃ H ₂₆ ON ₇ S 448.1919, found 448.1908.
MS (FAB) m / z: 448 [M + H] ⁺ , 447, 431, 391, 371, 341, 273, 235, 219, 186;
Anal.Calcd for C ₂₃ H ₂₅ N ₇ OS ・ 0.38H ₂ O: C, 60.79; H, 5.71; N, 21.58; S, 7.06.Found: C, 60.70; H, 5.70; N, 21.70; S, 7.12 .

［実施例１７］
３−アミノ−４−{４−[４−（１，３−ジメチル−１Ｈ−１，２，４−トリアゾール−５−イル）フェニル]−１，４−ジアゼパン−１−イル}チエノ[２，３−ｂ]ピリジン−２−カルボキサミド
出発原料（アミン化合物）：参考例１７の化合物
淡褐色粉末
Mp 152-155 ℃(dec.);
IR (KBr) ν_max 3439, 3325, 3181, 1650, 1610, 1489, 1369, 1196, 939, 823 cm^-1;
¹H NMR(DMSO-d₆, 500 MHz) δ 2.19 (2H, brs), 2.23 (3H, s), 3.23 (2H, brs), 3.31-3.33 (2H, m), 3.63 (2H, t, J = 6.3 Hz), 3.87 (5H, brs), 6.91 (2H, d, J = 9.0 Hz), 7.00 (2H, brs), 7.11 (1H, d, J = 5.1 Hz), 7.11 (2H, brs), 7.58 (2H, d, J = 9.0 Hz), 8.42 (1H, d, J = 5.1 Hz);
HRMS m/z calcd for C₂₃H₂₇ON₈S 463.2029, found 463.2053.
MS (ESI) m/z: 463 [M+H]⁺;
Anal. Calcd for C₂₃H₂₆N₈OS・4.2H₂O: C, 51.33; H, 6.44; N, 20.82; S, 5.96. Found: C, 51.06; H, 6.43; N, 20.54; S, 6.72。
[Example 17]
3-Amino-4- {4- [4- (1,3-dimethyl-1H-1,2,4-triazol-5-yl) phenyl] -1,4-diazepan-1-yl} thieno [2, 3-b] pyridine-2-carboxamide starting material (amine compound): compound of Reference Example 17 pale brown powder
Mp 152-155 ° C (dec.);
IR (KBr) ν _max 3439, 3325, 3181, 1650, 1610, 1489, 1369, 1196, 939, 823 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 500 MHz) δ 2.19 (2H, brs), 2.23 (3H, s), 3.23 (2H, brs), 3.31-3.33 (2H, m), 3.63 (2H, t, J = 6.3 Hz), 3.87 (5H, brs), 6.91 (2H, d, J = 9.0 Hz), 7.00 (2H, brs), 7.11 (1H, d, J = 5.1 Hz), 7.11 (2H, brs), 7.58 (2H, d, J = 9.0 Hz), 8.42 (1H, d, J = 5.1 Hz);
HRMS m / z calcd for C ₂₃ H ₂₇ ON ₈ S 463.2029, found 463.2053.
MS (ESI) m / z: 463 [M + H] ⁺ ;
Anal.Calcd for C ₂₃ H ₂₆ N ₈ OS ・ 4.2H ₂ O: C, 51.33; H, 6.44; N, 20.82; S, 5.96. Found: C, 51.06; H, 6.43; N, 20.54; S, 6.72 .

［実施例１８］
３−アミノ−４−{４−[４−（４−メチル−４Ｈ−１，２，４−トリアゾール−３−イル）フェニル]−１，４−ジアゼパン−１−イル}チエノ[２，３−ｂ]ピリジン−２−カルボキサミド
出発原料（アミン化合物）：参考例１８の化合物
淡黄色粉末
Mp 217-220 ℃;
IR (KBr) ν_max 3439, 3323, 1646, 1611, 1488, 1368, 1199, 938, 822 cm^-1;
¹H NMR(DMSO-d₆, 500 MHz) δ 2.16-2.20 (2H, m), 3.23 (2H, brs), 3.30-3.32 (2H, m), 3.63 (2H, t, J = 6.4 Hz), 3.72 (3H, s), 3.86 (2H, t, J = 4.9 Hz), 6.92 (2H, d, J = 8.8 Hz), 6.99 (2H, brs), 7.10 (2H, brs), 7.11 (1H, d, J = 5.4 Hz), 7.56 (2H, d, J = 8.8 Hz), 8.42 (1H, d, J = 5.4 Hz), 8.47 (1H, s);
HRMS m/z calcd for C₂₂H₂₅ON₈S 449.1872, found 449.1874.
MS (ESI) m/z: 449 [M+H]⁺;
Anal. Calcd for C₂₂H₂₄N₈OS・1.59H₂O: C, 55.37; H, 5.74; N, 23.48; S, 6.72. Found: C, 55.24; H, 5.63; N, 23.29; S, 6.98。
[Example 18]
3-Amino-4- {4- [4- (4-methyl-4H-1,2,4-triazol-3-yl) phenyl] -1,4-diazepan-1-yl} thieno [2,3- b] Pyridine-2-carboxamide starting material (amine compound): compound of Reference Example 18 pale yellow powder
Mp 217-220 ° C;
IR (KBr) ν _max 3439, 3323, 1646, 1611, 1488, 1368, 1199, 938, 822 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 500 MHz) δ 2.16-2.20 (2H, m), 3.23 (2H, brs), 3.30-3.32 (2H, m), 3.63 (2H, t, J = 6.4 Hz), 3.72 (3H, s), 3.86 (2H, t, J = 4.9 Hz), 6.92 (2H, d, J = 8.8 Hz), 6.99 (2H, brs), 7.10 (2H, brs), 7.11 (1H, d , J = 5.4 Hz), 7.56 (2H, d, J = 8.8 Hz), 8.42 (1H, d, J = 5.4 Hz), 8.47 (1H, s);
HRMS m / z calcd for C ₂₂ H ₂₅ ON ₈ S 449.1872, found 449.1874.
MS (ESI) m / z: 449 [M + H] ⁺ ;
Anal.Calcd for C ₂₂ H ₂₄ N ₈ OS 1.59H ₂ O: C, 55.37; H, 5.74; N, 23.48; S, 6.72. Found: C, 55.24; H, 5.63; N, 23.29; S, 6.98 .

［実施例１９］
３−アミノ−４−｛４−［４−（２−オキソピロリジン−１−イル）フェニル］−１，４−ジアゼパン−１−イル｝チエノ［２，３−ｂ］ピリジン−２−カルボキサミド
出発原料（アミン化合物）：参考例１９の化合物
Mp 237-240 ℃;
IR (KBr) ν_max 3436, 3325, 3193, 1649, 1578, 1517, 940, 818 cm^-1;
¹H NMR (DMSO-d₆, 400MHz) δ 1.99-2.07 (2H, m), 2.11-2.16 (2H, m), 2.40-2.44 (2H, m), 3.16-3.32 (4H, m), 3.54 (2H, t, J = 6.3 Hz), 3.74-3.77 (4H, m), 6.75 (2H, d, J = 9.0 Hz), 6.97 (2H, brs), 7.06 (1H, d, J = 5.1 Hz), 7.07 (2H, brs), 7.39 (2H, d, J = 9.0 Hz), 8.38 (1H, d, J = 5.1 Hz);
MS (FAB) m/z: 451 [M+H]⁺;
Anal. Calcd for C₂₃H₂₆N₆O₂S・1.8 H₂O: C, 57.20; H, 6.18; N, 17.40; S, 6.64. Found: C, 57.32; H, 5.86; N, 17.43; S, 6.50。
[Example 19]
3-Amino-4- {4- [4- (2-oxopyrrolidin-1-yl) phenyl] -1,4-diazepan-1-yl} thieno [2,3-b] pyridine-2-carboxamide starting material (Amine compound): Compound of Reference Example 19
Mp 237-240 ° C;
IR (KBr) ν _max 3436, 3325, 3193, 1649, 1578, 1517, 940, 818 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 400MHz) δ 1.99-2.07 (2H, m), 2.11-2.16 (2H, m), 2.40-2.44 (2H, m), 3.16-3.32 (4H, m), 3.54 ( 2H, t, J = 6.3 Hz), 3.74-3.77 (4H, m), 6.75 (2H, d, J = 9.0 Hz), 6.97 (2H, brs), 7.06 (1H, d, J = 5.1 Hz), 7.07 (2H, brs), 7.39 (2H, d, J = 9.0 Hz), 8.38 (1H, d, J = 5.1 Hz);
MS (FAB) m / z: 451 [M + H] ⁺ ;
Anal. Calcd for C ₂₃ H ₂₆ N ₆ O ₂ S1.8 H ₂ O: C, 57.20; H, 6.18; N, 17.40; S, 6.64. Found: C, 57.32; H, 5.86; N, 17.43; S , 6.50.

［実施例２０］
３−アミノ−４−｛４−［４−（５−メチル−１，２，４−オキサジアゾール−３−イル）フェニル］−１，４−ジアゼパン−１−イル｝チエノ［２，３−ｂ］ピリジン−２−カルボキサミド
出発原料（アミン化合物）：参考例２０の化合物
Mp 253-258 ℃ (dec);
IR (KBr) ν_max 3442, 3321, 3184, 1651, 1612, 1588, 1360, 1195, 938, 824, 755 cm^-1;
¹H NMR (DMSO-d₆, 400MHz) δ 2.16-2.21 (2H, m), 2.61 (3H, s), 3.19-3.34 (4H, m), 3.62-3.65 (2H, m), 3.85-3.87 (2H, m), 6.92 (2H, d, J = 8.6 Hz), 7.01 (2H, brs), 7.09 (1H, d, J = 5.1 Hz), 7.10 (2H, brs), 7.80 (2H, d, J = 8.6 Hz), 8.41 (1H, d, J = 5.1 Hz);
MS (FAB) m/z: 450 [M+H]⁺;
Anal. Calcd for C₂₂H₂₃N₇O₂S・0.6 H₂O: C, 57.40; H, 5.30; N, 21.30; S, 6.97. Found: C, 57.66; H, 5.26; N, 21.21; S, 6.52。
[Example 20]
3-Amino-4- {4- [4- (5-methyl-1,2,4-oxadiazol-3-yl) phenyl] -1,4-diazepan-1-yl} thieno [2,3- b] Pyridine-2-carboxamide starting material (amine compound): compound of Reference Example 20
Mp 253-258 ° C (dec);
IR (KBr) ν _max 3442, 3321, 3184, 1651, 1612, 1588, 1360, 1195, 938, 824, 755 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.16-2.21 (2H, m), 2.61 (3H, s), 3.19-3.34 (4H, m), 3.62-3.65 (2H, m), 3.85-3.87 ( 2H, m), 6.92 (2H, d, J = 8.6 Hz), 7.01 (2H, brs), 7.09 (1H, d, J = 5.1 Hz), 7.10 (2H, brs), 7.80 (2H, d, J = 8.6 Hz), 8.41 (1H, d, J = 5.1 Hz);
MS (FAB) m / z: 450 [M + H] ⁺ ;
Anal. Calcd for C ₂₂ H ₂₃ N ₇ O ₂ S ・ 0.6 H ₂ O: C, 57.40; H, 5.30; N, 21.30; S, 6.97. Found: C, 57.66; H, 5.26; N, 21.21; S , 6.52.

［実施例２１］
３−アミノ−４−｛４−［４−（３−メチル−１，２，４−オキサジアゾール−５−イル）フェニル］−１，４−ジアゼパン−１−イル｝チエノ［２，３−ｂ］ピリジン−２−カルボキサミド
出発原料（アミン化合物）：参考例２１の化合物
Mp 218-221 ℃;
IR (KBr) ν_max 3439, 3324, 3184, 1651, 1608, 1581, 1498, 1344, 1195, 938, 823, 757 cm^-1;
¹H NMR (DMSO-d₆, 400MHz) δ 2.16-2.22 (2H, m), 2.35 (3H, s), 3.19-3.35 (4H, m), 3.65-3.68 (2H, m), 3.88-3.91 (2H, m), 6.96 (2H, d, J = 8.6 Hz), 7.01 (2H, brs), 7.09 (1H, d, J = 5.5 Hz), 7.11 (2H, brs), 7.88 (2H, d, J = 8.6 Hz), 8.41 (1H, d, J = 5.5 Hz);
MS (FAB) m/z: 450 [M+H]⁺;
Anal. Calcd for C₂₂H₂₃N₇O₂S・1.2 H₂O: C, 56.08; H, 5.43; N, 20.81; S, 6.81. Found: C, 56.10; H, 5.23; N, 20.78; S, 6.67。
[Example 21]
3-Amino-4- {4- [4- (3-methyl-1,2,4-oxadiazol-5-yl) phenyl] -1,4-diazepan-1-yl} thieno [2,3- b] Pyridine-2-carboxamide starting material (amine compound): compound of Reference Example 21
Mp 218-221 ° C;
IR (KBr) ν _max 3439, 3324, 3184, 1651, 1608, 1581, 1498, 1344, 1195, 938, 823, 757 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.16-2.22 (2H, m), 2.35 (3H, s), 3.19-3.35 (4H, m), 3.65-3.68 (2H, m), 3.88-3.91 ( 2H, m), 6.96 (2H, d, J = 8.6 Hz), 7.01 (2H, brs), 7.09 (1H, d, J = 5.5 Hz), 7.11 (2H, brs), 7.88 (2H, d, J = 8.6 Hz), 8.41 (1H, d, J = 5.5 Hz);
MS (FAB) m / z: 450 [M + H] ⁺ ;
Anal.Calcd for C ₂₂ H ₂₃ N ₇ O ₂ S ・ 1.2 H ₂ O: C, 56.08; H, 5.43; N, 20.81; S, 6.81. Found: C, 56.10; H, 5.23; N, 20.78; S , 6.67.

［実施例２２］
３−アミノ−４−｛４−［４−（３−メチル−２−オキソイミダゾリジン−１−イル）フェニル］−１，４−ジアゼパン−１−イル｝チエノ［２，３−ｂ］ピリジン−２−カルボキサミド
出発原料（アミン化合物）：参考例２２の化合物
Mp 250-253 ℃;
IR (KBr) ν_max 3441, 3319, 3183, 1686, 1646, 1577, 1517, 940, 821 cm^-1;
¹H NMR (DMSO-d₆, 400MHz) δ 2.11-2.17 (2H, m), 2.73 (3H, s), 3.18-3.32 (4H, m), 3.36-3.40 (2H, m), 3.52-3.55 (2H, m), 3.69-3.75 (4H, m), 6.76 (2H, d, J = 9.0 Hz), 7.00 (2H, brs), 7.08 (1H, d, J = 5.5 Hz), 7.10 (2H, brs), 7.34 (2H, d, J = 9.0 Hz), 8.39 (1H, d, J = 5.5 Hz);
MS (FAB) m/z: 466 [M+H]⁺;
Anal. Calcd for C₂₃H₂₇N₇O₂S・1.3 H₂O: C, 56.49; H, 6.10; N, 20.05; S, 6.56. Found: C, 56.49; H, 5.95; N, 20.06; S, 6.59。
[Example 22]
3-Amino-4- {4- [4- (3-methyl-2-oxoimidazolidin-1-yl) phenyl] -1,4-diazepan-1-yl} thieno [2,3-b] pyridine- 2-Carboxamide starting material (amine compound): compound of Reference Example 22
Mp 250-253 ° C;
IR (KBr) ν _max 3441, 3319, 3183, 1686, 1646, 1577, 1517, 940, 821 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 400MHz) δ 2.11-2.17 (2H, m), 2.73 (3H, s), 3.18-3.32 (4H, m), 3.36-3.40 (2H, m), 3.52-3.55 ( 2H, m), 3.69-3.75 (4H, m), 6.76 (2H, d, J = 9.0 Hz), 7.00 (2H, brs), 7.08 (1H, d, J = 5.5 Hz), 7.10 (2H, brs ), 7.34 (2H, d, J = 9.0 Hz), 8.39 (1H, d, J = 5.5 Hz);
MS (FAB) m / z: 466 [M + H] ⁺ ;
Anal. Calcd for C ₂₃ H ₂₇ N ₇ O ₂ S ・ 1.3 H ₂ O: C, 56.49; H, 6.10; N, 20.05; S, 6.56. Found: C, 56.49; H, 5.95; N, 20.06; S , 6.59.

［実施例２３］
３−アミノ−４−｛４−［４−（３−メチル−２−オキソ−２，３−ジヒドロ−１Ｈ−イミダゾール−１−イル）フェニル］−１，４−ジアゼパン−１−イル｝チエノ［２，３−ｂ］ピリジン−２−カルボキサミド
出発原料（アミン化合物）：参考例２３の化合物
アモルファス粉末;
IR (KBr) ν_max 3440, 3325, 3184, 1681, 1646, 1579, 1520, 939, 820 cm^-1;
¹H NMR (DMSO-d₆, 400MHz) δ 2.12-2.19 (2H, m), 3.16 (3H, s), 3.15-3.23 (2H, m), 3.27-3.33 (2H, m), 3.36-3.40 (2H, m), 3.55-3.58 (2H, m), 3.77-3.79 (2H, m), 6.63 (1H, d, J = 3.1 Hz), 6.80 (1H, d, J = 3.1 Hz), 6.80 (2H, d, J = 9.0 Hz), 6.99 (2H, brs), 7.07 (1H, d, J = 5.5 Hz), 7.08 (2H, brs), 7.37 (2H, d, J = 9.0 Hz), 8.37 (1H, d, J = 5.5 Hz);
MS (FAB) m/z: 464 [M+H]⁺;
Anal. Calcd for C₂₃H₂₅N₇O₂S・1.6 H₂O: C, 56.11; H, 5.77; N, 19.91; S, 6.51. Found: C, 56.07; H, 5.54; N, 20.04; S, 6.38。
[Example 23]
3-amino-4- {4- [4- (3-methyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl) phenyl] -1,4-diazepan-1-yl} thieno [ 2,3-b] pyridine-2-carboxamide starting material (amine compound): Compound amorphous powder of Reference Example 23;
IR (KBr) ν _max 3440, 3325, 3184, 1681, 1646, 1579, 1520, 939, 820 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.12-2.19 (2H, m), 3.16 (3H, s), 3.15-3.23 (2H, m), 3.27-3.33 (2H, m), 3.36-3.40 ( 2H, m), 3.55-3.58 (2H, m), 3.77-3.79 (2H, m), 6.63 (1H, d, J = 3.1 Hz), 6.80 (1H, d, J = 3.1 Hz), 6.80 (2H , d, J = 9.0 Hz), 6.99 (2H, brs), 7.07 (1H, d, J = 5.5 Hz), 7.08 (2H, brs), 7.37 (2H, d, J = 9.0 Hz), 8.37 (1H , d, J = 5.5 Hz);
MS (FAB) m / z: 464 [M + H] ⁺ ;
Anal.Calcd for C ₂₃ H ₂₅ N ₇ O ₂ S ・ 1.6 H ₂ O: C, 56.11; H, 5.77; N, 19.91; S, 6.51.Found: C, 56.07; H, 5.54; N, 20.04; S , 6.38.

［実施例２４］
３−アミノ−４−{４−[４−(４，５−ジヒドロ−１，３−オキサゾール−２−イル)フェニル]−１，４−ジアゼパン−１−イル}チエノ[２，３−ｂ]ピリジン−２−カルボキサミド
出発原料（アミン化合物）：参考例２４の化合物
淡黄色粉末
Mp 165-171 ℃;
IR (KBr) ν_max 3441, 3323, 3181, 2947, 1642, 1607, 1521, 1363, 1264, 1189, 1076, 942, 823 cm^-1;
¹H NMR(DMSO-d₆, 400 MHz) δ 2.11-2.19 (2H, m), 3.13-3.22 (2H, m), 3.25-3.33 (2H, m), 3.56 (2H, t, J = 6.3 Hz), 3.81 (2H, t, J = 4.7 Hz), 3.86 (2H, t, J = 9.4 Hz), 4.29 (2H, t, J = 9.4 Hz), 6.79 (2H, d, J = 9.0 Hz), 6.97 (2H, brs), 7.05 (1H, d, J = 5.5 Hz), 7.07 (2H, brs), 7.64 (2H, d, J = 9.0 Hz), 8.37 (1H, d, J = 5.5 Hz);
MS (FAB) m/z: 437 [M+H⁺], 394, 380, 246, 165, 65;
Anal. Calcd for C₂₂H₂₄N₆O₂S・1.67H₂O: C, 56.64; H, 5.91; N, 18.01. Found: C, 56.72; H, 5.86; N, 18.11。
[Example 24]
3-Amino-4- {4- [4- (4,5-dihydro-1,3-oxazol-2-yl) phenyl] -1,4-diazepan-1-yl} thieno [2,3-b] Pyridine-2-carboxamide starting material (amine compound): compound of Reference Example 24 pale yellow powder
Mp 165-171 ° C;
IR (KBr) ν _max 3441, 3323, 3181, 2947, 1642, 1607, 1521, 1363, 1264, 1189, 1076, 942, 823 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.11-2.19 (2H, m), 3.13-3.22 (2H, m), 3.25-3.33 (2H, m), 3.56 (2H, t, J = 6.3 Hz ), 3.81 (2H, t, J = 4.7 Hz), 3.86 (2H, t, J = 9.4 Hz), 4.29 (2H, t, J = 9.4 Hz), 6.79 (2H, d, J = 9.0 Hz), 6.97 (2H, brs), 7.05 (1H, d, J = 5.5 Hz), 7.07 (2H, brs), 7.64 (2H, d, J = 9.0 Hz), 8.37 (1H, d, J = 5.5 Hz);
MS (FAB) m / z: 437 [M + H ⁺ ], 394, 380, 246, 165, 65;
_{_{. Anal Calcd for C 22 H 24}} N 6 O 2 S · 1.67H 2 O:. C, 56.64; H, 5.91; N, 18.01 Found: C, 56.72; H, 5.86; N, 18.11.

［実施例２５］
３−アミノ−４−{４−[３−(４，５−ジヒドロ−１，３−オキサゾール−２−イル)フェニル]−１，４−ジアゼパン−１−イル}チエノ[２，３−ｂ]ピリジン−２−カルボキサミド
出発原料（アミン化合物）：参考例２５の化合物
淡黄色粉末
Mp 245-249 ℃;
IR (KBr) ν_max 3449, 3331, 3186, 2931, 1648, 1576, 1498, 1365, 1250, 1092, 941, 714 cm^-1;
¹H NMR(DMSO-d₆, 500 MHz) δ 2.12-2.20 (2H, m), 3.16-3.23 (2H, m), 3.29-3.33 (2H, m), 3.58 (2H, t, J = 5.9 Hz), 3.70 (2H, t, J = 4.9 Hz), 3.93 (2H, t, J = 9.8 Hz), 4.37 (2H, t, J = 9.8 Hz), 6.96 (1H, dd, J = 2.4, 8.3 Hz), 7.00 (2H, brs), 7.07-7.11 (3H, m), 7.13 (1H, d, J = 7.8 Hz), 7.24 (1H, brs), 7.26 (1H, dd, J = 7.8, 8.3 Hz), 8.40 (1H, d, J = 5.4 Hz);
MS (FAB) m/z: 437 [M+H⁺], 420, 392, 346, 242;
Anal. Calcd for C₂₂H₂₄N₆O₂S・0.67H₂O: C, 58.91; H, 5.69; N, 18.74. Found: C, 58.71; H, 5.55; N, 18.78。
[Example 25]
3-Amino-4- {4- [3- (4,5-dihydro-1,3-oxazol-2-yl) phenyl] -1,4-diazepan-1-yl} thieno [2,3-b] Pyridine-2-carboxamide starting material (amine compound): compound of Reference Example 25 pale yellow powder
Mp 245-249 ° C;
IR (KBr) ν _max 3449, 3331, 3186, 2931, 1648, 1576, 1498, 1365, 1250, 1092, 941, 714 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 500 MHz) δ 2.12-2.20 (2H, m), 3.16-3.23 (2H, m), 3.29-3.33 (2H, m), 3.58 (2H, t, J = 5.9 Hz ), 3.70 (2H, t, J = 4.9 Hz), 3.93 (2H, t, J = 9.8 Hz), 4.37 (2H, t, J = 9.8 Hz), 6.96 (1H, dd, J = 2.4, 8.3 Hz) ), 7.00 (2H, brs), 7.07-7.11 (3H, m), 7.13 (1H, d, J = 7.8 Hz), 7.24 (1H, brs), 7.26 (1H, dd, J = 7.8, 8.3 Hz) , 8.40 (1H, d, J = 5.4 Hz);
MS (FAB) m / z: 437 [M + H ⁺ ], 420, 392, 346, 242;
_{_{. Anal Calcd for C 22 H 24}} N 6 O 2 S · 0.67H 2 O:. C, 58.91; H, 5.69; N, 18.74 Found: C, 58.71; H, 5.55; N, 18.78.

［実施例２６］
３−アミノ−４−{４−[４−(１，３−オキサゾール−２−イル)フェニル]−１，４−ジアゼパン−１−イル}チエノ[２，３−ｂ]ピリジン−２−カルボキサミド
出発原料（アミン化合物）：参考例２６の化合物
淡黄色粉末
Mp 243-250 ℃;
IR (KBr) ν_max 3442, 3324, 3179, 2950, 1647, 1611, 1499, 1365, 1193, 938, 821, 739 cm^-1;
¹H NMR(DMSO-d₆, 500 MHz) δ 2.14-2.22 (2H, m), 3.17-3.26 (2H, m), 3.28-3.36 (2H, m), 3.63 (2H, t, J = 6.3 Hz), 3.85 (2H, t, J = 4.9 Hz), 6.90 (2H, d, J = 9.3 Hz), 7.01 (2H, brs), 7.06-7.13 (3H, m), 7.25 (1H, s), 7.79 (2H, d, J = 9.3 Hz), 8.06 (1H, s), 8.41 (1H, d, J = 5.4 Hz);
MS (FAB) m/z: 435 [M+H⁺], 273, 242, 226, 165, 120, 63。
[Example 26]
3-amino-4- {4- [4- (1,3-oxazol-2-yl) phenyl] -1,4-diazepan-1-yl} thieno [2,3-b] pyridine-2-carboxamide Raw material (amine compound): compound of Reference Example 26 pale yellow powder
Mp 243-250 ° C;
IR (KBr) ν _max 3442, 3324, 3179, 2950, 1647, 1611, 1499, 1365, 1193, 938, 821, 739 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 500 MHz) δ 2.14-2.22 (2H, m), 3.17-3.26 (2H, m), 3.28-3.36 (2H, m), 3.63 (2H, t, J = 6.3 Hz ), 3.85 (2H, t, J = 4.9 Hz), 6.90 (2H, d, J = 9.3 Hz), 7.01 (2H, brs), 7.06-7.13 (3H, m), 7.25 (1H, s), 7.79 (2H, d, J = 9.3 Hz), 8.06 (1H, s), 8.41 (1H, d, J = 5.4 Hz);
MS (FAB) m / z: 435 [M + H ⁺ ], 273, 242, 226, 165, 120, 63.

［実施例２７］
３−アミノ−４−{４−[４−(４，５−ジヒドロ−１，３−チアゾール−２−イル)フェニル]−１，４−ジアゼパン−１−イル}チエノ[２，３−ｂ]ピリジン−２−カルボキサミド
出発原料（アミン化合物）：参考例２７の化合物
淡黄色粉末
Mp 212-214 ℃;
IR (KBr) ν_max 3445, 3322, 3182, 2941, 2846, 1647, 1602, 1517, 1366, 1186, 1101, 938, 818 cm^-1;
¹H NMR(DMSO-d₆, 400 MHz) δ 2.11-2.22 (2H, m), 3.14-3.22 (2H, m), 3.27-3.33 (2H, m), 3.35 (2H, t, J = 8.2 Hz), 3.61 (2H, t, J = 5.9 Hz), 3.79-3.86 (2H, m), 4.30 (2H, t, J = 8.2 Hz), 6.83 (2H, d, J = 8.6 Hz), 7.00 (2H, brs), 7.07 (1H, d, J = 5.5 Hz), 7.10 (2H, brs), 7.59 (2H, d, J = 8.6 Hz), 8.40 (1H, d, J = 5.5 Hz);
MS (453) m/z: 367 [M+H⁺], 242, 165, 93, 63;
Anal. Calcd for C₂₂H₂₄N₆OS₂・1.0H₂O: C, 56.15; H, 5.57; N, 17.86. Found: C, 56.25; H, 5.53; N, 17.60。
[Example 27]
3-Amino-4- {4- [4- (4,5-dihydro-1,3-thiazol-2-yl) phenyl] -1,4-diazepan-1-yl} thieno [2,3-b] Pyridine-2-carboxamide starting material (amine compound): compound of Reference Example 27 pale yellow powder
Mp 212-214 ° C;
IR (KBr) ν _max 3445, 3322, 3182, 2941, 2846, 1647, 1602, 1517, 1366, 1186, 1101, 938, 818 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.11-2.22 (2H, m), 3.14-3.22 (2H, m), 3.27-3.33 (2H, m), 3.35 (2H, t, J = 8.2 Hz ), 3.61 (2H, t, J = 5.9 Hz), 3.79-3.86 (2H, m), 4.30 (2H, t, J = 8.2 Hz), 6.83 (2H, d, J = 8.6 Hz), 7.00 (2H , brs), 7.07 (1H, d, J = 5.5 Hz), 7.10 (2H, brs), 7.59 (2H, d, J = 8.6 Hz), 8.40 (1H, d, J = 5.5 Hz);
MS (453) m / z: 367 [M + H ⁺ ], 242, 165, 93, 63;
_{_{. Anal Calcd for C 22 H 24}} N 6 OS 2 · 1.0H 2 O:. C, 56.15; H, 5.57; N, 17.86 Found: C, 56.25; H, 5.53; N, 17.60.

［実施例２８］
３−アミノ−４−{４−[４−(２−オキソ−１，３−オキサゾリジン−３−イル)フェニル]−１，４−ジアゼパン-1-イル}チエノ[２，３−ｂ]ピリジン−２−カルボキサミド
出発原料（アミン化合物）：参考例２８の化合物
淡黄色粉末
Mp 215-218 ℃;
IR (KBr) ν_max 3437, 3182, 2923, 1742, 1649, 1578, 1518, 1370, 1227, 1118, 939, 816 cm^-1;
¹H NMR(DMSO-d₆, 500 MHz) δ 2.11-2.18 (2H, m), 3.16-3.23 (2H, m), 3.26-3.33 (2H, m), 3.55 (2H, t, J = 5.9 Hz), 3.77 (2H, t, J = 4.9 Hz), 3.99 (2H, t, J = 8.3 Hz), 4.40 (2H, t, J = 8.3 Hz), 6.80 (2H, d, J = 9.3 Hz), 7.00 (2H, brs), 7.08 (1H, d, J = 5.4 Hz), 7.10 (2H, brs), 7.34 (2H, d, J = 9.3 Hz), 8.40 (1H, d, J = 5.4 Hz);
MS (FAB) m/z: 453 [M+H⁺], 426, 273, 242, 226;
Anal. Calcd for C₂₂H₂₄N₆O₃S・0.80H₂O: C, 56.59; H, 5.53; N, 18.00. Found: C, 56.38; H, 5.75; N, 18.20。
[Example 28]
3-Amino-4- {4- [4- (2-oxo-1,3-oxazolidine-3-yl) phenyl] -1,4-diazepan-1-yl} thieno [2,3-b] pyridine- 2-Carboxamide starting material (amine compound): compound of Reference Example 28 pale yellow powder
Mp 215-218 ° C;
IR (KBr) ν _max 3437, 3182, 2923, 1742, 1649, 1578, 1518, 1370, 1227, 1118, 939, 816 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 500 MHz) δ 2.11-2.18 (2H, m), 3.16-3.23 (2H, m), 3.26-3.33 (2H, m), 3.55 (2H, t, J = 5.9 Hz ), 3.77 (2H, t, J = 4.9 Hz), 3.99 (2H, t, J = 8.3 Hz), 4.40 (2H, t, J = 8.3 Hz), 6.80 (2H, d, J = 9.3 Hz), 7.00 (2H, brs), 7.08 (1H, d, J = 5.4 Hz), 7.10 (2H, brs), 7.34 (2H, d, J = 9.3 Hz), 8.40 (1H, d, J = 5.4 Hz);
MS (FAB) m / z: 453 [M + H ⁺ ], 426, 273, 242, 226;
_{_{. Anal Calcd for C 22 H 24}} N 6 O 3 S · 0.80H 2 O:. C, 56.59; H, 5.53; N, 18.00 Found: C, 56.38; H, 5.75; N, 18.20.

［実施例２９］
３−アミノ−４−{４−[５−(４，５−ジヒドロ−１，３−オキサゾール−２−イル)ピリジン−２−イル]−１，４−ジアゼパン−１−イル}チエノ[２，３−ｂ]ピリジン−２−カルボキサミド
出発原料（アミン化合物）：参考例２９の化合物
淡黄色粉末
Mp 153-156 ℃;
IR (KBr) ν_max 3431, 3324, 3179, 2933, 1604, 1506, 1367, 1085, 940 cm^-1;
¹H NMR(DMSO-d₆, 500 MHz) δ 2.12-2.20 (2H, m), 3.17-3.25 (2H, m), 3.28-3.35 (2H, m), 3.73-3.80 (2H, m), 3.89 (2H, t, J = 9.3 Hz), 4.01-4.11 (2H, m), 4.34 (2H, t, J = 9.3 Hz), 6.77 (1H, d, J = 9.3 Hz), 7.01 (2H, brs), 7.07 (1H, d, J = 5.4 Hz), 7.11 (2H, brs), 7.90 (1H, dd, J = 2.4, 9.3 Hz), 8.40 (1H, d, J = 5.4 Hz), 8.54 (1H, d, J = 2.4 Hz);
MS (FAB) m/z: 438 [M+H⁺], 338, 273, 242;
Anal. Calcd for C₂₁H₂₃N₇O₂S・3.50H₂O: C, 50.39; H, 6.04; N, 19.59. Found: C, 50.66; H, 5.79; N, 19.36。
[Example 29]
3-Amino-4- {4- [5- (4,5-dihydro-1,3-oxazol-2-yl) pyridin-2-yl] -1,4-diazepan-1-yl} thieno [2, 3-b] pyridine-2-carboxamide starting material (amine compound): compound of Reference Example 29, pale yellow powder
Mp 153-156 ° C;
IR (KBr) ν _max 3431, 3324, 3179, 2933, 1604, 1506, 1367, 1085, 940 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 500 MHz) δ 2.12-2.20 (2H, m), 3.17-3.25 (2H, m), 3.28-3.35 (2H, m), 3.73-3.80 (2H, m), 3.89 (2H, t, J = 9.3 Hz), 4.01-4.11 (2H, m), 4.34 (2H, t, J = 9.3 Hz), 6.77 (1H, d, J = 9.3 Hz), 7.01 (2H, brs) , 7.07 (1H, d, J = 5.4 Hz), 7.11 (2H, brs), 7.90 (1H, dd, J = 2.4, 9.3 Hz), 8.40 (1H, d, J = 5.4 Hz), 8.54 (1H, d, J = 2.4 Hz);
MS (FAB) m / z: 438 [M + H ⁺ ], 338, 273, 242;
_{_{. Anal Calcd for C 21 H 23}} N 7 O 2 S · 3.50H 2 O:. C, 50.39; H, 6.04; N, 19.59 Found: C, 50.66; H, 5.79; N, 19.36.

［実施例３０］
３−アミノ−４−{４−[４−(４，５−ジヒドロ−１，３−オキサゾール−２−イルメチル)フェニル]−１，４−ジアゼパン−１−イル}チエノ[２，３−ｂ]ピリジン−２−カルボキサミド
出発原料（アミン化合物）：参考例３０の化合物
淡黄色粉末
Mp 265-268 ℃;
IR (KBr) ν_max 3442, 3324, 3156, 2945, 1649, 1575, 1518, 1369, 1234, 936, 807 cm^-1;
¹H NMR(DMSO-d₆, 500 MHz) δ 2.09-2.19 (2H, m), 3.15-3.23 (2H, m), 3.25-3.33 (2H, m), 3.42 (2H, s), 3.53 (2H, t, J = 5.9 Hz), 3.70 (2H, t, J = 9.3 Hz), 3.73-3.80 (2H, m), 4.50 (2H, t, J = 9.3 Hz), 6.71 (2H, d, J = 8.8 Hz), 7.01 (2H, brs), 7.04-7.13 (5H, m), 8.40 (1H, d, J = 5.4 Hz);
MS (FAB) m/z: 451 [M+H⁺], 434, 406, 380, 242, 226, 165;
Anal. Calcd for C₂₃H₂₆N₆O₂S・0.40H₂O: C, 61.31; H, 5.82; N, 18.65. Found: C, 60.34; H, 5.77; N, 18.43。
[Example 30]
3-Amino-4- {4- [4- (4,5-dihydro-1,3-oxazol-2-ylmethyl) phenyl] -1,4-diazepan-1-yl} thieno [2,3-b] Pyridine-2-carboxamide starting material (amine compound): compound of Reference Example 30 pale yellow powder
Mp 265-268 ° C;
IR (KBr) ν _max 3442, 3324, 3156, 2945, 1649, 1575, 1518, 1369, 1234, 936, 807 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 500 MHz) δ 2.09-2.19 (2H, m), 3.15-3.23 (2H, m), 3.25-3.33 (2H, m), 3.42 (2H, s), 3.53 (2H , t, J = 5.9 Hz), 3.70 (2H, t, J = 9.3 Hz), 3.73-3.80 (2H, m), 4.50 (2H, t, J = 9.3 Hz), 6.71 (2H, d, J = 8.8 Hz), 7.01 (2H, brs), 7.04-7.13 (5H, m), 8.40 (1H, d, J = 5.4 Hz);
MS (FAB) m / z: 451 [M + H ⁺ ], 434, 406, 380, 242, 226, 165;
_{_{. Anal Calcd for C 23 H 26}} N 6 O 2 S · 0.40H 2 O:. C, 61.31; H, 5.82; N, 18.65 Found: C, 60.34; H, 5.77; N, 18.43.

［実施例３１］
３−アミノ−４−{４−[４−(１−メチル−１Ｈ−イミダゾール−２−イル)フェニル]−１，４−ジアゼパン−１−イル}チエノ[２，３−ｂ]ピリジン−２−カルボキサミド
出発原料（アミン化合物）：参考例３１の化合物
淡黄色粉末
Mp 140-143 ℃;
IR (KBr) ν_max 3440, 3323, 3178, 2947, 1649, 1611, 1507, 1368, 1196, 938, 821 cm^-1;
¹H NMR(DMSO-d₆, 400 MHz) δ 2.13-2.21 (2H, m), 3.17-3.26 (2H, m), 3.26-3.33 (2H, m), 3.60 (2H, t, J = 5.9 Hz), 3.70 (3H, s), 3.79-3.85 (2H, m), 6.81-6.88 (3H, m), 6.97 (2H, brs), 7.04-7.14 (4H, m), 7.47 (2H, d, J = 9.0 Hz), 8.39 (1H, d, J = 5.1 Hz);
MS (FAB) m/z: 448 [M⁺], 273, 246, 165, 93, 65;
Anal. Calcd for C₂₃H₂₅N₇OS・H₂O: C, 59.33; H, 5.85; N, 21.06. Found: C, 59.39; H, 5.76; N, 21.15。
[Example 31]
3-Amino-4- {4- [4- (1-methyl-1H-imidazol-2-yl) phenyl] -1,4-diazepan-1-yl} thieno [2,3-b] pyridine-2- Carboxamide starting material (amine compound): compound of Reference Example 31 pale yellow powder
Mp 140-143 ° C;
IR (KBr) ν _max 3440, 3323, 3178, 2947, 1649, 1611, 1507, 1368, 1196, 938, 821 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.13-2.21 (2H, m), 3.17-3.26 (2H, m), 3.26-3.33 (2H, m), 3.60 (2H, t, J = 5.9 Hz ), 3.70 (3H, s), 3.79-3.85 (2H, m), 6.81-6.88 (3H, m), 6.97 (2H, brs), 7.04-7.14 (4H, m), 7.47 (2H, d, J = 9.0 Hz), 8.39 (1H, d, J = 5.1 Hz);
MS (FAB) m / z: 448 [M ⁺ ], 273, 246, 165, 93, 65;
Anal. Calcd for C ₂₃ H ₂₅ N ₇ OS · H ₂ O: C, 59.33; H, 5.85; N, 21.06. Found: C, 59.39; H, 5.76; N, 21.15.

［実施例３２］
３−アミノ−４−{４−[４−(５−メチル−１，３，４−オキサジアゾール−２−イル)フェニル]−１，４−ジアゼパン−１−イル}チエノ[２，３−ｂ]ピリジン−２−カルボキサミド
出発原料（アミン化合物）：参考例３２の化合物
淡黄色粉末
Mp 250-253 ℃;
IR (KBr) ν_max 3440, 3324, 3184, 2932, 1645, 1612, 1504, 1366, 1194, 938, 821 cm^-1;
¹H NMR(DMSO-d₆, 500 MHz) δ 2.15-2.22 (2H, m), 2.53 (3H, m), 3.17-3.24 (2H, m), 3.28-3.35 (2H, m), 3.65 (2H, t, J = 6.4 Hz), 3.34-3.39 (2H, m), 6.94 (2H, d, J = 8.8 Hz), 7.01 (2H, brs), 7.09 (1H, d, J = 5.4 Hz), 7.10 (2H, brs), 7.76 (2H, d, J = 8.8 Hz), 8.41 (1H, d, J = 5.4 Hz);
MS (FAB) m/z: 450 [M⁺], 433, 399, 379, 273, 246, 182;
Anal. Calcd for C₂₂H₂₃N₇O₂S・0.80H₂O: C, 56.95; H, 5.34; N, 21.13. Found: C, 56.96; H, 5.21; N, 21.17。
[Example 32]
3-Amino-4- {4- [4- (5-methyl-1,3,4-oxadiazol-2-yl) phenyl] -1,4-diazepan-1-yl} thieno [2,3- b] Pyridine-2-carboxamide starting material (amine compound): compound of Reference Example 32, pale yellow powder
Mp 250-253 ° C;
IR (KBr) ν _max 3440, 3324, 3184, 2932, 1645, 1612, 1504, 1366, 1194, 938, 821 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 500 MHz) δ 2.15-2.22 (2H, m), 2.53 (3H, m), 3.17-3.24 (2H, m), 3.28-3.35 (2H, m), 3.65 (2H , t, J = 6.4 Hz), 3.34-3.39 (2H, m), 6.94 (2H, d, J = 8.8 Hz), 7.01 (2H, brs), 7.09 (1H, d, J = 5.4 Hz), 7.10 (2H, brs), 7.76 (2H, d, J = 8.8 Hz), 8.41 (1H, d, J = 5.4 Hz);
MS (FAB) m / z: 450 [M ⁺ ], 433, 399, 379, 273, 246, 182;
_{_{. Anal Calcd for C 22 H 23}} N 7 O 2 S · 0.80H 2 O:. C, 56.95; H, 5.34; N, 21.13 Found: C, 56.96; H, 5.21; N, 21.17.

［実施例３３］
３−アミノ−４−{４−[４−(１Ｈ−イミダゾール−２−イル)フェニル]−１，４−ジアゼパン−１−イル}チエノ[２，３−ｂ]ピリジン−２−カルボキサミド
（３３ａ）３−アミノ−４−{４−[４−(１−{[２−(トリメチルシリル)エトキシ]メチル}−１Ｈ−イミダゾール−２−イル)フェニル]−１，４−ジアゼパン-1-イル}チエノ[２，３−ｂ]ピリジン−２−カルボキサミド
出発原料（アミン化合物）：参考例３３の化合物
黄色泡状物質;
IR (KBr) ν_max 3440, 3323, 3177, 2950, 1611, 1504, 1369, 1249, 1079, 939, 836, 730 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ -0.01 (9H, s), 0.94 (2H, t, J = 8.2 Hz), 2.19-2.27 (2H, m), 3.22-3.33 (2H, m), 3.34-3.43 (2H, m), 3.59 (2H, t, J = 8.2 Hz), 3.67 (2H, t, J = 5.9 Hz), 3.78-3.84 (2H, m), 5.27 (4H, s), 6.78 (2H, d, J = 9.0 Hz), 6.92 (1H, d, J = 5.1 Hz), 6.98-7.06 (3H, m), 7.09 (1H, brs), 7.68 (2H, d, J = 9.0 Hz), 8.44 (1H, d, J = 5.1 Hz);
MS (FAB) m/z: 564 [M⁺], 316, 273, 258, 244, 226, 212, 186, 165, 73, 63。
[Example 33]
3-Amino-4- {4- [4- (1H-imidazol-2-yl) phenyl] -1,4-diazepan-1-yl} thieno [2,3-b] pyridine-2-carboxamide (33a) 3-amino-4- {4- [4- (1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-imidazol-2-yl) phenyl] -1,4-diazepan-1-yl} thieno [ 2,3-b] pyridine-2-carboxamide starting material (amine compound): compound of Reference Example 33, yellow foam;
IR (KBr) ν _max 3440, 3323, 3177, 2950, 1611, 1504, 1369, 1249, 1079, 939, 836, 730 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ -0.01 (9H, s), 0.94 (2H, t, J = 8.2 Hz), 2.19-2.27 (2H, m), 3.22-3.33 (2H, m), 3.34 -3.43 (2H, m), 3.59 (2H, t, J = 8.2 Hz), 3.67 (2H, t, J = 5.9 Hz), 3.78-3.84 (2H, m), 5.27 (4H, s), 6.78 ( 2H, d, J = 9.0 Hz), 6.92 (1H, d, J = 5.1 Hz), 6.98-7.06 (3H, m), 7.09 (1H, brs), 7.68 (2H, d, J = 9.0 Hz), 8.44 (1H, d, J = 5.1 Hz);
MS (FAB) m / z: 564 [M ⁺ ], 316, 273, 258, 244, 226, 212, 186, 165, 73, 63.

（３３ｂ）３−アミノ−４−{４−[４−(１Ｈ−イミダゾール−２−イル)フェニル]−１，４−ジアゼパン−１−イル}チエノ[２，３−ｂ]ピリジン−２−カルボキサミド
（３３ａ）で製造した３−アミノ−４−{４−[４−(１−{[２−(トリメチルシリル)エトキシ]メチル}−１Ｈ−イミダゾール−２−イル)フェニル]−１，４−ジアゼパン-1-イル}チエノ[２，３−ｂ]ピリジン−２−カルボキサミド（２７９ｍｇ、４９６μｍｏｌ）にトリフルオロ酢酸（７ｍＬ）を加え、室温で２時間撹拌した。反応液に水（３０ｍＬ）を加え、炭酸カリウムで液性を塩基性とし、塩化メチレン／２−プロパノール（（４：１）、５０ｍＬ）で３回抽出し、無水硫酸ナトリウムで乾燥後，溶媒を減圧下留去した。得られた残渣をエタノール／水（１：１）で粉末化し、標記目的化合物（１７４ｍｇ、収率８１％）を得た。
(33b) 3-Amino-4- {4- [4- (1H-imidazol-2-yl) phenyl] -1,4-diazepan-1-yl} thieno [2,3-b] pyridine-2-carboxamide 3-Amino-4- {4- [4- (1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-imidazol-2-yl) phenyl] -1,4-diazepane prepared in (33a) Trifluoroacetic acid (7 mL) was added to 1-yl} thieno [2,3-b] pyridine-2-carboxamide (279 mg, 496 μmol), and the mixture was stirred at room temperature for 2 hours. Water (30 mL) was added to the reaction solution, the solution was made basic with potassium carbonate, extracted three times with methylene chloride / 2-propanol ((4: 1), 50 mL), dried over anhydrous sodium sulfate, and the solvent was removed. Distilled off under reduced pressure. The obtained residue was triturated with ethanol / water (1: 1) to give the title object compound (174 mg, yield 81%).

淡黄色粉末
Mp 270-275 ℃;
IR (KBr) ν_max 3324, 1578, 1515, 1367, 1201, 1096, 939, 820, 733 cm^-1;
¹H NMR(DMSO-d₆, 400 MHz) δ 2.13-2.21 (2H, m), 3.16-3.24 (2H, m), 3.27-3.35 (2H, m), 3.50 (2H, t, J = 6.3 Hz), 3.78-3.84 (2H, m), 6.82 (2H, d, J = 9.0 Hz), 6.91-7.14 (7H, m), 7.73 (2H, d, J = 9.0 Hz), 8.38 (1H, d, J = 5.1 Hz), 12.07 (1H, brs);
MS (FAB) m/z: 434 [M⁺], 273, 257, 242, 219, 165, 120, 63;
Anal. Calcd for C₂₂H₂₃N₇OS・1.50H₂O: C, 57.37; H, 5.69; N, 21.29. Found: C, 57.37; H, 5.44; N, 20.93。
Pale yellow powder
Mp 270-275 ° C;
IR (KBr) ν _max 3324, 1578, 1515, 1367, 1201, 1096, 939, 820, 733 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.13-2.21 (2H, m), 3.16-3.24 (2H, m), 3.27-3.35 (2H, m), 3.50 (2H, t, J = 6.3 Hz ), 3.78-3.84 (2H, m), 6.82 (2H, d, J = 9.0 Hz), 6.91-7.14 (7H, m), 7.73 (2H, d, J = 9.0 Hz), 8.38 (1H, d, J = 5.1 Hz), 12.07 (1H, brs);
MS (FAB) m / z: 434 [M ⁺ ], 273, 257, 242, 219, 165, 120, 63;
_{_{. Anal Calcd for C 22 H 23}} N 7 OS · 1.50H 2 O:. C, 57.37; H, 5.69; N, 21.29 Found: C, 57.37; H, 5.44; N, 20.93.

［実施例３４］
３−アミノ−４−{４−[４−(４−メチル−５−オキソ−４，５−ジヒドロ−１，２，４−オキサジアゾール−３−イル)フェニル]−１，４−ジアゼパン-1-イル}チエノ[２，３−ｂ]ピリジン−２−カルボキサミド
出発原料（アミン化合物）：参考例３４の化合物
淡黄色粉末
Mp 242-246 ℃；
IR (KBr) ν_max 3441, 3323, 3177, 2948, 1766, 1607, 1453, 1369, 1196, 939, 761 cm^-1;
¹H NMR(DMSO-d₆, 500 MHz) δ 2.14-2.23 (2H, m), 3.18-3.25 (2H, m), 3.25 (3H, s), 3.28-3.35 (2H, m), 3.65 (2H, t, J = 5.9 Hz), 3.88 (2H, t, J = 4.9 Hz), 6.95 (2H, d, J = 8.8 Hz), 6.99 (2H, brs), 7.10 (1H, d, J = 5.4 Hz), 7.11 (2H, brs), 7.54 (2H, d, J = 8.8 Hz), 8.41 (1H, d, J = 5.4 Hz);
MS (FAB) m/z: 466 [M+H⁺], 449, 391, 371, 341, 273, 219, 165, 55;
Anal. Calcd for C₂₂H₂₃N₇O₃S・0.75H₂O: C, 55.16; H, 5.16; N, 20.47. Found: C, 54.99; H, 5.27; N, 20.52。
[Example 34]
3-Amino-4- {4- [4- (4-methyl-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) phenyl] -1,4-diazepan- 1-yl} thieno [2,3-b] pyridine-2-carboxamide starting material (amine compound): compound of Reference Example 34 pale yellow powder
Mp 242-246 ° C;
IR (KBr) ν _max 3441, 3323, 3177, 2948, 1766, 1607, 1453, 1369, 1196, 939, 761 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 500 MHz) δ 2.14-2.23 (2H, m), 3.18-3.25 (2H, m), 3.25 (3H, s), 3.28-3.35 (2H, m), 3.65 (2H , t, J = 5.9 Hz), 3.88 (2H, t, J = 4.9 Hz), 6.95 (2H, d, J = 8.8 Hz), 6.99 (2H, brs), 7.10 (1H, d, J = 5.4 Hz ), 7.11 (2H, brs), 7.54 (2H, d, J = 8.8 Hz), 8.41 (1H, d, J = 5.4 Hz);
MS (FAB) m / z: 466 [M + H ⁺ ], 449, 391, 371, 341, 273, 219, 165, 55;
_{_{. Anal Calcd for C 22 H 23}} N 7 O 3 S · 0.75H 2 O:. C, 55.16; H, 5.16; N, 20.47 Found: C, 54.99; H, 5.27; N, 20.52.

［実施例３５］
３−アミノ−４−{４−[４−(１，２−ジメチル−１Ｈ−イミダゾール−４−イル)フェニル]−１，４−ジアゼパン−１−イル}チエノ[２，３−ｂ]ピリジン−２−カルボキサミド
出発原料（アミン化合物）：参考例３５の化合物
黄色粉末
Mp 255-258 ℃;
IR (KBr) ν_max 3445, 3323, 3188, 2942, 1649, 1574, 1510, 1366, 1347, 1208, 940, 822 cm^-1;
¹H NMR(DMSO-d₆, 400 MHz) δ 2.11-2.20 (2H, m), 2.29 (3H, m), 3.16-3.25 (2H, m), 3.28-3.35 (2H, m), 3.49-3.59 (5H, m), 3.74-3.80 (2H, m), 6.75 (2H, d, J = 7.8 Hz), 7.02 (2H, brs), 7.06-7.14 (3H, m), 7.23 (1H, s), 7.50 (2H, d, J = 7.8 Hz), 8.40 (1H, d, J = 5.1 Hz);
MS (FAB) m/z: 462 [M⁺], 257, 242, 165, 93, 65;
Anal. Calcd for C₂₄H₂₇N₇OS・1.50H₂O: C, 59.00; H, 6.19; N, 20.07. Found: C, 59.04; H, 6.26; N, 19.95。
[Example 35]
3-Amino-4- {4- [4- (1,2-dimethyl-1H-imidazol-4-yl) phenyl] -1,4-diazepan-1-yl} thieno [2,3-b] pyridine- 2-Carboxamide starting material (amine compound): Compound yellow powder of Reference Example 35
Mp 255-258 ° C;
IR (KBr) ν _max 3445, 3323, 3188, 2942, 1649, 1574, 1510, 1366, 1347, 1208, 940, 822 cm ^-1 ;
^{_{1 H NMR (DMSO-d 6}} , 400 MHz) δ 2.11-2.20 (2H, m), 2.29 (3H, m), 3.16-3.25 (2H, m), 3.28-3.35 (2H, m), 3.49-3.59 (5H, m), 3.74-3.80 (2H, m), 6.75 (2H, d, J = 7.8 Hz), 7.02 (2H, brs), 7.06-7.14 (3H, m), 7.23 (1H, s), 7.50 (2H, d, J = 7.8 Hz), 8.40 (1H, d, J = 5.1 Hz);
MS (FAB) m / z: 462 [M ⁺ ], 257, 242, 165, 93, 65;
Anal. Calcd for C ₂₄ H ₂₇ N ₇ OS · 1.50H ₂ O: C, 59.00; H, 6.19; N, 20.07. Found: C, 59.04; H, 6.26; N, 19.95.

［実施例３６］
３−アミノ−４−（３−｛［２−（３−メチル−２，５−ジオキソイミダゾリジン−１−イル）エトキシ］メチル｝ピペリジン−１−イル）チエノ［２，３−ｂ］ピリジン−２−カルボキサミド
出発原料（アミン化合物）：参考例３６の化合物
黄色泡状物質;
IR (KBr) ν_max3438, 3329, 2931, 1711, 1648, 1579, 1500, 1373, 1121, 756 cm^-1;
¹H NMR(CDCl₃, 500 MHz) δ 1.07-1.19 (1H, m), 1.69-1.96 (3H, m), 2.01-2.13 (1H, m), 2.40-2.49 (1H, m), 2.53-2.62 (1H, m), 2.95 (3H, brs), 3.37-3.48 (3H, m), 3.57-3.84 (5H, m), 3.85 (2H, brs), 5.28 (2H, brs), 6.91 (1H, d, J = 5.4 Hz), 6.99 (2H, brs), 8.47 (1H, d, J = 5.4 Hz);
MS (FAB) m/z: 447 [M+H⁺], 259, 242, 165, 93, 65;
Anal. Calcd for C₂₀H₂₆N₆O₄S・1.30H₂O: C, 51.12; H, 6.13; N, 17.88. Found: C, 51.50; H, 6.32; N, 17.30。
[Example 36]
3-Amino-4- (3-{[2- (3-methyl-2,5-dioxoimidazolidin-1-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine 2-Carboxamide starting material (amine compound): compound of Reference Example 36, yellow foam;
IR (KBr) ν _max 3438, 3329, 2931, 1711, 1648, 1579, 1500, 1373, 1121, 756 cm ^-1 ;
¹ H NMR (CDCl ₃ , 500 MHz) δ 1.07-1.19 (1H, m), 1.69-1.96 (3H, m), 2.01-2.13 (1H, m), 2.40-2.49 (1H, m), 2.53-2.62 (1H, m), 2.95 (3H, brs), 3.37-3.48 (3H, m), 3.57-3.84 (5H, m), 3.85 (2H, brs), 5.28 (2H, brs), 6.91 (1H, d , J = 5.4 Hz), 6.99 (2H, brs), 8.47 (1H, d, J = 5.4 Hz);
MS (FAB) m / z: 447 [M + H ⁺ ], 259, 242, 165, 93, 65;
Anal. Calcd for C ₂₀ H ₂₆ N ₆ O ₄ S • 1.30H ₂ O: C, 51.12; H, 6.13; N, 17.88. Found: C, 51.50; H, 6.32; N, 17.30.

［実施例３７］
３−アミノ−４−（３−｛［２−（３−メチル−２−オキソイミダゾリジン−１−イル）エトキシ］メチル｝ピペリジン−１−イル）チエノ［２，３−ｂ］ピリジン−２−カルボキサミド
出発原料（アミン化合物）：参考例３７の化合物
淡黄色泡状物質;
IR (KBr) ν_max3439, 3322, 2930, 1692, 1649, 1579, 1500, 1447, 1370, 1251, 1121, 760 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.04-1.20 (1H, m), 1.69-1.95 (3H, m), 2.01-2.16 (1H, m), 2.34-2.45 (1H, m), 2.57-2.68 (1H, m), 2.73 (3H, brs), 3.12-3.60 (12H, m), 5.28 (2H, brs), 6.87 (1H, d, J = 5.4 Hz), 6.98 (2H, brs), 8.44 (1H, d, J = 5.4 Hz);
MS (FAB) m/z: 433 [M⁺], 416, 388, 341, 270, 244, 219, 202;
Anal. Calcd for C₂₀H₂₈N₆O₃S・0.50H₂O: C, 54.40; H, 6.62; N, 19.03; S, 7.26. Found: C, 54.71; H, 6.69; N, 18.45, S, 6.51。
[Example 37]
3-Amino-4- (3-{[2- (3-methyl-2-oxoimidazolidin-1-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine-2- Carboxamide starting material (amine compound): compound of Reference Example 37, pale yellow foam;
IR (KBr) ν _max 3439, 3322, 2930, 1692, 1649, 1579, 1500, 1447, 1370, 1251, 1121, 760 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.04-1.20 (1H, m), 1.69-1.95 (3H, m), 2.01-2.16 (1H, m), 2.34-2.45 (1H, m), 2.57-2.68 (1H, m), 2.73 (3H, brs), 3.12-3.60 (12H, m), 5.28 (2H, brs), 6.87 (1H, d, J = 5.4 Hz), 6.98 (2H, brs), 8.44 ( 1H, d, J = 5.4 Hz);
MS (FAB) m / z: 433 [M ⁺ ], 416, 388, 341, 270, 244, 219, 202;
Anal. Calcd for C ₂₀ H ₂₈ N ₆ O ₃ S ・ 0.50H ₂ O: C, 54.40; H, 6.62; N, 19.03; S, 7.26. Found: C, 54.71; H, 6.69; N, 18.45, S , 6.51.

［実施例３８］
３−アミノ−４−（（３Ｓ）−３−{[（５−メチル−１,３,４−オキサジアゾール−２−イル）メトキシ]メチル}ピペリジン−１−イル）チエノ[２,３−ｂ]ピリジン−２−カルボキサミド
出発原料（アミン化合物）：参考例３８の化合物
淡黄色泡状物質；
IR (KBr) ν_max3439, 3326, 3185, 2932, 1650, 1580, 1501, 1442, 1370, 1248, 1102, 960 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.07-1.23 (1H, m), 1.68-1.98 (3H, m), 2.08-2.24 (1H, m), 2.38-2.67 (2H, m), 2.55 (3H, s), 3.32-3.61 (4H, m), 4.65 (2H, s), 5.29 (2H, brs), 6.88 (1H, d, J = 5.5 Hz), 6.99 (2H, brs), 8.47 (1H, d, J = 5.5 Hz);
MS (FAB) m/z: 403 [M+H⁺], 273, 246, 182, 165;
Anal. Calcd for C₁₈H₂₂N₆O₃S・0.67H₂O: C, 52.16; H, 5.67; N, 20.28; S, 7.74. Found: C, 52.17; H, 5.74; N, 20.27, S, 7.62。
[Example 38]
3-Amino-4-((3S) -3-{[(5-methyl-1,3,4-oxadiazol-2-yl) methoxy] methyl} piperidin-1-yl) thieno [2,3- b] Pyridine-2-carboxamide starting material (amine compound): compound of Reference Example 38, pale yellow foam;
IR (KBr) ν _max 3439, 3326, 3185, 2932, 1650, 1580, 1501, 1442, 1370, 1248, 1102, 960 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.07-1.23 (1H, m), 1.68-1.98 (3H, m), 2.08-2.24 (1H, m), 2.38-2.67 (2H, m), 2.55 (3H , s), 3.32-3.61 (4H, m), 4.65 (2H, s), 5.29 (2H, brs), 6.88 (1H, d, J = 5.5 Hz), 6.99 (2H, brs), 8.47 (1H, d, J = 5.5 Hz);
MS (FAB) m / z: 403 [M + H ⁺ ], 273, 246, 182, 165;
Anal. Calcd for C ₁₈ H ₂₂ N ₆ O ₃ S ・ 0.67H ₂ O: C, 52.16; H, 5.67; N, 20.28; S, 7.74. Found: C, 52.17; H, 5.74; N, 20.27, S , 7.62.

［実施例３９］
３−アミノ−４−（（３Ｓ）−３−{[（３−メチル−１,２,４−オキサジアゾール−５−イル）メトキシ]メチル}ピペリジン−１−イル）チエノ[２,３−ｂ]ピリジン−２−カルボキサミド
（３９ａ）４−（（３Ｓ）−３−{[（３−メチル−１,２,４−オキサジアゾール−５−イル）メトキシ]メチル}ピペリジン−１−イル）−２−チオキソ−１,２−ジヒドロピリジン−３−カルボニトリル
参考例３９（３９ｂ）で製造した（３Ｓ）−３−{[（３−メチル−１,２,４−オキサジアゾール−５−イル）メトキシ]メチル}ピペリジン（５７０ｍｇ，２．０７ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（５．４０ｍＬ）溶液に、（２Ｚ）−２−シアノ−３−エトキシブテ−２−エンチオアミド（Ｊ．Ｏｒｇ．Ｃｈｅｍ．，（１９６２），２７，２４３３−２４３９）（４１３ｍｇ，２．４３ｍｍｏｌ）を加え、３０分室温攪拌した。次いでＮ，Ｎ−ジメチルホルムアミドジメチルアセタール（３６０μＬ，２．７０ｍｍｏｌ）を加え１時間室温攪拌したのち、７０℃で１時間加熱攪拌した。
[Example 39]
3-Amino-4-((3S) -3-{[(3-methyl-1,2,4-oxadiazol-5-yl) methoxy] methyl} piperidin-1-yl) thieno [2,3- b] Pyridine-2-carboxamide (39a) 4-((3S) -3-{[(3-Methyl-1,2,4-oxadiazol-5-yl) methoxy] methyl} piperidin-1-yl) 2-Thioxo-1,2-dihydropyridine-3-carbonitrile (3S) -3-{[(3-Methyl-1,2,4-oxadiazol-5-yl) prepared in Reference Example 39 (39b) )] Methoxy] methyl} piperidine (570 mg, 2.07 mmol) in N, N-dimethylformamide (5.40 mL) and (2Z) -2-cyano-3-ethoxybut-2-enethioamide (J. Org. Chem). , (1962), 27, 2433 2439) (413mg, 2.43mmol) was added and 30 minutes stirring at room temperature. Next, N, N-dimethylformamide dimethylacetal (360 μL, 2.70 mmol) was added and stirred at room temperature for 1 hour, and then heated and stirred at 70 ° C. for 1 hour.

反応液を濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／メタノール，３０：１）を用いて精製し、標記目的化合物（８５ｍｇ、収率１０％）を得た。 The reaction mixture was concentrated, and the resulting residue was purified using silica gel column chromatography (ethyl acetate / methanol, 30: 1) to give the title object compound (85 mg, yield 10%).

淡黄色粉末
Mp 142-144 ℃；
IR (KBr) ν_max3112, 2948, 2212, 1622, 1552, 1517, 1309, 1251, 1117, 793 cm^-1;
¹H NMR(CDCl₃, 500 MHz) δ 1.39-1.49 (1H, m), 1.67-1.79 (1H, m), 1.84-1.94 (2H, m), 2.06-2.15 (1H, m), 2.43 (3H, S), 3.14 (1H, dd, J = 10.2, 13.2 Hz), 3.30-3.38 (1H, m), 3.50 (1H, brt, J = 9.3 Hz), 3.59 (1H, dd, J = 4.9, 9.3 Hz), 4.05-4.17 (2H, m), 4.70 (2H, d, J = 4.9 Hz), 6.30 (1H, d, J = 7.8 Hz), 7.28 (1H, d, J = 7.8 Hz), 11.76 (1H, brs);
MS (FAB) m/z: 346 [M+H]⁺, 273, 248, 219, 165。
Pale yellow powder
Mp 142-144 ° C;
IR (KBr) ν _max 3112, 2948, 2212, 1622, 1552, 1517, 1309, 1251, 1117, 793 cm ^-1 ;
¹ H NMR (CDCl ₃ , 500 MHz) δ 1.39-1.49 (1H, m), 1.67-1.79 (1H, m), 1.84-1.94 (2H, m), 2.06-2.15 (1H, m), 2.43 (3H , S), 3.14 (1H, dd, J = 10.2, 13.2 Hz), 3.30-3.38 (1H, m), 3.50 (1H, brt, J = 9.3 Hz), 3.59 (1H, dd, J = 4.9, 9.3 Hz), 4.05-4.17 (2H, m), 4.70 (2H, d, J = 4.9 Hz), 6.30 (1H, d, J = 7.8 Hz), 7.28 (1H, d, J = 7.8 Hz), 11.76 ( 1H, brs);
MS (FAB) m / z: 346 [M + H] ⁺ , 273, 248, 219, 165.

（３９ｂ）３−アミノ−４−（（３Ｓ）−３−｛［（３−メチル−１，２，４−オキサジアゾール−５−イル）メトキシ］メチル｝ピペリジン−１−イル）チエノ［２，３−ｂ］ピリジン−２−カルボキサミド
実施例３９（３９ａ）で製造した４−（（３Ｓ）−３−｛［（３−メチル−１，２，４−オキサジアゾール−５−イル）メトキシ］メチル｝ピペリジン−１−イル）−２−チオキソ−１，２−ジヒドロピリジン−３−カルボニトリル（７３ｍｇ，２１２μｍｏｌ）をＮ，Ｎ−ジメチルホルムアミド（０．４ｍＬ）に溶解し、８Ｎ水酸化ナトリウム水溶液（９６μＬ）と２−クロロアセトアミド（２４ｍｇ，２５４μｍｏｌ）を加え、室温で６時間攪拌した。反応混合物に水（２ｍＬ）を加え、酢酸エチルで３回抽出した。有機層を合せ、無水硫酸ナトリウムで乾燥後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル）を用いて精製し、標記目的化合物（６０ｍｇ、７０％）を得た。
(39b) 3-Amino-4-((3S) -3-{[(3-methyl-1,2,4-oxadiazol-5-yl) methoxy] methyl} piperidin-1-yl) thieno [2 , 3-b] pyridine-2-carboxamide 4-((3S) -3-{[(3-methyl-1,2,4-oxadiazol-5-yl) methoxy prepared in Example 39 (39a) ] Methyl} piperidin-1-yl) -2-thioxo-1,2-dihydropyridine-3-carbonitrile (73 mg, 212 μmol) dissolved in N, N-dimethylformamide (0.4 mL), and 8N aqueous sodium hydroxide solution (96 μL) and 2-chloroacetamide (24 mg, 254 μmol) were added, and the mixture was stirred at room temperature for 6 hours. Water (2 mL) was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified using silica gel column chromatography (ethyl acetate) to obtain the title object compound (60 mg, 70%).

淡黄色粉末
Mp 134-136 ℃；
IR (KBr) ν_max3434, 3323, 3164, 2933, 1651, 1580, 1499, 1247, 1122 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.13-1.26 (1H, m), 1.72-1.99 (3H, m), 2.12-2.25 (1H, m), 2.42 (3H, brs), 2.45-2.65 (2H, m), 3.39-3.62 (4H, m), 4.70 (2H, s), 5.28 (2H, brs), 6.90 (1H, d, J = 5.4 Hz), 6.99 (2H, brs), 8.47 (1H, d, J = 5.4 Hz);
MS (FAB) m/z: 403 [M+H⁺], 386, 272, 258, 242, 165;
Anal. Calcd for C₁₈H₂₂N₆O₃S・0.20H₂O: C, 53.24; H, 5.56; N, 20.70; S, 7.90. Found: C, 53.34; H, 5.67; N, 20.52, S, 7.92。
Pale yellow powder
Mp 134-136 ° C;
IR (KBr) ν _max 3434, 3323, 3164, 2933, 1651, 1580, 1499, 1247, 1122 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.13-1.26 (1H, m), 1.72-1.99 (3H, m), 2.12-2.25 (1H, m), 2.42 (3H, brs), 2.45-2.65 (2H , m), 3.39-3.62 (4H, m), 4.70 (2H, s), 5.28 (2H, brs), 6.90 (1H, d, J = 5.4 Hz), 6.99 (2H, brs), 8.47 (1H, d, J = 5.4 Hz);
MS (FAB) m / z: 403 [M + H ⁺ ], 386, 272, 258, 242, 165;
Anal. Calcd for C ₁₈ H ₂₂ N ₆ O ₃ S ・ 0.20H ₂ O: C, 53.24; H, 5.56; N, 20.70; S, 7.90. Found: C, 53.34; H, 5.67; N, 20.52, S , 7.92.

［実施例４０］
３−アミノ−４−（（３Ｓ）−３−{［２−（２−メチル−２Ｈ−テトラゾール−５−イル）エトキシ］メチル}ピペリジン−１−イル）チエノ[２，３−ｂ]ピリジン−２−カルボキサミド
（４０ａ）４−（（３Ｓ）−３−{［２−（２−メチル−２Ｈ−テトラゾール−５−イル）エトキシ］メチル}ピペリジン−１−イル）−２−チオキソ−１，２−ジヒドロピリジン−３−カルボニトリル
参考例４０（４０ｄ）で製造した（３Ｓ）−３−｛［２−（２−メチル−２Ｈ−テトラゾール−５−イル）エトキシ］メチル｝ピペリジン（２２１ｍｇ，０．９８ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（１ｍＬ）溶液に、（２Ｚ）−２−シアノ−３−エトキシブテ−２−エンチオアミド（Ｊ．Ｏｒｇ．Ｃｈｅｍ．，（１９６２），２７，２４３３−２４３９）（１６７ｍｇ，０．９８ｍｍｏｌ）を加え、１５分室温攪拌した。次いでＮ，Ｎ−ジメチルホルムアミドジメチルアセタール（１３０μＬ，０．９８ｍｍｏｌ）を加え１時間攪拌したのち、８０℃で３０分加熱攪拌した。反応液を濃縮し、分取薄層クロマトグラフィー（塩化メチレン／メタノール＝３０：１）にて精製し、９１ｍｇ（収率２６％）の標記目的化合物を得た。
[Example 40]
3-Amino-4-((3S) -3-{[2- (2-methyl-2H-tetrazol-5-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine- 2-carboxamide (40a) 4-((3S) -3-{[2- (2-methyl-2H-tetrazol-5-yl) ethoxy] methyl} piperidin-1-yl) -2-thioxo-1,2 -Dihydropyridine-3-carbonitrile (3S) -3-{[2- (2-Methyl-2H-tetrazol-5-yl) ethoxy] methyl} piperidine (221 mg, 0.98 mmol) prepared in Reference Example 40 (40d) ) In N, N-dimethylformamide (1 mL), (2Z) -2-cyano-3-ethoxybute-2-enethioamide (J. Org. Chem., (1962), 27, 2433-2). 439) (167 mg, 0.98 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. Next, N, N-dimethylformamide dimethylacetal (130 μL, 0.98 mmol) was added and stirred for 1 hour, and then heated and stirred at 80 ° C. for 30 minutes. The reaction solution was concentrated and purified by preparative thin layer chromatography (methylene chloride / methanol = 30: 1) to obtain 91 mg (yield 26%) of the title compound.

白色粉末
Mp 122-125 ℃
IR (KBr) ν_max3120, 2931, 2206, 1622, 1540, 1304, 1250, 1165, 1114, 779, 601, 437 cm^-1;
¹H NMR(CDCl₃, 500 MHz) δ 1.37-2.00 (5H, m), 3.04 (1H, dd, J = 9.8, 13.7 Hz), 3.15 (2H, t, J = 6.8 Hz), 3.33-3.35 (2H, m), 3.44 (1H, dd, J = 4.4, 9.3 Hz), 3.78-3.89 (2H, m), 3.89 (1H, d, J = 11.7 Hz), 4.14 (1H, d, J = 14.2 Hz), 4.32 (3H, s), 6.34 (1H, d, J = 6.8 Hz), 7.81-8.85 (1H, m);
MS (FAB) m/z: 360 [M+H]⁺, 273, 257, 242, 226, 219, 189, 180, 165, 120, 65。
White powder
Mp 122-125 ° C
IR (KBr) ν _max 3120, 2931, 2206, 1622, 1540, 1304, 1250, 1165, 1114, 779, 601, 437 cm ^-1 ;
¹ H NMR (CDCl ₃ , 500 MHz) δ 1.37-2.00 (5H, m), 3.04 (1H, dd, J = 9.8, 13.7 Hz), 3.15 (2H, t, J = 6.8 Hz), 3.33-3.35 ( 2H, m), 3.44 (1H, dd, J = 4.4, 9.3 Hz), 3.78-3.89 (2H, m), 3.89 (1H, d, J = 11.7 Hz), 4.14 (1H, d, J = 14.2 Hz ), 4.32 (3H, s), 6.34 (1H, d, J = 6.8 Hz), 7.81-8.85 (1H, m);
MS (FAB) m / z: 360 [M + H] ⁺ , 273, 257, 242, 226, 219, 189, 180, 165, 120, 65.

（４０ｂ）３−アミノ−４−（（３Ｓ）−３−{［２−（２−メチル−２Ｈ−テトラゾール−５−イル）エトキシ］メチル}ピペリジン−１−イル）チエノ[２，３−ｂ]ピリジン−２−カルボキサミド
実施例４０（４０ａ）で製造した４−（（３Ｓ）−３−{［２−（２−メチル−２Ｈ−テトラゾール−５−イル）エトキシ］メチル}ピペリジン−１−イル）−２−チオキソ−１，２−ジヒドロピリジン−３−カルボニトリル（７８ｍｇ、０．２２ｍｍoｌ）をＮ，Ｎ−ジメチルホルムアミド（０．４ｍＬ）に溶解し、８Ｎ水酸化ナトリウム水溶液（９４μＬ，０．７５ｍｍｏｌ）と２−クロロアセトアミド（２５ｍｇ，０．２６ｍｍｏｌ）を加え、室温で１時間攪拌した。反応液に水（２ｍＬ）を加え、塩化メチレン／２−プロパノール混合溶媒（４：１）にて２回抽出した。無水硫酸ナトリウムで乾燥後，溶媒を減圧下留去し、得られた残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル）を用いて精製し、標記目的化合物（６６ｍｇ，収率７１％）を得た。
(40b) 3-Amino-4-((3S) -3-{[2- (2-methyl-2H-tetrazol-5-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b ] Pyridine-2-carboxamide 4-((3S) -3-{[2- (2-Methyl-2H-tetrazol-5-yl) ethoxy] methyl} piperidin-1-yl prepared in Example 40 (40a) ) -2-thioxo-1,2-dihydropyridine-3-carbonitrile (78 mg, 0.22 mmol) was dissolved in N, N-dimethylformamide (0.4 mL), and 8N aqueous sodium hydroxide solution (94 μL, 0.75 mmol) was dissolved. ) And 2-chloroacetamide (25 mg, 0.26 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Water (2 mL) was added to the reaction solution, and the mixture was extracted twice with a mixed solvent of methylene chloride / 2-propanol (4: 1). After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (ethyl acetate) to obtain the title object compound (66 mg, 71% yield).

淡黄泡状物質;
IR (KBr) ν_max3440, 3329, 2931, 1650, 1580, 1501, 1371, 1248, 1120, 960, 825, 739, 477 cm^-1;
¹H NMR(DMSO-d₆, 500 MHz) δ 1.09-1.10 (1H, m), 1.73-1.78 (2H, m), 2.08-2.10 (2H,m), 3.05 (2H, t, J = 6.4 Hz), 3.24-3.38 (6H, m), 3.71-3.79 (2H, m), 4.25 (3H, s), 6.92 (2H, brs), 6.99 (1H, d, J = 5.4 Hz), 7.10 (2H, brs), 8.44 (1H, d, J = 5.4 Hz);
HRMS m/z calcd for C₁₈H₂₅O₂N₈S 417.1821, found 417.1817.
MS (FAB) m/z: 417 [M+H]⁺, 400, 372, 343, 270, 258, 202, 165, 63, 39, 31;
Anal. Calcd for C₁₈H₂₄N₈O₂S・0.66H₂O: C, 50.45; H, 5.96; N, 26.15; S, 7.48. Found: C, 50.54; H, 5.77; N, 25.89; S, 7.74。

（２Ｚ）−２−シアノ−３−エトキシブタ−２−エンチオアミドと各種アミン化合物を出発原料として用いて、実施例３９乃至４０と同様に反応を行い、実施例４１乃至４４の化合物を得た。
Pale yellow foam;
IR (KBr) ν _max 3440, 3329, 2931, 1650, 1580, 1501, 1371, 1248, 1120, 960, 825, 739, 477 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 500 MHz) δ 1.09-1.10 (1H, m), 1.73-1.78 (2H, m), 2.08-2.10 (2H, m), 3.05 (2H, t, J = 6.4 Hz ), 3.24-3.38 (6H, m), 3.71-3.79 (2H, m), 4.25 (3H, s), 6.92 (2H, brs), 6.99 (1H, d, J = 5.4 Hz), 7.10 (2H, brs), 8.44 (1H, d, J = 5.4 Hz);
HRMS m / z calcd for C ₁₈ H ₂₅ O ₂ N ₈ S 417.1821, found 417.1817.
MS (FAB) m / z: 417 [M + H] ⁺ , 400, 372, 343, 270, 258, 202, 165, 63, 39, 31;
Anal. Calcd for C ₁₈ H ₂₄ N ₈ O ₂ S0.66H ₂ O: C, 50.45; H, 5.96; N, 26.15; S, 7.48. Found: C, 50.54; H, 5.77; N, 25.89; S , 7.74.

(2Z) -2-Cyano-3-ethoxybut-2-enethioamide and various amine compounds were used as starting materials to carry out the reaction in the same manner as in Examples 39 to 40 to obtain the compounds of Examples 41 to 44.

［実施例４１］
３−アミノ−４−（３−｛〔３−（２−オキソ−１，３−オキサゾリン−３−イル）プロポキシ〕メチル｝ピペリジン−１−イル）チエノ〔２，３−ｂ〕ピリジン−２−カルボキサミド
出発原料（アミン化合物）：参考例４１の化合物
黄色アモルファス
IR (KBr) ν_max3439, 3326, 3186, 2929, 2857, 1746, 1648, 1579, 1500, 1371 cm^-1;
¹H NMR (CDCl₃, 500MHz) δ 1.08-1.19 (1H, m), 1.74-1.86 (3H, m), 1.86-1.94 (2H, br), 2.06-2.15 (1H, br), 2.45 (1H, t, J = 11.0 Hz), 2.62 (1H, t, J = 11.5 Hz), 3.25-3.39 (4H, m), 3.40-3.60 (6H, m), 4.25-4.33 (2H, m), 5.31 (2H, brs), 6.92 (1H, d, J = 5.0 Hz), 7.01 (2H, brs), 8.47 (1H, d, J = 5.0 Hz);
MS (FAB) m/z: 434 [M+H]⁺;
Anal.calcd for C₂₀H₂₇N₅O₄S・1/2H₂O : C,54.28; H,6.38; N,15.83; S, 7.25. Found C,54.06; H,6.21; N,15.59; S,7.17。
[Example 41]
3-Amino-4- (3-{[3- (2-oxo-1,3-oxazolin-3-yl) propoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine-2- Carboxamide starting material (amine compound): Compound yellow amorphous of Reference Example 41
IR (KBr) ν _max 3439, 3326, 3186, 2929, 2857, 1746, 1648, 1579, 1500, 1371 cm ^-1 ;
¹ H NMR (CDCl ₃ , 500MHz) δ 1.08-1.19 (1H, m), 1.74-1.86 (3H, m), 1.86-1.94 (2H, br), 2.06-2.15 (1H, br), 2.45 (1H, t, J = 11.0 Hz), 2.62 (1H, t, J = 11.5 Hz), 3.25-3.39 (4H, m), 3.40-3.60 (6H, m), 4.25-4.33 (2H, m), 5.31 (2H , brs), 6.92 (1H, d, J = 5.0 Hz), 7.01 (2H, brs), 8.47 (1H, d, J = 5.0 Hz);
MS (FAB) m / z: 434 [M + H] ⁺ ;
Anal.calcd for C ₂₀ H ₂₇ N ₅ O ₄ S ・ 1 / 2H ₂ O: C, 54.28; H, 6.38; N, 15.83; S, 7.25.Found C, 54.06; H, 6.21; N, 15.59; S , 7.17.

［実施例４２］
３−アミノ−４−（３−｛〔２−（１−メチル−１Ｈ−テトラゾール−５−イル）エトキシ〕メチル｝ピペリジン−１−イル）チエノ〔２，３−ｂ〕ピリジン−２−カルボキサミド
出発原料（アミン化合物）：参考例４２の化合物
淡褐色の固体
Mp 195-196 ℃;
IR (KBr) ν_max 3446, 3329, 3176, 2936, 1652, 1600, 1579, 1501, 1369, 1345 cm^-1;
¹H NMR (CDCl₃, 500MHz) δ 0.98-1.08 (1H, m), 1.72-1.84 (2H, m), 1.87-1.94 (1H, m), 2.03-2.11 (1H, m), 2.28 (1H, t, J = 11.2 Hz), 2.64 (1H, t, J = 11.2 Hz), 3.12 (2H, t, J = 6.1 Hz), 3.23 (1H, t, J = 8.8 Hz), 3.34-3.41 (2H, m), 3.44 (1H, d, J = 10.3 Hz), 3.75-3.84 (2H, m), 4.01 (3H, s), 5.33 (2H, brs), 6.86 (1H, d, J = 5.4 Hz), 6.96 (2H, brs), 8.48 (1H, d, J = 5.4 Hz);
MS (FAB) m/z: 417 [M+H]⁺;
Anal.calcd for C₁₈H₂₄N₈O₂S・1/2H₂O : C,50.81; H,5.92; N,26.33; S, 7.54. Found C,50.83; H,5.70; N,26.06; S,7.51。
[Example 42]
3-amino-4- (3-{[2- (1-methyl-1H-tetrazol-5-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide Raw material (amine compound): Compound of Reference Example 42 Light brown solid
Mp 195-196 ° C;
IR (KBr) ν _max 3446, 3329, 3176, 2936, 1652, 1600, 1579, 1501, 1369, 1345 cm ^-1 ;
¹ H NMR (CDCl ₃ , 500MHz) δ 0.98-1.08 (1H, m), 1.72-1.84 (2H, m), 1.87-1.94 (1H, m), 2.03-2.11 (1H, m), 2.28 (1H, t, J = 11.2 Hz), 2.64 (1H, t, J = 11.2 Hz), 3.12 (2H, t, J = 6.1 Hz), 3.23 (1H, t, J = 8.8 Hz), 3.34-3.41 (2H, m), 3.44 (1H, d, J = 10.3 Hz), 3.75-3.84 (2H, m), 4.01 (3H, s), 5.33 (2H, brs), 6.86 (1H, d, J = 5.4 Hz), 6.96 (2H, brs), 8.48 (1H, d, J = 5.4 Hz);
MS (FAB) m / z: 417 [M + H] ⁺ ;
Anal.calcd for C ₁₈ H ₂₄ N ₈ O ₂ S ・ 1 / 2H ₂ O: C, 50.81; H, 5.92; N, 26.33; S, 7.54. Found C, 50.83; H, 5.70; N, 26.06; S 7.51.

［実施例４３］
３−アミノ−４−（３−｛〔（２−メチル−２Ｈ−テトラゾール−５−イル）メトキシ〕メチル｝ピペリジン−１−イル）チエノ〔２,３−ｂ〕ピリジン−２−カルボキサミド
出発原料（アミン化合物）：参考例４３の化合物
淡黄色の固体
Mp 165-166 ℃;
IR (KBr) ν_max3433, 3322, 3176, 2928, 1651, 1579, 1556, 1501, 1371, 1346 cm^-1;
¹H NMR (CDCl₃, 500MHz) δ 1.10-1.23 (1H, m), 1.72-1.95 (3H, m), 2.11-2.21 (1H, br), 2.48 (1H, t, J = 9.8 Hz), 2.58 (1H, t, J = 9.8 Hz), 3.38-3.59 (4H, m), 4.35 (3H, brs), 4.76 (2H, s), 5.28 (2H, b s), 6.88 (1H, d, J = 5.4 Hz), 6.98 (2H, brs), 8.46 (1H, d, J = 5.4 Hz);
MS (FAB) m/z: 403 [M+H]⁺;
Anal.calcd for C₁₇H₂₂N₈O₂S・4/5H₂O : C,48.98; H,5.71; N,26.88; S, 7.69. Found C, 48.97; H,5.35; N,26.84; S,7.74。
[Example 43]
3-amino-4- (3-{[(2-methyl-2H-tetrazol-5-yl) methoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide starting material ( Amine compound): compound of Reference Example 43 pale yellow solid
Mp 165-166 ° C;
IR (KBr) ν _max 3433, 3322, 3176, 2928, 1651, 1579, 1556, 1501, 1371, 1346 cm ^-1 ;
¹ H NMR (CDCl ₃ , 500MHz) δ 1.10-1.23 (1H, m), 1.72-1.95 (3H, m), 2.11-2.21 (1H, br), 2.48 (1H, t, J = 9.8 Hz), 2.58 (1H, t, J = 9.8 Hz), 3.38-3.59 (4H, m), 4.35 (3H, brs), 4.76 (2H, s), 5.28 (2H, bs), 6.88 (1H, d, J = 5.4 Hz), 6.98 (2H, brs), 8.46 (1H, d, J = 5.4 Hz);
MS (FAB) m / z: 403 [M + H] ⁺ ;
Anal.calcd for C ₁₇ H ₂₂ N ₈ O ₂ S ・ 4 / 5H ₂ O: C, 48.98; H, 5.71; N, 26.88; S, 7.69.Found C, 48.97; H, 5.35; N, 26.84; S , 7.74.

［実施例４４］
３−アミノ−４−（３−｛〔（１−メチル−１Ｈ−テトラゾール−５−イル）メトキシ〕メチル｝ピペリジン−１−イル）チエノ〔２，３−ｂ〕ピリジン−２−カルボキサミド
出発原料（アミン化合物）：参考例４４の化合物
淡黄色の固体
Mp 215-216 ℃;
IR (KBr) ν_max3440, 3311, 3161, 2936, 1648, 1582, 1556, 1502, 1370, 1348 cm^-1;
¹H NMR (CDCl₃, 500MHz) δ 1.06-1.17 (1H, m), 1.74-1.96 (3H, m), 2.11-2.20 (1H, m), 2.38 (1H, t, J = 11.2 Hz), 2.64 (1H, t, J = 11.2 Hz), 3.35-3.55 (4H, m), 4.11 (3H, brs), 4.84 (2H, s), 5.31 (2H, brs), 6.87 (1H, d, J = 5.3 Hz), 6.96 (2H, brs), 8.47 (1H, d, J = 5.3 Hz);
MS (FAB) m/z: 403 [M+H]⁺;
Anal.calcd for C₁₇H₂₂N₈O₂S: C, 50.73; H, 5.51; N, 27.84; S, 7.97. Found C, 50.65; H, 5.52; N, 27.86; S, 7.94。
[Example 44]
3-amino-4- (3-{[(1-methyl-1H-tetrazol-5-yl) methoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide starting material ( Amine Compound): Compound of Reference Example 44 Light Yellow Solid
Mp 215-216 ° C;
IR (KBr) ν _max 3440, 3311, 3161, 2936, 1648, 1582, 1556, 1502, 1370, 1348 cm ^-1 ;
¹ H NMR (CDCl ₃ , 500MHz) δ 1.06-1.17 (1H, m), 1.74-1.96 (3H, m), 2.11-2.20 (1H, m), 2.38 (1H, t, J = 11.2 Hz), 2.64 (1H, t, J = 11.2 Hz), 3.35-3.55 (4H, m), 4.11 (3H, brs), 4.84 (2H, s), 5.31 (2H, brs), 6.87 (1H, d, J = 5.3 Hz), 6.96 (2H, brs), 8.47 (1H, d, J = 5.3 Hz);
MS (FAB) m / z: 403 [M + H] ⁺ ;
_{_{_{Anal.calcd for C 17 H 22 N 8}}} O 2 S:. C, 50.73; H, 5.51; N, 27.84; S, 7.97 Found C, 50.65; H, 5.52; N, 27.86; S, 7.94.

［実施例４５］
３−アミノ−４−｛（３Ｓ）−３−［（シクロプロピルメトキシ）メチル］ピペリジン−１−イル｝−６−メチルチエノ［２，３−ｂ］ピリジン−２−カルボキサミド
（４５ａ）（１−エトキシエチリデン）マロノニトリル
マロノニトリル（４．４１ｇ、６６．８ｍｍｏｌ）、オルト酢酸トリエチル（１４．７ｍＬ、８０．２ｍｍｏｌ）及び酢酸（１ｍＬ）を混合し、８０℃で１時間撹拌した。反応液を室温に冷却し、生成した粉末をろ取し、標記目的化合物（７．１４ｇ，収率７９％）を得た。
白色粉末
¹H NMR(DMSO-d₆, 400 MHz) δ 1.32 (3H, t, J = 7.0 Hz), 2.45 (3H, s), 4.42 (2H, q, J = 7.0 Hz)。
[Example 45]
3-amino-4-{(3S) -3-[(cyclopropylmethoxy) methyl] piperidin-1-yl} -6-methylthieno [2,3-b] pyridine-2-carboxamide (45a) (1-ethoxy Ethylidene) malononitrile Malononitrile (4.41 g, 66.8 mmol), triethyl orthoacetate (14.7 mL, 80.2 mmol) and acetic acid (1 mL) were mixed and stirred at 80 ° C. for 1 hour. The reaction mixture was cooled to room temperature, and the resulting powder was collected by filtration to give the title object compound (7.14 g, yield 79%).
White powder
¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.32 (3H, t, J = 7.0 Hz), 2.45 (3H, s), 4.42 (2H, q, J = 7.0 Hz).

（４５ｂ）（１−{（３Ｓ）−３−[（シクロプロピルメトキシ）メチル]ピペリジン−１−イル}エチリデン）マロノニトリル
参考例４５（４５ｂ）で製造した（３Ｓ）−３−［（シクロプロピルメトキシ）メチル］ピペリジン塩酸塩（１．６９ｇ，８．２２ｍｍｏｌ）及び実施例４５（４５ａ）で製造した（１−エトキシエチリデン）マロノニトリル（１．０６ｇ、７．８１ｍｍｏｌ）のメタノール（２０ｍＬ）溶液にトリエチルアミン（１．１５ｍＬ、８．２２ｍｍｏｌ）を加え２４時間室温で撹拌した。反応液を濃縮し、得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル，１：１）を用いて精製し，標記目的化合物（１．５２ｇ，収率７１％）を得た。
(45b) (1-{(3S) -3-[(cyclopropylmethoxy) methyl] piperidin-1-yl} ethylidene) malononitrile (3S) -3-[(cyclopropylmethoxy) prepared in Reference Example 45 (45b) ) Methyl] piperidine hydrochloride (1.69 g, 8.22 mmol) and (1-ethoxyethylidene) malononitrile (1.06 g, 7.81 mmol) prepared in Example 45 (45a) in methanol (20 mL) in triethylamine (20 mL). 1.15 mL, 8.22 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated, and the resulting residue was purified using silica gel column chromatography (hexane / ethyl acetate, 1: 1) to obtain the title object compound (1.52 g, yield 71%).

淡黄色液体
IR (film) ν_max3006, 2936, 2862, 2218, 1581, 1451, 1449, 1381, 1287, 1085, 1019, 616 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 0.19-0.21 (2H, m), 0.53-0.57 (2H, m), 1.01-1.03 (1H, m), 1.45-1.50 (1H, m), 1.66-1.69 (1H, m), 1.87-1.89 (2H, m), 1.97-2.01 (1H, m), 2.31 (3H, s), 3.19-3.41 (6H, m), 4.04-4.13 (2H, m);
MS (FAB) m/z: 260 [M+H⁺], 200, 174, 120, 55。
Pale yellow liquid
IR (film) ν _max 3006, 2936, 2862, 2218, 1581, 1451, 1449, 1381, 1287, 1085, 1019, 616 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 0.19-0.21 (2H, m), 0.53-0.57 (2H, m), 1.01-1.03 (1H, m), 1.45-1.50 (1H, m), 1.66-1.69 (1H, m), 1.87-1.89 (2H, m), 1.97-2.01 (1H, m), 2.31 (3H, s), 3.19-3.41 (6H, m), 4.04-4.13 (2H, m);
MS (FAB) m / z: 260 [M + H ⁺ ], 200, 174, 120, 55.

（４５ｃ）[（２Ｅ）−１−{（３Ｓ）−３−[（シクロプロピルメトキシ）メチル]ピペリジン−１−イル}−３−(ジメチルアミノ)ブタ−２−エン−１−リデン]マロノニトリル
実施例４５（４５ｂ）で製造した（１−{（３Ｓ）−３−[（シクロプロピルメトキシ）メチル]ピペリジン−１−イル}エチリデン）マロノニトリル（１．９９ｇ，７．７ｍｍｏｌ）のキシレン（１５ｍＬ）溶液にＮ，Ｎ−ジメチルアセトアミドジメチルアセタール（１５ｍＬ）を加え２時間加熱還流した。反応液を濃縮し、反応液に酢酸エチル（５０ｍＬ）を加え、水（５０ｍＬ）にて２回洗浄し、無水硫酸ナトリウムで乾燥後，溶媒を減圧下留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝１：１）を用いて精製し，標記目的化合物（２．５２ｇ，収率９９％）を得た。
(45c) [(2E) -1-{(3S) -3-[(cyclopropylmethoxy) methyl] piperidin-1-yl} -3- (dimethylamino) but-2-ene-1-lidene] malononitrile A solution of (1-{(3S) -3-[(cyclopropylmethoxy) methyl] piperidin-1-yl} ethylidene) malononitrile (1.99 g, 7.7 mmol) prepared in Example 45 (45b) in xylene (15 mL). N, N-dimethylacetamide dimethylacetal (15 mL) was added to the mixture and heated to reflux for 2 hours. The reaction mixture was concentrated, ethyl acetate (50 mL) was added to the reaction mixture, washed twice with water (50 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1: 1) to obtain the title object compound (2.52 g, yield 99%).

黄色液体
IR (film) ν_max3004, 2931, 2858, 2195, 2174, 1564, 1506, 1441, 1373, 1339, 1264, 1094, 1026, 764, 552 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 0.19 (2H, q, J = 5.9 Hz), 0.50-0.54 (2H, m), 1.00-1.04 (1H, m), 1.31-1.36 (1H, m), 1.58-1.94 (4H, m), 2.22 (3H, s), 2.92-3.00 (2H, m), 3.01 (6H, s), 3.24 (2H, d, J = 6.7 Hz), 3.30-3.37 (2H, m), 3.91-3.97 (2H, m), 4.38 (1H, s);
MS (FAB) m/z: 329 [M⁺], 263, 242, 200, 180, 65。
Yellow liquid
IR (film) ν _max 3004, 2931, 2858, 2195, 2174, 1564, 1506, 1441, 1373, 1339, 1264, 1094, 1026, 764, 552 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 0.19 (2H, q, J = 5.9 Hz), 0.50-0.54 (2H, m), 1.00-1.04 (1H, m), 1.31-1.36 (1H, m), 1.58-1.94 (4H, m), 2.22 (3H, s), 2.92-3.00 (2H, m), 3.01 (6H, s), 3.24 (2H, d, J = 6.7 Hz), 3.30-3.37 (2H, m), 3.91-3.97 (2H, m), 4.38 (1H, s);
MS (FAB) m / z: 329 [M ⁺ ], 263, 242, 200, 180, 65.

（４５ｄ）２−クロロ−４−｛（３Ｓ）−３−［（シクロプロピルメトキシ）メチル］ピペリジン−１−イル｝−６−メチルニコチノニトリル
実施例４５（４５ｃ）で製造した[（２Ｅ）−１−{（３Ｓ）−３−[（シクロプロピルメトキシ）メチル]ピペリジン−１−イル}−３−(ジメチルアミノ)ブタ−２−エン−１−リデン]マロノニトリル（２．５２ｇ，７．７ｍｍｏｌ）のメタノール（２０ｍＬ）溶液に０℃にて塩化オキサリル（１．１ｍＬ，１５．３ｍｍｏｌ）を加え１０分加熱還流した。反応液を濃縮し、得られた残渣に炭酸水素ナトリウム水溶液（５０ｍＬ）を加え、酢酸エチル（２０ｍＬ）で２回抽出し、無水硫酸ナトリウムで乾燥後，溶媒を減圧下留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝５：１）を用いて精製し，標記目的化合物（０．４８ｇ，収率２０％）を得た。
(45d) 2-Chloro-4-{(3S) -3-[(cyclopropylmethoxy) methyl] piperidin-1-yl} -6-methylnicotinonitrile Prepared in Example 45 (45c) [(2E) -1-{(3S) -3-[(cyclopropylmethoxy) methyl] piperidin-1-yl} -3- (dimethylamino) but-2-ene-1-lidene] malononitrile (2.52 g, 7.7 mmol) ) In methanol (20 mL) at 0 ° C. was added oxalyl chloride (1.1 mL, 15.3 mmol) and heated to reflux for 10 minutes. The reaction mixture was concentrated, aqueous sodium hydrogen carbonate solution (50 mL) was added to the resulting residue, extracted twice with ethyl acetate (20 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 5: 1) to obtain the title object compound (0.48 g, yield 20%).

淡黄色液体
IR (film) ν_max3004, 2856, 2217, 1589, 1511, 1448, 1373, 1322, 1214, 1108, 1056, 897, 594 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 0.21 (2H, q, J = 5.1 Hz), 0.51-0.56 (2H, m), 1.02-1.08 (1H, m), 1.32-1.38 (1H, m), 1.71-1.86 (3H, m), 2.02-2.07 (1H, m), 2.44 (3H, s), 2.95 (1H, dd, J = 9.8, 12.9 Hz), 3.15 (1H, dt, J = 2.7, 10.6 Hz), 3.27 (2H, dd, J = 3.5, 6.6 Hz), 3.35-3.42 (2H, m), 3.88-3.93 (2H, m), 6.56 (1H, s);
MS (FAB) m/z: 319 [M+H⁺], 316, 234, 230, 194, 55, 41, 29。
Pale yellow liquid
IR (film) ν _max 3004, 2856, 2217, 1589, 1511, 1448, 1373, 1322, 1214, 1108, 1056, 897, 594 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 0.21 (2H, q, J = 5.1 Hz), 0.51-0.56 (2H, m), 1.02-1.08 (1H, m), 1.32-1.38 (1H, m), 1.71-1.86 (3H, m), 2.02-2.07 (1H, m), 2.44 (3H, s), 2.95 (1H, dd, J = 9.8, 12.9 Hz), 3.15 (1H, dt, J = 2.7, 10.6 Hz), 3.27 (2H, dd, J = 3.5, 6.6 Hz), 3.35-3.42 (2H, m), 3.88-3.93 (2H, m), 6.56 (1H, s);
MS (FAB) m / z: 319 [M + H ⁺ ], 316, 234, 230, 194, 55, 41, 29.

（４５ｅ）４−{（３Ｓ）−３−[（シクロプロピルメトキシ）メチル]ピペリジン−１−イル}−６−メチル−２−チオキソ−１，２−ジヒドロピリジン−３−カルボニトリル
実施例４５（４５ｄ）で製造した２−クロロ−４−｛（３Ｓ）−３−［（シクロプロピルメトキシ）メチル］ピペリジン−１−イル｝−６−メチルニコチノニトリル（４７８ｍｇ，１．５ｍｍｏｌ）、チオ尿素（２２７ｍｇ，３．０ｍｍｏｌ）及び４Ｍ塩化水素−１，４−ジオキサン溶液（１滴）のエタノール（１０ｍＬ）溶液を５時間加熱還流した。
(45e) 4-{(3S) -3-[(Cyclopropylmethoxy) methyl] piperidin-1-yl} -6-methyl-2-thioxo-1,2-dihydropyridine-3-carbonitrile Example 45 (45d) ) 2-chloro-4-{(3S) -3-[(cyclopropylmethoxy) methyl] piperidin-1-yl} -6-methylnicotinonitrile (478 mg, 1.5 mmol), thiourea (227 mg) , 3.0 mmol) and 4M hydrogen chloride-1,4-dioxane solution (1 drop) in ethanol (10 mL) were heated to reflux for 5 hours.

反応液を濃縮し、１Ｍ水酸化ナトリム水溶液（５ｍＬ）及び酢酸エチル（５ｍＬ）を加えた。分離した水相に１Ｍ塩化水素水溶液（１０ｍＬ）を加え、生成した結晶をろ過し、標記目的化合物（２６５ｍｇ，収率５６％）を得た。 The reaction mixture was concentrated, and 1M aqueous sodium hydroxide solution (5 mL) and ethyl acetate (5 mL) were added. A 1M hydrogen chloride aqueous solution (10 mL) was added to the separated aqueous phase, and the produced crystals were filtered to obtain the title object compound (265 mg, yield 56%).

白色粉末
Mp 159-162 ℃;
IR (KBr) ν_max3117, 2939, 2205, 1625, 1555, 1509, 1375, 1305, 1213, 1186, 1118, 1087, 933, 827, 633, 474 cm^-1;
¹H NMR(DMSO-d₆, 400 MHz) δ 0.16 (2H, q, J = 4.7 Hz), 0.42-0.47 (2H, m), 0.93-1.03 (1H, m), 1.28-1.36 (1H, m), 1.52-1.56 (1H, m), 1.72-1.85 (3H, m), 2.22 (3H, s), 3.04 (1H, dd, J = 9.8, 12.4 Hz), 3.17-3.33 (5H, m), 3.93 (2H, t, J = 18.0 Hz), 6.35 (1H, s);
MS (FAB) m/z: 318 [M+H⁺], 332, 200, 180, 120, 63。
White powder
Mp 159-162 ° C;
IR (KBr) ν _max 3117, 2939, 2205, 1625, 1555, 1509, 1375, 1305, 1213, 1186, 1118, 1087, 933, 827, 633, 474 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 400 MHz) δ 0.16 (2H, q, J = 4.7 Hz), 0.42-0.47 (2H, m), 0.93-1.03 (1H, m), 1.28-1.36 (1H, m ), 1.52-1.56 (1H, m), 1.72-1.85 (3H, m), 2.22 (3H, s), 3.04 (1H, dd, J = 9.8, 12.4 Hz), 3.17-3.33 (5H, m), 3.93 (2H, t, J = 18.0 Hz), 6.35 (1H, s);
MS (FAB) m / z: 318 [M + H ⁺ ], 332, 200, 180, 120, 63.

（４５ｆ）３−アミノ−４−{（３Ｓ）−３−[（シクロプロピルメトキシ）メチル]ピペリジン−１−イル}−６−メチルチエノ[２，３−ｂ]ピリジン−２−カルボキサミド
実施例４５（４５ｅ）で製造した４−{（３Ｓ）−３−[（シクロプロピルメトキシ）メチル]ピペリジン−１−イル}−６−メチル−２−チオキソ−１，２−ジヒドロピリジン−３−カルボニトリルを用いて実施例１（１ｂ）と同様に反応を行い、標記目的化合物を得た。
白色粉末
Mp 181-183 ℃;
IR (KBr) ν_max3426, 3319, 3161, 2930, 2853, 1655, 1583, 1490, 1366, 1092, 475 cm^-1;
¹H NMR(DMSO-d₆, 400 MHz) δ 0.14 (2H, q, J = 4.7 Hz), 0.41-0.45 (2H, m), 0.92-1.00 (2H, m), 1.78 (3H, brs), 2.11 (1H, brs), 2.33-2.60 (5H, m), 3.22 (2H, d, J = 7.0 Hz), 3.29-3.34 (4H, m), 6.90 (3H, brs), 7.01 (2H, brs);
HRMS m/z calcd for C₁₉H₂₇O₂N₄S 375.1855, found 375.1867.
MS (FAB) m/z: 375 [M+H]⁺, 374, 358, 272, 258, 216, 190, 55, 41, 39, 29;
Anal. Calcd for C₁₉H₂₆N₄O₂S・0.50H₂O: C, 59.51; H, 7.10; N, 14.61; S, 8.36. Found: C, 59.78; H, 7.00; N, 14.79; S, 8.06。
(45f) 3-Amino-4-{(3S) -3-[(cyclopropylmethoxy) methyl] piperidin-1-yl} -6-methylthieno [2,3-b] pyridine-2-carboxamide Example 45 ( Using the 4-{(3S) -3-[(cyclopropylmethoxy) methyl] piperidin-1-yl} -6-methyl-2-thioxo-1,2-dihydropyridine-3-carbonitrile prepared in 45e). The reaction was conducted in the same manner as in Example 1 (1b) to give the title object compound.
White powder
Mp 181-183 ° C;
IR (KBr) ν _max 3426, 3319, 3161, 2930, 2853, 1655, 1583, 1490, 1366, 1092, 475 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 400 MHz) δ 0.14 (2H, q, J = 4.7 Hz), 0.41-0.45 (2H, m), 0.92-1.00 (2H, m), 1.78 (3H, brs), 2.11 (1H, brs), 2.33-2.60 (5H, m), 3.22 (2H, d, J = 7.0 Hz), 3.29-3.34 (4H, m), 6.90 (3H, brs), 7.01 (2H, brs) ;
HRMS m / z calcd for C ₁₉ H ₂₇ O ₂ N ₄ S 375.1855, found 375.1867.
MS (FAB) m / z: 375 [M + H] ⁺ , 374, 358, 272, 258, 216, 190, 55, 41, 39, 29;
Anal.Calcd for C ₁₉ H ₂₆ N ₄ O ₂ S0.50H ₂ O: C, 59.51; H, 7.10; N, 14.61; S, 8.36.Found: C, 59.78; H, 7.00; N, 14.79; S , 8.06.

［実施例４６］
３−アミノ−４−{（３Ｓ）−３−[（シクロプロピルメトキシ）メチル]ピペリジン−１−イル}チエノ[２，３−ｂ]ピリジン−２−カルボキサミド
（４６ａ）２−クロロ−４−｛（３Ｓ）−３−［（シクロプロピルメトキシ）メチル］ピペリジン−１−イル｝ニコチノニトリル
実施例４５（４５ｂ）で製造した（１−{（３Ｓ）−３−[（シクロプロピルメトキシ）メチル]ピペリジン−１−イル}エチリデン）マロノニトリルとＮ，Ｎ，−ジメチルホルムアミドジメチルアセタールを用いて実施例４５（４５ｃ）及び実施例４５（４５ｄ）と同様に反応を行い、標記目的化合物を得た。
黄色液体
IR (film) ν_max3005, 2934, 2857, 2218, 1581, 1517, 1463, 1361, 1257, 1085, 1002, 960, 826 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 0.21 (2H, q, J = 5.5 Hz), 0.53 (2H, q, J = 7.0 Hz), 1.00-1.08 (1H, m), 1.32-1.40 (1H, m), 1.67-1.76 (1H, m), 1.83-1.90 (2H, m), 2.00-2.05 (1H, m), 3.02 (1H, dd, J = 9.8, 12.9 Hz), 3.18-3.23 (2H, m), 3.27 (1H, dd, J = 6.7, 9.8 Hz), 3.33 (1H, dd, J = 7.8, 17.6 Hz), 3.41 (1H, dd, J = 5.1, 9.4 Hz), 3.93-3.99 (2H, m), 6.72 (1H, d, J = 6.3 Hz), 8.08 (1H, d, J = 6.3 Hz);
MS (FAB) m/z: 306 [M+H⁺], 273, 250, 234, 220, 180, 165, 120, 115, 63, 55。
[Example 46]
3-Amino-4-{(3S) -3-[(cyclopropylmethoxy) methyl] piperidin-1-yl} thieno [2,3-b] pyridine-2-carboxamide (46a) 2-chloro-4- { (3S) -3-[(Cyclopropylmethoxy) methyl] piperidin-1-yl} nicotinonitrile (1-{(3S) -3-[(cyclopropylmethoxy) methyl] prepared in Example 45 (45b) Piperidin-1-yl} ethylidene) malononitrile and N, N, -dimethylformamide were used in the same manner as in Example 45 (45c) and Example 45 (45d) to give the title compound.
Yellow liquid
IR (film) ν _max 3005, 2934, 2857, 2218, 1581, 1517, 1463, 1361, 1257, 1085, 1002, 960, 826 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 0.21 (2H, q, J = 5.5 Hz), 0.53 (2H, q, J = 7.0 Hz), 1.00-1.08 (1H, m), 1.32-1.40 (1H, m), 1.67-1.76 (1H, m), 1.83-1.90 (2H, m), 2.00-2.05 (1H, m), 3.02 (1H, dd, J = 9.8, 12.9 Hz), 3.18-3.23 (2H, m), 3.27 (1H, dd, J = 6.7, 9.8 Hz), 3.33 (1H, dd, J = 7.8, 17.6 Hz), 3.41 (1H, dd, J = 5.1, 9.4 Hz), 3.93-3.99 (2H , m), 6.72 (1H, d, J = 6.3 Hz), 8.08 (1H, d, J = 6.3 Hz);
MS (FAB) m / z: 306 [M + H ⁺ ], 273, 250, 234, 220, 180, 165, 120, 115, 63, 55.

（４６ｂ）４−{（３Ｓ）−３−[（シクロプロピルメトキシ）メチル]ピペリジン−１−イル}−２−チオキソ−１，２−ジヒドロピリジン−３−カルボニトリル
実施例４６（４６ａ）で製造した２−クロロ−４−｛（３Ｓ）−３−［（シクロプロピルメトキシ）メチル］ピペリジン−１−イル｝ニコチノニトリルを用いて実施例４５（４５ｅ）と同様に反応を行い、標記目的化合物を得た。
白色粉末
Mp 159-161 ℃;
IR (KBr) ν_max3114, 2856, 2213, 1623, 1552, 1525, 1314, 1249, 1167, 1107, 1007, 789 cm^-1;
¹H NMR(DMSO-d₆, 500 MHz) δ 0.16 (2H, q, J = 4.4 Hz), 0.43-0.46 (2H, m), 0.96-0.99 (1H, m), 1.30-1.37 (1H, m), 1.52-1.56 (1H, m), 1.74-1.80 (2H, m), 1.85-1.88 (1H, m), 3.10 (1H, dd, J = 9.8, 13.2 Hz), 3.16-3.32 (5H, m), 3.06 (2H, t, J = 12.7 Hz), 6.46 (1H, d, J = 7.8 Hz), 7.46 (1H, d, J = 7.3 Hz), 12.61 (1H, brs);
MS (FAB) m/z: 304 [M+H⁺], 273, 246, 218, 182, 165, 120, 115, 85, 63, 52.
Anal. Calcd for C₁₆H₂₁N₃OS: C, 63.33; H, 6.98; N, 13.85; S, 10.57. Found: C, 63.25; H, 6.93; N, 13.84; S, 10.33。
(46b) 4-{(3S) -3-[(Cyclopropylmethoxy) methyl] piperidin-1-yl} -2-thioxo-1,2-dihydropyridine-3-carbonitrile Prepared in Example 46 (46a) 2-Chloro-4-{(3S) -3-[(cyclopropylmethoxy) methyl] piperidin-1-yl} nicotinonitrile is used to carry out the reaction in the same manner as in Example 45 (45e) to give the title compound. Obtained.
White powder
Mp 159-161 ° C;
IR (KBr) ν _max 3114, 2856, 2213, 1623, 1552, 1525, 1314, 1249, 1167, 1107, 1007, 789 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 500 MHz) δ 0.16 (2H, q, J = 4.4 Hz), 0.43-0.46 (2H, m), 0.96-0.99 (1H, m), 1.30-1.37 (1H, m ), 1.52-1.56 (1H, m), 1.74-1.80 (2H, m), 1.85-1.88 (1H, m), 3.10 (1H, dd, J = 9.8, 13.2 Hz), 3.16-3.32 (5H, m ), 3.06 (2H, t, J = 12.7 Hz), 6.46 (1H, d, J = 7.8 Hz), 7.46 (1H, d, J = 7.3 Hz), 12.61 (1H, brs);
MS (FAB) m / z: 304 [M + H ⁺ ], 273, 246, 218, 182, 165, 120, 115, 85, 63, 52.
Anal. Calcd for C ₁₆ H ₂₁ N ₃ OS: C, 63.33; H, 6.98; N, 13.85; S, 10.57. Found: C, 63.25; H, 6.93; N, 13.84; S, 10.33.

（４６ｃ）３−アミノ−４−｛（３Ｓ）−３−［（シクロプロピルメトキシ）メチル］ピペリジン−１−イル｝チエノ［２，３−ｂ］ピリジン−２−カルボキサミド
実施例４６（４６ｂ）で製造した４−{（３Ｓ）−３−[（シクロプロピルメトキシ）メチル]ピペリジン−１−イル}−２−チオキソ−１，２−ジヒドロピリジン−３−カルボニトリルを用いて実施例１（１ｂ）と同様に反応を行い、標記目的化合物を得た。
淡黄粉末
Mp 177-178 ℃;
IR (KBr) ν_max3420, 3323, 3170, 2929, 2857, 1656, 1579, 1502, 1371, 1247, 1083, 963, 823, 477 cm^-1;
¹H NMR(DMSO-d₆, 400 MHz) δ 0.14 (2H, q, J = 5.1 Hz), 0.41-0.45 (2H, m), 0.93-1.14 (2H, m), 1.78 (3H, brs), 2.12 (1H, brs), 2.22-2.62 (2H, m), 3.21 (2H, d, J = 6.7 Hz), 3.26-3.36 (4H, m), 6.92 (2H, brs), 7.00 (1H, d, J = 5.5 Hz), 7.08 (2H, brs), 8.41 (1H, d, J = 5.5 Hz);
HRMS m/z calcd for C₁₈H₂₅O₂N₄S 361.1698, found 361.1680.
MS (FAB) m/z: 417 [M+H]⁺, 400, 372, 343, 270, 258, 202, 165, 63, 39, 31;
Anal. Calcd for C₁₈H₂₄N₄O₂S: C, 59.97; H, 6.71; N, 15.54; S, 8.90. Found: C, 59.78; H, 6.83; N, 15.57; S, 8.76。
(46c) 3-Amino-4-{(3S) -3-[(cyclopropylmethoxy) methyl] piperidin-1-yl} thieno [2,3-b] pyridine-2-carboxamide In Example 46 (46b) Example 1 (1b) with 4-{(3S) -3-[(cyclopropylmethoxy) methyl] piperidin-1-yl} -2-thioxo-1,2-dihydropyridine-3-carbonitrile prepared The reaction was carried out in the same manner to obtain the title target compound.
Light yellow powder
Mp 177-178 ° C;
IR (KBr) ν _max 3420, 3323, 3170, 2929, 2857, 1656, 1579, 1502, 1371, 1247, 1083, 963, 823, 477 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 400 MHz) δ 0.14 (2H, q, J = 5.1 Hz), 0.41-0.45 (2H, m), 0.93-1.14 (2H, m), 1.78 (3H, brs), 2.12 (1H, brs), 2.22-2.62 (2H, m), 3.21 (2H, d, J = 6.7 Hz), 3.26-3.36 (4H, m), 6.92 (2H, brs), 7.00 (1H, d, J = 5.5 Hz), 7.08 (2H, brs), 8.41 (1H, d, J = 5.5 Hz);
HRMS m / z calcd for C ₁₈ H ₂₅ O ₂ N ₄ S 361.1698, found 361.1680.
MS (FAB) m / z: 417 [M + H] ⁺ , 400, 372, 343, 270, 258, 202, 165, 63, 39, 31;
_{_{. Anal Calcd for C 18 H 24}} N 4 O 2 S:. C, 59.97; H, 6.71; N, 15.54; S, 8.90 Found: C, 59.78; H, 6.83; N, 15.57; S, 8.76.

［実施例４７］
３−アミノ−６−メチル−４−（（３Ｓ）−３−｛［２−（２−メチル−２Ｈ−テトラゾール−５−イル）エトキシ］メチル｝ピペリジン−１−イル）チエノ［２，３−ｂ］ピリジン−２−カルボキサミド塩酸塩
（４７ａ）［（２Ｅ）−３−（ジメチルアミノ）−１−（（３Ｓ）−３−｛［２−（２−メチル−２Ｈ−テトラゾール−５−イル）エトキシ］メチル｝ピペリジン−１−イル）ブト−２−エン−１−イリデン］マロノニトリル
参考例４０（４０ｄ）で製造した（３Ｓ）−３−｛［２−（２−メチル−２Ｈ−テトラゾール−５−イル）エトキシ］メチル｝ピペリジンを用いて実施例４５（４５ｂ）と同様に反応を行い、標記目的化合物を得た。
褐色油状物;
IR (film) ν_max3507, 2931, 2862, 2194, 2173, 1560, 1507, 1441 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.23-1.37 (1H, m), 1.54-1.67 (1H, m), 1.73-1.96 (3H, m), 2.22 (3H, s), 2.84-2.99 (2H, m), 3.02 (6H, s), 3.08-3.18 (3H, m), 3.28-3.42 (2H, m), 3.75-3.98 (4H, m), 4.31 (3H, s);
MS (FAB) m/z: 385 [M+H]⁺, 273, 242。
[Example 47]
3-Amino-6-methyl-4-((3S) -3-{[2- (2-methyl-2H-tetrazol-5-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3- b] Pyridine-2-carboxamide hydrochloride (47a) [(2E) -3- (dimethylamino) -1-((3S) -3-{[2- (2-methyl-2H-tetrazol-5-yl)] [Ethoxy] methyl} piperidin-1-yl) but-2-en-1-ylidene] malononitrile (3S) -3-{[2- (2-Methyl-2H-tetrazole-5) prepared in Reference Example 40 (40d) -Il) ethoxy] methyl} piperidine was used in the same manner as in Example 45 (45b) to give the title object compound.
Brown oil;
IR (film) ν _max 3507, 2931, 2862, 2194, 2173, 1560, 1507, 1441 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.23-1.37 (1H, m), 1.54-1.67 (1H, m), 1.73-1.96 (3H, m), 2.22 (3H, s), 2.84-2.99 (2H , m), 3.02 (6H, s), 3.08-3.18 (3H, m), 3.28-3.42 (2H, m), 3.75-3.98 (4H, m), 4.31 (3H, s);
MS (FAB) m / z: 385 [M + H] ⁺ , 273, 242.

（４７ｂ）２−クロロ−６−メチル−４−（（３Ｓ）−３−｛［２−（２−メチル−２Ｈ−テトラゾール−５−イル）エトキシ］メチル｝ピペリジン−１−イル）ニコチノニトリル
実施例４７（４７ａ）で製造した［（２Ｅ）−３−（ジメチルアミノ）−１−（（３Ｓ）−３−｛［２−（２−メチル−２Ｈ−テトラゾール−５−イル）エトキシ］メチル｝ピペリジン−１−イル）ブト−２−エン−１−イリデン］マロノニトリルを用いて実施例４５（４５ｃ）と同様に反応を行い、標記目的化合物を得た。
淡褐色油状物;
IR (film) ν_max3467, 2932, 2860, 2217, 1589, 1510, 1447, 1117 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.21-1.34 (1H, m), 1.63-1.76 (1H, m), 1.77-1.86 (2H, m), 1.95-2.07 (1H, m), 2.46 (3H, s), 2.83 (1H, dd, J = 12.5, 9.8 Hz), 3.03-3.11 (1H, m), 3.16 (2H, t, J = 6.6 Hz), 3.35 (1H, dd, J = 9.8, 7.8 Hz), 3.44 (1H, dd, J = 9.8, 5.1 Hz), 3.77-3.97 (4H, m), 4.30 (3H, s), 6.54 (1H, s);
MS (FAB) m/z: 376 [M+H]⁺, 246, 200。
(47b) 2-Chloro-6-methyl-4-((3S) -3-{[2- (2-methyl-2H-tetrazol-5-yl) ethoxy] methyl} piperidin-1-yl) nicotinonitrile [(2E) -3- (dimethylamino) -1-((3S) -3-{[2- (2-methyl-2H-tetrazol-5-yl) ethoxy] methyl prepared in Example 47 (47a) } Piperidin-1-yl) but-2-en-1-ylidene] malononitrile was used in the same manner as in Example 45 (45c) to give the title object compound.
Light brown oil;
IR (film) ν _max 3467, 2932, 2860, 2217, 1589, 1510, 1447, 1117 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.21-1.34 (1H, m), 1.63-1.76 (1H, m), 1.77-1.86 (2H, m), 1.95-2.07 (1H, m), 2.46 (3H , s), 2.83 (1H, dd, J = 12.5, 9.8 Hz), 3.03-3.11 (1H, m), 3.16 (2H, t, J = 6.6 Hz), 3.35 (1H, dd, J = 9.8, 7.8 Hz), 3.44 (1H, dd, J = 9.8, 5.1 Hz), 3.77-3.97 (4H, m), 4.30 (3H, s), 6.54 (1H, s);
MS (FAB) m / z: 376 [M + H] ⁺ , 246, 200.

（４７ｃ）６−メチル−４−（（３Ｓ）−３−｛［２−（２−メチル−２Ｈ−テトラゾール−５−イル）エトキシ］メチル｝ピペリジン−１−イル）−２−チオキソ−１，２−ジヒドロピリジン−３−カルボニトリル
実施例４７（４７ｂ）で製造した２−クロロ−６−メチル−４−（（３Ｓ）−３−｛［２−（２−メチル−２Ｈ−テトラゾール−５−イル）エトキシ］メチル｝ピペリジン−１−イル）ニコチノニトリルを用いて実施例４５（４５ｄ）と同様に反応を行い、標記目的化合物を得た。
白色粉末;
Mp 99-101 ℃;
IR (KBr) ν_max3178, 3115, 3033, 2926, 2860, 2206, 1624, 1548, 1510 cm^-1;
¹H NMR(DMSO-d₆, 400 MHz) δ 1.18-1.31 (1H, m), 1.44-1.58 (1H, m), 1.66-1.89 (3H, m), 2.22 (3H, s), 2.92 (1H, dd, J = 12.9, 10.2 Hz), 3.05 (2H, t, J = 6.7 Hz), 3.08-3.17 (1H, m), 3.24-3.35 (2H, m), 3.66-3.80 (2H, m), 3.83-3.96 (2H, m), 4.29 (3H, s), 6.30 (1H, s), 12.54 (1H, br.s);
MS (FAB) m/z: 374 [M+H]⁺, 246, 180;
Anal. Calcd for C₁₇H₂₃N₇OS: C, 54.67; H, 6.21; N, 26.25; S, 8.59. Found: C, 54.49; H, 6.18; N, 26.17; S, 8.45。
(47c) 6-Methyl-4-((3S) -3-{[2- (2-methyl-2H-tetrazol-5-yl) ethoxy] methyl} piperidin-1-yl) -2-thioxo-1, 2-Dihydropyridine-3-carbonitrile 2-Chloro-6-methyl-4-((3S) -3-{[2- (2-methyl-2H-tetrazol-5-yl) prepared in Example 47 (47b) ) Ethoxy] methyl} piperidin-1-yl) nicotinonitrile was used in the same manner as in Example 45 (45d) to give the title object compound.
White powder;
Mp 99-101 ° C;
IR (KBr) ν _max 3178, 3115, 3033, 2926, 2860, 2206, 1624, 1548, 1510 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.18-1.31 (1H, m), 1.44-1.58 (1H, m), 1.66-1.89 (3H, m), 2.22 (3H, s), 2.92 (1H , dd, J = 12.9, 10.2 Hz), 3.05 (2H, t, J = 6.7 Hz), 3.08-3.17 (1H, m), 3.24-3.35 (2H, m), 3.66-3.80 (2H, m), 3.83-3.96 (2H, m), 4.29 (3H, s), 6.30 (1H, s), 12.54 (1H, br.s);
MS (FAB) m / z: 374 [M + H] ⁺ , 246, 180;
_{_{. Anal Calcd for C 17 H 23}} N 7 OS:. C, 54.67; H, 6.21; N, 26.25; S, 8.59 Found: C, 54.49; H, 6.18; N, 26.17; S, 8.45.

（４７ｄ）３−アミノ−６−メチル−４−（（３Ｓ）−３−｛［２−（２−メチル−２Ｈ−テトラゾール−５−イル）エトキシ］メチル｝ピペリジン−１−イル）チエノ［２，３−ｂ］ピリジン−２−カルボキサミド塩酸塩
実施例４７（４７ｃ）で製造した６−メチル−４−（（３Ｓ）−３−｛［２−（２−メチル−２Ｈ−テトラゾール−５−イル）エトキシ］メチル｝ピペリジン−１−イル）−２−チオキソ−１，２−ジヒドロピリジン−３−カルボニトリル（５３６ｍｇ，１．４４ｍｍｏｌ）をＮ，Ｎ−ジメチルホルムアミド（２．８８ｍＬ）に溶解し、８Ｎ水酸化ナトリウム水溶液（５４０μＬ，４．３２ｍｍｏｌ）と２−クロロアセトアミド（１６２ｍｇ，１．７３ｍｍｏｌ）を加え、室温で４時間攪拌した。反応混合物に水（３０ｍＬ）を加え、塩化メチレンで抽出（３０ｍＬ×３）した。有機層を合せ、無水硫酸ナトリウムで乾燥後、溶媒を減圧下に留去した。残渣をシリカゲルカラムクロマトグラフィ−（酢酸エチル／メタノール，２０／１）により精製した後、エタノール（１０ｍＬ）に溶解し、４Ｎ塩化水素−１，４−ジオキサン溶液（１ｍＬ）を加えた後、溶媒を減圧下に留去し、６２４ｍｇ（収率９３％）の標記目的化合物を得た。
(47d) 3-Amino-6-methyl-4-((3S) -3-{[2- (2-methyl-2H-tetrazol-5-yl) ethoxy] methyl} piperidin-1-yl) thieno [2 , 3-b] pyridine-2-carboxamide hydrochloride 6-methyl-4-((3S) -3-{[2- (2-methyl-2H-tetrazol-5-yl) prepared in Example 47 (47c) ) Ethoxy] methyl} piperidin-1-yl) -2-thioxo-1,2-dihydropyridine-3-carbonitrile (536 mg, 1.44 mmol) was dissolved in N, N-dimethylformamide (2.88 mL) and 8N Aqueous sodium hydroxide (540 μL, 4.32 mmol) and 2-chloroacetamide (162 mg, 1.73 mmol) were added, and the mixture was stirred at room temperature for 4 hours. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (30 mL × 3). The organic layers were combined and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol, 20/1), dissolved in ethanol (10 mL), 4N hydrogen chloride-1,4-dioxane solution (1 mL) was added, and the solvent was reduced under reduced pressure. Distilled down, yielding 624 mg (93% yield) of the title compound.

黄色アモルファス;
IR (KBr) ν_max3427, 3380, 3177, 2933, 2837, 1654, 1576, 1372 cm^-1;
¹H NMR(DMSO-d₆, 400 MHz) δ 1.07-1.23 (1H, m), 1.66-1.79 (3H, m), 1.97-2.10 (1H, m), 2.57 (3H, s), 2.64-2.76 (1H, m), 2.82-2.94 (1H, m), 3.04 (2H, t, J = 6.6 Hz), 3.26-3.38 (2H, m), 3.41-3.54 (2H, m), 3.66-3.80 (2H, m), 4.26 (3H, s), 6.96 (1H, s), 7.18 (2H, br.s);
MS (FAB) m/z: 431 [M+H]⁺, 273, 242。
Yellow amorphous;
IR (KBr) ν _max 3427, 3380, 3177, 2933, 2837, 1654, 1576, 1372 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.07-1.23 (1H, m), 1.66-1.79 (3H, m), 1.97-2.10 (1H, m), 2.57 (3H, s), 2.64-2.76 (1H, m), 2.82-2.94 (1H, m), 3.04 (2H, t, J = 6.6 Hz), 3.26-3.38 (2H, m), 3.41-3.54 (2H, m), 3.66-3.80 (2H , m), 4.26 (3H, s), 6.96 (1H, s), 7.18 (2H, br.s);
MS (FAB) m / z: 431 [M + H] ⁺ , 273, 242.

［実施例４８］
３−アミノ−４−（３−｛［２−（２−オキソ−１，３−オキサゾリジン−３−イル）エトキシ］メチル｝ピペリジン−１−イル）チエノ［２，３−ｂ］ピリジン−２−カルボキサミド
（４８ａ）ｔｅｒｔ−ブチル２−（｛１−［３−アミノ−２−（アミノカルボニル）チエノ［２，３−ｂ］ピリジン−４−イル］ピペリジン−３−イル｝メトキシ）エチルカルバマート
参考例４６（４６ｂ）で製造したｔｅｒｔ−ブチル２−（ピペリジン−３−イルメトキシ）エチルカルバマートを用いて、実施例１[（１ａ）及び（１ｂ）]と同様に反応を行い、標記目的化合物を得た。
淡黄色アモルファス
IR (KBr) ν_max3440, 3326, 3186, 2973, 2931, 2859, 1706, 1648, 1581, 1502, 1451, 1367, 1248, 1169, 1122, 1056, 995, 961, 865, 736, 557 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.05-1.22 (1H, m), 1.42 (9H, s), 1.71-1.95 (3H, m), 2.10 (1H, brs), 2.46 (1H, br t, J = 10.2 Hz), 2.59 (1H, br t, J = 10.2 Hz), 3.21-3.55 (8H, m), 4.82 (1H, brs), 5.33 (2H, br s), 6.90 (1H, d, J = 5.5 Hz), 6.99 (2H, brs), 8.46 (1H, d, J = 5.5 Hz);
HRMS m/z: found [M+H]⁺ 450.2160, calcd for C₂₁H₃₂N₅O₄S [M+H]⁺450.2175。
[Example 48]
3-Amino-4- (3-{[2- (2-oxo-1,3-oxazolidine-3-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine-2- Carboxamide (48a) tert-butyl 2-({1- [3-amino-2- (aminocarbonyl) thieno [2,3-b] pyridin-4-yl] piperidin-3-yl} methoxy) ethylcarbamate Reference Reaction was carried out in the same manner as in Example 1 [(1a) and (1b)] using tert-butyl 2- (piperidin-3-ylmethoxy) ethylcarbamate prepared in Example 46 (46b), and the title compound was obtained. Obtained.
Pale yellow amorphous
IR (KBr) ν _max 3440, 3326, 3186, 2973, 2931, 2859, 1706, 1648, 1581, 1502, 1451, 1367, 1248, 1169, 1122, 1056, 995, 961, 865, 736, 557 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.05-1.22 (1H, m), 1.42 (9H, s), 1.71-1.95 (3H, m), 2.10 (1H, brs), 2.46 (1H, br t, J = 10.2 Hz), 2.59 (1H, br t, J = 10.2 Hz), 3.21-3.55 (8H, m), 4.82 (1H, brs), 5.33 (2H, br s), 6.90 (1H, d, J = 5.5 Hz), 6.99 (2H, brs), 8.46 (1H, d, J = 5.5 Hz);
HRMS m / z: found [M + H] ⁺ 450.2160, calcd for C ₂₁ H ₃₂ N ₅ O ₄ S [M + H] ⁺ 450.2175.

（４８ｂ）２−クロロエチル２−（｛１−［３−アミノ−２−（アミノカルボニル）チエノ［２，３−ｂ］ピリジン−４−イル］ピペリジン−３−イル｝メトキシ）エチルカルバマート
実施例４８（４８ａ）で製造したｔｅｒｔ−ブチル２−（｛１−［３−アミノ−２−（アミノカルボニル）チエノ［２，３−ｂ］ピリジン−４−イル］ピペリジン−３−イル｝メトキシ）エチルカルバマート（４２５．１ｍｇ，０．９４５５ｍｍｏｌ）のメタノール（８ｍＬ）溶液に２Ｎ塩化水素―メタノール溶液（１８ｍＬ）を加え、室温下終夜撹拌した。溶媒を留去後、真空乾燥し、塩化メチレン（３５ｍＬ）を加え、氷浴で冷却した。トリエチルアミン（０．４６ｍＬ，３．３０ｍｍｏｌ）、２−クロロエチルギ酸クロリド（０．１２ｍＬ，１．１３ｍｍｏｌ）を加え１時間撹拌後、室温にして更に終夜撹拌した。飽和食塩水（１０ｍＬ）を加え、塩化メチレン（１０ｍＬ）で抽出した後、無水硫酸ナトリウムで乾燥し、減圧下に溶媒を留去し、残渣を分取薄層クロマトグラフィー（塩化メチレン：メタノール＝９６：４）にて精製し、標記目的化合物（３５８．９ｍｇ，収率８３％）を得た。
(48b) 2-Chloroethyl 2-({1- [3-amino-2- (aminocarbonyl) thieno [2,3-b] pyridin-4-yl] piperidin-3-yl} methoxy) ethylcarbamate Examples Tert-butyl 2-({1- [3-amino-2- (aminocarbonyl) thieno [2,3-b] pyridin-4-yl] piperidin-3-yl} methoxy) ethyl prepared in 48 (48a) To a solution of carbamate (425.1 mg, 0.9455 mmol) in methanol (8 mL) was added 2N hydrogen chloride-methanol solution (18 mL), and the mixture was stirred overnight at room temperature. After the solvent was distilled off, the residue was vacuum-dried, methylene chloride (35 mL) was added, and the mixture was cooled in an ice bath. Triethylamine (0.46 mL, 3.30 mmol) and 2-chloroethyl formic acid chloride (0.12 mL, 1.13 mmol) were added, and the mixture was stirred for 1 hour, then allowed to reach room temperature and further stirred overnight. Saturated brine (10 mL) was added, extracted with methylene chloride (10 mL), dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was subjected to preparative thin layer chromatography (methylene chloride: methanol = 96). : 4) to obtain the title compound (358.9 mg, yield 83%).

アモルファス
¹H NMR(CDCl₃, 400 MHz) δ 1.07-1.22 (1H, m), 1.75-1.97 (3H, m), 2.11 (1H, br s), 2.44 (1H, br t, J = 10.8 Hz), 2.61 (1H, br t, J = 10.8 Hz), 3.16-3.58 (8H, m), 3.61-3.73 (2H, m), 4.23-4.40 (2H, m), 5.19 (1H, br s), 5.38 (2H, br s), 6.89 (1H, d, J = 5.4 Hz), 6.99 (2H, br s), 8.47 (1H, d, J = 5.4 Hz)。
amorphous
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.07-1.22 (1H, m), 1.75-1.97 (3H, m), 2.11 (1H, br s), 2.44 (1H, br t, J = 10.8 Hz), 2.61 (1H, br t, J = 10.8 Hz), 3.16-3.58 (8H, m), 3.61-3.73 (2H, m), 4.23-4.40 (2H, m), 5.19 (1H, br s), 5.38 ( 2H, br s), 6.89 (1H, d, J = 5.4 Hz), 6.99 (2H, br s), 8.47 (1H, d, J = 5.4 Hz).

（４８ｂ）３−アミノ−４−（３−｛［２−（２−オキソ−１，３−オキサゾリジン−３−イル）エトキシ］メチル｝ピペリジン−１−イル）チエノ［２，３−ｂ］ピリジン−２−カルボキサミド
２−クロロエチル２−（｛１−［３−アミノ−２−（アミノカルボニル）チエノ［２，３−ｂ］ピリジン−４−イル］ピペリジン−３−イル｝メトキシ）エチルカルバメート（２４．２ｍｇ，０．０５３ｍｍｏｌ）のテトラヒドロフラン（２ｍＬ）溶液に８Ｎ水酸化ナトリウム水溶液（１．５ｍＬ）を加えて、５時間加熱撹拌した。酢酸エチル（２５ｍＬ）、飽和食塩水（１０ｍＬ）を加え、抽出した有機層を無水硫酸ナトリウムで乾燥し、減圧下に溶媒を留去して得られた粗生成物を分取薄層クロマトグラフィー（塩化メチレン：メタノール＝９６：４）にて精製し、標記目的化合物（１９．５ｍｇ，収率８９％）を得た。
(48b) 3-Amino-4- (3-{[2- (2-oxo-1,3-oxazolidine-3-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine 2-carboxamide 2-chloroethyl 2-({1- [3-amino-2- (aminocarbonyl) thieno [2,3-b] pyridin-4-yl] piperidin-3-yl} methoxy) ethyl carbamate (24 0.2 mg, 0.053 mmol) in tetrahydrofuran (2 mL) was added 8N aqueous sodium hydroxide solution (1.5 mL), and the mixture was stirred with heating for 5 hours. Ethyl acetate (25 mL) and saturated brine (10 mL) were added, the extracted organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting crude product was subjected to preparative thin layer chromatography ( Purification with methylene chloride: methanol = 96: 4) gave the title object compound (19.5 mg, 89% yield).

アモルファス
IR (KBr) ν_max 3429, 3332, 3158, 2941, 2861, 1730, 1661, 1579, 1499, 1446, 1375, 1266, 1123, 1051, 998, 963, 762, 594, 475 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.04-1.18 (1H, m), 1.69-1.99 (3H, m), 2.05-2.19 (1H, m), 2.35 (1H, brt, J = 11.3 Hz), 2.67 (1H, brt, J = 11.3 Hz), 3.23 (1H, brt, J = 8.2 Hz), 3.38-3.74 (10H, m), 4.19 (1H, q, J = 8.2 Hz), 4.23-4.34 (1H, m), 5.40 (2H, brs), 6.97 (1H, d, J = 5.4 Hz), 6.95 (2H, brs), 8.44 (1H, d, J = 5.4 Hz);
HRMS m/z: found [M+H]⁺420.1722, calcd for C₁₉H₂₆N₅O₄S [M+H]⁺ 420.1705。
amorphous
IR (KBr) ν _max 3429, 3332, 3158, 2941, 2861, 1730, 1661, 1579, 1499, 1446, 1375, 1266, 1123, 1051, 998, 963, 762, 594, 475 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.04-1.18 (1H, m), 1.69-1.99 (3H, m), 2.05-2.19 (1H, m), 2.35 (1H, brt, J = 11.3 Hz), 2.67 (1H, brt, J = 11.3 Hz), 3.23 (1H, brt, J = 8.2 Hz), 3.38-3.74 (10H, m), 4.19 (1H, q, J = 8.2 Hz), 4.23-4.34 (1H , m), 5.40 (2H, brs), 6.97 (1H, d, J = 5.4 Hz), 6.95 (2H, brs), 8.44 (1H, d, J = 5.4 Hz);
HRMS m / z: found [M + H] ⁺ 420.1722, calcd for C ₁₉ H ₂₆ N ₅ O ₄ S [M + H] ⁺ 420.1705.

［実施例４９］
３−アミノ−４−（３−｛［２−（２−オキソピロリジン−１−イル）エトキシ］メチル｝ピペリジン−１−イル）チエノ［２，３−ｂ］ピリジン−２−カルボキサミド
（４９ａ）３−アミノ−４−［３−（｛２−［（４−クロロブタノイル）アミノ］エトキシ｝メチル）ピペリジン−１−イル］チエノ［２，３−ｂ］ピリジン−２−カルボキサミド
２−クロロエチルギ酸クロリドの代わりに４−クロロブチリルクロリドを用いて実施例４８（４８ａ）と同様に反応を行い、標記目的化合物を得た。
アモルファス
¹H NMR(CDCl₃, 400 MHz) δ 1.05-1.20 (1H, m), 1.69-1.95 (3H, m), 2.00-2.19 (3H, m), 2.25-2.45 (3H, m), 2.61 (1H, br t, J = 10.3 Hz), 3.25-3.63 (10H, m), 5.33 (2H, brs), 5.88 (1H, br s), 6.87 (1H, d, J = 5.4 Hz), 6.97 (2H, brs), 8.45 (1H, d, J = 5.4 Hz)。
[Example 49]
3-Amino-4- (3-{[2- (2-oxopyrrolidin-1-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide (49a) 3 -Amino-4- [3-({2-[(4-chlorobutanoyl) amino] ethoxy} methyl) piperidin-1-yl] thieno [2,3-b] pyridine-2-carboxamide 2-chloroethyl formate chloride 4-Chlorobutyryl chloride was used in the same manner as in Example 48 (48a) to give the title object compound.
amorphous
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.05-1.20 (1H, m), 1.69-1.95 (3H, m), 2.00-2.19 (3H, m), 2.25-2.45 (3H, m), 2.61 (1H , br t, J = 10.3 Hz), 3.25-3.63 (10H, m), 5.33 (2H, brs), 5.88 (1H, br s), 6.87 (1H, d, J = 5.4 Hz), 6.97 (2H, brs), 8.45 (1H, d, J = 5.4 Hz).

（４９ｂ）３−アミノ−４−（３−｛［２−（２−オキソピロリジン−１−イル）エトキシ］メチル｝ピペリジン−１−イル）チエノ［２，３−ｂ］ピリジン−２−カルボキサミド
実施例４９（４９ａ）で製造した３−アミノ−４−［３−（｛２−［（４−クロロブタノイル）アミノ］エトキシ｝メチル）ピペリジン−１−イル］チエノ［２，３−ｂ］ピリジン−２−カルボキサミドを用いて実施例４８（４８ｂ）と同様に反応を行い、標記目的化合物を得た。
アモルファス
IR (KBr) ν_max 3439, 3322, 3184, 2928, 2857, 1674, 1650, 1499, 1445, 1372, 1287, 1248, 1123, 1056, 996, 961, 825, 762, 626, 475 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.03-1.19 (1H, m), 1.66-2.03 (5H, m), 2.09 (1H, brs), 2.25-2.47 (3H, m), 2.62 (1H, br t, J = 10.7 Hz), 3.22-3.61 (10H, m), 5.36 (2H, brs), 6.87 (1H, d, J = 5.4 Hz), 6.97 (2H, brs), 8.45 (1H, d, J = 5.4 Hz);
HRMS m/z: found [M+Na]⁺440.1732, calcd for C₂₀H₂₇N₅NaO₃S [M+Na]⁺ 440.1732。
(49b) 3-Amino-4- (3-{[2- (2-oxopyrrolidin-1-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide 3-Amino-4- [3-({2-[(4-chlorobutanoyl) amino] ethoxy} methyl) piperidin-1-yl] thieno [2,3-b] pyridine prepared in Example 49 (49a) The reaction was conducted in the same manner as in Example 48 (48b) using 2-carboxamide to obtain the title object compound.
amorphous
IR (KBr) ν _max 3439, 3322, 3184, 2928, 2857, 1674, 1650, 1499, 1445, 1372, 1287, 1248, 1123, 1056, 996, 961, 825, 762, 626, 475 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.03-1.19 (1H, m), 1.66-2.03 (5H, m), 2.09 (1H, brs), 2.25-2.47 (3H, m), 2.62 (1H, br t, J = 10.7 Hz), 3.22-3.61 (10H, m), 5.36 (2H, brs), 6.87 (1H, d, J = 5.4 Hz), 6.97 (2H, brs), 8.45 (1H, d, J = 5.4 Hz);
HRMS m / z: found [M + Na] ⁺ 440.1732, calcd for C ₂₀ H ₂₇ N ₅ NaO ₃ S [M + Na] ⁺ 440.1732.

［実施例５０］
３−アミノ−４−（３−｛［２−（２−オキソピぺリジン−１−イル）エトキシ］メチル｝ピペリジン−１−イル）チエノ［２，３−ｂ］ピリジン−２−カルボキサミド
（５０ａ）３−アミノ−４−［３−（｛２−［（４−クロロペンタノイル）アミノ］エトキシ｝メチル）ピペリジン−１−イル］チエノ［２，３−ｂ］ピリジン−２−カルボキサミド
２−クロロエチルギ酸クロリドの代わりに５−クロロバレリルクロリドを用いて実施例４８（４８ａ）と同様に反応を行い、標記目的化合物を得た。
アモルファス
¹H NMR(CDCl₃, 400 MHz) δ 1.02-1.20 (1H, m), 1.62-1.96 (8H, m), 2.07-2.23 (3H, m), 2.39 (1H, br t, J = 10.6 Hz), 2.64 (1H, br t, J = 10.6 Hz), 3.22-3.60 (10H, m), 5.40 (2H, brs), 5.88 (1H, brs), 6.87 (1H, d, J = 5.4 Hz), 6.96 (2H, brs), 8.45 (1H, d, J = 5.4 Hz)。
[Example 50]
3-Amino-4- (3-{[2- (2-oxopiperidin-1-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide (50a) 3-Amino-4- [3-({2-[(4-chloropentanoyl) amino] ethoxy} methyl) piperidin-1-yl] thieno [2,3-b] pyridine-2-carboxamide 2-chloroethyl formic acid The reaction was conducted in the same manner as in Example 48 (48a) using 5-chlorovaleryl chloride in place of chloride to obtain the title object compound.
amorphous
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.02-1.20 (1H, m), 1.62-1.96 (8H, m), 2.07-2.23 (3H, m), 2.39 (1H, br t, J = 10.6 Hz) , 2.64 (1H, br t, J = 10.6 Hz), 3.22-3.60 (10H, m), 5.40 (2H, brs), 5.88 (1H, brs), 6.87 (1H, d, J = 5.4 Hz), 6.96 (2H, brs), 8.45 (1H, d, J = 5.4 Hz).

（５０ｂ）３−アミノ−４−（３−｛［２−（２−オキソピぺリジン−１−イル）エトキシ］メチル｝ピペリジン−１−イル）チエノ［２，３−ｂ］ピリジン−２−カルボキサミド
実施例５０（５０ａ）で製造した３−アミノ−４−［３−（｛２−［（４−クロロペンタノイル）アミノ］エトキシ｝メチル）ピペリジン−１−イル］チエノ［２，３−ｂ］ピリジン−２−カルボキサミドを用いて実施例４８（４８ｂ）と同様に反応を行い、標記目的化合物を得た。
アモルファス
IR (KBr) ν_max 3438, 3323, 3182, 2933, 2857, 1624, 1579, 1499, 1447, 1371, 1290, 1248, 1122, 1055, 997, 959, 826, 736, 625, 474 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.04-1.19 (1H, m), 1.58-1.95 (7H, m), 2.10 (1H, brs), 2.24-2.45 (3H, m), 2.62 (1H, br t, J = 11.4 Hz), 3.19-3.63 (10H, m), 5.43 (2H, brs), 6.87 (1H, d, J = 5.4 Hz), 6.97 (2H, brs), 8.44 (1H, d, J = 5.4 Hz);
HRMS m/z: found [M+Na]⁺454.1889, calcd for C₂₁H₂₉N₅NaO₃S [M+Na]⁺ 454.1888。
(50b) 3-Amino-4- (3-{[2- (2-oxopiperidin-1-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide 3-Amino-4- [3-({2-[(4-chloropentanoyl) amino] ethoxy} methyl) piperidin-1-yl] thieno [2,3-b] prepared in Example 50 (50a) The reaction was carried out in the same manner as in Example 48 (48b) using pyridine-2-carboxamide to obtain the title object compound.
amorphous
IR (KBr) ν _max 3438, 3323, 3182, 2933, 2857, 1624, 1579, 1499, 1447, 1371, 1290, 1248, 1122, 1055, 997, 959, 826, 736, 625, 474 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.04-1.19 (1H, m), 1.58-1.95 (7H, m), 2.10 (1H, brs), 2.24-2.45 (3H, m), 2.62 (1H, br t, J = 11.4 Hz), 3.19-3.63 (10H, m), 5.43 (2H, brs), 6.87 (1H, d, J = 5.4 Hz), 6.97 (2H, brs), 8.44 (1H, d, J = 5.4 Hz);
HRMS m / z: found [M + Na] ⁺ 454.1889, calcd for C ₂₁ H ₂₉ N ₅ NaO ₃ S [M + Na] ⁺ 454.1888.

［実施例５１］
３−アミノ−４−（３−｛［２−（２−オキソ−１，３−オキサジナン−３−イル）エトキシ］メチル｝ピペリジン−１−イル）チエノ［２，３−ｂ］ピリジン−２−カルボキサミド
（５１ａ）２−クロロプロピル２−（｛１−［３−アミノ−２−（アミノカルボニル）チエノ［２，３−ｂ］ピリジン−４−イル］ピペリジン−３−イル｝メトキシ）エチルカルバメート
２−クロロエチルギ酸クロリドの代わりに３−クロロプロピルギ酸クロリドを用いて実施例４８（４８ａ）と同様に反応を行い、標記目的化合物を得た。
アモルファス
¹H NMR(CDCl₃, 400 MHz) δ 1.05-1.21 (1H, m), 1.71-1.96 (3H, m), 1.98-2.17 (3H, m), 2.43 (1H, brt, J = 11.3 Hz), 2.60 (1H, brt, J = 11.3 Hz), 3.18-3.62 (10H, m), 4.14-4.24 (2H, m), 5.03 (1H, brs), 5.37 (2H, brs), 6.87 (1H, d, J = 5.1 Hz), 6.97 (2H, brs), 8.45 (1H, d, J = 5.1 Hz)。
[Example 51]
3-Amino-4- (3-{[2- (2-oxo-1,3-oxazinan-3-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine-2- Carboxamide (51a) 2-chloropropyl 2-({1- [3-amino-2- (aminocarbonyl) thieno [2,3-b] pyridin-4-yl] piperidin-3-yl} methoxy) ethyl carbamate 2 Reaction was carried out in the same manner as in Example 48 (48a) using 3-chloropropyl formic acid chloride instead of -chloroethyl formic acid chloride to obtain the title compound.
amorphous
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.05-1.21 (1H, m), 1.71-1.96 (3H, m), 1.98-2.17 (3H, m), 2.43 (1H, brt, J = 11.3 Hz), 2.60 (1H, brt, J = 11.3 Hz), 3.18-3.62 (10H, m), 4.14-4.24 (2H, m), 5.03 (1H, brs), 5.37 (2H, brs), 6.87 (1H, d, J = 5.1 Hz), 6.97 (2H, brs), 8.45 (1H, d, J = 5.1 Hz).

（５１ｂ）３−アミノ−４−（３−｛［２−（２−オキソ−１，３−オキサジナン−３−イル）エトキシ］メチル｝ピペリジン−１−イル）チエノ［２，３−ｂ］ピリジン−２−カルボキサミド
実施例５１（５１ａ）で製造した２−クロロプロピル２−（｛１−［３−アミノ−２−（アミノカルボニル）チエノ［２，３−ｂ］ピリジン−４−イル］ピペリジン−３−イル｝メトキシ）エチルカルバメートを用いて実施例４８（４８ｂ）と同様に反応を行い、標記目的化合物を得た。
アモルファス
IR (KBr) ν_max 3439, 3325, 3186, 2933, 2856, 1686, 1647, 1579, 1495, 1447, 1370, 1280, 1213, 1149, 1119, 1081, 997, 959, 824, 760, 626, 487 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.03-1.19 (1H, m), 1.73-2.00 (5H, m), 2.11 (1H, brs), 2.36 (1H, brt, J = 11.0 Hz), 2.66 (1H, brt, J = 11.0 Hz), 3.23 (1H, brt, J = 8.6 Hz), 3.33-3.68 (9H, m), 4.10-4.23s (2H, m), 5.37 (2H, brs), 6.88 (1H, d, J = 5.4 Hz), 6.97 (2H, brs), 8.45 (1H, d, J = 5.4 Hz);
HRMS m/z: found [M+H]⁺434.1866, calcd for C₂₀H₂₈N₅O₄S [M+H]⁺ 434.1862。
(51b) 3-Amino-4- (3-{[2- (2-oxo-1,3-oxazinan-3-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine 2-Carboxamide 2-chloropropyl 2-({1- [3-amino-2- (aminocarbonyl) thieno [2,3-b] pyridin-4-yl] piperidine- prepared in Example 51 (51a) The reaction was performed in the same manner as in Example 48 (48b) using 3-yl} methoxy) ethyl carbamate to obtain the title object compound.
amorphous
IR (KBr) ν _max 3439, 3325, 3186, 2933, 2856, 1686, 1647, 1579, 1495, 1447, 1370, 1280, 1213, 1149, 1119, 1081, 997, 959, 824, 760, 626, 487 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.03-1.19 (1H, m), 1.73-2.00 (5H, m), 2.11 (1H, brs), 2.36 (1H, brt, J = 11.0 Hz), 2.66 ( 1H, brt, J = 11.0 Hz), 3.23 (1H, brt, J = 8.6 Hz), 3.33-3.68 (9H, m), 4.10-4.23s (2H, m), 5.37 (2H, brs), 6.88 ( 1H, d, J = 5.4 Hz), 6.97 (2H, brs), 8.45 (1H, d, J = 5.4 Hz);
HRMS m / z: found [M + H] ⁺ 434.1866, calcd for C ₂₀ H ₂₈ N ₅ O ₄ S [M + H] ⁺ 434.1862.

［実施例５２］
３−アミノ−４−（３−｛［（１−メチル−１Ｈ−テトラゾール−５−イル）チオ］メチル｝ピペリジン−１−イル）チエノ［２，３−ｂ］ピリジン−２−カルボキサミド
出発原料（アミン化合物）：参考例４７の化合物
黄色粉末;
Mp 202-204 ℃;
IR (KBr) ν_max3427, 3380, 3177, 2933, 2837, 1654, 1576, 1372 cm^-1;
¹H NMR(DMSO-d₆, 400 MHz) δ 1.09-1.26 (1H, m), 1.72-2.02 (3H, m), 2.15-2.28 (1H, m), 2.36-2.68 (2H, m), 3.16-3.53 (4H, m), 3.91 (3H, s), 6.79 (2H, br.s), 7.00 (1H, d, J = 5.5 Hz), 7.10 (2H, br.s), 8.41 (1H, d, J = 5.5 Hz);
MS (FAB) m/z: 405 [M+H]⁺, 273, 258, 242;
Anal. Calcd for C₁₆H₂₀N₈OS₂・0.1EtOAc:C,47.66;H,5.07;N,27.11;S,15.51.Found:C,47.57; H, 5.00; N, 27.00; S, 15.29。
[Example 52]
3-amino-4- (3-{[(1-methyl-1H-tetrazol-5-yl) thio] methyl} piperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide starting material ( Amine compound): Compound yellow powder of Reference Example 47;
Mp 202-204 ° C;
IR (KBr) ν _max 3427, 3380, 3177, 2933, 2837, 1654, 1576, 1372 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.09-1.26 (1H, m), 1.72-2.02 (3H, m), 2.15-2.28 (1H, m), 2.36-2.68 (2H, m), 3.16 -3.53 (4H, m), 3.91 (3H, s), 6.79 (2H, br.s), 7.00 (1H, d, J = 5.5 Hz), 7.10 (2H, br.s), 8.41 (1H, d , J = 5.5 Hz);
MS (FAB) m / z: 405 [M + H] ⁺ , 273, 258, 242;
Anal. Calcd for C ₁₆ H ₂₀ N ₈ OS ₂ · 0.1 EtOAc: C, 47.66; H, 5.07; N, 27.11; S, 15.51. Found: C, 47.57; H, 5.00; N, 27.00; S, 15.29.

［実施例５３］
３−アミノ−４−｛（３Ｓ）−３−［（ピリジン−２−イルメトキシ）メチル］ピペリジン−１−イル｝チエノ［２，３−ｂ］ピリジン−２−カルボキサミド
（５３ａ）（１−｛（３Ｓ）−３−［（ピリジン−２−イルメトキシ）メチル］ピペリジン−１−イル｝エチリデン）マロノニトリル
実施例４５（４５ａ）で製造した（１−エトキシエチリデン）マロノニトリル（１５８ｍｇ，１．２ｍｍｏｌ）と参考例４８（４８ｂ）で製造した２−｛［（３Ｓ）−ピペリジン−３−イルメトキシ］メチル｝ピリジン（２６３ｍｇ，１．３ｍｍｏｌ）のエタノール（３ｍＬ）溶液を室温にて１５時間攪拌した。減圧下にて溶媒を留去したのち得られた残留物をシリカゲルカラムクロマトグラフィー（１００％酢酸エチル）により精製し、２４６ｍｇ（収率７２％）の標記目的化合物を得た。
[Example 53]
3-amino-4-{(3S) -3-[(pyridin-2-ylmethoxy) methyl] piperidin-1-yl} thieno [2,3-b] pyridine-2-carboxamide (53a) (1-{( 3S) -3-[(Pyridin-2-ylmethoxy) methyl] piperidin-1-yl} ethylidene) malononitrile (1-ethoxyethylidene) malononitrile (158 mg, 1.2 mmol) prepared in Example 45 (45a) and Reference Example A solution of 2-{[(3S) -piperidin-3-ylmethoxy] methyl} pyridine (263 mg, 1.3 mmol) prepared in 48 (48b) in ethanol (3 mL) was stirred at room temperature for 15 hours. The residue obtained after distilling off the solvent under reduced pressure was purified by silica gel column chromatography (100% ethyl acetate) to obtain 246 mg (yield 72%) of the title compound.

油状物;
IR (liquid film) ν_max 2205, 2187, 1562, 764 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 1.42-1.52 (1H, m), 1.63-1.73 (1H, m), 1.86-1.94 (2H, m), 2.02-2.12 (1H, m), 2.29 (3H, s), 3.19 (1H, dd, J = 10.2, 13.7 Hz), 3.31-3.38 (1H, m), 3.43 (1H, dd, J = 7.4, 9.4 Hz), 3.52 (1H, dd, J = 4.7, 9.4 Hz), 4.07-4.23 (2H, m), 4.61 (1H, d, J = 13.0 Hz), 4.62 (1H, d, J = 13.0 Hz), 7.22 (1H, dd, J = 4.7, 7.4 Hz), 7.40 (1H, brd, J = 7.8 Hz), 7.72 (1H, ddd, J = 2.0, 7.4, 7.8 Hz), 8.56 (1H, brd, J = 4.7 Hz);
MS (EI) m/z: 296 [M⁺], 187, 174, 93。
Oily matter;
IR (liquid film) ν _max 2205, 2187, 1562, 764 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.42-1.52 (1H, m), 1.63-1.73 (1H, m), 1.86-1.94 (2H, m), 2.02-2.12 (1H, m), 2.29 (3H, s), 3.19 (1H, dd, J = 10.2, 13.7 Hz), 3.31-3.38 (1H, m), 3.43 (1H, dd, J = 7.4, 9.4 Hz), 3.52 (1H, dd, J = 4.7, 9.4 Hz), 4.07-4.23 (2H, m), 4.61 (1H, d, J = 13.0 Hz), 4.62 (1H, d, J = 13.0 Hz), 7.22 (1H, dd, J = 4.7, 7.4 Hz) , 7.40 (1H, brd, J = 7.8 Hz), 7.72 (1H, ddd, J = 2.0, 7.4, 7.8 Hz), 8.56 (1H, brd, J = 4.7 Hz);
MS (EI) m / z: 296 [M ⁺ ], 187, 174, 93.

（５３ｂ）（（２Ｅ）−３−（ジメチルアミノ）−１−｛（３Ｓ）−３−［（ピリジン−２−イルメトキシ）メチル］ピペリジン−１−イル｝プロパ−２−エニリデン）マロノニトリル
実施例５３（５３ａ）で製造した（１−｛（３Ｓ）−３−［（ピリジン−２−イルメトキシ）メチル］ピペリジン−１−イル｝エチリデン）マロノニトリル（２３０ｍｇ，０．７８ｍｍｏｌ）とＮ，Ｎ−ジメチルホルムアミドジメチルアセタール（０．４６ｇ，０．５１ｍＬ，３．８８ｍｍｏｌ）の混合物を８０℃にて３時間攪拌した。反応混合物を飽和食塩水（５０ｍＬ）と酢酸エチル（５０ｍＬ）で分液した後、有機層を無水硫酸ナトリウムで乾燥した後、減圧下で溶媒を留去し、標記目的化合物の粗生成物を得た。
(53b) ((2E) -3- (Dimethylamino) -1-{(3S) -3-[(pyridin-2-ylmethoxy) methyl] piperidin-1-yl} prop-2-enylidene) malononitrile Example 53 (1-{(3S) -3-[(pyridin-2-ylmethoxy) methyl] piperidin-1-yl} ethylidene) malononitrile (230 mg, 0.78 mmol) and N, N-dimethylformamide dimethyl prepared in (53a) A mixture of acetals (0.46 g, 0.51 mL, 3.88 mmol) was stirred at 80 ° C. for 3 hours. The reaction mixture is partitioned between saturated brine (50 mL) and ethyl acetate (50 mL), and the organic layer is dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure to give a crude product of the title object compound. It was.

油状物;
¹H NMR (CDCl₃, 400MHz) δ 1.35-1.44 (1H, m), 1.58-1.69 (1H, m), 1.78-1.92 (2H, m), 1.99-2.09 (1H, m), 2.75-3.25 (6H, br) 3.08 (1H, dd, J = 10.2, 13.3 Hz), 3.21 (1H, ddd, J = 3.1, 11.0, 13.3 Hz), 3.44 (1H, dd, J = 7.8, 9.4 Hz), 3.49 (1H, dd, J = 5.1, 9.4 Hz), 3.91 (1H, brd, J = 13.3 Hz), 4.01 (1H, brd, J = 13.3 Hz), 4.41 (1H, d, J = 12.5 Hz), 4.61 (1H, d, J = 13.3 Hz), 4.64 (1H, d, J = 13.3 Hz), 7.21 (1H, dd, J = 5.1, 7.4 Hz), 7.39 (1H, d, J = 12.5 Hz), 7.43 (1H, brd, J = 7.8 Hz), 7.71 (1H, ddd, J = 2.0, 7.4, 7.8 Hz), 8.55 (1H, brd, J = 5.1 Hz)。
Oily matter;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.35-1.44 (1H, m), 1.58-1.69 (1H, m), 1.78-1.92 (2H, m), 1.99-2.09 (1H, m), 2.75-3.25 ( 6H, br) 3.08 (1H, dd, J = 10.2, 13.3 Hz), 3.21 (1H, ddd, J = 3.1, 11.0, 13.3 Hz), 3.44 (1H, dd, J = 7.8, 9.4 Hz), 3.49 ( 1H, dd, J = 5.1, 9.4 Hz), 3.91 (1H, brd, J = 13.3 Hz), 4.01 (1H, brd, J = 13.3 Hz), 4.41 (1H, d, J = 12.5 Hz), 4.61 ( 1H, d, J = 13.3 Hz), 4.64 (1H, d, J = 13.3 Hz), 7.21 (1H, dd, J = 5.1, 7.4 Hz), 7.39 (1H, d, J = 12.5 Hz), 7.43 ( 1H, brd, J = 7.8 Hz), 7.71 (1H, ddd, J = 2.0, 7.4, 7.8 Hz), 8.55 (1H, brd, J = 5.1 Hz).

（５３ｃ）２−クロロ−４−｛（３Ｓ）−３−［（ピリジン−２−イルメトキシ）メチル］ピペリジン−１−イル｝ニコチノニトリル
実施例５３（５３ｂ）で製造した（（２Ｅ）−３−（ジメチルアミノ）−１−｛（３Ｓ）−３−［（ピリジン−２−イルメトキシ）メチル］ピペリジン−１−イル｝プロパ−２−エチリデン）マロノニトリルの粗生成物を１，４−ジオキサン（１．５ｍＬ）に溶解し、４Ｎ塩化水素−１，４−ジオキサン溶液（１．５ｍＬ）を加えたのち、さらにメタノール（1ｍＬ）を加えた。反応混合物を室温にて１５時間攪拌したのち、飽和重曹水（５０ｍＬ）と酢酸エチル（５０ｍＬ）で分液した。有機層を無水硫酸ナトリウムで乾燥後、減圧下で溶媒を留去して得られた残留物を、シリカゲルカラムクロマトグラフィー（１００％酢酸エチル）により精製し、２２３ｍｇ（収率８４％）の標記目的化合物を得た。
(53c) 2-Chloro-4-{(3S) -3-[(pyridin-2-ylmethoxy) methyl] piperidin-1-yl} nicotinonitrile Prepared in Example 53 (53b) ((2E) -3 The crude product of-(dimethylamino) -1-{(3S) -3-[(pyridin-2-ylmethoxy) methyl] piperidin-1-yl} prop-2-ethylidene) malononitrile is converted to 1,4-dioxane (1 5 mL), 4N hydrogen chloride-1,4-dioxane solution (1.5 mL) was added, and methanol (1 mL) was further added. The reaction mixture was stirred at room temperature for 15 hours and then partitioned between saturated aqueous sodium hydrogen carbonate (50 mL) and ethyl acetate (50 mL). The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (100% ethyl acetate) to give 223 mg (yield 84%) of the title. A compound was obtained.

油状物;
IR (liquid film) ν_max 2217, 1581, 1122, 762 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 1.33-1.43 (1H, m), 1.68-1.79 (1H, m), 1.83-1.94 (2H, m), 2.09-2.19 (1H, m), 3.03 (1H, dd, J = 9.8, 12.9 Hz), 3.19 (1H, ddd, J = 3.0, 11.0, 12.9 Hz), 3.46 (1H, dd, J = 8.2, 9.4 Hz), 3.54 (1H, dd, J = 4.7, 9.4 Hz), 3.96 (1H, brd, J = 13.3 Hz), 4.04 (1H, brd, J = 13.3 Hz), 4.61 (1H, d, J = 13.0 Hz), 4.65 (1H, d, J = 13.0 Hz), 6.71 (1H, d, J = 6.3 Hz), 7.20 (1H, dd, J = 4.7, 7.4 Hz), 7.44 (1H, brd, J = 7.8 Hz), 7.71 (1H, ddd, J = 1.6, 7.4, 7.8 Hz), 8.08 (1H, d, J = 6.3 Hz), 8.55 (1H, brd, J = 4.7 Hz);
MS (FAB) m/z: 343 [M+H]⁺。
Oily matter;
IR (liquid film) ν _max 2217, 1581, 1122, 762 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.33-1.43 (1H, m), 1.68-1.79 (1H, m), 1.83-1.94 (2H, m), 2.09-2.19 (1H, m), 3.03 (1H, dd, J = 9.8, 12.9 Hz), 3.19 (1H, ddd, J = 3.0, 11.0, 12.9 Hz), 3.46 (1H, dd, J = 8.2, 9.4 Hz), 3.54 (1H, dd, J = 4.7, 9.4 Hz), 3.96 (1H, brd, J = 13.3 Hz), 4.04 (1H, brd, J = 13.3 Hz), 4.61 (1H, d, J = 13.0 Hz), 4.65 (1H, d, J = 13.0 Hz) ), 6.71 (1H, d, J = 6.3 Hz), 7.20 (1H, dd, J = 4.7, 7.4 Hz), 7.44 (1H, brd, J = 7.8 Hz), 7.71 (1H, ddd, J = 1.6, 7.4, 7.8 Hz), 8.08 (1H, d, J = 6.3 Hz), 8.55 (1H, brd, J = 4.7 Hz);
MS (FAB) m / z: 343 [M + H] ^< +>.

（５３ｄ）４−｛（３Ｓ）−３−［（ピリジン−２−イルメトキシ）メチル］ピペリジン−１−イル｝−２−チオキソ−１，２−ジヒドロピリジン−３−カルボニトリル
実施例５３（５３ｃ）で製造した２−クロロ−４−｛（３Ｓ）−３−［（ピリジン−２−イルメトキシ）メチル］ピペリジン−１−イル｝ニコチノニトリル（２１６ｍｇ，０．６３ｍｍｏｌ）とチオ尿素（１４４ｍｇ，１．８９ｍｍｏｌ）のエタノール（３ｍＬ）溶液に、４Ｎ塩化水素−１，４−ジオキサン溶液（０．２ｍＬ）を加えたのち、反応混合物を加熱還流下に３０分間攪拌した。溶媒を減圧下に留去したのち得られた残留物に、飽和重曹水（３０ｍＬ）を加え、混合物を塩化メチレン（２ｘ３０ｍＬ）で抽出した。抽出液を無水硫酸ナトリウムで乾燥後、減圧下で溶媒を留去することで、２０４ｍｇ（収率９５％）の標記目的化合物を得た。
(53d) 4-{(3S) -3-[(Pyridin-2-ylmethoxy) methyl] piperidin-1-yl} -2-thioxo-1,2-dihydropyridine-3-carbonitrile In Example 53 (53c) Prepared 2-chloro-4-{(3S) -3-[(pyridin-2-ylmethoxy) methyl] piperidin-1-yl} nicotinonitrile (216 mg, 0.63 mmol) and thiourea (144 mg, 1.89 mmol) ) In ethanol (3 mL) was added 4N hydrogen chloride-1,4-dioxane solution (0.2 mL), and the reaction mixture was stirred with heating under reflux for 30 minutes. Saturated aqueous sodium hydrogen carbonate (30 mL) was added to the residue obtained after evaporation of the solvent under reduced pressure, and the mixture was extracted with methylene chloride (2 × 30 mL). The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 204 mg (yield 95%) of the title compound.

Mp 178-183 ℃;
IR (KBr) ν_max2202, 1625, 1511, 1256, 767 cm^-1;
¹H NMR (DMSO-d₆, 400MHz) δ 1.32-1.42 (1H, m), 1.51-1.62 (1H, m), 1.74-1.84 (2H, m), 1.93-2.03 (1H, m), 3.13 (1H, dd, J = 9.8, 13.3 Hz), 3.23 (1H, ddd, J = 2.5, 11.0, 13.3 Hz), 3.38-3.47 (2H, m), 3.98 (1H, brd, J = 13.3 Hz), 4.07 (1H, brd, J = 13.3 Hz), 4.53 (1H, d, J = 13.3 Hz), 4.56 (1H, d, J = 13.3 Hz), 6.49 (1H, d, J = 7.4 Hz), 7.29 (1H, dd, J = 4.7, 7.4 Hz), 7.44 (1H, d, J = 7.4 Hz), 7.46 (1H, d, J = 7.8 Hz), 7.79 (1H, ddd, J = 2.0, 7.4, 7.8 Hz), 8.51 (1H, brd, J = 4.7 Hz), 12.63 (1H, br);
MS (FAB) m/z: 341 [M+H]⁺.
Anal. Calcd for C₁₈H₂₀N₄SO・0.1 H₂O: C, 63.17; H, 5.95; N, 16.37; S, 9.37. Found: C, 63.19; H, 5.90; N, 16.39; S, 9.01。
Mp 178-183 ° C;
IR (KBr) ν _max 2202, 1625, 1511, 1256, 767 cm ^-1 ;
¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.32-1.42 (1H, m), 1.51-1.62 (1H, m), 1.74-1.84 (2H, m), 1.93-2.03 (1H, m), 3.13 ( 1H, dd, J = 9.8, 13.3 Hz), 3.23 (1H, ddd, J = 2.5, 11.0, 13.3 Hz), 3.38-3.47 (2H, m), 3.98 (1H, brd, J = 13.3 Hz), 4.07 (1H, brd, J = 13.3 Hz), 4.53 (1H, d, J = 13.3 Hz), 4.56 (1H, d, J = 13.3 Hz), 6.49 (1H, d, J = 7.4 Hz), 7.29 (1H , dd, J = 4.7, 7.4 Hz), 7.44 (1H, d, J = 7.4 Hz), 7.46 (1H, d, J = 7.8 Hz), 7.79 (1H, ddd, J = 2.0, 7.4, 7.8 Hz) , 8.51 (1H, brd, J = 4.7 Hz), 12.63 (1H, br);
MS (FAB) m / z: 341 [M + H] ⁺ .
Anal.Calcd for C ₁₈ H ₂₀ N ₄ SO ・ 0.1 H ₂ O: C, 63.17; H, 5.95; N, 16.37; S, 9.37. Found: C, 63.19; H, 5.90; N, 16.39; S, 9.01 .

（５３ｅ）３−アミノ−４−｛（３Ｓ）−３−［（ピリジン−２−イルメトキシ）メチル］ピペリジン−１−イル｝チエノ［２，３−ｂ］ピリジン−２−カルボキサミド
実施例５３（５３ｄ）で製造した４−｛（３Ｓ）−３−［（ピリジン−２−イルメトキシ）メチル］ピペリジン−１−イル｝−２−チオキソ−１，２−ジヒドロピリジン−３−カルボニトリルを用いて、実施例３９（３９ｂ）と同様に反応を行い、標記目的化合物を得た。
Mp 129-132 ℃;
IR (KBr) ν_max3439, 3324, 3177, 1650, 1591, 1579, 1511, 1371, 764 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 1.14-1.25 (1H, m), 1.76-1.99 (3H, m), 2.16-2.26 (1H, m), 2.48-2.64 (2H, m), 3.44-3.59 (2H, m), 4.61 (1H, d, J = 13.3 Hz), 4.64 (1H, d, J = 13.3 Hz), 5.33 (2H, br), 6.90 (1H, d, J = 5.5 Hz), 7.02 (2H, br), 7.17-7.20 (1H, m), 7.43 (1H, brd, J = 7.4 Hz), 7.68-7.72 (1H, m), 8.46 (1H, d, J = 5.5 Hz), 8.54 (1H, brd, J = 4.3 Hz);
MS (FAB) m/z: 398 [M+H]⁺.
Anal. Calcd for C₂₀H₂₃N₅SO₂・0.2H₂O: C, 59.89; H, 5.88; N, 17.46; S, 7.99. Found: C, 59.89; H, 6.02; N, 17.13; S, 7.89。
(53e) 3-Amino-4-{(3S) -3-[(pyridin-2-ylmethoxy) methyl] piperidin-1-yl} thieno [2,3-b] pyridine-2-carboxamide Example 53 (53d Example 4) Using 4-{(3S) -3-[(pyridin-2-ylmethoxy) methyl] piperidin-1-yl} -2-thioxo-1,2-dihydropyridine-3-carbonitrile prepared in the above Reaction was conducted in the same manner as in 39 (39b) to give the title object compound.
Mp 129-132 ° C;
IR (KBr) ν _max 3439, 3324, 3177, 1650, 1591, 1579, 1511, 1371, 764 cm ^-1 ;
¹ H NMR (CDCl ₃ , 400MHz) δ 1.14-1.25 (1H, m), 1.76-1.99 (3H, m), 2.16-2.26 (1H, m), 2.48-2.64 (2H, m), 3.44-3.59 ( 2H, m), 4.61 (1H, d, J = 13.3 Hz), 4.64 (1H, d, J = 13.3 Hz), 5.33 (2H, br), 6.90 (1H, d, J = 5.5 Hz), 7.02 ( 2H, br), 7.17-7.20 (1H, m), 7.43 (1H, brd, J = 7.4 Hz), 7.68-7.72 (1H, m), 8.46 (1H, d, J = 5.5 Hz), 8.54 (1H , brd, J = 4.3 Hz);
MS (FAB) m / z: 398 [M + H] ⁺ .
Anal. Calcd for C ₂₀ H ₂₃ N ₅ SO ₂ 0.2H ₂ O: C, 59.89; H, 5.88; N, 17.46; S, 7.99. Found: C, 59.89; H, 6.02; N, 17.13; S, 7.89.

［実施例５４］
３−アミノ−４−((３Ｓ)−３−{[２−(２Ｈ−テトラゾール−２−イル)エトキシ]メチル}ピペリジン−１−イル)チエノ[２，３−ｂ]ピリジン−２−カルボキサミド
（５４ａ） [１−((３Ｓ)−３−{[２−(２Ｈ−テトラゾール−２−イル)エトキシ]メチル}ピペリジン−１−イル)エチリデン]マロノニトリル
参考例４９（４９ｄ）で製造した（(３Ｓ)−３−{[２−(２Ｈ−テトラゾール−２−イル)エトキシ]メチル}ピペリジン塩酸塩を用いて、実施例４５（４５ｂ）と同様に反応を行い、標記目的化合物を得た。
淡黄色液体;
¹H NMR(CDCl₃, 400 MHz) δ 1.26-1.39 (1H, m), 1.54-1.69 (1H, m), 1.72-1.96 (3H, m), 2.23 (3H, s), 2.95 (1H, dd, J = 10.2, 13.3 Hz), 3.23 (1H, brt, J = 13.3 Hz), 3.29 (1H, dd, J = 7.4, 9.4 Hz), 3.41 (1H, dd, J = 4.3, 9.4 Hz), 3.92-4.05 (3H, m), 4.06-4.17 (1H, m), 4.81-4.86 (2H, m), 8.54 (1H, s)。
[Example 54]
3-amino-4-((3S) -3-{[2- (2H-tetrazol-2-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide ( 54a) [1-((3S) -3-{[2- (2H-tetrazol-2-yl) ethoxy] methyl} piperidin-1-yl) ethylidene] malononitrile Prepared in Reference Example 49 (49d) ((3S ) -3-{[2- (2H-tetrazol-2-yl) ethoxy] methyl} piperidine Hydrochloride was used in the same manner as in Example 45 (45b) to give the title object compound.
A pale yellow liquid;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.26-1.39 (1H, m), 1.54-1.69 (1H, m), 1.72-1.96 (3H, m), 2.23 (3H, s), 2.95 (1H, dd , J = 10.2, 13.3 Hz), 3.23 (1H, brt, J = 13.3 Hz), 3.29 (1H, dd, J = 7.4, 9.4 Hz), 3.41 (1H, dd, J = 4.3, 9.4 Hz), 3.92 -4.05 (3H, m), 4.06-4.17 (1H, m), 4.81-4.86 (2H, m), 8.54 (1H, s).

（５４ｂ） [(２Ｅ)−３−(ジメチルアミノ)−１−((３Ｓ)−３−{[２−(２Ｈ−テトラゾール−２−イル)エトキシ]メチル}ピペリジン−１−イル)プロプ−２−エニリデン]マロノニトリル
実施例５４（５４ａ）で製造した[１−((３Ｓ)−３−{[２−(２Ｈ−テトラゾール−２−イル)エトキシ]メチル}ピペリジン−１−イル)エチリデン]マロノニトリル（１．０８ｇ，３．５８ｍｍｏｌ）をＮ，Ｎ−ジメチルホルムアミドジメチルアセタール（２．４ｍＬ，１８ｍｍｏｌ）に溶解し、１００℃で２時間撹拌した。反応液を濃縮後、残渣を酢酸エチルに溶解し、水、飽和食塩水で順次洗浄した。無水硫酸ナトリウムで乾燥した後，溶媒を減圧下留去し、標記目的化合物（１．２８ｇ、収率１００％）を得た。
(54b) [(2E) -3- (Dimethylamino) -1-((3S) -3-{[2- (2H-tetrazol-2-yl) ethoxy] methyl} piperidin-1-yl) prop-2 -Enylidene] malononitrile [1-((3S) -3-{[2- (2H-tetrazol-2-yl) ethoxy] methyl} piperidin-1-yl) ethylidene] malononitrile prepared in Example 54 (54a) 1.08 g, 3.58 mmol) was dissolved in N, N-dimethylformamide dimethylacetal (2.4 mL, 18 mmol) and stirred at 100 ° C. for 2 hours. After concentration of the reaction solution, the residue was dissolved in ethyl acetate and washed successively with water and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain the title object compound (1.28 g, yield 100%).

橙色液体;
¹H NMR(CDCl₃, 400 MHz) δ 1.16-1.31 (1H, m), 1.50-1.65 (1H, m), 1.70-1.79 (2H, m), 1.80-1.91 (1H, m), 2.80 (1H, dd, J = 10.6, 13.3 Hz), 2.82-3.24 (7H, m), 3.27 (1H, dd, J = 7.8, 9.4 Hz), 3.36 (1H, dd, J = 5.1, 9.4 Hz), 3.83 (1H, brd, J = 13.3 Hz), 3.90 (1H, brd, J = 12.9 Hz), 3.92-4.05 (2H, m), 4.33 (1H, d, J = 12.5 Hz), 4.79-4.85 (2H, m), 7.39 (1H, d, J = 12.5 Hz), 8.52 (1H, s)。
Orange liquid;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.16-1.31 (1H, m), 1.50-1.65 (1H, m), 1.70-1.79 (2H, m), 1.80-1.91 (1H, m), 2.80 (1H , dd, J = 10.6, 13.3 Hz), 2.82-3.24 (7H, m), 3.27 (1H, dd, J = 7.8, 9.4 Hz), 3.36 (1H, dd, J = 5.1, 9.4 Hz), 3.83 ( 1H, brd, J = 13.3 Hz), 3.90 (1H, brd, J = 12.9 Hz), 3.92-4.05 (2H, m), 4.33 (1H, d, J = 12.5 Hz), 4.79-4.85 (2H, m ), 7.39 (1H, d, J = 12.5 Hz), 8.52 (1H, s).

（５４ｃ）（２−クロロ−４−((３Ｓ)−３−{[２−(２Ｈ−テトラゾール−２−イル)エトキシ]メチル}ピペリジン−１−イル)ニコチノニトリル
実施例５４（５４ｂ）で製造した[(２Ｅ)−３−(ジメチルアミノ)−１−((３Ｓ)−３−{[２−(２Ｈ−テトラゾール−２−イル)エトキシ]メチル}ピペリジン−１−イル)プロプ−２−エニリデン]マロノニトリル（１．２８ｇ，３．５８ｍｍｏｌ）の１，４−ジオキサン（４．０ｍＬ）溶液に、４Ｎ塩化水素−１，４−ジオキサン溶液（４．０ｍＬ，１６．０ｍｍｏｌ）を加え、室温で１３時間撹拌した。反応液に飽和炭酸カリウム水溶液（５０ｍＬ）を加え、酢酸エチルで２回抽出し、無水硫酸ナトリウムで乾燥後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル，１：５）を用いて精製し、標記目的化合物（１．１０ｇ、収率８９％）を得た。
(54c) (2-Chloro-4-((3S) -3-{[2- (2H-tetrazol-2-yl) ethoxy] methyl} piperidin-1-yl) nicotinonitrile In Example 54 (54b) Prepared [(2E) -3- (dimethylamino) -1-((3S) -3-{[2- (2H-tetrazol-2-yl) ethoxy] methyl} piperidin-1-yl) prop-2- [Enylidene] malononitrile (1.28 g, 3.58 mmol) in 1,4-dioxane (4.0 mL) was added 4N hydrogen chloride-1,4-dioxane solution (4.0 mL, 16.0 mmol) at room temperature. Saturated aqueous potassium carbonate solution (50 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. (Hexane / Ethyl acetate, 1: 5) to give the title object compound (1.10 g, yield 89%).

淡黄色液体；
¹H NMR(CDCl₃, 400 MHz) δ 1.18-1.31 (1H, m), 1.61-1.86 (3H, m), 1.91-2.03 (1H, m), 2.80 (1H, dd, J = 10.2, 13.3 Hz), 3.05-3.14 (1H, m), 3.32 (1H, dd, J = 7.8, 9.4 Hz), 3.41 (1H, dd, J = 4.7, 9.4 Hz), 3.82 (1H, brd, J = 13.3 Hz), 3.88-4.00 (2H, m), 4.01-4.08 (1H, m), 4.81-4.87 (2H, m), 6.63 (1H, d, J = 5.9 Hz), 8.11 (1H, d, J = 5.9 Hz), 8.52 (1H, s)。
Pale yellow liquid;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.18-1.31 (1H, m), 1.61-1.86 (3H, m), 1.91-2.03 (1H, m), 2.80 (1H, dd, J = 10.2, 13.3 Hz ), 3.05-3.14 (1H, m), 3.32 (1H, dd, J = 7.8, 9.4 Hz), 3.41 (1H, dd, J = 4.7, 9.4 Hz), 3.82 (1H, brd, J = 13.3 Hz) , 3.88-4.00 (2H, m), 4.01-4.08 (1H, m), 4.81-4.87 (2H, m), 6.63 (1H, d, J = 5.9 Hz), 8.11 (1H, d, J = 5.9 Hz ), 8.52 (1H, s).

（５４ｄ）４−((３Ｓ)−３−{[２−(２Ｈ−テトラゾール−２−イル)エトキシ]メチル}ピペリジン−１−イル)−２−チオキソ−１，２−ジヒドロピリジン−３−カルボニトリル
実施例５４（５４ｃ）で製造した（２−クロロ−４−((３Ｓ)−３−{[２−(２Ｈ−テトラゾール−２−イル)エトキシ]メチル}ピペリジン−１−イル)ニコチノニトリルを用いて、実施例４５（４５ｅ）と同様に反応を行い、標記目的化合物を得た。
淡黄色粉末
Mp 108-109 ℃；
¹H NMR(CDCl₃, 400 MHz) δ 1.23-1.37 (1H, m), 1.58-1.73 (1H, m), 1.73-1.88 (2H, m), 1.90-2.01 (1H, m), 2.94 (1H, dd, J = 10.2, 13.3 Hz), 3.22-3.34 (2H, m), 3.40 (1H, dd, J = 4.7, 9.4 Hz), 3.90-3.99 (2H, m), 4.00-4.07 (1H, m), 4.10 (1H, brd, J = 13.3 Hz), 4.80-4.88 (2H, m), 6.22 (1H, d, J = 7.4 Hz), 7.32 (1H, d, J = 7.4 Hz), 8.54 (1H, s), 11.89 (1H, brs)。
(54d) 4-((3S) -3-{[2- (2H-tetrazol-2-yl) ethoxy] methyl} piperidin-1-yl) -2-thioxo-1,2-dihydropyridine-3-carbonitrile The (2-chloro-4-((3S) -3-{[2- (2H-tetrazol-2-yl) ethoxy] methyl} piperidin-1-yl) nicotinonitrile prepared in Example 54 (54c) was prepared. And the reaction was conducted in the same manner as in Example 45 (45e) to give the title object compound.
Pale yellow powder
Mp 108-109 ° C;
¹ H NMR (CDCl ₃ , 400 MHz) δ 1.23-1.37 (1H, m), 1.58-1.73 (1H, m), 1.73-1.88 (2H, m), 1.90-2.01 (1H, m), 2.94 (1H , dd, J = 10.2, 13.3 Hz), 3.22-3.34 (2H, m), 3.40 (1H, dd, J = 4.7, 9.4 Hz), 3.90-3.99 (2H, m), 4.00-4.07 (1H, m ), 4.10 (1H, brd, J = 13.3 Hz), 4.80-4.88 (2H, m), 6.22 (1H, d, J = 7.4 Hz), 7.32 (1H, d, J = 7.4 Hz), 8.54 (1H , s), 11.89 (1H, brs).

（５４ｅ）３−アミノ−４−((３Ｓ)−３−{[２−(２Ｈ−テトラゾール−２−イル)エトキシ]メチル}ピペリジン−１−イル)チエノ[２，３−ｂ]ピリジン−２−カルボキサミド
実施例５４（５４ｄ）で製造した４−((３Ｓ)−３−{[２−(２Ｈ−テトラゾール−２−イル)エトキシ]メチル}ピペリジン−１−イル)−２−チオキソ−１，２−ジヒドロピリジン−３−カルボニトリルを用いて、実施例３９（３９ｂ）と同様に反応を行い、標記目的化合物を得た。
淡黄色泡状物質；
¹H NMR(CDCl₃, 400 MHz) δ 0.96-1.15 (1H, m), 1.66-1.92 (3H, m), 1.96-2.08 (1H, m), 2.34 (1H, t, J = 10.5 Hz), 2.54 (1H, t, J = 10.5 Hz), 3.21-3.50 (4H, m), 3.94-4.06 (2H, m), 4.82 (2H, t, J = 5.5 Hz), 5.45 (2H, brs), 6.85 (1H, d, J = 5.5 Hz), 6.95 (2H, brs), 8.46 (1H, d, J = 5.5 Hz), 8.50 (1H, s)。

(54e) 3-Amino-4-((3S) -3-{[2- (2H-tetrazol-2-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine-2 Carboxamide 4-((3S) -3-{[2- (2H-tetrazol-2-yl) ethoxy] methyl} piperidin-1-yl) -2-thioxo-1, prepared in Example 54 (54d) The reaction was performed in a similar manner to Example 39 (39b) using 2-dihydropyridine-3-carbonitrile to give the title object compound.
Pale yellow foam;
¹ H NMR (CDCl ₃ , 400 MHz) δ 0.96-1.15 (1H, m), 1.66-1.92 (3H, m), 1.96-2.08 (1H, m), 2.34 (1H, t, J = 10.5 Hz), 2.54 (1H, t, J = 10.5 Hz), 3.21-3.50 (4H, m), 3.94-4.06 (2H, m), 4.82 (2H, t, J = 5.5 Hz), 5.45 (2H, brs), 6.85 (1H, d, J = 5.5 Hz), 6.95 (2H, brs), 8.46 (1H, d, J = 5.5 Hz), 8.50 (1H, s).

実施例４５（４５ａ）で製造した（１−エトキシエチリデン）マロノニトリルと各種アミン化合物を出発原料として用いて、実施例４５、実施例４６、実施例５３或は実施例５４と同様に反応を行い、実施例５５乃至１０２の化合物を得た。なお、実施例５５乃至実施例１０２の化合物の構造式は、後述の例示化合物表に記載されている。
［実施例５５］
３−アミノ−６−メチル−４−（（３Ｓ）−３−｛［（３−メチル−１，２，４−オキサジアゾール−５−イル）メトキシ］メチル｝ピペリジン−１−イル）チエノ［２，３−ｂ］ピリジン−２−カルボキサミド塩酸塩（例示化合物番号１−２３１）
出発原料（アミン化合物）：参考例３９の化合物
黄色粉末
Mp 219-221℃(dec);
IR (KBr) νmax 3316, 3184, 2913, 2857, 2653, 1651, 1595, 1565, 1489 cm-1;
1H NMR(CD3OD-d6, 400 MHz) δ 1.36-1.46(1H, m), 1.81-1.83(1H, m), 1.86-1.93(2H, m), 2.15-2.24(1H, m), 2.36(3H, s), 2.66(3H, s), 3.12(1H, t, J=11.7Hz), 3.24(1H, t, J=11.7Hz), 3.49-3.53(1H, m), 3.56-3.65(1H, m), 3.82-3.85(1H, m), 3.93-3.97(1H, m), 4.73(2H, d, J=2.2Hz), 7.09(1H, s);
MS (FAB) m/z: 417[M+H]+,273,258,242,226;
Anal.Calcd for C19H24N6O3S.HCl:C, 50.38; H, 5.56; N, 18.55; Cl, 7.83; S, 7.08
Found: C, 50.08; H, 5.83; N, 18.26; Cl, 7.73; S,6.78

［実施例５６］
３−アミノ−４−（（３Ｓ）−3−｛［（5−メチル−１，２，４−オキサジアゾール−３−イル）メトキシ］メチル｝ピペリジン−１−イル）チエノ［２，３−ｂ］ピリジン−２−カルボキサミド（例示化合物番号１−９２）
出発原料（アミン化合物）：参考例５０の化合物
淡褐色粉末;
Mp 111-113 ℃;
IR (KBr) ν_max 3437, 3325, 3166, 2931, 2856, 2756, 1652, 1582, 1500 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.08-1.26 (1H, m), 1.70-1.99 (3H, m), 2.09-2.24 (1H, m), 2.40-2.67 (5H, m), 3.32-2.62 (4H, m), 4.58 (2H, s), 5.32 (2H, brs), 6.89 (1H, d, J = 5.5 Hz), 6.99 (2H, brs), 8.46 (1H, d, J = 5.5 Hz);
MS (FAB) m/z: 403 [M+H]⁺, 386, 273, 258;
Anal. Calcd for C₁₈H₂₂N₆O₃S・0.3H₂O: C, 53.01; H, 5.58; N, 20.60; S, 7.86. Found: C, 53.20; H, 5.54; N, 20.41; S, 7.87。

［実施例５７］
３−アミノ−６−メチル−４−（（３Ｓ）−３−｛［（５−メチル−１，２，４−オキサジアゾール−３−イル）メトキシ］メチル｝ピペリジン−１−イル）チエノ［２，３−ｂ］ピリジン−２−カルボキサミド（例示化合物番号１−２３２）
出発原料（アミン化合物）：参考例５０の化合物
微褐色粉末;
Mp 165-167 ℃;
IR (KBr) ν_max 3448, 3327, 3173, 2927, 2855, 1649, 1582 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 1.06-1.26 (1H, m), 1.70-1.98 (3H, m), 2.08-2.26 (1H, m), 2.39-2.68 (8H, m), 3.32-3.62 (4H, m), 4.59 (2H, s), 5.25 (2H, brs), 6.74 (1H, s), 6.94 (2H, brs);
MS (FAB) m/z: 417 [M+H]⁺, 400, 258, 242;
Anal. Calcd for C₁₉H₂₄N₆O₃S・0.2H₂O: C, 54.32; H, 5.85; N, 20.00. Found: C, 54.34; H, 5.79; N, 19.77。

［実施例５８］
３−アミノ−４−((３Ｓ)−３−{[（３−メチル−１，２，４−チアジアゾール−５−イル)メトキシ]メチル}ピペリジン−１−イル)チエノ[２，３−ｂ]ピリジン−２−カルボキサミド（例示化合物番号１−４０５）
出発原料（アミン化合物）：参考例５１の化合物
淡黄色非定型固体；
¹H NMR(CDCl₃, 500 MHz) δ 1.17-1.30 (1H, m), 1.78-2.02 (3H, m), 2.15-2.28 (1H, m) , 2.48-2.57 (1H, m), 2.59-2.69 (1H, m), 2.66 (3H, s), 3.42-3.68 (4H, m), 4.87 (2H, d, J = 2.9 Hz), 5.80 (2H, brs), 6.91 (1H, d, J = 5.5 Hz), 7.00 (2H, brs), 8.48 (1H, d, J = 5.5 Hz);
MS (FAB) m/z: 419 [M+H⁺], 402, 273, 246, 200, 165;

［実施例５９］
３−アミノ−４−｛（３Ｓ）−3−［（ピリジン−３−イルメトキシ）メチル］ピペリジン−１−イル）チエノ［２，３−ｂ］ピリジン−２−カルボキサミド（例示化合物番号１−６７）
出発原料（アミン化合物）：参考例５２の化合物
Mp 203-205 ℃;
IR (KBr) ν_max 3389, 3306, 3098, 1677, 1592, 1501, 1367, 1168, 712 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 1.13-1.23 (1H, m), 1.74-1.96 (3H, m), 2.11-2.21 (1H, m), 2.45-2.64 (2H, m), 3.37-3.53 (4H, m), 4.50 (1H, d, J = 12.1 Hz), 4.53 (1H, d, J = 12.1 Hz), 5.33 (2H, br), 6.88 (1H, d, J = 5.5 Hz), 7.01 (2H, br), 7.28 (1H, dd, J = 4.7, 7.8 Hz), 7.65 (1H, brd, J = 7.8 Hz), 8.46 (1H, d, J = 5.5 Hz), 8.53 (1H, d, J = 4.7 Hz), 8.55 (1H, d, J = 2.0 Hz);
MS (FAB) m/z: 398 [M+H]⁺;
Anal. Calcd for C₂₀H₂₃N₅SO_2・0.26 H₂O: C, 59.73; H, 5.89; N, 17.41; S, 7.97. Found: C, 60.10; H, 5.58; N, 17.05; S, 7.73.

［実施例６０］
３−アミノ−６−メチル−４−｛（３Ｓ）−3−［（ピリジン−３−イルメトキシ）メチル］ピペリジン−１−イル）チエノ［２，３−ｂ］ピリジン−２−カルボキサミド（例示化合物番号１−２０６）
出発原料（アミン化合物）：参考例５２の化合物
Mp 149-153 ℃;
IR (KBr) ν_max 3394, 3331, 3127, 1666, 1589, 1493, 1367, 1087, 712 cm^-1;
¹H NMR (CDCl₃, 400MHz) δ 1.12-1.24 (1H, m), 1.73-1.96 (3H, m), 2.10-2.20 (1H, m), 2.43-2.63 (2H, m), 2.59 (3H, s), 3.36-3.56 (4H, m), 4.51 (1H, d, J = 12.5 Hz), 4.54 (1H, d, J = 12.5 Hz), 5.30 (2H, br), 6.74 (1H, s), 6.97 (2H, br), 7.28 (1H, dd, J = 4.7, 7.8 Hz), 7.66 (1H, brd, J = 7.8 Hz), 8.53 (1H, d, J = 4.7 Hz), 8.56 (1H, d, J = 1.6 Hz);
MS (FAB) m/z: 412 [M+H]⁺;
Anal. Calcd for C₂₁H₂₅N₅SO₂: C, 61.29; H, 6.12; N, 17.02; S, 7.79. Found: C, 61.33; H, 6.14; N, 16.88; S, 7.86.

［実施例６１］
３−アミノ−４−｛（３Ｓ）−3−［（ピリジン−４−イルメトキシ）メチル］ピペリジン−１−イル）チエノ［２，３−ｂ］ピリジン−２−カルボキサミド（例示化合物番号１−８０）
出発原料（アミン化合物）：参考例５３の化合物
淡黄色粉末
Mp 245-250℃;
IR (KBr) νmax 3437, 2927, 2832, 2778, 2716, 2541, 1919, 1694, 1616 cm-1;
1H NMR(CDCl3-d6, 400 MHz) δ1.20-1.33(1H, m), 1.49-1.63(1H, m), 1.81-2.00(3H, m), 2.12-2.25(1H, m), 2.42-2.55(1H, m), 2.57-2.71(1H, m), 3.36-3.37(4H, m), 4.51(2H, d, J=4.3Hz), 5.29(2H, s), 6.09(1H, d, J=5.2Hz), 7.02(2H, s), 7.23(2H, d, J=3.5Hz), 8.46(1H, d, J=5.2Hz), 8.57(2H, d, J=3.5Hz);
MS (FAB) m/z:398[M+H]+,385,360,244,242;
Anal.Calcd for C20H23N5O2S:C, 60.43; H, 5.83; N 17.62; S 8.07
Found: C, 60.15; H,5.54; N 17.42; S, 7.89.

［実施例６２］
３−アミノ−４−（（３Ｓ）−３−｛［（２−メチル−１，３−チアゾール−５−イル）メトキシ］メチル｝ピペリジン−１−イル）チエノ［２，３−ｂ］ピリジン−２−カルボキサミド（例示化合物番号１−４０４）
出発原料（アミン化合物）：参考例５４の化合物
微褐色粉末;
Mp 189-191 ℃;
IR (KBr) ν_max 3439, 3383, 3332, 3170, 2926, 2854, 1649, 1590 cm^-1;
¹H NMR(CDCl₃, 500 MHz) δ 1.08-1.22 (1H, m), 1.72-1.96 (3H, m), 2.04-2.18 (1H, m), 2.37-2.74 (5H, m), 3.27-3.54 (4H, m), 4.57-4.67 (2H, m), 5.30 (2H, brs), 6.88 (1H, d, J = 5.5 Hz), 7.00 (1H, brs), 7.47 (1H, s), 8.46 (1H, d, J = 5.5 Hz);
MS (FAB) m/z: 418 [M+H]⁺, 273, 258;
Anal. Calcd for C₁₉H₂₃N₅O₂S₂: C, 54.65; H, 5.55; N, 16.77. Found: C, 54.46; H, 5.43; N, 16.69。

［実施例６３］
３−アミノ−４−（（３Ｓ）−３−｛［（１−メチル−１Ｈ−イミダゾール−４−イル）メトキシ］メチル｝ピペリジン−１−イル）チエノ［２，３−ｂ］ピリジン−2−カルボキサミド２塩酸塩（例示化合物番号１−４１３）
出発原料（アミン化合物）：参考例５５の化合物
微褐色アモルファス状物質;
¹H NMR(CDCl₃, 400 MHz) δ 1.05-1.23 (1H, m), 1.68-1.97 (3H, m), 2.08-2.21 (1H, m), 2.39-2.67 (2H, m), 3.29-3.73 (7H, m), 4.43 (2H, dd, J = 17.6, 11.7 Hz), 5.30 (2H, brs), 6.86 (1H, brs), 6.88 (1H, d, J = 5.5 Hz), 6.99 (2H, brs), 7.36 (1H, brs), 8.44 (1H, d, J = 5.5 Hz);
MS (FAB) m/z: 401 [M+H]⁺, 358, 242。

［実施例６４］
３−アミノ−６−メチル−４−（（３Ｓ）−３−｛［（１−メチル−１Ｈ−イミダゾール−４−イル）メトキシ］メチル｝ピペリジン−１−イル）チエノ［２，３−ｂ］ピリジン−２−カルボキサミド（例示化合物番号１−４３８）
出発原料（アミン化合物）：参考例５５の化合物
微褐色アモルファス状物質;
¹H NMR(CDCl₃, 400 MHz) δ 1.05-1.20 (1H, m), 1.69-1.976 (3H, m), 2.07-2.21 (1H, m), 2.37-2.61 (2H, m), 2.59 (3H, s), 3.33-3.70 (7H, m), 4.44 (2H, dd, J = 17.6, 11.7 Hz), 5.23 (2H, brs), 6.74 (1H, s), 6.87 (1H, brs), 6.96 (2H, brs), 7.36 (1H, brs);
MS (FAB) m/z: 415 [M+H]⁺, 242, 226。

［実施例６５］
３−アミノ−６−メチル−４−（（３Ｓ）−３−｛［（１−メチル−１Ｈ−イミダゾール−５−イル）メトキシ］メチル｝ピペリジン−１−イル）チエノ［２，３−ｂ］ピリジン−２−カルボキサミド（例示化合物番号１−４３９）
微褐色アモルファス状物質;
出発原料（アミン化合物）：参考例５６の化合物
¹H NMR(CDCl₃, 400 MHz) δ 1.03-1.17 (1H, m), 1.70-1.93 (3H, m), 2.00-2.14 (1H, m), 2.32-2.42 (1H, m), 2.52-2.63 (1H, m), 2.59 (3H, s), 3.23-3.48 (4H, m), 3.64 (3H, brs), 4.46 (2H, s), 5.27 (2H, brs), 6.72 (1H, s), 6.96 (2H, brs), 7.00 (1H, s), 7.44 (1H, s);
MS (FAB) m/z: 415 [M+H]⁺, 273, 242。

［実施例６６］
３−アミノ−４−((３Ｓ)−３−{[５−メチル−１，３，４−チアジアゾール−２−イル)メトキシ]メチル}ピペリジン−１−イル)チエノ[２，３−ｂ]ピリジン−２−カルボキサミド（例示化合物番号１−４０６）
出発原料（アミン化合物）：参考例５７の化合物
淡黄色粉末；
Mp 167-168 ℃；
¹H NMR(CDCl₃, 400 MHz) δ 1.08-1.23 (1H, m), 1.69-1.96 (3H, m), 2.09-2.23 (1H, m), 2.45 (1H, t, J = 11.3 Hz), 2.61 (1H, t, J = 11.3 Hz), 2.78 (3H, s), 3.37-3.57 (4H, m), 4.85 (2H, brs), 5.31 (2H, brs), 6.89 (1H, d, J = 5.5 Hz), 7.00 (2H, brs), 8.48 (1H, d, J = 5.5 Hz);
MS (FAB) m/z: 419 [M+H⁺], 402, 200.

［実施例６７］
３−アミノ−６−メチル−４−（（３Ｓ）−3−｛［（５−メチルー１，３，４−チアジアゾールー２−イル）メトキシ］メチル｝ピペリジン−１−イル）チエノ［２，３−ｂ］ピリジン−２−カルボキサミド（例示化合物番号１−４１２）
出発原料（アミン化合物）：参考例５７の化合物
黄色粉末;
MP 219-221℃(dec);
IR (KBr) νmax 3433, 3385, 3333, 3192, 2923, 2854, 2666, 2419, 1848 cm-1;
1H NMR(CDCl3-d3, 400 MHz) δ1.14-1.22(2H, m), 1.64-1.98(4H, m), 2.10-2.22(1H, m), 2.42-2.51(1H, m), 2.64(3H, s), 2.81(3H, s), 3.39-3.59(4H, m), 4.89(2H, s), 5.33(2H, s), 6.68(1H, s), 6.99(1H, s);
MS (FAB) m/z:433[M+H]+,416,273,258,242,226;
Anal.Calcd for C19H24N6O2S2:C, 57.27; H, 5.56; N 21.09; S 8.05
Found: C, 57.35; H,5.54; N 20.88; S, 87.76.

［実施例６８］
３−アミノ−４−((３Ｓ)−３−{[（４−メチル−５−オキソ−４,５−ジヒドロ−１，２，４−オキサジアゾール−３−イル）メトキシ]メチル}ピペリジン−１−イル) チエノ[２，３−ｂ]ピリジン−２−カルボキサミド塩酸塩（例示化合物番号１−４４１）
出発原料（アミン化合物）：参考例５８の化合物
黄色非定型固体；
¹H NMR(DMSO-d₆, 400 MHz) δ 1.15-1.31 (1H, m), 1.65-1.86 (3H, m), 2.05-2.18 (1H, m), 2.71-2.86 (1H, m), 2.90-3.04 (1H, m), 3.35-3.49 (2H, m), 3.50-3.68 (2H, m), 4.52 (2H, d, J = 2.0 Hz), 7.11 (1H, d, J = 5.5 Hz), 7.25 (2H, brs), 8.47 (1H, d, J = 5.5 Hz);
MS (FAB) m/z: 419 [M+H⁺], 273, 242.

［実施例６９］
３−アミノ−６−メチル−４−((３Ｓ)−３−{[（４−メチル−５−オキソ−４,５−ジヒドロ−１，２，４−オキサジアゾール−３−イル）メトキシ]メチル}ピペリジン−１−イル) チエノ[２，３−ｂ]ピリジン−２−カルボキサミド（例示化合物番号１−４４２）
出発原料（アミン化合物）：参考例５８の化合物
淡黄色粉末；
Mp 127-129 ℃；
¹H NMR(CDCl₃, 400 MHz) δ 1.06-1.21 (1H, m), 1.71-1.97 (3H, m), 2.07-2.21 (1H, m), 2.39 (1H, t, J = 11.0 Hz), 2.60 (3H, s), 2.62 (1H, t, J = 11.0 Hz), 3.28 (3H, s), 3.34-3.52 (4H, m), 4.44 (2H, s), 5.26 (2H, brs), 6.73 (1H, s), 6.92 (2H, brs);
MS (FAB) m/z: 433 [M+H⁺], 273, 242, 165.

［実施例７０］
３−アミノ−４−((３Ｓ)−３−{[(１−メチル−１Ｈ−イミダゾール−２−イル)メトキシ]メチル}ピペリジン−１−イル)チエノ[２，３−ｂ]ピリジン−２−カルボキサミド（例示化合物番号１−９１）
出発原料（アミン化合物）：参考例５９の化合物
淡黄色粉末；
Mp 137-138 ℃；
¹H NMR(CDCl₃, 400 MHz) δ 1.01-1.18 (1H, m), 1.68-1.94 (3H, m), 2.01-2.17 (1H, m), 2.39 (1H, t, J = 11.3 Hz), 2.59 (1H, t, J = 11.3 Hz), 3.25-3.52 (4H, m), 3.67 (3H, s), 4.57 (2H, s), 5.32 (2H, brs), 6.86 (1H, d, J = 5.5 Hz), 6.87 (1H, brs), 6.94 (1H, brs), 6.98 (2H, brs), 8.46 (1H, d, J = 5.5 Hz);
MS (FAB) m/z: 402 [M+H⁺], 242, 165.

［実施例７１］
３−アミノ−６−メチル−４−((３Ｓ)−３−{[(１−メチル−１Ｈ−イミダゾール−２−イル)メトキシ]メチル}ピペリジン−１−イル)チエノ[２，３−ｂ]ピリジン−２−カルボキサミド（例示化合物番号１−２３０）
出発原料（アミン化合物）：参考例５９の化合物
黄色粉末；
Mp 215-217 ℃；
¹H NMR(CDCl₃, 400 MHz) δ 1.02-1.17 (1H, m), 1.67-1.93 (3H, m), 2.01-2.15 (1H, m), 2.37 (1H, t, J = 11.3 Hz), 2.56 (1H, t, J = 11.3 Hz), 2.59 (3H, s), 3.27-3.47 (4H, m), 3.68 (3H, s), 4.58 (2H, s), 5.25 (2H, brs), 6.72 (1H, s), 6.87 (1H, brs), 6.92-6.97 (3H, m);
MS (FAB) m/z: 415 [M+H⁺], 273, 242, 226, 165.

［実施例７２］
３−アミノ−４−((３Ｓ)−３−{[(４−メチル−４Ｈ−１，２，４−トリアゾール−３−イル)メトキシ]メチル}ピペリジン−１−イル)チエノ[２，３−ｂ]ピリジン−２−カルボキサミド（例示化合物番号１−４１４）
出発原料（アミン化合物）：参考例６０の化合物
淡黄色泡状物質；
¹H NMR(CDCl₃, 400 MHz) δ 1.02-1.16 (1H, m), 1.69-1.95 (3H, m), 2.05-2.17 (1H, m), 2.36 (1H, t, J = 11.3 Hz), 2.63 (1H, t, J = 11.3 Hz), 3.30-3.54 (4H, m), 3.72 (3H, s), 4.71 (2H, s), 5.32 (2H, brs), 6.87 (1H, d, J = 5.5 Hz), 6.97 (2H, brs), 8.10 (1H, s), 8.47 (1H, d, J = 5.5 Hz);
MS (FAB) m/z: 402 [M+H⁺], 385, 273, 242, 165.

［実施例７３］
３−アミノ−４−((３Ｓ)−３−｛［（１−エチル−１Ｈ−イミダゾール−５−イル)メトキシ]メチル}ピペリジン−１−イル) −６−メチルチエノ[２，３−ｂ]ピリジン−２−カルボキサミド（例示化合物番号１−４４０）
出発原料（アミン化合物）：参考例６１の化合物
淡黄色泡状物質；
¹H NMR(CDCl₃, 400 MHz) δ 1.02-1.17 (1H, m), 1.42 (3H, t, J = 7.4 Hz), 1.69-1.94 (3H, m), 1.99-2.13 (1H, m), 2.32-2.42 (1H, m), 2.50-2.62 (1H, m), 2.59 (3H, s), 3.19-3.50 (4H, m), 3.91-4.05 (2H, m), 4.46 (2H, brs), 5.26 (2H, brs), 6.72 (1H, s), 6.95 (2H, brs), 6.99 (1H, s), 7.50 (1H, s);
MS (FAB) m/z: 429 [M+H⁺], 412, 384, 242, 165.

［実施例７４］
３−アミノ−４−((３Ｓ)−３−{[２−(１Ｈ−ピラゾール−１−イル)エトキシ]メチル}ピペリジン−１−イル)チエノ[２，３−ｂ]ピリジン−２−カルボキサミド（例示化合物番号１−２１）
出発原料（アミン化合物）：参考例６２の化合物
淡黄色非定型固体；
¹H NMR(CDCl₃, 400 MHz) δ 0.96-1.14 (1H, m), 1.69-1.94 (3H, m), 1.99-2.11 (1H, m), 2.30 (1H, t, J = 11.3 Hz), 2.57 (1H, t, J = 11.3 Hz), 3.16-3.45 (4H, m), 3.69-3.85 (2H, m), 4.28 (2H, t, J = 5.5 Hz), 5.33 (2H, brs), 6.13 (1H, brs), 6.85 (1H, d, J = 5.5 Hz), 6.99 (2H, brs), 7.44 (1H, brs), 7.46 (1H, brs), 8.47 (1H, d, J = 5.5 Hz);
MS (FAB) m/z: 401 [M+H⁺], 384, 356, 270, 200.

［実施例７５］
３−アミノ−４−((３Ｓ)−３−{[２−(１Ｈ−イミダゾール−１−イル)エトキシ]メチル}ピペリジン−１−イル)チエノ[２，３−ｂ]ピリジン−２−カルボキサミド（例示化合物番号１−１７）
出発原料（アミン化合物）：参考例６３の化合物
黄色粉末；
Mp 105-115 ℃；
¹H NMR(CDCl₃, 500 MHz) δ 1.06-1.18 (1H, m), 1.69-1.95 (3H, m), 2.05-2.15 (1H, m), 2.36 (1H, t, J = 11.2 Hz), 2.61 (1H, t, J = 11.2 Hz), 3.24-3.49 (4H, m), 3.58-3.73 (2H, m), 4.09 (2H, t, J = 5.5 Hz), 5.32 (2H, brs), 6.87 (1H, d, J = 5.5 Hz), 6.92-7.02 (4H, m), 7.50 (1H, s), 8.48 (1H, d, J = 5.5 Hz);
MS (FAB) m/z: 401 [M+H⁺], 384, 356, 200.

［実施例７６］
３−アミノ−４−((３Ｓ)−３−{[２−(１Ｈ−イミダゾール−１−イル)エトキシ]メチル}ピペリジン−１−イル) −６−メチルチエノ[２，３−ｂ]ピリジン−２−カルボキサミド（例示化合物番号１−１５３）
出発原料（アミン化合物）：参考例６３の化合物
淡黄色粉末；
Mp 105-110 ℃；
¹H NMR(CDCl₃, 400 MHz) δ 1.01-1.19 (1H, m), 1.68-1.94 (3H, m), 2.00-2.13 (1H, m), 2.28-2.40 (1H, m), 2.52-2.63 (1H, m), 2.61 (3H, s), 3.22-3.47 (4H, m), 3.67-3.74 (2H, m), 4.09 (2H, t, J = 5.1 Hz), 5.28 (2H, brs), 6.72 (1H, s), 6.95 (2H, brs), 6.96 (1H, s), 6.99 (1H, s), 7.49 (1H, s);
MS (FAB) m/z: 415 [M+H⁺], 398, 370, 242.

［実施例７７］
３−アミノ−６−メチル−４−((３Ｓ)−３−{[２−(２−メチル−１Ｈ−テトラゾール−１−イル)エトキシ]メチル}ピペリジン−１−イル)チエノ[２，３−ｂ]ピリジン−２−カルボキサミド塩酸塩（例示化合物番号１−１５６）
出発原料（アミン化合物）：参考例６４の化合物
黄色非定型固体；
¹H NMR(DMSO-d₆, 400 MHz) δ 1.02-1.21 (1H, m), 1.66-1.81 (3H, m), 2.00-2.12 (1H, m), 2.58 (3H, s), 2.55-2.65 (1H, m), 2.59 (3H, s), 2.81-2.95 (1H, m), 3.23-3.38 (2H, m), 3.43-3.55 (2H, m), 3.63-3.76 (2H, m), 4.27 (2H, t, J = 5.1 Hz), 6.97 (1H, s), 7.22 (2H, brs), 7.47 (1H, d, J = 2.0 Hz), 7.56 (1H, d, J = 2.0 Hz);
MS (FAB) m/z: 429 [M+H⁺], 412, 242, 200, 165.

［実施例７８］
３−アミノ−４−（（３Ｓ）−３−｛［２−（１Ｈ−１，２，３−トリアゾール−１−イル）エトキシ］メチル｝ピペリジン−１−イル）チエノ［２，３−ｂ］ピリジン−２−カルボキサミド（例示化合物番号１−２５）
出発原料（アミン化合物）：参考例６５の化合物
白色粉末;
Mp 184-186 ℃;
IR (KBr) ν_max 3433, 3324, 3169, 2931, 2858, 1651, 1582 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 0.97-1.14 (1H, m), 1.70-1.96 (3H, m), 2.02-2.15 (1H, m), 2.19-2.31 (1H, m), 2.57-2.70 (1H, m), 3.13-3.26 (1H, m), 3.32-3.50 (3H, m), 3.68-3.86 (2H, m), 4.47-4.62 (2H, m), 5.32 (2H, brs), 6.84 (1H, d, J = 5.5 Hz), 6.98 (2H, brs), 7.57 (1H, s), 7.67 (1H, brs), 8.47 (1H, d, J = 5.5 Hz);
MS (FAB) m/z: 402 [M+H]⁺, 385, 357, 273;
Anal. Calcd for C₁₈H₂₃N₇O₂S・0.2H₂O: C, 54.22; H, 6.13; N, 23.29. Found: C, 54.17; H, 6.03; N, 23.15。

［実施例７９］
３−アミノ−６−メチル−４−（（３Ｓ）−３−｛［２−（１Ｈ−１，２，３−トリアゾール−１−イル）エトキシ］メチル｝ピペリジン−１−イル）チエノ［２，３−ｂ］ピリジン−２−カルボキサミド（例示化合物番号１−１６１）
出発原料（アミン化合物）：参考例６５の化合物
淡黄色粉末;
Mp 147-149 ℃;
IR (KBr) ν_max 3436, 3321, 3165, 2942, 2860, 1649, 1580 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 0.96-1.12 (1H, m), 1.68-1.95 (3H, m), 2.00-2.14 (1H, m), 2.18-2.29 (1H, m), 2.52-2.66 (1H, m), 2.61 (3H, s), 3.14-3.24 (1H, m), 3.31-3.48 (3H, m), 3.68-3.86 (2H, m), 4.48-4.62 (2H, m), 5.27 (2H, brs), 6.70 (1H, s), 6.95 (2H, brs), 7.56 (1H, s), 7.68 (1H, brs);
MS (FAB) m/z: 416 [M+H]⁺, 399, 273;
Anal. Calcd for C₁₉H₂₅N₇O₂S: C, 53.85; H, 5.77; N, 24.42. Found: C, 53.95; H, 5.79; N, 24.47。

［実施例８０］
３−アミノ−４−（（３Ｓ）−３−｛［２−（２Ｈ−１，２，３−トリアゾール−２−イル）エトキシ］メチル｝ピペリジン−１−イル）チエノ［２，３−ｂ］ピリジン−２−カルボキサミド（例示化合物番号１−３９９）
出発原料（アミン化合物）：参考例６６の化合物
微黄色粉末;
Mp 108-110 ℃;
IR (KBr) ν_max 3447, 3325, 3169, 2929, 2860, 1650, 1580, 1502 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 0.96-1.14 (1H, m), 1.67-1.91 (3H, m), 1.94-2.11 (1H, m), 2.28-2.41 (1H, m), 2.45-2.60 (1H, m), 3.20-3.49 (4H, m), 3.88-4.00 (2H, m), 4.60 (2H, t, J = 5.5 Hz), 5.23-5.41 (2H, brs), 6.83 (1H, d, J = 5.5 Hz), 6.96 (2H, brs), 7.56 (2H, brs), 8.45 (1H, d, J = 5.5 Hz);
MS (FAB) m/z: 402 [M+H]⁺, 385, 357, 270;
Anal. Calcd for C₁₈H₂₃N₇O₂S・0.2H₂O: C, 53.37; H, 5.82; N, 24.20. Found: C, 53.30; H, 5.60; N, 24.14。

［実施例８１］
３−アミノ−４−((３Ｓ)−３−{[２−(１Ｈ−１，２，４−トリアゾール−１−イル)エトキシ]メチル}ピペリジン−１−イル)チエノ[２，３−ｂ]ピリジン−２−カルボキサミド（例示化合物番号１−２６）
出発原料（アミン化合物）：参考例６７の化合物
淡黄色粉末；
Mp 163-164 ℃；
¹H NMR(CDCl₃, 400 MHz) δ 0.99-1.16 (1H, m), 1.67-1.95 (3H, m), 1.99-2.14 (1H, m), 2.35 (1H, t, J = 11.3 Hz), 2.58 (1H, t, J = 11.3 Hz), 3.21-3.46 (4H, m), 3.69-3.82 (2H, m), 4.34 (2H, t, J = 5.1 Hz), 5.32 (2H, brs), 6.86 (1H, d, J = 5.5 Hz), 6.97 (2H, brs), 7.92 (1H, s), 8.13 (1H, s), 8.48 (1H, d, J = 5.5 Hz);
MS (FAB) m/z: 402 [M+H⁺], 385, 357, 273, 242, 226, 165.

［実施例８２］
３−アミノ−６−メチルー４−（（３Ｓ）−｛［２−（１Ｈ−１，２，４−トリアゾール−１−イル）エトキシ］メチル｝ピペリジン−１−イル）チエノ［２，３−ｂ］ピリジン−２−カルボキサミド塩酸塩（例示化合物番号１−１６２）
出発原料（アミン化合物）：参考例６７の化合物
黄色アモルファス;
¹H NMR(CD₃OD-d₆, 400 MHz) δ 1.25-1.33(1H, m), 1.61-1.72(1H, m), 1.80-1.91(2H, m), 2.60(3H, s), 2.79-2.84(1H, m), 2.98-3.06(2H, m), 3.21-3.40(1H, m), 3.50-3.63(1H, m), 3.82-3.85(1H, m), 3.93-3.97(1H, m), 4.20-4.23(2H, m), 4.35-4.40(2H, m), 7.07(1H, s), 7.75(1H, s), 7.80(1H, s);
MS (FAB) m/z: 416[M+H]⁺,272,241,206;
Anal.Calcd for C19H25N7O2S.HCl:C, 50.49; H, 5.80; N, 21.69; Cl, 7.84; S, 7.09
Found: C, 50.20; H, 6.02; N, 21.54; Cl, 7.67; S,6.88.

［実施例８３］
３−アミノ−４−((３Ｓ)−３−{[２−(４Ｈ−１，２，４−トリアゾール−４−イル)エトキシ]メチル}ピペリジン−１−イル)チエノ[２，３−ｂ]ピリジン−２−カルボキサミド（例示化合物番号１−２７）
出発原料（アミン化合物）：参考例６８の化合物
淡黄色泡状物質；
¹H NMR(CDCl₃, 400 MHz) δ 1.04-1.69 (1H, m), 1.69-1.99 (3H, m), 2.07-2.17 (1H, m), 2.38 (1H, t, J = 11.3 Hz), 2.63 (1H, t, J = 11.3 Hz), 3.26-3.51 (4H, m), 3.59-3.73 (2H, m), 4.18 (2H, t, J = 5.1 Hz), 5.35 (2H, brs), 6.88 (1H, d, J = 5.5 Hz), 6.96 (2H, brs), 8.21 (2H, s), 8.49 (1H, d, J = 5.5 Hz);
MS (FAB) m/z: 402 [M+H⁺], 385, 357.

［実施例８４］
３−アミノ−６−メチル−４−((３Ｓ)−３−{[２−(２Ｈ−テトラゾール−２−イル)エトキシ]メチル}ピペリジン−１−イル)チエノ[２，３−ｂ]ピリジン−２−カルボキサミド（例示化合物番号１−１６５）
出発原料（アミン化合物）：参考例４９の化合物
淡黄色粉末；
Mp 94-96 ℃；
IR (KBr) ν_max 3327, 2930, 1646, 1581, 1369, 1123 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 0.96-1.12 (1H, m), 1.68-1.90 (3H, m), 1.94-2.07 (1H, m), 2.27-2.39 (1H, m), 2.46-2.56 (1H, m), 2.61 (3H, s), 3.24-3.45 (4H, m), 3.93-4.06 (2H, m), 4.82 (2H, t, J = 5.5 Hz), 5.25 (2H, brs), 6.71 (1H, s), 6.92 (2H, brs), 8.49 (1H, s) ;
MS (FAB) m/z: 417 [M+H⁺], 400, 273, 242, 165;
Anal. Calcd for C₁₈H₂₄N₈O₂S・0.17H₂O: C, 51.54; H, 5.85; N, 26.71; S, 7.64. Found: C, 51.50; H, 5.64; N, 26.50; S, 7.73.

［実施例８５］
３−アミノ−４−((３Ｓ)−３−{[２−(１Ｈ−テトラゾール−１−イル)エトキシ]メチル}ピペリジン−１−イル)チエノ[２，３−ｂ]ピリジン−２−カルボキサミド（例示化合物番号１−２８）
出発原料（アミン化合物）：参考例６９の化合物
淡黄色泡状物質；
IR (KBr) ν_max 3327, 2934, 1648, 1581, 1502, 1373, 1106 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 0.99-1.14 (1H, m), 1.69-1.97 (3H, m), 2.02-2.16 (1H, m), 2.26-2.37 (1H, m), 2.57-2.68 (1H, m), 3.24-3.50 (4H, m), 3.71-3.85 (2H, m), 4.61 (2H, t, J = 5.5 Hz), 5.34 (2H, brs), 6.86 (1H, d, J = 5.5 Hz), 6.95 (2H, brs), 8.48 (1H, d, J = 5.5 Hz), 8.71 (1H, s);
MS (FAB) m/z: 403 [M+H⁺], 273, 180, 93;
Anal. Calcd for C₁₇H₂₂N₈O₂S・0.68H₂O: C, 49.23; H, 5.68; N, 27.02; S, 7.73. Found: C, 49.64; H, 5.90; N, 26.59; S, 7.40.

［実施例８６］
３−アミノ−６−メチル−４−((３Ｓ)−３−{[２−(１Ｈ−テトラゾール−１−イル)エトキシ]メチル}ピペリジン−１−イル)チエノ[２，３−ｂ]ピリジン−２−カルボキサミド（例示化合物番号１−１６４）
出発原料（アミン化合物）：参考例６９の化合物
淡黄色粉末；
Mp 177-179 ℃；
IR (KBr) ν_max 3328, 2930, 1648, 1582, 1490, 1371, 1106 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 0.99-1.14 (1H, m), 1.67-1.97 (3H, m), 2.01-2.15 (1H, m), 2.21-2.36 (1H, m), 2.52-2.66 (1H, m), 2.61 (3H, s), 3.25-3.47 (4H, m), 3.72-3.86 (2H, m), 4.58-4.64 (2H, m), 5.29 (2H, brs), 6.71 (1H, s), 6.91 (2H, brs), 8.71 (1H, s) ;
MS (FAB) m/z: 417 [M+H⁺], 400, 372, 353, 242, 200, 176;
Anal. Calcd for C₁₈H₂₄N₈O₂S・0.50H₂O: C, 50.81; H, 5.92; N, 26.33; S, 7.54. Found: C, 50.67; H, 5.78; N, 26.47; S, 7.58.

［実施例８７］
３−アミノ−４−((３Ｓ)−３−{[２−(５−メチル−２Ｈ−テトラゾール−２−イル)エトキシ]メチル}ピペリジン−１−イル)チエノ[２，３−ｂ]ピリジン−２−カルボキサミド（例示化合物番号１−２９０）
出発原料（アミン化合物）：参考例７０の化合物
淡黄色泡状物質；
IR (KBr) ν_max 3440, 3327, 2934, 1648, 1580, 1503, 1448, 1371, 1124 cm^-1;
¹H NMR(CDCl₃, 400 MHz) δ 0.99-1.15 (1H, m), 1.66-1.92 (3H, m), 1.96-2.10 (1H, m), 2.28-2.42 (1H, m), 2.49 (3H, s), 2.45-2.60 (1H, m), 3.22-3.47 (4H, m), 3.86-4.02 (2H, m), 4.72 (2H, t, J = 5.5 Hz), 5.31 (2H, brs), 6.86 (1H, d, J = 5.5 Hz), 6.96 (2H, brs), 8.47 (1H, d, J = 5.5 Hz);
MS (FAB) m/z: 417 [M+H⁺], 400, 273, 258, 242, 180;
Anal. Calcd for C₁₈H₂₄N₈O₂S・0.67H₂O: C, 50.45; H, 5.96; N, 26.15; S, 7.48. Found: C, 50.49; H, 5.69; N, 25.86; S, 7.40.

［実施例８８］
３−アミノ−６−メチル−４−((３Ｓ)−３−{[２−(５−メチル−２Ｈ−テトラゾール−２−イル)エトキシ]メチル}ピペリジン−１−イル)チエノ[２，３−ｂ]ピリジン−２−カルボキサミド塩酸塩（例示化合物番号１−３４５）
出発原料（アミン化合物）：参考例７０の化合物
淡黄色非定型固体；
IR (KBr) ν_max 3190, 2624, 1852, 1607, 1370, 1123 cm^-1;
¹H NMR(DMSO-d₆, 400 MHz) δ 1.03-1.17 (1H, m), 1.60-1.77 (3H, m), 1.91-2.06 (1H, m), 2.40 (3H, s), 2.56-2.74 (1H, m), 2.60 (3H, s), 2.79-2.96 (1H, m), 3.24-3.56 (4H, m), 3.81-3.94 (2H, m), 4.77 (2H, t, J = 5.1 Hz), 7.24 (2H, brs);
MS (FAB) m/z: 431 [M+H⁺], 414, 319, 216, 93;
Anal. Calcd for C₁₈H₂₄N₈O₂S・HCl: C, 48.87; H, 5.83; N, 23.99; Cl, 7.59; S, 6.87. Found: C, 48.82; H, 5.78; N, 23.85; Cl, 7.84; S, 7.37.

［実施例８９］
３−アミノ−４−((３Ｓ)−３−{[２−(５−メチル−１Ｈ−テトラゾール−１−イル)エトキシ]メチル}ピペリジン−１−イル)チエノ[２，３−ｂ]ピリジン−２−カルボキサミド（例示化合物番号１−２８９）
出発原料（アミン化合物）：参考例７１の化合物
淡黄色泡状物質；
¹H NMR(CDCl₃, 400 MHz) δ 0.95-1.09 (1H, m), 1.67-1.83 (2H, m), 1.85-1.94 (1H, m), 1.99-2.10 (1H, m), 2.27 (1H, t, J = 11.3 Hz), 2.55 (3H, s), 2.60 (1H, t, J = 11.3 Hz), 3.18-3.46 (4H, m), 3.74-3.90 (2H, m), 4.44 (2H, t, J = 5.1 Hz), 5.33 (2H, brs), 6.86 (1H, d, J = 5.5 Hz), 6.96 (2H, brs), 8.49 (1H, d, J = 5.5 Hz);
MS (FAB) m/z: 417 [M+H⁺], 400, 273, 246, 165, 93.

［実施例９０］
３−アミノ−６−メチル−４−((３Ｓ)−３−{[２−(５−メチル−１Ｈ−テトラゾール−１−イル)エトキシ]メチル}ピペリジン−１−イル)チエノ[２，３−ｂ]ピリジン−２−カルボキサミド（例示化合物番号１−３４４）
出発原料（アミン化合物）：参考例７１の化合物
淡黄色粉末；
Mp 126-131 ℃；
¹H NMR(CDCl₃, 400 MHz) δ 0.92-1.09 (1H, m), 1.67-1.81 (2H, m), 1.83-1.93 (1H, m), 1.97-2.10 (1H, m), 2.24 (1H, t, J = 11.3 Hz), 2.55 (3H, s), 2.48-2.64 (1H, m), 2.62 (3H, s), 3.18-3.43 (4H, m), 3.76-3.91 (2H, m), 4.44 (2H, t, J = 5.1 Hz), 5.27 (2H, brs), 6.70 (1H, s), 6.92 (2H, brs);
MS (FAB) m/z: 431 [M+H⁺], 414, 273, 242, 200;

［実施例９１］
３−アミノ−４−((３Ｓ)−３−{[３−(１Ｈ−イミダゾール−１−イル)プロポキシ]メチル}ピペリジン−１−イル)チエノ[２，３−ｂ]ピリジン−２−カルボキサミド（例示化合物番号１−３７）
出発原料（アミン化合物）：参考例７２の化合物
淡黄色粉末；
Mp 152-153 ℃；
¹H NMR(CDCl₃, 400 MHz) δ 1.07-1.23 (1H, m), 1.69-2.05 (5H, m), 2.06-2.19 (1H, m), 2.38-2.49 (1H, m), 2.58-2.69 (1H, m), 3.23-3.57 (6H, m), 4.04 (2H, t, J = 6.7 Hz), 5.31 (2H, brs), 6.89 (1H, brs), 6.91 (1H, t, J = 5.5 Hz), 7.01 (2H, brs), 7.05 (1H, brs), 7.45 (1H, brs), 8.48 (1H, d, J = 5.5 Hz);
MS (FAB) m/z: 415 [M+H⁺], 242, 165.

［実施例９２］
３−アミノ−４−((３Ｓ)−３−{[３−((１Ｈ−イミダゾール−１−イル)プロポキシ]メチル}ピペリジン−１−イル) −６−メチルチエノ[２，３−ｂ]ピリジン−２−カルボキサミド２塩酸塩（例示化合物番号１−１７５）
出発原料（アミン化合物）：参考例７２の化合物
黄色非定型固体；
¹H NMR(DMSO-d₆, 400 MHz) δ 1.09-1.26 (1H, m), 1.68-1.83 (3H, m), 2.00-2.13 (3H, m), 2.57 (3H, s), 2.62-2.76 (1H, m), 2.78-2.94 (1H, m), 3.20-3.57 (6H, m), 4.23 (2H, t, J = 7.4 Hz), 7.00 (1H, s), 7.19 (2H, brs), 7.67 (1H, brs), 7.76 (1H, brs), 9.15 (1H, brs);
MS (FAB) m/z: 429 [M+H⁺], 412, 273, 242, 165.

［実施例９３］
３−アミノ−６−メチル−４−((３Ｓ)−３−{[３−(１Ｈ−テトラゾール−１−イル)プロポキシ]メチル}ピペリジン−１−イル)チエノ[２，３−ｂ]ピリジン−２−カルボキサミド（例示化合物番号１−１８６）
出発原料（アミン化合物）：参考例７３の化合物
淡黄色粉末；
Mp 122-123 ℃；
¹H NMR(CDCl₃, 400 MHz) δ 1.03-1.18 (1H, m), 1.71-1.97 (3H, m), 2.06-2.16 (1H, m), 2.17-2.24 (2H, m), 2.29-2.39 (1H, m), 2.61 (3H, s), 2.62-2.70 (1H, m), 3.20-3.29 (1H, m), 3.31-3.50 (4H, m), 3.51-3.59 (1H, m), 4.54 (2H, t, J = 7.0 Hz), 5.26 (2H, brs), 6.76 (1H, s), 6.96 (2H, brs), 8.65 (1H, brs);
MS (FAB) m/z: 431 [M+H⁺], 414, 242, 165.

［実施例９４］
３−アミノ−４−((３Ｓ)−３−{[３−(２Ｈ−テトラゾール−２−イル)プロポキシ]メチル}ピペリジン−１−イル)チエノ[２，３−ｂ]ピリジン−２−カルボキサミド（例示化合物番号１−４９）
出発原料（アミン化合物）：参考例７４の化合物
淡黄色粉末；
Mp 88-90 ℃；
¹H NMR(CDCl₃, 400 MHz) δ 1.08-1.24 (1H, m), 1.72-1.96 (3H, m), 2.04-2.17 (1H, m), 2.22-2.31 (2H, m), 2.46 (1H, t, J = 11.3 Hz), 2.61 (1H, t, J = 11.3 Hz), 3.23-3.56 (6H, m), 4.77 (2H, t, J = 6.7 Hz), 5.30 (2H, brs), 6.93 (1H, d, J = 5.5 Hz), 7.01 (2H, brs), 8.47 (1H, d, J = 5.5 Hz), 8.48 (1H, s);
MS (FAB) m/z: 417 [M+H⁺], 273, 242, 165.

［実施例９５］
３−アミノ−６−メチル−４−((３Ｓ)−３−{[３−(２Ｈ−テトラゾール−２−イル)プロポキシ]メチル}ピペリジン−１−イル)チエノ[２，３−ｂ]ピリジン−２−カルボキサミド塩酸塩（例示化合物番号１−１８７）
出発原料（アミン化合物）：参考例７４の化合物
黄色非定型固体；
¹H NMR(DMSO-d₆, 400 MHz) δ 1.10-1.26 (1H, m), 1.69-1.82 (3H, m), 1.99-2.19 (3H, m), 2.58 (3H, s), 2.68-2.81 (1H, m), 2.84-2.98 (1H, m), 3.21-3.45 (4H, m), 3.47-3.60 (2H, m), 4.73 (2H, t, J = 6.7 Hz), 7.02 (1H, s), 7.20 (2H, brs), 8.93 (1H, s) ;
MS (FAB) m/z: 431 [M+H⁺], 414, 273, 242, 165.

［実施例９６］
３−アミノ−４−（（３Ｓ）−３−｛［２−（２−エチル−２Ｈ−テトラゾール−５−イル）エトキシ］メチル｝ピペリジン−１−イル）チエノ［２，３−ｂ］ピリジン−２−カルボキサミド塩酸塩（例示化合物番号１−４２９）
出発原料（アミン化合物）：参考例７５の化合物
黄色粉末;
Mp 200-203 ℃;
IR (KBr) ν_max 3315, 3160, 2938, 2864, 2597, 1653, 1608 cm^-1;
¹H NMR(DMSO-d₆, 400 MHz) δ 1.06-1.22 (1H, m), 1.43 (3H, t, J = 7.4 Hz), 1.65-1.80 (3H, m), 1.99-2.12 (1H, m), 2.59-2.74 (1H, m), 2.79-2.93 (1H, m), 3.05 (2H, t, J = 6.7 Hz), 3.27-3.39 (2H, m), 3.40-3.51 (2H, m), 3.68-3.82 (2H, m), 4.59 (2H, t, J = 7.4 Hz), 7.05 (1H, d, J = 5.9 Hz), 7.21 (2H, brs), 8.45 (1H, d, J = 5.9 Hz);
MS (FAB) m/z: 431 [M+H]⁺, 414, 329, 273;
Anal. Calcd for C₁₉H₂₆N₈O₂S・HCl: C, 48.87; H, 5.83; N, 23.99; Cl, 7.59. Found: C, 48.79; H, 5.61; N, 23.82; Cl, 7.57。

［実施例９７］
３−アミノ−４−（（３Ｓ）−３−｛［２−（１−エチル−１Ｈ−テトラゾール−５−イル）エトキシ］メチル｝ピペリジン−１−イル）チエノ［２，３−ｂ］ピリジン−２−カルボキサミド（例示化合物番号１−４１９）
出発原料（アミン化合物）：参考例７６の化合物
微褐色アモルファス状物質;
¹H NMR(CDCl₃, 400 MHz) δ 0.96-1.11 (1H, m), 1.49 (3H, t, J = 7.4 Hz), 1.68-1.94 (3H, m), 1.98-2.12 (1H, m), 2.23-2.35 (1H, m), 2.55-2.67 (1H, m), 3.11 (2H, t, J = 5.9 Hz), 3.21-3.29 (1H, m), 3.31-3.46 (3H, m), 3.75-3.89 (2H, m), 4.23-4.43 (2H, m), 5.30 (2H, brs), 6.85 (1H, d, J = 5.5 Hz), 6.97 (2H, brs), 8.47 (1H, d, J = 5.5 Hz);
MS (FAB) m/z: 431 [M+H]⁺, 414, 389。

［実施例９８］
３−アミノ−４−（（３Ｓ）−３−｛［２−（１−エチル−１Ｈ−テトラゾール−５−イル）エトキシ］メチル｝ピペリジン−１−イル）−６−メチルチエノ［２，３−ｂ］ピリジン−２−カルボキサミド（例示化合物番号１−４２４）
出発原料（アミン化合物）：参考例７６の化合物
微褐色アモルファス状物質;
¹H NMR(CDCl₃, 400 MHz) δ 0.96-1.09 (1H, m), 1.49 (3H, t, J = 7.4 Hz), 1.71-1.92 (3H, m), 1.98-2.11 (1H, m), 2.22-2.32 (1H, m), 2.52-2.65 (1H, m), 2.61 (3H, s), 3.11 (2H, t, J = 5.9 Hz), 3.21-3.29 (1H, m), 3.32-3.44 (3H, m), 3.76-3.90 (2H, m), 4.25-4.44 (2H, m), 5.31 (2H, brs), 6.71 (1H, s), 6.94 (2H, brs);
MS (FAB) m/z: 445 [M+H]⁺, 273, 242。

［実施例９９］
３−アミノ−６−メチル−４−（（３Ｓ）−３−｛［２−（１−プロピル−１Ｈ−テトラゾール−５−イル）エトキシ］メチル｝ピペリジン−１−イル）チエノ［２，３−ｂ］ピリジン−２−カルボキサミド二塩酸塩（例示化合物番号１−４２５）
出発原料（アミン化合物）：参考例７７の化合物
黄色粉末;
Mp 209-211 ℃;
IR (KBr) ν_max 3320, 3181, 2931, 2863, 2674, 1652, 1599 cm^-1;
¹H NMR(DMSO-d₆, 400 MHz) δ 0.82 (3H, t, J = 7.4 Hz), 1.02-1.21 (1H, m), 1.64-1.84 (5H, m), 1.97-2.10 (1H, m), 2.53-2.70 (1H, m), 2.57 (3H, s), 2.76-2.93 (1H, m), 3.14 (2H, t, J = 6.3 Hz), 3.23-3.53 (4H, m), 3.68-3.83 (2H, m), 4.23-4.32 (2H, m), 6.95 (1H, s), 7.19 (2H, brs);
MS (FAB) m/z: 459 [M+H]⁺, 329, 273;
Anal. Calcd for C₂₁H₃₀N₈O₂S・HCl・0.7H₂O: C, 49.69; H, 6.43; N, 22.07; Cl, 6.98. Found: C, 49.63; H, 6.38; N, 21.78; Cl, 7.30。

［実施例１００］
３−アミノ−４−((３Ｓ)−３−{[２−(１−イソプロピル−１Ｈ−テトラゾール−５−イル)エトキシ]メチル}ピペリジン−１−イル) −６−メチルチエノ[２，３−ｂ]ピリジン−２−カルボキサミド（例示化合物番号１−４２６）
出発原料（アミン化合物）：参考例７８の化合物
淡黄色粉末；
Mp 140-145 ℃；
¹H NMR(CDCl₃, 400 MHz) δ 0.97-1.13 (1H, m), 1.54 (3H, d, J = 6.7 Hz), 1.58 (3H, d, J = 6.7 Hz), 1.68-1.92 (3H, m), 1.99-2.10 (1H, m), 2.26-2.37 (1H, m), 2.50-2.63 (1H, m), 2.61 (3H, s), 3.11 (2H, t, J = 6.3 Hz), 3.24-3.45 (4H, m), 3.78-3.90 (2H, m), 4.59-4.71 (1H, m), 5.29 (2H, brs), 6.71 (1H, s), 6.94 (2H, brs);
MS (FAB) m/z: 459 [M+H⁺], 442, 273, 242, 165.

［実施例１０１］
３−アミノ−４−((３Ｓ)−３−{[２−(１−シクロプロピル−１Ｈ−テトラゾール−５−イル)エトキシ]メチル}ピペリジン−１−イル) −６−メチルチエノ[２，３−ｂ]ピリジン−２−カルボキサミド（例示化合物番号１−４２７）
出発原料（アミン化合物）：参考例７９の化合物
淡黄色泡状物質；
¹H NMR(CDCl₃, 400 MHz) δ 0.96-1.11 (1H, m), 1.12-1.32 (4H, m), 1.66-1.92 (3H, m), 1.98-2.10 (1H, m), 2.23-2.34 (1H, m), 2.50-2.64 (1H, m), 2.62 (3H, s), 3.21 (2H, t, J = 6.3 Hz), 3.23-3.31 (1H, m), 3.33-3.43 (3H, m), 3.51-3.57 (1H, m), 3.81-3.94 (2H, m), 5.28 (2H, brs), 6.71 (1H, s), 6.93 (2H, brs);
MS (FAB) m/z: 457 [M+H⁺], 440, 412, 357.

［実施例１０２］
３−アミノ−４−［（３Ｓ）−３−（｛２−［１−（２−メトキシエチル）−１Ｈ−テトラゾール−５−イル］エトキシ｝メチル）ピペリジン−１−イル］−６−メチルチエノ［２，３−ｂ］ピリジン−２−カルボキサミド（例示化合物番号１−４２８）
出発原料（アミン化合物）：参考例８０の化合物
微褐色アモルファス状物質;
¹H NMR(CDCl₃, 400 MHz) δ 0.95-1.11 (1H, m), 1.68-1.94 (3H, m), 1.98-2.12 (1H, m), 2.21-2.33 (1H, m), 2.53-2.66 (1H, m), 2.61 (3H, s), 3.18 (2H, t, J = 6.3 Hz), 3.19-3.26 (1H, m), 3.24 (3H, s), 3.30-3.59 (4H, m), 3.67-3.86 (4H, m), 4.39-4.59 (2H, m), 5.31 (2H, brs), 6.73 (1H, s), 6.94 (2H, brs);
MS (FAB) m/z: 475 [M+H]⁺, 458, 273, 242。 Using (1-ethoxyethylidene) malononitrile prepared in Example 45 (45a) and various amine compounds as starting materials, the reaction was carried out in the same manner as in Example 45, Example 46, Example 53 or Example 54. The compounds of Examples 55 to 102 were obtained. The structural formulas of the compounds of Example 55 to Example 102 are described in the exemplified compound table described later.
[Example 55]
3-Amino-6-methyl-4-((3S) -3-{[(3-methyl-1,2,4-oxadiazol-5-yl) methoxy] methyl} piperidin-1-yl) thieno [ 2,3-b] pyridine-2-carboxamide hydrochloride (Exemplary Compound No. 1-231)
Starting material (amine compound): compound of Reference Example 39
Yellow powder
Mp 219-221 ° C (dec);
IR (KBr) νmax 3316, 3184, 2913, 2857, 2653, 1651, 1595, 1565, 1489 cm-1;
1H NMR (CD3OD-d6, 400 MHz) δ 1.36-1.46 (1H, m), 1.81-1.83 (1H, m), 1.86-1.93 (2H, m), 2.15-2.24 (1H, m), 2.36 (3H , s), 2.66 (3H, s), 3.12 (1H, t, J = 11.7Hz), 3.24 (1H, t, J = 11.7Hz), 3.49-3.53 (1H, m), 3.56-3.65 (1H, m), 3.82-3.85 (1H, m), 3.93-3.97 (1H, m), 4.73 (2H, d, J = 2.2Hz), 7.09 (1H, s);
MS (FAB) m / z: 417 [M + H] +, 273,258,242,226;
Anal.Calcd for C19H24N6O3S.HCl: C, 50.38; H, 5.56; N, 18.55; Cl, 7.83; S, 7.08
Found: C, 50.08; H, 5.83; N, 18.26; Cl, 7.73; S, 6.78

[Example 56]
3-Amino-4-((3S) -3-{[(5-methyl-1,2,4-oxadiazol-3-yl) methoxy] methyl} piperidin-1-yl) thieno [2,3- b] Pyridine-2-carboxamide (Exemplified Compound No. 1-92)
Starting material (amine compound): compound of Reference Example 50
Light brown powder;
Mp 111-113 ° C;
IR (KBr) ν_max 3437, 3325, 3166, 2931, 2856, 2756, 1652, 1582, 1500 cm^-1;
¹H NMR (CDCl_Three, 400 MHz) δ 1.08-1.26 (1H, m), 1.70-1.99 (3H, m), 2.09-2.24 (1H, m), 2.40-2.67 (5H, m), 3.32-2.62 (4H, m), 4.58 (2H, s), 5.32 (2H, brs), 6.89 (1H, d, J = 5.5 Hz), 6.99 (2H, brs), 8.46 (1H, d, J = 5.5 Hz);
MS (FAB) m / z: 403 [M + H]⁺, 386, 273, 258;
Anal. Calcd for C₁₈H_{twenty two}N₆O_ThreeS ・ 0.3H₂O: C, 53.01; H, 5.58; N, 20.60; S, 7.86. Found: C, 53.20; H, 5.54; N, 20.41; S, 7.87.

[Example 57]
3-amino-6-methyl-4-((3S) -3-{[(5-methyl-1,2,4-oxadiazol-3-yl) methoxy] methyl} piperidin-1-yl) thieno [ 2,3-b] pyridine-2-carboxamide (Exemplary Compound No. 1-232)
Starting material (amine compound): compound of Reference Example 50
Fine brown powder;
Mp 165-167 ° C;
IR (KBr) ν_max 3448, 3327, 3173, 2927, 2855, 1649, 1582 cm^-1;
¹H NMR (CDCl_Three, 400 MHz) δ 1.06-1.26 (1H, m), 1.70-1.98 (3H, m), 2.08-2.26 (1H, m), 2.39-2.68 (8H, m), 3.32-3.62 (4H, m), 4.59 (2H, s), 5.25 (2H, brs), 6.74 (1H, s), 6.94 (2H, brs);
MS (FAB) m / z: 417 [M + H]⁺, 400, 258, 242;
Anal. Calcd for C₁₉H_{twenty four}N₆O_ThreeS ・ 0.2H₂O: C, 54.32; H, 5.85; N, 20.00. Found: C, 54.34; H, 5.79; N, 19.77.

[Example 58]
3-Amino-4-((3S) -3-{[(3-methyl-1,2,4-thiadiazol-5-yl) methoxy] methyl} piperidin-1-yl) thieno [2,3-b] Pyridine-2-carboxamide (Exemplified compound number 1-405)
Starting material (amine compound): compound of Reference Example 51
Pale yellow atypical solid;
¹H NMR (CDCl_Three, 500 MHz) δ 1.17-1.30 (1H, m), 1.78-2.02 (3H, m), 2.15-2.28 (1H, m), 2.48-2.57 (1H, m), 2.59-2.69 (1H, m), 2.66 (3H, s), 3.42-3.68 (4H, m), 4.87 (2H, d, J = 2.9 Hz), 5.80 (2H, brs), 6.91 (1H, d, J = 5.5 Hz), 7.00 (2H , brs), 8.48 (1H, d, J = 5.5 Hz);
MS (FAB) m / z: 419 [M + H⁺], 402, 273, 246, 200, 165;

[Example 59]
3-amino-4-{(3S) -3-[(pyridin-3-ylmethoxy) methyl] piperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide (Exemplary Compound No. 1-67)
Starting material (amine compound): compound of Reference Example 52
Mp 203-205 ° C;
IR (KBr) ν_max 3389, 3306, 3098, 1677, 1592, 1501, 1367, 1168, 712 cm^-1;
¹H NMR (CDCl_Three, 400MHz) δ 1.13-1.23 (1H, m), 1.74-1.96 (3H, m), 2.11-2.21 (1H, m), 2.45-2.64 (2H, m), 3.37-3.53 (4H, m), 4.50 (1H, d, J = 12.1 Hz), 4.53 (1H, d, J = 12.1 Hz), 5.33 (2H, br), 6.88 (1H, d, J = 5.5 Hz), 7.01 (2H, br), 7.28 (1H, dd, J = 4.7, 7.8 Hz), 7.65 (1H, brd, J = 7.8 Hz), 8.46 (1H, d, J = 5.5 Hz), 8.53 (1H, d, J = 4.7 Hz), 8.55 (1H, d, J = 2.0 Hz);
MS (FAB) m / z: 398 [M + H]⁺;
Anal. Calcd for C₂₀H_{twenty three}N_FiveSO_2.0.26 H₂O: C, 59.73; H, 5.89; N, 17.41; S, 7.97. Found: C, 60.10; H, 5.58; N, 17.05; S, 7.73.

[Example 60]
3-amino-6-methyl-4-{(3S) -3-[(pyridin-3-ylmethoxy) methyl] piperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide (Exemplary Compound Number) 1-206)
Starting material (amine compound): compound of Reference Example 52
Mp 149-153 ° C;
IR (KBr) ν_max 3394, 3331, 3127, 1666, 1589, 1493, 1367, 1087, 712 cm^-1;
¹H NMR (CDCl_Three, 400MHz) δ 1.12-1.24 (1H, m), 1.73-1.96 (3H, m), 2.10-2.20 (1H, m), 2.43-2.63 (2H, m), 2.59 (3H, s), 3.36-3.56 (4H, m), 4.51 (1H, d, J = 12.5 Hz), 4.54 (1H, d, J = 12.5 Hz), 5.30 (2H, br), 6.74 (1H, s), 6.97 (2H, br) , 7.28 (1H, dd, J = 4.7, 7.8 Hz), 7.66 (1H, brd, J = 7.8 Hz), 8.53 (1H, d, J = 4.7 Hz), 8.56 (1H, d, J = 1.6 Hz) ;
MS (FAB) m / z: 412 [M + H]⁺;
Anal. Calcd for C_{twenty one}H_{twenty five}N_FiveSO₂: C, 61.29; H, 6.12; N, 17.02; S, 7.79. Found: C, 61.33; H, 6.14; N, 16.88; S, 7.86.

[Example 61]
3-amino-4-{(3S) -3-[(pyridin-4-ylmethoxy) methyl] piperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide (Exemplified Compound No. 1-80)
Starting material (amine compound): compound of Reference Example 53
Pale yellow powder
Mp 245-250 ° C;
IR (KBr) νmax 3437, 2927, 2832, 2778, 2716, 2541, 1919, 1694, 1616 cm-1;
1H NMR (CDCl3-d6, 400 MHz) δ1.20-1.33 (1H, m), 1.49-1.63 (1H, m), 1.81-2.00 (3H, m), 2.12-2.25 (1H, m), 2.42- 2.55 (1H, m), 2.57-2.71 (1H, m), 3.36-3.37 (4H, m), 4.51 (2H, d, J = 4.3Hz), 5.29 (2H, s), 6.09 (1H, d, J = 5.2Hz), 7.02 (2H, s), 7.23 (2H, d, J = 3.5Hz), 8.46 (1H, d, J = 5.2Hz), 8.57 (2H, d, J = 3.5Hz);
MS (FAB) m / z: 398 [M + H] +, 385,360,244,242;
Anal.Calcd for C20H23N5O2S: C, 60.43; H, 5.83; N 17.62; S 8.07
Found: C, 60.15; H, 5.54; N 17.42; S, 7.89.

[Example 62]
3-Amino-4-((3S) -3-{[(2-methyl-1,3-thiazol-5-yl) methoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine- 2-carboxamide (Exemplary Compound No. 1-404)
Starting material (amine compound): compound of Reference Example 54
Fine brown powder;
Mp 189-191 ° C;
IR (KBr) ν_max 3439, 3383, 3332, 3170, 2926, 2854, 1649, 1590 cm^-1;
¹H NMR (CDCl_Three, 500 MHz) δ 1.08-1.22 (1H, m), 1.72-1.96 (3H, m), 2.04-2.18 (1H, m), 2.37-2.74 (5H, m), 3.27-3.54 (4H, m), 4.57-4.67 (2H, m), 5.30 (2H, brs), 6.88 (1H, d, J = 5.5 Hz), 7.00 (1H, brs), 7.47 (1H, s), 8.46 (1H, d, J = 5.5 Hz);
MS (FAB) m / z: 418 [M + H]⁺, 273, 258;
Anal. Calcd for C₁₉H_{twenty three}N_FiveO₂S₂: C, 54.65; H, 5.55; N, 16.77. Found: C, 54.46; H, 5.43; N, 16.69.

[Example 63]
3-Amino-4-((3S) -3-{[(1-methyl-1H-imidazol-4-yl) methoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine-2- Carboxamide dihydrochloride (Exemplified Compound Nos. 1-413)
Starting material (amine compound): compound of Reference Example 55
Fine brown amorphous material;
¹H NMR (CDCl_Three, 400 MHz) δ 1.05-1.23 (1H, m), 1.68-1.97 (3H, m), 2.08-2.21 (1H, m), 2.39-2.67 (2H, m), 3.29-3.73 (7H, m), 4.43 (2H, dd, J = 17.6, 11.7 Hz), 5.30 (2H, brs), 6.86 (1H, brs), 6.88 (1H, d, J = 5.5 Hz), 6.99 (2H, brs), 7.36 (1H , brs), 8.44 (1H, d, J = 5.5 Hz);
MS (FAB) m / z: 401 [M + H]⁺, 358, 242.

[Example 64]
3-Amino-6-methyl-4-((3S) -3-{[(1-methyl-1H-imidazol-4-yl) methoxy] methyl} piperidin-1-yl) thieno [2,3-b] Pyridine-2-carboxamide (Exemplified Compound No. 1-438)
Starting material (amine compound): compound of Reference Example 55
Fine brown amorphous material;
¹H NMR (CDCl_Three, 400 MHz) δ 1.05-1.20 (1H, m), 1.69-1.976 (3H, m), 2.07-2.21 (1H, m), 2.37-2.61 (2H, m), 2.59 (3H, s), 3.33- 3.70 (7H, m), 4.44 (2H, dd, J = 17.6, 11.7 Hz), 5.23 (2H, brs), 6.74 (1H, s), 6.87 (1H, brs), 6.96 (2H, brs), 7.36 (1H, brs);
MS (FAB) m / z: 415 [M + H]⁺, 242, 226.

[Example 65]
3-Amino-6-methyl-4-((3S) -3-{[(1-methyl-1H-imidazol-5-yl) methoxy] methyl} piperidin-1-yl) thieno [2,3-b] Pyridine-2-carboxamide (Exemplified Compound No. 1-439)
Fine brown amorphous material;
Starting material (amine compound): compound of Reference Example 56
¹H NMR (CDCl_Three, 400 MHz) δ 1.03-1.17 (1H, m), 1.70-1.93 (3H, m), 2.00-2.14 (1H, m), 2.32-2.42 (1H, m), 2.52-2.63 (1H, m), 2.59 (3H, s), 3.23-3.48 (4H, m), 3.64 (3H, brs), 4.46 (2H, s), 5.27 (2H, brs), 6.72 (1H, s), 6.96 (2H, brs) , 7.00 (1H, s), 7.44 (1H, s);
MS (FAB) m / z: 415 [M + H]⁺, 273, 242.

[Example 66]
3-Amino-4-((3S) -3-{[5-methyl-1,3,4-thiadiazol-2-yl) methoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine -2-carboxamide (Exemplary Compound No. 1-406)
Starting material (amine compound): compound of Reference Example 57
Pale yellow powder;
Mp 167-168 ° C;
¹H NMR (CDCl_Three, 400 MHz) δ 1.08-1.23 (1H, m), 1.69-1.96 (3H, m), 2.09-2.23 (1H, m), 2.45 (1H, t, J = 11.3 Hz), 2.61 (1H, t, J = 11.3 Hz), 2.78 (3H, s), 3.37-3.57 (4H, m), 4.85 (2H, brs), 5.31 (2H, brs), 6.89 (1H, d, J = 5.5 Hz), 7.00 ( 2H, brs), 8.48 (1H, d, J = 5.5 Hz);
MS (FAB) m / z: 419 [M + H⁺], 402, 200.

[Example 67]
3-Amino-6-methyl-4-((3S) -3-{[(5-methyl-1,3,4-thiadiazol-2-yl) methoxy] methyl} piperidin-1-yl) thieno [2,3 -B] Pyridine-2-carboxamide (Exemplified Compound No. 1-412)
Starting material (amine compound): compound of Reference Example 57
Yellow powder;
MP 219-221 ° C (dec);
IR (KBr) νmax 3433, 3385, 3333, 3192, 2923, 2854, 2666, 2419, 1848 cm-1;
1H NMR (CDCl3-d3, 400 MHz) δ1.14-1.22 (2H, m), 1.64-1.98 (4H, m), 2.10-2.22 (1H, m), 2.42-2.51 (1H, m), 2.64 ( 3H, s), 2.81 (3H, s), 3.39-3.59 (4H, m), 4.89 (2H, s), 5.33 (2H, s), 6.68 (1H, s), 6.99 (1H, s);
MS (FAB) m / z: 433 [M + H] +, 416,273,258,242,226;
Anal.Calcd for C19H24N6O2S2: C, 57.27; H, 5.56; N 21.09; S 8.05
Found: C, 57.35; H, 5.54; N 20.88; S, 87.76.

[Example 68]
3-Amino-4-((3S) -3-{[(4-methyl-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) methoxy] methyl} piperidine- 1-yl) thieno [2,3-b] pyridine-2-carboxamide hydrochloride (Exemplified Compound No. 1-441)
Starting material (amine compound): compound of Reference Example 58
Yellow atypical solid;
¹H NMR (DMSO-d₆, 400 MHz) δ 1.15-1.31 (1H, m), 1.65-1.86 (3H, m), 2.05-2.18 (1H, m), 2.71-2.86 (1H, m), 2.90-3.04 (1H, m), 3.35-3.49 (2H, m), 3.50-3.68 (2H, m), 4.52 (2H, d, J = 2.0 Hz), 7.11 (1H, d, J = 5.5 Hz), 7.25 (2H, brs), 8.47 (1H, d, J = 5.5 Hz);
MS (FAB) m / z: 419 [M + H⁺], 273, 242.

[Example 69]
3-Amino-6-methyl-4-((3S) -3-{[(4-methyl-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) methoxy] Methyl} piperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide (Exemplified Compound No. 1-442)
Starting material (amine compound): compound of Reference Example 58
Pale yellow powder;
Mp 127-129 ° C;
¹H NMR (CDCl_Three, 400 MHz) δ 1.06-1.21 (1H, m), 1.71-1.97 (3H, m), 2.07-2.21 (1H, m), 2.39 (1H, t, J = 11.0 Hz), 2.60 (3H, s) , 2.62 (1H, t, J = 11.0 Hz), 3.28 (3H, s), 3.34-3.52 (4H, m), 4.44 (2H, s), 5.26 (2H, brs), 6.73 (1H, s), 6.92 (2H, brs);
MS (FAB) m / z: 433 [M + H⁺], 273, 242, 165.

[Example 70]
3-Amino-4-((3S) -3-{[(1-methyl-1H-imidazol-2-yl) methoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine-2- Carboxamide (Exemplified Compound No. 1-91)
Starting material (amine compound): compound of Reference Example 59
Pale yellow powder;
Mp 137-138 ° C;
¹H NMR (CDCl_Three, 400 MHz) δ 1.01-1.18 (1H, m), 1.68-1.94 (3H, m), 2.01-2.17 (1H, m), 2.39 (1H, t, J = 11.3 Hz), 2.59 (1H, t, J = 11.3 Hz), 3.25-3.52 (4H, m), 3.67 (3H, s), 4.57 (2H, s), 5.32 (2H, brs), 6.86 (1H, d, J = 5.5 Hz), 6.87 ( 1H, brs), 6.94 (1H, brs), 6.98 (2H, brs), 8.46 (1H, d, J = 5.5 Hz);
MS (FAB) m / z: 402 [M + H⁺], 242, 165.

[Example 71]
3-Amino-6-methyl-4-((3S) -3-{[(1-methyl-1H-imidazol-2-yl) methoxy] methyl} piperidin-1-yl) thieno [2,3-b] Pyridine-2-carboxamide (Exemplary Compound No. 1-230)
Starting material (amine compound): compound of Reference Example 59
Yellow powder;
Mp 215-217 ° C;
¹H NMR (CDCl_Three, 400 MHz) δ 1.02-1.17 (1H, m), 1.67-1.93 (3H, m), 2.01-2.15 (1H, m), 2.37 (1H, t, J = 11.3 Hz), 2.56 (1H, t, J = 11.3 Hz), 2.59 (3H, s), 3.27-3.47 (4H, m), 3.68 (3H, s), 4.58 (2H, s), 5.25 (2H, brs), 6.72 (1H, s), 6.87 (1H, brs), 6.92-6.97 (3H, m);
MS (FAB) m / z: 415 [M + H⁺], 273, 242, 226, 165.

[Example 72]
3-Amino-4-((3S) -3-{[(4-methyl-4H-1,2,4-triazol-3-yl) methoxy] methyl} piperidin-1-yl) thieno [2,3- b] Pyridine-2-carboxamide (Exemplified Compound No. 1-414)
Starting material (amine compound): compound of Reference Example 60
Pale yellow foam;
¹H NMR (CDCl_Three, 400 MHz) δ 1.02-1.16 (1H, m), 1.69-1.95 (3H, m), 2.05-2.17 (1H, m), 2.36 (1H, t, J = 11.3 Hz), 2.63 (1H, t, J = 11.3 Hz), 3.30-3.54 (4H, m), 3.72 (3H, s), 4.71 (2H, s), 5.32 (2H, brs), 6.87 (1H, d, J = 5.5 Hz), 6.97 ( 2H, brs), 8.10 (1H, s), 8.47 (1H, d, J = 5.5 Hz);
MS (FAB) m / z: 402 [M + H⁺], 385, 273, 242, 165.

[Example 73]
3-Amino-4-((3S) -3-{[(1-ethyl-1H-imidazol-5-yl) methoxy] methyl} piperidin-1-yl) -6-methylthieno [2,3-b] pyridine -2-carboxamide (Exemplified Compound No. 1-440)
Starting material (amine compound): compound of Reference Example 61
Pale yellow foam;
¹H NMR (CDCl_Three, 400 MHz) δ 1.02-1.17 (1H, m), 1.42 (3H, t, J = 7.4 Hz), 1.69-1.94 (3H, m), 1.99-2.13 (1H, m), 2.32-2.42 (1H, m), 2.50-2.62 (1H, m), 2.59 (3H, s), 3.19-3.50 (4H, m), 3.91-4.05 (2H, m), 4.46 (2H, brs), 5.26 (2H, brs) , 6.72 (1H, s), 6.95 (2H, brs), 6.99 (1H, s), 7.50 (1H, s);
MS (FAB) m / z: 429 [M + H⁺], 412, 384, 242, 165.

[Example 74]
3-amino-4-((3S) -3-{[2- (1H-pyrazol-1-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide ( Exemplary Compound No. 1-21)
Starting material (amine compound): compound of Reference Example 62
Pale yellow atypical solid;
¹H NMR (CDCl_Three, 400 MHz) δ 0.96-1.14 (1H, m), 1.69-1.94 (3H, m), 1.99-2.11 (1H, m), 2.30 (1H, t, J = 11.3 Hz), 2.57 (1H, t, J = 11.3 Hz), 3.16-3.45 (4H, m), 3.69-3.85 (2H, m), 4.28 (2H, t, J = 5.5 Hz), 5.33 (2H, brs), 6.13 (1H, brs), 6.85 (1H, d, J = 5.5 Hz), 6.99 (2H, brs), 7.44 (1H, brs), 7.46 (1H, brs), 8.47 (1H, d, J = 5.5 Hz);
MS (FAB) m / z: 401 [M + H⁺], 384, 356, 270, 200.

[Example 75]
3-amino-4-((3S) -3-{[2- (1H-imidazol-1-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide ( Exemplified Compound No. 1-17)
Starting material (amine compound): Compound of Reference Example 63
Yellow powder;
Mp 105-115 ° C;
¹H NMR (CDCl_Three, 500 MHz) δ 1.06-1.18 (1H, m), 1.69-1.95 (3H, m), 2.05-2.15 (1H, m), 2.36 (1H, t, J = 11.2 Hz), 2.61 (1H, t, J = 11.2 Hz), 3.24-3.49 (4H, m), 3.58-3.73 (2H, m), 4.09 (2H, t, J = 5.5 Hz), 5.32 (2H, brs), 6.87 (1H, d, J = 5.5 Hz), 6.92-7.02 (4H, m), 7.50 (1H, s), 8.48 (1H, d, J = 5.5 Hz);
MS (FAB) m / z: 401 [M + H⁺], 384, 356, 200.

[Example 76]
3-Amino-4-((3S) -3-{[2- (1H-imidazol-1-yl) ethoxy] methyl} piperidin-1-yl) -6-methylthieno [2,3-b] pyridine-2 -Carboxamide (Exemplary Compound No. 1-153)
Starting material (amine compound): Compound of Reference Example 63
Pale yellow powder;
Mp 105-110 ° C;
¹H NMR (CDCl_Three, 400 MHz) δ 1.01-1.19 (1H, m), 1.68-1.94 (3H, m), 2.00-2.13 (1H, m), 2.28-2.40 (1H, m), 2.52-2.63 (1H, m), 2.61 (3H, s), 3.22-3.47 (4H, m), 3.67-3.74 (2H, m), 4.09 (2H, t, J = 5.1 Hz), 5.28 (2H, brs), 6.72 (1H, s) , 6.95 (2H, brs), 6.96 (1H, s), 6.99 (1H, s), 7.49 (1H, s);
MS (FAB) m / z: 415 [M + H⁺], 398, 370, 242.

[Example 77]
3-Amino-6-methyl-4-((3S) -3-{[2- (2-methyl-1H-tetrazol-1-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3- b] Pyridine-2-carboxamide hydrochloride (Exemplified Compound No. 1-156)
Starting material (amine compound): compound of Reference Example 64
Yellow atypical solid;
¹H NMR (DMSO-d₆, 400 MHz) δ 1.02-1.21 (1H, m), 1.66-1.81 (3H, m), 2.00-2.12 (1H, m), 2.58 (3H, s), 2.55-2.65 (1H, m), 2.59 ( 3H, s), 2.81-2.95 (1H, m), 3.23-3.38 (2H, m), 3.43-3.55 (2H, m), 3.63-3.76 (2H, m), 4.27 (2H, t, J = 5.1 Hz), 6.97 (1H, s), 7.22 (2H, brs), 7.47 (1H, d, J = 2.0 Hz), 7.56 (1H, d, J = 2.0 Hz);
MS (FAB) m / z: 429 [M + H⁺], 412, 242, 200, 165.

[Example 78]
3-Amino-4-((3S) -3-{[2- (1H-1,2,3-triazol-1-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b] Pyridine-2-carboxamide (Exemplified Compound No. 1-25)
Starting material (amine compound): compound of Reference Example 65
White powder;
Mp 184-186 ° C;
IR (KBr) ν_max 3433, 3324, 3169, 2931, 2858, 1651, 1582 cm^-1;
¹H NMR (CDCl_Three, 400 MHz) δ 0.97-1.14 (1H, m), 1.70-1.96 (3H, m), 2.02-2.15 (1H, m), 2.19-2.31 (1H, m), 2.57-2.70 (1H, m), 3.13-3.26 (1H, m), 3.32-3.50 (3H, m), 3.68-3.86 (2H, m), 4.47-4.62 (2H, m), 5.32 (2H, brs), 6.84 (1H, d, J = 5.5 Hz), 6.98 (2H, brs), 7.57 (1H, s), 7.67 (1H, brs), 8.47 (1H, d, J = 5.5 Hz);
MS (FAB) m / z: 402 [M + H]⁺, 385, 357, 273;
Anal. Calcd for C₁₈H_{twenty three}N₇O₂S ・ 0.2H₂O: C, 54.22; H, 6.13; N, 23.29. Found: C, 54.17; H, 6.03; N, 23.15.

[Example 79]
3-Amino-6-methyl-4-((3S) -3-{[2- (1H-1,2,3-triazol-1-yl) ethoxy] methyl} piperidin-1-yl) thieno [2, 3-b] pyridine-2-carboxamide (Exemplified Compound No. 1-161)
Starting material (amine compound): compound of Reference Example 65
Pale yellow powder;
Mp 147-149 ° C;
IR (KBr) ν_max 3436, 3321, 3165, 2942, 2860, 1649, 1580 cm^-1;
¹H NMR (CDCl_Three, 400 MHz) δ 0.96-1.12 (1H, m), 1.68-1.95 (3H, m), 2.00-2.14 (1H, m), 2.18-2.29 (1H, m), 2.52-2.66 (1H, m), 2.61 (3H, s), 3.14-3.24 (1H, m), 3.31-3.48 (3H, m), 3.68-3.86 (2H, m), 4.48-4.62 (2H, m), 5.27 (2H, brs), 6.70 (1H, s), 6.95 (2H, brs), 7.56 (1H, s), 7.68 (1H, brs);
MS (FAB) m / z: 416 [M + H]⁺, 399, 273;
Anal. Calcd for C₁₉H_{twenty five}N₇O₂S: C, 53.85; H, 5.77; N, 24.42. Found: C, 53.95; H, 5.79; N, 24.47.

[Example 80]
3-Amino-4-((3S) -3-{[2- (2H-1,2,3-triazol-2-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b] Pyridine-2-carboxamide (Exemplified Compound No. 1-399)
Starting material (amine compound): Compound of Reference Example 66
A slightly yellow powder;
Mp 108-110 ° C;
IR (KBr) ν_max 3447, 3325, 3169, 2929, 2860, 1650, 1580, 1502 cm^-1;
¹H NMR (CDCl_Three, 400 MHz) δ 0.96-1.14 (1H, m), 1.67-1.91 (3H, m), 1.94-2.11 (1H, m), 2.28-2.41 (1H, m), 2.45-2.60 (1H, m), 3.20-3.49 (4H, m), 3.88-4.00 (2H, m), 4.60 (2H, t, J = 5.5 Hz), 5.23-5.41 (2H, brs), 6.83 (1H, d, J = 5.5 Hz) , 6.96 (2H, brs), 7.56 (2H, brs), 8.45 (1H, d, J = 5.5 Hz);
MS (FAB) m / z: 402 [M + H]⁺, 385, 357, 270;
Anal. Calcd for C₁₈H_{twenty three}N₇O₂S ・ 0.2H₂O: C, 53.37; H, 5.82; N, 24.20. Found: C, 53.30; H, 5.60; N, 24.14.

[Example 81]
3-Amino-4-((3S) -3-{[2- (1H-1,2,4-triazol-1-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b] Pyridine-2-carboxamide (Exemplified Compound No. 1-26)
Starting material (amine compound): compound of Reference Example 67
Pale yellow powder;
Mp 163-164 ° C;
¹H NMR (CDCl_Three, 400 MHz) δ 0.99-1.16 (1H, m), 1.67-1.95 (3H, m), 1.99-2.14 (1H, m), 2.35 (1H, t, J = 11.3 Hz), 2.58 (1H, t, J = 11.3 Hz), 3.21-3.46 (4H, m), 3.69-3.82 (2H, m), 4.34 (2H, t, J = 5.1 Hz), 5.32 (2H, brs), 6.86 (1H, d, J = 5.5 Hz), 6.97 (2H, brs), 7.92 (1H, s), 8.13 (1H, s), 8.48 (1H, d, J = 5.5 Hz);
MS (FAB) m / z: 402 [M + H⁺], 385, 357, 273, 242, 226, 165.

[Example 82]
3-Amino-6-methyl-4-((3S)-{[2- (1H-1,2,4-triazol-1-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b Pyridine-2-carboxamide hydrochloride (Exemplified compound number 1-162)
Starting material (amine compound): compound of Reference Example 67
Yellow amorphous;
¹H NMR (CD_ThreeOD-d₆, 400 MHz) δ 1.25-1.33 (1H, m), 1.61-1.72 (1H, m), 1.80-1.91 (2H, m), 2.60 (3H, s), 2.79-2.84 (1H, m), 2.98- 3.06 (2H, m), 3.21-3.40 (1H, m), 3.50-3.63 (1H, m), 3.82-3.85 (1H, m), 3.93-3.97 (1H, m), 4.20-4.23 (2H, m ), 4.35-4.40 (2H, m), 7.07 (1H, s), 7.75 (1H, s), 7.80 (1H, s);
MS (FAB) m / z: 416 [M + H]⁺, 272,241,206;
Anal.Calcd for C19H25N7O2S.HCl: C, 50.49; H, 5.80; N, 21.69; Cl, 7.84; S, 7.09
Found: C, 50.20; H, 6.02; N, 21.54; Cl, 7.67; S, 6.88.

[Example 83]
3-Amino-4-((3S) -3-{[2- (4H-1,2,4-triazol-4-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b] Pyridine-2-carboxamide (Exemplified Compound No. 1-27)
Starting material (amine compound): compound of Reference Example 68
Pale yellow foam;
¹H NMR (CDCl_Three, 400 MHz) δ 1.04-1.69 (1H, m), 1.69-1.99 (3H, m), 2.07-2.17 (1H, m), 2.38 (1H, t, J = 11.3 Hz), 2.63 (1H, t, J = 11.3 Hz), 3.26-3.51 (4H, m), 3.59-3.73 (2H, m), 4.18 (2H, t, J = 5.1 Hz), 5.35 (2H, brs), 6.88 (1H, d, J = 5.5 Hz), 6.96 (2H, brs), 8.21 (2H, s), 8.49 (1H, d, J = 5.5 Hz);
MS (FAB) m / z: 402 [M + H⁺], 385, 357.

[Example 84]
3-Amino-6-methyl-4-((3S) -3-{[2- (2H-tetrazol-2-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine- 2-carboxamide (Exemplified Compound No. 1-165)
Starting material (amine compound): Compound of Reference Example 49
Pale yellow powder;
Mp 94-96 ° C;
IR (KBr) ν_max 3327, 2930, 1646, 1581, 1369, 1123 cm^-1;
¹H NMR (CDCl_Three, 400 MHz) δ 0.96-1.12 (1H, m), 1.68-1.90 (3H, m), 1.94-2.07 (1H, m), 2.27-2.39 (1H, m), 2.46-2.56 (1H, m), 2.61 (3H, s), 3.24-3.45 (4H, m), 3.93-4.06 (2H, m), 4.82 (2H, t, J = 5.5 Hz), 5.25 (2H, brs), 6.71 (1H, s) , 6.92 (2H, brs), 8.49 (1H, s);
MS (FAB) m / z: 417 [M + H⁺], 400, 273, 242, 165;
Anal. Calcd for C₁₈H_{twenty four}N₈O₂S ・ 0.17H₂O: C, 51.54; H, 5.85; N, 26.71; S, 7.64. Found: C, 51.50; H, 5.64; N, 26.50; S, 7.73.

[Example 85]
3-amino-4-((3S) -3-{[2- (1H-tetrazol-1-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide ( Exemplified Compound No. 1-28)
Starting material (amine compound): compound of Reference Example 69
Pale yellow foam;
IR (KBr) ν_max 3327, 2934, 1648, 1581, 1502, 1373, 1106 cm^-1;
¹H NMR (CDCl_Three, 400 MHz) δ 0.99-1.14 (1H, m), 1.69-1.97 (3H, m), 2.02-2.16 (1H, m), 2.26-2.37 (1H, m), 2.57-2.68 (1H, m), 3.24-3.50 (4H, m), 3.71-3.85 (2H, m), 4.61 (2H, t, J = 5.5 Hz), 5.34 (2H, brs), 6.86 (1H, d, J = 5.5 Hz), 6.95 (2H, brs), 8.48 (1H, d, J = 5.5 Hz), 8.71 (1H, s);
MS (FAB) m / z: 403 [M + H⁺], 273, 180, 93;
Anal. Calcd for C₁₇H_{twenty two}N₈O₂S ・ 0.68H₂O: C, 49.23; H, 5.68; N, 27.02; S, 7.73. Found: C, 49.64; H, 5.90; N, 26.59; S, 7.40.

[Example 86]
3-Amino-6-methyl-4-((3S) -3-{[2- (1H-tetrazol-1-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine- 2-carboxamide (Exemplified Compound No. 1-164)
Starting material (amine compound): compound of Reference Example 69
Pale yellow powder;
Mp 177-179 ° C;
IR (KBr) ν_max 3328, 2930, 1648, 1582, 1490, 1371, 1106 cm^-1;
¹H NMR (CDCl_Three, 400 MHz) δ 0.99-1.14 (1H, m), 1.67-1.97 (3H, m), 2.01-2.15 (1H, m), 2.21-2.36 (1H, m), 2.52-2.66 (1H, m), 2.61 (3H, s), 3.25-3.47 (4H, m), 3.72-3.86 (2H, m), 4.58-4.64 (2H, m), 5.29 (2H, brs), 6.71 (1H, s), 6.91 ( 2H, brs), 8.71 (1H, s);
MS (FAB) m / z: 417 [M + H⁺], 400, 372, 353, 242, 200, 176;
Anal. Calcd for C₁₈H_{twenty four}N₈O₂S ・ 0.50H₂O: C, 50.81; H, 5.92; N, 26.33; S, 7.54. Found: C, 50.67; H, 5.78; N, 26.47; S, 7.58.

[Example 87]
3-Amino-4-((3S) -3-{[2- (5-methyl-2H-tetrazol-2-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine- 2-carboxamide (Exemplified Compound No. 1-290)
Starting material (amine compound): compound of Reference Example 70
Pale yellow foam;
IR (KBr) ν_max 3440, 3327, 2934, 1648, 1580, 1503, 1448, 1371, 1124 cm^-1;
¹H NMR (CDCl_Three, 400 MHz) δ 0.99-1.15 (1H, m), 1.66-1.92 (3H, m), 1.96-2.10 (1H, m), 2.28-2.42 (1H, m), 2.49 (3H, s), 2.45- 2.60 (1H, m), 3.22-3.47 (4H, m), 3.86-4.02 (2H, m), 4.72 (2H, t, J = 5.5 Hz), 5.31 (2H, brs), 6.86 (1H, d, J = 5.5 Hz), 6.96 (2H, brs), 8.47 (1H, d, J = 5.5 Hz);
MS (FAB) m / z: 417 [M + H⁺], 400, 273, 258, 242, 180;
Anal. Calcd for C₁₈H_{twenty four}N₈O₂S ・ 0.67H₂O: C, 50.45; H, 5.96; N, 26.15; S, 7.48.Found: C, 50.49; H, 5.69; N, 25.86; S, 7.40.

[Example 88]
3-Amino-6-methyl-4-((3S) -3-{[2- (5-methyl-2H-tetrazol-2-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3- b] Pyridine-2-carboxamide hydrochloride (Exemplified Compound No. 1-345)
Starting material (amine compound): compound of Reference Example 70
Pale yellow atypical solid;
IR (KBr) ν_max 3190, 2624, 1852, 1607, 1370, 1123 cm^-1;
¹H NMR (DMSO-d₆, 400 MHz) δ 1.03-1.17 (1H, m), 1.60-1.77 (3H, m), 1.91-2.06 (1H, m), 2.40 (3H, s), 2.56-2.74 (1H, m), 2.60 ( 3H, s), 2.79-2.96 (1H, m), 3.24-3.56 (4H, m), 3.81-3.94 (2H, m), 4.77 (2H, t, J = 5.1 Hz), 7.24 (2H, brs) ;
MS (FAB) m / z: 431 [M + H⁺], 414, 319, 216, 93;
Anal. Calcd for C₁₈H_{twenty four}N₈O₂S ・ HCl: C, 48.87; H, 5.83; N, 23.99; Cl, 7.59; S, 6.87. Found: C, 48.82; H, 5.78; N, 23.85; Cl, 7.84; S, 7.37.

[Example 89]
3-Amino-4-((3S) -3-{[2- (5-methyl-1H-tetrazol-1-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine- 2-carboxamide (Exemplified Compound No. 1-289)
Starting material (amine compound): compound of Reference Example 71
Pale yellow foam;
¹H NMR (CDCl_Three, 400 MHz) δ 0.95-1.09 (1H, m), 1.67-1.83 (2H, m), 1.85-1.94 (1H, m), 1.99-2.10 (1H, m), 2.27 (1H, t, J = 11.3 Hz), 2.55 (3H, s), 2.60 (1H, t, J = 11.3 Hz), 3.18-3.46 (4H, m), 3.74-3.90 (2H, m), 4.44 (2H, t, J = 5.1 Hz ), 5.33 (2H, brs), 6.86 (1H, d, J = 5.5 Hz), 6.96 (2H, brs), 8.49 (1H, d, J = 5.5 Hz);
MS (FAB) m / z: 417 [M + H⁺], 400, 273, 246, 165, 93.

[Example 90]
3-Amino-6-methyl-4-((3S) -3-{[2- (5-methyl-1H-tetrazol-1-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3- b] Pyridine-2-carboxamide (Exemplified Compound No. 1-344)
Starting material (amine compound): compound of Reference Example 71
Pale yellow powder;
Mp 126-131 ° C;
¹H NMR (CDCl_Three, 400 MHz) δ 0.92-1.09 (1H, m), 1.67-1.81 (2H, m), 1.83-1.93 (1H, m), 1.97-2.10 (1H, m), 2.24 (1H, t, J = 11.3 Hz), 2.55 (3H, s), 2.48-2.64 (1H, m), 2.62 (3H, s), 3.18-3.43 (4H, m), 3.76-3.91 (2H, m), 4.44 (2H, t, J = 5.1 Hz), 5.27 (2H, brs), 6.70 (1H, s), 6.92 (2H, brs);
MS (FAB) m / z: 431 [M + H⁺], 414, 273, 242, 200;

[Example 91]
3-amino-4-((3S) -3-{[3- (1H-imidazol-1-yl) propoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide ( Exemplified Compound No. 1-37)
Starting material (amine compound): compound of Reference Example 72
Pale yellow powder;
Mp 152-153 ° C;
¹H NMR (CDCl_Three, 400 MHz) δ 1.07-1.23 (1H, m), 1.69-2.05 (5H, m), 2.06-2.19 (1H, m), 2.38-2.49 (1H, m), 2.58-2.69 (1H, m), 3.23-3.57 (6H, m), 4.04 (2H, t, J = 6.7 Hz), 5.31 (2H, brs), 6.89 (1H, brs), 6.91 (1H, t, J = 5.5 Hz), 7.01 (2H , brs), 7.05 (1H, brs), 7.45 (1H, brs), 8.48 (1H, d, J = 5.5 Hz);
MS (FAB) m / z: 415 [M + H⁺], 242, 165.

[Example 92]
3-amino-4-((3S) -3-{[3-((1H-imidazol-1-yl) propoxy] methyl} piperidin-1-yl) -6-methylthieno [2,3-b] pyridine- 2-carboxamide dihydrochloride (Exemplified Compound No. 1-175)
Starting material (amine compound): compound of Reference Example 72
Yellow atypical solid;
¹H NMR (DMSO-d₆, 400 MHz) δ 1.09-1.26 (1H, m), 1.68-1.83 (3H, m), 2.00-2.13 (3H, m), 2.57 (3H, s), 2.62-2.76 (1H, m), 2.78- 2.94 (1H, m), 3.20-3.57 (6H, m), 4.23 (2H, t, J = 7.4 Hz), 7.00 (1H, s), 7.19 (2H, brs), 7.67 (1H, brs), 7.76 (1H, brs), 9.15 (1H, brs);
MS (FAB) m / z: 429 [M + H⁺], 412, 273, 242, 165.

[Example 93]
3-Amino-6-methyl-4-((3S) -3-{[3- (1H-tetrazol-1-yl) propoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine- 2-carboxamide (Exemplified Compound No. 1-186)
Starting material (amine compound): compound of Reference Example 73
Pale yellow powder;
Mp 122-123 ° C;
¹H NMR (CDCl_Three, 400 MHz) δ 1.03-1.18 (1H, m), 1.71-1.97 (3H, m), 2.06-2.16 (1H, m), 2.17-2.24 (2H, m), 2.29-2.39 (1H, m), 2.61 (3H, s), 2.62-2.70 (1H, m), 3.20-3.29 (1H, m), 3.31-3.50 (4H, m), 3.51-3.59 (1H, m), 4.54 (2H, t, J = 7.0 Hz), 5.26 (2H, brs), 6.76 (1H, s), 6.96 (2H, brs), 8.65 (1H, brs);
MS (FAB) m / z: 431 [M + H⁺], 414, 242, 165.

[Example 94]
3-amino-4-((3S) -3-{[3- (2H-tetrazol-2-yl) propoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide ( Exemplified Compound No. 1-49)
Starting material (amine compound): compound of Reference Example 74
Pale yellow powder;
Mp 88-90 ° C;
¹H NMR (CDCl_Three, 400 MHz) δ 1.08-1.24 (1H, m), 1.72-1.96 (3H, m), 2.04-2.17 (1H, m), 2.22-2.31 (2H, m), 2.46 (1H, t, J = 11.3 Hz), 2.61 (1H, t, J = 11.3 Hz), 3.23-3.56 (6H, m), 4.77 (2H, t, J = 6.7 Hz), 5.30 (2H, brs), 6.93 (1H, d, J = 5.5 Hz), 7.01 (2H, brs), 8.47 (1H, d, J = 5.5 Hz), 8.48 (1H, s);
MS (FAB) m / z: 417 [M + H⁺], 273, 242, 165.

[Example 95]
3-Amino-6-methyl-4-((3S) -3-{[3- (2H-tetrazol-2-yl) propoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine- 2-carboxamide hydrochloride (Exemplified Compound No. 1-187)
Starting material (amine compound): compound of Reference Example 74
Yellow atypical solid;
¹H NMR (DMSO-d₆, 400 MHz) δ 1.10-1.26 (1H, m), 1.69-1.82 (3H, m), 1.99-2.19 (3H, m), 2.58 (3H, s), 2.68-2.81 (1H, m), 2.84- 2.98 (1H, m), 3.21-3.45 (4H, m), 3.47-3.60 (2H, m), 4.73 (2H, t, J = 6.7 Hz), 7.02 (1H, s), 7.20 (2H, brs) , 8.93 (1H, s);
MS (FAB) m / z: 431 [M + H⁺], 414, 273, 242, 165.

[Example 96]
3-Amino-4-((3S) -3-{[2- (2-ethyl-2H-tetrazol-5-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine- 2-carboxamide hydrochloride (Exemplified Compound No. 1-429)
Starting material (amine compound): compound of Reference Example 75
Yellow powder;
Mp 200-203 ° C;
IR (KBr) ν_max 3315, 3160, 2938, 2864, 2597, 1653, 1608 cm^-1;
¹H NMR (DMSO-d₆, 400 MHz) δ 1.06-1.22 (1H, m), 1.43 (3H, t, J = 7.4 Hz), 1.65-1.80 (3H, m), 1.99-2.12 (1H, m), 2.59-2.74 (1H, m), 2.79-2.93 (1H, m), 3.05 (2H, t, J = 6.7 Hz), 3.27-3.39 (2H, m), 3.40-3.51 (2H, m), 3.68-3.82 (2H, m) , 4.59 (2H, t, J = 7.4 Hz), 7.05 (1H, d, J = 5.9 Hz), 7.21 (2H, brs), 8.45 (1H, d, J = 5.9 Hz);
MS (FAB) m / z: 431 [M + H]⁺, 414, 329, 273;
Anal. Calcd for C₁₉H₂₆N₈O₂S.HCl: C, 48.87; H, 5.83; N, 23.99; Cl, 7.59. Found: C, 48.79; H, 5.61; N, 23.82; Cl, 7.57.

[Example 97]
3-Amino-4-((3S) -3-{[2- (1-ethyl-1H-tetrazol-5-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine- 2-carboxamide (Exemplified Compound Nos. 1-419)
Starting material (amine compound): compound of Reference Example 76
Fine brown amorphous material;
¹H NMR (CDCl_Three, 400 MHz) δ 0.96-1.11 (1H, m), 1.49 (3H, t, J = 7.4 Hz), 1.68-1.94 (3H, m), 1.98-2.12 (1H, m), 2.23-2.35 (1H, m), 2.55-2.67 (1H, m), 3.11 (2H, t, J = 5.9 Hz), 3.21-3.29 (1H, m), 3.31-3.46 (3H, m), 3.75-3.89 (2H, m) , 4.23-4.43 (2H, m), 5.30 (2H, brs), 6.85 (1H, d, J = 5.5 Hz), 6.97 (2H, brs), 8.47 (1H, d, J = 5.5 Hz);
MS (FAB) m / z: 431 [M + H]⁺, 414, 389.

[Example 98]
3-Amino-4-((3S) -3-{[2- (1-ethyl-1H-tetrazol-5-yl) ethoxy] methyl} piperidin-1-yl) -6-methylthieno [2,3-b Pyridine-2-carboxamide (Exemplified Compound No. 1-424)
Starting material (amine compound): compound of Reference Example 76
Fine brown amorphous material;
¹H NMR (CDCl_Three, 400 MHz) δ 0.96-1.09 (1H, m), 1.49 (3H, t, J = 7.4 Hz), 1.71-1.92 (3H, m), 1.98-2.11 (1H, m), 2.22-2.32 (1H, m), 2.52-2.65 (1H, m), 2.61 (3H, s), 3.11 (2H, t, J = 5.9 Hz), 3.21-3.29 (1H, m), 3.32-3.44 (3H, m), 3.76 -3.90 (2H, m), 4.25-4.44 (2H, m), 5.31 (2H, brs), 6.71 (1H, s), 6.94 (2H, brs);
MS (FAB) m / z: 445 [M + H]⁺, 273, 242.

Example 99
3-Amino-6-methyl-4-((3S) -3-{[2- (1-propyl-1H-tetrazol-5-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3- b] Pyridine-2-carboxamide dihydrochloride (Exemplified Compound No. 1-425)
Starting material (amine compound): compound of Reference Example 77
Yellow powder;
Mp 209-211 ° C;
IR (KBr) ν_max 3320, 3181, 2931, 2863, 2674, 1652, 1599 cm^-1;
¹H NMR (DMSO-d₆, 400 MHz) δ 0.82 (3H, t, J = 7.4 Hz), 1.02-1.21 (1H, m), 1.64-1.84 (5H, m), 1.97-2.10 (1H, m), 2.53-2.70 (1H, m), 2.57 (3H, s), 2.76-2.93 (1H, m), 3.14 (2H, t, J = 6.3 Hz), 3.23-3.53 (4H, m), 3.68-3.83 (2H, m), 4.23 -4.32 (2H, m), 6.95 (1H, s), 7.19 (2H, brs);
MS (FAB) m / z: 459 [M + H]⁺, 329, 273;
Anal. Calcd for C_{twenty one}H₃₀N₈O₂S ・ HCl ・ 0.7H₂O: C, 49.69; H, 6.43; N, 22.07; Cl, 6.98. Found: C, 49.63; H, 6.38; N, 21.78; Cl, 7.30.

[Example 100]
3-Amino-4-((3S) -3-{[2- (1-isopropyl-1H-tetrazol-5-yl) ethoxy] methyl} piperidin-1-yl) -6-methylthieno [2,3-b ] Pyridine-2-carboxamide (Exemplified Compound No. 1-426)
Starting material (amine compound): compound of Reference Example 78
Pale yellow powder;
Mp 140-145 ° C;
¹H NMR (CDCl_Three, 400 MHz) δ 0.97-1.13 (1H, m), 1.54 (3H, d, J = 6.7 Hz), 1.58 (3H, d, J = 6.7 Hz), 1.68-1.92 (3H, m), 1.99-2.10 (1H, m), 2.26-2.37 (1H, m), 2.50-2.63 (1H, m), 2.61 (3H, s), 3.11 (2H, t, J = 6.3 Hz), 3.24-3.45 (4H, m ), 3.78-3.90 (2H, m), 4.59-4.71 (1H, m), 5.29 (2H, brs), 6.71 (1H, s), 6.94 (2H, brs);
MS (FAB) m / z: 459 [M + H⁺], 442, 273, 242, 165.

[Example 101]
3-amino-4-((3S) -3-{[2- (1-cyclopropyl-1H-tetrazol-5-yl) ethoxy] methyl} piperidin-1-yl) -6-methylthieno [2,3- b] Pyridine-2-carboxamide (Exemplified Compound No. 1-427)
Starting material (amine compound): compound of Reference Example 79
Pale yellow foam;
¹H NMR (CDCl_Three, 400 MHz) δ 0.96-1.11 (1H, m), 1.12-1.32 (4H, m), 1.66-1.92 (3H, m), 1.98-2.10 (1H, m), 2.23-2.34 (1H, m), 2.50-2.64 (1H, m), 2.62 (3H, s), 3.21 (2H, t, J = 6.3 Hz), 3.23-3.31 (1H, m), 3.33-3.43 (3H, m), 3.51-3.57 ( 1H, m), 3.81-3.94 (2H, m), 5.28 (2H, brs), 6.71 (1H, s), 6.93 (2H, brs);
MS (FAB) m / z: 457 [M + H⁺], 440, 412, 357.

[Example 102]
3-amino-4-[(3S) -3-({2- [1- (2-methoxyethyl) -1H-tetrazol-5-yl] ethoxy} methyl) piperidin-1-yl] -6-methylthieno [ 2,3-b] pyridine-2-carboxamide (Exemplified Compound No. 1-428)
Starting material (amine compound): compound of Reference Example 80
Fine brown amorphous material;
¹H NMR (CDCl_Three, 400 MHz) δ 0.95-1.11 (1H, m), 1.68-1.94 (3H, m), 1.98-2.12 (1H, m), 2.21-2.33 (1H, m), 2.53-2.66 (1H, m), 2.61 (3H, s), 3.18 (2H, t, J = 6.3 Hz), 3.19-3.26 (1H, m), 3.24 (3H, s), 3.30-3.59 (4H, m), 3.67-3.86 (4H, m), 4.39-4.59 (2H, m), 5.31 (2H, brs), 6.73 (1H, s), 6.94 (2H, brs);
MS (FAB) m / z: 475 [M + H]⁺, 458, 273, 242.

参考例及び実施例に記載された手法に従って、以下のような化合物も容易に製造することができる。
例示化合物表１ The following compounds can also be easily produced according to the methods described in Reference Examples and Examples.
Exemplary compounds Table 1

(表６）
--------------------------------------------------------------------------------
化合物
番号 R¹ m W n X¹
--------------------------------------------------------------------------------
1-1 H 0 O 1 cPr
1-2 H 0 O 2 cPr
1-3 H 0 O 1 2-Me-cPr
1-4 H 0 O 2 2-Me-cPr
1-5 H 1 O 2 cPr
1-6 H 1 O 1 2-Me-cPr
1-7 H 1 O 2 2-Me-cPr
1-8 Me 0 O 1 cPr
1-9 Me 0 O 2 cPr
1-10 Me 0 O 1 2-Me-cPr
1-11 Me 0 O 2 2-Me-cPr
1-12 Me 1 O 2 cPr
1-13 Me 1 O 1 2-Me-cPr
1-14 Me 1 O 2 2-Me-cPr
1-15 H 1 O 2 1-Pyrl
1-16 H 1 O 2 2-Me-1-Pyrl
1-17 H 1 O 2 1-Imizl
1-18 H 1 O 2 4-Me-1-Imizl
1-19 H 1 O 2 5-Me-1-Imizl
1-20 H 1 O 2 2-Me-1-Imizl
1-21 H 1 O 2 1-Pyrazl
1-22 H 1 O 2 3-Me-1-Pyrazl
1-23 H 1 O 2 3-Me-2-Pyrazl
1-24 H 1 O 2 4-Me-1-Pyrazl
1-25 H 1 O 2 1-Triaz(1,2,3)
1-26 H 1 O 2 1-Triaz(1,2,4)
1-27 H 1 O 2 4-Triaz(1,2,4)
1-28 H 1 O 2 1-Tetraz
1-29 H 1 O 3 2-Oxo-1-Pyrldn
1-30 H 1 O 3 2-Oxo-1-Pip
1-31 H 1 O 3 2-Oxo-3-Oxazldn
1-32 H 1 O 3 2-Oxo-3-Oxaznn
1-33 H 1 O 3 3-Me-2-Oxo-1-Imizldn
1-34 H 1 O 3 1-Me-2,4-diOxo-3-Imizldn
1-35 H 1 O 3 1-Pyrl
1-36 H 1 O 3 2-Me-1-Pyrl
1-37 H 1 O 3 1-Imizl
1-38 H 1 O 3 4-Me-1-Imizl
1-39 H 1 O 3 5-Me-1-Imizl
1-40 H 1 O 3 2-Me-1-Imizl
1-41 H 1 O 3 1-Pyrazl
1-42 H 1 O 3 3-Me-1-Pyrazl
1-43 H 1 O 3 3-Me-2-Pyrazl
1-44 H 1 O 3 4-Me-1-Pyrazl
1-45 H 1 O 3 1-Triaz(1,2,3)
1-46 H 1 O 3 1-Triaz(1,2,4)
1-47 H 1 O 3 4-Triaz(1,2,4)
1-48 H 1 O 3 1-Tetraz
1-49 H 1 O 3 2-Tetraz
1-50 H 1 O 1 2-Fur
1-51 H 1 O 1 5-Me-2-Fur
1-52 H 1 O 1 2-Thi
1-53 H 1 O 1 5-Me-2-Thi
1-54 H 1 O 1 3-Thi
1-55 H 1 O 1 3-Me-2-Py
1-56 H 1 O 1 4-Me-2-Py
1-57 H 1 O 1 5-Me-2-Py
1-58 H 1 O 1 3-MeO-2-Py
1-59 H 1 O 1 4-MeO-2-Py
1-60 H 1 O 1 5-MeO-2-Py
1-61 H 1 O 1 3-F-2-Py
1-62 H 1 O 1 4-F-2-Py
1-63 H 1 O 1 5-F-2-Py
1-64 H 1 O 1 3-Cl-2-Py
1-65 H 1 O 1 4-Cl-2-Py
1-66 H 1 O 1 5-Cl-2-Py
1-67 H 1 O 1 3-Py
1-68 H 1 O 1 2-Me-3-Py
1-69 H 1 O 1 4-Me-3-Py
1-70 H 1 O 1 2-Me-5-Py
1-71 H 1 O 1 2-MeO-3-Py
1-72 H 1 O 1 4-MeO-3-Py
1-73 H 1 O 1 2-MeO-5-Py
1-74 H 1 O 1 2-F-3-Py
1-75 H 1 O 1 4-F-3-Py
1-76 H 1 O 1 2-F-5-Py
1-77 H 1 O 1 2-Cl-3-Py
1-78 H 1 O 1 4-Cl-3-Py
1-79 H 1 O 1 2-Cl-5-Py
1-80 H 1 O 1 4-Py
1-81 H 1 O 1 2-Me-4-Py
1-82 H 1 O 1 3-Me-4-Py
1-83 H 1 O 1 2-MeO-4-Py
1-84 H 1 O 1 3-MeO-4-Py
1-85 H 1 O 1 2-F-4-Py
1-86 H 1 O 1 3-F-4-Py
1-87 H 1 O 1 2-Cl-4-Py
1-88 H 1 O 1 3-Cl-4-Py
1-89 H 1 O 1 2-Oxaz
1-90 H 1 O 1 2-Thiz
1-91 H 1 O 1 1-Me-2-Imizl
1-92 H 1 O 1 5-Me-3-Oxadzl(1,2,4)
1-93 H 1 O 1 3-CF₃-5-Oxadzl(1,2,4)
1-94 H 1 O 1 5-CF₃-3-Oxadzl(1,2,4)
1-95 H 1 O 1 5-CF₃-2-Oxadzl(1,3,4)
1-96 H 1 O 2 2-Fur
1-97 H 1 O 2 5-Me-2-Fur
1-98 H 1 O 2 2-Thi
1-99 H 1 O 2 5-Me-2-Thi
1-100 H 1 O 2 3-Thi
1-101 H 1 O 2 2-Py
1-102 H 1 O 2 3-Me-2-Py
1-103 H 1 O 2 4-Me-2-Py
1-104 H 1 O 2 5-Me-2-Py
1-105 H 1 O 2 3-MeO-2-Py
1-106 H 1 O 2 4-MeO-2-Py
1-107 H 1 O 2 5-MeO-2-Py
1-108 H 1 O 2 3-F-2-Py
1-109 H 1 O 2 4-F-2-Py
1-110 H 1 O 2 5-F-2-Py
1-111 H 1 O 2 3-Cl-2-Py
1-112 H 1 O 2 4-Cl-2-Py
1-113 H 1 O 2 5-Cl-2-Py
1-114 H 1 O 2 3-Py
1-115 H 1 O 2 2-Me-3-Py
1-116 H 1 O 2 4-Me-3-Py
1-117 H 1 O 2 2-Me-5-Py
1-118 H 1 O 2 2-MeO-3-Py
1-119 H 1 O 2 4-MeO-3-Py
1-120 H 1 O 2 2-MeO-5-Py
1-121 H 1 O 2 2-F-3-Py
1-122 H 1 O 2 4-F-3-Py
1-123 H 1 O 2 2-F-5-Py
1-124 H 1 O 2 2-Cl-3-Py
1-125 H 1 O 2 4-Cl-3-Py
1-126 H 1 O 2 2-Cl-5-Py
1-127 H 1 O 2 4-Py
1-128 H 1 O 2 2-Me-4-Py
1-129 H 1 O 2 3-Me-4-Py
1-130 H 1 O 2 2-MeO-4-Py
1-131 H 1 O 2 3-MeO-4-Py
1-132 H 1 O 2 2-F-4-Py
1-133 H 1 O 2 3-F-4-Py
1-134 H 1 O 2 2-Cl-4-Py
1-135 H 1 O 2 3-Cl-4-Py
1-136 H 1 O 2 2-Oxaz
1-137 H 1 O 2 2-Thiz
1-138 H 1 O 2 1-Me-2-Imizl
1-139 H 1 O 2 3-Me-5-Oxadzl(1,2,4)
1-140 H 1 O 2 5-Me-3-Oxadzl(1,2,4)
1-141 H 1 O 2 5-Me-2-Oxadzl(1,3,4)
1-142 H 1 O 2 3-CF₃-5-Oxadzl(1,2,4)
1-143 H 1 O 2 5-CF₃-3-Oxadzl(1,2,4)
1-144 H 1 O 2 5-CF₃-2-Oxadzl(1,3,4)
1-145 Me 1 O 2 2-Oxo-1-Pyrldn
1-146 Me 1 O 2 2-Oxo-1-Pip
1-147 Me 1 O 2 2-Oxo-3-Oxazldn
1-148 Me 1 O 2 2-Oxo-3-Oxaznn
1-149 Me 1 O 2 3-Me-2-Oxo-1-Imizldn
1-150 Me 1 O 2 1-Me-2,4-diOxo-3-Imizldn
1-151 Me 1 O 2 1-Pyrl
1-152 Me 1 O 2 2-Me-1-Pyrl
1-153 Me 1 O 2 1-Imizl
1-154 Me 1 O 2 4-Me-1-Imizl
1-155 Me 1 O 2 5-Me-1-Imizl
1-156 Me 1 O 2 2-Me-1-Imizl
1-157 Me 1 O 2 1-Pyrazl
1-158 Me 1 O 2 3-Me-1-Pyrazl
1-159 Me 1 O 2 3-Me-2-Pyrazl
1-160 Me 1 O 2 4-Me-1-Pyrazl
1-161 Me 1 O 2 1-Triaz(1,2,3)
1-162 Me 1 O 2 1-Triaz(1,2,4)
1-163 Me 1 O 2 4-Triaz(1,2,4)
1-164 Me 1 O 2 1-Tetraz
1-165 Me 1 O 2 2-Tetraz
1-166 Me 1 O 3 2-Oxo-1-Pyrldn
1-167 Me 1 O 3 2-Oxo-1-Pip
1-168 Me 1 O 3 2-Oxo-3-Oxazldn
1-169 Me 1 O 3 2-Oxo-3-Oxazldn
1-170 Me 1 O 3 2-Oxo-3-Oxaznn
1-171 Me 1 O 3 3-Me-2-Oxo-1-Imizldn
1-172 Me 1 O 3 1-Me-2,4-diOxo-3-Imizldn
1-173 Me 1 O 3 1-Pyrl
1-174 Me 1 O 3 2-Me-1-Pyrl
1-175 Me 1 O 3 1-Imizl
1-176 Me 1 O 3 4-Me-1-Imizl
1-177 Me 1 O 3 5-Me-1-Imizl
1-178 Me 1 O 3 2-Me-1-Imizl
1-179 Me 1 O 3 1-Pyrazl
1-180 Me 1 O 3 3-Me-1-Pyrazl
1-181 Me 1 O 3 3-Me-2-Pyrazl
1-182 Me 1 O 3 4-Me-1-Pyrazl
1-183 Me 1 O 3 1-Triaz(1,2,3)
1-184 Me 1 O 3 1-Triaz(1,2,4)
1-185 Me 1 O 3 4-Triaz(1,2,4)
1-186 Me 1 O 3 1-Tetraz
1-187 Me 1 O 3 2-Tetraz
1-188 Me 1 O 1 2-Fur
1-189 Me 1 O 1 5-Me-2-Fur
1-190 Me 1 O 1 2-Thi
1-191 Me 1 O 1 5-Me-2-Thi
1-192 Me 1 O 1 3-Thi
1-193 Me 1 O 1 2-Py
1-194 Me 1 O 1 3-Me-2-Py
1-195 Me 1 O 1 4-Me-2-Py
1-196 Me 1 O 1 5-Me-2-Py
1-197 Me 1 O 1 3-MeO-2-Py
1-198 Me 1 O 1 4-MeO-2-Py
1-199 Me 1 O 1 5-MeO-2-Py
1-200 Me 1 O 1 3-F-2-Py
1-201 Me 1 O 1 4-F-2-Py
1-202 Me 1 O 1 5-F-2-Py
1-203 Me 1 O 1 3-Cl-2-Py
1-204 Me 1 O 1 4-Cl-2-Py
1-205 Me 1 O 1 5-Cl-2-Py
1-206 Me 1 O 1 3-Py
1-207 Me 1 O 1 2-Me-3-Py
1-208 Me 1 O 1 4-Me-3-Py
1-209 Me 1 O 1 2-Me-5-Py
1-210 Me 1 O 1 2-MeO-3-Py
1-211 Me 1 O 1 4-MeO-3-Py
1-212 Me 1 O 1 2-MeO-5-Py
1-213 Me 1 O 1 2-F-3-Py
1-214 Me 1 O 1 4-F-3-Py
1-215 Me 1 O 1 2-F-5-Py
1-216 Me 1 O 1 2-Cl-3-Py
1-217 Me 1 O 1 4-Cl-3-Py
1-218 Me 1 O 1 2-Cl-5-Py
1-219 Me 1 O 1 4-Py
1-220 Me 1 O 1 2-Me-4-Py
1-221 Me 1 O 1 3-Me-4-Py
1-222 Me 1 O 1 2-MeO-4-Py
1-223 Me 1 O 1 3-MeO-4-Py
1-224 Me 1 O 1 2-F-4-Py
1-225 Me 1 O 1 3-F-4-Py
1-226 Me 1 O 1 2-Cl-4-Py
1-227 Me 1 O 1 3-Cl-4-Py
1-228 Me 1 O 1 2-Oxaz
1-229 Me 1 O 1 2-Thiz
1-230 Me 1 O 1 1-Me-2-Imizl
1-231 Me 1 O 1 3-Me-5-Oxadzl(1,2,4)
1-232 Me 1 O 1 5-Me-3-Oxadzl(1,2,4)
1-233 Me 1 O 1 5-Me-2-Oxadzl(1,3,4)
1-234 Me 1 O 1 3-CF₃-5-Oxadzl(1,2,4)
1-235 Me 1 O 1 5-CF₃-3-Oxadzl(1,2,4)
1-236 Me 1 O 1 5-CF₃-2-Oxadzl(1,3,4)
1-237 Me 1 O 1 2-Me-5-Tetraz
1-238 Me 1 O 1 1-Me-5-Tetraz
1-239 Me 1 O 2 2-Fur
1-240 Me 1 O 2 5-Me-2-Fur
1-241 Me 1 O 2 2-Thi
1-242 Me 1 O 2 5-Me-2-Thi
1-243 Me 1 O 2 3-Thi
1-244 Me 1 O 2 2-Py
1-245 Me 1 O 2 3-Me-2-Py
1-246 Me 1 O 2 4-Me-2-Py
1-247 Me 1 O 2 5-Me-2-Py
1-248 Me 1 O 2 3-MeO-2-Py
1-249 Me 1 O 2 4-MeO-2-Py
1-250 Me 1 O 2 5-MeO-2-Py
1-251 Me 1 O 2 3-F-2-Py
1-252 Me 1 O 2 4-F-2-Py
1-253 Me 1 O 2 5-F-2-Py
1-254 Me 1 O 2 3-Cl-2-Py
1-255 Me 1 O 2 4-Cl-2-Py
1-256 Me 1 O 2 5-Cl-2-Py
1-257 Me 1 O 2 3-Py
1-258 Me 1 O 2 2-Me-3-Py
1-259 Me 1 O 2 4-Me-3-Py
1-260 Me 1 O 2 2-Me-5-Py
1-261 Me 1 O 2 2-MeO-3-Py
1-262 Me 1 O 2 4-MeO-3-Py
1-263 Me 1 O 2 2-MeO-5-Py
1-264 Me 1 O 2 2-F-3-Py
1-265 Me 1 O 2 4-F-3-Py
1-266 Me 1 O 2 2-F-5-Py
1-267 Me 1 O 2 2-Cl-3-Py
1-268 Me 1 O 2 4-Cl-3-Py
1-269 Me 1 O 2 2-Cl-5-Py
1-270 Me 1 O 2 4-Py
1-271 Me 1 O 2 2-Me-4-Py
1-272 Me 1 O 2 3-Me-4-Py
1-273 Me 1 O 2 2-MeO-4-Py
1-274 Me 1 O 2 3-MeO-4-Py
1-275 Me 1 O 2 2-F-4-Py
1-276 Me 1 O 2 3-F-4-Py
1-277 Me 1 O 2 2-Cl-4-Py
1-278 Me 1 O 2 3-Cl-4-Py
1-279 Me 1 O 2 2-Oxaz
1-280 Me 1 O 2 2-Thiz
1-281 Me 1 O 2 1-Me-2-Imizl
1-282 Me 1 O 2 3-Me-5-Oxadzl(1,2,4)
1-283 Me 1 O 2 5-Me-3-Oxadzl(1,2,4)
1-284 Me 1 O 2 5-Me-2-Oxadzl(1,3,4)
1-285 Me 1 O 2 3-CF₃-5-Oxadzl(1,2,4)
1-286 Me 1 O 2 5-CF₃-3-Oxadzl(1,2,4)
1-287 Me 1 O 2 5-CF₃-2-Oxadzl(1,3,4)
1-288 Me 1 O 2 1-Me-5-Tetraz
1-289 H 1 O 2 5-Me-1-Tetraz
1-290 H 1 O 2 5-Me-2-Tetraz
1-291 H 1 O 3 2-Fur
1-292 H 1 O 3 5-Me-2-Fur
1-293 H 1 O 3 2-Thi
1-294 H 1 O 3 5-Me-2-Thi
1-295 H 1 O 3 3-Thi
1-296 H 1 O 3 2-Py
1-297 H 1 O 3 3-Me-2-Py
1-298 H 1 O 3 4-Me-2-Py
1-299 H 1 O 3 5-Me-2-Py
1-300 H 1 O 3 3-MeO-2-Py
1-301 H 1 O 3 4-MeO-2-Py
1-302 H 1 O 3 5-MeO-2-Py
1-303 H 1 O 3 3-F-2-Py
1-304 H 1 O 3 4-F-2-Py
1-305 H 1 O 3 5-F-2-Py
1-306 H 1 O 3 3-Cl-2-Py
1-307 H 1 O 3 4-Cl-2-Py
1-308 H 1 O 3 5-Cl-2-Py
1-309 H 1 O 3 3-Py
1-310 H 1 O 3 2-Me-3-Py
1-311 H 1 O 3 4-Me-3-Py
1-312 H 1 O 3 2-Me-5-Py
1-313 H 1 O 3 2-MeO-3-Py
1-314 H 1 O 3 4-MeO-3-Py
1-315 H 1 O 3 2-MeO-5-Py
1-316 H 1 O 3 2-F-3-Py
1-317 H 1 O 3 4-F-3-Py
1-318 H 1 O 3 2-F-5-Py
1-319 H 1 O 3 2-Cl-3-Py
1-320 H 1 O 3 4-Cl-3-Py
1-321 H 1 O 3 2-Cl-5-Py
1-322 H 1 O 3 4-Py
1-323 H 1 O 3 2-Me-4-Py
1-324 H 1 O 3 3-Me-4-Py
1-325 H 1 O 3 2-MeO-4-Py
1-326 H 1 O 3 3-MeO-4-Py
1-327 H 1 O 3 2-F-4-Py
1-328 H 1 O 3 3-F-4-Py
1-329 H 1 O 3 2-Cl-4-Py
1-330 H 1 O 3 3-Cl-4-Py
1-331 H 1 O 3 2-Oxaz
1-332 H 1 O 3 2-Thiz
1-333 H 1 O 3 1-Me-2-Imizl
1-334 H 1 O 3 3-Me-5-Oxadzl(1,2,4)
1-335 H 1 O 3 5-Me-3-Oxadzl(1,2,4)
1-336 H 1 O 3 5-Me-2-Oxadzl(1,3,4)
1-337 H 1 O 3 3-CF₃-5-Oxadzl(1,2,4)
1-338 H 1 O 3 5-CF₃-3-Oxadzl(1,2,4)
1-339 H 1 O 3 5-CF₃-2-Oxadzl(1,3,4)
1-340 H 1 O 3 2-Me-5-Tetraz
1-341 H 1 O 3 1-Me-5-Tetraz
1-342 H 1 O 3 5-Me-1-Tetraz
1-343 H 1 O 3 5-Me-2-Tetraz
1-344 Me 1 O 2 5-Me-1-Tetraz
1-345 Me 1 O 2 5-Me-2-Tetraz
1-346 Me 1 O 3 2-Fur
1-347 Me 1 O 3 5-Me-2-Fur
1-348 Me 1 O 3 2-Thi
1-349 Me 1 O 3 5-Me-2-Thi
1-350 Me 1 O 3 3-Thi
1-351 Me 1 O 3 2-Py
1-352 Me 1 O 3 3-Me-2-Py
1-353 Me 1 O 3 4-Me-2-Py
1-354 Me 1 O 3 5-Me-2-Py
1-355 Me 1 O 3 3-MeO-2-Py
1-356 Me 1 O 3 4-MeO-2-Py
1-357 Me 1 O 3 5-MeO-2-Py
1-358 Me 1 O 3 3-F-2-Py
1-359 Me 1 O 3 4-F-2-Py
1-360 Me 1 O 3 5-F-2-Py
1-361 Me 1 O 3 3-Cl-2-Py
1-362 Me 1 O 3 4-Cl-2-Py
1-363 Me 1 O 3 5-Cl-2-Py
1-364 Me 1 O 3 3-Py
1-365 Me 1 O 3 2-Me-3-Py
1-366 Me 1 O 3 4-Me-3-Py
1-367 Me 1 O 3 2-Me-5-Py
1-368 Me 1 O 3 2-MeO-3-Py
1-369 Me 1 O 3 4-MeO-3-Py
1-370 Me 1 O 3 2-MeO-5-Py
1-371 Me 1 O 3 2-F-3-Py
1-372 Me 1 O 3 4-F-3-Py
1-373 Me 1 O 3 2-F-5-Py
1-374 Me 1 O 3 2-Cl-3-Py
1-375 Me 1 O 3 4-Cl-3-Py
1-376 Me 1 O 3 2-Cl-5-Py
1-377 Me 1 O 3 4-Py
1-378 Me 1 O 3 2-Me-4-Py
1-379 Me 1 O 3 3-Me-4-Py
1-380 Me 1 O 3 2-MeO-4-Py
1-381 Me 1 O 3 3-MeO-4-Py
1-382 Me 1 O 3 2-F-4-Py
1-383 Me 1 O 3 3-F-4-Py
1-384 Me 1 O 3 2-Cl-4-Py
1-385 Me 1 O 3 3-Cl-4-Py
1-386 Me 1 O 3 2-Oxaz
1-387 Me 1 O 3 2-Thiz
1-388 Me 1 O 3 1-Me-2-Imizl
1-389 Me 1 O 3 3-Me-5-Oxadzl(1,2,4)
1-390 Me 1 O 3 5-Me-3-Oxadzl(1,2,4)
1-391 Me 1 O 3 5-Me-2-Oxadzl(1,3,4)
1-392 Me 1 O 3 3-CF₃-5-Oxadzl(1,2,4)
1-393 Me 1 O 3 5-CF₃-3-Oxadzl(1,2,4)
1-394 Me 1 O 3 5-CF₃-2-Oxadzl(1,3,4)
1-395 Me 1 O 3 2-Me-5-Tetraz
1-396 Me 1 O 3 1-Me-5-Tetraz
1-397 Me 1 O 3 5-Me-1-Tetraz
1-398 Me 1 O 3 5-Me-2-Tetraz
1-399 H 1 O 2 2-Triaz(1,2,3)
1-400 Me 1 O 2 2-Triaz(1,2,3)
1-401 H 1 O 1 4,5-diMe-2-Thiz
1-402 H 1 O 1 4-Me-2-Thiz
1-403 H 1 O 1 5-Me-2-Thiz
1-404 H 1 O 1 2-Me-5-Thiz
1-405 H 1 O 1 3-Me-5-Thidz(1,2,4)
1-406 H 1 O 1 2-Me-5-Thidz(1,3,4)
1-407 Me 1 O 1 4,5-diMe-2-Thiz
1-408 Me 1 O 1 4-Me-2-Thiz
1-409 Me 1 O 1 5-Me-2-Thiz
1-410 Me 1 O 1 2-Me-5-Thiz
1-411 Me 1 O 1 3-Me-5-Thidz(1,2,4)
1-412 Me 1 O 1 2-Me-5-Thidz(1,3,4)
1-413 H 1 O 1 1-Me-4-Imizl
1-414 H 1 O 1 4-Me-3-Triaz(1,2,4)
1-415 H 1 O 1 3-Me-5-Py
1-416 Me 1 O 1 1-Me-4-Imizl
1-417 Me 1 O 1 4-Me-3-Triaz(1,2,4)
1-418 Me 1 O 1 3-Me-5-Py
1-419 H 1 O 2 1-Et-5-Tetraz
1-420 H 1 O 2 1-Pr-5-Tetraz
1-421 H 1 O 2 1-(i-Pr)-5-Tetraz
1-422 H 1 O 2 1-(c-Pr)-5-Tetraz
1-423 H 1 O 2 1-(2-MeO-Et)-5-Tetraz
1-424 Me 1 O 2 1-Et-5-Tetraz
1-425 Me 1 O 2 1-Pr-5-Tetraz
1-426 Me 1 O 2 1-(i-Pr)-5-Tetraz
1-427 Me 1 O 2 1-(c-Pr)-5-Tetraz
1-428 Me 1 O 2 1-(2-MeO-Et)-5-Tetraz
1-429 H 1 O 2 2-Et-5-Tetraz
1-430 Me 1 O 2 2-Et-5-Tetraz
1-431 H 1 O 3 2-Me-5-Tetraz
1-432 H 1 O 3 1-Me-5-Tetraz
1-433 Me 1 O 3 2-Me-5-Tetraz
1-434 Me 1 O 3 1-Me-5-Tetraz
1-435 H 1 O 1 1-Me-4-Imdzl
1-436 H 1 O 1 3-Me-4-Imdzl
1-437 H 1 O 1 3-Et-4-Imdzl
1-438 Me 1 O 1 1-Me-4-Imdzl
1-439 Me 1 O 1 3-Me-4-Imdzl
1-440 Me 1 O 1 3-Et-4-Imdzl
1-441 H 1 O 1 4-Me-5-Oxo-3-Oxadzl(1,2,4)
1-442 Me 1 O 1 4-Me-5-Oxo-3-Oxadzl(1,2,4)
------------------------------------------------------------------------------。 (Table 6)
-------------------------------------------------- ------------------------------
Compound number R ¹ m W n X ¹
-------------------------------------------------- ------------------------------
1-1 H 0 O 1 cPr
1-2 H 0 O 2 cPr
1-3 H 0 O 1 2-Me-cPr
1-4 H 0 O 2 2-Me-cPr
1-5 H 1 O 2 cPr
1-6 H 1 O 1 2-Me-cPr
1-7 H 1 O 2 2-Me-cPr
1-8 Me 0 O 1 cPr
1-9 Me 0 O 2 cPr
1-10 Me 0 O 1 2-Me-cPr
1-11 Me 0 O 2 2-Me-cPr
1-12 Me 1 O 2 cPr
1-13 Me 1 O 1 2-Me-cPr
1-14 Me 1 O 2 2-Me-cPr
1-15 H 1 O 2 1-Pyrl
1-16 H 1 O 2 2-Me-1-Pyrl
1-17 H 1 O 2 1-Imizl
1-18 H 1 O 2 4-Me-1-Imizl
1-19 H 1 O 2 5-Me-1-Imizl
1-20 H 1 O 2 2-Me-1-Imizl
1-21 H 1 O 2 1-Pyrazl
1-22 H 1 O 2 3-Me-1-Pyrazl
1-23 H 1 O 2 3-Me-2-Pyrazl
1-24 H 1 O 2 4-Me-1-Pyrazl
1-25 H 1 O 2 1-Triaz (1,2,3)
1-26 H 1 O 2 1-Triaz (1,2,4)
1-27 H 1 O 2 4-Triaz (1,2,4)
1-28 H 1 O 2 1-Tetraz
1-29 H 1 O 3 2-Oxo-1-Pyrldn
1-30 H 1 O 3 2-Oxo-1-Pip
1-31 H 1 O 3 2-Oxo-3-Oxazldn
1-32 H 1 O 3 2-Oxo-3-Oxaznn
1-33 H 1 O 3 3-Me-2-Oxo-1-Imizldn
1-34 H 1 O 3 1-Me-2,4-diOxo-3-Imizldn
1-35 H 1 O 3 1-Pyrl
1-36 H 1 O 3 2-Me-1-Pyrl
1-37 H 1 O 3 1-Imizl
1-38 H 1 O 3 4-Me-1-Imizl
1-39 H 1 O 3 5-Me-1-Imizl
1-40 H 1 O 3 2-Me-1-Imizl
1-41 H 1 O 3 1-Pyrazl
1-42 H 1 O 3 3-Me-1-Pyrazl
1-43 H 1 O 3 3-Me-2-Pyrazl
1-44 H 1 O 3 4-Me-1-Pyrazl
1-45 H 1 O 3 1-Triaz (1,2,3)
1-46 H 1 O 3 1-Triaz (1,2,4)
1-47 H 1 O 3 4-Triaz (1,2,4)
1-48 H 1 O 3 1-Tetraz
1-49 H 1 O 3 2-Tetraz
1-50 H 1 O 1 2-Fur
1-51 H 1 O 1 5-Me-2-Fur
1-52 H 1 O 1 2-Thi
1-53 H 1 O 1 5-Me-2-Thi
1-54 H 1 O 1 3-Thi
1-55 H 1 O 1 3-Me-2-Py
1-56 H 1 O 1 4-Me-2-Py
1-57 H 1 O 1 5-Me-2-Py
1-58 H 1 O 1 3-MeO-2-Py
1-59 H 1 O 1 4-MeO-2-Py
1-60 H 1 O 1 5-MeO-2-Py
1-61 H 1 O 1 3-F-2-Py
1-62 H 1 O 1 4-F-2-Py
1-63 H 1 O 1 5-F-2-Py
1-64 H 1 O 1 3-Cl-2-Py
1-65 H 1 O 1 4-Cl-2-Py
1-66 H 1 O 1 5-Cl-2-Py
1-67 H 1 O 1 3-Py
1-68 H 1 O 1 2-Me-3-Py
1-69 H 1 O 1 4-Me-3-Py
1-70 H 1 O 1 2-Me-5-Py
1-71 H 1 O 1 2-MeO-3-Py
1-72 H 1 O 1 4-MeO-3-Py
1-73 H 1 O 1 2-MeO-5-Py
1-74 H 1 O 1 2-F-3-Py
1-75 H 1 O 1 4-F-3-Py
1-76 H 1 O 1 2-F-5-Py
1-77 H 1 O 1 2-Cl-3-Py
1-78 H 1 O 1 4-Cl-3-Py
1-79 H 1 O 1 2-Cl-5-Py
1-80 H 1 O 1 4-Py
1-81 H 1 O 1 2-Me-4-Py
1-82 H 1 O 1 3-Me-4-Py
1-83 H 1 O 1 2-MeO-4-Py
1-84 H 1 O 1 3-MeO-4-Py
1-85 H 1 O 1 2-F-4-Py
1-86 H 1 O 1 3-F-4-Py
1-87 H 1 O 1 2-Cl-4-Py
1-88 H 1 O 1 3-Cl-4-Py
1-89 H 1 O 1 2-Oxaz
1-90 H 1 O 1 2-Thiz
1-91 H 1 O 1 1-Me-2-Imizl
1-92 H 1 O 1 5-Me-3-Oxadzl (1,2,4)
1-93 H 1 O 1 3-CF ₃ -5-Oxadzl (1,2,4)
1-94 H 1 O 1 5-CF ₃ -3-Oxadzl (1,2,4)
1-95 H 1 O 1 5-CF ₃ -2-Oxadzl (1,3,4)
1-96 H 1 O 2 2-Fur
1-97 H 1 O 2 5-Me-2-Fur
1-98 H 1 O 2 2-Thi
1-99 H 1 O 2 5-Me-2-Thi
1-100 H 1 O 2 3-Thi
1-101 H 1 O 2 2-Py
1-102 H 1 O 2 3-Me-2-Py
1-103 H 1 O 2 4-Me-2-Py
1-104 H 1 O 2 5-Me-2-Py
1-105 H 1 O 2 3-MeO-2-Py
1-106 H 1 O 2 4-MeO-2-Py
1-107 H 1 O 2 5-MeO-2-Py
1-108 H 1 O 2 3-F-2-Py
1-109 H 1 O 2 4-F-2-Py
1-110 H 1 O 2 5-F-2-Py
1-111 H 1 O 2 3-Cl-2-Py
1-112 H 1 O 2 4-Cl-2-Py
1-113 H 1 O 2 5-Cl-2-Py
1-114 H 1 O 2 3-Py
1-115 H 1 O 2 2-Me-3-Py
1-116 H 1 O 2 4-Me-3-Py
1-117 H 1 O 2 2-Me-5-Py
1-118 H 1 O 2 2-MeO-3-Py
1-119 H 1 O 2 4-MeO-3-Py
1-120 H 1 O 2 2-MeO-5-Py
1-121 H 1 O 2 2-F-3-Py
1-122 H 1 O 2 4-F-3-Py
1-123 H 1 O 2 2-F-5-Py
1-124 H 1 O 2 2-Cl-3-Py
1-125 H 1 O 2 4-Cl-3-Py
1-126 H 1 O 2 2-Cl-5-Py
1-127 H 1 O 2 4-Py
1-128 H 1 O 2 2-Me-4-Py
1-129 H 1 O 2 3-Me-4-Py
1-130 H 1 O 2 2-MeO-4-Py
1-131 H 1 O 2 3-MeO-4-Py
1-132 H 1 O 2 2-F-4-Py
1-133 H 1 O 2 3-F-4-Py
1-134 H 1 O 2 2-Cl-4-Py
1-135 H 1 O 2 3-Cl-4-Py
1-136 H 1 O 2 2-Oxaz
1-137 H 1 O 2 2-Thiz
1-138 H 1 O 2 1-Me-2-Imizl
1-139 H 1 O 2 3-Me-5-Oxadzl (1,2,4)
1-140 H 1 O 2 5-Me-3-Oxadzl (1,2,4)
1-141 H 1 O 2 5-Me-2-Oxadzl (1,3,4)
1-142 H 1 O 2 3-CF ₃ -5-Oxadzl (1,2,4)
1-143 H 1 O 2 5-CF ₃ -3-Oxadzl (1,2,4)
1-144 H 1 O 2 5-CF ₃ -2-Oxadzl (1,3,4)
1-145 Me 1 O 2 2-Oxo-1-Pyrldn
1-146 Me 1 O 2 2-Oxo-1-Pip
1-147 Me 1 O 2 2-Oxo-3-Oxazldn
1-148 Me 1 O 2 2-Oxo-3-Oxaznn
1-149 Me 1 O 2 3-Me-2-Oxo-1-Imizldn
1-150 Me 1 O 2 1-Me-2,4-diOxo-3-Imizldn
1-151 Me 1 O 2 1-Pyrl
1-152 Me 1 O 2 2-Me-1-Pyrl
1-153 Me 1 O 2 1-Imizl
1-154 Me 1 O 2 4-Me-1-Imizl
1-155 Me 1 O 2 5-Me-1-Imizl
1-156 Me 1 O 2 2-Me-1-Imizl
1-157 Me 1 O 2 1-Pyrazl
1-158 Me 1 O 2 3-Me-1-Pyrazl
1-159 Me 1 O 2 3-Me-2-Pyrazl
1-160 Me 1 O 2 4-Me-1-Pyrazl
1-161 Me 1 O 2 1-Triaz (1,2,3)
1-162 Me 1 O 2 1-Triaz (1,2,4)
1-163 Me 1 O 2 4-Triaz (1,2,4)
1-164 Me 1 O 2 1-Tetraz
1-165 Me 1 O 2 2-Tetraz
1-166 Me 1 O 3 2-Oxo-1-Pyrldn
1-167 Me 1 O 3 2-Oxo-1-Pip
1-168 Me 1 O 3 2-Oxo-3-Oxazldn
1-169 Me 1 O 3 2-Oxo-3-Oxazldn
1-170 Me 1 O 3 2-Oxo-3-Oxaznn
1-171 Me 1 O 3 3-Me-2-Oxo-1-Imizldn
1-172 Me 1 O 3 1-Me-2,4-diOxo-3-Imizldn
1-173 Me 1 O 3 1-Pyrl
1-174 Me 1 O 3 2-Me-1-Pyrl
1-175 Me 1 O 3 1-Imizl
1-176 Me 1 O 3 4-Me-1-Imizl
1-177 Me 1 O 3 5-Me-1-Imizl
1-178 Me 1 O 3 2-Me-1-Imizl
1-179 Me 1 O 3 1-Pyrazl
1-180 Me 1 O 3 3-Me-1-Pyrazl
1-181 Me 1 O 3 3-Me-2-Pyrazl
1-182 Me 1 O 3 4-Me-1-Pyrazl
1-183 Me 1 O 3 1-Triaz (1,2,3)
1-184 Me 1 O 3 1-Triaz (1,2,4)
1-185 Me 1 O 3 4-Triaz (1,2,4)
1-186 Me 1 O 3 1-Tetraz
1-187 Me 1 O 3 2-Tetraz
1-188 Me 1 O 1 2-Fur
1-189 Me 1 O 1 5-Me-2-Fur
1-190 Me 1 O 1 2-Thi
1-191 Me 1 O 1 5-Me-2-Thi
1-192 Me 1 O 1 3-Thi
1-193 Me 1 O 1 2-Py
1-194 Me 1 O 1 3-Me-2-Py
1-195 Me 1 O 1 4-Me-2-Py
1-196 Me 1 O 1 5-Me-2-Py
1-197 Me 1 O 1 3-MeO-2-Py
1-198 Me 1 O 1 4-MeO-2-Py
1-199 Me 1 O 1 5-MeO-2-Py
1-200 Me 1 O 1 3-F-2-Py
1-201 Me 1 O 1 4-F-2-Py
1-202 Me 1 O 1 5-F-2-Py
1-203 Me 1 O 1 3-Cl-2-Py
1-204 Me 1 O 1 4-Cl-2-Py
1-205 Me 1 O 1 5-Cl-2-Py
1-206 Me 1 O 1 3-Py
1-207 Me 1 O 1 2-Me-3-Py
1-208 Me 1 O 1 4-Me-3-Py
1-209 Me 1 O 1 2-Me-5-Py
1-210 Me 1 O 1 2-MeO-3-Py
1-211 Me 1 O 1 4-MeO-3-Py
1-212 Me 1 O 1 2-MeO-5-Py
1-213 Me 1 O 1 2-F-3-Py
1-214 Me 1 O 1 4-F-3-Py
1-215 Me 1 O 1 2-F-5-Py
1-216 Me 1 O 1 2-Cl-3-Py
1-217 Me 1 O 1 4-Cl-3-Py
1-218 Me 1 O 1 2-Cl-5-Py
1-219 Me 1 O 1 4-Py
1-220 Me 1 O 1 2-Me-4-Py
1-221 Me 1 O 1 3-Me-4-Py
1-222 Me 1 O 1 2-MeO-4-Py
1-223 Me 1 O 1 3-MeO-4-Py
1-224 Me 1 O 1 2-F-4-Py
1-225 Me 1 O 1 3-F-4-Py
1-226 Me 1 O 1 2-Cl-4-Py
1-227 Me 1 O 1 3-Cl-4-Py
1-228 Me 1 O 1 2-Oxaz
1-229 Me 1 O 1 2-Thiz
1-230 Me 1 O 1 1-Me-2-Imizl
1-231 Me 1 O 1 3-Me-5-Oxadzl (1,2,4)
1-232 Me 1 O 1 5-Me-3-Oxadzl (1,2,4)
1-233 Me 1 O 1 5-Me-2-Oxadzl (1,3,4)
1-234 Me 1 O 1 3-CF ₃ -5-Oxadzl (1,2,4)
1-235 Me 1 O 1 5-CF ₃ -3-Oxadzl (1,2,4)
1-236 Me 1 O 1 5-CF ₃ -2-Oxadzl (1,3,4)
1-237 Me 1 O 1 2-Me-5-Tetraz
1-238 Me 1 O 1 1-Me-5-Tetraz
1-239 Me 1 O 2 2-Fur
1-240 Me 1 O 2 5-Me-2-Fur
1-241 Me 1 O 2 2-Thi
1-242 Me 1 O 2 5-Me-2-Thi
1-243 Me 1 O 2 3-Thi
1-244 Me 1 O 2 2-Py
1-245 Me 1 O 2 3-Me-2-Py
1-246 Me 1 O 2 4-Me-2-Py
1-247 Me 1 O 2 5-Me-2-Py
1-248 Me 1 O 2 3-MeO-2-Py
1-249 Me 1 O 2 4-MeO-2-Py
1-250 Me 1 O 2 5-MeO-2-Py
1-251 Me 1 O 2 3-F-2-Py
1-252 Me 1 O 2 4-F-2-Py
1-253 Me 1 O 2 5-F-2-Py
1-254 Me 1 O 2 3-Cl-2-Py
1-255 Me 1 O 2 4-Cl-2-Py
1-256 Me 1 O 2 5-Cl-2-Py
1-257 Me 1 O 2 3-Py
1-258 Me 1 O 2 2-Me-3-Py
1-259 Me 1 O 2 4-Me-3-Py
1-260 Me 1 O 2 2-Me-5-Py
1-261 Me 1 O 2 2-MeO-3-Py
1-262 Me 1 O 2 4-MeO-3-Py
1-263 Me 1 O 2 2-MeO-5-Py
1-264 Me 1 O 2 2-F-3-Py
1-265 Me 1 O 2 4-F-3-Py
1-266 Me 1 O 2 2-F-5-Py
1-267 Me 1 O 2 2-Cl-3-Py
1-268 Me 1 O 2 4-Cl-3-Py
1-269 Me 1 O 2 2-Cl-5-Py
1-270 Me 1 O 2 4-Py
1-271 Me 1 O 2 2-Me-4-Py
1-272 Me 1 O 2 3-Me-4-Py
1-273 Me 1 O 2 2-MeO-4-Py
1-274 Me 1 O 2 3-MeO-4-Py
1-275 Me 1 O 2 2-F-4-Py
1-276 Me 1 O 2 3-F-4-Py
1-277 Me 1 O 2 2-Cl-4-Py
1-278 Me 1 O 2 3-Cl-4-Py
1-279 Me 1 O 2 2-Oxaz
1-280 Me 1 O 2 2-Thiz
1-281 Me 1 O 2 1-Me-2-Imizl
1-282 Me 1 O 2 3-Me-5-Oxadzl (1,2,4)
1-283 Me 1 O 2 5-Me-3-Oxadzl (1,2,4)
1-284 Me 1 O 2 5-Me-2-Oxadzl (1,3,4)
1-285 Me 1 O 2 3-CF ₃ -5-Oxadzl (1,2,4)
1-286 Me 1 O 2 5-CF ₃ -3-Oxadzl (1,2,4)
1-287 Me 1 O 2 5-CF ₃ -2-Oxadzl (1,3,4)
1-288 Me 1 O 2 1-Me-5-Tetraz
1-289 H 1 O 2 5-Me-1-Tetraz
1-290 H 1 O 2 5-Me-2-Tetraz
1-291 H 1 O 3 2-Fur
1-292 H 1 O 3 5-Me-2-Fur
1-293 H 1 O 3 2-Thi
1-294 H 1 O 3 5-Me-2-Thi
1-295 H 1 O 3 3-Thi
1-296 H 1 O 3 2-Py
1-297 H 1 O 3 3-Me-2-Py
1-298 H 1 O 3 4-Me-2-Py
1-299 H 1 O 3 5-Me-2-Py
1-300 H 1 O 3 3-MeO-2-Py
1-301 H 1 O 3 4-MeO-2-Py
1-302 H 1 O 3 5-MeO-2-Py
1-303 H 1 O 3 3-F-2-Py
1-304 H 1 O 3 4-F-2-Py
1-305 H 1 O 3 5-F-2-Py
1-306 H 1 O 3 3-Cl-2-Py
1-307 H 1 O 3 4-Cl-2-Py
1-308 H 1 O 3 5-Cl-2-Py
1-309 H 1 O 3 3-Py
1-310 H 1 O 3 2-Me-3-Py
1-311 H 1 O 3 4-Me-3-Py
1-312 H 1 O 3 2-Me-5-Py
1-313 H 1 O 3 2-MeO-3-Py
1-314 H 1 O 3 4-MeO-3-Py
1-315 H 1 O 3 2-MeO-5-Py
1-316 H 1 O 3 2-F-3-Py
1-317 H 1 O 3 4-F-3-Py
1-318 H 1 O 3 2-F-5-Py
1-319 H 1 O 3 2-Cl-3-Py
1-320 H 1 O 3 4-Cl-3-Py
1-321 H 1 O 3 2-Cl-5-Py
1-322 H 1 O 3 4-Py
1-323 H 1 O 3 2-Me-4-Py
1-324 H 1 O 3 3-Me-4-Py
1-325 H 1 O 3 2-MeO-4-Py
1-326 H 1 O 3 3-MeO-4-Py
1-327 H 1 O 3 2-F-4-Py
1-328 H 1 O 3 3-F-4-Py
1-329 H 1 O 3 2-Cl-4-Py
1-330 H 1 O 3 3-Cl-4-Py
1-331 H 1 O 3 2-Oxaz
1-332 H 1 O 3 2-Thiz
1-333 H 1 O 3 1-Me-2-Imizl
1-334 H 1 O 3 3-Me-5-Oxadzl (1,2,4)
1-335 H 1 O 3 5-Me-3-Oxadzl (1,2,4)
1-336 H 1 O 3 5-Me-2-Oxadzl (1,3,4)
1-337 H 1 O 3 3-CF ₃ -5-Oxadzl (1,2,4)
1-338 H 1 O 3 5-CF ₃ -3-Oxadzl (1,2,4)
1-339 H 1 O 3 5-CF ₃ -2-Oxadzl (1,3,4)
1-340 H 1 O 3 2-Me-5-Tetraz
1-341 H 1 O 3 1-Me-5-Tetraz
1-342 H 1 O 3 5-Me-1-Tetraz
1-343 H 1 O 3 5-Me-2-Tetraz
1-344 Me 1 O 2 5-Me-1-Tetraz
1-345 Me 1 O 2 5-Me-2-Tetraz
1-346 Me 1 O 3 2-Fur
1-347 Me 1 O 3 5-Me-2-Fur
1-348 Me 1 O 3 2-Thi
1-349 Me 1 O 3 5-Me-2-Thi
1-350 Me 1 O 3 3-Thi
1-351 Me 1 O 3 2-Py
1-352 Me 1 O 3 3-Me-2-Py
1-353 Me 1 O 3 4-Me-2-Py
1-354 Me 1 O 3 5-Me-2-Py
1-355 Me 1 O 3 3-MeO-2-Py
1-356 Me 1 O 3 4-MeO-2-Py
1-357 Me 1 O 3 5-MeO-2-Py
1-358 Me 1 O 3 3-F-2-Py
1-359 Me 1 O 3 4-F-2-Py
1-360 Me 1 O 3 5-F-2-Py
1-361 Me 1 O 3 3-Cl-2-Py
1-362 Me 1 O 3 4-Cl-2-Py
1-363 Me 1 O 3 5-Cl-2-Py
1-364 Me 1 O 3 3-Py
1-365 Me 1 O 3 2-Me-3-Py
1-366 Me 1 O 3 4-Me-3-Py
1-367 Me 1 O 3 2-Me-5-Py
1-368 Me 1 O 3 2-MeO-3-Py
1-369 Me 1 O 3 4-MeO-3-Py
1-370 Me 1 O 3 2-MeO-5-Py
1-371 Me 1 O 3 2-F-3-Py
1-372 Me 1 O 3 4-F-3-Py
1-373 Me 1 O 3 2-F-5-Py
1-374 Me 1 O 3 2-Cl-3-Py
1-375 Me 1 O 3 4-Cl-3-Py
1-376 Me 1 O 3 2-Cl-5-Py
1-377 Me 1 O 3 4-Py
1-378 Me 1 O 3 2-Me-4-Py
1-379 Me 1 O 3 3-Me-4-Py
1-380 Me 1 O 3 2-MeO-4-Py
1-381 Me 1 O 3 3-MeO-4-Py
1-382 Me 1 O 3 2-F-4-Py
1-383 Me 1 O 3 3-F-4-Py
1-384 Me 1 O 3 2-Cl-4-Py
1-385 Me 1 O 3 3-Cl-4-Py
1-386 Me 1 O 3 2-Oxaz
1-387 Me 1 O 3 2-Thiz
1-388 Me 1 O 3 1-Me-2-Imizl
1-389 Me 1 O 3 3-Me-5-Oxadzl (1,2,4)
1-390 Me 1 O 3 5-Me-3-Oxadzl (1,2,4)
1-391 Me 1 O 3 5-Me-2-Oxadzl (1,3,4)
1-392 Me 1 O 3 3-CF ₃ -5-Oxadzl (1,2,4)
1-393 Me 1 O 3 5-CF ₃ -3-Oxadzl (1,2,4)
1-394 Me 1 O 3 5-CF ₃ -2-Oxadzl (1,3,4)
1-395 Me 1 O 3 2-Me-5-Tetraz
1-396 Me 1 O 3 1-Me-5-Tetraz
1-397 Me 1 O 3 5-Me-1-Tetraz
1-398 Me 1 O 3 5-Me-2-Tetraz
1-399 H 1 O 2 2-Triaz (1,2,3)
1-400 Me 1 O 2 2-Triaz (1,2,3)
1-401 H 1 O 1 4,5-diMe-2-Thiz
1-402 H 1 O 1 4-Me-2-Thiz
1-403 H 1 O 1 5-Me-2-Thiz
1-404 H 1 O 1 2-Me-5-Thiz
1-405 H 1 O 1 3-Me-5-Thidz (1,2,4)
1-406 H 1 O 1 2-Me-5-Thidz (1,3,4)
1-407 Me 1 O 1 4,5-diMe-2-Thiz
1-408 Me 1 O 1 4-Me-2-Thiz
1-409 Me 1 O 1 5-Me-2-Thiz
1-410 Me 1 O 1 2-Me-5-Thiz
1-411 Me 1 O 1 3-Me-5-Thidz (1,2,4)
1-412 Me 1 O 1 2-Me-5-Thidz (1,3,4)
1-413 H 1 O 1 1-Me-4-Imizl
1-414 H 1 O 1 4-Me-3-Triaz (1,2,4)
1-415 H 1 O 1 3-Me-5-Py
1-416 Me 1 O 1 1-Me-4-Imizl
1-417 Me 1 O 1 4-Me-3-Triaz (1,2,4)
1-418 Me 1 O 1 3-Me-5-Py
1-419 H 1 O 2 1-Et-5-Tetraz
1-420 H 1 O 2 1-Pr-5-Tetraz
1-421 H 1 O 2 1- (i-Pr) -5-Tetraz
1-422 H 1 O 2 1- (c-Pr) -5-Tetraz
1-423 H 1 O 2 1- (2-MeO-Et) -5-Tetraz
1-424 Me 1 O 2 1-Et-5-Tetraz
1-425 Me 1 O 2 1-Pr-5-Tetraz
1-426 Me 1 O 2 1- (i-Pr) -5-Tetraz
1-427 Me 1 O 2 1- (c-Pr) -5-Tetraz
1-428 Me 1 O 2 1- (2-MeO-Et) -5-Tetraz
1-429 H 1 O 2 2-Et-5-Tetraz
1-430 Me 1 O 2 2-Et-5-Tetraz
1-431 H 1 O 3 2-Me-5-Tetraz
1-432 H 1 O 3 1-Me-5-Tetraz
1-433 Me 1 O 3 2-Me-5-Tetraz
1-434 Me 1 O 3 1-Me-5-Tetraz
1-435 H 1 O 1 1-Me-4-Imdzl
1-436 H 1 O 1 3-Me-4-Imdzl
1-437 H 1 O 1 3-Et-4-Imdzl
1-438 Me 1 O 1 1-Me-4-Imdzl
1-439 Me 1 O 1 3-Me-4-Imdzl
1-440 Me 1 O 1 3-Et-4-Imdzl
1-441 H 1 O 1 4-Me-5-Oxo-3-Oxadzl (1,2,4)
1-442 Me 1 O 1 4-Me-5-Oxo-3-Oxadzl (1,2,4)
-------------------------------------------------- ----------------------------.

例示化合物表２
Exemplary compounds Table 2

(表７)
--------------------------------------------------------------------------------
化合物 -(CH₂)m-X²
番号 R¹ k m Y 置換位置 X²
--------------------------------------------------------------------------------
2-1 H 1 0 CH a 2-Oxo-1-Pyrldn
2-2 H 1 0 CH a 2-Oxo-1-Pip
2-3 H 1 0 CH a 2-Oxo-3-Oxazldn
2-4 H 1 0 CH a 2-Oxo-3-Oxaznn
2-5 H 1 0 CH a 3-Me-2-Oxo-1-Imizldn
2-6 H 1 0 CH a 3-Me-1,3-dihydro-2-Oxo-2H-1-Imizl
2-7 H 1 0 CH a 3-Me-2-Oxo-1-tetrahydroPymd
2-8 H 1 0 CH a 1-Me-2,4-diOxo-3-Imizldn
2-9 H 1 0 CH a 2-Oxaz
2-10 H 1 0 CH a 4,5-dihydro-2-Oxaz
2-11 H 1 0 CH a 5,6-dihydro-4H-2-Oxazn(1,3)
2-12 H 1 0 CH a 2-Thiz
2-13 H 1 0 CH a 4,5-dihydro-2-Thiz
2-14 H 1 0 CH a 5,6-dihydro-4H-2-Thizn(1,3)
2-15 H 1 0 CH a 5-Me-3-IOxaz
2-16 H 1 0 CH a 4,5-dihydro3-IOxaz
2-17 H 1 0 CH a 1-Me-1H-5-Pyrazl
2-18 H 1 0 CH a 1,2-diMe-4-Imizl
2-19 H 1 0 CH a 2-Imizl
2-20 H 1 0 CH a 1-Me-2-Imizl
2-21 H 1 0 CH a 3,4-diMe-4H-5-Triaz(1,2,4)
2-22 H 1 0 CH a 1,3-diMe-1H-5-Triaz(1,2,4)
2-23 H 1 0 CH a 4-Me-4H-3-Triaz(1,2,4)
2-24 H 1 0 CH a 3-Me-5-Oxadzl(1,2,4)
2-25 H 1 0 CH a 5-Me-2-Oxadzl(1,3,4)
2-26 H 1 0 CH a 5-Me-3-Oxadzl(1,2,4)
2-27 H 1 0 CH a 4-Me-5-Oxo-3-Oxadzl(1,2,4)
2-28 H 1 0 CH a 3-Me-5-Thidz(1,2,4)
2-29 H 1 0 CH a 5-Me-3-Thidz(1,2,4)
2-30 H 1 0 CH a 2-Me-5-Tetraz
2-31 H 1 0 CH a 1-Me-5-Tetraz
2-32 H 1 0 CH a 2-Et-5-Tetraz
2-33 H 1 0 CH a 1-Et-5-Tetraz
2-34 H 1 0 CH a 2-(2-MeO-Et)5-Tetraz
2-35 H 1 0 CH a 1-(2-MeO-Et)5-Tetraz
2-36 H 1 0 CH a 2-(4-methoxybenzyl)5-Tetraz
2-37 H 2 0 CH a 2-Oxo-3-Oxaznn
2-38 H 2 0 CH a 3-Me-2-Oxo-1-tetrahydroPymd
2-39 H 2 0 CH a 1-Me-2,4-diOxo-3-Imizldn
2-40 H 2 0 CH a 5,6-dihydro-4H-2-Oxazn(1,3)
2-41 H 2 0 CH a 2-Thiz
2-42 H 2 0 CH a 5,6-dihydro-4H-2-Thizn(1,3)
2-43 H 2 0 CH a 5-Me-3-Thidz(1,2,4)
2-44 H 2 0 CH a 2-Pr-5-Tetraz
2-45 H 2 1 CH a 2-Oxo-1-Pyrldn
2-46 H 2 1 CH a 2-Oxo-1-Pip
2-47 H 2 1 CH a 2-Oxo-3-Oxazldn
2-48 H 2 1 CH a 2-Oxo-3-Oxaznn
2-49 H 2 1 CH a 3-Me-2-Oxo-1-Imizldn
2-50 H 2 1 CH a 3-Me-1,3-dihydro-2-Oxo-2H-1-Imizl
2-51 H 2 1 CH a 3-Me-2-Oxo-1-tetrahydroPymd
2-52 H 2 1 CH a 1-Me-2,4-diOxo-3-Imizldn
2-53 H 2 1 CH a 2-Oxaz
2-54 H 2 1 CH a 5,6-dihydro-4H-2-Oxazn(1,3)
2-55 H 2 1 CH a 2-Thiz
2-56 H 2 1 CH a 4,5-dihydro-2-Thiz
2-57 H 2 1 CH a 5,6-dihydro-4H-2-Thizn(1,3)
2-58 H 2 1 CH a 5-Me-3-IOxaz
2-59 H 2 1 CH a 4,5-dihydro3-IOxaz
2-60 H 2 1 CH a 1-Me-1H-5-Pyrazl
2-61 H 2 1 CH a 1,2-diMe-4-Imizl
2-62 H 2 1 CH a 2-Imizl
2-63 H 2 1 CH a 1-Me-2-Imizl
2-64 H 2 1 CH a 3,4-diMe-4H-5-Triaz(1,2,4)
2-65 H 2 1 CH a 1,3-diMe-1H-5-Triaz(1,2,4)
2-66 H 2 1 CH a 4-Me-4H-3-Triaz(1,2,4)
2-67 H 2 1 CH a 3-Me-5-Oxadzl(1,2,4)
2-68 H 2 1 CH a 5-Me-2-Oxadzl(1,3,4)
2-69 H 2 1 CH a 5-Me-3-Oxadzl(1,2,4)
2-70 H 2 1 CH a 4-Me-5-Oxo-3-Oxadzl(1,2,4)
2-71 H 2 1 CH a 3-Me-5-Thidz(1,2,4)
2-72 H 2 1 CH a 5-Me-3-Thidz(1,2,4)
2-73 H 2 1 CH a 2-Et-5-Tetraz
2-74 H 2 1 CH a 1-Et-5-Tetraz
2-75 H 2 1 CH a 2-(2-MeO-Et)5-Tetraz
2-76 H 2 1 CH a 1-(2-MeO-Et)5-Tetraz
2-77 H 2 1 CH a 2-Pr-5-Tetraz
2-78 H 1 0 CH b 2-Oxo-1-Pyrldn
2-79 H 1 0 CH b 2-Oxo-1-Pip
2-80 H 1 0 CH b 2-Oxo-3-Oxazldn
2-81 H 1 0 CH b 2-Oxo-3-Oxaznn
2-82 H 1 0 CH b 3-Me-2-Oxo-1-Imizldn
2-83 H 1 0 CH b 3-Me-1,3-dihydro-2-Oxo-2H-1-Imizl
2-84 H 1 0 CH b 3-Me-2-Oxo-1-tetrahydroPymd
2-85 H 1 0 CH b 1-Me-2,4-diOxo-3-Imizldn
2-86 H 1 0 CH b 2-Oxaz
2-87 H 1 0 CH b 4,5-dihydro-2-Oxaz
2-88 H 1 0 CH b 5,6-dihydro-4H-2-Oxazn(1,3)
2-89 H 1 0 CH b 2-Thiz
2-90 H 1 0 CH b 4,5-dihydro-2-Thiz
2-91 H 1 0 CH b 5,6-dihydro-4H-2-Thizn(1,3)
2-92 H 1 0 CH b 5-Me-3-IOxaz
2-93 H 1 0 CH b 4,5-dihydro3-IOxaz
2-94 H 1 0 CH b 1-Me-1H-5-Pyrazl
2-95 H 1 0 CH b 1,2-diMe-4-Imizl
2-96 H 1 0 CH b 2-Imizl
2-97 H 1 0 CH b 1-Me-2-Imizl
2-98 H 1 0 CH b 3,4-diMe-4H-5-Triaz(1,2,4)
2-99 H 1 0 CH b 1,3-diMe-1H-5-Triaz(1,2,4)
2-100 H 1 0 CH b 4-Me-4H-3-Triaz(1,2,4)
2-101 H 1 0 CH b 3-Me-5-Oxadzl(1,2,4)
2-102 H 1 0 CH b 5-Me-2-Oxadzl(1,3,4)
2-103 H 1 0 CH b 5-Me-3-Oxadzl(1,2,4)
2-104 H 1 0 CH b 4-Me-5-Oxo-3-Oxadzl(1,2,4)
2-105 H 1 0 CH b 3-Me-5-Thidz(1,2,4)
2-106 H 1 0 CH b 5-Me-3-Thidz(1,2,4)
2-107 H 1 0 CH b 2-Me-5-Tetraz
2-108 H 1 0 CH b 2-Et-5-Tetraz
2-109 H 1 0 CH b 1-Et-5-Tetraz
2-110 H 1 0 CH b 2-(2-MeO-Et)5-Tetraz
2-111 H 1 0 CH b 1-(2-MeO-Et)5-Tetraz
2-112 H 1 0 CH b 2-Pr-5-Tetraz
2-113 H 2 0 CH b 2-Oxo-1-Pyrldn
2-114 H 2 0 CH b 2-Oxo-1-Pip
2-115 H 2 0 CH b 2-Oxo-3-Oxazldn
2-116 H 2 0 CH b 2-Oxo-3-Oxaznn
2-117 H 2 0 CH b 3-Me-2-Oxo-1-Imizldn
2-118 H 2 0 CH b 3-Me-1,3-dihydro-2-Oxo-2H-1-Imizl
2-119 H 2 0 CH b 3-Me-2-Oxo-1-tetrahydroPymd
2-120 H 2 0 CH b 1-Me-2,4-diOxo-3-Imizldn
2-121 H 2 0 CH b 2-Oxaz
2-122 H 2 0 CH b 5,6-dihydro-4H-2-Oxazn(1,3)
2-123 H 2 0 CH b 2-Thiz
2-124 H 2 0 CH b 4,5-dihydro-2-Thiz
2-125 H 2 0 CH b 5,6-dihydro-4H-2-Thizn(1,3)
2-126 H 2 0 CH b 5-Me-3-IOxaz
2-127 H 2 0 CH b 4,5-dihydro3-IOxaz
2-128 H 2 0 CH b 1-Me-1H-5-Pyrazl
2-129 H 2 0 CH b 1,2-diMe-4-Imizl
2-130 H 2 0 CH b 2-Imizl
2-131 H 2 0 CH b 1-Me-2-Imizl
2-132 H 2 0 CH b 3,4-diMe-4H-5-Triaz(1,2,4)
2-133 H 2 0 CH b 1,3-diMe-1H-5-Triaz(1,2,4)
2-134 H 2 0 CH b 4-Me-4H-3-Triaz(1,2,4)
2-135 H 2 0 CH b 3-Me-5-Oxadzl(1,2,4)
2-136 H 2 0 CH b 5-Me-2-Oxadzl(1,3,4)
2-137 H 2 0 CH b 5-Me-3-Oxadzl(1,2,4)
2-138 H 2 0 CH b 4-Me-5-Oxo-3-Oxadzl(1,2,4)
2-139 H 2 0 CH b 3-Me-5-Thidz(1,2,4)
2-140 H 2 0 CH b 5-Me-3-Thidz(1,2,4)
2-141 H 2 0 CH b 2-Me-5-Tetraz
2-142 H 2 0 CH b 1-Me-5-Tetraz
2-143 H 2 0 CH b 2-Et-5-Tetraz
2-144 H 2 0 CH b 1-Et-5-Tetraz
2-145 H 2 0 CH b 2-(2-MeO-Et)5-Tetraz
2-146 H 2 0 CH b 1-(2-MeO-Et)5-Tetraz
2-147 H 2 0 CH b 2-Pr-5-Tetraz
2-148 Me 1 0 CH a 2-Oxo-1-Pyrldn
2-149 Me 1 0 CH a 2-Oxo-1-Pip
2-150 Me 1 0 CH a 2-Oxo-3-Oxazldn
2-151 Me 1 0 CH a 2-Oxo-3-Oxaznn
2-152 Me 1 0 CH a 3-Me-2-Oxo-1-Imizldn
2-153 Me 1 0 CH a 3-Me-1,3-dihydro-2-Oxo-2H-1-Imizl
2-154 Me 1 0 CH a 3-Me-2-Oxo-1-tetrahydroPymd
2-155 Me 1 0 CH a 1-Me-2,4-diOxo-3-Imizldn
2-156 Me 1 0 CH a 2-Oxaz
2-157 Me 1 0 CH a 4,5-dihydro-2-Oxaz
2-158 Me 1 0 CH a 5,6-dihydro-4H-2-Oxazn(1,3)
2-159 Me 1 0 CH a 2-Thiz
2-160 Me 1 0 CH a 4,5-dihydro-2-Thiz
2-161 Me 1 0 CH a 5,6-dihydro-4H-2-Thizn(1,3)
2-162 Me 1 0 CH a 5-Me-3-IOxaz
2-163 Me 1 0 CH a 4,5-dihydro3-IOxaz
2-164 Me 1 0 CH a 1-Me-1H-5-Pyrazl
2-165 Me 1 0 CH a 1,2-diMe-4-Imizl
2-166 Me 1 0 CH a 2-Imizl
2-167 Me 1 0 CH a 1-Me-2-Imizl
2-168 Me 1 0 CH a 3,4-diMe-4H-5-Triaz(1,2,4)
2-169 Me 1 0 CH a 1,3-diMe-1H-5-Triaz(1,2,4)
2-170 Me 1 0 CH a 4-Me-4H-3-Triaz(1,2,4)
2-171 Me 1 0 CH a 3-Me-5-Oxadzl(1,2,4)
2-172 Me 1 0 CH a 5-Me-2-Oxadzl(1,3,4)
2-173 Me 1 0 CH a 5-Me-3-Oxadzl(1,2,4)
2-174 Me 1 0 CH a 4-Me-5-Oxo-3-Oxadzl(1,2,4)
2-175 Me 1 0 CH a 3-Me-5-Thidz(1,2,4)
2-176 Me 1 0 CH a 5-Me-3-Thidz(1,2,4)
2-177 Me 1 0 CH a 2-Me-5-Tetraz
2-178 Me 1 0 CH a 1-Me-5-Tetraz
2-179 Me 1 0 CH a 2-Et-5-Tetraz
2-180 Me 1 0 CH a 1-Et-5-Tetraz
2-181 Me 1 0 CH a 2-(2-MeO-Et)5-Tetraz
2-182 Me 1 0 CH a 1-(2-MeO-Et)5-Tetraz
2-183 Me 1 0 CH a 2-Pr-5-Tetraz
2-184 Me 2 0 CH a 2-Oxo-1-Pyrldn
2-185 Me 2 0 CH a 2-Oxo-1-Pip
2-186 Me 2 0 CH a 2-Oxo-3-Oxazldn
2-187 Me 2 0 CH a 2-Oxo-3-Oxaznn
2-188 Me 2 0 CH a 3-Me-2-Oxo-1-Imizldn
2-189 Me 2 0 CH a 3-Me-1,3-dihydro-2-Oxo-2H-1-Imizl
2-190 Me 2 0 CH a 3-Me-2-Oxo-1-tetrahydroPymd
2-191 Me 2 0 CH a 1-Me-2,4-diOxo-3-Imizldn
2-192 Me 2 0 CH a 2-Oxaz
2-193 Me 2 0 CH a 4,5-dihydro-2-Oxaz
2-194 Me 2 0 CH a 5,6-dihydro-4H-2-Oxazn(1,3)
2-195 Me 2 0 CH a 2-Thiz
2-196 Me 2 0 CH a 4,5-dihydro-2-Thiz
2-197 Me 2 0 CH a 5,6-dihydro-4H-2-Thizn(1,3)
2-198 Me 2 0 CH a 5-Me-3-IOxaz
2-199 Me 2 0 CH a 4,5-dihydro3-IOxaz
2-200 Me 2 0 CH a 1-Me-1H-5-Pyrazl
2-201 Me 2 0 CH a 1,2-diMe-4-Imizl
2-202 Me 2 0 CH a 2-Imizl
2-203 Me 2 0 CH a 1-Me-2-Imizl
2-204 Me 2 0 CH a 3,4-diMe-4H-5-Triaz(1,2,4)
2-205 Me 2 0 CH a 1,3-diMe-1H-5-Triaz(1,2,4)
2-206 Me 2 0 CH a 4-Me-4H-3-Triaz(1,2,4)
2-207 Me 2 0 CH a 3-Me-5-Oxadzl(1,2,4)
2-208 Me 2 0 CH a 5-Me-2-Oxadzl(1,3,4)
2-209 Me 2 0 CH a 5-Me-3-Oxadzl(1,2,4)
2-210 Me 2 0 CH a 4-Me-5-Oxo-3-Oxadzl(1,2,4)
2-211 Me 2 0 CH a 3-Me-5-Thidz(1,2,4)
2-212 Me 2 0 CH a 5-Me-3-Thidz(1,2,4)
2-213 Me 2 0 CH a 2-Me-5-Tetraz
2-214 Me 2 0 CH a 1-Me-5-Tetraz
2-215 Me 2 0 CH a 2-Et-5-Tetraz
2-216 Me 2 0 CH a 1-Et-5-Tetraz
2-217 Me 2 0 CH a 2-(2-MeO-Et)5-Tetraz
2-218 Me 2 0 CH a 1-(2-MeO-Et)5-Tetraz
2-219 Me 2 0 CH a 2-Pr-5-Tetraz
2-220 Me 1 0 CH b 2-Oxo-1-Pyrldn
2-221 Me 1 0 CH b 2-Oxo-1-Pip
2-222 Me 1 0 CH b 2-Oxo-3-Oxazldn
2-223 Me 1 0 CH b 2-Oxo-3-Oxaznn
2-224 Me 1 0 CH b 3-Me-2-Oxo-1-Imizldn
2-225 Me 1 0 CH b 3-Me-1,3-dihydro-2-Oxo-2H-1-Imizl
2-226 Me 1 0 CH b 3-Me-2-Oxo-1-tetrahydroPymd
2-227 Me 1 0 CH b 1-Me-2,4-diOxo-3-Imizldn
2-228 Me 1 0 CH b 2-Oxaz
2-229 Me 1 0 CH b 4,5-dihydro-2-Oxaz
2-230 Me 1 0 CH b 5,6-dihydro-4H-2-Oxazn(1,3)
2-231 Me 1 0 CH b 2-Thiz
2-232 Me 1 0 CH b 4,5-dihydro-2-Thiz
2-233 Me 1 0 CH b 5,6-dihydro-4H-2-Thizn(1,3)
2-234 Me 1 0 CH b 5-Me-3-IOxaz
2-235 Me 1 0 CH b 4,5-dihydro3-IOxaz
2-236 Me 1 0 CH b 1-Me-1H-5-Pyrazl
2-237 Me 1 0 CH b 1,2-diMe-4-Imizl
2-238 Me 1 0 CH b 2-Imizl
2-239 Me 1 0 CH b 1-Me-2-Imizl
2-240 Me 1 0 CH b 3,4-diMe-4H-5-Triaz(1,2,4)
2-241 Me 1 0 CH b 1,3-diMe-1H-5-Triaz(1,2,4)
2-242 Me 1 0 CH b 4-Me-4H-3-Triaz(1,2,4)
2-243 Me 1 0 CH b 3-Me-5-Oxadzl(1,2,4)
2-244 Me 1 0 CH b 5-Me-2-Oxadzl(1,3,4)
2-245 Me 1 0 CH b 5-Me-3-Oxadzl(1,2,4)
2-246 Me 1 0 CH b 4-Me-5-Oxo-3-Oxadzl(1,2,4)
2-247 Me 1 0 CH b 3-Me-5-Thidz(1,2,4)
2-248 Me 1 0 CH b 5-Me-3-Thidz(1,2,4)
2-249 Me 1 0 CH b 2-Me-5-Tetraz
2-250 Me 1 0 CH b 1-Me-5-Tetraz
2-251 Me 1 0 CH b 2-Et-5-Tetraz
2-252 Me 1 0 CH b 1-Et-5-Tetraz
2-253 Me 1 0 CH b 2-(2-MeO-Et)5-Tetraz
2-254 Me 1 0 CH b 1-(2-MeO-Et)5-Tetraz
2-255 Me 1 0 CH b 2-Pr-5-Tetraz
2-256 Me 2 0 CH b 2-Oxo-1-Pyrldn
2-257 Me 2 0 CH b 2-Oxo-1-Pip
2-258 Me 2 0 CH b 2-Oxo-3-Oxazldn
2-259 Me 2 0 CH b 2-Oxo-3-Oxaznn
2-260 Me 2 0 CH b 3-Me-2-Oxo-1-Imizldn
2-261 Me 2 0 CH b 3-Me-1,3-dihydro-2-Oxo-2H-1-Imizl
2-262 Me 2 0 CH b 3-Me-2-Oxo-1-tetrahydroPymd
2-263 Me 2 0 CH b 1-Me-2,4-diOxo-3-Imizldn
2-264 Me 2 0 CH b 2-Oxaz
2-265 Me 2 0 CH b 4,5-dihydro-2-Oxaz
2-266 Me 2 0 CH b 5,6-dihydro-4H-2-Oxazn(1,3)
2-267 Me 2 0 CH b 2-Thiz
2-268 Me 2 0 CH b 4,5-dihydro-2-Thiz
2-269 Me 2 0 CH b 5,6-dihydro-4H-2-Thizn(1,3)
2-270 Me 2 0 CH b 5-Me-3-IOxaz
2-271 Me 2 0 CH b 4,5-dihydro3-IOxaz
2-272 Me 2 0 CH b 1-Me-1H-5-Pyrazl
2-273 Me 2 0 CH b 1,2-diMe-4-Imizl
2-274 Me 2 0 CH b 2-Imizl
2-275 Me 2 0 CH b 1-Me-2-Imizl
2-276 Me 2 0 CH b 3,4-diMe-4H-5-Triaz(1,2,4)
2-277 Me 2 0 CH b 1,3-diMe-1H-5-Triaz(1,2,4)
2-278 Me 2 0 CH b 4-Me-4H-3-Triaz(1,2,4)
2-279 Me 2 0 CH b 3-Me-5-Oxadzl(1,2,4)
2-280 Me 2 0 CH b 5-Me-2-Oxadzl(1,3,4)
2-281 Me 2 0 CH b 5-Me-3-Oxadzl(1,2,4)
2-282 Me 2 0 CH b 4-Me-5-Oxo-3-Oxadzl(1,2,4)
2-283 Me 2 0 CH b 3-Me-5-Thidz(1,2,4)
2-284 Me 2 0 CH b 5-Me-3-Thidz(1,2,4)
2-285 Me 2 0 CH b 2-Me-5-Tetraz
2-286 Me 2 0 CH b 1-Me-5-Tetraz
2-287 Me 2 0 CH b 2-Et-5-Tetraz
2-288 Me 2 0 CH b 1-Et-5-Tetraz
2-289 Me 2 0 CH b 2-(2-MeO-Et)5-Tetraz
2-290 Me 2 0 CH b 1-(2-MeO-Et)5-Tetraz
2-291 Me 2 0 CH b 2-Pr-5-Tetraz
2-292 H 2 0 CH a 2-Oxo-1-Pyrldn
2-293 H 2 0 CH a 2-Oxo-1-Pip
2-294 H 2 0 CH a 2-Oxo-3-Oxazldn
2-295 H 2 0 CH a 2-Oxo-3-Oxaznn
2-296 H 2 0 CH a 3-Me-2-Oxo-1-Imizldn
2-297 H 2 0 CH a 3-Me-1,3-dihydro-2-Oxo-2H-1-Imizl
2-298 H 2 0 CH a 3-Me-2-Oxo-1-tetrahydroPymd
2-299 H 2 0 CH a 1-Me-2,4-diOxo-3-Imizldn
2-300 H 2 0 CH a 2-Oxaz
2-301 H 2 0 CH a 4,5-dihydro-2-Oxaz
2-302 H 2 0 CH a 5,6-dihydro-4H-2-Oxazn(1,3)
2-303 H 2 0 CH a 2-Thiz
2-304 H 2 0 CH a 4,5-dihydro-2-Thiz
2-305 H 2 0 CH a 5,6-dihydro-4H-2-Thizn(1,3)
2-306 H 2 0 CH a 5-Me-3-IOxaz
2-307 H 2 0 CH a 4,5-dihydro3-IOxaz
2-308 H 2 0 CH a 1-Me-1H-5-Pyrazl
2-309 H 2 0 CH a 1,2-diMe-4-Imizl
2-310 H 2 0 CH a 2-Imizl
2-311 H 2 0 CH a 1-Me-2-Imizl
2-312 H 2 0 CH a 3,4-diMe-4H-5-Triaz(1,2,4)
2-313 H 2 0 CH a 1,3-diMe-1H-5-Triaz(1,2,4)
2-314 H 2 0 CH a 4-Me-4H-3-Triaz(1,2,4)
2-315 H 2 0 CH a 3-Me-5-Oxadzl(1,2,4)
2-316 H 2 0 CH a 5-Me-2-Oxadzl(1,3,4)
2-317 H 2 0 CH a 5-Me-3-Oxadzl(1,2,4)
2-318 H 2 0 CH a 4-Me-5-Oxo-3-Oxadzl(1,2,4)
2-319 H 2 0 CH a 3-Me-5-Thidz(1,2,4)
2-320 H 2 0 CH a 5-Me-3-Thidz(1,2,4)
2-321 H 2 0 CH a 2-Me-5-Tetraz
2-322 H 2 0 CH a 1-Me-5-Tetraz
2-323 H 2 0 CH a 2-Et-5-Tetraz
2-324 H 2 0 CH a 1-Et-5-Tetraz
2-325 H 2 0 CH a 2-(2-MeO-Et)5-Tetraz
2-326 H 2 0 CH a 1-(2-MeO-Et)5-Tetraz
2-327 H 2 0 CH a 2-Pr-5-Tetraz
2-328 Me 2 0 CH a 2-Oxo-1-Pyrldn
2-329 Me 2 0 CH a 2-Oxo-1-Pip
2-330 Me 2 0 CH a 2-Oxo-3-Oxazldn
2-331 Me 2 0 CH a 2-Oxo-3-Oxaznn
2-332 Me 2 0 CH a 3-Me-2-Oxo-1-Imizldn
2-333 Me 2 0 CH a 3-Me-1,3-dihydro-2-Oxo-2H-1-Imizl
2-334 Me 2 0 CH a 3-Me-2-Oxo-1-tetrahydroPymd
2-335 Me 2 0 CH a 1-Me-2,4-diOxo-3-Imizldn
2-336 Me 2 0 CH a 2-Oxaz
2-337 Me 2 0 CH a 4,5-dihydro-2-Oxaz
2-338 Me 2 0 CH a 5,6-dihydro-4H-2-Oxazn(1,3)
2-339 Me 2 0 CH a 2-Thiz
2-340 Me 2 0 CH a 4,5-dihydro-2-Thiz
2-341 Me 2 0 CH a 5,6-dihydro-4H-2-Thizn(1,3)
2-342 Me 2 0 CH a 5-Me-3-IOxaz
2-343 Me 2 0 CH a 4,5-dihydro3-IOxaz
2-344 Me 2 0 CH a 1-Me-1H-5-Pyrazl
2-345 Me 2 0 CH a 1,2-diMe-4-Imizl
2-346 Me 2 0 CH a 2-Imizl
2-347 Me 2 0 CH a 1-Me-2-Imizl
2-348 Me 2 0 CH a 3,4-diMe-4H-5-Triaz(1,2,4)
2-349 Me 2 0 CH a 1,3-diMe-1H-5-Triaz(1,2,4)
2-350 Me 2 0 CH a 4-Me-4H-3-Triaz(1,2,4)
2-351 Me 2 0 CH a 3-Me-5-Oxadzl(1,2,4)
2-352 Me 2 0 CH a 5-Me-2-Oxadzl(1,3,4)
2-353 Me 2 0 CH a 5-Me-3-Oxadzl(1,2,4)
2-354 Me 2 0 CH a 4-Me-5-Oxo-3-Oxadzl(1,2,4)
2-355 Me 2 0 CH a 3-Me-5-Thidz(1,2,4)
2-356 Me 2 0 CH a 5-Me-3-Thidz(1,2,4)
2-357 Me 2 0 CH a 2-Me-5-Tetraz
2-358 Me 2 0 CH a 1-Me-5-Tetraz
2-359 Me 2 0 CH a 2-Et-5-Tetraz
2-360 Me 2 0 CH a 1-Et-5-Tetraz
2-361 Me 2 0 CH a 2-(2-MeO-Et)5-Tetraz
2-362 Me 2 0 CH a 1-(2-MeO-Et)5-Tetraz
2-363 Me 2 0 CH a 2-Pr-5-Tetraz
2-364 Me 1 0 CH a 2-Oxo-1-Pyrldn
------------------------------------------------------------------------------。 (Table 7)
-------------------------------------------------- ------------------------------
Compound-(CH ₂ ) mX ²
Number R ¹ km Y Replacement position X ²
-------------------------------------------------- ------------------------------
2-1 H 1 0 CH a 2-Oxo-1-Pyrldn
2-2 H 1 0 CH a 2-Oxo-1-Pip
2-3 H 1 0 CH a 2-Oxo-3-Oxazldn
2-4 H 1 0 CH a 2-Oxo-3-Oxaznn
2-5 H 1 0 CH a 3-Me-2-Oxo-1-Imizldn
2-6 H 1 0 CH a 3-Me-1,3-dihydro-2-Oxo-2H-1-Imizl
2-7 H 1 0 CH a 3-Me-2-Oxo-1-tetrahydroPymd
2-8 H 1 0 CH a 1-Me-2,4-diOxo-3-Imizldn
2-9 H 1 0 CH a 2-Oxaz
2-10 H 1 0 CH a 4,5-dihydro-2-Oxaz
2-11 H 1 0 CH a 5,6-dihydro-4H-2-Oxazn (1,3)
2-12 H 1 0 CH a 2-Thiz
2-13 H 1 0 CH a 4,5-dihydro-2-Thiz
2-14 H 1 0 CH a 5,6-dihydro-4H-2-Thizn (1,3)
2-15 H 1 0 CH a 5-Me-3-IOxaz
2-16 H 1 0 CH a 4,5-dihydro3-IOxaz
2-17 H 1 0 CH a 1-Me-1H-5-Pyrazl
2-18 H 1 0 CH a 1,2-diMe-4-Imizl
2-19 H 1 0 CH a 2-Imizl
2-20 H 1 0 CH a 1-Me-2-Imizl
2-21 H 1 0 CH a 3,4-diMe-4H-5-Triaz (1,2,4)
2-22 H 1 0 CH a 1,3-diMe-1H-5-Triaz (1,2,4)
2-23 H 1 0 CH a 4-Me-4H-3-Triaz (1,2,4)
2-24 H 1 0 CH a 3-Me-5-Oxadzl (1,2,4)
2-25 H 1 0 CH a 5-Me-2-Oxadzl (1,3,4)
2-26 H 1 0 CH a 5-Me-3-Oxadzl (1,2,4)
2-27 H 1 0 CH a 4-Me-5-Oxo-3-Oxadzl (1,2,4)
2-28 H 1 0 CH a 3-Me-5-Thidz (1,2,4)
2-29 H 1 0 CH a 5-Me-3-Thidz (1,2,4)
2-30 H 1 0 CH a 2-Me-5-Tetraz
2-31 H 1 0 CH a 1-Me-5-Tetraz
2-32 H 1 0 CH a 2-Et-5-Tetraz
2-33 H 1 0 CH a 1-Et-5-Tetraz
2-34 H 1 0 CH a 2- (2-MeO-Et) 5-Tetraz
2-35 H 1 0 CH a 1- (2-MeO-Et) 5-Tetraz
2-36 H 1 0 CH a 2- (4-methoxybenzyl) 5-Tetraz
2-37 H 2 0 CH a 2-Oxo-3-Oxaznn
2-38 H 2 0 CH a 3-Me-2-Oxo-1-tetrahydroPymd
2-39 H 2 0 CH a 1-Me-2,4-diOxo-3-Imizldn
2-40 H 2 0 CH a 5,6-dihydro-4H-2-Oxazn (1,3)
2-41 H 2 0 CH a 2-Thiz
2-42 H 2 0 CH a 5,6-dihydro-4H-2-Thizn (1,3)
2-43 H 2 0 CH a 5-Me-3-Thidz (1,2,4)
2-44 H 2 0 CH a 2-Pr-5-Tetraz
2-45 H 2 1 CH a 2-Oxo-1-Pyrldn
2-46 H 2 1 CH a 2-Oxo-1-Pip
2-47 H 2 1 CH a 2-Oxo-3-Oxazldn
2-48 H 2 1 CH a 2-Oxo-3-Oxaznn
2-49 H 2 1 CH a 3-Me-2-Oxo-1-Imizldn
2-50 H 2 1 CH a 3-Me-1,3-dihydro-2-Oxo-2H-1-Imizl
2-51 H 2 1 CH a 3-Me-2-Oxo-1-tetrahydroPymd
2-52 H 2 1 CH a 1-Me-2,4-diOxo-3-Imizldn
2-53 H 2 1 CH a 2-Oxaz
2-54 H 2 1 CH a 5,6-dihydro-4H-2-Oxazn (1,3)
2-55 H 2 1 CH a 2-Thiz
2-56 H 2 1 CH a 4,5-dihydro-2-Thiz
2-57 H 2 1 CH a 5,6-dihydro-4H-2-Thizn (1,3)
2-58 H 2 1 CH a 5-Me-3-IOxaz
2-59 H 2 1 CH a 4,5-dihydro3-IOxaz
2-60 H 2 1 CH a 1-Me-1H-5-Pyrazl
2-61 H 2 1 CH a 1,2-diMe-4-Imizl
2-62 H 2 1 CH a 2-Imizl
2-63 H 2 1 CH a 1-Me-2-Imizl
2-64 H 2 1 CH a 3,4-diMe-4H-5-Triaz (1,2,4)
2-65 H 2 1 CH a 1,3-diMe-1H-5-Triaz (1,2,4)
2-66 H 2 1 CH a 4-Me-4H-3-Triaz (1,2,4)
2-67 H 2 1 CH a 3-Me-5-Oxadzl (1,2,4)
2-68 H 2 1 CH a 5-Me-2-Oxadzl (1,3,4)
2-69 H 2 1 CH a 5-Me-3-Oxadzl (1,2,4)
2-70 H 2 1 CH a 4-Me-5-Oxo-3-Oxadzl (1,2,4)
2-71 H 2 1 CH a 3-Me-5-Thidz (1,2,4)
2-72 H 2 1 CH a 5-Me-3-Thidz (1,2,4)
2-73 H 2 1 CH a 2-Et-5-Tetraz
2-74 H 2 1 CH a 1-Et-5-Tetraz
2-75 H 2 1 CH a 2- (2-MeO-Et) 5-Tetraz
2-76 H 2 1 CH a 1- (2-MeO-Et) 5-Tetraz
2-77 H 2 1 CH a 2-Pr-5-Tetraz
2-78 H 1 0 CH b 2-Oxo-1-Pyrldn
2-79 H 1 0 CH b 2-Oxo-1-Pip
2-80 H 1 0 CH b 2-Oxo-3-Oxazldn
2-81 H 1 0 CH b 2-Oxo-3-Oxaznn
2-82 H 1 0 CH b 3-Me-2-Oxo-1-Imizldn
2-83 H 1 0 CH b 3-Me-1,3-dihydro-2-Oxo-2H-1-Imizl
2-84 H 1 0 CH b 3-Me-2-Oxo-1-tetrahydroPymd
2-85 H 1 0 CH b 1-Me-2,4-diOxo-3-Imizldn
2-86 H 1 0 CH b 2-Oxaz
2-87 H 1 0 CH b 4,5-dihydro-2-Oxaz
2-88 H 1 0 CH b 5,6-dihydro-4H-2-Oxazn (1,3)
2-89 H 1 0 CH b 2-Thiz
2-90 H 1 0 CH b 4,5-dihydro-2-Thiz
2-91 H 1 0 CH b 5,6-dihydro-4H-2-Thizn (1,3)
2-92 H 1 0 CH b 5-Me-3-IOxaz
2-93 H 1 0 CH b 4,5-dihydro3-IOxaz
2-94 H 1 0 CH b 1-Me-1H-5-Pyrazl
2-95 H 1 0 CH b 1,2-diMe-4-Imizl
2-96 H 1 0 CH b 2-Imizl
2-97 H 1 0 CH b 1-Me-2-Imizl
2-98 H 1 0 CH b 3,4-diMe-4H-5-Triaz (1,2,4)
2-99 H 1 0 CH b 1,3-diMe-1H-5-Triaz (1,2,4)
2-100 H 1 0 CH b 4-Me-4H-3-Triaz (1,2,4)
2-101 H 1 0 CH b 3-Me-5-Oxadzl (1,2,4)
2-102 H 1 0 CH b 5-Me-2-Oxadzl (1,3,4)
2-103 H 1 0 CH b 5-Me-3-Oxadzl (1,2,4)
2-104 H 1 0 CH b 4-Me-5-Oxo-3-Oxadzl (1,2,4)
2-105 H 1 0 CH b 3-Me-5-Thidz (1,2,4)
2-106 H 1 0 CH b 5-Me-3-Thidz (1,2,4)
2-107 H 1 0 CH b 2-Me-5-Tetraz
2-108 H 1 0 CH b 2-Et-5-Tetraz
2-109 H 1 0 CH b 1-Et-5-Tetraz
2-110 H 1 0 CH b 2- (2-MeO-Et) 5-Tetraz
2-111 H 1 0 CH b 1- (2-MeO-Et) 5-Tetraz
2-112 H 1 0 CH b 2-Pr-5-Tetraz
2-113 H 2 0 CH b 2-Oxo-1-Pyrldn
2-114 H 2 0 CH b 2-Oxo-1-Pip
2-115 H 2 0 CH b 2-Oxo-3-Oxazldn
2-116 H 2 0 CH b 2-Oxo-3-Oxaznn
2-117 H 2 0 CH b 3-Me-2-Oxo-1-Imizldn
2-118 H 2 0 CH b 3-Me-1,3-dihydro-2-Oxo-2H-1-Imizl
2-119 H 2 0 CH b 3-Me-2-Oxo-1-tetrahydroPymd
2-120 H 2 0 CH b 1-Me-2,4-diOxo-3-Imizldn
2-121 H 2 0 CH b 2-Oxaz
2-122 H 2 0 CH b 5,6-dihydro-4H-2-Oxazn (1,3)
2-123 H 2 0 CH b 2-Thiz
2-124 H 2 0 CH b 4,5-dihydro-2-Thiz
2-125 H 2 0 CH b 5,6-dihydro-4H-2-Thizn (1,3)
2-126 H 2 0 CH b 5-Me-3-IOxaz
2-127 H 2 0 CH b 4,5-dihydro3-IOxaz
2-128 H 2 0 CH b 1-Me-1H-5-Pyrazl
2-129 H 2 0 CH b 1,2-diMe-4-Imizl
2-130 H 2 0 CH b 2-Imizl
2-131 H 2 0 CH b 1-Me-2-Imizl
2-132 H 2 0 CH b 3,4-diMe-4H-5-Triaz (1,2,4)
2-133 H 2 0 CH b 1,3-diMe-1H-5-Triaz (1,2,4)
2-134 H 2 0 CH b 4-Me-4H-3-Triaz (1,2,4)
2-135 H 2 0 CH b 3-Me-5-Oxadzl (1,2,4)
2-136 H 2 0 CH b 5-Me-2-Oxadzl (1,3,4)
2-137 H 2 0 CH b 5-Me-3-Oxadzl (1,2,4)
2-138 H 2 0 CH b 4-Me-5-Oxo-3-Oxadzl (1,2,4)
2-139 H 2 0 CH b 3-Me-5-Thidz (1,2,4)
2-140 H 2 0 CH b 5-Me-3-Thidz (1,2,4)
2-141 H 2 0 CH b 2-Me-5-Tetraz
2-142 H 2 0 CH b 1-Me-5-Tetraz
2-143 H 2 0 CH b 2-Et-5-Tetraz
2-144 H 2 0 CH b 1-Et-5-Tetraz
2-145 H 2 0 CH b 2- (2-MeO-Et) 5-Tetraz
2-146 H 2 0 CH b 1- (2-MeO-Et) 5-Tetraz
2-147 H 2 0 CH b 2-Pr-5-Tetraz
2-148 Me 1 0 CH a 2-Oxo-1-Pyrldn
2-149 Me 1 0 CH a 2-Oxo-1-Pip
2-150 Me 1 0 CH a 2-Oxo-3-Oxazldn
2-151 Me 1 0 CH a 2-Oxo-3-Oxaznn
2-152 Me 1 0 CH a 3-Me-2-Oxo-1-Imizldn
2-153 Me 1 0 CH a 3-Me-1,3-dihydro-2-Oxo-2H-1-Imizl
2-154 Me 1 0 CH a 3-Me-2-Oxo-1-tetrahydroPymd
2-155 Me 1 0 CH a 1-Me-2,4-diOxo-3-Imizldn
2-156 Me 1 0 CH a 2-Oxaz
2-157 Me 1 0 CH a 4,5-dihydro-2-Oxaz
2-158 Me 1 0 CH a 5,6-dihydro-4H-2-Oxazn (1,3)
2-159 Me 1 0 CH a 2-Thiz
2-160 Me 1 0 CH a 4,5-dihydro-2-Thiz
2-161 Me 1 0 CH a 5,6-dihydro-4H-2-Thizn (1,3)
2-162 Me 1 0 CH a 5-Me-3-IOxaz
2-163 Me 1 0 CH a 4,5-dihydro3-IOxaz
2-164 Me 1 0 CH a 1-Me-1H-5-Pyrazl
2-165 Me 1 0 CH a 1,2-diMe-4-Imizl
2-166 Me 1 0 CH a 2-Imizl
2-167 Me 1 0 CH a 1-Me-2-Imizl
2-168 Me 1 0 CH a 3,4-diMe-4H-5-Triaz (1,2,4)
2-169 Me 1 0 CH a 1,3-diMe-1H-5-Triaz (1,2,4)
2-170 Me 1 0 CH a 4-Me-4H-3-Triaz (1,2,4)
2-171 Me 1 0 CH a 3-Me-5-Oxadzl (1,2,4)
2-172 Me 1 0 CH a 5-Me-2-Oxadzl (1,3,4)
2-173 Me 1 0 CH a 5-Me-3-Oxadzl (1,2,4)
2-174 Me 1 0 CH a 4-Me-5-Oxo-3-Oxadzl (1,2,4)
2-175 Me 1 0 CH a 3-Me-5-Thidz (1,2,4)
2-176 Me 1 0 CH a 5-Me-3-Thidz (1,2,4)
2-177 Me 1 0 CH a 2-Me-5-Tetraz
2-178 Me 1 0 CH a 1-Me-5-Tetraz
2-179 Me 1 0 CH a 2-Et-5-Tetraz
2-180 Me 1 0 CH a 1-Et-5-Tetraz
2-181 Me 1 0 CH a 2- (2-MeO-Et) 5-Tetraz
2-182 Me 1 0 CH a 1- (2-MeO-Et) 5-Tetraz
2-183 Me 1 0 CH a 2-Pr-5-Tetraz
2-184 Me 2 0 CH a 2-Oxo-1-Pyrldn
2-185 Me 2 0 CH a 2-Oxo-1-Pip
2-186 Me 2 0 CH a 2-Oxo-3-Oxazldn
2-187 Me 2 0 CH a 2-Oxo-3-Oxaznn
2-188 Me 2 0 CH a 3-Me-2-Oxo-1-Imizldn
2-189 Me 2 0 CH a 3-Me-1,3-dihydro-2-Oxo-2H-1-Imizl
2-190 Me 2 0 CH a 3-Me-2-Oxo-1-tetrahydroPymd
2-191 Me 2 0 CH a 1-Me-2,4-diOxo-3-Imizldn
2-192 Me 2 0 CH a 2-Oxaz
2-193 Me 2 0 CH a 4,5-dihydro-2-Oxaz
2-194 Me 2 0 CH a 5,6-dihydro-4H-2-Oxazn (1,3)
2-195 Me 2 0 CH a 2-Thiz
2-196 Me 2 0 CH a 4,5-dihydro-2-Thiz
2-197 Me 2 0 CH a 5,6-dihydro-4H-2-Thizn (1,3)
2-198 Me 2 0 CH a 5-Me-3-IOxaz
2-199 Me 2 0 CH a 4,5-dihydro3-IOxaz
2-200 Me 2 0 CH a 1-Me-1H-5-Pyrazl
2-201 Me 2 0 CH a 1,2-diMe-4-Imizl
2-202 Me 2 0 CH a 2-Imizl
2-203 Me 2 0 CH a 1-Me-2-Imizl
2-204 Me 2 0 CH a 3,4-diMe-4H-5-Triaz (1,2,4)
2-205 Me 2 0 CH a 1,3-diMe-1H-5-Triaz (1,2,4)
2-206 Me 2 0 CH a 4-Me-4H-3-Triaz (1,2,4)
2-207 Me 2 0 CH a 3-Me-5-Oxadzl (1,2,4)
2-208 Me 2 0 CH a 5-Me-2-Oxadzl (1,3,4)
2-209 Me 2 0 CH a 5-Me-3-Oxadzl (1,2,4)
2-210 Me 2 0 CH a 4-Me-5-Oxo-3-Oxadzl (1,2,4)
2-211 Me 2 0 CH a 3-Me-5-Thidz (1,2,4)
2-212 Me 2 0 CH a 5-Me-3-Thidz (1,2,4)
2-213 Me 2 0 CH a 2-Me-5-Tetraz
2-214 Me 2 0 CH a 1-Me-5-Tetraz
2-215 Me 2 0 CH a 2-Et-5-Tetraz
2-216 Me 2 0 CH a 1-Et-5-Tetraz
2-217 Me 2 0 CH a 2- (2-MeO-Et) 5-Tetraz
2-218 Me 2 0 CH a 1- (2-MeO-Et) 5-Tetraz
2-219 Me 2 0 CH a 2-Pr-5-Tetraz
2-220 Me 1 0 CH b 2-Oxo-1-Pyrldn
2-221 Me 1 0 CH b 2-Oxo-1-Pip
2-222 Me 1 0 CH b 2-Oxo-3-Oxazldn
2-223 Me 1 0 CH b 2-Oxo-3-Oxaznn
2-224 Me 1 0 CH b 3-Me-2-Oxo-1-Imizldn
2-225 Me 1 0 CH b 3-Me-1,3-dihydro-2-Oxo-2H-1-Imizl
2-226 Me 1 0 CH b 3-Me-2-Oxo-1-tetrahydroPymd
2-227 Me 1 0 CH b 1-Me-2,4-diOxo-3-Imizldn
2-228 Me 1 0 CH b 2-Oxaz
2-229 Me 1 0 CH b 4,5-dihydro-2-Oxaz
2-230 Me 1 0 CH b 5,6-dihydro-4H-2-Oxazn (1,3)
2-231 Me 1 0 CH b 2-Thiz
2-232 Me 1 0 CH b 4,5-dihydro-2-Thiz
2-233 Me 1 0 CH b 5,6-dihydro-4H-2-Thizn (1,3)
2-234 Me 1 0 CH b 5-Me-3-IOxaz
2-235 Me 1 0 CH b 4,5-dihydro3-IOxaz
2-236 Me 1 0 CH b 1-Me-1H-5-Pyrazl
2-237 Me 1 0 CH b 1,2-diMe-4-Imizl
2-238 Me 1 0 CH b 2-Imizl
2-239 Me 1 0 CH b 1-Me-2-Imizl
2-240 Me 1 0 CH b 3,4-diMe-4H-5-Triaz (1,2,4)
2-241 Me 1 0 CH b 1,3-diMe-1H-5-Triaz (1,2,4)
2-242 Me 1 0 CH b 4-Me-4H-3-Triaz (1,2,4)
2-243 Me 1 0 CH b 3-Me-5-Oxadzl (1,2,4)
2-244 Me 1 0 CH b 5-Me-2-Oxadzl (1,3,4)
2-245 Me 1 0 CH b 5-Me-3-Oxadzl (1,2,4)
2-246 Me 1 0 CH b 4-Me-5-Oxo-3-Oxadzl (1,2,4)
2-247 Me 1 0 CH b 3-Me-5-Thidz (1,2,4)
2-248 Me 1 0 CH b 5-Me-3-Thidz (1,2,4)
2-249 Me 1 0 CH b 2-Me-5-Tetraz
2-250 Me 1 0 CH b 1-Me-5-Tetraz
2-251 Me 1 0 CH b 2-Et-5-Tetraz
2-252 Me 1 0 CH b 1-Et-5-Tetraz
2-253 Me 1 0 CH b 2- (2-MeO-Et) 5-Tetraz
2-254 Me 1 0 CH b 1- (2-MeO-Et) 5-Tetraz
2-255 Me 1 0 CH b 2-Pr-5-Tetraz
2-256 Me 2 0 CH b 2-Oxo-1-Pyrldn
2-257 Me 2 0 CH b 2-Oxo-1-Pip
2-258 Me 2 0 CH b 2-Oxo-3-Oxazldn
2-259 Me 2 0 CH b 2-Oxo-3-Oxaznn
2-260 Me 2 0 CH b 3-Me-2-Oxo-1-Imizldn
2-261 Me 2 0 CH b 3-Me-1,3-dihydro-2-Oxo-2H-1-Imizl
2-262 Me 2 0 CH b 3-Me-2-Oxo-1-tetrahydroPymd
2-263 Me 2 0 CH b 1-Me-2,4-diOxo-3-Imizldn
2-264 Me 2 0 CH b 2-Oxaz
2-265 Me 2 0 CH b 4,5-dihydro-2-Oxaz
2-266 Me 2 0 CH b 5,6-dihydro-4H-2-Oxazn (1,3)
2-267 Me 2 0 CH b 2-Thiz
2-268 Me 2 0 CH b 4,5-dihydro-2-Thiz
2-269 Me 2 0 CH b 5,6-dihydro-4H-2-Thizn (1,3)
2-270 Me 2 0 CH b 5-Me-3-IOxaz
2-271 Me 2 0 CH b 4,5-dihydro3-IOxaz
2-272 Me 2 0 CH b 1-Me-1H-5-Pyrazl
2-273 Me 2 0 CH b 1,2-diMe-4-Imizl
2-274 Me 2 0 CH b 2-Imizl
2-275 Me 2 0 CH b 1-Me-2-Imizl
2-276 Me 2 0 CH b 3,4-diMe-4H-5-Triaz (1,2,4)
2-277 Me 2 0 CH b 1,3-diMe-1H-5-Triaz (1,2,4)
2-278 Me 2 0 CH b 4-Me-4H-3-Triaz (1,2,4)
2-279 Me 2 0 CH b 3-Me-5-Oxadzl (1,2,4)
2-280 Me 2 0 CH b 5-Me-2-Oxadzl (1,3,4)
2-281 Me 2 0 CH b 5-Me-3-Oxadzl (1,2,4)
2-282 Me 2 0 CH b 4-Me-5-Oxo-3-Oxadzl (1,2,4)
2-283 Me 2 0 CH b 3-Me-5-Thidz (1,2,4)
2-284 Me 2 0 CH b 5-Me-3-Thidz (1,2,4)
2-285 Me 2 0 CH b 2-Me-5-Tetraz
2-286 Me 2 0 CH b 1-Me-5-Tetraz
2-287 Me 2 0 CH b 2-Et-5-Tetraz
2-288 Me 2 0 CH b 1-Et-5-Tetraz
2-289 Me 2 0 CH b 2- (2-MeO-Et) 5-Tetraz
2-290 Me 2 0 CH b 1- (2-MeO-Et) 5-Tetraz
2-291 Me 2 0 CH b 2-Pr-5-Tetraz
2-292 H 2 0 CH a 2-Oxo-1-Pyrldn
2-293 H 2 0 CH a 2-Oxo-1-Pip
2-294 H 2 0 CH a 2-Oxo-3-Oxazldn
2-295 H 2 0 CH a 2-Oxo-3-Oxaznn
2-296 H 2 0 CH a 3-Me-2-Oxo-1-Imizldn
2-297 H 2 0 CH a 3-Me-1,3-dihydro-2-Oxo-2H-1-Imizl
2-298 H 2 0 CH a 3-Me-2-Oxo-1-tetrahydroPymd
2-299 H 2 0 CH a 1-Me-2,4-diOxo-3-Imizldn
2-300 H 2 0 CH a 2-Oxaz
2-301 H 2 0 CH a 4,5-dihydro-2-Oxaz
2-302 H 2 0 CH a 5,6-dihydro-4H-2-Oxazn (1,3)
2-303 H 2 0 CH a 2-Thiz
2-304 H 2 0 CH a 4,5-dihydro-2-Thiz
2-305 H 2 0 CH a 5,6-dihydro-4H-2-Thizn (1,3)
2-306 H 2 0 CH a 5-Me-3-IOxaz
2-307 H 2 0 CH a 4,5-dihydro3-IOxaz
2-308 H 2 0 CH a 1-Me-1H-5-Pyrazl
2-309 H 2 0 CH a 1,2-diMe-4-Imizl
2-310 H 2 0 CH a 2-Imizl
2-311 H 2 0 CH a 1-Me-2-Imizl
2-312 H 2 0 CH a 3,4-diMe-4H-5-Triaz (1,2,4)
2-313 H 2 0 CH a 1,3-diMe-1H-5-Triaz (1,2,4)
2-314 H 2 0 CH a 4-Me-4H-3-Triaz (1,2,4)
2-315 H 2 0 CH a 3-Me-5-Oxadzl (1,2,4)
2-316 H 2 0 CH a 5-Me-2-Oxadzl (1,3,4)
2-317 H 2 0 CH a 5-Me-3-Oxadzl (1,2,4)
2-318 H 2 0 CH a 4-Me-5-Oxo-3-Oxadzl (1,2,4)
2-319 H 2 0 CH a 3-Me-5-Thidz (1,2,4)
2-320 H 2 0 CH a 5-Me-3-Thidz (1,2,4)
2-321 H 2 0 CH a 2-Me-5-Tetraz
2-322 H 2 0 CH a 1-Me-5-Tetraz
2-323 H 2 0 CH a 2-Et-5-Tetraz
2-324 H 2 0 CH a 1-Et-5-Tetraz
2-325 H 2 0 CH a 2- (2-MeO-Et) 5-Tetraz
2-326 H 2 0 CH a 1- (2-MeO-Et) 5-Tetraz
2-327 H 2 0 CH a 2-Pr-5-Tetraz
2-328 Me 2 0 CH a 2-Oxo-1-Pyrldn
2-329 Me 2 0 CH a 2-Oxo-1-Pip
2-330 Me 2 0 CH a 2-Oxo-3-Oxazldn
2-331 Me 2 0 CH a 2-Oxo-3-Oxaznn
2-332 Me 2 0 CH a 3-Me-2-Oxo-1-Imizldn
2-333 Me 2 0 CH a 3-Me-1,3-dihydro-2-Oxo-2H-1-Imizl
2-334 Me 2 0 CH a 3-Me-2-Oxo-1-tetrahydroPymd
2-335 Me 2 0 CH a 1-Me-2,4-diOxo-3-Imizldn
2-336 Me 2 0 CH a 2-Oxaz
2-337 Me 2 0 CH a 4,5-dihydro-2-Oxaz
2-338 Me 2 0 CH a 5,6-dihydro-4H-2-Oxazn (1,3)
2-339 Me 2 0 CH a 2-Thiz
2-340 Me 2 0 CH a 4,5-dihydro-2-Thiz
2-341 Me 2 0 CH a 5,6-dihydro-4H-2-Thizn (1,3)
2-342 Me 2 0 CH a 5-Me-3-IOxaz
2-343 Me 2 0 CH a 4,5-dihydro3-IOxaz
2-344 Me 2 0 CH a 1-Me-1H-5-Pyrazl
2-345 Me 2 0 CH a 1,2-diMe-4-Imizl
2-346 Me 2 0 CH a 2-Imizl
2-347 Me 2 0 CH a 1-Me-2-Imizl
2-348 Me 2 0 CH a 3,4-diMe-4H-5-Triaz (1,2,4)
2-349 Me 2 0 CH a 1,3-diMe-1H-5-Triaz (1,2,4)
2-350 Me 2 0 CH a 4-Me-4H-3-Triaz (1,2,4)
2-351 Me 2 0 CH a 3-Me-5-Oxadzl (1,2,4)
2-352 Me 2 0 CH a 5-Me-2-Oxadzl (1,3,4)
2-353 Me 2 0 CH a 5-Me-3-Oxadzl (1,2,4)
2-354 Me 2 0 CH a 4-Me-5-Oxo-3-Oxadzl (1,2,4)
2-355 Me 2 0 CH a 3-Me-5-Thidz (1,2,4)
2-356 Me 2 0 CH a 5-Me-3-Thidz (1,2,4)
2-357 Me 2 0 CH a 2-Me-5-Tetraz
2-358 Me 2 0 CH a 1-Me-5-Tetraz
2-359 Me 2 0 CH a 2-Et-5-Tetraz
2-360 Me 2 0 CH a 1-Et-5-Tetraz
2-361 Me 2 0 CH a 2- (2-MeO-Et) 5-Tetraz
2-362 Me 2 0 CH a 1- (2-MeO-Et) 5-Tetraz
2-363 Me 2 0 CH a 2-Pr-5-Tetraz
2-364 Me 1 0 CH a 2-Oxo-1-Pyrldn
-------------------------------------------------- ----------------------------.

上記例示化合物表において用いられている略号は、それぞれ、以下の基を意味する。
cPr: cycropropyl
Et: ethyl
Me: methyl
2-Fur: 2-Furyl
1-Imizl: Imidazol-1-yl
2-Imizl: Imidazol-2-yl
2-Oxo-2H-1-Imizl: 2H-imidazol-2-one-1-yl
4-Imizl: Imidazol-4-yl
1-Imizldn: imidazolidin-1-yl
3-Me-2-Oxo-1-Imizldn: 3-methylimidazolidin-2-one-1-yl
3-Imizldn: imidazolidin-3-yl
1-Me-2,4-diOxo-3-Imizldn: 1-methylimidazolidine-2,4-dione-3-yl
2-Oxaz: 1,3-Oxazol-2-yl
3-IOxaz: isoxazol-3-yl
2-Oxazn(1,3): 1,3-Oxazin-2-yl
3-Oxazldn: Oxazolidin-3-yl
2-Oxo-3-Oxazldn: Oxazolidin-2-one-3-yl
3-Oxaznn: 1,3-oxazinan-3-yl
2-Oxo-3-Oxaznn: 1,3-oxazinan-2-one-3-yl
3-Oxadzl(1,2,4): 1,2,4-oxadiazol-3-yl
5-Oxo-3-Oxadzl(1,2,4): 1,2,4-oxadiazol-5(4H)-one-3-yl
5-Oxadzl(1,2,4): 1,2,4-oxadiazol-5-yl
2-Oxadzl(1,3,4): 1,3,4-oxadiazol-2-yl
1-Pip: Piperidin-1-yl
2-Oxo-1-Pip: Piperidin-2-one-1-yl
2-Py: 2-pyridyl
3-Py: 3-pyridyl
4-Py: 4-pyridyl
5-Py: 5-pyridyl
2-Oxo-1-tetrahydroPymd: tetrahydropyrimidin-2(1H)-one-1-yl
1-Pyrazl: Pyrazol-1-yl
2-Pyrazl: Pyrazol-2-yl
5-Pyrazl: pyrazol-5-yl
1-Pyrl: Pyrrol-1-yl
1-Pyrldn: Pyrrolidin-1-yl
2-Oxo-1-Pyrldn: Pyrrolidin-2-one-1-yl
1-Tetraz: 1-tetrazolyl
2-Tetraz: 2-tetrazolyl
5-Tetraz: tetrazol-5-yl
2-Thi: 2-thienyl
3-Thi: 3-thienyl
2-Thiz: (1,3-)Thiazol-2-yl
2-Thizn(1,3): 1,3- thiazin-2-yl
3-Thidz(1,2,4): 1,2,4-thiadiazol-3-yl
5-Thidz(1,2,4): 1,2,4-thiadiazol-5-yl
1-Triaz(1,2,3): 1,2,3-triazol-1-yl
1-Triaz(1,2,4): 1,2,4-triazol-1-yl
3-Triaz(1,2,4): 1,2,4-triazol-3-yl
4-Triaz(1,2,4): 1,2,4-triazol-4-yl
5-Triaz(1,2,4): 1,2,4-triazol-5-yl。 The abbreviations used in the above exemplary compound table mean the following groups, respectively.
cPr: cycropropyl
Et: ethyl
Me: methyl
2-Fur: 2-Furyl
1-Imizl: Imidazol-1-yl
2-Imizl: Imidazol-2-yl
2-Oxo-2H-1-Imizl: 2H-imidazol-2-one-1-yl
4-Imizl: Imidazol-4-yl
1-Imizldn: imidazolidin-1-yl
3-Me-2-Oxo-1-Imizldn: 3-methylimidazolidin-2-one-1-yl
3-Imizldn: imidazolidin-3-yl
1-Me-2,4-diOxo-3-Imizldn: 1-methylimidazolidine-2,4-dione-3-yl
2-Oxaz: 1,3-Oxazol-2-yl
3-IOxaz: isoxazol-3-yl
2-Oxazn (1,3): 1,3-Oxazin-2-yl
3-Oxazldn: Oxazolidin-3-yl
2-Oxo-3-Oxazldn: Oxazolidin-2-one-3-yl
3-Oxaznn: 1,3-oxazinan-3-yl
2-Oxo-3-Oxaznn: 1,3-oxazinan-2-one-3-yl
3-Oxadzl (1,2,4): 1,2,4-oxadiazol-3-yl
5-Oxo-3-Oxadzl (1,2,4): 1,2,4-oxadiazol-5 (4H) -one-3-yl
5-Oxadzl (1,2,4): 1,2,4-oxadiazol-5-yl
2-Oxadzl (1,3,4): 1,3,4-oxadiazol-2-yl
1-Pip: Piperidin-1-yl
2-Oxo-1-Pip: Piperidin-2-one-1-yl
2-Py: 2-pyridyl
3-Py: 3-pyridyl
4-Py: 4-pyridyl
5-Py: 5-pyridyl
2-Oxo-1-tetrahydroPymd: tetrahydropyrimidin-2 (1H) -one-1-yl
1-Pyrazl: Pyrazol-1-yl
2-Pyrazl: Pyrazol-2-yl
5-Pyrazl: pyrazol-5-yl
1-Pyrl: Pyrrol-1-yl
1-Pyrldn: Pyrrolidin-1-yl
2-Oxo-1-Pyrldn: Pyrrolidin-2-one-1-yl
1-Tetraz: 1-tetrazolyl
2-Tetraz: 2-tetrazolyl
5-Tetraz: tetrazol-5-yl
2-Thi: 2-thienyl
3-Thi: 3-thienyl
2-Thiz: (1,3-) Thiazol-2-yl
2-Thizn (1,3): 1,3- thiazin-2-yl
3-Thidz (1,2,4): 1,2,4-thiadiazol-3-yl
5-Thidz (1,2,4): 1,2,4-thiadiazol-5-yl
1-Triaz (1,2,3): 1,2,3-triazol-1-yl
1-Triaz (1,2,4): 1,2,4-triazol-1-yl
3-Triaz (1,2,4): 1,2,4-triazol-3-yl
4-Triaz (1,2,4): 1,2,4-triazol-4-yl
5-Triaz (1,2,4): 1,2,4-triazol-5-yl.

上述した実施例化合物及び、例示化合物のうち、好適な化合物は、実施例１乃至８、１０乃至１４、１６乃至２８及び３１乃至５４の化合物、並びに例示化合物番号１−１７、１−２１、１−２５、１−２６、１−２８、１−３７、１−４９、１−６７、１−９１、１−９２、１−１４５乃至１−１４９、１−１５３、１−１６１、１−１６２、１−１６４、１−１６５、１−１６９、１−１７５、１−１８６、１−１８７、１−１９３、１−２０６、１−２３０乃至１−２３２、１−２８８乃至１−２９０、１−３４４、１−３４５、１−３９９、１−４０４乃至１−４０６、１−４１２乃至１−４１５、１−４１９、１−４２４乃至１−４２９、１−４３１、１−４３２及び１−４３８乃至１−４４２の化合物であり、
更に好適な化合物は、実施例１乃至８、１０乃至１４、１６、１８乃至２４、２８、３１乃至３５、３７乃至５１、５３及び５４の化合物、並びに例示化合物番号１−１７、１−２５、１−２６、１−２８、１−３７、１−４９、１−６７、１−９１、１−９２、１−１５３、１−１６１、１−１６２、１−１６４、１−１６５、１−１６９、１−１７５、１−１８６、１−１８７、１−１９３、１−２０６、１−２３０乃至１−２３２、１−２８９、１−２９０、１−３４４、１−３４５、１−４０４乃至１−４０６、１−４１２、１−４１３、１−４１５、１−４１９、１−４２４乃至１−４２８、１−４３１、１−４３２及び１−４３８乃至１−４４０の化合物であり、
特に好適な化合物は、実施例１乃至３、５乃至８、１１乃至１３、１９乃至２３、２８、３１、３２、３４、３５、３７乃至５１、５３及び５４の化合物、並びに例示化合物番号１−１７、１−２５、１−２６、１−２８、１−４９、１−６７、１−９１、１−９２、１−１５３、１−１６１、１−１６２、１−１６５、１−１８６、１−１８７、１−２０６、１−２３１、１−２３２、１−２８９、１−３４４、１−４０４、１−４０６、１−４１２、１−４１９、１−４２４乃至１−４２８、１−４３９及び１−４４０の化合物である。 Among the example compounds and exemplary compounds described above, suitable compounds are the compounds of Examples 1 to 8, 10 to 14, 16 to 28 and 31 to 54, and Exemplified Compound Nos. 1-17, 1-21, 1 -25, 1-26, 1-28, 1-37, 1-49, 1-67, 1-91, 1-92, 1-145 to 1-149, 1-153, 1-161, 1-162 1-164, 1-165, 1-169, 1-175, 1-186, 1-187, 1-193, 1-206, 1-230 to 1-232, 1-288 to 1-290, 1 -344, 1-345, 1-399, 1-404 to 1-406, 1-412 to 1-415, 1-419, 1-424 to 1-429, 1-431, 1-432 and 1-438. 1 to 442 compounds,
Further suitable compounds are the compounds of Examples 1 to 8, 10 to 14, 16, 18 to 24, 28, 31 to 35, 37 to 51, 53 and 54, and exemplified compound numbers 1-17, 1-25, 1-26, 1-28, 1-37, 1-49, 1-67, 1-91, 1-92, 1-153, 1-161, 1-162, 1-164, 1-165, 1- 169, 1-175, 1-186, 1-187, 1-193, 1-206, 1-230 to 1-232, 1-289, 1-290, 1-344, 1-345, 1-404 to 1-406, 1-412, 1-413, 1-415, 1-419, 1-424 to 1-428, 1-431, 1-432 and 1-438 to 1-440,
Particularly suitable compounds are the compounds of Examples 1 to 3, 5 to 8, 11 to 13, 19 to 23, 28, 31, 32, 34, 35, 37 to 51, 53 and 54, and exemplified compound number 1- 17, 1-25, 1-26, 1-28, 1-49, 1-67, 1-91, 1-92, 1-153, 1-161, 1-162, 1-165, 1-186, 1-187, 1-206, 1-231, 1-232, 1-289, 1-344, 1-404, 1-406, 1-412, 1-419, 1-424 to 1-428, 1- 439 and 1-440.

（製剤例）
（製剤例１）散剤
実施例１の化合物５ｇ、乳糖８９５ｇおよびトウモロコシデンプン１００ｇをブレンダーで混合することにより、散剤をえることができる。
（製剤例２）顆粒剤
実施例２８の化合物５ｇ、乳糖８６５ｇおよび低置換度ヒドロキシプロピルセルロース１００ｇを混合した後、１０％ヒドロキシプロピルセルロース水溶液３００ｇを加えて練合する。これを押し出し造粒機を用いて造粒し、乾燥すると顆粒剤が得られる。
（製剤例３）錠剤
実施例４８の化合物５ｇ、乳糖９０ｇ、トウモロコシデンプン３４ｇ、結晶セルロース２０ｇおよびステアリン酸マグネシウム１ｇをブレンダーで混合した後、錠剤機で打錠することにより、錠剤が得られる。 (Formulation example)
(Formulation example 1) Powder A powder can be obtained by mixing the compound of Example 1 5g, lactose 895g, and corn starch 100g with a blender.
(Formulation Example 2) Granules After mixing 5 g of the compound of Example 28, 865 g of lactose and 100 g of low-substituted hydroxypropylcellulose, 300 g of 10% hydroxypropylcellulose aqueous solution is added and kneaded. This is granulated using an extrusion granulator and dried to obtain granules.
(Formulation Example 3) Tablet After mixing 5 g of the compound of Example 48, lactose 90 g, corn starch 34 g, crystalline cellulose 20 g and magnesium stearate 1 g with a blender, tablets are obtained by tableting with a tablet machine.

（試験例）
（試験例１）骨芽細胞分化試験
マウス骨髄由来のストローマ細胞であるST2細胞（入手先：理化学研究所）を用いた。本試験において、非働化した牛胎児血清（入手先：Hyclone社、FBS）を10％(v/v)、Penicillin - Streptomycin,Liquid（入手先：GIBCO BRL Cat.No.15140-122）を1%(v/v)となるように混合したα-MEM培地（入手先：GIBCO BRL Cat.No.10370-021）（以下10％-FBS-αMEMと略す）を用いた。本試験での培養はすべてCO₂インキュベータ内（37℃、95％湿度、5％CO₂）で行った。 (Test example)
(Test Example 1) Osteoblast differentiation test ST2 cells (source: RIKEN), which are mouse bone marrow-derived stromal cells, were used. In this study, 10% (v / v) of inactivated fetal bovine serum (source: Hyclone, FBS), 1% of Penicillin-Streptomycin, Liquid (source: GIBCO BRL Cat. No. 15140-122) α-MEM medium (source: GIBCO BRL Cat. No. 10370-021) (hereinafter abbreviated as 10% -FBS-αMEM) was used so as to obtain (v / v). All cultures in this test were carried out in a CO ₂ incubator (37 ° C., 95% humidity, 5% CO ₂ ).

上記の細胞を0.25 %トリプシン溶液（入手先：GIBCO BRL Cat.No.15050-065）2 mLで剥離させ、10％-FBS-αMEM 10 mLを加え細胞を分散させた後、遠心分離により（25℃, 800 rpm, 5分間）細胞を回収した。回収した細胞を10％-FBS-αMEMを用いて、4万 cells/mLの細胞懸濁液を調製した。細胞懸濁液を96穴マイクロプレート（Falcon社）に、4,000個/wellになるように100μLずつ各ウェルに分注し、24時間培養した。下記のコントロール群を除くウェルには、化合物を終濃度0.01、0.03、0.1、0.3 μg/mlになるように分注した。コントロール群のウェルには最終濃度0.1％(v/v)のDMSOを分注した。4日間培養後、各群に対してアルカリホスファターゼ（ALP）活性の測定を行った。 The above cells were detached with 2 mL of a 0.25% trypsin solution (source: GIBCO BRL Cat. No. 15050-065), 10 mL of 10% -FBS-αMEM was added to disperse the cells, and then centrifuged (25 C., 800 rpm, 5 minutes) The cells were collected. A cell suspension of 40,000 cells / mL was prepared from the collected cells using 10% -FBS-αMEM. The cell suspension was dispensed into a 96-well microplate (Falcon) at 100 μL each well at 4,000 cells / well and cultured for 24 hours. The compounds were dispensed to the wells except for the control group described below so that the final concentrations were 0.01, 0.03, 0.1, and 0.3 μg / ml. DMSO at a final concentration of 0.1% (v / v) was dispensed into the wells of the control group. After culturing for 4 days, alkaline phosphatase (ALP) activity was measured for each group.

ALP活性の測定は、以下のように行った。即ち、培養プレートの各ウェルの培地を全量除去した後、Dulbecco’sリン酸バッファー（入手先：GIBCO BRL Cat.No.14190-144）100μLで分注し除去することにより、各wellを2回ずつ洗浄した。10 mM MgCl₂、2％(v/v)TritonX-100（Sigma社）を含む細胞溶解液を作製し、細胞溶解液を50 μL/wellで分注し室温で5分、撹拌した。50 mMジエタノールアミン（和光純薬Cat.No.099-03112）、20 mM p-ニトロフェニルホスファイト（和光純薬Cat.No.147-02343）を含むALP基質溶液を作成し、ALP基質溶液を50 μL/well分注し、室温で10分間放置後、マイクロプレートリーダー（Bio-rad社）を用いて吸光度を測定した。各プレートのコントロール群の測定値を100 %とした際の、被験化合物添加群のアルカリフォスファターゼ活性増加率（％）を算出し、骨芽細胞の分化度として評価した。 Measurement of ALP activity was performed as follows. That is, after removing all the culture medium from each well of the culture plate, each well was washed twice by dispensing and removing with 100 μL of Dulbecco's phosphate buffer (source: GIBCO BRL Cat. No. 14190-144). did. A cell lysate containing 10 mM MgCl ₂ and 2% (v / v) TritonX-100 (Sigma) was prepared, and the cell lysate was dispensed at 50 μL / well and stirred at room temperature for 5 minutes. Prepare an ALP substrate solution containing 50 mM diethanolamine (Wako Pure Chemicals Cat. No. 099-03112) and 20 mM p-nitrophenyl phosphite (Wako Pure Chemicals Cat. No. 147-02343). μL / well was dispensed, allowed to stand at room temperature for 10 minutes, and then the absorbance was measured using a microplate reader (Bio-rad). When the measured value of the control group of each plate was taken as 100%, the increase rate (%) of alkaline phosphatase activity in the test compound addition group was calculated and evaluated as the degree of osteoblast differentiation.

本試験において、実施例１乃至８、１０乃至１４、１６乃至２４、２６乃至２８、３１乃至３５及び３７乃至５４の化合物は、0.03μg/mLで、150%以上のアルカリフォスファターゼ活性増加率を示した。 In this test, the compounds of Examples 1 to 8, 10 to 14, 16 to 24, 26 to 28, 31 to 35, and 37 to 54 showed an increase in alkaline phosphatase activity of 150% or more at 0.03 μg / mL. It was.

（試験例２）破骨細胞形成抑制試験
18日齢ICRマウスを日本SLCより購入し、以下の実験に供した。マウスを頚椎脱臼死させ、左右大腿骨及び脛骨を摘出した。摘出した大腿骨及び脛骨の周囲の組織を除去した後、はさみで細かくミンスした。ミンスした大腿骨及び脛骨に15％-FBS-αMEM 10 mLを加え1分間攪拌後、上清を採取し、セルストレーナー（Becton Dickinson社）で濾過した。15％-FBS-αMEMを用いて、50万 cells/mLの細胞懸濁液を調製した。細胞懸濁液を96穴マイクロプレート（Falcon社）に、5万個/wellになるように100μLずつ各ウェルに分注し、24時間培養した。各ウェルは終濃度20 nMの活性型ビタミンD3(Sigma社、Cat.No.D1530)を分注した。下記のコントロール群を除くウェルには、化合物を終濃度0.01、0.03、0.1、0.3 μg/mlになるように分注した。コントロール群のウェルには最終濃度0.1％(v/v)のDMSOを分注した。5日間培養後、各群に対して酒石酸抵抗性酸性フォスファタ-ゼ（TRAP）活性の測定を行った。 (Test Example 2) Osteoclast formation inhibition test
18-day-old ICR mice were purchased from Japan SLC and subjected to the following experiments. The mouse was killed by cervical vertebra dislocation and the left and right femurs and tibia were removed. After removing the tissue around the removed femur and tibia, it was finely minced with scissors. After adding 10 mL of 15% -FBS-αMEM to the minced femur and tibia and stirring for 1 minute, the supernatant was collected and filtered with a cell strainer (Becton Dickinson). A cell suspension of 500,000 cells / mL was prepared using 15% -FBS-αMEM. The cell suspension was dispensed into a 96-well microplate (Falcon) at 100 μL each well at 50,000 cells / well and cultured for 24 hours. Each well was dispensed with active vitamin D3 (Sigma, Cat. No. D1530) at a final concentration of 20 nM. The compounds were dispensed to the wells except for the control group described below so that the final concentrations were 0.01, 0.03, 0.1, and 0.3 μg / ml. DMSO at a final concentration of 0.1% (v / v) was dispensed into the wells of the control group. After culturing for 5 days, tartrate-resistant acid phosphatase (TRAP) activity was measured for each group.

TRAP活性の測定は、以下のように行った。即ち、培養プレートの各ウェルの培地を全量除去した後、Dulbecco’sリン酸バッファー（GIBCO BRL Cat.No.14190-144）100μLで分注し除去することにより、各wellを2回ずつ洗浄した。アセトン・エタノール混合液（１：１）で1分間保定後、保定液を除去し、Lewkocyte acid phosphataseキット（Sigma社、Cat.No.387-A）を用い37度で30分間染色した。染色液を除去後、10％sodium dodecylsulfate（和光純薬 Cat.No.191-07145）100μLを分注し5分間撹拌後、マイクロプレートリーダー（Bio-rad社）を用いて吸光度を測定した。各プレートのコントロール群の測定値を100 %とした際の、被験化合物添加群のTRAP活性低下率（％）を算出し、破骨細胞形成抑制活性として評価した。 Measurement of TRAP activity was performed as follows. That is, after removing all the medium in each well of the culture plate, each well was washed twice by dispensing and removing with 100 μL of Dulbecco's phosphate buffer (GIBCO BRL Cat. No. 14190-144). After maintaining for 1 minute in an acetone / ethanol mixed solution (1: 1), the retention solution was removed, and staining was performed at 37 ° C. for 30 minutes using a Lewkocyte acid phosphatase kit (Sigma, Cat. No. 387-A). After removing the staining solution, 100 μL of 10% sodium dodecylsulfate (Wako Pure Chemicals Cat. No.191-07145) was dispensed and stirred for 5 minutes, and then the absorbance was measured using a microplate reader (Bio-rad). When the measured value of the control group of each plate was 100%, the TRAP activity decrease rate (%) of the test compound addition group was calculated and evaluated as osteoclast formation inhibitory activity.

本試験において、実施例１１及び２４の化合物は優れた破骨細胞形成抑制作用を示した。 In this test, the compounds of Examples 11 and 24 showed an excellent osteoclast formation inhibitory action.

（試験例３）骨密度への影響
８週齢雌性F344ラットをチャ-ルスリバーより購入し以下の実験に用いた。ケタミン(12.5 mg/ml)・キシラジン(2.5 mg/ml)混合液を0.25 ml/100 gの容量で腹腔内投与して麻酔した後、卵巣摘出又は偽手術を施した。手術翌日より0.5％carboxymethyl cellulose sodium salt溶液(和光純薬 Cat.No.039-01335)に懸濁した被験化合物を一日一回、週6日経口投与した。投与6週後、ケタミン・キシラジン麻酔下腹部大動脈より全採血して安楽死させ、左右大腿骨を摘出した。 (Test Example 3) Effect on bone density Eight-week-old female F344 rats were purchased from Charles River and used in the following experiments. Anesthesia was performed by intraperitoneally administering a mixed solution of ketamine (12.5 mg / ml) and xylazine (2.5 mg / ml) at a volume of 0.25 ml / 100 g, and then ovariectomy or sham operation was performed. From the day after surgery, the test compound suspended in 0.5% carboxymethyl cellulose sodium salt solution (Wako Pure Chemicals Cat. No. 039-01335) was orally administered once a day for 6 days a week. Six weeks after administration, whole blood was collected from the abdominal aorta under ketamine / xylazine anesthesia and euthanized, and the left and right femurs were removed.

摘出した大腿骨は、軟部組織を除去した後、DXA装置DCS-600R（アロカ株式会社）を用いて骨密度測定した。骨密度は、大腿骨全体、並びに、全体を三等分して近位端、骨幹部及び遠位端部分に分けて評価した。 The removed femur was subjected to bone density measurement using a DXA apparatus DCS-600R (Aloka Co., Ltd.) after removing soft tissue. Bone density was evaluated by dividing the whole femur and the whole into three equal parts, the proximal end, the diaphysis and the distal end.

本試験において、実施例４８の化合物は、10mg/kgで有意に骨密度を上昇させた。 In this test, the compound of Example 48 significantly increased bone density at 10 mg / kg.

（試験例４）骨折治癒への影響
12週齢雌性F344ラットを用いて、ケタミン・キシラジン麻酔下、Liらの方法（J.Bone Miner.Res 1999,14:969-979）に準じ骨折術を行ない、手術翌日より0.5％carboxymethyl cellulose sodium salt溶液(和光純薬 Cat.No.039-01335)に懸濁した被験化合物を一日一回、週6日経口投与する。投与39日後、ケタミン・キシラジン麻酔下腹部大動脈より全採血して安楽死させ、大腿骨を摘出する。 (Test Example 4) Effect on fracture healing
Using 12-week-old female F344 rats, under ketamine / xylazine anesthesia, fractures were performed according to the method of Li et al. (J. Bone Miner. Res 1999, 14: 969-979). 0.5% carboxymethyl cellulose sodium The test compound suspended in a salt solution (Wako Pure Chemicals Cat.No.039-01335) is orally administered once a day for 6 days a week. 39 days after administration, whole blood was collected from the abdominal aorta under ketamine / xylazine anesthesia and euthanized, and the femur was removed.

摘出した大腿骨は、軟部組織を除去した後、骨強度測定装置MZ-500D（株式会社マルト-）を用いて測定する。3点曲げ試験を行い最大荷重で被験化合物の効果を評価することができる。 The removed femur is measured using a bone strength measuring apparatus MZ-500D (Malto Co., Ltd.) after removing soft tissue. A three-point bending test can be performed to evaluate the effect of the test compound at the maximum load.

本発明の、一般式（Ｉ）を有する化合物又はその薬理上許容される塩を有効成分として含有する組成物は、骨形成を促進する作用、骨吸収を抑制する作用及び／又は骨密度を改善する作用を有するので、医薬｛特に、骨疾患［例えば、骨粗鬆症（例えば、閉経後骨粗鬆症、老人性骨粗鬆症又はステロイドや免疫抑制剤の使用による続発性骨粗鬆症）、関節リウマチに伴う骨減少症若しくは骨破壊、骨ページェット病、骨折、又は小人症に起因する骨形成不全］又は変形性関節症の予防若しくは治療のための医薬｝として有用である。 The composition of the present invention containing a compound having the general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient improves bone formation, suppresses bone resorption, and / or improves bone density. Drugs, especially bone diseases [eg osteoporosis (eg postmenopausal osteoporosis, senile osteoporosis or secondary osteoporosis due to the use of steroids or immunosuppressants), osteopenia or bone destruction associated with rheumatoid arthritis , Osteogenesis dysfunction caused by Paget's disease, bone fracture, or dwarfism] or a drug for the prevention or treatment of osteoarthritis}.

Claims

The following general formula (I)

[Where:
R ¹ represents a hydrogen atom, a cyclopropyl group or a C ₁ -C ₆ alkyl group,
R ² represents the following general formula (R ² a) or general formula (R ² b)

(Wherein m represents 0 or 1, n represents 0, 1, 2 or 3; k represents 1 or 2; R ³ represents a hydrogen atom or a C ₁ -C ₆ alkyl group; W represents Represents an oxygen atom or a sulfur atom; X ¹ represents a cyclopropyl group which may be substituted with 1 to 3 groups selected from substituent group α, and 1 to 4 groups selected from substituent group α in optionally substituted 5 or 6 membered heterocyclyl group, or represents a 1 to 4 may be substituted with a group 5 or 6 membered heteroaryl group selected from substituent group alpha; X ² is A 5- or 6-membered heterocyclyl group optionally substituted with 1 to 4 groups selected from the substituent group α, or a 1 to 4 group selected from substituent group α A good 5- or 6-membered heteroaryl group; Y represents CH or N; , Oxo _group, C 1 -C ₆ _alkyl, C 1 -C ₆ halogenated alkyl _groups, C 1 -C ₃ alkoxy _-C 1 -C ₆ alkyl group, C ₃ -C ₆ cycloalkyl group and a _C 1 -C Represents a group consisting of ₃ alkoxy groups.).
However, when X ¹ is a cyclopropyl group optionally substituted with 1 to 3 groups selected from the substituent group α, n is 1, 2 or 3.
When X ¹ or X ² is a 5- or 6-membered heterocyclyl group optionally substituted with 1 to 4 groups selected from the substituent group α, and the group is a saturated heterocyclyl group, the group Is a group substituted with at least one oxo group. ]
Or a pharmacologically acceptable salt thereof as an active ingredient.

The pharmaceutical composition according to claim 1, wherein R ¹ is a hydrogen atom, a cyclopropyl group, or a C ₁ -C ₄ alkyl group.

The pharmaceutical composition according to claim ¹ , wherein R ¹ is a hydrogen atom, a methyl group, an ethyl group, a propyl group or a cyclopropyl group.

The pharmaceutical composition according to claim 1, wherein R ¹ is a hydrogen atom or a methyl group.

R ² is the following general formula (R ² a), general formula (R ² b-1) or general formula (R ² b-2)

(Wherein, m, n, k, R ³ , W, X ¹ , X ² and Y are as defined above). The described pharmaceutical composition.

The pharmaceutical composition according to any one of claims 1 to 5, wherein R ³ is a hydrogen atom or a methyl group.

The pharmaceutical composition according to any one of claims 1 to 5, wherein R ³ is a hydrogen atom.

X ¹ is substituted with 1 to 4 groups selected from substituent group α and optionally substituted with 5 or 6 membered heterocyclyl group, or substituted with 1 to 4 groups selected from substituent group α The pharmaceutical composition according to any one of claims 1 to 7, wherein the composition is a 5- or 6-membered heteroaryl group, and n is 1, 2 or 3.

X ² is substituted with 5 to 6-membered heterocyclyl group optionally substituted with 1 to 4 groups selected from substituent group α, or 1 to 4 groups selected from substituent group α The pharmaceutical composition according to any one of claims 1 to 7, wherein the composition is a 5- or 6-membered heteroaryl group, and k is 2.

X ¹ or X ² is a group represented by any one general formula selected from

(Wherein R ^4a , R ^4b , R ^4c and R ^4d are the same or different and are a hydrogen atom or a halogen atom in the definition of substituent group α, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ halogenated group). An alkyl group, a C ₁ -C ₃ alkoxy-C ₁ -C ₆ alkyl group, a C ₃ -C ₆ cycloalkyl group or a C ₁ -C ₃ alkoxy group). Any one of the said pharmaceutical composition.

R ^4a , R ^4b , R ^4c and R ^4d are the same or different and are a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₃ -C ₆ cycloalkyl group or a C ₁ -C ₃ alkoxy-C ₁ -C _6. The pharmaceutical composition according to claim 11, which is an alkyl group.

The R ^4a , R ^4b , R ^4c and R ^4d are the same or different and are a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group or a 2-methoxyethyl group. Pharmaceutical composition.

The pharmaceutical composition according to any one of claims 1 to 7, wherein X ¹ or X ² is a group represented by any one formula selected from the following:
.

8. The compound according to claim 1, wherein R ² is a group represented by the general formula (R ² a), X ¹ is a cyclopropyl group, and n is 1. Pharmaceutical composition.

The pharmaceutical composition according to claim 1, comprising as an active ingredient one compound selected from the following or a salt thereof:
3-Amino-4- {4- [4- (2-methyl-2H-tetrazol-5-yl) phenyl] -1,4-diazepan-1-yl} thieno [2,3-b] pyridine-2- Carboxamide,
3-Amino-4- {4- [4- (1-methyl-1H-tetrazol-5-yl) phenyl] -1,4-diazepan-1-yl} thieno [2,3-b] pyridine-2- Carboxamide,
3-amino-4- {4- [4- (2-oxopyrrolidin-1-yl) phenyl] -1,4-diazepan-1-yl} thieno [2,3-b] pyridine-2-carboxamide;
3-Amino-4- {4- [4- (5-methyl-1,2,4-oxadiazol-3-yl) phenyl] -1,4-diazepan-1-yl} thieno [2,3- b] pyridine-2-carboxamide,
3-Amino-4- {4- [4- (3-methyl-1,2,4-oxadiazol-5-yl) phenyl] -1,4-diazepan-1-yl} thieno [2,3- b] pyridine-2-carboxamide,
3-Amino-4- {4- [4- (2-oxo-1,3-oxazolidine-3-yl) phenyl] -1,4-diazepan-1-yl} thieno [2,3-b] pyridine- 2-carboxamide,
3-Amino-4- {4- [4- (5-methyl-1,3,4-oxadiazol-2-yl) phenyl] -1,4-diazepan-1-yl} thieno [2,3- b] pyridine-2-carboxamide,
3-Amino-4-((3S) -3-{[(3-methyl-1,2,4-oxadiazol-5-yl) methoxy] methyl} piperidin-1-yl) thieno [2,3- b] pyridine-2-carboxamide,
3-Amino-4-((3S) -3-{[2- (2-methyl-2H-tetrazol-5-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine- 2-carboxamide,
3-amino-4- (3-{[(2-methyl-2H-tetrazol-5-yl) methoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide;
3-amino-4-{(3S) -3-[(cyclopropylmethoxy) methyl] piperidin-1-yl} -6-methylthieno [2,3-b] pyridine-2-carboxamide,
3-amino-4-{(3S) -3-[(cyclopropylmethoxy) methyl] piperidin-1-yl} thieno [2,3-b] pyridine-2-carboxamide,
3-Amino-6-methyl-4-((3S) -3-{[2- (2-methyl-2H-tetrazol-5-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3- b] pyridine-2-carboxamide,
3-Amino-4- (3-{[2- (2-oxo-1,3-oxazolidine-3-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine-2- Carboxamide,
3-amino-4-{(3S) -3-[(pyridin-2-ylmethoxy) methyl] piperidin-1-yl} thieno [2,3-b] pyridine-2-carboxamide, and 3-amino-4- ((3S) -3-{[2- (2H-tetrazol-2-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide.

The pharmaceutical composition according to claim 1, which contains, as an active ingredient, one compound selected from the following or a pharmacologically acceptable salt thereof:
3-Amino-6-methyl-4-((3S) -3-{[(3-methyl-1,2,4-oxadiazol-5-yl) methoxy] methyl} piperidin-1-yl) thieno [ 2,3-b] pyridine-2-carboxamide,
3-Amino-4-((3S) -3-{[(5-methyl-1,2,4-oxadiazol-3-yl) methoxy] methyl} piperidin-1-yl) thieno [2,3- b] pyridine-2-carboxamide,
3-amino-6-methyl-4-((3S) -3-{[(5-methyl-1,2,4-oxadiazol-3-yl) methoxy] methyl} piperidin-1-yl) thieno [ 2,3-b] pyridine-2-carboxamide,
3-amino-4-{(3S) -3-[(pyridin-3-ylmethoxy) methyl] piperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide;
3-amino-6-methyl-4-{(3S) -3-[(pyridin-3-ylmethoxy) methyl] piperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide;
3-Amino-6-methyl-4-((3S) -3-{[(1-methyl-1H-imidazol-5-yl) methoxy] methyl} piperidin-1-yl) thieno [2,3-b] Pyridine-2-carboxamide,
3-Amino-4-((3S) -3-{[(1-methyl-1H-imidazol-2-yl) methoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine-2- Carboxamide,
3-Amino-4-((3S) -3-{[(1-ethyl-1H-imidazol-5-yl) methoxy] methyl} piperidin-1-yl) -6-methylthieno [2,3-b] pyridine -2-carboxamide,
3-amino-4-((3S) -3-{[2- (1H-imidazol-1-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide;
3-Amino-4-((3S) -3-{[2- (1H-imidazol-1-yl) ethoxy] methyl} piperidin-1-yl) -6-methylthieno [2,3-b] pyridine-2 -Carboxamide,
3-Amino-4-((3S) -3-{[2- (1H-1,2,3-triazol-1-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b] Pyridine-2-carboxamide,
3-Amino-4-((3S) -3-{[2- (1H-1,2,4-triazol-1-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b] Pyridine-2-carboxamide,
3-Amino-6-methyl-4-((3S)-{[2- (1H-1,2,4-triazol-1-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b ] Pyridine-2-carboxamide,
3-Amino-6-methyl-4-((3S) -3-{[2- (2H-tetrazol-2-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine- 2-carboxamide,
3-amino-4-((3S) -3-{[2- (1H-tetrazol-1-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide;
3-Amino-6-methyl-4-((3S) -3-{[2- (1H-tetrazol-1-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine- 2-carboxamide,
3-Amino-4-((3S) -3-{[2- (5-methyl-1H-tetrazol-1-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine- 2-carboxamide,
3-Amino-6-methyl-4-((3S) -3-{[2- (5-methyl-1H-tetrazol-1-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3- b] pyridine-2-carboxamide,
3-Amino-6-methyl-4-((3S) -3-{[3- (1H-tetrazol-1-yl) propoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine- 2-carboxamide,
3-amino-4-((3S) -3-{[3- (2H-tetrazol-2-yl) propoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine-2-carboxamide;
3-Amino-6-methyl-4-((3S) -3-{[3- (2H-tetrazol-2-yl) propoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine- 2-carboxamide,
3-Amino-4-((3S) -3-{[2- (1-ethyl-1H-tetrazol-5-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3-b] pyridine- 2-carboxamide,
3-Amino-4-((3S) -3-{[2- (1-ethyl-1H-tetrazol-5-yl) ethoxy] methyl} piperidin-1-yl) -6-methylthieno [2,3-b ] Pyridine-2-carboxamide,
3-Amino-6-methyl-4-((3S) -3-{[2- (1-propyl-1H-tetrazol-5-yl) ethoxy] methyl} piperidin-1-yl) thieno [2,3- b] pyridine-2-carboxamide,
3-Amino-4-((3S) -3-{[2- (1-isopropyl-1H-tetrazol-5-yl) ethoxy] methyl} piperidin-1-yl) -6-methylthieno [2,3-b ] Pyridine-2-carboxamide,
3-amino-4-((3S) -3-{[2- (1-cyclopropyl-1H-tetrazol-5-yl) ethoxy] methyl} piperidin-1-yl) -6-methylthieno [2,3- b] Pyridin-2-carboxamide and 3-amino-4-[(3S) -3-({2- [1- (2-methoxyethyl) -1H-tetrazol-5-yl] ethoxy} methyl) piperidine- 1-yl] -6-methylthieno [2,3-b] pyridine-2-carboxamide.

The pharmaceutical composition according to any one of claims 1 to 17, which is used for the prevention or treatment of bone disease or osteoarthritis.

19. The pharmaceutical composition according to claim 18, wherein the bone disease is osteogenesis due to osteoporosis, osteopenia or bone destruction associated with rheumatoid arthritis, Paget's disease, bone fracture, or dwarfism.

20. The pharmaceutical composition according to claim 19, wherein the osteoporosis is postmenopausal osteoporosis, senile osteoporosis or secondary osteoporosis due to the use of steroids or immunosuppressive agents.