JP4932135B2

JP4932135B2 - Imidazole derivatives, their production and use

Info

Publication number: JP4932135B2
Application number: JP2003392992A
Authority: JP
Inventors: 惠司久保; 孝信黒板; 泰宏今枝; 正起川村
Original assignee: Takeda Pharmaceutical Co Ltd
Current assignee: Takeda Pharmaceutical Co Ltd
Priority date: 2002-11-22
Filing date: 2003-11-21
Publication date: 2012-05-16
Anticipated expiration: 2023-11-21
Also published as: JP2004182730A

Description

本発明は活性化血液凝固第Ｘ因子（ＦＸa）を阻害して抗凝固作用ならびに抗血栓作用を有する、動脈および静脈の血栓閉塞性疾患、炎症、癌などの予防および治療に有用な新規イミダゾール誘導体、その製造方法および用途に関する。 The present invention relates to a novel imidazole derivative useful for the prevention and treatment of arterial and venous thromboocclusive diseases, inflammation, cancer and the like, which inhibits activated blood coagulation factor X (FXa) and has anticoagulant action and antithrombotic action. And its manufacturing method and application.

心筋梗塞、脳血栓症等の予防および治療には血栓の形成を抑制することが重要であり、血栓抑制剤として抗トロンビン剤、血小板凝集阻害剤等の研究開発が種々行われている。しかしながら、血小板凝集阻害剤はもちろん、抗トロンビン剤も抗凝固作用と共に血小板の凝集を抑制することから、これらの薬剤は副作用として出血傾向等を示し、その安全性に問題がある。一方、ＦＸa阻害剤は、特異的に凝固因子のみを阻害するため安全な抗凝固剤になると考えられている。
これまで、ＦＸa阻害作用を有する化合物が、例えば特許文献１〜１２および非特許文献１等に開示されている。 In order to prevent and treat myocardial infarction, cerebral thrombosis and the like, it is important to suppress thrombus formation, and various research and developments such as antithrombin agents and platelet aggregation inhibitors have been conducted as thrombus inhibitors. However, not only platelet aggregation inhibitors but also antithrombin agents suppress platelet aggregation as well as anticoagulant action, so these drugs exhibit a tendency to bleed as a side effect and have a problem with their safety. On the other hand, FXa inhibitors are considered to be safe anticoagulants because they specifically inhibit only coagulation factors.
So far, compounds having FXa inhibitory action have been disclosed in, for example, Patent Documents 1 to 12 and Non-Patent Document 1.

特開平７−１１２９７０号公報Japanese Unexamined Patent Publication No. 7-112970 特開平５−２０８９４６号公報Japanese Patent Laid-Open No. 5-208946 国際公開第９６／１６９４０号パンフレットInternational Publication No. 96/16940 Pamphlet 国際公開第９６／４０６７９号パンフレットInternational Publication No. 96/40679 Pamphlet 国際公開第９６／１００２２号パンフレットInternational Publication No. 96/10022 Pamphlet 国際公開第９７／２１４３７号パンフレットInternational Publication No. 97/21437 Pamphlet 国際公開第９９／２６９１９号パンフレットWO99 / 26919 pamphlet 国際公開第９９／３３８０５号パンフレットInternational Publication No. 99/33805 Pamphlet 国際公開第００／０９４８０号パンフレットInternational Publication No. 00/09480 Pamphlet 国際公開第０１／４４１７２号パンフレットInternational Publication No. 01/44172 Pamphlet 国際公開第０２／０６２３４号パンフレットInternational Publication No. 02/06234 Pamphlet 米国特許出願公開第２００２／００４５６１６号パンフレットUS Patent Application Publication No. 2002/0045616 Pamphlet 「ジャーナル・オブ・メディシナル・ケミストリー，１９９８年，第４１巻，ｐ．３３５７」“Journal of Medicinal Chemistry, 1998, 41, p. 3357”

従来のＦＸa阻害剤と比べて、薬効、経口吸収性、作用持続性などに優れ、かつ副作用の少ない、血栓症治療薬として有用な新規化合物の開発が望まれている。 There is a demand for the development of a novel compound useful as a thrombosis therapeutic agent that is superior in drug efficacy, oral absorption, sustained action, etc., and has fewer side effects than conventional FXa inhibitors.

本発明者らは、ＦＸａに対し選択性が高く強力な阻害作用を有するイミダゾール誘導体が経口投与で持続的かつ十分な効果を発揮でき、動脈および静脈の血栓閉塞性疾患、炎症および癌の予防および治療に有用であると考えて、鋭意研究を重ねてきた。
その結果、下記式（Ｉ）で表される新規イミダゾール誘導体またはその塩〔以下、化合物（Ｉ）と称することがある〕が選択的で強力なＦＸａ阻害作用を有し、より安全性が高く、経口投与で持続的かつ十分な効果を発揮することを見い出し、本発明を完成するに至った。 The inventors of the present invention have demonstrated that imidazole derivatives having high selectivity and a strong inhibitory action on FXa can exert a sustained and sufficient effect by oral administration, and prevent arterial and venous thromboembolic diseases, inflammation and cancer and We have conducted extensive research on the idea that it is useful for treatment.
As a result, a novel imidazole derivative represented by the following formula (I) or a salt thereof (hereinafter sometimes referred to as compound (I)) has a selective and powerful FXa inhibitory action, and is more safe, It has been found that oral administration exerts a sustained and sufficient effect, and the present invention has been completed.

すなわち、本発明は、
（１）式（Ｉ）

〔式中、Ｒは置換されていてもよい環状の炭化水素基または置換されていてもよい複素環基を示し、Ｗは結合手または置換されていてもよい２価の鎖状の炭化水素基を示し、Ｘは置換されていてもよい２価の炭化水素基を示し、Ｙは-CO-, -S(O)-, -S(O)₂-または結合手を示し、環Ａは置換されていてもよいピロリジン環、置換されていてもよいピペリジン環または置換されていてもよいパーヒドロアゼピン環を示し、Ｚ^１およびＺ^３はそれぞれ独立して結合手または置換されていてもよい２価の鎖状の炭化水素基を示し、Ｚ^２は -N(R^１)-, -O-, -S(O)-, -S(O)₂-, -CO-, -CH(R^１)- または結合手（Ｒ^１は水素原子、置換されていてもよい炭化水素基、置換されていてもよいアシル基、エステル化されていてもよいカルボキシル基または置換されていてもよいカルバモイル基を示す）を示し、環Ｂは置換されていてもよいイミダゾール環を示し、環Ｂにおけるイミダゾール環が有していてもよい置換基とＲ^１とが互いに結合して置換されていてもよい環を形成していてもよく、ａは０，１または２を示す。〕で表される化合物またはその塩；
（２）前記（１）記載の化合物のプロドラッグ；
（３）Ｒが置換されていてもよいアリール基である前記（１）記載の化合物；
（４）Ｒがハロゲン原子で置換されていてもよいナフチルまたはハロゲン原子で置換されていてもよいインドリルである前記（１）記載の化合物；
（５）Ｗが結合手である前記（１）記載の化合物；
（６）Ｘが置換されていてもよい２価の鎖状の炭化水素基である前記（１）記載の化合物；
（７）Ｙが-CO-である前記（１）記載の化合物；
（８）環Ａが置換されていてもよいピペリジン環である前記（１）記載の化合物；
（９）式

が、式

〔式中、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、Ｒ^８、Ｒ^９、Ｒ^１０、Ｒ^１１、Ｒ^１２およびＲ^１３はそれぞれ独立して水素原子、置換されていてもよい炭化水素基、置換されていてもよい水酸基、置換されていてもよいチオ−ル基、置換されていてもよいアルキルスルフィニル基、置換されていてもよいアルキルスルホニル基、置換されていてもよいアシル基、エステル化されていてもよいカルボキシル基、置換されていてもよいカルバモイル基または置換されていてもよいアミノ基を示し、Ｒ^２とＲ^３、Ｒ^５とＲ^６、Ｒ^６とＲ^７、Ｒ^８とＲ^９、Ｒ^９とＲ^１０またはＲ^１１とＲ^１２とがそれぞれ互いに結合して置換されていてもよい環を形成していてもよい。〕である前記（１）記載の化合物；
（１０）式

が、式

〔式中、環Ｃは置換されていてもよい含窒素複素環を示し、他の記号は前記（９）記載と同意義を示す。〕である前記（１）記載の化合物；
（１１）環Ｂにおけるイミダゾール環が有していてもよい置換基とＲ^１とが環を形成していない前記（１）記載の化合物；
（１２）Ｚ^２が -N(R^１)- または -CH(R^１)-（Ｒ^１は前記（１）記載と同意義を示す。）であり、環Ｂにおけるイミダゾール環が有する置換基とＲ^１とが互いに結合して置換されていてもよい環を形成している前記（１）記載の化合物；
（１３）式（Ｉ）が、式（Ｉａ）

〔式中、環Ｂ’はさらに置換されていてもよいイミダゾール環を示し、Ｚ^２ａはＮまたはＣＨを示し、Ｚ^４は置換されていてもよい２価の鎖状の炭化水素基を示し、他の記号は前記（１）記載と同意義を示す。〕である前記（１）記載の化合物；
（１４）Ｚ^２ａが窒素原子である前記（１３）記載の化合物；
（１５）Ｚ^３およびＺ^４がそれぞれ独立してオキソ基で置換されていてもよい２価の鎖状の炭化水素基である前記（１３）記載の化合物；
（１６）式（Ｉ）が、式（Ｉｂ）

〔式中、Ｒ^１４およびＲ^１５はそれぞれ独立して水素原子、置換されていてもよい炭化水素基、置換されていてもよい水酸基、置換されていてもよいチオ−ル基、置換されていてもよいアルキルスルフィニル基、置換されていてもよいアルキルスルホニル基、置換されていてもよいアシル基、エステル化されていてもよいカルボキシル基、置換されていてもよいカルバモイル基または置換されていてもよいアミノ基を示し、Ｒ^１４とＲ^１５とが互いに結合して置換されていてもよい環を形成していてもよく、他の記号は前記（１）または（１３）記載と同意義を示す。〕である前記（１）記載の化合物；
（１７）式（Ｉ）が、式（Ｉｃ）

〔式中、Ｒ^１６およびＲ^１７はそれぞれ独立して水素原子、置換されていてもよい炭化水素基、置換されていてもよい水酸基、置換されていてもよいチオ−ル基、置換されていてもよいアルキルスルフィニル基、置換されていてもよいアルキルスルホニル基、置換されていてもよいアシル基、エステル化されていてもよいカルボキシル基、置換されていてもよいカルバモイル基または置換されていてもよいアミノ基を示し、Ｒ^１６とＲ^１７とが互いに結合して置換されていてもよい環を形成していてもよく、他の記号は前記（１）または（１３）記載と同意義を示す。〕である前記（１）記載の化合物；
（１８）式（Ｉ）が、式（Ｉｄ）

〔式中、Ｒ^１８およびＲ^１９はそれぞれ独立して水素原子、置換されていてもよい炭化水素基、置換されていてもよい水酸基、置換されていてもよいチオ−ル基、置換されていてもよいアルキルスルフィニル基、置換されていてもよいアルキルスルホニル基、置換されていてもよいアシル基、エステル化されていてもよいカルボキシル基、置換されていてもよいカルバモイル基または置換されていてもよいアミノ基を示し、他の記号は（１）または（１３）記載と同意義を示す。〕である前記（１）記載の化合物；
（１９）ａが２である前記（１）記載の化合物；
（２０）7-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-3-メチル-6,7-ジヒドロイミダゾ[1,5-a]ピラジン-8(5H)-オン、7-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-1-メチル-6,7-ジヒドロイミダゾ[1,5-a]ピラジン-8(5H)-オン、2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン、2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-5,7-ジメチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン、2-(1-{3-[(7-クロロ-2H-クロメン-3-イル)スルホニル]プロパノイル}-4-ピペリジニル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン、2-[1-(3-{[(E)-2-(4-クロロフェニル)ビニル]スルホニル}プロパノイル)-4-ピペリジニル]-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン、2-(1-{3-[(5-クロロ-1H-インドール-2-イル)スルホニル]プロパノイル}-4-ピペリジニル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン、2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-5-(ヒドロキシメチル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン、2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-5-(ヒドロキシメチル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン、1-アセチルピペリジン-4-カルボン酸[2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル、3-(2-オキソ-1-ピロリジニル)プロピオン酸[2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル、(2-オキソ-1-ピロリジニル)酢酸 [2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル、4-(アセチルアミノ)ブタン酸 [2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル、2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-5,7-ジメチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オンからなる群から選ばれた化合物またはその塩；
（２１）前記（１）または（２）記載の化合物を含有することを特徴とする医薬；
（２２）抗血液凝固剤である前記（２１）記載の医薬；
（２３）活性化血液凝固第Ｘ因子阻害剤である前記（２１）記載の医薬；
（２４）心筋梗塞、脳梗塞、深部静脈血栓症、肺血栓塞栓症または閉塞性動脈硬化症の予防・治療剤である前記（２１）記載の医薬；
（２５）エコノミークラス症候群、手術中・術後の血栓塞栓症または深部静脈血栓症の二次発症の予防・治療剤である前記（２１）記載の医薬；
（２６）式（ＩＩ）

〔式中、Ｌ^１は脱離基を、他の記号は前記（１）記載と同意義を示す。〕で表される化合物又はその塩と、式（III）

〔式中、Ｍ^１は水素原子、アルカリ金属、アルカリ土類金属または脱離基を、他の記号は前記（１）記載と同意義を示す。〕で表される化合物又はその塩とを反応させるか；
式（ＩＶ）

〔式中、Ｍ^２は水素原子、アルカリ金属、アルカリ土類金属または脱離基を、他の記号は前記（１）記載と同意義を示す。〕で表される化合物又はその塩と、式（Ｖ）

〔式中、Ｌ^２は脱離基またはホルミル基を、他の記号は前記（１）記載と同意義を示す。〕で表される化合物又はその塩とを反応させるか；
式（Ｉｅ）

〔式中、Ｌ^３は脱離基を、他の記号は前記（１）または（１３）記載と同意義を示す。〕で表される化合物又はその塩に塩基を反応させるか；
式（Ｉｆ）

〔式中の記号は前記（１）または（１３）記載と同意義を示す。〕で表される化合物又はその塩と、式（ＶＩ）

〔式中、Ｌ^４およびＬ^４’はそれぞれ脱離基を示し、他の記号は前記（１３）記載と同意義を示す。〕で表される化合物又はその塩とを反応させるか；
式（Ｉｇ）

〔式中の記号は前記（１）記載と同意義を示す。〕で表される化合物又はその塩を酸化することを特徴とし、所望により、上記反応で得られた化合物をさらに加水分解、エステル化、アミド化、アルキル化、アシル化、還元、酸化または／および脱保護反応に付すことを特徴とする前記（１）記載の化合物の製造法；
（２７）前記（１）記載の化合物またはそのプロドラッグの有効量を哺乳動物に投与することを特徴とする哺乳動物における血液凝固の阻害方法；
（２８）前記（１）記載の化合物またはそのプロドラッグの有効量を哺乳動物に投与することを特徴とする哺乳動物における活性化血液凝固第Ｘ因子の阻害方法；
（２９）前記（１）記載の化合物またはそのプロドラッグの有効量を哺乳動物に投与することを特徴とする哺乳動物における心筋梗塞、脳梗塞、深部静脈血栓症、肺血栓塞栓症または閉塞性動脈硬化症の予防・治療方法；
（３０）血液凝固阻害のための医薬の製造のための前記（１）記載の化合物またはそのプロドラッグの使用；
（３１）活性化血液凝固第Ｘ因子阻害のための医薬の製造のための前記（１）記載の化合物またはそのプロドラッグの使用；
（３２）心筋梗塞、脳梗塞、深部静脈血栓症、肺血栓塞栓症または閉塞性動脈硬化症の予防・治療のための医薬の製造のための前記（１）記載の化合物またはそのプロドラッグの使用；などに関する。 That is, the present invention
(1) Formula (I)

[Wherein, R represents a cyclic hydrocarbon group which may be substituted or a heterocyclic group which may be substituted; W represents a bond or a divalent chain hydrocarbon group which may be substituted; X represents an optionally substituted divalent hydrocarbon group, Y represents —CO—, —S (O) —, —S (O) ₂ — or a bond, and ring A represents a substituted group. Represents an optionally substituted pyrrolidine ring, an optionally substituted piperidine ring or an optionally substituted perhydroazepine ring, and Z ¹ and Z ³ each independently represent a bond or a substituted 2 Z ² represents -N (R ¹ )-, -O-, -S (O)-, -S (O) _2- , -CO-, -CH (R ¹ ) - or a bond (R ¹ is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted acyl group, be also good carboxyl group or substituted esterified Shows the shows the carbamoyl group), ring B represents an optionally imidazole ring which may be substituted, even substituent be an imidazole ring have and the R ¹ is not coupled to substituted for each other in the ring B A good ring may be formed, and a represents 0, 1 or 2. Or a salt thereof;
(2) a prodrug of the compound according to (1) above;
(3) The compound according to the above (1), wherein R is an optionally substituted aryl group;
(4) The compound according to (1) above, wherein R is naphthyl optionally substituted with a halogen atom or indolyl optionally substituted with a halogen atom;
(5) The compound according to (1), wherein W is a bond;
(6) The compound according to (1), wherein X is a divalent chain hydrocarbon group which may be substituted;
(7) The compound according to the above (1), wherein Y is -CO-;
(8) The compound according to (1), wherein ring A is an optionally substituted piperidine ring;
(9) Formula

But the expression

[Wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are each independently a hydrogen atom or substituted. An optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally substituted alkylsulfinyl group, an optionally substituted alkylsulfonyl group, a substituted An acyl group which may be esterified, a carboxyl group which may be esterified, an optionally substituted carbamoyl group or an optionally substituted amino group, R ² and R ³ , R ⁵ and R ⁶ , R ⁶ and R ⁷ , R ⁸ and R ⁹ , R ⁹ and R ^10, or R ¹¹ and R ¹² may be bonded to each other to form an optionally substituted ring. The compound according to (1), which is
(10) Formula

But the expression

[Wherein, ring C represents a nitrogen-containing heterocyclic ring which may be substituted, and other symbols have the same meanings as described in the above (9). The compound according to (1), which is
(11) The compound according to the above (1), wherein the substituent which the imidazole ring in ring B may have and R ¹ does not form a ring;
(12) Z ² is —N (R ¹ ) — or —CH (R ¹ ) — (R ¹ is as defined above in (1)), and the substituent of the imidazole ring in ring B is The compound according to the above (1), wherein R ¹ is bonded to each other to form an optionally substituted ring;
(13) Formula (I) is converted to Formula (Ia)

[In the formula, ring B ′ represents an imidazole ring which may be further substituted, Z ^2a represents N or CH, Z ⁴ represents a divalent chain hydrocarbon group which may be substituted, Other symbols have the same meaning as described in (1) above. The compound according to (1), which is
(14) The compound according to the above (13), wherein Z ^2a is a nitrogen atom;
(15) The compound according to the above (13), wherein Z ³ and Z ⁴ are each independently a divalent chain hydrocarbon group which may be substituted with an oxo group;
(16) Formula (I) is converted to Formula (Ib)

[Wherein R ¹⁴ and R ¹⁵ are each independently a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted thiol group, Alkylsulfinyl group which may be substituted, alkylsulfonyl group which may be substituted, acyl group which may be substituted, carboxyl group which may be esterified, carbamoyl group which may be substituted or may be substituted An amino group, R ¹⁴ and R ¹⁵ may be bonded to each other to form an optionally substituted ring, and other symbols have the same meanings as described in the above (1) or (13). The compound according to (1), which is
(17) Formula (I) is converted to Formula (Ic)

[Wherein R ¹⁶ and R ¹⁷ are each independently a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted thiol group, Alkylsulfinyl group which may be substituted, alkylsulfonyl group which may be substituted, acyl group which may be substituted, carboxyl group which may be esterified, carbamoyl group which may be substituted or may be substituted Represents an amino group, and R ¹⁶ and R ¹⁷ may be bonded to each other to form an optionally substituted ring, and other symbols have the same meanings as described in the above (1) or (13). The compound according to (1), which is
(18) Formula (I) is converted to Formula (Id)

[Wherein R ¹⁸ and R ¹⁹ are each independently a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted thiol group, Alkylsulfinyl group which may be substituted, alkylsulfonyl group which may be substituted, acyl group which may be substituted, carboxyl group which may be esterified, carbamoyl group which may be substituted or may be substituted An amino group is shown, and other symbols are as defined in (1) or (13). The compound according to (1), which is
(19) The compound according to (1), wherein a is 2;
(20) 7- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -3-methyl-6,7-dihydroimidazo [1,5-a] pyrazine- 8 (5H) -one, 7- (1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -1-methyl-6,7-dihydroimidazo [1,5- a] pyrazin-8 (5H) -one, 2- (1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -5-methyl-1,2-dihydro-3H -Imidazo [1,5-c] imidazol-3-one, 2- (1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -5,7-dimethyl-1 , 2-Dihydro-3H-imidazo [1,5-c] imidazol-3-one, 2- (1- {3-[(7-chloro-2H-chromen-3-yl) sulfonyl] propanoyl} -4- Piperidinyl) -5-methyl-1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one, 2- [1- (3-{[(E) -2- (4-chlorophenyl) Vinyl] sulfonyl} propanoyl) -4-piperidini ] -5-Methyl-1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one, 2- (1- {3-[(5-chloro-1H-indol-2-yl) Sulfonyl] propanoyl} -4-piperidinyl) -5-methyl-1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one, 2- (1- {3-[(6-chloro- 2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -5- (hydroxymethyl) -1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one, 2- (1-{( 2S) -3-[(6-Chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -5- (hydroxymethyl) -1,2-dihydro-3H-imidazo [1,5 -c] imidazol-3-one, 1-acetylpiperidine-4-carboxylic acid [2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -3-oxo-2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl, 3- (2-oxo-1-pyrrolidinyl) propionic acid [2- (1- {(2S) -3-[(6-Chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -3-oxo-2,3-dihydro-1H-imidazo [1,5- c] imidazol-5-yl] methyl, (2-oxo-1-pyrrolidinyl) acetic acid [2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxyprop Noyl} -4-piperidinyl) -3-oxo-2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl, 4- (acetylamino) butanoic acid [2- (1- {(2S) -3-[(6-Chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -3-oxo-2,3-dihydro-1H-imidazo [1,5- c] imidazol-5-yl] methyl, 2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -5,7 A compound selected from the group consisting of -dimethyl-1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one or a salt thereof;
(21) A pharmaceutical comprising the compound according to (1) or (2) above;
(22) The medicament according to (21) above, which is an anticoagulant;
(23) The medicament according to the above (21), which is an activated blood coagulation factor X inhibitor;
(24) The medicament according to the above (21), which is a prophylactic / therapeutic agent for myocardial infarction, cerebral infarction, deep vein thrombosis, pulmonary thromboembolism or obstructive arteriosclerosis;
(25) The medicament according to (21), which is a prophylactic / therapeutic agent for economy class syndrome, secondary onset of thromboembolism or deep vein thrombosis during or after surgery;
(26) Formula (II)

[Wherein, L ¹ represents a leaving group, and other symbols have the same meanings as described in the above (1). Or a salt thereof, and the formula (III)

[Wherein, M ¹ represents a hydrogen atom, an alkali metal, an alkaline earth metal or a leaving group, and other symbols have the same meanings as described in the above (1). Or a salt thereof or a salt thereof;
Formula (IV)

[Wherein, M ² represents a hydrogen atom, an alkali metal, an alkaline earth metal or a leaving group, and other symbols have the same meanings as described in the above (1). Or a salt thereof and the formula (V)

[Wherein L ² represents a leaving group or a formyl group, and other symbols have the same meanings as described in the above (1). Or a salt thereof or a salt thereof;
Formula (Ie)

[Wherein L ³ represents a leaving group, and other symbols have the same meanings as described in the above (1) or (13). Or a salt thereof, or a salt thereof;
Formula (If)

[The symbols in the formula are as defined in (1) or (13) above. Or a salt thereof, and the formula (VI)

[Wherein, L ⁴ and L ⁴ ′ each represent a leaving group, and other symbols have the same meanings as described in the above (13). Or a salt thereof or a salt thereof;
Formula (Ig)

[The symbols in the formula are as defined in the above (1). And the compound obtained by the above reaction is further hydrolyzed, esterified, amidated, alkylated, acylated, reduced, oxidized, and / or, if desired. A method for producing the compound according to (1) above, which is subjected to a deprotection reaction;
(27) A method for inhibiting blood coagulation in a mammal, comprising administering an effective amount of the compound according to (1) or a prodrug thereof to the mammal;
(28) A method for inhibiting activated blood coagulation factor X in a mammal, comprising administering an effective amount of the compound according to (1) or a prodrug thereof to the mammal;
(29) Myocardial infarction, cerebral infarction, deep vein thrombosis, pulmonary thromboembolism or occlusive artery in a mammal, characterized by administering an effective amount of the compound or prodrug thereof described in (1) above to the mammal How to prevent and treat sclerosis;
(30) Use of the compound according to (1) or a prodrug thereof for the manufacture of a medicament for inhibiting blood coagulation;
(31) Use of the compound according to (1) or a prodrug thereof for the manufacture of a medicament for inhibiting activated blood coagulation factor X;
(32) Use of the compound according to (1) or a prodrug thereof for the manufacture of a medicament for the prevention / treatment of myocardial infarction, cerebral infarction, deep vein thrombosis, pulmonary thromboembolism or obstructive arteriosclerosis ;

前記式中、Ｒは置換されていてもよい環状の炭化水素基または置換されていてもよい複素環基（好ましくは、置換されていてもよいアリール基または置換されていてもよい芳香族複素環基）を示す。
Ｒで示される「置換されていてもよい環状の炭化水素基」における「環状の炭化水素基」としては、例えば、脂環式炭化水素基、アリール基等が挙げられ、なかでもアリール基等が好ましい。
環状の炭化水素基の例としての「脂環式炭化水素基」としては、例えば、シクロアルキル基、シクロアルケニル基、シクロアルカジエニル基等の飽和又は不飽和の脂環式炭化水素基が挙げられる。
ここで、「シクロアルキル基」としては、例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチル、シクロノニル等のＣ_３−９シクロアルキル等が挙げられる。
「シクロアルケニル基」としては、例えば、２−シクロペンテン−１−イル、３−シクロペンテン−１−イル、２−シクロヘキセン−１−イル、３−シクロヘキセン−１−イル、１−シクロブテン−１−イル、１−シクロペンテン−１−イル、１−シクロヘキセン−１−イル、１−シクロヘプテン−１−イル等のＣ_３−９シクロアルケニル基等が挙げられる。
「シクロアルカジエニル基」としては、例えば、２,４−シクロペンタジエン−１−イル、２,４−シクロヘキサジエン−１−イル、２,５−シクロヘキサジエン−１−イル等のＣ_４−６シクロアルカジエニル基等が挙げられる。
環状の炭化水素基の例としての「アリール基」としては、単環式又は縮合多環式芳香族炭化水素基が挙げられ、例えば、フェニル、ナフチル、アントリル、フェナントリル、アセナフチレニル等のＣ_６−１４アリール基等が好ましく、中でもフェニル、１−ナフチル、２−ナフチル等が特に好ましい。
また、環状の炭化水素基の例としては、１,２−ジヒドロナフチル、１,２,３,４−テトラヒドロナフチル、インデニル、ジヒドロベンゾシクロヘプテニル、フルオレニルなどのように、上記した脂環式炭化水素基および芳香族炭化水素基を構成する環から選ばれる同一または異なった２〜３個の環（好ましくは２種以上の環）の縮合から誘導される二環式または三環式炭化水素基などが挙げられる。 In the above formula, R represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group (preferably an optionally substituted aryl group or an optionally substituted aromatic heterocyclic ring. Group).
Examples of the “cyclic hydrocarbon group” in the “optionally substituted cyclic hydrocarbon group” represented by R include an alicyclic hydrocarbon group, an aryl group, and the like. preferable.
Examples of the “alicyclic hydrocarbon group” as an example of the cyclic hydrocarbon group include saturated or unsaturated alicyclic hydrocarbon groups such as a cycloalkyl group, a cycloalkenyl group, and a cycloalkadienyl group. It is done.
Here, examples of the “cycloalkyl group” include C _3-9 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and the like.
Examples of the “cycloalkenyl group” include 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 1-cyclobuten-1-yl, Examples thereof include C _3-9 cycloalkenyl groups such as 1-cyclopenten-1-yl, 1-cyclohexen-1-yl, and 1-cyclohepten-1-yl.
Examples of the “cycloalkadienyl group” include C _4-6 such as 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yl and the like. And cycloalkadienyl group.
Examples of the “aryl group” as an example of the cyclic hydrocarbon group include monocyclic or condensed polycyclic aromatic hydrocarbon groups, and examples thereof include C _6-14 such as phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl and the like. An aryl group and the like are preferable, and among them, phenyl, 1-naphthyl, 2-naphthyl and the like are particularly preferable.
Examples of cyclic hydrocarbon groups include alicyclic carbonization such as 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, indenyl, dihydrobenzocycloheptenyl, fluorenyl and the like. A bicyclic or tricyclic hydrocarbon group derived from the condensation of two or three identical (preferably two or more) rings selected from a hydrogen group and a ring constituting an aromatic hydrocarbon group Etc.

Ｒで示される「置換されていてもよい複素環基」における「複素環基」としては、例えば、環系を構成する原子（環原子）として、酸素原子、硫黄原子および窒素原子等から選ばれたヘテロ原子１ないし３種（好ましくは１ないし２種）を少なくとも１個（好ましくは１ないし４個、さらに好ましくは１ないし２個）含む芳香族複素環基、飽和あるいは不飽和の非芳香族複素環基（脂肪族複素環基）等が挙げられる。
該「芳香族複素環基」としては、例えば、フリル、チエニル、ピロリル、オキサゾリル、イソオキサゾリル、チアゾリル、イソチアゾリル、イミダゾリル、ピラゾリル、１,２,３−オキサジアゾリル、１,２,４−オキサジアゾリル、１,３,４−オキサジアゾリル、フラザニル、１,２,３−チアジアゾリル、１,２,４−チアジアゾリル、１,３,４−チアジアゾリル、１,２,３−トリアゾリル、１,２,４−トリアゾリル、テトラゾリル、ピリジル、ピリダジニル、ピリミジニル、ピラジニル、トリアジニル等の５ないし６員の芳香族単環式複素環基、および、例えば、ベンゾフラニル、イソベンゾフラニル、ベンゾ〔ｂ〕チエニル、インドリル、イソインドリル、１Ｈ−インダゾリル、ベンズイミダゾリル、ベンゾオキサゾリル、１,２−ベンゾイソオキサゾリル、ベンゾチアゾリル、ベンゾピラニル、１,２−ベンゾイソチアゾリル、１Ｈ−ベンゾトリアゾリル、キノリル、イソキノリル、シンノリニル、キナゾリニル、キノキサリニル、フタラジニル、ナフチリジニル、プリニル、ブテリジニル、カルバゾリル、α−カルボリニル、β−カルボリニル、γ−カルボリニル、アクリジニル、フェノキサジニル、フェノチアジニル、フェナジニル、フェノキサチイニル、チアントレニル、フェナトリジニル、フェナトロリニル、インドリジニル、ピロロ〔１,２−ｂ〕ピリダジニル、ピラゾロ〔１,５−ａ〕ピリジル、イミダゾ〔１,２−ａ〕ピリジル、イミダゾ〔１,５−ａ〕ピリジル、イミダゾ〔１,２−ｂ〕ピリダジニル、イミダゾ〔１,２−ａ〕ピリミジニル、１,２,４−トリアゾロ〔４,３−ａ〕ピリジル、１,２,４−トリアゾロ〔４,３−ｂ〕ピリダジニル等の８〜１６員（好ましくは、８〜１２員）の芳香族縮合複素環基（好ましくは、前記した５ないし６員の芳香族単環式複素環基１〜２個（好ましくは、１個）がベンゼン環１〜２個（好ましくは、１個）と縮合した複素環または前記した５ないし６員の芳香族単環式複素環基の同一または異なった複素環２〜３個（好ましくは、２個）が縮合した複素環、より好ましくは前記した５ないし６員の芳香族単環式複素環基がベンゼン環と縮合した複素環、とりわけ好ましくはインドリル、ベンゾフラニル、ベンゾ〔ｂ〕チエニル、ベンゾピラニル等）等が挙げられる。
該「非芳香族複素環基」としては、例えば、オキシラニル、アゼチジニル、オキセタニル、チエタニル、ピロリジニル、テトラヒドロフリル、チオラニル、ピペリジル、テトラヒドロピラニル、モルホリニル、チオモルホリニル、ピペラジニル等の３〜８員（好ましくは５〜６員）の飽和あるいは不飽和（好ましくは飽和）の非芳香族単環式複素環基（脂肪族単環式複素環基）、１，３−ジヒドロイソインドリル等のように前記した非芳香族単環式複素環基１〜２個（好ましくは、１個）がベンゼン環１〜２個（好ましくは、１個）と縮合した複素環基、前記した非芳香族単環式複素環基１〜２個（好ましくは、１個）が前記した５ないし６員の芳香族単環式複素環基の複素環１〜２個（好ましくは、１個）と縮合した複素環基、あるいは１,２,３,４−テトラヒドロキノリル、１,２,３,４−テトラヒドロイソキノリル等のように前記した芳香族単環式複素環基又は芳香族縮合複素環基の一部又は全部の二重結合が飽和した非芳香族複素環基等が挙げられる。 The “heterocyclic group” in the “optionally substituted heterocyclic group” represented by R is, for example, selected from an oxygen atom, a sulfur atom, a nitrogen atom, etc. as an atom (ring atom) constituting the ring system. An aromatic heterocyclic group containing at least one (preferably 1 to 4, more preferably 1 to 2) heteroatoms of 1 to 3 heteroatoms (preferably 1 to 2), saturated or unsaturated non-aromatic A heterocyclic group (aliphatic heterocyclic group) etc. are mentioned.
Examples of the “aromatic heterocyclic group” include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3 1,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl 5- to 6-membered aromatic monocyclic heterocyclic groups such as pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like, and, for example, benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl, isoindolyl, 1H-indazolyl, benz Imidazolyl, benzoxazolyl, 1,2-benzisoo Sazolyl, benzothiazolyl, benzopyranyl, 1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, buteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thiantenyl, phenathidinyl, phenatrolinyl, indolizinyl, pyrrolo [1,2-b] pyridazinyl, pyrazolo [1,5-a] pyridyl, imidazo [1, 2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4-triazolo [4,3-a] 8-16 membered (preferably 8-12 membered) aromatic condensed heterocyclic group (preferably, 5-6 membered member as described above) such as lysyl, 1,2,4-triazolo [4,3-b] pyridazinyl A heterocyclic ring in which 1 to 2 (preferably 1) aromatic monocyclic heterocyclic groups are condensed with 1 to 2 (preferably 1) benzene rings, or the 5- to 6-membered aromatic monocyclic ring described above A heterocycle in which 2 to 3 (preferably 2) heterocycles of the same or different type of heterocyclic group are fused, more preferably the 5- to 6-membered aromatic monocyclic heterocyclic group described above is a benzene ring And condensed heterocyclic rings, particularly preferably indolyl, benzofuranyl, benzo [b] thienyl, benzopyranyl and the like.
Examples of the “non-aromatic heterocyclic group” include 3 to 8 members (preferably 5) of oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl and the like. To 6-membered) saturated or unsaturated (preferably saturated) non-aromatic monocyclic heterocyclic group (aliphatic monocyclic heterocyclic group), 1,3-dihydroisoindolyl, etc. A heterocyclic group in which 1 to 2 (preferably 1) aromatic monocyclic heterocyclic group is fused with 1 to 2 (preferably 1) benzene ring, the non-aromatic monocyclic heterocyclic ring described above A heterocyclic group in which 1 to 2 groups (preferably 1) are condensed with 1 to 2 (preferably 1) heterocycles of the 5- to 6-membered aromatic monocyclic heterocyclic group described above, or 1, A part or all of the aromatic monocyclic heterocyclic group or aromatic condensed heterocyclic group described above such as 2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, etc. Examples include non-aromatic heterocyclic groups saturated with heavy bonds.

Ｒで示される「置換されていてもよい環状の炭化水素基」および「置換されていてもよい複素環基」における置換基としては、例えば、置換されていてもよいアルキル、置換されていてもよいアルケニル、置換されていてもよいアルキニル、置換されていてもよいアリール、置換されていてもよいシクロアルキル、置換されていてもよいシクロアルケニル、置換されていてもよい複素環基、置換されていてもよいアミノ、置換されていてもよいイミドイル（例えば、式−Ｃ（Ｕ’）＝Ｎ−Ｕ［式中、ＵおよびＵ’はそれぞれ水素原子または置換基を示す（Ｕは好ましくは水素原子を示す）］で表される基等）、置換されていてもよいアミジノ（例えば、式−Ｃ（ＮＴ’Ｔ’’）＝Ｎ−Ｔ［式中、Ｔ，Ｔ’およびＴ’’はそれぞれ水素原子または置換基を示す（Ｔは好ましくは水素原子を示す）］で表される基等）、置換されていてもよい水酸基、置換されていてもよいチオール基、置換されていてもよいアルキルスルフィニル、置換されていてもよいアルキルスルホニル、エステル化されていてもよいカルボキシル、置換されていてもよいカルバモイル、置換されていてもよいチオカルバモイル、置換されていてもよいスルファモイル基、ハロゲン原子（例、フッ素、塩素、臭素、ヨウ素等、好ましくは塩素、臭素等）、シアノ基、ニトロ基、スルホン酸由来のアシル、カルボン酸由来のアシル等が挙げられ、これらの任意の置換基は置換可能な位置に１ないし５個（好ましくは１ないし３個）置換していてもよい。また、Ｒで示される「置換されていてもよい環状の炭化水素基」および「置換されていてもよい複素環基」は、オキソ基またはチオキソ基を有していてもよく、例えば、Ｒがベンゾピラニルである場合、Ｒはベンゾ−α−ピロニル、ベンゾ−γ−ピロニルなどを形成していてもよい。 Examples of the substituent in the “optionally substituted cyclic hydrocarbon group” and the “optionally substituted heterocyclic group” represented by R include, for example, an optionally substituted alkyl and a substituted Good alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclic group, substituted An optionally substituted amino, an optionally substituted imidoyl (for example, the formula —C (U ′) = N—U wherein U and U ′ each represent a hydrogen atom or a substituent (U is preferably a hydrogen atom) A group represented by the formula: -C (NT′T ″) = N−T [wherein T, T ′ and T ″ are each Hydrogen atom or A group represented by a substituent (T is preferably a hydrogen atom)], an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally substituted alkylsulfinyl, substituted Alkylsulfonyl which may be substituted, carboxyl which may be esterified, carbamoyl which may be substituted, thiocarbamoyl which may be substituted, sulfamoyl which may be substituted, halogen atom (eg, fluorine, Chlorine, bromine, iodine, etc., preferably chlorine, bromine, etc.), cyano group, nitro group, acyl derived from sulfonic acid, acyl derived from carboxylic acid, etc. These optional substituents are located at substitutable positions. Or 5 (preferably 1 to 3) may be substituted. In addition, the “optionally substituted cyclic hydrocarbon group” and the “optionally substituted heterocyclic group” represented by R may have an oxo group or a thioxo group. When it is benzopyranyl, R may form benzo-α-pyronyl, benzo-γ-pyronyl, and the like.

Ｒで示される「置換されていてもよい環状の炭化水素基」および「置換されていてもよい複素環基」における置換基としての「置換されていてもよいアリール」における「アリール」としては、例えば、フェニル、ナフチル、アントリル、フェナントリル、アセナフチレニル等のＣ_６−１４アリール等が挙げられる。ここで、アリールの置換基としては、低級アルコキシ基（例、メトキシ、エトキシ、プロポキシ等のＣ_１−６アルコキシ等）、ハロゲン原子（例、フッ素、塩素、臭素、ヨウ素等）、低級アルキル（例、メチル、エチル、プロピル等のＣ_１−６アルキル等）、低級アルケニル（例、ビニル、アリル等のＣ_２−６アルケニル等）、低級アルキニル（例、エチニル、プロパルギル等のＣ_２−６アルキニル等）、置換されていてもよいアミノ、置換されていてもよい水酸基、シアノ基、置換されていてもよいアミジノ、カルボキシ、低級アルコキシカルボニル基（例、メトキシカルボニル、エトキシカルボニル等のＣ_１−６アルコキシカルボニル等）、置換されていてもよいカルバモイル基（例、５ないし６員の芳香族単環式複素環基（例、ピリジニルなど）で置換されていてもよいＣ_１−６アルキル、アシル（例、ホルミル、Ｃ_２−６アルカノイル、ベンゾイル、ハロゲン化されていてもよいＣ_１−６アルキルスルホニル、ベンゼンスルホニル等）またはハロゲン化されていてもよいＣ_１−６アルコキシカルボニルで置換されていてもよいカルバモイル基、１−アゼチジニルカルボニル、１−ピロリジニルカルボニル、ピペリジノカルボニル、モルホリノカルボニル、チオモルホリノカルボニル（硫黄原子は酸化されていてもよい）、１−ピペラジニルカルボニル等）等が挙げられ、これらの任意の置換基は置換可能な位置に１ないし３個置換していてもよい。 As the “aryl” in the “optionally substituted aryl” as the substituent in the “optionally substituted cyclic hydrocarbon group” and the “optionally substituted heterocyclic group” represented by R, Examples thereof include C _6-14 aryl such as phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl and the like. Here, examples of the substituent for aryl include lower alkoxy groups (eg, C _1-6 alkoxy such as methoxy, ethoxy, propoxy, etc.), halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), lower alkyl (eg, C _1-6 alkyl such as methyl, ethyl, propyl, etc.), lower alkenyl (eg, C _2-6 alkenyl such as vinyl, allyl, etc.), lower alkynyl (eg, C _2-6 alkynyl such as ethynyl, propargyl, etc.) ), Optionally substituted amino, optionally substituted hydroxyl group, cyano group, optionally substituted amidino, carboxy, lower alkoxycarbonyl group (eg, C _1-6 alkoxy such as methoxycarbonyl, ethoxycarbonyl, etc.) Carbonyl, etc.), an optionally substituted carbamoyl group (eg 5- to 6-membered aromatic monocyclic heterocyclic group (eg Is optionally C _1-6 alkyl substituted with Jiniru etc.), acyl (e.g., formyl, C _2-6 alkanoyl, benzoyl, a C _1-6 alkylsulfonyl which may be halogenated, benzenesulfonyl and the like) or halogen A carbamoyl group optionally substituted with an optionally substituted C _1-6 alkoxycarbonyl, 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl (sulfur atom) May be oxidized), 1-piperazinylcarbonyl, etc.), and these optional substituents may be substituted at 1 to 3 substitutable positions.

Ｒで示される「置換されていてもよい環状の炭化水素基」および「置換されていてもよい複素環基」における置換基としての「置換されていてもよいアリール」における置換基としての「置換されていてもよいアミノ」、「置換されていてもよい水酸基」および「置換されていてもよいアミジノ」としては、後述するＲで示される「置換されていてもよい環状の炭化水素基」および「置換されていてもよい複素環基」における置換基としての「置換されていてもよいアミノ」、「置換されていてもよい水酸基」および「置換されていてもよいアミジノ」と同様の基などが挙げられる。 "Substitution as a substituent in" optionally substituted aryl "as a substituent in" optionally substituted cyclic hydrocarbon group "and" optionally substituted heterocyclic group "represented by R Examples of “optionally substituted amino”, “optionally substituted hydroxyl group” and “optionally substituted amidino” include “optionally substituted cyclic hydrocarbon group” represented by R described below and Groups similar to “optionally substituted amino”, “optionally substituted hydroxyl” and “optionally substituted amidino” as substituents in “optionally substituted heterocyclic group”, etc. Is mentioned.

Ｒで示される「置換されていてもよい環状の炭化水素基」および「置換されていてもよい複素環基」における置換基としての「置換されていてもよいアルキル」における「アルキル」としては、例えば、メチル、エチル、ｎ−プロピル、イソプロピル、ｎ−ブチル、イソブチル、tert−ブチル、ｎ−ペンチル、イソペンチル、ネオペンチル、１−メチルプロピル、ｎ−ヘキシル、イソヘキシル、１,１−ジメチルブチル、２,２−ジメチルブチル、３,３−ジメチルブチル等のＣ_１−６アルキル等が挙げられる。ここで、アルキルの置換基としては、前記した「置換されていてもよいアリール」における置換基と同様な数の同様の基、およびオキソ基、チオキソ基などが挙げられる。
Ｒで示される「置換されていてもよい環状の炭化水素基」および「置換されていてもよい複素環基」における置換基としての「置換されていてもよいアルケニル」における「アルケニル」としては、例えば、ビニル、アリル、イソプロペニル、２−メチルアリル、１−プロペニル、２−メチル−１−プロペニル、１−ブテニル、２−ブテニル、３−ブテニル、２−エチル−１−ブテニル、２−メチル−２−ブテニル、３−メチル−２−ブテニル、１−ペンテニル、２−ペンテニル、３−ペンテニル、４−ペンテニル、４−メチル−３−ペンテニル、１−ヘキセニル、２−ヘキセニル、３−ヘキセニル、４−ヘキセニル、５−ヘキセニル等のＣ_２−６アルケニル等が挙げられる。ここで、アルケニルの置換基としては、前記した「置換されていてもよいアリール」における置換基と同様な数の同様の基、およびオキソ基、チオキソ基などが挙げられる。
Ｒで示される「置換されていてもよい環状の炭化水素基」および「置換されていてもよい複素環基」における置換基としての「置換されていてもよいアルキニル」における「アルキニル」としては、例えば、エチニル、１−プロピニル、２−プロピニル、１−ブチニル、２−ブチニル、３−ブチニル、１−ペンチニル、２−ペンチニル、３−ペンチニル、４−ペンチニル、１−ヘキシニル、２−ヘキシニル、３−ヘキシニル、４−ヘキシニル、５−ヘキシニル等のＣ_２−６アルキニルが挙げられる。ここで、アルキニルの置換基としては、前記した「置換されていてもよいアリール」における置換基と同様な数の同様の基、およびオキソ基、チオキソ基などが挙げられる。 As the “alkyl” in the “optionally substituted alkyl” as the substituent in the “optionally substituted cyclic hydrocarbon group” and the “optionally substituted heterocyclic group” represented by R, For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1-methylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2, Examples thereof include C _1-6 alkyl such as 2-dimethylbutyl and 3,3-dimethylbutyl. Here, examples of the substituent of the alkyl include the same number of the same groups as the substituents in the above-mentioned “optionally substituted aryl”, an oxo group, a thioxo group, and the like.
As the “alkenyl” in the “optionally substituted alkenyl” as the substituent in the “optionally substituted cyclic hydrocarbon group” and the “optionally substituted heterocyclic group” represented by R, For example, vinyl, allyl, isopropenyl, 2-methylallyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 2-methyl-2 -Butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl C _2-6 alkenyl such as 5-hexenyl and the like. Here, examples of the substituent of alkenyl include the same number of the same groups as the substituents in the above-mentioned “optionally substituted aryl”, and oxo groups and thioxo groups.
As the “alkynyl” in the “optionally substituted alkynyl” as the substituent in the “optionally substituted cyclic hydrocarbon group” and the “optionally substituted heterocyclic group” represented by R, For example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3- C _2-6 alkynyl such as hexynyl, 4-hexynyl, 5-hexynyl and the like can be mentioned. Here, examples of the alkynyl substituent include the same number of the same groups as the substituents in the above-mentioned “optionally substituted aryl”, and oxo groups and thioxo groups.

Ｒで示される「置換されていてもよい環状の炭化水素基」および「置換されていてもよい複素環基」における置換基としての「置換されていてもよいシクロアルキル」における「シクロアルキル」としては、例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル等のＣ_３−７シクロアルキル等が挙げられる。ここで、シクロアルキルの置換基としては、前記した「置換されていてもよいアリール」が有していてもよい置換基と同様な数の同様の基などが挙げられる。
Ｒで示される「置換されていてもよい環状の炭化水素基」および「置換されていてもよい複素環基」における置換基としての「置換されていてもよいシクロアルケニル」における「シクロアルケニル」としては、例えば、シクロプロぺニル、シクロブテニル、シクロペンテニル、シクロヘキセニル等のＣ_３−６シクロアルケニル等が挙げられる。ここで、置換されていてもよいシクロアルケニルの置換基としては、前記した「置換されていてもよいアリール」における置換基と同様な数の同様な基、およびオキソ基、チオキソ基などが挙げられる。 As “cycloalkyl” in “optionally substituted cycloalkyl” as a substituent in “optionally substituted cyclic hydrocarbon group” and “optionally substituted heterocyclic group” represented by R Examples include C _3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Here, examples of the substituent of cycloalkyl include the same number of similar groups as the substituents which the above-mentioned “optionally substituted aryl” may have.
As “cycloalkenyl” in “optionally substituted cycloalkenyl” as a substituent in “optionally substituted cyclic hydrocarbon group” and “optionally substituted heterocyclic group” represented by R Examples thereof include C _3-6 cycloalkenyl such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and the like. Here, examples of the substituent of the cycloalkenyl which may be substituted include the same number of the same groups as the substituents in the above-mentioned “optionally substituted aryl”, and oxo groups and thioxo groups. .

Ｒで示される「置換されていてもよい環状の炭化水素基」および「置換されていてもよい複素環基」における置換基としての「置換されていてもよい複素環基」における「複素環基」としては、Ｒで示される「置換されていてもよい複素環基」における複素環基と同様の基などが挙げられる。
該「置換されていてもよい複素環基」における置換基としては、前記した「置換されていてもよいアリール」における置換基と同様な数の同様な基、およびオキソ基、チオキソ基などが挙げられる。 The “heterocyclic group” in the “optionally substituted heterocyclic group” as a substituent in the “optionally substituted cyclic hydrocarbon group” and the “optionally substituted heterocyclic group” represented by R "Includes the same group as the heterocyclic group in the" optionally substituted heterocyclic group "represented by R.
Examples of the substituent in the “optionally substituted heterocyclic group” include the same number of similar groups as those in the above-mentioned “optionally substituted aryl”, and oxo groups, thioxo groups, and the like. It is done.

Ｒで示される「置換されていてもよい環状の炭化水素基」および「置換されていてもよい複素環基」における置換基としての「置換されていてもよいアルキルスルフィニル」における「アルキルスルフィニル」としては、メタンスルフィニル、エタンスルフィニル、プロパンスルフィニル、シクロプロパンスルフィニル、シクロペンタンスルフィニル、シクロヘキサンスルフィニル等の鎖状もしくは環状のＣ_１−６アルキルスルフィニル等などが挙げられる。
Ｒで示される「置換されていてもよい環状の炭化水素基」および「置換されていてもよい複素環基」における置換基としての「置換されていてもよいアルキルスルホニル」における「アルキルスルホニル」としては、メタンスルホニル、エタンスルホニル、プロパンスルホニル、シクロプロパンスルホニル、シクロペンタンスルホニル、シクロヘキサンスルホニル等の鎖状もしくは環状のＣ_１−６アルキルスルホニル等などが挙げられる。 As "alkylsulfinyl" in "optionally substituted alkylsulfinyl" as a substituent in "optionally substituted cyclic hydrocarbon group" and "optionally substituted heterocyclic group" represented by R _Examples thereof include chain or cyclic C _1-6 alkylsulfinyl such as methanesulfinyl, ethanesulfinyl, propanesulfinyl, cyclopropanesulfinyl, cyclopentanesulfinyl, cyclohexanesulfinyl and the like.
As "alkylsulfonyl" in "optionally substituted alkylsulfonyl" as a substituent in "optionally substituted cyclic hydrocarbon group" and "optionally substituted heterocyclic group" represented by R _Examples thereof include chain or cyclic C _1-6 alkylsulfonyl such as methanesulfonyl, ethanesulfonyl, propanesulfonyl, cyclopropanesulfonyl, cyclopentanesulfonyl, and cyclohexanesulfonyl.

Ｒで示される「置換されていてもよい環状の炭化水素基」および「置換されていてもよい複素環基」における置換基としての「置換されていてもよいアミノ」、「置換されていてもよいイミドイル」、「置換されていてもよいアミジノ」、「置換されていてもよい水酸基」、「置換されていてもよいチオール基」、「置換されていてもよいアルキルスルフィニル」および「置換されていてもよいアルキルスルホニル」における置換基としては、例えば、(1) ハロゲン原子（例、フッ素、塩素、臭素、ヨウ素等）およびハロゲン化されていてもよいＣ_１−６アルコキシ（例、メトキシ、エトキシ、トリフルオロメトキシ、２，２，２−トリフルオロエトキシ、トリクロロメトキシ、２，２，２−トリクロロエトキシ等）から選ばれた置換基で置換されていてもよい低級アルキル（例、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、tert−ブチル、ペンチル、ヘキシル等のＣ_１−６アルキル等）、(2) Ｃ_１−６アルカノイル（例、ホルミル、アセチル、プロピオニル、バレロイル、ピバロイル等）、ベンゾイル、Ｃ_１−６アルキルスルホニル（例、メタンスルホニル等）、ベンゼンスルホニル等のアシル；該アシルは、Ｃ_１−６低級アルキル（例、メチル、エチル、ブチル、イソプロピル、シクロプロピル、シクロヘキシル等）、Ｃ_１−１０アシル（例、アセチル、プロピオニル、イソプロピオニル、ベンゾイル、パラクロロベンゾイル、4-メチルベンゾイル等）およびメタンスルホニルから選ばれた置換基で置換されていてもよいアミノ、2-オキソ-1-ピロリジニル、2-オキソ-1-ピペリジニル、1-アセチル-4-ピペリジニル、1-プロピオニル-4-ピペリジニルなどで置換されていてもよい（例、2-アミノプロピオニル、2-ベンゾイルアミノプロピオニル、2-(2-オキソ-1-ピロリジニル) プロピオニル、2-(2-オキソ-1-ピペリジニル) プロピオニル、2-(1-アセチル-4-ピペリジニル) プロピオニル等）、(3) ハロゲン化されていてもよいＣ_１−６アルコキシカルボニル（例、メトキシカルボニル、エトキシカルボニル、トリフルオロメトキシカルボニル、２，２，２−トリフルオロエトキシカルボニル、トリクロロメトキシカルボニル、２，２，２−トリクロロエトキシカルボニル等）、フェニルで置換されていてもよいＣ_１−６アルコキシカルボニル（例、ベンジルオキシカルボニル等）、(4) 複素環基（Ｒで示される「置換されていてもよい複素環基」における「複素環基」と同様な基など）等が挙げられるが、置換基としての「置換されていてもよいアミノ」における「アミノ」は、置換されていてもよいイミドイル（例、Ｃ_１−６アルキルイミドイル（例、ホルミルイミドイル、アセチルイミドイルなど）、Ｃ_１−６アルコキシイミドイル、Ｃ_１−６アルキルチオイミドイル、アミジノ等）、１〜２個のＣ_１−６アルキルで置換されていてもよいアミノなどで置換されていてもよく、また、２個の置換基が窒素原子と一緒になって環状アミノを形成する場合もあり、この様な場合の環状アミノとしては、例えば、１−アゼチジニル、１−ピロリジニル、ピペリジノ、チオモルホリノ、モルホリノ、１−ピペラジニルおよび４位に低級アルキル（例、メチル、エチル、プロピル、イソプロピル、ブチル、ｔ−ブチル、ペンチル、ヘキシル等のＣ_１−６アルキル等）、アラルキル（例、ベンジル、フェネチル等のＣ_７−１０アラルキル等）、アリール（例、フェニル、１−ナフチル、２−ナフチル等のＣ_６−１０アリール等）等を有していてもよい１−ピペラジニル、１−ピロリル、１−イミダゾリル等の３〜８員（好ましくは５〜６員）の環状アミノなどが挙げられる。 “Optionally substituted amino group” and “optionally substituted” as substituents in the “optionally substituted cyclic hydrocarbon group” and the “optionally substituted heterocyclic group” represented by R "Good imidoyl", "optionally substituted amidino", "optionally substituted hydroxyl group", "optionally substituted thiol group", "optionally substituted alkylsulfinyl" and "substituted Examples of the substituent in “optionally alkylsulfonyl” include (1) a halogen atom (eg, fluorine, chlorine, bromine, iodine and the like) and optionally halogenated C _1-6 alkoxy (eg, methoxy, ethoxy). , Trifluoromethoxy, 2,2,2-trifluoroethoxy, trichloromethoxy, 2,2,2-trichloroethoxy, etc.) Which may be lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert- butyl, pentyl, _{C 1-6} alkyl hexyl, etc.), _{(2) C 1-6} alkanoyl (e.g., Formyl, acetyl, propionyl, valeroyl, pivaloyl, etc.), benzoyl, C _1-6 alkylsulfonyl (eg, methanesulfonyl etc.), acyl such as benzenesulfonyl; the acyl is C _1-6 lower alkyl (eg, methyl, ethyl) , Butyl, isopropyl, cyclopropyl, cyclohexyl, etc.), C _1-10 acyl (eg, acetyl, propionyl, isopropionyl, benzoyl, parachlorobenzoyl, 4-methylbenzoyl, etc.) and a substituent selected from methanesulfonyl Optionally amino, 2-oxo-1-pyrrolidinyl, 2 Optionally substituted with 1-oxo-1-piperidinyl, 1-acetyl-4-piperidinyl, 1-propionyl-4-piperidinyl, etc. (eg 2-aminopropionyl, 2-benzoylaminopropionyl, 2- (2-oxo 1-pyrrolidinyl) propionyl, 2- (2-oxo-1-piperidinyl) propionyl, 2- (1-acetyl-4-piperidinyl) propionyl, etc.), (3) C _1-6 alkoxy optionally halogenated Carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, trifluoromethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl, trichloromethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, etc.), optionally substituted with phenyl C _1-6 alkoxycarbonyl (eg, benzyloxycarbonyl etc.), (4) heterocyclic group (“substituted” represented by R A group similar to the “heterocyclic group” in the “optionally substituted heterocyclic group” and the like, and the “amino” in the “optionally substituted amino” as the substituent may be substituted. Good imidoyl (eg, C _1-6 alkylimidoyl (eg, formylimidoyl, acetylimidoyl, etc.), C _1-6 alkoxyimidoyl, C _1-6 alkylthioimidoyl, amidino, etc.) 1-2 It may be substituted with amino which may be substituted with C _1-6 alkyl, etc., and two substituents may form a cyclic amino together with a nitrogen atom. Examples of the cyclic amino group include 1-azetidinyl, 1-pyrrolidinyl, piperidino, thiomorpholino, morpholino, 1-piperazinyl, and lower alkyl (eg, methyl, ethyl) at the 4-position. , Propyl, isopropyl, butyl, t-butyl, C _1-6 alkyl such as pentyl, hexyl, etc.), aralkyl (eg, C _7-10 aralkyl such as benzyl, phenethyl, etc.), aryl (eg, phenyl, 1- naphthyl, _{2-C 6-10} aryl, etc.) and the like have be 1-piperazinyl having a naphthyl, 1-pyrrolyl, cyclic amino 3-8 membered 1-imidazolyl and the like (preferably 5-6 membered) Etc.

Ｒで示される「置換されていてもよい環状の炭化水素基」および「置換されていてもよい複素環基」における置換基としての「エステル化されていてもよいカルボキシル」としては、遊離のカルボキシルのほか、例えば、低級アルコキシカルボニル、アリールオキシカルボニル、アラルキルオキシカルボニル等が挙げられる。
該「低級アルコキシカルボニル」としては、例えば、メトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、イソプロポキシカルボニル、ブトキシカルボニル、イソブトキシカルボニル、sec−ブトキシカルボニル、tert−ブトキシカルボニル、ペンチルオキシカルボニル、イソペンチルオキシカルボニル、ネオペンチルオキシカルボニル等のＣ_１−６アルコキシカルボニル等が挙げられ、中でもメトキシカルボニル、エトキシカルボニル、プロポキシカルボニル等のＣ_１−３アルコキシカルボニル等が好ましい。
該「アリールオキシカルボニル」としては、例えば、フェノキシカルボニル、１−ナフトキシカルボニル、２−ナフトキシカルボニル等のＣ_７−１２アリールオキシカルボニル等が好ましい。
該「アラルキルオキシカルボニル」としては、例えば、ベンジルオキシカルボニル、フェネチルオキシカルボニル等のＣ_７−１０アラルキルオキシカルボニル等（好ましくは、Ｃ_６−１０アリール−Ｃ_１−４アルコキシ−カルボニルなど）が好ましい。
該「アリールオキシカルボニル」、「アラルキルオキシカルボニル」は置換基を有していてもよく、その置換基としては、後述するＮ−モノ置換カルバモイルの置換基の例としてのアリール、アラルキルの置換基として挙げたものと同様のものが同様な数用いられる。 The “optionally esterified carboxyl” as a substituent in the “optionally substituted cyclic hydrocarbon group” and the “optionally substituted heterocyclic group” represented by R includes a free carboxyl In addition, for example, lower alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl and the like can be mentioned.
Examples of the “lower alkoxycarbonyl” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, Examples thereof include C _1-6 alkoxycarbonyl such as neopentyloxycarbonyl, etc. Among them, C _1-3 alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and the like are preferable.
As the “aryloxycarbonyl”, for example, C _7-12 aryloxycarbonyl such as phenoxycarbonyl, 1-naphthoxycarbonyl, 2-naphthoxycarbonyl and the like are preferable.
As the “aralkyloxycarbonyl”, for example, C _7-10 aralkyloxycarbonyl such as benzyloxycarbonyl, phenethyloxycarbonyl and the like (preferably C _6-10 aryl-C _1-4 alkoxy-carbonyl etc.) are preferable.
The “aryloxycarbonyl” and “aralkyloxycarbonyl” may have a substituent, and examples of the substituent include aryl and aralkyl as substituents of N-monosubstituted carbamoyl described later. Similar numbers are used as those listed.

Ｒで示される「置換されていてもよい環状の炭化水素基」および「置換されていてもよい複素環基」における置換基としての「置換されていてもよいカルバモイル」としては、無置換のカルバモイルのほか、Ｎ−モノ置換カルバモイルおよびＮ,Ｎ−ジ置換カルバモイルが挙げられる。
「Ｎ−モノ置換カルバモイル」の置換基としては、例えば、低級アルキル（例、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、tert−ブチル、ペンチル、ヘキシル等のＣ_１−６アルキル等）、低級アルケニル（例、ビニル、アリル、イソプロペニル、プロペニル、ブテニル、ペンテニル、ヘキセニル等のＣ_２−６アルケニル等）、シクロアルキル（例、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル等のＣ_３−６シクロアルキル等）、アリール（例、フェニル、１−ナフチル、２−ナフチル等のＣ_６−１０アリール等）、アラルキル（例、ベンジル、フェネチル等のＣ_７−１０アラルキル、好ましくはフェニル−Ｃ_１−４アルキル等）、アリールアルケニル（例、シンナミル等のＣ_８−１０アリールアルケニル、好ましくはフェニル−Ｃ_２−４アルケニル等）、複素環基（例えば、前記したＲで示される「置換されていてもよい複素環基」における「複素環基」と同様の基など）、１〜２個のＣ_１−６アルキルで置換されていてもよいアミノ等が挙げられる。該低級アルキル、低級アルケニル、シクロアルキル、アリール、アラルキル、アリールアルケニル、複素環基は置換基を有していてもよく、その置換基としては、例えば、水酸基、置換されていてもよいアミノ［該アミノは、例えば、低級アルキル（例、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、tert−ブチル、ペンチル、ヘキシル等のＣ_１−６アルキル等）、アシル（例、ホルミル、アセチル、プロピオニル、ピバロイル等のＣ_１−６アルカノイル、ベンゾイル等）、カルボキシル、Ｃ_１−６−アルコキシカルボニル等の１又は２個を置換基として有していてもよい。］、ハロゲン原子（例えば、フッ素、塩素、臭素、ヨウ素等）、ニトロ基、シアノ基、１ないし５個のハロゲン原子（例えば、フッ素、塩素、臭素、ヨウ素等）で置換されていてもよい低級アルキル、１ないし５個のハロゲン原子（例えば、フッ素、塩素、臭素、ヨウ素等）で置換されていてもよい低級アルコキシ等が挙げられる。該低級アルキルとしては、例えば、メチル、エチル、ｎ−プロピル、イソプロピル、ｎ−ブチル、イソブチル、sec−ブチル、tert−ブチル、ペンチル、ヘキシル等のＣ_１−６アルキル等が挙げられ、特にメチル、エチル等が好ましい。該低級アルコキシとしては、例えば、メトキシ、エトキシ、ｎ−プロポキシ、イソプロポキシ、ｎ−ブトキシ、イソブトキシ、sec−ブトキシ、tert−ブトキシ等のＣ_１−６アルコキシ等が挙げられ、特にメトキシ、エトキシ等が好ましい。また、これらの置換基は、同一または異なって１または２ないし３個（好ましくは１または２個）置換しているのが好ましい。
「Ｎ,Ｎ−ジ置換カルバモイル」は、窒素原子上に２個の置換基を有するカルバモイル基を意味し、該置換基の一方の例としては上記した「Ｎ−モノ置換カルバモイル」における置換基と同様のものが挙げられ、他方の例としては、例えば、低級アルキル（例、メチル、エチル、プロピル、イソプロピル、ブチル、tert−ブチル、ペンチル、ヘキシル等のＣ_１−６アルキル等）、Ｃ_３−６シクロアルキル（例、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル等）、Ｃ_７−１０アラルキル（例、ベンジル、フェネチル等、好ましくはフェニル−Ｃ_１−４アルキル等）等が挙げられる。また、２個の置換基が窒素原子と一緒になって環状アミノを形成する場合もあり、この様な場合の環状アミノカルバモイルとしては、例えば、１−アゼチジニルカルボニル、１−ピロリジニルカルボニル、ピペリジノカルボニル、モルホリノカルボニル、チオモルホリノカルボニル（硫黄原子は酸化されていてもよい）、１−ピペラジニルカルボニルおよび４位に低級アルキル（例、メチル、エチル、プロピル、イソプロピル、ブチル、tert−ブチル、ペンチル、ヘキシル等のＣ_１−６アルキル等）、アラルキル（例、ベンジル、フェネチル等のＣ_７−１０アラルキル等）、アリール（例、フェニル、１−ナフチル、２−ナフチル等のＣ_６−１０アリール等）等を有していてもよい１−ピペラジニルカルボニル等の３〜８員（好ましくは５〜６員）の環状アミノカルボニルなどが挙げられる。 The “optionally substituted carbamoyl” as a substituent in the “optionally substituted cyclic hydrocarbon group” and the “optionally substituted heterocyclic group” represented by R is an unsubstituted carbamoyl. And N-monosubstituted carbamoyl and N, N-disubstituted carbamoyl.
Examples of the substituent of “N-monosubstituted carbamoyl” include lower alkyl (eg, C _1-6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, etc.), lower Alkenyl (eg, C _2-6 alkenyl such as vinyl, allyl, isopropenyl, propenyl, butenyl, pentenyl, hexenyl, etc.), cycloalkyl (eg, C _3-6 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) ), Aryl (eg, C _6-10 aryl such as phenyl, 1-naphthyl, 2-naphthyl, etc.), aralkyl (eg, C _7-10 aralkyl such as benzyl, phenethyl, etc., preferably phenyl-C _1-4 alkyl, etc. ), arylalkenyl (e.g., _{C 8-10} arylene of cinnamyl etc. Alkenyl, preferably phenyl -C _2-4 alkenyl, etc.), a Hajime Tamaki (e.g., a group similar to the "heterocyclic group" of the "optionally substituted heterocyclic group" represented by the R), Examples include amino optionally substituted with 1 to 2 C _1-6 alkyl. The lower alkyl, lower alkenyl, cycloalkyl, aryl, aralkyl, arylalkenyl, heterocyclic group may have a substituent, and examples of the substituent include a hydroxyl group and an optionally substituted amino [ Amino is, for example, lower alkyl (eg, C _1-6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, etc.), acyl (eg, formyl, acetyl, propionyl, pivaloyl). _1-6 alkanoyl, benzoyl, etc.), carboxyl, C _1-6 -alkoxycarbonyl and the like may be substituted. ], Optionally substituted by a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a nitro group, a cyano group, or 1 to 5 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) Examples include alkyl, lower alkoxy optionally substituted with 1 to 5 halogen atoms (for example, fluorine, chlorine, bromine, iodine and the like). Examples of the lower alkyl include C _1-6 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like. Ethyl and the like are preferable. Examples of the lower alkoxy include C _1-6 alkoxy such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like, and particularly methoxy, ethoxy and the like. preferable. Further, these substituents are preferably the same or different and are substituted by 1 or 2 to 3 (preferably 1 or 2).
“N, N-disubstituted carbamoyl” means a carbamoyl group having two substituents on the nitrogen atom. One example of the substituent is the above-described substituent in “N-monosubstituted carbamoyl”. Examples of the other include, for example, lower alkyl (eg, C _1-6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, etc.), C _{3- 6} cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.), C _7-10 aralkyl (eg, benzyl, phenethyl etc., preferably phenyl-C _1-4 alkyl etc.) and the like. In some cases, two substituents may form a cyclic amino together with a nitrogen atom. In such a case, examples of the cyclic aminocarbamoyl include 1-azetidinylcarbonyl and 1-pyrrolidinylcarbonyl. , Piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl (the sulfur atom may be oxidized), 1-piperazinylcarbonyl and lower alkyl at the 4-position (eg, methyl, ethyl, propyl, isopropyl, butyl, tert -C _1-6 alkyl such as butyl, pentyl, hexyl, etc.), aralkyl (eg, C _7-10 aralkyl such as benzyl, phenethyl, etc.), aryl (eg, C ₆ such as phenyl, 1-naphthyl, 2-naphthyl, etc.) _-10 aryl etc.) 3-8 member (preferably 5-piperazinylcarbonyl) etc. 6-membered) cyclic aminocarbonyl and the like.

Ｒで示される「置換されていてもよい環状の炭化水素基」および「置換されていてもよい複素環基」における置換基としての「置換されていてもよいチオカルバモイル」および「置換されていてもよいスルファモイル」における置換基としては、前記した「置換されていてもよいカルバモイル」における置換基と同様のものなどが挙げられる。 “Optionally substituted thiocarbamoyl” and “substituted” as substituents in the “optionally substituted cyclic hydrocarbon group” and the “optionally substituted heterocyclic group” represented by R Examples of the substituent in the “optional sulfamoyl” include the same substituents as those in the “optionally substituted carbamoyl”.

Ｒで示される「置換されていてもよい環状の炭化水素基」および「置換されていてもよい複素環基」における置換基としての「スルホン酸由来のアシル」としては、前記した「Ｎ−モノ置換カルバモイル」が窒素原子上に１個有する置換基とスルホニルとが結合したものなどが挙げられるが、好ましくは、メタンスルホニル、エタンスルホニル等のＣ_１−６アルキルスルホニル、ベンゼンスルホニル、パラトルエンスルホニル等のアシルが挙げられる。
Ｒで示される「置換されていてもよい環状の炭化水素基」および「置換されていてもよい複素環基」における置換基としての「カルボン酸由来のアシル」としては、水素原子または前記した「Ｎ−モノ置換カルバモイル」が窒素原子上に１個有する置換基とカルボニルとが結合したものなどが挙げられるが、好ましくは、ホルミル、アセチル、プロピオニル、ピバロイル等のＣ_１−６アルカノイル、ベンゾイル等のアシルが挙げられる。 The “acyl derived from sulfonic acid” as a substituent in the “optionally substituted cyclic hydrocarbon group” and the “optionally substituted heterocyclic group” represented by R is the above-mentioned “N-mono”. Examples of the substituted carbamoyl ”include one in which a substituent having one on a nitrogen atom and sulfonyl are bonded, preferably C _1-6 alkylsulfonyl such as methanesulfonyl and ethanesulfonyl, benzenesulfonyl, paratoluenesulfonyl and the like. Of acyl.
The “acyl derived from carboxylic acid” as a substituent in the “optionally substituted cyclic hydrocarbon group” and the “optionally substituted heterocyclic group” represented by R is a hydrogen atom or the above-mentioned “ N-mono-substituted carbamoyl "is one in which a substituent having one on the nitrogen atom and carbonyl are bonded, and preferably C _1-6 alkanoyl such as formyl, acetyl, propionyl, pivaloyl, benzoyl, etc. Acyl.

Ｒとしては、ハロゲン原子、C_1-6アルキル、C_2-6アルケニル、 C_2-6アルキニル、置換されていてもよいアミノ、ニトロ、シアノ、置換されていてもよいアミジノおよびエステル化もしくはアミド化されていてもよいカルボキシルから選ばれた置換基で置換されていてもよいアリール基；またはハロゲン原子、C_1-6アルキル、C_2-6アルケニル、 C_2-6アルキニル、置換されていてもよいアミノ、ニトロ、シアノ、置換されていてもよいアミジノおよびエステル化もしくはアミド化されていてもよいカルボキシルから選ばれた置換基で置換されていてもよい複素環基が好ましい。
なかでも、Ｒとしては、置換されていてもよいアリールが好ましく、なかでも、ハロゲン原子またはＣ_２−４アルケニル（好ましくは、ハロゲン原子）で置換されていてもよいアリール（好ましくは、フェニル、１−ナフチル、２−ナフチル等のＣ_６−１４アリール等）が好ましい。
また、Ｒとしては、置換されていてもよい複素環基が好ましく、なかでも、ハロゲン原子で置換されていてもよい複素環基（好ましくは、インドリル、ベンゾフラニル、ベンゾピラニル等、さらに好ましくはインドリル）が好ましい。
とりわけ、Ｒとしては、ハロゲン原子で置換されていてもよいナフチルが好ましい。 R is a halogen atom, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, optionally substituted amino, nitro, cyano, optionally substituted amidino, and esterification or amidation An aryl group that may be substituted with a substituent selected from carboxyls that may be substituted; or a halogen atom, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, optionally substituted A heterocyclic group which may be substituted with a substituent selected from amino, nitro, cyano, amidino which may be substituted and carboxyl which may be esterified or amidated is preferable.
Among them, as R, aryl which may be substituted is preferable, and among them, aryl which may be substituted with a halogen atom or C _2-4 alkenyl (preferably a halogen atom) (preferably phenyl, 1 -C _6-14 aryl such as naphthyl and 2-naphthyl) is preferred.
R is preferably a heterocyclic group which may be substituted, and among them, a heterocyclic group which may be substituted with a halogen atom (preferably indolyl, benzofuranyl, benzopyranyl, etc., more preferably indolyl). preferable.
In particular, R is preferably naphthyl optionally substituted with a halogen atom.

前記式中、Ｗは結合手または置換されていてもよい２価の鎖状の炭化水素基を示す。
Ｗで示される「置換されていてもよい２価の鎖状の炭化水素基」における「２価の鎖状の炭化水素基」としては、例えば、C_1-6アルキレン（例えば、メチレン、エチレン、トリメチレン、テトラメチレン等）、C_2-6アルケニレン（例えば、ビニレン、プロピレン、１-または２-ブテニレン、ブタジエニレン等）およびC_2-8アルキニレン（例えば、エチニレン、１-または２-プロピニレン、１-または２-ブチニレン等）等が挙げられる。
Ｗで示される「置換されていてもよい２価の鎖状の炭化水素基」における置換基としては、例えば、前記したＲで示される「置換されていてもよい環状の炭化水素基」における置換基と同様の基などが挙げられる。
Ｗとしては、例えば、結合手またはC_1-6アルケニレンなどが好ましく、なかでも、結合手がより好ましい。 In the above formula, W represents a bond or a divalent chain hydrocarbon group which may be substituted.
As the “divalent chain hydrocarbon group” in the “optionally substituted divalent chain hydrocarbon group” represented by W, for example, C _1-6 alkylene (for example, methylene, ethylene, Trimethylene, tetramethylene, etc.), C _2-6 alkenylene (eg, vinylene, propylene, 1- or 2-butenylene, butadienylene, etc.) and C _2-8 alkynylene (eg, ethynylene, 1- or 2-propynylene, 1- or 2-butynylene, etc.).
Examples of the substituent in the “optionally substituted divalent chain hydrocarbon group” represented by W include, for example, the substitution in the “optionally substituted cyclic hydrocarbon group” represented by R described above. Examples thereof include the same group as the group.
As W, for example, a bond or C _1-6 alkenylene is preferable, and among these, a bond is more preferable.

前記式中、Ｘは置換されていてもよい２価の炭化水素基を示す。
Ｘで示される「置換されていてもよい２価の炭化水素基」における「２価の炭化水素基」としては、「２価の鎖状の炭化水素基」、「２価の環状の炭化水素基」、およびこれらの組み合わせからなる２価の炭化水素基などが挙げられる。
該「２価の鎖状の炭化水素基」としては、例えば、前記したＷで示される「置換されていてもよい２価の鎖状の炭化水素基」における「２価の鎖状の炭化水素基」と同様の基などが挙げられる。
該「２価の環状の炭化水素基」としては、例えば、前記したＲで示される「置換されていてもよい環状の炭化水素基」における「環状の炭化水素基」の任意の水素原子を１個除去して形成される「２価の環状の炭化水素基」などが挙げられるが、なかでも２価のアリール基、とりわけフェニレン基などが好ましく、該フェニレン基としては、１，２−フェニレン、１，３−フェニレンまたは１，４−フェニレンなどが挙げられる。
Ｘで示される「置換されていてもよい２価の炭化水素基」としては、置換されていてもよい２価の鎖状の炭化水素基または置換されていてもよいフェニレン基などが好ましく、なかでも置換されていてもよい２価の鎖状の炭化水素基（特に、置換されていてもよいＣ_１−6アルキレン）が好ましい。
Ｘで示される「置換されていてもよい２価の炭化水素基」における置換基としては、前記したＲで示される「置換されていてもよい環状の炭化水素基」における置換基と同様の基などが挙げられるが、なかでも、低級アルキル（例、メチル、エチル、プロピル等のＣ_１−６アルキル等）、低級アルケニル（例、ビニル、アリル等のＣ_２−６アルケニル等）、低級アルキニル（例、エチニル、プロパルギル等のＣ_２−６アルキニル等）、置換されていてもよいアミノ、置換されていてもよい水酸基、シアノ基、置換されていてもよいアミジノ、カルボキシ、低級アルコキシカルボニル（例、メトキシカルボニル、エトキシカルボニル等のＣ_１−６アルコキシカルボニル等）、置換されていてもよいカルバモイル基（例、Ｃ_１−６アルキルまたはアシル（例、ホルミル、Ｃ_２−６アルカノイル、ベンゾイル、ハロゲン化されていてもよいＣ_１−６アルコキシカルボニル、ハロゲン化されていてもよいＣ_１−６アルキルスルホニル、ベンゼンスルホニル、パラトルエンスルホニル等）で置換されていてもよいカルバモイル基等）またはオキソ基等が好ましく、これらの置換基は置換可能な任意の位置に１ないし３個置換していてもよい。
Ｘとしては、水酸基で置換されていてもよいＣ_１−6アルキレンなどが好ましく、なかでも水酸基で置換されていてもよいエチレン（とりわけ、Ｙに隣接する炭素原子が水酸基で置換されていてもよいエチレン）などが特に好ましく、その中でも無置換のエチレンが特に好ましい。 In the above formula, X represents an optionally substituted divalent hydrocarbon group.
As the “divalent hydrocarbon group” in the “optionally substituted divalent hydrocarbon group” represented by X, “divalent chain hydrocarbon group”, “divalent cyclic hydrocarbon group” Group ", and a divalent hydrocarbon group composed of a combination thereof.
Examples of the “divalent chain hydrocarbon group” include “divalent chain hydrocarbon group” in the “optionally substituted divalent chain hydrocarbon group” represented by W described above. Examples thereof include the same groups as “group”.
As the “divalent cyclic hydrocarbon group”, for example, any hydrogen atom of the “cyclic hydrocarbon group” in the “optionally substituted cyclic hydrocarbon group” represented by R described above is 1 Examples thereof include “divalent cyclic hydrocarbon groups” formed by removing the individual groups. Among them, divalent aryl groups, particularly phenylene groups are preferable, and the phenylene groups include 1,2-phenylene, 1,3-phenylene or 1,4-phenylene may be mentioned.
The “optionally substituted divalent hydrocarbon group” represented by X is preferably an optionally substituted divalent chain hydrocarbon group or an optionally substituted phenylene group. However, an _optionally substituted divalent chain hydrocarbon group (particularly an optionally substituted C _1-6 alkylene) is preferred.
The substituent in the “optionally substituted divalent hydrocarbon group” represented by X is the same group as the substituent in the above “optionally substituted cyclic hydrocarbon group” represented by R. Among them, lower alkyl (eg, C _1-6 alkyl such as methyl, ethyl, propyl etc.), lower alkenyl (eg C _2-6 alkenyl such as vinyl, allyl etc.), lower alkynyl ( Examples, C _2-6 alkynyl such as ethynyl, propargyl, etc.), optionally substituted amino, optionally substituted hydroxyl group, cyano group, optionally substituted amidino, carboxy, lower alkoxycarbonyl (eg, methoxycarbonyl, etc. C _1-6 alkoxycarbonyl such as methoxycarbonyl or ethoxycarbonyl), an optionally substituted carbamoyl group (e.g., C _1-6 alkyl or Acyl (example, formyl, C _2-6 alkanoyl, benzoyl, optionally halogenated C _1-6 alkoxycarbonyl, a C _1-6 alkylsulfonyl which may be halogenated, benzenesulfonyl, p-toluenesulfonyl, etc. ) Or an oxo group which may be substituted with 1) or 3), and 1 to 3 of these substituents may be substituted at any substitutable position.
X is preferably C _1-6 alkylene which may be substituted with a hydroxyl group, and in particular, ethylene which may be substituted with a hydroxyl group (especially, a carbon atom adjacent to Y may be substituted with a hydroxyl group). Ethylene) and the like are particularly preferable, and among these, unsubstituted ethylene is particularly preferable.

前記式中、Ｙは-CO-, -S(O)-, -S(O)₂- または結合手を示す。
Ｙとしては-CO-が好ましい。 In the above formula, Y represents —CO—, —S (O) —, —S (O) ₂ — or a bond.
Y is preferably -CO-.

前記式中、環Ａは置換されていてもよいピロリジン環、置換されていてもよいピペリジン環または置換されていてもよいパーヒドロアゼピン環を示す。
環Ａで示される「置換されていてもよいピロリジン環」、「置換されていてもよいピペリジン環」および「置換されていてもよいパーヒドロアゼピン環」における置換基としては、前記したＲで示される「置換されていてもよい複素環基」における置換基と同様の基などが挙げられ、これらの任意の置換基は置換可能な位置に１ないし５個（好ましくは、１ないし３個）置換していてもよい。なかでも、（C_1-6アルキルスルフィニル基、C_1-6アルキルスルホニル基、水酸基またはエステル化もしくはアミド化されていてもよいカルボキシルで置換されていてもよい）C_1-6アルキル基、水酸基、エステル化またはアミド化されていてもよいカルボキシル基およびオキソ基などが好ましい。
環Ａとしては置換されていてもよいピペリジン環が好ましく、なかでも、式

が、式

〔式中、環Ａ’は置換されていてもよい。〕であることがより好ましい。 In the above formula, ring A represents an optionally substituted pyrrolidine ring, an optionally substituted piperidine ring, or an optionally substituted perhydroazepine ring.
The substituents in the “optionally substituted pyrrolidine ring”, “optionally substituted piperidine ring” and “optionally substituted perhydroazepine ring” represented by ring A are the same as those of R described above. The same groups as the substituents in the “optionally substituted heterocyclic group” are mentioned, and these optional substituents are substituted with 1 to 5 (preferably 1 to 3) substituents at substitutable positions. You may do it. Among them, (C _1-6 alkylsulfinyl group, C _1-6 alkylsulfonyl group, hydroxyl group or optionally substituted with carboxyl which may be esterified or amidated) C _1-6 alkyl group, hydroxyl group, A carboxyl group and an oxo group which may be esterified or amidated are preferred.
Ring A is preferably an optionally substituted piperidine ring.

But the expression

[Wherein ring A ′ may be substituted. It is more preferable that

前記式中、Ｚ^１およびＺ^３はそれぞれ独立しては結合手または置換されていてもよい２価の鎖状の炭化水素基を示す。
Ｚ^１およびＺ^３でそれぞれ示される「置換されていてもよい２価の鎖状の炭化水素基」における「２価の鎖状の炭化水素基」としては、Ｗで示される「置換されていてもよい２価の鎖状の炭化水素基」における「２価の鎖状の炭化水素基」と同様の基などが挙げられる。
Ｚ^１およびＺ^３でそれぞれ示される「置換されていてもよい２価の鎖状の炭化水素基」における置換基としては、Ｗで示される「置換されていてもよい２価の鎖状の炭化水素基」における置換基と同様な数の同様の基などが挙げられる。
Ｚ^１としては、結合手またはC_1-6アルキレンなどが好ましい。
Ｚ^３としては、結合手またはC_1-6アルキレンなどが好ましい。 In the above formula, Z ¹ and Z ³ each independently represent a bond or a divalent chain hydrocarbon group which may be substituted.
As the “divalent chain hydrocarbon group” in the “optionally substituted divalent chain hydrocarbon group” represented by Z ¹ and Z ³ , “disubstituted chain hydrocarbon group” represented by W is Examples thereof include a group similar to the “divalent chain hydrocarbon group” in “a divalent chain hydrocarbon group”.
As the substituent in the “optionally substituted divalent chain hydrocarbon group” represented by each of Z ¹ and Z ³ , “the optionally substituted divalent chain carbonization represented by W” Examples thereof include the same number of the same groups as the substituents in “hydrogen group”.
Z ¹ is preferably a bond or C _1-6 alkylene.
Z ³ is preferably a bond or C _1-6 alkylene.

前記式中、Ｚ^２は -N(R^１)-, -O-, -S(O)-, -S(O)₂-, -CO-, -CH(R^１)- または結合手を示し、ここでＲ^１は水素原子、置換されていてもよい炭化水素基、置換されていてもよいアシル基、エステル化されていてもよいカルボキシル基または置換されていてもよいカルバモイル基を示す。
Ｒ^１で示される「置換されていてもよい炭化水素基」における「炭化水素基」としては、例えばアルキル、アルケニル、アルキニル、アリール、シクロアルキル、シクロアルケニル、アラルキルなどが挙げられる。
該アルキル、アルケニル、アルキニル、アリール、シクロアルキルおよびシクロアルケニルとしては、それぞれ、前記したＲで示される「置換されていてもよい環状の炭化水素基」における置換基としての「置換されていてもよいアルキル」、「置換されていてもよいアルケニル」、「置換されていてもよいアルキニル」、「置換されていてもよいアリール」、「置換されていてもよいシクロアルキル」および「置換されていてもよいシクロアルケニル」おけるアルキル、アルケニル、アルキニル、アリール、シクロアルキルおよびシクロアルケニルと同様の基などが挙げられる。
該アラルキルとしては、例えばベンジル、フェネチル、３−フェニルプロピル、４−フェニルブチルなどのフェニル−Ｃ_１−６アルキル基および、例えば（１−ナフチル）メチル、２−（１−ナフチル）エチル、２−（２−ナフチル）エチルなどのナフチル−Ｃ_１−６アルキル基などのＣ_７−１６アラルキル基などが挙げられる。
Ｒ^１で示される「置換されていてもよい炭化水素基」における置換基としては、前記したＲで示される「置換されていてもよい環状の炭化水素基」における置換基と同様な数の同様の基などが挙げられる。
Ｒ^１で示される「置換されていてもよいアシル基」としては、Ｒで示される「置換されていてもよい環状の炭化水素基」における置換基としての「スルホン酸由来のアシル」および「カルボン酸由来のアシル」と同様の基などが挙げられる。
Ｒ^１で示される「エステル化されていてもよいカルボキシル基」としては、Ｒで示される「置換されていてもよい環状の炭化水素基」における置換基としての「エステル化されていてもよいカルボキシル」と同様の基などが挙げられる。
Ｒ^１で示される「置換されていてもよいカルバモイル基」としては、Ｒで示される「置換されていてもよい環状の炭化水素基」における置換基としての「置換されていてもよいカルバモイル」と同様の基などが挙げられる。
また、Ｒ^１はホスホノ基（例えば、ジメチルホスホノ、ジエチルホスホノ、ジイソプロピルホスホノ、ジブチルホスホノ、２−オキシド−１,３,２−ジオキサホスフィナン−２−イルなどの、環を形成していてもよい（モノ−もしくはジ−Ｃ_１−４アルキル）ホスホノなど）であってもよい。
Ｚ^２としては、-N(R^１)-、-CO- または結合手などが好ましい。 In the above formula, Z ² represents —N (R ¹ ) —, —O—, —S (O) —, —S (O) ₂ —, —CO—, —CH (R ¹ ) — or a bond. Here, R ¹ represents a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted acyl group, an optionally esterified carboxyl group or an optionally substituted carbamoyl group.
Examples of the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R ¹ include alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, aralkyl and the like.
The alkyl, alkenyl, alkynyl, aryl, cycloalkyl and cycloalkenyl each may be “substituted” as a substituent in the “optionally substituted cyclic hydrocarbon group” represented by R described above. "Alkyl", "optionally substituted alkenyl", "optionally substituted alkynyl", "optionally substituted aryl", "optionally substituted cycloalkyl" and "optionally substituted" Examples thereof include a group similar to alkyl, alkenyl, alkynyl, aryl, cycloalkyl and cycloalkenyl in “good cycloalkenyl”.
Examples of the aralkyl include phenyl-C _1-6 alkyl groups such as benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, and (1-naphthyl) methyl, 2- (1-naphthyl) ethyl, 2- And C _7-16 aralkyl groups such as naphthyl-C _1-6 alkyl groups such as (2-naphthyl) ethyl.
The substituent in the “optionally substituted hydrocarbon group” represented by R ¹ is the same as the substituent in the “optionally substituted cyclic hydrocarbon group” represented by R described above. And the like.
Examples of the “optionally substituted acyl group” represented by R 1 include “acyl derived from sulfonic acid” and “carboxylic” as substituents in the “optionally substituted cyclic hydrocarbon group” represented by R ^1. Examples thereof include the same groups as “acyl derived from acid”.
The “optionally esterified carboxyl group” represented by R ¹ is the “optionally esterified carboxyl group” as a substituent in the “optionally substituted cyclic hydrocarbon group” represented by R ^1. And the like.
As the "optionally substituted carbamoyl group" represented by R ^1, a "carbamoyl which may be substituted" as the substituents of the "hydrocarbon group which may be substituted cyclic" represented by R The same group etc. are mentioned.
R ¹ forms a ring such as a phosphono group (for example, dimethylphosphono, diethylphosphono, diisopropylphosphono, dibutylphosphono, 2-oxide-1,3,2-dioxaphosphinan-2-yl). (Mono- or di-C _1-4 alkyl) phosphono and the like).
Z ² is preferably —N (R ¹ ) —, —CO— or a bond.

環Ｂは置換されていてもよいイミダゾール環を示す。
該イミダゾール環が有していてもよい置換基としては、前記したＲで示される「置換されていてもよい環状の炭化水素基」における置換基と同様の基（ただし、オキソ基およびチオキソ基を除く）などが挙げられ、これらの任意の置換基は置換可能な位置に１ないし３個（好ましくは、１ないし２個）置換していてもよい。 Ring B represents an optionally substituted imidazole ring.
The substituent that the imidazole ring may have is the same as the substituent in the “optionally substituted cyclic hydrocarbon group” represented by R described above (however, an oxo group and a thioxo group may be substituted). These optional substituents may be substituted with 1 to 3 (preferably 1 to 2) substituents at substitutable positions.

環Ｂにおけるイミダゾール環が置換基を有する場合、イミダゾール環が有する置換基とＲ^１とが互いに結合して「置換されていてもよい環」を形成していてもよく、該「置換されていてもよい環」における「環」は同素環または複素環のいずれであってもよい。
該「同素環または複素環」には、例えば、（i）炭素原子以外に窒素原子、硫黄原子および酸素原子から選ばれた１種または２種のヘテロ原子を、好ましくは１個ないし３個含む芳香族複素環または非芳香族複素環、および（ii)炭素原子からなる環状炭化水素（同素環）などが含まれる。
該「芳香族複素環」としては、例えば、炭素原子以外に、窒素原子、酸素原子および硫黄原子から選ばれたヘテロ原子を１個ないし３個含む５ないし６員の芳香族複素環（例えば、ピリジン、ピラジン、ピリミジン、ピリダジン、ピロール、イミダゾール、ピラゾール、トリアゾール、チオフェン、フラン、チアゾール、イソチアゾール、オキサゾールおよびイソオキサゾール環など）などが挙げられる。
該「非芳香族複素環」としては、例えば、炭素原子以外に、窒素原子、酸素原子および硫黄原子から選ばれたヘテロ原子を１個ないし３個含む５ないし９員（好ましくは５または６員）の非芳香族複素環（例えば、テトラヒドロピリジン、ジヒドロピリジン、テトラヒドロピラジン、テトラヒドロピリミジン、テトラヒドロピリダジン、ジヒドロピラン、ジヒドロピロール、ジヒドロチオフェン、ジヒドロフラン、ピペリジン、ピペラジン、ヘキサヒドロピリミジン、ヘキサヒドロピリダジン、テトラヒドロピラン、モルホリン、ピロリジン、ピラゾリン、イミダゾリジン、チアゾリン、イソチアゾリン、オキサゾリン、イソオキサゾリン、ピラゾリジン、テトラヒドロチオフェン、テトラヒドロフラン、テトラヒドロチアゾール、テトラヒドロイソチアゾール、テトラヒドロオキサゾール、テトラヒドロイソキサゾール環など）などが挙げられる。
該「環状炭化水素（同素環）」としては、例えば、３ないし１０員（好ましくは、５ないし９員、より好ましくは５または６員）の環状炭化水素などが挙げられ、例えば、ベンゼン、Ｃ_３−１０シクロアルケン（例えば、シクロブテン、シクロペンテン、シクロヘキセン、シクロヘプテン、シクロオクテンなど）、Ｃ_３−１０シクロアルカン（例えば、シクロブタン、シクロペンタン、シクロヘキサン、シクロヘプタン、シクロオクタンなど）などが挙げられる。シクロアルケンとしては、Ｃ_５−６シクロアルケン（例えば、シクロペンテン、シクロヘキセンなど）などが好ましく、シクロアルカンとしてはＣ_５−６シクロアルカン（例えば、シクロヘキサン、シクロペンタンなど）などが好ましい。
環Ｂにおけるイミダゾール環が有する置換基とＲ^１とが互いに結合して形成する「環」としては、例えば、炭素原子以外に窒素原子を１個ないし２個（好ましくは２個）含む５ないし９員（好ましくは５または６員）の非芳香族複素環が好ましく、なかでも、テトラヒドロピリジン、テトラヒドロピラジン、テトラヒドロピロール、テトラヒドロイミダゾールなどがより好ましい例として挙げられる。
環Ｂにおけるイミダゾール環が有する置換基とＲ^１とが互いに結合して形成する「置換されていてもよい環」における置換基としては、前記したＲで示される「置換されていてもよい複素環基」における置換基と同様の基などが挙げられ、これらの任意の置換基は置換可能な位置に１ないし４個（好ましくは、１ないし３個）置換していてもよい。該「置換されていてもよい環」における置換基としては、なかでも、水酸基で置換されていてもよいC_1-6アルキル基、水酸基およびオキソ基などが好ましい。 When the imidazole ring in ring B has a substituent, the substituent of the imidazole ring and R ¹ may be bonded to each other to form an “optionally substituted ring”. The “ring” in the “optional ring” may be either a homocyclic ring or a heterocyclic ring.
In the “homocyclic ring or heterocyclic ring”, for example, (i) one or two heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to the carbon atom, preferably 1 to 3 And an aromatic heterocyclic ring or a non-aromatic heterocyclic ring, and (ii) a cyclic hydrocarbon (homogeneous ring) composed of carbon atoms.
Examples of the “aromatic heterocycle” include, for example, a 5- to 6-membered aromatic heterocycle containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom (for example, Pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, imidazole, pyrazole, triazole, thiophene, furan, thiazole, isothiazole, oxazole and isoxazole rings).
Examples of the “non-aromatic heterocyclic ring” include 5 to 9 members (preferably 5 or 6 members) containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom. ) Non-aromatic heterocycles (eg, tetrahydropyridine, dihydropyridine, tetrahydropyrazine, tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, dihydropyrrole, dihydrothiophene, dihydrofuran, piperidine, piperazine, hexahydropyrimidine, hexahydropyridazine, tetrahydropyran , Morpholine, pyrrolidine, pyrazoline, imidazolidine, thiazoline, isothiazoline, oxazoline, isoxazoline, pyrazolidine, tetrahydrothiophene, tetrahydrofuran, tetrahydrothiazole, tetrahydro Roisochiazoru, tetrahydrophthalic oxazole, tetrahydronaphthyl isoxazole ring), and the like.
Examples of the “cyclic hydrocarbon (homocyclic ring)” include 3- to 10-membered (preferably 5- to 9-membered, more preferably 5- or 6-membered) cyclic hydrocarbons, such as benzene, C _3-10 cycloalkene (eg, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, etc.), C _3-10 cycloalkane (eg, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, etc.) and the like can be mentioned. As the cycloalkene, C _5-6 cycloalkene (eg, cyclopentene, cyclohexene, etc.) is preferable, and as the cycloalkane, C _5-6 cycloalkane (eg, cyclohexane, cyclopentane, etc.) is preferable.
Examples of the “ring” formed by bonding the substituent of the imidazole ring in ring B and R ¹ to each other include 5 to 9 containing 1 to 2 (preferably 2) nitrogen atoms in addition to carbon atoms. A member (preferably 5 or 6 membered) non-aromatic heterocyclic ring is preferable, and among them, tetrahydropyridine, tetrahydropyrazine, tetrahydropyrrole, tetrahydroimidazole and the like are more preferable examples.
The substituent in the “optionally substituted ring” formed by bonding the substituent of the imidazole ring in ring B and R ¹ to each other is the “optionally substituted heterocyclic ring” represented by R described above. Examples thereof include the same groups as the substituents in the “group”, and these optional substituents may be substituted by 1 to 4 (preferably 1 to 3) at substitutable positions. As the substituent in the “optionally substituted ring”, a C _1-6 alkyl group, a hydroxyl group and an oxo group which may be substituted with a hydroxyl group are particularly preferable.

環Ｂとしては、
式

が、式

〔式中、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、Ｒ^８、Ｒ^９、Ｒ^１０、Ｒ^１１、Ｒ^１２およびＲ^１３はそれぞれ独立して水素原子、置換されていてもよい炭化水素基、置換されていてもよい水酸基、置換されていてもよいチオ−ル基、置換されていてもよいアルキルスルフィニル基、置換されていてもよいアルキルスルホニル基、置換されていてもよいアシル基、エステル化されていてもよいカルボキシル基、置換されていてもよいカルバモイル基または置換されていてもよいアミノ基を示し、Ｒ^２とＲ^３、Ｒ^５とＲ^６、Ｒ^６とＲ^７、Ｒ^８とＲ^９、Ｒ^９とＲ^１０またはＲ^１１とＲ^１２とがそれぞれ互いに結合して置換されていてもよい環を形成していてもよい。〕であることが好ましい。
Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、Ｒ^８、Ｒ^９、Ｒ^１０、Ｒ^１１、Ｒ^１２およびＲ^１３で示される「置換されていてもよい炭化水素基」における「炭化水素基」としては、それぞれ、例えば、前記したＲ^１で示される「置換されていてもよい炭化水素基」における「炭化水素基」と同様の基などが挙げられ、該「炭化水素基」が有していてもよい置換基としては、前記したＲ^１で示される「置換されていてもよい炭化水素基」における置換基と同様な数の同様の基などが挙げられる。
Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、Ｒ^８、Ｒ^９、Ｒ^１０、Ｒ^１１、Ｒ^１２およびＲ^１３で示される「置換されていてもよい水酸基」、「置換されていてもよいチオ−ル基」、「置換されていてもよいアルキルスルフィニル基」および「置換されていてもよいアルキルスルホニル基」における置換基としては、それぞれ、Ｒで示される「置換されていてもよい環状の炭化水素基」における置換基としての「置換されていてもよい水酸基」、「置換されていてもよいチオール基」、「置換されていてもよいアルキルスルフィニル」および「置換されていてもよいアルキルスルホニル」における置換基と同様の基などが挙げられる。
Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、Ｒ^８、Ｒ^９、Ｒ^１０、Ｒ^１１、Ｒ^１２およびＲ^１３で示される「置換されていてもよいアシル基」としては、Ｒで示される「置換されていてもよい環状の炭化水素基」における置換基としての「スルホン酸由来のアシル」および「カルボン酸由来のアシル」と同様の基などが挙げられる。
Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、Ｒ^８、Ｒ^９、Ｒ^１０、Ｒ^１１、Ｒ^１２およびＲ^１３で示される「エステル化されていてもよいカルボキシル基」としては、前記したＲで示される「置換されていてもよい環状の炭化水素基」における置換基としての「エステル化されていてもよいカルボキシル」と同様の基などが挙げられる。
Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、Ｒ^８、Ｒ^９、Ｒ^１０、Ｒ^１１、Ｒ^１２およびＲ^１３で示される「置換されていてもよいカルバモイル基」としては、前記したＲで示される「置換されていてもよい環状の炭化水素基」における置換基としての「置換されていてもよいカルバモイル」と同様の基などが挙げられる。
Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、Ｒ^８、Ｒ^９、Ｒ^１０、Ｒ^１１、Ｒ^１２およびＲ^１３で示される「置換されていてもよいアミノ基」としては、前記したＲで示される「置換されていてもよい環状の炭化水素基」における置換基としての「置換されていてもよいアミノ」と同様の基などが挙げられる。
Ｒ^２とＲ^３、Ｒ^５とＲ^６、Ｒ^６とＲ^７、Ｒ^８とＲ^９、Ｒ^９とＲ^１０またはＲ^１１とＲ^１２とがそれぞれ互いに結合して形成していてもよい「置換されていてもよい環」における「環」としては、前記したＢ環における置換基とＲ^１とが互いに結合して形成する「環」と同様の環などが挙げられる。該「置換されていてもよい環」における置換基としては、前記したＲで示される「置換されていてもよい複素環基」における置換基と同様の基などが挙げられ、これらの任意の置換基は置換可能な位置に１ないし５個（好ましくは、１ないし３個）置換していてもよい。
また、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、Ｒ^８、Ｒ^９、Ｒ^１０、Ｒ^１１、Ｒ^１２およびＲ^１３はホスホノ基（例えば、ジメチルホスホノ、ジエチルホスホノ、ジイソプロピルホスホノ、ジブチルホスホノ、２−オキシド−１,３,２−ジオキサホスフィナン−２−イルなどの、環を形成していてもよい（モノ−もしくはジ−Ｃ_１−４アルキル）ホスホノなど）であってもよい。 As ring B,
formula

But the expression

[Wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are each independently a hydrogen atom or substituted. An optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally substituted alkylsulfinyl group, an optionally substituted alkylsulfonyl group, a substituted An acyl group which may be esterified, a carboxyl group which may be esterified, an optionally substituted carbamoyl group or an optionally substituted amino group, R ² and R ³ , R ⁵ and R ⁶ , R ⁶ and R ⁷ , R ⁸ and R ⁹ , R ⁹ and R ^10, or R ¹¹ and R ¹² may be bonded to each other to form an optionally substituted ring. It is preferable that
In the “optionally substituted hydrocarbon group” represented by R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ Examples of the “hydrocarbon group” include groups similar to the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R ¹ described above. Examples of the substituent that "may have" include the same number of similar groups as the substituent in the "optionally substituted hydrocarbon group" represented by R ¹ described above.
R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ and the “optionally substituted hydroxyl group” and “substituted” The substituents in the “optionally substituted thiol group”, “optionally substituted alkylsulfinyl group” and “optionally substituted alkylsulfonyl group” are the “substituted” represented by R, respectively. The “optionally substituted hydroxyl group”, “optionally substituted thiol group”, “optionally substituted alkylsulfinyl” and “substituted” as the substituent in the “optionally substituted cyclic hydrocarbon group” Examples thereof include the same groups as the substituents of “optional alkylsulfonyl”.
Examples of the “optionally substituted acyl group” represented by R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ And a group similar to “acyl derived from sulfonic acid” and “acyl derived from carboxylic acid” as a substituent in the “optionally substituted cyclic hydrocarbon group” represented by R, and the like.
As an “esterified carboxyl group” represented by R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ Includes the same group as the “optionally esterified carboxyl” as a substituent in the “optionally substituted cyclic hydrocarbon group” represented by R described above.
Examples of the “optionally substituted carbamoyl group” represented by R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ And a group similar to “optionally substituted carbamoyl” as a substituent in the “optionally substituted cyclic hydrocarbon group” represented by R described above.
Examples of the “optionally substituted amino group” represented by R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ And a group similar to “optionally substituted amino” as a substituent in the “optionally substituted cyclic hydrocarbon group” represented by R described above.
R ² and R ³ , R ⁵ and R ⁶ , R ⁶ and R ⁷ , R ⁸ and R ⁹ , R ⁹ and R ¹⁰ or R ¹¹ and R ¹² may be bonded to each other. Examples of the “ring” in the “optional ring” include the same ring as the “ring” formed by bonding the substituent in the B ring and R ¹ to each other. Examples of the substituent in the “optionally substituted ring” include the same groups as the substituents in the “optionally substituted heterocyclic group” represented by R described above. The group may be substituted with 1 to 5 (preferably 1 to 3) substituted positions.
R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are phosphono groups (for example, dimethylphosphono, diethylphosphono , Diisopropylphosphono, dibutylphosphono, 2-oxide-1,3,2-dioxaphosphinan-2-yl and the like, may form a ring (mono- or di- _C1-4 alkyl) Phosphono etc.).

環Ｂの好ましい態様として、例えば、式

が、式

〔式中、環Ｃは置換されていてもよい含窒素複素環を示し、他の記号は前記と同意義を示す。〕である場合などが挙げられる。
環Ｃで示される「置換されていてもよい含窒素複素環」における「含窒素複素環」としては、非芳香族含窒素複素環（例えば、ピロリジン、ピペリジン、パーヒドロアゼピンなど）あるいはイミダゾール環と縮合して芳香族縮合含窒素複素環を形成しうる環（例えば、式

〔式中、環Ｃ^１、Ｃ^２、Ｃ^３およびＣ^４は置換されていてもよい。〕で表される環など）などが挙げられ、これらの環がイミダゾール環と縮合することにより、例えば、式

〔式中、環Ｃ^１、Ｃ^２、Ｃ^３、Ｃ^４、Ｃ^５、Ｃ^６およびＣ^７は置換されていてもよい。〕で表される縮合環などを形成しうる。
環Ｃで示される「置換されていてもよい含窒素複素環」における「含窒素複素環」が有していてもよい置換基（および、環Ｃ^１、Ｃ^２、Ｃ^３、Ｃ^４、Ｃ^５、Ｃ^６およびＣ^７がそれぞれ有していてもよい置換基）としては、前記したＲで示される「置換されていてもよい複素環基」における置換基と同様の基などが挙げられ、これらの任意の置換基は置換可能な位置に１ないし５個（好ましくは、１ないし３個）置換していてもよい。 Preferred embodiments of ring B include, for example, the formula

But the expression

[Wherein, ring C represents a nitrogen-containing heterocyclic ring which may be substituted, and other symbols are as defined above. And the like.
The “nitrogen-containing heterocycle” in the “optionally substituted nitrogen-containing heterocycle” represented by ring C includes a non-aromatic nitrogen-containing heterocycle (eg, pyrrolidine, piperidine, perhydroazepine, etc.) or an imidazole ring. Rings that can be condensed to form an aromatic fused nitrogen-containing heterocycle (eg, the formula

[Wherein the rings C ¹ , C ² , C ³ and C ⁴ may be substituted. And the like, and these rings are condensed with an imidazole ring, for example,

[Wherein the rings C ¹ , C ² , C ³ , C ⁴ , C ⁵ , C ⁶ and C ⁷ may be substituted. A condensed ring represented by the formula:
The substituent (and rings C ¹ , C ² , C ³ , C ⁴ , C) that the “nitrogen-containing heterocycle” in the “optionally substituted nitrogen-containing heterocycle” represented by ring C may have ⁵ , C ⁶ and C ⁷ may each have the same substituents as those in the “optionally substituted heterocyclic group” represented by R, and the like. Any one of these optional substituents may be substituted at a substitutable position (preferably 1 to 3).

式（Ｉ）で表される化合物の好ましい態様として、例えば、環Ｂにおけるイミダゾール環が有する置換基とＲ^１とが環を形成していない構造が挙げられる。 In a preferred embodiment of the compound of formula (I), for example, substituents having the imidazole ring in the ring B and R ¹ can be mentioned the structures do not form a ring.

また、式（Ｉ）で表される化合物の好ましい態様として、例えば、Ｚ^２が -N(R^１)- または -CH(R^１)-（Ｒ^１は前記と同意義を示す。）であり、環Ｂにおけるイミダゾール環が有する置換基とＲ^１とが互いに結合して置換されていてもよい環を形成している構造が挙げられる。
式（Ｉ）で表される化合物の態様として、なかでも、式（Ｉ）が、式（Ｉａ）

〔式中、環Ｂ’はさらに置換されていてもよいイミダゾール環を示し、Ｚ^２ａはＮまたはＣＨを示し、Ｚ^４は置換されていてもよい２価の鎖状の炭化水素基を示し、他の記号は前記と同意義を示す。〕であることが好ましい態様として挙げられる。
ここで、Ｚ^２ａとしては窒素原子が好ましい。
Ｚ^４で示される「置換されていてもよい２価の鎖状の炭化水素基」における「２価の鎖状の炭化水素基」としては、Ｗで示される「置換されていてもよい２価の鎖状の炭化水素基」における「２価の鎖状の炭化水素基」と同様の基などが挙げられる。
Ｚ^４で示される「置換されていてもよい２価の鎖状の炭化水素基」における置換基としては、Ｗで示される「置換されていてもよい２価の鎖状の炭化水素基」における置換基と同様な数の同様の基などが挙げられる。
Ｚ^３およびＺ^４としては、それぞれ独立してオキソ基で置換されていてもよい２価の鎖状の炭化水素基（好ましくはオキソ基で置換されていてもよいC_1-6アルキレン）が好ましい。 Further, as a preferred embodiment of the compound represented by the formula (I), for example, Z ² is —N (R ¹ ) — or —CH (R ¹ ) — (R ¹ is as defined above). And a structure in which the substituent of the imidazole ring in ring B and R ¹ are bonded to each other to form an optionally substituted ring.
As an embodiment of the compound represented by formula (I), among them, formula (I) is represented by formula (Ia)

[In the formula, ring B ′ represents an imidazole ring which may be further substituted, Z ^2a represents N or CH, Z ⁴ represents a divalent chain hydrocarbon group which may be substituted, Other symbols are as defined above. It is mentioned as a preferable embodiment.
Here, as ^Z2a , a nitrogen atom is preferable.
The “divalent chain hydrocarbon group” in the “optionally substituted divalent chain hydrocarbon group” represented by Z ⁴ is the “divalent chain hydrocarbon group that may be substituted” represented by W. And the like as the “divalent chain hydrocarbon group” in the “chain hydrocarbon group”.
As the substituent in the “optionally substituted divalent chain hydrocarbon group” represented by Z ⁴ , the substituent in the “optionally substituted divalent chain hydrocarbon group” represented by W is exemplified. Examples include the same number of similar groups as the substituent.
Z ³ and Z ⁴ are each preferably a divalent chain hydrocarbon group which may be independently substituted with an oxo group (preferably a C _1-6 alkylene which may be substituted with an oxo group). .

式（Ｉ）で表される化合物の好ましい態様として、例えば、式（Ｉ）が、式（Ｉｂ）

〔式中、Ｒ^１４およびＲ^１５はそれぞれ独立して水素原子、置換されていてもよい炭化水素基、置換されていてもよい水酸基、置換されていてもよいチオ−ル基、置換されていてもよいアルキルスルフィニル基、置換されていてもよいアルキルスルホニル基、置換されていてもよいアシル基、エステル化されていてもよいカルボキシル基、置換されていてもよいカルバモイル基または置換されていてもよいアミノ基を示し、Ｒ^１４とＲ^１５とが互いに結合して置換されていてもよい環を形成していてもよく、他の記号は前記と同意義を示す。〕である化合物が挙げられる。
Ｒ^１４およびＲ^１５で示される「置換されていてもよい炭化水素基」における「炭化水素基」としては、例えば、前記したＲ^１で示される「置換されていてもよい炭化水素基」における「炭化水素基」と同様の基などが挙げられ、該「炭化水素基」が有していてもよい置換基としては、前記したＲ^１で示される「置換されていてもよい炭化水素基」における置換基と同様な数の同様の基などが挙げられる。
Ｒ^１４およびＲ^１５で示される「置換されていてもよい水酸基」、「置換されていてもよいチオ−ル基」、「置換されていてもよいアルキルスルフィニル基」および「置換されていてもよいアルキルスルホニル基」における置換基としては、それぞれ、Ｒで示される「置換されていてもよい環状の炭化水素基」における置換基としての「置換されていてもよい水酸基」、「置換されていてもよいチオール基」、「置換されていてもよいアルキルスルフィニル」および「置換されていてもよいアルキルスルホニル」における置換基と同様の基などが挙げられる。
Ｒ^１４およびＲ^１５で示される「置換されていてもよいアシル基」としては、Ｒで示される「置換されていてもよい環状の炭化水素基」における置換基としての「スルホン酸由来のアシル」および「カルボン酸由来のアシル」と同様の基などが挙げられる。
Ｒ^１４およびＲ^１５で示される「エステル化されていてもよいカルボキシル基」としては、Ｒで示される「置換されていてもよい環状の炭化水素基」における置換基としての「エステル化されていてもよいカルボキシル」と同様の基などが挙げられる。
Ｒ^１４およびＲ^１５で示される「置換されていてもよいカルバモイル基」としては、Ｒで示される「置換されていてもよい環状の炭化水素基」における置換基としての「置換されていてもよいカルバモイル」と同様の基などが挙げられる。
Ｒ^１４およびＲ^１５で示される「置換されていてもよいアミノ基」としては、前記したＲで示される「置換されていてもよい環状の炭化水素基」における置換基としての「置換されていてもよいアミノ」と同様の基などが挙げられる。
Ｒ^１４とＲ^１５とがそれぞれ互いに結合して形成していてもよい「置換されていてもよい環」における「環」としては、前記したＢ環における置換基とＲ^１とが互いに結合して形成する「環」と同様の環などが挙げられる。該「置換されていてもよい環」における置換基としては、前記したＲで示される「置換されていてもよい複素環基」における置換基と同様の基などが挙げられ、これらの任意の置換基は置換可能な位置に１ないし５個（好ましくは、１ないし３個）置換していてもよい。
また、Ｒ^１４およびＲ^１５はホスホノ基（例えば、ジメチルホスホノ、ジエチルホスホノ、ジイソプロピルホスホノ、ジブチルホスホノ、２−オキシド−１,３,２−ジオキサホスフィナン−２−イルなどの、環を形成していてもよい（モノ−もしくはジ−Ｃ_１−４アルキル）ホスホノなど）であってもよい。 As a preferable embodiment of the compound represented by the formula (I), for example, the formula (I) is represented by the formula (Ib)

[Wherein R ¹⁴ and R ¹⁵ are each independently a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted thiol group, Alkylsulfinyl group which may be substituted, alkylsulfonyl group which may be substituted, acyl group which may be substituted, carboxyl group which may be esterified, carbamoyl group which may be substituted or may be substituted Represents an amino group, R ¹⁴ and R ¹⁵ may be bonded to each other to form an optionally substituted ring, and other symbols are as defined above. The compound which is] is mentioned.
As the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R ¹⁴ and R ¹⁵ , for example, “in the optionally substituted hydrocarbon group” represented by R ¹ above “ Examples of the substituent that the “hydrocarbon group” may have include those in the “optionally substituted hydrocarbon group” represented by R ¹ described above. Examples include the same number of similar groups as the substituent.
The “optionally substituted hydroxyl group”, “optionally substituted thiol group”, “optionally substituted alkylsulfinyl group” and “optionally substituted” represented by R ¹⁴ and R ¹⁵ As the substituent in the “alkylsulfonyl group”, the “optionally substituted hydroxyl group” and the “substituted” as the substituent in the “optionally substituted cyclic hydrocarbon group” represented by R, respectively, Examples thereof include the same groups as the substituents in “good thiol group”, “optionally substituted alkylsulfinyl” and “optionally substituted alkylsulfonyl”.
As the “optionally substituted acyl group” represented by R ¹⁴ and R ¹⁵ , “the sulfonic acid-derived acyl” as a substituent in the “optionally substituted cyclic hydrocarbon group” represented by R And a group similar to “acyl derived from carboxylic acid”.
The “optionally esterified carboxyl group” represented by R ¹⁴ and R ¹⁵ is the “esterified ester group” as a substituent in the “optionally substituted cyclic hydrocarbon group” represented by R. And the same groups as those described above.
The “optionally substituted carbamoyl group” represented by R ¹⁴ and R ¹⁵ is “optionally substituted” as the substituent in the “optionally substituted cyclic hydrocarbon group” represented by R. Examples thereof include the same groups as those in “carbamoyl”.
As the “optionally substituted amino group” represented by R ¹⁴ and R ¹⁵ , the “substituted amino group” as the substituent in the “optionally substituted cyclic hydrocarbon group” represented by R described above is used. And the same groups as those described above.
The “ring” in the “optionally substituted ring” that R ¹⁴ and R ¹⁵ may be bonded to each other is the same as the above-mentioned substituent in the B ring and R ¹ bonded to each other. Examples include the same ring as the “ring” to be formed. Examples of the substituent in the “optionally substituted ring” include the same groups as the substituents in the “optionally substituted heterocyclic group” represented by R described above. The group may be substituted with 1 to 5 (preferably 1 to 3) substituted positions.
R ¹⁴ and R ¹⁵ are phosphono groups (for example, dimethylphosphono, diethylphosphono, diisopropylphosphono, dibutylphosphono, 2-oxide-1,3,2-dioxaphosphinan-2-yl, It may be a ring (mono- or di-C _1-4 alkyl) phosphono and the like).

式（Ｉ）で表される化合物の好ましい態様として、例えば、式（Ｉ）が、式（Ｉｃ）

〔式中、Ｒ^１６およびＲ^１７はそれぞれ独立して水素原子、置換されていてもよい炭化水素基、置換されていてもよい水酸基、置換されていてもよいチオ−ル基、置換されていてもよいアルキルスルフィニル基、置換されていてもよいアルキルスルホニル基、置換されていてもよいアシル基、エステル化されていてもよいカルボキシル基、置換されていてもよいカルバモイル基または置換されていてもよいアミノ基を示し、Ｒ^１６とＲ^１７とが互いに結合して置換されていてもよい環を形成していてもよく、他の記号は前記と同意義を示す。〕である化合物が挙げられる。
Ｒ^１６およびＲ^１７で示される「置換されていてもよい炭化水素基」における「炭化水素基」としては、例えば、前記したＲ^１で示される「置換されていてもよい炭化水素基」における「炭化水素基」と同様の基などが挙げられ、該「炭化水素基」が有していてもよい置換基としては、前記したＲ^１で示される「置換されていてもよい炭化水素基」における置換基と同様な数の同様の基などが挙げられる。
Ｒ^１６およびＲ^１７で示される「置換されていてもよい水酸基」、「置換されていてもよいチオ−ル基」、「置換されていてもよいアルキルスルフィニル基」および「置換されていてもよいアルキルスルホニル基」における置換基としては、それぞれ、Ｒで示される「置換されていてもよい環状の炭化水素基」における置換基としての「置換されていてもよい水酸基」、「置換されていてもよいチオール基」、「置換されていてもよいアルキルスルフィニル」および「置換されていてもよいアルキルスルホニル」における置換基と同様の基などが挙げられる。
Ｒ^１６およびＲ^１７で示される「置換されていてもよいアシル基」としては、Ｒで示される「置換されていてもよい環状の炭化水素基」における置換基としての「スルホン酸由来のアシル」および「カルボン酸由来のアシル」と同様の基などが挙げられる。
Ｒ^１６およびＲ^１７で示される「エステル化されていてもよいカルボキシル基」としては、Ｒで示される「置換されていてもよい環状の炭化水素基」における置換基としての「エステル化されていてもよいカルボキシル」と同様の基などが挙げられる。
Ｒ^１６およびＲ^１７で示される「置換されていてもよいカルバモイル基」としては、Ｒで示される「置換されていてもよい環状の炭化水素基」における置換基としての「置換されていてもよいカルバモイル」と同様の基などが挙げられる。
Ｒ^１６およびＲ^１７で示される「置換されていてもよいアミノ基」としては、前記したＲで示される「置換されていてもよい環状の炭化水素基」における置換基としての「置換されていてもよいアミノ」と同様の基などが挙げられる。
Ｒ^１６およびＲ^１７とがそれぞれ互いに結合して形成していてもよい「置換されていてもよい環」における「環」としては、前記したＢ環における置換基とＲ^１とが互いに結合して形成する「環」と同様の環などが挙げられる。該「置換されていてもよい環」における置換基としては、前記したＲで示される「置換されていてもよい複素環基」における置換基と同様の基などが挙げられ、これらの任意の置換基は置換可能な位置に１ないし５個（好ましくは、１ないし３個）置換していてもよい。
また、Ｒ^１６およびＲ^１７はホスホノ基（例えば、ジメチルホスホノ、ジエチルホスホノ、ジイソプロピルホスホノ、ジブチルホスホノ、２−オキシド−１,３,２−ジオキサホスフィナン−２−イルなどの、環を形成していてもよい（モノ−もしくはジ−Ｃ_１−４アルキル）ホスホノなど）であってもよい。 As a preferable embodiment of the compound represented by the formula (I), for example, the formula (I) is represented by the formula (Ic)

[Wherein R ¹⁶ and R ¹⁷ are each independently a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted thiol group, Alkylsulfinyl group which may be substituted, alkylsulfonyl group which may be substituted, acyl group which may be substituted, carboxyl group which may be esterified, carbamoyl group which may be substituted or may be substituted Represents an amino group, R ¹⁶ and R ¹⁷ may be bonded to each other to form an optionally substituted ring, and other symbols are as defined above. The compound which is] is mentioned.
As the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R ¹⁶ and R ¹⁷ , for example, “in the optionally substituted hydrocarbon group” represented by R ¹ above “ Examples of the substituent that the “hydrocarbon group” may have include those in the “optionally substituted hydrocarbon group” represented by R ¹ described above. Examples include the same number of similar groups as the substituent.
“Optionally substituted hydroxyl group”, “optionally substituted thiol group”, “optionally substituted alkylsulfinyl group” and “optionally substituted” represented by R ¹⁶ and R ¹⁷ As the substituent in the “alkylsulfonyl group”, the “optionally substituted hydroxyl group” and the “substituted” as the substituent in the “optionally substituted cyclic hydrocarbon group” represented by R, respectively, Examples thereof include the same groups as the substituents in “good thiol group”, “optionally substituted alkylsulfinyl” and “optionally substituted alkylsulfonyl”.
As the “optionally substituted acyl group” represented by R ¹⁶ and R ¹⁷ , “acyl derived from a sulfonic acid” as a substituent in the “optionally substituted cyclic hydrocarbon group” represented by R And a group similar to “acyl derived from carboxylic acid”.
The “optionally esterified carboxyl group” represented by R ¹⁶ and R ¹⁷ is the “esterified ester group” as a substituent in the “optionally substituted cyclic hydrocarbon group” represented by R. And the same groups as those described above.
The “optionally substituted carbamoyl group” represented by R ¹⁶ and R ¹⁷ is “optionally substituted” as the substituent in the “optionally substituted cyclic hydrocarbon group” represented by R. Examples thereof include the same groups as those in “carbamoyl”.
The “optionally substituted amino group” represented by R ¹⁶ and R ¹⁷ is the “substituted amino group” as the substituent in the “optionally substituted cyclic hydrocarbon group” represented by R described above. And the same groups as those described above.
The “ring” in the “optionally substituted ring” optionally formed by R ¹⁶ and R ¹⁷ being bonded to each other is the same as the substituent in the aforementioned B ring and R ¹ being bonded to each other. Examples include the same ring as the “ring” to be formed. Examples of the substituent in the “optionally substituted ring” include the same groups as the substituents in the “optionally substituted heterocyclic group” represented by R described above. The group may be substituted with 1 to 5 (preferably 1 to 3) substituted positions.
R ¹⁶ and R ¹⁷ are phosphono groups (for example, dimethylphosphono, diethylphosphono, diisopropylphosphono, dibutylphosphono, 2-oxide-1,3,2-dioxaphosphinan-2-yl, It may form a ring (such as mono- or di-C _1-4 alkyl) phosphono).

式（Ｉ）で表される化合物の好ましい態様として、例えば、式（Ｉ）が、式（Ｉｄ）

〔式中、Ｒ^１８およびＲ^１９はそれぞれ独立して水素原子、置換されていてもよい炭化水素基、置換されていてもよい水酸基、置換されていてもよいチオ−ル基、置換されていてもよいアルキルスルフィニル基、置換されていてもよいアルキルスルホニル基、置換されていてもよいアシル基、エステル化されていてもよいカルボキシル基、置換されていてもよいカルバモイル基または置換されていてもよいアミノ基を示し、他の記号は前記と同意義を示す。〕である化合物が挙げられる。
Ｒ^１８およびＲ^１９で示される「置換されていてもよい炭化水素基」における「炭化水素基」としては、例えば、前記したＲ^１で示される「置換されていてもよい炭化水素基」における「炭化水素基」と同様の基などが挙げられ、該「炭化水素基」が有していてもよい置換基としては、前記したＲ^１で示される「置換されていてもよい炭化水素基」における置換基と同様な数の同様の基などが挙げられる。
Ｒ^１８およびＲ^１９で示される「置換されていてもよい水酸基」、「置換されていてもよいチオ−ル基」、「置換されていてもよいアルキルスルフィニル基」および「置換されていてもよいアルキルスルホニル基」における置換基としては、それぞれ、Ｒで示される「置換されていてもよい環状の炭化水素基」における置換基としての「置換されていてもよい水酸基」、「置換されていてもよいチオール基」、「置換されていてもよいアルキルスルフィニル」および「置換されていてもよいアルキルスルホニル」における置換基と同様の基などが挙げられる。
Ｒ^１８およびＲ^１９で示される「置換されていてもよいアシル基」としては、Ｒで示される「置換されていてもよい環状の炭化水素基」における置換基としての「スルホン酸由来のアシル」および「カルボン酸由来のアシル」と同様の基などが挙げられる。
Ｒ^１８およびＲ^１９で示される「エステル化されていてもよいカルボキシル基」としては、Ｒで示される「置換されていてもよい環状の炭化水素基」における置換基としての「エステル化されていてもよいカルボキシル」と同様の基などが挙げられる。
Ｒ^１８およびＲ^１９で示される「置換されていてもよいカルバモイル基」としては、Ｒで示される「置換されていてもよい環状の炭化水素基」における置換基としての「置換されていてもよいカルバモイル」と同様の基などが挙げられる。
Ｒ^１８およびＲ^１９で示される「置換されていてもよいアミノ基」としては、前記したＲで示される「置換されていてもよい環状の炭化水素基」における置換基としての「置換されていてもよいアミノ」と同様の基などが挙げられる。
また、Ｒ^１８およびＲ^１９はホスホノ基（例えば、ジメチルホスホノ、ジエチルホスホノ、ジイソプロピルホスホノ、ジブチルホスホノ、２−オキシド−１,３,２−ジオキサホスフィナン−２−イルなどの、環を形成していてもよい（モノ−もしくはジ−Ｃ_１−４アルキル）ホスホノなど）であってもよい。 As a preferable embodiment of the compound represented by the formula (I), for example, the formula (I) is represented by the formula (Id).

[Wherein R ¹⁸ and R ¹⁹ are each independently a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted thiol group, Alkylsulfinyl group which may be substituted, alkylsulfonyl group which may be substituted, acyl group which may be substituted, carboxyl group which may be esterified, carbamoyl group which may be substituted or may be substituted An amino group is shown, and other symbols are as defined above. The compound which is] is mentioned.
As the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R ¹⁸ and R ¹⁹ , for example, “in the optionally substituted hydrocarbon group” represented by R ¹ above “ Examples of the substituent that the “hydrocarbon group” may have include those in the “optionally substituted hydrocarbon group” represented by R ¹ described above. Examples include the same number of similar groups as the substituent.
“Optionally substituted hydroxyl group”, “optionally substituted thiol group”, “optionally substituted alkylsulfinyl group” and “optionally substituted” represented by R ¹⁸ and R ¹⁹ As the substituent in the “alkylsulfonyl group”, the “optionally substituted hydroxyl group” and the “substituted” as the substituent in the “optionally substituted cyclic hydrocarbon group” represented by R, respectively, Examples thereof include the same groups as the substituents in “good thiol group”, “optionally substituted alkylsulfinyl” and “optionally substituted alkylsulfonyl”.
As the “optionally substituted acyl group” represented by R ¹⁸ and R ¹⁹ , “the sulfonic acid-derived acyl” as a substituent in the “optionally substituted cyclic hydrocarbon group” represented by R And a group similar to “acyl derived from carboxylic acid”.
The “optionally esterified carboxyl group” represented by R ¹⁸ and R ¹⁹ is the “esterified ester group” as a substituent in the “optionally substituted cyclic hydrocarbon group” represented by R. And the same groups as those described above.
The “optionally substituted carbamoyl group” represented by R ¹⁸ and R ¹⁹ is “optionally substituted” as the substituent in the “optionally substituted cyclic hydrocarbon group” represented by R. Examples thereof include the same groups as those in “carbamoyl”.
As the “optionally substituted amino group” represented by R ¹⁸ and R ¹⁹ , the “substituted amino group” as the substituent in the “optionally substituted cyclic hydrocarbon group” represented by R described above is used. And the same groups as those described above.
R ¹⁸ and R ¹⁹ are phosphono groups (for example, dimethylphosphono, diethylphosphono, diisopropylphosphono, dibutylphosphono, 2-oxide-1,3,2-dioxaphosphinan-2-yl, It may form a ring (such as mono- or di-C _1-4 alkyl) phosphono).

式（Ｉ）で表される化合物の態様としては、なかでも、式（Ｉ）が式（Ｉｄ）である場合がより好ましく、式（Ｉ）が式（Ｉｄ）であってＺ^２ａが窒素原子である場合が特に好ましい。 As an embodiment of the compound represented by the formula (I), the case where the formula (I) is the formula (Id) is more preferable, the formula (I) is the formula (Id), and Z ^2a is a nitrogen atom. Is particularly preferred.

前記式中、ａは０，１または２（好ましくは２）を示す。 In the above formula, a represents 0, 1 or 2 (preferably 2).

本発明における式（Ｉ）で表される化合物としては、7-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-3-メチル-6,7-ジヒドロイミダゾ[1,5-a]ピラジン-8(5H)-オン、7-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-1-メチル-6,7-ジヒドロイミダゾ[1,5-a]ピラジン-8(5H)-オン、2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン、2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-5,7-ジメチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン、2-(1-{3-[(7-クロロ-2H-クロメン-3-イル)スルホニル]プロパノイル}-4-ピペリジニル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン、2-[1-(3-{[(E)-2-(4-クロロフェニル)ビニル]スルホニル}プロパノイル)-4-ピペリジニル]-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン、2-(1-{3-[(5-クロロ-1H-インドール-2-イル)スルホニル]プロパノイル}-4-ピペリジニル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン、2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-5-(ヒドロキシメチル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン、2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-5-(ヒドロキシメチル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン、1-アセチルピペリジン-4-カルボン酸[2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル、3-(2-オキソ-1-ピロリジニル)プロピオン酸[2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル、(2-オキソ-1-ピロリジニル)酢酸 [2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル、4-(アセチルアミノ)ブタン酸 [2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル、2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-5,7-ジメチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オンなどがとりわけ好ましく用いられる。 The compound represented by the formula (I) in the present invention includes 7- (1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -3-methyl-6,7 -Dihydroimidazo [1,5-a] pyrazin-8 (5H) -one, 7- (1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -1-methyl -6,7-dihydroimidazo [1,5-a] pyrazin-8 (5H) -one, 2- (1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -5-methyl-1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one, 2- (1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl}- 4-piperidinyl) -5,7-dimethyl-1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one, 2- (1- {3-[(7-chloro-2H-chromene) -3-yl) sulfonyl] propanoyl} -4-piperidinyl) -5-methyl-1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one, 2- [1- (3- { [(E) -2- (4-chlorophenyl) bi L] sulfonyl} propanoyl) -4-piperidinyl] -5-methyl-1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one, 2- (1- {3-[(5- Chloro-1H-indol-2-yl) sulfonyl] propanoyl} -4-piperidinyl) -5-methyl-1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one, 2- (1 -{3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -5- (hydroxymethyl) -1,2-dihydro-3H-imidazo [1,5-c] imidazole-3 -One, 2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -5- (hydroxymethyl) -1,2 -Dihydro-3H-imidazo [1,5-c] imidazol-3-one, 1-acetylpiperidine-4-carboxylic acid [2- (1-{(2S) -3-[(6-chloro-2-naphthyl ) Sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -3-oxo-2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl, 3- (2-oxo-1-pyrrolidinyl) propionic acid [2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -3-oxo-2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl, (2-oxo-1-pyrrolidinyl) acetic acid [2- (1-{(2S)- 3-[(6-Chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -3-oxo-2,3-dihydro-1H-imidazo [1,5-c] imidazole-5 -Yl] methyl, 4- (acetylamino) butanoic acid [2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -3-oxo-2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl, 2- (1-{(2S) -3-[(6-chloro-2-naphthyl) ) Sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -5,7-dimethyl-1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one is particularly preferred. I can.

式（Ｉ）で表される化合物（以下、化合物（Ｉ）と略記することがある）の塩としては、薬理学的に許容しうる塩等が挙げられ、例えば、トリフロロ酢酸、酢酸、乳酸、コハク酸、マレイン酸、酒石酸、クエン酸、グルコン酸、アスコルビン酸、安息香酸、メタンスルホン酸、ｐ−トルエンスルホン酸、ケイ皮酸、フマル酸、ホスホン酸、塩酸、硝酸、臭化水素酸、ヨウ化水素酸、スルファミン酸、硫酸等の酸との酸付加塩、例えば、ナトリウム、カリウム、マグネシウム、カルシウム等の金属塩、例えば、トリメチルアミン、トリエチルアミン、ピリジン、ピコリン、Ｎ−メチルピロリジン、Ｎ−メチルピペリジン、Ｎ−メチルモルホリン等の有機塩等が挙げられる。
化合物（Ｉ）のプロドラッグは、生体内における生理条件下で酵素や胃酸等による反応により化合物（Ｉ）に変換する化合物、すなわち酵素的に酸化、還元、加水分解等を起こして化合物（Ｉ）に変化する化合物、胃酸等により加水分解などを起こして化合物（Ｉ）に変化する化合物をいう。化合物（Ｉ）のプロドラッグとしては、化合物（Ｉ）のアミノ基がアシル化、アルキル化、りん酸化された化合物（例えば、化合物（Ｉ）のアミノ基がエイコサノイル化、アラニル化、ペンチルアミノカルボニル化、（５−メチル−２−オキソ−１，３−ジオキソレン−４−イル）メトキシカルボニル化、テトラヒドロフラニル化、ピロリジルメチル化、ピバロイルオキシメチル化、ｔｅｒｔ−ブチル化された化合物など）、化合物（Ｉ）の水酸基がアシル化、アルキル化、りん酸化、ほう酸化された化合物（例えば、化合物（Ｉ）の水酸基がアセチル化、パルミトイル化、プロパノイル化、ピバロイル化、サクシニル化、フマリル化、アラニル化、ジメチルアミノメチルカルボニル化された化合物など）、あるいは、化合物（Ｉ）のカルボキシル基がエステル化、アミド化された化合物（例えば、化合物（Ｉ）のカルボキシル基がエチルエステル化、フェニルエステル化、カルボキシメチルエステル化、ジメチルアミノメチルエステル化、ピバロイルオキシメチルエステル化、エトキシカルボニルオキシエチルエステル化、フタリジルエステル化、（５−メチル−２−オキソ−１，３−ジオキソレン−４−イル）メチルエステル化、シクロヘキシルオキシカルボニルエチルエステル化、メチルアミド化された化合物など）等が挙げられる。これらの化合物は自体公知の方法によって化合物（Ｉ）から製造することができる。
また、化合物（Ｉ）のプロドラッグは、広川書店１９９０年刊「医薬品の開発」第７巻分子設計１６３頁から１９８頁に記載されているような、生理的条件で化合物（Ｉ）に変化するものであってもよい。
化合物（Ｉ）は、同位元素（例、³H, ¹⁴C, ³⁵S,¹²⁵Iなど）などで標識されていてもよい。 Examples of the salt of the compound represented by formula (I) (hereinafter sometimes abbreviated as compound (I)) include pharmacologically acceptable salts, and examples thereof include trifluoroacetic acid, acetic acid, lactic acid, Succinic acid, maleic acid, tartaric acid, citric acid, gluconic acid, ascorbic acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, cinnamic acid, fumaric acid, phosphonic acid, hydrochloric acid, nitric acid, hydrobromic acid, iodine Acid addition salts with acids such as hydrofluoric acid, sulfamic acid and sulfuric acid, for example, metal salts such as sodium, potassium, magnesium and calcium, such as trimethylamine, triethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylpiperidine And organic salts such as N-methylmorpholine.
A prodrug of compound (I) is a compound that is converted to compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, compound (I) that is enzymatically oxidized, reduced, hydrolyzed, etc. A compound that changes to compound (I) upon hydrolysis by gastric acid or the like. Compound (I) prodrugs include compounds in which the amino group of compound (I) is acylated, alkylated and phosphorylated (for example, the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated) (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compounds, etc.) Compounds in which the hydroxyl group of compound (I) is acylated, alkylated, phosphorylated or borated (for example, the hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanyl Compound, dimethylaminomethylcarbonylated compound, etc.) or carbohydrate of compound (I) Compounds in which a sil group is esterified or amidated (for example, the carboxyl group of compound (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxy Carbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidated compounds, etc.) Can be mentioned. These compounds can be produced from compound (I) by a method known per se.
In addition, the prodrug of compound (I) is a compound that changes to compound (I) under physiological conditions as described in Hirokawa Shoten 1990, “Drug Development”, Volume 7, Molecular Design, pages 163 to 198. It may be.
Compound (I) may be labeled with an isotope (eg, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.).

化合物（Ｉ）又はその塩は、例えば、以下に示す方法Ａ〜Ｅで製造することができる。以下の反応式に記載された各化合物は、反応を阻害しないのであれば、塩を形成していてもよく、かかる塩としては、化合物（I）の塩と同様なものなどが挙げられる。
方法Ａ

Compound (I) or a salt thereof can be produced, for example, by the methods A to E shown below. Each compound described in the following reaction formula may form a salt as long as it does not inhibit the reaction. Examples of such a salt include the same salts as the salt of compound (I).
Method A

方法Ｂ

Method B

方法Ｃ

Method C

方法Ｄ

Method D

方法Ｅ

Method E

方法Ａ
式（ＩＩ）

〔式中、Ｌ^１は脱離基（例えば、ハロゲン原子（例、フッ素、塩素、臭素、ヨウ素等）、１〜３個のハロゲン原子で置換されていてもよいC_1-6アルキルスルホニルオキシ基（例、メタンスルホニルオキシ、エタンスルホニルオキシ、トリフルオロメタンスルホニルオキシ等）、置換基を有していてもよいアリールスルホニルオキシ基（例、ベンゼンスルホニルオキシ、p-トルエンスルホニルオキシ、p-ブロモベンゼンスルホニルオキシ等）または水酸基などで、遊離カルボン酸、その塩（無機塩、有機塩等）あるいはその反応性誘導体（例、酸ハライド、エステル、酸アジド、酸無水物、混合酸無水物、活性アミド、活性エステル、活性チオエステル等）を形成する基等）を、他の記号は前記と同意義を示す。〕で表わされる化合物（II）（特に、Ｌ^１が水酸基である化合物（II）を遊離酸(II')とする）と、式（III）

〔式中、Ｍ^１は水素原子、アルカリ金属（例えば、リチウム、ナトリウム、カリウム、セシウムなど）、アルカリ土類金属（例えば、マグネシウム、カルシウムなど）または脱離基（例えば、トリメチルシリル基など）を、他の記号は前記と同意義を示す。〕で表わされる化合物（III）を反応させることにより化合物（I）を製造することができる。
また、本法は化合物（III）又はその塩と、遊離酸（II'）又はその塩（無機塩、有機塩等）あるいはその反応性誘導体（例えば、酸ハライド、エステル、酸アジド、酸無水物、混合酸無水物、活性アミド、活性エステル、活性チオエステル等）とを反応させることによっても行われる。化合物（III）の塩としては、前記した化合物（I）と酸付加塩を形成する酸として述べたものとの酸付加塩が挙げられる。
化合物（II）に用いられる無機塩としてはアルカリ金属塩（例えば、リチウム塩、ナトリウム塩、カリウム塩、セシウム塩等）、アルカリ土類金属塩（例えば、マグネシウム塩、カルシウム塩等）等が、有機塩としては例えば、トリメチルアミン塩、トリエチルアミン塩、tert−ブチルジメチルアミン塩、ジベンジルメチルアミン塩、ベンジルジメチルアミン塩、Ｎ,Ｎ−ジメチルアニリン塩、ピリジン塩、キノリン塩等が用いられる。また酸ハライドとしては例えば、酸クロライド、酸ブロマイド等が、エステルとしては例えば、メチル、エチル等の低級アルキルエステル類が、混合酸無水物としてはモノＣ_１−４アルキル炭酸混合酸無水物（例えば、遊離酸（II'）とモノメチル炭酸、モノエチル炭酸、モノイソプロピル炭酸、モノイソブチル炭酸、モノtert−ブチル炭酸、モノベンジル炭酸、モノ（ｐ−ニトロベンジル）炭酸、モノアリル炭酸等との混合酸無水物）、Ｃ_１−６脂肪族カルボン酸混合酸無水物（例えば、遊離酸（II）と酢酸、シアノ酢酸、プロピオン酸、酪酸、イソ酪酸、吉草酸、イソ吉草酸、ピバル酸、トリフルオロ酢酸、トリクロロ酢酸、アセト酢酸等との混合酸無水物）、Ｃ_７−１１芳香族カルボン酸混合酸無水物（例えば、遊離酸（II'）と安息香酸、ｐ−トルイル酸、ｐ−クロロ安息香酸等との混合酸無水物）、有機スルホン酸混合酸無水物（例えば、メタンスルホン酸、エタンスルホン酸、ベンゼンスルホン酸、ｐ−トルエンスルホン酸等との混合酸無水物）等が、活性アミドとしては含窒素複素環化合物とのアミド（例えば、遊離酸（II'）とピラゾール、イミダゾール、ベンゾトリアゾール等との酸アミドで、これらの含窒素複素環化合物はＣ_１−６アルキル（例えば、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、sec−ブチル、tert−ブチル等）、Ｃ_１−６アルコキシ（例えば、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、tert−ブトキシ等）、ハロゲン原子（例えば、フッ素、塩素、臭素等）、オキソ、チオキソ、Ｃ_１−６アルキルチオ（例えば、メチルチオ、エチルチオ、プロピルチオ、ブチルチオ等）等で置換されていてもよい）等が挙げられる。
活性エステルとしては、例えば、有機リン酸エステル（例えば、ジエトキシリン酸エステル、ジフェノキシリン酸エステル等）のほかｐ−ニトロフェニルエステル、２,４−ジニトロフェニルエステル、シアノメチルエステル、ペンタクロロフェニルエステル、Ｎ−ヒドロキシサクシンイミドエステル、Ｎ−ヒドロキシフタルイミドエステル、１−ヒドロキシベンゾトリアゾールエステル、６−クロロ−１−ヒドロキシベンゾトリアゾールエステル、１−ヒドロキシ−１Ｈ−２−ピリドンエステル等が挙げられる。活性チオエステルとしては芳香族複素環チオール化合物〔これらの複素環はＣ_１−６アルキル（例えば、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、sec−ブチル、tert−ブチル等）、Ｃ_１−６アルコキシ（例えば、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、tert−ブトキシ等）、ハロゲン原子（例えば、フッ素、塩素、臭素等）、Ｃ_１−６アルキルチオ（例えば、メチルチオ、エチルチオ、プロピルチオ、ブチルチオ等）等で置換されていてもよい〕とのエステル〔例、２−ピリジルチオールエステル、２−ベンゾチアゾリルチオールエステル〕等が挙げられる。
本反応は一般に溶媒中で行われ、必要により塩基又は縮合剤（例、カルボジイミド類（DCC、WSC、DIC等）、りん酸誘導体（例、シアノりん酸ジエチル、DPPA、BOP-Cl等）、塩化4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルフォリニウム（DMTMM：クニシマら、テトラヘドロン、１９９９、５５、１３１５９）等）の存在下に行われる。
溶媒としては反応を阻害しない溶媒が適宜選択され、例えば、アルコール類（例、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール、tert−ブタノール等）、エーテル類（例、ジオキサン、テトラヒドロフラン、ジエチルエーテル、tert−ブチルメチルエーテル、ジイソプロピルエーテル、エチレングリコール−ジメチルエーテル等）、エステル類（例、ギ酸エチル、酢酸エチル、酢酸ｎ−ブチル等）、カルボン酸類（例、ギ酸、酢酸、プロピオン酸等）、ハロゲン化炭化水素類（例、ジクロロメタン、クロロホルム、四塩化炭素、トリクロロエチレン、１,２−ジクロロエタン、クロロベンゼン等）、炭化水素類（例、ｎ−ヘキサン、ベンゼン、トルエン等）、アミド類（例、ホルムアミド、Ｎ,Ｎ−ジメチルホルムアミド、Ｎ,Ｎ−ジメチルアセトアミド等）、ケトン類（例、アセトン、メチルエチルケトン、メチルイソブチルケトン等）、ニトリル類（例、アセトニトリル、プロピオニトリル等）等のほか、ジメチルスルホキシド、スルホラン、ヘキサメチルホスホルアミド、水等が単独又は混合溶媒として用いられる。
塩基としては、例えば水酸化リチウム、水酸化カリウム、水酸化ナトリウム、水酸化カルシウム、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム、炭酸水素カリウム等の無機塩基、例えば、ギ酸ナトリウム、酢酸ナトリウム、酢酸カリウム等のC_1-6低級脂肪酸のアルカリ金属塩、例えばトリエチルアミン、トリ（ｎ−プロピル）アミン、トリ（ｎ−ブチル）アミン、ジイソプロピルエチルアミン、シクロヘキシルジメチルアミン、ピリジン、ルチジン、γ−コリジン、Ｎ,Ｎ−ジメチルアニリン、Ｎ−メチルピペリジン、Ｎ−メチルピロリジン、Ｎ−メチルモルホリン等の３級アミンが用いられる。
本反応において、化合物（II）に対して化合物（III）０.５〜５当量、好ましくは０.８〜２当量を用いる。
反応温度は−５０〜１５０℃、好ましくは−２０〜１００℃である。
反応時間は化合物（II）又は（III）の種類、溶媒及び塩基の種類、反応温度等により異なるが、通常約１分間ないし約１００時間、好ましくは約１５分間ないし約４８時間である。 Method A
Formula (II)

[Wherein L ¹ represents a leaving group (eg, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a C _1-6 alkylsulfonyloxy group optionally substituted with 1 to 3 halogen atoms) (Eg, methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy, etc.), arylsulfonyloxy groups optionally having substituents (eg, benzenesulfonyloxy, p-toluenesulfonyloxy, p-bromobenzenesulfonyloxy) Etc.) or hydroxyl groups, free carboxylic acids, salts thereof (inorganic salts, organic salts, etc.) or reactive derivatives thereof (eg, acid halides, esters, acid azides, acid anhydrides, mixed acid anhydrides, active amides, active Other groups are the same as defined above, for example, groups that form esters, active thioesters, etc.). A compound (II) represented by formula (III) (particularly, a compound (II) in which L ¹ is a hydroxyl group is defined as a free acid (II ′));

[Wherein M ¹ represents a hydrogen atom, an alkali metal (eg, lithium, sodium, potassium, cesium, etc.), an alkaline earth metal (eg, magnesium, calcium, etc.) or a leaving group (eg, a trimethylsilyl group, etc.) Other symbols are as defined above. The compound (I) can be produced by reacting the compound (III) represented by the formula:
This method also includes compound (III) or a salt thereof, free acid (II ′) or a salt thereof (inorganic salt, organic salt, etc.) or a reactive derivative thereof (eg, acid halide, ester, acid azide, acid anhydride) , Mixed acid anhydrides, active amides, active esters, active thioesters, and the like). Examples of the salt of compound (III) include acid addition salts of the above-described compound (I) with those described as acids that form acid addition salts.
Examples of inorganic salts used for compound (II) include alkali metal salts (for example, lithium salts, sodium salts, potassium salts, cesium salts, etc.), alkaline earth metal salts (for example, magnesium salts, calcium salts, etc.), and the like. Examples of the salt include trimethylamine salt, triethylamine salt, tert-butyldimethylamine salt, dibenzylmethylamine salt, benzyldimethylamine salt, N, N-dimethylaniline salt, pyridine salt, quinoline salt and the like. Examples of the acid halide include acid chloride and acid bromide, examples of the ester include lower alkyl esters such as methyl and ethyl, and examples of the mixed acid anhydride include mono C _1-4 alkyl carbonate mixed acid anhydrides (for example, , Mixed acid anhydrides of free acid (II ′) with monomethyl carbonate, monoethyl carbonate, monoisopropyl carbonate, monoisobutyl carbonate, mono tert-butyl carbonate, monobenzyl carbonate, mono (p-nitrobenzyl) carbonate, monoallyl carbonate, etc. ), C _1-6 aliphatic carboxylic acid mixed acid anhydrides (for example, free acid (II) and acetic acid, cyanoacetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, pivalic acid, trifluoroacetic acid, trichloroacetic acid, mixed acid anhydride with acetoacetic acid, etc.), C _7-11 aromatic carboxylic acid mixed acid anhydride (e.g., the free acid (II ') and benzoic acid Mixed acid anhydrides with p-toluic acid, p-chlorobenzoic acid, etc.), organic sulfonic acid mixed acid anhydrides (for example, mixed with methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.) Acid anhydrides), etc., as active amides, amides with nitrogen-containing heterocyclic compounds (for example, acid amides of free acid (II ′) with pyrazole, imidazole, benzotriazole, etc., and these nitrogen-containing heterocyclic compounds are C _1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.), C _1-6 alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert -Butoxy etc.), halogen atoms (eg fluorine, chlorine, bromine etc.), oxo, thioxo, C _1-6 alkylthio (eg For example, methylthio, ethylthio, propylthio, butylthio and the like may be substituted).
Examples of the active ester include organic phosphate esters (for example, diethoxyphosphate ester, diphenoxyphosphate ester, etc.), p-nitrophenyl ester, 2,4-dinitrophenyl ester, cyanomethyl ester, pentachlorophenyl ester, N -Hydroxysuccinimide ester, N-hydroxyphthalimide ester, 1-hydroxybenzotriazole ester, 6-chloro-1-hydroxybenzotriazole ester, 1-hydroxy-1H-2-pyridone ester and the like. As the active thioester, an aromatic heterocyclic thiol compound [these heterocyclic rings are C _1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl etc.), C _1-6 Alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, etc.), halogen atoms (eg, fluorine, chlorine, bromine, etc.), C _1-6 alkylthio (eg, methylthio, ethylthio, propylthio, butylthio, etc.) Etc.]] [Examples, 2-pyridylthiol ester, 2-benzothiazolylthiol ester] and the like.
This reaction is generally carried out in a solvent. If necessary, a base or a condensing agent (eg, carbodiimides (DCC, WSC, DIC, etc.), phosphoric acid derivatives (eg, diethyl cyanophosphate, DPPA, BOP-Cl, etc.), chloride In the presence of 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium (DMTMM: Kunishima et al., Tetrahedron, 1999, 55, 13159), etc.) Is called.
As the solvent, a solvent that does not inhibit the reaction is appropriately selected. For example, alcohols (eg, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, etc.), ethers (eg, dioxane, tetrahydrofuran, diethyl ether, tert- Butyl methyl ether, diisopropyl ether, ethylene glycol-dimethyl ether, etc.), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate, etc.), carboxylic acids (eg, formic acid, acetic acid, propionic acid, etc.), halogenated hydrocarbons (Eg, dichloromethane, chloroform, carbon tetrachloride, trichloroethylene, 1,2-dichloroethane, chlorobenzene, etc.), hydrocarbons (eg, n-hexane, benzene, toluene, etc.), amides (eg, formamide, N, N -Dimethylformami , N, N-dimethylacetamide, etc.), ketones (eg, acetone, methyl ethyl ketone, methyl isobutyl ketone, etc.), nitriles (eg, acetonitrile, propionitrile, etc.), dimethyl sulfoxide, sulfolane, hexamethylphospho Luamide, water and the like are used alone or as a mixed solvent.
Examples of the base include inorganic bases such as lithium hydroxide, potassium hydroxide, sodium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, such as sodium formate, sodium acetate, potassium acetate, etc. Alkali metal salts of C _1-6 lower fatty acids such as triethylamine, tri (n-propyl) amine, tri (n-butyl) amine, diisopropylethylamine, cyclohexyldimethylamine, pyridine, lutidine, γ-collidine, N, N- Tertiary amines such as dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine are used.
In this reaction, 0.5 to 5 equivalents, preferably 0.8 to 2 equivalents, of compound (III) are used with respect to compound (II).
The reaction temperature is −50 to 150 ° C., preferably −20 to 100 ° C.
While the reaction time varies depending on the kind of compound (II) or (III), the kind of solvent and base, the reaction temperature and the like, it is generally about 1 minute to about 100 hours, preferably about 15 minutes to about 48 hours.

方法Ｂ
式（ＩＶ）

〔式中、Ｍ^２は水素原子、アルカリ金属（例えば、リチウム、ナトリウム、カリウム、セシウムなど）、アルカリ土類金属（例えば、マグネシウム、カルシウムなど）または脱離基（例えば、トリメチルシリル基など）を、他の記号は前記と同意義を示す。〕で表される化合物（ＩＶ）又はその塩と式（Ｖ）

〔式中、Ｌ^２は脱離基（例えば、ハロゲン原子（例、フッ素、塩素、臭素、ヨウ素等）、１〜３個のハロゲン原子で置換されていてもよいC_1-6アルキルスルホニルオキシ基（例、メタンスルホニルオキシ、エタンスルホニルオキシ、トリフルオロメタンスルホニルオキシ等）、置換基を有していてもよいアリールスルホニルオキシ基（例、ベンゼンスルホニルオキシ、p-トルエンスルホニルオキシ、p-ブロモベンゼンスルホニルオキシ等）またはホルミル基を、他の記号は前記と同意義を示す。）で表される化合物（Ｖ）又はその塩とを反応させることによって化合物（I）を製造することができる。化合物（IＶ）又は（Ｖ）の塩としては、前記した化合物（I）と酸付加塩を形成する酸との酸付加塩などが挙げられる。
本反応は一般に溶媒中で行われ、反応を阻害しない溶媒が適宜選択される。本反応で用いる溶媒、塩基としては、前記した方法Ａで述べた溶媒、塩基と同様のものなどが用いられる。
Ｌ^２がホルミル基であるときは、還元剤（例えば、シアノ水素化ホウ素ナトリウム、トリアセトキシ水素化ホウ素ナトリウム、水素化ホウ素ナトリウム、ジボラン、ジボラン−テトラヒドロフラン錯体、ジボラン−ジメチルスルフィド錯体等）の存在下に行われる。かかる還元剤は、化合物（Ｖ）に対して０.５〜１０当量、好ましくは０.８〜５当量用いる。
本反応において、化合物（Ｖ）に対して化合物（IＶ）を０.５〜５当量、好ましくは０.８〜２当量用いる。
反応温度は−２０〜２００℃、好ましくは−５〜１７０℃である。
反応時間は化合物（IＶ）又は（Ｖ）の種類、溶媒の種類、反応温度等により異なるが、通常約１分ないし約７２時間、好ましくは約１５分ないし約２４時間である。 Method B
Formula (IV)

[Wherein M ² represents a hydrogen atom, an alkali metal (eg, lithium, sodium, potassium, cesium, etc.), an alkaline earth metal (eg, magnesium, calcium, etc.) or a leaving group (eg, trimethylsilyl group, etc.) Other symbols are as defined above. ] Compound (IV) or a salt thereof represented by formula (V)

[Wherein L ² is a leaving group (eg, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a C _1-6 alkylsulfonyloxy group optionally substituted by 1 to 3 halogen atoms) (Eg, methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy, etc.), arylsulfonyloxy groups optionally having substituents (eg, benzenesulfonyloxy, p-toluenesulfonyloxy, p-bromobenzenesulfonyloxy) Etc.) or a formyl group, and other symbols are as defined above.) Compound (I) can be produced by reacting compound (V) represented by the above or a salt thereof. Examples of the salt of compound (IV) or (V) include acid addition salts of the above-mentioned compound (I) with an acid forming an acid addition salt.
This reaction is generally performed in a solvent, and a solvent that does not inhibit the reaction is appropriately selected. As the solvent and base used in this reaction, those similar to the solvent and base described in the aforementioned method A can be used.
When L ² is a formyl group, in the presence of a reducing agent (for example, sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, diborane, diborane-tetrahydrofuran complex, diborane-dimethylsulfide complex, etc.) To be done. Such a reducing agent is used in an amount of 0.5 to 10 equivalents, preferably 0.8 to 5 equivalents, relative to compound (V).
In this reaction, the compound (IV) is used in an amount of 0.5 to 5 equivalents, preferably 0.8 to 2 equivalents, relative to the compound (V).
The reaction temperature is -20 to 200 ° C, preferably -5 to 170 ° C.
While the reaction time varies depending on the kind of compound (IV) or (V), the kind of solvent, the reaction temperature and the like, it is generally about 1 minute to about 72 hours, preferably about 15 minutes to about 24 hours.

方法Ｃ
式（Ｉｅ）

〔式中、Ｌ^３は脱離基を、他の記号は前記と同意義を示す。〕で表わされる化合物（Ｉｅ）又はその塩に塩基を反応させることにより化合物（Iａ）を製造することができる。
Ｌ^３で示される脱離基としては、Ｌ^１で示される脱離基と同様の基などが挙げられる。
化合物（Ｉｅ）の塩としては、前記した化合物（Ｉ）と酸付加塩を形成する酸として述べたものとの酸付加塩などが挙げられる。
本反応で用いられる塩基としては、前記した方法Ａで述べた塩基と同様のものなどが用いられる。
本反応は一般に溶媒中で行われ、必要により縮合剤の存在下に行われる。溶媒および縮合剤としては、前記した方法Ａで述べた溶媒および塩基と同様のものなどがそれぞれ用いられる。
本反応において、化合物（Ｉｅ）に対して塩基０.５〜５当量、好ましくは０.８〜２当量が用いられる。
反応温度は−５０〜１５０℃、好ましくは−２０〜１００℃である。
反応時間は化合物（Ｉｅ）又は塩基の種類、溶媒の種類、反応温度等により異なるが、通常約１分間ないし約１００時間、好ましくは約１５分間ないし約４８時間である。 Method C
Formula (Ie)

[Wherein L ³ represents a leaving group, and other symbols are as defined above. Compound (Ia) can be produced by reacting compound (Ie) represented by the formula (I) or a salt thereof with a base.
Examples of the leaving group represented by L ³ include the same groups as the leaving group represented by L ¹ .
Examples of the salt of compound (Ie) include acid addition salts of the above-described compound (I) with those described as acids forming acid addition salts.
As the base used in this reaction, the same bases as described in the above-mentioned method A can be used.
This reaction is generally performed in a solvent and, if necessary, in the presence of a condensing agent. As the solvent and the condensing agent, those similar to the solvents and bases described in the above-mentioned method A are used.
In this reaction, 0.5 to 5 equivalents, preferably 0.8 to 2 equivalents of a base are used with respect to compound (Ie).
The reaction temperature is −50 to 150 ° C., preferably −20 to 100 ° C.
While the reaction time varies depending on the kind of compound (Ie) or base, the kind of solvent, the reaction temperature and the like, it is generally about 1 minute to about 100 hours, preferably about 15 minutes to about 48 hours.

方法Ｄ
式（Ｉｆ）

〔式中の記号は前記と同意義を示す。〕で表される化合物（Ｉｆ）又はその塩と、式（ＶＩ）

〔式中、Ｌ^４およびＬ^４’はそれぞれ脱離基を示し、他の記号は前記と同意義を示す。〕を反応させることによって化合物（Iａ）又はその塩を製造することができる。 Method D
Formula (If)

[The symbols in the formula are as defined above. A compound (If) represented by the formula (VI) or a salt thereof;

[Wherein, L ⁴ and L ⁴ ′ each represent a leaving group, and other symbols are as defined above. ] Can be reacted to produce compound (Ia) or a salt thereof.

本法は化合物（Ｉｆ）又はその塩（無機塩、有機塩等）と化合物（ＶＩ）とを反応させることにより行われる。
化合物（Ｉｆ）の塩としては、前記した化合物（Ｉ）と酸付加塩を形成する酸として述べたものとの酸付加塩などが挙げられる。
化合物（ＶＩ）において、Ｌ^４およびＬ^４’として示される脱離基としては、それぞれ前記したＬ^１で示された脱離基と同様の基などが用いられる。
Ｚ^４が−ＣＯ−である場合、化合物（ＶＩ）としてはカルボニル化試薬が用いられる。該カルボニル化試薬としては、例えば、カルボニルジイミダゾール、ホスゲン、ジホスゲン、トリホスゲン、炭酸ジアルキル（例、炭酸メチル、炭酸ジエチル等）等が用いられる。
本法の反応は一般に溶媒中で行われ、反応を阻害しない溶媒が適宜選択される。このような溶媒としてはアルコール類（例、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール、tert−ブタノール等）、エーテル類（例、ジオキサン、テトラヒドロフラン、ジエチルエーテル、tert−ブチルメチルエーテル、ジイソプロピルエーテル、エチレングリコール−ジメチルエーテル等）、エステル類（例、ギ酸エチル、酢酸エチル、酢酸ｎ−ブチル等）、ハロゲン化炭化水素類（例、ジクロロメタン、クロロホルム、四塩化炭素、トリクレン、１,２−ジクロロエタン等）、炭化水素類（例、ｎ−ヘキサン、ベンゼン、トルエン等）、例えば、ホルムアミド、Ｎ,Ｎ−ジメチルホルムアミド、Ｎ,Ｎ−ジメチルアセトアミド等のアミド類、例えば、アセトニトリル、プロピオニトリル等のニトリル類等のほか、ジメチルスルホキシド、スルホラン、ヘキサメチルホスホルアミド、水等が単独又は混合溶媒として用いられる。
また本反応は塩基の存在下に行ってもよく、そのような塩基としては、例えば、水酸化リチウム、水酸化カリウム、水酸化ナトリウム、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム等の無機塩基、例えば、トリエチルアミン、トリ（ｎ−プロピル）アミン、トリ（ｎ−ブチル）アミン、ジイソプロピルエチルアミン、シクロヘキシルジメチルアミン、ピリジン、ルチジン、γ−コリジン、Ｎ,Ｎ−ジメチルアニリン、Ｎ−メチルピペリジン、Ｎ−メチルピロリジン、Ｎ−メチルモルホリン、ジアザビシクロウンデカン、ジアザビシクロウンデセン等の３級アミンが用いられる。
本反応において、化合物（Ｉｆ）に対して化合物（ＶＩ）０.５〜１０当量、好ましくは０.８〜３当量を用いる。
反応温度は−３０〜２５０℃、好ましくは−１０〜１００℃である。
反応時間は化合物（Ｉｆ）および（ＶＩ）の種類、溶媒の種類、反応温度等により異なるが、通常約１分ないし約７２時間、好ましくは約１５分ないし約２４時間である。 This method is performed by reacting compound (If) or a salt thereof (inorganic salt, organic salt, etc.) with compound (VI).
Examples of the salt of compound (If) include acid addition salts of the above-described compound (I) with those described as acids forming acid addition salts.
In the compound (VI), as the leaving groups represented by L ⁴ and L ⁴ ′, the same groups as the above-described leaving groups represented by L ¹ are used.
When Z ⁴ is —CO—, a carbonylating reagent is used as compound (VI). Examples of the carbonylation reagent include carbonyldiimidazole, phosgene, diphosgene, triphosgene, dialkyl carbonate (eg, methyl carbonate, diethyl carbonate, etc.) and the like.
The reaction of this method is generally carried out in a solvent, and a solvent that does not inhibit the reaction is appropriately selected. Such solvents include alcohols (eg, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, etc.), ethers (eg, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether, ethylene glycol). -Dimethyl ether, etc.), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, carbon tetrachloride, tricrene, 1,2-dichloroethane, etc.), carbonized Hydrogen (eg, n-hexane, benzene, toluene, etc.), for example, amides such as formamide, N, N-dimethylformamide, N, N-dimethylacetamide, etc., for example, nitriles such as acetonitrile, propionitrile, etc. Besides, di Sulfoxide, sulfolane, hexamethylphosphoramide, water and the like are used alone or as a mixed solvent.
Further, this reaction may be carried out in the presence of a base. Examples of such base include inorganic bases such as lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, for example, , Triethylamine, tri (n-propyl) amine, tri (n-butyl) amine, diisopropylethylamine, cyclohexyldimethylamine, pyridine, lutidine, γ-collidine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine , Tertiary amines such as N-methylmorpholine, diazabicycloundecane, diazabicycloundecene and the like are used.
In this reaction, 0.5 to 10 equivalents, preferably 0.8 to 3 equivalents, of compound (VI) are used with respect to compound (If).
The reaction temperature is -30 to 250 ° C, preferably -10 to 100 ° C.
While the reaction time varies depending on the kinds of compounds (If) and (VI), the kind of solvent, the reaction temperature and the like, it is generally about 1 minute to about 72 hours, preferably about 15 minutes to about 24 hours.

方法Ｅ
式（Ｉｇ）

〔式中、記号は前記と同意義を示す。〕で表される化合物（Ｉｇ）又はその塩を酸化して、化合物（Ｉ）を製造することができる。
本酸化反応は酸化剤の存在下に行われる。ここで酸化剤としては、酸素、過酸化水素、例えば、過安息香酸、m-クロロ過安息香酸、過酢酸等の有機過酸、例えば、過塩素酸リチウム、過塩素酸銀、過塩素酸テトラブチルアンモニウム等の過塩素酸塩、例えば、過ヨウ素酸ナトリウム等の過ヨウ素酸塩、過ヨウ素酸、二酸化マンガン、四酢酸鉛、例えば、過マンガン酸カリウム等の過マンガン酸塩、例えば、ヨウ素、臭素、塩素等のハロゲン、N-ブロモコハク酸イミド、N-クロロコハク酸イミド、塩化スルフリル、クロラミンＴ等が挙げられる。
本反応は一般に溶媒中で行われ、反応を阻害しない溶媒が適宜選択される。このような溶媒としては、例えば、アルコール類（例、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール、tert−ブタノール等）、エーテル類（例、ジオキサン、テトラヒドロフラン、ジエチルエーテル、tert−ブチルメチルエーテル、ジイソプロピルエーテル、エチレングリコール−ジメチルエーテル等）、エステル類（例、ギ酸エチル、酢酸エチル、酢酸ｎ−ブチル等）、カルボン酸類（例、ギ酸、酢酸、プロピオン酸等）、ハロゲン化炭化水素類（例、ジクロロメタン、クロロホルム、四塩化炭素、トリクロロエチレン、１,２−ジクロロエタン、クロロベンゼン等）、炭化水素類（例、ｎ−ヘキサン、ベンゼン、トルエン等）、アミド類（例、ホルムアミド、Ｎ,Ｎ−ジメチルホルムアミド、Ｎ,Ｎ−ジメチルアセトアミド等）、ケトン類（例、アセトン、メチルエチルケトン、メチルイソブチルケトン等）、ニトリル類（例、アセトニトリル、プロピオニトリル等）等のほか、スルホラン、ヘキサメチルホスホルアミド、水等が単独又は混合溶媒として用いられる。
本反応は塩基の存在下に行なうこともできる。そのような塩基としては、例えば、水酸化リチウム、水酸化ナトリウム、水酸化カリウムなどの水酸化アルカリ金属、水酸化マグネシウム、水酸化カルシウムなどの水酸化アルカリ土類金属、炭酸ナトリウム、炭酸カリウムなどの炭酸アルカリ金属、炭酸水素ナトリウム、炭酸水素カリウムなどの炭酸水素アルカリ金属などの無機塩基が用いられる。
本反応において、化合物（Ｉｇ）に対して酸化剤０．１〜２０当量（好ましくは約０．４〜１０当量）、塩基０.１〜２０当量（好ましくは０.４〜１０当量）が用いられる。
また本反応は必要により酸の存在下に行ってもよく、そのような酸としては、塩酸、臭化水素酸、硫酸、リン酸、過塩素酸等の鉱酸類、メタンスルホン酸、エタンスルホン酸、ベンゼンスルホン酸、トルエンスルホン酸、カンファースルホン酸等のスルホン酸類、ギ酸、酢酸、プロピオン酸、トリフルオロ酢酸等の有機酸が用いられる。これら酸の使用量は化合物（Ｉｇ）に対して０.１〜２０当量、好ましくは０.５〜１０当量である。
反応温度は約−１０℃〜約２５０℃、好ましくは約−５℃〜約１５０℃である。
反応時間は化合物（Ｉｇ)、塩基又は溶媒の種類、反応温度等により異なるが、通常約１分間〜約５０時間、好ましくは約５分間〜約２４時間である。 Method E
Formula (Ig)

[Wherein the symbols are as defined above. The compound (Ig) or a salt thereof can be oxidized to produce the compound (I).
This oxidation reaction is performed in the presence of an oxidizing agent. Examples of the oxidizing agent include oxygen, hydrogen peroxide, for example, organic peracids such as perbenzoic acid, m-chloroperbenzoic acid, peracetic acid, for example, lithium perchlorate, silver perchlorate, tetraperchlorate. Perchlorates such as butylammonium, for example, periodates such as sodium periodate, periodic acid, manganese dioxide, lead tetraacetate, for example, permanganates such as potassium permanganate, such as iodine, Halogens such as bromine and chlorine, N-bromosuccinimide, N-chlorosuccinimide, sulfuryl chloride, chloramine T and the like.
This reaction is generally performed in a solvent, and a solvent that does not inhibit the reaction is appropriately selected. Examples of such solvents include alcohols (eg, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, etc.), ethers (eg, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether). , Ethylene glycol-dimethyl ether, etc.), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate, etc.), carboxylic acids (eg, formic acid, acetic acid, propionic acid, etc.), halogenated hydrocarbons (eg, dichloromethane, Chloroform, carbon tetrachloride, trichloroethylene, 1,2-dichloroethane, chlorobenzene, etc.), hydrocarbons (eg, n-hexane, benzene, toluene, etc.), amides (eg, formamide, N, N-dimethylformamide, N, N-dimethylacetate Amide, etc.), ketones (eg, acetone, methyl ethyl ketone, methyl isobutyl ketone, etc.), nitriles (eg, acetonitrile, propionitrile, etc.), sulfolane, hexamethylphosphoramide, water, etc., alone or in a mixed solvent Used as
This reaction can also be performed in the presence of a base. Examples of such bases include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, alkaline earth metals such as magnesium hydroxide and calcium hydroxide, sodium carbonate and potassium carbonate. Inorganic bases such as alkali metal hydrogen carbonates such as alkali metal carbonates, sodium hydrogen carbonate, and potassium hydrogen carbonate are used.
In this reaction, 0.1 to 20 equivalents (preferably about 0.4 to 10 equivalents) of an oxidizing agent and 0.1 to 20 equivalents (preferably 0.4 to 10 equivalents) of a base are used with respect to compound (Ig). It is done.
In addition, this reaction may be carried out in the presence of an acid, if necessary, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, perchloric acid and other mineral acids, methanesulfonic acid, ethanesulfonic acid. In addition, sulfonic acids such as benzenesulfonic acid, toluenesulfonic acid and camphorsulfonic acid, and organic acids such as formic acid, acetic acid, propionic acid and trifluoroacetic acid are used. The amount of these acids to be used is 0.1 to 20 equivalents, preferably 0.5 to 10 equivalents, relative to compound (Ig).
The reaction temperature is about -10 ° C to about 250 ° C, preferably about -5 ° C to about 150 ° C.
While the reaction time varies depending on the kind of compound (Ig), base or solvent, reaction temperature and the like, it is generally about 1 min to about 50 hr, preferably about 5 min to about 24 hr.

上記各反応で用いる出発原料および中間体は、知られている方法、例えば実施例に記載した方法もしくはそれらの明らかに化学的に同等なものを適用または適合させることによって、または本発明による方法によって製造される。
このようにして得られる化合物（Ｉ）は、反応混合物から自体公知の手段、例えば抽出、濃縮、中和、濾過、再結晶、カラムクロマトグラフィー、薄層クロマトグラフィー等の手段を用いることによって、単離、精製することができる。
化合物（Ｉ）の塩は、それ自体公知の手段に従い、例えば化合物（Ｉ）に無機酸又は有機酸を加えることによって製造することができる。
化合物（Ｉ）に光学異性体が存在し得る場合、これら個々の光学異性体及びそれら混合物のいずれも当然本発明の範囲に包含されるものであり、所望によりこれらの異性体をそれ自体公知の手段に従い光学分割、もしくは個別に製造することもできる。
また、化合物（Ｉ）又はその塩は水和物であってもよく、水和物及び非水和物のいずれも本発明の範囲に包含されるものである。 The starting materials and intermediates used in each of the above reactions can be obtained by applying or adapting known methods, such as those described in the examples or their apparent chemical equivalents, or by the methods according to the invention. Manufactured.
Compound (I) thus obtained can be obtained from the reaction mixture by a means known per se, such as extraction, concentration, neutralization, filtration, recrystallization, column chromatography, thin layer chromatography and the like. And can be purified.
The salt of compound (I) can be produced according to a method known per se, for example, by adding an inorganic acid or an organic acid to compound (I).
When compound (I) may have optical isomers, any of these individual optical isomers and mixtures thereof are naturally included in the scope of the present invention, and these isomers are known per se if desired. Depending on the means, they can be optically divided or manufactured separately.
Compound (I) or a salt thereof may be a hydrate, and both hydrates and non-hydrates are included in the scope of the present invention.

本発明の化合物（I）又はその塩は、低毒性で安全であり（例えば、急性毒性、慢性毒性、遺伝毒性、生殖毒性、心毒性、薬物相互作用、癌原性などの点から医薬としてより優れており）、ＦＸａを阻害し、抗凝固作用を有するので、動物とりわけ哺乳動物（例えばヒト、サル、ネコ、ブタ、ウマ、ウシ、マウス、ラット、モルモット、イヌ、ウサギ等）の各種動脈および静脈血栓症、例えば、心筋梗塞、脳梗塞、深部静脈血栓症、肺血栓塞栓症、閉塞性動脈硬化症、エコノミークラス症候群、手術中・術後の血栓塞栓症、ならびに次のような疾患の予防又は治療に有用であり、中でも虚血性脳梗塞（特に、心房細動等による心原性脳塞栓症や動脈硬化の進展又は血液凝固系亢進に起因した虚血性脳梗塞）、深部静脈血栓症、肺血栓塞栓症等の予防又は治療に使用することが好ましい。
脳：
脳梗塞、虚血性脳血管障害、心房細動や心不全並びに弁膜症などに起因した脳塞栓症、急性虚血性脳卒中、急性期脳血栓症、くも膜下出血後の脳血管攣縮、アルツハイマー病、一過性脳虚血発作（TIA）、混合痴呆、脳血管性痴呆、無症候性/多発性脳梗塞、ラクナ梗塞等の予防・治療、脳梗塞の予後改善・二次発症予防、頭蓋外および内動脈バイパス術後の血栓予防・治療、脳梗塞（とりわけ虚血性脳血管障害）に対する血栓溶解剤との併用又は補助的使用、脳梗塞発症予防におけるアスピリンなどの抗血小板薬との併用療法等。
心臓：
急性心筋梗塞などの急性冠動脈疾患、心筋梗塞、虚血性冠動脈疾患、不安定狭心症、心筋症、急性心不全、うっ血性慢性心不全、弁膜症等の予防・治療、狭心症など急性冠動脈疾患の予後改善・二次発症予防、人工弁又は人工心臓置換術後の血栓予防・治療、ステント留置又はＰＴＣＡ（経皮的冠動脈血管形成術）施行又はアテレクトミー等冠動脈インターベンション後の血管再閉塞および狭窄の予防・治療、冠動脈バイパス術後の血管再閉塞および狭窄の予防・治療、急性冠動脈疾患に対する血栓溶解剤との併用又は補助的使用、心筋梗塞発症予防におけるアスピリンなど抗血小板薬との併用療法等。
末梢：
深部静脈血栓症、慢性動脈閉塞症、閉塞性動脈硬化症、バージャー病など末梢循環不全、凍傷後の末梢循環不全、動脈瘤、静脈瘤、成人性呼吸促迫症候群、急性腎不全、慢性腎疾患（例えば糖尿病性腎症、慢性糸球体腎炎、ＩｇＡ腎症等）、糖尿病性の循環障害、疼痛、神経障害、糖尿病性網膜症など糖尿病性合併症等の予防・治療、深部静脈血栓症の予後改善・二次発症予防、人工股関節全置換術（THA）・人工膝関節全置換術（TKA）を含む関節手術後の深部静脈血栓症・肺血栓塞栓症の予防・治療、脊椎手術を含む整形外科・形成外科・一般外科手術後の深部静脈血栓症・肺血栓塞栓症の予防・治療、末梢血管バイパス術又は人工血管・大静脈フィルター留置後の血栓予防・治療、ステント留置又はＰＴＡ（経皮的血管形成術）施行又はアテレクトミー等末梢血管インターベンション後の血管再閉塞および狭窄の予防・治療、急性内科疾患に伴う深部静脈血栓症・肺血栓塞栓症の予防・治療、深部静脈血栓症および肺血栓塞栓症に対する血栓溶解剤との併用又は補助療法、閉塞性動脈硬化症など末梢循環不全治療におけるアスピリンなど抗血小板薬との併用療法等。
その他：
肺塞栓症、急性肺塞栓症、エコノミークラス症候群、透析による血小板減少・血液凝固系亢進・補体活性化、大手術時の血小板減少、血小板減少性紫斑病、動脈硬化の進展・癌転移・全身性炎症反応症候群（ＳＩＲＳ）又は膵炎・癌・白血病・大手術・敗血症患者などで発症する播種性血管内凝固症候群（ＤＩＣ）、阻血又は虚血又は血液の鬱滞による肝機能障害などの各種臓器障害、ショック又はＤＩＣの進行によって生じる各種臓器不全（例えば、肺不全、肝不全、腎不全、心不全等）、全身性エリテマトーデス、膠原病、甲状腺機能亢進症、産褥麻痺などの予防・治療、移植時の拒絶反応抑制、移植時の臓器保護又は機能改善、血液体外循環時の灌流血液の凝固防止、ヘパリン投与に起因した血小板減少症発症時の代替療法的使用、褥創や創傷治癒の促進、各種ホルモン補充療法時の血液過凝固反応の亢進抑制、ワルファリンを含むクマリン系薬剤耐性又は禁忌患者への代替療法的使用、血液製剤又は血液凝固因子含有製剤投与時の過凝固反応の亢進抑制等。 The compound (I) or a salt thereof of the present invention is low in toxicity and safe (for example, as a pharmaceutical from the viewpoint of acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, drug interaction, carcinogenicity, etc.) Excellent), and inhibits FXa and has anticoagulant action, so that various arteries of animals, particularly mammals (eg, humans, monkeys, cats, pigs, horses, cows, mice, rats, guinea pigs, dogs, rabbits, etc.) and Prevention of venous thrombosis, such as myocardial infarction, cerebral infarction, deep vein thrombosis, pulmonary thromboembolism, obstructive arteriosclerosis, economy class syndrome, intraoperative and postoperative thromboembolism, and the following diseases Or is useful for treatment, especially ischemic cerebral infarction (especially ischemic cerebral infarction caused by cardiogenic cerebral embolism or arteriosclerosis due to atrial fibrillation, etc.), deep vein thrombosis, Such as pulmonary thromboembolism It is preferably used for prevention or treatment.
brain:
Cerebral infarction, ischemic cerebrovascular disorder, cerebral embolism caused by atrial fibrillation, heart failure and valvular disease, acute ischemic stroke, acute cerebral thrombosis, cerebral vasospasm after subarachnoid hemorrhage, Alzheimer's disease, transient Prevention and treatment of cerebral ischemic attack (TIA), mixed dementia, cerebrovascular dementia, asymptomatic / multiple cerebral infarction, lacunar infarction, cerebral infarction prognosis / secondary onset prevention, extracranial and internal artery bypass Post-operative thrombus prevention and treatment, combined or auxiliary use with thrombolytic agents for cerebral infarction (especially ischemic cerebrovascular disorder), combination therapy with antiplatelet drugs such as aspirin in prevention of cerebral infarction.
heart:
Prevention of acute coronary artery disease such as acute myocardial infarction, myocardial infarction, ischemic coronary artery disease, unstable angina pectoris, cardiomyopathy, acute heart failure, congestive chronic heart failure, valvular disease, acute coronary artery disease such as angina pectoris Prognosis improvement / secondary onset prevention, thrombus prevention / treatment after artificial valve or artificial heart replacement, stent placement or PTCA (percutaneous coronary artery angioplasty) or vascular re-occlusion and stenosis after coronary intervention such as atherectomy Prevention / treatment, prevention / treatment of vascular re-occlusion and stenosis after coronary artery bypass surgery, combined or auxiliary use with thrombolytic agents for acute coronary artery disease, combination therapy with antiplatelet drugs such as aspirin in preventing myocardial infarction.
Peripheral:
Peripheral circulatory failure such as deep vein thrombosis, chronic arterial occlusion, obstructive arteriosclerosis, Buerger's disease, peripheral circulatory failure after frostbite, aneurysm, varicose vein, adult respiratory distress syndrome, acute renal failure, chronic renal disease ( Prevention and treatment of diabetic complications such as diabetic nephropathy, chronic glomerulonephritis, IgA nephropathy), diabetic circulatory disorder, pain, neuropathy, diabetic retinopathy, etc., prognosis improvement of deep vein thrombosis・ Prevention and treatment of deep vein thrombosis and pulmonary thromboembolism after joint surgery including secondary onset prevention, total hip arthroplasty (THA) and total knee arthroplasty (TKA), orthopedic surgery including spinal surgery・ Plastic surgery ・ Prophylaxis and treatment of deep vein thrombosis and pulmonary thromboembolism after general surgery, peripheral blood vessel bypass surgery or thrombus prevention and treatment after placement of artificial blood vessel and vena cava filter, stent placement or PTA (percutaneous Angioplasty) Prevention and treatment of vascular re-occlusion and stenosis after peripheral vascular intervention such as lectomie, prevention and treatment of deep vein thrombosis and pulmonary thromboembolism associated with acute medical diseases, thrombolytic agent for deep vein thrombosis and pulmonary thromboembolism Combination therapy or adjuvant therapy, combined therapy with antiplatelet drugs such as aspirin in the treatment of peripheral circulatory failure such as obstructive arteriosclerosis.
Other:
Pulmonary embolism, acute pulmonary embolism, economy class syndrome, thrombocytopenia / blood coagulation / complement activation by dialysis, thrombocytopenia during major surgery, thrombocytopenic purpura, progression of arteriosclerosis / cancer metastasis / systemic Organ disorders such as disseminated intravascular coagulation syndrome (DIC) occurring in patients with pancreatitis, cancer, leukemia, major surgery, sepsis, etc., hepatic dysfunction due to ischemia or ischemia or blood stasis Prevention or treatment of various organ failures (eg, lung failure, liver failure, kidney failure, heart failure, etc.), systemic lupus erythematosus, collagen disease, hyperthyroidism, puerperal paralysis, etc. Suppression of rejection, protection of organs or improvement of function during transplantation, prevention of coagulation of perfused blood during extracorporeal circulation, use of alternative therapies at the onset of thrombocytopenia due to heparin administration, acupuncture , Promotion of wound healing, suppression of hypercoagulant response during hormone replacement therapy, alternative therapy for coumarin-resistant or contraindicated patients with warfarin, hypercoagulation during administration of blood products or blood coagulation factor-containing products Suppression of response enhancement.

本発明の化合物（Ｉ）又はその塩はそのままあるいは薬理学的に許容される担体を配合し、経口的又は非経口的に投与することができる。
化合物（Ｉ）又はその塩を含有する本発明の製剤は、経口投与する場合の剤形としては、例えば錠剤（糖衣錠、フィルムコーティング錠を含む）、丸剤、顆粒剤、散剤、カプセル剤（ソフトカプセル剤、マイクロカプセル剤を含む）、シロップ剤、乳剤、懸濁剤等が挙げられ、また、非経口投与する場合の剤形としては、例えば注射剤、注入剤、点滴剤、坐剤等が挙げられる。また、適当な基剤（例、酪酸の重合体、グリコール酸の重合体、酪酸-グリコール酸の共重合体、酪酸の重合体とグリコール酸の重合体との混合物、ポリグリセロール脂肪酸エステル等）と組合わせ徐放性製剤とすることも有効である。
本発明製剤中の化合物（Ｉ）又はその塩の含有量は、製剤の形態に応じて相違するが、通常、製剤全体に対して２ないし８５重量％、好ましくは５ないし７０重量％である。 Compound (I) or a salt thereof of the present invention can be administered orally or parenterally as it is or with a pharmacologically acceptable carrier.
The preparation of the present invention containing Compound (I) or a salt thereof may be used as a dosage form for oral administration, for example, tablets (including sugar-coated tablets and film-coated tablets), pills, granules, powders, capsules (soft capsules) And syrups, emulsions, suspensions, etc., and dosage forms for parenteral administration include injections, infusions, drops, suppositories, etc. It is done. In addition, a suitable base (eg, butyric acid polymer, glycolic acid polymer, butyric acid-glycolic acid copolymer, butyric acid polymer and glycolic acid mixture, polyglycerol fatty acid ester, etc.) It is also effective to make a combination sustained-release preparation.
The content of compound (I) or a salt thereof in the preparation of the present invention varies depending on the form of the preparation, but is usually 2 to 85% by weight, preferably 5 to 70% by weight, based on the whole preparation.

化合物（Ｉ）又はその塩を上記の剤形に製造する方法としては、当該分野で一般的に用いられている公知の製造方法を適用することができる。また、上記の剤形に製造する場合には、必要に応じて、その剤形に製する際に製剤分野において通常用いられる賦形剤、結合剤、崩壊剤、滑沢剤、甘味剤、界面活性剤、懸濁化剤、乳化剤等を適宜、適量含有させて製造することができる。
例えば、化合物（Ｉ）又はその塩を錠剤に製する場合には、賦形剤、結合剤、崩壊剤、滑沢剤等を含有させて製造することができ、丸剤及び顆粒剤に製する場合には、賦形剤、結合剤、崩壊剤等を含有させて製造することができる。また、散剤及びカプセル剤に製する場合には賦形剤等を、シロップ剤に製する場合には甘味剤等を、乳剤又は懸濁剤に製する場合には懸濁化剤、界面活性剤、乳化剤等を含有させて製造することができる。 As a method for producing Compound (I) or a salt thereof in the above-mentioned dosage form, a known production method generally used in the art can be applied. In addition, when manufacturing into the above-mentioned dosage forms, excipients, binders, disintegrants, lubricants, sweeteners, interfaces commonly used in the pharmaceutical field when manufacturing into the dosage forms, if necessary. An activator, a suspending agent, an emulsifier, etc. can be appropriately contained and produced.
For example, when compound (I) or a salt thereof is produced into a tablet, it can be produced by containing excipients, binders, disintegrants, lubricants, etc., and is produced into pills and granules. In some cases, it can be produced by containing an excipient, a binder, a disintegrant and the like. In addition, excipients and the like are used for powders and capsules, sweeteners and the like are used for syrups, and suspending agents and surfactants are used for emulsions and suspensions. It can be produced by adding an emulsifier and the like.

賦形剤の例としては、乳糖、白糖、ブドウ糖、でんぷん、蔗糖、微結晶セルロース、カンゾウ末、マンニトール、炭酸水素ナトリウム、リン酸カルシウム、硫酸カルシウム等が挙げられる。
結合剤の例としては、５ないし１０重量％デンプンのり液、１０ないし２０重量％アラビアゴム液又はゼラチン液、１ないし５重量％トラガント液、カルボキシメチルセルロース液、アルギン酸ナトリウム液、グリセリン等が挙げられる。
崩壊剤の例としては、でんぷん、炭酸カルシウム等が挙げられる。
滑沢剤の例としては、ステアリン酸マグネシウム、ステアリン酸、ステアリン酸カルシウム、精製タルク等が挙げられる。
甘味剤の例としては、ブドウ糖、果糖、転化糖、ソルビトール、キシリトール、グリセリン、単シロップ等が挙げられる。
界面活性剤の例としては、ラウリル硫酸ナトリウム、ポリソルベート８０、ソルビタンモノ脂肪酸エステル、ステアリン酸ポリオキシル４０等が挙げられる。
懸濁化剤の例としては、アラビアゴム、アルギン酸ナトリウム、カルボキシメチルセルロースナトリウム、メチルセルロース、ベントナイト等が挙げられる。
乳化剤の例としては、アラビアゴム、トラガント、ゼラチン、ポリソルベート８０等が挙げられる。
更に、化合物（Ｉ）又はその塩を上記の剤形に製造する場合には、所望により、精製分野において通常用いられる着色剤、保存剤、芳香剤、矯味剤、安定剤、粘稠剤等を適量、適量添加することができる。 Examples of excipients include lactose, sucrose, glucose, starch, sucrose, microcrystalline cellulose, licorice powder, mannitol, sodium bicarbonate, calcium phosphate, calcium sulfate and the like.
Examples of the binder include 5 to 10% by weight starch paste, 10 to 20% by weight gum arabic solution or gelatin solution, 1 to 5% by weight tragacanth solution, carboxymethyl cellulose solution, sodium alginate solution, glycerin and the like.
Examples of disintegrants include starch and calcium carbonate.
Examples of the lubricant include magnesium stearate, stearic acid, calcium stearate, purified talc and the like.
Examples of sweeteners include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin, simple syrup and the like.
Examples of the surfactant include sodium lauryl sulfate, polysorbate 80, sorbitan monofatty acid ester, polyoxyl 40 stearate and the like.
Examples of the suspending agent include gum arabic, sodium alginate, sodium carboxymethyl cellulose, methyl cellulose, bentonite and the like.
Examples of emulsifiers include gum arabic, tragacanth, gelatin, polysorbate 80 and the like.
Furthermore, when producing Compound (I) or a salt thereof in the above-mentioned dosage form, a coloring agent, a preservative, a fragrance, a flavoring agent, a stabilizer, a thickening agent and the like that are usually used in the purification field are optionally added. An appropriate amount can be added.

化合物（Ｉ）又はその塩を含有する本発明の製剤は、安定かつ低毒性で安全に使用することができる。その１日の投与量は患者の状態や体重、化合物の種類、投与経路等によって異なるが、例えば、血栓症の患者に経口投与する場合には、成人（体重約６０kg）１日当りの投与量は有効成分（化合物（Ｉ）又はその塩）として約１ないし１０００mg、好ましくは約３ないし５００mg、さら好ましくは約１０ないし３５０mgであり、これらを１回または２ないし３回に分けて投与することができる。
本発明の化合物（Ｉ）又はその塩を非経口的に投与する場合は、通常、液剤（例えば、注射剤）の形で投与する。その１回投与量は投与対象、対象臓器、症状、投与方法などによっても異なるが、例えば、注射剤の形にして、通常体重１ｋｇあたり約０．０１ｍｇ〜約１００ｍｇ、好ましくは約０．０１〜約５０ｍｇ、より好ましくは約０．０１〜約２０ｍｇを静脈注射により投与するのが好都合である。注射剤としては、静脈注射剤のほか、皮下注射剤、皮内注射剤、筋肉注射剤、点滴注射剤などが含まれ、また持続性製剤としては、イオントフォレシス経皮剤などが含まれる。かかる注射剤は自体公知の方法、すなわち、本発明の化合物（Ｉ）又はその塩を無菌の水性液もしくは油性液に溶解、懸濁または乳化することによって調製される。注射用の水性液としては生理食塩水、ブドウ糖やその他の補助薬を含む等張液（例えば、Ｄ−ソルビトール、Ｄ−マンニトール、塩化ナトリウムなど）などがあげられ、適当な溶解補助剤、例えば、アルコール（例えば、エタノール）、ポリアルコール（例えば、プロピレングリコール、ポリエチレングリコール）、非イオン性界面活性剤（例えば、ポリソルベート８０、ＨＣＯ−５０）などと併用してもよい。油性液としては、ゴマ油、大豆油などがあげられ、溶解補助剤として安息香酸ベンジル、ベンジルアルコールなどと併用してもよい。また、緩衝剤（例えば、リン酸緩衝液、酢酸ナトリウム緩衝液）、無痛化剤（例えば、塩化ベンザルコニウム、塩酸プロカインなど）、安定剤（例えば、ヒト血清アルブミン、ポリエチレングリコールなど）、保存剤（例えば、ベンジルアルコール、フェノールなど）などと配合してもよい。調製された注射液は、通常、アンプルに充填される。
本発明の製剤は、適宜、血栓溶解剤（例、ＴＰＡ、ウロキナーゼ等）、アルツハイマー治療薬（例えば、アバン、カラン等）、コレステロール治療薬（例、シンバスタチン、プラバスタチン等のＨＭＧ−ＣｏＡ還元酵素阻害薬等）、ＴＧ低下薬（例、クロフィブラート等）、ＡＩＩ拮抗薬（例、カンデサルタンシレキセチル、ロサルタン等）、抗血小板薬（例、クロピドグレル、アブシキシマブ、アスピリン等）、Ｃａ拮抗薬（例、カルスロット、アムロジピン等）、ACE阻害薬（例、エナラプリル、カプトプリル等）、β遮断薬（例、メトプロロール、カルベジロール等）、抗不整脈薬（例、プロカインアミド等）等の薬剤（以下、併用薬剤と略記する）と組み合わせて用いることができる。該併用薬剤は、低分子化合物であってもよく、また高分子の蛋白、ポリペプチド、抗体であるか、あるいはワクチン等であってもよい。この際、本発明の化合物と併用薬剤の投与形態は、特に限定されず、投与時に、本発明の化合物と併用薬剤とが組み合わされていればよい。このような投与形態としては、例えば、（１）本発明の化合物と併用薬剤とを同時に製剤化して得られる単一の製剤の投与、（２）本発明の化合物と併用薬剤とを別々に製剤化して得られる２種の製剤の同一投与経路での同時投与、（３）本発明の化合物と併用薬剤とを別々に製剤化して得られる２種の製剤の同一投与経路での時間差をおいての投与、（４）本発明の化合物と併用薬剤とを別々に製剤化して得られる２種の製剤の異なる投与経路での同時投与、（５）本発明の化合物と併用薬剤とを別々に製剤化して得られる２種の製剤の異なる投与経路での時間差をおいての投与（例えば、本発明の化合物→併用薬剤の順序での投与、あるいは逆の順序での投与）などが挙げられる。併用薬剤の投与量は、臨床上用いられている用量を基準として適宜選択することができる。また、本発明の化合物と併用薬剤の配合比は、投与対象、投与ルート、対象疾患、症状、組み合わせなどにより適宜選択することができる。例えば投与対象がヒトである場合、本発明の化合物１重量部に対し、併用薬剤を０．０１ないし１００重量部用いればよい。 The preparation of the present invention containing Compound (I) or a salt thereof can be used safely with stability and low toxicity. The daily dose varies depending on the patient's condition and body weight, the type of compound, the route of administration, etc. For example, when administered orally to a patient with thrombosis, the daily dose for an adult (body weight approximately 60 kg) is The active ingredient (compound (I) or a salt thereof) is about 1 to 1000 mg, preferably about 3 to 500 mg, more preferably about 10 to 350 mg, and these can be administered once or divided into 2 to 3 times. it can.
When the compound (I) or a salt thereof of the present invention is administered parenterally, it is usually administered in the form of a liquid (for example, injection). The single dose varies depending on the administration subject, target organ, symptom, administration method, and the like. For example, in the form of an injection, it is usually about 0.01 mg to about 100 mg per kg body weight, preferably about 0.01 to It is convenient to administer about 50 mg, more preferably about 0.01 to about 20 mg by intravenous injection. In addition to intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, infusions, and the like are included as injections, and sustained-release preparations include iontophoretic transdermal agents and the like. Such an injection is prepared by a method known per se, that is, by dissolving, suspending or emulsifying the compound (I) of the present invention or a salt thereof in a sterile aqueous or oily liquid. Examples of aqueous solutions for injection include physiological saline, isotonic solutions containing glucose and other adjuvants (for example, D-sorbitol, D-mannitol, sodium chloride, etc.), and suitable solubilizing agents such as You may use together with alcohol (for example, ethanol), polyalcohol (for example, propylene glycol, polyethylene glycol), a nonionic surfactant (for example, polysorbate 80, HCO-50), etc. Examples of the oily liquid include sesame oil and soybean oil, which may be used in combination with benzyl benzoate, benzyl alcohol or the like as a solubilizing agent. Buffers (eg, phosphate buffer, sodium acetate buffer), soothing agents (eg, benzalkonium chloride, procaine hydrochloride, etc.), stabilizers (eg, human serum albumin, polyethylene glycol, etc.), preservatives (For example, benzyl alcohol, phenol, etc.) may be blended. The prepared injection solution is usually filled in an ampoule.
The preparations of the present invention are appropriately prepared from thrombolytic agents (eg, TPA, urokinase, etc.), Alzheimer's therapeutic agents (eg, avan, curan, etc.), cholesterol therapeutic agents (eg, simvastatin, pravastatin, etc., HMG-CoA reductase inhibitors Etc.), TG lowering drugs (eg, clofibrate, etc.), AII antagonists (eg, candesartan cilexetil, losartan etc.), antiplatelet drugs (eg, clopidogrel, abciximab, aspirin etc.), Ca antagonists (eg, carlot, Amlodipine), ACE inhibitors (eg, enalapril, captopril, etc.), β-blockers (eg, metoprolol, carvedilol, etc.), antiarrhythmic drugs (eg, procainamide, etc.), etc. (hereinafter abbreviated as concomitant drugs) Can be used in combination. The concomitant drug may be a low molecular compound, a high molecular protein, a polypeptide, an antibody, or a vaccine. At this time, the administration mode of the compound of the present invention and the concomitant drug is not particularly limited, and it is sufficient that the compound of the present invention and the concomitant drug are combined at the time of administration. Examples of such administration forms include (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug, and (2) separate preparation of the compound of the present invention and the concomitant drug. Simultaneous administration of the two preparations obtained by the same administration by the same administration route, (3) with a time difference in the same administration route of the two preparations obtained by separately formulating the compound of the present invention and the concomitant drug. (4) Simultaneous administration of two types of preparations obtained by separately formulating the compound of the present invention and a concomitant drug by different administration routes, (5) Formulating the compound of the present invention and the concomitant drug separately Administration of the two types of preparations obtained by the preparation with different time routes in different administration routes (for example, administration in the order of the compound of the present invention → concomitant drug, or administration in the reverse order). The dose of the concomitant drug can be appropriately selected based on the clinically used dose. Moreover, the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, the concomitant drug may be used in an amount of 0.01 to 100 parts by weight per 1 part by weight of the compound of the present invention.

本発明の化合物（Ｉ）またはその塩は、優れたＦＸａ阻害作用を有し、医薬としてより安全性が高く、また経口吸収しうる抗血液凝固剤として有用である。 The compound (I) or a salt thereof of the present invention has an excellent FXa inhibitory action, is safer as a pharmaceutical, and is useful as an anticoagulant that can be absorbed orally.

本発明はさらに下記の実施例、製剤例及び実験例で詳しく説明されるが、これらの例は単なる実例であって本発明を限定するものではなく、また本発明の範囲を逸脱しない範囲で変化させてもよい。
実施例のカラムクロマトグラフィーにおける溶出はＴＬＣ（Ｔhin Ｌayer Ｃhromatography，薄層クロマトグラフィー）による観察下に行なわれた。ＴＬＣ観察においては、ＴＬＣプレートとしてメルク（Ｍerck）社製の６０Ｆ_２５４または富士シリシア化学社製のＮＨを、展開溶媒としてはカラムクロマトグラフィーで溶出溶媒として用いられた溶媒を、検出法としてＵＶ検出器を採用した。カラム用シリカゲルは同じくメルク社製のキーゼルゲル６０（７０ないし２３０メッシュ）またはキーゼルゲル６０（２３０ないし４００メッシュ）を用いた。カラム用塩基性シリカゲルは富士シリシア化学社製の塩基性シリカＮＨ−ＤＭ１０２０（１００ないし２００メッシュ）を用いた。ＮＭＲスペクトルは内部又は外部基準としてテトラメチルシランを用いてバリアンＧemini ２００型または３００型スペクトロメーターで測定し、化学シフトをδ値で、カップリング定数をHzで示した。ＩＲスペクトルは島津ＦＴＺＲ−８２００型スペクトロメーターで測定した。混合溶媒において（）内に示した数値は各溶媒の容量混合比である。また溶液における％は溶液１００ml中のｇ数を表わす。また実施例中の記号は次のような意味である。
s ：シングレット（singlet）
d ：ダブレット（doublet）
t ：トリプレット（triplet）
q ：クワルテット（quartet）
dd ：ダブルダブレット（double doublet）
m ：マルチプレット（multiplet）
br ：ブロード（broad）
brs ：ブロードシングレット（broad singlet）
J ：カップリング定数（coupling constant）
ＷＳＣ：水溶性カルボジイミド
ＴＨＦ：テトラヒドロフラン
ＤＭＦ：N,N'-ジメチルホルムアミド
ＤＭＳＯ：ジメチルスルホキシド
ＨＯＢｔ：１−ヒドロキシベンズトリアゾール The present invention is further described in detail in the following examples, formulation examples and experimental examples, which are merely illustrative and are not intended to limit the present invention, and may be modified without departing from the scope of the present invention. You may let them.
The elution in the column chromatography of the examples was carried out under observation by TLC (Thin Layer Chromatography, thin layer chromatography). In the TLC observation, 60F ₂₅₄ manufactured by Merck or NH manufactured by Fuji Silysia Chemical Co. is used as the TLC plate, the solvent used as the elution solvent in the column chromatography is used as the developing solvent, and the UV detector is used as the detection method. It was adopted. The silica gel for the column was Kieselgel 60 (70 to 230 mesh) or Kieselgel 60 (230 to 400 mesh) manufactured by Merck. As the basic silica gel for the column, basic silica NH-DM1020 (100 to 200 mesh) manufactured by Fuji Silysia Chemical Ltd. was used. NMR spectra were measured with a Varian Gemini 200 or 300 spectrometer using tetramethylsilane as an internal or external reference, chemical shifts were expressed as δ values, and coupling constants were expressed in Hz. The IR spectrum was measured with a Shimadzu FTZR-8200 type spectrometer. In the mixed solvent, the numerical value shown in parentheses is the volume mixing ratio of each solvent. % In the solution represents the number of grams in 100 ml of the solution. The symbols in the examples have the following meanings.
s: singlet
d: Doublet
t: triplet
q: quartet
dd—Double doublet
m: multiplet
br: Broad
brs: Broad singlet
J: coupling constant
WSC: Water-soluble carbodiimide THF: Tetrahydrofuran DMF: N, N'-dimethylformamide DMSO: Dimethyl sulfoxide HOBt: 1-hydroxybenztriazole

実施例１
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-(1H-イミダゾール-1-イル)ピペリジン
4-(1H-イミダゾール-1-イル)ピペリジン-1-カルボン酸tert-ブチル（特表平7-501556号公報）(0.28g)を４０％塩化水素エタノール(4mL)およびエタノール(5mL)に溶解し、室温で3時間かき混ぜた。反応混合物を減圧濃縮し、エタノールと共沸した。残留物をジイソプロピルエーテルで洗浄して得られた固体を、DBU(0.34g)、トリエチルアミン(0.34g)とともにアセトニトリル(15mL)に溶解した。この溶液を3-[(6-クロロ-2-ナフチル)スルホニル]プロピオン酸（0.33g）、HOBt(0.26g)およびWSC(0.32g)のアセトニトリル(15mL)懸濁液に加えて室温で15時間かき混ぜた。反応液を減圧濃縮し、酢酸エチルと炭酸カリウム水溶液で希釈した。有機層を分取し、無水硫酸ナトリウムで乾燥し、減圧濃縮した。残留物を塩基性シリカゲルカラム（酢酸エチル）で精製して題記化合物(0.40g, 83%)を淡黄色ガム状物質として得た。
NMR (300MHz, CDCl₃) δ: 1.70-1.92 (2H, m), 2.09-2.22 (2H, m), 2.64-2.72 (1H, m), 2.90-2.97 (2H, m), 3.17-3.25 (1H, m), 3.54-3.61 (2H, m), 4.00-4.09 (1H, m), 4.08-4.21 (1H, m), 4.69-4.73 (1H, m), 6.93 (1H, t, J = 1.2), 7.08 (1H, d, J = 1.2), 7.54 (1H, s), 7.60 (1H, dd, J = 8.7 and 2.1), 7.93-7.97 (4H, m), 8.49 (1H, d, J = 1.2).
元素分析値 C₂₁H₂₂ClN₃O₃S・0.5H₂Oとして
計算値（％）：C, 57.20； H, 5.26； N, 9.53
実測値（％）：C, 57.42； H, 5.46； N, 9.47 Example 1
1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- (1H-imidazol-1-yl) piperidine
Dissolve tert-butyl 4- (1H-imidazol-1-yl) piperidine-1-carboxylate (Japanese Patent Publication No. 7-501556) (0.28 g) in 40% ethanolic hydrogen chloride (4 mL) and ethanol (5 mL) And stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and azeotroped with ethanol. The solid obtained by washing the residue with diisopropyl ether was dissolved in acetonitrile (15 mL) together with DBU (0.34 g) and triethylamine (0.34 g). This solution was added to a suspension of 3-[(6-chloro-2-naphthyl) sulfonyl] propionic acid (0.33 g), HOBt (0.26 g) and WSC (0.32 g) in acetonitrile (15 mL) for 15 hours at room temperature. Stir. The reaction solution was concentrated under reduced pressure and diluted with ethyl acetate and an aqueous potassium carbonate solution. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column (ethyl acetate) to give the title compound (0.40 g, 83%) as a pale yellow gum.
NMR (300MHz, CDCl ₃ ) δ: 1.70-1.92 (2H, m), 2.09-2.22 (2H, m), 2.64-2.72 (1H, m), 2.90-2.97 (2H, m), 3.17-3.25 (1H , m), 3.54-3.61 (2H, m), 4.00-4.09 (1H, m), 4.08-4.21 (1H, m), 4.69-4.73 (1H, m), 6.93 (1H, t, J = 1.2) , 7.08 (1H, d, J = 1.2), 7.54 (1H, s), 7.60 (1H, dd, J = 8.7 and 2.1), 7.93-7.97 (4H, m), 8.49 (1H, d, J = 1.2 ).
Elemental analysis value Calculated as C ₂₁ H ₂₂ ClN ₃ O ₃ S · 0.5H ₂ O (%): C, 57.20; H, 5.26; N, 9.53
Found (%): C, 57.42; H, 5.46; N, 9.47

実施例２
1-{3-[(6-ブロモ-2-ナフチル)スルホニル]プロパノイル}-4-(1H-イミダゾール-1-イル)ピペリジン
3-[(6-ブロモ-2-ナフチル)スルホニル]プロピオン酸(0.38g)から実施例１と同様にして題記化合物(0.27g, 51%)を無色粉末として得た。
NMR (300MHz, CDCl₃) δ: 1.71-1.90 (2H, m), 2.08-2.22 (2H, m), 2.64-2.72 (1H, m), 2.90-2.97 (2H, m), 3.17-3.25 (1H, m), 3.54-3.61 (2H, m), 4.00-4.04 (1H, m), 4.09-4.21 (2H, m), 4.68-4.73 (1H, m), 6.93 (1H, d, J = 1.2), 7.09 (1H, s), 7.54 (1H, s), 7.73 (1H, dd, J = 8.8 and 2.0), 7.86-7.97 (3H, m), 8.14 (1H, d, J = 1.8), 8.48 (1H, s).
元素分析値 C₂₁H₂₂BrN₃O₃S・0.7H₂Oとして
計算値（％）：C, 51.58； H, 4.82； N, 8.59
実測値（％）：C, 51.47； H, 4.85； N, 8.56 Example 2
1- {3-[(6-Bromo-2-naphthyl) sulfonyl] propanoyl} -4- (1H-imidazol-1-yl) piperidine
The title compound (0.27 g, 51%) was obtained as a colorless powder from 3-[(6-bromo-2-naphthyl) sulfonyl] propionic acid (0.38 g) in the same manner as in Example 1.
NMR (300MHz, CDCl ₃ ) δ: 1.71-1.90 (2H, m), 2.08-2.22 (2H, m), 2.64-2.72 (1H, m), 2.90-2.97 (2H, m), 3.17-3.25 (1H , m), 3.54-3.61 (2H, m), 4.00-4.04 (1H, m), 4.09-4.21 (2H, m), 4.68-4.73 (1H, m), 6.93 (1H, d, J = 1.2) , 7.09 (1H, s), 7.54 (1H, s), 7.73 (1H, dd, J = 8.8 and 2.0), 7.86-7.97 (3H, m), 8.14 (1H, d, J = 1.8), 8.48 ( 1H, s).
Elemental analysis value Calculated as C ₂₁ H ₂₂ BrN ₃ O ₃ S · 0.7H ₂ O (%): C, 51.58; H, 4.82; N, 8.59
Found (%): C, 51.47; H, 4.85; N, 8.56

実施例３
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-(2-メチル-1H-イミダゾール-1-イル)ピペリジン
4-(2-メチル-1H-イミダゾール-1-イル)ピペリジン-1-カルボン酸tert-ブチル（特表平7-501556号公報）(0.27g)から実施例１と同様にして題記化合物(0.37g, 83%)を無色粉末として得た。
NMR (300MHz, CDCl₃) δ: 1.68-1.84 (2H, m), 1.97-2.09 (2H, m), 2.42 (3H, s), 2.61-2.69 (1H, m), 2.91-2.98(2H, m), 3.15-3.24 (1H, m), 3.54-3.62 (2H, m), 4.02-4.13 (2H, m), 4.73-4.77 (1H, m), 6.81 (1H, d, J = 1.5), 6.94 (1H, d, J = 1.5), 7.60 (1H, dd, J = 8.9 and 2.0), 7.91-7.97 (4H, m), 8.50 (1H, s).
元素分析値 C₂₂H₂₄ClN₃O₃S・0.9H₂Oとして
計算値（％）：C, 57.17； H, 5.63； N, 9.09
実測値（％）：C, 57.28； H, 5.71； N, 9.16 Example 3
1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- (2-methyl-1H-imidazol-1-yl) piperidine
The title compound (0.37 g, 83%) was obtained as a colorless powder.
NMR (300MHz, CDCl ₃ ) δ: 1.68-1.84 (2H, m), 1.97-2.09 (2H, m), 2.42 (3H, s), 2.61-2.69 (1H, m), 2.91-2.98 (2H, m ), 3.15-3.24 (1H, m), 3.54-3.62 (2H, m), 4.02-4.13 (2H, m), 4.73-4.77 (1H, m), 6.81 (1H, d, J = 1.5), 6.94 (1H, d, J = 1.5), 7.60 (1H, dd, J = 8.9 and 2.0), 7.91-7.97 (4H, m), 8.50 (1H, s).
Elemental analysis value Calculated as C ₂₂ H ₂₄ ClN ₃ O ₃ S · 0.9H ₂ O (%): C, 57.17; H, 5.63; N, 9.09
Found (%): C, 57.28; H, 5.71; N, 9.16

実施例４
1-{3-[(6-ブロモ-2-ナフチル)スルホニル]プロパノイル}-4-(2-メチル-1H-イミダゾール-1-イル)ピペリジン
4-(2-メチル-1H-イミダゾール-1-イル)ピペリジン-1-カルボン酸tert-ブチル(0.27g)および3-[(6-ブロモ-2-ナフチル)スルホニル]プロピオン酸(0.34g)から実施例１と同様にして題記化合物(0.47g, 96%)を無色粉末として得た。
NMR (300MHz, CDCl₃) δ: 1.69-1.85 (2H, m), 1.97-2.08 (2H, m), 2.42 (3H, s), 2.65 (1H, t, J = 12.1), 2.91-2.98 (2H, m), 3.16-3.25 (1H, m), 3.54-3.62 (2H, m), 4.02-4.11 (2H, m), 4.74-4.77 (1H, m), 6.81 (1H, d, J = 1.5), 6.94 (1H, d, J = 1.5), 7.73 (1H, dd, J = 8.9 and 1.9), 7.87-7.95 (3H, m), 8.14 (1H, s), 8.48 (1H, s).
元素分析値 C₂₂H₂₄BrN₃O₃S・0.7H₂Oとして
計算値（％）：C, 52.53； H, 5.09； N, 8.35
実測値（％）：C, 52.34； H, 5.30； N, 8.19 Example 4
1- {3-[(6-Bromo-2-naphthyl) sulfonyl] propanoyl} -4- (2-methyl-1H-imidazol-1-yl) piperidine
From tert-butyl 4- (2-methyl-1H-imidazol-1-yl) piperidine-1-carboxylate (0.27 g) and 3-[(6-bromo-2-naphthyl) sulfonyl] propionic acid (0.34 g) The title compound (0.47 g, 96%) was obtained as a colorless powder in the same manner as in Example 1.
NMR (300MHz, CDCl ₃ ) δ: 1.69-1.85 (2H, m), 1.97-2.08 (2H, m), 2.42 (3H, s), 2.65 (1H, t, J = 12.1), 2.91-2.98 (2H , m), 3.16-3.25 (1H, m), 3.54-3.62 (2H, m), 4.02-4.11 (2H, m), 4.74-4.77 (1H, m), 6.81 (1H, d, J = 1.5) , 6.94 (1H, d, J = 1.5), 7.73 (1H, dd, J = 8.9 and 1.9), 7.87-7.95 (3H, m), 8.14 (1H, s), 8.48 (1H, s).
Elemental analysis value Calculated as C ₂₂ H ₂₄ BrN ₃ O ₃ S · 0.7H ₂ O (%): C, 52.53; H, 5.09; N, 8.35
Found (%): C, 52.34; H, 5.30; N, 8.19

実施例５
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-(4-メチル-1H-イミダゾール-1-イル)ピペリジン
4-(4-メチル-1H-イミダゾール-1-イル)ピペリジン-1-カルボン酸tert-ブチル (0.39g)から実施例１と同様にして題記化合物(0.41g, 70%)を無色粉末として得た。
NMR (200MHz, CDCl₃) δ: 1.74-1.95 (2H, m), 2.12-2.27 (2H, m), 2.21 (3H, d, J = 0.8), 2.60-2.72 (1H, m), 2.89-2.97 (2H, m), 3.12-3.24 (1H, m), 3.53-3.62 (2H, m), 3.96-4.14 (2H, m), 4.65-4.72 (1H, m), 6.63 (1H, s), 7.41 (1H, d, J = 1.0), 7.60 (1H, dd, J = 8.8 and 1.8), 7.93-7.97 (4H, m), 8.49 (1H, s).
元素分析値 C₂₂H₂₄ClN₃O₃S・0.9H₂Oとして
計算値（％）：C, 58.08； H, 5.54； N, 9.24
実測値（％）：C, 57.81； H, 5.79； N, 9.53 Example 5
1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- (4-methyl-1H-imidazol-1-yl) piperidine
The title compound (0.41 g, 70%) was obtained as a colorless powder from tert-butyl 4- (4-methyl-1H-imidazol-1-yl) piperidine-1-carboxylate (0.39 g) in the same manner as in Example 1. It was.
NMR (200MHz, CDCl ₃ ) δ: 1.74-1.95 (2H, m), 2.12-2.27 (2H, m), 2.21 (3H, d, J = 0.8), 2.60-2.72 (1H, m), 2.89-2.97 (2H, m), 3.12-3.24 (1H, m), 3.53-3.62 (2H, m), 3.96-4.14 (2H, m), 4.65-4.72 (1H, m), 6.63 (1H, s), 7.41 (1H, d, J = 1.0), 7.60 (1H, dd, J = 8.8 and 1.8), 7.93-7.97 (4H, m), 8.49 (1H, s).
Elemental analysis value Calculated as C ₂₂ H ₂₄ ClN ₃ O ₃ S / 0.9H ₂ O (%): C, 58.08; H, 5.54; N, 9.24
Found (%): C, 57.81; H, 5.79; N, 9.53

実施例６
1-{3-[(6-ブロモ-2-ナフチル)スルホニル]プロパノイル}-4-(4-メチル-1H-イミダゾール-1-イル)ピペリジン
4-(4-メチル-1H-イミダゾール-1-イル)ピペリジン-1-カルボン酸tert-ブチル (0.39g)および3-[(6-ブロモ-2-ナフチル)スルホニル]プロピオン酸(0.45g)から実施例１と同様にして題記化合物(0.49g, 75%)を無色粉末として得た。
NMR (200MHz, CDCl₃) δ: 1.68-1.86 (2H, m), 2.12-2.27 (2H, m), 2.21 (3H, d, J = 0.6), 2.60-2.73 (1H, m), 2.89-2.96 (2H, m), 3.10-3.24 (1H, m), 3.53-3.61 (2H, m), 3.96-4.10 (2H, m), 4.65-4.71 (1H, m), 6.63 (1H, s), 7.41 (1H, d, J = 1.4), 7.73 (1H, dd, J = 8.8 and 2.0), 7.84-7.93 (3H, m), 8.13 (1H, d, J = 1.6), 8.48 (1H, s).
元素分析値 C₂₂H₂₄BrN₃O₃S・H₂Oとして
計算値（％）：C, 51.97； H, 5.15； N, 8.26
実測値（％）：C, 52.03； H, 4.99； N, 8.39 Example 6
1- {3-[(6-Bromo-2-naphthyl) sulfonyl] propanoyl} -4- (4-methyl-1H-imidazol-1-yl) piperidine
From tert-butyl 4- (4-methyl-1H-imidazol-1-yl) piperidine-1-carboxylate (0.39 g) and 3-[(6-bromo-2-naphthyl) sulfonyl] propionic acid (0.45 g) The title compound (0.49 g, 75%) was obtained as a colorless powder in the same manner as in Example 1.
NMR (200MHz, CDCl ₃ ) δ: 1.68-1.86 (2H, m), 2.12-2.27 (2H, m), 2.21 (3H, d, J = 0.6), 2.60-2.73 (1H, m), 2.89-2.96 (2H, m), 3.10-3.24 (1H, m), 3.53-3.61 (2H, m), 3.96-4.10 (2H, m), 4.65-4.71 (1H, m), 6.63 (1H, s), 7.41 (1H, d, J = 1.4), 7.73 (1H, dd, J = 8.8 and 2.0), 7.84-7.93 (3H, m), 8.13 (1H, d, J = 1.6), 8.48 (1H, s).
Elemental analysis value Calculated as C ₂₂ H ₂₄ BrN ₃ O ₃ S · H ₂ O (%): C, 51.97; H, 5.15; N, 8.26
Found (%): C, 52.03; H, 4.99; N, 8.39

実施例７
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-(2,4-ジメチル-1H-イミダゾール-1-イル)ピペリジン
7a) 4-(2,4-ジメチル-1H-イミダゾール-1-イル)ピペリジン-1-カルボン酸tert-ブチル
2,4-ジメチルイミダゾール(5.16g)と4-[(メチルスルホニル)オキシ]ピペリジン-1-カルボン酸tert-ブチル(10g)および炭酸カリウム(4.95g)のDMF懸濁液(80mL)を100℃で72時間かき混ぜた。反応混合物を減圧濃縮し、残留物を水と酢酸エチルで希釈した。有機層を分取し、飽和炭酸水素ナトリウムで洗浄し、無水硫酸ナトリウムで乾燥し、溶媒を減圧濃縮した。残留物をシリカゲルカラム（ジクロロメタン/メタノール/アンモニア水＝100／3.5／0.5から100/10/1）で精製して題記化合物(0.58g, 6%)を黄色油状物として得た。
NMR (300MHz, CDCl₃) δ: 1.43 (9H, s), 1.66-1.92 (3H, m), 2.16 (3H, s), 2.37 (3H, s), 2.77-2.85 (2H, m), 3.79-3.91 (2H, m), 4.26 (2H, m), 6.55 (1H, s).
7b) 1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-(2,4-ジメチル-1H-イミダゾール-1-イル)ピペリジン
実施例7a)で得た4-(2,4-ジメチル-1H-イミダゾール-1-イル)ピペリジン-1-カルボン酸tert-ブチル(0.28g)から実施例１と同様にして題記化合物(0.21g, 46%)を無色粉末として得た。
NMR (300MHz, CDCl₃) δ: 1.65-1.79 (2H, m), 1.93-2.05 (2H, m), 2.16 (3H, d, J = 0.9), 2.37 (3H, s), 2.58-2.67 (1H, m), 2.90-2.97 (2H, m), 3.13-3.22 (1H, m), 3.54-3.61 (2H, m), 3.95-4.04 (2H, m), 4.71-4.75 (1H, m), 6.50 (1H, d, J = 1.2), 7.60 (1H, dd, J = 8.7 and 1.8), 7.91-7.97 (4H, m), 8.49 (1H, s).
元素分析値 C₂₃H₂₆ClN₃O₃S・H₂Oとして
計算値（％）：C, 57.79； H, 5.90； N, 8.79
実測値（％）：C, 57.84； H, 5.90； N, 8.68 Example 7
1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- (2,4-dimethyl-1H-imidazol-1-yl) piperidine
7a) tert-Butyl 4- (2,4-dimethyl-1H-imidazol-1-yl) piperidine-1-carboxylate
DMF suspension (80 mL) of 2,4-dimethylimidazole (5.16 g), tert-butyl 4-[(methylsulfonyl) oxy] piperidine-1-carboxylate (10 g) and potassium carbonate (4.95 g) was added at 100 ° C. Stir for 72 hours. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water and ethyl acetate. The organic layer was separated, washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column (dichloromethane / methanol / aqueous ammonia = 100 / 3.5 / 0.5 to 100/10/1) to give the title compound (0.58 g, 6%) as a yellow oil.
NMR (300MHz, CDCl ₃ ) δ: 1.43 (9H, s), 1.66-1.92 (3H, m), 2.16 (3H, s), 2.37 (3H, s), 2.77-2.85 (2H, m), 3.79- 3.91 (2H, m), 4.26 (2H, m), 6.55 (1H, s).
7b) 1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- (2,4-dimethyl-1H-imidazol-1-yl) piperidine 4- (4) obtained in Example 7a) The title compound (0.21 g, 46%) was obtained as a colorless powder from tert-butyl 2,4-dimethyl-1H-imidazol-1-yl) piperidine-1-carboxylate (0.28 g) in the same manner as in Example 1. .
NMR (300MHz, CDCl ₃ ) δ: 1.65-1.79 (2H, m), 1.93-2.05 (2H, m), 2.16 (3H, d, J = 0.9), 2.37 (3H, s), 2.58-2.67 (1H , m), 2.90-2.97 (2H, m), 3.13-3.22 (1H, m), 3.54-3.61 (2H, m), 3.95-4.04 (2H, m), 4.71-4.75 (1H, m), 6.50 (1H, d, J = 1.2), 7.60 (1H, dd, J = 8.7 and 1.8), 7.91-7.97 (4H, m), 8.49 (1H, s).
Elemental analysis value Calculated as C ₂₃ H ₂₆ ClN ₃ O ₃ S · H ₂ O (%): C, 57.79; H, 5.90; N, 8.79
Found (%): C, 57.84; H, 5.90; N, 8.68

実施例８
1-{3-[(6-ブロモ-2-ナフチル)スルホニル]プロパノイル}-4-(2,4-ジメチル-1H-イミダゾール-1-イル)ピペリジン
実施例7a)で得た4-(2,4-ジメチル-1H-イミダゾール-1-イル)ピペリジン-1-カルボン酸tert-ブチル(0.29g)および3-[(6-ブロモ-2-ナフチル)スルホニル]プロピオン酸(0.36g)から実施例１と同様にして題記化合物(70mg, 14%)を無色粉末として得た。
NMR (300MHz, CDCl₃) δ: 1.65-1.79 (2H, m), 1.94-2.00 (2H, m), 2.16 (3H, d, J = 0.6), 2.37 (3H, s), 2.59-2.68 (1H, m), 2.90-2.97 (2H, m), 3.13-3.22 (1H, m), 3.54-3.61 (2H, m), 3.95-4.03 (2H, m), 4.71-4.76 (1H, m), 6.50 (1H, s), 7.74 (1H, dd, J = 8.8 and 2.0), 7.85-7.98 (3H, m), 8.14 (1H, d, J = 2.1), 8.48 (1H, s).
元素分析値 C₂₃H₂₆BrN₃O₃S・H₂Oとして
計算値（％）：C, 52.87； H, 5.40； N, 8.04
実測値（％）：C, 52.66； H, 5.23； N, 8.03 Example 8
1- {3-[(6-Bromo-2-naphthyl) sulfonyl] propanoyl} -4- (2,4-dimethyl-1H-imidazol-1-yl) piperidine 4- (2, Example 1 from tert-butyl 4-dimethyl-1H-imidazol-1-yl) piperidine-1-carboxylate (0.29 g) and 3-[(6-bromo-2-naphthyl) sulfonyl] propionic acid (0.36 g) In the same manner as the title compound (70 mg, 14%) was obtained as a colorless powder.
NMR (300MHz, CDCl ₃ ) δ: 1.65-1.79 (2H, m), 1.94-2.00 (2H, m), 2.16 (3H, d, J = 0.6), 2.37 (3H, s), 2.59-2.68 (1H , m), 2.90-2.97 (2H, m), 3.13-3.22 (1H, m), 3.54-3.61 (2H, m), 3.95-4.03 (2H, m), 4.71-4.76 (1H, m), 6.50 (1H, s), 7.74 (1H, dd, J = 8.8 and 2.0), 7.85-7.98 (3H, m), 8.14 (1H, d, J = 2.1), 8.48 (1H, s).
Elemental analysis value Calculated as C ₂₃ H ₂₆ BrN ₃ O ₃ S · H ₂ O (%): C, 52.87; H, 5.40; N, 8.04
Found (%): C, 52.66; H, 5.23; N, 8.03

実施例９
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-(2-エチル-1H-イミダゾール-1-イル)ピペリジン
9a) 4-(2-エチル-1H-イミダゾール-1-イル)ピペリジン-1-カルボン酸tert-ブチル
2-エチルイミダゾール(4.13g)から実施例7a)と同様にして題記化合物(1.10g, 11%)を黄色油状物として得た。
NMR (300MHz, CDCl₃) δ: 1.31-1.39 (3H, m), 1.49 (9H, s), 1.70-1.95 (4H, m), 2.67-2.87 (4H, m), 3.96-4.01 (1H, m), 4.29-4.33 (2H, m), 6.86 (1H, d, J = 1.5), 6.97 (1H, d, J = 1.5).
9b) 1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-(2-エチル-1H-イミダゾール-1-イル)ピペリジン
実施例9a)で得た4-(2-エチル-1H-イミダゾール-1-イル)ピペリジン-1-カルボン酸tert-ブチル(0.28g)から実施例１と同様にして題記化合物(0.45g, 98%)を無色粉末として得た。
NMR (300MHz, CDCl₃) δ: 1.36 (3H, t, J = 7.4), 1.65-1.86 (2H, m), 1.96-2.05 (2H, m), 2.61-2.68 (1H, m), 2.71 (2H, q, J = 7.5), 2.91-2.98 (2H, m), 3.16-3.24 (1H, m), 3.54-3.62 (2H, m), 4.01-4.13 (2H, m), 4.73-4.77 (1H, m), 6.81 (1H, d, J = 1.8), 6.98 (1H, d, J = 1.5), 7.60 (1H, dd, J = 8.7 and 1.8), 7.94-7.97 (4H, m), 8.49 (1H, d, J = 0.6).
元素分析値 C₂₃H₂₆ClN₃O₃S・0.5H₂Oとして
計算値（％）：C, 58.90； H, 5.80； N, 8.96
実測値（％）：C, 58.72； H, 6.05； N, 9.08 Example 9
1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4- (2-ethyl-1H-imidazol-1-yl) piperidine
9a) tert-Butyl 4- (2-ethyl-1H-imidazol-1-yl) piperidine-1-carboxylate
The title compound (1.10 g, 11%) was obtained as a yellow oil from 2-ethylimidazole (4.13 g) in the same manner as in Example 7a).
NMR (300MHz, CDCl ₃ ) δ: 1.31-1.39 (3H, m), 1.49 (9H, s), 1.70-1.95 (4H, m), 2.67-2.87 (4H, m), 3.96-4.01 (1H, m ), 4.29-4.33 (2H, m), 6.86 (1H, d, J = 1.5), 6.97 (1H, d, J = 1.5).
9b) 1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- (2-ethyl-1H-imidazol-1-yl) piperidine 4- (2- The title compound (0.45 g, 98%) was obtained as a colorless powder from tert-butyl (ethyl-1H-imidazol-1-yl) piperidine-1-carboxylate (0.28 g) in the same manner as in Example 1.
NMR (300MHz, CDCl ₃ ) δ: 1.36 (3H, t, J = 7.4), 1.65-1.86 (2H, m), 1.96-2.05 (2H, m), 2.61-2.68 (1H, m), 2.71 (2H , q, J = 7.5), 2.91-2.98 (2H, m), 3.16-3.24 (1H, m), 3.54-3.62 (2H, m), 4.01-4.13 (2H, m), 4.73-4.77 (1H, m), 6.81 (1H, d, J = 1.8), 6.98 (1H, d, J = 1.5), 7.60 (1H, dd, J = 8.7 and 1.8), 7.94-7.97 (4H, m), 8.49 (1H , d, J = 0.6).
Elemental analysis value Calculated as C ₂₃ H ₂₆ ClN ₃ O ₃ S · 0.5H ₂ O (%): C, 58.90; H, 5.80; N, 8.96
Found (%): C, 58.72; H, 6.05; N, 9.08

実施例10
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-(2-イソプロピル-1H-イミダゾール-1-イル)ピペリジン
10a) 4-(2-イソプロピル-1H-イミダゾール-1-イル)ピペリジン-1-カルボン酸tert-ブチル
2-イソプロピルイミダゾール(4.73g)から実施例7a)と同様にして題記化合物(0.40g, 4%)を黄色油状物として得た。
NMR (300MHz, CDCl₃) δ: 1.32 (3H, s), 1.36 (3H, s), 1.49 (9H, s), 1.76-1.95 (4H, m), 2.78-2.88 (2H, m), 2.95-3.08 (1H, m), 4.06-4.14 (1H, m), 4.29-4.34 (2H, m), 6.84 (1H, d, J = 1.6), 6.98 (1H, d, J = 1.2).
10b) 1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-(2-イソプロピル-1H-イミダゾール-1-イル)ピペリジン
実施例10a)で得た4-(2-イソプロピル-1H-イミダゾール-1-イル)ピペリジン-1-カルボン酸tert-ブチル(0.29g)から実施例１と同様にして題記化合物(0.36g, 76%)を無色粉末として得た。
NMR (300MHz, CDCl₃) δ: 1.32-1.36 (6H, m), 1.70-1.86 (2H, m), 1.96-2.05 (2H, m), 2.61-2.69 (1H, m), 2.91-3.05 (3H, m), 3.16-3.25 (1H, m), 3.55-3.62 (2H, m), 4.01-4.18 (2H, m), 4.73-4.78 (1H, m), 6.78 (1H, d, J = 1.5), 6.98 (1H, d, J = 1.2), 7.60 (1H, dd, J = 8.9 and 2.0), 7.94-7.97 (4H, m), 8.49 (1H, s).
元素分析値 C₂₄H₂₈ClN₃O₃S・0.5H₂Oとして
計算値（％）：C, 59.68； H, 6.05； N, 8.70
実測値（％）：C, 59.51； H, 6.22； N, 8.53 Example 10
1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- (2-isopropyl-1H-imidazol-1-yl) piperidine
10a) tert-Butyl 4- (2-isopropyl-1H-imidazol-1-yl) piperidine-1-carboxylate
The title compound (0.40 g, 4%) was obtained as a yellow oil from 2-isopropylimidazole (4.73 g) in the same manner as in Example 7a).
NMR (300MHz, CDCl ₃ ) δ: 1.32 (3H, s), 1.36 (3H, s), 1.49 (9H, s), 1.76-1.95 (4H, m), 2.78-2.88 (2H, m), 2.95- 3.08 (1H, m), 4.06-4.14 (1H, m), 4.29-4.34 (2H, m), 6.84 (1H, d, J = 1.6), 6.98 (1H, d, J = 1.2).
10b) 1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- (2-isopropyl-1H-imidazol-1-yl) piperidine 4- (2- The title compound (0.36 g, 76%) was obtained as a colorless powder from tert-butyl (isopropyl-1H-imidazol-1-yl) piperidine-1-carboxylate (0.29 g) in the same manner as in Example 1.
NMR (300MHz, CDCl ₃ ) δ: 1.32-1.36 (6H, m), 1.70-1.86 (2H, m), 1.96-2.05 (2H, m), 2.61-2.69 (1H, m), 2.91-3.05 (3H , m), 3.16-3.25 (1H, m), 3.55-3.62 (2H, m), 4.01-4.18 (2H, m), 4.73-4.78 (1H, m), 6.78 (1H, d, J = 1.5) , 6.98 (1H, d, J = 1.2), 7.60 (1H, dd, J = 8.9 and 2.0), 7.94-7.97 (4H, m), 8.49 (1H, s).
Elemental analysis value Calculated as C ₂₄ H ₂₈ ClN ₃ O ₃ S · 0.5H ₂ O (%): C, 59.68; H, 6.05; N, 8.70
Found (%): C, 59.51; H, 6.22; N, 8.53

実施例11
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-(2-プロピル-1H-イミダゾール-1-イル)ピペリジン
11a) 4-(2-プロピル-1H-イミダゾール-1-イル)ピペリジン-1-カルボン酸tert-ブチル
2-プロピルイミダゾール(4.73g, 43mmol)から実施例7a)と同様にして題記化合物(0.28g, 3%)を黄色油状物として得た。
NMR (300MHz, CDCl₃) δ: 0.98-1.04 (3H, m), 1.49 (9H, s), 1.71-1.94 (6H, m), 2.59-2.69 (2H, m), 2.79-2.87 (2H, m), 3.96-4.04 (1H, m), 4.28-4.33 (2H, m), 6.85 (1H, d, J = 1.2), 6.97 (1H, d, J = 1.5).
11b) 1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-(2-プロピル-1H-イミダゾール-1-イル)ピペリジン
実施例11a)で得た4-(2-プロピル-1H-イミダゾール-1-イル)ピペリジン-1-カルボン酸tert-ブチル(0.28g)から実施例１と同様にして題記化合物(0.30g, 66%)を無色粉末として得た。
NMR (200MHz, CDCl₃) δ: 1.02 (3H, t, J = 7.5), 1.68-2.05 (6H, m), 2.62-2.69 (3H, m), 2.90-2.99 (2H, m), 3.14-3.26 (1H, m), 3.54-3.63 (2H, m), 4.01-4.14 (2H, m), 4.71-4.78 (1H, m), 6.80 (1H, d, J = 1.4), 6.97 (1H, d, J = 1.0), 7.60 (1H, dd, J = 8.8 and 1.8), 7.89-7.98 (4H, m), 8.49 (1H, s).
元素分析値 C₂₄H₂₈ClN₃O₃S・0.5H₂Oとして
計算値（％）：C, 59.68； H, 6.05； N, 8.70
実測値（％）：C, 59.74； H, 6.30； N, 8.62 Example 11
1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4- (2-propyl-1H-imidazol-1-yl) piperidine
11a) tert-Butyl 4- (2-propyl-1H-imidazol-1-yl) piperidine-1-carboxylate
The title compound (0.28 g, 3%) was obtained as a yellow oil from 2-propylimidazole (4.73 g, 43 mmol) in the same manner as in Example 7a).
NMR (300MHz, CDCl ₃ ) δ: 0.98-1.04 (3H, m), 1.49 (9H, s), 1.71-1.94 (6H, m), 2.59-2.69 (2H, m), 2.79-2.87 (2H, m ), 3.96-4.04 (1H, m), 4.28-4.33 (2H, m), 6.85 (1H, d, J = 1.2), 6.97 (1H, d, J = 1.5).
11b) 1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- (2-propyl-1H-imidazol-1-yl) piperidine 4- (2- The title compound (0.30 g, 66%) was obtained as a colorless powder in the same manner as in Example 1 from propyl-lH-imidazol-1-yl) piperidine-1-carboxylate (tert-butyl) (0.28 g).
NMR (200MHz, CDCl ₃ ) δ: 1.02 (3H, t, J = 7.5), 1.68-2.05 (6H, m), 2.62-2.69 (3H, m), 2.90-2.99 (2H, m), 3.14-3.26 (1H, m), 3.54-3.63 (2H, m), 4.01-4.14 (2H, m), 4.71-4.78 (1H, m), 6.80 (1H, d, J = 1.4), 6.97 (1H, d, J = 1.0), 7.60 (1H, dd, J = 8.8 and 1.8), 7.89-7.98 (4H, m), 8.49 (1H, s).
Elemental analysis value Calculated as C ₂₄ H ₂₈ ClN ₃ O ₃ S · 0.5H ₂ O (%): C, 59.68; H, 6.05; N, 8.70
Found (%): C, 59.74; H, 6.30; N, 8.62

実施例12
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-(2-ブチル-1H-イミダゾール-1-イル)ピペリジン
12a) 4-(2-ブチル-1H-イミダゾール-1-イル)ピペリジン-1-カルボン酸tert-ブチル
2-ブチルイミダゾール(6.66g)から実施例7a)と同様にして題記化合物(0.33g, 3%)を黄色油状物として得た。
NMR (300MHz, CDCl₃) δ: 0.98-1.94 (11H, s), 1.49 (9H, s), 2.59-2.69 (2H, m), 2.79-2.87 (2H, m), 3.96-4.04 (1H, m), 4.28-4.33 (2H, m), 6.85 (1H, d, J = 1.2), 6.97 (1H, d, J = 1.5).
12b) 1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-(2-ブチル-1H-イミダゾール-1-イル)ピペリジン
実施例12a)で得た4-(2-ブチル-1H-イミダゾール-1-イル)ピペリジン-1-カルボン酸tert-ブチル(0.31g)から実施例１と同様にして題記化合物(0.41g, 85%)を無色粉末として得た。
NMR (200MHz, CDCl₃) δ: 0.96 (3H, t, J = 7.3), 1.33-1.52 (2H, m), 1.67-2.05 (6H, m), 2.50-2.90 (3H, m), 2.90-2.99 (2H, m), 3.08-3.27 (1H, m), 3.52-3.63 (2H, m), 4.01-4.14 (2H, m), 4.71-4.79 (1H, m), 6.80 (1H, d, J = 1.4), 6.97 (1H, d, J = 1.2), 7.58-7.63 (1H, m), 7.89-7.98 (4H, m), 8.49 (1H, s).
元素分析値 C₂₅H₃₀ClN₃O₃S・0.5H₂Oとして
計算値（％）：C, 60.41； H, 6.29； N, 8.45
実測値（％）：C, 60.33； H, 6.33； N, 8.40 Example 12
1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- (2-butyl-1H-imidazol-1-yl) piperidine
12a) tert-Butyl 4- (2-butyl-1H-imidazol-1-yl) piperidine-1-carboxylate
The title compound (0.33 g, 3%) was obtained as a yellow oil from 2-butylimidazole (6.66 g) in the same manner as in Example 7a).
NMR (300MHz, CDCl ₃ ) δ: 0.98-1.94 (11H, s), 1.49 (9H, s), 2.59-2.69 (2H, m), 2.79-2.87 (2H, m), 3.96-4.04 (1H, m ), 4.28-4.33 (2H, m), 6.85 (1H, d, J = 1.2), 6.97 (1H, d, J = 1.5).
12b) 1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- (2-butyl-1H-imidazol-1-yl) piperidine 4- (2- The title compound (0.41 g, 85%) was obtained as a colorless powder from tert-butyl (butyl-1H-imidazol-1-yl) piperidine-1-carboxylate (0.31 g) in the same manner as in Example 1.
NMR (200MHz, CDCl ₃ ) δ: 0.96 (3H, t, J = 7.3), 1.33-1.52 (2H, m), 1.67-2.05 (6H, m), 2.50-2.90 (3H, m), 2.90-2.99 (2H, m), 3.08-3.27 (1H, m), 3.52-3.63 (2H, m), 4.01-4.14 (2H, m), 4.71-4.79 (1H, m), 6.80 (1H, d, J = 1.4), 6.97 (1H, d, J = 1.2), 7.58-7.63 (1H, m), 7.89-7.98 (4H, m), 8.49 (1H, s).
Elemental analysis value Calculated as C ₂₅ H ₃₀ ClN ₃ O ₃ S · 0.5H ₂ O (%): C, 60.41; H, 6.29; N, 8.45
Found (%): C, 60.33; H, 6.33; N, 8.40

実施例13
[1-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-1H-イミダゾール-2-イル]メタノール
13a) 4-(2-ホルミル-1H-イミダゾール-1-イル)ピペリジン-1-カルボン酸tert-ブチル
2-ホルミルイミダゾール(2.06g)から実施例7a)と同様にして題記化合物(1.88g, 38%)を無色粉末として得た。
NMR (200MHz, CDCl₃+CD₃OD) δ: 1.48 (9H, s), 1.71-1.79 (2H, m), 2.10 (2H, m), 2.84-2.97 (2H, m), 4.26-4.32 (2H, m), 5.10-5.30 (1H, m), 7.32-7.36 (2H, m), 9.82 (1H, d, J = 0.8).
13b) 4-(2-ヒドロキシメチル-1H-イミダゾール-1-イル)ピペリジン-1-カルボン酸tert-ブチル
実施例13a)で得られた4-(2-ホルミル-1H-イミダゾール-1-イル)ピペリジン-1-カルボン酸tert-ブチル(0.48g)をメタノール(20mL)に溶解し、水素化ホウ素ナトリウム(0.14g)を加えて室温で3時間かき混ぜた。反応混合物を減圧濃縮し、残留物に飽和重曹水と酢酸エチルを加えて希釈した。有機層を分取し、飽和重曹水で洗浄し、無水硫酸ナトリウムで乾燥し、減圧濃縮して題記化合物(0.40g, 83%)を無色粉末として得た。
NMR (200MHz, CDCl₃) δ: 1.49 (9H, s), 1.68-1.85 (2H, m), 2.00-2.06 (2H, m), 2.79-2.92 (2H, m), 4.26-4.40 (3H, m), 4.68 (2H, s), 6.91 (2H, s).
13c) [1-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-1H-イミダゾール-2-イル]メタノール
実施例13b)で得た4-(2-ヒドロキシメチル-1H-イミダゾール-1-イル)ピペリジン-1-カルボン酸tert-ブチル(0.38g)から実施例１と同様にして題記化合物(0.26g, 42%)を無色粉末として得た。
NMR (200MHz, CDCl₃+CD₃OD) δ: 1.69-1.83 (2H, m), 2.05-2.18 (2H, m), 2.37-2.58 (2H, m), 2.63-2.75 (1H, m), 2.87-2.99 (2H, m), 3.18-3.30 (1H, m), 3.53-3.64 (2H, m), 3.98-4.05 (1H, m), 4.40-4.52 (1H, m), 4.68-4.76 (1H, m), 6.92 (2H, d, J = 4.8), 7.61 (1H, dd, J = 8.8 and 1.8), 7.90-8.00 (4H, m), 8.50 (1H, s).
元素分析値 C₂₂H₂₄ClN₃O₄S・0.4H₂Oとして
計算値（％）：C, 56.32； H, 5.33； N, 8.96
実測値（％）：C, 56.49； H, 5.08； N, 8.68 Example 13
[1- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -1H-imidazol-2-yl] methanol
13a) tert-Butyl 4- (2-formyl-1H-imidazol-1-yl) piperidine-1-carboxylate
The title compound (1.88 g, 38%) was obtained as a colorless powder from 2-formylimidazole (2.06 g) in the same manner as in Example 7a).
NMR (200MHz, CDCl ₃ + CD ₃ OD) δ: 1.48 (9H, s), 1.71-1.79 (2H, m), 2.10 (2H, m), 2.84-2.97 (2H, m), 4.26-4.32 (2H , m), 5.10-5.30 (1H, m), 7.32-7.36 (2H, m), 9.82 (1H, d, J = 0.8).
13b) 4- (2-hydroxymethyl-1H-imidazol-1-yl) piperidine-1-carboxylate tert-butyl 4- (2-formyl-1H-imidazol-1-yl) obtained in Example 13a) Piperidine-1-carboxylate tert-butyl (0.48 g) was dissolved in methanol (20 mL), sodium borohydride (0.14 g) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with saturated aqueous sodium hydrogen carbonate and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (0.40 g, 83%) as a colorless powder.
NMR (200MHz, CDCl ₃ ) δ: 1.49 (9H, s), 1.68-1.85 (2H, m), 2.00-2.06 (2H, m), 2.79-2.92 (2H, m), 4.26-4.40 (3H, m ), 4.68 (2H, s), 6.91 (2H, s).
13c) [1- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -1H-imidazol-2-yl] methanol 4- (obtained in Example 13b) The title compound (0.26 g, 42%) was obtained as a colorless powder from tert-butyl 2-hydroxymethyl-1H-imidazol-1-yl) piperidine-1-carboxylate (0.38 g) in the same manner as in Example 1.
NMR (200MHz, CDCl ₃ + CD ₃ OD) δ: 1.69-1.83 (2H, m), 2.05-2.18 (2H, m), 2.37-2.58 (2H, m), 2.63-2.75 (1H, m), 2.87 -2.99 (2H, m), 3.18-3.30 (1H, m), 3.53-3.64 (2H, m), 3.98-4.05 (1H, m), 4.40-4.52 (1H, m), 4.68-4.76 (1H, m), 6.92 (2H, d, J = 4.8), 7.61 (1H, dd, J = 8.8 and 1.8), 7.90-8.00 (4H, m), 8.50 (1H, s).
Elemental analysis value Calculated as C ₂₂ H ₂₄ ClN ₃ O ₄ S · 0.4H ₂ O (%): C, 56.32; H, 5.33; N, 8.96
Found (%): C, 56.49; H, 5.08; N, 8.68

実施例14
1-[1-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-1H-イミダゾール-2-イル]エタノール
実施例13a)で得られた4-(2-ホルミル-1H-イミダゾール-1-イル)ピペリジン-1-カルボン酸tert-ブチル(0.48g)をTHF(10mL)に溶解し、0℃に冷却しながらメチルマグネシウムブロミド(3M ジエチルエーテル溶液； 1.0mL)を加えて室温で１時間かき混ぜた。反応混合物に飽和塩化アンモニウム水溶液を加えて希釈した。有機層を分取し、無水硫酸ナトリウムで乾燥し、減圧濃縮して得られた残留物を４N塩化水素酢酸エチル(5mL)に溶解し、室温で3時間かき混ぜた。反応混合物を減圧濃縮し、水分をエタノールと共沸した。残留物をDBU(0.26g)、トリエチルアミン(0.26g)とともにアセトニトリル(15mL)に溶解した。この溶液を3-[(6-クロロ-2-ナフチル)スルホニル]プロピオン酸（0.25g）、HOBt(0.20g)およびWSC(0.24g)のアセトニトリル(15mL)懸濁液に加えて室温で15時間かき混ぜた。反応液を減圧濃縮し、酢酸エチルと炭酸カリウム水溶液で希釈した。有機層を分取し、無水硫酸ナトリウムで乾燥し、減圧濃縮した。残留物を塩基性シリカゲルカラム（酢酸エチル）で精製して題記化合物(50mg, 10%)を淡黄色粉末として得た。
NMR (200MHz, CDCl₃) δ: 1.67-2.20 (7H, m), 2.59-2.72 (1H, m), 2.88-2.99 (2H, m), 3.14-3.27 (1H, m), 3.40-3.70 (2H, m), 3.98-4.07 (1H, m), 4.38-4.60 (1H, m), 4.72-4.78 (1H, m), 4.88-4.98 (1H, m), 6.88 (1H, s), 6.98 (1H, d, J = 0.8), 7.60 (1H, dd, J = 8.8 and 1.8), 7.89-7.98 (4H, m), 8.49 (1H, s).
元素分析値 C₂₃H₂₆ClN₃O₄S・0.5H₂Oとして
計算値（％）：C, 56.96； H, 5.61； N, 8.66
実測値（％）：C, 57.18； H, 5.76； N, 8.47 Example 14
1- [1- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -1H-imidazol-2-yl] ethanol 4-obtained in Example 13a) Dissolve tert-butyl (2-formyl-1H-imidazol-1-yl) piperidine-1-carboxylate (0.48 g) in THF (10 mL) and cool to 0 ° C. with methylmagnesium bromide (3M diethyl ether solution; 1.0 mL) was added and stirred at room temperature for 1 hour. The reaction mixture was diluted with a saturated aqueous ammonium chloride solution. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue obtained was dissolved in 4N hydrogen chloride ethyl acetate (5 mL) and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and water was azeotroped with ethanol. The residue was dissolved in acetonitrile (15 mL) together with DBU (0.26 g) and triethylamine (0.26 g). This solution was added to a suspension of 3-[(6-chloro-2-naphthyl) sulfonyl] propionic acid (0.25 g), HOBt (0.20 g) and WSC (0.24 g) in acetonitrile (15 mL) for 15 hours at room temperature. Stir. The reaction solution was concentrated under reduced pressure and diluted with ethyl acetate and an aqueous potassium carbonate solution. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column (ethyl acetate) to give the title compound (50 mg, 10%) as a pale yellow powder.
NMR (200MHz, CDCl ₃ ) δ: 1.67-2.20 (7H, m), 2.59-2.72 (1H, m), 2.88-2.99 (2H, m), 3.14-3.27 (1H, m), 3.40-3.70 (2H , m), 3.98-4.07 (1H, m), 4.38-4.60 (1H, m), 4.72-4.78 (1H, m), 4.88-4.98 (1H, m), 6.88 (1H, s), 6.98 (1H , d, J = 0.8), 7.60 (1H, dd, J = 8.8 and 1.8), 7.89-7.98 (4H, m), 8.49 (1H, s).
Elemental analysis value Calculated as C ₂₃ H ₂₆ ClN ₃ O ₄ S · 0.5H ₂ O (%): C, 56.96; H, 5.61; N, 8.66
Found (%): C, 57.18; H, 5.76; N, 8.47

実施例15
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-(4,5-ジメチル-1H-イミダゾール-1-イル)ピペリジン
15a) 4-(4,5-ジメチル-1H-イミダゾール-1-イル)ピペリジン-1-カルボン酸tert-ブチル
4,5-ジメチルイミダゾール（特開昭60-56961号公報）(5.00g)から実施例7a)と同様にして題記化合物(0.27g, 3%)を黄色油状物として得た。
NMR (200MHz, CDCl₃) δ: 1.48 (9H, s), 1.74-1.89 (2H, m), 1.96-2.02 (2H, m), 2.14 (3H, s), 2.15 (3H, s), 2.76-2.89 (2H, m), 3.75-3.89 (1H, m), 4.26-4.33 (2H, m), 7.38 (1H, s).
15b) 1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-(4,5-ジメチル-1H-イミダゾール-1-イル)ピペリジン
実施例15a)で得た4-(4,5-ジメチル-1H-イミダゾール-1-イル)ピペリジン-1-カルボン酸tert-ブチル(0.27g)から実施例１と同様にして題記化合物(0.14g, 30%)を無色粉末として得た。
NMR (200MHz, CDCl₃) δ: 1.67-1.85 (2H, m), 2.00-2.19 (2H, m), 2.15 (6H, s), 2.58-2.70 (1H, m), 2.90-2.98 (2H, m), 3.13-3.25 (1H, m), 3.53-3.61 (2H, m), 3.86-4.07 (2H, m), 4.71-4.76 (1H, m), 7.35 (1H, s), 7.61 (1H, dd, J = 1.8 and 8.8), 7.93-7.98 (4H, m), 8.49 (1H, s).
元素分析値 C₂₃H₂₆ClN₃O₃S・H₂Oとして
計算値（％）：C, 57.79； H, 5.90； N, 8.79
実測値（％）：C, 57.95； H, 5.77； N, 8.72 Example 15
1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- (4,5-dimethyl-1H-imidazol-1-yl) piperidine
15a) tert-Butyl 4- (4,5-dimethyl-1H-imidazol-1-yl) piperidine-1-carboxylate
The title compound (0.27 g, 3%) was obtained as a yellow oil from 4,5-dimethylimidazole (JP-A-60-56961) (5.00 g) in the same manner as in Example 7a).
NMR (200MHz, CDCl ₃ ) δ: 1.48 (9H, s), 1.74-1.89 (2H, m), 1.96-2.02 (2H, m), 2.14 (3H, s), 2.15 (3H, s), 2.76- 2.89 (2H, m), 3.75-3.89 (1H, m), 4.26-4.33 (2H, m), 7.38 (1H, s).
15b) 1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- (4,5-dimethyl-1H-imidazol-1-yl) piperidine 4- (4) obtained in Example 15a) The title compound (0.14 g, 30%) was obtained as a colorless powder from tert-butyl 4,5-dimethyl-1H-imidazol-1-yl) piperidine-1-carboxylate (0.27 g) in the same manner as in Example 1. .
NMR (200MHz, CDCl ₃ ) δ: 1.67-1.85 (2H, m), 2.00-2.19 (2H, m), 2.15 (6H, s), 2.58-2.70 (1H, m), 2.90-2.98 (2H, m ), 3.13-3.25 (1H, m), 3.53-3.61 (2H, m), 3.86-4.07 (2H, m), 4.71-4.76 (1H, m), 7.35 (1H, s), 7.61 (1H, dd , J = 1.8 and 8.8), 7.93-7.98 (4H, m), 8.49 (1H, s).
Elemental analysis value Calculated as C ₂₃ H ₂₆ ClN ₃ O ₃ S · H ₂ O (%): C, 57.79; H, 5.90; N, 8.79
Found (%): C, 57.95; H, 5.77; N, 8.72

実施例16
1-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-2-メチル-1H-ベンゾイミダゾール
16a) 4-(2-メチル-1H-ベンゾイミダゾール-1-イル)ピペリジン-1-カルボン酸tert-ブチル
2-メチルベンズイミダゾール(5.20g)のDMF溶液(80mL)に水素化ナトリウム(1.50g)を0℃で加えて0℃で30分間かき混ぜた。4-[(メチルスルホニル)オキシ]ピペリジン-1-カルボン酸tert-ブチル(10g)を加えて100℃で48時間かき混ぜた。反応混合物を減圧濃縮し、残留物を炭酸水素ナトリウム水溶液と酢酸エチルで希釈した。有機層を分取し、飽和炭酸水素ナトリウムで洗浄し、無水硫酸ナトリウムで乾燥し、溶媒を減圧濃縮した。残留物をシリカゲルカラム（酢酸エチル/ヘキサン＝1/1から3/1）で精製して題記化合物(0.77g, 7%)を無色固体として得た。
NMR (300MHz, CDCl₃) δ: 1.53 (9H, s), 1.87-1.91 (2H, m), 2.37-2.50 (2H, m), 2.65 (3H, s), 2.84-2.94 (2H, m), 4.27-4.40 (3H, m), 7.18-7.22 (2H, m), 7.42-7.45 (1H, m), 7.68-7.71 (1H, m).
16b) 1-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-2-メチル-1H-ベンゾイミダゾール
実施例16a)で得た4-(2-メチル-1H-ベンゾイミダゾール-1-イル)ピペリジン-1-カルボン酸tert-ブチル(0.18g, 0.6mmol)から実施例１と同様にして題記化合物(0.24g, 48%)を無色粉末として得た。
NMR (200MHz, CDCl₃) δ: 1.90-2.05 (2H, m), 2.38-2.52 (2H, m), 2.65 (3H, s), 2.65-2.77 (1H, m), 2.95-3.06 (2H, m), 3.20-3.32 (1H, m), 3.57-3.67 (2H, m), 4.07-4.18 (1H, m), 4.34-4.46 (1H, m), 4.83-4.89 (1H, m), 7.17-7.23 (2H, m), 7.39-7.43 (1H, m), 7.61 (1H, dd, J = 8.9 and 1.9), 7.67-7.71 (1H, m), 7.95-7.99 (4H, m), 8.52 (1H, s).
元素分析値 C₂₆H₂₆ClN₃O₃S・H₂Oとして
計算値（％）：C, 60.75； H, 5.49； N, 8.17
実測値（％）：C, 60.88； H, 5.64； N, 7.99 Example 16
1- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -2-methyl-1H-benzimidazole
16a) tert-Butyl 4- (2-methyl-1H-benzimidazol-1-yl) piperidine-1-carboxylate
Sodium hydride (1.50 g) was added to a DMF solution (80 mL) of 2-methylbenzimidazole (5.20 g) at 0 ° C., and the mixture was stirred at 0 ° C. for 30 minutes. 4-[(Methylsulfonyl) oxy] piperidine-1-carboxylate tert-butyl (10 g) was added, and the mixture was stirred at 100 ° C. for 48 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was separated, washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column (ethyl acetate / hexane = 1/1 to 3/1) to give the title compound (0.77 g, 7%) as a colorless solid.
NMR (300MHz, CDCl ₃ ) δ: 1.53 (9H, s), 1.87-1.91 (2H, m), 2.37-2.50 (2H, m), 2.65 (3H, s), 2.84-2.94 (2H, m), 4.27-4.40 (3H, m), 7.18-7.22 (2H, m), 7.42-7.45 (1H, m), 7.68-7.71 (1H, m).
16b) 1- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -2-methyl-1H-benzimidazole 4- (2- The title compound (0.24 g, 48%) was obtained as a colorless powder from tert-butyl methyl-1H-benzoimidazol-1-yl) piperidine-1-carboxylate (0.18 g, 0.6 mmol) in the same manner as in Example 1. .
NMR (200MHz, CDCl ₃ ) δ: 1.90-2.05 (2H, m), 2.38-2.52 (2H, m), 2.65 (3H, s), 2.65-2.77 (1H, m), 2.95-3.06 (2H, m ), 3.20-3.32 (1H, m), 3.57-3.67 (2H, m), 4.07-4.18 (1H, m), 4.34-4.46 (1H, m), 4.83-4.89 (1H, m), 7.17-7.23 (2H, m), 7.39-7.43 (1H, m), 7.61 (1H, dd, J = 8.9 and 1.9), 7.67-7.71 (1H, m), 7.95-7.99 (4H, m), 8.52 (1H, s).
Elemental analysis value Calculated as C ₂₆ H ₂₆ ClN ₃ O ₃ S · H ₂ O (%): C, 60.75; H, 5.49; N, 8.17
Found (%): C, 60.88; H, 5.64; N, 7.99

実施例17
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-(1H-イミダゾール-4-イル)-4-ピペリジノール
4-ヒドロキシ-4-(1H-イミダゾール-4-イル)ピペリジン-1-カルボン酸tert-ブチル (Tetrahedron, 51, 13447 (1995))(0.27g)から実施例１と同様にして題記化合物(0.08g, 18%)を無色粉末として得た。
NMR (200MHz, CDCl₃) δ: 1.81-1.96 (4H, m), 2.86-2.93 (3H, m), 3.12-3.26 (2H, m), 3.53-3.63 (4H, m), 4.21-4.28 (1H, m), 6.87 (1H, d, J = 1.2), 7.56-7.61 (2H, m), 7.88-7.97 (4H, m), 8.48 (1H, s).
元素分析値 C₂₁H₂₂ClN₃O₄S・0.5H₂Oとして
計算値（％）：C, 55.20； H, 5.07； N, 9.20
実測値（％）：C, 55.45； H, 5.11； N, 9.30 Example 17
1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- (1H-imidazol-4-yl) -4-piperidinol
4-hydroxy-4- (1H-imidazol-4-yl) piperidine-1-carboxylate tert-butyl (Tetrahedron, 51, 13447 (1995)) (0.27 g) was used in the same manner as in Example 1 to obtain the title compound (0.08 g, 18%) was obtained as a colorless powder.
NMR (200MHz, CDCl ₃ ) δ: 1.81-1.96 (4H, m), 2.86-2.93 (3H, m), 3.12-3.26 (2H, m), 3.53-3.63 (4H, m), 4.21-4.28 (1H , m), 6.87 (1H, d, J = 1.2), 7.56-7.61 (2H, m), 7.88-7.97 (4H, m), 8.48 (1H, s).
Elemental analysis value Calculated as C ₂₁ H ₂₂ ClN ₃ O ₄ S · 0.5H ₂ O (%): C, 55.20; H, 5.07; N, 9.20
Found (%): C, 55.45; H, 5.11; N, 9.30

実施例18
1-{3-[(6-ブロモ-2-ナフチル)スルホニル]プロパノイル}-4-(1H-イミダゾール-4-イル)-4-ピペリジノール
4-ヒドロキシ-4-(1H-イミダゾール-4-イル)ピペリジン-1-カルボン酸tert-ブチル(0.27g)および3-[(6-ブロモ-2-ナフチル)スルホニル]プロピオン酸(0.34g)から実施例１と同様にして題記化合物(0.14g, 28%)を無色粉末として得た。
NMR (200MHz, CDCl₃) δ: 1.81-1.95 (4H, m), 2.86-2.93 (3H, m), 3.10-3.23 (2H, m), 3.47-3.63 (4H, m), 4.22-4.29 (1H, m), 6.87 (1H, d, J = 1.2), 7.61 (1H, d, J = 1.0), 7.71 (1H, dd, J = 2.0 and 8.6), 7.83-7.93 (3H, m), 8.12 (1H, s), 8.47 (1H, s).
元素分析値 C₂₁H₂₂BrN₃O₄S・0.5H₂Oとして
計算値（％）：C, 50.30； H, 4.62； N, 8.38
実測値（％）：C, 50.46； H, 4.86； N, 8.54 Example 18
1- {3-[(6-Bromo-2-naphthyl) sulfonyl] propanoyl} -4- (1H-imidazol-4-yl) -4-piperidinol
From tert-butyl 4-hydroxy-4- (1H-imidazol-4-yl) piperidine-1-carboxylate (0.27 g) and 3-[(6-bromo-2-naphthyl) sulfonyl] propionic acid (0.34 g) The title compound (0.14 g, 28%) was obtained as a colorless powder in the same manner as in Example 1.
NMR (200MHz, CDCl ₃ ) δ: 1.81-1.95 (4H, m), 2.86-2.93 (3H, m), 3.10-3.23 (2H, m), 3.47-3.63 (4H, m), 4.22-4.29 (1H , m), 6.87 (1H, d, J = 1.2), 7.61 (1H, d, J = 1.0), 7.71 (1H, dd, J = 2.0 and 8.6), 7.83-7.93 (3H, m), 8.12 ( 1H, s), 8.47 (1H, s).
Elemental analysis value Calculated as C ₂₁ H ₂₂ BrN ₃ O ₄ S · 0.5H ₂ O (%): C, 50.30; H, 4.62; N, 8.38
Found (%): C, 50.46; H, 4.86; N, 8.54

実施例19
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-(1H-イミダゾール-4-イル)-1,2,3,6-テトラヒドロピリジン
3-[(6-クロロ-2-ナフチル)スルホニル]プロピオン酸（0.15g）、HOBt(0.12g)およびWSC(0.14g)のアセトニトリル(10mL)懸濁液に4-(1H-イミダゾール-4-イル)-1,2,3,6-テトラヒドロピリジン2塩酸塩 (Tetrahedron, 51, 13447 (1995)) (0.13g) 、DBU(0.15g)およびトリエチルアミン(0.15g)のアセトニトリル(5mL)を加えて室温で15時間かき混ぜた。反応液を減圧濃縮し、酢酸エチルと炭酸カリウム水溶液で希釈した。有機層を分取し、無水硫酸ナトリウムで乾燥し、減圧濃縮した。残留物を塩基性シリカゲルカラム（酢酸エチルから酢酸エチル/メタノール=20/1）で精製して題記化合物(0.11g, 49%)を無色粉末として得た。
NMR (300MHz, CDCl₃) δ: 2.34 (1H, m), 2.53 (1H, m), 2.87 (1H, t, J = 7.7), 2.94 (1H, t, J = 7.8), 3.58-3.71 (4H, m), 4.11-4.13 (2H, m), 6.24 (1H, d, J = 16.5), 6.96 (1H, d, J = 6.9), 7.54-7.58 (1H, m), 7.63 (1H, s), 7.91-7.94 (4H, m), 8.47 (1H, s).
元素分析値 C₂₁H₂₀ClN₃O₃S・0.6H₂Oとして
計算値（％）：C, 57.23； H, 4.85； N, 9.53
実測値（％）：C, 57.04； H, 4.77； N, 9.35 Example 19
1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- (1H-imidazol-4-yl) -1,2,3,6-tetrahydropyridine
3-((6-Chloro-2-naphthyl) sulfonyl] propionic acid (0.15 g), HOBt (0.12 g) and WSC (0.14 g) in a suspension of acetonitrile (10 mL) in 4- (1H-imidazole-4- Yl) -1,2,3,6-tetrahydropyridine dihydrochloride (Tetrahedron, 51, 13447 (1995)) (0.13 g), DBU (0.15 g) and triethylamine (0.15 g) in acetonitrile (5 mL) were added. Stir at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure and diluted with ethyl acetate and an aqueous potassium carbonate solution. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column (ethyl acetate to ethyl acetate / methanol = 20/1) to give the title compound (0.11 g, 49%) as a colorless powder.
NMR (300MHz, CDCl ₃ ) δ: 2.34 (1H, m), 2.53 (1H, m), 2.87 (1H, t, J = 7.7), 2.94 (1H, t, J = 7.8), 3.58-3.71 (4H , m), 4.11-4.13 (2H, m), 6.24 (1H, d, J = 16.5), 6.96 (1H, d, J = 6.9), 7.54-7.58 (1H, m), 7.63 (1H, s) , 7.91-7.94 (4H, m), 8.47 (1H, s).
Elemental analysis value Calculated as C ₂₁ H ₂₀ ClN ₃ O ₃ S · 0.6H ₂ O (%): C, 57.23; H, 4.85; N, 9.53
Found (%): C, 57.04; H, 4.77; N, 9.35

実施例20
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-(1H-イミダゾール-4-イル)ピペリジン
4-(1H-イミダゾール-4-イル)ピペリジン2塩酸塩 (Tetrahedron, 51, 13447 (1995)) (0.46g)から実施例１と同様にして題記化合物(0.43g, 50%)を無色粉末として得た。
NMR (300MHz, CDCl₃+CD₃OD) δ: 1.40-1.60 (2H, m), 1.95-2.11 (2H, m), 2.66-2.91 (5H, m), 3.13-3.20 (1H, m), 3.54-3.61 (2H, m), 3.86-3.90 (1H, m), 4.47-4.51 (1H, m), 6.70 (1H, s), 7.53 (1H, d, J = 1.2), 7.59 (1H, dd, J = 8.4 and 2.4), 7.93-7.98 (4H, m), 8.48 (1H, s).
元素分析値 C₂₁H₂₂ClN₃O₃S・0.5H₂Oとして
計算値（％）：C, 57.20； H, 5.26； N, 9.53
実測値（％）：C, 57.48； H, 5.05； N, 9.44 Example 20
1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- (1H-imidazol-4-yl) piperidine
4- (1H-imidazol-4-yl) piperidine dihydrochloride (Tetrahedron, 51, 13447 (1995)) (0.46 g) was used in the same manner as in Example 1 to give the title compound (0.43 g, 50%) as a colorless powder. Obtained.
NMR (300MHz, CDCl ₃ + CD ₃ OD) δ: 1.40-1.60 (2H, m), 1.95-2.11 (2H, m), 2.66-2.91 (5H, m), 3.13-3.20 (1H, m), 3.54 -3.61 (2H, m), 3.86-3.90 (1H, m), 4.47-4.51 (1H, m), 6.70 (1H, s), 7.53 (1H, d, J = 1.2), 7.59 (1H, dd, J = 8.4 and 2.4), 7.93-7.98 (4H, m), 8.48 (1H, s).
Elemental analysis value Calculated as C ₂₁ H ₂₂ ClN ₃ O ₃ S · 0.5H ₂ O (%): C, 57.20; H, 5.26; N, 9.53
Found (%): C, 57.48; H, 5.05; N, 9.44

実施例21
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-(1-メチル-1H-イミダゾール-5-イル)ピペリジン
21a) 1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-(1-トリチル-1H-イミダゾール-4-イル)ピペリジン
実施例20で得られた1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-(1H-イミダゾール-4-イル)ピペリジン(0.35g)およびトリエチルアミン(0.10g)をDMF(10mL)に溶解し、トリフェニルクロロメタン(0.25g)を0℃で加えて0℃で1時間、室温で15時間かき混ぜた。反応混合物を減圧濃縮し、残留物を飽和重曹水と酢酸エチルで希釈した。有機層を分取し、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、減圧濃縮した。残留物を塩基性シリカゲルカラム（酢酸エチル）で精製して題記化合物(0.54g, 定量的)を無色粉末として得た。
NMR (200MHz, CDCl₃) δ: 1.40-1.50 (2H, m), 1.92-2.10 (2H, m), 2.58-2.87 (4H, m), 3.04-3.17 (1H, m), 3.51-3.59 (2H, m), 3.78-3.84 (1H, m), 4.41-4.47 (1H, m), 6.49 (1H, s), 7.09-7.35 (16H, m), 7.57 (1H, dd, J = 8.8 and 1.8), 7.92-8.02 (4H, m), 8.46 (1H, s).
21b) 1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-(1-メチル-1H-イミダゾール-5-イル)ピペリジン
実施例21a)で得られた1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-(1-トリチル-1H-イミダゾール-4-イル)ピペリジン (0.54g)およびヨウ化メチル(0.10mL)をDMF(5mL)に溶解し、室温で15時間かき混ぜた。反応混合物を減圧濃縮し、残留物を酢酸(5mL)、水(5mL)およびメタノール(2mL)に溶解し、95℃で2時間かき混ぜた。反応混合物を減圧濃縮し、残留物に飽和重曹水を加えて塩基性にした後、酢酸エチルを加えた。有機層を分取し、飽和重曹水で洗浄し、無水硫酸ナトリウムで乾燥し、減圧濃縮した。残留物を塩基性シリカゲルカラム（酢酸エチルから酢酸エチル/メタノール=10/1）で精製して題記化合物(0.27g, 76%)を無色粉末として得た。
NMR (200MHz, CDCl₃) δ: 1.43-1.70 (2H, m), 1.88-2.04 (2H, m), 2.60-2.78 (2H, m), 2.87-2.95 (2H, m), 3.09-3.22 (1H, m), 3.53-3.61 (2H, m), 3.60 (3H, s), 3.91-3.98 (1H, m), 4.55-4.62 (1H, m), 6.76 (1H, s), 7.38 (1H, s), 7.59 (1H, dd, J = 8.8 and 1.8), 7.93-7.97 (4H, m), 8.48 (1H, s).
元素分析値 C₂₂H₂₄ClN₃O₃S・0.5H₂Oとして
計算値（％）：C, 58.08； H, 5.54； N, 9.24
実測値（％）：C, 57.79； H, 5.74； N, 9.26 Example 21
1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- (1-methyl-1H-imidazol-5-yl) piperidine
21a) 1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- (1-trityl-1H-imidazol-4-yl) piperidine 1- {3- [(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- (1H-imidazol-4-yl) piperidine (0.35 g) and triethylamine (0.10 g) were dissolved in DMF (10 mL) to obtain triphenylchloromethane. (0.25 g) was added at 0 ° C., and the mixture was stirred at 0 ° C. for 1 hour and at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with saturated aqueous sodium hydrogen carbonate and ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column (ethyl acetate) to give the title compound (0.54 g, quantitative) as a colorless powder.
NMR (200MHz, CDCl ₃ ) δ: 1.40-1.50 (2H, m), 1.92-2.10 (2H, m), 2.58-2.87 (4H, m), 3.04-3.17 (1H, m), 3.51-3.59 (2H , m), 3.78-3.84 (1H, m), 4.41-4.47 (1H, m), 6.49 (1H, s), 7.09-7.35 (16H, m), 7.57 (1H, dd, J = 8.8 and 1.8) , 7.92-8.02 (4H, m), 8.46 (1H, s).
21b) 1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- (1-methyl-1H-imidazol-5-yl) piperidine 1- {3 obtained in Example 21a) -[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- (1-trityl-1H-imidazol-4-yl) piperidine (0.54 g) and methyl iodide (0.10 mL) in DMF (5 mL) Dissolved and stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in acetic acid (5 mL), water (5 mL) and methanol (2 mL), and the mixture was stirred at 95 ° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, and saturated aqueous sodium hydrogen carbonate was added to the residue to make it basic, and then ethyl acetate was added. The organic layer was separated, washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column (ethyl acetate to ethyl acetate / methanol = 10/1) to give the title compound (0.27 g, 76%) as a colorless powder.
NMR (200MHz, CDCl ₃ ) δ: 1.43-1.70 (2H, m), 1.88-2.04 (2H, m), 2.60-2.78 (2H, m), 2.87-2.95 (2H, m), 3.09-3.22 (1H , m), 3.53-3.61 (2H, m), 3.60 (3H, s), 3.91-3.98 (1H, m), 4.55-4.62 (1H, m), 6.76 (1H, s), 7.38 (1H, s ), 7.59 (1H, dd, J = 8.8 and 1.8), 7.93-7.97 (4H, m), 8.48 (1H, s).
Elemental analysis value Calculated as C ₂₂ H ₂₄ ClN ₃ O ₃ S · 0.5H ₂ O (%): C, 58.08; H, 5.54; N, 9.24
Found (%): C, 57.79; H, 5.74; N, 9.26

実施例22
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-(2-メチル-1H-イミダゾール-4-イル)ピペリジン
4-(2-メチル-1H-イミダゾール-4-イル)ピペリジン2塩酸塩（Farmaco, 47, 1343 (1992)）(1.00g)から実施例19と同様にして題記化合物(1.70g, 91%)を無色粉末として得た。
NMR (200MHz, CDCl₃) δ: 1.41-1.60 (2H, m), 1.93-2.10 (2H, m), 2.39 (3H, s), 2.59-2.71 (2H, m), 2.83-2.91 (2H, m), 3.07-3.21 (1H, m), 3.53-3.60 (2H, m), 3.83-3.90 (1H, m), 4.47-4.54 (1H, m), 6.56 (1H, s), 7.58 (1H, dd, J = 9.0 and 2.0), 7.88-7.97 (4H, m), 8.48 (1H, br).
元素分析値 C₂₂H₂₄ClN₃O₃S・0.2H₂Oとして
計算値（％）：C, 58.78； H, 5.47； N, 9.35
実測値（％）：C, 58.68； H, 5.25； N, 9.29 Example 22
1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- (2-methyl-1H-imidazol-4-yl) piperidine
4- (2-Methyl-1H-imidazol-4-yl) piperidine dihydrochloride (Farmaco, 47, 1343 (1992)) (1.00 g) was used in the same manner as in Example 19 to give the title compound (1.70 g, 91%) Was obtained as a colorless powder.
NMR (200MHz, CDCl ₃ ) δ: 1.41-1.60 (2H, m), 1.93-2.10 (2H, m), 2.39 (3H, s), 2.59-2.71 (2H, m), 2.83-2.91 (2H, m ), 3.07-3.21 (1H, m), 3.53-3.60 (2H, m), 3.83-3.90 (1H, m), 4.47-4.54 (1H, m), 6.56 (1H, s), 7.58 (1H, dd , J = 9.0 and 2.0), 7.88-7.97 (4H, m), 8.48 (1H, br).
Elemental analysis value Calculated as C ₂₂ H ₂₄ ClN ₃ O ₃ S · 0.2H ₂ O (%): C, 58.78; H, 5.47; N, 9.35
Found (%): C, 58.68; H, 5.25; N, 9.29

実施例23
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-(2-メチル-1-トリチル-1H-イミダゾール-4-イル)ピペリジン
実施例22で得られた1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-(2-メチル-1H-イミダゾール-5-イル)ピペリジン(1.30g) から実施例21a)と同様にして題記化合物(1.20g, 60%)を無色粉末として得た。
NMR (300MHz, CDCl₃) δ: 1.33-1.59 (2H, m), 1.90-2.06 (2H, m), 2.57-2.74 (2H, m), 2.82-2.89 (2H, m), 3.05-3.13 (1H, m), 3.52-3.57 (2H, m), 3.80-3.84 (1H, m), 4.45-4.49 (1H, m), 6.34 (1H, s), 7.09-7.12 (5H, m), 7.30-7.35 (10H, m), 7.58 (1H, dd, J = 8.7 and 1.8), 7.91-7.96 (4H, m), 8.47 (1H, s). Example 23
1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4- (2-methyl-1-trityl-1H-imidazol-4-yl) piperidine 1- {obtained in Example 22 3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- (2-methyl-1H-imidazol-5-yl) piperidine (1.30 g) to the title compound (1.20) in the same manner as in Example 21a) g, 60%) was obtained as a colorless powder.
NMR (300MHz, CDCl ₃ ) δ: 1.33-1.59 (2H, m), 1.90-2.06 (2H, m), 2.57-2.74 (2H, m), 2.82-2.89 (2H, m), 3.05-3.13 (1H , m), 3.52-3.57 (2H, m), 3.80-3.84 (1H, m), 4.45-4.49 (1H, m), 6.34 (1H, s), 7.09-7.12 (5H, m), 7.30-7.35 (10H, m), 7.58 (1H, dd, J = 8.7 and 1.8), 7.91-7.96 (4H, m), 8.47 (1H, s).

実施例24
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-(1,2-ジメチル-1H-イミダゾール-5-イル)ピペリジン
実施例23で得られた1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-(2-メチル-1-トリチル-1H-イミダゾール-4-イル)ピペリジン(0.28g)から実施例21b)と同様にして題記化合物(0.09g, 48%)を無色粉末として得た。
NMR (200MHz, CDCl₃) δ: 1.40-1.56 (2H, m), 1.87-2.00 (2H, m), 2.36 (3H, s), 2.60-2.71 (2H, m), 2.87-2.95 (2H, m), 3.09-3.21 (1H, m), 3.45 (3H, s), 3.53-3.61 (2H, m), 3.90-3.96 (1H, m), 4.54-4.60 (1H, m), 6.60 (1H, s), 7.60 (1H, dd, J = 8.8 and 1.8), 7.93-7.97 (4H, m), 8.49 (1H, s).
元素分析値 C₂₃H₂₆ClN₃O₃S・H₂Oとして
計算値（％）：C, 57.79； H, 5.90； N, 8.79
実測値（％）：C, 57.75； H, 5.87； N, 8.50 Example 24
1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- (1,2-dimethyl-1H-imidazol-5-yl) piperidine 1- {3- obtained in Example 23 [(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- (2-methyl-1-trityl-1H-imidazol-4-yl) piperidine (0.28 g) in the same manner as Example 21b) (0.09 g, 48%) was obtained as a colorless powder.
NMR (200MHz, CDCl ₃ ) δ: 1.40-1.56 (2H, m), 1.87-2.00 (2H, m), 2.36 (3H, s), 2.60-2.71 (2H, m), 2.87-2.95 (2H, m ), 3.09-3.21 (1H, m), 3.45 (3H, s), 3.53-3.61 (2H, m), 3.90-3.96 (1H, m), 4.54-4.60 (1H, m), 6.60 (1H, s ), 7.60 (1H, dd, J = 8.8 and 1.8), 7.93-7.97 (4H, m), 8.49 (1H, s).
Elemental analysis value Calculated as C ₂₃ H ₂₆ ClN ₃ O ₃ S · H ₂ O (%): C, 57.79; H, 5.90; N, 8.79
Found (%): C, 57.75; H, 5.87; N, 8.50

実施例25
2-[5-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-2-メチル-1H-イミダゾール-1-イル]アセトアミド
実施例23で得られた1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-(2-メチル-1-トリチル-1H-イミダゾール-4-イル)ピペリジン(0.69g)とヨードアセトアミド(0.28g)から実施例21b)と同様にして題記化合物(0.10g, 20%)を無色粉末として得た。
NMR (300MHz, CDCl₃) δ: 1.38-1.58 (2H, m), 1.94-2.10 (2H, m), 2.35 (3H, s), 2.60-2.77 (2H, m), 2.85-2.91 (2H, m), 3.08-3.18 (1H, m), 3.54-3.59 (2H, m), 3.86-3.90 (1H, m), 4.50 (2H, s), 4.50-4.56 (1H, m), 5.37 (1H, br), 5.55 (1H, br), 6.54 (1H, s), 7.59 (1H, dd, J = 9.0 and 2.1), 7.90-7.97 (4H, m), 8.48 (1H, d, J = 0.9).
元素分析値 C₂₄H₂₇ClN₄O₄S・0.8H₂Oとして
計算値（％）：C, 55.71； H, 5.57； N, 10.83
実測値（％）：C, 55.87； H, 5.57； N, 10.90 Example 25
2- [5- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -2-methyl-1H-imidazol-1-yl] acetamide obtained in Example 23 1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4- (2-methyl-1-trityl-1H-imidazol-4-yl) piperidine (0.69 g) and iodoacetamide (0.28) The title compound (0.10 g, 20%) was obtained as a colorless powder from g) in the same manner as in Example 21b).
NMR (300MHz, CDCl ₃ ) δ: 1.38-1.58 (2H, m), 1.94-2.10 (2H, m), 2.35 (3H, s), 2.60-2.77 (2H, m), 2.85-2.91 (2H, m ), 3.08-3.18 (1H, m), 3.54-3.59 (2H, m), 3.86-3.90 (1H, m), 4.50 (2H, s), 4.50-4.56 (1H, m), 5.37 (1H, br ), 5.55 (1H, br), 6.54 (1H, s), 7.59 (1H, dd, J = 9.0 and 2.1), 7.90-7.97 (4H, m), 8.48 (1H, d, J = 0.9).
Elemental analysis _{_{_{_{C 24 H 27 ClN 4 O 4}}}} S · 0.8H 2 O Calculated (%): C, 55.71; H, 5.57; N, 10.83
Found (%): C, 55.87; H, 5.57; N, 10.90

実施例26
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-(2-エチル-1H-イミダゾール-4-イル)ピペリジン
26a) 4-(2-エチル-1H-イミダゾール-4-イル)ピリジン
2,2-ジエトキシ-2-(4-ピリジニル)エチルアミン (Org. Synth., 64, 19 (1985)) (1.24g)およびプロパンイミド酸エチル(1.38g)をエタノール(30mL)に溶解し、24時間加熱還流した。反応混合物を減圧濃縮し、残留物に炭酸カリウム水溶液を加えて塩基性にした後、酢酸エチルを加えた。有機層を分取し、無水硫酸ナトリウムで乾燥し、減圧濃縮した。残留物を塩基性シリカゲルカラム（酢酸エチルから酢酸エチル/メタノール=10/1）で精製して題記化合物(0.65g, 38%)を黄色固体として得た。
NMR (300MHz, CDCl₃) δ: 1.36 (3H, t, J = 7.7), 2.83 (2H, q, J = 7.7), 7.42 (1H, s), 7.63 (2H, d, J = 5.1), 8.54 (2H, dd, J = 4.7 and 1.7), 10.50 (1H, br).
26b) 4-(2-エチル-1H-イミダゾール-4-イル)ピペリジン2塩酸塩
実施例26a)で得られた4-(2-エチル-1H-イミダゾール-4-イル)ピリジン(0.60g, 3.2mmol)と5％ロジウム炭素(50％含水、0.10g)を１N塩酸(40mL)に加えて5気圧の水素雰囲気下室温で6時間かき混ぜた。反応混合物をろ過し、ろ液を減圧濃縮して題記化合物(0.70g, 81%)を無色粉末として得た。
NMR (200MHz, DMSO-d₆) δ: 1.29 (3H, t, J = 7.6), 1.69-1.86 (2H, m), 2.14-2.20 (2H, m), 2.90 (2H, q, J = 7.6), 2.90-3.55 (5H, m), 7.37 (1H, d, J = 0.8), 9.06 (2H, br).
26c) 1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-(2-エチル-1H-イミダゾール-4-イル)ピペリジン
実施例26b)で得られた4-(2-エチル-1H-イミダゾール-4-イル)ピペリジン2塩酸塩(0.65g)から実施例19と同様にして題記化合物(0.30g, 25%)を無色粉末として得た。
NMR (300MHz, CDCl₃) δ: 1.30 (3H, t, J = 7.8), 1.40-1.55 (2H, m), 1.95-2.10 (2H, m), 2.61-2.70 (2H, m), 2.73 (2H, q, J = 7.8), 2.85-2.90 (2H, m), 3.08-3.18 (1H, m), 3.54-3.60 (2H, m), 3.84-3.88 (1H, m), 4.49-4.53 (1H, m), 6.58 (1H, s), 7.58 (1H, dd, J = 8.7 and 1.8), 7.92-7.96 (4H, m), 8.48 (1H, s), 8.62 (1H, br).
元素分析値 C₂₃H₂₆ClN₃O₃S・0.2H₂Oとして
計算値（％）：C, 59.59； H, 5.74； N, 9.06
実測値（％）：C, 59.50； H, 5.50； N, 8.98 Example 26
1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4- (2-ethyl-1H-imidazol-4-yl) piperidine
26a) 4- (2-Ethyl-1H-imidazol-4-yl) pyridine
2,2-diethoxy-2- (4-pyridinyl) ethylamine (Org. Synth., 64, 19 (1985)) (1.24 g) and ethyl propanoimidate (1.38 g) were dissolved in ethanol (30 mL) Heated to reflux for hours. The reaction mixture was concentrated under reduced pressure, and an aqueous potassium carbonate solution was added to the residue to make it basic, and then ethyl acetate was added. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column (ethyl acetate to ethyl acetate / methanol = 10/1) to give the title compound (0.65 g, 38%) as a yellow solid.
NMR (300MHz, CDCl ₃ ) δ: 1.36 (3H, t, J = 7.7), 2.83 (2H, q, J = 7.7), 7.42 (1H, s), 7.63 (2H, d, J = 5.1), 8.54 (2H, dd, J = 4.7 and 1.7), 10.50 (1H, br).
26b) 4- (2-Ethyl-1H-imidazol-4-yl) piperidine dihydrochloride 4- (2-ethyl-1H-imidazol-4-yl) pyridine (0.60 g, 3.2) obtained in Example 26a) mmol) and 5% rhodium carbon (50% water content, 0.10 g) were added to 1N hydrochloric acid (40 mL), and the mixture was stirred for 6 hours at room temperature in a hydrogen atmosphere of 5 atm. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (0.70 g, 81%) as a colorless powder.
NMR (200MHz, DMSO-d ₆ ) δ: 1.29 (3H, t, J = 7.6), 1.69-1.86 (2H, m), 2.14-2.20 (2H, m), 2.90 (2H, q, J = 7.6) , 2.90-3.55 (5H, m), 7.37 (1H, d, J = 0.8), 9.06 (2H, br).
26c) 1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- (2-ethyl-1H-imidazol-4-yl) piperidine 4- (2 The title compound (0.30 g, 25%) was obtained as a colorless powder from -ethyl-1H-imidazol-4-yl) piperidine dihydrochloride (0.65 g) in the same manner as in Example 19.
NMR (300MHz, CDCl ₃ ) δ: 1.30 (3H, t, J = 7.8), 1.40-1.55 (2H, m), 1.95-2.10 (2H, m), 2.61-2.70 (2H, m), 2.73 (2H , q, J = 7.8), 2.85-2.90 (2H, m), 3.08-3.18 (1H, m), 3.54-3.60 (2H, m), 3.84-3.88 (1H, m), 4.49-4.53 (1H, m), 6.58 (1H, s), 7.58 (1H, dd, J = 8.7 and 1.8), 7.92-7.96 (4H, m), 8.48 (1H, s), 8.62 (1H, br).
Elemental analysis value Calculated as C ₂₃ H ₂₆ ClN ₃ O ₃ S · 0.2H ₂ O (%): C, 59.59; H, 5.74; N, 9.06
Found (%): C, 59.50; H, 5.50; N, 8.98

実施例27
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-(2-エチル-1-トリチル-1H-イミダゾール-4-イル)ピペリジン
実施例26c)で得られた1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-(2-エチル-1H-イミダゾール-4-イル)ピペリジン(0.25g)から実施例21a)と同様にして題記化合物(0.30g, 79%)を無色粉末として得た。
NMR (200MHz, CDCl₃) δ: 0.71 (3H, t, J = 7.5), 1.30-1.46 (2H, m), 1.91 (2H, q, J = 7.6), 1.93-2.10 (2H, m), 2.53-2.89 (4H, m), 3.01-3.18 (1H, m), 3.50-3.58 (2H, m), 3.78-3.84 (1H, m), 4.43-4.49 (1H, m), 6.28 (1H, s), 7.08-7.13 (5H, m), 7.27-7.34 (10H, m), 7.58 (1H, dd, J = 8.8 and 1.8), 7.92-8.02 (4H, m), 8.47 (1H, s). Example 27
1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- (2-ethyl-1-trityl-1H-imidazol-4-yl) piperidine 1- obtained in Example 26c) {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- (2-ethyl-1H-imidazol-4-yl) piperidine (0.25 g) was used in the same manner as in Example 21a) to give the title compound ( 0.30 g, 79%) was obtained as a colorless powder.
NMR (200MHz, CDCl ₃ ) δ: 0.71 (3H, t, J = 7.5), 1.30-1.46 (2H, m), 1.91 (2H, q, J = 7.6), 1.93-2.10 (2H, m), 2.53 -2.89 (4H, m), 3.01-3.18 (1H, m), 3.50-3.58 (2H, m), 3.78-3.84 (1H, m), 4.43-4.49 (1H, m), 6.28 (1H, s) , 7.08-7.13 (5H, m), 7.27-7.34 (10H, m), 7.58 (1H, dd, J = 8.8 and 1.8), 7.92-8.02 (4H, m), 8.47 (1H, s).

実施例28
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-(2-エチル-1-メチル-1H-イミダゾール-5-イル)ピペリジン
実施例27で得られた1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-(2-エチル-1-トリチル-1H-イミダゾール-4-イル)ピペリジン(0.30g)から実施例21b)と同様にして題記化合物(0.09g, 45%)を無色粉末として得た。
NMR (200MHz, CDCl₃) δ: 1.33 (3H, t, J = 7.0), 1.48-1.63 (2H, m), 1.88-2.05 (2H, m), 2.61-2.73 (4H, m), 2.87-2.95 (2H, m), 3.08-3.22 (1H, m), 3.46 (3H, s), 3.53-3.61 (2H, m), 3.90-3.96 (1H, m), 4.54-4.61 (1H, m), 6.64 (1H, s), 7.60 (1H, dd, J = 9.0 and 2.0), 7.93-7.97 (4H, m), 8.48 (1H, d, J = 1.2).
元素分析値 C₂₄H₂₈ClN₃O₃S・H₂Oとして
計算値（％）：C, 58.59； H, 6.15； N, 8.54
実測値（％）：C, 58.72； H, 6.19； N, 8.38 Example 28
1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- (2-ethyl-1-methyl-1H-imidazol-5-yl) piperidine 1- {obtained in Example 27 3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- (2-ethyl-1-trityl-1H-imidazol-4-yl) piperidine (0.30 g) as in Example 21b) The title compound (0.09 g, 45%) was obtained as a colorless powder.
NMR (200MHz, CDCl ₃ ) δ: 1.33 (3H, t, J = 7.0), 1.48-1.63 (2H, m), 1.88-2.05 (2H, m), 2.61-2.73 (4H, m), 2.87-2.95 (2H, m), 3.08-3.22 (1H, m), 3.46 (3H, s), 3.53-3.61 (2H, m), 3.90-3.96 (1H, m), 4.54-4.61 (1H, m), 6.64 (1H, s), 7.60 (1H, dd, J = 9.0 and 2.0), 7.93-7.97 (4H, m), 8.48 (1H, d, J = 1.2).
Elemental analysis value Calculated as C ₂₄ H ₂₈ ClN ₃ O ₃ S · H ₂ O (%): C, 58.59; H, 6.15; N, 8.54
Found (%): C, 58.72; H, 6.19; N, 8.38

実施例29
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-(2,4-ジメチル-1H-イミダゾール-5-イル)ピペリジン
29a) 4-(2,4-ジメチル-1H-イミダゾール-5-イル)ピリジン
2,4-ジメチル-5-ヨードイミダゾール (Tetrahedron, 54, 3235 (1998)) (3.40g)のDMF溶液(20mL)に水素化ナトリウム(60%; 0.67g)を0℃で加え、0℃で30分間かき混ぜた後、臭化ベンジル(2.0mL)を加えて室温で15時間かき混ぜた。反応混合物を減圧濃縮し、残留物を水と酢酸エチルで希釈した。有機層を分取し、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、減圧濃縮した。残留物をシリカゲルカラム（酢酸エチル/ヘキサン=1/1から3/1）で精製してベンジル体(4.30g, 90%)を無色油状物として得た。
得られたベンジル体(1.60g)を4-ピリジンほう酸(0.63g)、テトラキストリフェニルホスフィンパラジウム(0.59g)、およびカリウムt-ブトキシド(4.60g)とともにジメトキシエタン(70mL)-水(25mL)混合液に加えて40時間加熱還流した。反応混合物を飽和重曹水と酢酸エチルで希釈し、有機層を分取し、無水硫酸ナトリウムで乾燥し、減圧濃縮した。残留物を塩基性シリカゲルカラム（酢酸エチル/ヘキサン=2/1から酢酸エチル）で精製してピリジン体(0.64g, 47%)を黄色油状物として得た。
ピリジン体(0.60g)のメタノール溶液(100mL)に10％パラジウム炭素(50%; 0.60g)を加え、ギ酸アンモニウム(3.00g)を加えて2時間加熱還流した。反応液を室温まで冷却し、ギ酸アンモニウム(4.00g)を加えてさらに15時間加熱還流した。反応混合物をろ過し、ろ液を減圧濃縮した。残留物を塩基性シリカゲルカラム（酢酸エチルから酢酸エチル/メタノール=10/1）で精製して題記化合物(0.10g, 25%)を無色粉末として得た。
NMR (300MHz, CDCl₃) δ: 2.45 (3H, s), 2.48 (3H, s), 7.57 (2H, br), 8.57 (2H, dd, J = 6.3 and 1.7), 8.88 (1H, br).
29b) 4-(2,4-ジメチル-1H-イミダゾール-5-イル)ピペリジン2塩酸塩
実施例29a)で得られた4-(2,4-ジメチル-1H-イミダゾール-5-イル)ピリジン(0.10g)から実施例26b)と同様にして題記化合物(0.15g, 定量的)を無色粉末として得た。
NMR (200MHz, CD₃OD) δ: 2.00-2.08 (4H, m), 2.29 (3H, s), 2.57 (3H, s), 3.08-3.23 (3H, m), 3.49-3.55 (2H, m).
29c) 1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-(2,4-ジメチル-1H-イミダゾール-5-イル)ピペリジン
実施例29b)で得られた4-(2,4-ジメチル-1H-イミダゾール-5-イル)ピペリジン2塩酸塩 (0.15g)から実施例19と同様にして題記化合物(0.16g, 60%)を無色粉末として得た。
NMR (200MHz, CDCl₃) δ: 1.62-1.80 (4H, m), 2.15 (3H, s), 2.32 (3H, s), 2.52-2.80 (2H, m), 2.84-2.92 (2H, m), 3.03-3.18 (1H, m), 3.53-3.60 (2H, m), 3.89-3.95 (1H, m), 4.57-4.63 (1H, m), 7.59 (1H, dd, J = 9.0 and 2.0), 7.94-7.98 (4H, m), 8.49 (1H, s).
元素分析値 C₂₃H₂₆ClN₃O₃Sとして
計算値（％）：C, 60.05； H, 5.70； N, 9.14
実測値（％）：C, 59.82； H, 5.73； N, 9.27 Example 29
1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- (2,4-dimethyl-1H-imidazol-5-yl) piperidine
29a) 4- (2,4-Dimethyl-1H-imidazol-5-yl) pyridine
Sodium hydride (60%; 0.67 g) was added to a DMF solution (20 mL) of 2,4-dimethyl-5-iodoimidazole (Tetrahedron, 54, 3235 (1998)) (3.40 g) at 0 ° C. After stirring for 30 minutes, benzyl bromide (2.0 mL) was added and stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water and ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by a silica gel column (ethyl acetate / hexane = 1/1 to 3/1) to obtain a benzyl compound (4.30 g, 90%) as a colorless oil.
The resulting benzyl compound (1.60 g) was mixed with 4-pyridine boric acid (0.63 g), tetrakistriphenylphosphine palladium (0.59 g), and potassium t-butoxide (4.60 g) in dimethoxyethane (70 mL) -water (25 mL). In addition to the liquid, it was heated to reflux for 40 hours. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate and ethyl acetate, the organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified with a basic silica gel column (ethyl acetate / hexane = 2/1 to ethyl acetate) to obtain a pyridine compound (0.64 g, 47%) as a yellow oily substance.
10% Palladium carbon (50%; 0.60 g) was added to a methanol solution (100 mL) of the pyridine compound (0.60 g), ammonium formate (3.00 g) was added, and the mixture was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature, ammonium formate (4.00 g) was added, and the mixture was further heated to reflux for 15 hr. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column (ethyl acetate to ethyl acetate / methanol = 10/1) to give the title compound (0.10 g, 25%) as a colorless powder.
NMR (300MHz, CDCl ₃ ) δ: 2.45 (3H, s), 2.48 (3H, s), 7.57 (2H, br), 8.57 (2H, dd, J = 6.3 and 1.7), 8.88 (1H, br).
29b) 4- (2,4-Dimethyl-1H-imidazol-5-yl) piperidine dihydrochloride 4- (2,4-dimethyl-1H-imidazol-5-yl) pyridine obtained in Example 29a) The title compound (0.15 g, quantitative) was obtained as a colorless powder from 0.10 g) in the same manner as in Example 26b).
NMR (200MHz, CD ₃ OD) δ: 2.00-2.08 (4H, m), 2.29 (3H, s), 2.57 (3H, s), 3.08-3.23 (3H, m), 3.49-3.55 (2H, m) .
29c) 1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- (2,4-dimethyl-1H-imidazol-5-yl) piperidine 4-obtained in Example 29b) The title compound (0.16 g, 60%) was obtained as a colorless powder from (2,4-dimethyl-1H-imidazol-5-yl) piperidine dihydrochloride (0.15 g) in the same manner as in Example 19.
NMR (200MHz, CDCl ₃ ) δ: 1.62-1.80 (4H, m), 2.15 (3H, s), 2.32 (3H, s), 2.52-2.80 (2H, m), 2.84-2.92 (2H, m), 3.03-3.18 (1H, m), 3.53-3.60 (2H, m), 3.89-3.95 (1H, m), 4.57-4.63 (1H, m), 7.59 (1H, dd, J = 9.0 and 2.0), 7.94 -7.98 (4H, m), 8.49 (1H, s).
Elemental analysis value Calculated as C ₂₃ H ₂₆ ClN ₃ O ₃ S (%): C, 60.05; H, 5.70; N, 9.14
Found (%): C, 59.82; H, 5.73; N, 9.27

実施例30
1-{3-[(5-クロロ-1H-インドール-2-イル)スルホニル]プロパノイル}-4-(2-メチル-1H-イミダゾール-4-イル)ピペリジン塩酸塩
30a) 5-クロロ-2-({3-[4-(2-メチル-1H-イミダゾール-4-イル)-1-ピペリジニル]-3-オキソプロピル}スルホニル)-1H-インドール-1-カルボン酸tert-ブチル
4-(2-メチル-1H-イミダゾール-4-イル)ピペリジン2塩酸塩 (0.71g) および3-{[1-(tert-ブトキシカルボニル)-5-クロロ-1H-インドール-2-イル]スルホニル}プロピオン酸(1.16g)から実施例19と同様にして題記化合物(0.70g, 44%)を無色粉末として得た。
NMR (200MHz, CDCl₃) δ: 1.46-2.10 (4H, m), 1.73 (9H, s), 2.39 (3H, s), 2.61-2.80 (2H, m), 2.88-2.96 (2H, m), 3.05-3.20 (1H, m), 3.84-3.91 (1H, m), 4.00-4.10 (2H, m), 4.48-4.56 (1H, m), 6.57 (1H, s), 7.43 (1H, dd, J = 9.4 and 2.2), 7.63 (1H, d, J = 2.0), 8.01 (1H, d, J = 9.2).
30b) 1-{3-[(5-クロロ-1H-インドール-2-イル)スルホニル]プロパノイル}-4-(2-メチル-1H-イミダゾール-4-イル)ピペリジン塩酸塩
実施例30a)で得られた5-クロロ-2-({3-[4-(2-メチル-1H-イミダゾール-4-イル)-1-ピペリジニル]-3-オキソプロピル}スルホニル)-1H-インドール-1-カルボン酸tert-ブチル(0.26g)を濃塩酸(1.5mL)に溶解して室温で30分かき混ぜた。反応液を減圧濃縮し、残留物をイソプロピルアルコールで洗浄して題記化合物(0.20g, 87%)を褐色粉末として得た。
NMR (200MHz, CD₃OD) δ: 1.22-1.63 (2H, m), 1.87-2.06 (2H, m), 2.59 (3H, s), 2.60-2.97 (4H, m), 3.11-3.29 (1H, m), 3.61-3.72 (2H, m), 3.95-4.01 (1H, m), 4.35-4.42 (1H, m), 7.30 (1H, dd, J = 8.8 and 2.2), 7.47 (1H, d, J = 9.0), 7.67 (1H, d, J = 2.2).
元素分析値 C₂₀H₂₃ClN₄O₃S・HCl・0.8C₃H₈O・H₂Oとして
計算値（％）：C, 50.06； H, 6.08； N, 10.42
実測値（％）：C, 49.75； H, 5.97； N, 10.13 Example 30
1- {3-[(5-Chloro-1H-indol-2-yl) sulfonyl] propanoyl} -4- (2-methyl-1H-imidazol-4-yl) piperidine hydrochloride
30a) 5-Chloro-2-({3- [4- (2-methyl-1H-imidazol-4-yl) -1-piperidinyl] -3-oxopropyl} sulfonyl) -1H-indole-1-carboxylic acid tert-butyl
4- (2-Methyl-1H-imidazol-4-yl) piperidine dihydrochloride (0.71 g) and 3-{[1- (tert-butoxycarbonyl) -5-chloro-1H-indol-2-yl] sulfonyl } The title compound (0.70 g, 44%) was obtained as a colorless powder from propionic acid (1.16 g) in the same manner as in Example 19.
NMR (200MHz, CDCl ₃ ) δ: 1.46-2.10 (4H, m), 1.73 (9H, s), 2.39 (3H, s), 2.61-2.80 (2H, m), 2.88-2.96 (2H, m), 3.05-3.20 (1H, m), 3.84-3.91 (1H, m), 4.00-4.10 (2H, m), 4.48-4.56 (1H, m), 6.57 (1H, s), 7.43 (1H, dd, J = 9.4 and 2.2), 7.63 (1H, d, J = 2.0), 8.01 (1H, d, J = 9.2).
30b) 1- {3-[(5-Chloro-1H-indol-2-yl) sulfonyl] propanoyl} -4- (2-methyl-1H-imidazol-4-yl) piperidine hydrochloride obtained in Example 30a) 5-chloro-2-({3- [4- (2-methyl-1H-imidazol-4-yl) -1-piperidinyl] -3-oxopropyl} sulfonyl) -1H-indole-1-carboxylic acid Tert-butyl (0.26 g) was dissolved in concentrated hydrochloric acid (1.5 mL) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was washed with isopropyl alcohol to give the title compound (0.20 g, 87%) as a brown powder.
NMR (200MHz, CD ₃ OD) δ: 1.22-1.63 (2H, m), 1.87-2.06 (2H, m), 2.59 (3H, s), 2.60-2.97 (4H, m), 3.11-3.29 (1H, m), 3.61-3.72 (2H, m), 3.95-4.01 (1H, m), 4.35-4.42 (1H, m), 7.30 (1H, dd, J = 8.8 and 2.2), 7.47 (1H, d, J = 9.0), 7.67 (1H, d, J = 2.2).
Elemental analysis value Calculated as C ₂₀ H ₂₃ ClN ₄ O ₃ S · HCl · 0.8C ₃ H ₈ O · H ₂ O (%): C, 50.06; H, 6.08; N, 10.42
Found (%): C, 49.75; H, 5.97; N, 10.13

実施例31
1-{3-[(5-クロロ-1H-インドール-2-イル)スルホニル]プロパノイル}-4-(2,4-ジメチル-1H-イミダゾール-5-イル)ピペリジン
31a) 5-クロロ-2-({3-[4-(2,4-ジメチル-1H-イミダゾール-5-イル)-1-ピペリジニル]-3-オキソプロピル}スルホニル)-1H-インドール-1-カルボン酸tert-ブチル
実施例29b)で得られた4-(2,4-ジメチル-1H-イミダゾール-5-イル)ピペリジン2塩酸塩(0.21g)および3-{[1-(tert-ブトキシカルボニル)-5-クロロ-1H-インドール-2-イル]スルホニル}プロピオン酸(0.32g)から実施例19と同様にして題記化合物(0.32g, 70%)を無色粉末として得た。
NMR (200MHz, CDCl₃) δ: 1.46-1.80 (4H, m), 1.73 (9H, s), 2.17 (3H, s), 2.38 (3H, s), 2.52-3.10 (5H, m), 3.83-3.90 (1H, m), 4.00-4.07 (2H, m), 4.57-4.64 (1H, m), 7.43 (1H, dd, J = 9.2 and 2.2), 7.50 (1H, s), 7.64 (1H, d, J = 2.0), 7.70 (1H, br), 7.99 (1H, d, J = 8.8).
31b) 1-{3-[(5-クロロ-1H-インドール-2-イル)スルホニル]プロパノイル}-4-(2,4-ジメチル-1H-イミダゾール-5-イル)ピペリジン
実施例31a)で得られた5-クロロ-2-({3-[4-(2,4-ジメチル-1H-イミダゾール-5-イル)-1-ピペリジニル]-3-オキソプロピル}スルホニル)-1H-インドール-1-カルボン酸tert-ブチル(0.32 g)を濃塩酸(3mL)に溶解して室温で30分かき混ぜた。反応液にトリエチルアミンを加えて中和してから減圧濃縮し、残留物をシリカゲルカラム（クロロホルム/メタノール=20/1から5/1）で精製して題記化合物(0.11 g, 42%)を黄色粉末として得た。
NMR (200MHz, CDCl₃) δ: 1.58-1.91 (4H, m), 2.19 (3H, s), 2.33-2.99 (5H, m), 2.46 (3H, s), 3.50-3.96 (3H, m), 4.56-4.63 (1H, m), 7.13 (1H, d, J = 0.8), 7.30 (1H, dd, J = 8.8 and 2.2), 7.46 (1H, d, J = 8.8), 7.68 (1H, d, J = 1.8).
元素分析値 C₂₁H₂₅ClN₄O₃S・1.1H₂Oとして
計算値（％）：C, 53.80； H, 5.85； N, 11.95
実測値（％）：C, 53.62； H, 5.51； N, 11.78 Example 31
1- {3-[(5-Chloro-1H-indol-2-yl) sulfonyl] propanoyl} -4- (2,4-dimethyl-1H-imidazol-5-yl) piperidine
31a) 5-Chloro-2-({3- [4- (2,4-dimethyl-1H-imidazol-5-yl) -1-piperidinyl] -3-oxopropyl} sulfonyl) -1H-indole-1- Tert-butyl carboxylate 4- (2,4-dimethyl-1H-imidazol-5-yl) piperidine dihydrochloride (0.21 g) and 3-{[1- (tert-butoxycarbonyl) obtained in Example 29b) ) -5-Chloro-1H-indol-2-yl] sulfonyl} propionic acid (0.32 g) was used to give the title compound (0.32 g, 70%) as a colorless powder in the same manner as in Example 19.
NMR (200MHz, CDCl ₃ ) δ: 1.46-1.80 (4H, m), 1.73 (9H, s), 2.17 (3H, s), 2.38 (3H, s), 2.52-3.10 (5H, m), 3.83- 3.90 (1H, m), 4.00-4.07 (2H, m), 4.57-4.64 (1H, m), 7.43 (1H, dd, J = 9.2 and 2.2), 7.50 (1H, s), 7.64 (1H, d , J = 2.0), 7.70 (1H, br), 7.99 (1H, d, J = 8.8).
31b) 1- {3-[(5-Chloro-1H-indol-2-yl) sulfonyl] propanoyl} -4- (2,4-dimethyl-1H-imidazol-5-yl) piperidine obtained in Example 31a) 5-chloro-2-({3- [4- (2,4-dimethyl-1H-imidazol-5-yl) -1-piperidinyl] -3-oxopropyl} sulfonyl) -1H-indole-1- Tert-butyl carboxylate (0.32 g) was dissolved in concentrated hydrochloric acid (3 mL) and stirred at room temperature for 30 minutes. The reaction mixture was neutralized with triethylamine and concentrated under reduced pressure. The residue was purified by silica gel column (chloroform / methanol = 20/1 to 5/1) to give the title compound (0.11 g, 42%) as a yellow powder. Got as.
NMR (200MHz, CDCl ₃ ) δ: 1.58-1.91 (4H, m), 2.19 (3H, s), 2.33-2.99 (5H, m), 2.46 (3H, s), 3.50-3.96 (3H, m), 4.56-4.63 (1H, m), 7.13 (1H, d, J = 0.8), 7.30 (1H, dd, J = 8.8 and 2.2), 7.46 (1H, d, J = 8.8), 7.68 (1H, d, J = 1.8).
Elemental analysis calculated as C ₂₁ H ₂₅ ClN ₄ O ₃ S · 1.1H ₂ O (%): C, 53.80; H, 5.85; N, 11.95
Found (%): C, 53.62; H, 5.51; N, 11.78

実施例32
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-(1H-イミダゾール-2-イル)-4-ピペリジノール
4-ヒドロキシ-4-(1H-イミダゾール-2-イル)ピペリジン-1-カルボン酸tert-ブチル(特表平7-501556号公報)(0.55g)から実施例1と同様にして題記化合物(0.11g, 12%)を淡褐色粉末として得た。
NMR (300MHz, CDCl₃+CD₃OD) δ: 1.79-2.11(4H, m), 2.87-2.96 (3H, m), 3.13-3.21 (1H, m), 3.50-3.61 (3H, m), 3.66-3.73 (1H, m), 4.11-4.19 (1H, m), 6.95 (1H, d, J = 1.5), 7.59 (1H, dd, J = 2.1 and 8.7), 7.90-7.99 (4H, m), 8.49 (1H, d, J = 1.5).
元素分析値 C₂₁H₂₂ClN₃O₄Sとして
計算値（％）：C, 56.31； H, 4.95； N, 9.38
実測値（％）：C, 56.16； H, 4.86； N, 9.43 Example 32
1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- (1H-imidazol-2-yl) -4-piperidinol
4-hydroxy-4- (1H-imidazol-2-yl) piperidine-1-carboxylate tert-butyl (JP 7-501556 A) (0.55 g) was used in the same manner as in Example 1 to obtain the title compound (0.11 g, 12%) was obtained as a light brown powder.
NMR (300MHz, CDCl ₃ + CD ₃ OD) δ: 1.79-2.11 (4H, m), 2.87-2.96 (3H, m), 3.13-3.21 (1H, m), 3.50-3.61 (3H, m), 3.66 -3.73 (1H, m), 4.11-4.19 (1H, m), 6.95 (1H, d, J = 1.5), 7.59 (1H, dd, J = 2.1 and 8.7), 7.90-7.99 (4H, m), 8.49 (1H, d, J = 1.5).
Elemental analysis value Calculated as C ₂₁ H ₂₂ ClN ₃ O ₄ S (%): C, 56.31; H, 4.95; N, 9.38
Found (%): C, 56.16; H, 4.86; N, 9.43

実施例33
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-(1H-イミダゾール-2-イル)ピペリジン
4-(1H-イミダゾール-2-イル)ピペリジン-1-カルボン酸tert-ブチル (特表平7-501556号公報)(0.26g)から実施例1と同様にして題記化合物(0.24g, 54%)を無色粉末として得た。
NMR (300MHz, CDCl₃) δ: 1.60-1.85 (2H, m), 1.98-2.14 (2H, m), 2.72-3.04 (4H, m), 3.15-3.24 (1H, m), 3.49-3.61 (2H, m), 3.90-3.95 (1H, m), 4.46-4.50 (1H, m), 6.96 (1H, br), 7.00 (1H, br), 7.58 (1H, dd, J = 2.1 and 9.0), 7.90-7.97 (4H, m), 8.48 (1H, d, J = 0.9), 8.88 (1H, br).
元素分析値 C₂₁H₂₂BrN₃O₃Sとして
計算値（％）：C, 58.39； H, 5.13； N, 9.73
実測値（％）：C, 58.14； H, 5.13； N, 9.73 Example 33
1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- (1H-imidazol-2-yl) piperidine
4- (1H-imidazol-2-yl) piperidine-1-carboxylate tert-butyl (JP 7-501556 A) (0.26 g) was used in the same manner as in Example 1 to obtain the title compound (0.24 g, 54% ) Was obtained as a colorless powder.
NMR (300MHz, CDCl ₃ ) δ: 1.60-1.85 (2H, m), 1.98-2.14 (2H, m), 2.72-3.04 (4H, m), 3.15-3.24 (1H, m), 3.49-3.61 (2H , m), 3.90-3.95 (1H, m), 4.46-4.50 (1H, m), 6.96 (1H, br), 7.00 (1H, br), 7.58 (1H, dd, J = 2.1 and 9.0), 7.90 -7.97 (4H, m), 8.48 (1H, d, J = 0.9), 8.88 (1H, br).
Elemental analysis value Calculated as C ₂₁ H ₂₂ BrN ₃ O ₃ S (%): C, 58.39; H, 5.13; N, 9.73
Found (%): C, 58.14; H, 5.13; N, 9.73

実施例34
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-(1-メチル-1H-イミダゾール-2-イル)ピペリジン
34a) 4-(1-メチル-1H-イミダゾール-2-イル)ピペリジン-1-カルボン酸tert-ブチル
4-(1H-イミダゾール-2-イル)ピペリジン-1-カルボン酸tert-ブチル(0.25g)のDMF溶液(3mL)に水素化ナトリウム(60%; 40mg)を0℃で加えて0℃で30分間かき混ぜた。ヨウ化メチル(0.06mL)を加えて0℃で2時間かき混ぜた。反応混合物を減圧濃縮し、残留物を炭酸水素ナトリウム水溶液と酢酸エチルで希釈した。有機層を分取し、無水硫酸ナトリウムで乾燥し、溶媒を減圧濃縮した。残留物をシリカゲルカラム（クロロホルム/メタノール＝10/1）で精製して題記化合物(0.27g, 定量的)を淡黄色油状物として得た。
NMR (200MHz, CDCl₃) δ: 1.46 (9H, s), 1.80-1.91 (4H, m), 2.70-2.96 (3H, m), 3.61 (3H, s), 4.18-4.25 (2H, m), 6.79 (1H, d, J = 1.0), 6.94 (1H, d, J = 1.0).
34b) 1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-(1-メチル-1H-イミダゾール-2-イル)ピペリジン
実施例34a)で得られた4-(1-メチル-1H-イミダゾール-2-イル)ピペリジン-1-カルボン酸tert-ブチル(0.27g)から実施例１と同様にして題記化合物(0.31g, 70%)を無色粉末として得た。
NMR (200MHz, CDCl₃) δ: 1.60-2.00 (4H, m), 2.70-2.94 (4H, m), 3.11-3.26 (1H, m), 3.52-3.61 (2H, m), 3.61 (3H, s), 3.93-4.00 (1H, m), 4.45-4.52 (1H, m), 6.79 (1H, d, J = 1.2), 6.92 (1H, d, J = 1.4), 7.58 (1H, dd, J = 2.0 and 8.8), 7.89-7.98 (4H, m), 8.48 (1H, s), 8.88 (1H, br).
元素分析値 C₂₂H₂₄ClN₃O₃S・0.5H₂Oとして
計算値（％）：C, 58.08； H, 5.54； N, 9.24
実測値（％）：C, 57.98； H, 5.64； N, 9.20 Example 34
1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- (1-methyl-1H-imidazol-2-yl) piperidine
34a) tert-Butyl 4- (1-methyl-1H-imidazol-2-yl) piperidine-1-carboxylate
Sodium hydride (60%; 40 mg) was added at 0 ° C. to a DMF solution (3 mL) of tert-butyl 4- (1H-imidazol-2-yl) piperidine-1-carboxylate (0.25 g) at 0 ° C. Stir for a minute. Methyl iodide (0.06 mL) was added and stirred at 0 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column (chloroform / methanol = 10/1) to give the title compound (0.27 g, quantitative) as a pale yellow oil.
NMR (200MHz, CDCl ₃ ) δ: 1.46 (9H, s), 1.80-1.91 (4H, m), 2.70-2.96 (3H, m), 3.61 (3H, s), 4.18-4.25 (2H, m), 6.79 (1H, d, J = 1.0), 6.94 (1H, d, J = 1.0).
34b) 1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- (1-methyl-1H-imidazol-2-yl) piperidine 4- (1 The title compound (0.31 g, 70%) was obtained as a colorless powder from tert-butyl (-methyl-1H-imidazol-2-yl) piperidine-1-carboxylate (0.27 g) in the same manner as in Example 1.
NMR (200MHz, CDCl ₃ ) δ: 1.60-2.00 (4H, m), 2.70-2.94 (4H, m), 3.11-3.26 (1H, m), 3.52-3.61 (2H, m), 3.61 (3H, s ), 3.93-4.00 (1H, m), 4.45-4.52 (1H, m), 6.79 (1H, d, J = 1.2), 6.92 (1H, d, J = 1.4), 7.58 (1H, dd, J = 2.0 and 8.8), 7.89-7.98 (4H, m), 8.48 (1H, s), 8.88 (1H, br).
Elemental analysis value Calculated as C ₂₂ H ₂₄ ClN ₃ O ₃ S · 0.5H ₂ O (%): C, 58.08; H, 5.54; N, 9.24
Found (%): C, 57.98; H, 5.64; N, 9.20

実施例35
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-(4,5-ジメチル-1H-イミダゾール-2-イル)ピペリジン
35a) 4-ヒドロキシ-4-(4,5-ジメチル-1H-イミダゾール-2-イル)ピペリジン-1-カルボン酸tert-ブチル
4,5-ジメチルイミダゾール(3.00g)、パラトルエンスルホン酸一水和物(1.50g)およびオルトギ酸トリエチル(60mL)の混合物を130℃で６時間かき混ぜた。炭酸ナトリウム(1.50g)を加えてから反応混合物を減圧濃縮し、残留物をTHF(50mL)に溶解した。溶液を-40℃以下に冷却しながらｎ-ブチルリチウム溶液（1.6Mヘキサン溶液、17mL, 27mmol）を加え、さらにBoc-ピペリドン(2.66g)のTHF溶液(20mL)を滴下して、滴下終了後-40℃以下で2時間かき混ぜた。反応液を室温まで昇温後、0.1N塩酸(40mL)を加えて15分間かき混ぜた後、酢酸エチル(50mL)を加えて混合物を5分間かき混ぜた。有機層を分取し、飽和重曹水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、溶媒を減圧濃縮した。残留物をシリカゲルカラム（クロロホルム/メタノール＝20/1から10/1）で精製して題記化合物(2.93g, 21％)を淡黄色油状物として得た。
NMR (200MHz, CDCl₃) δ: 1.45 (9H, s), 1.71-1.78 (4H, m), 1.98-2.24 (2H, m), 2.13 (6H, s), 3.17-3.33 (2H, m), 3.89-3.96 (2H, m).
35b) 4-(4,5-ジメチル-1H-イミダゾール-2-イル)-1,2,3,6-テトラヒドロピリジン-1-カルボン酸tert-ブチル
実施例35a)で得られた4-ヒドロキシ-4-(4,5-ジメチル-1H-イミダゾール-2-イル)ピペリジン-1-カルボン酸tert-ブチル(1.96g)およびジイソプロピルエチルアミン(1.68g)のDMF溶液(100mL)に溶解し、0℃に冷却しながら塩化メタンスルホニル(1.52g)を加えて0℃で2時間かき混ぜた。さらにジイソプロピルエチルアミン(1.68g)および塩化メタンスルホニル(1.52g)を加えて室温で16時間かき混ぜた。混合物を水で希釈し、１N水酸化ナトリウム水溶液を加えてpH9に調整し、酢酸エチルで抽出した。抽出液を無水硫酸ナトリウムで乾燥し、溶媒を減圧濃縮した。残留物をシリカゲルカラム（クロロホルム/メタノール＝20/1から10/1）で精製して題記化合物(1.3g, 70％)を淡黄色油状物として得た。
NMR (200MHz, CDCl₃) δ: 1.48 (9H, s), 2.16 (6H, s), 2.59 (2H, br), 3.58 (2H, t, J = 5.7), 4.02-4.06 (2H, m), 6.13 (1H, br).
35c) 4-(4,5-ジメチル-1H-イミダゾール-2-イル)ピペリジン-1-カルボン酸tert-ブチル
実施例35b)で得られた4-(4,5-ジメチル-1H-イミダゾール-2-イル)-1,2,3,6-テトラヒドロピリジン-1-カルボン酸tert-ブチル(1.30g)と10％パラジウム炭素(50％含水、0.20g)をメタノール(30mL)に加えて5気圧の水素雰囲気下室温で10時間かき混ぜた。反応混合物をろ過し、ろ液を減圧濃縮して題記化合物(1.18g, 90%)を無色粉末として得た。
NMR (200MHz, CDCl₃) δ: 1.45 (9H, s), 1.53-1.74 (2H, m), 1.93-1,98 (2H, m), 2.13 (6H, m), 2.75-2.89 (3H, m), 4.14-4.20 (2H, m).
35d) 1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-(4,5-ジメチル-1H-イミダゾール-2-イル)ピペリジン
実施例35c)で得られた4-(4,5-ジメチル-1H-イミダゾール-2-イル)ピペリジ-1-カルボン酸tert-ブチル(0.24g)から実施例１と同様にして題記化合物(53mg, 13%)を無色粉末として得た。
NMR (200MHz, CDCl₃) δ: 1.52-2.10 (4H, m), 2.12 (6H, s), 2.63-2.74 (1H, m), 2.83-2.94 (3H, m), 3.08-3.20 (1H, m), 3.52-3.61 (2H, m), 3.87-3.94 (1H, m), 4.48-4.54 (1H, m), 7.58 (1H, dd, J = 2.0 and 8.8), 7.88-7.97 (4H, m), 8.48 (1H, s).
元素分析値 C₂₃H₂₆ClN₃O₃Sとして
計算値（％）：C, 60.05； H, 5.70； N, 9.14
実測値（％）：C, 59.82； H, 5.67； N, 9.08 Example 35
1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- (4,5-dimethyl-1H-imidazol-2-yl) piperidine
35a) tert-butyl 4-hydroxy-4- (4,5-dimethyl-1H-imidazol-2-yl) piperidine-1-carboxylate
A mixture of 4,5-dimethylimidazole (3.00 g), paratoluenesulfonic acid monohydrate (1.50 g) and triethyl orthoformate (60 mL) was stirred at 130 ° C. for 6 hours. Sodium carbonate (1.50 g) was added, then the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in THF (50 mL). N-Butyllithium solution (1.6M hexane solution, 17mL, 27mmol) was added while cooling the solution to -40 ° C or lower, and Boc-piperidone (2.66g) in THF (20mL) was added dropwise. Stir for 2 hours at -40 ° C or lower. The temperature of the reaction mixture was raised to room temperature, 0.1N hydrochloric acid (40 mL) was added and stirred for 15 min, ethyl acetate (50 mL) was added and the mixture was stirred for 5 min. The organic layer was separated, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column (chloroform / methanol = 20/1 to 10/1) to give the title compound (2.93 g, 21%) as a pale yellow oil.
NMR (200MHz, CDCl ₃ ) δ: 1.45 (9H, s), 1.71-1.78 (4H, m), 1.98-2.24 (2H, m), 2.13 (6H, s), 3.17-3.33 (2H, m), 3.89-3.96 (2H, m).
35b) 4- (4,5-Dimethyl-1H-imidazol-2-yl) -1,2,3,6-tetrahydropyridine-1-carboxylate tert-butyl 4-hydroxy- obtained in Example 35a) 4- (4,5-dimethyl-1H-imidazol-2-yl) piperidine-1-carboxylate tert-butyl (1.96 g) and diisopropylethylamine (1.68 g) in DMF solution (100 mL) While cooling, methanesulfonyl chloride (1.52 g) was added and stirred at 0 ° C. for 2 hours. Diisopropylethylamine (1.68 g) and methanesulfonyl chloride (1.52 g) were further added, and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with water, adjusted to pH 9 with 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column (chloroform / methanol = 20/1 to 10/1) to give the title compound (1.3 g, 70%) as a pale yellow oil.
NMR (200MHz, CDCl ₃ ) δ: 1.48 (9H, s), 2.16 (6H, s), 2.59 (2H, br), 3.58 (2H, t, J = 5.7), 4.02-4.06 (2H, m), 6.13 (1H, br).
35c) 4- (4,5-Dimethyl-1H-imidazole-2-yl) piperidine-1-carboxylate tert-butyl 4- (4,5-Dimethyl-1H-imidazole-2 obtained in Example 35b) -Yl) -1,2,3,6-tetrahydropyridine-1-carboxylate tert-butyl (1.30 g) and 10% palladium on carbon (50% water content, 0.20 g) added to methanol (30 mL) at 5 atm. Stir for 10 hours at room temperature under hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (1.18 g, 90%) as a colorless powder.
NMR (200MHz, CDCl ₃ ) δ: 1.45 (9H, s), 1.53-1.74 (2H, m), 1.93-1,98 (2H, m), 2.13 (6H, m), 2.75-2.89 (3H, m ), 4.14-4.20 (2H, m).
35d) 1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- (4,5-dimethyl-1H-imidazol-2-yl) piperidine 4-derived from Example 35c) The title compound (53 mg, 13%) was obtained as a colorless powder from tert-butyl (0.24 g) of (4,5-dimethyl-1H-imidazol-2-yl) piperidi-1-carboxylate in the same manner as in Example 1. .
NMR (200MHz, CDCl ₃ ) δ: 1.52-2.10 (4H, m), 2.12 (6H, s), 2.63-2.74 (1H, m), 2.83-2.94 (3H, m), 3.08-3.20 (1H, m ), 3.52-3.61 (2H, m), 3.87-3.94 (1H, m), 4.48-4.54 (1H, m), 7.58 (1H, dd, J = 2.0 and 8.8), 7.88-7.97 (4H, m) , 8.48 (1H, s).
Elemental analysis value Calculated as C ₂₃ H ₂₆ ClN ₃ O ₃ S (%): C, 60.05; H, 5.70; N, 9.14
Found (%): C, 59.82; H, 5.67; N, 9.08

実施例36
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-(1,4,5-トリメチル-1H-イミダゾール-2-イル)ピペリジン
36a) 4-(1,4,5-トリメチル-1H-イミダゾール-2-イル)ピペリジン-1-カルボン酸tert-ブチル
実施例35c)で得られた4-(4,5-ジメチル-1H-イミダゾール-2-イル)ピペリジン-1-カルボン酸tert-ブチル(0.24g)から実施例34aと同様にして題記化合物(0.26g, 定量的)を褐色油状物として得た。
NMR (200MHz, CDCl₃) δ: 1.46 (9H, s), 1.76-1.82 (4H, m), 2.09 (3H, s), 2.13 (3H, s), 2.70-2.90 (3H, m), 3.42 (3H, s), 4.18-4.25 (2H, m).
36b) 1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-(1,4,5-トリメチル-1H-イミダゾール-2-イル)ピペリジン
実施例36a)で得られた4-(1,4,5-トリメチル-1H-イミダゾール-2-イル)ピペリジン-1-カルボン酸tert-ブチル(0.25g)から実施例１と同様にして題記化合物(0.16g, 38%)を無色粉末として得た。
NMR (200MHz, CDCl₃) δ: 1.60-2.05(4H, m), 2.09 (3H, s), 2.10 (3H, s), 2.30-3.35 (5H, m), 3.41 (3H, s), 3.51-3.61 (2H, m), 3.90-3.97 (1H, m), 4.52-4.58 (1H, m), 7.58 (1H, dd, J = 1.8 and 8.8), 7.89-7.99 (4H, m), 8.49 (1H, s).
元素分析値 C₂₄H₂₈ClN₃O₃S・0.7H₂Oとして
計算値（％）：C, 59.24； H, 6.09； N, 8.63
実測値（％）：C, 59.33； H, 6.13； N, 8.34 Example 36
1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- (1,4,5-trimethyl-1H-imidazol-2-yl) piperidine
36a) 4- (4,5-dimethyl-1H-imidazole) obtained in Example 35c) tert-butyl 4- (1,4,5-trimethyl-1H-imidazol-2-yl) piperidine-1-carboxylate The title compound (0.26 g, quantitative) was obtained as a brown oil from tert-butyl-2-yl) piperidine-1-carboxylate (0.24 g) in the same manner as in Example 34a.
NMR (200MHz, CDCl ₃ ) δ: 1.46 (9H, s), 1.76-1.82 (4H, m), 2.09 (3H, s), 2.13 (3H, s), 2.70-2.90 (3H, m), 3.42 ( 3H, s), 4.18-4.25 (2H, m).
36b) 1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- (1,4,5-trimethyl-1H-imidazol-2-yl) piperidine obtained in Example 36a) The title compound (0.16 g, 38%) was obtained from tert-butyl 4- (1,4,5-trimethyl-1H-imidazol-2-yl) piperidine-1-carboxylate (0.25 g) in the same manner as in Example 1. Obtained as a colorless powder.
NMR (200MHz, CDCl ₃ ) δ: 1.60-2.05 (4H, m), 2.09 (3H, s), 2.10 (3H, s), 2.30-3.35 (5H, m), 3.41 (3H, s), 3.51- 3.61 (2H, m), 3.90-3.97 (1H, m), 4.52-4.58 (1H, m), 7.58 (1H, dd, J = 1.8 and 8.8), 7.89-7.99 (4H, m), 8.49 (1H , s).
Elemental analysis _{_{_{_{C 24 H 28 ClN 3 O 3}}}} S · 0.7H 2 O Calculated (%): C, 59.24; H, 6.09; N, 8.63
Found (%): C, 59.33; H, 6.13; N, 8.34

実施例37
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-(1-エチル-4,5-ジメチル-1H-イミダゾール-2-イル)ピペリジン
37a) 4-(1-エチル-4,5-ジメチル-1H-イミダゾール-2-イル)ピペリジン-1-カルボン酸tert-ブチル
実施例35c)で得られた4-(4,5-ジメチル-1H-イミダゾール-2-イル)ピペリジン-1-カルボン酸tert-ブチル(0.24g)とヨウ化エチル(134mg)から実施例34a)と同様にして題記化合物(0.27g, 定量的)を褐色油状物として得た。
NMR (200MHz, CDCl₃) δ: 1.26 (3H, t, J = 3.6), 1.45 (9H, s), 1.70-2.22 (4H, m), 2.11 (3H, s), 2.12 (3H, s), 2.70-2.90 (3H, m), 3.81 (2H, q, J = 7.0), 4.18-4.25 (2H, m).
37b) 1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-(1-エチル-4,5-ジメチル-1H-イミダゾール-2-イル)ピペリジン
実施例37a)で得られた4-(1-エチル-4,5-ジメチル-1H-イミダゾール-2-イル)ピペリジン-1-カルボン酸tert-ブチル(0.26g)から実施例１と同様にして題記化合物(0.15g, 36%)を無色粉末として得た。
NMR (200MHz, CDCl₃) δ: 1.27 (3H, t, J = 7.2), 1.76-3.19(9H, m), 2.10 (6H, s), 3.15-3.61 (2H, m), 3.85 (2H, q, J = 7.2), 3.51-3.61 (2H, m), 3.91-3.99 (1H, m), 4.54-4.61 (1H, m), 7.58 (1H, dd, J = 2.0 and 8.8), 7.94-7.99 (4H, m), 8.49 (1H, s).
元素分析値 C₂₅H₃₀ClN₃O₃S・0.9H₂O・0.2C₄H₈O₂として
計算値（％）：C, 59.38； H, 6.45； N, 8.05
実測値（％）：C, 59.71； H, 6.72； N, 7.83 Example 37
1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- (1-ethyl-4,5-dimethyl-1H-imidazol-2-yl) piperidine
37a) 4- (4,5-Dimethyl-1H obtained in Example 35c) tert-butyl 4- (1-ethyl-4,5-dimethyl-1H-imidazol-2-yl) piperidine-1-carboxylate -Imidazole-2-yl) piperidine-1-carboxylate tert-butyl (0.24 g) and ethyl iodide (134 mg) as in Example 34a) to give the title compound (0.27 g, quantitative) as a brown oil Obtained.
NMR (200MHz, CDCl ₃ ) δ: 1.26 (3H, t, J = 3.6), 1.45 (9H, s), 1.70-2.22 (4H, m), 2.11 (3H, s), 2.12 (3H, s), 2.70-2.90 (3H, m), 3.81 (2H, q, J = 7.0), 4.18-4.25 (2H, m).
37b) 1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- (1-ethyl-4,5-dimethyl-1H-imidazol-2-yl) piperidine obtained in Example 37a) The title compound (0.15 g, 0.15 g, 4-tert-butyl 4- (1-ethyl-4,5-dimethyl-1H-imidazol-2-yl) piperidine-1-carboxylate) was prepared in the same manner as in Example 1. 36%) was obtained as a colorless powder.
NMR (200MHz, CDCl ₃ ) δ: 1.27 (3H, t, J = 7.2), 1.76-3.19 (9H, m), 2.10 (6H, s), 3.15-3.61 (2H, m), 3.85 (2H, q , J = 7.2), 3.51-3.61 (2H, m), 3.91-3.99 (1H, m), 4.54-4.61 (1H, m), 7.58 (1H, dd, J = 2.0 and 8.8), 7.94-7.99 ( 4H, m), 8.49 (1H, s).
Elemental analysis _{_{_{_{C 25 H 30 ClN 3 O 3}}}} S · 0.9H 2 O · 0.2C 4 H 8 O 2 Calculated (%): C, 59.38; H, 6.45; N, 8.05
Found (%): C, 59.71; H, 6.72; N, 7.83

実施例38
7-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-3-メチル-6,7-ジヒドロイミダゾ[1,5-a]ピラジン-8(5H)-オン
38a) 4-[(2-ヒドロキシエチル)アミノ]ピペリジン-1-カルボン酸tert-ブチル
4-オキソピペリジン-1-カルボン酸tert-ブチル（15.0g）、2-アミノエタノール（14.0mL）、酢酸（6.6mL）の1,2-ジクロロエタン（300mL）溶液を室温で１時間かき混ぜた。そこへ、トリアセトキシ水素化ホウ素ナトリウム(49.2g)を加え室温で15時間かき混ぜた。反応液を1N水酸化ナトリウム水溶液でpH12に調節した後、クロロホルム（100 mL）で抽出した。有機層を無水硫酸マグネシウムで乾燥した後、溶媒を減圧留去して題記化合物(18.0g, 89%)を無色油状物として得た。
NMR (200MHz, CDCl₃) δ: 1.17-1.37 (2H, m), 1.46 (9H, s), 1.88 (2H, t), 2.57-2.85 (5H, m), 3.66 (2H, t), 4.06 (2H, d).
38b) 4-{(2-ヒドロキシエチル)[(2-メチル-1H-イミダゾール-4-イル)カルボニル]アミノ}ピペリジン-1-カルボン酸tert-ブチル
2-メチルイミダゾール-4-カルボン酸（2.0g）のアセトニトリル（150mL）懸濁液へHOBt（3.7g）とWSC（4.6g）を順次加え、室温で20分かき混ぜた。この反応液に、実施例38a)で得た4-[(2-ヒドロキシエチル)アミノ]ピペリジン-1-カルボン酸tert-ブチル（4.7g）およびトリエチルアミン（8.0mL）をアセトニトリル（50mL）に溶かした溶液を加えて、室温で15時間かき混ぜた。アセトニトリルを減圧留去した後、残留物にクロロホルム（100mL）と水（100mL）を加えた。有機層を分液し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。残留物を塩基性シリカゲルカラム（酢酸エチル：エタノール＝５：１）で精製し、題記化合物(1.0g, 18%)を無色油状物として得た。
NMR (200MHz, CDCl₃) δ：1.47 (9H, s), 1.84 (4H, bs), 2.37 (2H, bs), 2.78 (2H, bs), 3.82 (4H, bs), 4.27 (3H, bs), 7.31 (1H, bs).
38c) 4-(3-メチル-8-オキソ-5,6-ジヒドロイミダゾ[1,5-a]ピラジン-7(8H)-イル)ピペリジン-1-カルボン酸tert-ブチル
実施例38b)で得た4-{(2-ヒドロキシエチル)[(2-メチル-1H-イミダゾール-5-イル)カルボニル]アミノ}ピペリジン-1-カルボン酸tert-ブチル（940mg）とトリエチルアミン（720μL）のTHF（30mL）溶液へ氷冷下、メタンスルホン酸クロリド（240 μL）を滴下し、室温で３時間かき混ぜた。反応液にクロロホルム（50mL）と水（50mL）を加えた。有機層を分液し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。残留物を塩基性シリカゲルカラム（酢酸エチル：エタノール＝５：１）で精製し、題記化合物(390mg, 44%)を白色固体として得た。
NMR (300MHz, CDCl₃) δ：1.47 (9H, s), 1.52-1.72 (4H, s), 2.41 (3H, s), 2.85 (2H, t), 3.57 (2H, t), 4.04 (2H, t), 4.23 (2H, bs), 4.73-4.81 (1H, m), 7.62 (1H, s).
38d) 7-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-3-メチル-6,7-ジヒドロイミダゾ[1,5-a]ピラジン-8(5H)-オン
実施例38c)で得た4-(3-メチル-8-オキソ-5,6-ジヒドロイミダゾ[1,5-a]ピラジン-7(8H)-イル)ピペリジン-1-カルボン酸tert-ブチル（420mg）に濃塩酸(5mL)を加えて溶かした。この溶液にエタノール（50mL）を加え、溶媒を減圧留去した。残留物に再びエタノールを加え、溶媒を減圧留去した。残留物にイソプロピルアルコールを加え、沈殿物をろ取した。沈殿物をイソプロピルアルコール、ジエチルエーテルで順次洗浄し、減圧乾燥して3-メチル-7-(4-ピペリジニル)-6,7-ジヒドロイミダゾ[1,5-a]ピラジン-8(5H)-オン・２塩酸塩を白色固体として得た。
3-[(6-クロロ-2-ナフチル)スルホニル]プロピオン酸（400mg）をアセトニトリル（10mL）に懸濁し、HOBt（310mg）とWSC（380mg）を順次加え、室温で20分かき混ぜた。この反応液に、実施例38c)で得た3-メチル-7-(4-ピペリジニル)-6,7-ジヒドロイミダゾ[1,5-a]ピラジン-8(5H)-オン２塩酸塩、DBU（330mL）およびトリエチルアミン（460mL）のアセトニトリル（10mL）溶液を加えて、室温で15時間かき混ぜた。アセトニトリルを減圧留去した後、残留物にクロロホルム（50mL）と水（50mL）を加えた。有機層を分液し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。残留物を塩基性シリカゲルカラム（酢酸エチル：エタノール＝５：１）で精製後、酢酸エチル：エタノールから再結晶して題記化合物(320mg, 48%)を白色結晶として得た。
NMR (300MHz, CDCl₃) δ: 1.54-1.67 (11H, m), 1.72-1.85 (2H, m), 2.41 (3H, s), 2.61-2.79 (1H, m), 2.80-2.87 (1H, m), 2.94-3.05 (1H, m), 3.17-3.25 (1H, m), 3.45-3.55 (1H, m), 3.60-3.70 (3H, m), 4.67-4.72 (1H, m), 4.83-4.90 (1H, m), 7.58-7.63 (2H, m), 7.89-7.96 (4H, m), 8.48 (1H, d).
元素分析値 C₂₅H₂₇ClN₄O₄Sとして
計算値（％）：C, 58.30； H, 5.28； N, 10.88
実測値（％）：C, 58.13； H, 5.15； N, 10.67 Example 38
7- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -3-methyl-6,7-dihydroimidazo [1,5-a] pyrazine-8 (5H )-on
38a) tert-butyl 4-[(2-hydroxyethyl) amino] piperidine-1-carboxylate
A solution of tert-butyl 4-oxopiperidine-1-carboxylate (15.0 g), 2-aminoethanol (14.0 mL) and acetic acid (6.6 mL) in 1,2-dichloroethane (300 mL) was stirred at room temperature for 1 hour. Thereto was added sodium triacetoxyborohydride (49.2 g), and the mixture was stirred at room temperature for 15 hours. The reaction mixture was adjusted to pH 12 with 1N aqueous sodium hydroxide solution, and extracted with chloroform (100 mL). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (18.0 g, 89%) as a colorless oil.
NMR (200MHz, CDCl ₃ ) δ: 1.17-1.37 (2H, m), 1.46 (9H, s), 1.88 (2H, t), 2.57-2.85 (5H, m), 3.66 (2H, t), 4.06 ( 2H, d).
38b) tert-butyl 4-{(2-hydroxyethyl) [(2-methyl-1H-imidazol-4-yl) carbonyl] amino} piperidine-1-carboxylate
HOBt (3.7 g) and WSC (4.6 g) were sequentially added to a suspension of 2-methylimidazole-4-carboxylic acid (2.0 g) in acetonitrile (150 mL), and the mixture was stirred at room temperature for 20 minutes. In this reaction solution, tert-butyl 4-[(2-hydroxyethyl) amino] piperidine-1-carboxylate (4.7 g) and triethylamine (8.0 mL) obtained in Example 38a) were dissolved in acetonitrile (50 mL). The solution was added and stirred at room temperature for 15 hours. Acetonitrile was distilled off under reduced pressure, and chloroform (100 mL) and water (100 mL) were added to the residue. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by basic silica gel column (ethyl acetate: ethanol = 5: 1) to give the title compound (1.0 g, 18%) as a colorless oil.
NMR (200MHz, CDCl ₃ ) δ: 1.47 (9H, s), 1.84 (4H, bs), 2.37 (2H, bs), 2.78 (2H, bs), 3.82 (4H, bs), 4.27 (3H, bs) , 7.31 (1H, bs).
38c) tert-butyl 4- (3-methyl-8-oxo-5,6-dihydroimidazo [1,5-a] pyrazin-7 (8H) -yl) piperidine-1-carboxylate obtained in Example 38b) 4-{(2-hydroxyethyl) [(2-methyl-1H-imidazol-5-yl) carbonyl] amino} piperidine-1-carboxylate tert-butyl (940 mg) and triethylamine (720 μL) in THF (30 mL) Methanesulfonic acid chloride (240 μL) was added dropwise to the solution under ice cooling, and the mixture was stirred at room temperature for 3 hours. Chloroform (50 mL) and water (50 mL) were added to the reaction solution. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by basic silica gel column (ethyl acetate: ethanol = 5: 1) to give the title compound (390 mg, 44%) as a white solid.
NMR (300MHz, CDCl ₃ ) δ: 1.47 (9H, s), 1.52-1.72 (4H, s), 2.41 (3H, s), 2.85 (2H, t), 3.57 (2H, t), 4.04 (2H, t), 4.23 (2H, bs), 4.73-4.81 (1H, m), 7.62 (1H, s).
38d) 7- (1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -3-methyl-6,7-dihydroimidazo [1,5-a] pyrazine-8 (5H) -one 4- (3-Methyl-8-oxo-5,6-dihydroimidazo [1,5-a] pyrazin-7 (8H) -yl) piperidine-1-carboxylic acid obtained in Example 38c) Concentrated hydrochloric acid (5 mL) was added to tert-butyl acid (420 mg) to dissolve. Ethanol (50 mL) was added to this solution, and the solvent was distilled off under reduced pressure. Ethanol was added to the residue again, and the solvent was distilled off under reduced pressure. Isopropyl alcohol was added to the residue, and the precipitate was collected by filtration. The precipitate was washed successively with isopropyl alcohol and diethyl ether and dried under reduced pressure to give 3-methyl-7- (4-piperidinyl) -6,7-dihydroimidazo [1,5-a] pyrazin-8 (5H) -one • Dihydrochloride was obtained as a white solid.
3-[(6-Chloro-2-naphthyl) sulfonyl] propionic acid (400 mg) was suspended in acetonitrile (10 mL), HOBt (310 mg) and WSC (380 mg) were successively added, and the mixture was stirred at room temperature for 20 minutes. To this reaction solution was added 3-methyl-7- (4-piperidinyl) -6,7-dihydroimidazo [1,5-a] pyrazin-8 (5H) -one dihydrochloride obtained in Example 38c), DBU. (330 mL) and triethylamine (460 mL) in acetonitrile (10 mL) were added and stirred at room temperature for 15 hours. Acetonitrile was distilled off under reduced pressure, and chloroform (50 mL) and water (50 mL) were added to the residue. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by basic silica gel column (ethyl acetate: ethanol = 5: 1) and recrystallized from ethyl acetate: ethanol to give the title compound (320 mg, 48%) as white crystals.
NMR (300MHz, CDCl ₃ ) δ: 1.54-1.67 (11H, m), 1.72-1.85 (2H, m), 2.41 (3H, s), 2.61-2.79 (1H, m), 2.80-2.87 (1H, m ), 2.94-3.05 (1H, m), 3.17-3.25 (1H, m), 3.45-3.55 (1H, m), 3.60-3.70 (3H, m), 4.67-4.72 (1H, m), 4.83-4.90 (1H, m), 7.58-7.63 (2H, m), 7.89-7.96 (4H, m), 8.48 (1H, d).
Elemental analysis value Calculated as C ₂₅ H ₂₇ ClN ₄ O ₄ S (%): C, 58.30; H, 5.28; N, 10.88
Found (%): C, 58.13; H, 5.15; N, 10.67

実施例39
7-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-1-メチル-6,7-ジヒドロイミダゾ[1,5-a]ピラジン-8(5H)-オン
39a) 4-{(2-ヒドロキシエチル)[(4-メチル-1H-イミダゾール-5-イル)カルボニル]アミノ}ピペリジン-1-カルボン酸tert-ブチル
4-メチルイミダゾール-5-カルボン酸・塩酸塩（G. Wellmann et al. Synthesis, 356 (1984)）(1.6g）のアセトニトリル（100mL）懸濁液へHOBt（2.8g）とWSC（3.5 g）を順次加え、室温で20分かき混ぜた（反応液Ａ）。別のフラスコに、4-[(2-ヒドロキシエチル)アミノ]ピペリジン-1-カルボン酸tert-ブチル（3.0g）、N-トリメチルシリルアセトアミド（8.1g）およびトリエチルアミン（5.0mL）のアセトニトリル（50mL）溶液を室温で20分かき混ぜた（反応液Ｂ）。反応液Ｂを反応液Ａに加え、室温で15時間かき混ぜた。アセトニトリルを減圧留去した後、残留物にクロロホルム（100mL）と水（100 mL）を加えた。有機層を分液し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。残留物を塩基性シリカゲルカラム（酢酸エチル：エタノール＝５：１）で精製し、題記化合物(2.0g, 59%)を無色油状物として得た。
NMR (300MHz, CDCl₃) δ：1.46 (9H, s), 1.84 (4H, bs), 2.27 (3H, s), 2.77 (2H, bs), 3.68 (2H, bs), 3.79-3.82 (2H, m), 4.20-4.33 (3H, m), 7.32 (1H, s).
39b) 4-(1-メチル-8-オキソ-5,6-ジヒドロイミダゾ[1,5-a]ピラジン-7(8H)-イル)ピペリジン-1-カルボン酸tert-ブチル
実施例39a)で得られた4-{(2-ヒドロキシエチル)[(4-メチル-1H-イミダゾール-5-イル)カルボニル]アミノ}ピペリジン-1-カルボン酸tert-ブチルから実施例38c)と同様にして題記化合物(560mg, 30％)を白色固体として得た。
NMR (300MHz, CDCl₃) δ：1.47 (9H, s), 1.55-1.71 (4H, m), 2.54 (3H, s), 2.84 (2H, t), 3.55 (2H, t), 4.13 (2H, t), 4.22 (2H, bs), 4.74-4.83 (1H, m), 7.39 (1H, s).
39c) 7-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-1-メチル-6,7-ジヒドロイミダゾ[1,5-a]ピラジン-8(5H)-オン
実施例39b)で得られた4-(1-メチル-8-オキソ-5,6-ジヒドロイミダゾ[1,5-a]ピラジン-7(8H)-イル)ピペリジン-1-カルボン酸tert-ブチルから実施例38d)と同様にして題記化合物(475mg, 46％)を白色結晶(エタノール/酢酸エチル)として得た。
NMR (300MHz, CDCl₃) δ：1.52-1.80 (6H, m), 2.54 (3H, s), 2.57-3.26 (3H, m), 3.43-3.68 (3H, m), 3.97 (1H, d), 4.14 (1H, t), 4.69 (1H, d), 4.81-4.93 (1H, m), 7.41 (1H, s), 7.61 (1H, dd), 7.89-7.98 (4H, m), 8.49 (1H, s).
元素分析値 C₂₅H₂₇ClN₄O₄S・0.2EtOAcとして
計算値（％）：C, 58.18； H, 5.41； N, 10.52
実測値（％）：C, 58.01； H, 5.19； N, 10.39 Example 39
7- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -1-methyl-6,7-dihydroimidazo [1,5-a] pyrazine-8 (5H )-on
39a) tert-butyl 4-{(2-hydroxyethyl) [(4-methyl-1H-imidazol-5-yl) carbonyl] amino} piperidine-1-carboxylate
To a suspension of 4-methylimidazole-5-carboxylic acid / hydrochloride (G. Wellmann et al. Synthesis, 356 (1984)) (1.6 g) in acetonitrile (100 mL) with HOBt (2.8 g) and WSC (3.5 g) Were sequentially added and stirred at room temperature for 20 minutes (reaction solution A). In a separate flask, tert-butyl 4-[(2-hydroxyethyl) amino] piperidine-1-carboxylate (3.0 g), N-trimethylsilylacetamide (8.1 g) and triethylamine (5.0 mL) in acetonitrile (50 mL) Was stirred at room temperature for 20 minutes (reaction solution B). The reaction solution B was added to the reaction solution A and stirred at room temperature for 15 hours. After acetonitrile was distilled off under reduced pressure, chloroform (100 mL) and water (100 mL) were added to the residue. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by basic silica gel column (ethyl acetate: ethanol = 5: 1) to give the title compound (2.0 g, 59%) as a colorless oil.
NMR (300MHz, CDCl ₃ ) δ: 1.46 (9H, s), 1.84 (4H, bs), 2.27 (3H, s), 2.77 (2H, bs), 3.68 (2H, bs), 3.79-3.82 (2H, m), 4.20-4.33 (3H, m), 7.32 (1H, s).
39b) tert-butyl 4- (1-methyl-8-oxo-5,6-dihydroimidazo [1,5-a] pyrazin-7 (8H) -yl) piperidine-1-carboxylate obtained in Example 39a) The title compound was obtained in the same manner as in Example 38c) from 4-tert-butyl 4-{(2-hydroxyethyl) [(4-methyl-1H-imidazol-5-yl) carbonyl] amino} piperidine-1-carboxylate 560 mg, 30%) was obtained as a white solid.
NMR (300MHz, CDCl ₃ ) δ: 1.47 (9H, s), 1.55-1.71 (4H, m), 2.54 (3H, s), 2.84 (2H, t), 3.55 (2H, t), 4.13 (2H, t), 4.22 (2H, bs), 4.74-4.83 (1H, m), 7.39 (1H, s).
39c) 7- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -1-methyl-6,7-dihydroimidazo [1,5-a] pyrazine-8 (5H) -one 4- (1-Methyl-8-oxo-5,6-dihydroimidazo [1,5-a] pyrazin-7 (8H) -yl) piperidin-1- from Example 39b) The title compound (475 mg, 46%) was obtained as white crystals (ethanol / ethyl acetate) from tert-butyl carboxylate in the same manner as in Example 38d).
NMR (300MHz, CDCl ₃ ) δ: 1.52-1.80 (6H, m), 2.54 (3H, s), 2.57-3.26 (3H, m), 3.43-3.68 (3H, m), 3.97 (1H, d), 4.14 (1H, t), 4.69 (1H, d), 4.81-4.93 (1H, m), 7.41 (1H, s), 7.61 (1H, dd), 7.89-7.98 (4H, m), 8.49 (1H, s).
Elemental analysis calculated as C ₂₅ H ₂₇ ClN ₄ O ₄ S · 0.2 EtOAc (%): C, 58.18; H, 5.41; N, 10.52
Found (%): C, 58.01; H, 5.19; N, 10.39

実施例40
7-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-1-エチル-6,7-ジヒドロイミダゾ[1,5-a]ピラジン-8(5H)-オン
40a) 4-{(2-ヒドロキシエチル)[(4-エチル-1H-イミダゾール-5-イル)カルボニル]アミノ}ピペリジン-1-カルボン酸tert-ブチル
4-エチルイミダゾール-5-カルボン酸エチル（2.3g）を8N 塩酸（50mL）に溶かし、100℃で15時間加熱した。溶媒を減圧留去することにより4-エチルイミダゾール-5-カルボン酸・塩酸塩を褐色固体として得た。この褐色固体を用いて実施例39a)と同様にして題記化合物(2.5g, 46%)を褐色油状物として得た。
NMR (200MHz, CDCl₃) δ：1.14-1.29 (3H, m), 1.46 (9H, s), 1.83 (4H, bs), 2.73-3.02 (4H, m), 3.60-3.81 (4H, m), 4.08-4.39 (3H, m), 7.32 (1H, s).
40b) 4-(1-エチル-8-オキソ-5,6-ジヒドロイミダゾ[1,5-a]ピラジン-7(8H)-イル)ピペリジン-1-カルボン酸tert-ブチル
実施例40a)で得られた4-{(2-ヒドロキシエチル)[(4-エチル-1H-イミダゾール-5-イル)カルボニル]アミノ}ピペリジン-1-カルボン酸tert-ブチルから実施例38c)と同様にして題記化合物(1.5g, 62％)を褐色油状物として得た。
NMR (200MHz, CDCl₃) δ：1.28 (3H, t), 1.46 (9H, s), 1.53-1.75 (4H, m), 2.84 (2H, t), 2.97 (2H, q), 3.52-3.58 (2H, m), 4.11-4.29 (4H, m), 4.73-4.85 (1H, m), 7.42 (1H, s).
40c) 7-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-1-エチル-6,7-ジヒドロイミダゾ[1,5-a]ピラジン-8(5H)-オン
実施例40b)で得られた4-(1-エチル-8-オキソ-5,6-ジヒドロイミダゾ[1,5-a]ピラジン-7(8H)-イル)ピペリジン-1-カルボン酸tert-ブチルから実施例38d)と同様にして題記化合物(1.3g, 57％)を白色結晶(酢酸エチル/ジエチルエーテル)として得た。
NMR (300MHz, CDCl₃) δ：1.28 (3H, t), 1.49-1.66 (2H, m), 1.69-1.85 (2H, m), 2.59-2.68 (1H, m), 2.77-2.92 (1H, m), 2.93-3.03 (3H, m), 3.14-3.24 (1H, m), 3.45-3.55 (3H, m), 3.59-3.69 (1H, m), 3.97 (1H, d), 4.10-4.15 (2H, m), 4.74 (1H, d), 4.80-4.90 (1H, m), 7.41 (1H, s), 7.59 (1H, dd), 7.89-7.93 (4H, m), 8.47 (1H, s).
元素分析値 C₂₆H₂₉ClN₄O₄S・0.5H₂O・0.1EtOAcとして
計算値（％）：C, 57.98； H, 5.68； N, 10.25
実測値（％）：C, 58.25； H, 5.64； N, 9.98 Example 40
7- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -1-ethyl-6,7-dihydroimidazo [1,5-a] pyrazine-8 (5H )-on
40a) 4-{(2-hydroxyethyl) [(4-ethyl-1H-imidazol-5-yl) carbonyl] amino} piperidine-1-carboxylate tert-butyl
Ethyl 4-ethylimidazole-5-carboxylate (2.3 g) was dissolved in 8N hydrochloric acid (50 mL) and heated at 100 ° C. for 15 hours. The solvent was distilled off under reduced pressure to obtain 4-ethylimidazole-5-carboxylic acid / hydrochloride as a brown solid. Using this brown solid, the title compound (2.5 g, 46%) was obtained as a brown oil in the same manner as in Example 39a).
NMR (200MHz, CDCl ₃ ) δ: 1.14-1.29 (3H, m), 1.46 (9H, s), 1.83 (4H, bs), 2.73-3.02 (4H, m), 3.60-3.81 (4H, m), 4.08-4.39 (3H, m), 7.32 (1H, s).
40b) tert-butyl 4- (1-ethyl-8-oxo-5,6-dihydroimidazo [1,5-a] pyrazin-7 (8H) -yl) piperidine-1-carboxylate obtained in Example 40a) The title compound was obtained in the same manner as in Example 38c) from 4-tert-butyl 4-{(2-hydroxyethyl) [(4-ethyl-1H-imidazol-5-yl) carbonyl] amino} piperidine-1-carboxylate 1.5 g, 62%) was obtained as a brown oil.
NMR (200MHz, CDCl ₃ ) δ: 1.28 (3H, t), 1.46 (9H, s), 1.53-1.75 (4H, m), 2.84 (2H, t), 2.97 (2H, q), 3.52-3.58 ( 2H, m), 4.11-4.29 (4H, m), 4.73-4.85 (1H, m), 7.42 (1H, s).
40c) 7- (1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -1-ethyl-6,7-dihydroimidazo [1,5-a] pyrazine-8 (5H) -one 4- (1-Ethyl-8-oxo-5,6-dihydroimidazo [1,5-a] pyrazin-7 (8H) -yl) piperidin-1- from Example 40b) The title compound (1.3 g, 57%) was obtained as white crystals (ethyl acetate / diethyl ether) from tert-butyl carboxylate in the same manner as in Example 38d).
NMR (300MHz, CDCl ₃ ) δ: 1.28 (3H, t), 1.49-1.66 (2H, m), 1.69-1.85 (2H, m), 2.59-2.68 (1H, m), 2.77-2.92 (1H, m ), 2.93-3.03 (3H, m), 3.14-3.24 (1H, m), 3.45-3.55 (3H, m), 3.59-3.69 (1H, m), 3.97 (1H, d), 4.10-4.15 (2H , m), 4.74 (1H, d), 4.80-4.90 (1H, m), 7.41 (1H, s), 7.59 (1H, dd), 7.89-7.93 (4H, m), 8.47 (1H, s).
Elemental analysis _{_{_{_{C 26 H 29 ClN 4 O 4}}}} S · 0.5H calcd _{2 O · 0.1EtOAc (%):} C, 57.98; H, 5.68; N, 10.25
Found (%): C, 58.25; H, 5.64; N, 9.98

実施例41
7-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-1-エチル-3-メチル-6,7-ジヒドロイミダゾ[1,5-a]ピラジン-8(5H)-オン
41a) 4-エチル-2-メチル-1H-イミダゾール-5-カルボン酸
4-エチル-2-メチル-1H-イミダゾール-5-カルバルデヒド（10g）およびリン酸二水素ナトリウム（26g）をtert-ブタノール：水：２−メチル−２−ブテン＝５：４：１の混合溶液（200mL）に懸濁し、そこへ亜塩素酸ナトリウム（35g）をゆっくりと加えた後、室温で５時間かき混ぜた。tert-ブタノールを減圧留去した後、残留物を１N塩酸でpH3に調節した。生成した沈殿物をろ取し、ジエチルエーテルで洗浄し、減圧乾燥して題記化合物(2.8g, 25%)を淡黄色固体として得た。
NMR (300MHz, DMSO-d₆) δ：1.17 (3H, t), 2.32 (3H, s), 2.56 (2H, q).
41b) 4-{[(4-エチル-2-メチル-1H-イミダゾール-5-イル)カルボニル](2-ヒドロキシエチル)アミノ}ピペリジン-1-カルボン酸tert-ブチル
実施例41a)で得られた4-エチル-2-メチル-1H-イミダゾール-5-カルボン酸から実施例39a)と同様にして題記化合物(3.3g, 57%)を黄色油状物として得た。
NMR (300MHz, CDCl₃) δ：1.24 (3H, t), 1.46 (9H, s), 1.67-1.87 (4H, m), 2.24 (3H, m), 2.61 (2H, q), 2.76-2.83 (4H, m), 3.64 (2H, t), 3.79-3.81 (2H, m).
41c) 4-(1-エチル-3-メチル-8-オキソ-5,6-ジヒドロイミダゾ[1,5-a]ピラジン-7(8H)-イル)ピペリジン-1-カルボン酸tert-ブチル
実施例41b)で得られた4-{[(4-エチル-2-メチル-1H-イミダゾール-5-イル)カルボニル](2-ヒドロキシエチル)アミノ}ピペリジン-1-カルボン酸tert-ブチルから実施例38c)と同様にして題記化合物(1.1g, 35％)を黄色油状物として得た。
NMR (200MHz, CDCl₃) δ：1.31 (3H, t), 1.47 (9H, s), 1.67-1.75 (4H, m), 2.52 (3H, s), 2.67 (2H, q), 2.84 (2H, t), 3.50-3.56 (2H, m), 3.91-4.02 (2H, m), 4.21-4.27 (2H, m), 4.72-4.84 (1H, m).
41d) 7-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-1-エチル-3-メチル-6,7-ジヒドロイミダゾ[1,5-a]ピラジン-8(5H)-オン
実施例41c)で得られた4-(1-エチル-3-メチル-8-オキソ-5,6-ジヒドロイミダゾ[1,5-a]ピラジン-7(8H)-イル)ピペリジン-1-カルボン酸tert-ブチルから実施例38d)と同様にして題記化合物(740mg, 45％)を白色結晶(酢酸エチル/エタノール)として得た。
NMR (300MHz, CDCl₃) δ：1.31 (3H, t), 1.50-1.84 (4H, m), 2.51 (3H, s), 2.60-2.70 (3H, m), 2.77-2.87 (1H, m), 2.93-3.04 (1H, m), 3.19 (1H, t), 3.45-3.55 (3H, m), 3.59-3.69 (1H, m), 3.96-4.00 (3H, m), 4.69 (1H, d), 4.85 (1H, tt), 7.59 (1H, dd), 7.89-7.96 (4H, m), 8.48 (1H, d).
元素分析値 C₂₇H₃₁ClN₄O₄S・0.1EtOAcとして
計算値（％）：C, 59.63； H, 5.81； N, 10.15
実測値（％）：C, 59.34； H, 5.61； N, 10.16 Example 41
7- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -1-ethyl-3-methyl-6,7-dihydroimidazo [1,5-a] pyrazine -8 (5H) -ON
41a) 4-Ethyl-2-methyl-1H-imidazole-5-carboxylic acid
Mixing 4-ethyl-2-methyl-1H-imidazole-5-carbaldehyde (10 g) and sodium dihydrogen phosphate (26 g) in tert-butanol: water: 2-methyl-2-butene = 5: 4: 1 The mixture was suspended in a solution (200 mL), sodium chlorite (35 g) was slowly added thereto, and the mixture was stirred at room temperature for 5 hours. After tert-butanol was distilled off under reduced pressure, the residue was adjusted to pH 3 with 1N hydrochloric acid. The resulting precipitate was collected by filtration, washed with diethyl ether, and dried under reduced pressure to give the title compound (2.8 g, 25%) as a pale yellow solid.
NMR (300 MHz, DMSO-d ₆ ) δ: 1.17 (3H, t), 2.32 (3H, s), 2.56 (2H, q).
41b) 4-{[(4-Ethyl-2-methyl-1H-imidazol-5-yl) carbonyl] (2-hydroxyethyl) amino} piperidine-1-carboxylate tert-butyl obtained in Example 41a) The title compound (3.3 g, 57%) was obtained as a yellow oil from 4-ethyl-2-methyl-1H-imidazole-5-carboxylic acid in the same manner as in Example 39a).
NMR (300MHz, CDCl ₃ ) δ: 1.24 (3H, t), 1.46 (9H, s), 1.67-1.87 (4H, m), 2.24 (3H, m), 2.61 (2H, q), 2.76-2.83 ( 4H, m), 3.64 (2H, t), 3.79-3.81 (2H, m).
41c) tert-Butyl 4- (1-ethyl-3-methyl-8-oxo-5,6-dihydroimidazo [1,5-a] pyrazin-7 (8H) -yl) piperidine-1-carboxylate Example 38c from tert-butyl 4-{[(4-ethyl-2-methyl-1H-imidazol-5-yl) carbonyl] (2-hydroxyethyl) amino} piperidine-1-carboxylate obtained in 41b) ) To give the title compound (1.1 g, 35%) as a yellow oil.
NMR (200MHz, CDCl ₃ ) δ: 1.31 (3H, t), 1.47 (9H, s), 1.67-1.75 (4H, m), 2.52 (3H, s), 2.67 (2H, q), 2.84 (2H, t), 3.50-3.56 (2H, m), 3.91-4.02 (2H, m), 4.21-4.27 (2H, m), 4.72-4.84 (1H, m).
41d) 7- (1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -1-ethyl-3-methyl-6,7-dihydroimidazo [1,5-a Pyrazin-8 (5H) -one 4- (1-ethyl-3-methyl-8-oxo-5,6-dihydroimidazo [1,5-a] pyrazine-7 (8H) obtained in Example 41c) The title compound (740 mg, 45%) was obtained as white crystals (ethyl acetate / ethanol) from tert-butyl) -yl) piperidine-1-carboxylate in the same manner as in Example 38d).
NMR (300MHz, CDCl ₃ ) δ: 1.31 (3H, t), 1.50-1.84 (4H, m), 2.51 (3H, s), 2.60-2.70 (3H, m), 2.77-2.87 (1H, m), 2.93-3.04 (1H, m), 3.19 (1H, t), 3.45-3.55 (3H, m), 3.59-3.69 (1H, m), 3.96-4.00 (3H, m), 4.69 (1H, d), 4.85 (1H, tt), 7.59 (1H, dd), 7.89-7.96 (4H, m), 8.48 (1H, d).
Elemental analysis calculated as C ₂₇ H ₃₁ ClN ₄ O ₄ S · 0.1 EtOAc (%): C, 59.63; H, 5.81; N, 10.15
Found (%): C, 59.34; H, 5.61; N, 10.16

実施例42
2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-5-エチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
42a) 4-{[(2-エチル-1H-イミダゾール-4-イル)メチル]アミノ}ピペリジン-1-カルボン酸tert-ブチル
2-エチルイミダゾール-4-カルバルデヒド（5.0g）、4-アミノピペリジン-1-カルボン酸tert-ブチル（8.9g）および酢酸（1.0mL）の1,2-ジクロロエタン（100mL）溶液を室温で１時間かき混ぜた後、トリアセトキシ水素化ホウ素ナトリウム（17g）を加え、室温で15時間かき混ぜた。反応液へ飽和炭酸水素ナトリウム水溶液（100mL）を加えた。有機層を分離し、無水硫酸マグネシウムで乾燥させた後、溶媒を減圧留去した。残留物を塩基性シリカゲルカラム（酢酸エチル：エタノール＝10：１）で精製し、題記化合物(10g, 81%)を黄色油状物として得た。
NMR (300MHz, CDCl₃) δ：1.19-1.31 (5H, m), 1.46 (9H, s), 1.46-1.84 (2H, m), 2.67-2.81 (4H, m), 3.75 (2H, s), 4.04-4.09 (3H, m), 6.73 (1H, s).
42b) 4-(5-エチル-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル)ピペリジン-1-カルボン酸 tert-ブチル
実施例42a)で得られた4-{[(2-エチル-1H-イミダゾール-4-イル)メチル]アミノ}ピペリジン-1-カルボン酸tert-ブチル（10g）およびDBU（5.8mL）のジクロロメタン（100mL）溶液へN,N'-カルボニルジイミダゾール（5.8g）を加え、室温で５時間かき混ぜた。反応液に水（100mL）を加え、有機層を分離した後、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残留物をシリカゲルカラム（酢酸エチル：エタノール＝５：１）で精製し、題記化合物(4.8g, 44%)を無色油状物として得た。
NMR (300MHz, CDCl₃) δ：1.35 (3H, t), 1.40-1.49 (11H, m), 1.64 (2H, qd), 1.85 (2H, d), 2.83 (2H, t), 3.02 (2H, t), 4.04-4.15 (1H, m), 4.30 (2H, m), 6.72 (1H, t).
42c) 2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-5-エチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
実施例42b)で得られた4-(5-エチル-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル)ピペリジン-1-カルボン酸 tert-ブチルから実施例38d)と同様にして題記化合物(1.7g, 47％)を白色結晶(エタノール/酢酸エチル)として得た。
NMR (300MHz, CDCl₃) δ：1.35 (3H, t), 1.58-1.75 (2H, m), 1.87-1.99 (2H, m), 2.63 (1H, t), 2.82-2.93 (2H, m), 3.00 (2H, q), 3.19 (1H, t), 3.47-3.65 (1H, m), 3.99 (1H, d), 4.08-4.22 (1H, m), 4.25 (2H, s), 4.72 (1H, d), 6.72 (1H, t), 7.59 (1H, dd), 7.89-7.26 (4H, m), 8.48 (1H, s).
元素分析値 C₂₅H₂₇ClN₄O₄S・0.5EtOAcとして
計算値（％）：C, 58.00； H, 5.59； N, 10.02
実測値（％）：C, 57.83； H, 5.32； N, 10.25 Example 42
2- (1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -5-ethyl-1,2-dihydro-3H-imidazo [1,5-c] imidazole- 3-on
42a) 4-{[(2-Ethyl-1H-imidazol-4-yl) methyl] amino} piperidine-1-carboxylate tert-butyl
A solution of 1,2-dichloroethane (100 mL) in 2-ethylimidazole-4-carbaldehyde (5.0 g), tert-butyl 4-aminopiperidine-1-carboxylate (8.9 g) and acetic acid (1.0 mL) at room temperature After stirring for a period of time, sodium triacetoxyborohydride (17 g) was added, and the mixture was stirred at room temperature for 15 hours. A saturated aqueous sodium hydrogen carbonate solution (100 mL) was added to the reaction solution. The organic layer was separated and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by basic silica gel column (ethyl acetate: ethanol = 10: 1) to give the title compound (10 g, 81%) as a yellow oil.
NMR (300 MHz, CDCl ₃ ) δ: 1.19-1.31 (5H, m), 1.46 (9H, s), 1.46-1.84 (2H, m), 2.67-2.81 (4H, m), 3.75 (2H, s), 4.04-4.09 (3H, m), 6.73 (1H, s).
42b) 4- (5-Ethyl-3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl) piperidine-1-carboxylate tert-butyl obtained in Example 42a) -{[(2-Ethyl-1H-imidazol-4-yl) methyl] amino} piperidine-1-carboxylate to a solution of tert-butyl (10 g) and DBU (5.8 mL) in dichloromethane (100 mL) N, N'- Carbonyldiimidazole (5.8 g) was added and stirred at room temperature for 5 hours. Water (100 mL) was added to the reaction solution, the organic layer was separated, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column (ethyl acetate: ethanol = 5: 1) to give the title compound (4.8 g, 44%) as a colorless oil.
NMR (300MHz, CDCl ₃ ) δ: 1.35 (3H, t), 1.40-1.49 (11H, m), 1.64 (2H, qd), 1.85 (2H, d), 2.83 (2H, t), 3.02 (2H, t), 4.04-4.15 (1H, m), 4.30 (2H, m), 6.72 (1H, t).
42c) 2- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -5-ethyl-1,2-dihydro-3H-imidazo [1,5-c] 4- (5-Ethyl-3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl) piperidine-1-carboxylic acid tert-obtained in Example 42b) The title compound (1.7 g, 47%) was obtained as white crystals (ethanol / ethyl acetate) in the same manner as in Example 38d) from -butyl.
NMR (300MHz, CDCl ₃ ) δ: 1.35 (3H, t), 1.58-1.75 (2H, m), 1.87-1.99 (2H, m), 2.63 (1H, t), 2.82-2.93 (2H, m), 3.00 (2H, q), 3.19 (1H, t), 3.47-3.65 (1H, m), 3.99 (1H, d), 4.08-4.22 (1H, m), 4.25 (2H, s), 4.72 (1H, d), 6.72 (1H, t), 7.59 (1H, dd), 7.89-7.26 (4H, m), 8.48 (1H, s).
Elemental analysis: Calculated as C ₂₅ H ₂₇ ClN ₄ O ₄ S · 0.5 EtOAc (%): C, 58.00; H, 5.59; N, 10.02
Found (%): C, 57.83; H, 5.32; N, 10.25

実施例43
2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-メチル-4-ピペリジニル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン塩酸塩
43a) 4-メチル-4-{[(2-メチル-1H-イミダゾール-4-イル)メチル]アミノ}ピペリジン-1-カルボン酸tert-ブチル
2-メチル-4-ホルミルイミダゾール（670mg）および4-アミノ-4-メチルピペリジン-1-カルボン酸 tert-ブチル（国際公開第01/40217号パンフレット）（1.3g）から実施例42a)と同様にして題記化合物(230mg, 12%)を無色油状物として得た。
NMR (200MHz, CDCl₃) δ：1.18 (3H, s), 1.45 (9H, s), 1.48-1.57 (4H, m), 2.39 (3H, s), 3.36-3.49 (4H, m), 3.66 (2H, s), 6.75 (1H, s).
43b) 4-メチル-4-(5-メチル-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル)ピペリジン-1-カルボン酸tert-ブチル
実施例43a)で得られた4-メチル-4-{[(2-メチル-1H-イミダゾール-4-イル)メチル]アミノ}ピペリジン-1-カルボン酸tert-ブチルから実施例42b)と同様にして題記化合物(170mg, 68%)を黄色油状物として得た。
NMR (300MHz, CDCl₃) δ：1.44 (3H, s), 1.46 (9H, s), 1.67-1.80 (2H, m), 2.04 (2H, bs), 2.59 (3H, s), 3.32-3.41 (2H, m), 3.55-3.60 (2H, m), 4.34 (2H, s), 6.66 (1H, s).
43c) 2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-メチル-4-ピペリジニル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン塩酸塩
実施例43b)で得られた4-メチル-4-(5-メチル-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル)ピペリジン-1-カルボン酸tert-ブチルから実施例38d)と同様にして2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-メチル-4-ピペリジニル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オンを無色油状物として得た。この油状物を酢酸エチル（2mL）に溶かし、4N塩化水素酢酸エチル溶液（200μL）を加え室温で10分かき混ぜた。沈殿物をろ取し、酢酸エチル、ジエチルエーテルで順次洗浄した後、減圧乾燥して題記化合物(153mg, 51%)を白色固体として得た。
NMR (200MHz, CDCl₃) δ：1.54 (3H, s), 1.75-2.02 (2H, m), 2.17-2.25 (1H, m), 2.47-2.55 (1H, m), 2.85-2.92 (2H, m), 2.96 (3H, s), 3.46-3.63 (6H, m), 4.65 (2H, s), 7.22 (1H, s), 7.57-7.62 (1H, m), 7.88-7.98 (4H, m), 8.48 (1H, s).
元素分析値 C₂₅H₂₇ClN₄O₄S・HClとして
計算値（％）：C, 51.90； H, 5.40； N, 9.68
実測値（％）：C, 52.16； H, 5.55； N, 9.81 Example 43
2- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-methyl-4-piperidinyl) -5-methyl-1,2-dihydro-3H-imidazo [1,5- c] imidazol-3-one hydrochloride
43a) tert-butyl 4-methyl-4-{[(2-methyl-1H-imidazol-4-yl) methyl] amino} piperidine-1-carboxylate
Similar to Example 42a) from 2-methyl-4-formylimidazole (670 mg) and tert-butyl 4-amino-4-methylpiperidine-1-carboxylate (WO 01/40217 pamphlet) (1.3 g). The title compound (230 mg, 12%) was obtained as a colorless oil.
NMR (200MHz, CDCl ₃ ) δ: 1.18 (3H, s), 1.45 (9H, s), 1.48-1.57 (4H, m), 2.39 (3H, s), 3.36-3.49 (4H, m), 3.66 ( 2H, s), 6.75 (1H, s).
43b) tert-butyl 4-methyl-4- (5-methyl-3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl) piperidine-1-carboxylate
Example 42b) was obtained from tert-butyl 4-methyl-4-{[(2-methyl-1H-imidazol-4-yl) methyl] amino} piperidine-1-carboxylate obtained in Example 43a). The title compound (170 mg, 68%) was obtained as a yellow oil.
NMR (300MHz, CDCl ₃ ) δ: 1.44 (3H, s), 1.46 (9H, s), 1.67-1.80 (2H, m), 2.04 (2H, bs), 2.59 (3H, s), 3.32-3.41 ( 2H, m), 3.55-3.60 (2H, m), 4.34 (2H, s), 6.66 (1H, s).
43c) 2- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-methyl-4-piperidinyl) -5-methyl-1,2-dihydro-3H-imidazo [1, 5-c] imidazol-3-one hydrochloride 4-methyl-4- (5-methyl-3-oxo-1H-imidazo [1,5-c] imidazole-2 (3H) obtained in Example 43b) 2- (1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4-methyl-4-l-yl) piperidine-1-carboxylate from tert-butyl as in Example 38d) Piperidinyl) -5-methyl-1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one was obtained as a colorless oil. This oil was dissolved in ethyl acetate (2 mL), 4N hydrogen chloride ethyl acetate solution (200 μL) was added, and the mixture was stirred at room temperature for 10 min. The precipitate was collected by filtration, washed successively with ethyl acetate and diethyl ether, and dried under reduced pressure to give the title compound (153 mg, 51%) as a white solid.
NMR (200MHz, CDCl ₃ ) δ: 1.54 (3H, s), 1.75-2.02 (2H, m), 2.17-2.25 (1H, m), 2.47-2.55 (1H, m), 2.85-2.92 (2H, m ), 2.96 (3H, s), 3.46-3.63 (6H, m), 4.65 (2H, s), 7.22 (1H, s), 7.57-7.62 (1H, m), 7.88-7.98 (4H, m), 8.48 (1H, s).
Elemental analysis value Calculated as C ₂₅ H ₂₇ ClN ₄ O ₄ S · HCl (%): C, 51.90; H, 5.40; N, 9.68
Found (%): C, 52.16; H, 5.55; N, 9.81

実施例44
2-(1-{3-[(4-ブロモフェニル)スルホニル]プロパノイル}-4-ピペリジニル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
3-[(4-ブロモフェニル)スルホニル]プロピオン酸（国際公開第98/05635号パンフレット）（1.1g）および実施例69b)で得られた5-メチル-2-(4-ピペリジニル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール（1.0g）から実施例38d)と同様にして題記化合物(720mg, 39%)を白色結晶(クロロホルム/ジエチルエーテル)として得た。
NMR (300MHz, CDCl₃) δ：1.56-1.77 (2H, m), 1.88-2.05 (2H, m), 2.61 (3H, s), 2.66-2.70 (1H, m), 2.76-2.99 (2H, m), 3.15-3.25 (1H, m), 3.38-3.59 (2H, m), 3.98 (1H, d), 4.18 (1H, m), 4.27 (2H, s), 4.73 (1H, d), 6.71 (1H, t), 7.71-7.80 (4H, m).
元素分析値 C₂₀H₂₃BrN₄O₄S・H₂Oとして
計算値（％）：C, 46.79； H, 4.91； N, 10.91
実測値（％）：C, 47.09； H, 4.77； N, 11.03 Example 44
2- (1- {3-[(4-Bromophenyl) sulfonyl] propanoyl} -4-piperidinyl) -5-methyl-1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one
3-[(4-Bromophenyl) sulfonyl] propionic acid (WO 98/05635 pamphlet) (1.1 g) and 5-methyl-2- (4-piperidinyl) -1, obtained in Example 69b) The title compound (720 mg, 39%) was obtained as white crystals (chloroform / diethyl ether) from 2-dihydro-3H-imidazo [1,5-c] imidazole (1.0 g) in the same manner as in Example 38d).
NMR (300MHz, CDCl ₃ ) δ: 1.56-1.77 (2H, m), 1.88-2.05 (2H, m), 2.61 (3H, s), 2.66-2.70 (1H, m), 2.76-2.99 (2H, m ), 3.15-3.25 (1H, m), 3.38-3.59 (2H, m), 3.98 (1H, d), 4.18 (1H, m), 4.27 (2H, s), 4.73 (1H, d), 6.71 ( 1H, t), 7.71-7.80 (4H, m).
Elemental analysis value Calculated as C ₂₀ H ₂₃ BrN ₄ O ₄ S · H ₂ O (%): C, 46.79; H, 4.91; N, 10.91
Found (%): C, 47.09; H, 4.77; N, 11.03

実施例45
6-(4-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-1-ピペリジニル)-2-メチル-6,7-ジヒドロ-5H-イミダゾ[1,5-a]イミダゾール-5-オン
45a) 4-メチルイミダゾール-2-カルバルデヒド
4-メチルイミダゾールから文献（N. J. Curtis et al. J. Org. Chem., 45, 4038 (1980)）に従って合成した（99%）。
NMR (300MHz, DMSO-d₆) δ：2.23 (3H, s), 6.81 (1H, s), 9.51 (1H, s).
45b) 4-{[(4-メチル-1H-イミダゾール-2-イル)メチル]アミノ}ピペリジン-1-カルボン酸tert-ブチル
実施例45a)で得られた4-メチルイミダゾール-2-カルバルデヒド（3.4g）および4-アミノピペリジン-1-カルボン酸tert-ブチル（6.3g）から実施例42a)と同様にして題記化合物(6.3g, 68%)を黄色油状物として得た。
NMR (300MHz, CDCl₃) δ：1.16-1.29 (2H, m), 1.45 (9H, s), 1.84 (2H, d), 2.22 (3H, s), 2.59-2.66 (1H, m), 2.76 (2H, t), 3.89 (2H, s), 4.00 (2H, bs), 6.63 (1H, s).
45c) 4-(2-メチル-5-オキソ-5H-イミダゾ[1,5-a]イミダゾール-6(7H)-イル)ピペリジン-1-カルボン酸tert-ブチル
実施例45b)で得られた4-{[(4-メチル-1H-イミダゾール-2-イル)メチル]アミノ}ピペリジン-1-カルボン酸tert-ブチルから実施例42b)と同様にして題記化合物(1.2g, 46%)を黄色油状物として得た。
NMR (300MHz, CDCl₃) δ：1.47 (9H, s), 1.56-1.70 (2H, m), 1.85 (2H, d), 2.28 (3H, s), 2.82 (2H, t), 4.10-4.24 (3H, m), 4.27 (2H, s), 7.00 (1H, s).
45d) 6-(4-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-1-ピペリジニル)-2-メチル-6,7-ジヒドロ-5H-イミダゾ[1,5-a]イミダゾール-5-オン
実施例45c)で得られた4-(2-メチル-5-オキソ-5H-イミダゾ[1,5-a]イミダゾール-6(7H)-イル)ピペリジン-1-カルボン酸tert-ブチルから実施例38b)と同様にして題記化合物(950mg, 51%)を白色結晶(酢酸エチル/エタノール)として得た。
NMR (300MHz, CDCl₃) δ：1.53-1.75 (2H, m), 1.88-2.01 (2H, m), 2.28 (3H, s), 2.62 (1H, t), 2.81-3.02 (2H, m), 3.18 (1H, t), 3.47-3.64 (2H, m), 3.99 (1H, d), 4.18-4.27 (3H, m), 4.71 (1H, d), 7.01 (1H, d), 7.59 (1H, dd), 7.89-7.96 (4H, m), 8.47 (1H, d).
元素分析値 C₂₄H₂₅N₄O₄SCl・0.1EtOAcとして
計算値（％）：C, 57.48； H, 5.10； N, 10.99
実測値（％）：C, 57.19； H, 5.17； N, 11.01 Example 45
6- (4- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -1-piperidinyl) -2-methyl-6,7-dihydro-5H-imidazo [1,5-a] imidazole- 5-on
45a) 4-Methylimidazole-2-carbaldehyde
Synthesized from 4-methylimidazole according to the literature (NJ Curtis et al. J. Org. Chem., 45, 4038 (1980)) (99%).
NMR (300 MHz, DMSO-d ₆ ) δ: 2.23 (3H, s), 6.81 (1H, s), 9.51 (1H, s).
45b) tert-butyl 4-{[(4-methyl-1H-imidazol-2-yl) methyl] amino} piperidine-1-carboxylate
In the same manner as in Example 42a), the title compound (4-methylimidazole-2-carbaldehyde obtained in Example 45a) (3.4 g) and tert-butyl 4-aminopiperidine-1-carboxylate (6.3 g) were used. 6.3 g, 68%) was obtained as a yellow oil.
NMR (300MHz, CDCl ₃ ) δ: 1.16-1.29 (2H, m), 1.45 (9H, s), 1.84 (2H, d), 2.22 (3H, s), 2.59-2.66 (1H, m), 2.76 ( 2H, t), 3.89 (2H, s), 4.00 (2H, bs), 6.63 (1H, s).
45c) 4- (2-Methyl-5-oxo-5H-imidazo [1,5-a] imidazol-6 (7H) -yl) piperidine-1-carboxylate tert-butyl obtained in Example 45b) -{[(4-Methyl-1H-imidazol-2-yl) methyl] amino} piperidine-1-carboxylate from tert-butyl in the same manner as in Example 42b) to give the title compound (1.2 g, 46%) as a yellow oil Obtained as a thing.
NMR (300MHz, CDCl ₃ ) δ: 1.47 (9H, s), 1.56-1.70 (2H, m), 1.85 (2H, d), 2.28 (3H, s), 2.82 (2H, t), 4.10-4.24 ( 3H, m), 4.27 (2H, s), 7.00 (1H, s).
45d) 6- (4- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -1-piperidinyl) -2-methyl-6,7-dihydro-5H-imidazo [1,5-a] 4- (2-Methyl-5-oxo-5H-imidazo [1,5-a] imidazol-6 (7H) -yl) piperidine-1-carboxylic acid tert obtained in Example 45c) The title compound (950 mg, 51%) was obtained as white crystals (ethyl acetate / ethanol) from -butyl in the same manner as in Example 38b).
NMR (300MHz, CDCl ₃ ) δ: 1.53-1.75 (2H, m), 1.88-2.01 (2H, m), 2.28 (3H, s), 2.62 (1H, t), 2.81-3.02 (2H, m), 3.18 (1H, t), 3.47-3.64 (2H, m), 3.99 (1H, d), 4.18-4.27 (3H, m), 4.71 (1H, d), 7.01 (1H, d), 7.59 (1H, dd), 7.89-7.96 (4H, m), 8.47 (1H, d).
Elemental Analysis Value Calculated as C ₂₄ H ₂₅ N ₄ O ₄ SCl · 0.1 EtOAc (%): C, 57.48; H, 5.10; N, 10.99
Found (%): C, 57.19; H, 5.17; N, 11.01

実施例46
6-(4-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-1-ピペリジニル)-2-メチル-6,7-ジヒドロ-5H-イミダゾ[1,5-a]イミダゾール-5-オン塩酸塩
46a) 4-ヒドロキシ-4-(7-オキソ-6,7-ジヒドロ-5H-ピロロ[1,2-c]イミダゾール-6-イル)ピペリジン-1-カルボン酸tert-ブチル
アルゴン雰囲気下、ビス(トリメチルシリル)アミドリチウムのヘキサン溶液（1.0 M, 13mL）をTHF（10mL）で希釈した後、−60℃に冷却した。この溶液へ5,6-ジヒドロ-7H-ピロロ[1,2-c]イミダゾール-7-オン（C. Christine et al. Tetrahedron, 56, 1837 (2000)）(1.0g)のTHF溶液（50mL）を-60℃で滴下し、その温度で２時間かき混ぜた。続いて、無水塩化セリウム（3.0g）のTHF懸濁液（20mL）を-60℃で加えた後、4-オキソピペリジン-1-カルボン酸tert-ブチル（1.4g）のTHF（20mL）溶液を滴下し、同温度で３時間かき混ぜた。-60℃で飽和塩化アンモニウム水溶液（50mL）を加え、室温に戻した後、クロロホルム（50mL）で抽出した。有機層を分液し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。残留物を塩基性シリカゲルカラム（酢酸エチル）で精製し、題記化合物(1.2g, 52%)を白色固体として得た。
NMR (300MHz, CDCl₃) δ：1.45 (9H, s), 1.48-1.71 (2H, m), 3.15 (2H, bs), 3.37 (1H, dd), 3.69-3.92 (4H, m), 4.24 (1H, dd), 4.48 (1H, dd), 7.60 (1H, s), 7.74 (1H, s).
46b) 6-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-5,6-ジヒドロ-7H-ピロロ[1,2-c]イミダゾール-7-オン塩酸塩
実施例46a)で得られた4-ヒドロキシ-4-(7-オキソ-6,7-ジヒドロ-5H-ピロロ[1,2-c]イミダゾール-6-イル)ピペリジン-1-カルボン酸tert-ブチル（480mg）を濃塩酸（10mL）に溶かし、100℃で15時間加熱した。室温に冷却し、溶媒を減圧留去した後、残留物をメタノール：水＝１：１混合溶媒（10mL）に溶かし、10% Pd/C（50 mg）を加え、水素雰囲気下で３時間かき混ぜた。反応液をセライトを用いてろ過した後、ろ液を減圧濃縮し、6-(4-ピペリジニル)-5,6-ジヒドロ-7H-ピロロ[1,2-c]イミダゾール-7-オン・２塩酸塩を褐色固体として得た。本化合物から実施例43c)と同様にして題記化合物(300mg, 34%)を白色固体として得た。
NMR (300MHz, CDCl₃) δ：1.17-1.55 (3H, m), 1.78-1.97 (1H, m), 2.29-2.55 (2H, m), 2.73-3.03 (3H, m), 3.41-3.57 (3H, m), 3.88 (1H, bs), 4.53 (1H, bs), 4.71 (1H, bs), 4.95 (1H, bs), 7.58 (1H, dd), 7.86-7.99 (5H, m), 8.47 (1H, s), 9.66 (1H, s).
元素分析値 C₂₄H₂₄N₃O₄SCl・HCl・0.5H₂Oとして
計算値（％）：C, 54.24； H, 4.93； N, 7.91
実測値（％）：C, 54.37； H, 4.93； N, 7.86 Example 46
6- (4- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -1-piperidinyl) -2-methyl-6,7-dihydro-5H-imidazo [1,5-a] imidazole- 5-one hydrochloride
46a) 4-hydroxy-4- (7-oxo-6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-6-yl) piperidine-1-carboxylate tert-butyl bis ( A hexane solution (1.0 M, 13 mL) of trimethylsilyl) amidolithium was diluted with THF (10 mL), and then cooled to −60 ° C. To this solution, THF solution (50 mL) of 5,6-dihydro-7H-pyrrolo [1,2-c] imidazol-7-one (C. Christine et al. Tetrahedron, 56, 1837 (2000)) (1.0 g) Was added dropwise at −60 ° C. and stirred at that temperature for 2 hours. Subsequently, a THF suspension (20 mL) of anhydrous cerium chloride (3.0 g) was added at −60 ° C., and then a THF (20 mL) solution of tert-butyl 4-oxopiperidine-1-carboxylate (1.4 g) was added. The solution was added dropwise and stirred at the same temperature for 3 hours. Saturated aqueous ammonium chloride solution (50 mL) was added at −60 ° C., the temperature was returned to room temperature, and the mixture was extracted with chloroform (50 mL). The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by basic silica gel column (ethyl acetate) to give the title compound (1.2 g, 52%) as a white solid.
NMR (300MHz, CDCl ₃ ) δ: 1.45 (9H, s), 1.48-1.71 (2H, m), 3.15 (2H, bs), 3.37 (1H, dd), 3.69-3.92 (4H, m), 4.24 ( 1H, dd), 4.48 (1H, dd), 7.60 (1H, s), 7.74 (1H, s).
46b) 6- (1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -5,6-dihydro-7H-pyrrolo [1,2-c] imidazole-7- On hydrochloride
4-hydroxy-4- (7-oxo-6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-6-yl) piperidine-1-carboxylate tert-butyl obtained in Example 46a) (480 mg) was dissolved in concentrated hydrochloric acid (10 mL) and heated at 100 ° C. for 15 hours. After cooling to room temperature and evaporating the solvent under reduced pressure, the residue was dissolved in a 1: 1 mixture of methanol: water = 1: 1, 10% Pd / C (50 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 3 hours. It was. After the reaction solution was filtered using Celite, the filtrate was concentrated under reduced pressure, and 6- (4-piperidinyl) -5,6-dihydro-7H-pyrrolo [1,2-c] imidazol-7-one · 2 hydrochloric acid. The salt was obtained as a brown solid. The title compound (300 mg, 34%) was obtained as a white solid from this compound in the same manner as in Example 43c).
NMR (300MHz, CDCl ₃ ) δ: 1.17-1.55 (3H, m), 1.78-1.97 (1H, m), 2.29-2.55 (2H, m), 2.73-3.03 (3H, m), 3.41-3.57 (3H , m), 3.88 (1H, bs), 4.53 (1H, bs), 4.71 (1H, bs), 4.95 (1H, bs), 7.58 (1H, dd), 7.86-7.99 (5H, m), 8.47 ( 1H, s), 9.66 (1H, s).
Elemental analysis value C ₂₄ H ₂₄ N ₃ O ₄ Calculated as SCl · HCl · 0.5H ₂ O (%): C, 54.24; H, 4.93; N, 7.91
Found (%): C, 54.37; H, 4.93; N, 7.86

実施例47
6-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ヒドロキシ-4-ピペリジニル)-1-メチル-5,6-ジヒドロ-7H-ピロロ[1,2-c]イミダゾール-7-オン
47a) 1-メチル-5,6-ジヒドロ-7H-ピロロ[1,2-c]イミダゾール-7-オン
4-メチル-1H-イミダゾール-5-カルバルデヒドから文献記載の方法（C. Christine et al. Tetrahedron, 56, 1837 (2000)）に従って合成した（収率 8.5%）。
NMR (300MHz, CDCl₃) δ：2.44 (3H, s), 3.19 (2H, t), 4.31 (2H, t), 7.58 (1H, s).
47b) 4-ヒドロキシ-4-(1-メチル-7-オキソ-6,7-ジヒドロ-5H-ピロロ[1,2-c]イミダゾール-6-イル)ピペリジン-1-カルボン酸tert-ブチル
実施例47a)で得られた1-メチル-5,6-ジヒドロ-7H-ピロロ[1,2-c]イミダゾール-7-オン（500mg）から実施例46a)と同様にして題記化合物(790mg, 64%)を白色固体として得た。
NMR (300MHz, CDCl₃) δ：1.45 (9H, s), 1.48-1.76 (4H, m), 3.15-3.21 (2H, m), 3.82-3.95 (2H, m), 4.09 (1H, dd), 4.39 (1H, dd), 7.60 (1H, s).
47c) 6-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ヒドロキシ-4-ピペリジニル)-1-メチル-5,6-ジヒドロ-7H-ピロロ[1,2-c]イミダゾール-7-オン
実施例47b)で得られた4-ヒドロキシ-4-(1-メチル-7-オキソ-6,7-ジヒドロ-5H-ピロロ[1,2-c]イミダゾール-6-イル)ピペリジン-1-カルボン酸tert-ブチルから実施例38d)と同様にして題記化合物(170mg, 50%)を白色結晶(酢酸エチル/エタノール/ジエチルエーテル)として得た。
NMR (300MHz, CDCl₃) δ：1.46-1.89 (2H, m), 2.44 (3H, s), 2.83-3.06 (3H, m), 3.32-3.73 (6H, m), 3.97-4.12 (2H, m), 4.39 (2H, dd), 7.58-7.61 (2H, m), 7.88-7.98 (4H, m), 8.48 (1H, m).
元素分析値 C₂₅H₂₆N₃O₅SCl・0.6H₂Oとして
計算値（％）：C, 57.00； H, 5.20； N, 7.98
実測値（％）：C, 56.79； H, 5.28； N, 7.83 Example 47
6- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-hydroxy-4-piperidinyl) -1-methyl-5,6-dihydro-7H-pyrrolo [1,2- c] imidazol-7-one
47a) 1-Methyl-5,6-dihydro-7H-pyrrolo [1,2-c] imidazol-7-one
It was synthesized from 4-methyl-1H-imidazole-5-carbaldehyde according to a method described in the literature (C. Christine et al. Tetrahedron, 56, 1837 (2000)) (yield 8.5%).
NMR (300 MHz, CDCl ₃ ) δ: 2.44 (3H, s), 3.19 (2H, t), 4.31 (2H, t), 7.58 (1H, s).
47b) tert-butyl 4-hydroxy-4- (1-methyl-7-oxo-6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-6-yl) piperidine-1-carboxylate
From 1-methyl-5,6-dihydro-7H-pyrrolo [1,2-c] imidazol-7-one (500 mg) obtained in Example 47a) in the same manner as in Example 46a), the title compound (790 mg, 64%) was obtained as a white solid.
NMR (300 MHz, CDCl ₃ ) δ: 1.45 (9H, s), 1.48-1.76 (4H, m), 3.15-3.21 (2H, m), 3.82-3.95 (2H, m), 4.09 (1H, dd), 4.39 (1H, dd), 7.60 (1H, s).
47c) 6- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-hydroxy-4-piperidinyl) -1-methyl-5,6-dihydro-7H-pyrrolo [1, 2-c] imidazol-7-one 4-hydroxy-4- (1-methyl-7-oxo-6,7-dihydro-5H-pyrrolo [1,2-c] imidazole- obtained in Example 47b) The title compound (170 mg, 50%) was obtained as white crystals (ethyl acetate / ethanol / diethyl ether) from tert-butyl 6-yl) piperidine-1-carboxylate in the same manner as in Example 38d).
NMR (300MHz, CDCl ₃ ) δ: 1.46-1.89 (2H, m), 2.44 (3H, s), 2.83-3.06 (3H, m), 3.32-3.73 (6H, m), 3.97-4.12 (2H, m ), 4.39 (2H, dd), 7.58-7.61 (2H, m), 7.88-7.98 (4H, m), 8.48 (1H, m).
Elemental analysis value Calculated as C ₂₅ H ₂₆ N ₃ O ₅ SCl · 0.6H ₂ O (%): C, 57.00; H, 5.20; N, 7.98
Found (%): C, 56.79; H, 5.28; N, 7.83

実施例48
6-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-1-メチル-5,6-ジヒドロ-7H-ピロロ[1,2-c]イミダゾール-7-オン塩酸塩
実施例47b)で得られた4-ヒドロキシ-4-(1-メチル-7-オキソ-6,7-ジヒドロ-5H-ピロロ[1,2-c]イミダゾール-6-イル)ピペリジン-1-カルボン酸tert-ブチルから実施例46b)と同様にして題記化合物(411mg, 38%)を白色固体として得た。
NMR (300MHz, CDCl₃) δ：1.31-1.40 (1H, m), 1.51-1.56 (1H, m), 1.80-1.98 (1H, m), 2.28 (1H, bs), 2.50 (1H, t), 2.62 (3H, s), 2.75-3.09 (3H, m), 3.25-3.31 (1H, m), 3.44-3.60 (2H, m), 3.88-3.89 (1H, m), 4.52-4.57 (2H, m), 4.78-4.87 (1H, m), 7.59 (1H, d), 7.88-7.97 (4H, m), 8.47 (1H, s), 9.54-9.58 (1H, m).
元素分析値 C₂₅H₂₇N₃O₄SCl₂・1.5H₂Oとして
計算値（％）：C, 53.29； H, 5.37； N, 7.46
実測値（％）：C, 53.08； H, 5.31； N, 7.65 Example 48
6- (1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -1-methyl-5,6-dihydro-7H-pyrrolo [1,2-c] imidazole- 7-one hydrochloride 4-hydroxy-4- (1-methyl-7-oxo-6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-6-yl) obtained in Example 47b) The title compound (411 mg, 38%) was obtained as a white solid from tert-butyl piperidine-1-carboxylate in the same manner as in Example 46b).
NMR (300 MHz, CDCl ₃ ) δ: 1.31-1.40 (1H, m), 1.51-1.56 (1H, m), 1.80-1.98 (1H, m), 2.28 (1H, bs), 2.50 (1H, t), 2.62 (3H, s), 2.75-3.09 (3H, m), 3.25-3.31 (1H, m), 3.44-3.60 (2H, m), 3.88-3.89 (1H, m), 4.52-4.57 (2H, m ), 4.78-4.87 (1H, m), 7.59 (1H, d), 7.88-7.97 (4H, m), 8.47 (1H, s), 9.54-9.58 (1H, m).
Elemental analysis value Calculated as C ₂₅ H ₂₇ N ₃ O ₄ SCl ₂ .1.5H ₂ O (%): C, 53.29; H, 5.37; N, 7.46
Found (%): C, 53.08; H, 5.31; N, 7.65

実施例49
6-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-6,7-ジヒドロ-5H-ピロロ[1,2-c]イミダゾール-7-オール
実施例46b)で得られた6-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-5,6-ジヒドロ-7H-ピロロ[1,2-c]イミダゾール-7-オン・塩酸塩（200mg）のジクロロエタン溶液（3mL）に酢酸（2mL）およびシアノ水素化ホウ素ナトリウム（390mg）を順次加え、室温で２時間かき混ぜた。反応液に飽和炭酸水素ナトリウム水溶液（30mL）を加え、酢酸エチル（30mL）で抽出した。有機層を分液し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。残留物を塩基性シリカゲルカラム（酢酸エチル：エタノール＝5:1）で精製後、酢酸エチル/エタノールから再結晶して題記化合物(45mg, 24%)を白色結晶として得た。
NMR (300MHz, CDCl₃) δ：1.12-1.38 (2H, m), 1.57-2.20 (5H, m), 2.48-2.60 (1H, m), 2.66-2.68 (1H, m), 2.83-2.89 (1H, m), 2.98-3.18 (1H, m), 3.54-3.64 (2H, m), 3.84-3.85 (1H, m), 4.06-4.24 (1H, m), 4.53-4.57 (1H, m), 4.98-4.99 (1H, m), 6.82 (1H, bs), 7.38 (1H, bs), 7.56-7.60 (1H, m), 7.88-7.95 (4H, m), 8.46 (1H, s).
元素分析値 C₂₄H₂₆N₃O₄SCl・0.5H₂O・0.1EtOAcとして
計算値（％）：C, 57.94； H, 5.54； N, 8.31
実測値（％）：C, 58.04； H, 5.53； N, 8.04 Example 49
6- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-ol
6- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -5,6-dihydro-7H-pyrrolo [1,2-] obtained in Example 46b) c] Acetic acid (2 mL) and sodium cyanoborohydride (390 mg) were sequentially added to a dichloroethane solution (3 mL) of imidazol-7-one hydrochloride (200 mg), and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate solution (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL). The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by basic silica gel column (ethyl acetate: ethanol = 5: 1) and recrystallized from ethyl acetate / ethanol to give the title compound (45 mg, 24%) as white crystals.
NMR (300MHz, CDCl ₃ ) δ: 1.12-1.38 (2H, m), 1.57-2.20 (5H, m), 2.48-2.60 (1H, m), 2.66-2.68 (1H, m), 2.83-2.89 (1H , m), 2.98-3.18 (1H, m), 3.54-3.64 (2H, m), 3.84-3.85 (1H, m), 4.06-4.24 (1H, m), 4.53-4.57 (1H, m), 4.98 -4.99 (1H, m), 6.82 (1H, bs), 7.38 (1H, bs), 7.56-7.60 (1H, m), 7.88-7.95 (4H, m), 8.46 (1H, s).
Elemental analysis: Calculated as C ₂₄ H ₂₆ N ₃ O ₄ SCl · 0.5H ₂ O · 0.1 EtOAc (%): C, 57.94; H, 5.54; N, 8.31
Found (%): C, 58.04; H, 5.53; N, 8.04

実施例50
N-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-1H-イミダゾール-4-カルボキサミド
50a) 1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}ピペリジン-4-アミン
ピペリジン-4-アミノ(26g)とベンズアルデヒド(27mL)から文献記載 (Synthetic Communications, 22, 1357-2360(1992))の方法に準じて、N-フェニルメチリデンピペリジニル-4-アミン(49g, 定量的)を合成し、精製することなく次の反応に用いた。
3-[(6-クロロ-2-ナフチル)スルホニル]プロピオン酸(2.4g)、N-フェニルメチリデンピペリジニル-4-アミン(1.5g) とHOBt(1.3g)のジクロロメタン(50mL)溶液へWSC(1.7g)を加え、室温で16時間かき混ぜた。反応液に1N HCl(30mL)を加え、室温で8時間かき混ぜた。反応液を炭酸カリウム水溶液でアルカリ性にした後、クロロホルムで抽出、抽出液を無水硫酸マグネシウムで乾燥した。溶媒を留去した後、残留物を塩基性シリカゲルカラムで精製して題記化合物(2.0g, 59%)を油状物として得た。
NMR (200MHz, CDCl₃) δ：1.59-1.70 (4H, m), 1.77-1.92 (2H, m), 2.62-2.75 (1H, m), 2.84-3.02 (2H, m), 3.06-3.25 (2H, m), 3.48-3.60 (2H, m), 3.76-3.84 (1H, m), 4.32-4.40 (1H, m), 7.59 (1H, dd, J = 8.8, 1.8), 7.93-7.98 (4H, m), 8.48 (1H, s).
50b) N-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-1H-イミダゾール-4-カルボキサミド
実施例50a)で得られた1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}ピペリジン-4-アミン(0.29g)、イミダゾール-4-カルボン酸(0.08g) とHOBt(0.13 g)のジクロロメタン(30mL)溶液へWSC(0.16g)を加え、室温で16時間かき混ぜた。反応液を炭酸カリウム水溶液でアルカリ性にした後、クロロホルムで抽出、抽出液を無水硫酸マグネシウムで乾燥した。溶媒を留去した後、残留物を塩基性シリカゲルカラムで精製して題記化合物(47mg, 13%)を白色粉末として得た。
NMR (300MHz, CDCl₃) δ：1.13-1.45 (2H, m), 1.92-2.08 (2H, m), 2.74 (1H, t, J = 11.7), 2.82-2.89 (2H, m), 3.15 (1H, t, J = 11.7), 3.52-3.57 (2H, m), 3.78-3.82 (1H, m), 4.10-4.13 (1H, m), 4.36-4.41 (1H, m), 7.17-7.20 (1H, br), 7.56-7.59 (3H, m), 7.86-7.94 (4H, m), 8.45 (1H, s). Example 50
N- (1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -1H-imidazole-4-carboxamide
50a) 1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} piperidin-4-amine Reference from piperidin-4-amino (26 g) and benzaldehyde (27 mL) (Synthetic Communications, 22, 1357- 2360 (1992)), N-phenylmethylidenepiperidinyl-4-amine (49 g, quantitative) was synthesized and used in the next reaction without purification.
To a solution of 3-[(6-chloro-2-naphthyl) sulfonyl] propionic acid (2.4 g), N-phenylmethylidenepiperidinyl-4-amine (1.5 g) and HOBt (1.3 g) in dichloromethane (50 mL) WSC (1.7 g) was added and stirred at room temperature for 16 hours. 1N HCl (30 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 8 hours. The reaction solution was made alkaline with an aqueous potassium carbonate solution, extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified with a basic silica gel column to give the title compound (2.0 g, 59%) as an oil.
NMR (200MHz, CDCl ₃ ) δ: 1.59-1.70 (4H, m), 1.77-1.92 (2H, m), 2.62-2.75 (1H, m), 2.84-3.02 (2H, m), 3.06-3.25 (2H , m), 3.48-3.60 (2H, m), 3.76-3.84 (1H, m), 4.32-4.40 (1H, m), 7.59 (1H, dd, J = 8.8, 1.8), 7.93-7.98 (4H, m), 8.48 (1H, s).
50b) N- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -1H-imidazole-4-carboxamide 1- {3- obtained in Example 50a) [(6-Chloro-2-naphthyl) sulfonyl] propanoyl} piperidin-4-amine (0.29 g), imidazole-4-carboxylic acid (0.08 g) and HOBt (0.13 g) in dichloromethane (30 mL) to a solution of WSC (0.16 g) was added and stirred at room temperature for 16 hours. The reaction solution was made alkaline with an aqueous potassium carbonate solution, extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified with a basic silica gel column to give the title compound (47 mg, 13%) as a white powder.
NMR (300MHz, CDCl ₃ ) δ: 1.13-1.45 (2H, m), 1.92-2.08 (2H, m), 2.74 (1H, t, J = 11.7), 2.82-2.89 (2H, m), 3.15 (1H , t, J = 11.7), 3.52-3.57 (2H, m), 3.78-3.82 (1H, m), 4.10-4.13 (1H, m), 4.36-4.41 (1H, m), 7.17-7.20 (1H, br), 7.56-7.59 (3H, m), 7.86-7.94 (4H, m), 8.45 (1H, s).

実施例51
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-N-[(1H-イミダゾール-4-イル)メチル]ピペリジン-4-アミン
実施例50a)で得られた1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}ピペリジン-4-アミン(2.0g)、1-トリチルイミダゾール-4-カルバルデヒド(1.8g) と酢酸(0.3mL)の1,2-ジクロロエタン(30mL)溶液へトリアセトキシ水素化ホウ素ナトリウム(1.3g)を加え、室温で3時間かき混ぜた。反応液を炭酸カリウム水溶液でアルカリ性にした後、クロロホルムで抽出、抽出液を無水硫酸マグネシウムで乾燥した。溶媒を留去した後、残留物を塩基性シリカゲルカラムで精製して1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-N-[(1-トリチルイミダゾール-4-イル)メチル]ピペリジン-4-アミン(3.0g, 84%)を得た。この中間体(0.5g)を、メタノール(10mL)および1N 塩酸(5mL)に溶解し、90℃で3時間かき混ぜた。反応液を炭酸カリウム水溶液でアルカリ性にした後、クロロホルムで抽出、抽出液を無水硫酸マグネシウムで乾燥した。溶媒を留去した後、残留物を塩基性シリカゲルカラムで精製して題記化合物(62mg, 19%)を白色粉末として得た。
NMR (300MHz, CDCl₃) δ：1.15-1.29 (2H, m), 1.79-1.93 (2H, m), 2.62-2.86 (4H, m), 2.97-3.09 (1H, m), 3.48-3.56 (2H, m), 3.63-3.75 (3H, m), 4.24-4.31 (1H, m), 6.85 (1H, s), 7.52-7.57 (2H, m), 7.87-7.93 (4H, m), 8.43(1H, s). Example 51
1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -N-[(1H-imidazol-4-yl) methyl] piperidin-4-amine 1- {obtained from Example 50a) 3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} piperidin-4-amine (2.0 g), 1-tritylimidazole-4-carbaldehyde (1.8 g) and acetic acid (0.3 mL) 1,2- To a dichloroethane (30 mL) solution was added sodium triacetoxyborohydride (1.3 g), and the mixture was stirred at room temperature for 3 hours. The reaction solution was made alkaline with an aqueous potassium carbonate solution, extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified on a basic silica gel column to give 1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -N-[(1-tritylimidazol-4-yl ) Methyl] piperidin-4-amine (3.0 g, 84%). This intermediate (0.5 g) was dissolved in methanol (10 mL) and 1N hydrochloric acid (5 mL) and stirred at 90 ° C. for 3 hours. The reaction solution was made alkaline with an aqueous potassium carbonate solution, extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified with a basic silica gel column to give the title compound (62 mg, 19%) as a white powder.
NMR (300MHz, CDCl ₃ ) δ: 1.15-1.29 (2H, m), 1.79-1.93 (2H, m), 2.62-2.86 (4H, m), 2.97-3.09 (1H, m), 3.48-3.56 (2H , m), 3.63-3.75 (3H, m), 4.24-4.31 (1H, m), 6.85 (1H, s), 7.52-7.57 (2H, m), 7.87-7.93 (4H, m), 8.43 (1H , s).

実施例52
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-N-[(2-メチル-1H-イミダゾール-4-イル)メチル]ピペリジン-4-アミン
52a) 1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-N-[(2-メチル-1-トリチルイミダゾール-4-イル)メチル]ピペリジン-4-アミン
実施例50a)で得られた1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジンアミン(4.0g)、2-メチル-1-トリチルイミダゾール-4-カルバルデヒド(3.7g)から実施例51と同様に還元的アミノ化を行い、題記化合物(1.9g, 24%)を白色粉末として得た。
NMR (200MHz, CDCl₃) δ：1.21-1.28(2H, m), 1.61(3H, s), 1.81-2.03(2H, m), 2.61-2.88(4H, m), 2.98-3.11(1H, m), 3.47-3.57(2H, m), 3.63(2H, s), 3.75-3.81(1H, m), 4.28-4.34(1H, m), 6.57(1H, s), 7.10-7.31(15H, m), 7.33-7.60(1H, m), 7.91-7.96(4H, m), 8.46(1H, s).
52b) 1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-N-[(2-メチル-1H-イミダゾール-4-イル)メチル]ピペリジン-4-アミン
実施例52a)で得られた1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-N-[(2-メチル-1-トリチルイミダゾール-4-イル)メチル]ピペリジン-4-アミン(0.4g)から実施例51と同様に脱トリチル化して、題記化合物(0.23g, 87%)を白色粉末として得た。
NMR (200MHz, CDCl₃) δ：1.19-1.31 (2H, m), 1.83-1.96 (2H, m), 2.37 (3H, s), 2.68-2.91 (4H, m), 3.00-3.13 (1H, m), 3.51-3.60 (2H, m), 3.72-3.82 (3H, m), 4.28-4.34 (1H, m), 6.74 (1H, s), 7.61 (1H, dd, J = 8.2, 1.8), 7.87-7.97(4H, m), 8.47(1H, m). Example 52
1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -N-[(2-methyl-1H-imidazol-4-yl) methyl] piperidin-4-amine
52a) 1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -N-[(2-methyl-1-tritylimidazol-4-yl) methyl] piperidin-4-amine Example 50a) 1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinamine (4.0 g), 2-methyl-1-tritylimidazole-4-carbaldehyde (3.7 g) To reductive amination in the same manner as in Example 51 to give the title compound (1.9 g, 24%) as a white powder.
NMR (200MHz, CDCl ₃ ) δ: 1.21-1.28 (2H, m), 1.61 (3H, s), 1.81-2.03 (2H, m), 2.61-2.88 (4H, m), 2.98-3.11 (1H, m ), 3.47-3.57 (2H, m), 3.63 (2H, s), 3.75-3.81 (1H, m), 4.28-4.34 (1H, m), 6.57 (1H, s), 7.10-7.31 (15H, m ), 7.33-7.60 (1H, m), 7.91-7.96 (4H, m), 8.46 (1H, s).
52b) 1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -N-[(2-methyl-1H-imidazol-4-yl) methyl] piperidin-4-amine In Example 52a) 1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -N-[(2-methyl-1-tritylimidazol-4-yl) methyl] piperidin-4-amine (0.4 g To give the title compound (0.23 g, 87%) as a white powder.
NMR (200MHz, CDCl ₃ ) δ: 1.19-1.31 (2H, m), 1.83-1.96 (2H, m), 2.37 (3H, s), 2.68-2.91 (4H, m), 3.00-3.13 (1H, m ), 3.51-3.60 (2H, m), 3.72-3.82 (3H, m), 4.28-4.34 (1H, m), 6.74 (1H, s), 7.61 (1H, dd, J = 8.2, 1.8), 7.87 -7.97 (4H, m), 8.47 (1H, m).

実施例53
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-N-[(4-メチル-1H-イミダゾール-5-イル)メチル]ピペリジン-4-アミン
53a) 1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-N-[(4-メチル-1-トリチルイミダゾール-5-イル)メチル]ピペリジン-4-アミン
実施例50a)で得られた1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}ピペリジン-4-アミン(2.0g)、4-メチル-1-トリチルイミダゾール-5-カルバルデヒド(1.9g)から実施例51と同様に還元的アミノ化を行い、題記化合物(2.2g, 59%)を白色粉末として得た。
NMR (200MHz, CDCl₃) δ：1.21-1.29(2H, m), 1.39(3H, s), 1.78-1.98(2H, m), 2.66-2.89(4H, m), 2.97-3.14(1H, m), 3.49-3.57(2H, m), 3.65(2H, s), 3.71-3.80(1H, m), 4.26-4.32(1H, m), 7.11-7.32(16H, m), 7.54-7.59(1H, m), 7.91-7.95(4H, m), 8.46(1H, s).
53b) 1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-N-[(4-メチル-1H-イミダゾール-5-イル)メチル]ピペリジン-4-アミン
実施例53a)で得られた1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-N-[(4-メチル-1-トリチルイミダゾール-5-イル)メチル]ピペリジン-4-アミン(0.7g)から実施例51と同様に脱トリチル化して、題記化合物(0.20g, 76%)を白色粉末として得た。
NMR (200MHz, CDCl₃) δ：1.20-1.30 (2H, m), 1.78-1.98 (2H, m), 2.15 (3H, s), 2.65-2.87 (4H, m), 2.95-3.12 (1H, m), 3.45-3.58 (2H, m), 3.67-3.78 (3H, m), 4.23-4.30 (1H, m), 5.01-5.68 (1H, br), 7.36-7.41 (1H, m), 7.54 (1H, dd), 7.88-7.93 (4H, m), 8.44(1H, s). Example 53
1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -N-[(4-methyl-1H-imidazol-5-yl) methyl] piperidin-4-amine
53a) 1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -N-[(4-methyl-1-tritylimidazol-5-yl) methyl] piperidin-4-amine Example 50a) 1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} piperidin-4-amine (2.0 g), 4-methyl-1-tritylimidazole-5-carbaldehyde (1.9 g) To reductive amination in the same manner as in Example 51 to give the title compound (2.2 g, 59%) as a white powder.
NMR (200MHz, CDCl ₃ ) δ: 1.21-1.29 (2H, m), 1.39 (3H, s), 1.78-1.98 (2H, m), 2.66-2.89 (4H, m), 2.97-3.14 (1H, m ), 3.49-3.57 (2H, m), 3.65 (2H, s), 3.71-3.80 (1H, m), 4.26-4.32 (1H, m), 7.11-7.32 (16H, m), 7.54-7.59 (1H , m), 7.91-7.95 (4H, m), 8.46 (1H, s).
53b) 1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -N-[(4-methyl-1H-imidazol-5-yl) methyl] piperidin-4-amine in Example 53a) The resulting 1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -N-[(4-methyl-1-tritylimidazol-5-yl) methyl] piperidin-4-amine (0.7 g ) To give the title compound (0.20 g, 76%) as a white powder.
NMR (200MHz, CDCl ₃ ) δ: 1.20-1.30 (2H, m), 1.78-1.98 (2H, m), 2.15 (3H, s), 2.65-2.87 (4H, m), 2.95-3.12 (1H, m ), 3.45-3.58 (2H, m), 3.67-3.78 (3H, m), 4.23-4.30 (1H, m), 5.01-5.68 (1H, br), 7.36-7.41 (1H, m), 7.54 (1H , dd), 7.88-7.93 (4H, m), 8.44 (1H, s).

実施例54
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-N-[(1H-イミダゾール-2-イル)メチル]ピペリジン-4-アミン
実施例50a)で得られた1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}ピペリジン-4-アミン(0.5g)、イミダゾール-2-カルバルデヒド(0.13g)から実施例51と同様に還元的アミノ化を行い、題記化合物(0.54g, 90%)を白色粉末として得た。
NMR (200MHz, CDCl₃) δ：1.02-1.48 (2H, m), 1.80-2.03 (2H, m), 2.69-3.06 (5H, m), 3.53-3.60 (2H, m), 3.75-3.96 (3H, m), 4.29-4.43 (1H, m), 7.02 (1H, s), 7.04 (1H, s), 7.51(1H, dd), 7.93-7.98 (4H, m), 8.49(1H, s). Example 54
1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -N-[(1H-imidazol-2-yl) methyl] piperidin-4-amine 1- {obtained from Example 50a) 3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} piperidin-4-amine (0.5 g), imidazole-2-carbaldehyde (0.13 g) was subjected to reductive amination in the same manner as in Example 51. The title compound (0.54 g, 90%) was obtained as a white powder.
NMR (200MHz, CDCl ₃ ) δ: 1.02-1.48 (2H, m), 1.80-2.03 (2H, m), 2.69-3.06 (5H, m), 3.53-3.60 (2H, m), 3.75-3.96 (3H , m), 4.29-4.43 (1H, m), 7.02 (1H, s), 7.04 (1H, s), 7.51 (1H, dd), 7.93-7.98 (4H, m), 8.49 (1H, s).

実施例55
N-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-N-(1H-イミダゾール-4-イル)メチルアセトアミド
実施例51で得られた1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-N-[(1-トリチルイミダゾール-4-イル)メチル]ピペリジン-4-アミン(0.6g)、トリエチルアミン(0.24mL)のジクロロメタン(30mL)溶液へ氷冷下、塩化アセチル(0.068mL)を加え、室温で16時間かき混ぜた。溶媒を留去後、残留物にトリフルオロ酢酸(5mL)加え、反応液を室温で1時間かき混ぜた。溶媒を留去後、残留物を炭酸カリウム水溶液でアルカリ性にした後、クロロホルムで抽出、抽出液を無水硫酸マグネシウムで乾燥した。溶媒を留去した後、残留物を塩基性シリカゲルカラムで精製して題記化合物(68mg, 16%)を淡黄色粉末として得た。
NMR (200MHz, CDCl₃) δ：1.52-1.84 (4H, m), 2.15 (3H, d), 2.44-2.60 (1H, m), 2.79-3.10 (3H, m), 3.49-3.56 (2H, m), 3.58-4.07 (2H, m), 4.32-4.37 (2H, m), 4.49-4.63 (1H, m), 6.79-6.89 (1H, m), 7.47-7.59 (2H, m), 7.89-7.95 (4H, m), 8.43-8.46 (1H, m). Example 55
N- (1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -N- (1H-imidazol-4-yl) methylacetamide 1- obtained in Example 51 {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -N-[(1-tritylimidazol-4-yl) methyl] piperidin-4-amine (0.6 g), triethylamine (0.24 mL) in dichloromethane Acetyl chloride (0.068 mL) was added to the (30 mL) solution under ice cooling, and the mixture was stirred at room temperature for 16 hr. After the solvent was distilled off, trifluoroacetic acid (5 mL) was added to the residue, and the reaction mixture was stirred at room temperature for 1 hour. After distilling off the solvent, the residue was made alkaline with an aqueous potassium carbonate solution, extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified with a basic silica gel column to give the title compound (68 mg, 16%) as a pale yellow powder.
NMR (200MHz, CDCl ₃ ) δ: 1.52-1.84 (4H, m), 2.15 (3H, d), 2.44-2.60 (1H, m), 2.79-3.10 (3H, m), 3.49-3.56 (2H, m ), 3.58-4.07 (2H, m), 4.32-4.37 (2H, m), 4.49-4.63 (1H, m), 6.79-6.89 (1H, m), 7.47-7.59 (2H, m), 7.89-7.95 (4H, m), 8.43-8.46 (1H, m).

実施例56
N-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-N-[(1H-イミダゾール-4-イル)メチル]メタンスルホンアミド
実施例51で得られた1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-N-[(1-トリチルイミダゾール-4-イル)メチル]ピペリジン-4-アミン(0.6g)、トリエチルアミン(0.24mL)のジクロロメタン(30mL)溶液へ氷冷下、塩化メタンスルホニル (0.074mL)を加え、室温で16時間かき混ぜた。溶媒を留去後、残留物にトリフルオロ酢酸(5mL)加え、反応液を室温で1時間かき混ぜた。溶媒を留去後、残留物を炭酸カリウム水溶液でアルカリ性にした後、クロロホルムで抽出、抽出液を無水硫酸マグネシウムで乾燥した。溶媒を留去した後、残留物を塩基性シリカゲルカラムで精製して題記化合物(90mg, 19%)を淡黄色粉末として得た。
NMR (200MHz, CDCl₃) δ：1.58-1.87 (4H, m), 2.17 (3H, s), 2.30-2.48 (1H, m), 2.64-3.09 (3H, m), 3.47-3.63 (2H, m), 3.72-3.94 (2H, m), 4.21-4.39 (2H, m), 4.51-4.57 (1H, m), 6.97 (1H, s), 7.51-7.55 (2H, m), 7.82-7.92 (4H, m), 8.42(1H, s). Example 56
N- (1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -N-[(1H-imidazol-4-yl) methyl] methanesulfonamide obtained in Example 51 1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -N-[(1-tritylimidazol-4-yl) methyl] piperidin-4-amine (0.6 g), triethylamine (0.24 mL) in dichloromethane (30 mL) was added methanesulfonyl chloride (0.074 mL) under ice-cooling, and the mixture was stirred at room temperature for 16 hours. After the solvent was distilled off, trifluoroacetic acid (5 mL) was added to the residue, and the reaction mixture was stirred at room temperature for 1 hour. After distilling off the solvent, the residue was made alkaline with an aqueous potassium carbonate solution, extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified with a basic silica gel column to give the title compound (90 mg, 19%) as a pale yellow powder.
NMR (200MHz, CDCl ₃ ) δ: 1.58-1.87 (4H, m), 2.17 (3H, s), 2.30-2.48 (1H, m), 2.64-3.09 (3H, m), 3.47-3.63 (2H, m ), 3.72-3.94 (2H, m), 4.21-4.39 (2H, m), 4.51-4.57 (1H, m), 6.97 (1H, s), 7.51-7.55 (2H, m), 7.82-7.92 (4H , m), 8.42 (1H, s).

実施例57
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-N-エチル-N-[(2-メチル1H-イミダゾール-4-イル)メチル]ピペリジン-4-アミン
実施例52a)で得られた1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-N-[(2-メチル-1-トリチルイミダゾール-4-イル)メチル]ピペリジン-4-アミン(0.5g)、アセトアルデヒド(0.05mL)から実施例51と同様にして題記化合物(0.23g, 65%)を淡黄色粉末として得た。
NMR (200MHz, CDCl₃) δ：1.03 (3H, t), 1.32-1.46 (2H, m), 1.72-1.86 (2H, m), 2.38 (3H, s), 2.46-2.58 (3H, m), 2.69-3.02 (4H, m), 3.52-3.60 (4H, m), 3.81-3.88 (1H, m), 4.49-4.56 (1H, m), 6.72 (1H, s), 7.29(1H, d), 7.58 (1H, dd), 7.92-7.97 (4H, m), 8.47 (1H, s). Example 57
1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -N-ethyl-N-[(2-methyl1H-imidazol-4-yl) methyl] piperidin-4-amine Example 52a) 1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -N-[(2-methyl-1-tritylimidazol-4-yl) methyl] piperidin-4-amine (0.5 g) and acetaldehyde (0.05 mL) were used to obtain the title compound (0.23 g, 65%) as a pale yellow powder in the same manner as in Example 51.
NMR (200MHz, CDCl ₃ ) δ: 1.03 (3H, t), 1.32-1.46 (2H, m), 1.72-1.86 (2H, m), 2.38 (3H, s), 2.46-2.58 (3H, m), 2.69-3.02 (4H, m), 3.52-3.60 (4H, m), 3.81-3.88 (1H, m), 4.49-4.56 (1H, m), 6.72 (1H, s), 7.29 (1H, d), 7.58 (1H, dd), 7.92-7.97 (4H, m), 8.47 (1H, s).

実施例58
N-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-N-[(2-メチル-1H-イミダゾール-4-イル)メチル]アセトアミド
実施例52a)で得られた1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-N-[(2-メチル-1-トリチルイミダゾール-4-イル)メチル]ピペリジン-4-アミン(0.5g)、塩化アセチル(0.06mL)から実施例55と同様にして題記化合物(0.11g, 31%)を淡黄色粉末として得た。
NMR (200MHz, CDCl₃) δ：1.25-1.77 (4H, m), 2.16 (3H, s), 2.33 (3H, s), 2.41-2.48 (1H, m), 2.58-3.05 (3H, m), 3.49-3.58 (2H, m), 3.79-4.03 (1H, m), 4.27-4.32 (2H, m), 4.56-4.67 (2H, m), 6.68(1H, d), 7.54-7.60 (1H, m), 7.89-7.97 (4H, m), 8.44-8.48 (1H, m). Example 58
N- (1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -N-[(2-methyl-1H-imidazol-4-yl) methyl] acetamide Example 52a 1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -N-[(2-methyl-1-tritylimidazol-4-yl) methyl] piperidin-4-amine ( The title compound (0.11 g, 31%) was obtained as a pale yellow powder from 0.5 g) and acetyl chloride (0.06 mL) in the same manner as in Example 55.
NMR (200 MHz, CDCl ₃ ) δ: 1.25-1.77 (4H, m), 2.16 (3H, s), 2.33 (3H, s), 2.41-2.48 (1H, m), 2.58-3.05 (3H, m), 3.49-3.58 (2H, m), 3.79-4.03 (1H, m), 4.27-4.32 (2H, m), 4.56-4.67 (2H, m), 6.68 (1H, d), 7.54-7.60 (1H, m ), 7.89-7.97 (4H, m), 8.44-8.48 (1H, m).

実施例59
7-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-3-メチル-7,8-ジヒドロイミダゾ[1,5-ａ]ピラジン-6(5H)-オン
実施例52a)で得られた1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-N-[(2-メチル-1-トリチルイミダゾール-4-イル)メチル]ピペリジン-4-アミン(0.5g)、塩化クロロアセチル(0.1mL)から実施例55と同様にして題記化合物(0.08g, 24%)を白色結晶として得た。
NMR (200MHz, CDCl₃) δ：1.60-1.80 (4H, m), 2.38(3H, s), 2.63-2.72 (1H, m), 2.86-2.99 (2H, m), 3.10-3.29 1H, m), 3.50-3.64 (2H, m), 3.97-4.03 (1H, m), 4.42 (2H, s), 4.55 (2H, s), 4.69-4.82 (2H, m), 6.80 (1H, s), 7.62(1H, dd), 7.90-7.99 (4H, m), 8.50 (1H, s). Example 59
7- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -3-methyl-7,8-dihydroimidazo [1,5-a] pyrazine-6 (5H 1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -N-[(2-methyl-1-tritylimidazol-4-yl) methyl] obtained in Example 52a) The title compound (0.08 g, 24%) was obtained as white crystals from piperidine-4-amine (0.5 g) and chloroacetyl chloride (0.1 mL) in the same manner as in Example 55.
NMR (200MHz, CDCl ₃ ) δ: 1.60-1.80 (4H, m), 2.38 (3H, s), 2.63-2.72 (1H, m), 2.86-2.99 (2H, m), 3.10-3.29 1H, m) , 3.50-3.64 (2H, m), 3.97-4.03 (1H, m), 4.42 (2H, s), 4.55 (2H, s), 4.69-4.82 (2H, m), 6.80 (1H, s), 7.62 (1H, dd), 7.90-7.99 (4H, m), 8.50 (1H, s).

実施例60
N-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-N-[(4-メチル-1H-イミダゾール-5-イル)メチル]アセトアミド
実施例53a)で得られた1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-N-[(4-メチル-1-トリチルイミダゾール-5-イル)メチル]ピペリジン-4-アミン(0.5g)、塩化アセチル(0.06mL)から実施例55と同様にして題記化合(0.10g, 28%)を物淡黄色粉末として得た。
NMR (200MHz, CDCl₃) δ：1.60-1.78 (4H, m), 2.18 (3H, s), 2.19 (3H, s), 2.49-2.55 (1H, m), 2.78-3.08 (3H, m), 3.48-3.62 (2H, m), 3.65-4.05 (1H, m), 4.24-4.39 (2H, m), 4.48-4.65 (2H, m), 7.34-7.43 (1H, m), 7.57 (1H, dd), 7.91-7.97 (4H, m), 8.45-8.47 (1H, m). Example 60
N- (1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -N-[(4-methyl-1H-imidazol-5-yl) methyl] acetamide Example 53a 1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -N-[(4-methyl-1-tritylimidazol-5-yl) methyl] piperidin-4-amine ( 0.5 g) and acetyl chloride (0.06 mL) were used to obtain the title compound (0.10 g, 28%) as a pale yellow powder in the same manner as in Example 55.
NMR (200MHz, CDCl ₃ ) δ: 1.60-1.78 (4H, m), 2.18 (3H, s), 2.19 (3H, s), 2.49-2.55 (1H, m), 2.78-3.08 (3H, m), 3.48-3.62 (2H, m), 3.65-4.05 (1H, m), 4.24-4.39 (2H, m), 4.48-4.65 (2H, m), 7.34-7.43 (1H, m), 7.57 (1H, dd ), 7.91-7.97 (4H, m), 8.45-8.47 (1H, m).

実施例61
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-N-エチル-N-[(4-メチル-1H-イミダゾール-5-イル)メチル]ピペリジン-4-アミン
実施例53a)で得られた1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-N-[(4-メチル-1-トリチルイミダゾール-5-イル)メチル]ピペリジン-4-アミン(0.5g)、アセトアルデヒド(0.05mL)から実施例51と同様にして題記化合物(0.14g, 40%)を淡黄色粉末として得た。
NMR (200MHz, CDCl₃) δ：0.99 (3H, t), 1.32-1.47 (2H, m), 1.71-1.84 (2H, m), 2.18 (3H, s), 2.38-2.55 (3H, m), 2.70-2.94 (4H, m), 3.52-3.58 (4H, m), 3.82-3.88 (1H, m), 4.49-4.56 (1H, m), 7.55 (1H, s), 7.57 (1H, dd), 7.92-7.96 (4H, m), 8.47 (1H, s). Example 61
1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -N-ethyl-N-[(4-methyl-1H-imidazol-5-yl) methyl] piperidin-4-amine Example 53a 1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -N-[(4-methyl-1-tritylimidazol-5-yl) methyl] piperidin-4-amine ( 0.5 g) and acetaldehyde (0.05 mL) were used to give the title compound (0.14 g, 40%) as a pale yellow powder in the same manner as in Example 51.
NMR (200MHz, CDCl ₃ ) δ: 0.99 (3H, t), 1.32-1.47 (2H, m), 1.71-1.84 (2H, m), 2.18 (3H, s), 2.38-2.55 (3H, m), 2.70-2.94 (4H, m), 3.52-3.58 (4H, m), 3.82-3.88 (1H, m), 4.49-4.56 (1H, m), 7.55 (1H, s), 7.57 (1H, dd), 7.92-7.96 (4H, m), 8.47 (1H, s).

実施例62
7-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-7,8-ジヒドロイミダゾ[1,2-ａ]ピラジン-6(5H)-オン
実施例54で得た1-(3{[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-N-[(1H-イミダゾール-2-イル)メチル]ピペリジン-4-アミン (0.5g)、塩化クロロアセチル(0.1mL)から実施例55と同様にして題記化合物(0.03g, 5%)を無色色粉末として得た。
NMR (200MHz, CDCl₃) δ：1.61-1.81 (4H, m), 2.56-2.72 (1H, m), 2.87-2.97 (2H, m), 3.11-3.28 (1H, m), 3.54-3.62 (2H, m), 3.97-4.09 (1H, m), 4.49 (2H, s), 4.69-4.78 (4H, m), 6.89 (1H, s), 7.11 (1H, s), 7.60 (1H, dd), 7.95-7.99 (4H, m), 8.49 (1H, s). Example 62
7- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -7,8-dihydroimidazo [1,2-a] pyrazin-6 (5H) -one 1- (3 {[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -N-[(1H-imidazol-2-yl) methyl] piperidin-4-amine (0.5 g) obtained in Example 54, chloride The title compound (0.03 g, 5%) was obtained as a colorless powder from chloroacetyl (0.1 mL) in the same manner as in Example 55.
NMR (200MHz, CDCl ₃ ) δ: 1.61-1.81 (4H, m), 2.56-2.72 (1H, m), 2.87-2.97 (2H, m), 3.11-3.28 (1H, m), 3.54-3.62 (2H , m), 3.97-4.09 (1H, m), 4.49 (2H, s), 4.69-4.78 (4H, m), 6.89 (1H, s), 7.11 (1H, s), 7.60 (1H, dd), 7.95-7.99 (4H, m), 8.49 (1H, s).

実施例63
7-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-3-メチル-5,6,7,8-テトラヒドロイミダゾ[1,5-a]ピラジン
4-アミノピペリジン-1-カルボン酸tert-ブチル(2.0g)と2-メチル-1-トリチルイミダゾール-4-カルバルデヒド(3.5g)から実施例51と同様にして4-[(2-メチル-1-トリチルイミダゾール-4-イル)メチル]アミノピペリジン-1-カルボン酸tert-ブチル(4.0g, 75%)を得た。次に、この化合物と塩化クロロアセチル(1.1mL)から実施例59と同様にして4-(3-メチル-6-オキソ-5,6-ジヒドロイミダゾ[1,5-a]ピラジン-7(8H)-イル)ピペリジン-1-カルボン酸tert-ブチル(2.0g, 80%)を得た。これをTHF(20mL)に溶解し、1Mのボラン・THF錯体THF(18mL)溶液を加え、一晩加熱還流した。反応液に1N塩酸(20mL)を加えかき混ぜた後、濃縮した。残留物をトリフルオロ酢酸(15mL)に溶解し、脱Boc化後、実施例50b)と同様に、3-[(6-クロロ-2-ナフチル)スルホニル]プロピオン酸(1.7g)と縮合して題記化合物(0.04g, 1.4%)を淡黄色粉末として得た。
NMR (200MHz, CDCl₃) δ：1.17-1.48 (2H, m), 1.80-1.94 (2H, m), 2.27 (3H, s), 2.58-2.63 (2H, m), 2.81-2.89 (4H, m), 2.98-3.12 (1H, m), 3.42-3.56 (2H, m), 3.70-3.81 (5H, m), 4.43-4.50 (1H, m), 6.59 (1H, s), 7.54 (1H, dd), 7.89-7.93 (4H, m), 8.44 (1H, s). Example 63
7- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -3-methyl-5,6,7,8-tetrahydroimidazo [1,5-a] pyrazine
4-[(2-Methyl- (4-methylpiperidine-1-carboxylate) was prepared in the same manner as in Example 51 from tert-butyl (2.0 g) and 2-methyl-1-tritylimidazole-4-carbaldehyde (3.5 g). 1-Tritylimidazol-4-yl) methyl] aminopiperidine-1-carboxylate (tert-butyl) (4.0 g, 75%) was obtained. Next, 4- (3-methyl-6-oxo-5,6-dihydroimidazo [1,5-a] pyrazine-7 (8H) was prepared from this compound and chloroacetyl chloride (1.1 mL) in the same manner as in Example 59. ) -Yl) piperidine-1-carboxylate tert-butyl (2.0 g, 80%) was obtained. This was dissolved in THF (20 mL), 1M borane-THF complex THF (18 mL) solution was added, and the mixture was heated to reflux overnight. 1N Hydrochloric acid (20 mL) was added to the reaction mixture, and the mixture was stirred and concentrated. The residue was dissolved in trifluoroacetic acid (15 mL), de-Bocated, and condensed with 3-[(6-chloro-2-naphthyl) sulfonyl] propionic acid (1.7 g) as in Example 50b). The title compound (0.04 g, 1.4%) was obtained as a pale yellow powder.
NMR (200MHz, CDCl ₃ ) δ: 1.17-1.48 (2H, m), 1.80-1.94 (2H, m), 2.27 (3H, s), 2.58-2.63 (2H, m), 2.81-2.89 (4H, m ), 2.98-3.12 (1H, m), 3.42-3.56 (2H, m), 3.70-3.81 (5H, m), 4.43-4.50 (1H, m), 6.59 (1H, s), 7.54 (1H, dd ), 7.89-7.93 (4H, m), 8.44 (1H, s).

実施例64
7-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-1,5-ジメチル-7,8-ジヒドロイミダゾ[1,5-a]ピラジン-6(5H)-オン
実施例53a)で得られた1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-N-[(4-メチル-1-トリチルイミダゾール-5-イル)メチル]ピペリジン-4-アミン(1.5g)、塩化2-クロロプロピオニル(0.24mL)から実施例59と同様にして題記化合物(0.66g, 62%)を白色結晶として得た。
NMR (200MHz, CDCl₃) δ：1.16 (3H, d), 1.69-1.76 (4H, m), 2.20 (3H, s), 2.48-2.78 (1H, m), 2.93-3.02 (2H, m), 3.11-3.30 (1H, m), 3.53-3.73 (2H, m), 3.98-4.05 (1H, m), 4.33 (2H, s), 4.72-4.78 (3H, m), 7.46 (1H, s), 7.62 (1H, dd), 7.96-7.99 (4H, m), 8.51 (1H, s). Example 64
7- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -1,5-dimethyl-7,8-dihydroimidazo [1,5-a] pyrazine-6 (5H) -one 1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -N-[(4-methyl-1-tritylimidazol-5-yl) obtained in Example 53a) The title compound (0.66 g, 62%) was obtained as white crystals from methyl] piperidin-4-amine (1.5 g) and 2-chloropropionyl chloride (0.24 mL) in the same manner as in Example 59.
NMR (200MHz, CDCl ₃ ) δ: 1.16 (3H, d), 1.69-1.76 (4H, m), 2.20 (3H, s), 2.48-2.78 (1H, m), 2.93-3.02 (2H, m), 3.11-3.30 (1H, m), 3.53-3.73 (2H, m), 3.98-4.05 (1H, m), 4.33 (2H, s), 4.72-4.78 (3H, m), 7.46 (1H, s), 7.62 (1H, dd), 7.96-7.99 (4H, m), 8.51 (1H, s).

実施例65
2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-7-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
実施例53a)で得られた1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-N-[(4-メチル-1-トリチルイミダゾール-5-イル)メチル]ピペリジン-4-アミン(1.5g)を1N塩酸(20mL)に溶解し、70℃で4時間かき混ぜた。冷却後、反応液を炭酸カリウム水溶液でアルカリ性にした後、クロロホルムで抽出、抽出液を無水硫酸マグネシウムで乾燥した。溶媒を留去した後、残留物をジクロロメタン(20mL)に溶解し、DBU(0.16mL)およびカルボニルジイミダゾール(0.19g)を加えた。反応液を一晩かき混ぜ、反応液を炭酸カリウム水溶液に注ぎ込んだ。反応液をクロロホルムで抽出、抽出液を無水硫酸マグネシウムで乾燥した。溶媒を留去した後、残留物をシリカゲルカラムで精製して題記化合物(83mg, 7%)を白色結晶として得た。
NMR (200MHz, CDCl₃) δ：1.64-1.88 (2H, m), 1.96-2.04 (2H, m), 2.24 (3H, s), 2.60-2.73 (1H, m), 2.87-3.01 (2H, m), 3.15-3.27 (1H, m), 3.46-3.73 (2H, m), 3.99-4.33 (2H, m), 4.28 (2H, s), 4.71-4.78 (1H, m), 7.62 (1H, dd), 7.87-8.00 (4H, m), 8.51 (1H, s). Example 65
2- (1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -7-methyl-1,2-dihydro-3H-imidazo [1,5-c] imidazole- 3-one 1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -N-[(4-methyl-1-tritylimidazol-5-yl) methyl] obtained in Example 53a) Piperidin-4-amine (1.5 g) was dissolved in 1N hydrochloric acid (20 mL) and stirred at 70 ° C. for 4 hours. After cooling, the reaction solution was made alkaline with an aqueous potassium carbonate solution, extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was dissolved in dichloromethane (20 mL), and DBU (0.16 mL) and carbonyldiimidazole (0.19 g) were added. The reaction solution was stirred overnight, and the reaction solution was poured into an aqueous potassium carbonate solution. The reaction solution was extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified with a silica gel column to give the title compound (83 mg, 7%) as white crystals.
NMR (200MHz, CDCl ₃ ) δ: 1.64-1.88 (2H, m), 1.96-2.04 (2H, m), 2.24 (3H, s), 2.60-2.73 (1H, m), 2.87-3.01 (2H, m ), 3.15-3.27 (1H, m), 3.46-3.73 (2H, m), 3.99-4.33 (2H, m), 4.28 (2H, s), 4.71-4.78 (1H, m), 7.62 (1H, dd ), 7.87-8.00 (4H, m), 8.51 (1H, s).

実施例66
7-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-1-メチル-7,8-ジヒドロイミダゾ[1,5-a]ピラジン-6(5H)-オン
実施例53a)で得られた1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-N-[(4-メチル-1-トリチルイミダゾール-5-イル)メチル]ピペリジン-4-アミン (0.5g)、塩化アセチル(0.1mL)から実施例59と同様にして題記化合物(0.11g, 30%)を白色結晶として得た。
NMR (200MHz, CDCl₃) δ：1.67-1.81 (4H, m), 2.19 (3H, s), 2.59-2.72 (1H, m), 2.87-3.02 (2H, m), 3.08-3.32 (1H, m), 3.50-3.65 (2H, m), 3.99-4.08 (1H, m), 4.19 (2H, s), 4.67 (2H, s), 4.71-4.82 (2H, m), 7.44 (1H, s), 7.62 (1H, dd), 7.90-7.99 (4H, m), 8.50 (1H, s). Example 66
7- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -1-methyl-7,8-dihydroimidazo [1,5-a] pyrazine-6 (5H 1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -N-[(4-methyl-1-tritylimidazol-5-yl) methyl] obtained in Example 53a) The title compound (0.11 g, 30%) was obtained as white crystals from piperidin-4-amine (0.5 g) and acetyl chloride (0.1 mL) in the same manner as in Example 59.
NMR (200MHz, CDCl ₃ ) δ: 1.67-1.81 (4H, m), 2.19 (3H, s), 2.59-2.72 (1H, m), 2.87-3.02 (2H, m), 3.08-3.32 (1H, m ), 3.50-3.65 (2H, m), 3.99-4.08 (1H, m), 4.19 (2H, s), 4.67 (2H, s), 4.71-4.82 (2H, m), 7.44 (1H, s), 7.62 (1H, dd), 7.90-7.99 (4H, m), 8.50 (1H, s).

実施例67
7-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-1-メチル-5,6,7,8-テトラハイドロイミダゾ[1,5-a]ピラジン
4-アミノピペリジン-1-カルボン酸tert-ブチル(2.0g)と4-メチル-1-トリチルイミダゾール-5-カルバルデヒド(3.5g)から実施例51と同様にして4-[(4-メチル-1-トリチルイミダゾール-5-イル)メチル]アミノピペリジン-1-カルボン酸tert-ブチル(4.5g, 84%)を得た。次に、この化合物(3.0g)と塩化ブロモアセチル(1.4mL)から実施例59と同様にして4-(1-メチル-6-オキソ-5,6-ジヒドロイミダゾ[1,5-a]ピラジン-7(8H)-イル)ピペリジン-1-カルボン酸tert-ブチル(2.0g, 67%)を得た。これをTHF(20mL)に溶解し、1Mのボラン・THF錯体THF(18mL)溶液を加え、一晩加熱還流した。反応液へ1N塩酸(20mL)を加えかき混ぜた後、濃縮した。残留物をトリフルオロ酢酸(15mL)に溶解し、脱Boc化後、実施例50b)と同様に、3-[(6-クロロ-2-ナフチル)スルホニル]プロピオン酸(1.7g)と縮合して題記化合物(0.12g, 4%)を淡黄色粉末として得た。
NMR (200MHz, CDCl₃) δ：1.39-1.57 (2H, m), 1.85-1.99 (2H, m), 2.11 (3H, s), 2.56-2.94 (6H, m), 3.02-3.14 (1H, m), 3.53-3.60 (2H, m), 3.69 (2H, s), 3.71-3.82 (1H, m), 3.89-4.00 (2H, m), 4.50-4.57 (1H, m), 7.30 (1H, d), 7.58 (1H, dd), 7.93-7.97 (4H, m), 8.48 (1H, s). Example 67
7- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -1-methyl-5,6,7,8-tetrahydroimidazo [1,5-a] Pyrazine
4-aminopiperidine-1-carboxylate tert-butyl (2.0 g) and 4-methyl-1-tritylimidazole-5-carbaldehyde (3.5 g) in the same manner as in Example 51, 4-[(4-methyl- 1-Tritylimidazol-5-yl) methyl] aminopiperidine-1-carboxylate (tert-butyl) (4.5 g, 84%) was obtained. Next, 4- (1-methyl-6-oxo-5,6-dihydroimidazo [1,5-a] pyrazine was prepared from this compound (3.0 g) and bromoacetyl chloride (1.4 mL) in the same manner as in Example 59. -7- (8H) -yl) piperidine-1-carboxylate tert-butyl (2.0 g, 67%) was obtained. This was dissolved in THF (20 mL), 1M borane-THF complex THF (18 mL) solution was added, and the mixture was heated to reflux overnight. 1N Hydrochloric acid (20 mL) was added to the reaction mixture, and the mixture was stirred and concentrated. The residue was dissolved in trifluoroacetic acid (15 mL), de-Bocated, and condensed with 3-[(6-chloro-2-naphthyl) sulfonyl] propionic acid (1.7 g) as in Example 50b). The title compound (0.12 g, 4%) was obtained as a pale yellow powder.
NMR (200MHz, CDCl ₃ ) δ: 1.39-1.57 (2H, m), 1.85-1.99 (2H, m), 2.11 (3H, s), 2.56-2.94 (6H, m), 3.02-3.14 (1H, m ), 3.53-3.60 (2H, m), 3.69 (2H, s), 3.71-3.82 (1H, m), 3.89-4.00 (2H, m), 4.50-4.57 (1H, m), 7.30 (1H, d ), 7.58 (1H, dd), 7.93-7.97 (4H, m), 8.48 (1H, s).

実施例68
2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
実施例69b)で得られた5-メチル-2-(4-ピペリジニル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン(2.0g)、3-[(6-クロロ-2-ナフチル)スルホニル]プロピオン酸(2.7g)、HOBt(1.5g)およびトリエチルアミン(1.27mL)のジクロロメタン(50mL)溶液へWSC(1.9g)を０℃で加え、室温で一夜かき混ぜた。反応液を炭酸カリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を留去し、残留物をシリカゲルカラムで精製した。生成物をエタノールから再結晶して、題記化合物(2.36g, 52%)を白色結晶(融点195℃)として得た。
NMR (200MHz, CDCl₃) δ：1.58-1.72 (2H, m), 1.86-1.99 (2H, m), 2.61 (3H, s), 2.63-2.68 (1H, m), 2.81-3.01 (2H, m), 3.14-3.23 (1H, m), 3.46-3.65 (2H, m), 3.97-4.02 (1H, m), 4.13-4.22 (1H, m), 4.25 (2H, s), 4.69-4.74 (1H, m), 6.70 (1H, d), 7.59 (1H, dd), 7.89-7.96 (4H, m), 8.47 (1H, d).
元素分析値 C₂₄H₂₅N₄O₄SClとして
計算値（％）：C, 57.54； H, 5.03； N, 11.18
実測値（％）：C, 57.28； H, 5.03； N, 10.91 Example 68
2- (1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -5-methyl-1,2-dihydro-3H-imidazo [1,5-c] imidazole- 3-one 5-Methyl-2- (4-piperidinyl) -1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one (2.0 g) obtained in Example 69b), 3 WSC (1.9 g) was added to a solution of-[(6-chloro-2-naphthyl) sulfonyl] propionic acid (2.7 g), HOBt (1.5 g) and triethylamine (1.27 mL) in dichloromethane (50 mL) at 0 ° C. Stir overnight. The reaction solution was washed with an aqueous potassium carbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified with a silica gel column. The product was recrystallized from ethanol to give the title compound (2.36 g, 52%) as white crystals (melting point 195 ° C.).
NMR (200MHz, CDCl ₃ ) δ: 1.58-1.72 (2H, m), 1.86-1.99 (2H, m), 2.61 (3H, s), 2.63-2.68 (1H, m), 2.81-3.01 (2H, m ), 3.14-3.23 (1H, m), 3.46-3.65 (2H, m), 3.97-4.02 (1H, m), 4.13-4.22 (1H, m), 4.25 (2H, s), 4.69-4.74 (1H m), 6.70 (1H, d), 7.59 (1H, dd), 7.89-7.96 (4H, m), 8.47 (1H, d).
Elemental analysis value Calculated as C ₂₄ H ₂₅ N ₄ O ₄ SCl (%): C, 57.54; H, 5.03; N, 11.18
Found (%): C, 57.28; H, 5.03; N, 10.91

実施例69
2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
69a) 2-(1-ベンジル-4-ピペリジニル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
2-メチルイミダゾール-4-カルバルデヒド(11.0g)、1-ベンジルピペリジン-4-アミン(19.0g)および酢酸(6.7mL)の1,2-ジクロロエタン溶液(200mL)へ氷冷下、トリアセトキシ水素化ホウ素ナトリウム(31.8g)を加え、室温で一夜かき混ぜた。反応液を炭酸カリウム水溶液で洗浄、無水硫酸マグネシウムで乾燥した。溶媒を留去した後、残留物をTHF(200mL)に溶解し、N,N'-カルボニルジイミダゾール(17.8g)とDBU(16.7g)を加えて室温で15時間かき混ぜた。反応液を濃縮し、水を加え、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、溶媒を留去した。残留物をシリカゲルカラムで精製して題記化合物(18.5g, 60%)を得た。
NMR (200MHz, CDCl₃)δ: 1.74-1.85 (4H, m), 2.07-2.20 (2H, m), 2.61 (3H, s, Me), 2.97-3.03 (2H, m), 3.53 (2H, s), 3.89-4.06 (1H, m), 4.30 (2H, s), 6.70 (1H, s), 7.32 (5H, m).
69b) 5-メチル-2-(4-ピペリジニル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
実施例69a)で得られた2-(1-ベンジル-4-ピペリジニル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン(18.2g)と10%Pd/C(50%含水：1.5g)をメタノール(300mL)に加え、水素雰囲気下2.5日間かき混ぜた。触媒をろ去、ろ液を濃縮した。残留物を酢酸エチル-ヘキサンで再結晶して題記化合物(10.7g, 83%)を得た。
NMR (200MHz, CDCl₃) δ: 1.56-1.89 (4H, m), 2.62 (3H, s, Me), 2.75 (2H, dt), 3.17-3.23 (2H, m), 3.97-4.13 (1H, m), 4.32 (2H, s), 6.71 (1H, s).
69c) 2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
実施例69b)で得られた5-メチル-2-(4-ピペリジニル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン(8.8g)とトリエチルアミン(6.7mL)のTHF(150mL)溶液へ実施例71d)で得られた塩化3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル(14.7g)のTHF(100mL)溶液を氷冷下で滴下した。反応液を0℃で5時間かき混ぜた後、溶媒を留去した。残留物を水で希釈し、酢酸エチル-THFで抽出した。抽出液を水洗後、無水硫酸マグネシウムで乾燥し、溶媒を留去した。残留物をシリカゲルカラムで精製し、生成物を酢酸エチル-メタノールから再結晶して題記化合物(11.2g, 51%)を無色結晶として得た。
元素分析値 C₂₄H₂₅N₄O₄SClとして
計算値（％）：C, 57.54； H, 5.03； N, 11.18
実測値（％）：C, 57.42； H, 5.13； N, 10.99 Example 69
2- (1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -5-methyl-1,2-dihydro-3H-imidazo [1,5-c] imidazole- 3-on
69a) 2- (1-Benzyl-4-piperidinyl) -5-methyl-1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one
Triacetoxyhydrogen under ice cooling to 1,2-dichloroethane solution (200 mL) of 2-methylimidazole-4-carbaldehyde (11.0 g), 1-benzylpiperidin-4-amine (19.0 g) and acetic acid (6.7 mL) Sodium borohydride (31.8 g) was added and stirred overnight at room temperature. The reaction solution was washed with an aqueous potassium carbonate solution and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was dissolved in THF (200 mL), N, N′-carbonyldiimidazole (17.8 g) and DBU (16.7 g) were added, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified with a silica gel column to give the title compound (18.5 g, 60%).
NMR (200MHz, CDCl ₃ ) δ: 1.74-1.85 (4H, m), 2.07-2.20 (2H, m), 2.61 (3H, s, Me), 2.97-3.03 (2H, m), 3.53 (2H, s ), 3.89-4.06 (1H, m), 4.30 (2H, s), 6.70 (1H, s), 7.32 (5H, m).
69b) 5-Methyl-2- (4-piperidinyl) -1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one 2- (1-benzyl-) obtained in Example 69a) 4-piperidinyl) -5-methyl-1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one (18.2 g) and 10% Pd / C (50% water content: 1.5 g) in methanol (300 mL) and stirred for 2.5 days under a hydrogen atmosphere. The catalyst was removed by filtration and the filtrate was concentrated. The residue was recrystallized from ethyl acetate-hexane to give the title compound (10.7 g, 83%).
NMR (200MHz, CDCl ₃ ) δ: 1.56-1.89 (4H, m), 2.62 (3H, s, Me), 2.75 (2H, dt), 3.17-3.23 (2H, m), 3.97-4.13 (1H, m ), 4.32 (2H, s), 6.71 (1H, s).
69c) 2- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -5-methyl-1,2-dihydro-3H-imidazo [1,5-c] Imidazol-3-one 5-methyl-2- (4-piperidinyl) -1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one obtained in Example 69b) (8.8 g) A solution of 3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl chloride (14.7 g) obtained in Example 71d) in THF (100 mL) was added to a THF (150 mL) solution of triethylamine (6.7 mL) with ice-cooling. It was dripped under. The reaction solution was stirred at 0 ° C. for 5 hours, and then the solvent was distilled off. The residue was diluted with water and extracted with ethyl acetate-THF. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column, and the product was recrystallized from ethyl acetate-methanol to give the title compound (11.2 g, 51%) as colorless crystals.
Elemental analysis value Calculated as C ₂₄ H ₂₅ N ₄ O ₄ SCl (%): C, 57.54; H, 5.03; N, 11.18
Found (%): C, 57.42; H, 5.13; N, 10.99

実施例70
2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン塩酸塩
実施例69c)で得られた2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン(0.50 g)のメタノール(20 mL)溶液へ1N塩化水素エーテル溶液(4 mL)を加えた後、溶媒を留去した。残留物にアセトンとエーテルを加え、析出した固体をろ取して題記化合物(0.51g, 86%)を無色粉末として得た。
NMR (200MHz, DMSO-d₆) δ：1.40-1.88 (4H, m), 2.54-2.65 (1H, m), 2.73-2.79(5H, m), 3.05-3.16 (1H, m), 3.63 (2H, t), 3.88-4.15 (2H, m), 4.23-4.39 (1H, m), 4.55 (2H, s), 7.49 (1H, s), 7.74 (1H, dd), 8.00 (1H, dd), 8.17-8.31 (3H, m), 8.66 (1H, s).
元素分析値 C₂₄H₂₅N₄O₄SCl・HCl・1.5H₂O・0.4Et₂Oとして
計算値（％）：C, 51.75； H, 5.60； N, 9.43
実測値（％）：C, 51.95； H, 5.56； N, 9.30 Example 70
2- (1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -5-methyl-1,2-dihydro-3H-imidazo [1,5-c] imidazole- 3-one hydrochloride 2- (1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -5-methyl-1,2-dihydro obtained in Example 69c) To a solution of -3H-imidazo [1,5-c] imidazol-3-one (0.50 g) in methanol (20 mL) was added 1N hydrogen chloride ether solution (4 mL), and the solvent was evaporated. Acetone and ether were added to the residue, and the precipitated solid was collected by filtration to give the title compound (0.51 g, 86%) as a colorless powder.
NMR (200MHz, DMSO-d ₆ ) δ: 1.40-1.88 (4H, m), 2.54-2.65 (1H, m), 2.73-2.79 (5H, m), 3.05-3.16 (1H, m), 3.63 (2H , t), 3.88-4.15 (2H, m), 4.23-4.39 (1H, m), 4.55 (2H, s), 7.49 (1H, s), 7.74 (1H, dd), 8.00 (1H, dd), 8.17-8.31 (3H, m), 8.66 (1H, s).
Elemental analysis value C ₂₄ H ₂₅ N ₄ O ₄ SCl · HCl · 1.5H ₂ O · 0.4Et ₂ O Calculated value (%): C, 51.75; H, 5.60; N, 9.43
Found (%): C, 51.95; H, 5.56; N, 9.30

実施例71
2-(1-{3-[(6-クロロ-2-ナフチル)スルホニ]プロパノイル}-4-ピペリジニル)-1,7-ジメチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
71a) 4-[(4-メチルイミダゾール-5-イル)メチルアミノ]ピペリジン-1-カルボン酸ベンジル
4-アミノピペリジン-1-カルボン酸ベンジル(10g), 4-メチルイミダゾール-5-カルバルデヒド(4.7g)および酢酸(3.0mL)を1,2-ジクロロエタン(100mL)に溶解し、氷冷下、トリアセトキシ水素化ホウ素ナトリウム(13.6g)を加え、室温で一晩かき混ぜた。反応液を炭酸カリウム水溶液に注ぎ込み、クロロホルムで抽出、抽出液を無水硫酸マグネシウムで乾燥した。溶媒を留去した後、シリカゲルカラムで精製して題記化合物(8.0g, 57%)を油状物として得た。
NMR (200MHz, CDCl₃) δ：1.23-1.38 (2H, m), 1.85-1.95 (2H, m), 2.19 (3H, s), 2.64-2.74 (1H, m), 2.83-2.95 (2H, m), 3.72 (2H, s), 4.07-4.18 (2H, m), 5.12 (2H, s), 7.28-7.37 (5H, m), 7.44 (1H, s).
71b) 4-(7-メチル-3-オキソ-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-2-イル)ピペリジン-1-カルボン酸ベンジル
実施例70a)で得られた4-[(4-メチルイミダゾール-5-イル)メチルアミノ]ピペリジン-1-カルボン酸ベンジル(7.0g)を、ジクロロメタン(70mL)に溶解し、DBU(3.4mL)およびN,N'-カルボニルジイミダゾール(3.5g)を加えた。反応液を一晩かき混ぜ、反応液を炭酸カリウム水溶液に注ぎ込み、クロロホルムで抽出、抽出液を無水硫酸マグネシウムで乾燥した。溶媒を留去した後、残留物をシリカゲルカラムで精製して題記化合物(5.1g, 69%)を白色結晶として得た。
NMR (200MHz, CDCl₃) δ：1.63-1.76 (2H, m), 1.84-1.90 (2H, m), 2.22 (3H, s), 2.85-2.98 (2H, m), 4.09-4.36 (3H, m), 4.27 (2H, s), 5.15 (2H, s), 7.28-7.37 (5H, m), 7.85(1H, s).
71c) 4-(1,7-ジメチル-3-オキソ-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-2-イル)ピペリジン-1-カルボン酸ベンジル
実施例71b)で得られた4-(7-メチル-3-オキソ-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-2-イル)ピペリジン-1-カルボン酸ベンジル(1.5g)をTHF(40 mL)に溶解し、-78℃で1.1MリチウムヘキサメチルジシラザンTHF溶液(4.2mL)を滴下し、-78℃で30分間かき混ぜた。次に-78℃でヨウ化メチル(0.31mL)を加え、30分間かき混ぜた。反応液に塩化アンモニウム水溶液を加え、酢酸エチルで抽出、抽出液を無水硫酸マグネシウムで乾燥した。溶媒を留去した後、残留物をシリカゲルカラムで精製して題記化合物(1.1g, 71%)を油状物として得た。
NMR (200MHz, CDCl) δ：1.54 (3H, t), 1.58-2.08 (4H, m), 2.22 (3H, s), 2.77-2.98 (2H, m), 3.75-3.92 (1H, m), 4.26-4.46 (2H, m), 4.65 (1H, q), 5.15 (2H, s), 7.37-7.40 (5H, m), 7.76 (1H, s).
71d) 塩化3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル
3-[(6-クロロ-2-ナフチル)スルホニル]プロピオン酸(14.9g)、塩化チオニル(4.4mL)とDMF(2滴)をトルエン(100mL)にけん濁し、1.5時間加熱還流した。溶媒を留去し、残留物をエーテルとヘキサンで洗浄して題記化合物(15.5g, 98%)を褐色固体として得た。
NMR (200MHz, CDCl₃) δ: 3.35-3.44 (2H, m), 3.49-3.57 (2H, m), 7.62 (1H, dd), 7.87-8.00 (4H, m), 8.48 (1H, s).
71e) 2-(1-{3-[(6-クロロ-2-ナフチル)スルホニ]プロパノイル}-4-ピペリジニル)-1,7-ジメチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
実施例71c)で得られた4-(1,7-ジメチル-3-オキソ-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-2-イル)ピペリジン-1-カルボン酸ベンジル(3.3g)をエタノ-ル(50mL)に溶解し、10%Pd/C(50%含水：1.6g)を加え、水素雰囲気下、一晩接触還元を行った。反応液をろ過し、ろ液を濃縮した。残留物を炭酸水素ナトリウム水溶液とクロロホルムの混合液に溶解し、氷冷下、実施例71d)で得られた塩化3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル(0.6g)を加えた。反応液を室温で2時間かき混ぜた後、クロロホルムで抽出、抽出液を無水硫酸マグネシウムで乾燥した。溶媒を留去した後、残留物をシリカゲルカラムで精製して題記化合物(1.2g, 28%)を淡黄色粉末として得た。
NMR (200MHz, CDCl₃) δ：1.54 (3H, t), 1.88-2.05 (4H, m), 2.23 (3H, s), 2.53-2.64 (1H, m), 2.87-2.95 (2H, m), 3.08-3.20 (1H, m), 3.54-3.62 (2H, m), 3.81-3.94 (2H, m), 4.62-4.72 (2H, m), 7.60 (1H, dd), 7.79 (1H, s), 7.85-7.98 (4H, m), 8.49 (1H, s). Example 71
2- (1- {3-[(6-Chloro-2-naphthyl) sulfoni] propanoyl} -4-piperidinyl) -1,7-dimethyl-1,2-dihydro-3H-imidazo [1,5-c] Imidazole-3-one
71a) Benzyl 4-[(4-methylimidazol-5-yl) methylamino] piperidine-1-carboxylate
Benzyl 4-aminopiperidine-1-carboxylate (10 g), 4-methylimidazole-5-carbaldehyde (4.7 g) and acetic acid (3.0 mL) were dissolved in 1,2-dichloroethane (100 mL). Sodium triacetoxyborohydride (13.6 g) was added and stirred at room temperature overnight. The reaction solution was poured into an aqueous potassium carbonate solution, extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to obtain the title compound (8.0 g, 57%) as an oil.
NMR (200MHz, CDCl ₃ ) δ: 1.23-1.38 (2H, m), 1.85-1.95 (2H, m), 2.19 (3H, s), 2.64-2.74 (1H, m), 2.83-2.95 (2H, m ), 3.72 (2H, s), 4.07-4.18 (2H, m), 5.12 (2H, s), 7.28-7.37 (5H, m), 7.44 (1H, s).
71b) Benzyl 4- (7-methyl-3-oxo-1,2-dihydro-3H-imidazo [1,5-c] imidazol-2-yl) piperidine-1-carboxylate obtained in Example 70a) Benzyl 4-[(4-methylimidazol-5-yl) methylamino] piperidine-1-carboxylate (7.0 g) is dissolved in dichloromethane (70 mL), and DBU (3.4 mL) and N, N′-carbonyldi- Imidazole (3.5 g) was added. The reaction solution was stirred overnight, the reaction solution was poured into an aqueous potassium carbonate solution, extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified with a silica gel column to give the title compound (5.1 g, 69%) as white crystals.
NMR (200MHz, CDCl ₃ ) δ: 1.63-1.76 (2H, m), 1.84-1.90 (2H, m), 2.22 (3H, s), 2.85-2.98 (2H, m), 4.09-4.36 (3H, m ), 4.27 (2H, s), 5.15 (2H, s), 7.28-7.37 (5H, m), 7.85 (1H, s).
71c) Benzyl 4- (1,7-dimethyl-3-oxo-1,2-dihydro-3H-imidazo [1,5-c] imidazol-2-yl) piperidine-1-carboxylate obtained in Example 71b) 4- (7-methyl-3-oxo-1,2-dihydro-3H-imidazo [1,5-c] imidazol-2-yl) piperidine-1-carboxylate (1.5 g) 1.1M lithium hexamethyldisilazane THF solution (4.2mL) was added dropwise at -78 ° C, and the mixture was stirred at -78 ° C for 30 minutes. Next, methyl iodide (0.31 mL) was added at −78 ° C., and the mixture was stirred for 30 minutes. An aqueous ammonium chloride solution was added to the reaction solution, extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified with a silica gel column to give the title compound (1.1 g, 71%) as an oil.
NMR (200MHz, CDCl) δ: 1.54 (3H, t), 1.58-2.08 (4H, m), 2.22 (3H, s), 2.77-2.98 (2H, m), 3.75-3.92 (1H, m), 4.26 -4.46 (2H, m), 4.65 (1H, q), 5.15 (2H, s), 7.37-7.40 (5H, m), 7.76 (1H, s).
71d) 3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl chloride
3-[(6-Chloro-2-naphthyl) sulfonyl] propionic acid (14.9 g), thionyl chloride (4.4 mL) and DMF (2 drops) were suspended in toluene (100 mL) and heated to reflux for 1.5 hours. The solvent was evaporated, and the residue was washed with ether and hexane to give the title compound (15.5 g, 98%) as a brown solid.
_{NMR (200MHz, CDCl 3) δ} : 3.35-3.44 (2H, m), 3.49-3.57 (2H, m), 7.62 (1H, dd), 7.87-8.00 (4H, m), 8.48 (1H, s).
71e) 2- (1- {3-[(6-Chloro-2-naphthyl) sulfoni] propanoyl} -4-piperidinyl) -1,7-dimethyl-1,2-dihydro-3H-imidazo [1,5- c] imidazol-3-one 4- (1,7-dimethyl-3-oxo-1,2-dihydro-3H-imidazo [1,5-c] imidazol-2-yl) obtained in Example 71c) Benzyl piperidine-1-carboxylate (3.3 g) was dissolved in ethanol (50 mL), 10% Pd / C (50% water content: 1.6 g) was added, and catalytic reduction was performed overnight under a hydrogen atmosphere. The reaction solution was filtered and the filtrate was concentrated. The residue was dissolved in a mixed solution of aqueous sodium hydrogen carbonate and chloroform, and 3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl chloride (0.6 g) obtained in Example 71d) was added under ice cooling. It was. The reaction mixture was stirred at room temperature for 2 hours, extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified with a silica gel column to give the title compound (1.2 g, 28%) as a pale yellow powder.
NMR (200MHz, CDCl ₃ ) δ: 1.54 (3H, t), 1.88-2.05 (4H, m), 2.23 (3H, s), 2.53-2.64 (1H, m), 2.87-2.95 (2H, m), 3.08-3.20 (1H, m), 3.54-3.62 (2H, m), 3.81-3.94 (2H, m), 4.62-4.72 (2H, m), 7.60 (1H, dd), 7.79 (1H, s), 7.85-7.98 (4H, m), 8.49 (1H, s).

実施例72
2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-5,7-ジメチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
72a) 4-[(2,4-メチルイミダゾール-5-イル)メチルアミノ]ピペリジン-1-カルボン酸tert-ブチル
4-アミノピペリジン-1-カルボン酸tert-ブチル(4.8g)、2,4-ジメチルイミダゾール-5-カルバルデヒド(3.0g)および酢酸(1.7ml)を1,2-ジクロロエタン(50ml)に溶解し、氷冷下、トリアセトキシ水素化ホウ素ナトリウム(7.7g)を加え、室温で一晩かき混ぜた。反応液を炭酸カリウム水溶液に注ぎ込み、クロロホルムで抽出、抽出液を無水硫酸マグネシウムで乾燥した。溶媒を留去した後、シリカゲルカラムで精製して題記化合物(8.0g, 定量的)を淡黄色油状として得た。
NMR (200MHz, CDCl₃)δ:1.27-1.40 (2H, m), 1.45 (9H, s), 1.85-1.90 (2H, m), 2.15 (3H, s), 2.31 (3H, s), 2.66-2.80 (3H, m), 3.71 (2H, s), 4.00-4.18 (2H, m), 6.06 (2H, brs).
72b) 4-(5,7-ジメチル-3-オキソ-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-2-イル)ピペリジン-1-カルボン酸tert-ブチル
実施例72a)で得た4-[(2,4-ジメチルイミダゾール-5-イル)メチルアミノ]ピペリジン-1-カルボン酸tert-ブチル(8.0g)を、ジクロロメタン(100ml)に溶解し、DBU(3.6ml)およびN,N'-カルボニルジイミダゾール(3.9g)を加えた。反応液を一晩かき混ぜ、反応液を炭酸カリウム水溶液へ注ぎ込み、クロロホルムで抽出、抽出液を無水硫酸マグネシウムで乾燥した。溶媒を留去した後、残留物をシリカゲルカラムで精製して標記化合物(7.8g, 97%)を淡黄色油状として得た。
NMR (200MHz, CDCl₃) δ:1.47 (9H, s), 1.57-1.72 (2H, m), 1.77-1.92 (2H, m), 2.15 (3H, s), 2.57 (3H, s), 2.77-2.88 (2H, m), 4.03-4.15 (2H, m), 4.20 (2H, s), 4.29 (1H, brs).
72c) 2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-5,7-ジメチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
実施例72b)で得た4-(5,7-ジメチル-3-オキソ-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-2-イル)ピペリジン-1-カルボン酸tert-ブチル(5.0g)を濃塩酸(10ml)に溶解し、室温で30分かき混ぜた。反応溶液をクロロホルム(150ml)および飽和炭酸水素ナトリウム水溶液(150ml)に溶解し、塩化3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル(4.7g)を加えた。反応液を室温で2時間かき混ぜた後、クロロホルムで抽出、抽出液を無水硫酸マグネシウムで乾燥した。溶媒を留去した後、残留物をシリカゲルカラムで精製して題記化合物(3.8 g, 50%)を白色結晶として得た。
NMR (200MHz, CDCl₃) δ：1.62-1.79 (2H, m), 1.83-1.99 (2H, m), 2.15 (3H, s), 2.57 (3H, s), 2.64-2.71 (1H, m), 2.86-2.99 (2H, m), 3.31-3.26 (1H, m), 3.49-3.63 (2H, m), 3.97-4.18 (4H, m), 4.75-4.96 (1H, m), 7.61 (1H, dd), 7.89-7.99 (4H, m), 8.49 (1H, s). Example 72
2- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -5,7-dimethyl-1,2-dihydro-3H-imidazo [1,5-c] Imidazole-3-one
72a) tert-butyl 4-[(2,4-methylimidazol-5-yl) methylamino] piperidine-1-carboxylate
Dissolve tert-butyl 4-aminopiperidine-1-carboxylate (4.8 g), 2,4-dimethylimidazole-5-carbaldehyde (3.0 g) and acetic acid (1.7 ml) in 1,2-dichloroethane (50 ml). Under ice-cooling, sodium triacetoxyborohydride (7.7 g) was added, and the mixture was stirred overnight at room temperature. The reaction solution was poured into an aqueous potassium carbonate solution, extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to obtain the title compound (8.0 g, quantitative) as a pale yellow oil.
NMR (200MHz, CDCl ₃ ) δ: 1.27-1.40 (2H, m), 1.45 (9H, s), 1.85-1.90 (2H, m), 2.15 (3H, s), 2.31 (3H, s), 2.66- 2.80 (3H, m), 3.71 (2H, s), 4.00-4.18 (2H, m), 6.06 (2H, brs).
72b) tert-butyl 4- (5,7-dimethyl-3-oxo-1,2-dihydro-3H-imidazo [1,5-c] imidazol-2-yl) piperidine-1-carboxylate Example 72a) 4-[(2,4-dimethylimidazol-5-yl) methylamino] piperidine-1-carboxylate (8.0 g) obtained in 1 above was dissolved in dichloromethane (100 ml), and DBU (3.6 ml) and N, N′-carbonyldiimidazole (3.9 g) was added. The reaction solution was stirred overnight, poured into an aqueous potassium carbonate solution, extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to obtain the title compound (7.8 g, 97%) as a pale yellow oil.
NMR (200MHz, CDCl ₃ ) δ: 1.47 (9H, s), 1.57-1.72 (2H, m), 1.77-1.92 (2H, m), 2.15 (3H, s), 2.57 (3H, s), 2.77- 2.88 (2H, m), 4.03-4.15 (2H, m), 4.20 (2H, s), 4.29 (1H, brs).
72c) 2- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -5,7-dimethyl-1,2-dihydro-3H-imidazo [1,5- c] imidazol-3-one 4- (5,7-dimethyl-3-oxo-1,2-dihydro-3H-imidazo [1,5-c] imidazol-2-yl) piperidine obtained in Example 72b) Tert-Butyl-1-carboxylate (5.0 g) was dissolved in concentrated hydrochloric acid (10 ml) and stirred at room temperature for 30 minutes. The reaction solution was dissolved in chloroform (150 ml) and saturated aqueous sodium hydrogen carbonate solution (150 ml), and 3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl chloride (4.7 g) was added. The reaction mixture was stirred at room temperature for 2 hours, extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified with a silica gel column to give the title compound (3.8 g, 50%) as white crystals.
NMR (200MHz, CDCl ₃ ) δ: 1.62-1.79 (2H, m), 1.83-1.99 (2H, m), 2.15 (3H, s), 2.57 (3H, s), 2.64-2.71 (1H, m), 2.86-2.99 (2H, m), 3.31-3.26 (1H, m), 3.49-3.63 (2H, m), 3.97-4.18 (4H, m), 4.75-4.96 (1H, m), 7.61 (1H, dd ), 7.89-7.99 (4H, m), 8.49 (1H, s).

実施例73
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-[2-(1H-イミダゾール-4-イル)エチル]ピペリジン
73a) 2-{1-[3-(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)エタノール
2-(4-ピペリジル)エタノール(3.70g)と炭酸水素ナトリウム(2.03g)の水(50 mL)-THF(50mL)混合液へ実施例71d)で得られた塩化3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル(7.57 g)を少量づつ加えた。反応液を0℃で1時間かき混ぜた後、有機溶媒を留去した。残留物を酢酸エチルで抽出し、抽出液を水洗、無水硫酸マグネシウムで乾燥した。溶媒を留去した後、残留物をシリカゲルカラムで精製して題記化合物(6.18g, 63%)を褐色油状物として得た。
NMR (200MHz, CDCl₃) δ: 1.01-1.13 (2H, m), 1.45-1.56 (2H, m), 1.67-1.81 (2H, m), 2.45-2.57 (1H, m), 2.80-2.90 (2H, m), 2.93-3.06 (1H, m), 3.52-3.60 (2H, m), 3.66-3.83 (3H, m), 4.44-4.50 (1H, m), 7.59 (1H, dd), 7.93-7.97 (4H, m), 8.47 (1H, s).
73b) よう化2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)エチル
実施例73a)で得られた2-{1-[3-(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)エタノール(6.18g)の酢酸エチル(100mL)溶液へ塩化メタンスルホニル(1.4mL)を氷冷下で加え、1.5時間かき混ぜた。反応液を水洗後、無水硫酸マグネシウムで乾燥した。溶媒を留去した後、残留物をアセトニトリル(100mL)に溶解し、よう化ナトリウム(11.3g)を加えて、室温で24時間かき混ぜた。溶媒を留去し、残留物を水で希釈後、酢酸エチルで抽出した。抽出液を水洗、無水硫酸マグネシウムで乾燥し、溶媒を留去して得た残留物をシリカゲルカラムで精製して題記化合物(5.58g, 71%)を得た。
NMR (200MHz, CDCl₃) δ: 0.90-1.23 (2H, m), 1.60-1.84 (5H, m), 2.46-2.58 (1H, m), 2.82-2.90 (2H, m), 2.95-3.08 (1H, m), 3.20 (2H, t, J = 6.7), 3.51-3.60 (2H, m), 3.79-3.86 (1H, m), 4.46-4.53 (1H, m), 7.60 (1H, dd), 7.92-7.97 (4H, m), 8.48 (1H, s).
73c) 1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-[2-(1H-イミダゾール-4-イル)エチル]ピペリジン
イミダゾール(0.1g)、炭酸カリウム(0.4g)をDMF(30mL)に溶解し、氷冷下、実施例73b)で得られたよう化2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)エチル(0.8g)を加えた。反応液を80℃で4時間かき混ぜた後、溶媒を濃縮した。残留物を水に注ぎ込み、クロロホルムで抽出、抽出液を無水硫酸マグネシウムで乾燥した。溶媒を留去した後、残留物をシリカゲルカラムで精製して題記化合物(0.13g, 19%)を淡黄色粉末として得た。
NMR (200MHz, CDCl₃) δ：1.01-1.18 (2H, m), 1.29-1.57 (1H, m), 1.64-1.77 (4H, m), 2.39-2.51 (1H, m), 2.80-3.01 (3H, m), 3.51-3.60 (3H, m), 3.77-3.84 (1H, m), 3.94-4.01 (2H, m), 4.44-4.51 (1H, m), 6.90 (1H, s), 7.07 (1H, s), 7.49 (1H, brs), 7.57 (1H, dd), 7.91-7.96 (4H, m), 8.47 (1H, s). Example 73
1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- [2- (1H-imidazol-4-yl) ethyl] piperidine
73a) 2- {1- [3- (6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) ethanol
2- (4-Piperidyl) ethanol (3.70 g) and sodium bicarbonate (2.03 g) in water (50 mL) -THF (50 mL) mixed solution obtained in Example 71d) 3-[(6-chloro chloride) -2-Naphthyl) sulfonyl] propanoyl (7.57 g) was added in small portions. The reaction solution was stirred at 0 ° C. for 1 hour, and then the organic solvent was distilled off. The residue was extracted with ethyl acetate, and the extract was washed with water and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified with a silica gel column to give the title compound (6.18 g, 63%) as a brown oil.
NMR (200MHz, CDCl ₃ ) δ: 1.01-1.13 (2H, m), 1.45-1.56 (2H, m), 1.67-1.81 (2H, m), 2.45-2.57 (1H, m), 2.80-2.90 (2H , m), 2.93-3.06 (1H, m), 3.52-3.60 (2H, m), 3.66-3.83 (3H, m), 4.44-4.50 (1H, m), 7.59 (1H, dd), 7.93-7.97 (4H, m), 8.47 (1H, s).
73b) 2- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) ethyl iodide 2- {1- [3- (6 To a solution of -chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) ethanol (6.18 g) in ethyl acetate (100 mL) was added methanesulfonyl chloride (1.4 mL) under ice cooling, and the mixture was stirred for 1.5 hours. The reaction solution was washed with water and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was dissolved in acetonitrile (100 mL), sodium iodide (11.3 g) was added, and the mixture was stirred at room temperature for 24 hours. The solvent was distilled off, and the residue was diluted with water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the residue obtained by evaporating the solvent was purified by a silica gel column to give the title compound (5.58 g, 71%).
NMR (200MHz, CDCl ₃ ) δ: 0.90-1.23 (2H, m), 1.60-1.84 (5H, m), 2.46-2.58 (1H, m), 2.82-2.90 (2H, m), 2.95-3.08 (1H , m), 3.20 (2H, t, J = 6.7), 3.51-3.60 (2H, m), 3.79-3.86 (1H, m), 4.46-4.53 (1H, m), 7.60 (1H, dd), 7.92 -7.97 (4H, m), 8.48 (1H, s).
73c) 1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- [2- (1H-imidazol-4-yl) ethyl] piperidine imidazole (0.1 g), potassium carbonate (0.4 g 2- (1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl iodide obtained in Example 73b) under ice cooling and dissolved in DMF (30 mL) ) Ethyl (0.8 g) was added. The reaction solution was stirred at 80 ° C. for 4 hours, and then the solvent was concentrated. The residue was poured into water, extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified with a silica gel column to give the title compound (0.13 g, 19%) as a pale yellow powder.
NMR (200MHz, CDCl ₃ ) δ: 1.01-1.18 (2H, m), 1.29-1.57 (1H, m), 1.64-1.77 (4H, m), 2.39-2.51 (1H, m), 2.80-3.01 (3H , m), 3.51-3.60 (3H, m), 3.77-3.84 (1H, m), 3.94-4.01 (2H, m), 4.44-4.51 (1H, m), 6.90 (1H, s), 7.07 (1H , s), 7.49 (1H, brs), 7.57 (1H, dd), 7.91-7.96 (4H, m), 8.47 (1H, s).

実施例74
5-クロロ-2-{3-オキソ-3-[4-(5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン-3-イル)-1-ピペリジニル]プロピル}スルホニル-1H-ベンズイミダゾール
74a) 3-(5-クロロ-1H-ベンズイミダゾール)チオプロピオン酸アリール
3-(5-クロロ-1H-ベンズイミダゾール)チオプロピオン酸(Indian J. Chem., 11(11), 1119-21 (1973)) (5.0g)をアリールアルコール(50mL)に溶解し、塩化チオニル(1.6mL)を加え、反応液を2時間還流後、濃縮した。残留物を炭酸カリウム水溶液でアルカリ性にした後、クロロホルムで抽出、抽出液を無水硫酸マグネシウムで乾燥した。溶媒を留去して標記化合物(5.1g, 90%)を黄色油状物として得た。
NMR (200MHz, CDCl₃) δ：1.72 (9H, s), 2.97 (2H, t), 3.54 (2H, t), 4.63 (2H, dd), 5.22-5.38 (2H, m), 5.86-6.04 (1H, m), 7.17-7.28 (2H, m), 7.47-7.58 (1H, m), 7.72-7.86 (1H, m)
74b) 5-クロロ-2-{3-オキソ-3-[4-(5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン-3-イル)-1-ピペリジニル]プロピル}チオベンズイミダゾール-1-カルボン酸tert-ブチル
実施例74a)で得た3-(5-クロロ-1H-ベンズイミダゾール)チオプロピオン酸アリール(4.0g)、4-(ジメチルアミノ)ピリジン(0.1g)をTHF(40mL)に溶解し、二炭酸ジ-tert-ブチル(3.4g)を加え、室温で１時間かき混ぜた。反応液を濃縮後、残留物のうち(1.5g)をTHF(40mL)に溶解し、メルドラム酸(0.81g)、テトラキストリフェニルホスフィンパラジウム(0.2g)を加え、室温で一晩かき混ぜた。反応液を濃縮後、ジクロロメタン(30mL)溶液に溶解し、その溶液へ実施例209b)で得た3-(4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン２塩酸塩(0.52g)、トリエチルアミン(0.53mL)、HOBt(0.32g)およびWSC(0.40g)を加え、室温で16時間かき混ぜた。反応液を炭酸カリウム水溶液でアルカリ性にした後、クロロホルムで抽出、抽出液を無水硫酸マグネシウムで乾燥した。溶媒を留去した後、残留物をシリカゲルカラムで精製して題記化合物(1.4g, 68%)を淡黄色結晶として得た。
NMR (300MHz, CDCl₃) δ：1.47 (9H, s), 1.51-1.77 (2H, m), 1.92-1.98 (6H, m), 2.63-2.75 (1H, m), 2.83-3.00 (5H, m), 3.03-3.23 (1H, m), 3.50-3.60 (2H, m), 3.79-3.85 (2H, m), 4.06-4.23 (1H, m), 4.69-4.76 (1H, m), 6.68 (1H, s), 7.17-7.25 (1H, m), 7.45-7.54 (1H, m), 7.74-7.87 (1H, m).
74c) 5-クロロ-2-{3-オキソ-3-[4-(5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン-3-イル)-1-ピペリジニル]プロピル}スルホニル-1H-ベンズイミダゾール
実施例74b)で得られた5-クロロ-2-{3-オキソ-3-[4-(5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン-3-イル)-1-ピペリジニル]プロピル}チオベンズイミダゾール-1-カルボン酸tert-ブチル(0.4g)をトリフルオロ酢酸(5mL)に溶解し、室温で0.5時間かき混ぜた。溶媒を濃縮後、残留物を炭酸カリウム水溶液でアルカリ性にした後、クロロホルムで抽出、抽出液を無水硫酸マグネシウムで乾燥した。溶媒を留去した後、残留物をクロロホルム(30mL)に溶解し、メタクロロ過安息香酸 (0.74g)を室温で加えた。反応液を3時間室温でかき混ぜ、溶媒を留去した後、残留物をシリカゲルカラムで精製して題記化合物(56mg, 16%)を淡黄色粉末として得た。
NMR (300MHz, CDCl₃) δ：1.14-1.68 (2H, m), 1.86-2.12 (6H, m), 2.57-2.78 (1H, m), 2.85-2.99 (5H, m), 3.10-3.23 (1H, m), 3.75-3.81 (2H, m), 3.94-3.99 (3H, m), 4.36-4.42 (1H, m), 6.87 (1H, s), 7.28-7.34 (1H, m), 7.63-7.69 (2H, m), 7.89-7.94 (1H, m). Example 74
5-Chloro-2- {3-oxo-3- [4- (5,6,7,8-tetrahydroimidazo [1,2-a] pyridin-3-yl) -1-piperidinyl] propyl} sulfonyl-1H -Benzimidazole
74a) Aryl 3- (5-chloro-1H-benzimidazole) thiopropionate
3- (5-Chloro-1H-benzimidazole) thiopropionic acid (Indian J. Chem., 11 (11), 1119-21 (1973)) (5.0 g) was dissolved in aryl alcohol (50 mL) and thionyl chloride (1.6 mL) was added, and the reaction solution was refluxed for 2 hours and then concentrated. The residue was made alkaline with an aqueous potassium carbonate solution, extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off to give the title compound (5.1 g, 90%) as a yellow oil.
NMR (200 MHz, CDCl ₃ ) δ: 1.72 (9H, s), 2.97 (2H, t), 3.54 (2H, t), 4.63 (2H, dd), 5.22-5.38 (2H, m), 5.86-6.04 ( 1H, m), 7.17-7.28 (2H, m), 7.47-7.58 (1H, m), 7.72-7.86 (1H, m)
74b) 5-chloro-2- {3-oxo-3- [4- (5,6,7,8-tetrahydroimidazo [1,2-a] pyridin-3-yl) -1-piperidinyl] propyl} thio Tert-butyl benzimidazole-1-carboxylate Aryl 3- (5-chloro-1H-benzimidazole) thiopropionate (4.0 g), 4- (dimethylamino) pyridine (0.1 g) obtained in Example 74a) Dissolved in THF (40 mL), di-tert-butyl dicarbonate (3.4 g) was added, and the mixture was stirred at room temperature for 1 hr. After the reaction solution was concentrated, (1.5 g) of the residue was dissolved in THF (40 mL), Meldrum acid (0.81 g) and tetrakistriphenylphosphine palladium (0.2 g) were added, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated and dissolved in a dichloromethane (30 mL) solution, and 3- (4-piperidinyl) -5,6,7,8-tetrahydroimidazo [1,2-a] obtained in Example 209b) was added to the solution. Pyridine dihydrochloride (0.52 g), triethylamine (0.53 mL), HOBt (0.32 g) and WSC (0.40 g) were added and stirred at room temperature for 16 hours. The reaction solution was made alkaline with an aqueous potassium carbonate solution, extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified with a silica gel column to give the title compound (1.4 g, 68%) as pale yellow crystals.
NMR (300MHz, CDCl ₃ ) δ: 1.47 (9H, s), 1.51-1.77 (2H, m), 1.92-1.98 (6H, m), 2.63-2.75 (1H, m), 2.83-3.00 (5H, m ), 3.03-3.23 (1H, m), 3.50-3.60 (2H, m), 3.79-3.85 (2H, m), 4.06-4.23 (1H, m), 4.69-4.76 (1H, m), 6.68 (1H , s), 7.17-7.25 (1H, m), 7.45-7.54 (1H, m), 7.74-7.87 (1H, m).
74c) 5-Chloro-2- {3-oxo-3- [4- (5,6,7,8-tetrahydroimidazo [1,2-a] pyridin-3-yl) -1-piperidinyl] propyl} sulfonyl 1-H-benzimidazole 5-chloro-2- {3-oxo-3- [4- (5,6,7,8-tetrahydroimidazo [1,2-a] pyridine-3 obtained in Example 74b) -Iyl) -1-piperidinyl] propyl} thiobenzimidazole-1-carboxylate tert-butyl (0.4 g) was dissolved in trifluoroacetic acid (5 mL) and stirred at room temperature for 0.5 h. After concentrating the solvent, the residue was made alkaline with an aqueous potassium carbonate solution, extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was dissolved in chloroform (30 mL), and metachloroperbenzoic acid (0.74 g) was added at room temperature. The reaction mixture was stirred for 3 hours at room temperature, the solvent was evaporated, and the residue was purified by silica gel column to give the title compound (56 mg, 16%) as a pale yellow powder.
NMR (300MHz, CDCl ₃ ) δ: 1.14-1.68 (2H, m), 1.86-2.12 (6H, m), 2.57-2.78 (1H, m), 2.85-2.99 (5H, m), 3.10-3.23 (1H , m), 3.75-3.81 (2H, m), 3.94-3.99 (3H, m), 4.36-4.42 (1H, m), 6.87 (1H, s), 7.28-7.34 (1H, m), 7.63-7.69 (2H, m), 7.89-7.94 (1H, m).

実施例75
2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-1-(1H-イミダゾ-ルー4-イル)エタノン
75a) 4-[2-(1H-イミダゾール-4-イル)-2-オキソエチル]ピペラジン-1-カルボン酸tert-ブチル
4-ヨード-1H-イミダゾール(2.1g)、テトラメチルエチレンジアミン(1.7mL)のTHF(15mL)溶液へ1MエチルマグネシウムブロマイドTHF溶液(22mL)を25℃以下で加えた。反応液を60℃で1時間かき混ぜた後、室温で4-[(N-メトキシ-N-メチルカルバモイル)メチル]ピペラジン-1-カルボン酸tert-ブチル(2.0g)のTHF(15mL)溶液を加え、室温で16時間かき混ぜた。反応液へ塩化アンモニウム水溶液を加えた後、酢酸エチルで抽出、抽出液を無水硫酸マグネシウムで乾燥した。溶媒を留去した後、残留物をシリカゲルカラムで精製して題記化合物(41.0g, 47%)を油状物として得た。
NMR (200MHz, CDCl₃) δ：1.20-1.27 (2H, m), 1.47 (9H, s), 1.71-1.78 (2H, m), 2.75-2.85 (4H, m), 3.31-3.39 (1H, m), 4.07-4.13 (2H, m), 7.19 (1H, s), 7.65 (1H, s).
75b) 2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-1-(1H-イミダゾール-4-イル)エタノン
実施例75a)で得られた4-[2-(1H-イミダゾール-4-イル)-2-オキソエチル]ピペラジン-1-カルボン酸tert-ブチル(1.0g)をトリフルオロ酢酸(10mL)に溶解し、脱Boc化後、実施例50b)と同様に、3-[(6-クロロ-2-ナフチル)スルホニル]プロピオン酸(1.0g)と縮合して題記化合物(0.04g, 1.4%)を淡黄色粉末として得た。
NMR (200MHz, CDCl₃) δ：1.08-1.26 (2H, m), 1.71-1.87 (2H, m), 2.10-2.32 (1H, m), 2.50-2.62 (1H, m), 2.78-2.91 (4H, m), 2.99-3.11 (1H, m), 3.54-3.61 (2H, m), 3.78-3.85 (1H, m), 4.45-4.51 (1H, m), 7.59 (1H, dd), 7.75-7.97 (4H, m), 8.47(1H, s). Example 75
2- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -1- (1H-imidazo-lu-4-yl) ethanone
75a) tert-butyl 4- [2- (1H-imidazol-4-yl) -2-oxoethyl] piperazine-1-carboxylate
To a solution of 4-iodo-1H-imidazole (2.1 g) and tetramethylethylenediamine (1.7 mL) in THF (15 mL) was added 1M ethylmagnesium bromide THF solution (22 mL) at 25 ° C. or lower. The reaction mixture was stirred at 60 ° C. for 1 hour, and then a solution of tert-butyl 4-[(N-methoxy-N-methylcarbamoyl) methyl] piperazine-1-carboxylate (2.0 g) in THF (15 mL) was added at room temperature. Stir at room temperature for 16 hours. An aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified with a silica gel column to give the title compound (41.0 g, 47%) as an oil.
NMR (200MHz, CDCl ₃ ) δ: 1.20-1.27 (2H, m), 1.47 (9H, s), 1.71-1.78 (2H, m), 2.75-2.85 (4H, m), 3.31-3.39 (1H, m ), 4.07-4.13 (2H, m), 7.19 (1H, s), 7.65 (1H, s).
75b) 2- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -1- (1H-imidazol-4-yl) ethanone obtained in Example 75a) 4- [2- (1H-imidazol-4-yl) -2-oxoethyl] piperazine-1-carboxylate tert-butyl (1.0 g) was dissolved in trifluoroacetic acid (10 mL) and de-Bocated. Similar to 50b), the title compound (0.04 g, 1.4%) was obtained as a pale yellow powder by condensation with 3-[(6-chloro-2-naphthyl) sulfonyl] propionic acid (1.0 g).
NMR (200MHz, CDCl ₃ ) δ: 1.08-1.26 (2H, m), 1.71-1.87 (2H, m), 2.10-2.32 (1H, m), 2.50-2.62 (1H, m), 2.78-2.91 (4H , m), 2.99-3.11 (1H, m), 3.54-3.61 (2H, m), 3.78-3.85 (1H, m), 4.45-4.51 (1H, m), 7.59 (1H, dd), 7.75-7.97 (4H, m), 8.47 (1H, s).

実施例76
2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-1-(1H-イミダゾール-4-イル)エタノール
実施例75b)で得た2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-1-(1H-イミダゾール-4-イル)エタノン(0.1g)をメタノール(10mL)に溶解し、氷冷下、水素化ホウ素ナトリウム(0.1g)を加え、室温で2時間かき混ぜた。反応液に1N塩酸を加え、溶媒を濃縮した。残留物を炭酸カリウムの水溶液に注ぎ込み、クロロホルムで抽出、抽出液を無水硫酸マグネシウムで乾燥した。溶媒を留去した後、残留物をシリカゲルカラムで精製して題記化合物(18mg, 17%)を淡黄色粉末として得た。
NMR (200MHz, CDCl₃) δ：0.92-1.20 (2H, m), 1.27 (1H, s), 1.71-1.79 (5H, m), 2.41-2.58 (1H, m), 2.84-3.07 (3H, m), 3.52-3.58 (2H, m), 3.74-3.81 (1H, m), 4.38-4.45 (1H, m), 4.80-4.98 (1H, m), 7.57 (1H, dd), 7.92-7.97 (4H, m), 8.47 (1H, s). Example 76
2- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -1- (1H-imidazol-4-yl) ethanol 2- (obtained in Example 75b) 1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -1- (1H-imidazol-4-yl) ethanone (0.1 g) was dissolved in methanol (10 mL), Under ice-cooling, sodium borohydride (0.1 g) was added, and the mixture was stirred at room temperature for 2 hr. 1N hydrochloric acid was added to the reaction solution, and the solvent was concentrated. The residue was poured into an aqueous solution of potassium carbonate, extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified with a silica gel column to give the title compound (18 mg, 17%) as a pale yellow powder.
NMR (200MHz, CDCl ₃ ) δ: 0.92-1.20 (2H, m), 1.27 (1H, s), 1.71-1.79 (5H, m), 2.41-2.58 (1H, m), 2.84-3.07 (3H, m ), 3.52-3.58 (2H, m), 3.74-3.81 (1H, m), 4.38-4.45 (1H, m), 4.80-4.98 (1H, m), 7.57 (1H, dd), 7.92-7.97 (4H , m), 8.47 (1H, s).

実施例77
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-(4-メチル-1H-イミダゾール-5-イル)ピペリジン
3-[(6-クロロ-2-ナフチル)スルホニル]プロピオン酸(0.5g)、4-(4-メチル-1H-イミダゾール-5-イル)ピペリジン 2塩酸塩(Farmaco, 47(11), 1343-65(1992))(0.63g)とHOBt(0.36g)のジクロロメタン(30mL)溶液へWSC(0.45g)を加え、室温で16時間かき混ぜた。反応液を炭酸カリウム水溶液でアルカリ性にした後、クロロホルムで抽出、抽出液を無水硫酸マグネシウムで乾燥した。溶媒を留去した後、残留物を塩基性シリカゲルカラムで精製して題記化合物(32mg, 4%)を淡黄色粉末として得た。
NMR (200MHz, CDCl₃) δ：1.63-1.83 (4H, m), 2.26 (3H, s), 2.54-2.66 (1H, m), 2.74-2.90 (3H, m), 3.07-3.17 (1H, m), 3.53-3.59 (2H, m), 3.89-3.93 (1H, m), 4.56-4.61 (1H, m), 6.76 (1H, s), 7.53 (1H, s), 7.58 (1H, dd), 7.89-7.96 (4H, m), 8.47 (1H, s). Example 77
1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- (4-methyl-1H-imidazol-5-yl) piperidine
3-[(6-Chloro-2-naphthyl) sulfonyl] propionic acid (0.5 g), 4- (4-methyl-1H-imidazol-5-yl) piperidine dihydrochloride (Farmaco, 47 (11), 1343- 65 (1992)) (0.63 g) and HOBt (0.36 g) in dichloromethane (30 mL) were added WSC (0.45 g) and stirred at room temperature for 16 hours. The reaction solution was made alkaline with an aqueous potassium carbonate solution, extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified with a basic silica gel column to give the title compound (32 mg, 4%) as a pale yellow powder.
NMR (200MHz, CDCl ₃ ) δ: 1.63-1.83 (4H, m), 2.26 (3H, s), 2.54-2.66 (1H, m), 2.74-2.90 (3H, m), 3.07-3.17 (1H, m ), 3.53-3.59 (2H, m), 3.89-3.93 (1H, m), 4.56-4.61 (1H, m), 6.76 (1H, s), 7.53 (1H, s), 7.58 (1H, dd), 7.89-7.96 (4H, m), 8.47 (1H, s).

実施例78
2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-5-エチル-7-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
78a) 1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-N-[(2-エチル-4-メチル-1H-イミダゾール-5-イル)メチル]ピペリジン-4-アミン
実施例50a)で得られた1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}ピペリジン-4-アミン(3.0g)、2-エチル-4-メチルイミダゾール-5-カルバルデヒド(1.1g)から実施例51と同様に還元的アミノ化を行い、題記化合物(2.0g, 50%)を淡黄色粉末として得た。
NMR (200MHz, CDCl₃) δ：1.33 (3H, t), 1.48-1.72 (2H, m), 1.84-1.97 (2H, m), 2.16 (3H, s), 2.45-2.66 (1H, m), 2.82-2.97 (5H, m), 3.11-3.22 (1H, m), 3.52-3.75 (4H, m), 3.81-4.01 (1H, m), 4.11-4.45 (1H, m), 7.39 (1H, s), 7.58 (1H, dd), 7.89-7.97 (4H, m), 8.47 (1H, s).
78b) 2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-5-エチル-7-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
実施例78a)で得られた1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-N-[(2-エチル-4-メチル-1H-イミダゾール-5-イル)メチル]ピペリジン-4-アミン(2.0g)、DBU(0.6mL)およびN,N'-カルボニルジイミダゾール(0.7g)から実施例65と同様にして題記化合物(71mg, 4%)を白色結晶として得た。
NMR (200MHz, CDCl₃) δ：1.33 (3H, t), 1.56-1.71 (2H, m), 1.84-1.93 (2H, m), 2.17 (3H, s), 2.58-2.66 (1H, m), 2.86-2.98 (4H, m), 3.13-3.22 (1H, m), 3.52-3.62 (2H, m), 3.97-4.01 (1H, m), 4.11-4.15 (1H, m), 4.18 (2H, s), 4.68-4.72 (1H, m), 7.58 (1H, dd), 7.89-7.96 (4H, m), 8.47 (1H, s). Example 78
2- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -5-ethyl-7-methyl-1,2-dihydro-3H-imidazo [1,5- c] imidazol-3-one
78a) 1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -N-[(2-ethyl-4-methyl-1H-imidazol-5-yl) methyl] piperidin-4-amine 1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} piperidin-4-amine (3.0 g) obtained in Example 50a), 2-ethyl-4-methylimidazole-5-carbaldehyde (3.0 g) From 1.1 g), reductive amination was carried out in the same manner as in Example 51 to obtain the title compound (2.0 g, 50%) as a pale yellow powder.
NMR (200MHz, CDCl ₃ ) δ: 1.33 (3H, t), 1.48-1.72 (2H, m), 1.84-1.97 (2H, m), 2.16 (3H, s), 2.45-2.66 (1H, m), 2.82-2.97 (5H, m), 3.11-3.22 (1H, m), 3.52-3.75 (4H, m), 3.81-4.01 (1H, m), 4.11-4.45 (1H, m), 7.39 (1H, s ), 7.58 (1H, dd), 7.89-7.97 (4H, m), 8.47 (1H, s).
78b) 2- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -5-ethyl-7-methyl-1,2-dihydro-3H-imidazo [1, 5-c] imidazol-3-one 1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -N-[(2-ethyl-4-methyl-1H) obtained in Example 78a) -Imidazole-5-yl) methyl] piperidin-4-amine (2.0 g), DBU (0.6 mL) and N, N′-carbonyldiimidazole (0.7 g) in the same manner as in Example 65 to give the title compound (71 mg, 4%) was obtained as white crystals.
NMR (200MHz, CDCl ₃ ) δ: 1.33 (3H, t), 1.56-1.71 (2H, m), 1.84-1.93 (2H, m), 2.17 (3H, s), 2.58-2.66 (1H, m), 2.86-2.98 (4H, m), 3.13-3.22 (1H, m), 3.52-3.62 (2H, m), 3.97-4.01 (1H, m), 4.11-4.15 (1H, m), 4.18 (2H, s ), 4.68-4.72 (1H, m), 7.58 (1H, dd), 7.89-7.96 (4H, m), 8.47 (1H, s).

実施例79
6-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-6,7-ジヒドロ-5H-イミダゾ[1,5-a]イミダゾール-5-オン
実施例54で得た1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-N-[(2-イミダゾリル)メチル]ピペリジン-4-アミン(1.5g)、DBU(0.16mL)およびN,N'-カルボニルジイミダゾール(0.19g)から実施例65と同様にして題記化合物(0.62g, 19%)を淡黄色粉末として得た。
NMR (200MHz, CDCL₃) δ：1.60-1.75 (2H, m), 1.90-2.05 (2H, m), 2.64 (3H,t), 2.85-3.15 (2H, m), 3.19 (3H, t), 3.49-3.70 (2H, m), 3.99-4.04 (1H, m), 4.22-4.30 (1H, m), 4.31 (2H, s), 4.70-4.75 (1H, m), 7.18 (1H, d), 7.31 (1H, d), 7.59 (1H, dd), 7.89-7.96 (4H, m), 8.48 (1H, s). Example 79
6- (1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -6,7-dihydro-5H-imidazo [1,5-a] imidazol-5-one 1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -N-[(2-imidazolyl) methyl] piperidin-4-amine (1.5 g), DBU (0.16 mL) obtained in Example 54 The title compound (0.62 g, 19%) was obtained as a pale yellow powder from N, N′-carbonyldiimidazole (0.19 g) in the same manner as in Example 65.
NMR (200 MHz, CDCL ₃ ) δ: 1.60-1.75 (2H, m), 1.90-2.05 (2H, m), 2.64 (3H, t), 2.85-3.15 (2H, m), 3.19 (3H, t), 3.49-3.70 (2H, m), 3.99-4.04 (1H, m), 4.22-4.30 (1H, m), 4.31 (2H, s), 4.70-4.75 (1H, m), 7.18 (1H, d), 7.31 (1H, d), 7.59 (1H, dd), 7.89-7.96 (4H, m), 8.48 (1H, s).

実施例80
N-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-N-(4-メチル-1H-イミダゾール-5-イル)メチルアクリルアミド
実施例53a)で得られた1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-N-[(4-メチル-1-トリチルイミダゾール-5-イル)メチル]ピペリジン-4-アミン(1.5g)、塩化3-ブロモプロピオニル(0.24mL)から実施例55と同様にして題記化合物(0.34g, 33%)を淡黄色粉末として得た。
NMR (200MHz, CDCl₃) δ：1.61-1.89 (4H, m), 2.23 (3H, s), 2.48-2.67 (1H, m), 2.82-3.17 (3H, m), 3.57-3.64 (2H, m), 3.80-4.07 (2H, m), 4.39 (2H, s), 4.60-4.82 (1H, m), 5.78-5.82 (1H, m), 6.38 (1H, dd), 6.50-6.78 (1H, m), 7.45 (1H, s), 7.61 (1H, dd), 7.91-7.99 (4H, m), 8.50 (1H, s). Example 80
N- (1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -N- (4-methyl-1H-imidazol-5-yl) methylacrylamide in Example 53a) The resulting 1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -N-[(4-methyl-1-tritylimidazol-5-yl) methyl] piperidin-4-amine (1.5 g ) And 3-bromopropionyl chloride (0.24 mL) to give the title compound (0.34 g, 33%) as a pale yellow powder in the same manner as in Example 55.
NMR (200MHz, CDCl ₃ ) δ: 1.61-1.89 (4H, m), 2.23 (3H, s), 2.48-2.67 (1H, m), 2.82-3.17 (3H, m), 3.57-3.64 (2H, m ), 3.80-4.07 (2H, m), 4.39 (2H, s), 4.60-4.82 (1H, m), 5.78-5.82 (1H, m), 6.38 (1H, dd), 6.50-6.78 (1H, m ), 7.45 (1H, s), 7.61 (1H, dd), 7.91-7.99 (4H, m), 8.50 (1H, s).

実施例81
3-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-8-メチルイミダゾ[1,2-a]ピリジン塩酸塩
81a) 4-(8-メチルイミダゾ[1,2-a]ピリジン-3-イル)ピペリジン-1-カルボン酸tert-ブチル
4-(1-ブロモ-2-オキソエチル)ピペリジン-1-カルボン酸tert-ブチル(1.0g)と3-メチル-2-アミノピリジン(0.28g)のエタノール溶液(10mL)を４時間還流した。反応液を減圧濃縮後、残留物を酢酸エチルと１Ｎ塩酸に溶解し、水層を分取した。水層を6N水酸化ナトリウムでアルカリ性とし、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥後、溶媒を留去して題記化合物(0.65g, 79%)を無色油状物として得た。
NMR (300MHz, CDCl₃) δ：1.49 (9H, s), 1.66-1.78 (2H, m), 1.90 (1H, br), 2.09 (1H, br), 2.61 (3H, s), 2.78-2.97 (3H, m), 3.24 (1H, m), 4.25 (1H, m), 6.73 (1H, q, J = 6.9), 6.95 (1H, m), 7.39 (1H, d, J = 2.4), 7.84 (1H, dd, J = 3.0, 6.3).
81b) 3-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-8-メチルイミダゾ[1,2-a]ピリジン塩酸塩
実施例81a)で得た4-(8-メチルイミダゾ[1,2-a]ピリジン-3-イル)ピペリジン-1-カルボン酸tert-ブチル(0.47g)に濃塩酸(2mL)を加えた後、エタノールで希釈、減圧濃縮した。残留物をアセトニトリル(10mL)にけん濁し、トリエチルアミン(0.63mL)とDBU(0.45mL)を加えた。この溶液を3-[(6-クロロ-2-ナフチル)スルホニル]プロピオン酸(0.45g)、WSC(0.43g)、HOBt(0.35g)のアセトニトリルけん濁液(10mL)に加え12時間かき混ぜた。反応液を減圧濃縮、残留物をクロロホルムと飽和重曹水に溶解させ、クロロホルム層を分取した。クロロホルム溶液を無水硫酸ナトリウムで乾燥、溶媒を留去した。残留物をシリカゲルカラム（酢酸エチル/メタノール=10/1）により精製した。得られた白色粉末を4N塩化水素酢酸エチル溶液で処理し、析出した固体をろ取した。得られた固体を減圧乾燥し、題記化合物(0.28g、38%)を白色固体として得た。
NMR (200MHz, CDCl₃) δ：1.53-1.84 (2H, m), 2.05-2.20 (2H, m), 2.60 (3H, s), 2.77 (1H, m), 2.90-2.96 (2H, m), 3.05 (1H, m), 3.26 (1H, m), 3.55-3.63 (2H, m), 4.00 (1H, d, J = 13.8), 4.62 (1H, d, J = 13.8), 6.76 (1H, t, J = 7.0), 6.97 (1H, d, J = 7.0), 7.36 (1H, s), 7.56-7.61 (1H, m), 7.82 (1H, d, J = 7.0), 7.90-7.97 (4H, m), 8.49 (1H, s).
元素分析C₂₆H₂₆N₃O₃SCl・HCl・H₂0 として
理論値（％）C, 56.73; H, 5.31; N, 7.63.
実測値（％）C, 57.09; H, 5.50, N, 7.32. Example 81
3- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -8-methylimidazo [1,2-a] pyridine hydrochloride
81a) tert-butyl 4- (8-methylimidazo [1,2-a] pyridin-3-yl) piperidine-1-carboxylate
A solution of ethanol (10 mL) of tert-butyl 4- (1-bromo-2-oxoethyl) piperidine-1-carboxylate (1.0 g) and 3-methyl-2-aminopyridine (0.28 g) was refluxed for 4 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate and 1N hydrochloric acid, and the aqueous layer was separated. The aqueous layer was made alkaline with 6N sodium hydroxide and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to give the title compound (0.65 g, 79%) as a colorless oil.
NMR (300MHz, CDCl ₃ ) δ: 1.49 (9H, s), 1.66-1.78 (2H, m), 1.90 (1H, br), 2.09 (1H, br), 2.61 (3H, s), 2.78-2.97 ( 3H, m), 3.24 (1H, m), 4.25 (1H, m), 6.73 (1H, q, J = 6.9), 6.95 (1H, m), 7.39 (1H, d, J = 2.4), 7.84 ( 1H, dd, J = 3.0, 6.3).
81b) 3- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -8-methylimidazo [1,2-a] pyridine hydrochloride obtained in Example 81a) Concentrated hydrochloric acid (2 mL) was added to tert-butyl 4- (8-methylimidazo [1,2-a] pyridin-3-yl) piperidine-1-carboxylate (0.47 g), diluted with ethanol, and reduced pressure Concentrated. The residue was suspended in acetonitrile (10 mL), and triethylamine (0.63 mL) and DBU (0.45 mL) were added. This solution was added to an acetonitrile suspension (10 mL) of 3-[(6-chloro-2-naphthyl) sulfonyl] propionic acid (0.45 g), WSC (0.43 g), and HOBt (0.35 g) and stirred for 12 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in chloroform and saturated aqueous sodium hydrogen carbonate, and the chloroform layer was separated. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by silica gel column (ethyl acetate / methanol = 10/1). The obtained white powder was treated with 4N hydrogen chloride ethyl acetate solution, and the precipitated solid was collected by filtration. The obtained solid was dried under reduced pressure to give the title compound (0.28 g, 38%) as a white solid.
NMR (200 MHz, CDCl ₃ ) δ: 1.53-1.84 (2H, m), 2.05-2.20 (2H, m), 2.60 (3H, s), 2.77 (1H, m), 2.90-2.96 (2H, m), 3.05 (1H, m), 3.26 (1H, m), 3.55-3.63 (2H, m), 4.00 (1H, d, J = 13.8), 4.62 (1H, d, J = 13.8), 6.76 (1H, t , J = 7.0), 6.97 (1H, d, J = 7.0), 7.36 (1H, s), 7.56-7.61 (1H, m), 7.82 (1H, d, J = 7.0), 7.90-7.97 (4H, m), 8.49 (1H, s).
Elemental Analysis C ₂₆ H ₂₆ N ₃ O ₃ SCl · HCl · H ₂ 0 Theoretical Value (%) C, 56.73; H, 5.31; N, 7.63.
Found (%) C, 57.09; H, 5.50, N, 7.32.

実施例82
3-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-7-メチルイミダゾ[1,2-a]ピリジン塩酸塩
82a) 4-(7-メチルイミダゾ[1,2-a]ピリジン-3-イル)ピペリジン-1-カルボン酸tert-ブチル
4-(1-ブロモ-2-オキソエチル)ピペリジン-1-カルボン酸tert-ブチル(1.0g)と4-メチル-2-アミノピリジン(0.28g)から、実施例81a)と同様にして題記化合物(0.65g, 79%)を得た。
NMR (200MHz, CDCl₃) δ: 1.49 (9H, s), 1.62-1.78 (2H, m), 2.04-2.08 (2H, m), 2.39 (3H, s), 2.85-2.98 (3H, m), 4.25 (2H, d, J = 14.6), 6.65 (1H, d, J = 7.4), 7.32 (1H, s), 7.37 (1H, s), 7.83 (1H, d, J = 7.4).
82b) 3-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-7-メチルイミダゾ[1,2-a]ピリジン塩酸塩
実施例82a)で得た4-(7-メチルイミダゾ[1,2-a]ピリジン-3-イル)ピペリジン-1-カルボン酸tert-ブチル(0.47g)と3-[6-クロロ-2-ナフチル)スルホニル]プロピオン酸(0.45g)から実施例81b)と同様にして題記化合物(0.30g, 39%)を得た。
NMR (300MHz, CDCl₃) δ：1.56-1.79 (2H, m), 2.06-2.18 (2H, m), 2.36 (3H, s), 2.73-2.82 (1H, m), 2.91-2.96 (2H, m), 3.00-3.09 (1H, m), 3.20-3.30 (1H, m), 3.58-3.62 (2H, m), 4.00 (1H, d, J = 14.4), 4.62 (1H, d, J = 14.4), 7.02 (1H, d, J = 7.2), 7.32 (1H, s), 7.50-7.60 (2H, m), 7.68 (1H, s), 7.86-7.96 (4H, m), 8.48 (1H, s).
元素分析C₂₆H₂₆N₃O₃SCl・HCl・H₂0 として
理論値（％）C, 56.73; H, 5.31; N, 7.63.
実測値（％）C, 56.95; H, 5.42, N, 7.50. Example 82
3- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -7-methylimidazo [1,2-a] pyridine hydrochloride
82a) tert-Butyl 4- (7-methylimidazo [1,2-a] pyridin-3-yl) piperidine-1-carboxylate
From tert-butyl 4- (1-bromo-2-oxoethyl) piperidine-1-carboxylate (1.0 g) and 4-methyl-2-aminopyridine (0.28 g) in the same manner as in Example 81a), the title compound ( 0.65 g, 79%).
NMR (200MHz, CDCl ₃ ) δ: 1.49 (9H, s), 1.62-1.78 (2H, m), 2.04-2.08 (2H, m), 2.39 (3H, s), 2.85-2.98 (3H, m), 4.25 (2H, d, J = 14.6), 6.65 (1H, d, J = 7.4), 7.32 (1H, s), 7.37 (1H, s), 7.83 (1H, d, J = 7.4).
82b) 3- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -7-methylimidazo [1,2-a] pyridine hydrochloride obtained in Example 82a) 4- (7-Methylimidazo [1,2-a] pyridin-3-yl) piperidine-1-carboxylate tert-butyl (0.47 g) and 3- [6-chloro-2-naphthyl) sulfonyl] propionic acid The title compound (0.30 g, 39%) was obtained from (0.45 g) in the same manner as in Example 81b).
NMR (300MHz, CDCl ₃ ) δ: 1.56-1.79 (2H, m), 2.06-2.18 (2H, m), 2.36 (3H, s), 2.73-2.82 (1H, m), 2.91-2.96 (2H, m ), 3.00-3.09 (1H, m), 3.20-3.30 (1H, m), 3.58-3.62 (2H, m), 4.00 (1H, d, J = 14.4), 4.62 (1H, d, J = 14.4) , 7.02 (1H, d, J = 7.2), 7.32 (1H, s), 7.50-7.60 (2H, m), 7.68 (1H, s), 7.86-7.96 (4H, m), 8.48 (1H, s) .
Elemental Analysis C ₂₆ H ₂₆ N ₃ O ₃ SCl · HCl · H ₂ 0 Theoretical Value (%) C, 56.73; H, 5.31; N, 7.63.
Found (%) C, 56.95; H, 5.42, N, 7.50.

実施例83
3-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-6-メチルイミダゾ[1,2-a]ピリジン塩酸塩
83a) 4-(6-メチルイミダゾ[1,2-a]ピリジン-3-イル)ピペリジン-1-カルボン酸tert-ブチル
4-(1-ブロモ-2-オキソエチル)ピペリジン-1-カルボン酸tert-ブチル(1.0g)と5-メチル-2-アミノピリジン(0.28g)から、実施例81a)と同様にして題記化合物(0.67g, 81%)を得た。
NMR (200MHz, CDCl₃) δ：1.49 (9H, s), 1.65-1.80 (2H, m), 1.95-2.09 (2H, m), 2.35 (3H, s), 2.88-3.00 (3H, m), 4.27 (2H, d, J = 13.2), 7.00 (1H, dd, J = 1.8, 9.4), 7.35 (1H, s), 7.52 (1H, d, J = 9.4), 7.70 (1H, d, J = 1.8).
83b) 3-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-6-メチルイミダゾ[1,2-a]ピリジン塩酸塩
実施例83a)で得た4-(6-メチルイミダゾ[1,2-a]ピリジン-3-イル)ピペリジン-1-カルボン酸tert-ブチル(0.47g)と3-[(6-クロロ-2-ナフチル)スルホニル]プロピオン酸(0.45g)から実施例81b)と同様にして題記化合物(0.36g, 45%)を得た。
NMR (200 Hz, CDCl₃) δ：1.56-1.76 (2H, m), 2.11-2.18 (2H, m), 2.40 (3H, s), 2.73-2.82 (1H, m), 2.91-2.96 (2H, m), 3.00-3.09 (1H, m), 3.20-3.30 (1H, m), 3.56-3.62 (2H, m), 3.97 (1H, d, J = 14.4), 4.61 (1H, d, J = 14.4), 6.66 (1H, d, J = 7.2), 7.28 (1H, d, J = 2.7), 7.37 (1H, s), 7.57-7.60 (1H, m), 7.81 (1H, d, J = 7.2), 7.89-7.96 (4H, m), 8.48 (1H, s).
元素分析 C₂₆H₂₆N₃O₃SCl・HCl・H₂0として
理論値（％） C, 56.73; H, 5.31; N, 7.63.
実測値（％） C, 56.54; H, 5.44, N, 7.54. Example 83
3- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -6-methylimidazo [1,2-a] pyridine hydrochloride
83a) tert-Butyl 4- (6-methylimidazo [1,2-a] pyridin-3-yl) piperidine-1-carboxylate
From tert-butyl 4- (1-bromo-2-oxoethyl) piperidine-1-carboxylate (1.0 g) and 5-methyl-2-aminopyridine (0.28 g) in the same manner as in Example 81a), the title compound ( 0.67 g, 81%) was obtained.
NMR (200MHz, CDCl ₃ ) δ: 1.49 (9H, s), 1.65-1.80 (2H, m), 1.95-2.09 (2H, m), 2.35 (3H, s), 2.88-3.00 (3H, m), 4.27 (2H, d, J = 13.2), 7.00 (1H, dd, J = 1.8, 9.4), 7.35 (1H, s), 7.52 (1H, d, J = 9.4), 7.70 (1H, d, J = 1.8).
83b) 3- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -6-methylimidazo [1,2-a] pyridine hydrochloride obtained in Example 83a) 4- (6-Methylimidazo [1,2-a] pyridin-3-yl) piperidine-1-carboxylate tert-butyl (0.47 g) and 3-[(6-chloro-2-naphthyl) sulfonyl] propion The title compound (0.36 g, 45%) was obtained from the acid (0.45 g) in the same manner as in Example 81b).
NMR (200 Hz, CDCl ₃ ) δ: 1.56-1.76 (2H, m), 2.11-2.18 (2H, m), 2.40 (3H, s), 2.73-2.82 (1H, m), 2.91-2.96 (2H, m), 3.00-3.09 (1H, m), 3.20-3.30 (1H, m), 3.56-3.62 (2H, m), 3.97 (1H, d, J = 14.4), 4.61 (1H, d, J = 14.4 ), 6.66 (1H, d, J = 7.2), 7.28 (1H, d, J = 2.7), 7.37 (1H, s), 7.57-7.60 (1H, m), 7.81 (1H, d, J = 7.2) , 7.89-7.96 (4H, m), 8.48 (1H, s).
Elemental analysis C ₂₆ H ₂₆ N ₃ O ₃ SCl / HCl / H ₂ 0
Theoretical value (%) C, 56.73; H, 5.31; N, 7.63.
Found (%) C, 56.54; H, 5.44, N, 7.54.

実施例84
3-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-5-メチルイミダゾ[1,2-a]ピリジン塩酸塩
84a) 4-(5-メチルイミダゾ[1,2-a]ピリジン-3-イル)ピペリジン-1-カルボン酸tert-ブチル
4-(1-ブロモ-2-オキソエチル)ピペリジン-1-カルボン酸tert-ブチル（1.0g）と6-メチル-2-アミノピリジン(0.28g)から、実施例81a)と同様にして題記化合物(0.65g, 79%)を得た。
NMR (200MHz, CDCl₃) δ：1.45 (9H, m), 1.66-1.78 (2H, m), 1.88-2.05 (2H, m), 2.84 (3H, s), 2.78-2.91 (2H, m), 3.41 (1H, m), 4.27 (2H, d, J = 13.2), 6.50 (1H, d, J= 7.0), 7.02 (1H, dd, J = 7.0, 9.2), 7.45 (1H, s), 7.47 (1H, d, J = 9.2).
84b) 3-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-5-メチルイミダゾ[1,2-a]ピリジン塩酸塩
84a)で得た4-(5-メチルイミダゾ[1,2-a]ピリジン-3-イル)ピペリジン-1-カルボン酸tert-ブチル(0.47g)と3-[(6-クロロ-2-ナフチル)スルホニル]プロピオン酸(0.45g)から実施例81b)と同様にして題記化合物(0.33g, 41%)を得た。
NMR (300MHz, CDCl₃)δ：1.53-1.77 (2H, m), 2.05-2.17 (2H, m), 2.65 (1H, m), 2.82 (3H, s), 2.90-2.95 (2H, m), 3.20 (1H, m), 3.44-3.62 (3H, m), 3.97 (1H, d, J = 13.5), 4.66 (1H, d, J = 13.5), 6.51 (1H, d, J = 6.9), 7.03 (1H, dd, J = 6.9, 9.0), 7.40 (1H, s), 7.47 (1H, d, J = 9.0), 7.57 (1H, dd, J = 2.1, 9.0), 7.88-7.95 (4H, m), 8.48 (1H, s).
元素分析 C₂₆H₂₆N₃O₃SCl・HCl・H₂0 として
理論値（％） C, 56.73; H, 5.31; N, 7.63.
実測値（％） C, 56.59; H, 5.31, N, 7.30. Example 84
3- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -5-methylimidazo [1,2-a] pyridine hydrochloride
84a) tert-butyl 4- (5-methylimidazo [1,2-a] pyridin-3-yl) piperidine-1-carboxylate
From tert-butyl 4- (1-bromo-2-oxoethyl) piperidine-1-carboxylate (1.0 g) and 6-methyl-2-aminopyridine (0.28 g) in the same manner as in Example 81a), the title compound ( 0.65 g, 79%).
NMR (200MHz, CDCl ₃ ) δ: 1.45 (9H, m), 1.66-1.78 (2H, m), 1.88-2.05 (2H, m), 2.84 (3H, s), 2.78-2.91 (2H, m), 3.41 (1H, m), 4.27 (2H, d, J = 13.2), 6.50 (1H, d, J = 7.0), 7.02 (1H, dd, J = 7.0, 9.2), 7.45 (1H, s), 7.47 (1H, d, J = 9.2).
84b) 3- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -5-methylimidazo [1,2-a] pyridine hydrochloride
84a) 4- (5-methylimidazo [1,2-a] pyridin-3-yl) piperidine-1-carboxylate tert-butyl (0.47 g) and 3-[(6-chloro-2-naphthyl) ) Sulfonyl] propionic acid (0.45 g) to give the title compound (0.33 g, 41%) in the same manner as in Example 81b).
NMR (300MHz, CDCl ₃ ) δ: 1.53-1.77 (2H, m), 2.05-2.17 (2H, m), 2.65 (1H, m), 2.82 (3H, s), 2.90-2.95 (2H, m), 3.20 (1H, m), 3.44-3.62 (3H, m), 3.97 (1H, d, J = 13.5), 4.66 (1H, d, J = 13.5), 6.51 (1H, d, J = 6.9), 7.03 (1H, dd, J = 6.9, 9.0), 7.40 (1H, s), 7.47 (1H, d, J = 9.0), 7.57 (1H, dd, J = 2.1, 9.0), 7.88-7.95 (4H, m ), 8.48 (1H, s).
Elemental analysis C ₂₆ H ₂₆ N ₃ O ₃ SCl ・ HCl ・ H ₂ 0
Theoretical value (%) C, 56.73; H, 5.31; N, 7.63.
Found (%) C, 56.59; H, 5.31, N, 7.30.

実施例85
3-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)イミダゾ[1,2-a]ピラジン
85a) 4-(イミダゾ[1,2-a]ピラジン-3-イル)ピペリジン-1-カルボン酸tert-ブチル
4-(1-ブロモ-2-オキソエチル)ピペリジン-1-カルボン酸tert-ブチル（1.0g）と2-アミノピラジン(0.28g)から、実施例81a)と同様にして題記化合物(0.44g, 56%)を得た。
NMR (200MHz, CDCl₃)δ：1.49 (9H, s), 1.64-1.85 (4H, m), 2.78-3.23 (3H, m), 4.30 (d, J = 13.2), 7.61 (1H, d, J = 2.2), 7.87-7.94 (2H, m), 9.09 (1H, d, J = 1.0)
85b) 3-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)イミダゾ[1,2-a]ピラジン
実施例85a)で得た4-(イミダゾ[1,2-a]ピラジン-3-イル)ピペリジン-1-カルボン酸tert-ブチル(0.38g)に濃塩酸(2mL)を加えたのち，エタノールで希釈，減圧濃縮した。残留物をアセトニトリル(10mL)にけん濁し、トリエチルアミン(0.63mL)とDBU(0.45mL)を加えた。この溶液を3-[(6-クロロ-2-ナフチル)スルホニル]プロピオン酸(0.45g)、WSC(0.43g)、HOBt(0.35g)のアセトニトリルけん濁液（10mL）に加え12時間かき混ぜた。反応液を減圧濃縮、残留物をクロロホルムと飽和重曹水に溶解させ、クロロホルム層を分取した。クロロホルム溶液を無水硫酸ナトリウムで乾燥、溶媒を留去した。残留物をシリカゲルカラム（8/1酢酸エチル-メタノール）により精製し、題記化合物を無色粉末固体(0.25g, 36%)として得た。
NMR (200MHz, CDCl₃) δ：1.63-1.82 (2H, m), 2.05-2.21 (2H, m), 2.78 (1H, m), 2.95 (2H, t, J = 7.0), 3.09-3.35 (2H, m), 3.59 (2H, t, J = 7.0), 4.03 (1H, d, J = 14.0), 4.68 (1H, d, J = 14.0), 7.58-7.63 (2H, m), 7.91-7.96 (6H, m), 8.49 (1H, s), 9.10 (1H, s).
元素分析 C₂₄H₂₃N₄O₃SCl・0.5H₂O・0.5AcOEtとして
理論値（％） C, 58.26; H, 5.26; N, 10.45.
実測値（％） C, 58.13; H, 5.29, N, 10.75. Example 85
3- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) imidazo [1,2-a] pyrazine
85a) tert-Butyl 4- (imidazo [1,2-a] pyrazin-3-yl) piperidine-1-carboxylate
From tert-butyl 4- (1-bromo-2-oxoethyl) piperidine-1-carboxylate (1.0 g) and 2-aminopyrazine (0.28 g) in the same manner as in Example 81a), the title compound (0.44 g, 56 %).
NMR (200MHz, CDCl ₃ ) δ: 1.49 (9H, s), 1.64-1.85 (4H, m), 2.78-3.23 (3H, m), 4.30 (d, J = 13.2), 7.61 (1H, d, J = 2.2), 7.87-7.94 (2H, m), 9.09 (1H, d, J = 1.0)
85b) 3- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) imidazo [1,2-a] pyrazine 4- (imidazo [ Concentrated hydrochloric acid (2 mL) was added to tert-butyl 1,2-a] pyrazin-3-yl) piperidine-1-carboxylate (0.38 g), diluted with ethanol, and concentrated under reduced pressure. The residue was suspended in acetonitrile (10 mL), and triethylamine (0.63 mL) and DBU (0.45 mL) were added. This solution was added to an acetonitrile suspension (10 mL) of 3-[(6-chloro-2-naphthyl) sulfonyl] propionic acid (0.45 g), WSC (0.43 g), and HOBt (0.35 g) and stirred for 12 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in chloroform and saturated aqueous sodium hydrogen carbonate, and the chloroform layer was separated. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by silica gel column (8/1 ethyl acetate-methanol) to give the title compound as a colorless powder solid (0.25 g, 36%).
NMR (200MHz, CDCl ₃ ) δ: 1.63-1.82 (2H, m), 2.05-2.21 (2H, m), 2.78 (1H, m), 2.95 (2H, t, J = 7.0), 3.09-3.35 (2H , m), 3.59 (2H, t, J = 7.0), 4.03 (1H, d, J = 14.0), 4.68 (1H, d, J = 14.0), 7.58-7.63 (2H, m), 7.91-7.96 ( 6H, m), 8.49 (1H, s), 9.10 (1H, s).
Elemental analysis Theoretical value (%) as C ₂₄ H ₂₃ N ₄ O ₃ SCl · 0.5H ₂ O · 0.5AcOEt C, 58.26; H, 5.26; N, 10.45.
Found (%) C, 58.13; H, 5.29, N, 10.75.

実施例86
3-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)イミダゾ[1,2-a]ピリミジン
86a) 4-(イミダゾ[1,2-a]ピリミジン-3-イル)ピペリジン-1-カルボン酸tert-ブチル
4-(1-ブロモ-2-オキソエチル)ピペリジン-1-カルボン酸tert-ブチル（1.0g）と2-アミノピリミジン(0.25g)から、実施例81a)と同様にして題記化合物(0.43g, 55%)を得た。
NMR (200MHz, CDCl₃)δ：1.49 (9H, s), 1.65-2.07 (4H, m), 2.87-3.02 (3H, m), 4.27 (2H, d, J = 14.0), 6.90 (1H, dd, J = 4.0, 7.0), 7.61 (1H, s), 8.30 (1H, dd, J = 2.0, 7.0), 8.55 (1H, dd, J = 2.0, 4.0)
86b) 3-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)イミダゾ[1,2-a]ピリミジン
86a)で得た4-(イミダゾ[1,2-a]ピリミジン-3-イル)ピペリジン-1-カルボン酸tert-ブチル(0.35g)と3-[(6-クロロ-2-ナフチル)スルホニル]プロピオン酸(0.38 g)から実施例85b)と同様にして題記化合物(0.12g, 20%)を得た。
NMR (200MHz, CDCl₃)δ：1.62-1.88(2H, m), 2.00-2.18 (2H, m), 2.71-2.84 (1H, m), 2.94 (2H, t, J = 7.0), 3.06-3.20 (1H, m), 3.21-3.33 (1H, m), 3.59 (2H, t, J = 7.0), 4.03 (1H, d, J = 13.4), 4.65 (1H, d, J = 13.4), 6.91 (1H, dd, J = 4.2, 7.0), 7.57-7.62 (2H, m), 7.89-7.97 (4H, m), 8.33 (1H, dd, J = 1.8, 7.0), 8.49 (1H, s), 8.55 (1H, dd, J = 1.8, 4.2)
元素分析 C₂₄H₂₃N₄O₃SCl・1.5H₂Oとして
理論値（％） C, 56.52; H, 5.14; N, 10.99.
実測値（％） C, 56.77; H, 4.82; N, 10.99. Example 86
3- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) imidazo [1,2-a] pyrimidine
86a) tert-Butyl 4- (imidazo [1,2-a] pyrimidin-3-yl) piperidine-1-carboxylate
From tert-butyl 4- (1-bromo-2-oxoethyl) piperidine-1-carboxylate (1.0 g) and 2-aminopyrimidine (0.25 g) in the same manner as in Example 81a), the title compound (0.43 g, 55 %).
NMR (200MHz, CDCl ₃ ) δ: 1.49 (9H, s), 1.65-2.07 (4H, m), 2.87-3.02 (3H, m), 4.27 (2H, d, J = 14.0), 6.90 (1H, dd , J = 4.0, 7.0), 7.61 (1H, s), 8.30 (1H, dd, J = 2.0, 7.0), 8.55 (1H, dd, J = 2.0, 4.0)
86b) 3- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) imidazo [1,2-a] pyrimidine
86a) 4- (imidazo [1,2-a] pyrimidin-3-yl) piperidine-1-carboxylate tert-butyl (0.35 g) and 3-[(6-chloro-2-naphthyl) sulfonyl] The title compound (0.12 g, 20%) was obtained from propionic acid (0.38 g) in the same manner as in Example 85b).
NMR (200 MHz, CDCl ₃ ) δ: 1.62-1.88 (2H, m), 2.00-2.18 (2H, m), 2.71-2.84 (1H, m), 2.94 (2H, t, J = 7.0), 3.06-3.20 (1H, m), 3.21-3.33 (1H, m), 3.59 (2H, t, J = 7.0), 4.03 (1H, d, J = 13.4), 4.65 (1H, d, J = 13.4), 6.91 ( 1H, dd, J = 4.2, 7.0), 7.57-7.62 (2H, m), 7.89-7.97 (4H, m), 8.33 (1H, dd, J = 1.8, 7.0), 8.49 (1H, s), 8.55 (1H, dd, J = 1.8, 4.2)
Elemental analysis Theoretical value (%) as C ₂₄ H ₂₃ N ₄ O ₃ SCl · 1.5H ₂ O C, 56.52; H, 5.14; N, 10.99.
Found (%) C, 56.77; H, 4.82; N, 10.99.

実施例87
3-(1-{3-[(7-クロロ-2H-クロメン-3-イル)スルホニル]プロパノイル}-4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン塩酸塩
87a) 3-[(7-クロロ-2H-クロメン-3-イル)スルホニル]プロピオン酸
炭酸水素ナトリウム(3.2g)、亜硫酸ナトリウム(2.6g)の水溶液(100mL)に塩化3-(7-クロロ-2H-クロメン-3-イル)スルホニル(5.0g)加え、70℃で90分かき混ぜ、続いて水酸化ナトリウム(1.9g)、ブロモコハク酸(9.3g)を加え、110℃で8時間かき混ぜた。反応液を放冷し、析出物をろ取、水洗後、減圧乾燥し題記化合物(4.1g, 71%)を茶色固体として得た。
NMR (300MHz, DMSO-d₆)δ：2.63 (2H, t, J = 7.2), 3.50 (2H, t, J = 7.2), 5.62 (2H, s), 7.04-7.11 (2H, m), 7.46-7.49 (2H, m).
87b) 3-(1-{3-[(7-クロロ-2H-クロメン-3-イル)スルホニル]プロパノイル}-4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン塩酸塩
実施例209b)で得た3-(4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン２塩酸塩(0.92g)、トリエチルアミン(1.3mL)、DBU(0.99mL)のアセトニトリル溶液(10mL)を、実施例87a)で得た3-[(7-クロロ-2H-クロメン-3-イル)スルホニル]プロピオン酸(0.91g)、WSC(0.86g), HOBt(0.64g)のアセトニトリル(20mL)けん濁液に加え、12時間かき混ぜた。反応液を減圧濃縮、残留物をクロロホルムと飽和重曹水に溶解させ、クロロホルム層を分取した。クロロホルム溶液を無水硫酸ナトリウムで乾燥、溶媒を留去した。残留物をシリカゲルカラムにより精製し、得られた淡黄色粘性物を飽和塩化水素エタノール溶液で処理し、題記化合物(1.36g, 86%)を得た。
NMR (200MHz, CDCl₃)δ：1.39-1.72 (2H, m), 1.84-2.03 (6H, m), 2.62-2.68 (2H, m), 2.83-2.89 (4H, m), 3.10-3.24 (1H, m), 3.44-3.52 (2H, m), 3.81 (2H, t, J = 6.0), 3.92 (1H, d, J = 13.8), 4.60 (1H, d, J = 13.8), 5.04 (2H, s), 6.64 (1H, s), 6.92-6.98 (2H, m), 7.10 (1H, d, J = 8.4), 7.32 (1H, s) Example 87
3- (1- {3-[(7-Chloro-2H-chromen-3-yl) sulfonyl] propanoyl} -4-piperidinyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine Hydrochloride
87a) 3-[(7-Chloro-2H-chromen-3-yl) sulfonyl] propionic acid Sodium bicarbonate (3.2 g), sodium sulfite (2.6 g) in aqueous solution (100 mL) 3- (7-chloro- 2H-chromen-3-yl) sulfonyl (5.0 g) was added, and the mixture was stirred at 70 ° C. for 90 minutes. Sodium hydroxide (1.9 g) and bromosuccinic acid (9.3 g) were added, and the mixture was stirred at 110 ° C. for 8 hours. The reaction mixture was allowed to cool, and the precipitate was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (4.1 g, 71%) as a brown solid.
NMR (300MHz, DMSO-d ₆ ) δ: 2.63 (2H, t, J = 7.2), 3.50 (2H, t, J = 7.2), 5.62 (2H, s), 7.04-7.11 (2H, m), 7.46 -7.49 (2H, m).
87b) 3- (1- {3-[(7-Chloro-2H-chromen-3-yl) sulfonyl] propanoyl} -4-piperidinyl) -5,6,7,8-tetrahydroimidazo [1,2-a ] Pyridine hydrochloride 3- (4-Piperidinyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine dihydrochloride (0.92 g), triethylamine (1.3 mL) obtained in Example 209b) A solution of DBU (0.99 mL) in acetonitrile (10 mL) was obtained from 3-[(7-chloro-2H-chromen-3-yl) sulfonyl] propionic acid (0.91 g), WSC (0.86 g) obtained in Example 87a). ), HOBt (0.64 g) in acetonitrile (20 mL), and the mixture was stirred for 12 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in chloroform and saturated aqueous sodium hydrogen carbonate, and the chloroform layer was separated. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by a silica gel column, and the obtained pale yellow viscous product was treated with saturated hydrogen chloride ethanol solution to obtain the title compound (1.36 g, 86%).
NMR (200MHz, CDCl ₃ ) δ: 1.39-1.72 (2H, m), 1.84-2.03 (6H, m), 2.62-2.68 (2H, m), 2.83-2.89 (4H, m), 3.10-3.24 (1H , m), 3.44-3.52 (2H, m), 3.81 (2H, t, J = 6.0), 3.92 (1H, d, J = 13.8), 4.60 (1H, d, J = 13.8), 5.04 (2H, s), 6.64 (1H, s), 6.92-6.98 (2H, m), 7.10 (1H, d, J = 8.4), 7.32 (1H, s)

実施例88
3-(1-{3-[(7-ブロモ-2H-クロメン-3-イル)スルホニル]プロパノイル}-4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン塩酸塩
実施例209b)で得た3-(4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン２塩酸塩(0.46g)と実施例87a)で得た3-[(7-ブロモ-2H-クロメン-3-イル)スルホニル]プロピオン酸(0.52g)から実施例87b)と同様にして題記化合物(0.51g, 58%)を無色固体として得た。
NMR (300MHz, CDCl₃)δ：1.35-1.63 (2H, m), 1.85-2.02 (6H, m), 2.62-2.71 (2H, m), 2.84-2.89 (4H, m), 3.10-3.22 (1H, m), 3.45-3.51 (2H, m), 3.81 (2H, t, J = 5.7), 3.92 (1H, t, J = 14.1), 4.60 (1H, d, J = 14.1), 5.03 (2H, s), 6.64 (1H, s), 7.02-7.14 (3H, m), 7.32 (1H, s) Example 88
3- (1- {3-[(7-Bromo-2H-chromen-3-yl) sulfonyl] propanoyl} -4-piperidinyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine Hydrochloride hydrochloride obtained from 3- (4-piperidinyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine dihydrochloride (0.46 g) obtained in Example 209b) and Example 87a) The title compound (0.51 g, 58%) was obtained as a colorless solid from 3-[(7-bromo-2H-chromen-3-yl) sulfonyl] propionic acid (0.52 g) in the same manner as in Example 87b).
NMR (300MHz, CDCl ₃ ) δ: 1.35-1.63 (2H, m), 1.85-2.02 (6H, m), 2.62-2.71 (2H, m), 2.84-2.89 (4H, m), 3.10-3.22 (1H , m), 3.45-3.51 (2H, m), 3.81 (2H, t, J = 5.7), 3.92 (1H, t, J = 14.1), 4.60 (1H, d, J = 14.1), 5.03 (2H, s), 6.64 (1H, s), 7.02-7.14 (3H, m), 7.32 (1H, s)

実施例89
3-[1-(3-{[(E)-2-(4-クロロフェニル)ビニル]スルホニル}プロパノイル)-4-ピペリジニル]-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン
89a) 3-[(E)-2-(4-クロロフェニル)ビニル]スルホニルプロピオン酸
塩化(E)-2-(4-クロロフェニル)エチレンスルホニル(3.0g)から実施例87a)と同様にして題記化合物(0.86g, 25%)を得た。
NMR (200MHz, DMSO-d₆)δ：2.66 (2H, t, J = 7.4), 3.41 (2H, t, J = 7.4), 7.48-7.57 (4H, m), 7.76-7.81 (2H, m).
89b) 3-[1-(3-{[(E)-2-(4-クロロフェニル)ビニル]スルホニル}プロパノイル)-4-ピペリジニル]-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン
実施例209b)で得た3-(4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン２塩酸塩(0.46g)のトリエチルアミン(0.65mL)、DBU(0.49mL)のアセトニトリル溶液(10mL)を、実施例89a)で得た3-[(E)-2-(4-クロロフェニル)ビニル]スルホニルプロピオン酸(0.41g)、WSC(0.43g)、HOBt(0.32g)のアセトニトリル(20mL)けん濁液に加え、12時間かき混ぜた。反応液を減圧濃縮、残留物をクロロホルムと飽和重曹水に溶解させ、クロロホルム層を分取した。クロロホルム溶液を無水硫酸ナトリウムで乾燥、溶媒を留去した。残留物をシリカゲルカラムにより精製し、題記化合物(0.12g, 18%)を無色固体として得た。
NMR (300MHz, CDCl₃)δ：1.39-1.68 (2H, m), 1.83-2.01(6H, m), 2.62-2.74 (2H, m), 3.83-3.92 (4H, m), 3.11-3.23 (1H, m), 3.50 (2H, t, J = 7.2), 3.80 (2H, t, J = 5.7), 3.94 (1H, d, J = 14.1), 4.61 (1H, d, J = 14.1), 6.62 (1H, s), 6.85 (1H, d, J = 15.3), 7.39-7.48 (4H, m), 7.54 (1H, d, J = 15.3).
元素分析 C₂₃H₂₈N₃O₃SCl・1.5H₂O として
理論値（％） C, 56.49; H, 6.39; N, 8.59.
実測値（％） C, 56.35; H, 6.12; N, 8.37. Example 89
3- [1- (3-{[(E) -2- (4-Chlorophenyl) vinyl] sulfonyl} propanoyl) -4-piperidinyl] -5,6,7,8-tetrahydroimidazo [1,2-a] Pyridine
89a) 3-[(E) -2- (4-Chlorophenyl) vinyl] sulfonylpropionic acid The title compound as in Example 87a) from chloride (E) -2- (4-chlorophenyl) ethylenesulfonyl (3.0 g) (0.86 g, 25%) was obtained.
NMR (200MHz, DMSO-d ₆ ) δ: 2.66 (2H, t, J = 7.4), 3.41 (2H, t, J = 7.4), 7.48-7.57 (4H, m), 7.76-7.81 (2H, m) .
89b) 3- [1- (3-{[(E) -2- (4-chlorophenyl) vinyl] sulfonyl} propanoyl) -4-piperidinyl] -5,6,7,8-tetrahydroimidazo [1,2- a] pyridine Triethylamine (0.65 mL) of 3- (4-piperidinyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine dihydrochloride (0.46 g) obtained in Example 209b), A solution of DBU (0.49 mL) in acetonitrile (10 mL) was obtained from 3-[(E) -2- (4-chlorophenyl) vinyl] sulfonylpropionic acid (0.41 g), WSC (0.43 g) obtained in Example 89a). HOBt (0.32 g) was added to a suspension of acetonitrile (20 mL) and stirred for 12 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in chloroform and saturated aqueous sodium hydrogen carbonate, and the chloroform layer was separated. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by silica gel column to give the title compound (0.12 g, 18%) as a colorless solid.
NMR (300MHz, CDCl ₃ ) δ: 1.39-1.68 (2H, m), 1.83-2.01 (6H, m), 2.62-2.74 (2H, m), 3.83-3.92 (4H, m), 3.11-3.23 (1H , m), 3.50 (2H, t, J = 7.2), 3.80 (2H, t, J = 5.7), 3.94 (1H, d, J = 14.1), 4.61 (1H, d, J = 14.1), 6.62 ( 1H, s), 6.85 (1H, d, J = 15.3), 7.39-7.48 (4H, m), 7.54 (1H, d, J = 15.3).
Elemental analysis C ₂₃ H ₂₈ N ₃ O ₃ SCl ・ 1.5H ₂ O
Theoretical value (%) C, 56.49; H, 6.39; N, 8.59.
Found (%) C, 56.35; H, 6.12; N, 8.37.

実施例90
3-[1-(3-{[(E)-2-(4-ブロモフェニル)ビニル]スルホニル}プロパノイル)-4-ピペリジニル]-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン
90a) 3-{[(E)-2-(4-ブロモフェニル)ビニル]スルホニル}プロピオン酸
塩化(E)-2-(4-ブロモフェニル)エチレンスルホニル(1.0g)から実施例87a)と同様にして題記化合物(0.31g, 27%)を得た。
NMR (200MHz, DMSO-d₆)δ：2.65 (2H, t, J = 7.4), 3.39 (2H, t, J = 7.4), 7.48-7.57 (4H, m), 7.76-7.85 (2H, m).
90b) 3-[1-(3-{[(E)-2-(4-ブロモフェニル)ビニル]スルホニル}プロパノイル)-4-ピペリジニル]-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン
実施例209b)で得た3-(4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン２塩酸塩(0.30g)と実施例90a)で得た3-{[(E)-2-(4-ブロモフェニル)ビニル]スルホニル}プロピオン酸(0.31g)から実施例89b)と同様にして題記化合物(0.17g, 34%)を得た。
NMR (300MHz, CDCl₃)δ：1.38-1.67 (2H, m), 1.88-2.00 (6H, m), 2.62-2.74 (2H, m), 2.83-2.89 (4H, m), 3.11-3.23 (1H, m), 3.50 (2H, t, J = 6.6), 3.80 (2H, t, J = 6.0), 3.93 (1, d, J = 12.6), 4.60 (1H, d, J = 12.6), 6.63 (1H, s), 6.87 (1H, d, J = 15.3), 7.37-7.59 (5H, m). Example 90
3- [1- (3-{[(E) -2- (4-Bromophenyl) vinyl] sulfonyl} propanoyl) -4-piperidinyl] -5,6,7,8-tetrahydroimidazo [1,2-a ] Pyridine
90a) 3-{[(E) -2- (4-Bromophenyl) vinyl] sulfonyl} propionic acid Same as Example 87a) from chloride (E) -2- (4-bromophenyl) ethylenesulfonyl (1.0 g) To give the title compound (0.31 g, 27%).
NMR (200MHz, DMSO-d ₆ ) δ: 2.65 (2H, t, J = 7.4), 3.39 (2H, t, J = 7.4), 7.48-7.57 (4H, m), 7.76-7.85 (2H, m) .
90b) 3- [1- (3-{[(E) -2- (4-Bromophenyl) vinyl] sulfonyl} propanoyl) -4-piperidinyl] -5,6,7,8-tetrahydroimidazo [1,2 -a] pyridine With 3- (4-piperidinyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine dihydrochloride (0.30 g) obtained in Example 209b) and Example 90a) The title compound (0.17 g, 34%) was obtained in the same manner as in Example 89b) from the obtained 3-{[(E) -2- (4-bromophenyl) vinyl] sulfonyl} propionic acid (0.31 g).
NMR (300MHz, CDCl ₃ ) δ: 1.38-1.67 (2H, m), 1.88-2.00 (6H, m), 2.62-2.74 (2H, m), 2.83-2.89 (4H, m), 3.11-3.23 (1H , m), 3.50 (2H, t, J = 6.6), 3.80 (2H, t, J = 6.0), 3.93 (1, d, J = 12.6), 4.60 (1H, d, J = 12.6), 6.63 ( 1H, s), 6.87 (1H, d, J = 15.3), 7.37-7.59 (5H, m).

実施例91
N-(6-{3-オキソ-3-[4-(5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン-3-イル)-1-ピペリジニル]プロピル}スルホニル-2-ナフチル)アセトアミド
91a) ピリジニウム 6-アセチルアミノナフタレン-2-スルホンナート
6-アミノナフタレン-2-スルホン酸(11.2g)、酢酸(23.6mL)、ピリジン(12.1mL)の混合物を室温で16時間かき混ぜた。反応液にジエチルエーテルを加え、析出物をろ取し、題記化合物(16.4g, 96%)を無色固体として得た。
NMR (200MHz, DMSO-d₆)δ：2.11 (3H, s), 7.57 (1H, dd, J = 2.2, 8.8), 7.65 (1H, dd, J = 1.5, 8.8), 7.74 (1H, d, J = 8.8), 7.65 (1H, dd, J = 1.5, 8.8), 7.74 (1H, d,J = 8.8), 7.90 (1H, d, J= 8.8), 8.02-8.09 (3H, m), 8.27 (1H, d, J = 1.5), 8.54-8.63 (1H, m), 8.91-8.95 (2H, m).
91b) 塩化6-アセチルアミノナフタレン-2-スルホニル
実施例91a)で得たピリジニウム 6-アセチルアミノナフタレン-2-スルホンナート(15.0g)のDMF溶液(20mL)に、氷冷下、塩化チオニル(3.5mL)を加えた。反応液を室温で90間分かき混ぜた後、酢酸エチルと氷水の混合液に注ぎこみ、酢酸エチル層を分取した。酢酸エチル溶液を１N塩酸で洗浄、無水硫酸マグネシウムで乾燥、濃縮した。残留物をシリカゲルカラムにより精製し、題記化合物(1.67g, 14%)を淡黄色固体として得た。
NMR (200MHz, CDCl₃)δ：2.29 (3H, s), 7.50 (1H, dd, J = 2.2, 8.8), 7.95-7.99 (3H, m), 8.44 (1H, s), 8.51 (1H, s).
91c) 3-[(6-アセチルアミノ-2-ナフチル)スルホニル]プロピオン酸
91b)で得た塩化6-アミノナフタレン-2-スルホニル(1.69 g)を用いて、実施例87a)と同様の方法を用いて題記化合物(0.68g, 36%)を得た。
NMR (200MHz, DMSO-d₆)δ：2.24 (3H, s), 2.59 (2H, t, J = 7.4), 3.66 (2H, t, J = 7.4), 8.00 (1H, dd, J = 1.8, 8.4), 8.08 (1H, dd, J = 1.8, 8.4), 8.33 (1H, d, J = 8.8), 8.44 (1H, d, J = 8.8), 8.75 (2H, d, J = 9.0).
91d) N-(6-{3-オキソ-3-[4-(5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン-3-イル)-1-ピペリジニル]プロピル}スルホニル-2-ナフチル)アセトアミド
実施例91c)で得た3-[(6-アセチルアミノ-2-ナフチル)スルホニル]プロピオン酸(0.68g)と実施例209b)で得た3-(4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン２塩酸塩(0.71g)から実施例89b)と同様にして題記化合物(0.38g, 35%)を得た。
NMR (300MHz, CDCl₃)δ：1.14-1.43 (2H, m), 1.79-2.00(6H, m), 2.26 (3H, s), 2.54-2.65 (2H, m), 2.80-2.88 (4H, m), 3.07 (1H, t, J = 11.1), 3.47-3.57 (1H, m), 3.66-3.88 (4H, m), 4.47 (1H, d, J = 13.2), 6.51 (1H, s), 7.59 (1H, dd, J = 2.4, 9.0), 7.80-7.93 (3H, m), 8.36 (1H, s), 8.44 (1H, s), 8.55 (1H, br)
元素分析 C₂₇H₃₂N₄O₄S・3.5H₂0 として
理論値（％） C, 56.73; H, 6.88; N, 9.80.
実測値（％） C, 56.75; H, 6.94, N, 9.80. Example 91
N- (6- {3-oxo-3- [4- (5,6,7,8-tetrahydroimidazo [1,2-a] pyridin-3-yl) -1-piperidinyl] propyl} sulfonyl-2- Naphthyl) acetamide
91a) Pyridinium 6-acetylaminonaphthalene-2-sulfonate
A mixture of 6-aminonaphthalene-2-sulfonic acid (11.2 g), acetic acid (23.6 mL), and pyridine (12.1 mL) was stirred at room temperature for 16 hours. Diethyl ether was added to the reaction mixture, and the precipitate was collected by filtration to give the title compound (16.4 g, 96%) as a colorless solid.
NMR (200MHz, DMSO-d ₆ ) δ: 2.11 (3H, s), 7.57 (1H, dd, J = 2.2, 8.8), 7.65 (1H, dd, J = 1.5, 8.8), 7.74 (1H, d, J = 8.8), 7.65 (1H, dd, J = 1.5, 8.8), 7.74 (1H, d, J = 8.8), 7.90 (1H, d, J = 8.8), 8.02-8.09 (3H, m), 8.27 (1H, d, J = 1.5), 8.54-8.63 (1H, m), 8.91-8.95 (2H, m).
91b) 6-Acetylaminonaphthalene-2-sulfonyl chloride
Thionyl chloride (3.5 mL) was added to a DMF solution (20 mL) of pyridinium 6-acetylaminonaphthalene-2-sulfonate (15.0 g) obtained in Example 91a) under ice cooling. The reaction solution was stirred at room temperature for 90 minutes and then poured into a mixture of ethyl acetate and ice water to separate the ethyl acetate layer. The ethyl acetate solution was washed with 1N hydrochloric acid, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column to give the title compound (1.67 g, 14%) as a pale yellow solid.
NMR (200MHz, CDCl ₃ ) δ: 2.29 (3H, s), 7.50 (1H, dd, J = 2.2, 8.8), 7.95-7.99 (3H, m), 8.44 (1H, s), 8.51 (1H, s ).
91c) 3-[(6-Acetylamino-2-naphthyl) sulfonyl] propionic acid
Using 6-aminonaphthalene-2-sulfonyl chloride (1.69 g) obtained in 91b) and using a method similar to Example 87a), the title compound (0.68 g, 36%) was obtained.
NMR (200MHz, DMSO-d ₆ ) δ: 2.24 (3H, s), 2.59 (2H, t, J = 7.4), 3.66 (2H, t, J = 7.4), 8.00 (1H, dd, J = 1.8, 8.4), 8.08 (1H, dd, J = 1.8, 8.4), 8.33 (1H, d, J = 8.8), 8.44 (1H, d, J = 8.8), 8.75 (2H, d, J = 9.0).
91d) N- (6- {3-oxo-3- [4- (5,6,7,8-tetrahydroimidazo [1,2-a] pyridin-3-yl) -1-piperidinyl] propyl} sulfonyl- 2-Naphtyl) acetamide 3-[(6-Acetylamino-2-naphthyl) sulfonyl] propionic acid obtained in Example 91c) (0.68 g) and 3- (4-piperidinyl) -5 obtained in Example 209b) , 6,7,8-Tetrahydroimidazo [1,2-a] pyridine dihydrochloride (0.71 g) was used in the same manner as Example 89b) to give the title compound (0.38 g, 35%).
NMR (300MHz, CDCl ₃ ) δ: 1.14-1.43 (2H, m), 1.79-2.00 (6H, m), 2.26 (3H, s), 2.54-2.65 (2H, m), 2.80-2.88 (4H, m ), 3.07 (1H, t, J = 11.1), 3.47-3.57 (1H, m), 3.66-3.88 (4H, m), 4.47 (1H, d, J = 13.2), 6.51 (1H, s), 7.59 (1H, dd, J = 2.4, 9.0), 7.80-7.93 (3H, m), 8.36 (1H, s), 8.44 (1H, s), 8.55 (1H, br)
Elemental analysis Theoretical value (%) as C ₂₇ H ₃₂ N ₄ O ₄ S · 3.5H ₂ 0 C, 56.73; H, 6.88; N, 9.80.
Found (%) C, 56.75; H, 6.94, N, 9.80.

実施例92
3-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-2-メチル-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン塩酸塩
92a) 2-メチル-3-(4-ピリジニル)イミダゾ[1,2-a]ピリジン
トリブチル(4-ピリジニル)スズ(5.0g)、3-ブロモ-2-メチル-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン(EP 556080 (1993)) (2.6g)、ジクロロビス(トリフェニルホスフィン)パラジウム(0.86g)、塩化リチウム(52mg)のトルエン溶液(20mL)をアルゴン雰囲気下、100℃で12時間かき混ぜた。不溶物をろ去し、ろ液を濃縮、残留物をシリカゲルカラムにより精製し、題記化合物(0.83g, 32%)を得た。
NMR (300MHz, CDCl₃)δ：2.54 (3H, s), 6.81 (1H, ddd, J = 2.4, 10.5, 12.3), 7.23 (1H, m), 7.42 (2H, dd, J = 2.7, 6.9), 7.61 (1H, ddd, J = 1.5, 1.5, 11.7), 8.22 (1H, ddd, J = 1.5, 1.5, 11.7), 8.77 (2H, dd, J = 2.7, 6.9).
92b) 2-メチル-3-(4-ピペリジニル)-5,6,7,8-テトラヒドロ-イミダゾ[1,2-a]ピリジン２塩酸塩
実施例92a)で得た2-メチル-3-(4-ピリジニル)イミダゾ[1,2-a]ピリジン(0.82g)の酢酸溶液(100mL)にパラジウム-炭素(0.10g)を加え、水素雰囲気下(10 MPa)、100℃で８時間かき混ぜた。不溶物をろ去し、ろ液を濃縮した。残留物を1N塩酸とエタノールに溶解し、溶媒を留去して題記化合物(1.02g, 89%)を無色固体として得た。
NMR (200MHz, D₂O)δ：1.91-2.18 (8H, m), 2.33 (3H, s), 2.94 (2H, t, J = 6.6), 3.09-3.23 (3H, m), 3.58 (2H, d, J = 12.8), 4.04 (2H, t, J = 5.8).
92c) 3-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-2-メチル-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン塩酸塩
実施例92b)で得た2-メチル-3-(4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン２塩酸塩(0.50g)と3-[(6-クロロ-2-ナフチル)スルホニル]プロピオン酸(0.51g)から実施例87b)と同様にして題記化合物(0.40g, 43%)を得た。
NMR (200MHz, CDCl₃)δ：1.70-2.00 (8H, m), 2.18 (3H, s), 2.54 (1H, m), 2.70-3.10 (6H, m), 3.57 (2H, t, J = 6.6), 3.77 (2H, t, J = 6.0), 3.96 (1H, d, J = 12.8), 4.57 (1H, d, J = 12.8), 7.60 (1H, dd, J = 1.8, 8.8), 7.93-7.97 (4H, m), 8.49 (1H, s)
元素分析 C₂₆H₃₀N₃O₃SCl・HCl・H₂0 として
理論値（％） C, 56.31; H, 6.00; N, 7.58.
実測値（％） C, 56.35; H, 6.37, N, 7.21. Example 92
3- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -2-methyl-5,6,7,8-tetrahydroimidazo [1,2-a] pyridine Hydrochloride
92a) 2-Methyl-3- (4-pyridinyl) imidazo [1,2-a] pyridine tributyl (4-pyridinyl) tin (5.0 g), 3-bromo-2-methyl-5,6,7,8- Tetrahydroimidazo [1,2-a] pyridine (EP 556080 (1993)) (2.6 g), dichlorobis (triphenylphosphine) palladium (0.86 g), a solution of lithium chloride (52 mg) in toluene (20 mL) under an argon atmosphere, Stir at 100 ° C. for 12 hours. The insoluble material was removed by filtration, the filtrate was concentrated, and the residue was purified with a silica gel column to give the title compound (0.83 g, 32%).
NMR (300MHz, CDCl ₃ ) δ: 2.54 (3H, s), 6.81 (1H, ddd, J = 2.4, 10.5, 12.3), 7.23 (1H, m), 7.42 (2H, dd, J = 2.7, 6.9) , 7.61 (1H, ddd, J = 1.5, 1.5, 11.7), 8.22 (1H, ddd, J = 1.5, 1.5, 11.7), 8.77 (2H, dd, J = 2.7, 6.9).
92b) 2-methyl-3- (4-piperidinyl) -5,6,7,8-tetrahydro-imidazo [1,2-a] pyridine dihydrochloride 2-methyl-3- (obtained in Example 92a) Palladium-carbon (0.10 g) was added to an acetic acid solution (100 mL) of 4-pyridinyl) imidazo [1,2-a] pyridine (0.82 g), and the mixture was stirred at 100 ° C. for 8 hours in a hydrogen atmosphere (10 MPa). Insoluble material was removed by filtration, and the filtrate was concentrated. The residue was dissolved in 1N hydrochloric acid and ethanol, and the solvent was evaporated to give the title compound (1.02 g, 89%) as a colorless solid.
NMR (200 MHz, D ₂ O) δ: 1.91-2.18 (8H, m), 2.33 (3H, s), 2.94 (2H, t, J = 6.6), 3.09-3.23 (3H, m), 3.58 (2H, d, J = 12.8), 4.04 (2H, t, J = 5.8).
92c) 3- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -2-methyl-5,6,7,8-tetrahydroimidazo [1,2-a ] Pyridine hydrochloride 2-methyl-3- (4-piperidinyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine dihydrochloride (0.50 g) obtained in Example 92b) and 3 The title compound (0.40 g, 43%) was obtained from-[(6-chloro-2-naphthyl) sulfonyl] propionic acid (0.51 g) in the same manner as in Example 87b).
NMR (200MHz, CDCl ₃ ) δ: 1.70-2.00 (8H, m), 2.18 (3H, s), 2.54 (1H, m), 2.70-3.10 (6H, m), 3.57 (2H, t, J = 6.6 ), 3.77 (2H, t, J = 6.0), 3.96 (1H, d, J = 12.8), 4.57 (1H, d, J = 12.8), 7.60 (1H, dd, J = 1.8, 8.8), 7.93- 7.97 (4H, m), 8.49 (1H, s)
Elemental analysis C ₂₆ H ₃₀ N ₃ O ₃ SCl ・ HCl ・ H ₂ 0
Theoretical value (%) C, 56.31; H, 6.00; N, 7.58.
Found (%) C, 56.35; H, 6.37, N, 7.21.

実施例93
3-(1-{[3-(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-6,7,8,9-テトラヒドロ-5H-イミダゾ[1,2-a]アゼピン塩酸塩
93a) 3-ブロモ-6,7,8,9-テトラヒドロ-5H-イミダゾ[1,2-a]アゼピン
6,7,8,9-テトラヒドロ-5H-イミダゾ[1,2-a]アゼピン(Hua, D. H. et al., J. Org. Chem., 59, 5084 (1994)) (1.0g)の四塩化炭素(20mL)溶液にN-ブロモこはく酸イミド(1.3g)を加え１時間かき混ぜた。反応液に飽和重曹水を加え、クロロホルムで抽出した。抽出液を無水硫酸ナトリウムで乾燥後、濃縮して得られた残留物をシリカゲルカラムにより精製し，題記化合物(1.29g, 81%)を淡黄色固体として得た。
NMR (300MHz, CDCl₃)δ：1.66-1.90 (6H, m), 2.89-2.93 (2H,m), 3.98 (2H, t, J = 4.8), 6.80 (1H, s).
93b) 3-(4-ピリジニル)-6,7,8,9-テトラヒドロ-5H-イミダゾ[1,2-a]アゼピン
実施例93a)で得られた3-ブロモ-6,7,8,9-テトラヒドロ-5H-イミダゾ[1,2-a]アゼピン(1.29g)から実施例92a)と同様にして題記化合物(0.90g, 71%)を得た。
NMR (200MHz, CDCl₃)δ：1.76-1.93 (6H, m), 2.99 (2H, t, J = 4.8), 3.99 (2H, t, J = 4.8), 7.01 (1H, s), 7.21 (2H, m), 8.64 (2H, m).
93c) 3-(4-ピペリジニル)-6,7,8,9-テトラヒドロ-5H-イミダゾ[1,2-a]アゼピン2塩酸塩
実施例93b)で得られた3-(4-ピリジニル)-6,7,8,9-テトラヒドロ-5H-イミダゾ[1,2-a]アゼピン(0.90g)から実施例92b)と同様にして題記化合物(1.19g, 96%)を得た。
NMR (200MHz, D₂O)δ：176-1.95 (8H, m), 2.24 (2H, d, J = 10.2), 3.06-3.26 (5H, m), 3.57 (2H, d, J = 13.2), 4.21 (2H, t, J = 4.8), 7.11 (1H, s).
93d) 3-(1-{[3-(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-6,7,8,9-テトラヒドロ-5H-イミダゾ[1,2-a]アゼピン塩酸塩
実施例93c)で得た3-(4-ピペリジニル)-6,7,8,9-テトラヒドロ-5H-イミダゾ[1,2-a]アゼピン2塩酸塩(0.50g)と3-[(6-クロロ-2-ナフチル)スルホニル]プロピオン酸(0.56g)から実施例87b)と同様にして題記化合物(0.47g, 52%)を得た。
NMR (200MHz, CDCl₃)δ：1.39-2.00 (10H, m), 2.61-2.69 (2H, m), 2.88-2.96 (4H, m), 3.11-3.23 (1H, m), 3.51-3.60 (2H, m), 3.81-3.84 (2H, m), 3.92 (1H, d, J = 14.4), 4.56 (1H, d, J = 14.4), 6.52 (1H, s), 7.59 (1H, m), 7.90-7.97 (4H, m), 8.48 (1H, s).
元素分析 C₂₆H₃₀N₃O₃SCl・HCl・0.25H₂0 として
理論値（％） C, 53.70; H, 6.24; N, 7.23.
実測値（％） C, 53.96; H, 6.44, N, 7.11. Example 93
3- (1-{[3- (6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -6,7,8,9-tetrahydro-5H-imidazo [1,2-a] azepine Hydrochloride salt
93a) 3-Bromo-6,7,8,9-tetrahydro-5H-imidazo [1,2-a] azepine
Tetrachloride of 6,7,8,9-tetrahydro-5H-imidazo [1,2-a] azepine (Hua, DH et al., J. Org. Chem., 59, 5084 (1994)) (1.0 g) N-bromosuccinimide (1.3 g) was added to a carbon (20 mL) solution and stirred for 1 hour. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and concentrated to give a residue, which was purified by a silica gel column to give the title compound (1.29 g, 81%) as a pale yellow solid.
NMR (300 MHz, CDCl ₃ ) δ: 1.66-1.90 (6H, m), 2.89-2.93 (2H, m), 3.98 (2H, t, J = 4.8), 6.80 (1H, s).
93b) 3- (4-Pyridinyl) -6,7,8,9-tetrahydro-5H-imidazo [1,2-a] azepine 3-Bromo-6,7,8,9 obtained in Example 93a) The title compound (0.90 g, 71%) was obtained in the same manner as Example 92a) from -tetrahydro-5H-imidazo [1,2-a] azepine (1.29 g).
NMR (200MHz, CDCl ₃ ) δ: 1.76-1.93 (6H, m), 2.99 (2H, t, J = 4.8), 3.99 (2H, t, J = 4.8), 7.01 (1H, s), 7.21 (2H , m), 8.64 (2H, m).
93c) 3- (4-Piperidinyl) -6,7,8,9-tetrahydro-5H-imidazo [1,2-a] azepine dihydrochloride 3- (4-Pyridinyl)-obtained in Example 93b) The title compound (1.19 g, 96%) was obtained from 6,7,8,9-tetrahydro-5H-imidazo [1,2-a] azepine (0.90 g) in the same manner as in Example 92b).
NMR (200MHz, D ₂ O) δ: 176-1.95 (8H, m), 2.24 (2H, d, J = 10.2), 3.06-3.26 (5H, m), 3.57 (2H, d, J = 13.2), 4.21 (2H, t, J = 4.8), 7.11 (1H, s).
93d) 3- (1-{[3- (6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -6,7,8,9-tetrahydro-5H-imidazo [1,2-a] Azepine hydrochloride 3- (4-piperidinyl) -6,7,8,9-tetrahydro-5H-imidazo [1,2-a] azepine dihydrochloride (0.50 g) obtained in Example 93c) and 3- [ The title compound (0.47 g, 52%) was obtained from (6-chloro-2-naphthyl) sulfonyl] propionic acid (0.56 g) in the same manner as in Example 87b).
NMR (200MHz, CDCl ₃ ) δ: 1.39-2.00 (10H, m), 2.61-2.69 (2H, m), 2.88-2.96 (4H, m), 3.11-3.23 (1H, m), 3.51-3.60 (2H , m), 3.81-3.84 (2H, m), 3.92 (1H, d, J = 14.4), 4.56 (1H, d, J = 14.4), 6.52 (1H, s), 7.59 (1H, m), 7.90 -7.97 (4H, m), 8.48 (1H, s).
Elemental analysis C ₂₆ H ₃₀ N ₃ O ₃ SCl ・ HCl ・ 0.25H ₂ 0
Theoretical value (%) C, 53.70; H, 6.24; N, 7.23.
Actual value (%) C, 53.96; H, 6.44, N, 7.11.

実施例94
3-(1-{3-[(6-ビニル-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン塩酸塩
94a) 3-[(6-ブロモ-2-ナフチル)スルホニル]プロピオン酸tert-ブチル
水素化ホウ素ナトリウム(7.57g)のTHF溶液(200mL)へ塩化6-ブロモナフタレン-2-スルホニル(30.6g)のTHF溶液(200mL)を室温で滴下した。反応液を40℃で10時間かき混ぜた後、反応液に氷と6N塩酸を加えて酸性にした。酢酸エチルで抽出し、抽出液を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥後、濃縮した。残留物を酢酸エチル(200mL)に溶解させ、トリエチルアミン(20.8mL)とアクリル酸tert-ブチル(9.5mL)を加え、24時間還流した。反応液を酢酸エチルで希釈し、1N塩酸、飽和炭酸水素ナトリウム水溶液、飽和食塩水の順に洗浄、無水硫酸ナトリウムで乾燥した。溶媒を留去して題記化合物(28.3g, 71%)を淡黄色固体として得た。
NMR (200MHz, CDCl₃)δ：1.36 (9H, s), 2.69 (2H, t, J = 8.0), 3.46 (2H, t, J = 8.0), 7.72 (1H, dd, J = 1.8, 8.8), 7.86-7.92 (3H, m), 8.12 (1H, brs), 8.46 (1H, s).
94b) 3-[(6-ビニル-2-ナフチル)スルホニル]プロピオン酸tert-ブチル
実施例94a)で得た3-[(6-ブロモ-2-ナフチル)スルホニル]プロピオン酸tert-ブチル(2.0g)、トリブチル(ビニル)スズ(2.4g)、塩化リチウム(1.5g)、ジクロロビス(トリフェニルホスフィン)パラジウム(0.18g)のトルエン溶液(40mL)を、アルゴン雰囲気下、90℃で3時間かき混ぜた。不溶物をろ去し、ろ液を酢酸エチルで希釈、10％フッ化カリウム水溶液を加え、析出した不溶物をセライトでろ去した。ろ液から有機層を分取し、飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥、濃縮した。残留物をシリカゲルカラムにより精製し、題記化合物(0.96g, 55%)を無色固体として得た。
NMR (300MHz, CDCl₃)δ：1.36 (9H, s), 2.69 (2H, t, J = 7.2), 3.47 (2H, t, J = 7.2), 5.46 (1H, d, J = 10.8), 5.97 (1H, d, J = 17.7), 6.90 (1H, dd, J = 10.8, 17.7), 7.76-7.87 (3H, m), 7.93-7.99 (2H, m), 8.43 (1H, d, J = 1.5).
94c) 3-(6-ビニル-2-ナフチル)スルホニルプロピオン酸
実施例94b)で得た3-[(6-ビニル-2-ナフチル)スルホニル]プロピオン酸tert-ブチル(0.96g)のトルエン溶液(10mL)にトリフルオロ酢酸(10mL)を加え室温で12時間かき混ぜた。反応液を濃縮し、題記化合物(0.67g, 83%)を茶色固体として得た。
NMR (200MHz, DMSO-d₆)δ：2.59 (2H, t, J = 7.4), 3.66 (2H, t, J = 7.4), 5.46 (1H, d, J = 10.8), 5.97 (1H, d, J = 17.7), 6.90 (1H, dd, J = 10.8, 17.7), 8.00 (1H, dd, J = 1.8, 8.4), 8.08 (1H, dd, J = 1.8, 8.4), 8.33 (1H, d, J = 8.8), 8.44 (1H, d, J = 8.8), 8.75 (2H, d, J = 9.0).
94d) 3-(1-{3-[(6-ビニル-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン塩酸塩
実施例94c)で得た3-(6-ビニル-2-ナフチル)スルホニルプロピオン酸(0.33g)と実施例209b)で得た3-(4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン２塩酸塩(0.38g)から実施例87b)と同様にして題記化合物(0.36g, 57%)を白色固体として得た。
NMR (200MHz, CDCl₃)δ：1.36-1.75 (2H, m), 1.87-2.04 (6H, m), 2.57-2.70 (2H, m), 2.82-2.93 (4H, m), 3.11 (1H, m), 3.53-3.61 (2H, m), 3.80 (2H, t, J = 5.8), 3.91 (1H, d, J = 13.6), 4.57 (1H, d, J = 13.6), 5.47 (1H, d, J = 11.0), 5.96 (1H, d, J = 17.6), 6.65 (1H, s), 6.90 (1H, dd, J = 11.0, 17.6), 7.75-8.01 (5H, m), 8.45(1H, s).
元素分析 C₂₇H₃₁N₃O₃S・HCl・1.8H₂0 として
理論値（％） C, 59.34; H, 6.57; N, 7.69.
実測値（％） C, 59.55; H, 6.96, N, 7.79. Example 94
3- (1- {3-[(6-vinyl-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine hydrochloride
94a) tert-Butyl 3-[(6-bromo-2-naphthyl) sulfonyl] propionate Sodium 6-bromonaphthalene-2-sulfonyl chloride (30.6 g) into a THF solution (200 mL) of sodium borohydride (7.57 g) A THF solution (200 mL) was added dropwise at room temperature. After stirring the reaction solution at 40 ° C. for 10 hours, the reaction solution was acidified by adding ice and 6N hydrochloric acid. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was dissolved in ethyl acetate (200 mL), triethylamine (20.8 mL) and tert-butyl acrylate (9.5 mL) were added, and the mixture was refluxed for 24 hours. The reaction mixture was diluted with ethyl acetate, washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off to give the title compound (28.3 g, 71%) as a pale yellow solid.
NMR (200MHz, CDCl ₃ ) δ: 1.36 (9H, s), 2.69 (2H, t, J = 8.0), 3.46 (2H, t, J = 8.0), 7.72 (1H, dd, J = 1.8, 8.8) , 7.86-7.92 (3H, m), 8.12 (1H, brs), 8.46 (1H, s).
94b) tert-butyl 3-[(6-vinyl-2-naphthyl) sulfonyl] propionate tert-butyl 3-[(6-bromo-2-naphthyl) sulfonyl] propionate obtained in Example 94a) (2.0 g ), Tributyl (vinyl) tin (2.4 g), lithium chloride (1.5 g), dichlorobis (triphenylphosphine) palladium (0.18 g) in toluene (40 mL) was stirred at 90 ° C. for 3 hours under an argon atmosphere. Insoluble matter was removed by filtration, the filtrate was diluted with ethyl acetate, 10% aqueous potassium fluoride solution was added, and the precipitated insoluble matter was removed by filtration through Celite. The organic layer was separated from the filtrate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column to give the title compound (0.96 g, 55%) as a colorless solid.
NMR (300MHz, CDCl ₃ ) δ: 1.36 (9H, s), 2.69 (2H, t, J = 7.2), 3.47 (2H, t, J = 7.2), 5.46 (1H, d, J = 10.8), 5.97 (1H, d, J = 17.7), 6.90 (1H, dd, J = 10.8, 17.7), 7.76-7.87 (3H, m), 7.93-7.99 (2H, m), 8.43 (1H, d, J = 1.5 ).
94c) 3- (6-Vinyl-2-naphthyl) sulfonylpropionic acid 3-[(6-vinyl-2-naphthyl) sulfonyl] propionic acid tert-butyl (0.96 g) obtained in Example 94b) in toluene solution ( 10 mL) was added trifluoroacetic acid (10 mL), and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated to give the title compound (0.67 g, 83%) as a brown solid.
NMR (200MHz, DMSO-d ₆ ) δ: 2.59 (2H, t, J = 7.4), 3.66 (2H, t, J = 7.4), 5.46 (1H, d, J = 10.8), 5.97 (1H, d, J = 17.7), 6.90 (1H, dd, J = 10.8, 17.7), 8.00 (1H, dd, J = 1.8, 8.4), 8.08 (1H, dd, J = 1.8, 8.4), 8.33 (1H, d, J = 8.8), 8.44 (1H, d, J = 8.8), 8.75 (2H, d, J = 9.0).
94d) 3- (1- {3-[(6-vinyl-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine hydrochloride 3- (6-vinyl-2-naphthyl) sulfonylpropionic acid (0.33 g) obtained in Example 94c) and 3- (4-piperidinyl) -5,6,7,8-tetrahydrohydride obtained in Example 209b) The title compound (0.36 g, 57%) was obtained as a white solid from imidazo [1,2-a] pyridine dihydrochloride (0.38 g) in the same manner as in Example 87b).
NMR (200MHz, CDCl ₃ ) δ: 1.36-1.75 (2H, m), 1.87-2.04 (6H, m), 2.57-2.70 (2H, m), 2.82-2.93 (4H, m), 3.11 (1H, m ), 3.53-3.61 (2H, m), 3.80 (2H, t, J = 5.8), 3.91 (1H, d, J = 13.6), 4.57 (1H, d, J = 13.6), 5.47 (1H, d, J = 11.0), 5.96 (1H, d, J = 17.6), 6.65 (1H, s), 6.90 (1H, dd, J = 11.0, 17.6), 7.75-8.01 (5H, m), 8.45 (1H, s ).
Elemental analysis C ₂₇ H ₃₁ N ₃ O ₃ S ・ HCl ・ 1.8H ₂ 0
Theoretical value (%) C, 59.34; H, 6.57; N, 7.69.
Found (%) C, 59.55; H, 6.96, N, 7.79.

実施例95
3-(1-{3-[(6-ビニル-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)イミダゾ[1,2-a]ピリジン塩酸塩
実施例94c)で得た3-(6-ビニル-2-ナフチル)スルホニルプロピオン酸(0.33g)と実施例209b)で得た3-(4-ピペリジニル)イミダゾ[1,2-a]ピリジン２塩酸塩(0.37g)から実施例89b)と同様にして題記化合物(0.15g, 26%)を得た。
NMR (300MHz, CDCl₃)δ：1.54-1.80 (2H, m), 2.07-2.20 (2H, m), 2.77 (1H, m), 2.93 (2H, t, J = 7.5), 3.08 (1H, m), 3.26 (1H, m), 3.57-3.62 (2H, m), 3.99 (1H, d, J = 13.5), 4.62 (1H, d, J = 13.5), 5.47 (1H, d, J = 11.1), 5.97 (1H, d, J = 17.7), 6.82-6.96 (2H, m), 7.38 (1H, s), 7.61-7.65 (1H, d, J = 10.8), 7.77-8.01 (6H, m), 8.46 (1H, s).
元素分析 C₂₇H₃₁N₃O₃S・HCl・2H₂0 として
理論値（％） C, 59.39; H, 5.91; N, 7.69.
実測値（％） C, 59.45; H, 5.94, N, 7.56. Example 95
3- (1- {3-[(6-vinyl-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) imidazo [1,2-a] pyridine hydrochloride 3- (6- Example 89b) from vinyl-2-naphthyl) sulfonylpropionic acid (0.33 g) and 3- (4-piperidinyl) imidazo [1,2-a] pyridine dihydrochloride (0.37 g) obtained in Example 209b) In the same manner, the title compound (0.15 g, 26%) was obtained.
NMR (300MHz, CDCl ₃ ) δ: 1.54-1.80 (2H, m), 2.07-2.20 (2H, m), 2.77 (1H, m), 2.93 (2H, t, J = 7.5), 3.08 (1H, m ), 3.26 (1H, m), 3.57-3.62 (2H, m), 3.99 (1H, d, J = 13.5), 4.62 (1H, d, J = 13.5), 5.47 (1H, d, J = 11.1) , 5.97 (1H, d, J = 17.7), 6.82-6.96 (2H, m), 7.38 (1H, s), 7.61-7.65 (1H, d, J = 10.8), 7.77-8.01 (6H, m), 8.46 (1H, s).
Elemental analysis C ₂₇ H ₃₁ N ₃ O ₃ S ・ HCl ・ 2H ₂ 0
Theoretical value (%) C, 59.39; H, 5.91; N, 7.69.
Found (%) C, 59.45; H, 5.94, N, 7.56.

実施例96
6-{3-オキソ-3-[4-(5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン-3-イル)-1-ピペリジニル]プロピル}スルホニル-2-ナフトニトリル
96a) 3-[(6-シアノ-2-ナフチル)スルホニル]プロピオン酸tert-ブチル
実施例94a)で得た3-[(6-ブロモ-2-ナフチル)スルホニル]プロピオン酸tert-ブチル(3.9g)、シアン化亜鉛(0.69g)、テトラキス(トリフェニルホスフィン)パラジウム(0.56g)のDMF溶液(40mL)をアルゴン雰囲気下、80℃で5時間かき混ぜた。放冷後、反応液を酢酸エチルと水の混合物へ注ぎ込み、酢酸エチル層を分取した。酢酸エチル溶液を５％アンモニア水、飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥、濃縮した。残留物をイソプロピルエーテルで固化させ、題記化合物(2.04g, 60%)を淡黄色固体として得た。
NMR (200MHz, CDCl₃)δ：1.36 (9H, s), 2.71 (2H, t, J = 7.6), 3.50 (2H, t, J = 7.6), 7.79 (1H, dd, J = 1.6, 8.4), 7.99-8.15 (3H, m), 8.35 (1H, s), 8.55 (1H, s).
96b) 3-[(6-シアノ-2-ナフチル)スルホニル]プロピオン酸
実施例96a)で得た3-[(6-シアノ-2-ナフチル)スルホニル]プロピオン酸tert-ブチル(0.85 g)から実施例94c)と同様にして題記化合物(0.70g, 98%)を得た。
NMR (200MHz, DMSO-d₆)δ：2.59 (2H, t, J = 7.4), 3.66 (2H, t, J = 7.4), 8.00 (1H, dd, J = 1.8, 8.4), 8.08 (1H, dd, J = 1.8, 8.4), 8.33 (1H, d, J = 8.8), 8.44 (1H, d, J = 8.8), 8.75 (2H, d, J = 9.0).
96c) 6-{3-オキソ-3-[4-(5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン-3-イル)-1-ピペリジニル]プロピル}スルホニル-2-ナフトニトリル
実施例96b)で得た3-[(6-シアノ-2-ナフチル)スルホニル]プロピオン酸(0.35g)と実施例209b)で得た3-(4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン２塩酸塩(0.34g)から実施例89b)と同様にして題記化合物(0.42g, 68%)を得た。
NMR (300MHz, CDCl₃)δ：1.35-1.75 (2H, m), 1.80-2.00 (6H, m), 2.55-2.63 (2H, m), 2.83-2.91 (4H, m), 3.10 (1H, m), 3.56 (1H, m), 3.70 (1H, m), 3.78 (2H, t, J = 5.7), 3.86 (1H, d, J = 12.9), 4.47 (1H, d, J = 12.9), 6.50 (1H, s), 7.95-8.14 (4H, m), 8.43 (1H, s), 8.54 (1H, s). Example 96
6- {3-oxo-3- [4- (5,6,7,8-tetrahydroimidazo [1,2-a] pyridin-3-yl) -1-piperidinyl] propyl} sulfonyl-2-naphthonitrile
96a) tert-butyl 3-[(6-cyano-2-naphthyl) sulfonyl] propionate tert-butyl 3-[(6-bromo-2-naphthyl) sulfonyl] propionate obtained in Example 94a) (3.9 g ), Zinc cyanide (0.69 g), tetrakis (triphenylphosphine) palladium (0.56 g) in DMF (40 mL) was stirred at 80 ° C. for 5 hours under an argon atmosphere. After allowing to cool, the reaction solution was poured into a mixture of ethyl acetate and water, and the ethyl acetate layer was separated. The ethyl acetate solution was washed with 5% aqueous ammonia and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was solidified with isopropyl ether to give the title compound (2.04 g, 60%) as a pale yellow solid.
NMR (200MHz, CDCl ₃ ) δ: 1.36 (9H, s), 2.71 (2H, t, J = 7.6), 3.50 (2H, t, J = 7.6), 7.79 (1H, dd, J = 1.6, 8.4) , 7.99-8.15 (3H, m), 8.35 (1H, s), 8.55 (1H, s).
96b) 3-[(6-Cyano-2-naphthyl) sulfonyl] propionic acid Performed from tert-butyl 3-[(6-cyano-2-naphthyl) sulfonyl] propionate obtained in Example 96a) (0.85 g) The title compound (0.70 g, 98%) was obtained in the same manner as in Example 94c).
NMR (200MHz, DMSO-d ₆ ) δ: 2.59 (2H, t, J = 7.4), 3.66 (2H, t, J = 7.4), 8.00 (1H, dd, J = 1.8, 8.4), 8.08 (1H, dd, J = 1.8, 8.4), 8.33 (1H, d, J = 8.8), 8.44 (1H, d, J = 8.8), 8.75 (2H, d, J = 9.0).
96c) 6- {3-oxo-3- [4- (5,6,7,8-tetrahydroimidazo [1,2-a] pyridin-3-yl) -1-piperidinyl] propyl} sulfonyl-2-naphtho Nitrile 3-[(6-Cyano-2-naphthyl) sulfonyl] propionic acid obtained in Example 96b) (0.35 g) and 3- (4-piperidinyl) -5,6,7, obtained in Example 209b) The title compound (0.42 g, 68%) was obtained from 8-tetrahydroimidazo [1,2-a] pyridine dihydrochloride (0.34 g) in the same manner as in Example 89b).
NMR (300MHz, CDCl ₃ ) δ: 1.35-1.75 (2H, m), 1.80-2.00 (6H, m), 2.55-2.63 (2H, m), 2.83-2.91 (4H, m), 3.10 (1H, m ), 3.56 (1H, m), 3.70 (1H, m), 3.78 (2H, t, J = 5.7), 3.86 (1H, d, J = 12.9), 4.47 (1H, d, J = 12.9), 6.50 (1H, s), 7.95-8.14 (4H, m), 8.43 (1H, s), 8.54 (1H, s).

実施例97
6-{3-オキソ-3-[4-(5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン-3-イル)-1-ピペリジニル]プロピル}スルホニル-2-ナフトアミド
97a) 3-[(6-カルバモイル-2-ナフチル)スルホニル]プロピオン酸tert-ブチル
実施例96a)で得た3-[(6-シアノ-2-ナフチル)スルホニル]プロピオン酸tert-ブチル(1.1g)のDMSO溶液(20mL)に過酸化水素水(4mL)と炭酸カリウム(0.7g)を加え、室温にて20分間かき混ぜた。反応液を酢酸エチルと水で希釈、有機層を分取した。酢酸エチル溶液を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥した。溶媒を留去し、題記化合物(0.88g, 76%)を無色固体として得た。
NMR (200MHz, CDCl₃)δ：1.36 (9H, s), 2.70 (2H, t, J = 7.0), 3.48 (2H, t, J = 7.0), 6.20 (1H, br), 6.55 (1H, br), 7.91 (1H, dd, J = 1.8, 8.8), 8.02-8.10 (3H, m), 8.42 (1H, s), 8.47 (1H, br).
97b) 3-[(6-カルバモイル-2-ナフチル)スルホニル]プロピオン酸
実施例97a)で得た3-[(6-カルバモイル-2-ナフチル)スルホニル]プロピオン酸tert-ブチル(0.85g)から実施例94c)と同様にして題記化合物(0.73g, 定量的)を得た。
NMR (200MHz, DMSO-d₆)δ：2.59 (2H, t, J = 7.0), 3.63 (2H, t, J = 7.0), 7.64 (1H, br), 7.97 (1H, dd, J = 1.8, 8.4), 8.11 (1H, dd, J = 1.8, 8.4), 8.26-8.32 (3H, m), 8.63 (2H, br).
97c) 6-{3-オキソ-3-[4-(5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン-3-イル)-1-ピペリジニル]プロピル}スルホニル-2-ナフトアミド
実施例97b)で得た3-[(6-カルバモイル-2-ナフチル)スルホニル]プロピオン酸(0.35g)と実施例209b)で得た3-(4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン２塩酸塩(0.32g)から実施例89b)と同様にして題記化合物(0.41g, 73%)を得た。
NMR (300MHz, CDCl₃)δ：1.38-1.67 (2H, m),1.88-2.05 (6H, m), 2.61-2.71 (2H, m), 2.84-2.97 (4H, m), 3.15 (1H, m), 3.57-3.62 (2H, m), 3.81 (2H, t, J = 5.7), 3.93 (1H, d, J = 14.1), 4.55 (1H, d, J = 14.1), 6.56 (1H, s), 7.79 (1H, dd, J = 1.2, 8.4), 8.02-8.13 (3H, m), 8.34 (1H, s), 8.56 (1H, s).
元素分析 C₂₆H₃₀N₄O₄S・H₂O・0.1i-Pr₂O として
理論値（％） C, 61.11; H, 6.44; N, 10.72.
実測値（％） C, 61.33; H, 6.28, N, 10.56. Example 97
6- {3-oxo-3- [4- (5,6,7,8-tetrahydroimidazo [1,2-a] pyridin-3-yl) -1-piperidinyl] propyl} sulfonyl-2-naphthamide
97a) tert-butyl 3-[(6-carbamoyl-2-naphthyl) sulfonyl] propionate tert-butyl 3-[(6-cyano-2-naphthyl) sulfonyl] propionate obtained in Example 96a) (1.1 g Hydrogen peroxide solution (4 mL) and potassium carbonate (0.7 g) were added to a DMSO solution (20 mL) and stirred at room temperature for 20 minutes. The reaction solution was diluted with ethyl acetate and water, and the organic layer was separated. The ethyl acetate solution was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off to give the title compound (0.88 g, 76%) as a colorless solid.
NMR (200MHz, CDCl ₃ ) δ: 1.36 (9H, s), 2.70 (2H, t, J = 7.0), 3.48 (2H, t, J = 7.0), 6.20 (1H, br), 6.55 (1H, br ), 7.91 (1H, dd, J = 1.8, 8.8), 8.02-8.10 (3H, m), 8.42 (1H, s), 8.47 (1H, br).
97b) 3-[(6-Carbamoyl-2-naphthyl) sulfonyl] propionic acid Performed from tert-butyl 3-[(6-carbamoyl-2-naphthyl) sulfonyl] propionate obtained in Example 97a) (0.85 g) The title compound (0.73 g, quantitative) was obtained in the same manner as in Example 94c).
NMR (200MHz, DMSO-d ₆ ) δ: 2.59 (2H, t, J = 7.0), 3.63 (2H, t, J = 7.0), 7.64 (1H, br), 7.97 (1H, dd, J = 1.8, 8.4), 8.11 (1H, dd, J = 1.8, 8.4), 8.26-8.32 (3H, m), 8.63 (2H, br).
97c) 6- {3-oxo-3- [4- (5,6,7,8-tetrahydroimidazo [1,2-a] pyridin-3-yl) -1-piperidinyl] propyl} sulfonyl-2-naphthamide 3-[(6-Carbamoyl-2-naphthyl) sulfonyl] propionic acid (0.35 g) obtained in Example 97b) and 3- (4-piperidinyl) -5,6,7,8 obtained in Example 209b) The title compound (0.41 g, 73%) was obtained in the same manner as Example 89b) from tetrahydroimidazo [1,2-a] pyridine dihydrochloride (0.32 g).
NMR (300MHz, CDCl ₃ ) δ: 1.38-1.67 (2H, m), 1.88-2.05 (6H, m), 2.61-2.71 (2H, m), 2.84-2.97 (4H, m), 3.15 (1H, m ), 3.57-3.62 (2H, m), 3.81 (2H, t, J = 5.7), 3.93 (1H, d, J = 14.1), 4.55 (1H, d, J = 14.1), 6.56 (1H, s) , 7.79 (1H, dd, J = 1.2, 8.4), 8.02-8.13 (3H, m), 8.34 (1H, s), 8.56 (1H, s).
Elemental analysis C ₂₆ H ₃₀ N ₄ O ₄ S ・ H ₂ O ・ 0.1i-Pr ₂ O
Theoretical value (%) C, 61.11; H, 6.44; N, 10.72.
Found (%) C, 61.33; H, 6.28, N, 10.56.

実施例98
3-(1-{3-[(6-エチル-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン塩酸塩
実施例94d)で得た3-(1-{3-[(6-エテニル-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン塩酸塩(0.2g)とパラジウム-炭素(0.04g)のメタノール溶液(4mL)を水素雰囲気下、1時間かき混ぜた。不溶物をろ去し、ろ液を濃縮して題記化合物を得た(0.2g, 99%)。
NMR (300MHz, CDCl₃)δ：1.35 (3H, t, J = 7.8), 1.42-1.63 (2H, m), 1.88-1.99 (6H, m), 2.60-2.69 (2H, m), 2.83-2.91 (6H, m), 3.12 (1H, m), 3.53-3.59 (2H, m), 3.80 (2H, t, J = 6.0), 3.91 (1H, d, J = 13.2), 4.56 (1H,d, J = 13.2), 6.65 (1H, s), 7.51 (1H, dd, J = 1.8, 8.7), 7.73 (1H, s), 7.83-7.97 (3H, m), 8.45 (1H, s).
元素分析 C₂₇H₃₃N₃O₃SHCl・1.25H₂O として
理論値（％） C, 60.21; H, 6.83; N, 7.80.
実測値（％） C, 60.29; H, 6.77, N, 7.53. Example 98
3- (1- {3-[(6-Ethyl-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine hydrochloride Examples 94d) 3- (1- {3-[(6-ethenyl-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -5,6,7,8-tetrahydroimidazo [1,2-a] Pyridine hydrochloride (0.2 g) and palladium-carbon (0.04 g) in methanol (4 mL) were stirred in a hydrogen atmosphere for 1 hour. The insoluble material was removed by filtration, and the filtrate was concentrated to give the title compound (0.2 g, 99%).
NMR (300MHz, CDCl ₃ ) δ: 1.35 (3H, t, J = 7.8), 1.42-1.63 (2H, m), 1.88-1.99 (6H, m), 2.60-2.69 (2H, m), 2.83-2.91 (6H, m), 3.12 (1H, m), 3.53-3.59 (2H, m), 3.80 (2H, t, J = 6.0), 3.91 (1H, d, J = 13.2), 4.56 (1H, d, J = 13.2), 6.65 (1H, s), 7.51 (1H, dd, J = 1.8, 8.7), 7.73 (1H, s), 7.83-7.97 (3H, m), 8.45 (1H, s).
Elemental analysis C ₂₇ H ₃₃ N ₃ O ₃ SHCl ・ 1.25H ₂ O
Theoretical value (%) C, 60.21; H, 6.83; N, 7.80.
Found (%) C, 60.29; H, 6.77, N, 7.53.

実施例99
7-アセチル-3-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピラジン
99a) 4-(7-アセチル-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピラジン-3-イル)ピペリジン-1-カルボン酸tert-ブチル
実施例85a)で得られた4-(イミダゾ[1,2-a]ピラジン-3-イル)ピペリジン-1-カルボン酸tert-ブチル(1.0g)と無水酢酸(1.0mL)、パラジウム-炭素(0.2g)の酢酸エチル溶液(5 mL)を水素雰囲気下、室温で3日間かき混ぜた。不溶物をろ去し、ろ液を濃縮、残留物をシリカゲルカラムで精製し、題記化合物(0.47g, 41%)を淡黄色固体として得た。
NMR (300MHz, CDCl₃)δ：1.48 (9H, s), 1.51-1.89 (4H, m), 2.19 (3H, s), 2.59 (1H, m), 2.76-2.85 (2H, m), 3.87 (2H, t, J = 5.4), 4.04 (2H, t, J = 5.4), 4.18-4.22 (2H, m), 4.74 (2H, s), 6.76 (1H, s).
99b) 7-アセチル-3-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピラジン
実施例99a)で得た4-(7-アセチル-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピラジン-3-イル)ピペリジン-1-カルボン酸tert-ブチル(0.45g)のトルエン溶液(5mL)にトリフルオロ酢酸(5mL)を加え、室温で2時間かき混ぜた。反応液を濃縮後、残留物をアセトニトリルに溶解し、DBU(0.41g)とトリエチルアミン(0.56mL)を加えた。この溶液を3-[(6-クロロ-2-ナフチル)スルホニル]プロピオン酸(0.45g)、WSC(0.43g)およびHOBt (0.35g)のアセトニトリル(10 mL)けん濁液へ加え、12時間かき混ぜた。反応液を減圧濃縮し、残留物をクロロホルムと飽和重曹水に溶解させ、クロロホルム層を分取した。クロロホルム溶液を無水硫酸ナトリウムで乾燥、溶媒を留去した。残留物をシリカゲルカラムにより精製し、題記化合物(0.39g, 54%)を白色粉末固体として得た。
NMR (300MHz, CDCl₃)δ：1.45-1.65 (2H, m), 1.88-2.00 (2H, m), 2.19 (3H, s), 2.61-2.78 (3H, m), 2.91 (2H, t, J = 8.4), 3.15 (1H, t, J = 14.4), 3.56 (2H, t, J = 8.4), 3.84-4.10 (4H, m), 4.58 (1H, d, J = 13.5), 4.75 (2H, s), 6.74 (1H, s), 7.59 (1H, dd, J = 1.2, 8.7), 7.90-7.96 (4H, m), 8.48 (1H, s). Example 99
7-acetyl-3- (1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyrazine
99a) 4- (7-acetyl-5,6,7,8-tetrahydroimidazo [1,2-a] pyrazin-3-yl) piperidine-1-carboxylate tert-butyl obtained in Example 85a) -(Imidazo [1,2-a] pyrazin-3-yl) piperidine-1-carboxylate tert-butyl (1.0 g), acetic anhydride (1.0 mL), palladium-carbon (0.2 g) in ethyl acetate solution (5 mL) was stirred in a hydrogen atmosphere at room temperature for 3 days. The insoluble material was removed by filtration, the filtrate was concentrated, and the residue was purified by silica gel column to give the title compound (0.47 g, 41%) as a pale yellow solid.
NMR (300MHz, CDCl ₃ ) δ: 1.48 (9H, s), 1.51-1.89 (4H, m), 2.19 (3H, s), 2.59 (1H, m), 2.76-2.85 (2H, m), 3.87 ( 2H, t, J = 5.4), 4.04 (2H, t, J = 5.4), 4.18-4.22 (2H, m), 4.74 (2H, s), 6.76 (1H, s).
99b) 7-acetyl-3- (1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -5,6,7,8-tetrahydroimidazo [1,2-a Pyrazine 4- (7-acetyl-5,6,7,8-tetrahydroimidazo [1,2-a] pyrazin-3-yl) piperidine-1-carboxylate tert-butyl (0.45) obtained in Example 99a) To a toluene solution (5 mL) of g) was added trifluoroacetic acid (5 mL), and the mixture was stirred at room temperature for 2 hours. After the reaction solution was concentrated, the residue was dissolved in acetonitrile, and DBU (0.41 g) and triethylamine (0.56 mL) were added. Add this solution to a suspension of 3-[(6-chloro-2-naphthyl) sulfonyl] propionic acid (0.45 g), WSC (0.43 g) and HOBt (0.35 g) in acetonitrile (10 mL) and stir for 12 hours. It was. The reaction solution was concentrated under reduced pressure, the residue was dissolved in chloroform and saturated aqueous sodium hydrogen carbonate, and the chloroform layer was separated. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by silica gel column to give the title compound (0.39 g, 54%) as a white powder solid.
NMR (300MHz, CDCl ₃ ) δ: 1.45-1.65 (2H, m), 1.88-2.00 (2H, m), 2.19 (3H, s), 2.61-2.78 (3H, m), 2.91 (2H, t, J = 8.4), 3.15 (1H, t, J = 14.4), 3.56 (2H, t, J = 8.4), 3.84-4.10 (4H, m), 4.58 (1H, d, J = 13.5), 4.75 (2H, s), 6.74 (1H, s), 7.59 (1H, dd, J = 1.2, 8.7), 7.90-7.96 (4H, m), 8.48 (1H, s).

実施例100
(6-{3-オキソ-3-[4-(5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン-3-イル)-1-ピペリジニル]プロピル}スルホニル-2-ナフチル)メチルアミン２塩酸塩
100a) 3-[(6-ホルミル-2-ナフチル)スルホニル]プロピオン酸tert-ブチル
実施例94b)で得た3-[(6-ビニル-2-ナフチル)スルホニル]プロピオン酸tert-ブチル(5.5g)、過ヨウ素酸ナトリウム(13.8g)のアセトニトリル-アセトン-水(1:1:1, 300mL)溶液へ酸化オスミウム（10% enmicrocapsulated, 1.1g）を加え、室温で2日間かき混ぜた。不溶物をろ去し、ろ液から有機溶媒を減圧留去した。残留物を酢酸エチルで抽出し、抽出液を飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥した。溶媒を留去し、残留物をシリカゲルカラムで精製して題記化合物(2.56g, 46%)を淡黄色固体として得た。
NMR (300MHz CDCl₃)δ：0.36 (9H, s), 2.72 (2H, t, J = 8.0), 3.50 (2H, t, J = 8.0), 8.00 (1H, dd, J = 1.2, 8.8), 8.12-8.23 (3H, m), 8.45 (1H, s), 8.55 (1H, s), 10.24 (1H, s).
100b) 3-[(6-ヒドロキシメチル-2-ナフチル)スルホニル]プロピオン酸tert-ブチル
実施例100a)で得た3-[(6-ホルミル-2-ナフチル)スルホニル]プロピオン酸tert-ブチル(2.0g)のエタノール溶液に水素化ホウ素ナトリウム(0.46g)を加え、室温で30分間かき混ぜた。反応液を濃縮し、残留物に酢酸エチルを加え、1N塩酸、飽和炭酸水素ナトリウム水溶液、飽和食塩水の順で洗浄、無水硫酸ナトリウムで乾燥した。溶媒を留去して、題記化合物(2.0g, 99%)を無色固体として得た。
NMR (200MHz, CDCl₃)δ：1.36 (9H, s), 2.12 (1H, t, J = 5.8), 2.67 (2H, t, J =7.8), 3.45 (2H, t, J = 7.8), 4.92 (2H, d, J = 5.8), 7.61 (1H, dd, J = 1.8, 8.8), 7.83 (1H, dd, J = 1.8, 8.8), 7.91-7.98 (3H, m), 8.42 (1H, s).
100c) 3-(6-アジドメチル-2-ナフチル)スルホニルプロピオン酸tert-ブチル
実施例100b)で得た3-[(6-ヒドロキシメチル-2-ナフチル)スルホニル]プロピオン酸tert-ブチル(0.46g)とピリジン(0.30mL)のジクロロメタン(10mL)溶液へ氷冷下、塩化メタンスルホニル(0.15mL)を加えた。２時間かき混ぜた後、反応液に氷を加え、酢酸エチルと水で希釈した。有機層を分取し、飽和炭酸水素ナトリウム水溶液、飽和食塩水の順で洗浄、無水硫酸ナトリウムで乾燥、濃縮した。残留物をアセトン(10 mL)に溶解し、臭化リチウム(1.0g)を加えた。３時間かき混ぜた後、酢酸エチルと水で希釈し、有機層を分取し、飽和炭酸水素ナトリウム水溶液，飽和食塩水で洗浄、無水硫酸ナトリウムの順で乾燥、濃縮した。残留物をDMF(10mL)に溶解させ、アジ化アトリウム(0.19g)を加え12時間かき混ぜた。反応液を酢酸エチルと水で希釈し、有機層を分取、飽和炭酸水素ナトリウム水溶液、飽和食塩水の順で洗浄、無水硫酸ナトリウムで乾燥した。溶媒を留去して題記化合物(0.32g, 73%)を無色粉末固体として得た。
NMR (200MHz, CDCl₃)δ：0.35 (9H, s), 2.69 (2H, t, J = 7.8), 3.47 (2H, t, J = 7.8), 4.59 (2H, s), 7.61 (1H, d, J = 1.4), 7.90 (2H, dd, J = 1.4, 8.8), 8.01-8.06 (2H, m), 8.49 (1H, br).
100d) 3-[(6-アジドメチル-2-ナフチル)スルホニル]プロピオン酸
実施例100c)で得た3-[6-アジドメチル-2-ナフチル)スルホニル]プロピオン酸tert-ブチル(0.24g)のギ酸(5mL)溶液を室温で２時間かき混ぜた。反応液を濃縮し、題記化合物(0.22g, 99%)を白色固体として得た。
NMR (200MHz, DMSO-d₆)δ：2.57 (2H, t, J = 7.8), 3.61 (2H, t, J = 7.8), 4.73 (2H, s), 7.69 (1H, dd, J = 1.8, 8.4), 7.92 (1H, dd, J = 1.8, 8.8), 8.09 (1H, s), 8.19-8.29 (2H, m), 8.59 (1H, s).
100e) 3-(1-{3-[(6-アジドメチル-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン
実施例100d)で得た3-[(6-アジドメチル-2-ナフチル)スルホニル]プロピオン酸(0.22g)と実施例209b)で得た3-(4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン２塩酸塩(0.23g)から実施例89b)と同様にして題記化合物(0.26g, 74%)を得た。
NMR (200MHz, CDCl₃)δ：1.40-1.72 (2H, m), 1.82-2.05 (6H, m), 2.65 (1H, m), 2.83-2.94 (3H, m), 3.07-3.30 (3H, m), 3.53-3.61 (2H, m), 3.81 (2H, t, J = 5.8), 3.91 (1H, d, J = 13.4), 4.56 (1H, d, J = 13.4), 5.32 (2H, s), 6.65 (1H, s), 7.61 (1H, dd, J = 2.2, 8.8), 7.88-8.05 (4H, m), 8.50 (1H, s).
100f) (6-{3-オキソ-3-[4-(5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン-3-イル)-1-ピペリジニル]プロピル}スルホニル-2-ナフチル)メチルアミン２塩酸塩
実施例100e)で得た3-(1-{3-[(6-アジドメチル-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン(0.25g)とパラジウム-炭素(0.05g)のメタノール(5mL)溶液を水素雰囲気下、２時間かき混ぜた。不溶物をろ去、ろ液を濃縮し、残留物をシリカゲルカラムにより精製、飽和塩化水素エタノール溶液で処理して、題記化合物(0.27g, 定量的)を得た。
NMR (200MHz, DMSO-d₆)δ：1.26 (1H, m), 1.44 (1H, m), 1.81-1.98 (6H, m), 2.58 (1H, m), 2.76 (2H, t, J = 6.9), 2.93-2.97 (3H, m), 3.08 (1H, t, J = 14.2), 3.88 (1H, d, J = 14.2), 4.03-4.07 (2H, m), 4.25-4.34 (3H, m), 7.33 (1H, s), 7.84 (1H, dd, J = 1.5, 8.7), 7.97 (1H, dd, J = 1.8, 8.7), 8.16-8.19 (2H, m), 8.27 (1H, d, J = 7.8), 8.63 (1H, s) Example 100
(6- {3-oxo-3- [4- (5,6,7,8-tetrahydroimidazo [1,2-a] pyridin-3-yl) -1-piperidinyl] propyl} sulfonyl-2-naphthyl) Methylamine dihydrochloride
100a) tert-butyl 3-[(6-formyl-2-naphthyl) sulfonyl] propionate tert-butyl 3-[(6-vinyl-2-naphthyl) sulfonyl] propionate obtained in Example 94b) (5.5 g ), Osmium oxide (10% enmicrocapsulated, 1.1 g) was added to a solution of sodium periodate (13.8 g) in acetonitrile-acetone-water (1: 1, 300 mL), and the mixture was stirred at room temperature for 2 days. Insolubles were removed by filtration, and the organic solvent was distilled off from the filtrate under reduced pressure. The residue was extracted with ethyl acetate, and the extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified with a silica gel column to give the title compound (2.56 g, 46%) as a pale yellow solid.
NMR (300MHz CDCl ₃ ) δ: 0.36 (9H, s), 2.72 (2H, t, J = 8.0), 3.50 (2H, t, J = 8.0), 8.00 (1H, dd, J = 1.2, 8.8), 8.12-8.23 (3H, m), 8.45 (1H, s), 8.55 (1H, s), 10.24 (1H, s).
100b) tert-butyl 3-[(6-hydroxymethyl-2-naphthyl) sulfonyl] propionate tert-butyl 3-[(6-formyl-2-naphthyl) sulfonyl] propionate obtained in Example 100a) (2.0 Sodium borohydride (0.46 g) was added to the ethanol solution of g) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated, ethyl acetate was added to the residue, and the mixture was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order, and dried over anhydrous sodium sulfate. The solvent was distilled off to give the title compound (2.0 g, 99%) as a colorless solid.
NMR (200MHz, CDCl ₃ ) δ: 1.36 (9H, s), 2.12 (1H, t, J = 5.8), 2.67 (2H, t, J = 7.8), 3.45 (2H, t, J = 7.8), 4.92 (2H, d, J = 5.8), 7.61 (1H, dd, J = 1.8, 8.8), 7.83 (1H, dd, J = 1.8, 8.8), 7.91-7.98 (3H, m), 8.42 (1H, s ).
100c) tert-butyl 3- (6-azidomethyl-2-naphthyl) sulfonylpropionate tert-butyl 3-[(6-hydroxymethyl-2-naphthyl) sulfonyl] propionate obtained in Example 100b) (0.46 g) Methanesulfonyl chloride (0.15 mL) was added to a solution of pyridine and pyridine (0.30 mL) in dichloromethane (10 mL) under ice cooling. After stirring for 2 hours, ice was added to the reaction mixture, and the mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order, dried over anhydrous sodium sulfate, and concentrated. The residue was dissolved in acetone (10 mL) and lithium bromide (1.0 g) was added. After stirring for 3 hours, the mixture was diluted with ethyl acetate and water, and the organic layer was separated, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried and concentrated in the order of anhydrous sodium sulfate. The residue was dissolved in DMF (10 mL), atrium azide (0.19 g) was added, and the mixture was stirred for 12 hr. The reaction solution was diluted with ethyl acetate and water, and the organic layer was separated, washed with a saturated aqueous sodium hydrogen carbonate solution and then saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off to give the title compound (0.32 g, 73%) as a colorless powder solid.
NMR (200MHz, CDCl ₃ ) δ: 0.35 (9H, s), 2.69 (2H, t, J = 7.8), 3.47 (2H, t, J = 7.8), 4.59 (2H, s), 7.61 (1H, d , J = 1.4), 7.90 (2H, dd, J = 1.4, 8.8), 8.01-8.06 (2H, m), 8.49 (1H, br).
100d) 3-[(6-Azidomethyl-2-naphthyl) sulfonyl] propionic acid Formic acid of tert-butyl 3- [6-azidomethyl-2-naphthyl) sulfonyl] propionate obtained in Example 100c) (0.24 g) The solution was stirred for 2 hours at room temperature. The reaction mixture was concentrated to give the title compound (0.22 g, 99%) as a white solid.
NMR (200MHz, DMSO-d ₆ ) δ: 2.57 (2H, t, J = 7.8), 3.61 (2H, t, J = 7.8), 4.73 (2H, s), 7.69 (1H, dd, J = 1.8, 8.4), 7.92 (1H, dd, J = 1.8, 8.8), 8.09 (1H, s), 8.19-8.29 (2H, m), 8.59 (1H, s).
100e) 3- (1- {3-[(6-Azidomethyl-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine Examples 3-[(6-Azidomethyl-2-naphthyl) sulfonyl] propionic acid (0.22 g) obtained in 100d) and 3- (4-piperidinyl) -5,6,7,8-tetrahydro obtained in Example 209b) The title compound (0.26 g, 74%) was obtained from imidazo [1,2-a] pyridine dihydrochloride (0.23 g) in the same manner as in Example 89b).
NMR (200MHz, CDCl ₃ ) δ: 1.40-1.72 (2H, m), 1.82-2.05 (6H, m), 2.65 (1H, m), 2.83-2.94 (3H, m), 3.07-3.30 (3H, m ), 3.53-3.61 (2H, m), 3.81 (2H, t, J = 5.8), 3.91 (1H, d, J = 13.4), 4.56 (1H, d, J = 13.4), 5.32 (2H, s) , 6.65 (1H, s), 7.61 (1H, dd, J = 2.2, 8.8), 7.88-8.05 (4H, m), 8.50 (1H, s).
100f) (6- {3-oxo-3- [4- (5,6,7,8-tetrahydroimidazo [1,2-a] pyridin-3-yl) -1-piperidinyl] propyl} sulfonyl-2- Naphthyl) methylamine dihydrochloride 3- (1- {3-[(6-azidomethyl-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -5,6,7,8- obtained in Example 100e) A solution of tetrahydroimidazo [1,2-a] pyridine (0.25 g) and palladium-carbon (0.05 g) in methanol (5 mL) was stirred under a hydrogen atmosphere for 2 hours. The insoluble material was removed by filtration, the filtrate was concentrated, and the residue was purified with a silica gel column and treated with saturated hydrogen chloride ethanol solution to obtain the title compound (0.27 g, quantitative).
NMR (200MHz, DMSO-d ₆ ) δ: 1.26 (1H, m), 1.44 (1H, m), 1.81-1.98 (6H, m), 2.58 (1H, m), 2.76 (2H, t, J = 6.9 ), 2.93-2.97 (3H, m), 3.08 (1H, t, J = 14.2), 3.88 (1H, d, J = 14.2), 4.03-4.07 (2H, m), 4.25-4.34 (3H, m) , 7.33 (1H, s), 7.84 (1H, dd, J = 1.5, 8.7), 7.97 (1H, dd, J = 1.8, 8.7), 8.16-8.19 (2H, m), 8.27 (1H, d, J = 7.8), 8.63 (1H, s)

実施例101
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-[(2-メチル-1H-イミダゾール-1-イル)メチル]ピペリジン塩酸塩
101a) 4-[(2-メチル-1H-イミダゾール-1-イル)メチル]ピペリジン-1-カルボン酸tert-ブチル
2-メチルイミダゾール(1.8g)と4-(ブロモメチル)ピペリジン-1-カルボン酸tert-ブチル(DeVita, Robert, J. et al., Bioorg. Med. Chem. Lett., 9, 261 (1999)) (8.5g)のDMF溶液(100mL)に水素化ナトリウム(60%油性: 0.87g)を加え、80℃で12時間かき混ぜた。反応液を濃縮し、残留物をクロロホルムに溶解、炭酸カリウム水溶液で洗浄、無水硫酸ナトリウムで乾燥、濃縮した。残留物をシリカゲルカラムにより精製し、題記化合物(0.43g, 7%)を茶色油状物質として得た。
NMR (300MHz, CDCl₃)δ：1.13-1.28 (2H, m), 1.46 (9H, s), 1.57-1.63 (4H, m), 1.82 (1H, m), 2.37 (3H, s), 2.65 (2H, t, J = 12.9), 3.71 (2H, d, J = 7.5), 4.16 (2H, brs), 6.78 (1H, d, J = 1.5), 6.91 (1H, d, J = 1.5).
101b) 1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-[(2-メチル-1H-イミダゾール-1-イル)メチル]ピペリジン塩酸塩
実施例101a)で得た4-[(2-メチル-1H-イミダゾール-1-イル)メチル]ピペリジン-1-カルボン酸tert-ブチル(0.42g)と3-[(6-クロロ-2-ナフチル)スルホニル]プロピオン酸(0.45g)から実施例81b) と同様にして題記化合物(0.55g, 74%)を無色固体として得た。
NMR (200MHz, CDCl₃)δ：1.00-1.24 (2H, m), 1.48 (1H, m),1.63-1.77 (4H, m), 2.37 (3H, s), 2.49 (1H, t, J = 13.2), 2.83-2.90 (2H, m), 2.98 (1H, t, J = 13.2), 3.47-3.60 (2H, m), 3.80-3.88 (3H, m), 4.49 (1H, d, J = 11.4), 6.79 (1H, s), 6.91 (1H, s), 7.59 (1H, dd, J = 1.8, 9.0), 7.90-7.96 (4H, m), 8.47 (1H, s) Example 101
1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-[(2-methyl-1H-imidazol-1-yl) methyl] piperidine hydrochloride
101a) tert-butyl 4-[(2-methyl-1H-imidazol-1-yl) methyl] piperidine-1-carboxylate
2-methylimidazole (1.8 g) and tert-butyl 4- (bromomethyl) piperidine-1-carboxylate (DeVita, Robert, J. et al., Bioorg. Med. Chem. Lett., 9, 261 (1999)) Sodium hydride (60% oiliness: 0.87 g) was added to a DMF solution (100 mL) of (8.5 g), and the mixture was stirred at 80 ° C. for 12 hours. The reaction solution was concentrated, and the residue was dissolved in chloroform, washed with an aqueous potassium carbonate solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column to give the title compound (0.43 g, 7%) as a brown oil.
NMR (300MHz, CDCl ₃ ) δ: 1.13-1.28 (2H, m), 1.46 (9H, s), 1.57-1.63 (4H, m), 1.82 (1H, m), 2.37 (3H, s), 2.65 ( 2H, t, J = 12.9), 3.71 (2H, d, J = 7.5), 4.16 (2H, brs), 6.78 (1H, d, J = 1.5), 6.91 (1H, d, J = 1.5).
101b) 1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-[(2-methyl-1H-imidazol-1-yl) methyl] piperidine hydrochloride obtained in Example 101a) 4-[(2-Methyl-1H-imidazol-1-yl) methyl] piperidine-1-carboxylate tert-butyl (0.42 g) and 3-[(6-chloro-2-naphthyl) sulfonyl] propionic acid (0.45 The title compound (0.55 g, 74%) was obtained as a colorless solid from g) in the same manner as in Example 81b).
NMR (200MHz, CDCl ₃ ) δ: 1.00-1.24 (2H, m), 1.48 (1H, m), 1.63-1.77 (4H, m), 2.37 (3H, s), 2.49 (1H, t, J = 13.2 ), 2.83-2.90 (2H, m), 2.98 (1H, t, J = 13.2), 3.47-3.60 (2H, m), 3.80-3.88 (3H, m), 4.49 (1H, d, J = 11.4) , 6.79 (1H, s), 6.91 (1H, s), 7.59 (1H, dd, J = 1.8, 9.0), 7.90-7.96 (4H, m), 8.47 (1H, s)

実施例102
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-[2-(2-メチル-1H-イミダゾール-1-イル)エチル]ピペリジン塩酸塩
102a) 4-[2-(2-メチル-1H-イミダゾール-1-イル)エチル]ピペリジン-1-カルボン酸tert-ブチル
4-(2-ブロモエチル)ピペリジン-1-カルボン酸tert-ブチル(Dereck, B. et al., J. Med. Chem., 42, 4584 (1999)) (6.46g)と2-メチルイミダゾール(0.93g)から実施例101a)と同様にして題記化合物(5.45g, 80%)を茶色油状物として得た。
NMR (300MHz, CDCl₃)δ：1.13-1.28 (2H, m), 1.46 (9H, s), 1.57-1.63 (4H, m), 1.82 (1H, m), 2.37 (3H, s), 2.65 (2H, t, J = 12.9), 3.71 (2H, d, J = 7.5), 4.16 (2H, brs), 6.78 (1H, d, J = 1.5), 6.91 (1H, d, J = 1.5).
102b) 1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-[2-(2-メチル-1H-イミダゾール-1-イル)エチル]ピペリジン塩酸塩
実施例101a)で得た4-[2-(2-メチル-1H-イミダゾール-1-イル)エチル]ピペリジン-1-カルボン酸tert-ブチル(0.43g)と3-[(6-クロロ-2-ナフチル)スルホニル]プロピオン酸(0.45g)から実施例81b)と同様にして題記化合物(0.52g, 69%)を無色固体として得た。
NMR (200MHz, CDCl₃)δ：1.00-1.24 (2H, m), 1.48 (1H, m),1.63-1.77 (4H, m), 2.37 (3H, s), 2.49 (1H, t, J = 13.2), 2.83-2.90 (2H, m), 2.98 (1H, t, J = 13.2), 3.47-3.60 (2H, m), 3.80-3.88 (3H, m), 4.49 (1H, d, J = 11.4), 6.79 (1H, s), 6.91 (1H, s), 7.59 (1H, dd, J = 1.8, 9.0), 7.90-7.96 (4H, m), 8.47 (1H, s).
元素分析 C₂₄H₂₈N₃O₃SCl・HCl・0.25H₂O として
理論値（％） C, 55.97; H, 5.77; N, 8.16.
実測値（％） C, 55.98; H, 5.74; N, 8.16. Example 102
1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- [2- (2-methyl-1H-imidazol-1-yl) ethyl] piperidine hydrochloride
102a) tert-Butyl 4- [2- (2-methyl-1H-imidazol-1-yl) ethyl] piperidine-1-carboxylate
4- (2-bromoethyl) piperidine-1-carboxylate tert-butyl (Dereck, B. et al., J. Med. Chem., 42, 4584 (1999)) (6.46 g) and 2-methylimidazole (0.93 The title compound (5.45 g, 80%) was obtained as a brown oil in the same manner as in Example 101a) from g).
NMR (300MHz, CDCl ₃ ) δ: 1.13-1.28 (2H, m), 1.46 (9H, s), 1.57-1.63 (4H, m), 1.82 (1H, m), 2.37 (3H, s), 2.65 ( 2H, t, J = 12.9), 3.71 (2H, d, J = 7.5), 4.16 (2H, brs), 6.78 (1H, d, J = 1.5), 6.91 (1H, d, J = 1.5).
102b) 1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- [2- (2-methyl-1H-imidazol-1-yl) ethyl] piperidine hydrochloride In Example 101a) Obtained 4- [2- (2-methyl-1H-imidazol-1-yl) ethyl] piperidine-1-carboxylate tert-butyl (0.43 g) and 3-[(6-chloro-2-naphthyl) sulfonyl] The title compound (0.52 g, 69%) was obtained as a colorless solid from propionic acid (0.45 g) in the same manner as in Example 81b).
NMR (200MHz, CDCl ₃ ) δ: 1.00-1.24 (2H, m), 1.48 (1H, m), 1.63-1.77 (4H, m), 2.37 (3H, s), 2.49 (1H, t, J = 13.2 ), 2.83-2.90 (2H, m), 2.98 (1H, t, J = 13.2), 3.47-3.60 (2H, m), 3.80-3.88 (3H, m), 4.49 (1H, d, J = 11.4) , 6.79 (1H, s), 6.91 (1H, s), 7.59 (1H, dd, J = 1.8, 9.0), 7.90-7.96 (4H, m), 8.47 (1H, s).
Elemental analysis C ₂₄ H ₂₈ N ₃ O ₃ SCl ・ HCl ・ 0.25H ₂ O
Theoretical value (%) C, 55.97; H, 5.77; N, 8.16.
Found (%) C, 55.98; H, 5.74; N, 8.16.

実施例103
5-クロロ-2-(3-{4-[2-(2-メチル-1H-イミダゾール-1-イル)エチル]-1-ピペリジニル}-3-オキソプロピル)スルホニル-1H-インドール
103a) 5-クロロ-2-(3-{4-[2-(2-メチル-1H-イミダゾール-1-イル)エチル]-1-ピペリジニル}-3-オキソプロピル)スルホニル-1H-インドール-1-カルボン酸tert-ブチル
実施例102a)で得た4-[(2-メチル-1H-イミダゾール-1-イル)エチル]ピペリジン-1-カルボン酸tert-ブチル(0.59g)と実施例211d)で得た3-[(1-tert-ブトキシカルボニル-5-クロロ-1H-インドール-2-イル)スルホニル]プロピオン酸(0.78g)から実施例85b)と同様にして題記化合物(0.64g, 57%)を得た。
NMR (200MHz, CDCl₃)δ：1.00-1.05 (2H, m), 1.53 (1H, m), 1.62-1.75 (4H, m), 1.73 (9H, m), 2.37 (3H, s), 2.50 (1H, t, J = 13.2), 2.87-3.04 (3H, m), 3.82-3.90 (3H, m), 4.00-4.08 (2H, m), 4.51 (1H, d, J = 12.8), 6.79 (1H, d, J = 1.0), 6.91 (1H, d, J = 1.0), 7.45 (1H, dd, J = 1.8, 8.8), 7.50 (1H, s), 7.65 (1H, d, J = 1.8) 7.99 (1H, d, J = 8.8).
103b) 5-クロロ-2-(3-{4-[2-(2-メチル-1H-イミダゾール-1-イル)エチル]-1-ピペリジニル}-3-オキソプロピル)スルホニル-1H-インドール
実施例103a)で得た5-クロロ-2-(3-{4-[2-(2-メチル-1H-イミダゾール-1-イル)エチル]-1-ピペリジニル}-3-オキソプロピル)スルホニル-1H-インドール-1-カルボン酸tert-ブチル(0.50g)のジクロロメタン(10mL)溶液にトリフロロ酢酸(10mL)を加え室温で２時間かき混ぜた。反応液に炭酸カリウムを加えアルカリ性にし、クロロホルムで抽出した。抽出液を無水硫酸ナトリウムで乾燥し、溶媒を留去して題記化合物(0.37g, 90%)を得た。
NMR (200MHz, DMSO-d₆)δ：0.74-0.84 (2H, m), 1.38-1.75 (5H, m), 2.27 (3H, s), 2.40 (1H, t, J = 11.8), 2.70 (2H, t, J = 7.4), 2.89 (1H, t, J = 11.8), 3.57-3.70 (3H, m), 3.86 (2H, t, J = 7.4), 4.15 (1H, d, J = 11.8), 6.74 (1H, s,), 7.05 (1H, s), 7.14 (1H, s), 7.32 (1H, dd, J = 2.0, 9.0), 7.50 (1H, d, J = 9.0), 7.79 (1H, d, J = 2.0). Example 103
5-chloro-2- (3- {4- [2- (2-methyl-1H-imidazol-1-yl) ethyl] -1-piperidinyl} -3-oxopropyl) sulfonyl-1H-indole
103a) 5-chloro-2- (3- {4- [2- (2-methyl-1H-imidazol-1-yl) ethyl] -1-piperidinyl} -3-oxopropyl) sulfonyl-1H-indole-1 Tert-butyl carboxylate 4-[(2-methyl-1H-imidazol-1-yl) ethyl] piperidine-1-carboxylate (0.59 g) obtained in Example 102a) and Example 211d) The title compound (0.64 g, 57%) was obtained in the same manner as in Example 85b) from the obtained 3-[(1-tert-butoxycarbonyl-5-chloro-1H-indol-2-yl) sulfonyl] propionic acid (0.78 g). )
NMR (200MHz, CDCl ₃ ) δ: 1.00-1.05 (2H, m), 1.53 (1H, m), 1.62-1.75 (4H, m), 1.73 (9H, m), 2.37 (3H, s), 2.50 ( 1H, t, J = 13.2), 2.87-3.04 (3H, m), 3.82-3.90 (3H, m), 4.00-4.08 (2H, m), 4.51 (1H, d, J = 12.8), 6.79 (1H , d, J = 1.0), 6.91 (1H, d, J = 1.0), 7.45 (1H, dd, J = 1.8, 8.8), 7.50 (1H, s), 7.65 (1H, d, J = 1.8) 7.99 (1H, d, J = 8.8).
103b) 5-Chloro-2- (3- {4- [2- (2-methyl-1H-imidazol-1-yl) ethyl] -1-piperidinyl} -3-oxopropyl) sulfonyl-1H-indole Examples 103a) 5-chloro-2- (3- {4- [2- (2-methyl-1H-imidazol-1-yl) ethyl] -1-piperidinyl} -3-oxopropyl) sulfonyl-1H- Trifluoroacetic acid (10 mL) was added to a solution of tert-butyl indole-1-carboxylate (0.50 g) in dichloromethane (10 mL), and the mixture was stirred at room temperature for 2 hours. The reaction solution was made alkaline by adding potassium carbonate, and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain the title compound (0.37 g, 90%).
NMR (200MHz, DMSO-d ₆ ) δ: 0.74-0.84 (2H, m), 1.38-1.75 (5H, m), 2.27 (3H, s), 2.40 (1H, t, J = 11.8), 2.70 (2H , t, J = 7.4), 2.89 (1H, t, J = 11.8), 3.57-3.70 (3H, m), 3.86 (2H, t, J = 7.4), 4.15 (1H, d, J = 11.8), 6.74 (1H, s,), 7.05 (1H, s), 7.14 (1H, s), 7.32 (1H, dd, J = 2.0, 9.0), 7.50 (1H, d, J = 9.0), 7.79 (1H, d, J = 2.0).

実施例104
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-[3-(2-メチル-1H-イミダゾール-1-イル)プロピル]ピペリジン塩酸塩
104a) 4-[3-(2-メチル-1H-イミダゾール-1-イル)プロピル]ピペリジン-1-カルボン酸tert-ブチル
4-(3-ブロモプロピル)ピペリジン-1-カルボン酸tert-ブチル(Siegel, M. G. et al., Tetrahedron，55, 11619 (1999)) (2.0g)と2-メチルイミダゾール(0.56g)から実施例101a)と同様にして題記化合物(2.05g, 定量的)を茶色油状物として得た。
NMR (200MHz, CDCl₃)δ：1.03-1.35 (4H, m), 1.45 (9H, s), 1.59-1.82 (5H, m), 2.37 (3H, s), 2.66 (2H, t, J = 12.4), 3.81 (2H, t, J = 7.0), 4.06 (2H, br), 6.80 (1H, d, J = 1.4), 6.90 (1H, d, J = 1.4).
104b) 1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-[3-(2-メチル-1H-イミダゾール-1-イル)プロピル]ピペリジン塩酸塩
実施例104a)で得られた4-[3-(2-メチル-1H-イミダゾール-1-イル)プロピル]ピペリジン-1-カルボン酸tert-ブチル(0.61g)と3-[(6-クロロ-2-ナフチル)スルホニル]プロピオン酸(0.60g)から実施例81b)と同様にして題記化合物(0.56g, 53%)を得た。
NMR (300MHz, CDCl₃)δ：1.00-1.31 (4H, m), 1.52 (1H, m), 1.65-1.88 (4H, m), 2.37 (3H, s), 2.49 (1H, t, J = 11.1), 2.83-2.90 (2H, m), 3.00 (1H, t, J = 11.1), 3.47-3.58 (2H, m), 3.84 (1H, d, J= 14.1), 4.02 (2H, t, J = 6.9), 4.51 (1H, d, J = 14.1), 7.05 1H, s), 7.05 (1H, s), 7.28 (1H, s), 7.61 (1H, dd, J = 2.1, 9.0), 7.89-7.97 (4H, m), 8.47 (1H, s). Example 104
1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- [3- (2-methyl-1H-imidazol-1-yl) propyl] piperidine hydrochloride
104a) tert-Butyl 4- [3- (2-methyl-1H-imidazol-1-yl) propyl] piperidine-1-carboxylate
Example from tert-butyl 4- (3-bromopropyl) piperidine-1-carboxylate (Siegel, MG et al., Tetrahedron, 55, 11619 (1999)) (2.0 g) and 2-methylimidazole (0.56 g) In the same manner as in 101a), the title compound (2.05 g, quantitative) was obtained as a brown oil.
NMR (200MHz, CDCl ₃ ) δ: 1.03-1.35 (4H, m), 1.45 (9H, s), 1.59-1.82 (5H, m), 2.37 (3H, s), 2.66 (2H, t, J = 12.4 ), 3.81 (2H, t, J = 7.0), 4.06 (2H, br), 6.80 (1H, d, J = 1.4), 6.90 (1H, d, J = 1.4).
104b) 1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- [3- (2-methyl-1H-imidazol-1-yl) propyl] piperidine hydrochloride In Example 104a) The resulting 4- [3- (2-methyl-1H-imidazol-1-yl) propyl] piperidine-1-carboxylate tert-butyl (0.61 g) and 3-[(6-chloro-2-naphthyl) sulfonyl The title compound (0.56 g, 53%) was obtained from propionic acid (0.60 g) in the same manner as in Example 81b).
NMR (300MHz, CDCl ₃ ) δ: 1.00-1.31 (4H, m), 1.52 (1H, m), 1.65-1.88 (4H, m), 2.37 (3H, s), 2.49 (1H, t, J = 11.1 ), 2.83-2.90 (2H, m), 3.00 (1H, t, J = 11.1), 3.47-3.58 (2H, m), 3.84 (1H, d, J = 14.1), 4.02 (2H, t, J = 6.9), 4.51 (1H, d, J = 14.1), 7.05 1H, s), 7.05 (1H, s), 7.28 (1H, s), 7.61 (1H, dd, J = 2.1, 9.0), 7.89-7.97 (4H, m), 8.47 (1H, s).

実施例105
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-[3-(2-エチル-1H-イミダゾール-1-イル)プロピル]ピペリジン塩酸塩
105a) 4-[3-(2-エチル-1H-イミダゾール-1-イル)プロピル]ピペリジン-1-カルボン酸tert-ブチル
4-(3-ブロモプロピル)ピペリジン-1-カルボン酸tert-ブチル(2.0g)と2-エチルイミダゾール(0.66g)から実施例101a)と同様にして題記化合物(2.06g, 98%)を茶色油状物として得た。
NMR (200MHz, CDCl₃)δ：1.03-1.38 (6H, m), 1.45 (9H, s), 1.60-1.82 (3H, s), 2.61-2.72 (4H, m), 3.82 (2H, t, J = 7.0), 4.07 (2H, br), 6.80 (1H, d, J = 1.4), 6.94 (1H, d, J = 1.4).
105b) 1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-[3-(2-エチル-1H-イミダゾール-1-イル)プロピル]ピペリジン塩酸塩
実施例105a)で得られた4-[3-(2-エチル-1H-イミダゾール-1-イル)プロピル]ピペリジン-1-カルボン酸tert-ブチル(0.61g)と3-[(6-クロロ-2-ナフチル)スルホニル]プロピオン酸(0.60g)から実施例81b)と同様にして題記化合物(0.50g, 46%)を得た。
NMR (300MHz, CDCl₃)δ：0.95-1.25 (2H, m), 1.20-1.27 (2H, m), 1.34 (3H, t, J = 7.5), 1.43 (1H, m), 1.64-1.76 (4H, m), 2.47 (1H, t, J = 13.2), 2.65 (2H, q, J = 7.5), 2.83-2.88 (2H, m), 2.97 (1H, t, J = 13.2), 3.52-3.58 (2H, m), 3.82 (2H, t, J = 7.2), 4.47 (1H, d, J = 13.5), 6.79 (1H, d, J = 1.0), 6.94 (1H, J = 1.0), 7.59 (1H, dd, J = 2.4, 8.7), 7.89-7.96 (4H, m), 8.47 (1H, s). Example 105
1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- [3- (2-ethyl-1H-imidazol-1-yl) propyl] piperidine hydrochloride
105a) tert-Butyl 4- [3- (2-ethyl-1H-imidazol-1-yl) propyl] piperidine-1-carboxylate
The title compound (2.06 g, 98%) was browned from tert-butyl 4- (3-bromopropyl) piperidine-1-carboxylate (2.0 g) and 2-ethylimidazole (0.66 g) in the same manner as in Example 101a). Obtained as an oil.
NMR (200MHz, CDCl ₃ ) δ: 1.03-1.38 (6H, m), 1.45 (9H, s), 1.60-1.82 (3H, s), 2.61-2.72 (4H, m), 3.82 (2H, t, J = 7.0), 4.07 (2H, br), 6.80 (1H, d, J = 1.4), 6.94 (1H, d, J = 1.4).
105b) 1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- [3- (2-ethyl-1H-imidazol-1-yl) propyl] piperidine hydrochloride In Example 105a) Obtained 4- [3- (2-ethyl-1H-imidazol-1-yl) propyl] piperidine-1-carboxylate tert-butyl (0.61 g) and 3-[(6-chloro-2-naphthyl) sulfonyl The title compound (0.50 g, 46%) was obtained from propionic acid (0.60 g) in the same manner as in Example 81b).
NMR (300MHz, CDCl ₃ ) δ: 0.95-1.25 (2H, m), 1.20-1.27 (2H, m), 1.34 (3H, t, J = 7.5), 1.43 (1H, m), 1.64-1.76 (4H , m), 2.47 (1H, t, J = 13.2), 2.65 (2H, q, J = 7.5), 2.83-2.88 (2H, m), 2.97 (1H, t, J = 13.2), 3.52-3.58 ( 2H, m), 3.82 (2H, t, J = 7.2), 4.47 (1H, d, J = 13.5), 6.79 (1H, d, J = 1.0), 6.94 (1H, J = 1.0), 7.59 (1H , dd, J = 2.4, 8.7), 7.89-7.96 (4H, m), 8.47 (1H, s).

実施例106
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-[2-(2-エチル-1H-イミダゾール-1-イル)エチル]ピペリジン塩酸塩
106a) 4-[2-(2-エチル-1H-イミダゾール-1-イル)エチル]ピペリジン-1-カルボン酸tert-ブチル
4-(2-ブロモエチル)ピペリジン-1-カルボン酸tert-ブチル(3.0g)と2-エチルイミダゾール(1.0g)から実施例101a)と同様にして題記化合物(1.55g, 52%)を茶色油状物として得た。
NMR (200MHz, CDCl₃)δ：1.18-1.38 (7H, m), 1.46 (9H, s), 1.63-1.74 (3H, m), 2.61-2.88 (4H, m), 3.87 (2H, t, J = 7.8), 4.08 (2H, d, J = 14.2), 6.80 (1H, d, J = 1.0), 6.94 (1H, d, J = 1.0).
106b) 1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-[2-(2-エチル-1H-イミダゾール-1-イル)エチル]ピペリジン塩酸塩
実施例106a)で得られた4-[2-(2-エチル-1H-イミダゾール-1-イル)エチル]ピペリジン-1-カルボン酸tert-ブチル(0.58g)と3-[(6-クロロ-2-ナフチル)スルホニル]プロピオン酸(0.66g)から実施例81b)と同様にして題記化合物(0.29g, 28%)を得た。
NMR (300MHz CDCl₃)δ：1.02-1.27 (2H. m), 1.35 (3H, t, J = 7.2), 1.50 (1H, m), 1.64-1.84 (4H, m), 2.49 (1H, t, J = 10.8), 2.68 (2H, q, J = 7.2), 2.84-2.90 (2H, m), 2.99 (1H, t, J = 10.8), 3.50-3.59 (2H, m), 3.81-3.89 (3H, m), 4.50 (1H, J = 13.5), 6.79 (1H, d, J = 1.2), 6.95 (1H, d, J = 1.2), 7.59 (1H, dd, J = 1.5, 9.3), 7.89-7.94 (4H, m), 8.48 (1H, s). Example 106
1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- [2- (2-ethyl-1H-imidazol-1-yl) ethyl] piperidine hydrochloride
106a) tert-Butyl 4- [2- (2-ethyl-1H-imidazol-1-yl) ethyl] piperidine-1-carboxylate
The title compound (1.55 g, 52%) was obtained as a brown oil from tert-butyl 4- (2-bromoethyl) piperidine-1-carboxylate (3.0 g) and 2-ethylimidazole (1.0 g) in the same manner as in Example 101a). Obtained as a thing.
NMR (200MHz, CDCl ₃ ) δ: 1.18-1.38 (7H, m), 1.46 (9H, s), 1.63-1.74 (3H, m), 2.61-2.88 (4H, m), 3.87 (2H, t, J = 7.8), 4.08 (2H, d, J = 14.2), 6.80 (1H, d, J = 1.0), 6.94 (1H, d, J = 1.0).
106b) 1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- [2- (2-ethyl-1H-imidazol-1-yl) ethyl] piperidine hydrochloride In Example 106a) The resulting 4- [2- (2-ethyl-1H-imidazol-1-yl) ethyl] piperidine-1-carboxylate tert-butyl (0.58 g) and 3-[(6-chloro-2-naphthyl) sulfonyl The title compound (0.29 g, 28%) was obtained from propionic acid (0.66 g) in the same manner as in Example 81b).
NMR (300MHz CDCl ₃ ) δ: 1.02-1.27 (2H.m), 1.35 (3H, t, J = 7.2), 1.50 (1H, m), 1.64-1.84 (4H, m), 2.49 (1H, t, J = 10.8), 2.68 (2H, q, J = 7.2), 2.84-2.90 (2H, m), 2.99 (1H, t, J = 10.8), 3.50-3.59 (2H, m), 3.81-3.89 (3H , m), 4.50 (1H, J = 13.5), 6.79 (1H, d, J = 1.2), 6.95 (1H, d, J = 1.2), 7.59 (1H, dd, J = 1.5, 9.3), 7.89- 7.94 (4H, m), 8.48 (1H, s).

実施例107
5-クロロ-2-(3-{4-[2-(2-エチル-1H-イミダゾール-1-イル)エチル]-1-ピペリジニル}-3-オキソプロピル)スルホニル-1H-インドール
107a) 5-クロロ-2-(3-{4-[2-(2-エチル-1H-イミダゾール-1-イル)エチル]-1-ピペリジニル}-3-オキソプロピル)スルホニル-1H-インドール-1-カルボン酸tert-ブチル
実施例106a)で得た4-(2-エチル-1H-イミダゾール-1-イル)メチルピペリジン-1-カルボン酸tert-ブチル(0.58g)と実施例211d)で得た3-[(1-tert-ブトキシカルボニル-5-クロロ-1H-インドール-2-イル)スルホニル]プロピオン酸(0.85g)から実施例85b)と同様にして題記化合物(0.62g, 54%)を得た。
NMR (300MHz, CDCl₃)δ：1.05-1.21 (2H, m), 1.35 (3H, t, J = 7.5), 1.52 (1H, m), 1.53-1.73 (4H, m), 1.73 (9H, s), 2.49 (1H, t, J = 9.9), 2.65 (2H, q, J = 7.5), 2.88-3.03 (3H, m), 3.81-3.89 (3H, m), 4.02-4.08 (2H, m), 4.51 (1H, d, J = 13.2), 6.79 (1H, s), 6.95 (1H, s) 7.43-7.53 (2H, m), 7.63 (1H, m), 8.98 (1H, d, J = 9.0).
107b) 5-クロロ-2-(3-{4-[2-(2-エチル-1H-イミダゾール-1-イル)エチル]-1-ピペリジニル}-3-オキソプロピル)スルホニル-1H-インドール
実施例107a)で得た5-クロロ-2-(3-{4-[2-(2-エチル-1H-イミダゾール-1-イル)エチル]-1-ピペリジニル}-3-オキソプロピル)スルホニル-1H-インドール-1-カルボン酸tert-ブチル(0.60g)から実施例103b)と同様にして題記化合物(0.45g, 91%)を得た。
NMR (200MHz, DMSO-d₆)δ：0.75-0.85 (2H, m), 1.19 (3H, t, J = 7.4), 1.49-1.62 (5H, m), 2.40 (1H, t, J = 11.8), 2.48-2.52 (2H, m), 2.57 (2H, q, J = 7.4), 2.70 (2H, t, J = 7.0), 2.89 (1H, t, J = 11.8), 3.57-3.76 (3H, m), 3.85 (2H, t, J = 7.0), 4.16 (1H, d, J = 11.8), 6.73 (1H, d, J = 1.4), 7.02 (1H, d, J = 1.4), 7.14 (1H, s), 7.32 (1H, dd, J = 1.8, 8.8), 7.51 (1H, d, J = 8.8), 7.90 (1H, d, J = 1.8). Example 107
5-Chloro-2- (3- {4- [2- (2-ethyl-1H-imidazol-1-yl) ethyl] -1-piperidinyl} -3-oxopropyl) sulfonyl-1H-indole
107a) 5-chloro-2- (3- {4- [2- (2-ethyl-1H-imidazol-1-yl) ethyl] -1-piperidinyl} -3-oxopropyl) sulfonyl-1H-indole-1 Tert-butyl carboxylate obtained in tert-butyl 4- (2-ethyl-1H-imidazol-1-yl) methylpiperidine-1-carboxylate (0.58 g) obtained in Example 106a) and in Example 211d) The title compound (0.62 g, 54%) was prepared from 3-[(1-tert-butoxycarbonyl-5-chloro-1H-indol-2-yl) sulfonyl] propionic acid (0.85 g) in the same manner as in Example 85b). Obtained.
NMR (300MHz, CDCl ₃ ) δ: 1.05-1.21 (2H, m), 1.35 (3H, t, J = 7.5), 1.52 (1H, m), 1.53-1.73 (4H, m), 1.73 (9H, s ), 2.49 (1H, t, J = 9.9), 2.65 (2H, q, J = 7.5), 2.88-3.03 (3H, m), 3.81-3.89 (3H, m), 4.02-4.08 (2H, m) , 4.51 (1H, d, J = 13.2), 6.79 (1H, s), 6.95 (1H, s) 7.43-7.53 (2H, m), 7.63 (1H, m), 8.98 (1H, d, J = 9.0 ).
107b) 5-Chloro-2- (3- {4- [2- (2-ethyl-1H-imidazol-1-yl) ethyl] -1-piperidinyl} -3-oxopropyl) sulfonyl-1H-indole Examples 107a) 5-chloro-2- (3- {4- [2- (2-ethyl-1H-imidazol-1-yl) ethyl] -1-piperidinyl} -3-oxopropyl) sulfonyl-1H- The title compound (0.45 g, 91%) was obtained from tert-butyl indole-1-carboxylate (0.60 g) in the same manner as in Example 103b).
NMR (200MHz, DMSO-d ₆ ) δ: 0.75-0.85 (2H, m), 1.19 (3H, t, J = 7.4), 1.49-1.62 (5H, m), 2.40 (1H, t, J = 11.8) , 2.48-2.52 (2H, m), 2.57 (2H, q, J = 7.4), 2.70 (2H, t, J = 7.0), 2.89 (1H, t, J = 11.8), 3.57-3.76 (3H, m ), 3.85 (2H, t, J = 7.0), 4.16 (1H, d, J = 11.8), 6.73 (1H, d, J = 1.4), 7.02 (1H, d, J = 1.4), 7.14 (1H, s), 7.32 (1H, dd, J = 1.8, 8.8), 7.51 (1H, d, J = 8.8), 7.90 (1H, d, J = 1.8).

実施例108
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-[2-(4,5-ジメチル-1H-イミダゾール-1-イル)エチル]ピペリジン
108a) 4-[2-(4,5-ジメチル-1H-イミダゾール-1-イル)エチル]ピペリジン-1-カルボン酸tert-ブチル
4,5-ジメチルイミダゾール(特開昭60-56961号公報)(0.66g)と4-(2-ブロモエチル)ピペリジン-1-カルボン酸tert-ブチル(2.0g)から実施例101a)と同様にして題記化合物(0.38g, 18%)を茶褐色油状物として得た。
NMR (300MHz, CDCl₃)δ：1.07-1.91 (2H, m), 1.45 (9H, s), 1.59-1.70 (5H, m), 2.11 (3H, s), 2.15 (3H, s), 2.67 (2H, t, J = 11.4), 3.81 (2H, t, J = 7.0), 4.07-4.14 (2H, m), 7.30 (1H, s).
108b) 1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-[2-(4,5-ジメチル-1H-イミダゾール-1-イル)エチル]ピペリジン
実施例108a)で得た4-[2-(4,5-ジメチル-1H-イミダゾール-1-イル)エチル]ピペリジン-1-カルボン酸tert-ブチル(0.38g)と3-[(6-クロロ-2-ナフチル)スルホニル]プロピオン酸(0.37g)から実施例85b)と同様にして題記化合物(0.36g, 57%)を得た。
NMR (300MHz, CDCl₃)δ：1.04-1.23 (2H, m), 1.48 (1H, m), 1.60-1.77 (4H, m), 2.11 (3H, s), 2.15 (3H, s), 2.49 (1H, t, J = 13.2), 2.83-2.90 (2H, m), 2.99 (1H, t, J = 13.2), 3.50-3.58 (2H, m), 3.79-3.84 (3H, m), 4.49 (1H, d, J = 13.2), 7.30 (1H, s), 7.59 (1H, dd, J = 2.4, 9.0), 7.89-7.94 (4H, m), 8.47 (1H, s).
元素分析 C₂₅H₃₀N₃O₃SCl・0.5H₂Oとして
理論値（％） C, 60.41; H, 6.29; N, 8.45.
実測値（％） C, 60.40; H, 6.42; N, 8.22. Example 108
1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- [2- (4,5-dimethyl-1H-imidazol-1-yl) ethyl] piperidine
108a) tert-Butyl 4- [2- (4,5-dimethyl-1H-imidazol-1-yl) ethyl] piperidine-1-carboxylate
Example 101a) from 4,5-dimethylimidazole (JP 60-56961 A) (0.66 g) and tert-butyl 4- (2-bromoethyl) piperidine-1-carboxylate (2.0 g) The title compound (0.38 g, 18%) was obtained as a brown oil.
NMR (300MHz, CDCl ₃ ) δ: 1.07-1.91 (2H, m), 1.45 (9H, s), 1.59-1.70 (5H, m), 2.11 (3H, s), 2.15 (3H, s), 2.67 ( 2H, t, J = 11.4), 3.81 (2H, t, J = 7.0), 4.07-4.14 (2H, m), 7.30 (1H, s).
108b) 1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- [2- (4,5-dimethyl-1H-imidazol-1-yl) ethyl] piperidine Example 108a) Obtained 4- [2- (4,5-dimethyl-1H-imidazol-1-yl) ethyl] piperidine-1-carboxylate tert-butyl (0.38 g) and 3-[(6-chloro-2-naphthyl) The title compound (0.36 g, 57%) was obtained from sulfonyl] propionic acid (0.37 g) in the same manner as in Example 85b).
NMR (300MHz, CDCl ₃ ) δ: 1.04-1.23 (2H, m), 1.48 (1H, m), 1.60-1.77 (4H, m), 2.11 (3H, s), 2.15 (3H, s), 2.49 ( 1H, t, J = 13.2), 2.83-2.90 (2H, m), 2.99 (1H, t, J = 13.2), 3.50-3.58 (2H, m), 3.79-3.84 (3H, m), 4.49 (1H , d, J = 13.2), 7.30 (1H, s), 7.59 (1H, dd, J = 2.4, 9.0), 7.89-7.94 (4H, m), 8.47 (1H, s).
Elemental analysis Theoretical value (%) as C ₂₅ H ₃₀ N ₃ O ₃ SCl · 0.5H ₂ O C, 60.41; H, 6.29; N, 8.45.
Found (%) C, 60.40; H, 6.42; N, 8.22.

実施例109
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-[2-(2,4,5-トリメチル-1H-イミダゾール-1-イル)エチル]ピペリジン
109a) 4-[2-(2,4,5-トリメチル-1H-イミダゾール-1-イル)エチル]ピペリジン-1-カルボン酸tert-ブチル
2,4,5-トリメチルイミダゾール(特開昭60-56961号公報)(1.8g)と4-(2-ブロモエチル)ピペリジン-1-カルボン酸tert-ブチル(4.77g)から実施例101a)と同様にして題記化合物(1.18g, 23%)を茶褐色油状物として得た。
NMR (300MHz, CDCl₃)δ：1.07-1.91 (2H, m), 1.46 (9H, s), 1.59-1.70 (5H, m), 2.08 (3H, s), 2.11 (3H, s), 2.15 (3H, s), 2.69 (2H, t, J = 11.4), 3.72 (2H, t, J = 7.0), 4.07-4.14 (2H, m).
109b) 1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-[2-(2,4,5-トリメチル-1H-イミダゾール-1-イル)エチル]ピペリジン
実施例109a)で得た4-[2-(2,4,5-トリメチル-1H-イミダゾール-1-イル)エチル]ピペリジン-1-カルボン酸tert-ブチル(0.73g)と3-[(6-クロロ-2-ナフチル)スルホニル]プロピオン酸(0.70g)から実施例85b)と同様にして題記化合物(0.39g, 33%)を得た。
NMR (300MHz, CDCl₃)δ：1.07-1.23 (2H, m), 1.51-1.55 (3H, m), 1.70-1.79 (2H, m), 2.07 (3H, s), 2.09 (3H, s), 2.31 (3H, s), 2.51 (1H, t, J = 12.6), 2.84-2.90 (2H, m), 2.97 (1H, t, J = 12.6), 3.50-3.57 (2H, m), 3.71 (2H, t, J = 7.8), 3.83 (1H, d, J = 13.2), 7.59 (1H, dd, J = 2.1, 9.0), 7.88-7.96 (4H, m), 8.47 (1H, s). Example 109
1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- [2- (2,4,5-trimethyl-1H-imidazol-1-yl) ethyl] piperidine
109a) tert-butyl 4- [2- (2,4,5-trimethyl-1H-imidazol-1-yl) ethyl] piperidine-1-carboxylate
Same as Example 101a) from 2,4,5-trimethylimidazole (JP 60-56961 A) (1.8 g) and tert-butyl 4- (2-bromoethyl) piperidine-1-carboxylate (4.77 g) The title compound (1.18 g, 23%) was obtained as a brown oil.
NMR (300MHz, CDCl ₃ ) δ: 1.07-1.91 (2H, m), 1.46 (9H, s), 1.59-1.70 (5H, m), 2.08 (3H, s), 2.11 (3H, s), 2.15 ( 3H, s), 2.69 (2H, t, J = 11.4), 3.72 (2H, t, J = 7.0), 4.07-4.14 (2H, m).
109b) 1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- [2- (2,4,5-trimethyl-1H-imidazol-1-yl) ethyl] piperidine Example 109a ) 4- [2- (2,4,5-trimethyl-1H-imidazol-1-yl) ethyl] piperidine-1-carboxylate (0.73 g) and 3-[(6-chloro- The title compound (0.39 g, 33%) was obtained from 2-naphthyl) sulfonyl] propionic acid (0.70 g) in the same manner as in Example 85b).
NMR (300 MHz, CDCl ₃ ) δ: 1.07-1.23 (2H, m), 1.51-1.55 (3H, m), 1.70-1.79 (2H, m), 2.07 (3H, s), 2.09 (3H, s), 2.31 (3H, s), 2.51 (1H, t, J = 12.6), 2.84-2.90 (2H, m), 2.97 (1H, t, J = 12.6), 3.50-3.57 (2H, m), 3.71 (2H , t, J = 7.8), 3.83 (1H, d, J = 13.2), 7.59 (1H, dd, J = 2.1, 9.0), 7.88-7.96 (4H, m), 8.47 (1H, s).

実施例110
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-[(2-メチル-1H-イミダゾール-4-イル)メトキシ]ピペリジン
110a) 4-[(2-メチル-1-トリチル-1H-イミダゾール-4-イル)メトキシ]ピペリジン-1-カルボン酸tert-ブチル
4-ヒドロキシピペリジン-1-カルボン酸tert-ブチル(0.50g)のDMF溶液(20mL)に水素化ナトリウム(60%油性：0.12g)を加え15分かき混ぜた後、4-クロロメチル-2-メチル-1-トリチル-1H-イミダゾール(Cordi, A. A. et al., Eur. J. Med. Chem., 25, 557 (1990)) (0.93g)のDMF溶液(10mL)を加えた。12時間かき混ぜた後、反応液を濃縮した。残留物を酢酸エチルに溶解させ、飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥、溶媒を留去した。残留物をシリカゲルカラムにより精製し、題記化合物(0.58g, 43%)を得た。
NMR (200MHz, CDCl₃)δ：1.45 (9H, s), 1.45-1.63 (2H, m), 1.72 (3H, s), 1.83-1.91 (2H, m), 2.92-3.05 (2H, m), 3.58 (1H, m), 3.79-3.90 (2H, m), 4.02 (2H, s), 6.68 (1H, s), 7.10-7.17 (6H, m), 7.26-7.39 (9H, m).
110b) 1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-[(2-メチル-1H-イミダゾール-4-イル)メトキシ]ピペリジン
実施例110a)で得られた4-[(2-メチル-1-トリチル-1H-イミダゾール-4-イル)メトキシ]ピペリジン-1-カルボン酸tert-ブチル(0.57g)のメタノール(10mL)−1N塩酸(5mL)溶液を80℃で12時間かき混ぜた。反応液をジエチルエーテルと水の混合液に注ぎ込み、水層を分取し、濃縮した。残留物にDBU(0.32mL)とトリエチルアミン(0.44mL)を加えアセトニトリル(10mL)に溶解し、この溶液を3-[(6-クロロ-2-ナフチル)スルホニル]プロピオン酸(0.32g)、WSC(0.30g)、HOBt(0.24g)のアセトニトリル(10mL)けん濁液へ加え、12時間かき混ぜた。反応液を減圧濃縮し、残留物をクロロホルムと飽和重曹水に溶解させ、クロロホルム層を分取した。クロロホルム溶液を無水硫酸ナトリウムで乾燥し、溶媒を留去した。残留物をシリカゲルカラムにより精製し、題記化合物(0.27g, 54%)を得た。
NMR (200MHz, CDCl₃)δ：1.65-1.84 (4H, m), 2.42 (3H, s), 2.86 (2H, t, J = 8.4), 3.18-3.26 (2H, m), 3.55 (2H, t, J = 8.4), 3.58-3.72 (2H, m), 3.83 (1H, m), 4.46 (2H, s), 6.87 (1H, s), 7.59 (1H, dd, J = 2.0, 9.0), 7.92-7.97 (4H, m), 8.47 (1H, s). Example 110
1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-[(2-methyl-1H-imidazol-4-yl) methoxy] piperidine
110a) tert-butyl 4-[(2-methyl-1-trityl-1H-imidazol-4-yl) methoxy] piperidine-1-carboxylate
Sodium hydride (60% oiliness: 0.12 g) was added to a DMF solution (20 mL) of tert-butyl 4-hydroxypiperidine-1-carboxylate (0.50 g), and the mixture was stirred for 15 minutes, and then 4-chloromethyl-2-methyl A DMF solution (10 mL) of -1-trityl-1H-imidazole (Cordi, AA et al., Eur. J. Med. Chem., 25, 557 (1990)) (0.93 g) was added. After stirring for 12 hours, the reaction solution was concentrated. The residue was dissolved in ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column to give the title compound (0.58 g, 43%).
NMR (200MHz, CDCl ₃ ) δ: 1.45 (9H, s), 1.45-1.63 (2H, m), 1.72 (3H, s), 1.83-1.91 (2H, m), 2.92-3.05 (2H, m), 3.58 (1H, m), 3.79-3.90 (2H, m), 4.02 (2H, s), 6.68 (1H, s), 7.10-7.17 (6H, m), 7.26-7.39 (9H, m).
110b) 1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-[(2-methyl-1H-imidazol-4-yl) methoxy] piperidine 4 obtained in Example 110a) A solution of tert-butyl-[(2-methyl-1-trityl-1H-imidazol-4-yl) methoxy] piperidine-1-carboxylate (0.57 g) in methanol (10 mL) -1N hydrochloric acid (5 mL) at 80 ° C. Stir for 12 hours. The reaction solution was poured into a mixture of diethyl ether and water, and the aqueous layer was separated and concentrated. DBU (0.32 mL) and triethylamine (0.44 mL) were added to the residue, dissolved in acetonitrile (10 mL), and this solution was dissolved in 3-[(6-chloro-2-naphthyl) sulfonyl] propionic acid (0.32 g), WSC ( 0.30 g) and HOBt (0.24 g) in acetonitrile (10 mL) were added and stirred for 12 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in chloroform and saturated aqueous sodium hydrogen carbonate, and the chloroform layer was separated. The chloroform solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by silica gel column to give the title compound (0.27 g, 54%).
NMR (200MHz, CDCl ₃ ) δ: 1.65-1.84 (4H, m), 2.42 (3H, s), 2.86 (2H, t, J = 8.4), 3.18-3.26 (2H, m), 3.55 (2H, t , J = 8.4), 3.58-3.72 (2H, m), 3.83 (1H, m), 4.46 (2H, s), 6.87 (1H, s), 7.59 (1H, dd, J = 2.0, 9.0), 7.92 -7.97 (4H, m), 8.47 (1H, s).

実施例111
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-[2-(1-メチル-1H-イミダゾール-5-イル)エチル]ピペリジン
111a) 4-[(Z)-2-(1-トリチル-1H-イミダゾール-4-イル)ビニル]ピペリジン-1-カルボン酸tert-ブチル
1-トリチル-1H-イミダゾール-4-カルバルデヒド(Kelly, J. L. et al., J. Med. Chem., 20, 721 (1977)) (0.63g)とヨウ化(1-tert-ブトキシカルボニル-4-ピペリジニル)メチル(トリフェニル)ホスホニウム(国際公開第99/24421号パンフレット)(1.0g)のTHF(35mL)溶液にカリウムtert-ブトキシド(0.21g)を加えた。12時間かき混ぜた後、反応液を酢酸エチルと飽和塩化アンモニウム水溶液の混合溶液に注ぎ込み、有機層を分取した。酢酸エチル溶液を無水硫酸ナトリウムで乾燥し、溶媒を留去した。残留物をシリカゲルカラムにより精製し、題記化合物(0.45g, 51%)を得た。
NMR (200MHz, CDCl₃)δ：1.20-1.36 (2H, m), 1.45 (9H, s), 1.64-1.69 (2H, m), 2.67 (2H, t, J = 12.2), 3.05 (1H, m), 4.01 (2H, d, J = 12.8), 5.32 (1H, dd, J = 9.0, 11.6), 6.16 (1H, d, J = 11.6), 6.69 (1H, s), 7.10-7.20 (6H, m), 7.30-7.36 (9H, m), 7.43 (1H, s).
111b) 4-[2-(1-トリチル-1H-イミダゾール-4-イル)エチル]ピペリジン-1-カルボン酸tert-ブチル
実施例111a)で得た4-[(Z)-2-(1-トリチル-1H-イミダゾール-4-イル)ビニル]ピペリジン-1-カルボン酸tert-ブチル(0.43 g)と酸化白金(0.08g)のメタノール(20 mL)けん濁液を水素雰囲気下、室温で1時間かき混ぜた。不溶物をろ去し、ろ液を濃縮して題記化合物(0.43g, 99%)を得た。
NMR (200MHz, CDCl₃)δ：1.05-1.17 (2H, m), 1.45 (9H, s), 1.51-1.66 (5H, m), 2.52-2.68 (4H, m), 4.04 (2H, d, J = 13.5), 6.49 (1H, s), 7.11-7.18 (6H, s), 7.29-7.35 (10H, m).
111c) 1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-[2-(1-メチル-1H-イミダゾール-5-イル)エチル]ピペリジン
実施例111b)で得られた4-[2-(1-トリチル-1H-イミダゾール-4-イル)エチル]ピペリジン-1-カルボン酸tert-ブチル(0.43g)のアセトニトリル溶液(10mL)にヨウ化メチル(1mL)を加え、12時間かき混ぜた。反応液を濃縮し、残留物をメタノール(10 mL)と1N塩酸(5mL)に溶かし、80℃で３時間かき混ぜた。反応液をジエチルエーテルと水の混合液に注ぎ込み、水層を分取し、濃縮した。残留物にDBU(0.25mL)とトリエチルアミン(0.35ml)およびアセトニトリル(10mL)を加え、この溶液を3-[(6-クロロ-2-ナフチル)スルホニル]プロピオン酸(0.25g)、WSC(0.24g)およびHOBt(0.19g)のアセトニトリル(10mL)けん濁液に加え、12時間かき混ぜた。反応液を減圧濃縮し、残留物をクロロホルムと飽和重曹水に溶解させ、クロロホルム層を分取した。クロロホルム溶液を無水硫酸ナトリウムで乾燥、溶媒を留去した、残留物をシリカゲルカラムにより精製し、題記化合物(0.29g, 74%)を得た。
NMR (200MHz, CDCl₃)δ：1.05-1.28 (2H, m), 1.57-1.66 (3H, m), 1.73-1.86 (2H, m), 2.53-2.60 (2H, m), 2.85-3.07 (3H, m), 3.53-3.62 (2H, m), 3.56 (3H, s), 3.85 (1H, d, J = 13.8), 4.51 (1H, d, J = 13.8), 6.78 (1H, s), 7.40 (1H, s), 7.51 (1H, dd, J = 1.8, 8.8), 7.90-7.99 (4H, m), 8.50 (1H, s).
元素分析 C₂₄H₂₈N₃O₃SCl・0.5H₂O として
理論値（％） C, 59.68; H, 6.05; N, 8.70.
実測値（％） C, 59.58; H, 6.14; N, 8.43. Example 111
1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- [2- (1-methyl-1H-imidazol-5-yl) ethyl] piperidine
111a) 4-[(Z) -2- (1-trityl-1H-imidazol-4-yl) vinyl] piperidine-1-carboxylate tert-butyl
1-trityl-1H-imidazole-4-carbaldehyde (Kelly, JL et al., J. Med. Chem., 20, 721 (1977)) (0.63 g) and iodide (1-tert-butoxycarbonyl-4 Potassium tert-butoxide (0.21 g) was added to a solution of -piperidinyl) methyl (triphenyl) phosphonium (WO99 / 24421 pamphlet) (1.0 g) in THF (35 mL). After stirring for 12 hours, the reaction solution was poured into a mixed solution of ethyl acetate and saturated aqueous ammonium chloride solution, and the organic layer was separated. The ethyl acetate solution was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by silica gel column to give the title compound (0.45 g, 51%).
NMR (200MHz, CDCl ₃ ) δ: 1.20-1.36 (2H, m), 1.45 (9H, s), 1.64-1.69 (2H, m), 2.67 (2H, t, J = 12.2), 3.05 (1H, m ), 4.01 (2H, d, J = 12.8), 5.32 (1H, dd, J = 9.0, 11.6), 6.16 (1H, d, J = 11.6), 6.69 (1H, s), 7.10-7.20 (6H, m), 7.30-7.36 (9H, m), 7.43 (1H, s).
111b) 4- [2- (1-Trityl-1H-imidazol-4-yl) ethyl] tert-butyl 4-piperidine-1-carboxylate 4-[(Z) -2- (1- Trityl-1H-imidazol-4-yl) vinyl] piperidine-1-carboxylate tert-butyl (0.43 g) and platinum oxide (0.08 g) in methanol (20 mL) in a hydrogen atmosphere at room temperature for 1 hour Stir. The insoluble material was removed by filtration, and the filtrate was concentrated to give the title compound (0.43 g, 99%).
NMR (200MHz, CDCl ₃ ) δ: 1.05-1.17 (2H, m), 1.45 (9H, s), 1.51-1.66 (5H, m), 2.52-2.68 (4H, m), 4.04 (2H, d, J = 13.5), 6.49 (1H, s), 7.11-7.18 (6H, s), 7.29-7.35 (10H, m).
111c) 1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- [2- (1-methyl-1H-imidazol-5-yl) ethyl] piperidine obtained in Example 111b) 4- [2- (1-trityl-1H-imidazol-4-yl) ethyl] piperidine-1-carboxylate tert-butyl (0.43 g) in acetonitrile (10 mL) was added methyl iodide (1 mL), Stir for 12 hours. The reaction mixture was concentrated, the residue was dissolved in methanol (10 mL) and 1N hydrochloric acid (5 mL), and the mixture was stirred at 80 ° C. for 3 hr. The reaction solution was poured into a mixture of diethyl ether and water, and the aqueous layer was separated and concentrated. To the residue was added DBU (0.25 mL), triethylamine (0.35 ml) and acetonitrile (10 mL), and this solution was added to 3-[(6-chloro-2-naphthyl) sulfonyl] propionic acid (0.25 g), WSC (0.24 g ) And HOBt (0.19 g) in acetonitrile (10 mL) and stirred for 12 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in chloroform and saturated aqueous sodium hydrogen carbonate, and the chloroform layer was separated. The chloroform solution was dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by a silica gel column to obtain the title compound (0.29 g, 74%).
NMR (200MHz, CDCl ₃ ) δ: 1.05-1.28 (2H, m), 1.57-1.66 (3H, m), 1.73-1.86 (2H, m), 2.53-2.60 (2H, m), 2.85-3.07 (3H , m), 3.53-3.62 (2H, m), 3.56 (3H, s), 3.85 (1H, d, J = 13.8), 4.51 (1H, d, J = 13.8), 6.78 (1H, s), 7.40 (1H, s), 7.51 (1H, dd, J = 1.8, 8.8), 7.90-7.99 (4H, m), 8.50 (1H, s).
Elemental analysis C ₂₄ H ₂₈ N ₃ O ₃ SCl ・ 0.5H ₂ O
Theoretical value (%) C, 59.68; H, 6.05; N, 8.70.
Found (%) C, 59.58; H, 6.14; N, 8.43.

実施例112
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-[(Z)-2-(2-メチル-1H-イミダゾール-4-イル)エテニル]ピペリジン
112a) 4-[(Z)-2-(2-メチル-1-トリチル-1H-イミダゾール-4-イル)エテニル]ピペリジン-1-カルボン酸tert-ブチル
2-メチル-1-トリチル-1H-イミダゾール-4-カルバルデヒド(EP 451538 (1991)) (3.3g)とヨウ化(1-tert-ブトキシカルボニル-4-ピペリジニル)メチル(トリフェニル)ホスホニウム(5.0g)から実施例111a)と同様にして題記化合物(1.0g, 22%)を無色粉末として得た。
NMR (200MHz, CDCl₃)δ：1.20-1.31 (2H, m), 1.46 (3H, s), 1.56-1.63 (2H, m), 2.49-2.62 (3H, m), 3.97 (2H, d, J = 12.4), 5.28 (1H, dd, J = 8.8, 11.8), 6.18 (1H, d, J = 11.8), 6.61 (1H, s), 7.13-7.20 (6H, m), 7.30-7.37 (9H, m).
112b) 1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-[(Z)-2-(2-メチル-1H-イミダゾール-4-イル)エテニル]ピペリジン
実施例112a)で得た4-[(Z)-2-(2-メチル-1-トリチル-1H-イミダゾール-4-イル) エテニル]ピペリジン-1-カルボン酸tert-ブチル(0.39g)と3-[(6-クロロ-2-ナフチル)スルホニル]プロピオン酸(0.22g)から実施例85b)と同様にして題記化合物(0.25g, 73%)を無色粉末として得た。
NMR (300MHz, CDCl₃)δ：0.94-1.14 (2H, m), 1.19-1.26 (2H, m), 1.42 (1H, m), 1.64-1.76 (4H, m), 2.37 (3H, s), 2.47 (1H, m), 2.83-2.88 (2H, m), 2.96 (1H, m), 3.52-3.58 (2H, m), 3.79-3.84 (3H, m), 4.47 (1H, d, J = 12.8), 6.79 (1H, d, J = 1.2), 6.91 (1H, d, J = 1.2), 7.59 (1H, dd, J = 1.8, 8.7), 7.89-7.96 (4H, m), 8.47 (1H, s). Example 112
1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4-[(Z) -2- (2-methyl-1H-imidazol-4-yl) ethenyl] piperidine
112a) tert-butyl 4-[(Z) -2- (2-methyl-1-trityl-1H-imidazol-4-yl) ethenyl] piperidine-1-carboxylate
2-Methyl-1-trityl-1H-imidazole-4-carbaldehyde (EP 451538 (1991)) (3.3 g) and (1-tert-butoxycarbonyl-4-piperidinyl) methyl (triphenyl) phosphonium (5.0 g) The title compound (1.0 g, 22%) was obtained as a colorless powder from g) in the same manner as in Example 111a).
NMR (200MHz, CDCl ₃ ) δ: 1.20-1.31 (2H, m), 1.46 (3H, s), 1.56-1.63 (2H, m), 2.49-2.62 (3H, m), 3.97 (2H, d, J = 12.4), 5.28 (1H, dd, J = 8.8, 11.8), 6.18 (1H, d, J = 11.8), 6.61 (1H, s), 7.13-7.20 (6H, m), 7.30-7.37 (9H, m).
112b) 1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-[(Z) -2- (2-methyl-1H-imidazol-4-yl) ethenyl] piperidine Example 112a ) 4-[(Z) -2- (2-methyl-1-trityl-1H-imidazol-4-yl) ethenyl] piperidine-1-carboxylate (0.39 g) and 3-[( The title compound (0.25 g, 73%) was obtained as a colorless powder from 6-chloro-2-naphthyl) sulfonyl] propionic acid (0.22 g) in the same manner as in Example 85b).
NMR (300MHz, CDCl ₃ ) δ: 0.94-1.14 (2H, m), 1.19-1.26 (2H, m), 1.42 (1H, m), 1.64-1.76 (4H, m), 2.37 (3H, s), 2.47 (1H, m), 2.83-2.88 (2H, m), 2.96 (1H, m), 3.52-3.58 (2H, m), 3.79-3.84 (3H, m), 4.47 (1H, d, J = 12.8 ), 6.79 (1H, d, J = 1.2), 6.91 (1H, d, J = 1.2), 7.59 (1H, dd, J = 1.8, 8.7), 7.89-7.96 (4H, m), 8.47 (1H, s).

実施例113
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-[(Z)-2-(1,2-ジメチル-1H-イミダゾール-5-イル)エテニル]ピペリジン
実施例112a)で得た4-[(Z)-2-(2-メチル-1-トリチル-1H-イミダゾール-4-イル) エテニル]ピペリジン-1-カルボン酸tert-ブチル(0.50g)から実施例111c)と同様にして題記化合物(0.16g, 35%)を無色粉末として得た。
NMR (200MHz, CDCl₃)δ：1.22-1.35 (2H, m), 1.65-1.82 (3H, m), 2.39 (3H, s), 2.59 (1H, t, J = 11.2), 2.82-2.92 (2H, m), 3.08 (1H, t, J = 11.2), 3.45 (3H, s), 3.52-3.62 (2H, m), 3.82 (1H, d, J = 11.2), 4.47 (1H, d, J= 11.8), 5.44 (1H, d, J = 9.6, 11.4), 6.05 (1H, d, J = 11.4), 6.88 (1H, s), 7.59 (1H, dd, J = 2.2, 11.2), 7.92-7.97 (4H, m), 8.48 (1H, s).
元素分析 C₂₄H₂₆N₃O₃SCl・H₂O として
理論値（％） C, 58.83; H, 5.76; N, 8.58.
実測値（％） C, 59.01; H, 5.46; N, 8.84. Example 113
1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-[(Z) -2- (1,2-dimethyl-1H-imidazol-5-yl) ethenyl] piperidine Example 112a 4-[(Z) -2- (2-methyl-1-trityl-1H-imidazol-4-yl) ethenyl] piperidine-1-carboxylate (0.50 g) obtained in Example 111c) In the same manner as the title compound (0.16 g, 35%) was obtained as a colorless powder.
NMR (200MHz, CDCl ₃ ) δ: 1.22-1.35 (2H, m), 1.65-1.82 (3H, m), 2.39 (3H, s), 2.59 (1H, t, J = 11.2), 2.82-2.92 (2H , m), 3.08 (1H, t, J = 11.2), 3.45 (3H, s), 3.52-3.62 (2H, m), 3.82 (1H, d, J = 11.2), 4.47 (1H, d, J = 11.8), 5.44 (1H, d, J = 9.6, 11.4), 6.05 (1H, d, J = 11.4), 6.88 (1H, s), 7.59 (1H, dd, J = 2.2, 11.2), 7.92-7.97 (4H, m), 8.48 (1H, s).
Elemental analysis C ₂₄ H ₂₆ N ₃ O ₃ SCl ・ H ₂ O
Theoretical value (%) C, 58.83; H, 5.76; N, 8.58.
Found (%) C, 59.01; H, 5.46; N, 8.84.

実施例114
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-[(1,2-ジメチル-1H-イミダゾール-5-イル)メトキシ]ピペリジン
実施例110a)で得た4-(2-メチル-1-トリチル-1H-イミダゾール-4-イル)メトキシピペリジン-1-カルボン酸tert-ブチル(0.50g)から実施例111c)と同様にして題記化合物(0.20g, 44%)を無色粉末として得た。
NMR (200MHz, CDCl₃)δ：1.42-1.61 (2H, m), 1.70-1.84 (2H, m), 2.37 (3H, s), 2.84-2.89 (2H, m), 3.18-3.28 (2H, m), 3.53 (3H, s), 3.51-3.67 (4H, m), 3.77-3.84 (1H, m), 4.46 (2H, s), 6.85 (1H, s), 7.58(1H, dd, J = 1.8, 8.7), 7.88-7.95 (4H, m), 8.46 (1H, s).
元素分析 C₂₄H₂₈N₃O₄SCl・0.25H₂O として
理論値（％） C, 58.29; H, 5.81; N, 8.50.
実測値（％） C, 58.29; H, 5.67; N, 8.56. Example 114
1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-[(1,2-dimethyl-1H-imidazol-5-yl) methoxy] piperidine 4-obtained in Example 110a) The title compound (0.20 g, 44%) was prepared from tert-butyl (2-methyl-1-trityl-1H-imidazol-4-yl) methoxypiperidine-1-carboxylate (0.50 g) in the same manner as in Example 111c). Obtained as a colorless powder.
NMR (200MHz, CDCl ₃ ) δ: 1.42-1.61 (2H, m), 1.70-1.84 (2H, m), 2.37 (3H, s), 2.84-2.89 (2H, m), 3.18-3.28 (2H, m ), 3.53 (3H, s), 3.51-3.67 (4H, m), 3.77-3.84 (1H, m), 4.46 (2H, s), 6.85 (1H, s), 7.58 (1H, dd, J = 1.8 , 8.7), 7.88-7.95 (4H, m), 8.46 (1H, s).
Elemental analysis C ₂₄ H ₂₈ N ₃ O ₄ SCl ・ 0.25H ₂ O
Theoretical value (%) C, 58.29; H, 5.81; N, 8.50.
Found (%) C, 58.29; H, 5.67; N, 8.56.

実施例115
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-[2-(2-メチル-1H-イミダゾール-4-イル)エチル]ピペリジン
実施例112b)で得た1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-[(Z)-2-(2-メチル-1H-イミダゾール-4-イル)エテニル]ピペリジン(0.1g) と酸化白金(0.01g)のTHF(2mL)溶液を素雰囲気下、6時間かき混ぜた。不溶物をろ去、ろ液を濃縮し、残留物をシリカゲルカラムにより精製して、題記化合物(0.06g, 60%)を無色粉末として得た。
NMR (300MHz, CDCl₃)δ：0.98-1.15 (2H, m), 1.53-1.60 (3H, m), 1.69-1.81 (2H, m), 2.39 (3H, s), 2.41-2.57 (3H, m), 2.82-2.88 (2H, m), 3.01 (1H, dt, J = 2.7, 13.2), 3.52-3.58 (2H, m), 3.78 (1H, d, J = 13.5), 4.44 (1H, d, J = 13.5), 6.60 (1H, s), 7.60 (1H, dd, J = 1.8, 8.7), 7.88-7.96 (4H, m), 8.47 (1H, s). Example 115
1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- [2- (2-methyl-1H-imidazol-4-yl) ethyl] piperidine 1- obtained from Example 112b) {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-[(Z) -2- (2-methyl-1H-imidazol-4-yl) ethenyl] piperidine (0.1 g) and platinum oxide A solution of (0.01 g) in THF (2 mL) was stirred for 6 hours under an atmosphere. The insoluble material was removed by filtration, the filtrate was concentrated, and the residue was purified by silica gel column to give the title compound (0.06 g, 60%) as a colorless powder.
NMR (300MHz, CDCl ₃ ) δ: 0.98-1.15 (2H, m), 1.53-1.60 (3H, m), 1.69-1.81 (2H, m), 2.39 (3H, s), 2.41-2.57 (3H, m ), 2.82-2.88 (2H, m), 3.01 (1H, dt, J = 2.7, 13.2), 3.52-3.58 (2H, m), 3.78 (1H, d, J = 13.5), 4.44 (1H, d, J = 13.5), 6.60 (1H, s), 7.60 (1H, dd, J = 1.8, 8.7), 7.88-7.96 (4H, m), 8.47 (1H, s).

実施例116
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-[2-(1,2-ジメチル-1H-イミダゾール-5-イル)エチル]ピペリジン
実施例113)で得た1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-[(Z)-2-(1,2-ジメチル-1H-イミダゾール-5-イル)エテニル]ピペリジン(0.5g)から実施例115)と同様にして題記化合物(0.3g, 60%)を無色粉末として得た。
NMR (300MHz, CDCl₃)δ：1.02-1.19 (2H, m), 1.53-1.57 (3H, m), 1.76 (2H, dd, J = 15.9, 19.2), 2.36 (3H, s), 2.45-2.53 (3H, m), 2.84-2.90 (2H, m), 2.98 (1H, m), 3.41 (3H, s), 3.53-3.59 (2H, m), 3.84 (1H, d, J = 13.5), 4.48 (1H, d, J = 13.5), 6.14 (1H, s), 7.59 (1H, dd, J = 2.4, 9.3), 7.89-7.96 (4H, m), 8.48 (1H, s).
元素分析 C₂₅H₃₀N₃O₃SCl・0.5H₂O として
理論値（％） C, 60.41; H, 6.29; N, 8.45.
実測値（％） C, 60.40; H, 6.12; N, 8.24. Example 116
1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4- [2- (1,2-dimethyl-1H-imidazol-5-yl) ethyl] piperidine obtained in Example 113) 1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-[(Z) -2- (1,2-dimethyl-1H-imidazol-5-yl) ethenyl] piperidine (0.5 g ) To give the title compound (0.3 g, 60%) as a colorless powder in the same manner as in Example 115).
NMR (300MHz, CDCl ₃ ) δ: 1.02-1.19 (2H, m), 1.53-1.57 (3H, m), 1.76 (2H, dd, J = 15.9, 19.2), 2.36 (3H, s), 2.45-2.53 (3H, m), 2.84-2.90 (2H, m), 2.98 (1H, m), 3.41 (3H, s), 3.53-3.59 (2H, m), 3.84 (1H, d, J = 13.5), 4.48 (1H, d, J = 13.5), 6.14 (1H, s), 7.59 (1H, dd, J = 2.4, 9.3), 7.89-7.96 (4H, m), 8.48 (1H, s).
Elemental analysis as C ₂₅ H ₃₀ N ₃ O ₃ SCl0.5H ₂ O
Theoretical value (%) C, 60.41; H, 6.29; N, 8.45.
Found (%) C, 60.40; H, 6.12; N, 8.24.

実施例117
1-[2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)エチル]-2-メチル-4,5,6,7-テトラヒドロ-1H-ベンゾイミダゾール
117a) 4-[2-(2-メチル-4,5,6,7-テトラヒドロ-1H-ベンゾイミダゾール-1-イル)エチル]ピペリジン-1-カルボン酸tert-ブチル
2-メチル-4,5,6,7-テトラヒドロ-1H-ベンゾイミダゾール(特開昭49-31666号公報)(0.93g)と4-(2-ブロモエチル)ピペリジン-1-カルボン酸tert-ブチル(2.0g)から実施例101a)と同様にして題記化合物(0.65g, 27%)を茶褐色油状物として得た。
NMR (200MHz, CDCl₃)δ：1.13-1.19 (2H, m), 1.45 (9H, s), 1.50-1.80 (9H, m), 2.33 (3H, s), 2.43-2.60 (4H, m), 2.60-2.78 (2H, m), 3.71 (2H, t, J = 7.2), 4.06 (2H, d, J = 14.2).
117b) 1-[2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)エチル]-2-メチル-4,5,6,7-テトラヒドロ-1H-ベンゾイミダゾール
実施例117a)で得た4-[2-(2-メチル-4,5,6,7-テトラヒドロ-1H-ベンゾイミダゾール-1-イル)エチル]ピペリジン-1-カルボン酸tert-ブチル(0.57g)と3-[(6-クロロ-2-ナフチル)スルホニル]プロピオン酸(0.56g)から実施例85b)と同様にして題記化合物(0.60g, 61%)を得た。
NMR (300MHz, CDCl₃)δ：10.7-1.19 (2H, m), 1.54-1.81 (10H, m), 2.34 (3H, s), 2.42-2.45 (2H, m), 2.52-2.56 (2H, m), 2.87 (2H, dt, J = 3.0, 7.2), 3.01 (1H, dt, J = 2.7, 13.5), 3.52-3.60 (2H, m), 3.72 (2H, t, J = 7.5), 3.84 (1H, d, J = 12.9), 4.50 (1H, d, J = 12.9), 7.59 (1H, dd, J = 2.4, 9.0), 7.89-7.96 (4H, m), 8.48 (1H, s). Example 117
1- [2- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) ethyl] -2-methyl-4,5,6,7-tetrahydro-1H-benzo Imidazole
117a) tert-butyl 4- [2- (2-methyl-4,5,6,7-tetrahydro-1H-benzoimidazol-1-yl) ethyl] piperidine-1-carboxylate
2-methyl-4,5,6,7-tetrahydro-1H-benzimidazole (JP-A-49-31666) (0.93 g) and tert-butyl 4- (2-bromoethyl) piperidine-1-carboxylate ( The title compound (0.65 g, 27%) was obtained as a brown oil in the same manner as Example 101a) from 2.0 g).
NMR (200MHz, CDCl ₃ ) δ: 1.13-1.19 (2H, m), 1.45 (9H, s), 1.50-1.80 (9H, m), 2.33 (3H, s), 2.43-2.60 (4H, m), 2.60-2.78 (2H, m), 3.71 (2H, t, J = 7.2), 4.06 (2H, d, J = 14.2).
117b) 1- [2- (1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) ethyl] -2-methyl-4,5,6,7-tetrahydro-1H -Benzimidazole 4- [2- (2-Methyl-4,5,6,7-tetrahydro-1H-benzimidazol-1-yl) ethyl] piperidine-1-carboxylate tert-butyl obtained in Example 117a) The title compound (0.60 g, 61%) was obtained from (0.57 g) and 3-[(6-chloro-2-naphthyl) sulfonyl] propionic acid (0.56 g) in the same manner as in Example 85b).
NMR (300MHz, CDCl ₃ ) δ: 10.7-1.19 (2H, m), 1.54-1.81 (10H, m), 2.34 (3H, s), 2.42-2.45 (2H, m), 2.52-2.56 (2H, m ), 2.87 (2H, dt, J = 3.0, 7.2), 3.01 (1H, dt, J = 2.7, 13.5), 3.52-3.60 (2H, m), 3.72 (2H, t, J = 7.5), 3.84 ( 1H, d, J = 12.9), 4.50 (1H, d, J = 12.9), 7.59 (1H, dd, J = 2.4, 9.0), 7.89-7.96 (4H, m), 8.48 (1H, s).

実施例118
1-(2-{1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル}エチル)-4,5,6,7-テトラヒドロ-1H-ベンゾイミダゾール
118a) 4-[2-(4,5,6,7-テトラヒドロ-1H-ベンゾイミダゾール-1-イル)エチル]ピペリジン-1-カルボン酸tert-ブチル
4,5,6,7-テトラヒドロ-1H-ベンゾイミダゾール(国際公開第99/25710号パンフレット)(0.84g)と4-(2-ブロモエチル)ピペリジン-1-カルボン酸tert-ブチル(2.0g)から実施例101a)と同様にして題記化合物(1.37g, 60%)を茶褐色油状物として得た。
NMR (200MHz, CDCl₃)δ：1.13-1.19 (2H, m), 1.44 (9H, s), 1.50-1.80 (9H, m), 2.43-2.728 (6H, m), 3.80 (2H, t, J = 7.2), 4.06 (2H, d, J = 14.2), 7.29 (1H, s).
118b) 1-(2-{1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル}エチル)-4,5,6,7-テトラヒドロ-1H-ベンゾイミダゾール
実施例118a)で得た4-[2-(4,5,6,7-テトラヒドロ-1H-ベンゾイミダゾール-1-イル)エチル]ピペリジン-1-カルボン酸tert-ブチル(0.54g)と3-[(6-クロロ-2-ナフチル)スルホニル]プロピオン酸(0.56g)から実施例85b)と同様にして題記化合物(0.46g, 47%)を得た。
NMR (200MHz, CDCl₃)δ：1.07-1.16 (2H, m), 1.48 (1H, m), 1.59-1.82 (9H, m), 2.45-2.48 (2H, m), 2.58-2.61 (2H, m), 2.83-2.90 (2H, m), 2.99 (1H, m), 3.13-3.25 (3H, m), 3.52-3.58 (2H, m), 3.81 (3H, m), 4.49 (1H, d, J = 13.2), 7.30 (1H, s), 7.59 1H, dd, J = 2.1, 9.0), 7.89-7.96 (4H, m), 8.47 (1H, s). Example 118
1- (2- {1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl} ethyl) -4,5,6,7-tetrahydro-1H-benzimidazole
118a) tert-butyl 4- [2- (4,5,6,7-tetrahydro-1H-benzimidazol-1-yl) ethyl] piperidine-1-carboxylate
From 4,5,6,7-tetrahydro-1H-benzimidazole (WO 99/25710 pamphlet) (0.84 g) and tert-butyl 4- (2-bromoethyl) piperidine-1-carboxylate (2.0 g) The title compound (1.37 g, 60%) was obtained as a brown oil in the same manner as Example 101a).
NMR (200MHz, CDCl ₃ ) δ: 1.13-1.19 (2H, m), 1.44 (9H, s), 1.50-1.80 (9H, m), 2.43-2.728 (6H, m), 3.80 (2H, t, J = 7.2), 4.06 (2H, d, J = 14.2), 7.29 (1H, s).
118b) 1- (2- {1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl} ethyl) -4,5,6,7-tetrahydro-1H-benzimidazole 4- [2- (4,5,6,7-tetrahydro-1H-benzoimidazol-1-yl) ethyl] piperidine-1-carboxylate (0.54 g) obtained in Example 118a) and 3- [ The title compound (0.46 g, 47%) was obtained from (6-chloro-2-naphthyl) sulfonyl] propionic acid (0.56 g) in the same manner as in Example 85b).
NMR (200MHz, CDCl ₃ ) δ: 1.07-1.16 (2H, m), 1.48 (1H, m), 1.59-1.82 (9H, m), 2.45-2.48 (2H, m), 2.58-2.61 (2H, m ), 2.83-2.90 (2H, m), 2.99 (1H, m), 3.13-3.25 (3H, m), 3.52-3.58 (2H, m), 3.81 (3H, m), 4.49 (1H, d, J = 13.2), 7.30 (1H, s), 7.59 1H, dd, J = 2.1, 9.0), 7.89-7.96 (4H, m), 8.47 (1H, s).

実施例119
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-[2-(1,4-ジメチル-1H-イミダゾール-5-イル)エチル]ピペリジン
119a) 4-[(Z)-2-(5-メチル-1-トリチル-1H-イミダゾール-4-イル)エテニル]ピペリジン-1-カルボン酸tert-ブチル
5-メチル-1-トリチル-1H-イミダゾール-4-カルバルデヒド(Yuan, W. et al., J. Med. Chem., 36, 211 (1993)) (3.3g)とヨウ化(1-tert-ブトキシカルボニル-4-ピペリジニル)メチル(トリフェニル)ホスホニウム(5.0g)から実施例111a)と同様にして題記化合物(2.55g, 56%)を無色粉末として得た。
NMR (300MHz, CDCl₃)δ：1.22-1.39 (2H, m), 1.45 (3H, s), 1.46 (9H, s), 1.77-1.82 (2H, m), 2.80-2.88 (2H, m) 3.66 (1H, m), 4.08 (2H, br), 5.29 (1H, dd, J = 9.3, 11.7), 6.04 (1H, d, J = 11.7), 7.13-7.17 (6H, m), 7.27-7.36 (9H, m).
119b) 4-[2-(1-トリチル-5-メチル-1H-イミダゾール-4-イル)エチル]ピペリジン-1-カルボン酸tert-ブチル
実施例119a)で得た4-[(Z)-2-(5-メチル-1-トリチル-1H-イミダゾール-4-イル)エテニル]ピペリジン-1-カルボン酸tert-ブチル(1.5g)から実施例111b)と同様にして題記化合物(1.5g, 99%)を無色粉末として得た。
NMR (300MHz, CDCl₃)δ：1.22-1.39 (2H, m), 1.45 (3H, s), 1.46 (9H, s), 1.77-1.82 (2H, m), 2.80-2.88 (2H, m), 3.66 (1H, m), 4.08 (2H, br), 5.29 (1H, dd, J = 9.3, 11.7), 6.04 (1H, d, J = 11.7), 7.13-7.17 (6H, m), 7.27-7.36 (9H, m).
119c) 1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-[2-(1,4-ジメチル-1H-イミダゾール-5-イル)エチル]ピペリジン
実施例119b)で得られた4-[2-(1-トリチル-5-メチル-1H-イミダゾール-4-イル)エチル]ピペリジン-1-カルボン酸tert-ブチル(0.75g)から実施例111c)と同様にして題記化合物(0.22g, 33%)を無色粉末として得た。
NMR (300MHz, CDCl₃)δ：0.99-1.12 (2H, m), 1.37-1.52 (3H, m), 1.72-1.81(4H, m), 2.15 (3H, s), 2.45-2.56 (3H, m), 2.84-2.90 (2H, dt, J = 4.2, 6.9), 2.99 (1H, dt, J = 3.0, 12.3), 3.51 (3H, s), 3.55 (2H, dt, J = 4.2, 6.9), 3.83 (1H, d, J = 13.2), 7.28 (1H, s), 7.59 (1H, dd, J = 2.1, 9.0), 7.89-7.94 (4H, m), 8.48 (1H, s).
元素分析 C₂₅H₃₀N₃O₃SCl・0.75H₂O として
理論値（％） C, 59.87; H, 6.33; N, 8.38.
実測値（％） C, 60.01; H, 6.33; N, 8.38. Example 119
1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- [2- (1,4-dimethyl-1H-imidazol-5-yl) ethyl] piperidine
119a) tert-butyl 4-[(Z) -2- (5-methyl-1-trityl-1H-imidazol-4-yl) ethenyl] piperidine-1-carboxylate
5-methyl-1-trityl-1H-imidazole-4-carbaldehyde (Yuan, W. et al., J. Med. Chem., 36, 211 (1993)) (3.3 g) and iodide (1-tert The title compound (2.55 g, 56%) was obtained as a colorless powder from -butoxycarbonyl-4-piperidinyl) methyl (triphenyl) phosphonium (5.0 g) in the same manner as in Example 111a).
NMR (300MHz, CDCl ₃ ) δ: 1.22-1.39 (2H, m), 1.45 (3H, s), 1.46 (9H, s), 1.77-1.82 (2H, m), 2.80-2.88 (2H, m) 3.66 (1H, m), 4.08 (2H, br), 5.29 (1H, dd, J = 9.3, 11.7), 6.04 (1H, d, J = 11.7), 7.13-7.17 (6H, m), 7.27-7.36 ( 9H, m).
119b) 4- [2- (1-Trityl-5-methyl-1H-imidazol-4-yl) ethyl] piperidine-1-carboxylate tert-butyl 4-[(Z) -2 obtained in Example 119a) -(5-Methyl-1-trityl-1H-imidazol-4-yl) ethenyl] piperidine-1-carboxylate from tert-butyl (1.5 g) in the same manner as in Example 111b) (1.5 g, 99% ) Was obtained as a colorless powder.
NMR (300 MHz, CDCl ₃ ) δ: 1.22-1.39 (2H, m), 1.45 (3H, s), 1.46 (9H, s), 1.77-1.82 (2H, m), 2.80-2.88 (2H, m), 3.66 (1H, m), 4.08 (2H, br), 5.29 (1H, dd, J = 9.3, 11.7), 6.04 (1H, d, J = 11.7), 7.13-7.17 (6H, m), 7.27-7.36 (9H, m).
119c) 1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- [2- (1,4-dimethyl-1H-imidazol-5-yl) ethyl] piperidine in Example 119b) The title was obtained in the same manner as in Example 111c) from the obtained 4- [2- (1-trityl-5-methyl-1H-imidazol-4-yl) ethyl] piperidine-1-carboxylate (tert-butyl). The compound (0.22 g, 33%) was obtained as a colorless powder.
NMR (300MHz, CDCl ₃ ) δ: 0.99-1.12 (2H, m), 1.37-1.52 (3H, m), 1.72-1.81 (4H, m), 2.15 (3H, s), 2.45-2.56 (3H, m ), 2.84-2.90 (2H, dt, J = 4.2, 6.9), 2.99 (1H, dt, J = 3.0, 12.3), 3.51 (3H, s), 3.55 (2H, dt, J = 4.2, 6.9), 3.83 (1H, d, J = 13.2), 7.28 (1H, s), 7.59 (1H, dd, J = 2.1, 9.0), 7.89-7.94 (4H, m), 8.48 (1H, s).
Elemental analysis As C ₂₅ H ₃₀ N ₃ O ₃ SCl ・ 0.75H ₂ O
Theoretical value (%) C, 59.87; H, 6.33; N, 8.38.
Found (%) C, 60.01; H, 6.33; N, 8.38.

実施例120
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-[2-(5-メチル-1H-イミダゾール-4-イル)エチル]ピペリジン
実施例119b)で得られた4-[2-(1-トリチル-5-メチル-1H-イミダゾール-4-イル)エチル]ピペリジン-1-カルボン酸tert-ブチル(0.66g)から実施例110b)と同様にして題記化合物(0.33g, 57%)を無色粉末として得た。
NMR (300MHz, CDCl₃)δ：0.99-1.16 (2H, m), 1.51-1.59 (3H, m), 1.70-1.81 (2H, m), 2.18 (3H, s),2.44-2.55 (3H, m), 2.83-2.88 (2H, m), 2.98 (1H, dt, J = 2.4, 12.6), 3.53-3.59 (2H, m), 3.79 (1H, d, J = 13.5), 4.45 (1H, d, J = 13.5), 7.44 (1H, s), 7.59 (1H, dd, J = 1.8, 8.7), 7.88-7.96 (4H, m), 8.47 (1H, s).
元素分析 C₂₄H₂₈N₃O₃SCl・0.5H₂O として
理論値（％） C, 59.68; H, 6.05; N, 8.70.
実測値（％） C, 60.05; H, 6.24; N, 8.90. Example 120
1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- [2- (5-methyl-1H-imidazol-4-yl) ethyl] piperidine 4 obtained in Example 119b) The title compound (0.33 g) was obtained in the same manner as in Example 110b) from tert-butyl (0.66 g)-[2- (1-trityl-5-methyl-1H-imidazol-4-yl) ethyl] piperidine-1-carboxylate , 57%) as a colorless powder.
NMR (300MHz, CDCl ₃ ) δ: 0.99-1.16 (2H, m), 1.51-1.59 (3H, m), 1.70-1.81 (2H, m), 2.18 (3H, s), 2.44-2.55 (3H, m ), 2.83-2.88 (2H, m), 2.98 (1H, dt, J = 2.4, 12.6), 3.53-3.59 (2H, m), 3.79 (1H, d, J = 13.5), 4.45 (1H, d, J = 13.5), 7.44 (1H, s), 7.59 (1H, dd, J = 1.8, 8.7), 7.88-7.96 (4H, m), 8.47 (1H, s).
Elemental analysis C ₂₄ H ₂₈ N ₃ O ₃ SCl ・ 0.5H ₂ O
Theoretical value (%) C, 59.68; H, 6.05; N, 8.70.
Found (%) C, 60.05; H, 6.24; N, 8.90.

実施例121
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-[(Z)-2-(1-メチル-1H-イミダゾール-2-イル)エテニル]ピペリジン
121a) 4-[(Z)-2-(1-メチル-1H-イミダゾール-2-イル)エテニル]ピペリジン-1-カルボン酸tert-ブチル
1-メチルイミダゾール-2-カルバルデヒド(0.5g)とヨウ化(1-tert-ブトキシカルボニル-4-ピペリジニル)メチル(トリフェニル)ホスホニウム(4.0g)から実施例111a)と同様にして題記化合物を(0.72g, 54%)無色粉末として得た。
NMR (200MHz, CDCl₃)δ：1.22-1.34 (3H, m), 1.46 (9H, s), 1.72-1.79 (2H, m), 2.86 (2H, t, J = 12.8), 3.61 (3H, s), 4.03-4.14 (2H, m), 5.63 (1H, dd, J = 9.6, 11.8), 6.10 (1H, d, J = 11.8), 6.82 (1H, d, J = 1.0), 7.07 (1H, d, J = 1.0).
121b) 1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-[(Z)-2-(1-メチル-1H-イミダゾール-2-イル)エテニル]ピペリジン
121a)で得た4-[(Z)-2-(1-メチル-1H-イミダゾール-2-イル)ビニル]ピペリジン-1-カルボン酸tert-ブチル(0.40g)と3-[(6-クロロ-2-ナフチル)スルホニル]プロピオン酸(0.45 g)から実施例85b)と同様にして題記化合物(0.45g, 71%)を無色粉末として得た。
NMR (300MHz, CDCl₃)δ：1.14-1.34 (2H, m), 1.75-1.91 (3H, m), 2.67 (1H, dt, J = 3.0. 12.9), 2.83-2.90 (2H, m), 3.17 (1H, dt, J = 3.0, 12.9), 3.49-3.59 (2H, m), 3.62 (3H, s), 3.76 (1H, m), 4.24 (1H, d, J = 13.5), 5.55 (1H, dd, J = 9.3, 11.7), 6.11 (1H, d, J = 11.7), 6.83 (1H, d, J = 1.2), 7.06 (1H, d, J = 1.2), 7.59 (1H, dd, J = 1.8, 8.7), 7.89-7.96 (4H, m), 8.48 (1H, s).
元素分析 C₂₄H₂₆N₃O₃SCl・0.25H₂O として
理論値（％） C, 60.49; H, 5.61; N, 5.83.
実測値（％） C, 60.67; H, 5.85; N, 8.59. Example 121
1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-[(Z) -2- (1-methyl-1H-imidazol-2-yl) ethenyl] piperidine
121a) 4-[(Z) -2- (1-Methyl-1H-imidazol-2-yl) ethenyl] piperidine-1-carboxylate tert-butyl
The title compound was prepared from 1-methylimidazole-2-carbaldehyde (0.5 g) and iodide (1-tert-butoxycarbonyl-4-piperidinyl) methyl (triphenyl) phosphonium (4.0 g) in the same manner as Example 111a). Obtained as a colorless powder (0.72 g, 54%).
NMR (200MHz, CDCl ₃ ) δ: 1.22-1.34 (3H, m), 1.46 (9H, s), 1.72-1.79 (2H, m), 2.86 (2H, t, J = 12.8), 3.61 (3H, s ), 4.03-4.14 (2H, m), 5.63 (1H, dd, J = 9.6, 11.8), 6.10 (1H, d, J = 11.8), 6.82 (1H, d, J = 1.0), 7.07 (1H, d, J = 1.0).
121b) 1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4-[(Z) -2- (1-methyl-1H-imidazol-2-yl) ethenyl] piperidine
4-((Z) -2- (1-methyl-1H-imidazol-2-yl) vinyl] piperidine-1-carboxylate (0.40 g) obtained in 121a) and 3-[(6-chloro The title compound (0.45 g, 71%) was obtained as a colorless powder from 2-naphthyl) sulfonyl] propionic acid (0.45 g) in the same manner as in Example 85b).
NMR (300MHz, CDCl ₃ ) δ: 1.14-1.34 (2H, m), 1.75-1.91 (3H, m), 2.67 (1H, dt, J = 3.0. 12.9), 2.83-2.90 (2H, m), 3.17 (1H, dt, J = 3.0, 12.9), 3.49-3.59 (2H, m), 3.62 (3H, s), 3.76 (1H, m), 4.24 (1H, d, J = 13.5), 5.55 (1H, dd, J = 9.3, 11.7), 6.11 (1H, d, J = 11.7), 6.83 (1H, d, J = 1.2), 7.06 (1H, d, J = 1.2), 7.59 (1H, dd, J = 1.8, 8.7), 7.89-7.96 (4H, m), 8.48 (1H, s).
Elemental analysis C ₂₄ H ₂₆ N ₃ O ₃ SCl ・ 0.25H ₂ O
Theoretical value (%) C, 60.49; H, 5.61; N, 5.83.
Found (%) C, 60.67; H, 5.85; N, 8.59.

実施例122
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-[2-(1-メチル-1H-イミダゾール-2-イル)エチル]ピペリジン
実施例121b)で得た1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-[(Z)-2-(1-メチル-1H-イミダゾール-2-イル)エテニル]ピペリジン(0.20g)から実施例115)と同様にして題記化合物(0.19g, 95%)を無色粉末として得た。
NMR (300MHz, CDCl₃)δ：1.02-1.16 (2H, m), 1.58-1.86 (5H, m), 2.52 (1H, dt, J = 2.7, 12.9), 2.67 (2H, t, J = 8.1), 2.83-2.88 (2H, m), 3.00 (1H, dt, J = 2.7, 12.9), 3.53-3.59 (2H, m), 3.57 (3H, s), 3.81 (1H, d, J = 13.2), 4.46 (1H, d, J = 13.2), 6.79 (1H, d, J = 1.5), 6.91 (1H, d, J = 1.5), 7.59 (1H, dd, J = 1.8, 8.7), 7.89-7.96 (4H, m), 8.48 (1H, s).
元素分析 C₂₄H₂₈N₃O₃SCl・0.3H₂O として
理論値（％） C, 60.13; H, 6.01; N, 8.76.
実測値（％） C, 60.21; H, 6.06; N, 8.46. Example 122
1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4- [2- (1-methyl-1H-imidazol-2-yl) ethyl] piperidine 1- obtained in Example 121b) Example from {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4-[(Z) -2- (1-methyl-1H-imidazol-2-yl) ethenyl] piperidine (0.20 g) 115) The title compound (0.19 g, 95%) was obtained as a colorless powder.
NMR (300MHz, CDCl ₃ ) δ: 1.02-1.16 (2H, m), 1.58-1.86 (5H, m), 2.52 (1H, dt, J = 2.7, 12.9), 2.67 (2H, t, J = 8.1) , 2.83-2.88 (2H, m), 3.00 (1H, dt, J = 2.7, 12.9), 3.53-3.59 (2H, m), 3.57 (3H, s), 3.81 (1H, d, J = 13.2), 4.46 (1H, d, J = 13.2), 6.79 (1H, d, J = 1.5), 6.91 (1H, d, J = 1.5), 7.59 (1H, dd, J = 1.8, 8.7), 7.89-7.96 ( 4H, m), 8.48 (1H, s).
Elemental analysis Theoretical value (%) for C ₂₄ H ₂₈ N ₃ O ₃ SCl · 0.3H ₂ O C, 60.13; H, 6.01; N, 8.76.
Found (%) C, 60.21; H, 6.06; N, 8.46.

実施例123
5-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)イミダゾ[2,1-b][1,3]チアゾール
123a) 4-(イミダゾ[2,1-b][1,3]チアゾール-5-イル)ピペリジン-1-カルボン酸tert-ブチル
4-(1-ブロモ-2-オキソエチル)ピペリジン-1-カルボン酸tert-ブチル(2.0g)と2-アミノチアゾール(0.77g)から実施例81a)と同様にして題記化合物(0.55g, 23%)を得た。
NMR (200MHz, CDCl₃)δ：1.48 (9H, s), 1.55-1.76 (2H, m), 1.96-2.05 (2H, m), 2.82-2.95 (3H,m), 4.19-4.26 (2H, m), 6.85 (1H, d, J = 4.4), 7.03 (1H, s), 7.33 (1H, d, J = 4.4).
123b) 5-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)イミダゾ[2,1-b][1,3]チアゾール
実施例123a)で得た4-(イミダゾ[2,1-b][1,3]チアゾール-5-イル)ピペリジン-1-カルボン酸tert-ブチル(0.55g)から実施例85b)と同様にして題記化合物(0.48g, 55%)を無色粉末として得た。
NMR (300MHz, CDCl₃)δ：1.52-1.77 (2H, m), 2.00-2.12 (2H, m), 2.75 (1H, t, J = 15.6), 2.90-3.05 (3H, m), 3.22 (1H, t, J = 15.6), 3.53-3.62 (2H, m), 3.97 (1H, d, J = 13.8), 4.59 (1H, d, J = 13.8), 6.86 (1H, d, J = 4.5), 7.01 (1H, s), 7.34 (1H, d, J = 4.5), 7.59 (1H, dd, J = 2.1, 9.0), 7.90-7.97 (4H, m), 8.49 (1H, s). Example 123
5- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) imidazo [2,1-b] [1,3] thiazole
123a) tert-butyl 4- (imidazo [2,1-b] [1,3] thiazol-5-yl) piperidine-1-carboxylate
4- (1-Bromo-2-oxoethyl) piperidine-1-carboxylate tert-butyl (2.0 g) and 2-aminothiazole (0.77 g) were used in the same manner as in Example 81a) to give the title compound (0.55 g, 23% )
NMR (200MHz, CDCl ₃ ) δ: 1.48 (9H, s), 1.55-1.76 (2H, m), 1.96-2.05 (2H, m), 2.82-2.95 (3H, m), 4.19-4.26 (2H, m ), 6.85 (1H, d, J = 4.4), 7.03 (1H, s), 7.33 (1H, d, J = 4.4).
123b) 5- (1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) imidazo [2,1-b] [1,3] thiazole obtained in Example 123a) The title compound (0.48 g, 4- (imidazo [2,1-b] [1,3] thiazol-5-yl) piperidine-1-carboxylate from tert-butyl (0.55 g) was prepared in the same manner as in Example 85b). 55%) was obtained as a colorless powder.
NMR (300MHz, CDCl ₃ ) δ: 1.52-1.77 (2H, m), 2.00-2.12 (2H, m), 2.75 (1H, t, J = 15.6), 2.90-3.05 (3H, m), 3.22 (1H , t, J = 15.6), 3.53-3.62 (2H, m), 3.97 (1H, d, J = 13.8), 4.59 (1H, d, J = 13.8), 6.86 (1H, d, J = 4.5), 7.01 (1H, s), 7.34 (1H, d, J = 4.5), 7.59 (1H, dd, J = 2.1, 9.0), 7.90-7.97 (4H, m), 8.49 (1H, s).

実施例124
1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-[4-(2-メチル-1H-イミダゾール-1-イル)ブチル]ピペリジン
124a) 4-[4-(2-メチル-1H-イミダゾール-1-イル)ブチル]ピペリジン-1-カルボン酸tert-ブチル
4-(4-ブロモブチル)ピペリジン-1-カルボン酸tert-ブチル(Egbertson, M. S. et al., J. Med. Chem., 37, 2537 (1994)) (2.0g)と2-メチルイミダゾール(0.56g)から実施例101a)と同様にして題記化合物(0.94g, 47%)を茶色油状物として得た。
NMR (200MHz, CDCl₃)δ：1.03-1.35 (4H, m), 1.45 (9H, s), 1.59-1.82 (7H, m), 2.37 (3H, s), 2.66 (2H, t, J = 12.4), 3.81 (2H, t, J = 7.0), 4.06 (2H, m), 6.80 (1H, d, J = 1.4), 6.90 (1H, d, J = 1.4).
124b) 1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-[4-(2-メチル-1H-イミダゾール-1-イル)ブチル]ピペリジン
実施例124a)で得た4-[4-(2-メチル-1H-イミダゾール-1-イル)ブチル]ピペリジン-1-カルボン酸tert-ブチル(0.93g)から実施例85b)と同様にして題記化合物(0.1g, 15%)を無色粉末として得た。
NMR (200MHz, CDCl₃)δ：0.91-1.08 (2H, m), 1.22-1.43 (5H, m), 1.61-1.74 (4H, m), 2.37 (3H, s), 2.40-2.54 (1H, m), 2.81 -3.02 (3H, m), 3.52-3.60 (2H, m), 3.78-3.85 (3H, m), 4.26 (1H, d, J = 13.2), 6.79 (1H, d, J = 1.4), 6.90 (1H, d, J = 1.4), 7.58 (1H, dd, J = 2.0, 8.8), 7.92-7.97 (4H, m), 8.47 (1H, s).
元素分析 C₂₆H₃₂N₃O₃SCl・0.5H₂O として
理論値（％） C, 61.10; H, 6.51; N, 8.22.
実測値（％） C, 61.21; N, 6.57; N, 7.95. Example 124
1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- [4- (2-methyl-1H-imidazol-1-yl) butyl] piperidine
124a) tert-butyl 4- [4- (2-methyl-1H-imidazol-1-yl) butyl] piperidine-1-carboxylate
Tert-Butyl 4- (4-bromobutyl) piperidine-1-carboxylate (Egbertson, MS et al., J. Med. Chem., 37, 2537 (1994)) (2.0 g) and 2-methylimidazole (0.56 g ) To give the title compound (0.94 g, 47%) as a brown oil in the same manner as Example 101a).
NMR (200MHz, CDCl ₃ ) δ: 1.03-1.35 (4H, m), 1.45 (9H, s), 1.59-1.82 (7H, m), 2.37 (3H, s), 2.66 (2H, t, J = 12.4 ), 3.81 (2H, t, J = 7.0), 4.06 (2H, m), 6.80 (1H, d, J = 1.4), 6.90 (1H, d, J = 1.4).
124b) 1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4- [4- (2-methyl-1H-imidazol-1-yl) butyl] piperidine obtained in Example 124a) 4- [4- (2-Methyl-1H-imidazol-1-yl) butyl] piperidine-1-carboxylate tert-butyl (0.93 g) was used in the same manner as in Example 85b) to give the title compound (0.1 g, 15% ) Was obtained as a colorless powder.
NMR (200MHz, CDCl ₃ ) δ: 0.91-1.08 (2H, m), 1.22-1.43 (5H, m), 1.61-1.74 (4H, m), 2.37 (3H, s), 2.40-2.54 (1H, m ), 2.81 -3.02 (3H, m), 3.52-3.60 (2H, m), 3.78-3.85 (3H, m), 4.26 (1H, d, J = 13.2), 6.79 (1H, d, J = 1.4) , 6.90 (1H, d, J = 1.4), 7.58 (1H, dd, J = 2.0, 8.8), 7.92-7.97 (4H, m), 8.47 (1H, s).
Elemental analysis As C ₂₆ H ₃₂ N ₃ O ₃ SCl0.5H ₂ O
Theoretical value (%) C, 61.10; H, 6.51; N, 8.22.
Found (%) C, 61.21; N, 6.57; N, 7.95.

実施例125
2-(1-{3-[(6-ブロモ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
3-[(6-ブロモ-2-ナフチル)スルホニル]プロピオン酸（0.17g）および実施例69b)で得られた5-メチル-2-(4-ピペリジニル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン(0.11g)から実施例89b)と同様にして題記化合物(0.11g, 40%)を白色結晶として得た。
NMR (300MHz, CDCl₃)δ：1.62-1.99 (4H, m), 2.61 (3H, s), 2.61-2.67 (1H, m), 2.82-3.01 (2H, m), 3.15-3.23 (1H, m), 3.46-3.65 (2H, m), 3.97-4.02 (1H, m), 4.08-4.21 (1H, m), 4.25 (2H, s), 4.69-4.74 (1H, m), 6.70 (1H, t, J = 1.5), 7.72 (1H, dd, J = 2.1, 8.7), 7.84-7.96 (3H, m), 8.13 (1H, d, J = 1.8), 8.47 (1H, s).
元素分析値 C₂₄H₂₅BrN₄O₄S・0.3H₂Oとして
計算値（％）：C, 52.33； H, 4.68； N, 10.17
実測値（％）：C, 52.57； H, 4.66； N, 9.88 Example 125
2- (1- {3-[(6-Bromo-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -5-methyl-1,2-dihydro-3H-imidazo [1,5-c] imidazole- 3-on
3-[(6-Bromo-2-naphthyl) sulfonyl] propionic acid (0.17 g) and 5-methyl-2- (4-piperidinyl) -1,2-dihydro-3H-imidazo obtained in Example 69b) The title compound (0.11 g, 40%) was obtained as white crystals from [1,5-c] imidazol-3-one (0.11 g) in the same manner as in Example 89b).
NMR (300MHz, CDCl ₃ ) δ: 1.62-1.99 (4H, m), 2.61 (3H, s), 2.61-2.67 (1H, m), 2.82-3.01 (2H, m), 3.15-3.23 (1H, m ), 3.46-3.65 (2H, m), 3.97-4.02 (1H, m), 4.08-4.21 (1H, m), 4.25 (2H, s), 4.69-4.74 (1H, m), 6.70 (1H, t , J = 1.5), 7.72 (1H, dd, J = 2.1, 8.7), 7.84-7.96 (3H, m), 8.13 (1H, d, J = 1.8), 8.47 (1H, s).
Elemental analysis value Calculated as C ₂₄ H ₂₅ BrN ₄ O ₄ S · 0.3H ₂ O (%): C, 52.33; H, 4.68; N, 10.17
Found (%): C, 52.57; H, 4.66; N, 9.88

実施例126
2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-5-メチル-1H-イミダゾ[1,5-c]イミダゾール-1,3(2H)-ジオン
126a) 4-{[(2-メチル-1H-イミダゾール-4-イル)カルボニル]アミノ}ピペリジン-1-カルボン酸ベンジル
4-アミノピペリジン-1-カルボン酸ベンジル(3.3g)と2-メチル-1H-イミダゾール-4-カルボン酸(2.0g)のアセトニトリル(50mL)溶液へWSC(4.0g)、HOBt(3.2g)およびトリエチルアミン(3.8mL)を加え12時間かき混ぜた。反応液を濃縮し、残留物をクロロホルムと飽和重曹水に溶解した。クロロホルム層を分取し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。残留物をシリカゲルカラムクロマトにより精製して、題記化合物(2.4 g, 49%)を無色粉末として得た．
NMR (300MHz, CDCl₃)δ：1.41-1.56 (2H, m), 1.93-2.06 (3H, m), 2.40 (3H, s), 2.92-3.07 (2H, m), 4.06-4.21 (2H, m), 5.14 (2H, s), 7.07 (1H, d, J = 8.3), 7.30-7.42 (5H, m), 10.92 (1H, br)
126b) 4-(5-メチル-1,3-ジオキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル)ピペリジン-1-カルボン酸ベンジル
126a)で得られた4-{[(2-メチル-1H-イミダゾール-4-イル)カルボニル]アミノ}ピペリジン-1-カルボン酸ベンジル(1.16g)の1,2-ジクロロエタン(20mL)溶液にN,N'-カルボニルジイミダゾール(1.65g)とDBU(3.0mL)を加え、還流下、3時間かき混ぜた。反応液をクロロホルムで希釈し、水、飽和食塩水で順次に洗浄し、無水硫酸ナトリウムで乾燥後、濃縮した。残留物をシリカゲルカラムにより精製し、題記化合物(0.43g, 34%)を無色固体として得た。
NMR (300MHz, CDCl₃)δ：1.69-1.81 (2H, m), 2.27-2.42 (2H, m), 2.67 (3H, s), 2.77-2.92 (2H, m), 4.14 (1H, m), 4.29-4.45 (2H, m), 5.15 (2H, s), 7.31-7.40 (6H, m)
126c) 2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-5-メチル-1H-イミダゾ[1,5-c]イミダゾール-1,3(2H)-ジオン
126b)で得た4-(5-メチル-1,3-ジオキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル)ピペリジン-1-カルボン酸ベンジル(0.38g)に25％臭化水素酢酸溶液(10mL)を加え1時間かき混ぜた。反応液を濃縮し、残留物とトリエチルアミン(0.53mL)をアセトニトリル(20mL)に溶かした。この溶液を3-[(6-クロロ-2-ナフチル)スルホニル]プロピオン酸(0.38g)、WSC(0.37g)およびHOBt(0.29g)のアセトニトリル(20mL)けん濁液へ加え、12時間かき混ぜた。反応液を濃縮し、残留物をクロロホルムと飽和重曹水に溶解した。クロロホルム層を分取して無水硫酸ナトリウムで乾燥後、減圧濃縮した。残留物をシリカゲルカラムにより精製し、題記化合物(0.42g, 65%)を無色固体として得た。
NMR (300MHz, CDCl₃)δ：1.74-1.90 (2H, m), 2.22-2.33 (2H, m), 2.55 (1H, m), 2.67 (3H, s), 2.88-3.02 (2H, m), 3.11 (1H, m), 3.52-3.67 (2H, m), 4.00 (1H, m), 4.12 (1H, m), 4.69 (1H, m), 7.34 (1H, s), 7.60 (1H, dd, J = 2.1, 8.7), 7.90-8.01 (4H, m), 8.49 (1H, s).
元素分析値 C₂₄H₂₃N₄O₅SCl・0.1iPr₂Oとして
計算値（％）：C, 56.26； H, 4.68； N, 11.67
実測値（％）：C, 56.41； H, 4.79； N, 11.03 Example 126
2- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -5-methyl-1H-imidazo [1,5-c] imidazole-1,3 (2H) -Zeon
126a) 4-{[(2-Methyl-1H-imidazol-4-yl) carbonyl] amino} piperidine-1-carboxylate benzyl
To a solution of benzyl 4-aminopiperidine-1-carboxylate (3.3 g) and 2-methyl-1H-imidazole-4-carboxylic acid (2.0 g) in acetonitrile (50 mL), WSC (4.0 g), HOBt (3.2 g) and Triethylamine (3.8 mL) was added and stirred for 12 hours. The reaction mixture was concentrated, and the residue was dissolved in chloroform and saturated aqueous sodium hydrogen carbonate. The chloroform layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (2.4 g, 49%) as a colorless powder.
NMR (300MHz, CDCl ₃ ) δ: 1.41-1.56 (2H, m), 1.93-2.06 (3H, m), 2.40 (3H, s), 2.92-3.07 (2H, m), 4.06-4.21 (2H, m ), 5.14 (2H, s), 7.07 (1H, d, J = 8.3), 7.30-7.42 (5H, m), 10.92 (1H, br)
126b) Benzyl 4- (5-methyl-1,3-dioxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl) piperidine-1-carboxylate
To a solution of benzyl 4-{[(2-methyl-1H-imidazol-4-yl) carbonyl] amino} piperidine-1-carboxylate (1.16 g) obtained in 126a) in 1,2-dichloroethane (20 mL) , N′-carbonyldiimidazole (1.65 g) and DBU (3.0 mL) were added, and the mixture was stirred under reflux for 3 hours. The reaction solution was diluted with chloroform, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column to give the title compound (0.43 g, 34%) as a colorless solid.
NMR (300MHz, CDCl ₃ ) δ: 1.69-1.81 (2H, m), 2.27-2.42 (2H, m), 2.67 (3H, s), 2.77-2.92 (2H, m), 4.14 (1H, m), 4.29-4.45 (2H, m), 5.15 (2H, s), 7.31-7.40 (6H, m)
126c) 2- (1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -5-methyl-1H-imidazo [1,5-c] imidazole-1,3 ( 2H) -Dione
126 (b) to 4- (5-methyl-1,3-dioxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl) piperidine-1-carboxylate (0.38 g) % Hydrogen bromide acetic acid solution (10 mL) was added and stirred for 1 hour. The reaction mixture was concentrated, and the residue and triethylamine (0.53 mL) were dissolved in acetonitrile (20 mL). This solution was added to a suspension of 3-[(6-chloro-2-naphthyl) sulfonyl] propionic acid (0.38 g), WSC (0.37 g) and HOBt (0.29 g) in acetonitrile (20 mL) and stirred for 12 hours. . The reaction mixture was concentrated, and the residue was dissolved in chloroform and saturated aqueous sodium hydrogen carbonate. The chloroform layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column to give the title compound (0.42 g, 65%) as a colorless solid.
NMR (300MHz, CDCl ₃ ) δ: 1.74-1.90 (2H, m), 2.22-2.33 (2H, m), 2.55 (1H, m), 2.67 (3H, s), 2.88-3.02 (2H, m), 3.11 (1H, m), 3.52-3.67 (2H, m), 4.00 (1H, m), 4.12 (1H, m), 4.69 (1H, m), 7.34 (1H, s), 7.60 (1H, dd, J = 2.1, 8.7), 7.90-8.01 (4H, m), 8.49 (1H, s).
Elemental analysis value Calculated as C ₂₄ H ₂₃ N ₄ O ₅ SCl · 0.1iPr ₂ O (%): C, 56.26; H, 4.68; N, 11.67
Found (%): C, 56.41; H, 4.79; N, 11.03

実施例127
2-(1-{3-[(7-クロロ-2H-クロメン-3-イル)スルホニル]プロパノイル}-4-ピペリジニル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
5-メチル-2-(4-ピペリジニル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン２塩酸塩(0.44g)と3-[(7-クロロ-2H-クロメン-3-イル)スルホニル]プロピオン酸(0.61g)のアセトニトリル(20mL)けん濁液へトリエチルアミン(0.56 mL)、WSC(0.57g)およびHOBt(0.46g)を加え、12時間かき混ぜた。反応液を濃縮し、残留物へクロロホルムと水を加え、クロロホルム層を分取した。クロロホルム溶液を無水硫酸ナトリウムで乾燥後、減圧濃縮した。残留物を酢酸エチルで結晶化させた後、粗結晶を酢酸エチル-メタノールから再結晶して、題記化合物(0.79g, 78%)を無色針状結晶として得た。
NMR (300MHz, CDCl₃)δ：1.50-1.72 (2H, m), 1.87-2.00 (2H, m), 2.61 (3H, s), 2.65 (1H, m), 2.81-2.93 (2H, m), 3.20 (1H, m), 3.38-3.57 (2H, m), 3.99 (1H, d, J = 11.1), 4.16 (1H, m), 4.22 (2H, s), 4.75 (1H, d, J = 11.1), 5.04 (1H, s), 6.72 (1H, s), 6.93 (1H, d, J = 1.5), 7.00 (1H, dd, J = 1.8, 7.8), 7.13 (1H, d, J = 7.8), 7.35 (1H, d, J = 1.8)
元素分析値 C₂₃H₂₅N₄O₅SClとして
計算値（％）：C, 54.70； H, 4.99； N, 11.90
実測値（％）：C, 54.55； H, 4.81； N, 11.24 Example 127
2- (1- {3-[(7-Chloro-2H-chromen-3-yl) sulfonyl] propanoyl} -4-piperidinyl) -5-methyl-1,2-dihydro-3H-imidazo [1,5- c] imidazol-3-one
5-methyl-2- (4-piperidinyl) -1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one dihydrochloride (0.44 g) and 3-[(7-chloro-2H -Chromen-3-yl) sulfonyl] propionic acid (0.61 g) in acetonitrile (20 mL) was added triethylamine (0.56 mL), WSC (0.57 g) and HOBt (0.46 g), and the mixture was stirred for 12 hours. The reaction solution was concentrated, chloroform and water were added to the residue, and the chloroform layer was separated. The chloroform solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was crystallized from ethyl acetate, and the crude crystal was recrystallized from ethyl acetate-methanol to give the title compound (0.79 g, 78%) as colorless needle crystals.
NMR (300MHz, CDCl ₃ ) δ: 1.50-1.72 (2H, m), 1.87-2.00 (2H, m), 2.61 (3H, s), 2.65 (1H, m), 2.81-2.93 (2H, m), 3.20 (1H, m), 3.38-3.57 (2H, m), 3.99 (1H, d, J = 11.1), 4.16 (1H, m), 4.22 (2H, s), 4.75 (1H, d, J = 11.1 ), 5.04 (1H, s), 6.72 (1H, s), 6.93 (1H, d, J = 1.5), 7.00 (1H, dd, J = 1.8, 7.8), 7.13 (1H, d, J = 7.8) , 7.35 (1H, d, J = 1.8)
Elemental analysis value Calculated as C ₂₃ H ₂₅ N ₄ O ₅ SCl (%): C, 54.70; H, 4.99; N, 11.90
Found (%): C, 54.55; H, 4.81; N, 11.24

実施例128
2-[1-(3-{[(E)-2-(4-クロロフェニル)ビニル]スルホニル}プロパノイル)-4-ピペリジニル]-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
5-メチル-2-(4-ピペリジニル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン２塩酸塩(0.44g)と実施例89a)で得られた3-{[(E)-2-(4-クロロフェニル)ビニル]スルホニル}プロピオン酸(0.55g)のアセトニトリル(20mL)けん濁液にトリエチルアミン(0.56mL)、WSC(0.57g)およびHOBt(0.46g)を加え、12時間かき混ぜた。反応液を濃縮し、残留物へクロロホルムと水を加え、クロロホルム層を分取した。クロロホルム溶液を無水硫酸ナトリウムで乾燥後、減圧濃縮した。残留物を塩基性シリカゲルカラムにより精製して、題記化合物(0.71g, 74%)を無色固体として得た。
NMR (300MHz, CDCl₃)δ：1.55-1.69 (2H, m), 1.88-1.98 (2H, m), 2.61 (3H, s), 2.65 (1H, m), 2.86-2.95 (2H, m), 3.20 (1H, m), 3.39-3.59 (2H, m), 4.00 (1H, d, J = 13.5), 4.15 (1H, m), 4.21 (2H, s), 4.75 (1H, d, J = 13.5), 6.71 (1H, s), 6.87 (1H, d, J = 15.3), 7.40-7.49 (4H, m), 7.56 (1H, d, J = 15.3)
元素分析値 C₂₂H₂₅N₄O₄SClとして
計算値（％）：C, 55.40； H, 5.28； N, 11.75
実測値（％）：C, 55.40； H, 5.28； N, 11.79 Example 128
2- [1- (3-{[(E) -2- (4-Chlorophenyl) vinyl] sulfonyl} propanoyl) -4-piperidinyl] -5-methyl-1,2-dihydro-3H-imidazo [1,5 -c] imidazol-3-one
3 obtained with 5-methyl-2- (4-piperidinyl) -1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one dihydrochloride (0.44 g) and Example 89a) -{[(E) -2- (4-chlorophenyl) vinyl] sulfonyl} propionic acid (0.55 g) in acetonitrile (20 mL) suspension in triethylamine (0.56 mL), WSC (0.57 g) and HOBt (0.46 g) And stirred for 12 hours. The reaction solution was concentrated, chloroform and water were added to the residue, and the chloroform layer was separated. The chloroform solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column to give the title compound (0.71 g, 74%) as a colorless solid.
NMR (300MHz, CDCl ₃ ) δ: 1.55-1.69 (2H, m), 1.88-1.98 (2H, m), 2.61 (3H, s), 2.65 (1H, m), 2.86-2.95 (2H, m), 3.20 (1H, m), 3.39-3.59 (2H, m), 4.00 (1H, d, J = 13.5), 4.15 (1H, m), 4.21 (2H, s), 4.75 (1H, d, J = 13.5 ), 6.71 (1H, s), 6.87 (1H, d, J = 15.3), 7.40-7.49 (4H, m), 7.56 (1H, d, J = 15.3)
Elemental analysis value Calculated as C ₂₂ H ₂₅ N ₄ O ₄ SCl (%): C, 55.40; H, 5.28; N, 11.75
Found (%): C, 55.40; H, 5.28; N, 11.79

実施例129
7-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-5-ヒドロキシ-3-メチル-6,7-ジヒドロイミダゾ[1,5-a]ピラジン-8(5H)-オン
129a) 4-[(2,2-ジメトキシエチル)アミノ]ピペリジン-1-カルボン酸tert-ブチル
4-アミノピペリジン-1-カルボン酸tert-ブチル(0.50g)、2-ブロモ-1,1-ジメトキシエタン(1.5mL)および炭酸カリウム(1.4g)のアセトニトリル(10mL)けん濁液を20時間加熱還流した。反応液を室温まで冷却し、セライトを用いてろ過した後、ろ液を減圧濃縮した。残留物をシリカゲルカラム（酢酸エチル）で精製し、題記化合物(0.35g, 49%)を淡黄色油状物として得た。
NMR (200MHz, CDCl₃)δ：1.09-1.35 (2H, m), 1.45 (9H, s), 1.80-1.86 (2H, m), 2.52-2.67 (1H, m), 2.75-2.84 (4H, m), 3.39 (6H, s), 4.04 (2H, d, J = 13.2), 4.45 (1H, t, J = 5.5).
129b) 4-{(2,2-ジメトキシエチル)[(2-メチル-1H-イミダゾール-4-イル)カルボニル]アミノ}ピペリジン-1-カルボン酸tert-ブチル
2-メチル-1H-イミダゾール-4-カルボン酸(1.4g)と実施例129a)で得た4-[(2,2-ジメトキシエチル)アミノ]ピペリジン-1-カルボン酸 tert-ブチル(3.3g)から実施例38b)と同様にして題記化合物(2.4g, 53%)を淡黄色油状物として得た。
NMR (200MHz, CDCl₃)δ：1.47 (9H, s), 1.77-1.86 (4H, m), 2.39-2.45 (3H, m), 2.71-2.82 (2H, m), 3.43 (6H, s), 3.57 (2H, bs), 4.22-4.42 (3H, m), 4.63 (1H, t, J = 4.7), 7.32-7.45 (1H, m).
129c) 5-ヒドロキシ-3-メチル-7-(4-ピペリジニル)-6,7-ジヒドロイミダゾ[1,5-a]ピラジン-8(5H)-オン２塩酸塩
実施例129b)で得た4-{(2,2-ジメトキシエチル)[(2-メチル-1H-イミダゾール-4-イル)カルボニル]アミノ}ピペリジン-1-カルボン酸 tert-ブチル(1.4g)を濃塩酸(3mL)に溶かし、室温で30分かき混ぜた。水分を減圧下にトルエンと共沸させることにより濃縮し、題記化合物（1.1g, 97%）を白色粉末として得た。
NMR (300MHz, DMSO-d₆)δ：1.66-1.78 (2H, m), 2.00-2.17 (2H, m), 2.79 (3H, s), 3.03 (2H, d, J= 11.9), 3.33 (2H, d, J = 11.9), 3.63 (1H, d, J = 13.1), 3.79 (1H, d, J = 13.1), 4.68-4.76 (1H, m), 6.15 (1H, s), 8.20 (1H, s).
129d) 7-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-5-ヒドロキシ-3-メチル-6,7-ジヒドロイミダゾ[1,5-a]ピラジン-8(5H)-オン
3-[(6-クロロ-2-ナフチル)スルホニル]プロピオン酸（0.56g）および実施例129c)で得た5-ヒドロキシ-3-メチル-7-(4-ピペリジニル)-6,7-ジヒドロイミダゾ[1,5-a]ピラジン-8(5H)-オン２塩酸塩（0.56g）から実施例128)と同様にして題記化合物（0.48g, 54%）を無色結晶として得た。
NMR (300MHz, CDCl₃)δ：1.42-1.66 (2H, m), 1.66-1.82 (2H, m), 2.28-2.30 (m, 3H), 2.59 (1H, t, J = 3.0), 2.78-2.97 (2H, m), 3.15 (1H, t, J = 13.0), 3.44-3.66 (4H, m), 3.90-3.95 (1H, m), 4.62-4.74 (2H, m), 5.65 (1H, d, J = 1.5), 7.39 (1H, d, J = 3.6), 7.59 (1H, dd, J = 8.7, 2.1), 7.88-7.97 (4H, m), 8.47 (1H, s).
元素分析値 C₂₅H₂₇ClN₄O₅S・0.5H₂O・0.1EtOAcとして
計算値（％）：C, 55.58； H, 5.29； N, 10.21
実測値（％）：C, 55.80； H, 5.48； N, 9.91 Example 129
7- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -5-hydroxy-3-methyl-6,7-dihydroimidazo [1,5-a] pyrazine -8 (5H) -ON
129a) tert-Butyl 4-[(2,2-dimethoxyethyl) amino] piperidine-1-carboxylate
A suspension of tert-butyl 4-aminopiperidine-1-carboxylate (0.50 g), 2-bromo-1,1-dimethoxyethane (1.5 mL) and potassium carbonate (1.4 g) in acetonitrile (10 mL) is heated for 20 hours. Refluxed. The reaction solution was cooled to room temperature and filtered using Celite, and then the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column (ethyl acetate) to give the title compound (0.35 g, 49%) as a pale yellow oil.
NMR (200MHz, CDCl ₃ ) δ: 1.09-1.35 (2H, m), 1.45 (9H, s), 1.80-1.86 (2H, m), 2.52-2.67 (1H, m), 2.75-2.84 (4H, m ), 3.39 (6H, s), 4.04 (2H, d, J = 13.2), 4.45 (1H, t, J = 5.5).
129b) tert-butyl 4-{(2,2-dimethoxyethyl) [(2-methyl-1H-imidazol-4-yl) carbonyl] amino} piperidine-1-carboxylate
2-methyl-1H-imidazole-4-carboxylic acid (1.4 g) and 4-[(2,2-dimethoxyethyl) amino] piperidine-1-carboxylic acid tert-butyl (3.3 g) obtained in Example 129a) To give the title compound (2.4 g, 53%) as a pale yellow oil in the same manner as in Example 38b).
NMR (200MHz, CDCl ₃ ) δ: 1.47 (9H, s), 1.77-1.86 (4H, m), 2.39-2.45 (3H, m), 2.71-2.82 (2H, m), 3.43 (6H, s), 3.57 (2H, bs), 4.22-4.42 (3H, m), 4.63 (1H, t, J = 4.7), 7.32-7.45 (1H, m).
129c) 5-hydroxy-3-methyl-7- (4-piperidinyl) -6,7-dihydroimidazo [1,5-a] pyrazin-8 (5H) -one dihydrochloride obtained in Example 129b) -{(2,2-dimethoxyethyl) [(2-methyl-1H-imidazol-4-yl) carbonyl] amino} piperidine-1-carboxylate tert-butyl (1.4 g) was dissolved in concentrated hydrochloric acid (3 mL), Stir at room temperature for 30 minutes. Water was concentrated by azeotroping with toluene under reduced pressure to give the title compound (1.1 g, 97%) as a white powder.
NMR (300MHz, DMSO-d ₆ ) δ: 1.66-1.78 (2H, m), 2.00-2.17 (2H, m), 2.79 (3H, s), 3.03 (2H, d, J = 11.9), 3.33 (2H , d, J = 11.9), 3.63 (1H, d, J = 13.1), 3.79 (1H, d, J = 13.1), 4.68-4.76 (1H, m), 6.15 (1H, s), 8.20 (1H, s).
129d) 7- (1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -5-hydroxy-3-methyl-6,7-dihydroimidazo [1,5-a ] Pyrazine-8 (5H) -one
3-[(6-Chloro-2-naphthyl) sulfonyl] propionic acid (0.56 g) and 5-hydroxy-3-methyl-7- (4-piperidinyl) -6,7-dihydroimidazo obtained in Example 129c) The title compound (0.48 g, 54%) was obtained as colorless crystals from [1,5-a] pyrazin-8 (5H) -one dihydrochloride (0.56 g) in the same manner as in Example 128).
NMR (300MHz, CDCl ₃ ) δ: 1.42-1.66 (2H, m), 1.66-1.82 (2H, m), 2.28-2.30 (m, 3H), 2.59 (1H, t, J = 3.0), 2.78-2.97 (2H, m), 3.15 (1H, t, J = 13.0), 3.44-3.66 (4H, m), 3.90-3.95 (1H, m), 4.62-4.74 (2H, m), 5.65 (1H, d, J = 1.5), 7.39 (1H, d, J = 3.6), 7.59 (1H, dd, J = 8.7, 2.1), 7.88-7.97 (4H, m), 8.47 (1H, s).
Elemental analysis _{_{_{_{C 25 H 27 ClN 4 O 5}}}} S · 0.5H calcd _{2 O · 0.1EtOAc (%):} C, 55.58; H, 5.29; N, 10.21
Found (%): C, 55.80; H, 5.48; N, 9.91

実施例130
2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
130a) 4-[(1H-イミダゾール-4-イルメチル)アミノ]ピペリジン-1-カルボン酸 tert-ブチル
4-アミノピペリジン-1-カルボン酸tert-ブチル(2.1g)およびイミダゾール-4-カルバルデヒド(1.0g)から実施例42a)と同様にして題記化合物(2.4g, 82%)を黄色油状物として得た。
NMR (200MHz, CDCl₃)δ：1.18-1.38 (2H, m), 1.45 (9H, s), 1.86 (2H, d, J = 12.3), 2.61-2.85 (3H, m), 3.82 (2H, m), 4.03 (2H, d, J = 12.3), 6.89 (1H, s), 7.57 (1H, s).
130b) 4-(3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル)ピペリジン-1-カルボン酸tert-ブチル
130a)で得た4-[(1H-イミダゾール-4-イル)メチルアミノ]ピペリジン-1-カルボン酸tert-ブチル(2.4g)から実施例42b)と同様にして、題記化合物(1.8g, 70%)を白色固体として得た。
NMR (300MHz, CDCl₃)δ：1.48 (9H, s), 1.58-1.70 (2H, m), 1.71-1.88 (2H, m), 2.83 (2H, t, J = 12.6), 4.08-4.18 (1H, m), 4.27 (2H, d, J = 10.8), 4.36 (2H, s), 6.91 (1H, s), 7.94 (1H, s).
130c) 2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
3-[(6-クロロ-2-ナフチル)スルホニル]プロピオン酸(1.7g)および130b)で得た4-(3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル)ピペリジン-1-カルボン酸tert-ブチル(1.6g)から実施例38d)と同様にして題記化合物(2.0g, 72%)を無色結晶として得た。
NMR (300MHz, CDCl₃)δ：1.58-1.82 (2H, m), 1.88-2.04 (2H, m), 2.64 (1H, t, J = 12.6), 2.85-3.05 (2H, m), 3.20 (1H, t, J = 12.6), 3.43-3.64 (2H, m), 4.03 (1H, d, J = 14.1), 4.15-4.27 (1H, m), 4.33 (2H, s), 4.74 (1H, d, J = 14.1), 6.92 (1H, d J = 1.0), 7.60 (1H, dd, J = 8.8, 1.8), 7.89-7.98 (5H, m), 8.49 (1H, s).
元素分析値 C₂₃H₂₃ClN₄O₄Sとして
計算値（％）：C, 56.73; H, 4.76; N, 11.51
実測値（％）：C, 56.36; H, 4.67; N, 11.37 Example 130
2- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one
130a) tert-Butyl 4-[(1H-imidazol-4-ylmethyl) amino] piperidine-1-carboxylate
The title compound (2.4 g, 82%) was obtained as a yellow oil from tert-butyl 4-aminopiperidine-1-carboxylate (2.1 g) and imidazole-4-carbaldehyde (1.0 g) in the same manner as in Example 42a). Obtained.
NMR (200MHz, CDCl ₃ ) δ: 1.18-1.38 (2H, m), 1.45 (9H, s), 1.86 (2H, d, J = 12.3), 2.61-2.85 (3H, m), 3.82 (2H, m ), 4.03 (2H, d, J = 12.3), 6.89 (1H, s), 7.57 (1H, s).
130b) tert-Butyl 4- (3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl) piperidine-1-carboxylate
The title compound (1.8 g, 70) was obtained in the same manner as in Example 42b) from tert-butyl 4-[(1H-imidazol-4-yl) methylamino] piperidine-1-carboxylate (2.4 g) obtained in 130a). %) Was obtained as a white solid.
NMR (300MHz, CDCl ₃ ) δ: 1.48 (9H, s), 1.58-1.70 (2H, m), 1.71-1.88 (2H, m), 2.83 (2H, t, J = 12.6), 4.08-4.18 (1H m), 4.27 (2H, d, J = 10.8), 4.36 (2H, s), 6.91 (1H, s), 7.94 (1H, s).
130c) 2- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -1,2-dihydro-3H-imidazo [1,5-c] imidazole-3- on
4- (3-oxo-1H-imidazo [1,5-c] imidazole-2 (3H)-obtained with 3-[(6-chloro-2-naphthyl) sulfonyl] propionic acid (1.7 g) and 130b) Yl) The title compound (2.0 g, 72%) was obtained as colorless crystals from tert-butyl piperidine-1-carboxylate (1.6 g) in the same manner as in Example 38d).
NMR (300MHz, CDCl ₃ ) δ: 1.58-1.82 (2H, m), 1.88-2.04 (2H, m), 2.64 (1H, t, J = 12.6), 2.85-3.05 (2H, m), 3.20 (1H , t, J = 12.6), 3.43-3.64 (2H, m), 4.03 (1H, d, J = 14.1), 4.15-4.27 (1H, m), 4.33 (2H, s), 4.74 (1H, d, J = 14.1), 6.92 (1H, d J = 1.0), 7.60 (1H, dd, J = 8.8, 1.8), 7.89-7.98 (5H, m), 8.49 (1H, s).
Elemental analysis value Calculated as C ₂₃ H ₂₃ ClN ₄ O ₄ S (%): C, 56.73; H, 4.76; N, 11.51
Found (%): C, 56.36; H, 4.67; N, 11.37

実施例131
6-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-7,8-ジヒドロイミダゾ[1,5-c]ピリミジン-5(6H)-オン
131a) 4-(5-オキソ-7,8-ジヒドロイミダゾ[1,5-c]ピリミジン-6(5H)-イル)ピペリジン-1-カルボン酸 tert-ブチル
4-オキソピペリジン-1-カルボン酸tert-ブチル(10.8g)、ヒスタミン２塩酸塩(10.0g)のジクロロエタン(300mL)溶液にトリアセトキシ水素化ホウ素ナトリウム(17.3g)を加え、室温で15時間かき混ぜた。反応液に1N水酸化ナトリウム水溶液を加えpH12程度に調節した後、クロロホルム(100mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥した後、溶媒を減圧留去した。得られた黄色油状物をジクロロメタン(300mL)に溶かし、その溶液へDBU(13.4mL)およびN,N'-カルボニルジイミダゾール(7.64g)を加え、室温で15時間かき混ぜた。反応混合物を水とクロロホルムで希釈し、有機層を分取した後、無水硫酸マグネシウムで乾燥し、溶媒を減圧濃縮した。残留物をシリカゲルカラム（酢酸エチル：エタノール＝５：１）で精製して、題記化合物(13.4g, 77%)を無色油状物として得た。
NMR (200MHz, CDCl₃)δ：1.49 (9H, s), 1.54-1.79 (4H, m), 2.78-2.99 (4H, m), 3.43 (2H, t, J = 6.4), 4.26 (2H, d, J = 12.4), 4.48-4.64 (1H, m), 6.81 (1H, d, J = 1.1), 8.14 (1H, d, J = 1.1).
131b) 6-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-7,8-ジヒドロイミダゾ[1,5-c]ピリミジン-5(6H)-オン
3-[(6-クロロ-2-ナフチル)スルホニル]プロピオン酸(0.26g)および実施例131a)で得た4-(5-オキソ-7,8-ジヒドロイミダゾ[1,5-c]ピリミジン-6(5H)-イル)ピペリジン-1-カルボン酸tert-ブチル(0.25g)から実施例38d)と同様にして題記化合物(0.27g, 64%)を無色結晶として得た。
NMR (200MHz, CDCl₃)δ：1.60-1.85 (5H, m), 2.59-2.70 (1H, m), 2.84-2.99 (3H, m), 3.13-3.26 (1H, m), 3.40 (2H, t, J = 6.4), 3.50-3.65 (2H, m), 4.02 (1H, d, J = 14.0), 4.58-4.74 (2H, m), 6.82 (1H, s), 7.61 (1H, dd, J = 8.8, 1.8), 7.94-7.98 (4H, m), 8.14 (1H, s), 8.49 (1H, s).
元素分析値 C₂₄H₂₅ClN₄O₄Sとして
計算値（％）：C, 57.54; H, 5.03; N, 11.18
実測値（％）：C, 57.32; H, 5.05; N, 10.91 Example 131
6- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -7,8-dihydroimidazo [1,5-c] pyrimidin-5 (6H) -one
131a) 4- (5-oxo-7,8-dihydroimidazo [1,5-c] pyrimidin-6 (5H) -yl) piperidine-1-carboxylate tert-butyl
To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (10.8 g) and histamine dihydrochloride (10.0 g) in dichloroethane (300 mL), add sodium triacetoxyborohydride (17.3 g) and stir at room temperature for 15 hours. It was. The reaction solution was adjusted to pH 12 by adding 1N aqueous sodium hydroxide solution, and extracted with chloroform (100 mL). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained yellow oil was dissolved in dichloromethane (300 mL), DBU (13.4 mL) and N, N′-carbonyldiimidazole (7.64 g) were added to the solution, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and chloroform, the organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column (ethyl acetate: ethanol = 5: 1) to give the title compound (13.4 g, 77%) as a colorless oil.
NMR (200MHz, CDCl ₃ ) δ: 1.49 (9H, s), 1.54-1.79 (4H, m), 2.78-2.99 (4H, m), 3.43 (2H, t, J = 6.4), 4.26 (2H, d , J = 12.4), 4.48-4.64 (1H, m), 6.81 (1H, d, J = 1.1), 8.14 (1H, d, J = 1.1).
131b) 6- (1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -7,8-dihydroimidazo [1,5-c] pyrimidine-5 (6H)- on
4- [5-oxo-7,8-dihydroimidazo [1,5-c] pyrimidine- from 3-[(6-chloro-2-naphthyl) sulfonyl] propionic acid (0.26 g) and Example 131a) The title compound (0.27 g, 64%) was obtained as colorless crystals from tert-butyl 6 (5H) -yl) piperidine-1-carboxylate (0.25 g) in the same manner as in Example 38d).
NMR (200MHz, CDCl ₃ ) δ: 1.60-1.85 (5H, m), 2.59-2.70 (1H, m), 2.84-2.99 (3H, m), 3.13-3.26 (1H, m), 3.40 (2H, t , J = 6.4), 3.50-3.65 (2H, m), 4.02 (1H, d, J = 14.0), 4.58-4.74 (2H, m), 6.82 (1H, s), 7.61 (1H, dd, J = 8.8, 1.8), 7.94-7.98 (4H, m), 8.14 (1H, s), 8.49 (1H, s).
Elemental analysis value Calculated as C ₂₄ H ₂₅ ClN ₄ O ₄ S (%): C, 57.54; H, 5.03; N, 11.18
Found (%): C, 57.32; H, 5.05; N, 10.91

実施例132
2-(1-{3-[(5-クロロ-1H-インドール-2-イル)スルホニル]プロパノイル}-4-ピペリジニル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
132a) 5-クロロ-2-({3-[4-(5-メチル-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル)-1-ピペリジニル]-3-オキソプロピル}スルホニル)-1H-インドール-1-カルボン酸tert-ブチル
3-{[1-(tert-ブトキシカルボニル)-5-クロロ-1H-インドール-2-イル]スルホニル}プロピオン酸(5.00 g)および実施例69b)で得られた5-メチル-2-(4-ピペリジニル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン２塩酸塩(2.8g)から実施例128)と同様にして題記化合物(2.9g, 38%)を白色固体として得た。
NMR (300MHz, CDCl₃)δ：1.54-1.71 (2H, m), 1.74 (9H, s), 1.85-1.98 (2H, m), 2.59-2.67 (4H, m), 2.88-3.00 (2H, m), 3.18 (1H, t, J = 12.2), 3.98-4.20 (4H, m), 4.26 (2H, s), 4.72 (1H, d, J = 13.5), 6.71 (1H, t, J = 1.5), 7.44 (1H, dd, J = 9.0, 2.4), 7.51 (1H, s), 7.65 (1H, d, J = 2.4), 7.98 (1H, d, J = 9.0).
132b) 2-(1-{3-[(5-クロロ-1H-インドール-2-イル)スルホニル]プロパノイル}-4-ピペリジニル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
実施例132a)で得た5-クロロ-2-({3-[4-(5-メチル-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル)-1-ピペリジニル]-3-オキソプロピル}スルホニル)-1H-インドール-1-カルボン酸tert-ブチル(2.9g)から実施例103b)と同様にして題記化合物(2.0g, 83%)を無色結晶として得た。
NMR (300MHz, CDCl₃)δ：1.49-2.04 (2H, m), 2.61-2.70 (4H, m), 2.81-3.06 (2H, m), 3.20 (1H, t, J = 12.3), 3.56-3.65 (1H, m), 3.73-3.83 (1H, m), 3.98 (1H, d, J = 14.7), 4.08-4.17 (1H, m), 4.22 (2H, s), 4.72 (1H, d, J = 13.8), 6.71 (1H, s), 7.15 (1H, d, J = 1.8 ), 7.33 (1H, dd, J = 9.0, 1.8), 7.42 (1H, d, J = 9.0), 7.69 (1H, d, J = 1.8).
元素分析値 C₂₂H₂₄ClN₅O₄S・0.5H₂Oとして
計算値（％）：C, 52.95; H, 5.05; N, 14.04
実測値（％）：C, 53.05; H, 4.89; N, 14.03 Example 132
2- (1- {3-[(5-Chloro-1H-indol-2-yl) sulfonyl] propanoyl} -4-piperidinyl) -5-methyl-1,2-dihydro-3H-imidazo [1,5- c] imidazol-3-one
132a) 5-chloro-2-({3- [4- (5-methyl-3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl) -1-piperidinyl] -3 -Oxopropyl} sulfonyl) -1H-indole-1-carboxylate tert-butyl
3-{[1- (tert-butoxycarbonyl) -5-chloro-1H-indol-2-yl] sulfonyl} propionic acid (5.00 g) and 5-methyl-2- (4 -Piperidinyl) -1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one dihydrochloride (2.8 g) in the same manner as in Example 128) to give the title compound (2.9 g, 38%) Was obtained as a white solid.
NMR (300MHz, CDCl ₃ ) δ: 1.54-1.71 (2H, m), 1.74 (9H, s), 1.85-1.98 (2H, m), 2.59-2.67 (4H, m), 2.88-3.00 (2H, m ), 3.18 (1H, t, J = 12.2), 3.98-4.20 (4H, m), 4.26 (2H, s), 4.72 (1H, d, J = 13.5), 6.71 (1H, t, J = 1.5) , 7.44 (1H, dd, J = 9.0, 2.4), 7.51 (1H, s), 7.65 (1H, d, J = 2.4), 7.98 (1H, d, J = 9.0).
132b) 2- (1- {3-[(5-Chloro-1H-indol-2-yl) sulfonyl] propanoyl} -4-piperidinyl) -5-methyl-1,2-dihydro-3H-imidazo [1, 5-c] imidazol-3-one 5-chloro-2-({3- [4- (5-methyl-3-oxo-1H-imidazo [1,5-c] imidazole-) obtained in Example 132a) 2 (3H) -yl) -1-piperidinyl] -3-oxopropyl} sulfonyl) -1H-indole-1-carboxylate from tert-butyl (2.9 g) in the same manner as Example 103b) in the same manner as the title compound (2.0 g , 83%) as colorless crystals.
NMR (300MHz, CDCl ₃ ) δ: 1.49-2.04 (2H, m), 2.61-2.70 (4H, m), 2.81-3.06 (2H, m), 3.20 (1H, t, J = 12.3), 3.56-3.65 (1H, m), 3.73-3.83 (1H, m), 3.98 (1H, d, J = 14.7), 4.08-4.17 (1H, m), 4.22 (2H, s), 4.72 (1H, d, J = 13.8), 6.71 (1H, s), 7.15 (1H, d, J = 1.8), 7.33 (1H, dd, J = 9.0, 1.8), 7.42 (1H, d, J = 9.0), 7.69 (1H, d , J = 1.8).
Elemental analysis value Calculated as C ₂₂ H ₂₄ ClN ₅ O ₄ S · 0.5H ₂ O (%): C, 52.95; H, 5.05; N, 14.04
Found (%): C, 53.05; H, 4.89; N, 14.03

実施例133
2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}ピロリジン-3-イル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
133a) 2-(1-ベンジルピロリジン-3-イル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
1-ベンジル-3-ピロリジンアミン(14.1g)およびイミダゾール-2-カルバルデヒド(7.7g)から実施例69a)と同様にして題記化合物(2.7g, 12%)を黄色油状物として得た。
NMR (300MHz, CDCl₃) δ: 1.79-1.90 (1H, m), 2.24-2.41 (2H, m), 2.45-2.51 (1H, m), 2.80 (1H, d, J = 10.5), 3.02-3.09 (1H, m), 3.51 (1H, d, J = 12.6), 3.70 (1H, d, J = 12.6), 4.49 (2H, s), 4.79-4.86 (1H, m), 7.16 (1H, d, J = 1.5), 7.22-7.35 (6H, m).
133b) 6-(3-ピロリジニル)-6,7-ジヒドロ-5H-イミダゾ[1,5-a]イミダゾール-5-オン
133a)で得た2-(1-ベンジルピロリジン-3-イル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン(2.7g)、ぎ酸アンモニウム(1.8g)および10% パラジウム炭素(0.54g)をメタノール(100mL)にけん濁し、2時間加熱還流した。室温まで冷却した後、沈殿物をセライトを用いてろ過し、ろ液を減圧濃縮した。残留物に酢酸エチル：クロロホルム＝５：１の混合溶媒を加え、沈殿物をろ別した後、ろ液を再び濃縮して、題記化合物(1.4g, 78%)を淡黄色固体として得た。
NMR (300MHz, CDCl₃)δ：1.85-1.96 (1H, m), 2.18-2.30 (1H, m), 2.96-3.07 (2H, m), 3.15-3.28 (2H, m), 4.42 (1H, d, J = 16.8), 4.49 (1H, d, J = 16.8), 4.65-4.74 (1H, m), 7.19 (1H, d, J = 1.2), 7.30 (1H, d, J = 1.2).
133c) 2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}ピロリジン-3-イル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
3-[(6-クロロ-2-ナフチル)スルホニル]プロピオン酸(0.51g)および実施例133b)で得た6-(3-ピロリジニル)-6,7-ジヒドロ-5H-イミダゾ[1,5-a]イミダゾール-5-オン(0.50g)から実施例89b)と同様にして題記化合物(0.47g, 56%)を無色結晶として得た。
NMR (300MHz, CDCl₃)δ：2.07-2.39 (2H, m), 2.59-2.61 (3H, m), 2.72-2.94 (2H, m), 3.38-3.87 (6H, m), 4.30 (1H, m), 4.36 (1H, s), 4.60-4.76 (1H, m), 6.69-6.71 (1H, m), 7.57-7.60 (1H, m), 7.88-7.96 (4H, m), 8.47 (1H, s).
元素分析値 C₂₃H₂₃ClN₄O₄S・0.5H₂O・0.3EtOAcとして
計算値（％）：C, 55.64; H, 5.09; N, 10.72
実測値（％）：C, 55.64; H, 5.00; N, 10.62 Example 133
2- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} pyrrolidin-3-yl) -5-methyl-1,2-dihydro-3H-imidazo [1,5-c] imidazole -3- ON
133a) 2- (1-Benzylpyrrolidin-3-yl) -5-methyl-1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one
The title compound (2.7 g, 12%) was obtained as a yellow oil from 1-benzyl-3-pyrrolidinamine (14.1 g) and imidazole-2-carbaldehyde (7.7 g) in the same manner as in Example 69a).
NMR (300MHz, CDCl ₃ ) δ: 1.79-1.90 (1H, m), 2.24-2.41 (2H, m), 2.45-2.51 (1H, m), 2.80 (1H, d, J = 10.5), 3.02-3.09 (1H, m), 3.51 (1H, d, J = 12.6), 3.70 (1H, d, J = 12.6), 4.49 (2H, s), 4.79-4.86 (1H, m), 7.16 (1H, d, J = 1.5), 7.22-7.35 (6H, m).
133b) 6- (3-Pyrrolidinyl) -6,7-dihydro-5H-imidazo [1,5-a] imidazol-5-one
2- (1-Benzylpyrrolidin-3-yl) -5-methyl-1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one (2.7 g) obtained in 133a), formic acid Ammonium (1.8 g) and 10% palladium carbon (0.54 g) were suspended in methanol (100 mL) and heated to reflux for 2 hours. After cooling to room temperature, the precipitate was filtered using celite, and the filtrate was concentrated under reduced pressure. To the residue was added a mixed solvent of ethyl acetate: chloroform = 5: 1, the precipitate was filtered off, and the filtrate was concentrated again to obtain the title compound (1.4 g, 78%) as a pale yellow solid.
NMR (300MHz, CDCl ₃ ) δ: 1.85-1.96 (1H, m), 2.18-2.30 (1H, m), 2.96-3.07 (2H, m), 3.15-3.28 (2H, m), 4.42 (1H, d , J = 16.8), 4.49 (1H, d, J = 16.8), 4.65-4.74 (1H, m), 7.19 (1H, d, J = 1.2), 7.30 (1H, d, J = 1.2).
133c) 2- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} pyrrolidin-3-yl) -5-methyl-1,2-dihydro-3H-imidazo [1,5-c ] Imidazole-3-one
3-[(6-Chloro-2-naphthyl) sulfonyl] propionic acid (0.51 g) and 6- (3-pyrrolidinyl) -6,7-dihydro-5H-imidazo [1,5- a] The title compound (0.47 g, 56%) was obtained as colorless crystals in the same manner as in Example 89b) from imidazol-5-one (0.50 g).
NMR (300MHz, CDCl ₃ ) δ: 2.07-2.39 (2H, m), 2.59-2.61 (3H, m), 2.72-2.94 (2H, m), 3.38-3.87 (6H, m), 4.30 (1H, m ), 4.36 (1H, s), 4.60-4.76 (1H, m), 6.69-6.71 (1H, m), 7.57-7.60 (1H, m), 7.88-7.96 (4H, m), 8.47 (1H, s ).
Elemental analysis _{_{_{_{C 23 H 23 ClN 4 O 4}}}} S · 0.5H calcd _{2 O · 0.3EtOAc (%):} C, 55.64; H, 5.09; N, 10.72
Found (%): C, 55.64; H, 5.00; N, 10.62

実施例134
2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
134a) 3-[(6-クロロ-2-ナフチル)チオ]-2-ヒドロキシプロピオン酸エチルおよび2-[(6-クロロ-2-ナフチル)チオ]-3-ヒドロキシプロピオン酸エチル
オキシラン-2-カルボン酸エチル (W. D. Emmons et al. J. Am. Chem. Soc., 77, 89, (1955)) (0.60g)、6-クロロナフタレン-2-チオール(1.0g)およびトリエチルアミン(1.4mL)のDMF(10mL)溶液をアルゴン雰囲気下60℃で3時間かき混ぜた。反応液を室温まで冷却した後、酢酸エチル(50mL)および水(50mL)を加えた。有機層を分液し、飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、減圧濃縮した。残留物をシリカゲルカラム（ヘキサン：酢酸エチル＝１：１から１：２）により精製した。第一分画より題記化合物(0.27g, 17%)を白色固体として得た。
NMR (300MHz, CDCl₃)δ：1.18 (3H, t, J = 7.1), 3.21 (1H, d, J = 6.2), 3.37 (1H, dd, J = 13.8, 5.4), 3.49 (1H, dd, J = 13.8, 4.2), 3.93-4.04 (1H, m), 4.06-4.17 (1H, m), 4.42-4.47 (1H, m), 7.40 (1H, dd, J = 8.7, 1.8), 7.50 (1H, dd, J = 8.7, 1.8), 7.65 (1H, d, J = 3.0), 7.67 (1H, d, J = 3.0), 7.75 (1H, s), 7.83 (1H, s).
第二分画より2-[(6-クロロ-2-ナフチル)チオ]-3-ヒドロキシプロピオン酸エチル(0.31g, 19%)を無色油状物として得た。
NMR (300MHz, CDCl₃)δ：1.22 (3H, t, J = 7.2), 2.39-2.44 (1H, m), 3.87-4.01 (3H, m), 4.14-4.24 (2H, m), 7.44 (1H, dd, J = 8.7, 2.1), 7.54 (1H, dd, J = 8.7, 1.8), 7.69 (1H, d, J = 3.2), 7.72 (1H, d, J = 3.2), 7.79 (1H, d, J = 2.1), 7.95 (1H, d, J = 1.8).
134b) 2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン塩酸塩
実施例134a)で得られた3-[(6-クロロ-2-ナフチル)チオ]-2-ヒドロキシプロピオン酸エチル(0.27g)のエタノール(2mL)溶液に1N水酸化ナトリウム水溶液(1.7mL)を加え、室温で2時間かき混ぜた。反応液を1N塩酸で中和した後、減圧濃縮した。残留物を酢酸エチルと水で希釈し、有機層を分液し、飽和食塩水で洗浄した。酢酸エチル溶液を無水硫酸マグネシウムで乾燥し、減圧濃縮した。得られた残留物と実施例69b)で得られた5-メチル-2-(4-ピペリジニル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン２塩酸塩（0.29g）、HOBt（0.16g）、DBU（0.24mL）およびトリエチルアミン（0.34mL）をアセトニトリル（3mL）に溶かし、WSC（0.20g）を加え室温で5時間かき混ぜた。反応液を濃縮し、残留物をクロロホルムと水で希釈した。有機層分液し、飽和食塩水で洗浄した。クロロホルム溶液を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残留物をクロロホルムに溶かし、メタクロロ過安息香酸（0.15g）を加え、室温で3時間かき混ぜた。反応液をクロロホルムとチオ硫酸ナトリウム水溶液で希釈した。有機層を分液し、飽和炭酸水素ナトリウム水溶液および飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥し、減圧濃縮した。残留物を分取HPLCにより精製し、4N塩化水素酢酸エチル溶液(0.5mL)で処理して、題記化合物（0.033g, 11%）を白色固体として得た。
NMR (300MHz, CDCl₃)δ：1.52-1.57 (1H, m), 1.71-1.87 (2H, m), 2.45-2.73 (4H, m), 3.14-3.67 (3H, m), 3.80 (1H, dd, J = 15.2, 4.1), 4.05-4.07 (2H, m), 4.33 (1H, d, J = 12.6), 4.54 (2H, d, J = 9.9), 4.79-4.81 (1H, m), 7.43 (1H, d, J = 12.9), 7.72 (1H, d, J = 9.0), 7.98 (1H, d, J = 8.7), 8.15 (1H, d, J = 9.0), 8.24-8.28 (2H, m), 8.62 (1H, s).
元素分析値 C₂₄H₂₅ClN₄O₅S・HCl・H₂O・0.2Et₂Oとして
計算値（％）：C, 50.98; H, 5.18; N, 9.59
実測値（％）：C, 51.16; H, 5.44; N, 9.49 Example 134
2- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -5-methyl-1,2-dihydro-3H-imidazo [1,5 -c] imidazol-3-one
134a) Ethyl 3-[(6-chloro-2-naphthyl) thio] -2-hydroxypropionate and ethyl 2-[(6-chloro-2-naphthyl) thio] -3-hydroxypropionate Oxirane-2-carvone DMF of ethyl acid (WD Emmons et al. J. Am. Chem. Soc., 77, 89, (1955)) (0.60 g), 6-chloronaphthalene-2-thiol (1.0 g) and triethylamine (1.4 mL) The (10 mL) solution was stirred at 60 ° C. for 3 hours under an argon atmosphere. After the reaction solution was cooled to room temperature, ethyl acetate (50 mL) and water (50 mL) were added. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column (hexane: ethyl acetate = 1: 1 to 1: 2). The title compound (0.27 g, 17%) was obtained as a white solid from the first fraction.
NMR (300 MHz, CDCl ₃ ) δ: 1.18 (3H, t, J = 7.1), 3.21 (1H, d, J = 6.2), 3.37 (1H, dd, J = 13.8, 5.4), 3.49 (1H, dd, J = 13.8, 4.2), 3.93-4.04 (1H, m), 4.06-4.17 (1H, m), 4.42-4.47 (1H, m), 7.40 (1H, dd, J = 8.7, 1.8), 7.50 (1H , dd, J = 8.7, 1.8), 7.65 (1H, d, J = 3.0), 7.67 (1H, d, J = 3.0), 7.75 (1H, s), 7.83 (1H, s).
From the second fraction, ethyl 2-[(6-chloro-2-naphthyl) thio] -3-hydroxypropionate (0.31 g, 19%) was obtained as a colorless oil.
NMR (300MHz, CDCl ₃ ) δ: 1.22 (3H, t, J = 7.2), 2.39-2.44 (1H, m), 3.87-4.01 (3H, m), 4.14-4.24 (2H, m), 7.44 (1H , dd, J = 8.7, 2.1), 7.54 (1H, dd, J = 8.7, 1.8), 7.69 (1H, d, J = 3.2), 7.72 (1H, d, J = 3.2), 7.79 (1H, d , J = 2.1), 7.95 (1H, d, J = 1.8).
134b) 2- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -5-methyl-1,2-dihydro-3H-imidazo [1 , 5-c] imidazol-3-one hydrochloride Ethyl 3-[(6-chloro-2-naphthyl) thio] -2-hydroxypropionate (0.27 g) obtained in Example 134a) in ethanol (2 mL) To the solution was added 1N aqueous sodium hydroxide solution (1.7 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was neutralized with 1N hydrochloric acid and concentrated under reduced pressure. The residue was diluted with ethyl acetate and water, and the organic layer was separated and washed with saturated brine. The ethyl acetate solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue and 5-methyl-2- (4-piperidinyl) -1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one dihydrochloride obtained in Example 69b) (0.29 g), HOBt (0.16 g), DBU (0.24 mL) and triethylamine (0.34 mL) were dissolved in acetonitrile (3 mL), WSC (0.20 g) was added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated and the residue was diluted with chloroform and water. The organic layer was separated and washed with saturated brine. The chloroform solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in chloroform, metachloroperbenzoic acid (0.15 g) was added, and the mixture was stirred at room temperature for 3 hr. The reaction solution was diluted with chloroform and aqueous sodium thiosulfate solution. The organic layer was separated, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC and treated with 4N hydrogen chloride ethyl acetate solution (0.5 mL) to give the title compound (0.033 g, 11%) as a white solid.
NMR (300MHz, CDCl ₃ ) δ: 1.52-1.57 (1H, m), 1.71-1.87 (2H, m), 2.45-2.73 (4H, m), 3.14-3.67 (3H, m), 3.80 (1H, dd , J = 15.2, 4.1), 4.05-4.07 (2H, m), 4.33 (1H, d, J = 12.6), 4.54 (2H, d, J = 9.9), 4.79-4.81 (1H, m), 7.43 ( 1H, d, J = 12.9), 7.72 (1H, d, J = 9.0), 7.98 (1H, d, J = 8.7), 8.15 (1H, d, J = 9.0), 8.24-8.28 (2H, m) , 8.62 (1H, s).
Elemental analysis _{_{_{_{C 24 H 25 ClN 4 O 5}}}} S · HCl · H 2 O · 0.2Et 2 O Calculated (%): C, 50.98; H, 5.18; N, 9.59
Found (%): C, 51.16; H, 5.44; N, 9.49

実施例135
2-(1-{2-[(6-クロロ-2-ナフチル)スルホニル]-3-ヒドロキシプロパノイル}-4-ピペリジニル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
実施例134a)で得られた2-[(6-クロロ-2-ナフチル)チオ]-3-ヒドロキシプロピオン酸エチル（0.31g）から実施例134b)と同様にして題記化合物（0.030g, 6%）を白色固体として得た。
NMR (300MHz, CDCl₃)δ：1.62-2.02 (5H, m), 2.62-2.83 (4H, m), 3.30-3.46 (1H, m), 4.04-4.40 (5H, m), 4.62-4.67 (1H, m), 4.77-4.86 (1H, m), 6.74-6.75 (1H, m), 7.58-7.62 (1H, m), 7.80-8.01 (4H, m), 8.41-8.48 (1H, m).
元素分析値 C₂₄H₂₅ClN₄O₅S・0.5H₂Oとして
計算値（％）：C, 54.80; H, 4.98; N, 10.65
実測値（％）：C, 54.89; H, 4.96; N, 10.48 Example 135
2- (1- {2-[(6-Chloro-2-naphthyl) sulfonyl] -3-hydroxypropanoyl} -4-piperidinyl) -5-methyl-1,2-dihydro-3H-imidazo [1,5 -c] imidazol-3-one from ethyl 2-[(6-chloro-2-naphthyl) thio] -3-hydroxypropionate (0.31 g) obtained in Example 134a) in the same manner as in Example 134b) The title compound (0.030 g, 6%) was obtained as a white solid.
NMR (300MHz, CDCl ₃ ) δ: 1.62-2.02 (5H, m), 2.62-2.83 (4H, m), 3.30-3.46 (1H, m), 4.04-4.40 (5H, m), 4.62-4.67 (1H , m), 4.77-4.86 (1H, m), 6.74-6.75 (1H, m), 7.58-7.62 (1H, m), 7.80-8.01 (4H, m), 8.41-8.48 (1H, m).
Elemental analysis _{_{_{_{C 24 H 25 ClN 4 O 5}}}} S · 0.5H 2 O Calculated (%): C, 54.80; H, 4.98; N, 10.65
Found (%): C, 54.89; H, 4.96; N, 10.48

実施例136
2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
136a) (2S)-3-[(6-クロロ-2-ナフチル)チオ]-2-ヒドロキシプロピオン酸メチル
アルゴン雰囲気下、3Mエチルマグネシウムブロミドのジエチルエーテル溶液をTHF(25mL)へ氷冷下で滴下した。この溶液へ6-クロロナフタレン-2-チオール（5.0g）のTHF(50mL)溶液を０℃で滴下し、室温で30分間かき混ぜた。この溶液へ(2R)-オキシラン-2-カルボン酸メチル（2.3mL）のTHF（15mL）溶液を滴下し、反応液を室温で3時間かき混ぜた。反応液に塩化アンモニウム水溶液（50mL）を加え、酢酸エチル（100mL）で抽出した。抽出液を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥し、減圧濃縮した。残留物をヘキサン/酢酸エチル(３：１)から再結晶して、題記化合物（5.9g, 77%）を無色針状晶として得た。
NMR (300MHz, CDCl₃)δ：3.12 (1H, d, J = 6.0), 3.35 (1H, dd, J = 14.1, 5.7), 3.48 (1H, dd, J = 14.1, 4.2), 3.58 (3H, s), 4.43-4.48 (1H, m), 7.39-7.43 (1H, m), 7.49-7.52 (1H, m), 7.66-7.69 (2H, m), 7.76-7.77 (1H, m), 7.83-7.84 (1H, m).
136b) (2S)-3-[(6-クロロ-2-ナフチル)チオ]-2-ヒドロキシプロピオン酸
136a)で得られた(2S)-3-[(6-クロロ-2-ナフチル)チオ]-2-ヒドロキシプロピオン酸メチル（5.4g）のエタノール（150mL）けん濁液へ8N 水酸化ナトリウム水溶液（6.8mL）を加え、室温で3時間かき混ぜた。エタノールを減圧留去した後、析出物をろ取した。固体を水（100mL）にけん濁し、1N塩酸によりpH3程度に調節した後、沈殿物をろ取して、題記化合物（5.0g, 97%）を白色固体として得た。
NMR (300MHz, CD₃OD)δ：3.27 (1H, dd, J = 14.1, 6.9), 3.51 (1H, dd, J = 14.1, 4.2), 4.33 (1H, dd, J = 6.9, 4.2), 7.40-7.43 (1H, m), 7.51-7.54 (1H, m), 7.71-7.77 (2H, m), 7.82 (1H, s), 7.86 (1H, s).
136c) 2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)チオ]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
136b)で得られた(2S)-3-[(6-クロロ-2-ナフチル)チオ]-2-ヒドロキシプロピオン酸（3.0g）、実施例69b)で得られた5-メチル-2-(4-ピペリジニル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン２塩酸塩（3.3 g）、HOBt（2.4g）およびトリエチルアミン（5.2mL）をアセトニトリル（300mL）とジクロロメタン（100mL）の混合液にけん濁し、WSC（3.1g）を加え室温で18時間かき混ぜた。反応液を濃縮し、残留物をクロロホルムと水で希釈した。有機層を分液し、飽和食塩水で洗浄した。クロロホルム溶液を無水硫酸マグネシウムで乾燥し、減圧濃縮した。残留物を塩基性シリカゲルカラム（酢酸エチルから酢酸エチル：エタノール＝１０：１）で精製して、題記化合物（3.6g, 71%）を無色粉末として得た。
NMR (300MHz, CDCl₃)δ：1.54-1.83 (4H, m), 2.39-2.98 (4H, m), 2.98-3.44 (4H, m), 3.76-4.20 (3H, m), 4.61-4.73 (2H, m), 6.67-6.68 (1H, m), 7.41-7.51 (2H, m), 7.64-7.70 (2H, m), 7.75-7.83 (2H, m).
136d) 2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
実施例136c)で得た2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)チオ]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン（3.1g）のジクロロメタン(100mL)溶液へ氷冷下でメタクロロ過安息香酸(1.7g)を加え、室温で5時間かき混ぜた。反応液をクロロホルムとチオ硫酸ナトリウム水溶液で希釈し、有機層を分液した。クロロホルム溶液を飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残留物を塩基性シリカゲルカラム（酢酸エチルから酢酸エチル：エタノール＝１０：１）により精製し、題記化合物（2.7g, 81%）を無色粉末として得た。
NMR (300MHz, CDCl₃)δ：1.65-1.88 (2H, m), 1.93-2.04 (2H, m), 2.61 (3H, s), 2.76-2.85 (1H, m), 3.18-3.31 (1H, m), 3.44-3.51 (2H, m), 3.75-3.88 (1H, m), 4.10-4.30 (3H, m), 4.68-4.72 (1H, m), 5.03-5.04 (1H, m), 6.71 (1H, s), 7.59 (1H, dd, J = 8.9, 2.0), 7.87-8.00 (4H, m), 8.50 (1H, s).
元素分析値 C₂₄H₂₅ClN₄O₅Sとして
計算値（％）：C, 55.76; H, 4.87; N, 10.84
実測値（％）：C, 55.60; H, 4.98; N, 10.85 Example 136
2- (1-{(2S) -3-[(6-Chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -5-methyl-1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one
136a) Methyl (2S) -3-[(6-chloro-2-naphthyl) thio] -2-hydroxypropionate A solution of 3M ethylmagnesium bromide in diethyl ether was added dropwise to THF (25 mL) under ice-cooling in an argon atmosphere. did. To this solution was added dropwise a solution of 6-chloronaphthalene-2-thiol (5.0 g) in THF (50 mL) at 0 ° C., and the mixture was stirred at room temperature for 30 minutes. To this solution was added dropwise a solution of methyl (2R) -oxirane-2-carboxylate (2.3 mL) in THF (15 mL), and the reaction mixture was stirred at room temperature for 3 hours. Aqueous ammonium chloride solution (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from hexane / ethyl acetate (3: 1) to give the title compound (5.9 g, 77%) as colorless needle crystals.
NMR (300MHz, CDCl ₃ ) δ: 3.12 (1H, d, J = 6.0), 3.35 (1H, dd, J = 14.1, 5.7), 3.48 (1H, dd, J = 14.1, 4.2), 3.58 (3H, s), 4.43-4.48 (1H, m), 7.39-7.43 (1H, m), 7.49-7.52 (1H, m), 7.66-7.69 (2H, m), 7.76-7.77 (1H, m), 7.83- 7.84 (1H, m).
136b) (2S) -3-[(6-Chloro-2-naphthyl) thio] -2-hydroxypropionic acid
To the suspension of methyl (2S) -3-[(6-chloro-2-naphthyl) thio] -2-hydroxypropionate (5.4 g) obtained in 136a) in ethanol (150 mL), 8N aqueous sodium hydroxide solution ( 6.8 mL) was added, and the mixture was stirred at room temperature for 3 hours. Ethanol was distilled off under reduced pressure, and the precipitate was collected by filtration. The solid was suspended in water (100 mL), adjusted to about pH 3 with 1N hydrochloric acid, and the precipitate was collected by filtration to give the title compound (5.0 g, 97%) as a white solid.
NMR (300MHz, CD ₃ OD) δ: 3.27 (1H, dd, J = 14.1, 6.9), 3.51 (1H, dd, J = 14.1, 4.2), 4.33 (1H, dd, J = 6.9, 4.2), 7.40 -7.43 (1H, m), 7.51-7.54 (1H, m), 7.71-7.77 (2H, m), 7.82 (1H, s), 7.86 (1H, s).
136c) 2- (1-{(2S) -3-[(6-chloro-2-naphthyl) thio] -2-hydroxypropanoyl} -4-piperidinyl) -5-methyl-1,2-dihydro-3H -Imidazo [1,5-c] imidazol-3-one
(2S) -3-[(6-Chloro-2-naphthyl) thio] -2-hydroxypropionic acid (3.0 g) obtained in 136b), 5-methyl-2- ( 4-piperidinyl) -1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one dihydrochloride (3.3 g), HOBt (2.4 g) and triethylamine (5.2 mL) in acetonitrile (300 mL) Suspended in a mixture of methane and dichloromethane (100 mL), WSC (3.1 g) was added and stirred at room temperature for 18 hours. The reaction mixture was concentrated and the residue was diluted with chloroform and water. The organic layer was separated and washed with saturated brine. The chloroform solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column (ethyl acetate to ethyl acetate: ethanol = 10: 1) to give the title compound (3.6 g, 71%) as a colorless powder.
NMR (300MHz, CDCl ₃ ) δ: 1.54-1.83 (4H, m), 2.39-2.98 (4H, m), 2.98-3.44 (4H, m), 3.76-4.20 (3H, m), 4.61-4.73 (2H , m), 6.67-6.68 (1H, m), 7.41-7.51 (2H, m), 7.64-7.70 (2H, m), 7.75-7.83 (2H, m).
136d) 2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -5-methyl-1,2-dihydro-3H -Imidazo [1,5-c] imidazol-3-one 2- (1-{(2S) -3-[(6-Chloro-2-naphthyl) thio] -2-hydroxypropatide obtained in Example 136c) Noyl} -4-piperidinyl) -5-methyl-1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one (3.1 g) in dichloromethane (100 mL) under ice-cooling Benzoic acid (1.7 g) was added and stirred at room temperature for 5 hours. The reaction solution was diluted with chloroform and an aqueous sodium thiosulfate solution, and the organic layer was separated. The chloroform solution was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column (ethyl acetate to ethyl acetate: ethanol = 10: 1) to give the title compound (2.7 g, 81%) as a colorless powder.
NMR (300MHz, CDCl ₃ ) δ: 1.65-1.88 (2H, m), 1.93-2.04 (2H, m), 2.61 (3H, s), 2.76-2.85 (1H, m), 3.18-3.31 (1H, m ), 3.44-3.51 (2H, m), 3.75-3.88 (1H, m), 4.10-4.30 (3H, m), 4.68-4.72 (1H, m), 5.03-5.04 (1H, m), 6.71 (1H , s), 7.59 (1H, dd, J = 8.9, 2.0), 7.87-8.00 (4H, m), 8.50 (1H, s).
Elemental analysis value Calculated as C ₂₄ H ₂₅ ClN ₄ O ₅ S (%): C, 55.76; H, 4.87; N, 10.84
Found (%): C, 55.60; H, 4.98; N, 10.85

実施例137
2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-5-(ヒドロキシメチル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
137a) 1-ベンジル-N-(1H-イミダゾール-4-イル)メチルピペリジン-4-アミン
1-ベンジル-4-ピペリジンアミン（3.4g）、4-ホルミルイミダゾール（1.4g）および酢酸（1.7mL）のジクロロエタン溶液（100mL）にトリアセトキシ水素化ホウ素ナトリウム（4.7g）を加え、室温で15時間かき混ぜた。反応液を1 N 水酸化ナトリウム水溶液でpH12程度に調節した後、クロロホルム（100 mL）で抽出した。抽出液を無水硫酸マグネシウムで乾燥した後、溶媒を減圧留去して、題記化合物（3.4g）を黄色油状物として得た。これ以上の精製は行わずに、この粗生成物を次の反応に用いた。
NMR (300MHz, CDCl₃)δ: 1.36-1.53 (2H, m), 1.75-2.08 (6H, m), 2.50-2.65 (1H, m), 2.66-2.86 (2H, m), 3.49 (2H, s), 4.31 (1H, bs), 6.86 (1H, s), 7.23-7.31 (5H, m), 7.51 (1H, s).
137b) (1-ベンジル-4-ピペリジニル)[(1H-イミダゾール-4-イル)メチル]カルバミン酸 tert-ブチル
実施例137a)で得た1-ベンジル-N-(1H-イミダゾール-4-イル)メチル-4-ピペリジンアミン（3.4g）のエタノール溶液（50mL）に、二炭酸ジ-tert-ブチル（6.3mL）を加え、室温で5時間かき混ぜた。ヒドラジン一水和物（10mL）を加え、室温で18時間かき混ぜた。溶媒を減圧留去した後、残留物に酢酸エチル（100mL）および水（100mL）を加え、有機層を分液した。酢酸エチル溶液を飽和食塩水（100mL）で洗浄し、無水硫酸マグネシウムで乾燥した後、溶媒を減圧留去した。残留物を塩基性シリカゲルカラム（酢酸エチル：エタノール＝10:1）により精製し、題記化合物（2.3g, 42%）を無色油状物として得た。
NMR (200MHz, CDCl₃)δ: 1.42-1.61 (12H, m), 1.66-1.84 (2H, m), 1.93-2.04 (2H, m), 2.92 (2H, d, J = 7.6), 3.47 (2H, s), 3.70 (1H, bs), 4.29 (2H, s), 6.86 (1H, s), 7.24-7.33 (5H, m), 7.49 (1H, s).
137c) (1-ベンジル-4-ピペリジニル)[(1-{[2-(トリメチルシリル)エトキシ]メチル}-1H-イミダゾール-4-イル)メチル]カルバミン酸tert-ブチル
実施例137b)で得得られた(1-ベンジル-4-ピペリジニル)[(1H-イミダゾール-4-イル)メチル]カルバミン酸tert-ブチル（1.3g）のDMF溶液（30mL）に水素化ナトリウム（0.22g）を氷冷下で加え、室温で１時間かき混ぜた。続いて、塩化2-(トリメチルシリル)エトキシメチル（1.3mL）を氷冷下で加えた後、室温で2時間かき混ぜた。反応液に酢酸エチル（50mL）および水（50mL）を加え、有機層を分液した。酢酸エチル溶液を飽和食塩水（50mL）で洗浄し、無水硫酸マグネシウムで乾燥した後、溶媒を減圧留去した。残留物を塩基性シリカゲルカラム（酢酸エチル：ヘキサン＝1:1）により精製して、題記化合物（4.9g, 24%）を淡黄色油状物として得た。
NMR (300MHz, CDCl₃)δ: 0.05 (9H, s), 0.91 (2H, t, J = 8.1), 1.47 (9H, s), 1.62-1.66 (2H, m), 1.84-1.90 (3H, m), 2.03-2.09 (2H, m), 2.91-2.95 (2H, m), 3.41-3.54 (4H, m), 4.35 (2H, s), 5.22 (2H, s), 6.90 (1H, bs), 7.24-7.43 (5H, m), 7.48 (1H, s).
137d) (1-ベンジル-4-ピペリジニル)[(2-ホルミル-1-{[2-(トリメチルシリル)エトキシ]メチル}-1H-イミダゾール-4-イル)メチル]カルバミン酸tert-ブチル
n-ブチルリチウムのヘキサン溶液（1.5M, 5.7mL）をアルゴン雰囲気下、実施例137c)で得た(1-ベンジル-4-ピペリジニル)[(1-{[2-(トリメチルシリル)エトキシ]メチル}-1H-イミダゾール-4-イル)メチル]カルバミン酸tert-ブチル（3.9g）のTHF溶液（50mL）に-40℃で滴下した。反応液を-40℃で15分かき混ぜた後、DMF（0.7mL）を加え、室温で15時間かき混ぜた。反応液に飽和塩化アンモニウム水溶液（50mL）を加え、酢酸エチル（50mL）で抽出した。抽出液を飽和食塩水（50mL）で洗浄し、無水硫酸マグネシウムで乾燥した後、溶媒を減圧留去した。残留物をシリカゲルカラム（酢酸エチル：エタノール＝10:1）により精製し、題記化合物（2.52g, 61%）を淡黄色油状物として得た。
NMR (300MHz, CDCl₃)δ：-0.04 (9H, s), 0.90 (2H, t, J = 8.2), 1.45 (9H, s), 1.63-1.77 (5H, m), 1.99-2.05 (2H, m), 2.91 (2H, d, J = 11.1), 3.47 (2H, s), 3.53 (2H, t, J = 8.2), 4.37 (2H, s), 5.71 (2H, s), 7.20-7.35 (5H, m), 9.74 (1H, s).
137e) (1-ベンジル-4-ピペリジニル)[(2-(ヒドロキシメチル)-1-{[2-(トリメチルシリル)エトキシ]メチル}-1H-イミダゾール-4-イル)メチル]カルバミン酸 tert-ブチル
実施例137d)で得た(1-ベンジル-4-ピペリジニル)[(2-ホルミル-1-{[2-(トリメチルシリル)エトキシ]メチル}-1H-イミダゾール-4-イル)メチル]カルバミン酸tert-ブチル（1.3g）のエタノール（10mL）溶液に水素化ホウ素ナトリウム（95mg）を氷冷下で加え、室温で1時間かき混ぜた。水（1mL）を加えた後、溶媒を減圧留去し、残留物へ酢酸エチル（50mL）および水（50mL）を加えた。有機層を分液、飽和食塩水（50mL）で洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、題記化合物（1.3g, 98%）を無色油状物として得た。
NMR (300MHz, CDCl₃)δ：-0.05 (9H, s), 0.88 (2H, t, J = 8.4), 1.43 (9H, s), 1.57-1.60 (2H, m), 1.75-1.76 (1H, m), 1.98-1.99 (2H, m), 2.87 (2H, d, J = 12.0), 3.44-3.49 (4H, m), 4.28 (2H, s), 4.66 (2H, s), 5.26 (2H, s), 6.75 (1H, bs), 7.19-7.29 (5H, m).
137f) (4-{[(1-ベンジル-4-ピペリジニル)アミノ]メチル}-1H-イミダゾール-2-イル)メタノール
実施例137e)で得た(1-ベンジル-4-ピペリジニル)[(2-(ヒドロキシメチル)-1-{[2-(トリメチルシリル)エトキシ]メチル}-1H-イミダゾール-4-イル)メチル]カルバミン酸 tert-ブチル（480mg）のトリフルオロ酢酸(1mL)−水(1mL)溶液を80℃で3時間かき混ぜた。室温まで冷却した後、飽和炭酸水素ナトリウム水溶液で中和し、クロロホルム（50mL）で抽出した。抽出液を飽和食塩水（50mL）で洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、題記化合物（280mg, 定量的）を黄色油状物として得た。
NMR (300MHz, CDCl₃)δ：1.48-1.55 (2H, m), 1.63-1.75 (2H, m), 1.87-2.02 (2H, m), 2.64-2.65 (1H, m), 2.84-2.88 (2H, m), 3.47 (2H, s), 3.74 (2H, s), 4.46 (2H, s), 5.42 (1H, bs), 6.76 (1H, s), 7.19-7.34 (5H, m).
137g) 1-ベンジル-N-{[2-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-1H-イミダゾール-4-イル]メチル}ピペリジン-4-アミン
実施例137f)で得た(4-{[(1-ベンジル-4-ピペリジニル)アミノ]メチル}-1H-イミダゾール-2-イル)メタノール（0.28g）およびトリエチルアミン（0.26mL）のジクロロメタン（5mL）溶液にtert-ブチルジメチルクロロシラン（170mg）を加え、室温で、3時間かき混ぜた。反応液にクロロホルム（20mL）および水（20mL）を加え、有機層を分液した。クロロホルム溶液を飽和食塩水（20mL）で洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残留物を塩基性シリカゲルカラム（酢酸エチル：エタノール＝10:1）により精製して、題記化合物（0.20g, 52%）を淡黄色油状物として得た。
NMR (300MHz, CDCl₃)δ：0.10 (6H, s), 0.92 (9H, s), 1.41-1.44 (2H, m), 1.84-1.88 (2H, m), 1.97-2.04 (2H, m), 2.50-2.51 (1H, m), 2.82-2.86 (2H, m), 3.49 (2H, s), 3.75 (2H, s), 4.77 (2H, s), 6.81 (1H, s), 7.18-7.36 (5H, m).
137h) 2-(1-ベンジル-4-ピペリジニル)-5-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
実施例137g)で得られた1-ベンジル-N-{[2-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-1H-イミダゾール-4-イル]メチル}ピペリジン-4-アミン(0.20g）およびDBU（0.14mL）のジクロロエタン（3mL）溶液にN,N'-カルボニルジイミダゾール（94mg）を加え、60℃で30分かき混ぜた。室温まで冷却した後、反応液へクロロホルム（20mL）および水（20mL）を加え、有機層を分液した。クロロホルム溶液を飽和食塩水（20mL）で洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残留物をシリカゲルカラム（酢酸エチル：エタノール＝5:1）により精製し、題記化合物（0.18g, 85%）を淡黄色油状物として得た。
NMR (300MHz, CDCl₃)δ：0.13 (6H, s), 0.91 (9H, s), 1.72-1.83 (4H, m), 2.08-2.17 (2H, m), 2.99 (2H, d, J = 11.4), 3.52 (2H, s), 3.95-4.02 (1H, m), 4.30-4.31 (2H, m), 4.92 (2H, s), 6.79-6.80 (1H, m), 7.24-7.37 (5H, m).
137i) 5-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2-(4-ピペリジニル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
実施例137h)で得られた2-(1-ベンジル-4-ピペリジニル)-5-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン（0.18g）および10% パラジウム炭素（36mg）をメタノール（3mL）にけん濁し、水素雰囲気下室温で18時間かき混ぜた。反応液をセライトを用いてろ過し、ろ液を減圧濃縮して、題記化合物（0.16g, 定量的）を白色固体として得た。
NMR (300MHz, CDCl₃)δ：0.14 (6H, s), 0.92 (9H, s), 1.61-1.74 (2H, m), 1.85-1.88 (2H, m), 2.71-2.79 (2H, m), 3.20 (2H, d, J = 11.7), 4.02-4.10 (1H, m), 4.32-4.33 (2H, m), 4.93 (2H, s), 6.80-6.81 (1H, m).
137j) 5-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
3-[(6-クロロ-2-ナフチル)スルホニル]プロピオン酸（0.18g）および実施例137i)で得られた5-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2-(4-ピペリジニル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン (0.16g)から実施例89b)と同様にして題記化合物（0.22g, 76%）を無色油状物として得た。
NMR (300MHz, CDCl₃) δ：0.14 (6H, s), 0.92 (9H, s), 1.57-1.74 (2H, m), 1.87-1.99 (2H, m), 2.59-2.66 (1H, m), 2.83-3.01 (2H, m), 3.14-3.22 (1H, m), 3.48-3.65 (2H, m), 4.00 (1H, d, J = 14.4), 4.08-4.27 (1H, m), 4.27 (2H, s), 4.72 (1H, d, J = 14.1), 4.91 (2H, s), 6.80-6.81 (1H, m), 7.54-7.61 (2H, m), 7.89-7.96 (3H, m), 8.47 (1H, s).
137k) 2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-5-(ヒドロキシメチル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
実施例137j)で得られた5-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン（0.22g）の酢酸(4mL)−THF(2mL)−水(2mL)溶液を60℃で3時間かき混ぜた。室温まで冷却した後、減圧濃縮し、残留物にクロロホルムと飽和炭酸水素ナトリウム水溶液を加え、有機層を分液した。クロロホルム溶液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残留物を塩基性シリカゲルカラム（酢酸エチル：エタノール＝１０：１）により精製し、題記化合物（99mg, 55%）を白色固体として得た。
NMR (300MHz, CDCl₃)δ：1.56-1.80 (2H, m), 1.89-2.02 (2H, m), 2.80-2.91 (1H, m), 2.95-3.06 (1H, m), 3.17-3.25 (1H, m), 3.46-3.56 (1H, m), 3.59-3.69 (1H, m), 3.86 (1H, t, J = 6.6), 4.03 (1H, d, J = 15.3), 4.15-4.23 (1H, m), 4.36 (2H, s), 4.75 (1H, d, J = 11.7), 4.87 (2H, d, J = 6.6), 6.78 (1H, s), 7.61 (1H, dd, J = 9.0, 2.1), 7.90-7.98 (4H, m), 8.49 (1H, s).
元素分析値 C₂₄H₂₅ClN₄O₅Sとして
計算値（％）：C, 55.76; H, 4.87; N, 10.84
実測値（％）：C, 55.52; H, 4.94; N, 10.74 Example 137
2- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -5- (hydroxymethyl) -1,2-dihydro-3H-imidazo [1,5-c ] Imidazole-3-one
137a) 1-Benzyl-N- (1H-imidazol-4-yl) methylpiperidin-4-amine
To a solution of 1-benzyl-4-piperidineamine (3.4 g), 4-formylimidazole (1.4 g) and acetic acid (1.7 mL) in dichloroethane (100 mL) was added sodium triacetoxyborohydride (4.7 g), and the mixture was stirred at room temperature for 15 Stir for hours. The reaction mixture was adjusted to about pH 12 with 1 N aqueous sodium hydroxide solution, and extracted with chloroform (100 mL). The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (3.4 g) as a yellow oil. The crude product was used in the next reaction without further purification.
NMR (300MHz, CDCl ₃ ) δ: 1.36-1.53 (2H, m), 1.75-2.08 (6H, m), 2.50-2.65 (1H, m), 2.66-2.86 (2H, m), 3.49 (2H, s ), 4.31 (1H, bs), 6.86 (1H, s), 7.23-7.31 (5H, m), 7.51 (1H, s).
137b) (1-Benzyl-4-piperidinyl) [(1H-imidazol-4-yl) methyl] carbamate tert-butyl 1-benzyl-N- (1H-imidazol-4-yl) obtained in Example 137a) Di-tert-butyl dicarbonate (6.3 mL) was added to an ethanol solution (50 mL) of methyl-4-piperidineamine (3.4 g), and the mixture was stirred at room temperature for 5 hours. Hydrazine monohydrate (10 mL) was added, and the mixture was stirred at room temperature for 18 hours. After the solvent was distilled off under reduced pressure, ethyl acetate (100 mL) and water (100 mL) were added to the residue, and the organic layer was separated. The ethyl acetate solution was washed with saturated brine (100 mL) and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column (ethyl acetate: ethanol = 10: 1) to give the title compound (2.3 g, 42%) as a colorless oil.
NMR (200MHz, CDCl ₃ ) δ: 1.42-1.61 (12H, m), 1.66-1.84 (2H, m), 1.93-2.04 (2H, m), 2.92 (2H, d, J = 7.6), 3.47 (2H , s), 3.70 (1H, bs), 4.29 (2H, s), 6.86 (1H, s), 7.24-7.33 (5H, m), 7.49 (1H, s).
137c) tert-butyl (1-benzyl-4-piperidinyl) [(1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-imidazol-4-yl) methyl] carbamate obtained in Example 137b) (1-benzyl-4-piperidinyl) [(1H-imidazol-4-yl) methyl] carbamate tert-butyl (1.3 g) in DMF solution (30 mL) with sodium hydride (0.22 g) under ice-cooling In addition, the mixture was stirred at room temperature for 1 hour. Subsequently, 2- (trimethylsilyl) ethoxymethyl chloride (1.3 mL) was added under ice cooling, followed by stirring at room temperature for 2 hours. Ethyl acetate (50 mL) and water (50 mL) were added to the reaction solution, and the organic layer was separated. The ethyl acetate solution was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column (ethyl acetate: hexane = 1: 1) to give the title compound (4.9 g, 24%) as a pale yellow oil.
NMR (300MHz, CDCl ₃ ) δ: 0.05 (9H, s), 0.91 (2H, t, J = 8.1), 1.47 (9H, s), 1.62-1.66 (2H, m), 1.84-1.90 (3H, m ), 2.03-2.09 (2H, m), 2.91-2.95 (2H, m), 3.41-3.54 (4H, m), 4.35 (2H, s), 5.22 (2H, s), 6.90 (1H, bs), 7.24-7.43 (5H, m), 7.48 (1H, s).
137d) tert-butyl (1-benzyl-4-piperidinyl) [(2-formyl-1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-imidazol-4-yl) methyl] carbamate
(1-Benzyl-4-piperidinyl) [(1-{[2- (trimethylsilyl) ethoxy] methyl}) obtained in Example 137c) under an argon atmosphere in a hexane solution of n-butyllithium (1.5 M, 5.7 mL) [-1H-imidazol-4-yl) methyl] carbamate tert-butyl (3.9 g) was added dropwise at −40 ° C. to a THF solution (50 mL). The reaction mixture was stirred at −40 ° C. for 15 minutes, DMF (0.7 mL) was added, and the mixture was stirred at room temperature for 15 hours. A saturated aqueous ammonium chloride solution (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL). The extract was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate: ethanol = 10: 1) to give the title compound (2.52 g, 61%) as a pale yellow oil.
NMR (300MHz, CDCl ₃ ) δ: -0.04 (9H, s), 0.90 (2H, t, J = 8.2), 1.45 (9H, s), 1.63-1.77 (5H, m), 1.99-2.05 (2H, m), 2.91 (2H, d, J = 11.1), 3.47 (2H, s), 3.53 (2H, t, J = 8.2), 4.37 (2H, s), 5.71 (2H, s), 7.20-7.35 ( 5H, m), 9.74 (1H, s).
137e) tert-butyl (1-benzyl-4-piperidinyl) [(2- (hydroxymethyl) -1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-imidazol-4-yl) methyl] carbamate Tert-butyl (1-benzyl-4-piperidinyl) [(2-formyl-1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-imidazol-4-yl) methyl] carbamate obtained in Example 137d) Sodium borohydride (95 mg) was added to a solution of (1.3 g) in ethanol (10 mL) under ice cooling, and the mixture was stirred at room temperature for 1 hour. Water (1 mL) was added, the solvent was evaporated under reduced pressure, and ethyl acetate (50 mL) and water (50 mL) were added to the residue. The organic layer was separated, washed with saturated brine (50 mL), and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (1.3 g, 98%) as a colorless oil.
NMR (300MHz, CDCl ₃ ) δ: -0.05 (9H, s), 0.88 (2H, t, J = 8.4), 1.43 (9H, s), 1.57-1.60 (2H, m), 1.75-1.76 (1H, m), 1.98-1.99 (2H, m), 2.87 (2H, d, J = 12.0), 3.44-3.49 (4H, m), 4.28 (2H, s), 4.66 (2H, s), 5.26 (2H, s), 6.75 (1H, bs), 7.19-7.29 (5H, m).
137f) (4-{[(1-Benzyl-4-piperidinyl) amino] methyl} -1H-imidazol-2-yl) methanol (1-Benzyl-4-piperidinyl) [(2- (Hydroxymethyl) -1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-imidazol-4-yl) methyl] carbamate tert-butyl (480 mg) in trifluoroacetic acid (1 mL) -water (1 mL) solution Was stirred at 80 ° C. for 3 hours. After cooling to room temperature, the mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform (50 mL). The extract was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (280 mg, quantitative) as a yellow oil.
NMR (300MHz, CDCl ₃ ) δ: 1.48-1.55 (2H, m), 1.63-1.75 (2H, m), 1.87-2.02 (2H, m), 2.64-2.65 (1H, m), 2.84-2.88 (2H , m), 3.47 (2H, s), 3.74 (2H, s), 4.46 (2H, s), 5.42 (1H, bs), 6.76 (1H, s), 7.19-7.34 (5H, m).
137g) 1-benzyl-N-{[2-({[tert-butyl (dimethyl) silyl] oxy} methyl) -1H-imidazol-4-yl] methyl} piperidin-4-amine obtained in Example 137f) (4-{[(1-Benzyl-4-piperidinyl) amino] methyl} -1H-imidazol-2-yl) methanol (0.28 g) and triethylamine (0.26 mL) in dichloromethane (5 mL) in tert-butyldimethylchlorosilane (170 mg) was added and stirred at room temperature for 3 hours. Chloroform (20 mL) and water (20 mL) were added to the reaction solution, and the organic layer was separated. The chloroform solution was washed with saturated brine (20 mL) and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by basic silica gel column (ethyl acetate: ethanol = 10: 1) to obtain the title compound (0.20 g, 52%) as a pale yellow oil.
NMR (300MHz, CDCl ₃ ) δ: 0.10 (6H, s), 0.92 (9H, s), 1.41-1.44 (2H, m), 1.84-1.88 (2H, m), 1.97-2.04 (2H, m), 2.50-2.51 (1H, m), 2.82-2.86 (2H, m), 3.49 (2H, s), 3.75 (2H, s), 4.77 (2H, s), 6.81 (1H, s), 7.18-7.36 ( 5H, m).
137h) 2- (1-Benzyl-4-piperidinyl) -5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -1,2-dihydro-3H-imidazo [1,5-c] imidazole- 3-one 1-benzyl-N-{[2-({[tert-butyl (dimethyl) silyl] oxy} methyl) -1H-imidazol-4-yl] methyl} piperidine-4 obtained in Example 137g) -N, N′-carbonyldiimidazole (94 mg) was added to a solution of amine (0.20 g) and DBU (0.14 mL) in dichloroethane (3 mL), and the mixture was stirred at 60 ° C. for 30 minutes. After cooling to room temperature, chloroform (20 mL) and water (20 mL) were added to the reaction solution, and the organic layer was separated. The chloroform solution was washed with saturated brine (20 mL) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (ethyl acetate: ethanol = 5: 1) to give the title compound (0.18 g, 85%) as a pale yellow oil.
NMR (300MHz, CDCl ₃ ) δ: 0.13 (6H, s), 0.91 (9H, s), 1.72-1.83 (4H, m), 2.08-2.17 (2H, m), 2.99 (2H, d, J = 11.4 ), 3.52 (2H, s), 3.95-4.02 (1H, m), 4.30-4.31 (2H, m), 4.92 (2H, s), 6.79-6.80 (1H, m), 7.24-7.37 (5H, m ).
137i) 5-({[tert-Butyl (dimethyl) silyl] oxy} methyl) -2- (4-piperidinyl) -1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one 2- (1-Benzyl-4-piperidinyl) -5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -1,2-dihydro-3H-imidazo [1,5 obtained in Example 137h) -c] Imidazol-3-one (0.18 g) and 10% palladium carbon (36 mg) were suspended in methanol (3 mL) and stirred at room temperature for 18 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound (0.16 g, quantitative) as a white solid.
NMR (300MHz, CDCl ₃ ) δ: 0.14 (6H, s), 0.92 (9H, s), 1.61-1.74 (2H, m), 1.85-1.88 (2H, m), 2.71-2.79 (2H, m), 3.20 (2H, d, J = 11.7), 4.02-4.10 (1H, m), 4.32-4.33 (2H, m), 4.93 (2H, s), 6.80-6.81 (1H, m).
137j) 5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -2- (1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -1, 2-Dihydro-3H-imidazo [1,5-c] imidazol-3-one
3-[(6-Chloro-2-naphthyl) sulfonyl] propionic acid (0.18 g) and 5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -2- () obtained in Example 137i) 4-piperidinyl) -1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one (0.16 g) was purified from the title compound (0.22 g, 76%) in the same manner as in Example 89b). Obtained as an oil.
NMR (300 MHz, CDCl ₃ ) δ: 0.14 (6H, s), 0.92 (9H, s), 1.57-1.74 (2H, m), 1.87-1.99 (2H, m), 2.59-2.66 (1H, m), 2.83-3.01 (2H, m), 3.14-3.22 (1H, m), 3.48-3.65 (2H, m), 4.00 (1H, d, J = 14.4), 4.08-4.27 (1H, m), 4.27 (2H , s), 4.72 (1H, d, J = 14.1), 4.91 (2H, s), 6.80-6.81 (1H, m), 7.54-7.61 (2H, m), 7.89-7.96 (3H, m), 8.47 (1H, s).
137k) 2- (1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -5- (hydroxymethyl) -1,2-dihydro-3H-imidazo [1,5 -c] imidazol-3-one 5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -2- (1- {3-[(6-chloro-2-] obtained in Example 137j) Naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one (0.22 g) in acetic acid (4 mL) -THF (2 mL) -water ( The solution was stirred at 60 ° C. for 3 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure, chloroform and saturated aqueous sodium hydrogen carbonate solution were added to the residue, and the organic layer was separated. The chloroform solution was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by basic silica gel column (ethyl acetate: ethanol = 10: 1) to obtain the title compound (99 mg, 55%) as a white solid.
NMR (300MHz, CDCl ₃ ) δ: 1.56-1.80 (2H, m), 1.89-2.02 (2H, m), 2.80-2.91 (1H, m), 2.95-3.06 (1H, m), 3.17-3.25 (1H , m), 3.46-3.56 (1H, m), 3.59-3.69 (1H, m), 3.86 (1H, t, J = 6.6), 4.03 (1H, d, J = 15.3), 4.15-4.23 (1H, m), 4.36 (2H, s), 4.75 (1H, d, J = 11.7), 4.87 (2H, d, J = 6.6), 6.78 (1H, s), 7.61 (1H, dd, J = 9.0, 2.1 ), 7.90-7.98 (4H, m), 8.49 (1H, s).
Elemental analysis value Calculated as C ₂₄ H ₂₅ ClN ₄ O ₅ S (%): C, 55.76; H, 4.87; N, 10.84
Found (%): C, 55.52; H, 4.94; N, 10.74

実施例138
酢酸 [2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル塩酸塩
実施例137k)で得た2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-5-(ヒドロキシメチル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン（0.17g）、無水酢酸（0.5mL）およびピリジン（1mL）のジクロロメタン（2mL）けん濁液を18時間かき混ぜた。反応液へジクロロメタンおよび水を加え、有機層を分液した。ジクロロメタン溶液を水で3回洗浄し、無水硫酸マグネシウムで乾燥した後、溶媒を減圧留去した。残留物を塩基性シリカゲルカラム（酢酸エチル：エタノール＝１０：１）により精製した後、4N塩化水素酢酸エチル溶液(0.5mL)で処理し、題記化合物（0.13g, 65%）を白色粉末として得た。
NMR (200MHz, DMSO)δ：1.44-1.77 (4H, m), 2.06 (3H, s), 2.50-2.61 (1H, m), 2.75 (2H, t, J = 7.2), 3.08 (1H, t, J = 11.5), 3.87-4.05 (4H, m), 4.35 (1H, d, J = 9.4), 4.48 (2H, s), 5.29 (2H, s), 7.10 (1H, s), 7.72-7.77 (1H, m), 7.97-8.03 (1H, m), 8.17-8.31 (3H, m), 8.65-8.66 (1H, m).
元素分析値 C₂₆H₂₇ClN₄O₆S・HCl・H₂Oとして
計算値（％）：C, 50.90; H, 4.93; N, 9.13
実測値（％）：C, 50.84; H, 5.26; N, 8.98 Example 138
Acetic acid [2- (1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -3-oxo-2,3-dihydro-1H-imidazo [1,5-c] Imidazole-5-yl] methyl hydrochloride 2- (1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -5- (hydroxymethyl) obtained in Example 137k) Stir a suspension of -1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one (0.17g), acetic anhydride (0.5mL) and pyridine (1mL) in dichloromethane (2mL) for 18 hours It was. Dichloromethane and water were added to the reaction solution, and the organic layer was separated. The dichloromethane solution was washed 3 times with water and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by basic silica gel column (ethyl acetate: ethanol = 10: 1) and then treated with 4N hydrogen chloride ethyl acetate solution (0.5 mL) to give the title compound (0.13 g, 65%) as a white powder. It was.
NMR (200MHz, DMSO) δ: 1.44-1.77 (4H, m), 2.06 (3H, s), 2.50-2.61 (1H, m), 2.75 (2H, t, J = 7.2), 3.08 (1H, t, J = 11.5), 3.87-4.05 (4H, m), 4.35 (1H, d, J = 9.4), 4.48 (2H, s), 5.29 (2H, s), 7.10 (1H, s), 7.72-7.77 ( 1H, m), 7.97-8.03 (1H, m), 8.17-8.31 (3H, m), 8.65-8.66 (1H, m).
Elemental analysis value Calculated as C ₂₆ H ₂₇ ClN ₄ O ₆ S · HCl · H ₂ O (%): C, 50.90; H, 4.93; N, 9.13
Found (%): C, 50.84; H, 5.26; N, 8.98

実施例139
2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-5-(ヒドロキシメチル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
139a) 5-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)チオ]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
実施例136b)で得た(2S)-3-[(6-クロロ-2-ナフチル)チオ]-2-ヒドロキシプロピオン酸（0.44g）と実施例137i)で得た5-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2-(4-ピペリジニル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン(0.50g)から実施例136c)と同様にして題記化合物（0.69g, 78%）を無色油状物として得た。
NMR (200MHz, CDCl₃)δ：0.13 (6H, s), 0.91 (9H, s), 1.51-1.62 (2H, m), 1.80-1.83 (2H, m), 2.35-2.42 (1H, m), 2.69-2.75 (1H, m), 2.95-3.44 (2H, m), 3.81-4.23 (4H, m), 4.58-4.61 (2H, m), 4.89 (2H, s), 6.79 (1H, s), 7.42-7.52 (2H, m), 7.68 (1H, s), 7.72 (1H, s), 7.79 (1H, s), 7.83 (1H, s).
139b) 5-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
実施例139a)で得た5-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)チオ]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン（0.69g）から実施例136d)と同様にして題記化合物（0.60g, 83%）を無色非晶性粉末として得た。
NMR (300MHz, CDCl₃)δ：0.14 (6H, s), 0.92 (9H, s), 1.71-1.81 (2H, m), 1.85-2.07 (2H, m), 2.70-2.84 (1H, m), 3.03-3.16 (1H, m), 3.43-3.51 (2H, m), 4.10-4.32 (4H, m), 4.67-4.76 (1H, m), 4.92 (2H, s), 5.03-5.05 (1H, m), 6.81 (1H, s), 7.59 (1H, dd, J = 8.7, 2.1), 7.91-7.97 (4H, m), 8.51 (1H, s).
139c) 2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-5-(ヒドロキシメチル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
実施例139b) で得られた5-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン（0.24g）、酢酸（64μL）およびフッ化テトラブチルアンモニウム（0.29g）のTHF(3mL)溶液を室温で72時間かき混ぜた。反応液に酢酸エチルと水を加え、有機層を分液した。酢酸エチル溶液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した後、溶媒を減圧留去した。残留物を塩基性シリカゲルカラム（酢酸エチル：エタノール＝５：１）により精製し、題記化合物（150mg, 75%）を白色固体として得た。
NMR (300MHz, CDCl₃)δ：1.72-1.88 (2H, m), 1.88-2.04 (2H, m), 2.72-2.85 (1H, m), 3.18-3.32 (1H, m), 3.44-3.52 (2H, m), 3.71 (1H, bs), 3.85 (1H, bs), 4.08-4.26 (2H, m), 4.37-4.41 (2H, m), 4.69-4.78 (1H, m), 4.87 (2H, s), 5.04-5.06 (1H, m), 6.78 (1H, s), 7.57-7.61 (1H, m), 7.90-7.96 (4H, m), 8.50 (1H, s).
元素分析値 C₂₄H₂₅ClN₄O₆S・0.5H₂O・0.2Et₂Oとして
計算値（％）：C, 53.49; H, 5.07; N, 10.06
実測値（％）：C, 55.49; H, 5.09; N, 9.81 Example 139
2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -5- (hydroxymethyl) -1,2-dihydro- 3H-imidazo [1,5-c] imidazol-3-one
139a) 5-({[tert-Butyl (dimethyl) silyl] oxy} methyl) -2- (1-{(2S) -3-[(6-chloro-2-naphthyl) thio] -2-hydroxypropanoyl } -4-piperidinyl) -1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one (2S) -3-[(6-chloro-2-naphthyl) obtained in Example 136b) ) Thio] -2-hydroxypropionic acid (0.44 g) and 5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -2- (4-piperidinyl) -1,2 obtained in Example 137i) The title compound (0.69 g, 78%) was obtained as a colorless oil from -dihydro-3H-imidazo [1,5-c] imidazol-3-one (0.50 g) in the same manner as in Example 136c).
NMR (200MHz, CDCl ₃ ) δ: 0.13 (6H, s), 0.91 (9H, s), 1.51-1.62 (2H, m), 1.80-1.83 (2H, m), 2.35-2.42 (1H, m), 2.69-2.75 (1H, m), 2.95-3.44 (2H, m), 3.81-4.23 (4H, m), 4.58-4.61 (2H, m), 4.89 (2H, s), 6.79 (1H, s), 7.42-7.52 (2H, m), 7.68 (1H, s), 7.72 (1H, s), 7.79 (1H, s), 7.83 (1H, s).
139b) 5-({[tert-Butyl (dimethyl) silyl] oxy} methyl) -2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl } -4-piperidinyl) -1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one 5-({[tert-butyl (dimethyl) silyl] oxy} obtained in Example 139a) Methyl) -2- (1-{(2S) -3-[(6-chloro-2-naphthyl) thio] -2-hydroxypropanoyl} -4-piperidinyl) -1,2-dihydro-3H-imidazo [ The title compound (0.60 g, 83%) was obtained as a colorless amorphous powder from 1,5-c] imidazol-3-one (0.69 g) in the same manner as in Example 136d).
NMR (300MHz, CDCl ₃ ) δ: 0.14 (6H, s), 0.92 (9H, s), 1.71-1.81 (2H, m), 1.85-2.07 (2H, m), 2.70-2.84 (1H, m), 3.03-3.16 (1H, m), 3.43-3.51 (2H, m), 4.10-4.32 (4H, m), 4.67-4.76 (1H, m), 4.92 (2H, s), 5.03-5.05 (1H, m ), 6.81 (1H, s), 7.59 (1H, dd, J = 8.7, 2.1), 7.91-7.97 (4H, m), 8.51 (1H, s).
139c) 2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -5- (hydroxymethyl) -1,2- Dihydro-3H-imidazo [1,5-c] imidazol-3-one 5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -2- (1-{( 2S) -3-[(6-Chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -1,2-dihydro-3H-imidazo [1,5-c] imidazole-3- A solution of ON (0.24 g), acetic acid (64 μL) and tetrabutylammonium fluoride (0.29 g) in THF (3 mL) was stirred at room temperature for 72 hours. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The ethyl acetate solution was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column (ethyl acetate: ethanol = 5: 1) to give the title compound (150 mg, 75%) as a white solid.
NMR (300MHz, CDCl ₃ ) δ: 1.72-1.88 (2H, m), 1.88-2.04 (2H, m), 2.72-2.85 (1H, m), 3.18-3.32 (1H, m), 3.44-3.52 (2H , m), 3.71 (1H, bs), 3.85 (1H, bs), 4.08-4.26 (2H, m), 4.37-4.41 (2H, m), 4.69-4.78 (1H, m), 4.87 (2H, s ), 5.04-5.06 (1H, m), 6.78 (1H, s), 7.57-7.61 (1H, m), 7.90-7.96 (4H, m), 8.50 (1H, s).
Elemental analysis _{_{_{_{C 24 H 25 ClN 4 O 6}}}} S · 0.5H 2 O · 0.2Et 2 O Calculated (%): C, 53.49; H, 5.07; N, 10.06
Found (%): C, 55.49; H, 5.09; N, 9.81

実施例140
安息香酸 [2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル
実施例139c)で得られた2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-5-(ヒドロキシメチル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン（0.14g）と塩化ベンゾイル（31μL）から実施例138)と同様にして題記化合物（58mg, 34%）を白色粉末として得た。
NMR (300MHz, CDCl₃)δ：1.67-1.78 (2H, m), 1.90-2.05 (2H, m), 2.70-2.84 (1H, m), 3.17-3.31 (1H, m), 3.45-3.52 (2H, m), 3.80 (1H, bs), 4.11-4.38 (4H, m), 4.69-4.77 (1H, m), 5.04-5.05 (1H, m), 5.63 (2H, s), 6.91 (1H, s), 7.39-7.44 (2H, m), 7.53-7.62 (2H, m), 7.94-7.97 (4H, m), 8.05 (1H, s), 8.08 (1H, s), 8.51 (1H, s).
元素分析値 C₃₁H₂₉ClN₄O₇S・0.5H₂Oとして
計算値（％）：C, 57.63; H, 4.68; N, 8.67
実測値（％）：C, 57.91; H, 4.90; N, 8.64 Example 140
Benzoic acid [2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -3-oxo-2,3-dihydro- 1H-imidazo [1,5-c] imidazol-5-yl] methyl 2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl]-obtained in Example 139c) 2-Hydroxypropanoyl} -4-piperidinyl) -5- (hydroxymethyl) -1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one (0.14 g) and benzoyl chloride (31 μL) To 138) to give the title compound (58 mg, 34%) as a white powder.
NMR (300MHz, CDCl ₃ ) δ: 1.67-1.78 (2H, m), 1.90-2.05 (2H, m), 2.70-2.84 (1H, m), 3.17-3.31 (1H, m), 3.45-3.52 (2H , m), 3.80 (1H, bs), 4.11-4.38 (4H, m), 4.69-4.77 (1H, m), 5.04-5.05 (1H, m), 5.63 (2H, s), 6.91 (1H, s ), 7.39-7.44 (2H, m), 7.53-7.62 (2H, m), 7.94-7.97 (4H, m), 8.05 (1H, s), 8.08 (1H, s), 8.51 (1H, s).
Elemental analysis value Calculated as C ₃₁ H ₂₉ ClN ₄ O ₇ S · 0.5H ₂ O (%): C, 57.63; H, 4.68; N, 8.67
Found (%): C, 57.91; H, 4.90; N, 8.64

実施例141
2-[1-(trans-{2-[(6-クロロ-2-ナフチル)スルホニル]シクロプロピル}カルボニル)-4-ピペリジニル]-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
141a) 2-クロロ-6-(ビニルスルホニル)ナフタレン
2-クロロナフタレン-6-スルフィン酸（4.3g）、1,2-ジブロモエタン（3.3mL）および炭酸カリウム（4.0g）のDMF(30mL)けん濁液を70℃で18時間かき混ぜた。室温まで冷却した後、酢酸エチルと水を加え、有機層を分液した。酢酸エチル溶液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した後、溶媒を減圧留去した。残留物をシリカゲルカラム（酢酸エチル：ヘキサン＝１：５）により精製し、題記化合物（1.9g, 39%）を淡黄色固体として得た。
NMR (300MHz, CDCl₃)δ：6.09 (1H, d, J = 9.6), 6.53 (1H, d, J = 16.5), 6.72 (1H, dd, J = 16.5, 9.6), 7.55 (1H, dd, J = 8.6, 2.0), 7.82-7.92 (4H, m), 8.46 (1H, d, J = 0.6).
141b) trans-2-[(6-クロロ-2-ナフチル)スルホニル]シクロプロパンカルボン酸tert-ブチル
1,4-ジアザビシクロ[2.2.2]オクタン（0.89g）およびクロロ酢酸tert-ブチル(1.1mL)のアセトニトリル(30mL)溶液を室温で、30分かき混ぜた。その溶液に実施例141a)で得た2-クロロ-6-(ビニルスルホニル)ナフタレン（2.0g）および水酸化ナトリウム（0.48g）を加え、80℃で18時間かき混ぜた。アセトニトリルを減圧留去した後、酢酸エチルと水を加え、有機層を分液した。酢酸エチル溶液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した後、減圧濃縮した。残留物をシリカゲルカラム（酢酸エチル：ヘキサン＝１：３）により精製して、題記化合物（0.44g, 15%）を黄色油状物として得た。
NMR (200MHz, CDCl₃)δ：1.41 (9H, s), 1.44-1.55 (1H, m), 1.64-1.74 (1H, m), 2.47-2.57 (1H, m), 2.93-3.02 (1H, m), 7.58 (1H, dd, J = 8.8, 1.8), 7.86-7.96 (4H, m), 8.45 (1H, s).
141c) trans-2-[(6-クロロ-2-ナフチル)スルホニル]シクロプロパンカルボン酸
実施例141b)で得た2-[(6-クロロ-2-ナフチル)スルホニル]シクロプロパンカルボン酸tert-ブチル（0.44g）のトリフルオロ酢酸（2mL）溶液を室温で15分かき混ぜた。反応液を減圧濃縮して、題記化合物（0.35g, 94%）を淡褐色固体として得た。
NMR (200MHz, CDCl₃)δ：1.57-1.67 (1H, m), 1.81-1.91 (1H, m), 2.50-2.59 (1H, m), 3.02-3.11 (1H, m), 7.60 (1H, dd, J = 8.8, 1.8), 7.84-7.97 (4H, m), 8.45 (1H, s).
141d) 2-[1-(trans-{2-[(6-クロロ-2-ナフチル)スルホニル]シクロプロピル}カルボニル)-4-ピペリジニル]-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
実施例141c)で得られた2-[(6-クロロ-2-ナフチル)スルホニル]シクロプロパンカルボン酸（0.20g）および実施例69b)で得られた5-メチル-2-(4-ピペリジニル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン２塩酸塩(0.23g)から実施例128)と同様にして題記化合物（0.12g, 36%）を白色粉末として得た。
NMR (300MHz, CDCl₃)δ：1.44-2.05 (6H, m), 2.62 (3H, s), 2.65-2.82 (2H, m), 3.03-3.09 (1H, m), 3.20-3.30 (1H, m), 4.06-4.37 (4H, m), 4.70 (1H, d, J = 13.2), 6.73 (1H, d, J = 7.5), 7.58-7.61 (1H, m), 7.87-7.97 (4H, m), 8.45 (1H, s).
元素分析値 C₂₅H₂₅ClN₄O₄S・0.2H₂Oとして
計算値（％）：C, 58.12; H, 4.96; N, 10.85
実測値（％）：C, 57.97; H, 5.08; N, 11.13 Example 141
2- [1- (trans- {2-[(6-Chloro-2-naphthyl) sulfonyl] cyclopropyl} carbonyl) -4-piperidinyl] -5-methyl-1,2-dihydro-3H-imidazo [1, 5-c] imidazol-3-one
141a) 2-Chloro-6- (vinylsulfonyl) naphthalene
A suspension of 2-chloronaphthalene-6-sulfinic acid (4.3 g), 1,2-dibromoethane (3.3 mL) and potassium carbonate (4.0 g) in DMF (30 mL) was stirred at 70 ° C. for 18 hours. After cooling to room temperature, ethyl acetate and water were added, and the organic layer was separated. The ethyl acetate solution was 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 (ethyl acetate: hexane = 1: 5) to give the title compound (1.9 g, 39%) as a pale yellow solid.
NMR (300 MHz, CDCl ₃ ) δ: 6.09 (1H, d, J = 9.6), 6.53 (1H, d, J = 16.5), 6.72 (1H, dd, J = 16.5, 9.6), 7.55 (1H, dd, J = 8.6, 2.0), 7.82-7.92 (4H, m), 8.46 (1H, d, J = 0.6).
141b) tert-butyl trans-2-[(6-chloro-2-naphthyl) sulfonyl] cyclopropanecarboxylate
A solution of 1,4-diazabicyclo [2.2.2] octane (0.89 g) and tert-butyl chloroacetate (1.1 mL) in acetonitrile (30 mL) was stirred at room temperature for 30 minutes. 2-Chloro-6- (vinylsulfonyl) naphthalene (2.0 g) and sodium hydroxide (0.48 g) obtained in Example 141a) were added to the solution, and the mixture was stirred at 80 ° C. for 18 hours. Acetonitrile was distilled off under reduced pressure, ethyl acetate and water were added, and the organic layer was separated. The ethyl acetate solution was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column (ethyl acetate: hexane = 1: 3) to give the title compound (0.44 g, 15%) as a yellow oil.
NMR (200MHz, CDCl ₃ ) δ: 1.41 (9H, s), 1.44-1.55 (1H, m), 1.64-1.74 (1H, m), 2.47-2.57 (1H, m), 2.93-3.02 (1H, m ), 7.58 (1H, dd, J = 8.8, 1.8), 7.86-7.96 (4H, m), 8.45 (1H, s).
141c) trans-2-[(6-Chloro-2-naphthyl) sulfonyl] cyclopropanecarboxylic acid tert-butyl 2-[(6-chloro-2-naphthyl) sulfonyl] cyclopropanecarboxylate obtained in Example 141b) A solution of (0.44 g) in trifluoroacetic acid (2 mL) was stirred at room temperature for 15 minutes. The reaction mixture was concentrated under reduced pressure to give the title compound (0.35 g, 94%) as a light brown solid.
NMR (200MHz, CDCl ₃ ) δ: 1.57-1.67 (1H, m), 1.81-1.91 (1H, m), 2.50-2.59 (1H, m), 3.02-3.11 (1H, m), 7.60 (1H, dd , J = 8.8, 1.8), 7.84-7.97 (4H, m), 8.45 (1H, s).
141d) 2- [1- (trans- {2-[(6-chloro-2-naphthyl) sulfonyl] cyclopropyl} carbonyl) -4-piperidinyl] -5-methyl-1,2-dihydro-3H-imidazo [ 1,5-c] imidazol-3-one Obtained from 2-[(6-chloro-2-naphthyl) sulfonyl] cyclopropanecarboxylic acid (0.20 g) obtained in Example 141c) and Example 69b) 5-Methyl-2- (4-piperidinyl) -1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one dihydrochloride (0.23 g) to title as in Example 128) The compound (0.12 g, 36%) was obtained as a white powder.
NMR (300MHz, CDCl ₃ ) δ: 1.44-2.05 (6H, m), 2.62 (3H, s), 2.65-2.82 (2H, m), 3.03-3.09 (1H, m), 3.20-3.30 (1H, m ), 4.06-4.37 (4H, m), 4.70 (1H, d, J = 13.2), 6.73 (1H, d, J = 7.5), 7.58-7.61 (1H, m), 7.87-7.97 (4H, m) , 8.45 (1H, s).
Elemental analysis value Calculated as C ₂₅ H ₂₅ ClN ₄ O ₄ S · 0.2H ₂ O (%): C, 58.12; H, 4.96; N, 10.85
Found (%): C, 57.97; H, 5.08; N, 11.13

実施例142
2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシ-2-メチルプロパノイル}-4-ピペリジニル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン塩酸塩
142a) 3-[(6-クロロ-2-ナフチル)チオ]-2-ヒドロキシ-2-メチルプロピオン酸メチル
6-クロロナフタレン-2-チオール（5.0g）および2-メチルオキシラン-2-カルボン酸メチル（2.7mL）から実施例136a)と同様にして題記化合物（5.1g, 63%）を無色針状晶として得た。
NMR (300MHz, CDCl₃)δ：1.52 (3H, s), 3.27 (1H, d, J = 13.8), 3.44 (3H, s), 3.48 (1H, d, J = 13.8), 3.53 (1H, s), 7.38-7.42 (1H, m), 7.48-7.51 (1H, m), 7.64-7.69 (2H, m), 7.75 (1H, d, J = 2.1), 7.82 (1H, s).
142b) 3-[(6-クロロ-2-ナフチル)チオ]-2-ヒドロキシ-2-メチルプロピオン酸
実施例142a)で得られた3-[(6-クロロ-2-ナフチル)チオ]-2-ヒドロキシ-2-メチルプロピオン酸メチル（1.5g）から実施例136b)と同様にして題記化合物（1.3g, 91%）を白色粉末として得た。
NMR (300MHz, CDCl₃)δ：1.51 (3H, s), 3.38 (1H, d, J = 13.2), 3.48 (1H, d, J = 13.2), 7.41 (1H, dd, J = 8.7, 2.1), 7.53 (1H, dd, J = 8.7, 1.8), 7.69-7.77 (2H, m), 7.81 (1H, d, J = 2.1), 7.87 (1H, d, J = 1.8).
142c) 2-(1-{3-[(6-クロロ-2-ナフチル)チオ]-2-ヒドロキシ-2-メチルプロパノイル}-4-ピペリジニル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
実施例142b)で得られた3-[(6-クロロ-2-ナフチル)チオ]-2-ヒドロキシ-2-メチルプロピオン酸（0.50g）および実施例69b)で得られた5-メチル-2-(4-ピペリジニル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン２塩酸塩（0.59g）から実施例136c)と同様にして題記化合物（0.16g, 20%）を白色粉末として得た。
NMR (300MHz, CDCl₃)δ：1.45-1.61 (6H, m), 1.84-1.88 (2H, m), 2.59 (3H, s), 2.80 (1H, bs), 3.33 (1H, d, J = 13.4), 3.70 (1H, d, J = 13.4), 4.07-4.15 (2H, m), 4.31 (1H, bs), 4.60 (1H, d, J = 12.2), 4.72 (1H, d, J = 12.2), 6.66 (1H, t, J = 1.5), 7.42 (1H, dd, J = 8.7, 2.1), 7.51 (1H, dd, J = 8.7, 2.1), 7.66 (1H, s), 7.69 (1H, s), 7.77-7.78 (1H, m), 7.83-7.84 (1H, m).
142d) 2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシ-2-メチルプロパノイル}-4-ピペリジニル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン塩酸塩
142c)で得られた 2-(1-{3-[(6-クロロ-2-ナフチル)チオ]-2-ヒドロキシ-2-メチルプロパノイル}-4-ピペリジニル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン（0.16g）から実施例136d)と同様にして無色油状物を得た。この油状物を4N塩化水素酢酸エチル溶液(0.5mL)で処理して、題記化合物（20mg, 11%）を白色粉末として得た。
NMR (300MHz, CDCl₃)δ：1.55 (3H, s), 1.79-1.80 (2H, m), 2.76 (3H, s), 3.41-3.45 (4H, m), 3.71-3.80 (2H, m), 4.03-4.10 (2H, m), 4.58 (2H, s), 4.80-4.91 (1H, m), 5.92 (1H, bs), 7.45 (1H, s), 7.74 (1H, dd, J = 8.7, 2.1), 8.00 (1H, d, J = 8.7), 8.17 (1H, d, J = 8.7), 8.26-8.31 (2H, m), 8.60 (1H, s).
元素分析値 C₂₅H₂₇ClN₄O₄S・HCl・1.2H₂O・0.1Et₂Oとして
計算値（％）：C, 51.14; H, 5.31; N, 9.39
実測値（％）：C, 51.03; H, 5.55; N, 9.31 Example 142
2- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] -2-hydroxy-2-methylpropanoyl} -4-piperidinyl) -5-methyl-1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one hydrochloride
142a) Methyl 3-[(6-chloro-2-naphthyl) thio] -2-hydroxy-2-methylpropionate
Colorless needle crystals of the title compound (5.1 g, 63%) from 6-chloronaphthalene-2-thiol (5.0 g) and methyl 2-methyloxirane-2-carboxylate (2.7 mL) in the same manner as in Example 136a) Got as.
NMR (300MHz, CDCl ₃ ) δ: 1.52 (3H, s), 3.27 (1H, d, J = 13.8), 3.44 (3H, s), 3.48 (1H, d, J = 13.8), 3.53 (1H, s ), 7.38-7.42 (1H, m), 7.48-7.51 (1H, m), 7.64-7.69 (2H, m), 7.75 (1H, d, J = 2.1), 7.82 (1H, s).
142b) 3-[(6-Chloro-2-naphthyl) thio] -2-hydroxy-2-methylpropionic acid 3-[(6-Chloro-2-naphthyl) thio] -2 obtained in Example 142a) The title compound (1.3 g, 91%) was obtained as a white powder from methyl 2-hydroxy-2-methylpropionate (1.5 g) in the same manner as in Example 136b).
NMR (300MHz, CDCl ₃ ) δ: 1.51 (3H, s), 3.38 (1H, d, J = 13.2), 3.48 (1H, d, J = 13.2), 7.41 (1H, dd, J = 8.7, 2.1) , 7.53 (1H, dd, J = 8.7, 1.8), 7.69-7.77 (2H, m), 7.81 (1H, d, J = 2.1), 7.87 (1H, d, J = 1.8).
142c) 2- (1- {3-[(6-chloro-2-naphthyl) thio] -2-hydroxy-2-methylpropanoyl} -4-piperidinyl) -5-methyl-1,2-dihydro-3H -Imidazo [1,5-c] imidazol-3-one 3-[(6-Chloro-2-naphthyl) thio] -2-hydroxy-2-methylpropionic acid (0.50 g) obtained in Example 142b) And from 5-methyl-2- (4-piperidinyl) -1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one dihydrochloride (0.59 g) obtained in Example 69b) The title compound (0.16 g, 20%) was obtained as a white powder in the same manner as Example 136c).
NMR (300MHz, CDCl ₃ ) δ: 1.45-1.61 (6H, m), 1.84-1.88 (2H, m), 2.59 (3H, s), 2.80 (1H, bs), 3.33 (1H, d, J = 13.4 ), 3.70 (1H, d, J = 13.4), 4.07-4.15 (2H, m), 4.31 (1H, bs), 4.60 (1H, d, J = 12.2), 4.72 (1H, d, J = 12.2) , 6.66 (1H, t, J = 1.5), 7.42 (1H, dd, J = 8.7, 2.1), 7.51 (1H, dd, J = 8.7, 2.1), 7.66 (1H, s), 7.69 (1H, s ), 7.77-7.78 (1H, m), 7.83-7.84 (1H, m).
142d) 2- (1- {3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxy-2-methylpropanoyl} -4-piperidinyl) -5-methyl-1,2-dihydro-3H -Imidazo [1,5-c] imidazol-3-one hydrochloride
142c) 2- (1- {3-[(6-chloro-2-naphthyl) thio] -2-hydroxy-2-methylpropanoyl} -4-piperidinyl) -5-methyl-1,2 A colorless oil was obtained in the same manner as in Example 136d) from -dihydro-3H-imidazo [1,5-c] imidazol-3-one (0.16 g). This oil was treated with 4N hydrogen chloride ethyl acetate solution (0.5 mL) to give the title compound (20 mg, 11%) as a white powder.
NMR (300MHz, CDCl ₃ ) δ: 1.55 (3H, s), 1.79-1.80 (2H, m), 2.76 (3H, s), 3.41-3.45 (4H, m), 3.71-3.80 (2H, m), 4.03-4.10 (2H, m), 4.58 (2H, s), 4.80-4.91 (1H, m), 5.92 (1H, bs), 7.45 (1H, s), 7.74 (1H, dd, J = 8.7, 2.1 ), 8.00 (1H, d, J = 8.7), 8.17 (1H, d, J = 8.7), 8.26-8.31 (2H, m), 8.60 (1H, s).
Elemental Analysis Value Calculated as C ₂₅ H ₂₇ ClN ₄ O ₄ S · HCl · 1.2H ₂ O · 0.1 Et ₂ O (%): C, 51.14; H, 5.31; N, 9.39
Found (%): C, 51.03; H, 5.55; N, 9.31

実施例143
1-{[(6-クロロ-2-ナフチル)スルホニル]メチル}-2-[4-(5-メチル-3-オキソ-1H-イミダゾール[1,5-c]イミダゾール-2-イル)-1-ピペリジニル]-2-オキソエチルカルバミン酸tert-ブチル
143a) 2-(tert-ブトキシカルボニルアミノ)-3-[(6-クロロ-2-ナフチル)チオ]プロピオン酸メチル
N-tert-ブトキシカルボニルセリンメチルエステル(2.82g)とトリエチルアミン(5.35mL)のTHF(50mL)溶液へ塩化メタンスルホニル(0.99mL)を滴下し、室温で１時間かき混ぜた後、6-クロロナフタレン-2-チオール(2.50g)を加えた。反応液を室温で20時間かき混ぜた後、溶媒を減圧留去した。残留物へ水を加え、酢酸エチルで抽出した。抽出液を水洗後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去した後、残留物をシリカゲルカラムで精製して、題記化合物(2.79g, 55%)を淡褐色油状物として得た。
NMR (200MHz, CDCl₃)δ：1.37 (9H, s), 3.46-3.50 (5H, m), 4.60 (1H, m), 5.34 (1H, m), 7.42 (1H, dd, J = 1.4, 8.8), 7.49 (1H , dd, J = 1.8, 8.4), 7.66-7.71 (2H, m), 7.77 (1H, d, J = 2.2), 7.84 (1H, d, J = 1.4)
143b) 2-(tert-ブトキシカルボニルアミノ)-3-[(6-クロロ-2-ナフチル)チオ]プロピオン酸
実施例143a)で得られた2-(tert-ブトキシカルボニルアミノ)-3-[(6-クロロ-2-ナフチル)チオ]プロピオン酸メチル(2.79g)と1N水酸化ナトリウム(7.7mL)の2-プロパノール(70mL)溶液を室温で３時間かき混ぜた。溶媒を減圧留去した後、残留物に水を加え、1NHClで酸性にし、酢酸エチルで抽出した。抽出液を水洗後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残留物をシリカゲルカラムで精製して、題記化合物(1.1g, 41%)を固体として得た。
NMR (200MHz, CDCl₃)δ：1.36 (9H, s), 3.38-3.58 (3H, m), 7.41 (1H, dd, J = 2.2, 8.8), 7.50 (1H, dd, J = 1.8, 8.8), 7.65-7.84 (4H, m).
143c) 1-{[(6-クロロ-2-ナフチル)チオ]メチル}-2-[4-(5-メチル-3-オキソ-1H-イミダゾール[1,5-c]イミダゾール-2-イル)-1-ピペリジニル]-2-オキソエチルカルバミン酸tert-ブチル
実施例143b)で得られた2-(tert-ブトキシカルボニルアミノ)-3-[(6-クロロ-2-ナフチル)チオ]プロピオン酸(1.1g)と実施例69b)で得られた5-メチル-2-(4-ピペリジニル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン２塩酸塩(0.85g)から実施例136c)と同様にして、題記化合物(0.55g, 33%)を得た。
NMR (200MHz, CDCl₃)δ：1.45 (9H, s), 1.55-1.81 (4H, m), 2.59 (3H, s), 3.01-3.08 (1H, m), 3.30-3.40 (2H, m), 3.90 (2H, s), 3.98-4.19 (3H, m), 4.60-4.77 (1H, m), 4.91 (1H, m), 5.49-5.52 (1H,m), 6.68 (1H, s), 7.41-7.48 (2H, m), 7.67-7.78 (3H, m), 7.86-7.90 (1H, m).
143d) 1-{[(6-クロロ-2-ナフチル)スルホニル]メチル}-2-[4-(5-メチル-3-オキソ-1H-イミダゾール[1,5-c]イミダゾール-2-イル)-1-ピペリジニル]-2-オキソエチルカルバミン酸tert-ブチル
実施例143c)で得られた1-{[(6-クロロ-2-ナフチル)チオ]メチル}-2-[4-(5-メチル-3-オキソ-1H-イミダゾール[1,5-c]イミダゾール-2-イル)-1-ピペリジニル]-2-オキソエチルカルバミン酸tert-ブチル(0.55g)から実施例136d)と同様にして題記化合物(0.15g, 26%)を無色粉末として得た。
NMR (200MHz, CDCl₃)δ：1.27-1.44 (11H, m), 1.82-2.02 (2H, m), 2.40-2.77 (4H, m), 3.21-3.89 (2H, m), 4.23-4.29 (4H, m), 4.56-4.85 (1H, m), 5.14-5.36 (2H, m), 6.66-6.71 (1H,m), 7.60 (1H, dd, J = 2.0, 9.0), 7.94-7.98 (4H, m), 8.50 (1H, s). Example 143
1-{[(6-chloro-2-naphthyl) sulfonyl] methyl} -2- [4- (5-methyl-3-oxo-1H-imidazole [1,5-c] imidazol-2-yl) -1 -Piperidinyl] -2-oxoethylcarbamate tert-butyl
143a) Methyl 2- (tert-butoxycarbonylamino) -3-[(6-chloro-2-naphthyl) thio] propionate
Methanesulfonyl chloride (0.99 mL) was added dropwise to a solution of N-tert-butoxycarbonylserine methyl ester (2.82 g) and triethylamine (5.35 mL) in THF (50 mL), and the mixture was stirred at room temperature for 1 hour, and then 6-chloronaphthalene- 2-thiol (2.50 g) was added. The reaction mixture was stirred at room temperature for 20 hours, and the solvent was evaporated under reduced pressure. Water was added to the residue and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by a silica gel column to give the title compound (2.79 g, 55%) as a pale brown oil.
NMR (200MHz, CDCl ₃ ) δ: 1.37 (9H, s), 3.46-3.50 (5H, m), 4.60 (1H, m), 5.34 (1H, m), 7.42 (1H, dd, J = 1.4, 8.8 ), 7.49 (1H, dd, J = 1.8, 8.4), 7.66-7.71 (2H, m), 7.77 (1H, d, J = 2.2), 7.84 (1H, d, J = 1.4)
143b) 2- (tert-butoxycarbonylamino) -3-[(6-chloro-2-naphthyl) thio] propionic acid 2- (tert-butoxycarbonylamino) -3-[( A solution of methyl 6-chloro-2-naphthyl) thio] propionate (2.79 g) and 1N sodium hydroxide (7.7 mL) in 2-propanol (70 mL) was stirred at room temperature for 3 hours. After the solvent was distilled off under reduced pressure, water was added to the residue, acidified with 1N HCl, and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with a silica gel column to give the title compound (1.1 g, 41%) as a solid.
NMR (200MHz, CDCl ₃ ) δ: 1.36 (9H, s), 3.38-3.58 (3H, m), 7.41 (1H, dd, J = 2.2, 8.8), 7.50 (1H, dd, J = 1.8, 8.8) , 7.65-7.84 (4H, m).
143c) 1-{[(6-chloro-2-naphthyl) thio] methyl} -2- [4- (5-methyl-3-oxo-1H-imidazole [1,5-c] imidazol-2-yl) Tert-Butyl-1-piperidinyl] -2-oxoethylcarbamate 2- (tert-butoxycarbonylamino) -3-[(6-chloro-2-naphthyl) thio] propionic acid obtained in Example 143b) 1.1 g) and Example 69b) 5-methyl-2- (4-piperidinyl) -1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one dihydrochloride (0.85 The title compound (0.55 g, 33%) was obtained in the same manner as in Example 136c) from g).
NMR (200MHz, CDCl ₃ ) δ: 1.45 (9H, s), 1.55-1.81 (4H, m), 2.59 (3H, s), 3.01-3.08 (1H, m), 3.30-3.40 (2H, m), 3.90 (2H, s), 3.98-4.19 (3H, m), 4.60-4.77 (1H, m), 4.91 (1H, m), 5.49-5.52 (1H, m), 6.68 (1H, s), 7.41- 7.48 (2H, m), 7.67-7.78 (3H, m), 7.86-7.90 (1H, m).
143d) 1-{[(6-chloro-2-naphthyl) sulfonyl] methyl} -2- [4- (5-methyl-3-oxo-1H-imidazole [1,5-c] imidazol-2-yl) 1-piperidinyl] -2-oxoethylcarbamate tert-butyl 1-{[(6-chloro-2-naphthyl) thio] methyl} -2- [4- (5-methyl) obtained in Example 143c) Titled from tert-butyl-3-oxo-1H-imidazole [1,5-c] imidazol-2-yl) -1-piperidinyl] -2-oxoethylcarbamate (0.55 g) as in Example 136d) The compound (0.15 g, 26%) was obtained as a colorless powder.
NMR (200MHz, CDCl ₃ ) δ: 1.27-1.44 (11H, m), 1.82-2.02 (2H, m), 2.40-2.77 (4H, m), 3.21-3.89 (2H, m), 4.23-4.29 (4H , m), 4.56-4.85 (1H, m), 5.14-5.36 (2H, m), 6.66-6.71 (1H, m), 7.60 (1H, dd, J = 2.0, 9.0), 7.94-7.98 (4H, m), 8.50 (1H, s).

実施例144
2-(1-{2-アミノ-3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン２塩酸塩
実施例143d)で得られた1-{[(6-クロロ-2-ナフチル)スルホニル]メチル}-2-[4-(5-メチル-3-オキソ-1H-イミダゾール[1,5-c]イミダゾール-2-イル)-1-ピペリジニル]-2-オキソエチルカルバミン酸tert-ブチル(0.10g)のエタノール(0.5mL)溶液へ飽和塩化水素エタノール溶液(1.5mL)を加え室温で30分間かき混ぜた後、溶媒を減圧留去した。残留物をエーテルで洗浄して、題記化合物(85mg, 90%)を無色粉末として得た。
NMR (200MHz, DMSO-d₆)δ：1.53-1.86 (4H, m), 2.07-2.42 (1H, m), 2.72 (3H, br s), 3.13-3.26 (1H, m), 3.71-4.37 (5H, m), 4.50-4.55 (2H, m), 4.86 (1H, m), 7.42 (1H, s), 7.77 (1H, d, J = 8.4), 8.02 (1H, dt, J = 1.8, 7.3), 8.20-8.34 (3H, m), 8.5-9.0 (3H, m). Example 144
2- (1- {2-amino-3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -5-methyl-1,2-dihydro-3H-imidazo [1,5- c] imidazol-3-one dihydrochloride 1-{[(6-chloro-2-naphthyl) sulfonyl] methyl} -2- [4- (5-methyl-3-oxo-) obtained in Example 143d) 1H-imidazole [1,5-c] imidazol-2-yl) -1-piperidinyl] -2-oxoethylcarbamate tert-butyl (0.10 g) in ethanol (0.5 mL) solution to saturated hydrogen chloride ethanol solution (1.5 mL) was added and stirred at room temperature for 30 minutes, and then the solvent was distilled off under reduced pressure. The residue was washed with ether to give the title compound (85 mg, 90%) as a colorless powder.
NMR (200MHz, DMSO-d ₆ ) δ: 1.53-1.86 (4H, m), 2.07-2.42 (1H, m), 2.72 (3H, br s), 3.13-3.26 (1H, m), 3.71-4.37 ( 5H, m), 4.50-4.55 (2H, m), 4.86 (1H, m), 7.42 (1H, s), 7.77 (1H, d, J = 8.4), 8.02 (1H, dt, J = 1.8, 7.3 ), 8.20-8.34 (3H, m), 8.5-9.0 (3H, m).

実施例145
2-(1-{3-[(6-クロロ-3,4-ジヒドロイソキノリン-2(1H)-イル)スルホニル]プロパノイル}-4-ピペリジニル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
145a) 3-[(6-クロロ-3,4-ジヒドロイソキノリン-2(1H)-イル)スルホニル]プロピオン酸メチル
6-クロロ-1,2,3,4-テトラヒドロイソキノリン塩酸塩(0.19g)とトリエチルアミン(0.26mL)のアセトニトリル(1mL)溶液を3-(クロロスルホニル)プロピオン酸メチル(0.19g)のアセトニトリル(1mL)溶液に加え、0℃で0.5時間かき混ぜた。反応液を減圧濃縮し、クロロホルムと水を加えた。有機層を分取し、飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去して、題記化合物(0.30g, 定量的)を茶色固体として得た。
NMR (300MHz, CDCl₃)δ: 2.82 (2H, t, J = 7.2), 2.93 (2H, t, J = 6.0), 3.32 (2H, t, J = 7.5), 3.57 (2H, t, J = 6.0), 3.67 (3H, s), 4.44 (2H, s), 7.01-7.03 (1H, m), 7.16-7.19 (2H, m).
145b) 3-[(6-クロロ-3,4-ジヒドロイソキノリン-2(1H)-イル)スルホニル]プロピオン酸
実施例145a)で得られた3-[(6-クロロ-3,4-ジヒドロイソキノリン-2(1H)-イル)スルホニル]プロピオン酸メチル(0.30g)を1N水酸化ナトリウム水溶液(2.7mL)に加え、100℃で20分間加熱した。0℃に冷却した後、1N塩酸を加え酸性にし、析出した固体をろ取し題記化合物(0.04g, 16%)を茶色粉末として得た。
NMR (300MHz, CDCl₃)δ: 2.86 (2H, t, J = 7.5), 2.93 (2H, t, J = 6.0), 3.31 (2H, t, J = 7.5), 3.57 (2H, t, J = 6.0), 4.44 (2H, s), 7.01 (1H, d, J = 8.1), 7.14-7.25 (2H, m).
145c) 2-(1-(3-((6-クロロ-3,4-ジヒドロ-2(1H)-イソキノリニル)スルホニル)プロパノイル)-4-ピペリジニル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
実施例145b)で得られた3-[(6-クロロ-3,4-ジヒドロイソキノリン-2(1H)-イル)スルホニル]プロピオン酸(0.04g)、WSC(0.05g)およびHOBt(0.04g)のTHF溶液(3mL)にトリエチルアミン(0.06mL)を加え室温で30分間かき混ぜた後、実施例69b)で得られた5-メチル-2-(4-ピペリジニル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン２塩酸塩(0.03g)を加え室温で3時間かき混ぜた。溶媒を減圧留去し、残留物を酢酸エチルに溶解した。酢酸エチル溶液を飽和炭酸水素ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残留物を酢酸エチル-エーテルより再結晶し、題記化合物(0.01g, 18%)を白色粉末として得た。
NMR (300MHz, CDCl₃)δ: 1.19-1.28 (1H, m), 1.60-1.75 (2H, m), 1.89-1.99 (2H, m), 2.69 (3H, s), 2.77-2.97 (3H, m), 3.19-3.52 (3H, m), 3.58 (2H, t, J = 6.0), 3.97-4.02 (1H, m), 4.09-4.23 (2H, m), 4.30 (2H, s), 4.46 (2H, s), 4.75-4.79 (1H, m), 6.81 (1H, s), 7.03 (1H, d, J = 8.1), 7.17 (1H, s), 7.18 (1H, d, J = 8.1).
元素分析値 C₂₃H₂₈ClN₅O₄S・H₂Oとして
計算値（％）：C, 52.72； H, 5.77； N, 13.36
実測値（％）：C, 52.65； H, 5.55； N, 13.12 Example 145
2- (1- {3-[(6-Chloro-3,4-dihydroisoquinolin-2 (1H) -yl) sulfonyl] propanoyl} -4-piperidinyl) -5-methyl-1,2-dihydro-3H- Imidazo [1,5-c] imidazol-3-one
145a) Methyl 3-[(6-chloro-3,4-dihydroisoquinolin-2 (1H) -yl) sulfonyl] propionate
A solution of 6-chloro-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.19 g) and triethylamine (0.26 mL) in acetonitrile (1 mL) was added to methyl 3- (chlorosulfonyl) propionate (0.19 g) in acetonitrile (1 mL). ) Added to the solution and stirred at 0 ° C. for 0.5 hour. The reaction solution was concentrated under reduced pressure, and chloroform and water were added. The organic layer was separated, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (0.30 g, quantitative) as a brown solid.
NMR (300MHz, CDCl ₃ ) δ: 2.82 (2H, t, J = 7.2), 2.93 (2H, t, J = 6.0), 3.32 (2H, t, J = 7.5), 3.57 (2H, t, J = 6.0), 3.67 (3H, s), 4.44 (2H, s), 7.01-7.03 (1H, m), 7.16-7.19 (2H, m).
145b) 3-[(6-Chloro-3,4-dihydroisoquinolin-2 (1H) -yl) sulfonyl] propionic acid 3-[(6-Chloro-3,4-dihydroisoquinoline) obtained in Example 145a) -2 (1H) -yl) sulfonyl] methyl propionate (0.30 g) was added to 1N aqueous sodium hydroxide solution (2.7 mL) and heated at 100 ° C. for 20 minutes. After cooling to 0 ° C., 1N hydrochloric acid was added to acidify, and the precipitated solid was collected by filtration to give the title compound (0.04 g, 16%) as a brown powder.
NMR (300MHz, CDCl ₃ ) δ: 2.86 (2H, t, J = 7.5), 2.93 (2H, t, J = 6.0), 3.31 (2H, t, J = 7.5), 3.57 (2H, t, J = 6.0), 4.44 (2H, s), 7.01 (1H, d, J = 8.1), 7.14-7.25 (2H, m).
145c) 2- (1- (3-((6-Chloro-3,4-dihydro-2 (1H) -isoquinolinyl) sulfonyl) propanoyl) -4-piperidinyl) -5-methyl-1,2-dihydro-3H -Imidazo [1,5-c] imidazol-3-one 3-[(6-Chloro-3,4-dihydroisoquinolin-2 (1H) -yl) sulfonyl] propionic acid (0.04) obtained in Example 145b) g), WSC (0.05 g) and HOBt (0.04 g) in THF solution (3 mL), triethylamine (0.06 mL) was added, and the mixture was stirred at room temperature for 30 min. (4-Piperidinyl) -1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one dihydrochloride (0.03 g) was added and stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with a saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate-ether to give the title compound (0.01 g, 18%) as a white powder.
NMR (300MHz, CDCl ₃ ) δ: 1.19-1.28 (1H, m), 1.60-1.75 (2H, m), 1.89-1.99 (2H, m), 2.69 (3H, s), 2.77-2.97 (3H, m ), 3.19-3.52 (3H, m), 3.58 (2H, t, J = 6.0), 3.97-4.02 (1H, m), 4.09-4.23 (2H, m), 4.30 (2H, s), 4.46 (2H , s), 4.75-4.79 (1H, m), 6.81 (1H, s), 7.03 (1H, d, J = 8.1), 7.17 (1H, s), 7.18 (1H, d, J = 8.1).
Elemental analysis value Calculated as C ₂₃ H ₂₈ ClN ₅ O ₄ S · H ₂ O (%): C, 52.72; H, 5.77; N, 13.36
Found (%): C, 52.65; H, 5.55; N, 13.12

実施例146
2-[1-(4-{[(E)-2-(4-クロロフェニル)ビニル]スルホニル}ブタノイル)-4-ピペリジニル]-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
146a) [(E)-2-(4-クロロフェニル)ビニル]スルフィン酸ナトリウム
亜硫酸ナトリウム(3.8g)および炭酸水素ナトリウム(2.5g)の水溶液(40mL)に塩化 (E)-2-(4-クロロフェニル)エチレンスルホニル(Matier, W. L. et al., J. Med. Chem., 17, 549 (1974)) (3.5g)を加え、70℃で2時間かき混ぜた。反応液を室温に冷却し、析出した結晶をろ取、乾燥して、題記化合物(1.7g, 50%)を淡黄色粉末として得た。
NMR (200MHz, DMSO-d₆)δ: 6.57 (1H, d, J = 16.0), 6.78 (1H, d, J = 16.0), 7.34-7.56 (4H, m).
146b) 4-{[(E)-2-(4-クロロフェニル)ビニル]スルホニル}ブタン酸
実施例146a)で得られた[(E)-2-(4-クロロフェニル)ビニル]スルフィン酸ナトリウム(0.23g)および4-ブロモブタン酸エチル(0.16mL)のDMF(1.0mL)溶液を100℃で1時間かき混ぜた。反応混合物を室温に冷却後、酢酸エチルを加え、水洗し、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、4-{[(E)-2-(4-クロロフェニル)ビニル]スルホニル}ブタン酸エチル(0.27g)を黄色油状物として得た。これを精製することなく実施例145b)と同様にして題記化合物(0.05g, 16%)を白色粉末として得た。
NMR (200MHz, CDCl₃)δ: 1.83-1.94 (2H, m), 2.36-2.43 (2H, m), 3.16-3.28 (2H, m), 7.42-7.56 (4H, m), 7.78-7.82 (2H, m).
146c) 2-[1-(4-{[(E)-2-(4-クロロフェニル)ビニル]スルホニル}ブタノイル)-4-ピペリジニル]-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
実施例146b)で得た4-{[(E)-2-(4-クロロフェニル)ビニル]スルホニル}ブタン酸(0.04g)から実施例145c)と同様にして題記化合物(0.02g, 29%)を無色粉末として得た。
NMR (300MHz, CDCl₃)δ: 1.60-1.74 (2H, m), 1.83-1.97 (3H, m), 2.15-2.25 (2H, m), 2.55-2.69 (5H, m), 3.12-3.28 (3H, m), 3.96-4.00 (1H, m), 4.13-4.21 (1H, m), 4.27 (2H, s), 4.76-4.81 (1H, m), 6.71 (1H, s), 6.83 (1H, d, J = 15.6), 7.35-7.47 (4H, m), 7.54 (1H, d, J = 15.6).
元素分析値 C₂₃H₂₇ClN₄O₄S・1.5H₂O・0.5AcOEtとして
計算値（％）：C, 53.42； H, 6.10； N, 9.97
実測値（％）：C, 53.68； H, 5.85； N, 10.28 Example 146
2- [1- (4-{[(E) -2- (4-Chlorophenyl) vinyl] sulfonyl} butanoyl) -4-piperidinyl] -5-methyl-1,2-dihydro-3H-imidazo [1,5 -c] imidazol-3-one
146a) [(E) -2- (4-Chlorophenyl) vinyl] sodium sulfinate Sodium chloride (3.8 g) and sodium bicarbonate (2.5 g) in aqueous solution (40 mL) chloride (E) -2- (4-chlorophenyl) ) Ethylenesulfonyl (Matier, WL et al., J. Med. Chem., 17, 549 (1974)) (3.5 g) was added, and the mixture was stirred at 70 ° C. for 2 hours. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration and dried to give the title compound (1.7 g, 50%) as a pale yellow powder.
NMR (200MHz, DMSO-d ₆ ) δ: 6.57 (1H, d, J = 16.0), 6.78 (1H, d, J = 16.0), 7.34-7.56 (4H, m).
146b) 4-{[((E) -2- (4-chlorophenyl) vinyl] sulfonyl} butanoic acid [(E) -2- (4-chlorophenyl) vinyl] sodium sulfinate (0.23) obtained in Example 146a) g) and ethyl 4-bromobutanoate (0.16 mL) in DMF (1.0 mL) were stirred at 100 ° C. for 1 hour. The reaction mixture was cooled to room temperature, ethyl acetate was added, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain ethyl 4-{[(E) -2- (4-chlorophenyl) vinyl] sulfonyl} butanoate (0.27 g) as a yellow oil. The title compound (0.05 g, 16%) was obtained as a white powder in the same manner as Example 145b) without purification.
NMR (200MHz, CDCl ₃ ) δ: 1.83-1.94 (2H, m), 2.36-2.43 (2H, m), 3.16-3.28 (2H, m), 7.42-7.56 (4H, m), 7.78-7.82 (2H , m).
146c) 2- [1- (4-{[(E) -2- (4-chlorophenyl) vinyl] sulfonyl} butanoyl) -4-piperidinyl] -5-methyl-1,2-dihydro-3H-imidazo [1 , 5-c] imidazol-3-one 4-{[(E) -2- (4-chlorophenyl) vinyl] sulfonyl} butanoic acid (0.04 g) obtained in Example 146b) was used in the same manner as in Example 145c). The title compound (0.02 g, 29%) was obtained as a colorless powder.
NMR (300MHz, CDCl ₃ ) δ: 1.60-1.74 (2H, m), 1.83-1.97 (3H, m), 2.15-2.25 (2H, m), 2.55-2.69 (5H, m), 3.12-3.28 (3H , m), 3.96-4.00 (1H, m), 4.13-4.21 (1H, m), 4.27 (2H, s), 4.76-4.81 (1H, m), 6.71 (1H, s), 6.83 (1H, d , J = 15.6), 7.35-7.47 (4H, m), 7.54 (1H, d, J = 15.6).
Elemental analysis _{_{_{_{C 23 H 27 ClN 4 O 4}}}} S · 1.5H calcd _{2 O · 0.5AcOEt (%):} C, 53.42; H, 6.10; N, 9.97
Found (%): C, 53.68; H, 5.85; N, 10.28

実施例147
2-(1-{3-[(6-クロロ-2-ナフチル)チオ]-3-メチルブタノイル}-4-ピペリジニル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン塩酸塩
147a) 3-[(6-クロロ-2-ナフチル)チオ]-3-メチルブタン酸
6-クロロナフタレン-2-チオール(1.0g)と3-メチル-2-ブテン酸(0.50g)およびトリエチルアミン(0.35mL)のTHF(40mL)溶液を一夜加熱還流した。反応液を室温に冷却後、溶媒を減圧留去し、残留物に酢酸エチルを加えた。混合液を水で洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残留物をシリカゲルカラム(酢酸エチル/ヘキサン=3/7から1/1)で精製して、題記化合物(0.10g, 7%)を白色粉末として得た。
NMR (300MHz, CDCl₃)δ: 1.46 (6H, s), 2.60 (2H, s), 7.45 (1H, dd, J = 1.8, 8.4), 7.63 (1H, dd, J = 1.8, 8.3), 7.72 (1H, d, J = 8.4), 7.77 (1H, d, J = 8.7), 7.83 (1H, d, J = 2.1), 8.07 (1H, s).
147b) 2-(1-{3-[(6-クロロ-2-ナフチル)チオ]-3-メチルブタノイル}-4-ピペリジニル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン塩酸塩
実施例147a)で得えられた3-[(6-クロロ-2-ナフチル)チオ]-3-メチルブタン酸(0.10g)と実施例69b)で得られた5-メチル-2-(4-ピペリジニル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン２塩酸塩(0.15g)から実施例145c)と同様にして題記化合物(0.13g, 74%)を白色粉末として得た。
NMR (300MHz, CDCl₃)δ: 1.46 (3H, s), 1.49 (3H, s), 1.70 (1H, s), 1.92-1.99 (1H, m), 2.57-2.65 (1H, m), 2.70 (2H, s), 2.99 (3H, s), 3.11-3.19 (1H, m), 4.01-4.06 (1H, m), 4.10-4.23 (1H, m), 4.53 (2H, s), 4.87-4.91 (1H, m), 7.24 (1H, s), 7.46 (1H, dd, J = 1.8, 8.7), 7.59 (1H, dd, J = 1.8, 8.4), 7.72 (1H, d, J = 8.7), 7.77 (1H, d, J = 8.7), 7.83 (1H, d, J = 1.8), 8.04 (1H, s).
元素分析値 C₂₆H₂₉N₄O₂SCl・HCl・1.5H₂Oとして
計算値（％）：C, 55.71； H, 5.93； N, 10.00
実測値（％）：C, 55.92； H, 6.02； N, 10.21 Example 147
2- (1- {3-[(6-Chloro-2-naphthyl) thio] -3-methylbutanoyl} -4-piperidinyl) -5-methyl-1,2-dihydro-3H-imidazo [1,5 -c] imidazol-3-one hydrochloride
147a) 3-[(6-Chloro-2-naphthyl) thio] -3-methylbutanoic acid
A solution of 6-chloronaphthalene-2-thiol (1.0 g), 3-methyl-2-butenoic acid (0.50 g) and triethylamine (0.35 mL) in THF (40 mL) was heated to reflux overnight. After cooling the reaction solution to room temperature, the solvent was distilled off under reduced pressure, and ethyl acetate was added to the residue. The mixture was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (ethyl acetate / hexane = 3/7 to 1/1) to give the title compound (0.10 g, 7%) as a white powder.
NMR (300MHz, CDCl ₃ ) δ: 1.46 (6H, s), 2.60 (2H, s), 7.45 (1H, dd, J = 1.8, 8.4), 7.63 (1H, dd, J = 1.8, 8.3), 7.72 (1H, d, J = 8.4), 7.77 (1H, d, J = 8.7), 7.83 (1H, d, J = 2.1), 8.07 (1H, s).
147b) 2- (1- {3-[(6-Chloro-2-naphthyl) thio] -3-methylbutanoyl} -4-piperidinyl) -5-methyl-1,2-dihydro-3H-imidazo [1 , 5-c] imidazol-3-one hydrochloride 3-[(6-chloro-2-naphthyl) thio] -3-methylbutanoic acid (0.10 g) obtained in Example 147a) and Example 69b) Similar to Example 145c) from the obtained 5-methyl-2- (4-piperidinyl) -1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one dihydrochloride (0.15 g) The title compound (0.13 g, 74%) was obtained as a white powder.
NMR (300MHz, CDCl ₃ ) δ: 1.46 (3H, s), 1.49 (3H, s), 1.70 (1H, s), 1.92-1.99 (1H, m), 2.57-2.65 (1H, m), 2.70 ( 2H, s), 2.99 (3H, s), 3.11-3.19 (1H, m), 4.01-4.06 (1H, m), 4.10-4.23 (1H, m), 4.53 (2H, s), 4.87-4.91 ( 1H, m), 7.24 (1H, s), 7.46 (1H, dd, J = 1.8, 8.7), 7.59 (1H, dd, J = 1.8, 8.4), 7.72 (1H, d, J = 8.7), 7.77 (1H, d, J = 8.7), 7.83 (1H, d, J = 1.8), 8.04 (1H, s).
Elemental analysis value Calculated as C ₂₆ H ₂₉ N ₄ O ₂ SCl · HCl · 1.5H ₂ O (%): C, 55.71; H, 5.93; N, 10.00
Found (%): C, 55.92; H, 6.02; N, 10.21

実施例148
2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]-3-メチルブタノイル}-4-ピペリジニル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
実施例147b)で得られた2-(1-{3-[(6-クロロ-2-ナフチル)チオ]-3-メチルブタノイル}-4-ピペリジニル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン塩酸塩(0.13g)のメタノール(2.5mL)溶液にメタクロロ過安息香酸(0.10g)を0℃で加え、3時間かき混ぜた。反応溶液にチオ硫酸ナトリウム水溶液を加え、酢酸エチルで抽出した。抽出液を飽和炭酸水素ナトリウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残留物を塩基性シリカゲルカラム(酢酸エチル)で精製して、題記化合物(0.09g, 70%)を白色粉末として得た。
NMR (300MHz, CDCl₃)δ: 1.48 (3H, s), 1.56 (3H, s), 1.60-1.83 (2H, m), 1.86-1.99 (3H, m), 2.61 (3H, s), 2.64-2.68 (1H, m), 2.88-2.98 (2H, m), 3.18-3.26 (1H, m), 4.13-4.23 (2H, m), 4.28 (2H, s), 4.79-4.84 (1H, m), 6.70 (1H, t, J = 1.5), 7.59 (1H, dd, J = 2.1, 8.7), 7.86-7.96 (4H, m), 8.41 (1H, s).
元素分析値 C₂₆H₂₉N₄O₄SCl・0.5H₂O・AcOEtとして
計算値（％）：C, 57.54； H, 6.12； N, 8.95
実測値（％）：C, 57.82； H, 5.90； N, 9.22 Example 148
2- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] -3-methylbutanoyl} -4-piperidinyl) -5-methyl-1,2-dihydro-3H-imidazo [1,5 -c] imidazol-3-one 2- (1- {3-[(6-chloro-2-naphthyl) thio] -3-methylbutanoyl} -4-piperidinyl) -5 obtained in Example 147b) -Methyl-1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one Hydrochloric acid (0.13g) in methanol (2.5mL) with metachloroperbenzoic acid (0.10g) at 0 ° C In addition, it was stirred for 3 hours. A sodium thiosulfate aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with a basic silica gel column (ethyl acetate) to obtain the title compound (0.09 g, 70%) as a white powder.
NMR (300MHz, CDCl ₃ ) δ: 1.48 (3H, s), 1.56 (3H, s), 1.60-1.83 (2H, m), 1.86-1.99 (3H, m), 2.61 (3H, s), 2.64- 2.68 (1H, m), 2.88-2.98 (2H, m), 3.18-3.26 (1H, m), 4.13-4.23 (2H, m), 4.28 (2H, s), 4.79-4.84 (1H, m), 6.70 (1H, t, J = 1.5), 7.59 (1H, dd, J = 2.1, 8.7), 7.86-7.96 (4H, m), 8.41 (1H, s).
Elemental Analysis Value Calculated as C ₂₆ H ₂₉ N ₄ O ₄ SCl · 0.5H ₂ O · AcOEt (%): C, 57.54; H, 6.12; N, 8.95
Found (%): C, 57.82; H, 5.90; N, 9.22

実施例149
2-[1-(3-{[2-(4-クロロフェニル)エチル]チオ}プロパノイル)-4-ピペリジニル]-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン塩酸塩
4-メチルベンゼンスルホン酸 2-(4-クロロフェニル)エチル(Schadt, F. L. et al., J. Am. Chem. Soc., 100, 228-246 (1978)) (1.2g)と3-メルカプトプロピオン酸(0.35mL)および1N水酸化ナトリウム水溶液(12mL)の混合物を100℃で一夜かき混ぜた。反応混合物を室温に冷却後、1N塩酸で酸性にし、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、3-{[2-(4-クロロフェニル)エチル]チオ}プロピオン酸(0.26g)の粗生成物を得た。このカルボン酸と実施例69b)で得られた5-メチル-2-(4-ピペリジニル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン２塩酸塩(0.24g)から実施例145c)と同様にして題記化合物(0.06g, 13%)を白色粉末として得た。
NMR (300MHz, CDCl₃)δ:1.56-1.70 (2H, m), 1.79-1.96 (3H, m), 2.57-2.70 (5H, m), 2.76-2.91 (5H, m), 3.11-3.19 (1H, m), 3.92-3.97 (2H, m), 4.10-4.29 (3H, m), 4.79-4.84 (1H, m), 6.69-6.71 (1H, m), 7.11-7.16 (2H, m), 7.24-7.33 (2H, m).
元素分析値 C₂₂H₂₇N₄O₂SCl・HCl・H₂Oとして
計算値（％）：C, 52.69； H, 6.03； N, 11.17
実測値（％）：C, 52.75； H, 6.43； N, 11.57 Example 149
2- [1- (3-{[2- (4-Chlorophenyl) ethyl] thio} propanoyl) -4-piperidinyl] -5-methyl-1,2-dihydro-3H-imidazo [1,5-c] imidazole -3-one hydrochloride
2- (4-Chlorophenyl) ethyl 4-methylbenzenesulfonate (Schadt, FL et al., J. Am. Chem. Soc., 100, 228-246 (1978)) (1.2 g) and 3-mercaptopropionic acid A mixture of (0.35 mL) and 1N aqueous sodium hydroxide solution (12 mL) was stirred at 100 ° C. overnight. The reaction mixture was cooled to room temperature, acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product of 3-{[2- (4-chlorophenyl) ethyl] thio} propionic acid (0.26 g). This carboxylic acid and 5-methyl-2- (4-piperidinyl) -1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one dihydrochloride obtained in Example 69b) (0.24 The title compound (0.06 g, 13%) was obtained as a white powder from g) in the same manner as in Example 145c).
NMR (300MHz, CDCl ₃ ) δ: 1.56-1.70 (2H, m), 1.79-1.96 (3H, m), 2.57-2.70 (5H, m), 2.76-2.91 (5H, m), 3.11-3.19 (1H , m), 3.92-3.97 (2H, m), 4.10-4.29 (3H, m), 4.79-4.84 (1H, m), 6.69-6.71 (1H, m), 7.11-7.16 (2H, m), 7.24 -7.33 (2H, m).
Elemental analysis value Calculated as C ₂₂ H ₂₇ N ₄ O ₂ SCl · HCl · H ₂ O (%): C, 52.69; H, 6.03; N, 11.17
Found (%): C, 52.75; H, 6.43; N, 11.57

実施例150
2-[1-(3-{[2-(4-クロロフェニル)エチル]スルホニル}プロパノイル)-4-ピペリジニル]-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
実施例149で得られた2-[1-(3-{[2-(4-クロロフェニル)エチル]チオ}プロパノイル)-4-ピペリジニル]-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン塩酸塩(0.29g)から実施例148と同様にして題記化合物(0.17g, 54%)を白色粉末として得た。
NMR (300MHz, CDCl₃)δ: 1.61-1.76 (2H, m), 1.90-1.99 (2H, m), 2.61 (3H, s), 2.66-2.74 (1H, m), 2.85-2.96 (2H, m), 3.13-3.21 (3H, m), 3.25-3.46 (4H, m), 3.98-4.02 (1H, m), 4.17-4.23 (1H, m), 4.26 (2H, s), 4.75-4.80 (1H, m), 6.71 (1H, s), 7.18 (2H, d, J = 7.2), 7.30 (2H, d, J = 7.2).
元素分析値 C₂₂H₂₇N₄O₄SCl・0.5H₂Oとして
計算値（％）：C, 54.15； H, 5.78； N, 11.48
実測値（％）：C, 54.35； H, 6.01； N, 11.44 Example 150
2- [1- (3-{[2- (4-Chlorophenyl) ethyl] sulfonyl} propanoyl) -4-piperidinyl] -5-methyl-1,2-dihydro-3H-imidazo [1,5-c] imidazole -3-one 2- [1- (3-{[2- (4-chlorophenyl) ethyl] thio} propanoyl) -4-piperidinyl] -5-methyl-1,2-dihydro- obtained in Example 149 The title compound (0.17 g, 54%) was obtained as a white powder from 3H-imidazo [1,5-c] imidazol-3-one hydrochloride (0.29 g) in the same manner as in Example 148.
NMR (300MHz, CDCl ₃ ) δ: 1.61-1.76 (2H, m), 1.90-1.99 (2H, m), 2.61 (3H, s), 2.66-2.74 (1H, m), 2.85-2.96 (2H, m ), 3.13-3.21 (3H, m), 3.25-3.46 (4H, m), 3.98-4.02 (1H, m), 4.17-4.23 (1H, m), 4.26 (2H, s), 4.75-4.80 (1H , m), 6.71 (1H, s), 7.18 (2H, d, J = 7.2), 7.30 (2H, d, J = 7.2).
Elemental analysis value Calculated as C ₂₂ H ₂₇ N ₄ O ₄ SCl · 0.5H ₂ O (%): C, 54.15; H, 5.78; N, 11.48
Found (%): C, 54.35; H, 6.01; N, 11.44

実施例151
(1S)-1-{[(6-クロロ-2-ナフチル)チオ]メチル}-2-[4-(5-メチル-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル)-1-ピペリジニル]-2-オキソエチルカルバミン酸 tert-ブチル
151a) (2S)-2-(tert-ブトキシカルボニルアミノ)-3-[(6-クロロ-2-ナフチル)チオ]プロピオン酸メチル
水素化ナトリウム(60%油性：0.88g)のDMF(22mL)けん濁液へ6-クロロナフタレン-2-チオール(4.3g)を0℃で加え20分間かき混ぜた後、N-(tert-ブトキシカルボニル)-O-[(4-メチルフェニル)スルホニル]-D-セリンメチルエステル(E. M. Stocking, J. Chem. Soc. Perkin Trans. 1, 2443, (1997)) (8.2g)のDMF溶液(22mL)を滴下し、0℃で2時間かき混ぜた。反応混合物へ水を加え、エーテルで抽出した。抽出液を炭酸カリウム水溶液、飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残留物をシリカゲルカラム(酢酸エチル/ヘキサン1/10から3/10)で精製して、題記化合物(6.2g, 71%)を白色固体として得た。
NMR (300MHz, CDCl₃)δ: 1.37 (9H, s), 3.46-3.55 (5H, m), 4.60-4.63 (1H, m), 5.36 (1H, d, J = 7.2), 7.25-7.50 (2H, m), 7.65-7.82 (4H, m).
151b) (2S)-2-(tert-ブトキシカルボニルアミノ)-3-[(6-クロロ-2-ナフチル)チオ]プロピオン酸
実施例151a)で得られた(2S)-2-(tert-ブトキシカルボニルアミノ)-3-[(6-クロロ-2-ナフチル)チオ]プロピオン酸メチル(6.2g)のメタノール(50mL)溶液へ1N水酸化ナトリウム水溶液(17mL)を加え、室温で1時間かき混ぜた。溶媒を減圧留去し、残留物に水を加え、エーテルで洗浄した。水層を1N塩酸で酸性にし、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去して、題記化合物(5.3g, 88%)を淡黄色油状物として得た。
NMR (300MHz, CDCl₃)δ: 1.36 (9H, s), 3.48-3.50 (2H, m), 4.59-4.63 (1H, m), 5.34-5.36 (1H, m), 7.33-7.52 (2H, m), 7.65-7.84 (4H, m).
151c) (1S)-1-{[(6-クロロ-2-ナフチル)チオ]メチル}-2-[4-(5-メチル-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル)-1-ピペリジニル]-2-オキソエチルカルバミン酸 tert-ブチル
実施例151b)で得られた(2S)-2-(tert-ブトキシカルボニルアミノ)-3-[(6-クロロ-2-ナフチル)チオ]プロピオン酸(2.8g)のアセトニトリル(36mL)溶液へHOBt(1.7g)、トリエチルアミン(3.5mL)および実施例69b)で得られた5-メチル-2-(4-ピペリジニル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン２塩酸塩(1.7g)を0℃で加え、次いでWSC(2.1g)を加え室温で一夜かき混ぜた。溶媒を減圧留去し、残留物を酢酸エチルに溶解し、炭酸水素ナトリウム水溶液および飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残留物を塩基性シリカゲルカラム(酢酸エチル/ヘキサン=1/4から酢酸エチル)で精製した。生成物を酢酸エチルから再結晶して、題記化合物(1.9g, 45%)を無色針状晶として得た。
NMR (300MHz, CDCl₃)δ: 1.45 (9H, s), 1.49-1.81 (4H, m), 2.59 (3H, s), 2.96-3.08 (1H, m), 3.30-3.40 (2H, m), 3.90-3.99 (2H, m), 4.07-4.19 (3H, m), 4.60-4.91 (2H, m), 5.52 (1H, d, J = 8.0), 6.69 (1H, s), 7.41-7.48 (2H, m), 7.67-7.78 (3H, m), 7.85-7.90 (1H, m).
元素分析値 C₂₉H₃₄ClN₅O₄S・0.5H₂Oとして
計算値（％）：C, 58.72； H, 5.95； N, 11.81
実測値（％）：C, 58.82； H, 6.11； N, 11.71 Example 151
(1S) -1-{[(6-Chloro-2-naphthyl) thio] methyl} -2- [4- (5-methyl-3-oxo-1H-imidazo [1,5-c] imidazole-2 ( 3H) -yl) -1-piperidinyl] -2-oxoethylcarbamate tert-butyl
151a) Methyl (2S) -2- (tert-butoxycarbonylamino) -3-[(6-chloro-2-naphthyl) thio] propionate Sodium hydride (60% oiliness: 0.88 g) in DMF (22 mL) 6-Chloronaphthalene-2-thiol (4.3g) was added to the suspension at 0 ° C and stirred for 20 minutes, and then N- (tert-butoxycarbonyl) -O-[(4-methylphenyl) sulfonyl] -D-serine A DMF solution (22 mL) of methyl ester (EM Stocking, J. Chem. Soc. Perkin Trans. 1, 2443, (1997)) (8.2 g) was added dropwise, and the mixture was stirred at 0 ° C. for 2 hours. Water was added to the reaction mixture and extracted with ether. The extract was washed with aqueous potassium carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (ethyl acetate / hexane 1/10 to 3/10) to give the title compound (6.2 g, 71%) as a white solid.
NMR (300MHz, CDCl ₃ ) δ: 1.37 (9H, s), 3.46-3.55 (5H, m), 4.60-4.63 (1H, m), 5.36 (1H, d, J = 7.2), 7.25-7.50 (2H , m), 7.65-7.82 (4H, m).
151b) (2S) -2- (tert-butoxycarbonylamino) -3-[(6-chloro-2-naphthyl) thio] propionic acid (2S) -2- (tert-butoxy) obtained in Example 151a) To a solution of methyl carbonylamino) -3-[(6-chloro-2-naphthyl) thio] propionate (6.2 g) in methanol (50 mL) was added 1N aqueous sodium hydroxide solution (17 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was washed with ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (5.3 g, 88%) as a pale yellow oil.
NMR (300MHz, CDCl ₃ ) δ: 1.36 (9H, s), 3.48-3.50 (2H, m), 4.59-4.63 (1H, m), 5.34-5.36 (1H, m), 7.33-7.52 (2H, m ), 7.65-7.84 (4H, m).
151c) (1S) -1-{[(6-Chloro-2-naphthyl) thio] methyl} -2- [4- (5-methyl-3-oxo-1H-imidazo [1,5-c] imidazole- 2 (3H) -yl) -1-piperidinyl] -2-oxoethylcarbamate tert-butyl (2S) -2- (tert-butoxycarbonylamino) -3-[(6- Chloro-2-naphthyl) thio] propionic acid (2.8 g) in acetonitrile (36 mL) to HOBt (1.7 g), triethylamine (3.5 mL) and 5-methyl-2- (4- Piperidinyl) -1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one dihydrochloride (1.7 g) was added at 0 ° C., then WSC (2.1 g) was added and stirred overnight at room temperature. . The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, washed with aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with a basic silica gel column (ethyl acetate / hexane = 1/4 to ethyl acetate). The product was recrystallized from ethyl acetate to give the title compound (1.9 g, 45%) as colorless needle crystals.
NMR (300MHz, CDCl ₃ ) δ: 1.45 (9H, s), 1.49-1.81 (4H, m), 2.59 (3H, s), 2.96-3.08 (1H, m), 3.30-3.40 (2H, m), 3.90-3.99 (2H, m), 4.07-4.19 (3H, m), 4.60-4.91 (2H, m), 5.52 (1H, d, J = 8.0), 6.69 (1H, s), 7.41-7.48 (2H , m), 7.67-7.78 (3H, m), 7.85-7.90 (1H, m).
Elemental analysis value Calculated as C ₂₉ H ₃₄ ClN ₅ O ₄ S · 0.5H ₂ O (%): C, 58.72; H, 5.95; N, 11.81
Found (%): C, 58.82; H, 6.11; N, 11.71

実施例152
(1S)-1-{[(6-クロロ-2-ナフチル)スルホニル]メチル}-2-[4-(5-メチル-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル)-1-ピペリジニル]-2-オキソエチルカルバミン酸 tert-ブチル
実施例151c)で得られた(1S)-1-{[(6-クロロ-2-ナフチル)チオ]メチル}-2-[4-(5-メチル-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル)-1-ピペリジニル]-2-オキソエチルカルバミン酸 tert-ブチル(0.51g)のメタノール(3.0mL)溶液へオキソン(0.64g)の水溶液(3.0mL)を加え、室温で1時間かき混ぜた。溶媒を減圧留去し、残留物を水で希釈し酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。残留物を塩基性シリカゲルカラム(酢酸エチル/ヘキサン=1/4から酢酸エチル)で精製して、題記化合物(0.51g, 95%：90%ee)を白色粉末として得た。
NMR (300MHz, CDCl₃)δ: 1.34 (9H, s), 1.92-2.15 (4H, m), 2.61 (3H, s), 3.13-3.61 (3H, m), 3.78-3.89 (1H, m), 4.11-4.41 (4H, m), 4.58-4.84 (1H, m), 5.22-5.35 (2H, m), 6.66-6.70 (1H, m), 7.57-7.62 (1H, m), 7.93-7.98 (4H, m), 8.50 (1H, s).
元素分析値 C₂₉H₃₄ClN₅O₆S・0.5H₂O・0.5AcOEtとして
計算値（％）：C, 55.64； H, 5.87； N, 10.47
実測値（％）：C, 55.64； H, 6.11； N, 10.54 Example 152
(1S) -1-{[(6-Chloro-2-naphthyl) sulfonyl] methyl} -2- [4- (5-methyl-3-oxo-1H-imidazo [1,5-c] imidazole-2 ( 3H) -yl) -1-piperidinyl] -2-oxoethylcarbamate tert-butyl (1S) -1-{[(6-chloro-2-naphthyl) thio] methyl}-obtained in Example 151c) 2- [4- (5-Methyl-3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl) -1-piperidinyl] -2-oxoethylcarbamate tert-butyl (0.51 An aqueous solution (3.0 mL) of oxone (0.64 g) was added to a methanol (3.0 mL) solution of g), and the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the residue was diluted with water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by basic silica gel column (ethyl acetate / hexane = 1/4 to ethyl acetate) to give the title compound (0.51 g, 95%: 90% ee) as a white powder.
NMR (300MHz, CDCl ₃ ) δ: 1.34 (9H, s), 1.92-2.15 (4H, m), 2.61 (3H, s), 3.13-3.61 (3H, m), 3.78-3.89 (1H, m), 4.11-4.41 (4H, m), 4.58-4.84 (1H, m), 5.22-5.35 (2H, m), 6.66-6.70 (1H, m), 7.57-7.62 (1H, m), 7.93-7.98 (4H , m), 8.50 (1H, s).
Elemental analysis value C ₂₉ H ₃₄ ClN ₅ O ₆ S · 0.5H ₂ O · 0.5AcOEt (%): C, 55.64; H, 5.87; N, 10.47
Found (%): C, 55.64; H, 6.11; N, 10.54

実施例153
N-((1S)-1-{[(6-クロロ-2-ナフチル)スルホニル]メチル}-2-[4-(5-メチル-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル)-1-ピペリジニル]-2-オキソエチル)-2,2,2-トリフルオロアセトアミド
実施例152で得られた(1S)-1-{[(6-クロロ-2-ナフチル)スルホニル]メチル}-2-[4-(5-メチル-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル)-1-ピペリジニル]-2-オキソエチルカルバミン酸 tert-ブチル(0.51g)のジクロロメタン(2.0mL)溶液へトリフルオロ酢酸(2.0mL)を0℃で加え、室温で一夜かき混ぜた。反応液へ飽和炭酸水素ナトリウム水溶液と炭酸カリウムを加え、塩基性にした後、ジクロロメタンで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残留物を塩基性シリカゲルカラム(酢酸エチル/ヘキサン=1/4から酢酸エチル)で精製して、題記化合物(0.13g, 26%)を白色粉末として得た。
NMR (200MHz, CDCl₃)δ: 1.94-2.60 (3H, m), 2.66 (3H, s), 2.72-2.85 (1H, m), 3.27-3.88 (4H, m), 4.17-4.31 (4H, m), 4.56-4.83 (1H, m), 5.47-5.60 (1H, m), 6.67-6.71 (1H, m), 7.46-7.64 (2H, m), 7.74-7.99 (5H, m), 8.48-8.49 (1H, m).
元素分析値 C₂₆H₂₅ClN₅O₅S・3H₂Oとして
計算値（％）：C, 46.88； H, 4.69； N, 10.51
実測値（％）：C, 46.91； H, 4.95； N, 10.36 Example 153
N-((1S) -1-{[(6-Chloro-2-naphthyl) sulfonyl] methyl} -2- [4- (5-methyl-3-oxo-1H-imidazo [1,5-c] imidazole -2 (3H) -yl) -1-piperidinyl] -2-oxoethyl) -2,2,2-trifluoroacetamide (1S) -1-{[(6-Chloro-2- Naphthyl) sulfonyl] methyl} -2- [4- (5-methyl-3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl) -1-piperidinyl] -2-oxoethyl Trifluoroacetic acid (2.0 mL) was added to a solution of tert-butyl carbamate (0.51 g) in dichloromethane (2.0 mL) at 0 ° C., and the mixture was stirred overnight at room temperature. A saturated aqueous sodium hydrogen carbonate solution and potassium carbonate were added to the reaction solution to make it basic, and then extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by basic silica gel column (ethyl acetate / hexane = 1/4 to ethyl acetate) to give the title compound (0.13 g, 26%) as a white powder.
NMR (200MHz, CDCl ₃ ) δ: 1.94-2.60 (3H, m), 2.66 (3H, s), 2.72-2.85 (1H, m), 3.27-3.88 (4H, m), 4.17-4.31 (4H, m ), 4.56-4.83 (1H, m), 5.47-5.60 (1H, m), 6.67-6.71 (1H, m), 7.46-7.64 (2H, m), 7.74-7.99 (5H, m), 8.48-8.49 (1H, m).
Elemental analysis value Calculated as C ₂₆ H ₂₅ ClN ₅ O ₅ S · 3H ₂ O (%): C, 46.88; H, 4.69; N, 10.51
Found (%): C, 46.91; H, 4.95; N, 10.36

実施例154
2-(1-{(2S)-2-アミノ-3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル)-4-ピペリジニル}-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン２塩酸塩
実施例152で得られた(1S)-1-{[(6-クロロ-2-ナフチル)スルホニル]メチル}-2-[4-(5-メチル-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル)-1-ピペリジニル]-2-オキソエチルカルバミン酸 tert-ブチル(1.1g)のメタノール(2.0mL)溶液へ40%塩化水素エタノール溶液(5.0mL)を0℃で加え、10分間かき混ぜた。溶媒を減圧留去し、残留物にエーテルを加え結晶化して、題記化合物(0.83g, 77%)を白色粉末として得た。
NMR (300MHz, DMSO-d₆)δ: 1.41-1.89 (3H, m), 2.15-2.37 (1H, m), 2.74-2.76 (3H, m), 3.16-3.33 (1H, m), 3.78-4.32 (5H, m), 4.52-4.57 (2H, m), 4.80-4.89 (1H, m), 7.50-7.53 (1H, m), 7.73-7.77 (1H, m), 7.96-8.07 (1H, m), 8.18-8.33 (3H, m), 8.64-8.93 (4H, m).
元素分析値 C₂₄H₂₆ClN₅O₄S・2HCl・2.5H₂O・0.1Et₂Oとして
計算値（％）：C, 45.76； H, 5.35； N, 10.94
実測値（％）：C, 45.64； H, 5.74； N, 11.12 Example 154
2- (1-{(2S) -2-amino-3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl) -4-piperidinyl} -5-methyl-1,2-dihydro-3H-imidazo [ 1,5-c] imidazol-3-one dihydrochloride (1S) -1-{[(6-chloro-2-naphthyl) sulfonyl] methyl} -2- [4- (5 -Methyl-3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl) -1-piperidinyl] -2-oxoethylcarbamate tert-butyl (1.1 g) in methanol (2.0 mL ) 40% hydrogen chloride ethanol solution (5.0 mL) was added to the solution at 0 ° C. and stirred for 10 minutes. The solvent was distilled off under reduced pressure, ether was added to the residue and crystallized to obtain the title compound (0.83 g, 77%) as a white powder.
NMR (300MHz, DMSO-d ₆ ) δ: 1.41-1.89 (3H, m), 2.15-2.37 (1H, m), 2.74-2.76 (3H, m), 3.16-3.33 (1H, m), 3.78-4.32 (5H, m), 4.52-4.57 (2H, m), 4.80-4.89 (1H, m), 7.50-7.53 (1H, m), 7.73-7.77 (1H, m), 7.96-8.07 (1H, m) , 8.18-8.33 (3H, m), 8.64-8.93 (4H, m).
Elemental Analysis Value Calculated as C ₂₄ H ₂₆ ClN ₅ O ₄ S · 2HCl · 2.5H ₂ O · 0.1Et ₂ O (%): C, 45.76; H, 5.35; N, 10.94
Found (%): C, 45.64; H, 5.74; N, 11.12

実施例155
N-((1S)-1-{[(6-クロロ-2-ナフチル)スルホニル]メチル}-2-[4-(5-メチル-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル)-1-ピペリジニル]-2-オキソエチル)アセトアミド
実施例154で得られた2-(1-{(2S)-2-アミノ-3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル}-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン２塩酸塩(0.15g)のジクロロメタン(2.0mL)溶液へトリエチルアミン(0.11mL)と塩化アセチル(0.02mL)を0℃で加え、2時間かき混ぜた。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、ジクロロメタンで抽出した。抽出液を無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。残留物を分取高速液体クロマトグラフィーで精製して、題記化合物(0.08g, 54%)を白色固体として得た。
NMR (300MHz, CDCl₃)δ: 1.72-1.80 (5H, m), 1.86-2.17 (3H, m), 2.61-2.80 (4H, m), 3.16-3.32 (1H, m), 3.43-3.87 (2H, m), 4.18-4.39 (4H, m), 4.58-4.83 (1H, m), 5.52-5.69 (1H, m), 6.25-6.40 (1H, m), 6.66-6.70 (1H, m), 7.61 (1H, dd, J = 2.0, 8.8), 7.87-7.98 (4H, m), 8.50 (1H, s).
元素分析値 C₂₆H₂₈ClN₅O₅S・2.5H₂O・0.25AcOEtとして
計算値（％）：C, 51.88； H, 5.64； N, 11.20
実測値（％）：C, 51.71； H, 5.26； N, 11.03 Example 155
N-((1S) -1-{[(6-Chloro-2-naphthyl) sulfonyl] methyl} -2- [4- (5-methyl-3-oxo-1H-imidazo [1,5-c] imidazole -2 (3H) -yl) -1-piperidinyl] -2-oxoethyl) acetamide 2- (1-{(2S) -2-amino-3-[(6-chloro-2- Naphthyl) sulfonyl] propanoyl} -4-piperidinyl} -5-methyl-1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one dihydrochloride (0.15 g) in dichloromethane (2.0 mL) To the solution were added triethylamine (0.11 mL) and acetyl chloride (0.02 mL) at 0 ° C., and the mixture was stirred for 2 hours, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The solvent was evaporated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to give the title compound (0.08 g, 54%) as a white solid.
NMR (300MHz, CDCl ₃ ) δ: 1.72-1.80 (5H, m), 1.86-2.17 (3H, m), 2.61-2.80 (4H, m), 3.16-3.32 (1H, m), 3.43-3.87 (2H , m), 4.18-4.39 (4H, m), 4.58-4.83 (1H, m), 5.52-5.69 (1H, m), 6.25-6.40 (1H, m), 6.66-6.70 (1H, m), 7.61 (1H, dd, J = 2.0, 8.8), 7.87-7.98 (4H, m), 8.50 (1H, s).
Elemental analysis value Calculated as C ₂₆ H ₂₈ ClN ₅ O ₅ S · 2.5H ₂ O · 0.25 AcOEt (%): C, 51.88; H, 5.64; N, 11.20
Found (%): C, 51.71; H, 5.26; N, 11.03

実施例156
N-((1S)-1-{[(6-クロロ-2-ナフチル)スルホニル]メチル}-2-[4-(5-メチル-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル)-1-ピペリジニル]-2-オキソエチル)カルバミン酸メチル
実施例154で得られた2-(1-{(2S)-2-アミノ-3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル)-4-ピペリジニル}-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン２塩酸塩(0.10g)とクロロギ酸メチル(0.01mL)から実施例155と同様にして題記化合物(0.06g, 61%)を白色固体として得た。
NMR (300MHz, CDCl₃)δ: 1.63-2.02 (3H, m), 2.61 (3H, s), 2.67-2.81 (1H, m), 3.20-3.33 (1H, m), 3.43-3.55 (4H, m), 3.80-3.87 (1H, m), 4.18-4.39 (4H, m), 4.60-4.82 (1H, m), 5.30-5.40 (2H, m), 6.66-6.70 (1H, m), 7.60 (1H, dd, J = 2.1, 8.9), 7.87-7.97 (4H, m), 8.49 (1H, s).
元素分析値 C₂₆H₂₈ClN₅O₆S・1.5H₂O・0.25AcOEtとして
計算値（％）：C, 52.04； H, 5.34； N, 11.24
実測値（％）：C, 51.82； H, 5.03； N, 11.06 Example 156
N-((1S) -1-{[(6-Chloro-2-naphthyl) sulfonyl] methyl} -2- [4- (5-methyl-3-oxo-1H-imidazo [1,5-c] imidazole -2 (3H) -yl) -1-piperidinyl] -2-oxoethyl) methyl carbamate 2- (1-{(2S) -2-amino-3-[(6-chloro- 2-Naphthyl) sulfonyl] propanoyl) -4-piperidinyl} -5-methyl-1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one dihydrochloride (0.10 g) and methyl chloroformate (0.01 mL) was used to give the title compound (0.06 g, 61%) as a white solid in the same manner as in Example 155.
NMR (300MHz, CDCl ₃ ) δ: 1.63-2.02 (3H, m), 2.61 (3H, s), 2.67-2.81 (1H, m), 3.20-3.33 (1H, m), 3.43-3.55 (4H, m ), 3.80-3.87 (1H, m), 4.18-4.39 (4H, m), 4.60-4.82 (1H, m), 5.30-5.40 (2H, m), 6.66-6.70 (1H, m), 7.60 (1H , dd, J = 2.1, 8.9), 7.87-7.97 (4H, m), 8.49 (1H, s).
Elemental Analysis Value Calculated as C ₂₆ H ₂₈ ClN ₅ O ₆ S · 1.5H ₂ O · 0.25 AcOEt (%): C, 52.04; H, 5.34; N, 11.24
Found (%): C, 51.82; H, 5.03; N, 11.06

実施例157
N-((1S)-1-{[(6-クロロ-2-ナフチル)スルホニル]メチル}-2-[4-(5-メチル-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル)-1-ピペリジニル]-2-オキソエチル)メタンスルホンアミド
実施例154で得られた2-(1-{(2S)-2-アミノ-3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル)-4-ピペリジニル}-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン２塩酸塩(0.10g)と塩化メタンスルホニル(0.07mL)から実施例155と同様にして、題記化合物(0.04g, 41%)を白色固体として得た。
NMR (300MHz, CDCl₃)δ: 1.61-1.91 (4H, m), 2.61 (3H, s), 2.63-2.80 (1H, m), 2.95-3.07 (3H, m), 3.21-3.77 (3H, m), 4.17-4.28 (4H, m), 4.59-4.81 (1H, m), 5.10-5.19 (1H, m), 5.50-5.65 (1H, m), 6.67-6.70 (1H, m), 7.60-7.63 (1H, m), 7.88-7.98 (4H, m), 8.49-8.51 (1H, m).
元素分析値 C₂₅H₂₈ClN₅O₆S・2H₂O・0.5AcOEtとして
計算値（％）：C, 48.10； H, 5.38； N, 10.39
実測値（％）：C, 48.04； H, 5.00； N, 10.37 Example 157
N-((1S) -1-{[(6-Chloro-2-naphthyl) sulfonyl] methyl} -2- [4- (5-methyl-3-oxo-1H-imidazo [1,5-c] imidazole -2 (3H) -yl) -1-piperidinyl] -2-oxoethyl) methanesulfonamide 2- (1-{(2S) -2-amino-3-[(6-chloro- 2-naphthyl) sulfonyl] propanoyl) -4-piperidinyl} -5-methyl-1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one dihydrochloride (0.10 g) and methanesulfonyl chloride The title compound (0.04 g, 41%) was obtained as a white solid from (0.07 mL) in the same manner as in Example 155.
NMR (300MHz, CDCl ₃ ) δ: 1.61-1.91 (4H, m), 2.61 (3H, s), 2.63-2.80 (1H, m), 2.95-3.07 (3H, m), 3.21-3.77 (3H, m ), 4.17-4.28 (4H, m), 4.59-4.81 (1H, m), 5.10-5.19 (1H, m), 5.50-5.65 (1H, m), 6.67-6.70 (1H, m), 7.60-7.63 (1H, m), 7.88-7.98 (4H, m), 8.49-8.51 (1H, m).
Elemental Analysis Value Calculated as C ₂₅ H ₂₈ ClN ₅ O ₆ S · 2H ₂ O · 0.5 AcOEt (%): C, 48.10; H, 5.38; N, 10.39
Found (%): C, 48.04; H, 5.00; N, 10.37

実施例158
N-((1S)-1-{[(6-クロロ-2-ナフチル)スルホニル]メチル}-2-{4-(5-メチル-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル)-1-ピペリジニル}-2-オキソエチル)-4-メチルベンゼンスルホンアミド
実施例154で得られた2-(1-{(2S)-2-アミノ-3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル)-4-ピペリジニル}-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン２塩酸塩(0.10g)と塩化 p-トルエンスルホニル(0.03g)から実施例155と同様にして題記化合物(0.08g, 70%)を白色固体として得た。
NMR (300MHz, CDCl₃)δ: 1.68-1.94 (4H, m), 2.26-2.36 (1H, m), 2.43-2.45 (3H, m), 2.60-2.61 (3H, m), 2.82-3.37 (2H, m), 3.60-3.76 (1H, m), 4.09-4.24 (3H, m), 4.43-4.56 (1H, m), 4.49-4.98 (1H, m), 5.69-5.84 (1H, m), 6.14-6.71 (1H, m), 7.28-7.32 (3H, m), 7.59-7.96 (7H, m), 8.37-8.45 (1H, m).
元素分析値 C₃₁H₃₂ClN₅O₆S・H₂O・0.5AcOEtとして
計算値（％）：C, 51.78； H, 4.83； N, 9.58
実測値（％）：C, 51.74； H, 4.87； N, 9.37 Example 158
N-((1S) -1-{[(6-Chloro-2-naphthyl) sulfonyl] methyl} -2- {4- (5-methyl-3-oxo-1H-imidazo [1,5-c] imidazole -2 (3H) -yl) -1-piperidinyl} -2-oxoethyl) -4-methylbenzenesulfonamide 2- (1-{(2S) -2-amino-3-[( 6-chloro-2-naphthyl) sulfonyl] propanoyl) -4-piperidinyl} -5-methyl-1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one dihydrochloride (0.10 g) And p-toluenesulfonyl chloride (0.03 g) were used to give the title compound (0.08 g, 70%) as a white solid in the same manner as in Example 155.
NMR (300MHz, CDCl ₃ ) δ: 1.68-1.94 (4H, m), 2.26-2.36 (1H, m), 2.43-2.45 (3H, m), 2.60-2.61 (3H, m), 2.82-3.37 (2H , m), 3.60-3.76 (1H, m), 4.09-4.24 (3H, m), 4.43-4.56 (1H, m), 4.49-4.98 (1H, m), 5.69-5.84 (1H, m), 6.14 -6.71 (1H, m), 7.28-7.32 (3H, m), 7.59-7.96 (7H, m), 8.37-8.45 (1H, m).
Elemental Analysis Value Calculated as C ₃₁ H ₃₂ ClN ₅ O ₆ S · H ₂ O · 0.5 AcOEt (%): C, 51.78; H, 4.83; N, 9.58
Found (%): C, 51.74; H, 4.87; N, 9.37

実施例159
N-((1S)-1-{[(6-クロロ-2-ナフチル)スルホニル]メチル}-2-[4-(5-メチル-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル)-1-ピペリジニル]-2-オキソエチル)-N'-エチル尿素
実施例154で得られた2-(1-{(2S)-2-アミノ-3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル)-4-ピペリジニル}-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン２塩酸塩(0.12g)とイソシアン酸エチル(0.02mL)から実施例155と同様にして、題記化合物(0.06g, 52%)を白色固体として得た。
NMR (300MHz, CDCl₃)δ: 0.96-1.04 (3H, m), 1.79-2.19 (3H, m), 2.60-2.79 (4H, m), 3.00-3.33 (3H, m), 3.46-3.81 (2H, m), 4.09-4.16 (2H, m), 4.24-4.29 (2H, m), 4.41-4.77 (3H, m), 5.44-5.61 (2H, m), 6.66-6.69 (1H, m), 7.56-7.61 (1H, m), 7.89-7.95 (4H, m), 8.48 (1H, s).
元素分析値 C₂₇H₃₁ClN₆O₅S・1.5H₂O・0.25AcOEtとして
計算値（％）：C, 52.87； H, 5.70； N, 13.21
実測値（％）：C, 53.05； H, 5.48； N, 13.28 Example 159
N-((1S) -1-{[(6-Chloro-2-naphthyl) sulfonyl] methyl} -2- [4- (5-methyl-3-oxo-1H-imidazo [1,5-c] imidazole -2 (3H) -yl) -1-piperidinyl] -2-oxoethyl) -N'-ethylurea 2- (1-{(2S) -2-amino-3-[(6 -Chloro-2-naphthyl) sulfonyl] propanoyl) -4-piperidinyl} -5-methyl-1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one dihydrochloride (0.12 g) The title compound (0.06 g, 52%) was obtained as a white solid from ethyl isocyanate (0.02 mL) in the same manner as in Example 155.
NMR (300MHz, CDCl ₃ ) δ: 0.96-1.04 (3H, m), 1.79-2.19 (3H, m), 2.60-2.79 (4H, m), 3.00-3.33 (3H, m), 3.46-3.81 (2H , m), 4.09-4.16 (2H, m), 4.24-4.29 (2H, m), 4.41-4.77 (3H, m), 5.44-5.61 (2H, m), 6.66-6.69 (1H, m), 7.56 -7.61 (1H, m), 7.89-7.95 (4H, m), 8.48 (1H, s).
Elemental analysis value Calculated as C ₂₇ H ₃₁ ClN ₆ O ₅ S · 1.5H ₂ O · 0.25AcOEt (%): C, 52.87; H, 5.70; N, 13.21
Found (%): C, 53.05; H, 5.48; N, 13.28

実施例160
N-((1S)-1-{[(6-クロロ-2-ナフチル)スルホニル]メチル}-2-[4-(5-メチル-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル)-1-ピペリジニル]-2-オキソエチル)尿素
実施例154で得られた2-(1-{(2S)-2-アミノ-3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル)-4-ピペリジニル}-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン２塩酸塩(0.12g)とイソシアン酸トリメチルシリル(0.03mL)から実施例155と同様にして、題記化合物(0.07g, 61%)を白色固体として得た。
NMR (300MHz, CDCl₃)δ: 1.74-2.15 (4H, m), 2.60-2.79 (3H, m), 3.13-3.35 (1H, m), 3.46-3.56 (2H, m), 3.75-3.81 (1H, m), 4.11-4.43 (4H, m), 4.58-4.77 (3H, m), 5.37-5.58 (1H, m), 5.75-5.87 (1H, m), 6.66-6.68 (1H, m), 7.58-7.61 (1H, m), 7.89-7.96 (4H, m), 8.48 (1H, s).
元素分析値 C₂₅H₂₇ClN₆O₅S・0.75H₂Oとして
計算値（％）：C, 52.44； H, 5.02； N, 14.68
実測値（％）：C, 52.45； H, 5.28； N, 14.40 Example 160
N-((1S) -1-{[(6-Chloro-2-naphthyl) sulfonyl] methyl} -2- [4- (5-methyl-3-oxo-1H-imidazo [1,5-c] imidazole -2 (3H) -yl) -1-piperidinyl] -2-oxoethyl) urea 2- (1-{(2S) -2-amino-3-[(6-chloro-2-) obtained in Example 154 Naphthyl) sulfonyl] propanoyl) -4-piperidinyl} -5-methyl-1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one dihydrochloride (0.12 g) and trimethylsilyl isocyanate (0.03 to give the title compound (0.07 g, 61%) as a white solid.
NMR (300MHz, CDCl ₃ ) δ: 1.74-2.15 (4H, m), 2.60-2.79 (3H, m), 3.13-3.35 (1H, m), 3.46-3.56 (2H, m), 3.75-3.81 (1H , m), 4.11-4.43 (4H, m), 4.58-4.77 (3H, m), 5.37-5.58 (1H, m), 5.75-5.87 (1H, m), 6.66-6.68 (1H, m), 7.58 -7.61 (1H, m), 7.89-7.96 (4H, m), 8.48 (1H, s).
Elemental analysis value Calculated as C ₂₅ H ₂₇ ClN ₆ O ₅ S · 0.75H ₂ O (%): C, 52.44; H, 5.02; N, 14.68
Found (%): C, 52.45; H, 5.28; N, 14.40

実施例161
(1S)-1-{[(6-クロロ-2-ナフチル)スルホニル]メチル}-2-[4-(5-メチル-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル)-1-ピペリジニル]-2-オキソエチルカルバミン酸エチル
実施例154で得られた2-(1-{(2S)-2-アミノ-3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル)-4-ピペリジニル}-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン２塩酸塩(0.12g)とクロロ炭酸エチル(0.03mL)から実施例155と同様にして、題記化合物(0.12g, 70%)を白色固体として得た。
NMR (300MHz, CDCl₃)δ: 1.07-1.15 (3H, m), 1.85-2.07 (4H, m), 2.61 (3H, s), 2.66-2.81 (1H, m), 3.19-3.56 (2H, m), 3.80-4.44 (7H, m), 4.59-4.84 (1H, m), 5.30-5.41 (2H, m), 6.66-6.70 (1H, m), 7.53-7.62 (1H, m), 7.87-7.97 (4H, m), 8.49 (1H, s).
元素分析値 C₂₇H₃₀ClN₅O₆S・0.5H₂O・0.5AcOEtとして
計算値（％）：C, 54.33； H, 5.50； N, 10.92
実測値（％）：C, 54.30； H, 5.45； N, 11.16 Example 161
(1S) -1-{[(6-Chloro-2-naphthyl) sulfonyl] methyl} -2- [4- (5-methyl-3-oxo-1H-imidazo [1,5-c] imidazole-2 ( 3H) -yl) -1-piperidinyl] -2-oxoethylcarbamate 2- (1-{(2S) -2-amino-3-[(6-chloro-2-naphthyl) obtained in Example 154 ) Sulfonyl] propanoyl) -4-piperidinyl} -5-methyl-1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one dihydrochloride (0.12 g) and ethyl chlorocarbonate (0.03 mL) ) To give the title compound (0.12 g, 70%) as a white solid in the same manner as Example 155.
NMR (300MHz, CDCl ₃ ) δ: 1.07-1.15 (3H, m), 1.85-2.07 (4H, m), 2.61 (3H, s), 2.66-2.81 (1H, m), 3.19-3.56 (2H, m ), 3.80-4.44 (7H, m), 4.59-4.84 (1H, m), 5.30-5.41 (2H, m), 6.66-6.70 (1H, m), 7.53-7.62 (1H, m), 7.87-7.97 (4H, m), 8.49 (1H, s).
Elemental analysis value C ₂₇ H ₃₀ ClN ₅ O ₆ S · 0.5H ₂ O · 0.5AcOEt (%): C, 54.33; H, 5.50; N, 10.92
Found (%): C, 54.30; H, 5.45; N, 11.16

実施例162
N-((1S)-1-{[(6-クロロ-2-ナフチル)スルホニル]メチル}-2-[4-(5-メチル-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル)-1-ピペリジニル]-2-オキソエチル)-2-メトキシアセトアミド
実施例154で得られた2-(1-{(2S)-2-アミノ-3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル)-4-ピペリジニル}-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン２塩酸塩(0.20g)と塩化メトキシアセチル(0.04mL)から実施例155と同様にして、題記化合物(0.09g, 44%)を白色固体として得た。
NMR (300MHz, CDCl₃)δ: 1.83-2.17 (3H, m), 2.62-2.81 (4H, m), 3.22 (3H, s), 3.26-3.36 (1H, m), 3.43-3.95 (5H, m), 4.11-4.39 (4H, m), 4.60-4.84 (1H, m), 5.53-5.74 (1H, m), 6.69-6.71 (1H, m), 6.99-7.06 (1H, m), 7.59-7.63 (1H, m), 7.90-7.98 (4H, m), 8.50 (1H, s).
元素分析値 C₂₇H₃₀ClN₅O₆S・0.5H₂Oとして
計算値（％）：C, 54.31； H, 5.23； N, 11.73
実測値（％）：C, 54.24； H, 5.01； N, 11.56 Example 162
N-((1S) -1-{[(6-Chloro-2-naphthyl) sulfonyl] methyl} -2- [4- (5-methyl-3-oxo-1H-imidazo [1,5-c] imidazole -2 (3H) -yl) -1-piperidinyl] -2-oxoethyl) -2-methoxyacetamide 2- (1-{(2S) -2-amino-3-[(6- Chloro-2-naphthyl) sulfonyl] propanoyl) -4-piperidinyl} -5-methyl-1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one dihydrochloride (0.20 g) and chloride The title compound (0.09 g, 44%) was obtained as a white solid from methoxyacetyl (0.04 mL) in the same manner as in Example 155.
NMR (300MHz, CDCl ₃ ) δ: 1.83-2.17 (3H, m), 2.62-2.81 (4H, m), 3.22 (3H, s), 3.26-3.36 (1H, m), 3.43-3.95 (5H, m ), 4.11-4.39 (4H, m), 4.60-4.84 (1H, m), 5.53-5.74 (1H, m), 6.69-6.71 (1H, m), 6.99-7.06 (1H, m), 7.59-7.63 (1H, m), 7.90-7.98 (4H, m), 8.50 (1H, s).
Elemental analysis calculated as C ₂₇ H ₃₀ ClN ₅ O ₆ S.0.5H ₂ O (%): C, 54.31; H, 5.23; N, 11.73
Found (%): C, 54.24; H, 5.01; N, 11.56

実施例163
(1R)-1-{[(6-クロロ-2-ナフチル)スルホニル]メチル}-2-[4-(5-メチル-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル)-1-ピペリジニル]-2-オキソエチルカルバミン酸 tert-ブチル
実施例152で得た(1S)-1-{[(6-クロロ-2-ナフチル)スルホニル]メチル}-2-[4-(5-メチル-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル)-1-ピペリジニル]-2-オキソエチルカルバミン酸 tert-ブチル(2.01g, 90%ee)をCHIRALCEL OD(ヘキサン/イソプロパノール=20/80)を用いて光学分割し題記化合物(0.15g, 96.8%ee)を無色固体として得た。
NMR (300MHz, CDCl₃)δ: 1.35 (9H, s), 1.63-2.24 (4H, m), 2.57-2.82 (4H, m), 3.17-3.67 (8H, m), 3.82-3.89 (1H, m), 4.16-4.42 (4H, m), 4.61-4.86 (1H, m), 5.14-5.54 (2H, m), 6.96 (1H, s), 7.59-7.62 (1H, m), 7.90-7.97 (4H, m), 8.49 (1H, s).
元素分析値 C₂₉H₃₄ClN₅O₆S・H₂O・0.6CH₂Cl₂として
計算値（％）：C, 51.89； H, 5.47； N, 10.22
実測値（％）：C, 52.02； H, 5.44； N, 9.99 Example 163
(1R) -1-{[(6-Chloro-2-naphthyl) sulfonyl] methyl} -2- [4- (5-methyl-3-oxo-1H-imidazo [1,5-c] imidazole-2 ( 3H) -yl) -1-piperidinyl] -2-oxoethylcarbamate tert-butyl (1S) -1-{[(6-chloro-2-naphthyl) sulfonyl] methyl} -2- from Example 152 [4- (5-Methyl-3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl) -1-piperidinyl] -2-oxoethylcarbamate tert-butyl (2.01 g, 90% ee) was optically resolved using CHIRALCEL OD (hexane / isopropanol = 20/80) to give the title compound (0.15 g, 96.8% ee) as a colorless solid.
NMR (300MHz, CDCl ₃ ) δ: 1.35 (9H, s), 1.63-2.24 (4H, m), 2.57-2.82 (4H, m), 3.17-3.67 (8H, m), 3.82-3.89 (1H, m ), 4.16-4.42 (4H, m), 4.61-4.86 (1H, m), 5.14-5.54 (2H, m), 6.96 (1H, s), 7.59-7.62 (1H, m), 7.90-7.97 (4H , m), 8.49 (1H, s).
Elemental analysis value C ₂₉ H ₃₄ ClN ₅ O ₆ S · H ₂ O · 0.6 CH ₂ Cl ₂ (%): C, 51.89; H, 5.47; N, 10.22
Found (%): C, 52.02; H, 5.44; N, 9.99

実施例164
N-((1S)-1-{[(6-クロロ-2-ナフチル)スルホニル]メチル}-2-[4-(5-メチル-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル)-1-ピペリジニル]-2-オキソエチル)ベンズアミド
実施例154で得られた2-(1-{(2S)-2-アミノ-3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル)-4-ピペリジニル}-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン２塩酸塩(0.20g)と塩化ベンゾイル(0.05mL)から実施例155と同様にして、題記化合物(0.08g, 36%)を白色固体として得た。
NMR (300MHz, CDCl₃)δ: 1.88-2.14 (4H, m), 2.61-2.79 (4H, m), 3.23-3.37 (1H, m), 3.58-4.02 (2H, m), 4.22-4.42 (4H, m), 4.64-4.88 (1H, m), 5.68-5.77 (1H, m), 6.69 (1H, s), 6.80-6.91 (1H, m), 7.26-7.30 (2H, m), 7.45-7.61 (4H, m), 7.80-7.93 (4H, m), 8.48-8.50 (1H, m).
元素分析値 C₃₁H₃₀ClN₅O₅S・0.5H₂Oとして
計算値（％）：C, 59.18； H, 4.97； N, 11.13
実測値（％）：C, 58.96； H, 5.10； N, 10.89 Example 164
N-((1S) -1-{[(6-Chloro-2-naphthyl) sulfonyl] methyl} -2- [4- (5-methyl-3-oxo-1H-imidazo [1,5-c] imidazole -2 (3H) -yl) -1-piperidinyl] -2-oxoethyl) benzamide 2- (1-{(2S) -2-amino-3-[(6-chloro-2-] obtained in Example 154 Naphthyl) sulfonyl] propanoyl) -4-piperidinyl} -5-methyl-1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one dihydrochloride (0.20 g) and benzoyl chloride (0.05 mL) ) To give the title compound (0.08 g, 36%) as a white solid in the same manner as Example 155.
NMR (300MHz, CDCl ₃ ) δ: 1.88-2.14 (4H, m), 2.61-2.79 (4H, m), 3.23-3.37 (1H, m), 3.58-4.02 (2H, m), 4.22-4.42 (4H , m), 4.64-4.88 (1H, m), 5.68-5.77 (1H, m), 6.69 (1H, s), 6.80-6.91 (1H, m), 7.26-7.30 (2H, m), 7.45-7.61 (4H, m), 7.80-7.93 (4H, m), 8.48-8.50 (1H, m).
Elemental analysis value Calculated as C ₃₁ H ₃₀ ClN ₅ O ₅ S · 0.5H ₂ O (%): C, 59.18; H, 4.97; N, 11.13
Found (%): C, 58.96; H, 5.10; N, 10.89

実施例165
(1S)-1-{[(6-クロロ-2-ナフチル)スルホニル]メチル}-2-[4-(5-メチル-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル)-1-ピペリジニル]-2-オキソエチルカルバミン酸フェニル
実施例154で得られた2-(1-{(2S)-2-アミノ-3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル)-4-ピペリジニル}-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン２塩酸塩(0.20g)とクロロギ酸フェニル(0.04mL)から実施例155と同様にして、題記化合物(0.11g, 52%)を白色固体として得た。
NMR (300MHz, CDCl₃)δ: 1.55-2.14 (3H, m), 2.61 (3H, s), 2.66-2.83 (1H, m), 3.20-3.35 (1H, m), 3.54-3.91 (2H, m), 4.16-4.40 (4H, m), 4.63-4.85 (1H, m), 5.30-5.46 (1H, m), 5.85-5.99 (1H, m), 6.67 (1H, s), 6.81-6.91 (2H, m), 7.16-7.30 (4H, m), 7.56-7.61 (1H, m), 7.91-7.97 (4H, m), 8.51 (1H, s).
元素分析値 C₃₁H₃₀ClN₅O₆S・H₂Oとして
計算値（％）：C, 56.92； H, 4.93； N, 10.71
実測値（％）：C, 57.29； H, 5.00； N, 10.34 Example 165
(1S) -1-{[(6-Chloro-2-naphthyl) sulfonyl] methyl} -2- [4- (5-methyl-3-oxo-1H-imidazo [1,5-c] imidazole-2 ( 3H) -yl) -1-piperidinyl] -2-oxoethylcarbamate phenyl 2- (1-{(2S) -2-amino-3-[(6-chloro-2-naphthyl) obtained in Example 154 ) Sulfonyl] propanoyl) -4-piperidinyl} -5-methyl-1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one dihydrochloride (0.20 g) and phenyl chloroformate (0.04 mL) ) To give the title compound (0.11 g, 52%) as a white solid in the same manner as Example 155.
NMR (300MHz, CDCl ₃ ) δ: 1.55-2.14 (3H, m), 2.61 (3H, s), 2.66-2.83 (1H, m), 3.20-3.35 (1H, m), 3.54-3.91 (2H, m ), 4.16-4.40 (4H, m), 4.63-4.85 (1H, m), 5.30-5.46 (1H, m), 5.85-5.99 (1H, m), 6.67 (1H, s), 6.81-6.91 (2H , m), 7.16-7.30 (4H, m), 7.56-7.61 (1H, m), 7.91-7.97 (4H, m), 8.51 (1H, s).
Elemental analysis value Calculated as C ₃₁ H ₃₀ ClN ₅ O ₆ S · H ₂ O (%): C, 56.92; H, 4.93; N, 10.71
Found (%): C, 57.29; H, 5.00; N, 10.34

実施例166
3-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロピオニル}-4-ヒドロキシ-4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,5-a]ピリジン塩酸塩
166a) N-(2-ピリジニル)メチルホルムアミド
2-アミノメチルピリジン(20.0g)のギ酸(56mL)溶液を3時間還流した。溶媒を減圧留去し、残留物に氷水を加え、8N水酸化ナトリウム水溶液でpH10に調節した後、クロロホルムで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残留物を蒸留して、題記化合物(14.69g, 58％)を黄色液体として得た。
NMR (200Mz, CDCl₃)δ：4.61 (2H, d, J = 5.2), 7.06 (1H, br), 7.18-7.30 (2H, m), 7.64-7.73 (1H, m), 8.33 (1H, s), 8.54 (1H, d, J = 4.8).
166b) イミダゾ[1,5-a]ピリジン
実施例166a)で得られたN-(2-ピリジニル)メチルホルムアミド(10.0g)から実施例225b)と同様にして、題記化合物(6.38g, 74%)を淡黄色固体して得た。
NMR (200Mz, CDCl₃)δ：6.50-6.57 (1H, m), 6.65-6.73 (1H, m), 7.41-7.46 (2H, m), 7.91 (1H, dd, J = 7.0, 1.2), 8.10 (1H, s).
166c) 4-ヒドロキシ-4-(イミダゾ[1,5-a]ピリジン-3-イル)ピペリジン-1-カルボン酸tert-ブチル
実施例166b)で得られたイミダゾ[1,5-a]ピリジン(5.91g)のジエチルエーテル(60mL)-THF(10mL)溶液へ2MフェニルリチウムTHF溶液(35mL)を室温で加え、アルゴン下室温で3時間かき混ぜた。得れられた赤色けん濁液へ0℃で4-オキソピペリジン-1-カルボン酸-tert-ブチル(24.91g)を少量づつ加えた。反応液をアルゴン下室温で16時間かき混ぜた後、氷水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残留物をシリカゲルカラム (酢酸エチル)により精製して、題記化合物(3.97g, 25%)を白色固体として得た。
NMR (200Mz, CDCl₃)δ：1.45 (9H, s), 1.88-2.07 (2H, m), 2.12-2.37 (2H, m), 2.99 (1H, br), 3.29-3.51 (2H, m), 3.74-3.91 (2H, m), 6.48-6.56 (1H, m), 6.67-6.74 (1H, m), 7.21 (1H, s), 7.38-7.43 (1H, m), 8.53 (1H, dd, J = 7.4, 0.8).
166d) 3-(4-ヒドロキシ-4-ピペリジニル)イミダゾ[1,5-a]ピリジン２塩酸塩
実施例166c)で得られた4-ヒドロキシ-4-(イミダゾ[1,5-a]ピリジン-3-イル)ピペリジン-1-カルボン酸tert-ブチル(3.17g)から実施例207c)と同様にして、題記化合物(2.55g, 88％)を白色固体として得た。
NMR (200Mz, DMSO-d₆)δ：2.21-2.36 (2H, m), 2.43-2.62 (2H, m), 3.16-3.38 (4H, m), 7.07 (1H, t, J = 4.2), 7.18 (1H, t, J = 4.4), 7.83 (1H, d, J = 6.2), 8.00 (1H, s), 8.88 (1H, d, J = 4.6), 9.24-9.57 (2H, br).
166e) 3-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロピオニル}-4-ヒドロキシ-4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,5-a]ピリジン塩酸塩
実施例166d)で得られた3-(4-ヒドロキシ-4-ピペリジニル)イミダゾ[1,5-a]ピリジン２塩酸塩(0.65g)と3-[2-(6-クロロ-2-ナフチル)スルホニル]プロピオン酸(0.45g)から実施例207d)と同様にして、題記化合物(0.52g, 70%)を白色固体として得た。
NMR (200Mz, DMSO-d₆)δ：1.80-2.24 (4H, m), 2.77 (2H, t, J = 7.4), 3.07-3.30 (2H, m), 3.44-3.56 (1H, m), 3.64 (2H, t, J = 7.2), 3.79-3.95 (1H, m), 5.72 (1H, s), 6.60 (1H, t, J = 7.4), 6.74 (1H, dd, J = 8.8, 2.2), 7.28 (1H, s), 7.53 (1H, d, J = 8.8), 7.68 (1H, dd, J = 8.8, 2.2), 7.99 (1H, dd, J = 8.8, 1.6), 8.14-8.27 (3H, m), 8.58-8.64 (2H, m). Example 166
3- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propionyl} -4-hydroxy-4-piperidinyl) -5,6,7,8-tetrahydroimidazo [1,5-a] pyridine Hydrochloride
166a) N- (2-pyridinyl) methylformamide
A solution of 2-aminomethylpyridine (20.0 g) in formic acid (56 mL) was refluxed for 3 hours. The solvent was distilled off under reduced pressure, ice water was added to the residue, pH was adjusted to 10 with 8N aqueous sodium hydroxide solution, and the mixture was extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was distilled to obtain the title compound (14.69 g, 58%) as a yellow liquid.
NMR (200Mz, CDCl ₃ ) δ: 4.61 (2H, d, J = 5.2), 7.06 (1H, br), 7.18-7.30 (2H, m), 7.64-7.73 (1H, m), 8.33 (1H, s ), 8.54 (1H, d, J = 4.8).
166b) Imidazo [1,5-a] pyridine The title compound (6.38 g, 74%) was prepared in the same manner as in Example 225b) from N- (2-pyridinyl) methylformamide (10.0 g) obtained in Example 166a). ) Was obtained as a pale yellow solid.
NMR (200Mz, CDCl ₃ ) δ: 6.50-6.57 (1H, m), 6.65-6.73 (1H, m), 7.41-7.46 (2H, m), 7.91 (1H, dd, J = 7.0, 1.2), 8.10 (1H, s).
166c) imidazo [1,5-a] pyridine (4-hydroxy-4- (imidazo [1,5-a] pyridin-3-yl) piperidine-1-carboxylate tert-butyl Example 166b) To a solution of 5.91 g) in diethyl ether (60 mL) -THF (10 mL) was added 2M phenyllithium THF solution (35 mL) at room temperature, and the mixture was stirred at room temperature for 3 hours under argon. To the obtained red suspension, 4-oxopiperidine-1-carboxylate-tert-butyl (24.91 g) was added in small portions at 0 ° C. The reaction mixture was stirred at room temperature under argon for 16 hours, ice water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (ethyl acetate) to obtain the title compound (3.97 g, 25%) as a white solid.
NMR (200Mz, CDCl ₃ ) δ: 1.45 (9H, s), 1.88-2.07 (2H, m), 2.12-2.37 (2H, m), 2.99 (1H, br), 3.29-3.51 (2H, m), 3.74-3.91 (2H, m), 6.48-6.56 (1H, m), 6.67-6.74 (1H, m), 7.21 (1H, s), 7.38-7.43 (1H, m), 8.53 (1H, dd, J = 7.4, 0.8).
166d) 3- (4-Hydroxy-4-piperidinyl) imidazo [1,5-a] pyridine dihydrochloride 4-hydroxy-4- (imidazo [1,5-a] pyridine-- obtained in Example 166c) The title compound (2.55 g, 88%) was obtained as a white solid from tert-butyl 3-yl) piperidine-1-carboxylate (3.17 g) in the same manner as in Example 207c).
NMR (200Mz, DMSO-d ₆ ) δ: 2.21-2.36 (2H, m), 2.43-2.62 (2H, m), 3.16-3.38 (4H, m), 7.07 (1H, t, J = 4.2), 7.18 (1H, t, J = 4.4), 7.83 (1H, d, J = 6.2), 8.00 (1H, s), 8.88 (1H, d, J = 4.6), 9.24-9.57 (2H, br).
166e) 3- (1- {3-[(6-chloro-2-naphthyl) sulfonyl] propionyl} -4-hydroxy-4-piperidinyl) -5,6,7,8-tetrahydroimidazo [1,5-a ] Pyridine hydrochloride 3- (4-hydroxy-4-piperidinyl) imidazo [1,5-a] pyridine dihydrochloride (0.65 g) obtained in Example 166d) and 3- [2- (6-chloro- The title compound (0.52 g, 70%) was obtained as a white solid from 2-naphthyl) sulfonyl] propionic acid (0.45 g) in the same manner as in Example 207d).
NMR (200Mz, DMSO-d ₆ ) δ: 1.80-2.24 (4H, m), 2.77 (2H, t, J = 7.4), 3.07-3.30 (2H, m), 3.44-3.56 (1H, m), 3.64 (2H, t, J = 7.2), 3.79-3.95 (1H, m), 5.72 (1H, s), 6.60 (1H, t, J = 7.4), 6.74 (1H, dd, J = 8.8, 2.2), 7.28 (1H, s), 7.53 (1H, d, J = 8.8), 7.68 (1H, dd, J = 8.8, 2.2), 7.99 (1H, dd, J = 8.8, 1.6), 8.14-8.27 (3H, m), 8.58-8.64 (2H, m).

実施例167
(1S)-1-{[(6-クロロ-2-ナフチル)スルホニル]メチル}-2-[4-(5-メチル-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル)-1-ピペリジニル]-2-オキソエチルカルバミン酸2-メトキシエチル
実施例154で得られた2-(1-{(2S)-2-アミノ-3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル)-4-ピペリジニル}-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン２塩酸塩(0.40g)とクロロ炭酸メトキシエチル(0.19mL)から実施例155と同様にして、題記化合物(0.20g, 47%)を白色固体として得た。
NMR (300MHz, CDCl₃)δ: 1.83-2.14 (6H, m), 2.61 (3H, s), 2.65-2.80 (1H, m), 3.31-3.32 (3H, m), 3.44-3.86 (5H, m), 4.25-4.41 (4H, m), 4.59-4.82 (1H, m), 5.26-5.50 (2H, m), 6.66-6.70 (1H, m), 7.58-7.62 (1H, m), 7.87-7.97 (4H, m), 8.48-8.49 (1H, m).
元素分析値 C₂₈H₃₂ClN₅O₇S・H₂Oとして
計算値（％）：C, 52.87； H, 5.39； N, 11.01
実測値（％）：C, 52.60； H, 5.10； N, 10.91 Example 167
(1S) -1-{[(6-Chloro-2-naphthyl) sulfonyl] methyl} -2- [4- (5-methyl-3-oxo-1H-imidazo [1,5-c] imidazole-2 ( 3H) -yl) -1-piperidinyl] -2-oxoethylcarbamate 2-methoxyethyl 2- (1-{(2S) -2-amino-3-[(6-chloro- 2-naphthyl) sulfonyl] propanoyl) -4-piperidinyl} -5-methyl-1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one dihydrochloride (0.40 g) and methoxychlorocarbonate The title compound (0.20 g, 47%) was obtained as a white solid from ethyl (0.19 mL) in the same manner as in Example 155.
NMR (300MHz, CDCl ₃ ) δ: 1.83-2.14 (6H, m), 2.61 (3H, s), 2.65-2.80 (1H, m), 3.31-3.32 (3H, m), 3.44-3.86 (5H, m ), 4.25-4.41 (4H, m), 4.59-4.82 (1H, m), 5.26-5.50 (2H, m), 6.66-6.70 (1H, m), 7.58-7.62 (1H, m), 7.87-7.97 (4H, m), 8.48-8.49 (1H, m).
Elemental analysis value Calculated as C ₂₈ H ₃₂ ClN ₅ O ₇ S · H ₂ O (%): C, 52.87; H, 5.39; N, 11.01
Found (%): C, 52.60; H, 5.10; N, 10.91

実施例168
N-{(1S)-1-{[(6-クロロ-2-ナフチル)スルホニル]メチル}-2-[4-(5-メチル-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル)ピペリジン-1-イル]-2-オキソエチル}イソニコチンアミド
実施例154で得られた2-(1-{(2S)-2-アミノ-3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル)-4-ピペリジニル}-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン２塩酸塩(0.20g)と塩化イソニコチノイル塩酸塩(0.06mg)から実施例155と同様にして、題記化合物(0.08g, 38%)を白色固体として得た。
NMR (300MHz, DMSO-d₆)δ: 1.52-1.74 (4H, m), 2.57-2.72 (1H, m), 3.12-3.26 (7H, m), 3.89-4.03 (3H, m), 4.18-4.37 (2H, m), 5.26-5.39 (1H, m), 6.62-6.70 (1H, m), 7.30 (2H, d, J = 4.5), 7.61-7.64 (1H, m), 7.87-7.91 (1H, m), 8.00-8.04 (1H, m), 8.15 (1H, d, J = 8.7), 8.48 (2H, d, J = 5.7), 8.54 (1H, d, J = 4.8), 8.98-9.00 (1H, m).
元素分析値 C₃₀H₂₉ClN₆O₅S・H₂Oとして
計算値（％）：C, 56.38； H, 4.89； N, 13.15
実測値（％）：C, 56.76； H, 4.83； N, 13.31 Example 168
N-{(1S) -1-{[(6-Chloro-2-naphthyl) sulfonyl] methyl} -2- [4- (5-methyl-3-oxo-1H-imidazo [1,5-c] imidazole -2 (3H) -yl) piperidin-1-yl] -2-oxoethyl} isonicotinamide 2- (1-{(2S) -2-amino-3-[(6-chloro -2-naphthyl) sulfonyl] propanoyl) -4-piperidinyl} -5-methyl-1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one dihydrochloride (0.20 g) and isonicotinoyl chloride The title compound (0.08 g, 38%) was obtained as a white solid from the hydrochloride (0.06 mg) in the same manner as in Example 155.
NMR (300MHz, DMSO-d ₆ ) δ: 1.52-1.74 (4H, m), 2.57-2.72 (1H, m), 3.12-3.26 (7H, m), 3.89-4.03 (3H, m), 4.18-4.37 (2H, m), 5.26-5.39 (1H, m), 6.62-6.70 (1H, m), 7.30 (2H, d, J = 4.5), 7.61-7.64 (1H, m), 7.87-7.91 (1H, m), 8.00-8.04 (1H, m), 8.15 (1H, d, J = 8.7), 8.48 (2H, d, J = 5.7), 8.54 (1H, d, J = 4.8), 8.98-9.00 (1H , m).
Elemental analysis value Calculated as C ₃₀ H ₂₉ ClN ₆ O ₅ S · H ₂ O (%): C, 56.38; H, 4.89; N, 13.15
Found (%): C, 56.76; H, 4.83; N, 13.31

実施例169
(1S)-1-{[(6-クロロ-2-ナフチル)スルホニル]メチル}-2-[4-(5-メチル-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル)-1-ピペリジニル]-2-オキソエチルカルバミン酸2-(ベンジルオキシ)エチル
実施例154で得られた2-(1-{(2S)-2-アミノ-3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル)-4-ピペリジニル}-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン２塩酸塩(0.60g)とクロロギ酸 2-ベンジルオキシエチル(0.38mL)から実施例155と同様にして、題記化合物(0.50g, 70%)を白色固体として得た。
NMR (300MHz, CDCl₃)δ: 1.69-2.06 (4H, m), 2.61 (3H, s), 3.21-3.25 (1H, m), 3.42-3.53 (4H, m), 3.81-3.87 (1H, m), 3.95-4.28 (4H, m), 4.49 (2H, s), 4.58-4.82 (1H, m), 5.25-5.50 (2H, m), 6.66 (1H, s), 7.27-7.35 (6H, m), 7.57-7.61 (1H, m), 7.90-7.96 (4H, m), 8.48 (1H, s).
元素分析値 C₃₄H₃₆ClN₅O₇Sとして
計算値（％）：C, 58.83； H, 5.23； N, 10.09
実測値（％）：C, 58.51； H, 5.37； N, 9.84 Example 169
(1S) -1-{[(6-Chloro-2-naphthyl) sulfonyl] methyl} -2- [4- (5-methyl-3-oxo-1H-imidazo [1,5-c] imidazole-2 ( 3H) -yl) -1-piperidinyl] -2-oxoethylcarbamate 2- (benzyloxy) ethyl 2- (1-{(2S) -2-amino-3-[(6 -Chloro-2-naphthyl) sulfonyl] propanoyl) -4-piperidinyl} -5-methyl-1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one dihydrochloride (0.60 g) The title compound (0.50 g, 70%) was obtained as a white solid from 2-benzyloxyethyl chloroformate (0.38 mL) in the same manner as in Example 155.
NMR (300MHz, CDCl ₃ ) δ: 1.69-2.06 (4H, m), 2.61 (3H, s), 3.21-3.25 (1H, m), 3.42-3.53 (4H, m), 3.81-3.87 (1H, m ), 3.95-4.28 (4H, m), 4.49 (2H, s), 4.58-4.82 (1H, m), 5.25-5.50 (2H, m), 6.66 (1H, s), 7.27-7.35 (6H, m ), 7.57-7.61 (1H, m), 7.90-7.96 (4H, m), 8.48 (1H, s).
Elemental analysis calculated as C ₃₄ H ₃₆ ClN ₅ O ₇ S (%): C, 58.83; H, 5.23; N, 10.09
Found (%): C, 58.51; H, 5.37; N, 9.84

実施例170
(1S)-1-{[(6-クロロ-2-ナフチル)スルホニル]メチル}-2-[4-(5-メチル-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル)-1-ピペリジニル]-2-オキソエチルカルバミン酸2-クロロエチル
実施例154で得られた2-(1-{(2S)-2-アミノ-3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル)-4-ピペリジニル}-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン２塩酸塩(0.59g)とクロロギ酸2-クロロエチル(0.11mL)から実施例155と同様にして、題記化合物(0.43g, 69%)を白色固体として得た。
NMR (300MHz, CDCl₃)δ: 1.61-2.13 (4H, m), 2.60 (3H, s), 2.65-2.81 (1H, m), 3.19-3.34 (1H, m), 3.45-3.56 (3H, m), 3.80-3.87 (1H, m), 4.17-4.87 (5H, m), 4.59-4.82 (1H, m), 5.25-5.44 (1H, m), 5.61-5.71 (1H, m), 6.66-6.70 (1H, m), 7.59-7.62 (1H, m), 7.87-7.97 (4H, m), 8.50 (1H, s).
元素分析値 C₂₇H₂₉Cl₂N₅O₆Sとして
計算値（％）：C, 52.09； H, 4.70； N, 11.25
実測値（％）：C, 51.75； H, 4.80； N, 10.92 Example 170
(1S) -1-{[(6-Chloro-2-naphthyl) sulfonyl] methyl} -2- [4- (5-methyl-3-oxo-1H-imidazo [1,5-c] imidazole-2 ( 3H) -yl) -1-piperidinyl] -2-oxoethylcarbamate 2-chloroethyl 2- (1-{(2S) -2-amino-3-[(6-chloro-2 -Naphtyl) sulfonyl] propanoyl) -4-piperidinyl} -5-methyl-1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one dihydrochloride (0.59 g) and 2-chloroformate The title compound (0.43 g, 69%) was obtained as a white solid from chloroethyl (0.11 mL) in the same manner as in Example 155.
NMR (300MHz, CDCl ₃ ) δ: 1.61-2.13 (4H, m), 2.60 (3H, s), 2.65-2.81 (1H, m), 3.19-3.34 (1H, m), 3.45-3.56 (3H, m ), 3.80-3.87 (1H, m), 4.17-4.87 (5H, m), 4.59-4.82 (1H, m), 5.25-5.44 (1H, m), 5.61-5.71 (1H, m), 6.66-6.70 (1H, m), 7.59-7.62 (1H, m), 7.87-7.97 (4H, m), 8.50 (1H, s).
Elemental analysis calculated as C ₂₇ H ₂₉ Cl ₂ N ₅ O ₆ S (%): C, 52.09; H, 4.70; N, 11.25
Found (%): C, 51.75; H, 4.80; N, 10.92

実施例171
2-{1-[(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-(2-オキソ-1,3-オキサゾリジン-3-イル)プロパノイル]-4-ピペリジニル}-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
実施例170で得られた(1S)-1-{[(6-クロロ-2-ナフチル)スルホニル]メチル}-2-[4-(5-メチル-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル)-1-ピペリジニル]-2-オキソエチルカルバミン酸2-クロロエチル(0.20g)のDMF(3mL)溶液へ0℃で水素化ナトリウム(60%油性：0.03g)を加え、10分間かき混ぜた。反応混合物に水を加え、ジクロロメタンで抽出し、有機層を無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残留物を分取高速液体クロマトグラフィーで精製して、題記化合物(0.11g, 60%)を白色固体として得た。
NMR (300MHz, CDCl₃)δ: 1.88-2.02 (3H, m), 2.56-2.79 (4H, m), 3.08-3.75 (5H, m), 3.93-4.44 (7H, m), 4.57-4.76 (1H, m), 5.41-5.61 (1H, m), 6.67 (1H, s), 7.60-7.63 (1H, m), 7.95-8.00 (4H, m), 8.52 (1H, s).
元素分析値 C₂₇H₂₈ClN₅O₆S・H₂O・AcOEtとして
計算値（％）：C, 48.50； H, 4.35； N, 9.75
実測値（％）：C, 48.11； H, 4.39； N, 10.15 Example 171
2- {1-[(2S) -3-[(6-Chloro-2-naphthyl) sulfonyl] -2- (2-oxo-1,3-oxazolidine-3-yl) propanoyl] -4-piperidinyl}- 5-Methyl-1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one (1S) -1-{[(6-chloro-2-naphthyl) sulfonyl obtained in Example 170 ] Methyl} -2- [4- (5-methyl-3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl) -1-piperidinyl] -2-oxoethylcarbamic acid 2 -Sodium hydride (60% oiliness: 0.03 g) was added to a solution of chloroethyl (0.20 g) in DMF (3 mL) at 0 ° C., and the mixture was stirred for 10 minutes. Water was added to the reaction mixture, extracted with dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to give the title compound (0.11 g, 60%) as a white solid.
NMR (300MHz, CDCl ₃ ) δ: 1.88-2.02 (3H, m), 2.56-2.79 (4H, m), 3.08-3.75 (5H, m), 3.93-4.44 (7H, m), 4.57-4.76 (1H , m), 5.41-5.61 (1H, m), 6.67 (1H, s), 7.60-7.63 (1H, m), 7.95-8.00 (4H, m), 8.52 (1H, s).
Elemental analysis value C ₂₇ H ₂₈ ClN ₅ O ₆ S · H ₂ O · AcOEt Calculated value (%): C, 48.50; H, 4.35; N, 9.75
Found (%): C, 48.11; H, 4.39; N, 10.15

実施例172
((1S)-1-{[(6-クロロ-2-ナフチル)スルホニル]メチル}-2-[4-(5-メチル-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル)-1-ピペリジニル]-2-オキソエチル)メチルカルバミン酸tert-ブチル
実施例152で得た(1S)-1-{[(6-クロロ-2-ナフチル)スルホニル]メチル}-2-[4-(5-メチル-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル)-1-ピペリジニル]-2-オキソエチルカルバミン酸 tert-ブチル(0.31g)のDMF(2.0mL)溶液へヨウ化メチル(0.31mL)および水素化ナトリウム(0.04g)を0℃で加え、10分間かき混ぜた。水を加え酢酸エチルで抽出し、抽出液を無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残留物を分取高速液体クロマトグラフィーで精製し題記化合物(0.30g, 96%)を白色粉末として得た。
NMR (300MHz, CDCl₃)δ: 1.46-1.98 (16H, m), 2.61 (3H, s), 2.69-2.75 (3H, m), 2.89-3.73 (3H, m), 4.24-4.69 (5H, m), 5.67-5.82 (1H, m), 6.70 (1H, s), 7.57-7.61 (1H, m), 7.88-7.98 (4H, m), 8.51 (1H, s).
元素分析値 C₃₀H₃₆ClN₅O₆S・0.2H₂O・0.5AcOEtとして
計算値（％）：C, 56.70； H, 6.01； N, 10.33
実測値（％）：C, 56.91； H, 6.41； N, 10.03 Example 172
((1S) -1-{[(6-Chloro-2-naphthyl) sulfonyl] methyl} -2- [4- (5-methyl-3-oxo-1H-imidazo [1,5-c] imidazole-2 (3H) -yl) -1-piperidinyl] -2-oxoethyl) methylcarbamate tert-butyl (1S) -1-{[(6-chloro-2-naphthyl) sulfonyl] methyl} -2 obtained in Example 152 Tert-Butyl- [4- (5-methyl-3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl) -1-piperidinyl] -2-oxoethylcarbamate (0.31 g ) In DMF (2.0 mL) was added methyl iodide (0.31 mL) and sodium hydride (0.04 g) at 0 ° C., and the mixture was stirred for 10 minutes. Water was added and the mixture was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to give the title compound (0.30 g, 96%) as a white powder.
NMR (300MHz, CDCl ₃ ) δ: 1.46-1.98 (16H, m), 2.61 (3H, s), 2.69-2.75 (3H, m), 2.89-3.73 (3H, m), 4.24-4.69 (5H, m ), 5.67-5.82 (1H, m), 6.70 (1H, s), 7.57-7.61 (1H, m), 7.88-7.98 (4H, m), 8.51 (1H, s).
Elemental analysis value C ₃₀ H ₃₆ ClN ₅ O ₆ S · 0.2H ₂ O · 0.5AcOEt (%): C, 56.70; H, 6.01; N, 10.33
Found (%): C, 56.91; H, 6.41; N, 10.03

実施例173
2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-3-(メチルアミノ)プロパノイル}-4-ピペリジニル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン２塩酸塩
実施例172で得られた((1S)-1-{[(6-クロロ-2-ナフチル)スルホニル]メチル}-2-[4-(5-メチル-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル)-1-ピペリジニル]-2-オキソエチル)メチルカルバミン酸tert-ブチル (0.20g)に4N塩化水素酢酸エチル溶液(3mL)を加え、室温で10分間かき混ぜた。溶媒を減圧留去し、題記化合物(0.10g, 49%)を白色固体として得た。
NMR (300MHz, DMSO-d₆)δ: 1.70-2.12 (2H, m), 2.32-2.40 (1H, m), 2.57-2.59 (3H, m), 2.75-2.77 (3H, m), 3.22-4.41 (8H, m), 4.53-4.60 (2H, m), 4.93-4.96 (1H, m), 7.49 (1H, s), 7.78 (1H, d, J = 8.9), 7.98-8.07 (1H, m), 8.20-8.36 (3H, m), 8.64-8.72 (1H, m), 9.84 (1H, s).
元素分析値 C₂₅H₂₈ClN₅O₄S・2HCl・1.5H₂O・1.0AcOEtとして
計算値（％）：C, 48.51； H, 5.75； N, 9.75
実測値（％）：C, 48.29； H, 5.96； N, 9.92 Example 173
2- (1-{(2S) -3-[(6-Chloro-2-naphthyl) sulfonyl] -3- (methylamino) propanoyl} -4-piperidinyl) -5-methyl-1,2-dihydro-3H -Imidazo [1,5-c] imidazol-3-one dihydrochloride ((1S) -1-{[(6-chloro-2-naphthyl) sulfonyl] methyl} -2- [obtained in Example 172 4- (5-Methyl-3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl) -1-piperidinyl] -2-oxoethyl) methylcarbamate to tert-butyl (0.20 g) 4N Hydrogen chloride ethyl acetate solution (3 mL) was added, and the mixture was stirred at room temperature for 10 min. The solvent was distilled off under reduced pressure to obtain the title compound (0.10 g, 49%) as a white solid.
NMR (300MHz, DMSO-d ₆ ) δ: 1.70-2.12 (2H, m), 2.32-2.40 (1H, m), 2.57-2.59 (3H, m), 2.75-2.77 (3H, m), 3.22-4.41 (8H, m), 4.53-4.60 (2H, m), 4.93-4.96 (1H, m), 7.49 (1H, s), 7.78 (1H, d, J = 8.9), 7.98-8.07 (1H, m) , 8.20-8.36 (3H, m), 8.64-8.72 (1H, m), 9.84 (1H, s).
Elemental Analysis Value Calculated as C ₂₅ H ₂₈ ClN ₅ O ₄ S · 2HCl · 1.5H ₂ O · 1.0 AcOEt (%): C, 48.51; H, 5.75; N, 9.75
Found (%): C, 48.29; H, 5.96; N, 9.92

実施例174
シクロヘキシルカルバミン酸[2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル
174a) (2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロピオン酸
実施例136b)で得られた(2S)-3-[(6-クロロ-2-ナフチル)チオ]-2-ヒドロキシプロピオン酸(1.5g)のアセトン(150mL)けん濁液へオキソン(6.6g)の水溶液(150mL)を０℃で加え、室温で５時間かき混ぜた。沈殿物をろ取、水洗後、乾燥して、題記化合物(1.4g, 82%)を白色粉末として得た。
NMR (300MHz, CD₃OD)δ: 3.65 (1H, dd, J = 14.7, 8.1), 3.76 (1H, dd, J = 14.7, 3.3), 4.59 (1H, dd, J = 8.1, 3.3), 7.62 (1H, dd, J = 8.9, 2.3), 7.94-8.09 (4H, m), 8.55 (1H, s).
174b) 4-[5-({[(シクロヘキシルアミノ)カルボニル]オキシ}メチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル
実施例185b)で得られた4-[5-(ヒドロキシメチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸tert-ブチル(0.20g)のTHF(5.0mL)溶液にイソシアン酸シクロヘキシル(0.61mL)を室温で加え、50℃で2日間かき混ぜた。反応混合物を室温に冷却後、ジクロロメタンを加え、飽和炭酸ナトリウム水溶液で洗浄、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残留物を塩基性シリカゲルカラム(酢酸エチル)で精製して、題記化合物(0.28g, 99%)を無色油状物として得た。
NMR (300MHz, CDCl₃)δ: 1.05-1.41 (6H, m), 1.47 (9H, s), 1.50-1.71 (6H, m), 1.83-1.95 (4H, m), 2.77-2.86 (2H, m), 3.48-3.51 (1H, m), 4.25-4.32 (3H, m), 4.72 (1H, d, J = 7.8), 5.35 (2H, s), 6.85 (1H, t, J = 1.2).
174c) シクロヘキシルカルバミン酸(3-オキソ-2-(4-ピペリジニル)-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル)メチル２塩酸塩
実施例174b) で得られた4-[5-({[(シクロヘキシルアミノ)カルボニル]オキシ}メチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル(0.28g)のエタノール(2.0mL)溶液に40%塩化水素エタノール溶液(2.0mL)を加え、室温で30分間かき混ぜた。溶媒を減圧留去し、題記化合物(0.26g, 定量的)を無色固体として得た。
NMR (300MHz, DMSO-d₆)δ: 1.03-1.30 (5H, m), 1.52-2.13 (5H, m), 2.98-3.45 (4H, m), 4.08-4.16 (1H, m), 4.58 (2H, s), 5,25 (2H, s), 5.36-5.76 (4H, m), 7.22-7.34 (2H, m), 9.05-9.18 (2H, m).
174d) シクロヘキシルカルバミン酸[2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル
実施例174c)で得られたシクロヘキシルカルバミン酸[3-オキソ-2-(4-ピペリジニル)-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル２塩酸塩(0.26g)と実施例174a)で得られた(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロピオン酸(0.21g)から実施例128)と同様にして、題記化合物(0.11g, 34%)を無色固体として得た。
NMR (300MHz, CDCl₃)δ: 1.09-1.31 (6H, m), 1.53-1.96 (8H, m), 2.70-2.88 (1H, m), 3.15-3.31 (1H, m), 3.44-3.52 (3H, m), 3.74-3.89 (1H, m), 4.20-4.35 (4H, m), 4.68-4.78 (2H, m), 5.00-5.06 (1H, m), 5.36 (2H, s), 6.87 (1H, s), 7.58-7.62 (1H, m), 7.91-7.98 (4H, m), 8.51 (1H, s).
元素分析値 C₃₁H₃₆ClN₅O₇S・0.5H₂Oとして
計算値（％）：C, 55.81； H, 5.59； N, 10.50
実測値（％）：C, 55.93； H, 5.79； N, 10.15 Example 174
Cyclohexylcarbamic acid [2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -3-oxo-2,3-dihydro -1H-imidazo [1,5-c] imidazol-5-yl] methyl
174a) (2S) -3-[(6-Chloro-2-naphthyl) sulfonyl] -2-hydroxypropionic acid (2S) -3-[(6-Chloro-2-naphthyl) obtained in Example 136b) An aqueous solution (150 mL) of oxone (6.6 g) was added to a suspension of thio] -2-hydroxypropionic acid (1.5 g) in acetone (150 mL) at 0 ° C., and the mixture was stirred at room temperature for 5 hours. The precipitate was collected by filtration, washed with water, and dried to give the title compound (1.4 g, 82%) as a white powder.
NMR (300MHz, CD ₃ OD) δ: 3.65 (1H, dd, J = 14.7, 8.1), 3.76 (1H, dd, J = 14.7, 3.3), 4.59 (1H, dd, J = 8.1, 3.3), 7.62 (1H, dd, J = 8.9, 2.3), 7.94-8.09 (4H, m), 8.55 (1H, s).
174b) 4- [5-({[(Cyclohexylamino) carbonyl] oxy} methyl) -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1-carboxylic acid tert-Butyl 4- [5- (hydroxymethyl) -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1-carboxylic acid obtained in Example 185b) To a solution of tert-butyl (0.20 g) in THF (5.0 mL) was added cyclohexyl isocyanate (0.61 mL) at room temperature, and the mixture was stirred at 50 ° C. for 2 days. The reaction mixture was cooled to room temperature, dichloromethane was added, washed with a saturated aqueous sodium carbonate solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with a basic silica gel column (ethyl acetate) to give the title compound (0.28 g, 99%) as a colorless oil.
NMR (300MHz, CDCl ₃ ) δ: 1.05-1.41 (6H, m), 1.47 (9H, s), 1.50-1.71 (6H, m), 1.83-1.95 (4H, m), 2.77-2.86 (2H, m ), 3.48-3.51 (1H, m), 4.25-4.32 (3H, m), 4.72 (1H, d, J = 7.8), 5.35 (2H, s), 6.85 (1H, t, J = 1.2).
174c) Cyclohexylcarbamic acid (3-oxo-2- (4-piperidinyl) -2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl) methyl dihydrochloride obtained in Example 174b) 4- [5-({[(Cyclohexylamino) carbonyl] oxy} methyl) -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1-carboxylic acid A 40% hydrogen chloride ethanol solution (2.0 mL) was added to a solution of tert-butyl (0.28 g) in ethanol (2.0 mL), and the mixture was stirred at room temperature for 30 min. The solvent was distilled off under reduced pressure to obtain the title compound (0.26 g, quantitative) as a colorless solid.
NMR (300MHz, DMSO-d ₆ ) δ: 1.03-1.30 (5H, m), 1.52-2.13 (5H, m), 2.98-3.45 (4H, m), 4.08-4.16 (1H, m), 4.58 (2H , s), 5,25 (2H, s), 5.36-5.76 (4H, m), 7.22-7.34 (2H, m), 9.05-9.18 (2H, m).
174d) cyclohexyl carbamic acid [2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -3-oxo-2,3 -Dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl cyclohexylcarbamic acid obtained in Example 174c) [3-oxo-2- (4-piperidinyl) -2,3-dihydro- 1H-imidazo [1,5-c] imidazol-5-yl] methyl dihydrochloride (0.26 g) and (2S) -3-[(6-chloro-2-naphthyl) sulfonyl obtained in Example 174a) ] -2-Hydroxypropionic acid (0.21 g) was used in the same manner as in Example 128) to give the title compound (0.11 g, 34%) as a colorless solid.
NMR (300MHz, CDCl ₃ ) δ: 1.09-1.31 (6H, m), 1.53-1.96 (8H, m), 2.70-2.88 (1H, m), 3.15-3.31 (1H, m), 3.44-3.52 (3H , m), 3.74-3.89 (1H, m), 4.20-4.35 (4H, m), 4.68-4.78 (2H, m), 5.00-5.06 (1H, m), 5.36 (2H, s), 6.87 (1H , s), 7.58-7.62 (1H, m), 7.91-7.98 (4H, m), 8.51 (1H, s).
Elemental analysis value Calculated as C ₃₁ H ₃₆ ClN ₅ O ₇ S · 0.5H ₂ O (%): C, 55.81; H, 5.59; N, 10.50
Found (%): C, 55.93; H, 5.79; N, 10.15

実施例175
1-アセチルピペリジン-4-カルボン酸[2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル
175a) 4-[5-({[(1-アセチル-1-ピペリジニル)カルボニル]オキシ}メチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル
実施例185b)で得られた4-[5-(ヒドロキシメチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル(0.25g)と1-アセチルピペリジン-4-カルボン酸(0.15g)およびDMAP(0.02g)のジクロロメタン(3.0mL)溶液にWSC(0.23g)を加え、室温で2時間かき混ぜた。反応混合物にジクロロメタンを加え、飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去して、題記化合物を無色油状物として得た。これを精製することなく次の反応に用いた。
LCMS (m/z) 490.2
175b) 1-アセチルピペリジン-4-カルボン酸 [3-オキソ-2-(4-ピペリジニル)-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル２塩酸塩
実施例175a)で得られた4-[5-({[(1-アセチル-1-ピペリジニル)カルボニル]オキシ}メチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチルから実施例174c)と同様にして題記化合物(0.35g, 定量的)を白色粉末として得た。
NMR (300MHz, CDCl₃) δ: 1.37-2.14 (5H, m), 2.64-2.72 (4H, m), 2.96-3.19 (5H, m), 3.32-3.37 (2H, m), 3.72-3.76 (1H, m), 4.11-4.20 (2H, m), 4.58 (2H ,s), 5.38 (2H, s), 6.97-7.00 (1H, m), 7.24 (1H, s), 9.14-9.27 (2H, m).
175c) 1-アセチルピペリジン-4-カルボン酸[2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル
実施例175b)で得られた1-アセチルピペリジン-4-カルボン酸 [3-オキソ-2-(4-ピペリジニル)-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル２塩酸塩(0.35g)と実施例174a)で得られた(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロピオン酸(0.26g)から実施例128と同様にして題記化合物(0.14g, 27%)を白色粉末として得た。
NMR (300MHz, CDCl₃)δ: 1.12-1.28 (2H, m), 1.61-2.14 (16H, m), 2.58-2.86 (4H, m), 3.08-3.80 (7H, m), 4.11-4.38 (6H, m), 4.70-4.78 (1H, m), 5.02-5.07 (1H, m), 5.39 (2H, s), 6.90 (1H, s), 7.59-7.62 (1H, m), 7.91-7.98 (4H, m), 8.51 (1H, s).
元素分析値 C₃₂H₃₆ClN₅O₈S・0.5H₂Oとして
計算値（％）：C, 55.29； H, 5.36； N, 10.07
実測値（％）：C, 55.43； H, 5.60； N, 9.92 Example 175
1-acetylpiperidine-4-carboxylic acid [2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -3-oxo -2,3-Dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl
175a) 4- [5-({[(1-Acetyl-1-piperidinyl) carbonyl] oxy} methyl) -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine Tert-butyl-1-carboxylate 4- [5- (hydroxymethyl) -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine obtained in Example 185b) Add WSC (0.23 g) to a solution of tert-butyl-1-carboxylate (0.25 g), 1-acetylpiperidine-4-carboxylic acid (0.15 g) and DMAP (0.02 g) in dichloromethane (3.0 mL) at room temperature. Stir for 2 hours. Dichloromethane was added to the reaction mixture, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as a colorless oil. This was used in the next reaction without purification.
LCMS (m / z) 490.2
175b) 1-acetylpiperidine-4-carboxylic acid [3-oxo-2- (4-piperidinyl) -2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl dihydrochloride 4- [5-({[(1-acetyl-1-piperidinyl) carbonyl] oxy} methyl) -3-oxo-1H-imidazo [1,5-c] imidazole-2 () obtained in Example 175a) The title compound (0.35 g, quantitative) was obtained as a white powder from tert-butyl 3H) -yl] piperidine-1-carboxylate in the same manner as in Example 174c).
NMR (300MHz, CDCl ₃ ) δ: 1.37-2.14 (5H, m), 2.64-2.72 (4H, m), 2.96-3.19 (5H, m), 3.32-3.37 (2H, m), 3.72-3.76 (1H , m), 4.11-4.20 (2H, m), 4.58 (2H, s), 5.38 (2H, s), 6.97-7.00 (1H, m), 7.24 (1H, s), 9.14-9.27 (2H, m ).
175c) 1-acetylpiperidine-4-carboxylic acid [2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -3 -Oxo-2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl 1-acetylpiperidine-4-carboxylic acid obtained in Example 175b) [3-oxo-2- (2S) -3 obtained in (4-piperidinyl) -2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl dihydrochloride (0.35 g) and Example 174a) The title compound (0.14 g, 27%) was obtained as a white powder from-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropionic acid (0.26 g) in the same manner as in Example 128.
NMR (300MHz, CDCl ₃ ) δ: 1.12-1.28 (2H, m), 1.61-2.14 (16H, m), 2.58-2.86 (4H, m), 3.08-3.80 (7H, m), 4.11-4.38 (6H , m), 4.70-4.78 (1H, m), 5.02-5.07 (1H, m), 5.39 (2H, s), 6.90 (1H, s), 7.59-7.62 (1H, m), 7.91-7.98 (4H , m), 8.51 (1H, s).
Elemental analysis value Calculated as C ₃₂ H ₃₆ ClN ₅ O ₈ S · 0.5H ₂ O (%): C, 55.29; H, 5.36; N, 10.07
Found (%): C, 55.43; H, 5.60; N, 9.92

実施例176
3-(2-オキソ-1-ピロリジニル)プロピオン酸[2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル
176a) 3-(2-オキソ-1-ピロリジニル)プロピオン酸
アクリル酸メチル(1.4mL)のTHF(100mL)溶液に水酸化ナトリウム(0.06g)およびピロリジン-2-オン(1.2mL)を加え、室温で4日間かき混ぜた。溶媒を減圧留去し、残留物にメタノール(150mL)と1N水酸化ナトリウム水溶液(30mL)を加え、室温で2日間かき混ぜた。溶媒を減圧留去し、残留物に1N塩酸を加え酸性にしてジクロロメタンで抽出した。抽出液を無水硫酸マグネシウムで乾燥した後、溶媒を減圧留去し、題記化合物(1.1g, 45%)を無色油状物として得た。
NMR (300MHz, CDCl₃)δ: 2.13-2.23 (1H, m), 2.46-2.54 (2H, m), 2.60 (2H, t, J = 6.8), 3.49-3.57 (2H, m), 3.61 (2H, t, J = 6.8), 10.5 (1H, s).
176b) 4-[3-オキソ-5-({[3-(2-オキソ-1-ピロリジニル)プロパノイル]オキシ}メチル)-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル
実施例185b)で得られた4-[5-(ヒドロキシメチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル(0.34g)と実施例176a)で得られた3-(2-オキソ-1-ピロリジニル)プロピオン酸(0.19g) から実施例175a)と同様にして題記化合物を無色油状物(0.26g, 55%)として得た。
NMR (300MHz, CDCl₃) δ: 1.47 (9H, s), 1.61-1.71 (2H, m), 1.84-2.05 (4H, m), 2.34 (2H, t, J = 8.3), 2.63 (2H, t, J = 6.8), 2.78-2.88 (2H, m), 3.43 (2H, t, J = 7.0), 3.59 (2H, t, J = 6.8), 4.05-4.34 (5H, m), 5.39 (2H, s), 6.87 (1H, s).
176c) 3-(2-オキソ-1-ピロリジニル)プロピオン酸[3-オキソ-2-(4-ピペリジニル)-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル
実施例176b)で得られた4-[3-オキソ-5-({[3-(2-オキソ-1-ピロリジニル)プロパノイル]オキシ}メチル)-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル(0.26g)の酢酸エチル(1.0mL)溶液へ4N塩化水素酢酸エチル溶液(2mL)を加え、室温で20分間かき混ぜた。溶媒を減圧留去し、残留物に飽和炭酸水素ナトリウム水溶液と炭酸カリウムを加え、ジクロロメタンで抽出した。抽出液を無水硫酸マグネシウムで乾燥した。溶媒を減圧留去して、題記化合物(0.13g, 65%)を白色粉末として得た。
NMR (300MHz, CDCl₃)δ: 1.57-2.07 (7H, m), 2.35 (2H, t, J = 7.8), 2.62 (2H, t, J = 6.6), 2.74 (2H, dt, J = 2.2 and 7.8), 3.17-3.23 (2H, m), 3.43 (2H, t, J = 6.6), 3.59 (2H, t, J = 6.6), 3.96-4.12 (1H, m), 4.37 (2H, s), 5.39 (2H, s), 6.86 (1H, s).
176d) 3-(2-オキソ-1-ピロリジニル)プロピオン酸[2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル
実施例176c)で得られた3-(2-オキソ-1-ピロリジニル)プロピオン酸[3-オキソ-2-(4-ピペリジニル)-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル(0.13g)と実施例174a)で得られた(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロピオン酸(0.12g)から実施例89b)と同様にして題記化合物(0.07g, 28%)を白色粉末として得た。
NMR (300MHz, CDCl₃)δ: 1.67-2.07 (7H, m), 2.35 (2H, t, J = 8.3), 2.62 (2H, t, J = 6.8), 2.71-2.85 (1H, m), 3.16-3.73 (6H, m), 4.10-4.37 (4H, m), 4.68-4.78 (1H, m), 5.00-5.08 (1H, m), 5.39 (2H, s), 6.71 (1H, s), 6.88 (1H, s), 7.58-7.62 (1H, m), 7.91-7.98 (4H, m), 8.51 (1H, s).
元素分析値 C₃₁H₃₄ClN₅O₈S・0.5H₂O・0.5AcOEtとして
計算値（％）：C, 54.65； H, 5.42； N, 9.66
実測値（％）：C, 54.66； H, 5.64； N, 9.90 Example 176
3- (2-oxo-1-pyrrolidinyl) propionic acid [2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -3-oxo-2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl
176a) 3- (2-oxo-1-pyrrolidinyl) propionic acid To a solution of methyl acrylate (1.4 mL) in THF (100 mL) was added sodium hydroxide (0.06 g) and pyrrolidin-2-one (1.2 mL) at room temperature. Stir for 4 days. The solvent was distilled off under reduced pressure, methanol (150 mL) and 1N aqueous sodium hydroxide solution (30 mL) were added to the residue, and the mixture was stirred at room temperature for 2 days. The solvent was distilled off under reduced pressure, and the residue was acidified with 1N hydrochloric acid and extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (1.1 g, 45%) as a colorless oil.
NMR (300MHz, CDCl ₃ ) δ: 2.13-2.23 (1H, m), 2.46-2.54 (2H, m), 2.60 (2H, t, J = 6.8), 3.49-3.57 (2H, m), 3.61 (2H , t, J = 6.8), 10.5 (1H, s).
176b) 4- [3-oxo-5-({[3- (2-oxo-1-pyrrolidinyl) propanoyl] oxy} methyl) -1H-imidazo [1,5-c] imidazol-2 (3H) -yl Tert-butyl piperidine-1-carboxylate 4- [5- (hydroxymethyl) -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl obtained in Example 185b) From piperidine-1-carboxylate tert-butyl (0.34 g) and 3- (2-oxo-1-pyrrolidinyl) propionic acid (0.19 g) obtained in Example 176a) in the same manner as in Example 175a) The compound was obtained as a colorless oil (0.26 g, 55%).
NMR (300MHz, CDCl ₃ ) δ: 1.47 (9H, s), 1.61-1.71 (2H, m), 1.84-2.05 (4H, m), 2.34 (2H, t, J = 8.3), 2.63 (2H, t , J = 6.8), 2.78-2.88 (2H, m), 3.43 (2H, t, J = 7.0), 3.59 (2H, t, J = 6.8), 4.05-4.34 (5H, m), 5.39 (2H, s), 6.87 (1H, s).
176c) 3- (2-oxo-1-pyrrolidinyl) propionic acid [3-oxo-2- (4-piperidinyl) -2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] 4- [3-oxo-5-({[3- (2-oxo-1-pyrrolidinyl) propanoyl] oxy} methyl) -1H-imidazo [1,5-c] imidazole obtained in Example 176b) To a solution of tert-butyl -2 (3H) -yl] piperidine-1-carboxylate (0.26 g) in ethyl acetate (1.0 mL) was added 4N hydrogen chloride ethyl acetate solution (2 mL), and the mixture was stirred at room temperature for 20 min. The solvent was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate solution and potassium carbonate were added to the residue, and the mixture was extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (0.13 g, 65%) as a white powder.
NMR (300MHz, CDCl ₃ ) δ: 1.57-2.07 (7H, m), 2.35 (2H, t, J = 7.8), 2.62 (2H, t, J = 6.6), 2.74 (2H, dt, J = 2.2 and 7.8), 3.17-3.23 (2H, m), 3.43 (2H, t, J = 6.6), 3.59 (2H, t, J = 6.6), 3.96-4.12 (1H, m), 4.37 (2H, s), 5.39 (2H, s), 6.86 (1H, s).
176d) 3- (2-oxo-1-pyrrolidinyl) propionic acid [2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4- Piperidinyl) -3-oxo-2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl 3- (2-oxo-1-pyrrolidinyl) propion obtained in Example 176c) Obtained with the acid [3-oxo-2- (4-piperidinyl) -2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl (0.13 g) and Example 174a) (2S) -3-[(6-Chloro-2-naphthyl) sulfonyl] -2-hydroxypropionic acid (0.12 g) was used in the same manner as Example 89b) to give the title compound (0.07 g, 28%) as a white powder. Obtained.
NMR (300MHz, CDCl ₃ ) δ: 1.67-2.07 (7H, m), 2.35 (2H, t, J = 8.3), 2.62 (2H, t, J = 6.8), 2.71-2.85 (1H, m), 3.16 -3.73 (6H, m), 4.10-4.37 (4H, m), 4.68-4.78 (1H, m), 5.00-5.08 (1H, m), 5.39 (2H, s), 6.71 (1H, s), 6.88 (1H, s), 7.58-7.62 (1H, m), 7.91-7.98 (4H, m), 8.51 (1H, s).
Elemental analysis value Calculated as C ₃₁ H ₃₄ ClN ₅ O ₈ S · 0.5H ₂ O · 0.5AcOEt (%): C, 54.65; H, 5.42; N, 9.66
Found (%): C, 54.66; H, 5.64; N, 9.90

実施例177
(2-オキソ-1-ピロリジニル)酢酸 [2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル
177a) (2-オキソ-1-ピロリジニル)酢酸
(2-オキソ-1-ピロリジニル)酢酸メチル(1.4mL)のメタノール(20mL)溶液に1N水酸化ナトリウム水溶液(11mL)を加え、70℃で2時間かき混ぜた。溶媒を減圧留去し、残留物を水で希釈してエーテルで洗浄し、ジクロロメタンで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去して、題記化合物(0.16g, 11%)を白色固体として得た。
NMR (300MHz, CDCl₃)δ: 2.06-2.16 (2H, m), 2.47-2.56 (2H, m), 3.48-3.57 (2H, m), 4.09 (2H, s), 8.11 (1H, s).
177b) 4-(3-オキソ-5-{[(2-オキソ-1-ピロリジニル)アセトキシ]メチル}-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル)ピペリジン-1-カルボン酸 tert-ブチル
実施例185b)で得られた4-[5-(ヒドロキシメチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル(0.29g)と実施例177a)で得られた(2-オキソ-1-ピロリジニル)酢酸(0.16g) から実施例175a)と同様にして題記化合物(0.41g, 定量的)を無色固体として得た。
NMR (300MHz, CDCl₃)δ: 1.48 (9H, s), 1.61-1.89 (4H, m), 2.02-2.12 (3H, m), 2.41 (2H, t, J = 8.3), 2.79-2.87 (2H, m), 3.00-3.01 (1H, m), 3.51 (2H, t, J = 7.0), 4.06-4.34 (5H, m), 5.44 (2H, s), 6.87 (1H, s).
177c) (2-オキソ-1-ピロリジニル)酢酸 [3-オキソ-2-(4-ピペリジニル)-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル２塩酸塩
実施例177b)で得られた4-(3-オキソ-5-{[(2-オキソ-1-ピロリジニル)アセトキシ]メチル}-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル)ピペリジン-1-カルボン酸 tert-ブチル(0.26g)から実施例174c)と同様にして題記化合物(0.37g, 定量的)を白色粉末として得た。
NMR (300MHz, DMSO-d₆)δ: 1.91-2.28 (8H, m), 3.01-3.42 (7H, m), 4.11-4.18 (3H, m), 4.60 (2H, s), 5.46 (2H, s), 7.32 (1H, s).
177d) (2-オキソ-1-ピロリジニル)酢酸 [2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル
実施例177c)で得られた(2-オキソ-1-ピロリジニル)酢酸 [3-オキソ-2-(4-ピペリジニル)-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル２塩酸塩(0.37g)と実施例174a)で得られた(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロピオン酸(0.30g)から実施例128と同様にして題記化合物(0.09g, 16%)を白色粉末として得た。
NMR (300MHz, CDCl₃)δ: 1.67-2.12 (8H, m), 2.41 (2H, t, J = 8.3), 2.70-2.78 (1H, m), 3.17-3.26 (1H, m), 3.46-3.55 (4H, m), 4.08-4.36 (5H, m), 4.68-4.72 (1H, m), 5.04-5.08 (1H, m), 5.43 (2H, s), 6.87 (1H, s), 7.58-7.61 (1H, m), 7.91-7.97 (4H, m), 8.51 (1H, s).
元素分析値 C₃₀H₃₂ClN₅O₈S・0.5H₂Oとして
計算値（％）：C, 54.01； H, 4.99； N, 10.50
実測値（％）：C, 54.12； H, 5.25； N, 10.27 Example 177
(2-Oxo-1-pyrrolidinyl) acetic acid [2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -3- Oxo-2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl
177a) (2-Oxo-1-pyrrolidinyl) acetic acid
To a solution of methyl (2-oxo-1-pyrrolidinyl) acetate (1.4 mL) in methanol (20 mL) was added 1N aqueous sodium hydroxide solution (11 mL), and the mixture was stirred at 70 ° C. for 2 hr. The solvent was removed in vacuo, the residue diluted with water, washed with ether and extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.16 g, 11%) as a white solid.
NMR (300MHz, CDCl ₃ ) δ: 2.06-2.16 (2H, m), 2.47-2.56 (2H, m), 3.48-3.57 (2H, m), 4.09 (2H, s), 8.11 (1H, s).
177b) 4- (3-oxo-5-{[(2-oxo-1-pyrrolidinyl) acetoxy] methyl} -1H-imidazo [1,5-c] imidazol-2 (3H) -yl) piperidine-1- Tert-butyl carboxylate 4- [5- (hydroxymethyl) -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1- obtained in Example 185b) The title compound (0.41 g, quantitative) was obtained in the same manner as in Example 175 a) from (2-oxo-1-pyrrolidinyl) acetic acid (0.16 g) obtained in tert-butyl carboxylate (0.29 g) and Example 177a). Was obtained as a colorless solid.
NMR (300MHz, CDCl ₃ ) δ: 1.48 (9H, s), 1.61-1.89 (4H, m), 2.02-2.12 (3H, m), 2.41 (2H, t, J = 8.3), 2.79-2.87 (2H , m), 3.00-3.01 (1H, m), 3.51 (2H, t, J = 7.0), 4.06-4.34 (5H, m), 5.44 (2H, s), 6.87 (1H, s).
177c) (2-oxo-1-pyrrolidinyl) acetic acid [3-oxo-2- (4-piperidinyl) -2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl dihydrochloride Salt 4- (3-oxo-5-{[(2-oxo-1-pyrrolidinyl) acetoxy] methyl} -1H-imidazo [1,5-c] imidazole-2 (3H) obtained in Example 177b) The title compound (0.37 g, quantitative) was obtained as a white powder from tert-butyl (-yl) piperidine-1-carboxylate (0.26 g) in the same manner as in Example 174c).
NMR (300MHz, DMSO-d ₆ ) δ: 1.91-2.28 (8H, m), 3.01-3.42 (7H, m), 4.11-4.18 (3H, m), 4.60 (2H, s), 5.46 (2H, s ), 7.32 (1H, s).
177d) (2-oxo-1-pyrrolidinyl) acetic acid [2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl)- 3-Oxo-2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl (2-oxo-1-pyrrolidinyl) acetic acid obtained in Example 177c) [3-oxo- 2- (4-Piperidinyl) -2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl dihydrochloride (0.37 g) and obtained in Example 174a) (2S) The title compound (0.09 g, 16%) was obtained as a white powder from -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropionic acid (0.30 g) in the same manner as in Example 128.
NMR (300MHz, CDCl ₃ ) δ: 1.67-2.12 (8H, m), 2.41 (2H, t, J = 8.3), 2.70-2.78 (1H, m), 3.17-3.26 (1H, m), 3.46-3.55 (4H, m), 4.08-4.36 (5H, m), 4.68-4.72 (1H, m), 5.04-5.08 (1H, m), 5.43 (2H, s), 6.87 (1H, s), 7.58-7.61 (1H, m), 7.91-7.97 (4H, m), 8.51 (1H, s).
Elemental analysis value Calculated as C ₃₀ H ₃₂ ClN ₅ O ₈ S · 0.5H ₂ O (%): C, 54.01; H, 4.99; N, 10.50
Found (%): C, 54.12; H, 5.25; N, 10.27

実施例178
{1-{[(6-クロロ-2-ナフチル)スルホニル]メチル}-2-[4-(5-メチル-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル)ピペリジン-1-イル]-2-オキソエチル}メチルカルバミン酸メチル
実施例156で得たN-((1S)-1-{[(6-クロロ-2-ナフチル)スルホニル]メチル}-2-[4-(5-メチル-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル)-1-ピペリジニル]-2-オキソエチル)カルバミン酸メチル(0.39g)とヨウ化メチル(0.42mL)から実施例172と同様にして題記化合物(0.32g, 79%)を白色固体として得た。
NMR (300MHz, CDCl₃)δ: 1.86-1.98 (3H, m), 2.60 (3H, s), 2.68-2.75 (3H, m), 2.88 (3H, s), 2.96 (3H, s), 3.02-3.77 (2H, m), 4.23-4.69 (4H, m), 5.62-5.87 (1H, m), 6.69 (1H, s), 7.58-7.61 (1H, m), 7.92-8.02 (5H, m), 8.45-8.50 (1H, m).
元素分析値 C₂₇H₃₀ClN₅O₆S・0.7AcOEtとして
計算値（％）：C, 55.09； H, 5.52； N, 10.78
実測値（％）：C, 55.47； H, 5.78； N, 10.70 Example 178
{1-{[(6-Chloro-2-naphthyl) sulfonyl] methyl} -2- [4- (5-methyl-3-oxo-1H-imidazo [1,5-c] imidazole-2 (3H)- Yl) piperidin-1-yl] -2-oxoethyl} methyl carbamate N-((1S) -1-{[(6-chloro-2-naphthyl) sulfonyl] methyl} -2- [ 4- (5-Methyl-3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl) -1-piperidinyl] -2-oxoethyl) carbamate methyl (0.39 g) and iodide The title compound (0.32 g, 79%) was obtained as a white solid from methyl (0.42 mL) in the same manner as in Example 172.
NMR (300MHz, CDCl ₃ ) δ: 1.86-1.98 (3H, m), 2.60 (3H, s), 2.68-2.75 (3H, m), 2.88 (3H, s), 2.96 (3H, s), 3.02- 3.77 (2H, m), 4.23-4.69 (4H, m), 5.62-5.87 (1H, m), 6.69 (1H, s), 7.58-7.61 (1H, m), 7.92-8.02 (5H, m), 8.45-8.50 (1H, m).
Elemental Analysis Value Calculated as C ₂₇ H ₃₀ ClN ₅ O ₆ S · 0.7AcOEt (%): C, 55.09; H, 5.52; N, 10.78
Found (%): C, 55.47; H, 5.78; N, 10.70

実施例179
3-(2-オキソ-1-ピロリジニル)プロピオン酸[2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル
179a) 3-(2-オキソ-1-ピペリジニル)プロピオン酸メチル
アクリル酸メチル(18mL) のTHF(200mL)溶液に水酸化ナトリウム(0.16g)およびピペリジン-2-オン(4.1g)を加え、80℃で5時間かき混ぜた。溶媒を減圧留去し、残留物にジクロロメタンを加え、飽和炭酸水素ナトリウム水溶液で洗浄、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去して、題記化合物(4.6g, 62%)を淡黄色油状物として得た。
NMR (300MHz, CDCl₃)δ: 1.74-1.86 (4H, m), 2.34-2.39 (2H, m), 2.62 (2H, t, J = 7.0), 3.32-3.36 (2H, m), 3.62 (2H, t, J = 7.0), 3.68 (3H ,s).
179b) 3-(2-オキソ-1-ピロリジニル)プロピオン酸
実施例179a)で得られた3-(2-オキソ-1-ピペリジニル)プロピオン酸メチル(4.6g)から実施例177a)と同様にして、題記化合物(2.3g, 55%)を淡茶色粉末として得た。
NMR (300MHz, CDCl₃)δ: 1.77-1.87 (4H, m), 2.38-2.42 (2H, m), 2.64 (2H, t, J = 7.0), 3.30-3.41 (2H, m), 3.63 (2H, t, J = 7.0), 6.29 (1H ,s).
179c) 4-[3-オキソ-5-({[3-(2-オキソ-1-ピペリジニル)プロパノイル]オキシ}メチル)-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル
実施例185b)で得られた4-[5-(ヒドロキシメチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル(0.34g)と実施例179b)で得られた3-(2-オキソ-1-ピロリジニル)プロピオン酸(0.20g) から実施例175a)と同様にして題記化合物(0.49g, 定量的)を無色油状物として得た。
NMR (300MHz, CDCl₃)δ: 1.47 (9H, s), 1.66-1.88 (2H, m), 2.32-2.38 (3H, m), 2.67 (2H, t, J = 7.0), 2.78-2.87 (2H, m), 3.33-3.36 (2H, m), 3.62 (2H, t, J = 6.8), 4.05-4.34 (5H, m), 5.38 (2H, s), 6.86 (1H, s).
179d) 3-(2-オキソ-1-ピペリジニル)プロピオン酸[3-オキソ-2-(4-ピペリジニル)-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル 2塩酸塩
実施例179c)で得られた4-[3-オキソ-5-({[3-(2-オキソ-1-ピペリジニル)プロパノイル]オキシ}メチル)-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル(0.49g)から実施例174c)と同様にして題記化合物(0.46g, 99%)を白色粉末として得た。
NMR (300MHz, DMSO-d₆)δ: 1.63-1.72 (5H, m), 2.06-2.20 (4H, m), 2.60-2.65 (2H, m), 2.97-3.52 (5H, m), 4.12-4.20 (2H, m), 4.63-4.66 (2H, m), 5.46 (2H, s), 7.46 (1H, s), 9.27-9.44 (2H, m).
179e) 3-(2-オキソ-1-ピペリジニル)プロピオン酸[2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル
実施例179d)で得られた3-(2-オキソ-1-ピペリジニル)プロピオン酸[3-オキソ-2-(4-ピペリジニル)-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル 2塩酸塩(0.46g)と実施例174a)で得られた(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロピオン酸(0.35g)から実施例89b)と同様にして、題記化合物(0.02g, 2%)を白色粉末として得た。
NMR (300MHz, CDCl₃)δ: 1.76-2.11 (9H, m), 2.33-2.39 (2H, m), 2.65-2.91 (3H, m), 3.17-3.74 (7H, m), 4.05-4.36 (4H, m), 4.68-4.77 (1H, m), 5.05 (1H, s), 5.37 (2H, s), 6.86 (1H, s), 7.57-7.61 (1H, m), 7.93-7.96 (4H, m), 8.50 (1H, s). Example 179
3- (2-oxo-1-pyrrolidinyl) propionic acid [2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -3-oxo-2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl
179a) Methyl 3- (2-oxo-1-piperidinyl) propionate To a solution of methyl acrylate (18 mL) in THF (200 mL) was added sodium hydroxide (0.16 g) and piperidin-2-one (4.1 g). Stir at 5 ° C. for 5 hours. The solvent was distilled off under reduced pressure, dichloromethane was added to the residue, washed with a saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (4.6 g, 62%) as a pale yellow oil.
NMR (300MHz, CDCl ₃ ) δ: 1.74-1.86 (4H, m), 2.34-2.39 (2H, m), 2.62 (2H, t, J = 7.0), 3.32-3.36 (2H, m), 3.62 (2H , t, J = 7.0), 3.68 (3H, s).
179b) 3- (2-oxo-1-pyrrolidinyl) propionic acid From methyl 3- (2-oxo-1-piperidinyl) propionate (4.6 g) obtained in Example 179a) in the same manner as in Example 177a) The title compound (2.3 g, 55%) was obtained as a light brown powder.
NMR (300MHz, CDCl ₃ ) δ: 1.77-1.87 (4H, m), 2.38-2.42 (2H, m), 2.64 (2H, t, J = 7.0), 3.30-3.41 (2H, m), 3.63 (2H , t, J = 7.0), 6.29 (1H, s).
179c) 4- [3-oxo-5-({[3- (2-oxo-1-piperidinyl) propanoyl] oxy} methyl) -1H-imidazo [1,5-c] imidazol-2 (3H) -yl Tert-butyl piperidine-1-carboxylate 4- [5- (hydroxymethyl) -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl obtained in Example 185b) From piperidine-1-carboxylate tert-butyl (0.34 g) and 3- (2-oxo-1-pyrrolidinyl) propionic acid (0.20 g) obtained in Example 179b) in the same manner as in Example 175a) The compound (0.49 g, quantitative) was obtained as a colorless oil.
NMR (300MHz, CDCl ₃ ) δ: 1.47 (9H, s), 1.66-1.88 (2H, m), 2.32-2.38 (3H, m), 2.67 (2H, t, J = 7.0), 2.78-2.87 (2H , m), 3.33-3.36 (2H, m), 3.62 (2H, t, J = 6.8), 4.05-4.34 (5H, m), 5.38 (2H, s), 6.86 (1H, s).
179d) 3- (2-oxo-1-piperidinyl) propionic acid [3-oxo-2- (4-piperidinyl) -2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] Methyl dihydrochloride 4- [3-oxo-5-({[3- (2-oxo-1-piperidinyl) propanoyl] oxy} methyl) -1H-imidazo [1,5- c] Imidazole-2 (3H) -yl] piperidine-1-carboxylate The title compound (0.46 g, 99%) was obtained as a white powder in the same manner as in Example 174c) from tert-butyl (0.49 g).
NMR (300MHz, DMSO-d ₆ ) δ: 1.63-1.72 (5H, m), 2.06-2.20 (4H, m), 2.60-2.65 (2H, m), 2.97-3.52 (5H, m), 4.12-4.20 (2H, m), 4.63-4.66 (2H, m), 5.46 (2H, s), 7.46 (1H, s), 9.27-9.44 (2H, m).
179e) 3- (2-oxo-1-piperidinyl) propionic acid [2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4- Piperidinyl) -3-oxo-2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl 3- (2-oxo-1-piperidinyl) propion obtained in Example 179d) With the acid [3-oxo-2- (4-piperidinyl) -2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl dihydrochloride (0.46 g) and Example 174a) The title compound (0.02 g, 2%) was obtained from the obtained (2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropionic acid (0.35 g) in the same manner as in Example 89b). Was obtained as a white powder.
NMR (300MHz, CDCl ₃ ) δ: 1.76-2.11 (9H, m), 2.33-2.39 (2H, m), 2.65-2.91 (3H, m), 3.17-3.74 (7H, m), 4.05-4.36 (4H , m), 4.68-4.77 (1H, m), 5.05 (1H, s), 5.37 (2H, s), 6.86 (1H, s), 7.57-7.61 (1H, m), 7.93-7.96 (4H, m ), 8.50 (1H, s).

実施例180
(2-オキソ-1-ピペリジニル)酢酸 [2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル
180a) 4-(3-オキソ-5-{[(2-オキソ-1-ピペリジニル)アセトキシ]メチル}-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル)ピペリジン-1-カルボン酸 tert-ブチル
実施例185b)で得た4-[5-(ヒドロキシメチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸tert-ブチル(0.34g)と(2-オキソ-1-ピペリジニル)酢酸(Hassner, A. et al., J. Org. Chem., 57, 3070 (1992)) (0.19g) から実施例175a)と同様にして、題記化合物(0.47g, 99%)を無色油状物として得た。
NMR (300MHz, CDCl₃)δ: 1.47 (9H, s), 1.62-1.66 (4H, m), 1.83-1.88 (5H, m), 2.39-2.42 (2H, m), 4.06-4.33 (6H, m), 5.44 (2H, s), 6.86 (1H, s).
180b) (2-オキソ-1-ピペリジニル)酢酸[3-オキソ-2-(4-ピペリジニル)-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル２塩酸塩
実施例180a)で得られた4-(3-オキソ-5-{[(2-オキソ-1-ピペリジニル)アセトキシ]メチル}-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル)ピペリジン-1-カルボン酸 tert-ブチル(0.47g)から実施例174c)と同様にして題記化合物(0.44g, 98%)を白色粉末として得た。
NMR (300MHz, DMSO-d₆)δ: 1.68-1.78 (5H, m), 2.10-2.27 (4H, m), 2.97-3.05 (2H, m), 3.31-3.36 (4H, m), 4.12-4.20 (3H, m), 4.63 (2H, s), 5.49 (2H, s), 7.44 (1H, s), 9.26-9.41 (2H, m).
180c) (2-オキソ-1-ピペリジニル)酢酸 [2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル
実施例180b)で得られた(2-オキソ-1-ピペリジニル)酢酸[3-オキソ-2-(4-ピペリジニル)-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル２塩酸塩(0.44g)と実施例174a)で得られた(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロピオン酸(0.35g)から実施例89b)と同様にして題記化合物を白色粉末(0.06g, 8%)として得た。
NMR (300MHz, CDCl₃)δ: 1.69-2.12 (7H, m), 2.39-2.43 (2H, m), 2.70-2.84 (1H, m), 3.16-3.54 (5H, m), 4.19-4.36 (6H, m), 4.68-4.77 (1H, m), 5.03-5.07 (1H, m), 5.44 (2H, s), 6.87 (1H, s), 7.58-7.62 (1H, m), 7.94-7.97 (4H, m), 8.51 (1H, s). Example 180
(2-Oxo-1-piperidinyl) acetic acid [2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -3- Oxo-2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl
180a) 4- (3-oxo-5-{[(2-oxo-1-piperidinyl) acetoxy] methyl} -1H-imidazo [1,5-c] imidazol-2 (3H) -yl) piperidine-1- Tert-butyl carboxylate 4- [5- (hydroxymethyl) -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1-carboxylic acid obtained in Example 185b) Example 175a from tert-butyl acid (0.34 g) and (2-oxo-1-piperidinyl) acetic acid (Hassner, A. et al., J. Org. Chem., 57, 3070 (1992)) (0.19 g) ) To give the title compound (0.47 g, 99%) as a colorless oil.
NMR (300MHz, CDCl ₃ ) δ: 1.47 (9H, s), 1.62-1.66 (4H, m), 1.83-1.88 (5H, m), 2.39-2.42 (2H, m), 4.06-4.33 (6H, m ), 5.44 (2H, s), 6.86 (1H, s).
180b) (2-Oxo-1-piperidinyl) acetic acid [3-oxo-2- (4-piperidinyl) -2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl dihydrochloride Salt 4- (3-oxo-5-{[(2-oxo-1-piperidinyl) acetoxy] methyl} -1H-imidazo [1,5-c] imidazole-2 (3H) obtained in Example 180a) The title compound (0.44 g, 98%) was obtained as a white powder in the same manner as in Example 174c) from tert-butyl (-yl) piperidine-1-carboxylate (0.47 g).
NMR (300MHz, DMSO-d ₆ ) δ: 1.68-1.78 (5H, m), 2.10-2.27 (4H, m), 2.97-3.05 (2H, m), 3.31-3.36 (4H, m), 4.12-4.20 (3H, m), 4.63 (2H, s), 5.49 (2H, s), 7.44 (1H, s), 9.26-9.41 (2H, m).
180c) (2-oxo-1-piperidinyl) acetic acid [2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl)- 3-oxo-2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl (2-oxo-1-piperidinyl) acetic acid [3-oxo-] obtained in Example 180b) 2- (4-Piperidinyl) -2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl dihydrochloride (0.44 g) and obtained in Example 174a) (2S) The title compound was obtained as a white powder (0.06 g, 8%) from -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropionic acid (0.35 g) in the same manner as in Example 89b).
NMR (300MHz, CDCl ₃ ) δ: 1.69-2.12 (7H, m), 2.39-2.43 (2H, m), 2.70-2.84 (1H, m), 3.16-3.54 (5H, m), 4.19-4.36 (6H , m), 4.68-4.77 (1H, m), 5.03-5.07 (1H, m), 5.44 (2H, s), 6.87 (1H, s), 7.58-7.62 (1H, m), 7.94-7.97 (4H , m), 8.51 (1H, s).

実施例181
2-(1-{(2R)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
181a) (2R)-3-[(6-クロロ-2-ナフチル)チオ]-2-ヒドロキシプロピオン酸メチル
(2S)-オキシラン-2-カルボン酸メチル(2.6g)から実施例136a)と同様にして、題記化合物(5.6g, 74%)を白色結晶(へキサン-酢酸エチル)として得た。
NMR (300MHz, CDCl₃)δ: 3.13 (1H, d, J = 6.0), 3.36 (1H, dd, J = 14.1, 5.7), 3.48 (1H, dd, J = 14.1, 4.2), 4.46 (1H, ddd, J = 6.0, 5.7, 4.2), 7.41 (1H, dd, J = 6.9, 1.8), 7.51 (1H, dd, J = 6.9, 1.8), 7.67 (1H, d, J =1.8), 7.70 (1H, d, J = 1.8), 7.77 (1H, d, J = 2.1), 7.84 (1H, d, J = 2.1).
181b) (2R)-3-[(6-クロロ-2-ナフチル)チオ]-2-ヒドロキシプロピオン酸
実施例181a)で得られた(2R)-3-[(6-クロロ-2-ナフチル)チオ]-2-ヒドロキシプロピオン酸メチル(5.0g)から実施例136b)と同様にして、題記化合物(4.7g, 99%)を白色粉末として得た。
NMR (300MHz, CD₃OD)δ: 3.20 (1H, dd, J = 13.5, 3.3), 3.57 (1H, dd, J = 13.5, 3.3), 4.19 (1H, dd, J = 13.5, 3.3), 7.40 (1H, dd, J = 8.7, 2.1), 7.52 (1H, dd, J = 8.7, 2.1), 7.71 (1H, d, J = 8.7), 7.77 (1H, d, J = 8.7), 7.80 (1H, s), 7.87 (1H, s).
181c) 2-(1-{(2R)-3-[(6-クロロ-2-ナフチル)チオ]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
実施例181b)で得られた(2R)-3-[(6-クロロ-2-ナフチル)チオ]-2-ヒドロキシプロピオン酸(4.5g)から実施例136c)と同様にして、題記化合物(5.6g, 73%)を白色粉末として得た。
NMR (300MHz,CDCl₃) δ: 1.28-1.65 (2H, m), 1.66-1.88 (2H, m), 2.40-2.73 (1H, m), 2.58 (3H, s), 2.98-3.10 (1H, m), 3.20-3.44 (2H, m), 3.68-3.77 (1H, m), 3.80 (2H, s), 4.00-4.15 (1H, m), 4.19 (1H, s), 4.55-4.73 (2H, m), 6.67 (1H, s), 7.40-7.50 (2H, m), 7.66 (1H, s), 7.69 (1H, s), 7.70 (1H, s), 7.81 (1H, d, J = 5.4).
181d) 2-(1-{(2R)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
実施例181c)で得られた2-(1-{(2R)-3-[(6-クロロ-2-ナフチル)チオ]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン(3.0g)から実施例136d)と同様にして、題記化合物(2.2g, 67%)を白色粉末として得た。
NMR (300MHz, CDCl₃)δ: 1.66-1.99 (4H, m), 2.61 (3H, s), 2.69-2.88 (1H, m), 3.14-3.33 (1H, m), 3.48 (2H, dd, J = 11.8, 5.6), 3.84 (1H, m), 4.07-4.22 (1H, m), 4.27 (2H, s), 4.65-4.88 (1H, m), 4.98-5.09 (1H, m), 6.71 (1H, s), 7.59 (1H, dd, J = 8.8, 1.0), 7.95 (3H, s), 7.96 (1H, d, J = 8.8), 8.51 (1H, s).
元素分析値 C₂₄H₂₅N₄O₅SClとして
計算値（％）：C, 55.76； H, 4.87； N, 10.84
実測値（％）：C, 55.79； H, 4.92； N, 10.94 Example 181
2- (1-{(2R) -3-[(6-Chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -5-methyl-1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one
181a) (2R) -3-[(6-Chloro-2-naphthyl) thio] -2-hydroxypropionic acid methyl ester
The title compound (5.6 g, 74%) was obtained as white crystals (hexane-ethyl acetate) from methyl (2S) -oxirane-2-carboxylate (2.6 g) in the same manner as in Example 136a).
NMR (300MHz, CDCl ₃ ) δ: 3.13 (1H, d, J = 6.0), 3.36 (1H, dd, J = 14.1, 5.7), 3.48 (1H, dd, J = 14.1, 4.2), 4.46 (1H, ddd, J = 6.0, 5.7, 4.2), 7.41 (1H, dd, J = 6.9, 1.8), 7.51 (1H, dd, J = 6.9, 1.8), 7.67 (1H, d, J = 1.8), 7.70 ( 1H, d, J = 1.8), 7.77 (1H, d, J = 2.1), 7.84 (1H, d, J = 2.1).
181b) (2R) -3-[(6-Chloro-2-naphthyl) thio] -2-hydroxypropionic acid (2R) -3-[(6-Chloro-2-naphthyl) obtained in Example 181a) The title compound (4.7 g, 99%) was obtained as a white powder from methyl thio] -2-hydroxypropionate (5.0 g) in the same manner as in Example 136b).
NMR (300MHz, CD ₃ OD) δ: 3.20 (1H, dd, J = 13.5, 3.3), 3.57 (1H, dd, J = 13.5, 3.3), 4.19 (1H, dd, J = 13.5, 3.3), 7.40 (1H, dd, J = 8.7, 2.1), 7.52 (1H, dd, J = 8.7, 2.1), 7.71 (1H, d, J = 8.7), 7.77 (1H, d, J = 8.7), 7.80 (1H , s), 7.87 (1H, s).
181c) 2- (1-{(2R) -3-[(6-chloro-2-naphthyl) thio] -2-hydroxypropanoyl} -4-piperidinyl) -5-methyl-1,2-dihydro-3H -Imidazo [1,5-c] imidazol-3-one (2R) -3-[(6-Chloro-2-naphthyl) thio] -2-hydroxypropionic acid (4.5 g) obtained in Example 181b) To give the title compound (5.6 g, 73%) as a white powder in the same manner as in Example 136c).
NMR (300MHz, CDCl ₃ ) δ: 1.28-1.65 (2H, m), 1.66-1.88 (2H, m), 2.40-2.73 (1H, m), 2.58 (3H, s), 2.98-3.10 (1H, m ), 3.20-3.44 (2H, m), 3.68-3.77 (1H, m), 3.80 (2H, s), 4.00-4.15 (1H, m), 4.19 (1H, s), 4.55-4.73 (2H, m ), 6.67 (1H, s), 7.40-7.50 (2H, m), 7.66 (1H, s), 7.69 (1H, s), 7.70 (1H, s), 7.81 (1H, d, J = 5.4).
181d) 2- (1-{(2R) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -5-methyl-1,2-dihydro-3H -Imidazo [1,5-c] imidazol-3-one 2- (1-{(2R) -3-[(6-chloro-2-naphthyl) thio] -2-hydroxy obtained in Example 181c) Propanoyl} -4-piperidinyl) -5-methyl-1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one (3.0 g) as in Example 136d), the title compound (2.2 g, 67%) was obtained as a white powder.
NMR (300MHz, CDCl ₃ ) δ: 1.66-1.99 (4H, m), 2.61 (3H, s), 2.69-2.88 (1H, m), 3.14-3.33 (1H, m), 3.48 (2H, dd, J = 11.8, 5.6), 3.84 (1H, m), 4.07-4.22 (1H, m), 4.27 (2H, s), 4.65-4.88 (1H, m), 4.98-5.09 (1H, m), 6.71 (1H , s), 7.59 (1H, dd, J = 8.8, 1.0), 7.95 (3H, s), 7.96 (1H, d, J = 8.8), 8.51 (1H, s).
Elemental analysis value Calculated as C ₂₄ H ₂₅ N ₄ O ₅ SCl (%): C, 55.76; H, 4.87; N, 10.84
Found (%): C, 55.79; H, 4.92; N, 10.94

実施例182
エチルカルバミン酸[2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル
182a) 2-(1-ベンジル-4-ピペリジニル)-5-(ヒドロキシメチル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
実施例137h)で得られた2-(1-ベンジル-4-ピペリジニル)-5-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン(2.1 g)を酢酸(56mL)、THF(14mL)および水(14mL)の混合溶媒に溶解して、60℃で12時間かき混ぜた。THFを減圧留去した後、反応液を飽和炭酸水素ナトリウム水溶液でpH8程度に調節した。混合液をクロロホルムで抽出し、抽出液を無水硫酸ナトリウムで乾燥後、減圧濃縮した。残留物を酢酸エチルで洗浄して、題記化合物(1.1g, 70%)を白色固体として得た。
NMR (300MHz, CDCl₃)δ: 1.74-1.85 (4H, m), 2.09-2.18 (2H, m), 3.01 (2H, d, J = 12.0), 3.54 (2H, s), 3.92-4.03 (1H, m), 4.11 (1H, brs), 4.39 (2H, s), 4.86 (2H, s), 6.76 (1H, t, J = 1.5), 7.24-7.37 (5H, m).
182b) エチルカルバミン酸 [2-(1-ベンジル-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル
実施例182a)で得た2-(1-ベンジル-4-ピペリジニル)-5-(ヒドロキシメチル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン(0.5g)のTHF溶液(30mL)へイソシアン酸エチル(0.13g)を加え、50℃で5時間かき混ぜた。溶媒を減圧留去した後、残留物をヘキサンで洗浄して、題記化合物(0.58g, 95%)を白色固体として得た。
NMR (300MHz, CDCl₃)δ: 1.12 (3H, t, J = 7.2), 1.72-1.84 (4H, m), 2.12 (2H, dt, J = 12.0, 3.6), 3.00 (2H, d, J = 12.0), 3.19-3.28 (2H, m), 3.53 (2H, s), 3.93-4.04 (1H, m), 4.33 (2H, s), 4.76 (1H, brs), 5.37 (2H, s), 6.85 (1H, t, J = 1.5), 7.24-7.36 (5H, m).
182c) エチルカルバミン酸[2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル
実施例182b)で得たエチルカルバミン酸[2-(1-ベンジル-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル(0.55g）、ギ酸アンモニウム(0.87g)および10% パラジウム炭素(0.1g)のメタノール(50mL)けん濁液を2時間加熱還流した。反応液を室温まで冷却した後、不溶物をセライトを用いてろ去し、ろ液を減圧濃縮した。残留物にクロロホルムを加え、不溶物をろ去した後、ろ液を再び濃縮した。得られた残留物と実施例174a)で得られた(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロピオン酸(0.42g)およびHOBt(0.31g)のDMF(5mL)-アセトニトリル(30mL)溶液へWSC(0.38g)を加え、室温で15時間かき混ぜた。反応液を減圧濃縮し、酢酸エチルと炭酸水素ナトリウム水溶液で希釈した。有機層を分液し、無水硫酸ナトリウムで乾燥し、減圧濃縮した。残留物をシリカゲルカラム（酢酸エチル/エタノール＝5/1）で精製後、さらに逆相分取HPLCで精製して、題記化合物(0.19g, 24%)を白色固体として得た。
NMR (300MHz, CDCl₃)δ:1.13 (3H, t, J = 11.4), 1.65-2.50 (4H, m), 2.63-2.81 (1H, m), 3.17-3.28 (3H, m), 3.48 (2H, dd, J = 18.9 and 8.7), 4.07-4.23 (1H, m), 4.31-4.35 (2H, s), 4.65-4.85 (2H, m), 5.00-5.06 (1H, m), 5.38(2H, s), 6.87 (1H, s), 7.60 (1H, dd, J = 11.4, 0.9), 7.94 (3H, s), 7.96 (1H, d, J = 11.4), 8.51 (1H, s).
元素分析値 C₂₇H₃₀N₅O₇SCl・H₂Oとして
計算値（％）：C, 52.13； H, 5.18； N, 11.26
実測値（％）：C, 52.13； H, 5.40； N, 11.05 Example 182
Ethylcarbamic acid [2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -3-oxo-2,3-dihydro -1H-imidazo [1,5-c] imidazol-5-yl] methyl
182a) 2- (1-benzyl-4-piperidinyl) -5- (hydroxymethyl) -1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one obtained in Example 137h) 2- (1-Benzyl-4-piperidinyl) -5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -1,2-dihydro-3H-imidazo [1,5-c] imidazole-3- On (2.1 g) was dissolved in a mixed solvent of acetic acid (56 mL), THF (14 mL) and water (14 mL), and the mixture was stirred at 60 ° C. for 12 hours. After THF was distilled off under reduced pressure, the reaction solution was adjusted to about pH 8 with a saturated aqueous solution of sodium bicarbonate. The mixture was extracted with chloroform, and the extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was washed with ethyl acetate to give the title compound (1.1 g, 70%) as a white solid.
NMR (300MHz, CDCl ₃ ) δ: 1.74-1.85 (4H, m), 2.09-2.18 (2H, m), 3.01 (2H, d, J = 12.0), 3.54 (2H, s), 3.92-4.03 (1H , m), 4.11 (1H, brs), 4.39 (2H, s), 4.86 (2H, s), 6.76 (1H, t, J = 1.5), 7.24-7.37 (5H, m).
182b) Ethylcarbamic acid [2- (1-benzyl-4-piperidinyl) -3-oxo-2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl in Example 182a) A THF solution of the obtained 2- (1-benzyl-4-piperidinyl) -5- (hydroxymethyl) -1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one (0.5 g) ( 30 mL) was added ethyl isocyanate (0.13 g), and the mixture was stirred at 50 ° C. for 5 hours. After evaporating the solvent under reduced pressure, the residue was washed with hexane to give the title compound (0.58 g, 95%) as a white solid.
NMR (300MHz, CDCl ₃ ) δ: 1.12 (3H, t, J = 7.2), 1.72-1.84 (4H, m), 2.12 (2H, dt, J = 12.0, 3.6), 3.00 (2H, d, J = 12.0), 3.19-3.28 (2H, m), 3.53 (2H, s), 3.93-4.04 (1H, m), 4.33 (2H, s), 4.76 (1H, brs), 5.37 (2H, s), 6.85 (1H, t, J = 1.5), 7.24-7.36 (5H, m).
182c) Ethylcarbamic acid [2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -3-oxo-2,3 -Dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl ethylcarbamate [2- (1-benzyl-4-piperidinyl) -3-oxo-2,3 obtained in Example 182b) 2-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl (0.55 g), ammonium formate (0.87 g) and 10% palladium on carbon (0.1 g) in methanol (50 mL) Heated to reflux for hours. The reaction mixture was cooled to room temperature, insolubles were removed by filtration through celite, and the filtrate was concentrated under reduced pressure. Chloroform was added to the residue, the insoluble material was removed by filtration, and the filtrate was concentrated again. DMF of (2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropionic acid (0.42 g) and HOBt (0.31 g) obtained in Example 174a) with the obtained residue WSC (0.38 g) was added to a (5 mL) -acetonitrile (30 mL) solution, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate and aqueous sodium hydrogen carbonate solution. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column (ethyl acetate / ethanol = 5/1), and further purified by reverse phase preparative HPLC to give the title compound (0.19 g, 24%) as a white solid.
NMR (300MHz, CDCl ₃ ) δ: 1.13 (3H, t, J = 11.4), 1.65-2.50 (4H, m), 2.63-2.81 (1H, m), 3.17-3.28 (3H, m), 3.48 (2H , dd, J = 18.9 and 8.7), 4.07-4.23 (1H, m), 4.31-4.35 (2H, s), 4.65-4.85 (2H, m), 5.00-5.06 (1H, m), 5.38 (2H, s), 6.87 (1H, s), 7.60 (1H, dd, J = 11.4, 0.9), 7.94 (3H, s), 7.96 (1H, d, J = 11.4), 8.51 (1H, s).
Elemental analysis value C ₂₇ H ₃₀ N ₅ O ₇ Calculated as SCl · H ₂ O (%): C, 52.13; H, 5.18; N, 11.26
Found (%): C, 52.13; H, 5.40; N, 11.05

実施例183
2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-5-[(ジメチルアミノ)メチル]-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
183a) 1-トリチル-1H-イミダゾール-4-カルバルデヒド
1H-イミダゾール-4-カルバルデヒド(15g)とトリエチルアミン(23mL)のジクロロメタン(300mL)けん濁液へ塩化トリチル(42g)を加え、室温で15時間かき混ぜた。反応液をジクロロメタンと水で希釈した。有機層を分液し、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去して、題記化合物(51g, 定量的)を白色粉末として得た。
NMR (300MHz, CDCl₃)δ: 7.07-7.13 (6H, m), 7.25-7.41 (9H, m), 7.52 (1H, d, J = 1.5), 7.60 (1H, d, J = 1.5), 9.86 (1H, s).
183b) 1-ベンジル-N-[(1-トリチル-1H-イミダゾール-4-イル)メチル]ピペリジン-4-アミン
実施例183a)で得られた1-トリチル-1H-イミダゾール-4-カルバルデヒド(105g）、1-ベンジル-4-ピペリジンアミン(59g)および酢酸(20mL)のジクロロメタン溶液(2L)にトリアセトキシ水素化ホウ素ナトリウム(7.5g)を加え、室温で15時間かき混ぜた。反応液に1 N 水酸化ナトリウム水溶液を加え、水層をpH14程度に調節した後、一時間かき混ぜた。反応液をジクロロメタンで抽出し、抽出液を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残留物をヘキサン-酢酸エチルから再結晶して、題記化合物(146g, 92%)を白色結晶として得た。
NMR (200MHz, CDCl₃)δ: 1.45-1.65 (2H, m), 1.84-2.12 (4H, m), 2.57-2.68 (1H, m), 2.85-2.96 (2H, m), 3.57 (2H, s), 3.80 (2H, s), 6.75 (1H, d, J = 1.3), 7.09-7.16 (6H, m), 7.30-7.39 (14H, m), 7.41 (1H, d, J = 1.3).
183c) (1-ベンジル-4-ピペリジニル)[(1-トリチル-1H-イミダゾール-4-イル)メチル]カルバミン酸 tert-ブチル
実施例183b)で得られた1-ベンジル-N-[(1-トリチル-1H-イミダゾール-4-イル)メチル]ピペリジン-4-アミン(146g)のエタノール(500mL)溶液へ二炭酸ジtert-ブチル(65g)を加え、室温で15時間かき混ぜた。溶媒を減圧留去した後、残留物を酢酸エチルおよび飽和食塩水で希釈した。有機層を分液し、水および飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去して、題記化合物(175g, 定量的)を白色粉末として得た。
NMR (300MHz, CDCl₃)δ: 1.28 (9H, s), 1.50 (2H, d, J = 11.4), 1.65-1.80 (2H, m), 1.98 (2H, t, J = 8.4), 2.87 (2H, d, J = 11.4), 3.45 (2H, s), 3.95-4.05 (1H, m), 4.29 (2H, s), 6.55 (1H, s), 7.09-7.14 (6H, m), 7.20-7.33 (15H, m).
183d) (1-ベンジル-4-ピペリジニル)[(2-ホルミル-1-トリチル-1H-イミダゾール-4-イル)メチル]カルバミン酸 tert-ブチル
実施例183c)で得られた(1-ベンジル-4-ピペリジニル)[(1-トリチル-1H-イミダゾール-4-イル)メチル]カルバミン酸 tert-ブチル(175g)のTHF(2L)溶液へn-ブチルリチウムのヘキサン溶液(1.6M, 890mL)をアルゴン雰囲気下、-78^oCで滴下した。反応液を2時間かけて-40^oCまで昇温させた後、DMF(110mL)を加え、室温で1時間かき混ぜた。反応液に水(500mL)を加え、エーテル(2L)で抽出した。抽出液を水(500mL×3)、飽和食塩水(500mL)で洗浄し、無水硫酸マグネシウムでで乾燥した後、溶媒を減圧留去した。残留物をへキサン-エーテルから再結晶して、題記化合物(85g, 48%)を淡黄色粉末として得た。
NMR (300MHz, CDCl₃)δ: 1.26 (9H, s), 1.42-1.54 (2H, m), 1.74-1.79 (2H, m), 1.95-1.99 (2H, m), 2.88 (2H, d, J = 11.1), 3.45 (2H, s), 3.98-4.03 (1H, m), 4.34 (2H, s), 6.85 (1H, s), 7.05-7.09 (6H, m), 7.20-7.35 (14H, m), 9.10 (1H, s).
183e) 1-ベンジル-4-ピペリジニル({2-[(ジメチルアミノ)メチル]-1-トリチル-1H-イミダゾール-4-イル}メチル)カルバミン酸 tert-ブチル
実施例183d)で得た (1-ベンジル-4-ピペリジニル)[(2-ホルミル-1-トリチル-1H-イミダゾール-4-イル)メチル]カルバミン酸 tert-ブチル(3g)、ジメチルアミンのTHF溶液（2.0M, 4.7mL）および酢酸（1mL）のジクロロエタン(100mL)溶液にトリアセトキシ水素化ホウ素ナトリウム(1.5g)を加え、室温で15時間かき混ぜた。反応液に飽和炭酸カリウム水溶液を加え、pHを12程度に調節した後、ジクロロメタンで抽出した。抽出液を無水硫酸マグネシウムで乾燥した後、溶媒を減圧留去した。残留物を塩基性シリカゲルカラム（ヘキサン-酢酸エチル＝1/1）により精製し、題記化合物(2.4g, 75%)を白色粉末として得た。
NMR (300MHz, CDCl₃)δ: 1.26 (9H, s), 1.45-1.51 (2H, d, J = 12.0), 1.82-2.02 (4H, m), 1.91 (6H, s), 2.65 (2H, s), 2.86 (2H, d, J = 9.6), 3.45 (2H, s), 3.92-3.97 (1H, m), 4.30 (2H, s), 6.54 (1H, s), 7.10-7.15 (6H, m), 7.15-7.31 (14H, m).
183f) 2-(1-ベンジル-4-ピペリジニル)-5-[(ジメチルアミノ)メチル]-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
実施例183e)で得た(1-ベンジル-4-ピペリジニル)({2-[(ジメチルアミノ)メチル]-1-トリチル-1H-イミダゾール-4-イル}メチル)カルバミン酸 tert-ブチル(2.35g)のトリフロロ酢酸(20mL)とジクロロメタン(60mL)の混合溶液を室温で2時間かき混ぜた。反応液を水(80mL)で希釈し、ジクロロメタンを減圧留去した。水層を酢酸エチル(150mL)で洗浄し、炭酸カリウムでpH14に節した後、ジクロロメタン(150mL×2)で抽出した。抽出液を無水硫酸マグネシウムで乾燥した後、溶媒を減圧留去した。残留物をTHF(100mL)に溶解し、N,N'-カルボニルジイミダゾール(0.68g)およびDBU(1.28g)を加え、室温で15時間かき混ぜた。溶媒を減圧留去し、残留物を酢酸エチルおよび飽和食塩水溶液で希釈した。有機層を分液し、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残留物を塩基性シリカゲルカラム（酢酸エチル）により精製し、題記化合物(0.83g, 67%)を淡黄色粉末として得た。
NMR (300MHz, CDCl₃)δ: 1.71-1.82 (4H, m), 2.07-2.16 (2H, m), 2.36 (6H, s), 2.99 (2H, d, J = 12.0), 3.52 (2H, s), 3.80 (2H, s), 3.91-4.13 (1H, m), 4.30 (2H, s), 6.78 (1H, t, J = 1.5), 7.22-7.34 (5H, m).
183g) 5-[(ジメチルアミノ)メチル]-2-(4-ピペリジニル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
183f)で得られた2-(1-ベンジル-4-ピペリジニル)-5-[(ジメチルアミノ)メチル]-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン(0.80g)、ギ酸アンモニウム(1.4g)および10% パラジウム炭素(0.16g)をメタノール(40mL)のけん濁液を2時間加熱還流した。反応液を室温まで冷却した後、不溶物をセライトを用いてろ過し、ろ液を減圧濃縮した。残留物にクロロホルムを加え、不溶物をろ去した後、ろ液を再び濃縮して、題記化合物(0.52g, 87%)を淡黄色粉末として得た。
NMR (300MHz, CDCl₃)δ: 1.54-1.75 (2H, m), 1.83-1.89 (2H, m), 2.37 (6H, s), 2.73 (2H, dt, J = 12.2 and 2.6), 3.19 (2H, d, J = 12.2), 3.96-4.12 (1H, m), 4.31 (2H, s), 6.79 (1H, s).
183h) 2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-5-[(ジメチルアミノ)メチル]-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
実施例183g)で得られた5-[(ジメチルアミノ)メチル]-2-(4-ピペリジニル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン(0.45g)と実施例174a)で得られた(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロピオン酸(0.54g)およびHOBt(0.29g)のDMF(5mL)とアセトニトリル(45mL)の混合溶液へWSC(0.36g)を加え、室温で15時間かき混ぜた。溶媒を減圧留去した後、残留物をクロロホルムに溶解し、炭酸水素ナトリウム水溶液で洗浄、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残留物を塩基性シリカゲルカラム(酢酸エチルから酢酸エチル/エタノール=20/1)で精製して、題記化合物(0.40g, 42%)を白色粉末として得た。
NMR (300MHz, CDCl₃)δ: 1.60-2.04 (4H, m), 2.36 (6H, s), 2.62-2.90 (1H, m), 3.10-3.25 (1H, m), 3.43-3.53 (2H, m), 3.79 (2H, s), 4.07-4.31 (4H, m), 4.62-4.80 (1H, m), 5.02-5.08 (1H, m), 6.80 (1H, s), 7.59 (1H, dd, J = 8.8, 1.8), 7.94 (3H, s), 7.96 (1H, d, J = 8.8), 8.51 (1H, s).
元素分析値 C₂₆H₃₀N₅O₅SCl・0.8H₂Oとして
計算値（％）：C, 54.36； H, 5.54； N, 12.19
実測値（％）：C, 54.39； H, 5.61； N, 11.90 Example 183
2- (1-{(2S) -3-[(6-Chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -5-[(dimethylamino) methyl] -1,2 -Dihydro-3H-imidazo [1,5-c] imidazol-3-one
183a) 1-trityl-1H-imidazole-4-carbaldehyde
Trityl chloride (42 g) was added to a suspension of 1H-imidazole-4-carbaldehyde (15 g) and triethylamine (23 mL) in dichloromethane (300 mL), and the mixture was stirred at room temperature for 15 hours. The reaction was diluted with dichloromethane and water. The organic layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (51 g, quantitative) as a white powder.
NMR (300MHz, CDCl ₃ ) δ: 7.07-7.13 (6H, m), 7.25-7.41 (9H, m), 7.52 (1H, d, J = 1.5), 7.60 (1H, d, J = 1.5), 9.86 (1H, s).
183b) 1-benzyl-N-[(1-trityl-1H-imidazol-4-yl) methyl] piperidin-4-amine 1-trityl-1H-imidazole-4-carbaldehyde obtained in Example 183a) 105 g), 1-benzyl-4-piperidinamine (59 g) and acetic acid (20 mL) in dichloromethane (2 L) were added sodium triacetoxyborohydride (7.5 g), and the mixture was stirred at room temperature for 15 hours. A 1 N aqueous sodium hydroxide solution was added to the reaction solution, and the aqueous layer was adjusted to about pH 14, followed by stirring for 1 hour. The reaction solution was extracted with dichloromethane, and the extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was recrystallized from hexane-ethyl acetate to give the title compound (146 g, 92%) as white crystals.
NMR (200MHz, CDCl ₃ ) δ: 1.45-1.65 (2H, m), 1.84-2.12 (4H, m), 2.57-2.68 (1H, m), 2.85-2.96 (2H, m), 3.57 (2H, s ), 3.80 (2H, s), 6.75 (1H, d, J = 1.3), 7.09-7.16 (6H, m), 7.30-7.39 (14H, m), 7.41 (1H, d, J = 1.3).
183c) tert-butyl (1-benzyl-4-piperidinyl) [(1-trityl-1H-imidazol-4-yl) methyl] carbamate 1-benzyl-N-[(1- Ditert-butyl dicarbonate (65 g) was added to a solution of (trityl-1H-imidazol-4-yl) methyl] piperidin-4-amine (146 g) in ethanol (500 mL), and the mixture was stirred at room temperature for 15 hours. After the solvent was distilled off under reduced pressure, the residue was diluted with ethyl acetate and saturated brine. The organic layer was separated, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (175 g, quantitative) as a white powder.
NMR (300MHz, CDCl ₃ ) δ: 1.28 (9H, s), 1.50 (2H, d, J = 11.4), 1.65-1.80 (2H, m), 1.98 (2H, t, J = 8.4), 2.87 (2H , d, J = 11.4), 3.45 (2H, s), 3.95-4.05 (1H, m), 4.29 (2H, s), 6.55 (1H, s), 7.09-7.14 (6H, m), 7.20-7.33 (15H, m).
183d) (1-Benzyl-4-piperidinyl) [(2-formyl-1-trityl-1H-imidazol-4-yl) methyl] carbamate tert-butyl (1-benzyl-4) obtained in Example 183c) -Piperidinyl) [(1-trityl-1H-imidazol-4-yl) methyl] carbamate tert-butyl (175 g) in THF (2 L) solution of n-butyllithium in hexane (1.6 M, 890 mL) in an argon atmosphere The solution was added dropwise at −78 ^° C. below. The reaction solution was heated to −40 ^° C. over 2 hours, DMF (110 mL) was added, and the mixture was stirred at room temperature for 1 hour. Water (500 mL) was added to the reaction mixture, and the mixture was extracted with ether (2 L). The extract was washed with water (500 mL × 3) and saturated brine (500 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from hexane-ether to give the title compound (85 g, 48%) as a pale yellow powder.
NMR (300MHz, CDCl ₃ ) δ: 1.26 (9H, s), 1.42-1.54 (2H, m), 1.74-1.79 (2H, m), 1.95-1.99 (2H, m), 2.88 (2H, d, J = 11.1), 3.45 (2H, s), 3.98-4.03 (1H, m), 4.34 (2H, s), 6.85 (1H, s), 7.05-7.09 (6H, m), 7.20-7.35 (14H, m ), 9.10 (1H, s).
183e) tert-butyl 1-benzyl-4-piperidinyl ({2-[(dimethylamino) methyl] -1-trityl-1H-imidazol-4-yl} methyl) carbamate obtained in Example 183d) Benzyl-4-piperidinyl) [(2-formyl-1-trityl-1H-imidazol-4-yl) methyl] carbamate tert-butyl (3 g), dimethylamine in THF (2.0 M, 4.7 mL) and acetic acid ( 1 mL) in dichloroethane (100 mL) was added sodium triacetoxyborohydride (1.5 g), and the mixture was stirred at room temperature for 15 hours. A saturated aqueous potassium carbonate solution was added to the reaction solution to adjust the pH to about 12, and then extracted with dichloromethane. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by basic silica gel column (hexane-ethyl acetate = 1/1) to give the title compound (2.4 g, 75%) as a white powder.
NMR (300MHz, CDCl ₃ ) δ: 1.26 (9H, s), 1.45-1.51 (2H, d, J = 12.0), 1.82-2.02 (4H, m), 1.91 (6H, s), 2.65 (2H, s ), 2.86 (2H, d, J = 9.6), 3.45 (2H, s), 3.92-3.97 (1H, m), 4.30 (2H, s), 6.54 (1H, s), 7.10-7.15 (6H, m ), 7.15-7.31 (14H, m).
183f) 2- (1-Benzyl-4-piperidinyl) -5-[(dimethylamino) methyl] -1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one in Example 183e) Trifluoroacetic acid (tert-butyl (2.35 g) of (1-benzyl-4-piperidinyl) ({2-[(dimethylamino) methyl] -1-trityl-1H-imidazol-4-yl} methyl) carbamate ( A mixed solution of 20 mL) and dichloromethane (60 mL) was stirred at room temperature for 2 hours. The reaction solution was diluted with water (80 mL), and dichloromethane was distilled off under reduced pressure. The aqueous layer was washed with ethyl acetate (150 mL), adjusted to pH 14 with potassium carbonate, and extracted with dichloromethane (150 mL × 2). After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was dissolved in THF (100 mL), N, N′-carbonyldiimidazole (0.68 g) and DBU (1.28 g) were added, and the mixture was stirred at room temperature for 15 hr. The solvent was distilled off under reduced pressure, and the residue was diluted with ethyl acetate and saturated brine solution. The organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with a basic silica gel column (ethyl acetate) to obtain the title compound (0.83 g, 67%) as a pale yellow powder.
NMR (300MHz, CDCl ₃ ) δ: 1.71-1.82 (4H, m), 2.07-2.16 (2H, m), 2.36 (6H, s), 2.99 (2H, d, J = 12.0), 3.52 (2H, s ), 3.80 (2H, s), 3.91-4.13 (1H, m), 4.30 (2H, s), 6.78 (1H, t, J = 1.5), 7.22-7.34 (5H, m).
183g) 5-[(Dimethylamino) methyl] -2- (4-piperidinyl) -1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one
183f) 2- (1-benzyl-4-piperidinyl) -5-[(dimethylamino) methyl] -1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one ( A suspension of 0.80 g), ammonium formate (1.4 g) and 10% palladium on carbon (0.16 g) in methanol (40 mL) was heated to reflux for 2 hours. After cooling the reaction solution to room temperature, the insoluble material was filtered using celite, and the filtrate was concentrated under reduced pressure. Chloroform was added to the residue, insoluble material was filtered off, and the filtrate was concentrated again to obtain the title compound (0.52 g, 87%) as a pale yellow powder.
NMR (300MHz, CDCl ₃ ) δ: 1.54-1.75 (2H, m), 1.83-1.89 (2H, m), 2.37 (6H, s), 2.73 (2H, dt, J = 12.2 and 2.6), 3.19 (2H , d, J = 12.2), 3.96-4.12 (1H, m), 4.31 (2H, s), 6.79 (1H, s).
183h) 2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -5-[(dimethylamino) methyl] -1 , 2-Dihydro-3H-imidazo [1,5-c] imidazol-3-one 5-[(dimethylamino) methyl] -2- (4-piperidinyl) -1,2- obtained in Example 183g) Dihydro-3H-imidazo [1,5-c] imidazol-3-one (0.45 g) and (2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2 obtained in Example 174a) -WSC (0.36 g) was added to a mixed solution of hydroxypropionic acid (0.54 g) and HOBt (0.29 g) in DMF (5 mL) and acetonitrile (45 mL), and the mixture was stirred at room temperature for 15 hours. After the solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, washed with an aqueous sodium hydrogen carbonate solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with a basic silica gel column (ethyl acetate to ethyl acetate / ethanol = 20/1) to obtain the title compound (0.40 g, 42%) as a white powder.
NMR (300MHz, CDCl ₃ ) δ: 1.60-2.04 (4H, m), 2.36 (6H, s), 2.62-2.90 (1H, m), 3.10-3.25 (1H, m), 3.43-3.53 (2H, m ), 3.79 (2H, s), 4.07-4.31 (4H, m), 4.62-4.80 (1H, m), 5.02-5.08 (1H, m), 6.80 (1H, s), 7.59 (1H, dd, J = 8.8, 1.8), 7.94 (3H, s), 7.96 (1H, d, J = 8.8), 8.51 (1H, s).
Elemental analysis value Calculated as C ₂₆ H ₃₀ N ₅ O ₅ SCl · 0.8H ₂ O (%): C, 54.36; H, 5.54; N, 12.19
Found (%): C, 54.39; H, 5.61; N, 11.90

実施例184
ジメチルカルバミン酸[2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル
184a) ジメチルカルバミン酸[2-(1-ベンジル-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル
実施例182a)で得られた2-(1-ベンジル-4-ピペリジニル)-5-(ヒドロキシメチル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン(0.27g)と塩化ジメチルカルバモイル(0.17g)のTHF溶液(20mL)に水素化ナトリウム(60%油性：62mg)を氷冷下加えて、氷冷下で3時間かき混ぜた。反応液へ飽和塩化アンモニウム水溶液と酢酸エチルを加えた。有機層を分液し、食塩水で洗浄して、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去、残留物を塩基性シリカゲルカラム（酢酸エチル）で精製して、題記化合物(0.31g, 定量的)を白色粉末として得た。
NMR (200MHz, CDCl₃)δ: 1.70-1.86 (4H, m), 2.08-2.19 (2H, m), 2.91 (6H, s), 2.99 (2H, d, J = 11.6), 3.53 (2H, s), 3.91-4.10 (1H, m), 4.34 (2H, s), 5.37 (2H, s), 6.84 (1H, t, J = 1.4), 7.23-7.38 (5H, m).
184b) ジメチルカルバミン酸[3-オキソ-2-(-4-ピペリジニル)-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル
実施例184a)で得られたジメチルカルバミン酸[2-(1-ベンジル-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル(0.30g)から実施例183g)と同様にして、題記化合物(0.19g, 82%)を白色粉末として得た。
NMR (200MHz, CDCl₃)δ: 1.80-1.96 (4H, m), 2.76-2.85 (2H, m), 2.92 (6H, s), 3.32 (2H, d, J = 12.4), 4.04-4.21 (1H, m), 4.38 (2H, s), 5.37 (2H, s), 6.86 (1H, s).
184c) ジメチルカルバミン酸[2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル
実施例184b)で得られたジメチルカルバミン酸[3-オキソ-2-(-4-ピペリジニル)-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル(0.48g)から実施例183h)と同様にして、題記化合物(0.17g,18%)を白色粉末として得た。
NMR (300MHz, CDCl₃)δ: 1.62-2.04 (4H, m), 2.70-2.80 (1H, m), 2.85 (6H, s), 3.17-3.31 (1H, m), 3.45-3.53 (1H, m), 3.81 (1H, dd, J = 15.0 and 6.0), 4.09-5.04 (2H, m), 4.32 (1.4H, s), 4.35 (0.6H, s), 4.68-4.77 (1H, m), 5.03-5.07 (1H, m), 5.37 (2H, s), 6.87 (1H, s), 7.60 (1H, dd, J =9.0, 1.2), 7.94 (3H, s), 7.96 (1H, d, J = 9.0), 8.51 (1H, s).
元素分析値 C₂₇H₃₀N₅O₇SCl・0.5H₂Oとして
計算値（％）：C, 52.89； H, 5.10； N, 11.42
実測値（％）：C, 52.83； H, 5.13； N, 11.15 Example 184
Dimethylcarbamic acid [2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -3-oxo-2,3-dihydro -1H-imidazo [1,5-c] imidazol-5-yl] methyl
184a) Dimethylcarbamic acid [2- (1-benzyl-4-piperidinyl) -3-oxo-2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl in Example 182a) The resulting 2- (1-benzyl-4-piperidinyl) -5- (hydroxymethyl) -1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one (0.27 g) and dimethyl chloride Sodium hydride (60% oily: 62 mg) was added to a THF solution (20 mL) of carbamoyl (0.17 g) under ice cooling, and the mixture was stirred under ice cooling for 3 hours. A saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction solution. The organic layer was separated, washed with brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with a basic silica gel column (ethyl acetate) to obtain the title compound (0.31 g, quantitative) as a white powder.
NMR (200MHz, CDCl ₃ ) δ: 1.70-1.86 (4H, m), 2.08-2.19 (2H, m), 2.91 (6H, s), 2.99 (2H, d, J = 11.6), 3.53 (2H, s ), 3.91-4.10 (1H, m), 4.34 (2H, s), 5.37 (2H, s), 6.84 (1H, t, J = 1.4), 7.23-7.38 (5H, m).
184b) Dimethylcarbamic acid [3-oxo-2-(-4-piperidinyl) -2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl obtained in Example 184a) Example from [2- (1-Benzyl-4-piperidinyl) -3-oxo-2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl (0.30 g) dimethylcarbamate 183 g), and the title compound (0.19 g, 82%) was obtained as a white powder.
NMR (200MHz, CDCl ₃ ) δ: 1.80-1.96 (4H, m), 2.76-2.85 (2H, m), 2.92 (6H, s), 3.32 (2H, d, J = 12.4), 4.04-4.21 (1H m), 4.38 (2H, s), 5.37 (2H, s), 6.86 (1H, s).
184c) Dimethylcarbamic acid [2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -3-oxo-2,3 -Dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl dimethylcarbamate [3-oxo-2-(-4-piperidinyl) -2,3-dihydro hydrate obtained in Example 184b) The title compound (0.17 g, 18%) was obtained as a white powder from -1H-imidazo [1,5-c] imidazol-5-yl] methyl (0.48 g) in the same manner as in Example 183h).
NMR (300MHz, CDCl ₃ ) δ: 1.62-2.04 (4H, m), 2.70-2.80 (1H, m), 2.85 (6H, s), 3.17-3.31 (1H, m), 3.45-3.53 (1H, m ), 3.81 (1H, dd, J = 15.0 and 6.0), 4.09-5.04 (2H, m), 4.32 (1.4H, s), 4.35 (0.6H, s), 4.68-4.77 (1H, m), 5.03 -5.07 (1H, m), 5.37 (2H, s), 6.87 (1H, s), 7.60 (1H, dd, J = 9.0, 1.2), 7.94 (3H, s), 7.96 (1H, d, J = 9.0), 8.51 (1H, s).
Elemental analysis value Calculated as C ₂₇ H ₃₀ N ₅ O ₇ SCl · 0.5H ₂ O (%): C, 52.89; H, 5.10; N, 11.42
Found (%): C, 52.83; H, 5.13; N, 11.15

実施例185
3-アセチルアミノプロピオン酸[2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル
185a) 5-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2-(-4-ピペリジニル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
実施例137h)で得られた2-(1-ベンジル-4-ピペリジニル)-5-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン(4.0g)から実施例183g)と同様にして、題記化合物(3.1g, 98%)を白色粉末として得た。
NMR (300MHz, CDCl₃)δ: 0.13 (6H, s), 1.54-1.74 (2H, m), 1.81-1.88 (2H, m), 2.73 (2H, dt, J = 12.0, 2.6), 3.18 (2H, d, J = 12.0), 3.47 (2H, s), 3.97 -4.12 (1H, m), 4.32 (2H, d, J = 1.6), 4.32 (2H, d, J = 1.6), 4.92 (2H, s), 6.79 (1H, t, J = 1.6).
185b) 4-[5-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル
実施例185a)で得られた5-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2-(-4-ピペリジニル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン(1.9g)のエタノール(50mL)溶液へ二炭酸ジ-tert-ブチル(1.3g)を加え、室温で15時間かき混ぜた。エタノールを減圧留去して、題記化合物(2.4g, 定量的)を白色粉末として得た。
NMR (300MHz, CDCl₃)δ: 0.14 (6H, s), 0.92 (9H, s), 1.47 (9H, s), 1.59-1.73 (2H, m), 1.82-1.97 (2H, m), 2.83 (2H, t, J = 12.2), 3.64-3.77 (1H, m), 4.04-4.23 (2H, m), 4.31 (2H, s), 4.92 (2H, s), 6.80 (1H, s).
185c) 4-[5-(ヒドロキシメチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル
実施例185b)で得られた4-[5-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル(2.4g)とフッ化テトラブチルアンモニウム(4.2g)のTHF溶液を室温で3時間かき混ぜた。溶媒を減圧留去した後、残留物を酢酸エチルに溶解した。酢酸エチル溶液を食塩水で洗浄、無水硫酸ナトリウムで乾燥した後、減圧濃縮した。残留物を塩基性シリカゲルカラム（酢酸エチル/エタノール=40/1）で精製し、ヘキサン-酢酸エチルから再結晶して、題記化合物(1.0g, 55%)を白色結晶として得た。
NMR (300MHz, CDCl₃)δ: 1.48 (9H, s), 1.65 (2H, m), 1.86 (2H, d, J =12.3), 2.83 (2H, d, J = 12.3), 4.04-4.18 (3H, m), 4.27 (1H, d, J = 12.3), 4.38 (2H, s), 4.86 (2H, d, J = 4.2), 6.77 (1H, s).
185d) 4-[5-{[(3-アセチルアミノプロピオニル)オキシ]メチル}-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル
実施例185c)で得られた4-[5-(ヒドロキシメチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル(0.34g)、3-アセチルアミノプロピオン酸(0.13g)、ジメチルアミノピリジン(0.12g)およびトリエチルアミン(0.10g)のTHF(30mL)とアセトニトリル(30mL)溶液へWSC(0.19g)を加え、室温で15時間かき混ぜた。溶媒を減圧留去した後、残留物を酢酸エチルで希釈して、飽和炭酸水素ナトリウム水溶液および飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残留物を塩基性シリカゲルカラム（酢酸エチル/へキサン＝10/1から酢酸エチル）により精製して、題記化合物(0.38g, 85%)を白色粉末として得た。
NMR (200MHz, CDCl₃)δ: 1.48 (9H, s), 1.54-1.90 (4H, m), 1.98 (3H, s), 2.59 (2H, t, J = 5.8), 2.82 (2H, t, J = 12.2), 3.58 (2H, t, J = 5.8), 4.02-4.18 (1H, m), 4.28 (2H, d, J = 12.2), 4.37 (2H, s), 5.44 (2H, s), 6.85 (1H, t, J = 1.4).
185e) 3-アセチルアミノプロピオン酸[2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル
実施例185d)で得られた4-[5-{[(3-アセチルアミノプロピオニル)オキシ]メチル}-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル(0.46g)の酢酸エチル(10mL)溶液に4N塩化水素酢酸エチル溶液(4mL)を加えて、室温で1時間かき混ぜた。溶媒を減圧留去し、残留物をジクロロメタン(40mL)とDMF(10mL)の混合溶液にけん濁した。このけん濁液へトリエチルアミン（0.49mL）、実施例174a)で得られた(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロピオン酸(0.36g)、HOBt(0.17g)およびWSC(0.22g)を順次加え、室温で15時間かき混ぜた。溶媒を減圧留去し、残留物をクロロホルムと飽和炭酸水素ナトリウム水溶液で希釈した。有機層を分液し、食塩水で洗浄、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残留物を塩基性シリカゲルカラム（酢酸エチル/エタノール＝10/1）、続いて逆相分取HPLCで精製して、題記化合物(98mg, 25%)を白色粉末として得た。
NMR (200MHz, CDCl₃)δ: 1.62-2.08 (4H, m), 1.98 (3H, s), 2.59 (2H, t, J = 6.0), 2.68-2.86 (1H, m), 3.15-3.35 (1H, m), 3.43-3.61(4H, m), 4.10-4.23 (2H, m), 4.35 (1.4H, s), 4.38 (0.6H, s), 4.65-4.80 (1H, m), 5.00-5.07 (1H, m), 5.44 (2H, s), 6.85 (1H, s), 7.62 (1H, dd, J = 8.8, 1.8), 7.94 (3H, s), 7.96 (1H, d, J = 8.8), 8.50 (1H, s)
元素分析値 C₂₉H₃₂N₅O₈SCl・2H₂Oとして
計算値（％）：C, 51.06； H, 5.32； N, 10.27
実測値（％）：C, 51.29； H, 5.15； N, 10.11 Example 185
3-acetylaminopropionic acid [2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -3-oxo-2, 3-Dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl
185a) 5-({[tert-Butyl (dimethyl) silyl] oxy} methyl) -2-(-4-piperidinyl) -1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one 2- (1-Benzyl-4-piperidinyl) -5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -1,2-dihydro-3H-imidazo [1, obtained in Example 137h) The title compound (3.1 g, 98%) was obtained as a white powder from 5-c] imidazol-3-one (4.0 g) in the same manner as in Example 183 g).
NMR (300MHz, CDCl ₃ ) δ: 0.13 (6H, s), 1.54-1.74 (2H, m), 1.81-1.88 (2H, m), 2.73 (2H, dt, J = 12.0, 2.6), 3.18 (2H , d, J = 12.0), 3.47 (2H, s), 3.97 -4.12 (1H, m), 4.32 (2H, d, J = 1.6), 4.32 (2H, d, J = 1.6), 4.92 (2H, s), 6.79 (1H, t, J = 1.6).
185b) 4- [5-({[tert-Butyl (dimethyl) silyl] oxy} methyl) -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1- Tert-butyl carboxylate 5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -2-(-4-piperidinyl) -1,2-dihydro-3H-imidazo obtained in Example 185a) Di-tert-butyl dicarbonate (1.3 g) was added to a solution of 1,5-c] imidazol-3-one (1.9 g) in ethanol (50 mL), and the mixture was stirred at room temperature for 15 hours. Ethanol was distilled off under reduced pressure to obtain the title compound (2.4 g, quantitative) as a white powder.
NMR (300MHz, CDCl ₃ ) δ: 0.14 (6H, s), 0.92 (9H, s), 1.47 (9H, s), 1.59-1.73 (2H, m), 1.82-1.97 (2H, m), 2.83 ( 2H, t, J = 12.2), 3.64-3.77 (1H, m), 4.04-4.23 (2H, m), 4.31 (2H, s), 4.92 (2H, s), 6.80 (1H, s).
185c) 4- [5- (hydroxymethyl) -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1-carboxylate tert-butyl obtained in Example 185b) 4- [5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1- A THF solution of tert-butyl carboxylate (2.4 g) and tetrabutylammonium fluoride (4.2 g) was stirred at room temperature for 3 hours. After the solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column (ethyl acetate / ethanol = 40/1) and recrystallized from hexane-ethyl acetate to give the title compound (1.0 g, 55%) as white crystals.
NMR (300MHz, CDCl ₃ ) δ: 1.48 (9H, s), 1.65 (2H, m), 1.86 (2H, d, J = 12.3), 2.83 (2H, d, J = 12.3), 4.04-4.18 (3H , m), 4.27 (1H, d, J = 12.3), 4.38 (2H, s), 4.86 (2H, d, J = 4.2), 6.77 (1H, s).
185d) 4- [5-{[(3-acetylaminopropionyl) oxy] methyl} -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1-carboxylic acid tert-Butyl 4- [5- (hydroxymethyl) -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1-carboxylic acid obtained in Example 185c) Add WSC (0.19 g) to a solution of tert-butyl (0.34 g), 3-acetylaminopropionic acid (0.13 g), dimethylaminopyridine (0.12 g) and triethylamine (0.10 g) in THF (30 mL) and acetonitrile (30 mL). In addition, the mixture was stirred at room temperature for 15 hours. After evaporating the solvent under reduced pressure, the residue was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column (ethyl acetate / hexane = 10/1 to ethyl acetate) to give the title compound (0.38 g, 85%) as a white powder.
NMR (200MHz, CDCl ₃ ) δ: 1.48 (9H, s), 1.54-1.90 (4H, m), 1.98 (3H, s), 2.59 (2H, t, J = 5.8), 2.82 (2H, t, J = 12.2), 3.58 (2H, t, J = 5.8), 4.02-4.18 (1H, m), 4.28 (2H, d, J = 12.2), 4.37 (2H, s), 5.44 (2H, s), 6.85 (1H, t, J = 1.4).
185e) 3-acetylaminopropionic acid [2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -3-oxo- 2,3-Dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl 4- [5-{[(3-acetylaminopropionyl) oxy] methyl}-obtained in Example 185d) 3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1-carboxylate tert-butyl (0.46 g) in ethyl acetate (10 mL) in 4N hydrogen chloride in ethyl acetate (4 mL) was added and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was suspended in a mixed solution of dichloromethane (40 mL) and DMF (10 mL). To this suspension, triethylamine (0.49 mL), (2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropionic acid (0.36 g) obtained in Example 174a), HOBt ( 0.17 g) and WSC (0.22 g) were sequentially added, and the mixture was stirred at room temperature for 15 hours. The solvent was distilled off under reduced pressure, and the residue was diluted with chloroform and saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column (ethyl acetate / ethanol = 10/1), followed by reverse phase preparative HPLC to give the title compound (98 mg, 25%) as a white powder.
NMR (200MHz, CDCl ₃ ) δ: 1.62-2.08 (4H, m), 1.98 (3H, s), 2.59 (2H, t, J = 6.0), 2.68-2.86 (1H, m), 3.15-3.35 (1H , m), 3.43-3.61 (4H, m), 4.10-4.23 (2H, m), 4.35 (1.4H, s), 4.38 (0.6H, s), 4.65-4.80 (1H, m), 5.00-5.07 (1H, m), 5.44 (2H, s), 6.85 (1H, s), 7.62 (1H, dd, J = 8.8, 1.8), 7.94 (3H, s), 7.96 (1H, d, J = 8.8) , 8.50 (1H, s)
Elemental analysis value Calculated as C ₂₉ H ₃₂ N ₅ O ₈ SCl · 2H ₂ O (%): C, 51.06; H, 5.32; N, 10.27
Found (%): C, 51.29; H, 5.15; N, 10.11

実施例186
2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-5-(フルオロメチル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
186a) 4-[5-(フルオロメチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル
実施例185c)で得られた4-[5-(ヒドロキシメチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル(0.15g)のジクロロメタン(10mL)溶液へジエチルアミノ硫黄三フッ化物(0.071mL)を氷冷下加え、アルゴン雰囲気下に室温で3時間かき混ぜた。反応液をジクロロメタンで希釈し、飽和炭酸水素ナトリウム水溶液および飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、減圧濃縮した。残留物をシリカゲルカラム（酢酸エチル）により精製して、題記化合物(70mg, 46%)を淡黄色粉末として得た。
NMR (200MHz, CDCl₃)δ: 1.48 (9H, s), 1.58-1.71 (2H, m), 1.87 (2H, t, J = 12.2), 2.84 (2H, t, J = 12.2), 4.08-4.19 (1H, m), 4.32 (2H, d, J = 12.2), 4.36 (2H, dd, J = 4.5, 1.2), 5.59 (2H, d, J = 48.0), 6.92 (1H, s).
186b) 2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-5-(フルオロメチル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
実施例186a)で得られた4-[5-(フルオロメチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル(0.20g)から実施例185e)と同様にして、題記化合物(76mg, 24%)を白色粉末として得た。
NMR (200MHz, CDCl₃)δ: 1.60-2.10 (4H, m), 2.70-2.88 (1H, m), 3.14-3.31 (1H, m), 3.48 (2H, dd, J = 12.6, 5.0), 3.68-3.87 (1H, m), 4.10-4.25 (2H, m), 4.35 (2H, d, J = 4.8), 4.65-4.81 (1H, m), 4.95-5.11 (1H, m), 5.59 (2H, d, J = 48.0), 6.93 (1H, s), 7.60 (1H, d, J = 9.4), 7.94 (3H, s), 7.96 (2H, d, J = 9.4), 8.51 (1H, s).
元素分析値 C₂₄H₂₄N₄O₅SClF・H₂Oとして
計算値（％）：C, 52.13； H, 4.74； N, 10.13
実測値（％）：C, 52.42； H, 4.45； N, 10.29 Example 186
2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -5- (fluoromethyl) -1,2-dihydro- 3H-imidazo [1,5-c] imidazol-3-one
186a) 4- [5- (fluoromethyl) -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1-carboxylate tert-butyl obtained in Example 185c) 4- [5- (hydroxymethyl) -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1-carboxylate tert-butyl (0.15 g) in dichloromethane To the (10 mL) solution, diethylaminosulfur trifluoride (0.071 mL) was added under ice cooling, and the mixture was stirred at room temperature for 3 hours under an argon atmosphere. The reaction mixture was diluted with dichloromethane, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column (ethyl acetate) to give the title compound (70 mg, 46%) as a pale yellow powder.
NMR (200MHz, CDCl ₃ ) δ: 1.48 (9H, s), 1.58-1.71 (2H, m), 1.87 (2H, t, J = 12.2), 2.84 (2H, t, J = 12.2), 4.08-4.19 (1H, m), 4.32 (2H, d, J = 12.2), 4.36 (2H, dd, J = 4.5, 1.2), 5.59 (2H, d, J = 48.0), 6.92 (1H, s).
186b) 2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -5- (fluoromethyl) -1,2- Dihydro-3H-imidazo [1,5-c] imidazol-3-one 4- [5- (fluoromethyl) -3-oxo-1H-imidazo [1,5-c] imidazole obtained in Example 186a) -2 (3H) -yl] piperidine-1-carboxylate The title compound (76 mg, 24%) was obtained as a white powder in the same manner as in Example 185e) from tert-butyl (0.20 g).
NMR (200MHz, CDCl ₃ ) δ: 1.60-2.10 (4H, m), 2.70-2.88 (1H, m), 3.14-3.31 (1H, m), 3.48 (2H, dd, J = 12.6, 5.0), 3.68 -3.87 (1H, m), 4.10-4.25 (2H, m), 4.35 (2H, d, J = 4.8), 4.65-4.81 (1H, m), 4.95-5.11 (1H, m), 5.59 (2H, d, J = 48.0), 6.93 (1H, s), 7.60 (1H, d, J = 9.4), 7.94 (3H, s), 7.96 (2H, d, J = 9.4), 8.51 (1H, s).
Elemental analysis C ₂₄ H ₂₄ N ₄ O ₅ Calculated as SClF · H ₂ O (%): C, 52.13; H, 4.74; N, 10.13
Found (%): C, 52.42; H, 4.45; N, 10.29

実施例187
N-アセチル-L-バリン [2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチルエステル
187a) 4-[5-{[(N-アセチル-L-バリル)オキシ]メチル}-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル
実施例185c)で得られた 4-[5-(ヒドロキシメチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル(0.80g)、N-アセチル-L-バリン(0.73g)およびトリフェニルホスフィン(1.2g)のTHF(30mL)溶液へアゾジカルボン酸ジエチルの40%トルエン溶液(2mL)を加え、室温で2時間かき混ぜた。反応液を酢酸エチルと水で希釈し、有機層を分液した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した後、減圧濃縮した。残留物を塩基性シリカゲルカラム（酢酸エチル）で精製して、題記化合物(0.47g, 42%)を白色粉末として得た。
NMR (300MHz, CDCl₃)δ: 0.89 (3H, d, J = 7.4), 0.93 (3H, d, J =7.4), 1.48 (9H, s), 1.60-1.90 (4H, m), 2.03 (3H, s), 2.11-2.24 (1H, m), 2.83 (2H, t, J = 12.2), 4.05-4.30 (3H, m), 4.32-4.35 (2H, s), 6.64 (1H, dd, J = 8.8, 4.8), 5.35 (1H, d, J = 12.8), 5.48 (1H, d, J = 12.8), 6.88 (1H, s).
187b) N-アセチル-L-バリン [2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチルエステル
実施例187a)で得られた4-[5-{[(N-アセチル-L-バリル)オキシ]メチル}-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル(0.45g)から実施例185e)と同様にして、題記化合物(108mg, 17%)を白色粉末として得た。
NMR (200MHz, CDCl₃)δ: 0.89 (3H, d, J = 7.4), 0.94 (3H, d, J = 7.4), 1.63-1.84 (2H, m), 1.85-2.10 (5H, m), 2.21 (1H, m), 2.74-2.90 (1H, m), 3.18-3.30 (1H, m), 3.43-3.58 (2H, m), 3.68-3.89 (1H, m), 4.08-4.32 (2H, m), 4.34-4.37 (2H, m), 4.64 (1H, dd, J = 9.2, 4.8), 4.68-4.80 (1H, m), 4.96-5.12 (1H, m), 5.35 (1H, d, J = 12.4), 5.49 (1H, d, J = 12.4), 6.05 (1H, d, J = 8.2), 6.88 (1H, s), 7.60 (1H, dd, J = 8.8, 1.8), 7.94 (3H, s), 7.96 (1H, d, J = 8.8), 8.51 (1H, s). Example 187
N-acetyl-L-valine [2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -3-oxo-2 , 3-Dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl ester
187a) 4- [5-{[(N-acetyl-L-valyl) oxy] methyl} -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1- Tert-butyl carboxylate 4- [5- (hydroxymethyl) -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1- obtained in Example 185c) To a solution of tert-butyl carboxylate (0.80 g), N-acetyl-L-valine (0.73 g) and triphenylphosphine (1.2 g) in THF (30 mL) was added 40% toluene solution of diethyl azodicarboxylate (2 mL). Stir at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate and water, and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column (ethyl acetate) to give the title compound (0.47 g, 42%) as a white powder.
NMR (300MHz, CDCl ₃ ) δ: 0.89 (3H, d, J = 7.4), 0.93 (3H, d, J = 7.4), 1.48 (9H, s), 1.60-1.90 (4H, m), 2.03 (3H , s), 2.11-2.24 (1H, m), 2.83 (2H, t, J = 12.2), 4.05-4.30 (3H, m), 4.32-4.35 (2H, s), 6.64 (1H, dd, J = 8.8, 4.8), 5.35 (1H, d, J = 12.8), 5.48 (1H, d, J = 12.8), 6.88 (1H, s).
187b) N-acetyl-L-valine [2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -3-oxo -2,3-Dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl ester 4- [5-{[(N-acetyl-L-valyl) oxy] obtained in Example 187a) ] Methyl} -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1-carboxylate from tert-butyl (0.45 g) as in Example 185e) The title compound (108 mg, 17%) was obtained as a white powder.
NMR (200MHz, CDCl ₃ ) δ: 0.89 (3H, d, J = 7.4), 0.94 (3H, d, J = 7.4), 1.63-1.84 (2H, m), 1.85-2.10 (5H, m), 2.21 (1H, m), 2.74-2.90 (1H, m), 3.18-3.30 (1H, m), 3.43-3.58 (2H, m), 3.68-3.89 (1H, m), 4.08-4.32 (2H, m) , 4.34-4.37 (2H, m), 4.64 (1H, dd, J = 9.2, 4.8), 4.68-4.80 (1H, m), 4.96-5.12 (1H, m), 5.35 (1H, d, J = 12.4 ), 5.49 (1H, d, J = 12.4), 6.05 (1H, d, J = 8.2), 6.88 (1H, s), 7.60 (1H, dd, J = 8.8, 1.8), 7.94 (3H, s) , 7.96 (1H, d, J = 8.8), 8.51 (1H, s).

実施例188
炭酸 [2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチルイソプロピル
188a) 4-[5-{[(イソプロポキシカルボニル)オキシ]メチル}-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル
実施例185c)で得られた4-[5-(ヒドロキシメチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル(0.52g)のTHF(30mL)溶液へリチウムビス（トリメチルシリル）アミドの1.1MTHF溶液(1.69mL)を氷冷下滴下し、10分間かき混ぜた。反応液に氷冷下でクロロ炭酸イソプロピル(0.35mL)を滴下し、氷冷下で30分間かき混ぜた。反応液に飽和塩化アンモニウム水溶液を滴下し、酢酸エチルで希釈した。有機層を分液し、飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥、減圧濃縮した。残留物をシリカゲルカラム（酢酸エチル/へキサン＝4/1）により精製して、題記化合物(0.48g, 73%)を白色粉末として得た。
NMR (200MHz, CDCl₃)δ: 1.30 (6H, d, J = 6.3), 1.48 (9H, s), 1.56-1.69 (2H, m), 1.85 (2H, dd, J = 11.7, 2.1), 2.82 (2H, t, J = 11.7), 4.05-4.18 (1H, m), 4.27 (2H, d, J = 11.7), 4.32 (2H, d, J = 2.1), 4.88-4.96 (1H, m), 5.42 (2H, s), 6.87 (1H, t, J = 1.5).
188b)炭酸 [2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチルイソプロピル
実施例188a)で得られた4-[5-{[(イソプロポキシカルボニル)オキシ]メチル}-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル(0.45g)から実施例185e)と同様にして、題記化合物(120mg, 18%)を白色粉末として得た。
NMR (200MHz, CDCl₃)δ: 1.31 (6H, d, J = 6.2), 1.63-1.83 (2H, m), 1.90-2.06 (2H, m), 2.64-2.86 (2H, m), 3.15-3.36 (2H, m), 3.44-3.54 (2H, m), 3.78 (2H, dd, J = 28.2, 7.0), 4.05-4.23 (2H, m), 4.31-3.34 (2H, m), 4.66-4.80 (1H, dd, J = 8.8, 2.0), 7.94 (3H, s), 7.96 (1H, d, J = 8.8), 8.51 (1H, s).
元素分析値 C₂₈H₃₁N₆O₈SCl・0.2Et₂Oとして
計算値（％）：C, 54.57； H, 5.25； N, 8.84
実測値（％）：C, 54.38； H, 5.36； N, 8.63 Example 188
Carbonic acid [2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -3-oxo-2,3-dihydro-1H -Imidazo [1,5-c] imidazol-5-yl] methyl isopropyl
188a) 4- [5-{[(Isopropoxycarbonyl) oxy] methyl} -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1-carboxylic acid tert- Butyl 4- [5- (hydroxymethyl) -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1-carboxylic acid tert- To a solution of butyl (0.52 g) in THF (30 mL), a 1.1 MTHF solution (1.69 mL) of lithium bis (trimethylsilyl) amide was added dropwise with ice cooling, and the mixture was stirred for 10 minutes. To the reaction solution was added dropwise isopropyl chlorocarbonate (0.35 mL) under ice cooling, and the mixture was stirred for 30 minutes under ice cooling. A saturated aqueous ammonium chloride solution was added dropwise to the reaction solution, and the mixture was diluted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column (ethyl acetate / hexane = 4/1) to give the title compound (0.48 g, 73%) as a white powder.
NMR (200MHz, CDCl ₃ ) δ: 1.30 (6H, d, J = 6.3), 1.48 (9H, s), 1.56-1.69 (2H, m), 1.85 (2H, dd, J = 11.7, 2.1), 2.82 (2H, t, J = 11.7), 4.05-4.18 (1H, m), 4.27 (2H, d, J = 11.7), 4.32 (2H, d, J = 2.1), 4.88-4.96 (1H, m), 5.42 (2H, s), 6.87 (1H, t, J = 1.5).
188b) Carbonic acid [2- (1-{(2S) -3-[(6-Chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -3-oxo-2,3-dihydro -1H-imidazo [1,5-c] imidazol-5-yl] methyl isopropyl 4- [5-{[(isopropoxycarbonyl) oxy] methyl} -3-oxo-1H- obtained in Example 188a) Imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1-carboxylate from tert-butyl (0.45 g) in the same manner as in Example 185e) to give the title compound (120 mg, 18%) in white Obtained as a powder.
NMR (200MHz, CDCl ₃ ) δ: 1.31 (6H, d, J = 6.2), 1.63-1.83 (2H, m), 1.90-2.06 (2H, m), 2.64-2.86 (2H, m), 3.15-3.36 (2H, m), 3.44-3.54 (2H, m), 3.78 (2H, dd, J = 28.2, 7.0), 4.05-4.23 (2H, m), 4.31-3.34 (2H, m), 4.66-4.80 ( 1H, dd, J = 8.8, 2.0), 7.94 (3H, s), 7.96 (1H, d, J = 8.8), 8.51 (1H, s).
Elemental Analysis Value Calculated as C ₂₈ H ₃₁ N ₆ O ₈ SCl · 0.2Et ₂ O (%): C, 54.57; H, 5.25; N, 8.84
Found (%): C, 54.38; H, 5.36; N, 8.63

実施例189
2-{1-[3-[(6-クロロ-2-ナフチル)スルホニル]-2-(ヒドロキシメチル)プロパノイル]-4-ピペリジニル}-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
189a)3-[(6-クロロ-2-ナフチル)チオ]-2-(ヒドロキシメチル)プロピオン酸
6-クロロナフタレン-2-チオール(1.9g)と2-(ヒドロキシメチル)アクリル酸エチル(1.3g)のジクロロメタン(50mL)溶液へアルゴン雰囲気下でトリエチルアミン(1.5mL)を加え、室温で15時間かき混ぜた。反応液をジクロロメタンで希釈し、水と飽和食塩水で順次洗浄、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残留物をシリカゲルカラム（ヘキサン/酢酸エチル＝4/1）により精製して、無色油状物を得た。得られた油状物をエタノール(20mL)に溶解し、1N水酸化ナトリウム水溶液(10mL)を加え、室温で15時間かき混ぜた。反応液を減圧濃縮し、残留物を水で希釈後、ジエチルエーテルで洗浄した。水層を１Ｎ塩酸でpH3程度に調節した後、酢酸エチルで抽出し、抽出液を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残留物をヘキサン-ジエチルエーテルで洗浄して、題記化合物(0.86g, 52%)を白色固体として得た。
NMR (200MHz, CDCl₃)δ: 2.74-2.86 (2H, m), 3.25 (1H, dd, J = 13.8, 8.0), 3.48 (1H, dd, J = 13.8, 5.8), 3.93 (2H, d, J = 5.2), 7.40 (1H, dd, J = 8.8, 1.8), 7.47 (1H, dd, J = 8.8, 1.8), 7.65 (1H, d, J = 3.6), 7.69 (1H, d, J = 3.6), 7.76 (2H, m).
189b) 2-{1-[3-[(6-クロロ-2-ナフチル)チオ]-2-(ヒドロキシメチル)プロパノイル]-4-ピペリジニル}-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
実施例189a)で得られた3-[(6-クロロ-2-ナフチル)チオ]-2-(ヒドロキシメチル)プロピオン酸(0.75g)と実施例69b)で得られた5-メチル-2-(4-ピペリジニル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン２塩酸塩(0.74g)から実施例128)と同様にして、題記化合物(0.62g, 32%)を白色固体として得た。
NMR (200MHz, CDCl₃)δ: 1.40-1.67 (2H, m), 1.68-1.85 (2H, m), 2.56-2.65 (1H, m), 2.59 (3H, s), 2.98-3.06 (1H, m), 3.07-3.47 (3H, m), 3.81-3.95 (4H, m), 4.07-4.16 (2H, m), 4.80 (1H, t, J = 13.5), 6.68 (1H, t, J = 1.5), 7.42-7.46 (2H, m), 7.69 (2H, dd, J = 8.7, 2.1), 7.81 (2H, dd, J =8.7, 2.1).
189c)2-{1-[3-[(6-クロロ-2-ナフチル)スルホニル]-2-(ヒドロキシメチル)プロパノイル]-4-ピペリジニル}-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
実施例189b)で得られた2-{1-[3-[(6-クロロ-2-ナフチル)チオ]-2-(ヒドロキシメチル)プロパノイル]-4-ピペリジニル}-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン(0.55g)のメタノール(20mL)溶液へオキソン(1.5g)の水溶液(20mL)を加え、室温で3時間かき混ぜた。反応液にチオ硫酸ナトリウム水溶液を加え、室温で30分間かき混ぜた。メタノールを減圧留去し、反応液を飽和炭酸水素ナトリウム水溶液で中和した後、クロロホルムで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残留物を塩基性シリカゲルカラム（酢酸エチル）により精製し、エタノール−水から再結晶して、題記化合物(0.40g, 68%)を白色固体として得た。
NMR (300MHz, CDCl₃)δ: 1.57-1.99 (3H, m), 2.09-2.22 (1H, m), 2.22-2.42 (0.5H, m), 2.61 (3H, s), 2.69-2.79 (0.5H, m), 3.14-3.44 (3H, m), 3.65-3.97 (4H, m), 4.06-4.17 (0.3H, m), 4.25-4.34 (3.7H, m), 4.58 (0.3H, d, J = 12.0), 4.85 (0.7H, d, J = 12.0), 6.65 (0.7H, s), 6.69 (0.3H, s), 7.61 (1H, dd, J = 9.0, 1.8), 7.87-7.96 (4H, m), 8.45 (0.3H, s), 8.49 (0.7H, s).
元素分析値 C₂₅H₂₇N₄O₅SCl・0.5H₂Oとして
計算値（％）：C, 55.60； H, 5.23； N, 10.37
実測値（％）：C, 55.55； H, 5.14； N, 10.54 Example 189
2- {1- [3-[(6-Chloro-2-naphthyl) sulfonyl] -2- (hydroxymethyl) propanoyl] -4-piperidinyl} -5-methyl-1,2-dihydro-3H-imidazo [1 , 5-c] imidazol-3-one
189a) 3-[(6-Chloro-2-naphthyl) thio] -2- (hydroxymethyl) propionic acid
Add triethylamine (1.5 mL) to a solution of 6-chloronaphthalene-2-thiol (1.9 g) and ethyl 2- (hydroxymethyl) acrylate (1.3 g) in dichloromethane (50 mL) under an argon atmosphere, and stir at room temperature for 15 hours. It was. The reaction solution was diluted with dichloromethane, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by a silica gel column (hexane / ethyl acetate = 4/1) to obtain a colorless oil. The obtained oil was dissolved in ethanol (20 mL), 1N aqueous sodium hydroxide solution (10 mL) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water and washed with diethyl ether. The aqueous layer was adjusted to about pH 3 with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was washed with hexane-diethyl ether to give the title compound (0.86 g, 52%) as a white solid.
NMR (200MHz, CDCl ₃ ) δ: 2.74-2.86 (2H, m), 3.25 (1H, dd, J = 13.8, 8.0), 3.48 (1H, dd, J = 13.8, 5.8), 3.93 (2H, d, J = 5.2), 7.40 (1H, dd, J = 8.8, 1.8), 7.47 (1H, dd, J = 8.8, 1.8), 7.65 (1H, d, J = 3.6), 7.69 (1H, d, J = 3.6), 7.76 (2H, m).
189b) 2- {1- [3-[(6-Chloro-2-naphthyl) thio] -2- (hydroxymethyl) propanoyl] -4-piperidinyl} -5-methyl-1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one 3-[(6-Chloro-2-naphthyl) thio] -2- (hydroxymethyl) propionic acid (0.75 g) obtained in Example 189a) and the example Example 128 from 5-methyl-2- (4-piperidinyl) -1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one dihydrochloride (0.74 g) obtained in 69b) ) To give the title compound (0.62 g, 32%) as a white solid.
NMR (200MHz, CDCl ₃ ) δ: 1.40-1.67 (2H, m), 1.68-1.85 (2H, m), 2.56-2.65 (1H, m), 2.59 (3H, s), 2.98-3.06 (1H, m ), 3.07-3.47 (3H, m), 3.81-3.95 (4H, m), 4.07-4.16 (2H, m), 4.80 (1H, t, J = 13.5), 6.68 (1H, t, J = 1.5) , 7.42-7.46 (2H, m), 7.69 (2H, dd, J = 8.7, 2.1), 7.81 (2H, dd, J = 8.7, 2.1).
189c) 2- {1- [3-[(6-chloro-2-naphthyl) sulfonyl] -2- (hydroxymethyl) propanoyl] -4-piperidinyl} -5-methyl-1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one 2- {1- [3-[(6-chloro-2-naphthyl) thio] -2- (hydroxymethyl) propanoyl]-obtained in Example 189b) 4-piperidinyl} -5-methyl-1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one (0.55 g) in methanol (20 mL) in oxone (1.5 g) ) And stirred at room temperature for 3 hours. An aqueous sodium thiosulfate solution was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. Methanol was distilled off under reduced pressure, and the reaction solution was neutralized with a saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by basic silica gel column (ethyl acetate) and recrystallized from ethanol-water to give the title compound (0.40 g, 68%) as a white solid.
NMR (300MHz, CDCl ₃ ) δ: 1.57-1.99 (3H, m), 2.09-2.22 (1H, m), 2.22-2.42 (0.5H, m), 2.61 (3H, s), 2.69-2.79 (0.5H , m), 3.14-3.44 (3H, m), 3.65-3.97 (4H, m), 4.06-4.17 (0.3H, m), 4.25-4.34 (3.7H, m), 4.58 (0.3H, d, J = 12.0), 4.85 (0.7H, d, J = 12.0), 6.65 (0.7H, s), 6.69 (0.3H, s), 7.61 (1H, dd, J = 9.0, 1.8), 7.87-7.96 (4H m), 8.45 (0.3H, s), 8.49 (0.7H, s).
Elemental analysis value Calculated as C ₂₅ H ₂₇ N ₄ O ₅ SCl · 0.5H ₂ O (%): C, 55.60; H, 5.23; N, 10.37
Found (%): C, 55.55; H, 5.14; N, 10.54

実施例190
2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-5-(ジフルオロメチル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
190a) 4-(5-ホルミル-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル)ピペリジン-1-カルボン酸 tert-ブチル
塩化オキサリル(1.3g)のジクロロメタン(100mL)溶液へ-60℃でDMSO(0.78g)を滴下し、10分間かき混ぜた。反応液へ実施例185c)で得られた4-[5-(ヒドロキシメチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル(2.7g)のジクロロメタン(20mL)溶液を-60℃で滴下し、10分間かき混ぜた。次にトリエチルアミン(7.0mL)を-60℃で滴下し、同温度で10分間かき混ぜた後、3時間かけて室温まで昇温した。反応液を水洗し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。残留物をシリカゲルカラム（EtOAc/EtOH＝30/1）により精製して、題記化合物(1.7g, 62%)を淡黄色固体として得た。
NMR (200MHz, CDCl₃)δ: 1.48 (9H, s), 1.58-1.77 (2H, m), 1.79-1.98 (2H, m), 2.85 (2H, t, J = 12.4), 4.10-4.18 (1H, m), 4.28 (2H, d, J = 14.8), 4.48 (2H, s), 7.19 (1H, s), 10.1 (1H, s).
190b) 4-[5-(ジフルオロメチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル
実施例190a)で得られた4-(5-ホルミル-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル)ピペリジン-1-カルボン酸 tert-ブチル(0.4g)のジクロロメタン(20mL)溶液へジエチルアミノ硫黄三フッ化物(0.48mL)をゆっくり滴下し、室温で15時間かき混ぜた。反応混合物をジクロロメタンと水で希釈した。有機層を分液し、無水硫酸ナトリウムで乾燥、減圧濃縮した。残留物を塩基性シリカゲルカラム（酢酸エチル/ヘキサン＝4/1）により精製して、題記化合物(0.42g, 98%)を淡黄色固体として得た。
NMR (300MHz, CDCl₃)δ: 1.48 (9H, s), 1.65 (2H, dt, J = 12.6, 3.0), 1.88 (2H, d, J = 8.7), 2.84 (2H, t, J = 12.6), 4.09-4.17 (1H, m), 4.24-4.32 (2H, m), 4.39 (2H, dd, J = 3.9, 2.4), 6.95 (1H, t, J = 52.8), 6.97 (1H, t, J = 1.5).
190c) 2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-5-(ジフルオロメチル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
実施例190b)で得られた4-[5-(ジフルオロメチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル(0.33g)から実施例185e)と同様にして、題記化合物(0.20g, 39%)を白色結晶(エタノール-水)として得た。
NMR (300MHz, CDCl₃)δ: 1.42-1.86 (2H, m), 1.90-2.08 (2H, m), 2.72-2.86 (1H, m), 3.18-3.33 (1H, m), 3.41-3.54 (2H, m), 3.74 (0.4H, d, J = 6.3), 3.90 (0.6H, d, J = 6.3), 4.09-4.30 (2H, m), 4.39 (0.6H, s), 4.43 (0.4H, s), 4.73 (1H, t, J = 13.5), 5.02-5.09 (1H, m), 6.94 (1H, t, J = 52.8), 6.97 (1H, s), 7.60 (1H, dd, J = 9.0, 2.1), 7.94 (3H, s), 7.96 (1H, d, J = 9.0), 8.51 (1H, s).
元素分析値 C₂₄H₂₃N₄O₅SClF₂として
計算値（％）：C, 52.13； H, 4.19； N, 10.13
実測値（％）：C, 52.03； H, 4.18； N, 9.99 Example 190
2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -5- (difluoromethyl) -1,2-dihydro- 3H-imidazo [1,5-c] imidazol-3-one
190a) 4- (5-formyl-3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl) piperidine-1-carboxylate tert-butyl oxalyl chloride (1.3 g) in dichloromethane ( DMSO (0.78 g) was added dropwise to the (100 mL) solution at −60 ° C. and stirred for 10 minutes. 4- [5- (hydroxymethyl) -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1-carboxylic acid obtained in Example 185c) A solution of tert-butyl (2.7 g) in dichloromethane (20 mL) was added dropwise at −60 ° C. and stirred for 10 minutes. Next, triethylamine (7.0 mL) was added dropwise at −60 ° C., and the mixture was stirred at the same temperature for 10 minutes, and then warmed to room temperature over 3 hours. The reaction solution was washed with water and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column (EtOAc / EtOH = 30/1) to give the title compound (1.7 g, 62%) as a pale yellow solid.
NMR (200MHz, CDCl ₃ ) δ: 1.48 (9H, s), 1.58-1.77 (2H, m), 1.79-1.98 (2H, m), 2.85 (2H, t, J = 12.4), 4.10-4.18 (1H , m), 4.28 (2H, d, J = 14.8), 4.48 (2H, s), 7.19 (1H, s), 10.1 (1H, s).
190b) 4- [5- (Difluoromethyl) -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1-carboxylate tert-butyl obtained in Example 190a) 4- (5-formyl-3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl) piperidine-1-carboxylate tert-butyl (0.4 g) in dichloromethane (20 mL) Diethylaminosulfur trifluoride (0.48 mL) was slowly added dropwise to the solution, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was diluted with dichloromethane and water. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column (ethyl acetate / hexane = 4/1) to give the title compound (0.42 g, 98%) as a pale yellow solid.
NMR (300MHz, CDCl ₃ ) δ: 1.48 (9H, s), 1.65 (2H, dt, J = 12.6, 3.0), 1.88 (2H, d, J = 8.7), 2.84 (2H, t, J = 12.6) , 4.09-4.17 (1H, m), 4.24-4.32 (2H, m), 4.39 (2H, dd, J = 3.9, 2.4), 6.95 (1H, t, J = 52.8), 6.97 (1H, t, J = 1.5).
190c) 2- (1-{(2S) -3-[(6-Chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -5- (difluoromethyl) -1,2- Dihydro-3H-imidazo [1,5-c] imidazol-3-one 4- [5- (Difluoromethyl) -3-oxo-1H-imidazo [1,5-c] imidazole obtained in Example 190b) -2 (3H) -yl] piperidine-1-carboxylic acid tert-butyl (0.33 g) was used in the same manner as in Example 185e) to give the title compound (0.20 g, 39%) as white crystals (ethanol-water). It was.
NMR (300MHz, CDCl ₃ ) δ: 1.42-1.86 (2H, m), 1.90-2.08 (2H, m), 2.72-2.86 (1H, m), 3.18-3.33 (1H, m), 3.41-3.54 (2H , m), 3.74 (0.4H, d, J = 6.3), 3.90 (0.6H, d, J = 6.3), 4.09-4.30 (2H, m), 4.39 (0.6H, s), 4.43 (0.4H, s), 4.73 (1H, t, J = 13.5), 5.02-5.09 (1H, m), 6.94 (1H, t, J = 52.8), 6.97 (1H, s), 7.60 (1H, dd, J = 9.0 , 2.1), 7.94 (3H, s), 7.96 (1H, d, J = 9.0), 8.51 (1H, s).
Elemental analysis value Calculated as C ₂₄ H ₂₃ N ₄ O ₅ SClF ₂ (%): C, 52.13; H, 4.19; N, 10.13
Found (%): C, 52.03; H, 4.18; N, 9.99

実施例191
N-{[2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル}-N-メチルアセトアミド
191a) (1-ベンジル-4-ピペリジニル)({2-[(メチルアミノ)メチル]-1-トリチル-1H-イミダゾール-4-イル}メチル)カルバミン酸 tert-ブチル
実施例183d)で得られた(1-ベンジル-4-ピペリジニル)[(2-ホルミル-1-トリチル-1H-イミダゾール-4-イル)メチル]カルバミン酸 tert-ブチル(19.5g)とメチルアミンの2.0ＭTHF溶液(18mL）から実施例183e)と同様にして、題記化合物(19g, 93%)を淡黄色粉末として得た。
NMR (200MHz, CDCl₃)δ: 1.28 (9H, s), 1.48-1.55 (2H, m), 1.81-1.97 (4H, m), 2.20 (3H, s), 2.87 (2H, d, J = 7.4), 2.89 (2H, s), 3.46 (2H, s), 3.84-4.04 (1H, m), 4.27(2H, s), 6.55 (1H, s), 7.08-7.17 (6H, m), 7.22-7.31 (16H, m).
191b) (2-{[アセチル(メチル)アミノ]メチル}-1-トリチル-1H-イミダゾール-4-イル)メチル(1-ベンジル-4-ピペリジニル)カルバミン酸 tert-ブチル
実施例191a)で得られた(1-ベンジル-4-ピペリジニル)({2-[(メチルアミノ)メチル]-1-トリチル-1H-イミダゾール-4-イル}メチル)カルバミン酸 tert-ブチル(2.4g)とトリエチルアミン(0.62mL)のTHF(30mL)溶液へ塩化アセチル(0.32mL)を氷冷下滴下し、室温で15時間かき混ぜた。反応混合物を濃縮し、残留物に酢酸エチルを加え、飽和食塩水溶液で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残留物を塩基性シリカゲルカラム（酢酸エチル）により精製して、題記化合物(2.2g, 87%)を無色粉末として得た。
NMR (200MHz, CDCl₃)δ: 1.26 (9H, s), 1.51 (2H, d, J = 11.0), 1.78-1.98 (4H, m), 1.98 (1.5H, s), 2.04 (1.5H, s), 2.53 (1.5 H, s), 2.65 (1.5H, s), 2.87 (2H, d, J = 11.0), 3.39 (1H, s), 3.45 (2H, s), 3.70 (1H, s), 3.85-4.01 (1H, m), 4.22 (2H, s), 6.65 (0.5H, s), 6.68 (0.5H, s), 7.10-7.22 (6H, m), 7.26-7.35 (1H, m).
191c) N-{[2-(1-ベンジル-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル}-N-メチルアセトアミド
実施例191b)で得られた(2-{[アセチル(メチル)アミノ]メチル}-1-トリチル-1H-イミダゾール-4-イル)メチル(1-ベンジル-4-ピペリジニル)カルバミン酸 tert-ブチル(2.2g)から実施例183f)と同様にして、題記化合物(0.75g, 62%)を無色粉末として得た。
NMR (200MHz, CDCl₃)δ: 1.69-1.86 (4H, m), 2.06-2.15 (2H, m), 2.15 (1.5H, s), 2.31 (1.5H, s), 2.98 (1.5H, s), 3.01 (2H, d, J = 8.6), 3.12 (1.5H, s), 3.52 (2H, s), 3.89-4.10 (1H, m), 4.31 (1H, s), 4.35 (1H, s), 4.79 (1H, s), 4.92 (1H, s), 6.78 (0.5H, t, J = 1.4), 6.83 (0.5H, t, J = 1.4), 7.21-7.33 (5H, m).
191d) N-メチル-N-{[3-オキソ-2-(4-ピペリジニル)-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル}アセトアミド
実施例191c)で得られたN-{[2-(1-ベンジル-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル}-N-メチルアセトアミド(0.70g)から実施例183g)と同様にして、題記化合物(0.49g, 86%)を無色粉末として得た。
NMR (300MHz, CDCl₃)δ: 1.59-1.75 (2H, m), 1.85-1.88 (2H, m), 2.16 (1.5H, s), 2.32 (1.5H, s), 2.69-2.80 (2H, m), 2.99 (1.5H, s), 3.13 (1.5H, s), 3.20 (2H, d, J = 11.1), 3.98-4.08 (1H, m), 4.34 (0.5H, s), 4.38 (0.5H, s), 4.80 (0.5H, s), 4.80 (0.5H, s), 4.93 (0.5H, s), 6.78 (0.5H, s), 6.84 (0.5H, s).
191e) N-{[2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル}-N-メチルアセトアミド
実施例191d)で得られた N-メチル-N-{[3-オキソ-2-(4-ピペリジニル)-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル}アセトアミド(0.45g)、実施例174a)で得られた(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロピオン酸(0.58g)およびHOBt(0.28g)のジクロロメタン(40mL)とアセトニトリル(10mL)の混合溶液へWSC(0.36g)を加え、室温で15時間かき混ぜた。溶媒を減圧留去し、残留物をクロロホルムと飽和炭酸水素ナトリウム水溶液で希釈した。有機層を分液し、飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残留物を塩基性シリカゲルカラム（酢酸エチルから酢酸エチル/エタノール＝10/1）により精製して、題記化合物(0.39g, 66%)を白色粉末として得た。
NMR (300MHz, CDCl₃)δ: 1.40-1.86 (2H, m), 1.87-2.06 (2H, m), 2.15 (1.8H, s), 2.31 (1.2H, s), 2.68-2.83 (1H, m), 2.97 (1.2H, s), 3.13 (1.8H, s), 3.19-3.26 (1H, m), 3.48-3.56 (2H, m), 4.08-4.36 (4H, m), 4.63-4.75 (1H, m), 4.79 (1.2H, s), 4.91 (1.8H, s), 5.06 (1H, brs), 6.78 (1.8H, s), 6.84 (1.2H, s), 7.59 (1H, dd, J = 9.0, 1.5), 7.94 (3H, s), 7.96 (1H, d, J = 9.0), 8.51 (1H, s).
元素分析値 C₂₇H₃₀N₅O₆SCl・2H₂Oとして
計算値（％）：C, 51.96； H, 5.49； N, 11.22
実測値（％）：C, 52.05； H, 5.23； N, 11.26 Example 191
N-{[2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -3-oxo-2,3-dihydro -1H-imidazo [1,5-c] imidazol-5-yl] methyl} -N-methylacetamide
191a) (1-benzyl-4-piperidinyl) ({2-[(methylamino) methyl] -1-trityl-1H-imidazol-4-yl} methyl) carbamate tert-butyl obtained in Example 183d) (1-Benzyl-4-piperidinyl) [(2-formyl-1-trityl-1H-imidazol-4-yl) methyl] Carbamate tert-butyl (19.5 g) and methylamine in 2.0M THF solution (18 mL) In the same manner as in Example 183e), the title compound (19 g, 93%) was obtained as a pale yellow powder.
NMR (200MHz, CDCl ₃ ) δ: 1.28 (9H, s), 1.48-1.55 (2H, m), 1.81-1.97 (4H, m), 2.20 (3H, s), 2.87 (2H, d, J = 7.4 ), 2.89 (2H, s), 3.46 (2H, s), 3.84-4.04 (1H, m), 4.27 (2H, s), 6.55 (1H, s), 7.08-7.17 (6H, m), 7.22- 7.31 (16H, m).
191b) tert-butyl (2-{[acetyl (methyl) amino] methyl} -1-trityl-1H-imidazol-4-yl) methyl (1-benzyl-4-piperidinyl) carbamate obtained in Example 191a) (1-benzyl-4-piperidinyl) ({2-[(methylamino) methyl] -1-trityl-1H-imidazol-4-yl} methyl) carbamate tert-butyl (2.4 g) and triethylamine (0.62 mL) ) In THF (30 mL) was added dropwise acetyl chloride (0.32 mL) under ice-cooling, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated, ethyl acetate was added to the residue, washed with saturated brine solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with a basic silica gel column (ethyl acetate) to obtain the title compound (2.2 g, 87%) as a colorless powder.
NMR (200MHz, CDCl ₃ ) δ: 1.26 (9H, s), 1.51 (2H, d, J = 11.0), 1.78-1.98 (4H, m), 1.98 (1.5H, s), 2.04 (1.5H, s ), 2.53 (1.5 H, s), 2.65 (1.5H, s), 2.87 (2H, d, J = 11.0), 3.39 (1H, s), 3.45 (2H, s), 3.70 (1H, s), 3.85-4.01 (1H, m), 4.22 (2H, s), 6.65 (0.5H, s), 6.68 (0.5H, s), 7.10-7.22 (6H, m), 7.26-7.35 (1H, m).
191c) N-{[2- (1-benzyl-4-piperidinyl) -3-oxo-2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl} -N-methyl Acetamide tert-Butyl (2-{[acetyl (methyl) amino] methyl} -1-trityl-1H-imidazol-4-yl) methyl (1-benzyl-4-piperidinyl) carbamate obtained in Example 191b) The title compound (0.75 g, 62%) was obtained as a colorless powder in the same manner as in Example 183f) from (2.2 g).
NMR (200MHz, CDCl ₃ ) δ: 1.69-1.86 (4H, m), 2.06-2.15 (2H, m), 2.15 (1.5H, s), 2.31 (1.5H, s), 2.98 (1.5H, s) , 3.01 (2H, d, J = 8.6), 3.12 (1.5H, s), 3.52 (2H, s), 3.89-4.10 (1H, m), 4.31 (1H, s), 4.35 (1H, s), 4.79 (1H, s), 4.92 (1H, s), 6.78 (0.5H, t, J = 1.4), 6.83 (0.5H, t, J = 1.4), 7.21-7.33 (5H, m).
191d) N-methyl-N-{[3-oxo-2- (4-piperidinyl) -2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl} acetamide Example 191c N-{[2- (1-Benzyl-4-piperidinyl) -3-oxo-2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl}- The title compound (0.49 g, 86%) was obtained as a colorless powder from N-methylacetamide (0.70 g) in the same manner as in Example 183 g).
NMR (300MHz, CDCl ₃ ) δ: 1.59-1.75 (2H, m), 1.85-1.88 (2H, m), 2.16 (1.5H, s), 2.32 (1.5H, s), 2.69-2.80 (2H, m ), 2.99 (1.5H, s), 3.13 (1.5H, s), 3.20 (2H, d, J = 11.1), 3.98-4.08 (1H, m), 4.34 (0.5H, s), 4.38 (0.5H , s), 4.80 (0.5H, s), 4.80 (0.5H, s), 4.93 (0.5H, s), 6.78 (0.5H, s), 6.84 (0.5H, s).
191e) N-{[2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -3-oxo-2,3 -Dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl} -N-methylacetamide N-methyl-N-{[3-oxo-2- (4) obtained in Example 191d) -Piperidinyl) -2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl} acetamide (0.45 g), (2S) -3-[( 6-Chloro-2-naphthyl) sulfonyl] -2-hydroxypropionic acid (0.58 g) and HOBt (0.28 g) in a mixed solution of dichloromethane (40 mL) and acetonitrile (10 mL) were added WSC (0.36 g) at room temperature. Stir for 15 hours. The solvent was distilled off under reduced pressure, and the residue was diluted with chloroform and saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by basic silica gel column (ethyl acetate to ethyl acetate / ethanol = 10/1) to give the title compound (0.39 g, 66%) as a white powder.
NMR (300MHz, CDCl ₃ ) δ: 1.40-1.86 (2H, m), 1.87-2.06 (2H, m), 2.15 (1.8H, s), 2.31 (1.2H, s), 2.68-2.83 (1H, m ), 2.97 (1.2H, s), 3.13 (1.8H, s), 3.19-3.26 (1H, m), 3.48-3.56 (2H, m), 4.08-4.36 (4H, m), 4.63-4.75 (1H , m), 4.79 (1.2H, s), 4.91 (1.8H, s), 5.06 (1H, brs), 6.78 (1.8H, s), 6.84 (1.2H, s), 7.59 (1H, dd, J = 9.0, 1.5), 7.94 (3H, s), 7.96 (1H, d, J = 9.0), 8.51 (1H, s).
Elemental analysis value Calculated as C ₂₇ H ₃₀ N ₅ O ₆ SCl · 2H ₂ O (%): C, 51.96; H, 5.49; N, 11.22
Found (%): C, 52.05; H, 5.23; N, 11.26

実施例192
N-{[2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル}-N-メチルメタンスルホンアミド
192a) (1-ベンジル-4-ピペリジニル)[(2-{[メチル(メチルスルホニル)アミノ]メチル}-1-トリチル-1H-イミダゾール-4-イル)メチル]カルバミン酸 tert-ブチル
実施例191a)で得られた(1-ベンジル-4-ピペリジニル)({2-[(メチルアミノ)メチル]-1-トリチル-1H-イミダゾール-4-イル}メチル)カルバミン酸 tert-ブチル(2.4g)とトリエチルアミン(0.62mL)のTHF(30mL)溶液へ塩化メタンスルホニル(0.35mL)を滴下し、室温で15時間かき混ぜた。反応混合物を減圧濃縮し、酢酸エチルと水で希釈した。有機層を分液し、飽和食塩水溶液で洗浄した後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残留物をシリカゲルカラム（酢酸エチル-ヘキサン＝4/1 から酢酸エチル）により精製して、題記化合物(1.2g, 45%)を無色粉末として得た。
NMR (200MHz, CDCl₃)δ: 1.28 (9H, s), 1.54 (2H, d, J = 11.4), 1.70-2.00 (4H, m), 2.31 (3H, s), 2.86 (2H, d, J = 10.8), 3.15 (3H, s), 3.45 (2H, s), 3.70 (2H, s), 3.87-3.98 (1H, m), 4.20 (2H, s), 6.71 (1H, s), 7.09-7.16 (6H, m), 7.20-7.33 (15H, m).
192b) N-{[2-(1-ベンジル-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル}-N-メチルメタンスルホンアミド
実施例192a)で得られた(1-ベンジル-4-ピペリジニル)[(2-{[メチル(メチルスルホニル)アミノ]メチル}-1-トリチル-1H-イミダゾール-4-イル)メチル]カルバミン酸 tert-ブチル(1.2g)から実施例183f)と同様にして、題記化合物(0.25g, 38%)を白色粉末として得た。
NMR (200MHz, CDCl₃)δ: 1.75-1.86 (4H, m), 2.06-2.20 (2H, m), 3.01 (2H, d, J = 10.2), 2.95 (3H, s), 3.03 (3H, s), 3.53 (2H, s), 3.89-4.06 (1H, m), 4.34 (2H, s), 4.78 (2H, s), 6.83 (1H, t, J = 1.4), 7.23-7.35 (5H, m).
192c) N-メチル-N-{[3-オキソ-2-(4-ピペリジニル)-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル}メタンスルホンアミド
実施例192b)で得られたN-{[2-(1-ベンジル-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル}-N-メチルメタンスルホンアミド(0.25g)から実施例183g)と同様にして、題記化合物(0.16g, 83%)を無色粉末として得た。
NMR (300MHz, CDCl₃)δ: 1.68 (2H, dt, J = 12.0 and 4.2), 1.78-1.89 (2H, m), 2.75 (2H, t, J = 10.5), 2.95 (3H, s), 3.03 (3H, s), 3.24 (2H, d, J = 12.0), 3.96-4.10 (1H, m), 4.38 (2H, s), 4.79 (2H, s), 6.84 (1H, s).
192d) N-{[2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル}-N-メチルメタンスルホンアミド
実施例192c)で得られたN-メチル-N-{[3-オキソ-2-(4-ピペリジニル)-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル}メタンスルホンアミド(0.15g)から実施例191e)と同様にして、題記化合物(98mg, 29%)を白色粉末として得た。
NMR (300MHz, CDCl₃)δ: 1.64-1.83 (2H, m), 1.90-2.06 (2H, m), 2.71-2.85 (1H, m), 2.97 (3H, s), 3.71-3.87 (1H, m), 4.09-4.29(2H, m), 4.32 (1.2H, s), 4.36 (0.8H, s), 4.74 (1H, t, J = 13.8), 4.79 (2H, s), 5.05 (1H, brs), 6.85 (1H, s), 7.60 (1H, dd, J = 8.7, 2.1), 7.95 (3H, s), 7.96 (1H, d, J = 8.7), 8.51 (1H, s).
元素分析値 C₂₆H₃₀N₅O₇S₂Cl・H₂Oとして
計算値（％）：C, 48.63； H, 5.02； N, 10.91
実測値（％）：C, 48.76； H, 5.00； N, 10.85 Example 192
N-{[2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -3-oxo-2,3-dihydro -1H-imidazo [1,5-c] imidazol-5-yl] methyl} -N-methylmethanesulfonamide
192a) (1-benzyl-4-piperidinyl) [(2-{[methyl (methylsulfonyl) amino] methyl} -1-trityl-1H-imidazol-4-yl) methyl] carbamate tert-butyl Example 191a) (1-benzyl-4-piperidinyl) ({2-[(methylamino) methyl] -1-trityl-1H-imidazol-4-yl} methyl) carbamate tert-butyl (2.4 g) and triethylamine obtained in Methanesulfonyl chloride (0.35 mL) was added dropwise to a solution of (0.62 mL) in THF (30 mL), and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate and water. The organic layer was separated, washed with a saturated saline solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (ethyl acetate-hexane = 4/1 to ethyl acetate) to give the title compound (1.2 g, 45%) as a colorless powder.
NMR (200MHz, CDCl ₃ ) δ: 1.28 (9H, s), 1.54 (2H, d, J = 11.4), 1.70-2.00 (4H, m), 2.31 (3H, s), 2.86 (2H, d, J = 10.8), 3.15 (3H, s), 3.45 (2H, s), 3.70 (2H, s), 3.87-3.98 (1H, m), 4.20 (2H, s), 6.71 (1H, s), 7.09- 7.16 (6H, m), 7.20-7.33 (15H, m).
192b) N-{[2- (1-Benzyl-4-piperidinyl) -3-oxo-2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl} -N-methyl Methanesulfonamide (1-Benzyl-4-piperidinyl) [(2-{[methyl (methylsulfonyl) amino] methyl} -1-trityl-1H-imidazol-4-yl) methyl] obtained in Example 192a) The title compound (0.25 g, 38%) was obtained as a white powder from tert-butyl carbamate (1.2 g) in the same manner as in Example 183f).
NMR (200MHz, CDCl ₃ ) δ: 1.75-1.86 (4H, m), 2.06-2.20 (2H, m), 3.01 (2H, d, J = 10.2), 2.95 (3H, s), 3.03 (3H, s ), 3.53 (2H, s), 3.89-4.06 (1H, m), 4.34 (2H, s), 4.78 (2H, s), 6.83 (1H, t, J = 1.4), 7.23-7.35 (5H, m ).
192c) N-methyl-N-{[3-oxo-2- (4-piperidinyl) -2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl} methanesulfonamide N-{[2- (1-Benzyl-4-piperidinyl) -3-oxo-2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl obtained in Example 192b) } -N-methylmethanesulfonamide (0.25 g) was used in the same manner as Example 183 g) to give the title compound (0.16 g, 83%) as a colorless powder.
NMR (300MHz, CDCl ₃ ) δ: 1.68 (2H, dt, J = 12.0 and 4.2), 1.78-1.89 (2H, m), 2.75 (2H, t, J = 10.5), 2.95 (3H, s), 3.03 (3H, s), 3.24 (2H, d, J = 12.0), 3.96-4.10 (1H, m), 4.38 (2H, s), 4.79 (2H, s), 6.84 (1H, s).
192d) N-{[2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -3-oxo-2,3 -Dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl} -N-methylmethanesulfonamide N-methyl-N-{[3-oxo-2-] obtained in Example 192c) In the same manner as in Example 191e) from (4-piperidinyl) -2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl} methanesulfonamide (0.15 g), the title compound ( 98 mg, 29%) was obtained as a white powder.
NMR (300MHz, CDCl ₃ ) δ: 1.64-1.83 (2H, m), 1.90-2.06 (2H, m), 2.71-2.85 (1H, m), 2.97 (3H, s), 3.71-3.87 (1H, m ), 4.09-4.29 (2H, m), 4.32 (1.2H, s), 4.36 (0.8H, s), 4.74 (1H, t, J = 13.8), 4.79 (2H, s), 5.05 (1H, brs ), 6.85 (1H, s), 7.60 (1H, dd, J = 8.7, 2.1), 7.95 (3H, s), 7.96 (1H, d, J = 8.7), 8.51 (1H, s).
Elemental analysis value Calculated as C ₂₆ H ₃₀ N ₅ O ₇ S ₂ Cl · H ₂ O (%): C, 48.63; H, 5.02; N, 10.91
Found (%): C, 48.76; H, 5.00; N, 10.85

実施例193
4-(アセチルアミノ)ブタン酸 [2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル
193a) 4-[5-({[4-(アセチルアミノ)ブタノイル]オキシ}メチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル
実施例185c)で得られた4-[5-(ヒドロキシメチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル(0.60g)、4-(アセチルアミノ)ブタン酸(0.26g)およびジメチルアミノピリジン(0.043g)のジクロロメタン(20mL)とアセトニトリル(20mL)の混合溶液へWSC(0.19g)を加え、室温で15時間かき混ぜた。溶媒を留去した後、残留物を酢酸エチルで希釈して、飽和炭酸水素ナトリウム水溶液と飽和食塩水で順次洗浄、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残留物を塩基性シリカゲルカラム（酢酸エチルから酢酸エチル/エタノール＝19/1）により精製して、題記化合物(0.56g, 68%)を白色粉末として得た。
NMR (200MHz, CDCl₃)δ: 1.48 (9H, s), 1.63 (2H, dt, J = 12.4, 4.4), 1.84-1.92 (4H, m), 1.96 (3H, s), 2.43 (2H, t, J = 6.4), 2.83 (2H, t, J = 12.4), 3.20 (2H, dt, J = 6.4, 6.4), 4.02-4.17 (1H, m), 4.27 (2H, d, J = 13.2), 4.35 (2H, d, J = 1.2), 5.38 (2H, s), 6.22 (1H, brs), 6.86 (1H, t, J = 1.2).
193b) 4-(アセチルアミノ)ブタン酸 [2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル
実施例193a)で得られた4-[5-({[4-(アセチルアミノ)ブタノイル]オキシ}メチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル(0.50g)へ40%塩化水素エタノール溶液(10mL)を加え、室温で2時間かき混ぜた。溶媒を減圧留去し、残留物をジクロロメタン(40mL)とアセトニトリル(20mL)の混合溶媒にけん濁し、DBU(0.52mL)と実施例174a)で得られた(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロピオン酸(0.41g）、HOBt(0.20g)およびWSC(0.25g)を順次加え、室温で15時間かき混ぜた。溶媒を減圧留去し、残留物をクロロホルムと飽和炭酸水素ナトリウム水溶液で希釈した。有機層を分液し、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残留物を塩基性シリカゲルカラム（酢酸エチルから酢酸エチル-メタノール＝19/1）により精製して、題記化合物(100mg, 15%)を白色粉末として得た。
NMR (200MHz, CDCl₃)δ: 1.67-2.04 (6H, m), 1.95 (3H, s), 2.43 (2H, t, J = 7.0), 2.68-2.85 (2H, m), 3.15-3.30 (1H, m), 3.29 (2H, dt, J = 6.4, 6.4), 3.47-3.55 (2H, m), 4.10-4.23 (1H, m), 4.35 (1.2H, s), 4.38 (0.8H, s), 4.67-4.80 (1H, m), 5.01-5.07 (1H, m), 5.38 (2H, s), 6.20 (1H, brs), 6.87 (1H, s), 7.69 (1H, dd, J = 8.8, 1.8), 7.94 (3H, s), 7.96 (1H, d, J = 8.8), 8.51 (1H, s).
元素分析値 C₃₀H₃₄N₅O₈SCl・H₂Oとして
計算値（％）：C, 53.13； H, 5.35； N, 10.33
実測値（％）：C, 53.13； H, 5.46； N, 10.54 Example 193
4- (acetylamino) butanoic acid [2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -3-oxo- 2,3-Dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl
193a) 4- [5-({[4- (acetylamino) butanoyl] oxy} methyl) -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1- Tert-butyl carboxylate 4- [5- (hydroxymethyl) -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1- from Example 185c) Add WSC (0.19 g) to a mixed solution of tert-butyl carboxylate (0.60 g), 4- (acetylamino) butanoic acid (0.26 g) and dimethylaminopyridine (0.043 g) in dichloromethane (20 mL) and acetonitrile (20 mL). In addition, the mixture was stirred at room temperature for 15 hours. After the solvent was distilled off, the residue was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by basic silica gel column (ethyl acetate to ethyl acetate / ethanol = 19/1) to give the title compound (0.56 g, 68%) as a white powder.
NMR (200MHz, CDCl ₃ ) δ: 1.48 (9H, s), 1.63 (2H, dt, J = 12.4, 4.4), 1.84-1.92 (4H, m), 1.96 (3H, s), 2.43 (2H, t , J = 6.4), 2.83 (2H, t, J = 12.4), 3.20 (2H, dt, J = 6.4, 6.4), 4.02-4.17 (1H, m), 4.27 (2H, d, J = 13.2), 4.35 (2H, d, J = 1.2), 5.38 (2H, s), 6.22 (1H, brs), 6.86 (1H, t, J = 1.2).
193b) 4- (acetylamino) butanoic acid [2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -3- Oxo-2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl 4- [5-({[4- (acetylamino) butanoyl] oxy obtained in Example 193a) } Methyl) -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1-carboxylate in tert-butyl (0.50 g) in 40% hydrogen chloride in ethanol (10 mL) And stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the residue was suspended in a mixed solvent of dichloromethane (40 mL) and acetonitrile (20 mL), and DB2 (0.52 mL) and (2S) -3-[(6- Chloro-2-naphthyl) sulfonyl] -2-hydroxypropionic acid (0.41 g), HOBt (0.20 g) and WSC (0.25 g) were sequentially added, and the mixture was stirred at room temperature for 15 hours. The solvent was distilled off under reduced pressure, and the residue was diluted with chloroform and saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by basic silica gel column (ethyl acetate to ethyl acetate-methanol = 19/1) to give the title compound (100 mg, 15%) as a white powder.
NMR (200MHz, CDCl ₃ ) δ: 1.67-2.04 (6H, m), 1.95 (3H, s), 2.43 (2H, t, J = 7.0), 2.68-2.85 (2H, m), 3.15-3.30 (1H , m), 3.29 (2H, dt, J = 6.4, 6.4), 3.47-3.55 (2H, m), 4.10-4.23 (1H, m), 4.35 (1.2H, s), 4.38 (0.8H, s) , 4.67-4.80 (1H, m), 5.01-5.07 (1H, m), 5.38 (2H, s), 6.20 (1H, brs), 6.87 (1H, s), 7.69 (1H, dd, J = 8.8, 1.8), 7.94 (3H, s), 7.96 (1H, d, J = 8.8), 8.51 (1H, s).
Elemental analysis C ₃₀ H ₃₄ N ₅ O ₈ Calculated as SCl · H ₂ O (%): C, 53.13; H, 5.35; N, 10.33
Found (%): C, 53.13; H, 5.46; N, 10.54

実施例194
5-(ベンゾイルアミノ)ペンタン酸 [2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル
194a) 4-[5-({[5-(ベンゾイルアミノ)ペンタノイル]オキシ}メチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル
実施例185c)で得られた4-[5-(ヒドロキシメチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル(0.6g)と5-(ベンゾイルアミノ)ペンタン酸(0.51g)から実施例193a)と同様にして、題記化合物(0.58g, 71%)を白色粉末として得た。
NMR (300MHz, CDCl₃)δ: 1.47 (9H, s), 1.53-1.84 (8H, m), 2.42 (2H, t, J = 6.9), 2.75 (2H, t, J = 12.3), 3.43 (2H, dt, J = 6.6 and 6.6), 3.99-4.12 (1H, m), 4.23 (2H, d, J = 11.7), 4.33 (2H, s), 5.37 (2H, s), 6.83 (1H, s), 6.87 (1H, t, J = 5.1), 7.37-7.50 (3H, m), 7.78-7.82 (2H, m).
194b) 5-(ベンゾイルアミノ)ペンタン酸 [2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル
実施例194a)で得られた4-[5-({[5-(ベンゾイルアミノ)ペンタノイル]オキシ}メチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル(0.54g)の酢酸エチル(10mL)溶液へ4N塩化水素酢酸エチル溶液(10mL)を加え、室温で3時間かき混ぜた。溶媒を減圧留去し、残留物に飽和炭酸水素ナトリウム水溶液を加えてpH8以上に調節し、クロロホルムで繰り返し抽出した。抽出液を無水硫酸マグネシウムで乾燥し、減圧濃縮した。得られた残留物、実施例174a)で得られた(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロピオン酸(0.38g)およびHOBt(0.18g)のジクロロメタン(20mL)とアセトニトリル(20mL)の混合溶媒へWSC(0.23g)を加えて室温下15時間かき混ぜた。溶媒を減圧留去し、残留物をクロロホルムと飽和炭酸水素ナトリウム水溶液で希釈した。有機層を分液し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残留物を塩基性シリカゲルカラム（酢酸エチルから酢酸エチル/メタノール=9/1）およびシリカゲルカラム（酢酸エチル/メタノール=9/1）で精製して、題記化合物(180mg, 24%)を白色粉末として得た。
NMR (300MHz, CDCl₃)δ: 1.58-1.83 (6H, m), 1.85-2.00 (2H, m), 2.5 (2H, d, J =6.9), 2.69 (1H, dt, J = 12.0, 12.0), 3.08-3.23 (1H, m), 3.41-3.53 (4H, m), 3.91 (1H, brs), 4.07-4.20 (2H, m), 4.30 (1.2H, s), 4.34 (0.8H, s), 4.69 (1H, t, J = 13.5), 4.98-5.08 (1H, m), 5.37 (2H, s), 6.51 (1H, brs), 6.84 (1H, s), 7.38-7.50 (3H, m), 7.58 (1H, dd, J = 8.7, 2.1), 7.76-7.80 (2H, m), 7.93 (3H, s), 7.94 (1H, d, J = 8.7), 8.49 (1H, s).
元素分析値 C₃₆H₃₈N₅O₈SCl・H₂Oとして
計算値（％）：C, 57.33； H, 5.35； N, 9.29
実測値（％）：C, 57.17； H, 5.35； N, 9.24 Example 194
5- (Benzoylamino) pentanoic acid [2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -3-oxo- 2,3-Dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl
194a) 4- [5-({[5- (Benzoylamino) pentanoyl] oxy} methyl) -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1- Tert-butyl carboxylate 4- [5- (hydroxymethyl) -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1- from Example 185c) The title compound (0.58 g, 71%) was obtained as a white powder in the same manner as in Example 193a) from tert-butyl carboxylate (0.6 g) and 5- (benzoylamino) pentanoic acid (0.51 g).
NMR (300MHz, CDCl ₃ ) δ: 1.47 (9H, s), 1.53-1.84 (8H, m), 2.42 (2H, t, J = 6.9), 2.75 (2H, t, J = 12.3), 3.43 (2H , dt, J = 6.6 and 6.6), 3.99-4.12 (1H, m), 4.23 (2H, d, J = 11.7), 4.33 (2H, s), 5.37 (2H, s), 6.83 (1H, s) , 6.87 (1H, t, J = 5.1), 7.37-7.50 (3H, m), 7.78-7.82 (2H, m).
194b) 5- (Benzoylamino) pentanoic acid [2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -3- Oxo-2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl 4- [5-({[5- (benzoylamino) pentanoyl] oxy obtained in Example 194a) } Methyl) -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1-carboxylate 4N chloride to a solution of tert-butyl (0.54g) in ethyl acetate (10mL) Hydrogen ethyl acetate solution (10 mL) was added, and the mixture was stirred at room temperature for 3 hr. The solvent was distilled off under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the residue to adjust to pH 8 or higher, and the mixture was repeatedly extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue, (2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropionic acid (0.38 g) and HOBt (0.18 g) obtained in Example 174a) in dichloromethane WSC (0.23 g) was added to a mixed solvent of (20 mL) and acetonitrile (20 mL), and the mixture was stirred at room temperature for 15 hours. The solvent was distilled off under reduced pressure, and the residue was diluted with chloroform and saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column (ethyl acetate to ethyl acetate / methanol = 9/1) and silica gel column (ethyl acetate / methanol = 9/1) to give the title compound (180 mg, 24%) as a white powder. Obtained.
NMR (300MHz, CDCl ₃ ) δ: 1.58-1.83 (6H, m), 1.85-2.00 (2H, m), 2.5 (2H, d, J = 6.9), 2.69 (1H, dt, J = 12.0, 12.0) , 3.08-3.23 (1H, m), 3.41-3.53 (4H, m), 3.91 (1H, brs), 4.07-4.20 (2H, m), 4.30 (1.2H, s), 4.34 (0.8H, s) , 4.69 (1H, t, J = 13.5), 4.98-5.08 (1H, m), 5.37 (2H, s), 6.51 (1H, brs), 6.84 (1H, s), 7.38-7.50 (3H, m) , 7.58 (1H, dd, J = 8.7, 2.1), 7.76-7.80 (2H, m), 7.93 (3H, s), 7.94 (1H, d, J = 8.7), 8.49 (1H, s).
Elemental analysis C ₃₆ H ₃₈ N ₅ O ₈ Calculated as SCl · H ₂ O (%): C, 57.33; H, 5.35; N, 9.29
Found (%): C, 57.17; H, 5.35; N, 9.24

実施例195
3-(ブチリルアミノ)プロピオン酸[2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル
195a) 3-(ブチリルアミノ)プロピオン酸tert-ブチル
3-アミノプロピオン酸tert-ブチル２塩酸塩(1.82g)とトリエチルアミン(2.8mL)のジクロロメタン(50mL)溶液へ塩化ブタノイル(0.85g)を氷冷下滴下し、室温で15時間かき混ぜた。反応液に飽和炭酸水素ナトリウム水溶液を加え、有機層を分液し、飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去して、題記化合物(1.96g, 91%)を無色油状物として得た。
NMR (200MHz, CDCl₃)δ: 0.94 (3H, t, J = 7.4), 1.45 (9H, s), 1.64 (2H, quintet, J = 7.4), 2.14 (2H, t, J = 7.4), 2.45 (2H, t, J = 6.0), 3.45 (2H, dt, J = 6.0 and 6.0).
195b) 4-[5-({[(3-ブチリルアミノ)プロピオニル]オキシ}メチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル
実施例195a)で得られた3-(ブチリルアミノ)プロピオン酸tert-ブチル(0.52g)へ濃塩酸(3mL)を加え、室温で6時間かき混ぜた。反応液にトルエンとTHFを加えて減圧濃縮し、淡黄色油状物を得た。得られた油状物、実施例185c)で得られた4-[5-(ヒドロキシメチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル(0.61g)およびジメチルアミノピリジン(0.048g)のジクロロメタン(30mL)溶液へWSC(0.35g)を加え、室温で15時間かき混ぜた。反応液をジクロロメタンと飽和食塩水で希釈し、有機層を分液し、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残留物を塩基性シリカゲルカラム（酢酸エチルから酢酸エチル-メタノール=19/1）により精製し、題記化合物(0.75g, 70%)を白色粉末として得た。
NMR (300MHz, CDCl₃)δ: 0.93 (3H, t, J = 7.5), 1.47 (9H, s), 1.54-1.72 (4H, m), 1.86 (2H, d, J = 13.2), 2.16 (2H, t, J = 7.5), 2.58 (2H, t, J = 5.4), 2.82 (2H, t, J = 12.6), 3.57 (2H ,dt, J = 5.4 and 5.4), 4.03-4.15 (1H, m), 4.28 (2H, d, J = 10.5), 4.36 (1H, s), 5.43 (2H, s), 6.84 (1H, s).
195c) 3-(ブチリルアミノ)プロピオン酸[2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル
実施例195b)で得られた4-[5-({[(3-ブチリルアミノ)プロピオニル]オキシ}メチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル(0.65g)から実施例194b)と同様にして、題記化合物(60mg, 7%)を白色粉末として得た。
NMR (300MHz, CDCl₃)δ: 0.93 (3H, t, J = 7.5), 1.65-1.86 (4H, m), 1.92-2.05 (2H, m), 2.16 (2H, t, J = 7.5), 2.59 (2H, t, J = 6.3), 2.75 (2H, dt, J = 13.8 and 13.8), 3.13-3.30 (1H, m), 3.49-3.59 (4H, m), 4.09-4.24 (2H, m), 4.34 (1.2H, s), 4.38 (0.8H, s), 4.72 (1H, J = 13.8), 5.07-5.09 (1H, m), 5.42 (2H, s), 6.84 (1H, s), 7.59 (1H, dd, J = 9.0 and 2.1), 7.94 (3H, s), 7.96 (1H, d, J = 9.0), 8.51 (1H, s).
元素分析値 C₃₁H₃₆N₅O₈SCl・0.5H₂Oとして
計算値（％）：C, 54.50； H, 5.46； N, 10.25
実測値（％）：C, 54.56； H, 5.75； N, 10.19 Example 195
3- (Butyrylamino) propionic acid [2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -3-oxo-2 , 3-Dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl
195a) tert-Butyl 3- (butyrylamino) propionate
Butanoyl chloride (0.85 g) was added dropwise to a solution of tert-butyl 3-aminopropionate dihydrochloride (1.82 g) and triethylamine (2.8 mL) in dichloromethane (50 mL) under ice-cooling, and the mixture was stirred at room temperature for 15 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the organic layer was separated, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (1.96 g, 91%) as a colorless oil.
NMR (200MHz, CDCl ₃ ) δ: 0.94 (3H, t, J = 7.4), 1.45 (9H, s), 1.64 (2H, quintet, J = 7.4), 2.14 (2H, t, J = 7.4), 2.45 (2H, t, J = 6.0), 3.45 (2H, dt, J = 6.0 and 6.0).
195b) 4- [5-({[(3-Butyrylamino) propionyl] oxy} methyl) -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1-carboxyl Acid tert-butyl Concentrated hydrochloric acid (3 mL) was added to tert-butyl 3- (butyrylamino) propionate (0.52 g) obtained in Example 195a), and the mixture was stirred at room temperature for 6 hr. Toluene and THF were added to the reaction mixture, and the mixture was concentrated under reduced pressure to give a pale yellow oil. The resulting oil, 4- [5- (hydroxymethyl) -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1 obtained in Example 185c) -WSC (0.35 g) was added to a solution of tert-butyl carboxylate (0.61 g) and dimethylaminopyridine (0.048 g) in dichloromethane (30 mL), and the mixture was stirred at room temperature for 15 hours. The reaction solution was diluted with dichloromethane and saturated brine, and the organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by basic silica gel column (ethyl acetate to ethyl acetate-methanol = 19/1) to obtain the title compound (0.75 g, 70%) as a white powder.
NMR (300MHz, CDCl ₃ ) δ: 0.93 (3H, t, J = 7.5), 1.47 (9H, s), 1.54-1.72 (4H, m), 1.86 (2H, d, J = 13.2), 2.16 (2H , t, J = 7.5), 2.58 (2H, t, J = 5.4), 2.82 (2H, t, J = 12.6), 3.57 (2H, dt, J = 5.4 and 5.4), 4.03-4.15 (1H, m ), 4.28 (2H, d, J = 10.5), 4.36 (1H, s), 5.43 (2H, s), 6.84 (1H, s).
195c) 3- (Butyrylamino) propionic acid [2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -3-oxo -2,3-Dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl 4- [5-({[(3-butyrylamino) propionyl] oxy} methyl obtained in Example 195b) ) -3-Oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1-carboxylate from tert-butyl (0.65 g) in the same manner as in Example 194b) (60 mg, 7%) was obtained as a white powder.
NMR (300MHz, CDCl ₃ ) δ: 0.93 (3H, t, J = 7.5), 1.65-1.86 (4H, m), 1.92-2.05 (2H, m), 2.16 (2H, t, J = 7.5), 2.59 (2H, t, J = 6.3), 2.75 (2H, dt, J = 13.8 and 13.8), 3.13-3.30 (1H, m), 3.49-3.59 (4H, m), 4.09-4.24 (2H, m), 4.34 (1.2H, s), 4.38 (0.8H, s), 4.72 (1H, J = 13.8), 5.07-5.09 (1H, m), 5.42 (2H, s), 6.84 (1H, s), 7.59 ( 1H, dd, J = 9.0 and 2.1), 7.94 (3H, s), 7.96 (1H, d, J = 9.0), 8.51 (1H, s).
Elemental analysis value Calculated as C ₃₁ H ₃₆ N ₅ O ₈ SCl · 0.5H ₂ O (%): C, 54.50; H, 5.46; N, 10.25
Found (%): C, 54.56; H, 5.75; N, 10.19

実施例196
3-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロピオニル}-4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,5-a]ピリジン塩酸塩
3-[(6-クロロ-2-ナフチル)スルホニル]プロピオン酸と実施例225c)で得られた3-(4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾピリジン２塩酸塩から実施例207d)と同様にして、題記化合物(76%)を白色結晶として得た。
NMR (200Mz, DMSO-d₆)δ：1.42-1.68 (2H, m), 1.68-2.03 (6H, m), 2.47-2.68 (1H, m), 2.68-2.87 (3H, m), 2.99-3.20 (1H, m), 3.24-3.54 (2H, m), 3.65 (2H, t, J = 5.8), 3.88-4.03 (1H, m), 4.14 (2H, t, J = 5.8), 4.31-4.48 (1H, m), 7.34 (1H, s), 7.73 (1H, dd, J = 8.8, 2.2), 8.01 (1H, dd, J = 8.8, 2.0), 8.18-8.32 (3H, m), 8.67 (1H, s). Example 196
3- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propionyl} -4-piperidinyl) -5,6,7,8-tetrahydroimidazo [1,5-a] pyridine hydrochloride
Examples from 3-[(6-chloro-2-naphthyl) sulfonyl] propionic acid and 3- (4-piperidinyl) -5,6,7,8-tetrahydroimidazopyridine dihydrochloride obtained in Example 225c) In the same manner as in 207d), the title compound (76%) was obtained as white crystals.
NMR (200Mz, DMSO-d ₆ ) δ: 1.42-1.68 (2H, m), 1.68-2.03 (6H, m), 2.47-2.68 (1H, m), 2.68-2.87 (3H, m), 2.99-3.20 (1H, m), 3.24-3.54 (2H, m), 3.65 (2H, t, J = 5.8), 3.88-4.03 (1H, m), 4.14 (2H, t, J = 5.8), 4.31-4.48 ( 1H, m), 7.34 (1H, s), 7.73 (1H, dd, J = 8.8, 2.2), 8.01 (1H, dd, J = 8.8, 2.0), 8.18-8.32 (3H, m), 8.67 (1H , s).

実施例197
2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-5,7-ジメチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
197a) 2-(1-ベンジル-4-ピペリジニル)-5,7-ジメチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
2,4-ジメチル-1H-イミダゾール-5-カルバルデヒド(1.5g)と1-ベンジル-4-ピペリジンアミン(2.3g)から実施例69a)と同様にして、題記化合物(2.9g, 74%)を白色粉末として得た。
NMR (300MHz, CDCl₃)δ: 1.75-1.85 (4H, m), 2.06-2.17 (4H, m), 2.56 (3H, s), 2.98 (2H, d, J = 12.0), 3.52 (3H, s), 3.89-4.00 (1H, m), 4.21 (2H, s), 7.22-7.37 (5H, m).
197b) 5,7-ジメチル-2-(4-ピペリジニル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
実施例197a)で得た2-(1-ベンジル-4-ピペリジニル)-5,7-ジメチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン(0.77g)から実施例183g)と同様にして、題記化合物(0.53g, 95%)を白色粉末として得た。
NMR (300MHz, CDCl₃)δ: 1.55-1.75 (2H, m), 1.80-1.87 (2H, m), 2.16 (3H, s), 2.57 (3H, s), 2.72 (2H, dt, J = 10.0, 2.6), 3.19 (2H, d, J = 12.0), 3.94-4.11 (1H, m), 4.23 (2H, s).
197c) 2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-5,7-ジメチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
実施例197b)で得られた5,7-ジメチル-2-(4-ピペリジニル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン(0.74g)から実施例191e)と同様にして、題記化合物(0.30g, 27%)を白色粉末として得た。
NMR (300MHz, CDCl₃)δ: 1.60-1.86 (2H, m), 1.88-2.15 (2H, m), 2.14 (3H, s), 2.57 (3H, s), 2.71-2.85 (1H, m), 3.16-3.31 (1H, m), 3.47 (2H, dd, J = 16.5, 5.7), 3.75-3.84 (1H, m), 4.07-4.22 (4H, m), 4.71 (1H, t, J = 12.0), 5.03 (1H, s), 7.58 (1H, dd, J = 9.0, 2.1), 7.93 (3H, s), 7.95 (1H, d, J = 9.0), 8.50 (1H, s).
元素分析値 C₂₅H₂₇N₄O₅SCl・1.7H₂O・0.3EtOAcとして
計算値（％）：C, 53.51； H, 5.62； N, 9.53
実測値（％）：C, 53.65； H, 5.63； N, 9.27 Example 197
2- (1-{(2S) -3-[(6-Chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -5,7-dimethyl-1,2-dihydro-3H -Imidazo [1,5-c] imidazol-3-one
197a) 2- (1-Benzyl-4-piperidinyl) -5,7-dimethyl-1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one
The title compound (2.9 g, 74%) was prepared in the same manner as Example 69a) from 2,4-dimethyl-1H-imidazole-5-carbaldehyde (1.5 g) and 1-benzyl-4-piperidineamine (2.3 g). Was obtained as a white powder.
NMR (300MHz, CDCl ₃ ) δ: 1.75-1.85 (4H, m), 2.06-2.17 (4H, m), 2.56 (3H, s), 2.98 (2H, d, J = 12.0), 3.52 (3H, s ), 3.89-4.00 (1H, m), 4.21 (2H, s), 7.22-7.37 (5H, m).
197b) 5,7-Dimethyl-2- (4-piperidinyl) -1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one 2- (1-benzyl) obtained in Example 197a) 4-piperidinyl) -5,7-dimethyl-1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one (0.77 g) in the same manner as in Example 183 g), and the title compound ( 0.53 g, 95%) was obtained as a white powder.
NMR (300MHz, CDCl ₃ ) δ: 1.55-1.75 (2H, m), 1.80-1.87 (2H, m), 2.16 (3H, s), 2.57 (3H, s), 2.72 (2H, dt, J = 10.0 , 2.6), 3.19 (2H, d, J = 12.0), 3.94-4.11 (1H, m), 4.23 (2H, s).
197c) 2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -5,7-dimethyl-1,2-dihydro -3H-imidazo [1,5-c] imidazol-3-one 5,7-dimethyl-2- (4-piperidinyl) -1,2-dihydro-3H-imidazo [1, obtained in Example 197b) The title compound (0.30 g, 27%) was obtained as a white powder from 5-c] imidazol-3-one (0.74 g) in the same manner as in Example 191e).
NMR (300MHz, CDCl ₃ ) δ: 1.60-1.86 (2H, m), 1.88-2.15 (2H, m), 2.14 (3H, s), 2.57 (3H, s), 2.71-2.85 (1H, m), 3.16-3.31 (1H, m), 3.47 (2H, dd, J = 16.5, 5.7), 3.75-3.84 (1H, m), 4.07-4.22 (4H, m), 4.71 (1H, t, J = 12.0) , 5.03 (1H, s), 7.58 (1H, dd, J = 9.0, 2.1), 7.93 (3H, s), 7.95 (1H, d, J = 9.0), 8.50 (1H, s).
Elemental analysis calculated as C ₂₅ H ₂₇ N ₄ O ₅ SCl · 1.7H ₂ O · 0.3 EtOAc (%): C, 53.51; H, 5.62; N, 9.53
Found (%): C, 53.65; H, 5.63; N, 9.27

実施例198
2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-5-(メトキシメチル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
198a)4-[5-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸ベンジル
実施例185a)で得られた5-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-2-(4-ピペリジニル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン(3.3g)とトリエチルアミン(1,5mL)のTHF(50mL)溶液へクロロギ酸ベンジル(1.5mL)のTHF(30mL)溶液を加え、室温で15時間かき混ぜた。溶媒を減圧留去し、残留物へ酢酸エチルを加え、水および飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、題記化合物(4.6g, 定量的)を淡黄色油状物として得た。
NMR (200MHz, CDCl₃)δ: 0.14 (6H, s), 0.92 (9H, s), 1.64 (2H, ddd, J = 12.0, 12.0 and 4.0), 1.86 (2H, d, J= 9.4), 2.90 (2H, t, J = 12.0), 4.06-4.22 (1H, m), 4.28 (2H, s), 4.28-4.39 (2H, m), 4.92 (2H, s), 5.14 (2H, s), 6.81 (1H, s), 7.33-7.40 (5H, m).
198b) 4-[5-(ヒドロキシメチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸ベンジル
実施例198a)で得た4-[5-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸ベンジル(4.6g)から実施例185c)と同様にして、題記化合物(3.3g, 94%)を白色粉末として得た。
NMR (300MHz, CDCl₃)δ: 1.58-1.75 (2H, m), 1.88 (2H, d, J = 11.1), 2.91 (2H, t, J = 12.6), 4.06 (1H, t, J = 6.9), 4.07-4.18 (1H, m), 4.30-4.40 (4H, m), 4.86 (2H, d, J = 6.9), 5.15 (1H, s), 6.78 (1H, t, J = 1.8), 7.29-7.42 (5H, m).
198c) 4-[5-(メトキシメチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸ベンジル
実施例198b)で得られた4-[5-(ヒドロキシメチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸ベンジル(1.2g)と水素化ナトリウム(60%油性：0.072g)を氷冷下THF(40mL)にけん濁し、ヨウ化メチル(0.19mL)を加えて室温で2時間かき混ぜた。反応液を飽和塩化アンモニウム水溶液に注ぎ込み、有機層を分液し、飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残留物を塩基性シリカゲルカラム（酢酸エチル）により精製して、題記化合物(0.50g, 43%)を白色粉末として得た。
NMR (300MHz, CDCl₃)δ: 1.60-1.76 (2H, m), 1.87 (2H, d, J = 11.4), 2.90 (2H, d, J =11.4), 3.44 (3H, s), 4.07-4.18 (1H, m), 4.28-4.40 (2H, m), 4.29 (2H, s), 4.70 (2H, s), 5.13 (2H, s), 6.82 (1H, s), 7.27-7.40 (5H, m).
198d) 5-(メトキシメチル)-2-(4-ピペリジニル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
実施例198c)で得られた4-[5-(メトキシメチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸ベンジル(0.50g)および10% パラジウム炭素(100mg)のメタノール(30mL)けん濁液を水素雰囲気下室温で15時間かき混ぜた。反応液をセライトを用いてろ過し、ろ液を減圧濃縮して、題記化合物(300mg, 92%)を白色粉末として得た。
NMR (200MHz, CD₃OD)δ: 2.10-2.22 (4H, m), 3.10-3.25 (2H, m), 3.33 (3H, s), 3.47 (3H, s), 3.54 (2H, d, J = 12.6), 4.10-4.30 (1H, m), 4.65 (2H, s), 7.20 (1H, s).
198e) 2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-5-(メトキシメチル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン
実施例198d)で得られた5-(メトキシメチル)-2-(4-ピペリジニル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン(0.30g)から実施例191e)と同様にして、題記化合物(36mg, 5%)を白色粉末として得た。
NMR (300MHz, CDCl₃)δ: 1.61-1.83 (2H, m), 1.93-2.05 (2H, m), 2.71-2.84 (1H, m), 3.15-3.27 (1H, m), 3.27- 3.52 (2H, m), 3.46 (3H, s), 3.72-3.90 (1H, m), 4.08-4.28 (2H, m), 4.31 (1.2H, s), 4.35 (0.8H, s), 4.65-4.80 (1H, m), 4.72 (2H, s), 5.00-5.08 (1H, m), 6.85 (1H, s), 7.60 (1H, dd, J = 9.0, 2.1), 7.95 (3H, s), 7.96 (1H, d, J = 9.0), 8.51 (1H, s).
元素分析値 C₂₅H₂₇N₄O₆SCl・0.5H₂Oとして
計算値（％）：C, 54.00； H, 5.08； N, 10.08
実測値（％）：C, 54.24； H, 5.15； N, 10.21 Example 198
2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -5- (methoxymethyl) -1,2-dihydro- 3H-imidazo [1,5-c] imidazol-3-one
198a) 4- [5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1- Benzyl carboxylate 5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -2- (4-piperidinyl) -1,2-dihydro-3H-imidazo [1,5] obtained in Example 185a) To a solution of -c] imidazol-3-one (3.3 g) and triethylamine (1,5 mL) in THF (50 mL) was added a solution of benzyl chloroformate (1.5 mL) in THF (30 mL), and the mixture was stirred at room temperature for 15 hours. The solvent was evaporated under reduced pressure, ethyl acetate was added to the residue, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (4.6 g, quantitative) as a pale yellow oil.
NMR (200MHz, CDCl ₃ ) δ: 0.14 (6H, s), 0.92 (9H, s), 1.64 (2H, ddd, J = 12.0, 12.0 and 4.0), 1.86 (2H, d, J = 9.4), 2.90 (2H, t, J = 12.0), 4.06-4.22 (1H, m), 4.28 (2H, s), 4.28-4.39 (2H, m), 4.92 (2H, s), 5.14 (2H, s), 6.81 (1H, s), 7.33-7.40 (5H, m).
198b) 4- [5- (hydroxymethyl) -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1-carboxylate benzyl obtained in Example 198a) Benzyl- [5-({[tert-butyl (dimethyl) silyl] oxy} methyl) -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1-carboxylate The title compound (3.3 g, 94%) was obtained as a white powder in the same manner as in Example 185c) from (4.6 g).
NMR (300MHz, CDCl ₃ ) δ: 1.58-1.75 (2H, m), 1.88 (2H, d, J = 11.1), 2.91 (2H, t, J = 12.6), 4.06 (1H, t, J = 6.9) , 4.07-4.18 (1H, m), 4.30-4.40 (4H, m), 4.86 (2H, d, J = 6.9), 5.15 (1H, s), 6.78 (1H, t, J = 1.8), 7.29- 7.42 (5H, m).
198c) benzyl 4- [5- (methoxymethyl) -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1-carboxylate obtained in Example 198b) 4- [5- (Hydroxymethyl) -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1-carboxylate benzyl (1.2 g) and sodium hydride (60 % Oily: 0.072 g) was suspended in THF (40 mL) under ice-cooling, methyl iodide (0.19 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction solution was poured into a saturated aqueous ammonium chloride solution, and the organic layer was separated, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by basic silica gel column (ethyl acetate) to give the title compound (0.50 g, 43%) as a white powder.
NMR (300MHz, CDCl ₃ ) δ: 1.60-1.76 (2H, m), 1.87 (2H, d, J = 11.4), 2.90 (2H, d, J = 11.4), 3.44 (3H, s), 4.07-4.18 (1H, m), 4.28-4.40 (2H, m), 4.29 (2H, s), 4.70 (2H, s), 5.13 (2H, s), 6.82 (1H, s), 7.27-7.40 (5H, m ).
198d) 5- (methoxymethyl) -2- (4-piperidinyl) -1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one 4- [5 obtained in Example 198c) -(Methoxymethyl) -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1-carboxylate benzyl (0.50 g) and 10% palladium on carbon (100 mg) in methanol (30 mL) The suspension was stirred at room temperature for 15 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound (300 mg, 92%) as a white powder.
NMR (200MHz, CD ₃ OD) δ: 2.10-2.22 (4H, m), 3.10-3.25 (2H, m), 3.33 (3H, s), 3.47 (3H, s), 3.54 (2H, d, J = 12.6), 4.10-4.30 (1H, m), 4.65 (2H, s), 7.20 (1H, s).
198e) 2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -5- (methoxymethyl) -1,2- Dihydro-3H-imidazo [1,5-c] imidazol-3-one 5- (methoxymethyl) -2- (4-piperidinyl) -1,2-dihydro-3H-imidazo [Example 198d) The title compound (36 mg, 5%) was obtained as a white powder from 1,5-c] imidazol-3-one (0.30 g) in the same manner as in Example 191e).
NMR (300MHz, CDCl ₃ ) δ: 1.61-1.83 (2H, m), 1.93-2.05 (2H, m), 2.71-2.84 (1H, m), 3.15-3.27 (1H, m), 3.27- 3.52 (2H , m), 3.46 (3H, s), 3.72-3.90 (1H, m), 4.08-4.28 (2H, m), 4.31 (1.2H, s), 4.35 (0.8H, s), 4.65-4.80 (1H , m), 4.72 (2H, s), 5.00-5.08 (1H, m), 6.85 (1H, s), 7.60 (1H, dd, J = 9.0, 2.1), 7.95 (3H, s), 7.96 (1H , d, J = 9.0), 8.51 (1H, s).
Elemental analysis value Calculated as C ₂₅ H ₂₇ N ₄ O ₆ SCl · 0.5H ₂ O (%): C, 54.00; H, 5.08; N, 10.08
Found (%): C, 54.24; H, 5.15; N, 10.21

実施例199
3-(ヘキサノイルアミノ)プロピオン酸[2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル
199a) 3-(ヘキサノイルアミノ)プロピオン酸tert-ブチル
3-アミノプロピオン酸tert-ブチル２塩酸塩(1.82g)と塩化ヘキサノイル(1.1g)から実施例195a)と同様にして、題記化合物(1.5g, 86%)を無色油状物として得た。
NMR (300MHz, CDCl₃)δ：0,89 (3H, t, J = 6.9), 1.23-1.35 (4H, m), 1.45 (9H, s), 1.56-1.66 (2H, m), 2.15 (2H, t, J = 7.8), 2.44 (2H, t, J = 6.3), 3.47 (2H, dt, J = 6.3, 6.3), 6.07 (1H, brs).
199b) 4-[5-({[3-(ヘキサノイルアミノ)プロピオニル]オキシ}メチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル
実施例199a)で得られた3-(ヘキサノイルアミノ)プロピオン酸tert-ブチル(0.60g)と実施例185c)で得られた4-[5-(ヒドロキシメチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル(0.61g)から実施例195b)と同様にして、題記化合物(0.80g, 64%)を白色粉末として得た。
NMR (300MHz, CDCl₃)δ: 0.86 (3H, t, J = 6.9), 1.23-1.29 (4H, m), 1.45 (9H, s), 1.57-1.68 (4H, m), 1.84 (2H, d, J = 12.0), 2.15 (2H, t, J =7.5), 2.56 (2H, t, J = 8.4), 2.80 (2H, t, J = 13.5), 3.51-3.59 (2H, m), 4.01-4.14 (1H, m), 4.25 (2H, d, J = 10.5), 4.34 (2H, s), 5.41 (2H, s), 6.82 (1H, s).
199c) 3-(ヘキサノイルアミノ)プロピオン酸[2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル
実施例199b)で得られた4-[5-({[3-(ヘキサノイルアミノ)プロピオニル]オキシ}メチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル(0.40g)から実施例194b)と同様にして、題記化合物(0.15, 21%)を白色粉末として得た。
NMR (300MHz, CDCl₃)δ: 0.89 (3H, t, J = 6.9), 1.26-1.35 (4H, m), 1.57-1.67 (2H, m), 1.70-1.87 (2H, m), 1.96-2.07 (2H, m), 2.17 (2H, t, J = 7.5), 2.59 (2H, t, J = 6.0), 2.71-2.85 (1H, m), 3.17-3.32 (1H, m), 3.45-3.60 (4H, m), 3.69-3.88 (1H, m), 3.17-3.32 (1H, m), 3.45-3.60 (4H, m), 3.69-3.88 (1H, m), 4.09-4.26 (2H, m), 4.35 (1.4H, s), 4.39 (0.6H, s), 4.69-4.80 (1H, m), 5.03-5.09 (1H, m), 5.44 (2H, s), 6.76 (1H, brs), 6.85 (1H, s), 7.60 (1H, dd, J = 9.0, 1.8), 7.95 (3H, s), 7.96 (1H, d, J = 9.0), 8.51 (1H, s).
元素分析値 C₃₃H₃₀N₅O₈SCl・H₂Oとして
計算値（％）：C, 55.03； H, 5.88； N, 9.72
実測値（％）：C, 55.13； H, 6.01； N, 9.84 Example 199
3- (Hexanoylamino) propionic acid [2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -3-oxo -2,3-Dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl
199a) tert-Butyl 3- (hexanoylamino) propionate
The title compound (1.5 g, 86%) was obtained as a colorless oil from tert-butyl 3-aminopropionate dihydrochloride (1.82 g) and hexanoyl chloride (1.1 g) in the same manner as in Example 195a).
NMR (300MHz, CDCl ₃ ) δ: 0,89 (3H, t, J = 6.9), 1.23-1.35 (4H, m), 1.45 (9H, s), 1.56-1.66 (2H, m), 2.15 (2H , t, J = 7.8), 2.44 (2H, t, J = 6.3), 3.47 (2H, dt, J = 6.3, 6.3), 6.07 (1H, brs).
199b) 4- [5-({[3- (Hexanoylamino) propionyl] oxy} methyl) -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1 Tert-butyl carboxylate tert-butyl 3- (hexanoylamino) propionate obtained in Example 199a) (0.60 g) and 4- [5- (hydroxymethyl) -3 obtained in Example 185c) -Oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1-carboxylate from tert-butyl (0.61 g) to Example 195b) in the same manner as the title compound (0.80 g , 64%) was obtained as a white powder.
NMR (300MHz, CDCl ₃ ) δ: 0.86 (3H, t, J = 6.9), 1.23-1.29 (4H, m), 1.45 (9H, s), 1.57-1.68 (4H, m), 1.84 (2H, d , J = 12.0), 2.15 (2H, t, J = 7.5), 2.56 (2H, t, J = 8.4), 2.80 (2H, t, J = 13.5), 3.51-3.59 (2H, m), 4.01- 4.14 (1H, m), 4.25 (2H, d, J = 10.5), 4.34 (2H, s), 5.41 (2H, s), 6.82 (1H, s).
199c) 3- (Hexanoylamino) propionic acid [2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -3 4-Oxo-2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl 4- [5-({[3- (hexanoylamino) propionyl] obtained in Example 199b) ] Oxy} methyl) -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1-carboxylate from tert-butyl (0.40 g) as in Example 194b) The title compound (0.15, 21%) was obtained as a white powder.
NMR (300MHz, CDCl ₃ ) δ: 0.89 (3H, t, J = 6.9), 1.26-1.35 (4H, m), 1.57-1.67 (2H, m), 1.70-1.87 (2H, m), 1.96-2.07 (2H, m), 2.17 (2H, t, J = 7.5), 2.59 (2H, t, J = 6.0), 2.71-2.85 (1H, m), 3.17-3.32 (1H, m), 3.45-3.60 ( 4H, m), 3.69-3.88 (1H, m), 3.17-3.32 (1H, m), 3.45-3.60 (4H, m), 3.69-3.88 (1H, m), 4.09-4.26 (2H, m), 4.35 (1.4H, s), 4.39 (0.6H, s), 4.69-4.80 (1H, m), 5.03-5.09 (1H, m), 5.44 (2H, s), 6.76 (1H, brs), 6.85 ( 1H, s), 7.60 (1H, dd, J = 9.0, 1.8), 7.95 (3H, s), 7.96 (1H, d, J = 9.0), 8.51 (1H, s).
Elemental Analysis Value Calculated as C ₃₃ H ₃₀ N ₅ O ₈ SCl · H ₂ O (%): C, 55.03; H, 5.88; N, 9.72
Found (%): C, 55.13; H, 6.01; N, 9.84

実施例200
3-(N-エチル-N-プロピオニルアミノ)プロピオン酸[2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル
200a) 3-(エチルアミノ)プロピオン酸tert-ブチル
アクリル酸 tert-ブチル(5.0g)のTHF(30mL)溶液にエチルアミンの2.0MTHF溶液(30mL)を加え、室温で3日間かき混ぜた。反応液を減圧濃縮し、残留物を塩基性シリカゲルカラム（ヘキサン-酢酸エチル＝19/1から1/4）により精製して、題記化合物(4.9g, 73%)を無色油状物として得た。
NMR (300MHz, CDCl₃)δ: 1.11 (3H, t, J = 6.9), 1.45 (9H, s), 2.44 (2H, t, J = 6.6), 2.66 (2H, q, J = 6.9), 2.84 (2H, t, J = 6.6).
200b) 3-(N-エチル-N-プロピオニルアミノ)プロピオン酸tert-ブチル
実施例200a)で得られた3-(エチルアミノ)プロピオン酸tert-ブチル(1.0g）と塩化プロパノイル(0.67g)から実施例195a)と同様にして、題記化合物(1.2g, 91%)を淡黄色油状物として得た。
NMR (300MHz, CDCl₃)δ: 1.15 (3H, t, J = 7.5), 1.17 (3H, t, J = 7.5), 1.44 (5.5H, s), 1.45 (3.5H, s), 2.32 (1.2H, q, J = 7.5), 2.36 (0.8H, q, J = 7.5), 2.46-2.54 (2H, m), 3.31-3.41 (2H, m), 3.55 (2H, t, J = 7.5).
200c) 4-[5-({[3-(N-エチル-N-プロピオニルアミノ)プロピオニル]オキシ}メチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル
実施例200b)で得られた3-(N-エチル-N-プロピオニルアミノ)プロピオン酸tert-ブチル(0.40g)と実施例185c)で得られた4-[5-(ヒドロキシメチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル(0.50g)から実施例195b)と同様にして、題記化合物(0.51g, 70%）を白色粉末として得た。
NMR (300MHz, CDCl₃)δ: 1.07-1.20 (6H, m), 1.47 (9H, s), 1.59-1.72 (2H, m), 1.87 (2H, d, J = 11.4), 2.28-2.37 (2H, m), 2.60-2.69 (2H, m), 2.83 (2H, t, J = 12.0), 3.36 (2H, t, J = 7.2, 7.2), 3.56-3.63 (2H, m), 4.04-4.15 (1H, m), 4.27 (2H, d, J = 12.6), 4.36-4.39 (2H, m), 5.36 (1.2H, s), 5.40 (0.8H, s), 6.85 (0.6H, s), 6.87 (0.4H, s).
200d) 3-(N-エチル-N-プロピオニルアミノ)プロピオン酸[2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル
実施例200c)で得られた4-[5-({[3-(N-エチル-N-プロピオニルアミノ)プロピオニル]オキシ}メチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル(0.45g)から実施例194b)と同様にして、題記化合物(0.17g, 42%)を白色粉末として得た。
NMR (300MHz, CDCl₃)δ: 1.07-1.18 (6H, m), 1.66-1.90 (2H, m), 1.92-2.08 (2H, m), 2.28-2.36 (2H, m), 2.63-2.88 (3H, m), 3.25-3.30 (1H, m), 3.35 (2H, q, J = 7.2), 3.45-3.63 (4H, m), 3.74-3.94 (1H, m), 4.08-4.28 (2H, m), 4.33 (1.4H, s), 4.36 (0.6H, s), 4.65-4.83 (1H, m), 4.98-5.10 (1H, m), 5.37 (1.4H, s), 5.41 (0.6H, s), 6.87 (1H, s), 7.60 (1H, dd, J = 8.7, 1.4), 7.94 (3H, s), 7.95 (1H, d, J = 8.7), 8.51 (1H, s).
元素分析値 C₃₂H₃₈N₅O₈SCl・2H₂Oとして
計算値（％）：C, 53.07； H, 5.85； N, 9.67
実測値（％）：C, 53.37； H, 5.75； N, 9.68 Example 200
3- (N-ethyl-N-propionylamino) propionic acid [2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl ) -3-Oxo-2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl
200a) tert-Butyl 3- (ethylamino) propionate To a solution of tert-butyl acrylate (5.0 g) in THF (30 mL) was added a 2.0 MTHF solution (30 mL) of ethylamine, and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by basic silica gel column (hexane-ethyl acetate = 19/1 to 1/4) to give the title compound (4.9 g, 73%) as a colorless oil.
NMR (300MHz, CDCl ₃ ) δ: 1.11 (3H, t, J = 6.9), 1.45 (9H, s), 2.44 (2H, t, J = 6.6), 2.66 (2H, q, J = 6.9), 2.84 (2H, t, J = 6.6).
200b) tert-butyl 3- (N-ethyl-N-propionylamino) propionate From tert-butyl 3- (ethylamino) propionate (1.0 g) obtained in Example 200a) and propanoyl chloride (0.67 g) In the same manner as in Example 195a), the title compound (1.2 g, 91%) was obtained as a pale yellow oil.
NMR (300MHz, CDCl ₃ ) δ: 1.15 (3H, t, J = 7.5), 1.17 (3H, t, J = 7.5), 1.44 (5.5H, s), 1.45 (3.5H, s), 2.32 (1.2 H, q, J = 7.5), 2.36 (0.8H, q, J = 7.5), 2.46-2.54 (2H, m), 3.31-3.41 (2H, m), 3.55 (2H, t, J = 7.5).
200c) 4- [5-({[3- (N-ethyl-N-propionylamino) propionyl] oxy} methyl) -3-oxo-1H-imidazo [1,5-c] imidazole-2 (3H)- Yl] piperidine-1-carboxylate tert-butyl 3- (N-ethyl-N-propionylamino) propionate tert-butyl (0.40 g) obtained in Example 200b) and 4 obtained in Example 185c) Example 195b) from tert-butyl (0.50 g)-[5- (hydroxymethyl) -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1-carboxylate In the same manner as the above, the title compound (0.51 g, 70%) was obtained as a white powder.
NMR (300MHz, CDCl ₃ ) δ: 1.07-1.20 (6H, m), 1.47 (9H, s), 1.59-1.72 (2H, m), 1.87 (2H, d, J = 11.4), 2.28-2.37 (2H , m), 2.60-2.69 (2H, m), 2.83 (2H, t, J = 12.0), 3.36 (2H, t, J = 7.2, 7.2), 3.56-3.63 (2H, m), 4.04-4.15 ( 1H, m), 4.27 (2H, d, J = 12.6), 4.36-4.39 (2H, m), 5.36 (1.2H, s), 5.40 (0.8H, s), 6.85 (0.6H, s), 6.87 (0.4H, s).
200d) 3- (N-ethyl-N-propionylamino) propionic acid [2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4 4-piperidinyl) -3-oxo-2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl 4- [5-({[3- ( N-ethyl-N-propionylamino) propionyl] oxy} methyl) -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1-carboxylate tert-butyl (0.45 The title compound (0.17 g, 42%) was obtained as a white powder in the same manner as in Example 194b) from g).
NMR (300MHz, CDCl ₃ ) δ: 1.07-1.18 (6H, m), 1.66-1.90 (2H, m), 1.92-2.08 (2H, m), 2.28-2.36 (2H, m), 2.63-2.88 (3H , m), 3.25-3.30 (1H, m), 3.35 (2H, q, J = 7.2), 3.45-3.63 (4H, m), 3.74-3.94 (1H, m), 4.08-4.28 (2H, m) , 4.33 (1.4H, s), 4.36 (0.6H, s), 4.65-4.83 (1H, m), 4.98-5.10 (1H, m), 5.37 (1.4H, s), 5.41 (0.6H, s) , 6.87 (1H, s), 7.60 (1H, dd, J = 8.7, 1.4), 7.94 (3H, s), 7.95 (1H, d, J = 8.7), 8.51 (1H, s).
Elemental analysis value Calculated as C ₃₂ H ₃₈ N ₅ O ₈ SCl · 2H ₂ O (%): C, 53.07; H, 5.85; N, 9.67
Found (%): C, 53.37; H, 5.75; N, 9.68

実施例201
3-(N-ブチリル-N-エチルアミノ)プロピオン酸[2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル
201a) 3-(N-ブチリル-N-エチルアミノ)プロピオン酸tert-ブチル
実施例200a)で得られた3-(エチルアミノ)プロピオン酸tert-ブチル(1.0g)と塩化ブタノイル(0.88g)から実施例195a)と同様にして、題記化合物(1.3g, 97%)を淡黄色油状物として得た。
NMR (300MHz, CDCl₃)δ: 0.93-1.02 (3H, m), 1.11 (1.2H, t, J = 7.2), 1.17 (1.8H, t, J = 7.2), 1.44 (6H, s), 1.46 (3H, s), 1.63-1.74 (2H, m), 2.25-2.33 (2H, m), 2.41-2.54 (2H, m), 3.32-3.41 (2H, m), 3.54 (2H, t, J = 6.9).
201b) 4-[5-({[3-(N-ブチリル-N-エチルアミノ)プロピオニル]オキシ}メチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル
実施例201a)で得られた3-(N-ブチリル-N-エチルアミノ)プロピオン酸tert-ブチル(0.40g)と実施例185c)で得られた4-[5-(ヒドロキシメチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル(0.50g)から実施例195b）と同様にして、題記化合物を白色粉末(0.54g, 73%)として得た。
NMR (300MHz, CDCl₃)δ: 0.94 (3H, t, J = 7.5), 1.09 (1.2H, t, J = 6.9), 1.18 (1.8H, t, J = 6.9), 1.47 (9H, s), 1.58-1.71 (4H, m), 1.87 (2H, d. J = 10.8), 2.24-2.30 (2H, m), 2.61-2.69 (2H, m), 2.83 (2H, t, J = 12.6), 3.31-3.40 (2H, m), 3.56-3.63 (2H, m), 4.05-4.13 (1H, m), 4.27 (2H, d, J = 10.8), 4.34-4.39 (2H, m), 5.36 (1.2H, s), 5.40 (0.8H, s), 6.85 (0.6H, s), 6.87 (0.4H, s).
201c) 3-(N-ブチリル-N-エチルアミノ)プロピオン酸[2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル
実施例201b)で得られた4-[5-({[3-(N-ブチリル-N-エチルアミノ)プロピオニル]オキシ}メチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル(0.54g)から実施例194b)と同様にして、題記化合物(0.18g, 25%)を白色粉末として得た。
NMR (300MHz, CDCl₃)δ: 0.94 (3H, t, J =7.2), 1.90-2.09 (2H, m), 2.24-2.30 (2H, m), 2.61-2.88 (3H, m), 3.15-3.40 (2H, m), 3.44-3.64 (4H, m), 3.72-3.91 (1H, m), 4.10-4.27 (2H, m), 4.30-4.38 (2H, m), 4.68-4.83 (1H, m), 4.98-5.13 (1H, m), 5.37 (1.4H, s), 5.41 (0.6H, s), 6.87 (1H, s), 7.60 (1H, dd, J = 8.7 and 2.1), 7.95 (3H, s), 7.96 (1H, d, J = 8.7), 8.51 (1H, s).
元素分析値 C₃₃H₄₀N₅O₈SCl・H₂Oとして
計算値（％）：C, 55.03； H, 5.88； N, 9.72
実測値（％）：C, 54.95； H, 6.06； N, 9.73 Example 201
3- (N-butyryl-N-ethylamino) propionic acid [2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl ) -3-Oxo-2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl
201a) tert-butyl 3- (N-butyryl-N-ethylamino) propionate
The title compound (1.3 g, 97%) was obtained in the same manner as in Example 195a) from tert-butyl 3- (ethylamino) propionate (1.0 g) obtained in Example 200a) and butanoyl chloride (0.88 g). Obtained as a pale yellow oil.
NMR (300MHz, CDCl ₃ ) δ: 0.93-1.02 (3H, m), 1.11 (1.2H, t, J = 7.2), 1.17 (1.8H, t, J = 7.2), 1.44 (6H, s), 1.46 (3H, s), 1.63-1.74 (2H, m), 2.25-2.33 (2H, m), 2.41-2.54 (2H, m), 3.32-3.41 (2H, m), 3.54 (2H, t, J = 6.9).
201b) 4- [5-({[3- (N-butyryl-N-ethylamino) propionyl] oxy} methyl) -3-oxo-1H-imidazo [1,5-c] imidazole-2 (3H)- Yl] piperidine-1-carboxylate tert-butyl 3- (N-butyryl-N-ethylamino) propionate tert-butyl (0.40 g) obtained in Example 201a) and 4 obtained in Example 185c) Example 195b) from tert-butyl (0.50 g)-[5- (hydroxymethyl) -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1-carboxylate In the same manner as the above, the title compound was obtained as a white powder (0.54 g, 73%).
NMR (300MHz, CDCl ₃ ) δ: 0.94 (3H, t, J = 7.5), 1.09 (1.2H, t, J = 6.9), 1.18 (1.8H, t, J = 6.9), 1.47 (9H, s) , 1.58-1.71 (4H, m), 1.87 (2H, d. J = 10.8), 2.24-2.30 (2H, m), 2.61-2.69 (2H, m), 2.83 (2H, t, J = 12.6), 3.31-3.40 (2H, m), 3.56-3.63 (2H, m), 4.05-4.13 (1H, m), 4.27 (2H, d, J = 10.8), 4.34-4.39 (2H, m), 5.36 (1.2 H, s), 5.40 (0.8H, s), 6.85 (0.6H, s), 6.87 (0.4H, s).
201c) 3- (N-butyryl-N-ethylamino) propionic acid [2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4 4-piperidinyl) -3-oxo-2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl 4- [5-({[3- ( N-butyryl-N-ethylamino) propionyl] oxy} methyl) -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1-carboxylate tert-butyl (0.54 The title compound (0.18 g, 25%) was obtained as a white powder in the same manner as in Example 194b) from g).
NMR (300MHz, CDCl ₃ ) δ: 0.94 (3H, t, J = 7.2), 1.90-2.09 (2H, m), 2.24-2.30 (2H, m), 2.61-2.88 (3H, m), 3.15-3.40 (2H, m), 3.44-3.64 (4H, m), 3.72-3.91 (1H, m), 4.10-4.27 (2H, m), 4.30-4.38 (2H, m), 4.68-4.83 (1H, m) , 4.98-5.13 (1H, m), 5.37 (1.4H, s), 5.41 (0.6H, s), 6.87 (1H, s), 7.60 (1H, dd, J = 8.7 and 2.1), 7.95 (3H, s), 7.96 (1H, d, J = 8.7), 8.51 (1H, s).
Elemental analysis value Calculated as C ₃₃ H ₄₀ N ₅ O ₈ SCl · H ₂ O (%): C, 55.03; H, 5.88; N, 9.72
Found (%): C, 54.95; H, 6.06; N, 9.73

実施例202
3-(N-アセチル-N-メチルアミノ)プロピオン酸[2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル
202a) 3-(メチルアミノ)プロピオン酸tert-ブチル
アクリル酸 tert-ブチル(5.0g)とメチルアミン(30mL)から実施例200a)と同様にして、題記化合物(3.1g, 49%)を無色油状物として得た。
NMR (300MHz, CDCl₃)δ: 1.43 (9H, s), 2.40 (3H, s), 2.40 (2H, t, J = 8.4), 2.78 (2H, t, J = 8.4).
202b) 3-(N-アセチル-N-メチルアミノ)プロピオン酸tert-ブチル
実施例202a)で得られた3-(メチルアミノ)プロピオン酸tert-ブチル(0.90g)と塩化アセチル(0.50g)から実施例195a)と同様にして、題記化合物(1.0g, 89%)を淡黄色状物として得た。
NMR (300MHz, CDCl₃)δ: 1.45 (6H, s), 1.46 (3H, s), 2.07 (2H, s), 2.14 (1H, s), 2.49 (2H, t, J = 6.9), 2.91 (1.2H, s), 3.03 (1.8H, s), 3.56-3.62 (2H, m).
202c) 4-[5-({[3-(N-アセチル-N-メチルアミノ)プロピオニル]オキシ}メチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル
実施例202b)で得られた3-(N-アセチル-N-メチルアミノ)プロピオン酸tert-ブチル(0.40g)と実施例185c)で得られた4-[5-(ヒドロキシメチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル(0.50g)から実施例195b)と同様にして題記化合物(0.40g, 59%)を白色粉末として得た。
NMR (300MHz, CDCl₃)δ: 1.45 (9H, s), 1.56-1.73 (2H, m), 1.85 (2H, d, J = 12.0), 2.03 (2H, s), 2.07 (1H, s), 2.55-2.68 (2H, m), 2.80 (1H, s), 2.86 (2H, s), 2.98-3.05 (2H, m), 3.55-3.69 (2H, m), 3.98-4.17 (1H, m), 4.18-4.32 (2H, m), 4.33 (2H, s), 5.37 (2H, s), 6.85 (1H, s).
202d) 3-(N-アセチル-N-メチルアミノ)プロピオン酸[2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル
実施例202c)で得られた4-[5-({[3-(N-アセチル-N-メチルアミノ)プロピオニル]オキシ}メチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル(0.35g)から実施例194b)と同様にして、題記化合物(5mg, 1%)を白色粉末で得た。
NMR (300MHz, CDCl₃)δ: 1.60-1.88 (2H, m), 1.92-2.10 (5H, m), 2.65 (2H, t, J = 6.9), 2.70-2.84 (1H, m), 2.88 (1H, s), 3.05 (1H, s), 3.14-3.34 (1H, m), 3.44-3.55 (2H, m), 3.64 (2H, t, J = 7.2), 3.74-3.98 (1H, m), 4.08-4.28 (2H, m), 4.30-4.43 (2H, m), 4.66-4.83 (1H, m), 5.00-5.10 (1H, m), 5.38 (1.4H, s), 5.41 (0.6H, s), 6.87 (1H, s), 7.60 (1H, dd, J = 9.0, 1.8), 7.95 (3H, s), 7.96 (1H, d, J = 9.0), 8.51 (1H, s). Example 202
3- (N-acetyl-N-methylamino) propionic acid [2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl ) -3-Oxo-2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl
202a) tert-butyl 3- (methylamino) propionate tert-butyl acrylate (5.0 g) and methylamine (30 mL) were used in the same manner as in Example 200a) to give the title compound (3.1 g, 49%) as a colorless oil Obtained as a thing.
NMR (300MHz, CDCl ₃ ) δ: 1.43 (9H, s), 2.40 (3H, s), 2.40 (2H, t, J = 8.4), 2.78 (2H, t, J = 8.4).
202b) tert-butyl 3- (N-acetyl-N-methylamino) propionate From tert-butyl 3- (methylamino) propionate (0.90 g) obtained in Example 202a) and acetyl chloride (0.50 g) In the same manner as in Example 195a), the title compound (1.0 g, 89%) was obtained as a pale yellow product.
NMR (300MHz, CDCl ₃ ) δ: 1.45 (6H, s), 1.46 (3H, s), 2.07 (2H, s), 2.14 (1H, s), 2.49 (2H, t, J = 6.9), 2.91 ( 1.2H, s), 3.03 (1.8H, s), 3.56-3.62 (2H, m).
202c) 4- [5-({[3- (N-acetyl-N-methylamino) propionyl] oxy} methyl) -3-oxo-1H-imidazo [1,5-c] imidazole-2 (3H)- Yl] piperidine-1-carboxylate tert-butyl 3- (N-acetyl-N-methylamino) propionate tert-butyl (0.40 g) obtained in Example 202b) and 4 obtained in Example 185c) Example 195b) from tert-butyl (0.50 g)-[5- (hydroxymethyl) -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1-carboxylate In the same manner as the title compound (0.40 g, 59%) was obtained as a white powder.
NMR (300MHz, CDCl ₃ ) δ: 1.45 (9H, s), 1.56-1.73 (2H, m), 1.85 (2H, d, J = 12.0), 2.03 (2H, s), 2.07 (1H, s), 2.55-2.68 (2H, m), 2.80 (1H, s), 2.86 (2H, s), 2.98-3.05 (2H, m), 3.55-3.69 (2H, m), 3.98-4.17 (1H, m), 4.18-4.32 (2H, m), 4.33 (2H, s), 5.37 (2H, s), 6.85 (1H, s).
202d) 3- (N-acetyl-N-methylamino) propionic acid [2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4 4-piperidinyl) -3-oxo-2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl 4- [5-({[3- ( N-acetyl-N-methylamino) propionyl] oxy} methyl) -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1-carboxylate tert-butyl (0.35 The title compound (5 mg, 1%) was obtained as a white powder in the same manner as in Example 194b) from g).
NMR (300MHz, CDCl ₃ ) δ: 1.60-1.88 (2H, m), 1.92-2.10 (5H, m), 2.65 (2H, t, J = 6.9), 2.70-2.84 (1H, m), 2.88 (1H , s), 3.05 (1H, s), 3.14-3.34 (1H, m), 3.44-3.55 (2H, m), 3.64 (2H, t, J = 7.2), 3.74-3.98 (1H, m), 4.08 -4.28 (2H, m), 4.30-4.43 (2H, m), 4.66-4.83 (1H, m), 5.00-5.10 (1H, m), 5.38 (1.4H, s), 5.41 (0.6H, s) , 6.87 (1H, s), 7.60 (1H, dd, J = 9.0, 1.8), 7.95 (3H, s), 7.96 (1H, d, J = 9.0), 8.51 (1H, s).

実施例203
3-(N-アセチル-N-エチルアミノ)プロピオン酸[2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル
203a) 3-(N-アセチル-N-エチルアミノ)プロピオン酸tert-ブチル
実施例200a)で得られた3-(エチルアミノ)プロピオン酸tert-ブチル(1.0g)と塩化アセチル(0.50g)から実施例195a)と同様にして、題記化合物(1.1g, 90%)を淡黄色油状物として得た。
NMR (300MHz, CDCl₃)δ: 1.12 (1.4H, t, J = 7.2), 1.18 (1.6H, t, J = 7.2), 1.44 (5H, s), 1.46 (4H, s), 2.08 (1.8H, s), 2.12 (1.2H, s), 2.50 (2H, q, J = 7.2), 3.37 (2H, quintet, J = 7.2), 3.55 (2H, t, J = 7.2).
203b) 4-[5-({[3-(N-アセチル-N-エチルアミノ)プロピオニル]オキシ}メチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル
実施例203a)で得られた3-(N-アセチル-N-エチルアミノ)プロピオン酸tert-ブチル(0.40g)と実施例185c)で得られた4-[5-(ヒドロキシメチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル(0.50g)から実施例195b)と同様にして、題記化合物(0.27g, 40%)を白色粉末として得た。
NMR (300MHz, CDCl₃)δ: 1.10 (1H, t, J = 7.2), 1.17 (2H, t, J = 7.2), 1.48 (9H, s), 1.55-1.72 (2H, m), 1.83-1.93 (2H, m), 2.07 (2H, s), 2.08 (1H, s), 2.61-2.70 (2H, m), 2.83 (2H, t, J = 12.3), 3.31-3.40 (2H, m), 3.56-3.64 (2H, m), 4.05 4.16 (1H, m), 4.21-4.33 (2H, m), 4.35 (2H, s), 5.37 (1.3H, s), 5.41 (0.7H, s), 6.87 (0.6H, s), 6.88 (0.4H, s).
203c) 3-(N-アセチル-N-エチルアミノ)プロピオン酸[2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル
実施例203b)で得られた4-[5-({[3-(N-アセチル-N-エチルアミノ)プロピオニル]オキシ}メチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル(0.27g)から実施例194b)と同様にして、題記化合物(35mg, 9%)を白色粉末として得た。
NMR (300MHz, CDCl₃)δ: 1.09 (1H, t, J = 7.2), 1.17 (2H, t, J = 7.2), 1.60-1.86 (2H, m), 1.90-2.06 (2H, m), 2.07 (2H, s), 2.08 (1H, s), 2.61-2.85 (3H, m), 3.17-3.40 (3H, m), 3.45-3.65 (4H, m), 3.80-4.01 (1H, m), 4.09-4.27 (2H, m), 4.30-4.40 (2H, m), 4.98-5.10 (1H, m), 4.65-4.80 (1H, m), 5.37 (1.4H, s), 5.41 (0.6H, s), 6.87 (1H, s), 7.60 (1H, dd, J = 9.0, 2.1), 7.94 (3H, s), 7.96 (1H, d, J = 9.0), 8.51 (1H, s).
元素分析値 C₃₁H₃₆N₅O₈SCl・2.5H₂Oとして
計算値（％）：C, 51.77； H, 5.75； N, 9.74
実測値（％）：C, 51.55； H, 5.58； N, 9.72 Example 203
3- (N-acetyl-N-ethylamino) propionic acid [2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl ) -3-Oxo-2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl
203a) tert-Butyl 3- (N-acetyl-N-ethylamino) propionate
The title compound (1.1 g, 90%) was obtained from tert-butyl 3- (ethylamino) propionate obtained in Example 200a) and acetyl chloride (0.50 g) in the same manner as in Example 195a). Obtained as a pale yellow oil.
NMR (300MHz, CDCl ₃ ) δ: 1.12 (1.4H, t, J = 7.2), 1.18 (1.6H, t, J = 7.2), 1.44 (5H, s), 1.46 (4H, s), 2.08 (1.8 H, s), 2.12 (1.2H, s), 2.50 (2H, q, J = 7.2), 3.37 (2H, quintet, J = 7.2), 3.55 (2H, t, J = 7.2).
203b) 4- [5-({[3- (N-acetyl-N-ethylamino) propionyl] oxy} methyl) -3-oxo-1H-imidazo [1,5-c] imidazole-2 (3H)- Yl] piperidine-1-carboxylate tert-butyl 3- (N-acetyl-N-ethylamino) propionate tert-butyl obtained in Example 203a) and 4 obtained in Example 185c) Example 195b) from tert-butyl (0.50 g)-[5- (hydroxymethyl) -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1-carboxylate The title compound (0.27 g, 40%) was obtained as a white powder in the same manner as described above.
NMR (300MHz, CDCl ₃ ) δ: 1.10 (1H, t, J = 7.2), 1.17 (2H, t, J = 7.2), 1.48 (9H, s), 1.55-1.72 (2H, m), 1.83-1.93 (2H, m), 2.07 (2H, s), 2.08 (1H, s), 2.61-2.70 (2H, m), 2.83 (2H, t, J = 12.3), 3.31-3.40 (2H, m), 3.56 -3.64 (2H, m), 4.05 4.16 (1H, m), 4.21-4.33 (2H, m), 4.35 (2H, s), 5.37 (1.3H, s), 5.41 (0.7H, s), 6.87 ( 0.6H, s), 6.88 (0.4H, s).
203c) 3- (N-acetyl-N-ethylamino) propionic acid [2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4 4-piperidinyl) -3-oxo-2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl 4- [5-({[3- ( N-acetyl-N-ethylamino) propionyl] oxy} methyl) -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1-carboxylate tert-butyl (0.27 The title compound (35 mg, 9%) was obtained as a white powder in the same manner as in Example 194b) from g).
NMR (300MHz, CDCl ₃ ) δ: 1.09 (1H, t, J = 7.2), 1.17 (2H, t, J = 7.2), 1.60-1.86 (2H, m), 1.90-2.06 (2H, m), 2.07 (2H, s), 2.08 (1H, s), 2.61-2.85 (3H, m), 3.17-3.40 (3H, m), 3.45-3.65 (4H, m), 3.80-4.01 (1H, m), 4.09 -4.27 (2H, m), 4.30-4.40 (2H, m), 4.98-5.10 (1H, m), 4.65-4.80 (1H, m), 5.37 (1.4H, s), 5.41 (0.6H, s) , 6.87 (1H, s), 7.60 (1H, dd, J = 9.0, 2.1), 7.94 (3H, s), 7.96 (1H, d, J = 9.0), 8.51 (1H, s).
Elemental Analysis Value Calculated as C ₃₁ H ₃₆ N ₅ O ₈ SCl · 2.5H ₂ O (%): C, 51.77; H, 5.75; N, 9.74
Found (%): C, 51.55; H, 5.58; N, 9.72

実施例204
3-(N-ブチリル-N-メチルアミノ)プロピオン酸[2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル
204a) 3-(N-ブチリル-N-メチルアミノ)プロピオン酸tert-ブチル
実施例202a)で得られた3-(メチルアミノ)プロピオン酸tert-ブチル(0.90g)と塩化ブタノイル(0.67g)から実施例195a)と同様にして、題記化合物(1.2g, 93%)を淡黄色状物として得た。
NMR (300MHz, CDCl₃)δ: 0.96 (3H, t, J =7.2), 1.44 (6H, s), 1.46 (3H, s), 1.62-1.74 (2H, m), 2.27 (1.2H, t, J = 7.5), 2.34 (0.8H, t, J = 7.5), 2.49 (2H, t, J = 7.2), 2.92 (1.2H, s), 3.02 (1.8H, s), 3.56-3.63 (2H, m).
204b) 4-[5-({[3-(N-ブチリル-N-メチルアミノ)プロピオニル]オキシ}メチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル
実施例204a)で得られた3-(N-ブチリル-N-メチルアミノ)プロピオン酸tert-ブチル(0.50g)と実施例185c)で得られた4-[5-(ヒドロキシメチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル(0.54g)から実施例195b)と同様にして、題記化合物(0.30g, 38%)を白色粉末として得た。
NMR (300MHz, CDCl₃)δ: 0.94 (3H, t, J = 7.4), 1.47 (9H, s), 1.54-1.78 (4H, m), 1.80-1.91 (2H, m), 2.21-2.30 (2H, m), 2.56-2.68 (2H, m), 2.70-2.90 (2H, m), 2.89 (1H, s), 3.03 (2H, s), 3.56-3.69 (2H, m), 4.00-4.18 (1H, m), 4.19-4.35 (2H, m), 4.33 (2H, s), 5.37 (1.4H, s), 5.40 (0.6H, s), 6.85 (1H, s).
204c) 3-(N-ブチリル-N-メチルアミノ)プロピオン酸[2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル
実施例204b)で得られた4-[5-({[3-(N-ブチリル-N-メチルアミノ)プロピオニル]オキシ}メチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル(0.30g)から実施例194b)と同様にして、題記化合物(55mg, 8%)を白色粉末として得た。
NMR (300MHz, CDCl₃)δ: 0.94 (3H, t, J = 6.9), 1.56-1.89 (4H, m), 1.92-2.10 (2H, m), 2.22-2.29 (2H, m), 2.64 (2H, t, J = 6.9), 2.68-2.82 (1H, m), 2.89 (1H, s), 3.03 (2H, s), 3.12-3.26 (1H, m), 3.45-3.55 (2H, m), 3.64 (2H, t, J = 6.9 ), 4.10-4.23 (2H, m), 4.32-4.40 (2H, m), 4.65-4.80 (1H, m), 5.01-5.08 (1H, m), 5.37 (1.4H, s), 5.40 (0.6H, s), 6.87 (1H, s), 7.59 (1H, dd, J = 9.0, 2.1), 7.94 (3H, s), 7.96 (1H, d, J = 9.0), 8.51 (1H, s).
元素分析値 C₃₂H₃₈N₅O₈SCl・H₂Oとして
計算値（％）：C, 54.42； H, 5.71； N, 9.92
実測値（％）：C, 54.61； H, 5.71； N, 9.69 Example 204
3- (N-butyryl-N-methylamino) propionic acid [2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl ) -3-Oxo-2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl
204a) tert-butyl 3- (N-butyryl-N-methylamino) propionate From tert-butyl 3- (methylamino) propionate (0.90 g) obtained in Example 202a) and butanoyl chloride (0.67 g) In the same manner as in Example 195a), the title compound (1.2 g, 93%) was obtained as a pale yellow product.
NMR (300MHz, CDCl ₃ ) δ: 0.96 (3H, t, J = 7.2), 1.44 (6H, s), 1.46 (3H, s), 1.62-1.74 (2H, m), 2.27 (1.2H, t, J = 7.5), 2.34 (0.8H, t, J = 7.5), 2.49 (2H, t, J = 7.2), 2.92 (1.2H, s), 3.02 (1.8H, s), 3.56-3.63 (2H, m).
204b) 4- [5-({[3- (N-butyryl-N-methylamino) propionyl] oxy} methyl) -3-oxo-1H-imidazo [1,5-c] imidazole-2 (3H)- Yl] piperidine-1-carboxylate tert-butyl 3- (N-butyryl-N-methylamino) propionate tert-butyl (0.50 g) obtained in Example 204a) and 4 obtained in Example 185c) Example 195b) from tert-butyl (0.54 g)-[5- (hydroxymethyl) -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1-carboxylate In the same manner as the above, the title compound (0.30 g, 38%) was obtained as a white powder.
NMR (300MHz, CDCl ₃ ) δ: 0.94 (3H, t, J = 7.4), 1.47 (9H, s), 1.54-1.78 (4H, m), 1.80-1.91 (2H, m), 2.21-2.30 (2H , m), 2.56-2.68 (2H, m), 2.70-2.90 (2H, m), 2.89 (1H, s), 3.03 (2H, s), 3.56-3.69 (2H, m), 4.00-4.18 (1H , m), 4.19-4.35 (2H, m), 4.33 (2H, s), 5.37 (1.4H, s), 5.40 (0.6H, s), 6.85 (1H, s).
204c) 3- (N-butyryl-N-methylamino) propionic acid [2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4 4-piperidinyl) -3-oxo-2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl 4- [5-({[3- ( N-butyryl-N-methylamino) propionyl] oxy} methyl) -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1-carboxylate tert-butyl (0.30 The title compound (55 mg, 8%) was obtained as a white powder in the same manner as in Example 194b) from g).
NMR (300MHz, CDCl ₃ ) δ: 0.94 (3H, t, J = 6.9), 1.56-1.89 (4H, m), 1.92-2.10 (2H, m), 2.22-2.29 (2H, m), 2.64 (2H , t, J = 6.9), 2.68-2.82 (1H, m), 2.89 (1H, s), 3.03 (2H, s), 3.12-3.26 (1H, m), 3.45-3.55 (2H, m), 3.64 (2H, t, J = 6.9), 4.10-4.23 (2H, m), 4.32-4.40 (2H, m), 4.65-4.80 (1H, m), 5.01-5.08 (1H, m), 5.37 (1.4H , s), 5.40 (0.6H, s), 6.87 (1H, s), 7.59 (1H, dd, J = 9.0, 2.1), 7.94 (3H, s), 7.96 (1H, d, J = 9.0), 8.51 (1H, s).
Elemental analysis C ₃₂ H ₃₈ N ₅ O ₈ Calculated as SCl · H ₂ O (%): C, 54.42; H, 5.71; N, 9.92
Found (%): C, 54.61; H, 5.71; N, 9.69

実施例205
3-(N-ヘキサノイル-N-メチルアミノ)プロピオン酸[2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル
205a) 3-(N-ヘキサノイル-N-メチルアミノ)プロピオン酸tert-ブチル
実施例202a)で得られた3-(メチルアミノ)プロピオン酸tert-ブチル(0.90g)と塩化ヘキサノイル(0.85g)から実施例195a)と同様にして、題記化合物(1.2g, 83%)を淡黄色状物として得た。
NMR (300MHz, CDCl₃)δ: 0.90 (3H, t, J = 6.9), 1.31-1.39 (4H, m), 1.44 (6H, s), 1.45 (3H, s), 1.57-1.69 (2H, m), 2.30 (1.2H, t, J = 7.5), 2.35 (0.8H, t, J = 7.5), 2.48 (2H, t, J = 6.9), 2.91 (1.2H, s), 3.02 (1.8H, s), 3.56-3.62 (2H, m).
205b) 4-[5-({[3-(N-ヘキサノイル-N-メチルアミノ)プロピオニル]オキシ}メチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル
実施例205a)で得られた3-(N-ヘキサノイル-N-メチルアミノ)プロピオン酸tert-ブチル(0.50g)と実施例185c)で得られた4-[5-(ヒドロキシメチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル(0.54g)から実施例195b)と同様にして、題記化合物(0.31g, 37%)を白色粉末として得た。
NMR (200MHz, CDCl₃)δ: 0.87 (3H, t, J = 6.6), 1.26-1.35 (4H, m), 1.45 (9H, s), 1.51-1.72 (2H, m), 1.76-1.87 (2H, m), 2.24 (2H, t, J = 7.6), 2.61 (2H, t, J = 6.8), 2.80 (2H, t, J = 12.0), 3.61 (2H, t, J = 7.0), 3.99-4.15 (1H, m), 4.21-4.32 (2H, m), 4.32 (2H, s), 5.34 (1.4H, s), 5.38 (0.6H, s), 6.83 (1H, s).
205c) 3-(N-ヘキサノイル-N-メチルアミノ)プロピオン酸[2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル
実施例205b)で得られた4-[5-({[3-(N-ヘキサノイル-N-メチルアミノ)プロピオニル]オキシ}メチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル(0.30g)から実施例194b)と同様にして、題記化合物を得た。
LCMS（M+H⁺）716 Example 205
3- (N-Hexanoyl-N-methylamino) propionic acid [2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl ) -3-Oxo-2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl
205a) tert-butyl 3- (N-hexanoyl-N-methylamino) propionate From tert-butyl 3- (methylamino) propionate (0.90 g) obtained in Example 202a) and hexanoyl chloride (0.85 g) In the same manner as in Example 195a), the title compound (1.2 g, 83%) was obtained as a pale yellow product.
NMR (300MHz, CDCl ₃ ) δ: 0.90 (3H, t, J = 6.9), 1.31-1.39 (4H, m), 1.44 (6H, s), 1.45 (3H, s), 1.57-1.69 (2H, m ), 2.30 (1.2H, t, J = 7.5), 2.35 (0.8H, t, J = 7.5), 2.48 (2H, t, J = 6.9), 2.91 (1.2H, s), 3.02 (1.8H, s), 3.56-3.62 (2H, m).
205b) 4- [5-({[3- (N-hexanoyl-N-methylamino) propionyl] oxy} methyl) -3-oxo-1H-imidazo [1,5-c] imidazole-2 (3H)- Yl] piperidine-1-carboxylate tert-butyl 3- (N-hexanoyl-N-methylamino) propionate tert-butyl (0.50 g) obtained in Example 205a) and 4 obtained in Example 185c) Example 195b) from tert-butyl (0.54 g)-[5- (hydroxymethyl) -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1-carboxylate In the same manner as the above, the title compound (0.31 g, 37%) was obtained as a white powder.
NMR (200MHz, CDCl ₃ ) δ: 0.87 (3H, t, J = 6.6), 1.26-1.35 (4H, m), 1.45 (9H, s), 1.51-1.72 (2H, m), 1.76-1.87 (2H , m), 2.24 (2H, t, J = 7.6), 2.61 (2H, t, J = 6.8), 2.80 (2H, t, J = 12.0), 3.61 (2H, t, J = 7.0), 3.99- 4.15 (1H, m), 4.21-4.32 (2H, m), 4.32 (2H, s), 5.34 (1.4H, s), 5.38 (0.6H, s), 6.83 (1H, s).
205c) 3- (N-hexanoyl-N-methylamino) propionic acid [2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4 4-piperidinyl) -3-oxo-2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl 4- [5-({[3- ( N-hexanoyl-N-methylamino) propionyl] oxy} methyl) -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1-carboxylate tert-butyl (0.30 The title compound was obtained in the same manner as in Example 194b) from g).
LCMS (M + H ⁺ ) 716

実施例206
3-(N-アセチル-N-プロピルアミノ)プロピオン酸[2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル
206a) 3-(プロピルアミノ)プロピオン酸tert-ブチル
アクリル酸 tert-ブチル(5.0g)のTHF(40mL)溶液にプロピルアミン(2.8g)を加え、室温で24時間かき混ぜた。反応液を減圧濃縮し、残留物を塩基性シリカゲルカラム（へキサンからヘキサン-酢酸エチル＝3/2）により精製して、題記化合物(0.69g、10%)を無色油状物として得た。
NMR (300MHz, CDCl₃)δ: 0.92 (3H, t, J = 7.5), 1.45 (9H, s), 1.46-1.55 (2H, m), 2.43 (2H, t, J = 6.6), 2.58 (2H, t, J = 7.5), 2.83 (2H, t, J = 6.6).
206b) 3-(N-アセチル-N-プロピルアミノ)プロピオン酸tert-ブチル
実施例206a)で得られた3-(プロピルアミノ)プロピオン酸tert-ブチル(0.69g)と塩化アセチル(0.35g)から実施例195a)と同様にして、題記化合物(0.82g, 97%)を無色油状物として得た。
NMR (300MHz, CDCl₃)δ: 0.89 (1H, t, J = 7.5), 0.92 (2H, t, J = 7.5), 1.43 (6H, s), 1.46 (3H, s), 1.50-1.67 (2H, m), 2.07 (2H, s), 2.12 (1H, s), 2.48 (0.7H, t, J = 7.0), 2.52 (1.3H, t, J = 7.0), 3.20-3.31 (2H, m), 3.55 (2H, t, J = 7.0).
206c) 4-[5-({[3-(N-アセチル-N-プロピルアミノ)プロピオニル]オキシ}メチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル
実施例206b)で得られた3-(N-アセチル-N-プロピルアミノ)プロピオン酸tert-ブチル(0.60g)と実施例185c)で得られた4-[5-(ヒドロキシメチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル(0.54g)から実施例195b)と同様にして、題記化合物(0.66g, 84%)を白色粉末として得た。
NMR (300MHz, CDCl₃)δ: 0.87 (1H, t, J = 7.2), 0.91 (2H, t, J = 7.2), 1.48 (9H, s), 1.55-1.74 (4H, m), 1.86 (2H, d, J =12.0), 2.06 (2H, s), 2.09 (1H, s), 2.61-2.70 (2H, m), 2.75-2.88 (2H, m), 3.25 (2H, t, J = 7.8), 3.56-3.63 (2H, m), 4.04-4.15 (1H, m), 4.20-4.40 (4H, m), 5.37 (1.4H, s), 5.41 (0.6H, s), 6.86 (1H, s).
206d) 3-(N-アセチル-N-プロピルアミノ)プロピオン酸[2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロピオニル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル
実施例206c)で得られた4-[5-({[3-(N-アセチル-N-プロピルアミノ)プロピオニル]オキシ}メチル)-3-オキソ-1H-イミダゾ[1,5-c]イミダゾール-2(3H)-イル]ピペリジン-1-カルボン酸 tert-ブチル(0.50g)から実施例194b)と同様にして、題記化合物(0.27g, 39%)を白色粉末として得た。
NMR (300MHz, CDCl₃)δ: 0.82 (1H, t, J = 7.5), 0.92 (2H, t, J = 7.5), 1.49-1.90 (4H, m), 1.91-2.05 (2H, m), 2.06 (2H, s), 2.08 (1H, s), 2.61-2.85 (3h, m), 3.17-3.31 (3H, m), 3.45-3.63 (4H, m), 3.79-3.98 (1H, m), 4.08-4.26 (2H, m), 4.30-4.38 (2H, m), 4.73 (1H, t, J = 13.5), 5.01-5.09 (1H, m), 5.37 (0.3H, s), 5.41 (0.7H, s), 6.87 (1H, s), 7.60 (1H, dd, J = 9.0, 2.1), 7.95 (3H, s), 7.96 (1H, d, J = 9.0), 8.51 (1H, s).
元素分析値 C₃₂H₃₈N₅O₈SCl・H₂Oとして
計算値（％）：C, 54.42； H, 5.71； N, 9.92
実測値（％）：C, 54.63； H, 5.87； N, 9.89 Example 206
3- (N-acetyl-N-propylamino) propionic acid [2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl ) -3-Oxo-2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl
206a) Tert-butyl 3- (propylamino) propionate To a solution of tert-butyl acrylate (5.0 g) in THF (40 mL) was added propylamine (2.8 g), and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by basic silica gel column (hexane to hexane-ethyl acetate = 3/2) to give the title compound (0.69 g, 10%) as a colorless oil.
NMR (300MHz, CDCl ₃ ) δ: 0.92 (3H, t, J = 7.5), 1.45 (9H, s), 1.46-1.55 (2H, m), 2.43 (2H, t, J = 6.6), 2.58 (2H , t, J = 7.5), 2.83 (2H, t, J = 6.6).
206b) tert-butyl 3- (N-acetyl-N-propylamino) propionate From tert-butyl 3- (propylamino) propionate (0.69 g) obtained in Example 206a) and acetyl chloride (0.35 g) In the same manner as in Example 195a), the title compound (0.82 g, 97%) was obtained as a colorless oil.
NMR (300MHz, CDCl ₃ ) δ: 0.89 (1H, t, J = 7.5), 0.92 (2H, t, J = 7.5), 1.43 (6H, s), 1.46 (3H, s), 1.50-1.67 (2H , m), 2.07 (2H, s), 2.12 (1H, s), 2.48 (0.7H, t, J = 7.0), 2.52 (1.3H, t, J = 7.0), 3.20-3.31 (2H, m) , 3.55 (2H, t, J = 7.0).
206c) 4- [5-({[3- (N-acetyl-N-propylamino) propionyl] oxy} methyl) -3-oxo-1H-imidazo [1,5-c] imidazole-2 (3H)- Yl] piperidine-1-carboxylate tert-butyl 3- (N-acetyl-N-propylamino) propionate tert-butyl (0.60 g) obtained in Example 206b) and 4 obtained in Example 185c) Example 195b) from tert-butyl (0.54 g)-[5- (hydroxymethyl) -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1-carboxylate In the same manner as the above, the title compound (0.66 g, 84%) was obtained as a white powder.
NMR (300MHz, CDCl ₃ ) δ: 0.87 (1H, t, J = 7.2), 0.91 (2H, t, J = 7.2), 1.48 (9H, s), 1.55-1.74 (4H, m), 1.86 (2H , d, J = 12.0), 2.06 (2H, s), 2.09 (1H, s), 2.61-2.70 (2H, m), 2.75-2.88 (2H, m), 3.25 (2H, t, J = 7.8) , 3.56-3.63 (2H, m), 4.04-4.15 (1H, m), 4.20-4.40 (4H, m), 5.37 (1.4H, s), 5.41 (0.6H, s), 6.86 (1H, s) .
206d) 3- (N-acetyl-N-propylamino) propionic acid [2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropionyl} -4- Piperidinyl) -3-oxo-2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl 4- [5-({[3- (N -Acetyl-N-propylamino) propionyl] oxy} methyl) -3-oxo-1H-imidazo [1,5-c] imidazol-2 (3H) -yl] piperidine-1-carboxylate tert-butyl (0.50 g ) To give the title compound (0.27 g, 39%) as a white powder in the same manner as in Example 194b).
NMR (300MHz, CDCl ₃ ) δ: 0.82 (1H, t, J = 7.5), 0.92 (2H, t, J = 7.5), 1.49-1.90 (4H, m), 1.91-2.05 (2H, m), 2.06 (2H, s), 2.08 (1H, s), 2.61-2.85 (3h, m), 3.17-3.31 (3H, m), 3.45-3.63 (4H, m), 3.79-3.98 (1H, m), 4.08 -4.26 (2H, m), 4.30-4.38 (2H, m), 4.73 (1H, t, J = 13.5), 5.01-5.09 (1H, m), 5.37 (0.3H, s), 5.41 (0.7H, s), 6.87 (1H, s), 7.60 (1H, dd, J = 9.0, 2.1), 7.95 (3H, s), 7.96 (1H, d, J = 9.0), 8.51 (1H, s).
Elemental analysis C ₃₂ H ₃₈ N ₅ O ₈ Calculated as SCl · H ₂ O (%): C, 54.42; H, 5.71; N, 9.92
Found (%): C, 54.63; H, 5.87; N, 9.89

実施例207
3-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロピオニル}-4-ピペリジニル)イミダゾ[1,2-a]ピリジン塩酸塩
207a) 4-(2-オキソエチル)ピペリジン-1-カルボン酸tert-ブチル
4-(2-ヒドロキシエチル)ピペリジン-1-カルボン酸tert-ブチル(11.5g)から実施例190a)と同様にして、題記化合物(10.91g, 96%)を淡黄色油状物として得た。
NMR (300Mz, CDCl₃) δ：1.07-1.28 (2H, m), 1.47 (9H, s), 1.63-1.74 (2H, m), 1.98-2.13 (1H, m), 2.39 (2H, d, J = 6.6), 2.68-2.84 (2H, m), 3.98-4.18 (2H, m), 9.78 (1H, s).
207b) 4-(イミダゾ[1,2-a]ピリジン-3-イル)ピペリジン-1-カルボン酸tert-ブチル
実施例207a)で得られた4-(2-オキソエチル)ピペリジン-1-カルボン酸tert-ブチル(10.2g)のジエチルエーテル(100 mL)溶液へ5,5-ジブロモバルビツール酸(6.41g)を加え、室温で16時間かき混ぜた。生成した沈殿物をろ去し、ろ液を飽和炭酸水素ナトリウム水溶液と飽和食塩水で順次洗浄、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残留物をエタノール(100mL)に溶かし、2-アミノピリジン(2.63g)を加えて3時間還流した。溶媒を減圧留去し、残留物に水を加え、酢酸エチルで洗浄した。氷冷下に水層を8N水酸化ナトリウムでpH9に調節し、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残留物をシリカゲルカラム (酢酸エチル/エタノール=10/1)で精製して、題記化合物(8.11g, 60%)を淡黄色固体として得た。
NMR (200Mz, CDCl₃)δ：1.49 (9H, s), 1.59-1.85 (2H, m), 1.98-2.17 (2H, m), 2.83-3.10 (3H, m), 4.18-4.38 (2H, m), 6.83 (1H, t, J = 6.4), 7.16 (1H, t, J = 8.0), 7.41 (1H, s), 7.62 (1H, d, J = 9.2), 7.97 (1H, d, J = 6.8).
207c) 3-(4-ピペリジニル)イミダゾ[1,2-a]ピリジン２塩酸塩
実施例207a)で得られた4-(2-オキソエチル)ピペリジン-1-カルボン酸tert-ブチル(9.04g)を濃塩酸(49mL)に溶解し、室温で10分間かき混ぜた。反応液へエタノールを加え、減圧濃縮した。析出した結晶をろ取し、エタノールとエーテルで洗浄して、題記化合物(7.92g, 91%)を白色結晶として得た。
NMR (200Mz, D₂O)δ：1.94-2.22 (2H, m), 2.39-2.59 (2H, m), 3.23-3.48 (2H, m), 3.52-3.78 (3H, m), 7.48-7.61 (1H, m), 7.86 (1H, s), 7.98-8.04 (2H, m), 8.71 (1H, d, J = 7.0).
207d) 3-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロピオニル}-4-ピペリジニル)イミダゾ[1,2-a]ピリジン塩酸塩
実施例207c)で得られた3-(4-ピペリジニル)イミダゾ[1,2-a]ピリジン２塩酸塩から実施例19と同様にして、3-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロピオニル}-4-ピペリジニル)イミダゾ[1,2-a]ピリジンを得た。これをエタノールに溶かし、濃塩酸を加えた後、溶媒を減圧留去した。残留物をエタノール−エーテルで洗浄して、題記化合物(収率81%)を白色粉末として得た。
NMR (300Mz, DMSO-d₆)δ：1.28-1.39 (1H, m), 1.39-1.68 (1H, m), 1.93-2.11 (2H, m), 2.62-2.84 (3H, m), 3.12-3.28 (1H, m), 3.32-3.57 (1H, m), 3.61-3.72 (2H, m), 3.88-4.01 (1H, m), 4.31-4.45 (1H, m), 7.54 (1H, t, J = 6.6), 7.73 (1H, dd, J = 7.4, 6.0), 7.93-8.04 (4H, m), 8.19 (1H, d, J = 8.7), 8.26-8.31 (2H, m), 8.68 (1H, s), 9.02 (1H, d, J = 6.9).
元素分析値 C₂₅H₂₄ClN₃O₃S・HCl・H₂Oとして
計算値（％）：C, 55.97; H, 5.07; N, 7.83
実測値（％）：C, 56.15, H, 5.06; N, 7.81. Example 207
3- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propionyl} -4-piperidinyl) imidazo [1,2-a] pyridine hydrochloride
207a) tert-Butyl 4- (2-oxoethyl) piperidine-1-carboxylate
The title compound (10.91 g, 96%) was obtained as a pale yellow oil from tert-butyl 4- (2-hydroxyethyl) piperidine-1-carboxylate (11.5 g) in the same manner as in Example 190a).
NMR (300Mz, CDCl ₃ ) δ: 1.07-1.28 (2H, m), 1.47 (9H, s), 1.63-1.74 (2H, m), 1.98-2.13 (1H, m), 2.39 (2H, d, J = 6.6), 2.68-2.84 (2H, m), 3.98-4.18 (2H, m), 9.78 (1H, s).
207b) tert-butyl 4- (imidazo [1,2-a] pyridin-3-yl) piperidine-1-carboxylate tert-butyl 4- (2-oxoethyl) piperidine-1-carboxylate obtained in Example 207a) 5,5-Dibromobarbituric acid (6.41 g) was added to a solution of -butyl (10.2 g) in diethyl ether (100 mL), and the mixture was stirred at room temperature for 16 hours. The formed precipitate was removed by filtration, and the filtrate was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was dissolved in ethanol (100 mL), 2-aminopyridine (2.63 g) was added, and the mixture was refluxed for 3 hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was washed with ethyl acetate. Under ice cooling, the aqueous layer was adjusted to pH 9 with 8N sodium hydroxide and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (ethyl acetate / ethanol = 10/1) to obtain the title compound (8.11 g, 60%) as a pale yellow solid.
NMR (200Mz, CDCl ₃ ) δ: 1.49 (9H, s), 1.59-1.85 (2H, m), 1.98-2.17 (2H, m), 2.83-3.10 (3H, m), 4.18-4.38 (2H, m ), 6.83 (1H, t, J = 6.4), 7.16 (1H, t, J = 8.0), 7.41 (1H, s), 7.62 (1H, d, J = 9.2), 7.97 (1H, d, J = 6.8).
207c) 3- (4-Piperidinyl) imidazo [1,2-a] pyridine dihydrochloride tert-butyl 4- (2-oxoethyl) piperidine-1-carboxylate (9.04 g) obtained in Example 207a) Dissolved in concentrated hydrochloric acid (49 mL) and stirred at room temperature for 10 minutes. Ethanol was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The precipitated crystals were collected by filtration and washed with ethanol and ether to give the title compound (7.92 g, 91%) as white crystals.
NMR (200Mz, D ₂ O) δ: 1.94-2.22 (2H, m), 2.39-2.59 (2H, m), 3.23-3.48 (2H, m), 3.52-3.78 (3H, m), 7.48-7.61 ( 1H, m), 7.86 (1H, s), 7.98-8.04 (2H, m), 8.71 (1H, d, J = 7.0).
207d) 3- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propionyl} -4-piperidinyl) imidazo [1,2-a] pyridine hydrochloride 3-207 obtained in Example 207c) 3- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propionyl} -4 from (4-piperidinyl) imidazo [1,2-a] pyridine dihydrochloride in the same manner as in Example 19. -Piperidinyl) imidazo [1,2-a] pyridine was obtained. This was dissolved in ethanol, concentrated hydrochloric acid was added, and then the solvent was distilled off under reduced pressure. The residue was washed with ethanol-ether to give the title compound (yield 81%) as a white powder.
NMR (300Mz, DMSO-d ₆ ) δ: 1.28-1.39 (1H, m), 1.39-1.68 (1H, m), 1.93-2.11 (2H, m), 2.62-2.84 (3H, m), 3.12-3.28 (1H, m), 3.32-3.57 (1H, m), 3.61-3.72 (2H, m), 3.88-4.01 (1H, m), 4.31-4.45 (1H, m), 7.54 (1H, t, J = 6.6), 7.73 (1H, dd, J = 7.4, 6.0), 7.93-8.04 (4H, m), 8.19 (1H, d, J = 8.7), 8.26-8.31 (2H, m), 8.68 (1H, s ), 9.02 (1H, d, J = 6.9).
Elemental analysis value Calculated as C ₂₅ H ₂₄ ClN ₃ O ₃ S · HCl · H ₂ O (%): C, 55.97; H, 5.07; N, 7.83
Found (%): C, 56.15, H, 5.06; N, 7.81.

実施例208
3-(1-{3-[(6-ブロモ-2-ナフチル)スルホニル]プロピオニル}-4-ピペリジニル)イミダゾ[1,2-a]ピリジン塩酸塩
3-[(6-ブロモ-2-ナフチル)スルホニル]プロピオン酸と実施例207c)で得られた3-(4-ピペリジニル)イミダゾ[1,2-a]ピリジン２塩酸塩から実施例207d)と同様にして、題記化合物(収率91%)を淡黄色粉末として得た。
NMR (200Mz, DMSO-d₆)δ：1.28-1.49 (1H, m), 1.49-1.70 (1H, m), 1.89-2.12 (2H, m), 2.61-2.89 (3H, m), 3.11-3.32 (1H, m), 3.32-3.57 (1H, m), 3.57-3.77 (2H, m), 3.88-4.04 (1H, m), 4.32-4.48 (1H, m), 7.51-7.57 (1H, m), 7.84 (1H, dd, J = 6.0, 1.4), 7.93-8.16 (4H, m), 8.16-8.32 (2H, m), 8.43 (1H, s), 8.67 (1H, s), 9.04 (1H, d, J = 4.6). Example 208
3- (1- {3-[(6-Bromo-2-naphthyl) sulfonyl] propionyl} -4-piperidinyl) imidazo [1,2-a] pyridine hydrochloride
Example 207d) from 3-[(6-bromo-2-naphthyl) sulfonyl] propionic acid and 3- (4-piperidinyl) imidazo [1,2-a] pyridine dihydrochloride obtained in Example 207c) In the same manner, the title compound (yield 91%) was obtained as a pale yellow powder.
NMR (200Mz, DMSO-d ₆ ) δ: 1.28-1.49 (1H, m), 1.49-1.70 (1H, m), 1.89-2.12 (2H, m), 2.61-2.89 (3H, m), 3.11-3.32 (1H, m), 3.32-3.57 (1H, m), 3.57-3.77 (2H, m), 3.88-4.04 (1H, m), 4.32-4.48 (1H, m), 7.51-7.57 (1H, m) , 7.84 (1H, dd, J = 6.0, 1.4), 7.93-8.16 (4H, m), 8.16-8.32 (2H, m), 8.43 (1H, s), 8.67 (1H, s), 9.04 (1H, d, J = 4.6).

実施例209
3-[1-[3-[(6-クロロ-2-ナフチル)スルホニル]プロピオニル]-4-ピペリジニル]-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン塩酸塩
209a) 4-(5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン-3-イル)ピペリジン-1-カルボン酸tert-ブチル
実施例207b)で得られた4-(イミダゾ[1,2-a]ピリジン-3-イル)ピペリジン-1-カルボン酸tert-ブチルの酢酸(15 mL)溶液へ酸化白金(114mg)を加え、水素雰囲気下で16時間かき混ぜた。触媒をろ去し、ろ液を減圧濃縮後、残留物に水を加え、8N水酸化ナトリウムでpH 12に調節した。混合物をクロロホルムで抽出し、抽出液を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去して、題記化合物(1.53g, 定量的)を淡黄色粉末として得た。
NMR (200Mz, CDCl₃)δ：1.38-1.69 (11H, m), 1.81-2.22 (6H, m), 2.57-2.93 (3H, m), 3.11 (2H, t, J = 6.6), 3.95 (2H, t, J = 5.6), 4.12-4.36 (2H, m), 6.98 (1H, s).
209b) 3-(4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン２塩酸塩
実施例209a)で得られた4-(5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン-3-イル)ピペリジン-1-カルボン酸tert-ブチル(1.53g)から実施例207c)と同様にして、題記化合物(1.32g, 95%)を白色結晶として得た。
NMR (200Mz, D₂O)δ：1.74-2.19 (6H, m), 2.20-2.37 (2H, m), 2.95-3.31 (5H, m), 3.50-3.66 (2H, m), 4.11 (2H, t, J = 5.4), 7.20 (1H, s).
209c) 3-[1-[3-[(6-クロロ-2-ナフチル)スルホニル]プロピオニル]-4-ピペリジニル]-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン塩酸塩
実施例209b)で得られた3-(4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン２塩酸塩から実施例207d)と同様にして、題記化合物(収率78%)を白色粉末として得た。
NMR (200Mz, DMSO-d₆)δ：1.12-1.58 (2H, m), 1.76-2.08 (6H, m), 2.48-2.68 (1H, m), 2.75 (2H, t, J = 7.4), 2.84-3.19 (4H, m), 3.64 (2H, t, J = 7.0), 3.34-3.99 (1H, m), 4.00-4.12 (2H, m), 4.26-4.40 (1H, m), 7.34 (1H, s), 7.74 (1H, dd, J = 8.8, 2.2), 8.01 (1H, dd, J = 8.8, 1.8), 8.17-8.32 (3H, m), 8.67 (1H, s).
元素分析値 C₂₅H₂₈ClN₃O₃S・HCl・H₂Oとして
計算値（％）：C, 55.55; H, 5.78; N, 7.77
実測値（％）：C, 55.72, H, 5.82; N, 7.75. Example 209
3- [1- [3-[(6-Chloro-2-naphthyl) sulfonyl] propionyl] -4-piperidinyl] -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine hydrochloride
209a) 4- (5,6,7,8-tetrahydroimidazo [1,2-a] pyridin-3-yl) piperidine-1-carboxylate tert-butyl 4- (imidazo [ Platinum oxide (114 mg) was added to a solution of tert-butyl 1,2-a] pyridin-3-yl) piperidine-1-carboxylate in acetic acid (15 mL), and the mixture was stirred under a hydrogen atmosphere for 16 hr. The catalyst was removed by filtration, the filtrate was concentrated under reduced pressure, water was added to the residue, and the pH was adjusted to 12 with 8N sodium hydroxide. The mixture was extracted with chloroform, and the extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (1.53 g, quantitative) as a pale yellow powder.
NMR (200Mz, CDCl ₃ ) δ: 1.38-1.69 (11H, m), 1.81-2.22 (6H, m), 2.57-2.93 (3H, m), 3.11 (2H, t, J = 6.6), 3.95 (2H , t, J = 5.6), 4.12-4.36 (2H, m), 6.98 (1H, s).
209b) 3- (4-Piperidinyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine dihydrochloride 4- (5,6,7,8- obtained in Example 209a) Tetrahydroimidazo [1,2-a] pyridin-3-yl) piperidine-1-carboxylate from tert-butyl (1.53 g) in the same manner as in Example 207c) to give the title compound (1.32 g, 95%) as white crystals Got as.
NMR (200Mz, D ₂ O) δ: 1.74-2.19 (6H, m), 2.20-2.37 (2H, m), 2.95-3.31 (5H, m), 3.50-3.66 (2H, m), 4.11 (2H, t, J = 5.4), 7.20 (1H, s).
209c) 3- [1- [3-[(6-Chloro-2-naphthyl) sulfonyl] propionyl] -4-piperidinyl] -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine hydrochloride In a similar manner to Example 207d) from 3- (4-piperidinyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine dihydrochloride obtained in Example 209b), the title compound ( Yield 78%) was obtained as a white powder.
NMR (200Mz, DMSO-d ₆ ) δ: 1.12-1.58 (2H, m), 1.76-2.08 (6H, m), 2.48-2.68 (1H, m), 2.75 (2H, t, J = 7.4), 2.84 -3.19 (4H, m), 3.64 (2H, t, J = 7.0), 3.34-3.99 (1H, m), 4.00-4.12 (2H, m), 4.26-4.40 (1H, m), 7.34 (1H, s), 7.74 (1H, dd, J = 8.8, 2.2), 8.01 (1H, dd, J = 8.8, 1.8), 8.17-8.32 (3H, m), 8.67 (1H, s).
Elemental analysis _{_{_{_{C 25 H 28 ClN 3 O 3}}}} S · HCl · H 2 O Calculated (%): C, 55.55; H, 5.78; N, 7.77
Found (%): C, 55.72, H, 5.82; N, 7.75.

実施例210
3-(1-{3-[(6-ブロモ-2-ナフチル)スルホニル]プロピオニル}-4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン塩酸塩
3-[(6-ブロモ-2-ナフチル)スルホニル]プロピオン酸と実施例209b)で得られた3-(4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン２塩酸塩から実施例207d)と同様にして、題記化合物(収率84%)を白色粉末として得た。
NMR (200Mz, DMSO-d₆)δ：1.17-1.38 (1H, m), 1.38-1.58 (1H, m), 1.74-2.07 (6H, m), 2.54-2.68 (1H, m), 2.75 (2H, t, J = 7.2), 2.83-3.18 (4H, m), 3.64 (2H, t, J = 7.8), 3.74-3.97 (1H, m), 3.97-4.11 (2H, m), 4.22-4.40 (1H, m), 7.34 (1H, s), 7.84 (1H, dd, J = 8.2, 2.0), 8.00 (1H, dd, J = 8.2, 2.0), 8.17-8.23 (2H, m), 8.43 (1H, s), 8.65 (1H, s). Example 210
3- (1- {3-[(6-Bromo-2-naphthyl) sulfonyl] propionyl} -4-piperidinyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine hydrochloride
3-[(6-Bromo-2-naphthyl) sulfonyl] propionic acid and 3- (4-piperidinyl) -5,6,7,8-tetrahydroimidazo [1,2-a] obtained in Example 209b) The title compound (yield 84%) was obtained as a white powder from pyridine dihydrochloride in the same manner as in Example 207d).
NMR (200Mz, DMSO-d ₆ ) δ: 1.17-1.38 (1H, m), 1.38-1.58 (1H, m), 1.74-2.07 (6H, m), 2.54-2.68 (1H, m), 2.75 (2H , t, J = 7.2), 2.83-3.18 (4H, m), 3.64 (2H, t, J = 7.8), 3.74-3.97 (1H, m), 3.97-4.11 (2H, m), 4.22-4.40 ( 1H, m), 7.34 (1H, s), 7.84 (1H, dd, J = 8.2, 2.0), 8.00 (1H, dd, J = 8.2, 2.0), 8.17-8.23 (2H, m), 8.43 (1H , s), 8.65 (1H, s).

実施例211
3-(1-{3-[(5-クロロ-1H-インドール-2-イル)スルホニル]プロピオニル}-4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン塩酸塩
211a) 3-[(5-クロロ-1H-インドリール-2-イル)チオ]プロピオン酸tert-ブチル
5-クロロ-1,3-ジヒドロ-2H-インドール-2-オン(25.82g)とローソン試薬(93.47g)をピリジン(300 mL)に加え、16時間還流した。反応液を氷水(2L)に注ぎ込み、室温で18時間放置し、析出した沈殿物をろ取し、水洗後、乾燥した。得られた黄色固体のアセトニトリル(200mL)けん濁液へアクリル酸tert-ブチル(22.6mL)とトリエチルアミン(21.5mL)を加え、1時間還流した。溶媒を減圧留去し、残留物へ水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。残留物をシリカゲルカラム (酢酸エチル/ヘキサン=1/4)により精製して、題記化合物(24.12g, 50％)を淡黄色固体として得た。
NMR (300MHz, CDCl₃)δ：1.47 (9H, s), 2.55 (2H, t, J = 6.9), 3.03 (2H, t, J = 6.9), 6.58-6.59 (1H, m), 7.12-7.15 (1H, m), 7.24-7.27 (1H, m), 7.51-7.52 (1H, m), 8.73 (1H, br).
211b) 3-[(5-クロロ-1H-インドール-2-イル)スルホニル]プロピオン酸tert-ブチル
実施例211a)で得られた3-[(5-クロロ-1H-インドール-2-イル)チオ]プロピオン酸tert-ブチル(1.56g)のジクロロメタン(15mL)溶液へメタクロロ過安息香酸(3.08g)を0℃で加え、室温で1時間かき混ぜた。反応液をジクロロメタン(50mL)で希釈し、飽和チオ硫酸ナトリウム水溶液、飽和炭酸水素ナトリウム水溶液および飽和食塩水で順番に洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残留物をシリカゲルカラム (酢酸エチル/ヘキサン=1/4)で精製し、題記化合物(1.58g, 92％)を白色固体として得た。
NMR (200MHz, CDCl₃)δ：1.38 (9H, s), 2.72 (2H, t, J = 7.4), 3.56 (2H, t, J = 7.4), 7.13-7.14 (1H, m), 7.30-7.36 (1H, m), 7.40-7.44 (1H, m), 7.68-7.69 (1H, m), 9.52 (1H, br).
211c) 2-{[3-(アリルオキシ)-3-オキソプロピル]スルホニル}-5-クロロ-1H-インドール-1-カルボン酸 tert-ブチル
実施例211b)で得られた3-[(5-クロロ-1H-インドール-2-イル)スルホニル]プロピオン酸tert-ブチル(13.75g)の酢酸(250mL)溶液へ濃塩酸(33mL)を加え、60℃で1時間かき混ぜた。溶媒を減圧留去し、残留物をDMF(100mL)に溶かし、トリエチルアミン(6.7mL)と臭化アリル(10.4mL)を加え、60℃で2時間かき混ぜた。反応液を氷水中に注ぎ込み、酢酸エチルで抽出した。抽出液を水洗し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。得られた固体と4-ジメチルアミノピリジン(4.89g)のアセトニトリル(150mL)溶液へ二炭酸ジ-tert-ブチル(8.73g)を室温で滴下し、さらに1時間かき混ぜた。溶媒を減圧留去し、残留物へ水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。残留物をシリカゲルカラム (溶出液；酢酸エチル/ヘキサン=1/4)で精製して、題記化合物(10.61g, 62％)を淡茶色固体として得た。
NMR (200MHz, CDCl₃)δ：1.74 (9H, s), 2.90 (2H, t, J = 7.4), 4.03 (2H, t, J = 7.4), 4.47-4.52 (2H, m), 5.17-5.30 (2H, m), 5.72-5.93 (1H, m), 7.42-7.53 (2H, m), 7.64-7.65 (1H, m), 7.98 (1H, d, J = 9.2).
211d) 3-[(1-tert-ブトキシカルボニル-5-クロロ-1H-インドール-2-イル)スルホニル]プロピオン酸
実施例211c)で得られた2-{[3-(アリルオキシ)-3-オキソプロピル]スルホニル}-5-クロロ-1H-インドール-1-カルボン酸 tert-ブチル(4.27g)、メルドラム酸(2.16g)およびパラジウム(0)テトラキストリフェニルホスフィン(0.58g)のTHF(40mL)溶液をアルゴン下、室温で3時間かき混ぜた。溶媒を減圧留去し、残留物に1N塩酸(50mL)を加え、酢酸エチルで抽出した。抽出液を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残留物へジイソプロピルエーテルを加え、生じた沈殿をろ取し、題記化合物(3.29g, 85%)を淡茶色固体として得た。
NMR (200MHz, DMSO-d₆)δ：1.68 (9H, s), 2.71 (2H, t, J = 7.0), 3.96 (2H, t, J = 7.0), 7.57-7.62 (2H, m), 7.93-7.94 (1H, m), 8.05 (1H, d, J = 9.2).
211e) 5-クロロ-2-({3-オキソ-3-[4-(5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン-3-イル)-1-ピペリジニル]プロピル}スルホニル)-1H-インドール-1-カルボン酸tert-ブチル
実施例211d)で得られた3-[(1-tert-ブトキシカルボニル-5-クロロ-1H-インドール-2-イル)スルホニル]プロピオン酸(0.78g)と実施例209b)で得られた3-(4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン２塩酸塩(0.67g)から実施例19と同様にして、題記化合物(1.11g, 92%)を淡黄色粉末として得た。
NMR (200Mz, CDCl₃)δ：1.33-1.66 (2H, m), 1.74 (9H, s), 1.78-2.08 (6H, m), 2.62-2.77 (2H, m), 2.80-3.02 (4H, m), 3.02-3.23 (1H, m), 3.81 (2H, t, J = 5.2), 3.87-4.02 (1H, m), 4.02-4.12 (2H, m), 4.52-4.67 (1H, m), 6.66 (1H, s), 7.45 (1H, dd, J = 9.2, 2.2), 7.51 (1H, s), 7.64 (1H, d, J = 2.2), 8.00 (1H, d, J = 9.2).
211f) 3-(1-{3-[(5-クロロ-1H-インドール-2-イル)スルホニル]プロピオニル}-4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン塩酸塩
実施例211e)で得られた5-クロロ-2-({3-オキソ-3-[4-(5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン-3-イル)-1-ピペリジニル]プロピル}スルホニル)-1H-インドール-1-カルボン酸tert-ブチル(0.68g)から実施例207c)と同様にして、題記化合物(0.54g, 90%)を淡茶色粉末として得た。
NMR (200Mz, DMSO-d₆)δ：1.16-1.57 (2H, m), 1.77-2.07 (6H, m), 2.47-2.68 (2H, m), 2.76 (2H, t, J = 7.2), 2.84-3.18 (3H, m), 3.66 (2H, t, J = 6.6), 3.81-3.97 (1H, m), 3.98-4.12 (2H, m), 4.26-4.39 (1H, m), 7.16 (1H, d, J = 1.6), 7.31-7.37 (2H, m), 7.53 (1H, d, J = 8.8), 7.74 (1H, br), 7.79 (1H, d, J = 1.8).
元素分析値 C₂₃H₂₇ClN₄O₃S・HCl・2H₂Oとして
計算値（％）：C, 50.46; H, 5.89; N, 10.23
実測値（％）：C, 50.57, H, 5.82; N, 9.99. Example 211
3- (1- {3-[(5-Chloro-1H-indol-2-yl) sulfonyl] propionyl} -4-piperidinyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine Hydrochloride
211a) tert-Butyl 3-[(5-chloro-1H-indolyl-2-yl) thio] propionate
5-Chloro-1,3-dihydro-2H-indol-2-one (25.82 g) and Lawesson's reagent (93.47 g) were added to pyridine (300 mL), and the mixture was refluxed for 16 hours. The reaction solution was poured into ice water (2 L) and allowed to stand at room temperature for 18 hours. The deposited precipitate was collected by filtration, washed with water and dried. To the obtained yellow solid acetonitrile (200 mL) suspension, tert-butyl acrylate (22.6 mL) and triethylamine (21.5 mL) were added and refluxed for 1 hour. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was 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 (ethyl acetate / hexane = 1/4) to give the title compound (24.12 g, 50%) as a pale yellow solid.
NMR (300MHz, CDCl ₃ ) δ: 1.47 (9H, s), 2.55 (2H, t, J = 6.9), 3.03 (2H, t, J = 6.9), 6.58-6.59 (1H, m), 7.12-7.15 (1H, m), 7.24-7.27 (1H, m), 7.51-7.52 (1H, m), 8.73 (1H, br).
211b) 3-[(5-Chloro-1H-indol-2-yl) thiol obtained in Example 211a) tert-butyl 3-[(5-chloro-1H-indol-2-yl) sulfonyl] propionate ] To a solution of tert-butyl propionate (1.56 g) in dichloromethane (15 mL) was added metachloroperbenzoic acid (3.08 g) at 0 ° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with dichloromethane (50 mL), washed successively with saturated aqueous sodium thiosulfate solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (ethyl acetate / hexane = 1/4) to obtain the title compound (1.58 g, 92%) as a white solid.
NMR (200MHz, CDCl ₃ ) δ: 1.38 (9H, s), 2.72 (2H, t, J = 7.4), 3.56 (2H, t, J = 7.4), 7.13-7.14 (1H, m), 7.30-7.36 (1H, m), 7.40-7.44 (1H, m), 7.68-7.69 (1H, m), 9.52 (1H, br).
211c) 2-{[3- (allyloxy) -3-oxopropyl] sulfonyl} -5-chloro-1H-indole-1-carboxylate tert-butyl 3-[(5-chloro Concentrated hydrochloric acid (33 mL) was added to a solution of tert-butyl-1H-indol-2-yl) sulfonyl] propionate (13.75 g) in acetic acid (250 mL), and the mixture was stirred at 60 ° C. for 1 hr. The solvent was distilled off under reduced pressure, the residue was dissolved in DMF (100 mL), triethylamine (6.7 mL) and allyl bromide (10.4 mL) were added, and the mixture was stirred at 60 ° C. for 2 hr. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Di-tert-butyl dicarbonate (8.73 g) was added dropwise to a solution of the obtained solid and 4-dimethylaminopyridine (4.89 g) in acetonitrile (150 mL) at room temperature, and the mixture was further stirred for 1 hour. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was 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 (eluent; ethyl acetate / hexane = 1/4) to obtain the title compound (10.61 g, 62%) as a light brown solid.
NMR (200MHz, CDCl ₃ ) δ: 1.74 (9H, s), 2.90 (2H, t, J = 7.4), 4.03 (2H, t, J = 7.4), 4.47-4.52 (2H, m), 5.17-5.30 (2H, m), 5.72-5.93 (1H, m), 7.42-7.53 (2H, m), 7.64-7.65 (1H, m), 7.98 (1H, d, J = 9.2).
211d) 3-[(1-tert-Butoxycarbonyl-5-chloro-1H-indol-2-yl) sulfonyl] propionic acid 2-{[3- (allyloxy) -3-oxo obtained in Example 211c) Propyl] sulfonyl} -5-chloro-1H-indole-1-carboxylate tert-butyl (4.27 g), meldrum acid (2.16 g) and palladium (0) tetrakistriphenylphosphine (0.58 g) in THF (40 mL) Was stirred for 3 hours at room temperature under argon. The solvent was distilled off under reduced pressure, 1N hydrochloric acid (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the residue, and the resulting precipitate was collected by filtration to give the title compound (3.29 g, 85%) as a light brown solid.
NMR (200MHz, DMSO-d ₆ ) δ: 1.68 (9H, s), 2.71 (2H, t, J = 7.0), 3.96 (2H, t, J = 7.0), 7.57-7.62 (2H, m), 7.93 -7.94 (1H, m), 8.05 (1H, d, J = 9.2).
211e) 5-chloro-2-({3-oxo-3- [4- (5,6,7,8-tetrahydroimidazo [1,2-a] pyridin-3-yl) -1-piperidinyl] propyl} Sulfonyl) -1H-indole-1-carboxylate tert-butyl 3-[(1-tert-butoxycarbonyl-5-chloro-1H-indole-2-yl) sulfonyl] propionic acid obtained in Example 211d) 0.78 g) and 3- (4-piperidinyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine dihydrochloride (0.67 g) obtained in Example 209b) In the same manner, the title compound (1.11 g, 92%) was obtained as a pale yellow powder.
NMR (200Mz, CDCl ₃ ) δ: 1.33-1.66 (2H, m), 1.74 (9H, s), 1.78-2.08 (6H, m), 2.62-2.77 (2H, m), 2.80-3.02 (4H, m ), 3.02-3.23 (1H, m), 3.81 (2H, t, J = 5.2), 3.87-4.02 (1H, m), 4.02-4.12 (2H, m), 4.52-4.67 (1H, m), 6.66 (1H, s), 7.45 (1H, dd, J = 9.2, 2.2), 7.51 (1H, s), 7.64 (1H, d, J = 2.2), 8.00 (1H, d, J = 9.2).
211f) 3- (1- {3-[(5-chloro-1H-indol-2-yl) sulfonyl] propionyl} -4-piperidinyl) -5,6,7,8-tetrahydroimidazo [1,2-a ] Pyridine hydrochloride 5-chloro-2-({3-oxo-3- [4- (5,6,7,8-tetrahydroimidazo [1,2-a] pyridine-3) obtained in Example 211e) -Yl) -1-piperidinyl] propyl} sulfonyl) -1H-indole-1-carboxylate from tert-butyl (0.68 g) in the same manner as in Example 207c) to give the title compound (0.54 g, 90%) as a light brown Obtained as a powder.
NMR (200Mz, DMSO-d ₆ ) δ: 1.16-1.57 (2H, m), 1.77-2.07 (6H, m), 2.47-2.68 (2H, m), 2.76 (2H, t, J = 7.2), 2.84 -3.18 (3H, m), 3.66 (2H, t, J = 6.6), 3.81-3.97 (1H, m), 3.98-4.12 (2H, m), 4.26-4.39 (1H, m), 7.16 (1H, d, J = 1.6), 7.31-7.37 (2H, m), 7.53 (1H, d, J = 8.8), 7.74 (1H, br), 7.79 (1H, d, J = 1.8).
Elemental analysis _{_{_{_{C 23 H 27 ClN 4 O 3}}}} S · HCl · 2H 2 O Calculated (%): C, 50.46; H, 5.89; N, 10.23
Found (%): C, 50.57, H, 5.82; N, 9.99.

実施例212
3-(1-{3-[(5-クロロ-1H-インドール-2-イル)スルホニル]プロピオニル}-4-ピペリジニル)イミダゾ[1,2-a]ピリジン塩酸塩
212a) 5-クロロ-2-({3-オキソ-3-[4-(イミダゾ[1,2-a]ピリジン-3-イル)-1-ピペリジニル]プロピル}スルホニル)-1H-インドール-1-カルボン酸tert-ブチル
実施例211d)で得られた3-[(1-tert-ブトキシカルボニル-5-クロロ-1H-インドール-2-イル)スルホニル]プロピオン酸(0.78g)と実施例207c)で得られた 3-(4-ピペリジニル)イミダゾ[1,2-a]ピリジン２塩酸塩(0.66g)から実施例19)と同様にして、題記化合物(1.04g, 91%)を淡黄色粉末として得た。
NMR (200Mz, CDCl₃)δ：1.52-1.83 (2H, m), 1.75 (9H, s), 2.03-2.27 (2H, m), 2.71-2.92 (1H, m), 2.92-3.07 (2H, m), 3.07-3.20 (1H, m), 3.20-3.37 (1H, m), 3.93-4.17 (3H, m), 4.58-4.74 (1H, m), 6.82-6.90 (1H, m), 7.15-7.24 (1H, m), 7.41 (1H, s), 7.47 (1H, dd, J = 9.2, 2.2), 7.54 (1H, s), 7.54-7.67 (2H, m), 7.95-8.04 (2H, m)
212b) 3-(1-{3-[(5-クロロ-1H-インドール-2-イル)スルホニル]プロピオニル}-4-ピペリジニル)イミダゾ[1,2-a]ピリジン塩酸塩
実施例212a)で得られた5-クロロ-2-({3-オキソ-3-[4-(イミダゾ[1,2-a]ピリジン-3-イル)-1-ピペリジニル]プロピル}スルホニル)-1H-インドール-1-カルボン酸tert-ブチルから実施例207c)と同様にして、題記化合物(0.23g, 84%)を淡茶色粉末として得た。
NMR (200Mz, DMSO-d₆)δ：1.23-1.47 (1H, m), 1.47-1.63 (1H, m), 1.89-2.12 (2H, m), 2.60-2.74 (1H, m), 2.79 (2H, t, J = 7.0), 3.09-3.56 (2H, m), 3.68 (2H, t, J = 7.0), 3.88-4.03 (1H, m), 4.28-4.47 (1H, m), 7.18 (1H, m), 7.33 (1H, dd, J = 8.8, 2.2), 7.51-7.57 (2H, m), 7.89 (1H, d, J = 2.2), 7.91-8.04 (3H, m), 9.01 (1H, d, J = 7.0). Example 212
3- (1- {3-[(5-Chloro-1H-indol-2-yl) sulfonyl] propionyl} -4-piperidinyl) imidazo [1,2-a] pyridine hydrochloride
212a) 5-chloro-2-({3-oxo-3- [4- (imidazo [1,2-a] pyridin-3-yl) -1-piperidinyl] propyl} sulfonyl) -1H-indole-1- Tert-Butyl carboxylate 3-[(1-tert-Butoxycarbonyl-5-chloro-1H-indol-2-yl) sulfonyl] propionic acid obtained in Example 211d) with Example 207c) The title compound (1.04 g, 91%) was obtained as a pale yellow powder from the obtained 3- (4-piperidinyl) imidazo [1,2-a] pyridine dihydrochloride (0.66 g) in the same manner as in Example 19). Obtained.
NMR (200Mz, CDCl ₃ ) δ: 1.52-1.83 (2H, m), 1.75 (9H, s), 2.03-2.27 (2H, m), 2.71-2.92 (1H, m), 2.92-3.07 (2H, m ), 3.07-3.20 (1H, m), 3.20-3.37 (1H, m), 3.93-4.17 (3H, m), 4.58-4.74 (1H, m), 6.82-6.90 (1H, m), 7.15-7.24 (1H, m), 7.41 (1H, s), 7.47 (1H, dd, J = 9.2, 2.2), 7.54 (1H, s), 7.54-7.67 (2H, m), 7.95-8.04 (2H, m)
212b) 3- (1- {3-[(5-Chloro-1H-indol-2-yl) sulfonyl] propionyl} -4-piperidinyl) imidazo [1,2-a] pyridine hydrochloride obtained in Example 212a) 5-chloro-2-({3-oxo-3- [4- (imidazo [1,2-a] pyridin-3-yl) -1-piperidinyl] propyl} sulfonyl) -1H-indole-1- The title compound (0.23 g, 84%) was obtained as a light brown powder from tert-butyl carboxylate in the same manner as in Example 207c).
NMR (200Mz, DMSO-d ₆ ) δ: 1.23-1.47 (1H, m), 1.47-1.63 (1H, m), 1.89-2.12 (2H, m), 2.60-2.74 (1H, m), 2.79 (2H , t, J = 7.0), 3.09-3.56 (2H, m), 3.68 (2H, t, J = 7.0), 3.88-4.03 (1H, m), 4.28-4.47 (1H, m), 7.18 (1H, m), 7.33 (1H, dd, J = 8.8, 2.2), 7.51-7.57 (2H, m), 7.89 (1H, d, J = 2.2), 7.91-8.04 (3H, m), 9.01 (1H, d , J = 7.0).

実施例213
6-クロロ-2-({3-オキソ-3-[4-(5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン-3-イル)-1-ピペリジニル]プロピル}スルホニル)-1,2,3,4-テトラヒドロイソキノリン塩酸塩
213a) 2-[(4-クロロフェニル)メチル]アミノエタノール塩酸塩
生成する水を除去しながら4-クロロベンズアルデヒド(14.06g)とエタノールアミン(6.18g)のトルエン(150mL)溶液を1時間還流した後、溶媒を減圧留去した。残留物のメタノール(150mL)溶液へトリアセトキシ水素化ホウ素ナトリウム(42.39g)を加え、室温で1時間かき混ぜた。溶媒を減圧留去し、残留物に水を加え、8N水酸化ナトリウム水溶液でpH 12に調節した後、クロロホルムで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。残留物をエタノール(100mL)に溶かし濃塩酸(8.2mL)を加え、溶媒を減圧留去した。残留物に2-プロパノール−エーテルを加え、沈殿をろ取、エーテルで洗浄して、題記化合物(18.21g, 82%)を白色粉末として得た。
NMR (200Mz, DMSO-d₆)δ：2.93 (2H, br), 3.69 (2H, t, J = 3.6), 4.15 (2H, br), 5.27 (1H, br), 7.50 (2H, d, J = 8.8), 7.62 (2H, d, J = 8.8), 9.43 (2H, br).
213b)6-クロロ-1,2,3,4-テトラヒドロイソキノリン塩酸塩
実施例213a)で得られた2-[(4-クロロフェニル)メチル]アミノエタノール塩酸塩(22.21g)、塩化アンモニウム(4.01g)、塩化アルミニウム(26.67g)の混合物を180℃でかき混ぜた。反応後40分後と80分後に塩化アルミニウム(それぞれ26.67g,および53.34g)を加え、混合物を180℃で18時間かき混ぜた。残留物に氷水を加え、8N水酸化ナトリウム水溶液でpH12に調節した後、クロロホルムで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。残留物をエタノール(50 mL)に溶かし、濃塩酸(8.2mL)を加え、溶媒を減圧留去した。残留物に2-プロパノール−エーテルを加え、沈殿をろ取、エーテルで洗浄して、題記化合物(4.08g, 20%)を淡黄色粉末として得た。
NMR (200Mz, DMSO-d₆)δ：3.01 (2H, t, J = 6.2), 3.35 (2H, t, J = 6.4), 4.21 (2H, s), 7.19-7.33 (3H, m), 9.80 (2H, br).
213c) 3-(クロロスルホニル)プロピオン酸メチル
3, 3'-ジチオプロピオン酸ジメチル(23.83g)の水(250mL)溶液へ氷冷下で塩素ガスを5℃以下で4時間通じた。反応液をジエチルエーテルで抽出し、抽出液を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残留物を減圧蒸留して、題記化合物(10.26g, 55%)を黄色液体として得た。
NMR (200Mz, CDCl₃)δ：3.06 (2H, t, J = 7.6), 3.78 (3H, s), 4.01 (2H, t, J = 7.4).
213d) 3-[(6-クロロ-1,2,3,4-テトラヒドロイソキノリン-2(1H)-イル)スルホニル]プロピオン酸メチル
実施例213c)で得られた3-クロロスルホニルプロピオン酸メチル(2.05g)のアセトニトリル(10mL)溶液へ実施例213b)で得られた6-クロロ-1,2,3,4-テトラヒドロイソキノリン・塩酸塩(2.04g)、DBU(1.5mL)およびトリエチルアミン(2.8mL)のアセトニトリル(10mL)溶液を0℃で滴下した。反応混合物を0℃で30分間かき混ぜた後、溶媒を減圧留去した。残留物に水を加え、クロロホルムで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残留物をクロロホルム−エタノールから再結晶して、題記化合物(2.70g, 85%)を淡茶色結晶として得た。
NMR (200Mz, CDCl₃)δ：2.82 (2H, t, J = 7.2), 2.93 (2H, t, J = 5.8), 3.32 (2H, t, J = 7.8), 3.57 (2H, t, J = 5.8), 3.67 (3H, s), 4.44 (2H, s), 7.01 (1H, d, J = 8.2), 7.15 (1H, s), 7.17 (1H, d, J = 8.2).
213e) 3-[(6-クロロ-1,2,3,4-テトラヒドロイソキノリン-2(1H)-イル)スルホニル]プロピオン酸
実施例213d)で得られた3-[(6-クロロ-1,2,3,4-テトラヒドロイソキノリン-2(1H)-イル)スルホニル]プロピオン酸メチル(1.59g)を1N水酸化ナトリウム水溶液(15 mL)に加え、100℃で40分間かき混ぜた。反応液へ0℃で1N塩酸(15mL)を加え、析出した沈殿をろ取し、水とエーテルで洗浄して、題記化合物(0.38g, 25%)を淡茶色粉末として得た。
NMR (200Mz, DMSO-d₆)δ：2.86 (2H, t, J = 7.5), 2.93 (2H, t, J = 6.0), 3.31 (2H, t, J = 7.5), 3.57 (2H, t, J = 6.0), 4.44 (2H, s), 7.01 (1H, d, J = 8.1), 7.14-7.25 (2H, m).
213f) 6-クロロ-2-({3-オキソ-3-[4-(5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン-3-イル)-1-ピペリジニル]プロピル}スルホニル)-1,2,3,4-テトラヒドロイソキノリン塩酸塩
実施例213e)で得られた3-[(6-クロロ-1,2,3,4-テトラヒドロイソキノリン-2(1H)-イル)スルホニル]プロピオン酸と実施例209b)で得られた3-(4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン２塩酸塩から実施例207d)と同様にして、題記化合物(62%)を白色粉末として得た。
NMR (200Mz, DMSO-d₆)δ：1.14-1.59 (2H, m), 1.78-2.07 (6H, m), 2.48-2.68 (1H, m), 2.75-2.84 (4H, m), 2.84-3.19 (6H, m), 3.65 (2H, t, J = 7.0), 3.34-3.99 (1H, m), 4.00-4.12 (2H, m), 4.26-4.40 (1H, m), 4.44 (2H, d, J = 6.8), 7.21-7.46 (4H, m). Example 213
6-chloro-2-({3-oxo-3- [4- (5,6,7,8-tetrahydroimidazo [1,2-a] pyridin-3-yl) -1-piperidinyl] propyl} sulfonyl) -1,2,3,4-tetrahydroisoquinoline hydrochloride
213a) 2-[(4-Chlorophenyl) methyl] aminoethanol hydrochloride After removing water formed, refluxing 4-chlorobenzaldehyde (14.06 g) and ethanolamine (6.18 g) in toluene (150 mL) for 1 hour The solvent was distilled off under reduced pressure. To a solution of the residue in methanol (150 mL) was added sodium triacetoxyborohydride (42.39 g), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, water was added to the residue, the pH was adjusted to 12 with 8N aqueous sodium hydroxide solution, and the mixture was extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in ethanol (100 mL), concentrated hydrochloric acid (8.2 mL) was added, and the solvent was evaporated under reduced pressure. To the residue was added 2-propanol-ether, and the precipitate was collected by filtration and washed with ether to give the title compound (18.21 g, 82%) as a white powder.
NMR (200Mz, DMSO-d ₆ ) δ: 2.93 (2H, br), 3.69 (2H, t, J = 3.6), 4.15 (2H, br), 5.27 (1H, br), 7.50 (2H, d, J = 8.8), 7.62 (2H, d, J = 8.8), 9.43 (2H, br).
213b) 6-chloro-1,2,3,4-tetrahydroisoquinoline hydrochloride 2-[(4-chlorophenyl) methyl] aminoethanol hydrochloride (22.21 g) obtained in Example 213a), ammonium chloride (4.01 g) ) And aluminum chloride (26.67 g) were stirred at 180 ° C. Aluminum chloride (26.67 g and 53.34 g, respectively) was added after 40 minutes and 80 minutes after the reaction, and the mixture was stirred at 180 ° C. for 18 hours. Ice water was added to the residue, pH was adjusted to 12 with 8N aqueous sodium hydroxide solution, and the mixture was extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in ethanol (50 mL), concentrated hydrochloric acid (8.2 mL) was added, and the solvent was evaporated under reduced pressure. To the residue was added 2-propanol-ether, and the precipitate was collected by filtration and washed with ether to give the title compound (4.08 g, 20%) as a pale yellow powder.
NMR (200Mz, DMSO-d ₆ ) δ: 3.01 (2H, t, J = 6.2), 3.35 (2H, t, J = 6.4), 4.21 (2H, s), 7.19-7.33 (3H, m), 9.80 (2H, br).
213c) Methyl 3- (chlorosulfonyl) propionate
Chlorine gas was passed through a solution of dimethyl 3,3′-dithiopropionate (23.83 g) in water (250 mL) under ice cooling at 5 ° C. or lower for 4 hours. The reaction solution was extracted with diethyl ether, and the extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was distilled under reduced pressure to obtain the title compound (10.26 g, 55%) as a yellow liquid.
NMR (200Mz, CDCl ₃ ) δ: 3.06 (2H, t, J = 7.6), 3.78 (3H, s), 4.01 (2H, t, J = 7.4).
213d) Methyl 3-[(6-chloro-1,2,3,4-tetrahydroisoquinolin-2 (1H) -yl) sulfonyl] propionate Methyl 3-chlorosulfonylpropionate (2.05) obtained in Example 213c) g) in acetonitrile (10 mL) in 6-chloro-1,2,3,4-tetrahydroisoquinoline hydrochloride (2.04 g), DBU (1.5 mL) and triethylamine (2.8 mL) obtained in Example 213b) Of acetonitrile (10 mL) was added dropwise at 0 ° C. The reaction mixture was stirred at 0 ° C. for 30 min, and the solvent was evaporated under reduced pressure. Water was added to the residue and extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from chloroform-ethanol to obtain the title compound (2.70 g, 85%) as light brown crystals.
NMR (200Mz, CDCl ₃ ) δ: 2.82 (2H, t, J = 7.2), 2.93 (2H, t, J = 5.8), 3.32 (2H, t, J = 7.8), 3.57 (2H, t, J = 5.8), 3.67 (3H, s), 4.44 (2H, s), 7.01 (1H, d, J = 8.2), 7.15 (1H, s), 7.17 (1H, d, J = 8.2).
213e) 3-[(6-Chloro-1,2,3,4-tetrahydroisoquinolin-2 (1H) -yl) sulfonyl] propionic acid 3-[(6-Chloro-1, obtained from Example 213d) Methyl 2,3,4-tetrahydroisoquinolin-2 (1H) -yl) sulfonyl] propionate (1.59 g) was added to 1N aqueous sodium hydroxide solution (15 mL), and the mixture was stirred at 100 ° C. for 40 min. 1N Hydrochloric acid (15 mL) was added to the reaction mixture at 0 ° C., and the deposited precipitate was collected by filtration and washed with water and ether to give the title compound (0.38 g, 25%) as a pale brown powder.
NMR (200Mz, DMSO-d ₆ ) δ: 2.86 (2H, t, J = 7.5), 2.93 (2H, t, J = 6.0), 3.31 (2H, t, J = 7.5), 3.57 (2H, t, J = 6.0), 4.44 (2H, s), 7.01 (1H, d, J = 8.1), 7.14-7.25 (2H, m).
213f) 6-chloro-2-({3-oxo-3- [4- (5,6,7,8-tetrahydroimidazo [1,2-a] pyridin-3-yl) -1-piperidinyl] propyl} (Sulfonyl) -1,2,3,4-tetrahydroisoquinoline hydrochloride 3-[(6-chloro-1,2,3,4-tetrahydroisoquinolin-2 (1H) -yl) sulfonyl obtained in Example 213e) From propionic acid and 3- (4-piperidinyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine dihydrochloride obtained in Example 209b) as in Example 207d) The title compound (62%) was obtained as a white powder.
NMR (200Mz, DMSO-d ₆ ) δ: 1.14-1.59 (2H, m), 1.78-2.07 (6H, m), 2.48-2.68 (1H, m), 2.75-2.84 (4H, m), 2.84-3.19 (6H, m), 3.65 (2H, t, J = 7.0), 3.34-3.99 (1H, m), 4.00-4.12 (2H, m), 4.26-4.40 (1H, m), 4.44 (2H, d, J = 6.8), 7.21-7.46 (4H, m).

実施例214
N-({1-[3-(6-クロロ-2-ナフチル)スルホニル]プロピオニル}-4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン-3-カルボキサミド
214a) 3-トリクロロアセチルイミダゾ[1,2-a]ピリジン
イミダゾ[1,2-a]ピリジン(5.52g)と4-ジメチルアミノピリジン(25.69g)のTHF(150mL)溶液へ塩化トリクロロアセチル(15.65mL)を室温で加え、激しくかき混ぜながら16時間還流した。沈殿をろ去し、ろ液を水および飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残留物をシリカゲルカラム (酢酸エチル)により精製して、題記化合物(11.70g, 95%)を淡黄色固体として得た。
NMR (200Mz, CDCl₃)δ：7.26 (1H, dt, J = 7.0, 1.2), 7.65 (1H, ddd, J = 8.8, 7.0, 1.4), 7.89 (1H, td, J = 8.8, 1.4), 8.88 (1H, s), 9.62 (1H, td, J = 7.0, 1.4).
214b) 4-{[(イミダゾ[1,2-a]ピリジン-3-イル)カルボニル]アミノ}ピペリジン-1-カルボン酸tert-ブチル
実施例213a)で得られた3-トリクロロアセチルイミダゾ[1,2-a]ピリジン(2.64g)のアセトニトリル(30mL)溶液へ4-アミノピペリジン-1-カルボン酸tert-ブチル(2.40g)とトリエチルアミン(2.8mL)を加え、60℃で3時間かき混ぜた。溶媒を減圧留去し、残留物に水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残留物をシリカゲルカラム(酢酸エチル/エタノール=10/1)により精製して、題記化合物(2.96g, 86%)を白色固体として得た。
NMR (200Mz, CDCl₃)δ：1.32-2.63 (2H, m), 1.45 (9H, s), 1.95-2.12 (2H, m), 2.81-3.02 (2H, m), 4.01-4.31 (3H, m), 6.13 (1H, d, J = 8.0), 6.99 (1H, dt, J = 7.0, 1.0), 7.37 (1H, ddd, J = 8.8, 6.6, 1.2), 7.68 (1H, td, J = 8.8, 1.0), 8.04 (1H, s), 9.48 (1H, td, J = 7.0, 1.2).
214c) 4-{[(5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン-3-イル)カルボニル]アミノ}ピペリジン-1-カルボン酸tert-ブチル
実施例213b)で得られた4-{[(イミダゾ[1,2-a]ピリジン-3-イル)カルボニル]アミノ}ピペリジン-1-カルボン酸tert-ブチル(0.69g)から実施例209a)と同様にして、題記化合物(0.66g, 94%)を白色固体として得た。
NMR (200Mz, CDCl₃)δ：1.18-1.52 (2H, m), 1.46 (9H, s), 1.81-2.07 (6H, m), 2.74-2.98 (4H, m), 3.93-4.19 (3H, m), 4.31 (2H, t, J = 5.4), 5.89 (1H, d, J = 8.2), 7.34 (1H, s).
214d) N-({1-[3-(6-クロロ-2-ナフチル)スルホニル]プロピオニル}-4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン-3-カルボキサミド
実施例213c)で得られた4-{[(5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン-3-イル)カルボニル]アミノ}ピペリジン-1-カルボン酸tert-ブチル(0.70g)から実施例207c)および実施例19)と同様の反応を順次行い、題記化合物(収率82%)を淡黄色粉末として得た。
NMR (200Mz, DMSO-d₆)δ：1.10-1.52 (2H, m), 1.64-1.93 (6H, m), 2.37-2.68 (2H, m), 2.68-2.83 (3H, m), 2.95-3.17 (1H, m), 3.20-3.41 (2H, m), 3.63 (2H, t, J = 7.6), 3.72-4.00 (2H, m), 4.17 (2H, t, J = 5.6), 7.50 (1H, s), 7.73 (1H, dd, J = 8.8, 2.2), 7.90 (1H, d, J = 7.8), 8.00 (1H, dd, J = 8.4, 1.8), 8.19 (1H, d, J = 8.8), 8.29 (1H, d, J = 9.0), 8.66 (1H, s). Example 214
N-({1- [3- (6-Chloro-2-naphthyl) sulfonyl] propionyl} -4-piperidinyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine-3-carboxamide
214a) 3-Trichloroacetylimidazo [1,2-a] pyridine Trichloroacetyl chloride (15.65) to a solution of imidazo [1,2-a] pyridine (5.52 g) and 4-dimethylaminopyridine (25.69 g) in THF (150 mL) mL) was added at room temperature and refluxed for 16 hours with vigorous stirring. The precipitate was removed by filtration, and the filtrate was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (ethyl acetate) to obtain the title compound (11.70 g, 95%) as a pale yellow solid.
NMR (200Mz, CDCl ₃ ) δ: 7.26 (1H, dt, J = 7.0, 1.2), 7.65 (1H, ddd, J = 8.8, 7.0, 1.4), 7.89 (1H, td, J = 8.8, 1.4), 8.88 (1H, s), 9.62 (1H, td, J = 7.0, 1.4).
214b) 4-{[(Imidazo [1,2-a] pyridin-3-yl) carbonyl] amino} piperidine-1-carboxylate tert-butyl 3-trichloroacetylimidazo [1, obtained in Example 213a) To a solution of 2-a] pyridine (2.64 g) in acetonitrile (30 mL) were added tert-butyl 4-aminopiperidine-1-carboxylate (2.40 g) and triethylamine (2.8 mL), and the mixture was stirred at 60 ° C. for 3 hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column (ethyl acetate / ethanol = 10/1) to obtain the title compound (2.96 g, 86%) as a white solid.
NMR (200Mz, CDCl ₃ ) δ: 1.32-2.63 (2H, m), 1.45 (9H, s), 1.95-2.12 (2H, m), 2.81-3.02 (2H, m), 4.01-4.31 (3H, m ), 6.13 (1H, d, J = 8.0), 6.99 (1H, dt, J = 7.0, 1.0), 7.37 (1H, ddd, J = 8.8, 6.6, 1.2), 7.68 (1H, td, J = 8.8 , 1.0), 8.04 (1H, s), 9.48 (1H, td, J = 7.0, 1.2).
214c) 4-{[(5,6,7,8-tetrahydroimidazo [1,2-a] pyridin-3-yl) carbonyl] amino} piperidine-1-carboxylate tert-butyl obtained in Example 213b) 4-{[(imidazo [1,2-a] pyridin-3-yl) carbonyl] amino} piperidine-1-carboxylate from tert-butyl (0.69 g) in the same manner as in Example 209a) 0.66 g, 94%) was obtained as a white solid.
NMR (200Mz, CDCl ₃ ) δ: 1.18-1.52 (2H, m), 1.46 (9H, s), 1.81-2.07 (6H, m), 2.74-2.98 (4H, m), 3.93-4.19 (3H, m ), 4.31 (2H, t, J = 5.4), 5.89 (1H, d, J = 8.2), 7.34 (1H, s).
214d) N-({1- [3- (6-chloro-2-naphthyl) sulfonyl] propionyl} -4-piperidinyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine-3 -Carboxamide 4-{[((5,6,7,8-tetrahydroimidazo [1,2-a] pyridin-3-yl) carbonyl] amino} piperidine-1-carboxylic acid tert- The same reaction as in Example 207c) and Example 19) was sequentially performed from butyl (0.70 g) to obtain the title compound (yield 82%) as a pale yellow powder.
NMR (200Mz, DMSO-d ₆ ) δ: 1.10-1.52 (2H, m), 1.64-1.93 (6H, m), 2.37-2.68 (2H, m), 2.68-2.83 (3H, m), 2.95-3.17 (1H, m), 3.20-3.41 (2H, m), 3.63 (2H, t, J = 7.6), 3.72-4.00 (2H, m), 4.17 (2H, t, J = 5.6), 7.50 (1H, s), 7.73 (1H, dd, J = 8.8, 2.2), 7.90 (1H, d, J = 7.8), 8.00 (1H, dd, J = 8.4, 1.8), 8.19 (1H, d, J = 8.8) , 8.29 (1H, d, J = 9.0), 8.66 (1H, s).

実施例215
3-(1-{3-[(3,5-ジクロロ-1H-インドール-2-イル)スルホニル]プロピオニル}-4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン塩酸塩
215a) 3-[(3,5-ジクロロ-1H-インドール-2-イル)チオ]プロピオン酸tert-ブチル
実施例211a)で得られた3-[(5-クロロ-1H-インドール-2-イル)チオ]プロピオン酸tert-ブチル(9.36g)の酢酸エチル(100mL)溶液へN-クロロこはく酸イミド(4.81g)を加え、室温で１時間かき混ぜた。反応液に水を加え、有機層を分液し、飽和チオ硫酸ナトリウム水溶液および飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、題記化合物(10.3g, 99％)を淡灰色固体と得た。
NMR (200Mz, CDCl₃)δ：1.47 (9H, s), 2.54 (2H, t, J = 6.6), 3.07 (2H, t, J = 7.0), 7.17-7.31 (2H, m), 7.52-7.59 (1H, m), 8.93 (1H, br).
215b) 3-[(3,5-ジクロロ-2-インドリル)スルホニル]プロピオン酸tert-ブチル
実施例215a)で得られた3-[(3,5-ジクロロ-1H-インドール-2-イル)チオ]プロピオン酸tert-ブチル(10.30g)から実施例211b)と同様にして、題記化合物(11.15g, 99％)を白色固体として得た。
NMR (200MHz, CDCl₃)δ：1.38 (9H, s), 2.73 (2H, t, J = 7.6), 3.68 (2H, t, J = 7.2), 7.39-7.40 (2H, m), 7.70 (1H, s), 9.30 (1H, br).
215c) 2-{[3-(アリルオキシ)-3-オキソプロピル]スルホニル}-3,5-ジクロロ-1H-インドール-1-カルボン酸 tert-ブチル
実施例215b)で得られた3-[(3,5-ジクロロ-1H-インドール-2-イル)スルホニル]プロピオン酸tert-ブチル(11.15 g, 29.47 mmol)のアリルアルコール(120mL)溶液へ濃塩酸(5.5mL)を加え、60℃で1時間かき混ぜた。溶媒を減圧留去し、残留物に水を加え、酢酸エチルで抽出した。抽出液を飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残留物と4-ジメチルアミノピリジン(3.60g)のアセトニトリル(120mL)溶液へ二炭酸ジ-tert-ブチル(6.43g)を室温で滴下し、室温で1時間かき混ぜた。溶媒を減圧留去し、残留物へ水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残留物をシリカゲルカラム (酢酸エチル/ヘキサン=1/4)で精製して、題記化合物(11.78g, 86％)を淡茶色固体として得た。
NMR (200MHz, CDCl₃)δ：1.71 (9H, s), 3.01 (2H, t, J = 8.0), 4.02 (2H, t, J = 7.8), 4.55-4.59 (2H, m), 5.20-5.35 (2H, m), 5.77-5.97 (1H, m), 7.49 (1H, dd, J = 8.8, 2.2), 7.72 (1H, d, J = 2.2), 7.87 (1H, d, J = 8.8).
215d) 3-[(1-tert-ブトキシカルボニル-3,5-ジクロロ-1H-インドール-2-イル)スルホニル]プロピオン酸
実施例215c)で得られた2-{[3-(アリルオキシ)-3-オキソプロピル]スルホニル}-3,5-ジクロロ-1H-インドール-1-カルボン酸 tert-ブチル(2.16g)から実施例211d)と同様にして、題記化合物(4.01g, 95%)を淡茶色固体として得た。
NMR (200MHz, CDCl₃)δ：1.71 (9H, s), 3.01 (2H, t, J = 7.2), 3.99 (2H, t, J = 7.6), 7.50 (1H, dd, J = 8.8, 2.2), 7.72 (1H, d, J = 2.2), 7.87 (1H, d, J = 8.8 ).
215e) 3,5-ジクロロ-2-({3-オキソ-3-[4-(5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン-3-イル)-1-ピペリジニル]プロピル}スルホニル)-1H-インドール-1-カルボン酸tert-ブチル
実施例215d)で得られた3-[(1-tert-ブトキシカルボニル-3,5-ジクロロ-1H-インドール-2-イル)スルホニル]プロピオン酸(0.42g)と実施例209b)で得られた3-(4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン２塩酸塩(0.33g)から実施例19)と同様にして、題記化合物(0.494g, 81%)を無色粉末として得た。
NMR (200MHz, CDCl₃)δ：1.50-1.68 (2H, m), 1.71 (9H, s), 1.77-2.08 (6H, m), 2.54-2.81 (1H, m), 2.83 (2H, t, J = 6.2), 2.93-3.24 (3H, m), 3.82 (2H, t, J = 6.2), 3.88-4.12 (3H, m), 4.12-4.28 (1H, m), 4.53-4.68 (1H, m), 6.67 (1H, s), 7.49 (1H, dd, J = 8.8, 2.2), 7.72 (1H, d, J = 2.2), 7.90 (1H, d, J = 8.8).
215f) 3-(1-{3-[(3,5-ジクロロ-1H-インドール-2-イル)スルホニル]プロピオニル}-4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン塩酸塩
実施例215e)で得られた3,5-ジクロロ-2-({3-オキソ-3-[4-(5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン-3-イル)-1-ピペリジニル]プロピル}スルホニル)-1H-インドール-1-カルボン酸tert-ブチル(0.31g)から実施例207c)と同様にして、題記化合物(0.17g, 62%)を白色粉末として得た。
NMR (200MHz, DMSO-d₆)δ：1.01-1.32 (1H, m), 1.32-1.61 (1H, m), 1.73-2.11 (6H, m), 2.52-2.68 (1H, m), 2.83 (2H, t, J = 6.8), 2.93-3.19 (3H, m), 3.23-3.38 (1H, m), 3.74 (2H, t, J = 7.0), 3.79-3.95 (1H, m), 4.06 (2H, t, J = 5.8), 4.18-4.32 (1H, m), 7.34 (1H, s), 7.43 (1H, dd, J = 8.8, 2.2), 7.58 (1H, d, J = 8.8), 7.70 (1H, d, J = 2.2), 7.38 (1H, br). Example 215
3- (1- {3-[(3,5-dichloro-1H-indol-2-yl) sulfonyl] propionyl} -4-piperidinyl) -5,6,7,8-tetrahydroimidazo [1,2-a ] Pyridine hydrochloride
215a) tert-Butyl 3-[(3,5-dichloro-1H-indol-2-yl) thio] propionate 3-[(5-Chloro-1H-indol-2-yl) obtained in Example 211a) N-chlorosuccinimide (4.81 g) was added to a solution of tert-butyl thio] propionate (9.36 g) in ethyl acetate (100 mL), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, and the organic layer was separated, washed with a saturated aqueous sodium thiosulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (10.3 g, 99%) as a light gray solid.
NMR (200Mz, CDCl ₃ ) δ: 1.47 (9H, s), 2.54 (2H, t, J = 6.6), 3.07 (2H, t, J = 7.0), 7.17-7.31 (2H, m), 7.52-7.59 (1H, m), 8.93 (1H, br).
215b) tert-butyl 3-[(3,5-dichloro-2-indolyl) sulfonyl] propionate 3-[(3,5-dichloro-1H-indol-2-yl) thio obtained in example 215a) The title compound (11.15 g, 99%) was obtained as a white solid from tert-butyl propionate (10.30 g) in the same manner as in Example 211b).
NMR (200MHz, CDCl ₃ ) δ: 1.38 (9H, s), 2.73 (2H, t, J = 7.6), 3.68 (2H, t, J = 7.2), 7.39-7.40 (2H, m), 7.70 (1H , s), 9.30 (1H, br).
215c) 2-{[3- (allyloxy) -3-oxopropyl] sulfonyl} -3,5-dichloro-1H-indole-1-carboxylate tert-butyl 3-[(3 Concentrated hydrochloric acid (5.5 mL) was added to a solution of tert-butyl propionate (11.15 g, 29.47 mmol) in allyl alcohol (120 mL), and the mixture was stirred at 60 ° C. for 1 hour. It was. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Di-tert-butyl dicarbonate (6.43 g) was added dropwise to a solution of the obtained residue and 4-dimethylaminopyridine (3.60 g) in acetonitrile (120 mL) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (ethyl acetate / hexane = 1/4) to obtain the title compound (11.78 g, 86%) as a light brown solid.
NMR (200MHz, CDCl ₃ ) δ: 1.71 (9H, s), 3.01 (2H, t, J = 8.0), 4.02 (2H, t, J = 7.8), 4.55-4.59 (2H, m), 5.20-5.35 (2H, m), 5.77-5.97 (1H, m), 7.49 (1H, dd, J = 8.8, 2.2), 7.72 (1H, d, J = 2.2), 7.87 (1H, d, J = 8.8).
215d) 3-[(1-tert-Butoxycarbonyl-3,5-dichloro-1H-indol-2-yl) sulfonyl] propionic acid 2-{[3- (allyloxy) -3 obtained in Example 215c) -Oxopropyl] sulfonyl} -3,5-dichloro-1H-indole-1-carboxylate from tert-butyl (2.16 g) in the same manner as in Example 211 d) to give the title compound (4.01 g, 95%) as a light brown Obtained as a solid.
NMR (200MHz, CDCl ₃ ) δ: 1.71 (9H, s), 3.01 (2H, t, J = 7.2), 3.99 (2H, t, J = 7.6), 7.50 (1H, dd, J = 8.8, 2.2) , 7.72 (1H, d, J = 2.2), 7.87 (1H, d, J = 8.8).
215e) 3,5-dichloro-2-({3-oxo-3- [4- (5,6,7,8-tetrahydroimidazo [1,2-a] pyridin-3-yl) -1-piperidinyl] Propyl} sulfonyl) -1H-indole-1-carboxylate tert-butyl 3-[(1-tert-butoxycarbonyl-3,5-dichloro-1H-indol-2-yl) sulfonyl obtained in Example 215d) ] From propionic acid (0.42 g) and 3- (4-piperidinyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine dihydrochloride (0.33 g) obtained in Example 209b) In the same manner as in Example 19), the title compound (0.494 g, 81%) was obtained as a colorless powder.
NMR (200MHz, CDCl ₃ ) δ: 1.50-1.68 (2H, m), 1.71 (9H, s), 1.77-2.08 (6H, m), 2.54-2.81 (1H, m), 2.83 (2H, t, J = 6.2), 2.93-3.24 (3H, m), 3.82 (2H, t, J = 6.2), 3.88-4.12 (3H, m), 4.12-4.28 (1H, m), 4.53-4.68 (1H, m) , 6.67 (1H, s), 7.49 (1H, dd, J = 8.8, 2.2), 7.72 (1H, d, J = 2.2), 7.90 (1H, d, J = 8.8).
215f) 3- (1- {3-[(3,5-dichloro-1H-indol-2-yl) sulfonyl] propionyl} -4-piperidinyl) -5,6,7,8-tetrahydroimidazo [1,2 -a] pyridine hydrochloride 3,5-dichloro-2-({3-oxo-3- [4- (5,6,7,8-tetrahydroimidazo [1,2-a] obtained in Example 215e) ] Pyridin-3-yl) -1-piperidinyl] propyl} sulfonyl) -1H-indole-1-carboxylate from tert-butyl (0.31 g) in the same manner as in Example 207c) to give the title compound (0.17 g, 62% ) Was obtained as a white powder.
NMR (200MHz, DMSO-d ₆ ) δ: 1.01-1.32 (1H, m), 1.32-1.61 (1H, m), 1.73-2.11 (6H, m), 2.52-2.68 (1H, m), 2.83 (2H , t, J = 6.8), 2.93-3.19 (3H, m), 3.23-3.38 (1H, m), 3.74 (2H, t, J = 7.0), 3.79-3.95 (1H, m), 4.06 (2H, t, J = 5.8), 4.18-4.32 (1H, m), 7.34 (1H, s), 7.43 (1H, dd, J = 8.8, 2.2), 7.58 (1H, d, J = 8.8), 7.70 (1H , d, J = 2.2), 7.38 (1H, br).

実施例216
3-(1-{3-[(3,5-ジクロロ-1H-インドール-2-イル)スルホニル]プロピオニル}-4-ピペリジニル)イミダゾ[1,2-a]ピリジン塩酸塩
216a) 3,5-ジクロロ-2-({3-オキソ-3-[4-(イミダゾ[1,2-a]ピリジン-3-イル)-1-ピペリジニル]プロピル}スルホニル)-1H-インドール-1-カルボン酸tert-ブチル
実施例211d)で得られた3-[(1-tert-ブトキシカルボニル-5-クロロ-1H-インドール-2-イル)スルホニル]プロピオン酸(0.42g)と実施例207c)で得られた 3-(4-ピペリジニル)イミダゾ[1,2-a]ピリジン２塩酸塩(0.33g)から実施例19)と同様にして、題記化合物(0.50g, 83%)を無色粉末として得た。
NMR (200Mz, CDCl₃)δ：1.56-1.86 (2H, m), 1.74 (9H, s), 1.99-2.28 (2H, m), 2.73-2.91 (1H, m), 2.91-3.21 (3H, m), 3.21-3.39 (1H, m), 3.95-4.36 (3H, m), 4.60-4.75 (1H, m), 6.82-6.89 (1H, m), 7.15-7.22 (1H, m), 7.40 (1H, s), 7.49 (1H, dd, J = 8.8, 2.2), 7.65 (1H, dd, J = 8.8, 2.2), 7.72 (1H, d, J = 2.2), 7.90 (1H, d, J = 8.4), 7.96 (1H, d, J = 7.0).
216b) 3-(1-{3-[(3,5-ジクロロ-1H-インドール-2-イル)スルホニル]プロピオニル}-4-ピペリジニル)イミダゾ[1,2-a]ピリジン塩酸塩
実施例216a)で得られた3,5-ジクロロ-2-({3-オキソ-3-[4-(イミダゾ[1,2-a]ピリジン-3-イル)-1-ピペリジニル]プロピル}スルホニル)-1H-インドール-1-カルボン酸tert-ブチル(0.30g)から実施例207c)と同様にして、題記化合物(0.13g, 48%)を白色粉末として得た。
NMR (200Mz, DMSO-d₆)δ：1.24-1.74 (2H, m), 1.88-2.12 (2H, m), 2.56-2.78 (1H, m), 2.86 (2H, t, J = 7.0), 3.08-3.57 (2H, m), 2.66-2.81 (2H, m), 2.85-4.02 (1H, m), 4.25-4.40 (1H, m), 7.43 (1H, dd, J = 8.8, 2.2), 7.50-7.60 (2H, m), 7.69 (1H, d, J = 2.2), 7.95-8.04 (3H, m), 9.02 (1H, d, J = 6.8), 9.38 (1H, br). Example 216
3- (1- {3-[(3,5-Dichloro-1H-indol-2-yl) sulfonyl] propionyl} -4-piperidinyl) imidazo [1,2-a] pyridine hydrochloride
216a) 3,5-dichloro-2-({3-oxo-3- [4- (imidazo [1,2-a] pyridin-3-yl) -1-piperidinyl] propyl} sulfonyl) -1H-indole- Tert-Butyl 1-carboxylate 3-[(1-tert-Butoxycarbonyl-5-chloro-1H-indol-2-yl) sulfonyl] propionic acid (0.42 g) obtained in Example 211d) and Example 207c The title compound (0.50 g, 83%) was obtained as a colorless powder in the same manner as in Example 19) from 3- (4-piperidinyl) imidazo [1,2-a] pyridine dihydrochloride (0.33 g) obtained in (1). Got as.
NMR (200Mz, CDCl ₃ ) δ: 1.56-1.86 (2H, m), 1.74 (9H, s), 1.99-2.28 (2H, m), 2.73-2.91 (1H, m), 2.91-3.21 (3H, m ), 3.21-3.39 (1H, m), 3.95-4.36 (3H, m), 4.60-4.75 (1H, m), 6.82-6.89 (1H, m), 7.15-7.22 (1H, m), 7.40 (1H , s), 7.49 (1H, dd, J = 8.8, 2.2), 7.65 (1H, dd, J = 8.8, 2.2), 7.72 (1H, d, J = 2.2), 7.90 (1H, d, J = 8.4 ), 7.96 (1H, d, J = 7.0).
216b) 3- (1- {3-[(3,5-dichloro-1H-indol-2-yl) sulfonyl] propionyl} -4-piperidinyl) imidazo [1,2-a] pyridine hydrochloride Example 216a) 3,5-dichloro-2-({3-oxo-3- [4- (imidazo [1,2-a] pyridin-3-yl) -1-piperidinyl] propyl} sulfonyl) -1H- The title compound (0.13 g, 48%) was obtained as a white powder from tert-butyl indole-1-carboxylate (0.30 g) in the same manner as in Example 207c).
NMR (200Mz, DMSO-d ₆ ) δ: 1.24-1.74 (2H, m), 1.88-2.12 (2H, m), 2.56-2.78 (1H, m), 2.86 (2H, t, J = 7.0), 3.08 -3.57 (2H, m), 2.66-2.81 (2H, m), 2.85-4.02 (1H, m), 4.25-4.40 (1H, m), 7.43 (1H, dd, J = 8.8, 2.2), 7.50- 7.60 (2H, m), 7.69 (1H, d, J = 2.2), 7.95-8.04 (3H, m), 9.02 (1H, d, J = 6.8), 9.38 (1H, br).

実施例217
3-(1-{3-[(5-クロロ-1,3-ジヒドロ-2H-イソインドール-2-イル)スルホニル]プロピオニル}-4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン塩酸塩
217a) 5-クロロ-2-[(4-メチルフェニル)スルホニル]イソインドリン
1-クロロ-3,4-ジメチルベンゼン(10.85g)、N-ブロモこはく酸イミド(30.22g)および2,2'-アゾビスイソブチロニトリル(0.63g)の四塩化炭素(100mL)けん濁液を3時間還流した。反応液へ2,2'-アゾビスイソブチロニトリル(0.63g)を追加し、さらに3時間還流した。沈殿物をろ去し、ろ液を減圧濃縮した。残留物のDMF(250mL)溶液へパラトルエンスルホンアミド(15.9g)と炭酸カリウム(32.0g)を加え、室温で24時間かき混ぜた。生成した沈殿物をろ取し、酢酸エチルに溶解した。酢酸エチル溶液を水と飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残留物を酢酸エチル-ジエチルエーテルから結晶化して、題記化合物(14.25g, 60%)を白色結晶として得た。
NMR (200Mz, CDCl₃)δ：2.41 (3H, s), 4.58 (4H, s), 7.07-7.22 (3H, m), 7.32 (2H, d, J = 8.0), 7.76 (2H, d, J = 8.0).
217b) 5-クロロイソインドリン臭化水素酸塩
実施例217a)で得られた5-クロロ-2-[(4-メチルフェニル)スルホニル]イソインドリン(13.85g)を25%臭化水素酸酢酸溶液(135mL)に加え、室温で16時間かき混ぜた。溶媒を減圧留去し、残留物へ酢酸エチルを加え、不溶物をろ取、ジエチルエーテルで洗浄して、題記化合物(10.1g, 96%)を白色固体として得た。
NMR (200Mz, DMSO-d₆)δ：4.52 (4H, br), 7.38-7.49 (2H, m), 7.52 (1H, s), 9.57 (2H, br).
217c) 3-[(5-クロロ-1,3-ジヒドロ-2H-イソインドール-2-イル)スルホニル]プロピオン酸メチル
実施例217b)で得られた5-クロロイソインドリン臭化水素酸塩(7.04g)と実施例213c)で得られた3-クロロスルホニルプロピオン酸メチル(6.72g)から実施例213d)と同様にして、題記化合物(7.93g, 87%)を淡黄色固体として得た。
NMR (200Mz, CDCl₃)δ：2.86 (2H, t, J = 7.4), 3.40 (2H, t, J = 7.2), 3.61 (3H, s), 4.69 (4H, s), 7.13-7.32 (3H, m).
217d) 3-[(5-クロロ-1,3-ジヒドロ-2H-イソインドール-2-イル)スルホニル]プロピオン酸
実施例217c)で得られた3-[(5-クロロ-1,3-ジヒドロ-2H-イソインドール-2-イル)スルホニル]プロピオン酸メチル(7.00g)から実施例213e)と同様にして、題記化合物(1.65g, 25%)を淡紫色粉末として得た。
NMR (200Mz, DMSO-d₆)δ：2.67 (2H, t, J = 7.0), 3.41 (2H, t, J = 7.4), 4.65 (4H, s), 7.06-7.52 (3H, m).
217e) 3-(1-{3-[(5-クロロ-1,3-ジヒドロ-2H-イソインドール-2-イル)スルホニル]プロピオニル}-4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン塩酸塩
実施例217d)で得られた3-[(5-クロロ-1,3-ジヒドロ-2H-イソインドール-2-イル)スルホニル]プロピオン酸と実施例209b)で得られた3-(4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン２塩酸塩から実施例207d)と同様にして、題記化合物(72%)を白色粉末として得た。
NMR (200Mz, DMSO-d₆)δ：1.14-1.63 (2H, m), 1.77-2.08 (6H, m), 2.54-2.73 (1H, m), 2.80 (2H, t, J = 7.0), 2.96 (2H, t, J = 5.4), 3.01-3.22 (1H, m), 3.32-3.48 (2H, m), 3.69-4.02 (2H, m), 4.07 (2H, t, J = 5.4), 4.29-4.48 (1H, m), 4.66 (4H, s), 7.36-7.47 (4H, m). Example 217
3- (1- {3-[(5-Chloro-1,3-dihydro-2H-isoindol-2-yl) sulfonyl] propionyl} -4-piperidinyl) -5,6,7,8-tetrahydroimidazo [ 1,2-a] pyridine hydrochloride
217a) 5-Chloro-2-[(4-methylphenyl) sulfonyl] isoindoline
Carbon tetrachloride (100 mL) suspension of 1-chloro-3,4-dimethylbenzene (10.85 g), N-bromosuccinimide (30.22 g) and 2,2'-azobisisobutyronitrile (0.63 g) The solution was refluxed for 3 hours. 2,2′-Azobisisobutyronitrile (0.63 g) was added to the reaction solution, and the mixture was further refluxed for 3 hours. The precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. To a DMF (250 mL) solution of the residue were added paratoluenesulfonamide (15.9 g) and potassium carbonate (32.0 g), and the mixture was stirred at room temperature for 24 hours. The formed precipitate was collected by filtration and dissolved in ethyl acetate. The ethyl acetate solution was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was crystallized from ethyl acetate-diethyl ether to give the title compound (14.25 g, 60%) as white crystals.
NMR (200Mz, CDCl ₃ ) δ: 2.41 (3H, s), 4.58 (4H, s), 7.07-7.22 (3H, m), 7.32 (2H, d, J = 8.0), 7.76 (2H, d, J = 8.0).
217b) 5-Chloroisoindoline hydrobromide 5-chloro-2-[(4-methylphenyl) sulfonyl] isoindoline (13.85 g) obtained in Example 217a) was added to a 25% acetic acid hydrobromic acid solution (135 mL) and stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure, ethyl acetate was added to the residue, the insoluble material was collected by filtration, and washed with diethyl ether to give the title compound (10.1 g, 96%) as a white solid.
NMR (200Mz, DMSO-d ₆ ) δ: 4.52 (4H, br), 7.38-7.49 (2H, m), 7.52 (1H, s), 9.57 (2H, br).
217c) Methyl 3-[(5-chloro-1,3-dihydro-2H-isoindol-2-yl) sulfonyl] propionate 5-chloroisoindoline hydrobromide (7.04) obtained in Example 217b) The title compound (7.93 g, 87%) was obtained as a pale yellow solid from methyl 3-chlorosulfonylpropionate (6.72 g) obtained in g) and Example 213c) in the same manner as in Example 213d).
NMR (200Mz, CDCl ₃ ) δ: 2.86 (2H, t, J = 7.4), 3.40 (2H, t, J = 7.2), 3.61 (3H, s), 4.69 (4H, s), 7.13-7.32 (3H , m).
217d) 3-[(5-Chloro-1,3-dihydro-2H-isoindol-2-yl) sulfonyl] propionic acid 3-[(5-Chloro-1,3-dihydro) obtained in Example 217c) The title compound (1.65 g, 25%) was obtained as a pale purple powder from methyl -2H-isoindol-2-yl) sulfonyl] propionate (7.00 g) in the same manner as in Example 213e).
NMR (200Mz, DMSO-d ₆ ) δ: 2.67 (2H, t, J = 7.0), 3.41 (2H, t, J = 7.4), 4.65 (4H, s), 7.06-7.52 (3H, m).
217e) 3- (1- {3-[(5-Chloro-1,3-dihydro-2H-isoindol-2-yl) sulfonyl] propionyl} -4-piperidinyl) -5,6,7,8-tetrahydro Imidazo [1,2-a] pyridine hydrochloride 3-[(5-Chloro-1,3-dihydro-2H-isoindol-2-yl) sulfonyl] propionic acid obtained in Example 217d) and Example 209b The title compound (72%) was obtained in the same manner as in Example 207d) from 3- (4-piperidinyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine dihydrochloride obtained in (1). Was obtained as a white powder.
NMR (200Mz, DMSO-d ₆ ) δ: 1.14-1.63 (2H, m), 1.77-2.08 (6H, m), 2.54-2.73 (1H, m), 2.80 (2H, t, J = 7.0), 2.96 (2H, t, J = 5.4), 3.01-3.22 (1H, m), 3.32-3.48 (2H, m), 3.69-4.02 (2H, m), 4.07 (2H, t, J = 5.4), 4.29- 4.48 (1H, m), 4.66 (4H, s), 7.36-7.47 (4H, m).

実施例218
3-(1-{3-[(5-クロロ-1,3-ジヒドロ-2H-イソインドール-2-イル)スルホニル]プロピオニル}-4-ピペリジニル)イミダゾ[1,2-a]ピリジン塩酸塩
実施例217d)で得られた3-[(5-クロロ-1,3-ジヒドロ-2H-イソインドール-2-イル)スルホニル]プロピオン酸と実施例207c)で得られた 3-(4-ピペリジニル)イミダゾ[1,2-a]ピリジン２塩酸塩から実施例207d)と同様にして、題記化合物(54%)を白色粉末として得た。
NMR (200Mz, DMSO-d₆)δ：1.52-1.76 (2H, m), 1.95-2.16 (2H, m), 2.65-2.90 (3H, m), 3.13-3.34 (1H, m), 3.38-3.72 (3H, m), 3.92-4.09 (1H, m), 4.37-4.52 (1H, m), 4.67 (4H, s), 7.36-7.44 (3H, m), 7.51-7.59 (1H, m), 7.92-7.99 (2H, m), 8.07 (1H, s), 9.05 (1H, d, J = 7.0). Example 218
3- (1- {3-[(5-Chloro-1,3-dihydro-2H-isoindol-2-yl) sulfonyl] propionyl} -4-piperidinyl) imidazo [1,2-a] pyridine hydrochloride 3-[(5-Chloro-1,3-dihydro-2H-isoindol-2-yl) sulfonyl] propionic acid obtained in Example 217d) and 3- (4-piperidinyl) obtained in Example 207c) The title compound (54%) was obtained as a white powder from imidazo [1,2-a] pyridine dihydrochloride in the same manner as in Example 207d).
NMR (200Mz, DMSO-d ₆ ) δ: 1.52-1.76 (2H, m), 1.95-2.16 (2H, m), 2.65-2.90 (3H, m), 3.13-3.34 (1H, m), 3.38-3.72 (3H, m), 3.92-4.09 (1H, m), 4.37-4.52 (1H, m), 4.67 (4H, s), 7.36-7.44 (3H, m), 7.51-7.59 (1H, m), 7.92 -7.99 (2H, m), 8.07 (1H, s), 9.05 (1H, d, J = 7.0).

実施例219
N-{[5-クロロ-2-({3-オキソ-3-[4-(5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン-3-イル)-1-ピペリジニル]プロピル}スルホニル)-1H-インドール-3-イル]メチル}-N-メチルアセトアミド塩酸塩
219a) 2-[(3-tert-ブトキシ-3-オキソプロピル)チオ]-5-クロロ-1H-インドール-1-カルボン酸tert-ブチル
実施例211a)で得られた3-[(5-クロロ-1H-インドール-2-イル)チオ]プロピオン酸tert-ブチル(6.24g)と4-ジメチルアミノピリジン(3.67g)のアセトニトリル(65mL)溶液へ二炭酸ジ-tert-ブチル(6.55g)を室温で滴下し、さらに室温で30分間かき混ぜた。溶媒を減圧留去し、残留物へ水を加え、酢酸エチルで抽出した。抽出液を1N塩酸、1N水酸化ナトリウム水溶液、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去して、題記化合物(8.22g, 定量的)を白色固体として得た。
NMR (200Mz, CDCl₃)δ：1.48 (9H, s), 1.70 (9H, s), 2.69 (2H, t, J = 7.8), 3.18 (2H, t, J = 7.2), 6.29 (1H, s), 7.14 (1H, dd, J = 8.8, 2.2), 7.37 (1H, d, J = 2.2), 7.92 (1H, d, J = 8.8).
219b) 2-[(3-tert-ブトキシ-3-オキソプロピル)チオ]-5-クロロ-3-ホルミル-1H-インドール-1-カルボン酸tert-ブチル
実施例219a)で得られた2-[(3-tert-ブトキシ-3-オキソプロピル)チオ]-5-クロロ-1H-インドール-1-カルボン酸tert-ブチル(8.22g)のアセトニトリル(100mL)溶液へ室温で塩化(クロロメチレン)ジメチルアンモニウム(6.40g)を加え、室温で16時間かき混ぜた。溶媒を減圧留去し、残留物へ飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去して、題記化合物(8.80g, 定量的)を淡黄色固体として得た。
NMR (200Mz, CDCl₃)δ：1.41 (9H, s), 1.74 (9H, s), 2.52 (2H, t, J = 7.0), 3.23 (2H, t, J = 7.0), 7.36 (1H, dd, J = 8.8, 2.2), 7.94 (1H, d, J = 8.8), 8.38 (1H, d, J = 2.2), 10.41 (1H, s).
219c) 3-{[アセチル(メチル)アミノ]メチル}-2-[(3-tert-ブトキシ-3-オキソプロピル)チオ]-5-クロロ-1H-インドール-1-カルボン酸tertブチル
実施例219b)で得られた2-[(3-tert-ブトキシ-3-オキソプロピル)チオ]-5-クロロ-3-ホルミル-1H-インドール-1-カルボン酸tert-ブチル(8.80g)のクロロホルム(50mL)-酢酸(50mL)溶液へ40%メチルアミンメタノール溶液(21mL)を0℃で滴下し、室温で30分間かき混ぜた。反応液へ室温でトリアセトキシ水素化ホウ素ナトリウム(8.48g)を少量づつ加え、室温で3時間かき混ぜた。溶媒を減圧留去し、残留物へ水を加え、酢酸エチルで抽出した。抽出液を飽和炭酸水素ナトリウム水溶液および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。残留物のアセトニトリル(100mL)溶液へ4-ジメチルアミノピリジン(3.67g)とトリエチルアミン(5.6mL)を加え、次に無水酢酸(2.8mL)を室温で滴下した。反応液を室温で30分間かき混ぜた後、溶媒を減圧留去した。残留物へ水を加え、酢酸エチルで抽出した。抽出液を1N塩酸、1N水酸化ナトリウム水溶液、ついで飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、題記化合物(9.94g, 定量的)を黄色粉末として得た。
NMR (200Mz, CDCl₃)δ：1.42 (9H, s), 1.72 (9H, s), 2.14 (3H, s), 2.44 (2H, t, J = 7.0), 2.81 (3H, s), 3.08 (2H, t, J = 6.8), 4.96 (2H, s), 7.29 (1H, dd, J = 8.4, 2.2), 7.71 (1H, d, J = 2.2), 7.97 (1H, d, J = 8.4).
219d) 3-{[アセチル(メチル)アミノ]メチル}-2-[(3-tert-ブトキシ-3-オキソプロピル)スルホニル]-5-クロロ-1H-インドール-1-カルボン酸tertブチル
実施例219c)で得られた3-{[アセチル(メチル)アミノ]メチル}-2-[(3-tert-ブトキシ-3-オキソプロピル)チオ]-5-クロロ-1H-インドール-1-カルボン酸tertブチル(9.94g)から実施例211b)と同様にして、題記化合物(10.6g, 定量的)を褐色油状物として得た。
NMR (200MHz, CDCl₃)δ：1.42 (9H, s), 1.73 (9H, s), 2.19 (3H, s), 2.79 (2H, t, J = 7.2), 2.90 (3H, s), 4.00 (2H, t, J = 7.2), 5.23 (2H, s), 7.38-7.48 (2H, m), 7.80-7.84 (1H, m).
219e) 3-{[アセチル(メチル)アミノ]メチル}-2-{[3-(アリルオキシ)-3-オキソプロピル]スルホニル}-5-クロロ-1H-インドール-1-カルボン酸 tert-ブチル
実施例219d)で得られた3-{[アセチル(メチル)アミノ]メチル}-2-[(3-tert-ブトキシ-3-オキソプロピル)スルホニル]-5-クロロ-1H-インドール-1-カルボン酸tertブチル(10.6g)から実施例215c)と同様にして、題記化合物(2.98g, 29%)を褐色油状物として得た。
NMR (200MHz, CDCl₃)δ：1.71 (9H, s), 2.16 (3H, s), 2.90 (3H, s), 2.95 (2H, t, J = 7.8), 4.07 (2H, t, J = 7.8), 4.57 (2H, d, J = 5.8), 5.20 (2H, s), 5.26-5.36 (2H, m), 5.77-5.98 (1H, m), 7.41-7.47 (1H, m), 7.79-7.86 (2H, m).
219f) 3-{[3-{[アセチル(メチル)アミノ]メチル}-1-(tert-ブトキシカルボニル)-5-クロロ-1H-インドール-2-イル]スルホニル}プロピオン酸
実施例219e)で得られた3-{[アセチル(メチル)アミノ]メチル}-2-{[3-(アリルオキシ)-3-オキソプロピル]スルホニル}-5-クロロ-1H-インドール-1-カルボン酸 tert-ブチル(2.98g)から実施例211d)と同様にして、題記化合物(1.73g, 63%)を淡褐色粉末として得た。
NMR (200MHz, DMSO-d₆)δ：1.67 (9H, s), 2.08 (3H, s), 2.76 (2H, t, J = 7.2), 2.85 (3H, s), 4.03 (2H, t, J = 7.0), 5.03 (2H, s), 7.60 (1H, dd, J = 8.8, 2.2), 7.77 (1H, d, J = 2.2), 7.90 (1H, d, J = 8.8).
219g) N-{[5-クロロ-2-({3-オキソ-3-[4-(5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン-3-イル)-1-ピペリジニル]プロピル}スルホニル)-1H-インドール-3-イル]メチル}-N-メチルアセトアミド塩酸塩
実施例219f)で得られた3-{[3-{[アセチル(メチル)アミノ]メチル}-1-(tert-ブトキシカルボニル)-5-クロロ-1H-インドール-2-イル]スルホニル}プロピオン酸と実施例209b)で得られた3-(4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン２塩酸塩から実施例207d)と同様にして、題記化合物(収率 30%)を無色粉末として得た。
NMR (200MHz, DMSO-d₆)δ：1.15-1.56 (2H, m), 1.75-2.09 (6H, m), 2.09 (3H, s), 2.48-2.69 (2H, m), 2.77 (2H, t, J = 7.2 ), 2.83-3.18 (3H, m), 2.86 (3H, s), 3.68 (2H, t, J = 6.6), 3.82-3.98 (1H, m), 3.99-4.13 (2H, m), 4.25-4.40 (1H, m), 5.22 (2H, s), 7.32-7.38 (2H, m), 7.54 (1H, d, J = 8.8), 7.77 (1H, br), 7.80 (1H, d, J = 1.8). Example 219
N-{[5-Chloro-2-({3-oxo-3- [4- (5,6,7,8-tetrahydroimidazo [1,2-a] pyridin-3-yl) -1-piperidinyl] Propyl} sulfonyl) -1H-indol-3-yl] methyl} -N-methylacetamide hydrochloride
219a) tert-Butyl 2-[(3-tert-butoxy-3-oxopropyl) thio] -5-chloro-1H-indole-1-carboxylate 3-[(5-Chloroform) obtained in Example 211a) -1H-Indol-2-yl) thio] propionate tert-butyl (6.24 g) and 4-dimethylaminopyridine (3.67 g) in acetonitrile (65 mL) solution with di-tert-butyl dicarbonate (6.55 g) at room temperature The mixture was added dropwise and stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (8.22 g, quantitative) as a white solid.
NMR (200Mz, CDCl ₃ ) δ: 1.48 (9H, s), 1.70 (9H, s), 2.69 (2H, t, J = 7.8), 3.18 (2H, t, J = 7.2), 6.29 (1H, s ), 7.14 (1H, dd, J = 8.8, 2.2), 7.37 (1H, d, J = 2.2), 7.92 (1H, d, J = 8.8).
219b) 2-[(3-tert-Butoxy-3-oxopropyl) thio] -5-chloro-3-formyl-1H-indole-1-carboxylate tert-butyl obtained in Example 219a) (Chloromethylene) dimethylammonium chloride to a solution of tert-butyl (3-tert-butoxy-3-oxopropyl) thio] -5-chloro-1H-indole-1-carboxylate (8.22 g) in acetonitrile (100 mL) at room temperature (6.40 g) was added and stirred at room temperature for 16 hours. The solvent was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (8.80 g, quantitative) as a pale yellow solid.
NMR (200Mz, CDCl ₃ ) δ: 1.41 (9H, s), 1.74 (9H, s), 2.52 (2H, t, J = 7.0), 3.23 (2H, t, J = 7.0), 7.36 (1H, dd , J = 8.8, 2.2), 7.94 (1H, d, J = 8.8), 8.38 (1H, d, J = 2.2), 10.41 (1H, s).
219c) tertbutyl 3-{[acetyl (methyl) amino] methyl} -2-[(3-tert-butoxy-3-oxopropyl) thio] -5-chloro-1H-indole-1-carboxylate Example 219b ) 2-[(3-tert-butoxy-3-oxopropyl) thio] -5-chloro-3-formyl-1H-indole-1-carboxylate (8.80 g) in chloroform (50 mL) ) -Acetic acid (50 mL) solution was added dropwise with 40% methylamine methanol solution (21 mL) at 0 ° C. and stirred at room temperature for 30 minutes. To the reaction solution, sodium triacetoxyborohydride (8.48 g) was added little by little at room temperature, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a solution of the residue in acetonitrile (100 mL), 4-dimethylaminopyridine (3.67 g) and triethylamine (5.6 mL) were added, and then acetic anhydride (2.8 mL) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 30 minutes, and the solvent was evaporated under reduced pressure. Water was added to the residue and extracted with ethyl acetate. The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (9.94 g, quantitative) as a yellow powder.
NMR (200Mz, CDCl ₃ ) δ: 1.42 (9H, s), 1.72 (9H, s), 2.14 (3H, s), 2.44 (2H, t, J = 7.0), 2.81 (3H, s), 3.08 ( 2H, t, J = 6.8), 4.96 (2H, s), 7.29 (1H, dd, J = 8.4, 2.2), 7.71 (1H, d, J = 2.2), 7.97 (1H, d, J = 8.4) .
219d) tertbutyl 3-{[acetyl (methyl) amino] methyl} -2-[(3-tert-butoxy-3-oxopropyl) sulfonyl] -5-chloro-1H-indole-1-carboxylate Example 219c ) 3-{[acetyl (methyl) amino] methyl} -2-[(3-tert-butoxy-3-oxopropyl) thio] -5-chloro-1H-indole-1-carboxylate The title compound (10.6 g, quantitative) was obtained as a brown oil in the same manner as in Example 211b) from (9.94 g).
NMR (200MHz, CDCl ₃ ) δ: 1.42 (9H, s), 1.73 (9H, s), 2.19 (3H, s), 2.79 (2H, t, J = 7.2), 2.90 (3H, s), 4.00 ( 2H, t, J = 7.2), 5.23 (2H, s), 7.38-7.48 (2H, m), 7.80-7.84 (1H, m).
219e) tert-Butyl 3-{[acetyl (methyl) amino] methyl} -2-{[3- (allyloxy) -3-oxopropyl] sulfonyl} -5-chloro-1H-indole-1-carboxylate 219d) 3-{[acetyl (methyl) amino] methyl} -2-[(3-tert-butoxy-3-oxopropyl) sulfonyl] -5-chloro-1H-indole-1-carboxylic acid tert The title compound (2.98 g, 29%) was obtained as a brown oil in the same manner as in Example 215c) from butyl (10.6 g).
NMR (200MHz, CDCl ₃ ) δ: 1.71 (9H, s), 2.16 (3H, s), 2.90 (3H, s), 2.95 (2H, t, J = 7.8), 4.07 (2H, t, J = 7.8 ), 4.57 (2H, d, J = 5.8), 5.20 (2H, s), 5.26-5.36 (2H, m), 5.77-5.98 (1H, m), 7.41-7.47 (1H, m), 7.79-7.86 (2H, m).
219f) 3-{[3-{[acetyl (methyl) amino] methyl} -1- (tert-butoxycarbonyl) -5-chloro-1H-indol-2-yl] sulfonyl} propionic acid obtained in Example 219e) 3-{[acetyl (methyl) amino] methyl} -2-{[3- (allyloxy) -3-oxopropyl] sulfonyl} -5-chloro-1H-indole-1-carboxylate tert-butyl (2.98 The title compound (1.73 g, 63%) was obtained as a pale brown powder in the same manner as in Example 211d) from g).
NMR (200MHz, DMSO-d ₆ ) δ: 1.67 (9H, s), 2.08 (3H, s), 2.76 (2H, t, J = 7.2), 2.85 (3H, s), 4.03 (2H, t, J = 7.0), 5.03 (2H, s), 7.60 (1H, dd, J = 8.8, 2.2), 7.77 (1H, d, J = 2.2), 7.90 (1H, d, J = 8.8).
219 g) N-{[5-Chloro-2-({3-oxo-3- [4- (5,6,7,8-tetrahydroimidazo [1,2-a] pyridin-3-yl) -1- Piperidinyl] propyl} sulfonyl) -1H-indol-3-yl] methyl} -N-methylacetamide hydrochloride 3-{[3-{[acetyl (methyl) amino] methyl} -1 obtained in Example 219f) -(tert-Butoxycarbonyl) -5-chloro-1H-indol-2-yl] sulfonyl} propionic acid and 3- (4-piperidinyl) -5,6,7,8-tetrahydro The title compound (yield 30%) was obtained as a colorless powder from imidazo [1,2-a] pyridine dihydrochloride in the same manner as in Example 207d).
NMR (200MHz, DMSO-d ₆ ) δ: 1.15-1.56 (2H, m), 1.75-2.09 (6H, m), 2.09 (3H, s), 2.48-2.69 (2H, m), 2.77 (2H, t , J = 7.2), 2.83-3.18 (3H, m), 2.86 (3H, s), 3.68 (2H, t, J = 6.6), 3.82-3.98 (1H, m), 3.99-4.13 (2H, m) , 4.25-4.40 (1H, m), 5.22 (2H, s), 7.32-7.38 (2H, m), 7.54 (1H, d, J = 8.8), 7.77 (1H, br), 7.80 (1H, d, J = 1.8).

実施例220
2-{[5-クロロ-2-({3-オキソ-3-[4-(5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン-3-イル)-1-ピペリジニル]プロピル}スルホニル)-1H-インドール-1-イル]-N,N-ジメチルアセトアミド塩酸塩
220a) 3-{5-クロロ-1-[(ジメチルカルバモイル)メチル]-1H-インドール-2-イル}チオ]プロピオン酸tert-ブチル
実施例211a)で得られた3-[(5-クロロ-1H-インドリル-2-イル)チオ]プロピオン酸tert-ブチル(6.24g)のTHF(65mL)溶液へ0℃で水素化ナトリウム(60%油性：0.96g)を加えアルゴン下0℃で30分間かき混ぜた後、2-クロロ-N,N-ジメチルアセトアミド(4.86g)を加え、さらに室温で3時間かき混ぜた。反応液に氷水を加え、酢酸エチルで抽出した。抽出液を水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残留物をシリカゲルカラム(酢酸エチル/ヘキサン=1/1)で精製して、題記化合物(2.89g, 36％)を白色固体として得た。
NMR (200MHz, CDCl₃)δ：1.44 (9H, s), 2.49 (2H, t, J = 6.6), 2.89 (2H, t, J = 6.6), 2.95 (3H, s), 3.09 (3H, s), 5.00 (2H, s), 6.71 (1H, s), 7.00-7.14 (2H, m), 7.52 (1H, d, J = 1.8).
220b) 3-{5-クロロ-1-[(ジメチルカルバモイル)メチル]-1H-インドール-2-イル}スルホニル]プロピオン酸tert-ブチル
実施例220a)で得られた3-{5-クロロ-1-[(ジメチルカルバモイル)メチル]-1H-インドール-2-イル}チオ]プロピオン酸tert-ブチル(3.82g)から実施例211b)と同様にして、題記化合物(3.26g, 79％)を白色固体として得た。
NMR (200MHz, CDCl₃)δ：1.41 (9H, s), 2.65 (2H, t, J = 8.0), 2.98 (3H, s), 3.16 (3H, s), 3.52 (2H t, J = 7.4), 5.28 (2H, s), 7.14 (1H, d, J = 9.2), 7.23 (1H, s), 7.30 (1H, dd, J = 9.2, 2.2), 7.66 (1H, d, J = 2.2).
220c) 3-{5-クロロ-1-[(ジメチルカルバモイル)メチル]-1H-インドール-2-イル}スルホニル]プロピオン酸
実施例220b)で得られた3-{5-クロロ-1-[(ジメチルカルバモイル)メチル]-1H-インドール-2-イル}スルホニル]プロピオン酸tert-ブチル(3.26g)の酢酸(30mL)溶液へ2N塩酸(6.24mL)を加え、60℃で1時間かき混ぜた。溶媒を減圧留去し、残留物をエーテルで洗浄して、題記化合物(2.46g, 87%)を白色固体として得た。
NMR (200MHz, DMSO-d₆)δ：2.58 (2H, t, J = 4.8), 2.85 (3H, s), 3.14 (3H, s), 3.57 (2H, t, J = 4.8), 5.43 (2H, s), 7.28 (1H, s), 7.40 (1H, dd, J = 6.0, 1.4), 7.64 (1H, d, J = 6.0), 7.85 (1H, d, J = 1.4).
220d) 2-{[5-クロロ-2-({3-オキソ-3-[4-(5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン-3-イル)-1-ピペリジニル]プロピル}スルホニル)-1H-インドール-1-イル]-N,N-ジメチルアセトアミド塩酸塩
実施例220c)で得られた3-{5-クロロ-1-[(ジメチルカルバモイル)メチル]-1H-インドール-2-イル}スルホニル]プロピオン酸と実施例209b)で得られた3-(4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン２塩酸塩から実施例207d)と同様にして、題記化合物(42%)を白色粉末として得た。
NMR (200MHz, DMSO-d₆)δ：1.18-1.55 (2H, m), 1.76-2.05 (6H, m), 2.46-2.70 (2H, m), 2.77 (2H, t, J = 7.2), 2.82-3.15 (3H, m), 2.83 (3H, s), 3.16 (3H, s), 3.68 (2H, t, J = 6.6), 3.83-3.99 (1H, m), 3.96-4.11 (2H, m), 4.25-4.40 (1H, m), 5.42 (2H, s), 7.18 (1H, d, J = 1.6), 7.32-7.38 (2H, m), 7.54 (1H, d, J = 8.8), 7.81 (1H, d, J = 1.8). Example 220
2-{[5-Chloro-2-({3-oxo-3- [4- (5,6,7,8-tetrahydroimidazo [1,2-a] pyridin-3-yl) -1-piperidinyl] Propyl} sulfonyl) -1H-indol-1-yl] -N, N-dimethylacetamide hydrochloride
220a) tert-Butyl 3- {5-chloro-1-[(dimethylcarbamoyl) methyl] -1H-indol-2-yl} thio] propionate 3-[(5-Chloro--) obtained in Example 211a) 1H-Indolyl-2-yl) thio] propionate tert-butyl (6.24 g) in THF (65 mL) was added sodium hydride (60% oiliness: 0.96 g) at 0 ° C. and stirred at 0 ° C. for 30 minutes under argon. Thereafter, 2-chloro-N, N-dimethylacetamide (4.86 g) was added, and the mixture was further stirred at room temperature for 3 hours. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by a silica gel column (ethyl acetate / hexane = 1/1) to obtain the title compound (2.89 g, 36%) as a white solid.
NMR (200MHz, CDCl ₃ ) δ: 1.44 (9H, s), 2.49 (2H, t, J = 6.6), 2.89 (2H, t, J = 6.6), 2.95 (3H, s), 3.09 (3H, s ), 5.00 (2H, s), 6.71 (1H, s), 7.00-7.14 (2H, m), 7.52 (1H, d, J = 1.8).
220b) 3- {5-Chloro-1-[(dimethylcarbamoyl) methyl] -1H-indol-2-yl} sulfonyl] tert-butyl propionate 3- {5-chloro-1 obtained in Example 220a) The title compound (3.26 g, 79%) was obtained in the same manner as in Example 211b) from tert-butyl-[(dimethylcarbamoyl) methyl] -1H-indol-2-yl} thio] propionate (3.82 g) Got as.
NMR (200MHz, CDCl ₃ ) δ: 1.41 (9H, s), 2.65 (2H, t, J = 8.0), 2.98 (3H, s), 3.16 (3H, s), 3.52 (2H t, J = 7.4) , 5.28 (2H, s), 7.14 (1H, d, J = 9.2), 7.23 (1H, s), 7.30 (1H, dd, J = 9.2, 2.2), 7.66 (1H, d, J = 2.2).
220c) 3- {5-Chloro-1-[(dimethylcarbamoyl) methyl] -1H-indol-2-yl} sulfonyl] propionic acid 3- {5-Chloro-1-[( 2N Hydrochloric acid (6.24 mL) was added to a solution of tert-butyl (dimethylcarbamoyl) methyl] -1H-indol-2-yl} sulfonyl] propionate (3.26 g) in acetic acid (30 mL), and the mixture was stirred at 60 ° C. for 1 hr. The solvent was removed under reduced pressure, and the residue was washed with ether to give the title compound (2.46 g, 87%) as a white solid.
NMR (200MHz, DMSO-d ₆ ) δ: 2.58 (2H, t, J = 4.8), 2.85 (3H, s), 3.14 (3H, s), 3.57 (2H, t, J = 4.8), 5.43 (2H , s), 7.28 (1H, s), 7.40 (1H, dd, J = 6.0, 1.4), 7.64 (1H, d, J = 6.0), 7.85 (1H, d, J = 1.4).
220d) 2-{[5-chloro-2-({3-oxo-3- [4- (5,6,7,8-tetrahydroimidazo [1,2-a] pyridin-3-yl) -1- Piperidinyl] propyl} sulfonyl) -1H-indol-1-yl] -N, N-dimethylacetamide hydrochloride 3- {5-chloro-1-[(dimethylcarbamoyl) methyl] -1H obtained in Example 220c) -Indol-2-yl} sulfonyl] propionic acid and 3- (4-piperidinyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine dihydrochloride obtained in Example 209b) In the same manner as in Example 207d), the title compound (42%) was obtained as a white powder.
NMR (200MHz, DMSO-d ₆ ) δ: 1.18-1.55 (2H, m), 1.76-2.05 (6H, m), 2.46-2.70 (2H, m), 2.77 (2H, t, J = 7.2), 2.82 -3.15 (3H, m), 2.83 (3H, s), 3.16 (3H, s), 3.68 (2H, t, J = 6.6), 3.83-3.99 (1H, m), 3.96-4.11 (2H, m) , 4.25-4.40 (1H, m), 5.42 (2H, s), 7.18 (1H, d, J = 1.6), 7.32-7.38 (2H, m), 7.54 (1H, d, J = 8.8), 7.81 ( 1H, d, J = 1.8).

実施例221
3-(1-{3-[(5-クロロ-3-メチル-1H-インドール-2-イル)スルホニル]プロピオニル}-4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン塩酸塩
221a) 5-クロロ-3-メチル-1,3-ジヒドロ-2H-インドール-2-オン
2-メチル-2-(2-ニトロ-5-クロロフェニル)酢酸メチル(11.4g)の酢酸(120mL)溶液へ鉄粉(10.5g)を加え、100℃で1時間かき混ぜた。溶媒を減圧留去し、残留物に水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残留物をヘキサンとジイソプロピルエーテルで洗浄して、題記化合物(7.12g, 84%)を淡褐色固体として得た。
NMR (200MHz, DMSO-d₆)δ：1.33 (3H, d, J = 7.8), 3.44 (1H, dd, J = 7.8), 6.82 (1H, d, J = 8.4), 7.20 (1H, d, J = 8.4), 7.33 (1H, s), 10.44 (1H, br).
221b) 3-[(5-クロロ-3-メチル-1H-インドール-2-イル)チオ]プロピオン酸tert-ブチル
実施例221a)で得られた5-クロロ-3-メチル-1,3-ジヒドロ-2H-インドール-2-オン(7.12g)から実施例211a)と同様にして、題記化合物(5.05g, 40％)を淡褐色固体として得た。NMR (300MHz, CDCl₃)δ：1.47 (9H, s), 2.47 (2H, t, J = 7.2), 2.95 (2H, t, J = 7.0), 7.13-7.17 (1H, m), 7.21-7.26 (1H, m), 7.48-7.49 (1H, m), 8.45 (1H, br).
221c) 3-[(5-クロロ-3-メチル-1H-インドール-2-イル)スルホニル]プロピオン酸 tert-ブチル
実施例221b)で得られた3-[(5-クロロ-3-メチル-1H-インドール-2-イル)チオ]プロピオン酸tert-ブチル(5.05g)から実施例211b)と同様にして、題記化合物(4.82g, 87％)を淡褐色固体として得た。
NMR (200MHz, CDCl₃)δ：1.36 (9H, s), 2.56 (3H, s), 2.69 (2H, t, J = 7.4), 3.52 (2H, t, J = 7.4), 7.29-7.35 (2H, m), 7.63 (1H, s), 9.09 (1H, br).
221d) 2-[(3-アリルオキシ-3-オキソプロピル)スルホニル]-5-クロロ-3-メチル-1H-インドール-1-カルボン酸tert-ブチル
実施例221c)で得られた3-[(5-クロロ-3-メチル-1H-インドール-2-イル)スルホニル]プロピオン酸 tert-ブチル(4.82g)から実施例211c)と同様にして、題記化合物(2.62g, 44％)を淡褐色液体として得た。
NMR (200MHz, CDCl₃)δ：1.71 (9H, s), 2.59 (3H, s), 2.94 (2H, t, J = 7.2), 4.04 (2H, t, J = 7.4), 4.53-4.57 (2H, m), 5.20-5.34 (2H, m), 5.77-5.97 (1H, m), 7.43 (1H, dd, J = 8.8, 2.2), 7.62 (1H, d, J = 2.2), 7.85 (1H, d, J = 8.8).
221e) 3-{[1-(tert-ブトキシカルボニル)-5-クロロ-3-メチル-1H-インドール-2-イル]スルホニル}プロピオン酸
実施例221d)で得られた2-[(3-アリルオキシ-3-オキソプロピル)スルホニル]-5-クロロ-3-メチル-1H-インドール-1-カルボン酸tert-ブチル(2.62g)から実施例211d)と同様にして、題記化合物(1.50g, 63%)を淡茶色固体として得た。
NMR (200MHz, DMSO-d₆)δ：1.62 (9H, s), 2.51 (3H, s), 2.73 (2H, t, J = 7.2), 3.91 (2H, t, J = 7.2), 7.56 (1H, dd, J = 8.8, 2.2), 7.86 (1H, d, J = 8.8), 7.92 (1H, d, J = 2.2).
221f) 5-クロロ-3-メチル-2-({3-オキソ-3-[4-(5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン-3-イル)-1-ピペリジニル]プロピル}スルホニル)-1H-インドール-1-カルボン酸tert-ブチル
実施例221e)で得られた3-{[1-(tert-ブトキシカルボニル)-5-クロロ-3-メチル-1H-インドール-2-イル]スルホニル}プロピオン酸(0.80g)と実施例209b)で得られた3-(4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン２塩酸塩(0.33g)から実施例19と同様にして、題記化合物(0.84g, 71%)を無色粉末として得た。
NMR (200MHz, CDCl₃)δ：1.39-1.68 (2H, m), 1.69 (9H, s), 1.80-2.07 (6H, m), 2.54-2.79 (2H, m), 2.58 (3H, s), 2.86 (2H, t, J = 6.2), 2.93-3.07 (2H, m), 3.09-3.24 (1H, m), 3.81 (2H, t, J = 6.0), 3.87-4.28 (3H, m), 4.56-4.72 (1H, m), 6.67 (1H, s), 7.42 (1H, dd, J = 8.8, 2.2), 7.62 (1H, d, J = 2.2), 7.85 (1H, d, J = 8.8).
221g) 3-(1-{3-[(5-クロロ-3-メチル-1H-インドール-2-イル)スルホニル]プロピオニル}-4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン塩酸塩
実施例221f)で得られた5-クロロ-3-メチル-2-({3-オキソ-3-[4-(5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン-3-イル)-1-ピペリジニル]プロピル}スルホニル)-1H-インドール-1-カルボン酸tert-ブチル(0.30g) から実施例207c)と同様にして、題記化合物(0.16g, 61%)を白色粉末として得た。
NMR (200MHz, DMSO-d₆)δ：1.08-1.58 (2H, m), 1.71-2.10 (6H, m), 2.49 (3H, m), 2.53-2.66 (1H, m), 2.75 (2H, t, J = 7.2), 2.83-3.04 (3H, m), 3.04-3.19 (1H, m), 3.61 (2H, t, J = 7.2), 3.77-3.92 (1H, m), 4.05 (2H, t, J = 5.2), 4.23-4.38 (1H, m), 7.29-7.35 (2H, m), 7.47 (1H, d, J = 8.8), 7.79 (1H, d, J = 2.2), 9.31 (1H, br). Example 221
3- (1- {3-[(5-Chloro-3-methyl-1H-indol-2-yl) sulfonyl] propionyl} -4-piperidinyl) -5,6,7,8-tetrahydroimidazo [1,2 -a] pyridine hydrochloride
221a) 5-Chloro-3-methyl-1,3-dihydro-2H-indol-2-one
Iron powder (10.5 g) was added to a solution of methyl 2-methyl-2- (2-nitro-5-chlorophenyl) acetate (11.4 g) in acetic acid (120 mL), and the mixture was stirred at 100 ° C. for 1 hour. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was washed with hexane and diisopropyl ether to give the title compound (7.12 g, 84%) as a light brown solid.
NMR (200MHz, DMSO-d ₆ ) δ: 1.33 (3H, d, J = 7.8), 3.44 (1H, dd, J = 7.8), 6.82 (1H, d, J = 8.4), 7.20 (1H, d, J = 8.4), 7.33 (1H, s), 10.44 (1H, br).
221b) tert-Butyl 3-[(5-chloro-3-methyl-1H-indol-2-yl) thio] propionate 5-chloro-3-methyl-1,3-dihydro obtained in Example 221a) The title compound (5.05 g, 40%) was obtained as a pale-brown solid from -2H-indol-2-one (7.12 g) in the same manner as Example 211a). NMR (300MHz, CDCl ₃ ) δ: 1.47 (9H, s), 2.47 (2H, t, J = 7.2), 2.95 (2H, t, J = 7.0), 7.13-7.17 (1H, m), 7.21-7.26 (1H, m), 7.48-7.49 (1H, m), 8.45 (1H, br).
221c) tert-butyl 3-[(5-chloro-3-methyl-1H-indol-2-yl) sulfonyl] propionate 3-[(5-chloro-3-methyl-1H obtained in Example 221b) The title compound (4.82 g, 87%) was obtained as a light brown solid from tert-butyl (indol-2-yl) thio] propionate (5.05 g) in the same manner as in Example 211b).
NMR (200MHz, CDCl ₃ ) δ: 1.36 (9H, s), 2.56 (3H, s), 2.69 (2H, t, J = 7.4), 3.52 (2H, t, J = 7.4), 7.29-7.35 (2H , m), 7.63 (1H, s), 9.09 (1H, br).
221d) 2-[(3-allyloxy-3-oxopropyl) sulfonyl] -5-chloro-3-methyl-1H-indole-1-carboxylate tert-butyl 3-[(5 -Chloro-3-methyl-1H-indol-2-yl) sulfonyl] propionate from tert-butyl (4.82 g) in the same manner as in Example 211c) to give the title compound (2.62 g, 44%) as a light brown liquid Obtained.
NMR (200MHz, CDCl ₃ ) δ: 1.71 (9H, s), 2.59 (3H, s), 2.94 (2H, t, J = 7.2), 4.04 (2H, t, J = 7.4), 4.53-4.57 (2H , m), 5.20-5.34 (2H, m), 5.77-5.97 (1H, m), 7.43 (1H, dd, J = 8.8, 2.2), 7.62 (1H, d, J = 2.2), 7.85 (1H, d, J = 8.8).
221e) 3-{[1- (tert-Butoxycarbonyl) -5-chloro-3-methyl-1H-indol-2-yl] sulfonyl} propionic acid 2-[(3-allyloxy) obtained in Example 221d) 3-Oxopropyl) sulfonyl] -5-chloro-3-methyl-1H-indole-1-carboxylate from tert-butyl (2.62 g) in the same manner as in Example 211 d), the title compound (1.50 g, 63% ) Was obtained as a light brown solid.
NMR (200MHz, DMSO-d ₆ ) δ: 1.62 (9H, s), 2.51 (3H, s), 2.73 (2H, t, J = 7.2), 3.91 (2H, t, J = 7.2), 7.56 (1H , dd, J = 8.8, 2.2), 7.86 (1H, d, J = 8.8), 7.92 (1H, d, J = 2.2).
221f) 5-chloro-3-methyl-2-({3-oxo-3- [4- (5,6,7,8-tetrahydroimidazo [1,2-a] pyridin-3-yl) -1- Piperidinyl] propyl} sulfonyl) -1H-indole-1-carboxylate tert-butyl 3-{[1- (tert-butoxycarbonyl) -5-chloro-3-methyl-1H-indole obtained in Example 221e) 2-yl] sulfonyl} propionic acid (0.80 g) and 3- (4-piperidinyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine dihydrochloride obtained in Example 209b) The title compound (0.84 g, 71%) was obtained as a colorless powder from the salt (0.33 g) in the same manner as in Example 19.
NMR (200MHz, CDCl ₃ ) δ: 1.39-1.68 (2H, m), 1.69 (9H, s), 1.80-2.07 (6H, m), 2.54-2.79 (2H, m), 2.58 (3H, s), 2.86 (2H, t, J = 6.2), 2.93-3.07 (2H, m), 3.09-3.24 (1H, m), 3.81 (2H, t, J = 6.0), 3.87-4.28 (3H, m), 4.56 -4.72 (1H, m), 6.67 (1H, s), 7.42 (1H, dd, J = 8.8, 2.2), 7.62 (1H, d, J = 2.2), 7.85 (1H, d, J = 8.8).
221g) 3- (1- {3-[(5-Chloro-3-methyl-1H-indol-2-yl) sulfonyl] propionyl} -4-piperidinyl) -5,6,7,8-tetrahydroimidazo [1 , 2-a] pyridine hydrochloride 5-chloro-3-methyl-2-({3-oxo-3- [4- (5,6,7,8-tetrahydroimidazo [1] obtained in Example 221f) , 2-a] pyridin-3-yl) -1-piperidinyl] propyl} sulfonyl) -1H-indole-1-carboxylate from tert-butyl (0.30 g) in the same manner as in Example 207c), the title compound (0.16 g, 61%) was obtained as a white powder.
NMR (200MHz, DMSO-d ₆ ) δ: 1.08-1.58 (2H, m), 1.71-2.10 (6H, m), 2.49 (3H, m), 2.53-2.66 (1H, m), 2.75 (2H, t , J = 7.2), 2.83-3.04 (3H, m), 3.04-3.19 (1H, m), 3.61 (2H, t, J = 7.2), 3.77-3.92 (1H, m), 4.05 (2H, t, J = 5.2), 4.23-4.38 (1H, m), 7.29-7.35 (2H, m), 7.47 (1H, d, J = 8.8), 7.79 (1H, d, J = 2.2), 9.31 (1H, br ).

実施例222
3-(1-{3-[(5-クロロ-3-メチル-1H-インドール-2-イル)スルホニル]プロピオニル}-4-ピペリジニル)イミダゾ[1,2-a]ピリジン塩酸塩
222a) 5-クロロ-2-{[3-(4-イミダゾ[1,2-a]ピリジン-3-イル)-1-ピペリジニル]-3-オキシプロピル}スルホニル)-3-メチル-1H-インドール-1-カルボン酸tert-ブチル
実施例221e)で得られた3-{[1-(tert-ブトキシカルボニル)-5-クロロ-3-メチル-1H-インドール-2-イル]スルホニル}プロピオン酸(0.80g)と実施例207c)で得られた 3-(4-ピペリジニル)イミダゾ[1,2-a]ピリジン２塩酸塩(0.66g)から実施例19)と同様にして、題記化合物(0.81g, 78%)を無色粉末として得た。
NMR (200MHz, CDCl₃)δ：1.70 (9H, s), 1.77-1.88 (2H, m), 2.08-2.27 (2H, m), 2.60 (3H, s), 2.74-2.96 (1H, m), 2.96-3.21 (3H, m), 3.21-3.40 (1H, m), 3.96-4.35 (3H, m), 4.62-4.81 (1H, m), 6.81-6.88 (1H, m), 7.13-7.22 (1H, m), 7.41-7.46 (2H, m), 7.61-7.66 (2H, m), 7.86 (1H, d, J = 8.8), 7.96 (1H, d, J = 7.0).
222b) 3-(1-{3-[(5-クロロ-3-メチル-1H-インドール-2-イル)スルホニル]プロピオニル}-4-ピペリジニル)イミダゾ[1,2-a]ピリジン塩酸塩
実施例222a)で得られた5-クロロ-2-{[3-(4-イミダゾ[1,2-a]ピリジン-3-イル)-1-ピペリジニル]-3-オキシプロピル}スルホニル)-3-メチル-1H-インドール-1-カルボン酸tert-ブチル(0.29g) から実施例207c)と同様にして、題記化合物(0.20g, 76%)を白色粉末として得た。
NMR (200MHz, DMSO-d₆)δ：1.24-1.71 (2H, m), 1.88-2.28 (2H, m), 2.50 (3H, s), 2.57-2.71 (1H, m), 2.79 (2H, t, J = 7.0), 3.07-3.55 (2H, m), 3.63 (2H, t, J = 7.2), 3.84-3.99 (1H, m), 4.28-4.45 (1H, m), 7.31 (1H, dd, J = 8.8, 2.2), 7.45-7.57 (2H, m), 7.79 (1H, d, J = 2.2), 7.91-8.02 (3H, m), 9.02 (1H, d, J = 7.0), 9.37 (1H, br). Example 222
3- (1- {3-[(5-Chloro-3-methyl-1H-indol-2-yl) sulfonyl] propionyl} -4-piperidinyl) imidazo [1,2-a] pyridine hydrochloride
222a) 5-Chloro-2-{[3- (4-imidazo [1,2-a] pyridin-3-yl) -1-piperidinyl] -3-oxypropyl} sulfonyl) -3-methyl-1H-indole Tert-Butyl-1-carboxylate 3-{[1- (tert-Butoxycarbonyl) -5-chloro-3-methyl-1H-indol-2-yl] sulfonyl} propionic acid obtained in Example 221e) 0.80 g) and 3- (4-piperidinyl) imidazo [1,2-a] pyridine dihydrochloride (0.66 g) obtained in Example 207c) in the same manner as in Example 19), and the title compound (0.81 g) , 78%) was obtained as a colorless powder.
NMR (200MHz, CDCl ₃ ) δ: 1.70 (9H, s), 1.77-1.88 (2H, m), 2.08-2.27 (2H, m), 2.60 (3H, s), 2.74-2.96 (1H, m), 2.96-3.21 (3H, m), 3.21-3.40 (1H, m), 3.96-4.35 (3H, m), 4.62-4.81 (1H, m), 6.81-6.88 (1H, m), 7.13-7.22 (1H , m), 7.41-7.46 (2H, m), 7.61-7.66 (2H, m), 7.86 (1H, d, J = 8.8), 7.96 (1H, d, J = 7.0).
222b) 3- (1- {3-[(5-Chloro-3-methyl-1H-indol-2-yl) sulfonyl] propionyl} -4-piperidinyl) imidazo [1,2-a] pyridine hydrochloride Examples 5-chloro-2-{[3- (4-imidazo [1,2-a] pyridin-3-yl) -1-piperidinyl] -3-oxypropyl} sulfonyl) -3-methyl obtained in 222a) The title compound (0.20 g, 76%) was obtained as a white powder from tert-butyl-1H-indole-1-carboxylate (0.29 g) in the same manner as in Example 207c).
NMR (200MHz, DMSO-d ₆ ) δ: 1.24-1.71 (2H, m), 1.88-2.28 (2H, m), 2.50 (3H, s), 2.57-2.71 (1H, m), 2.79 (2H, t , J = 7.0), 3.07-3.55 (2H, m), 3.63 (2H, t, J = 7.2), 3.84-3.99 (1H, m), 4.28-4.45 (1H, m), 7.31 (1H, dd, J = 8.8, 2.2), 7.45-7.57 (2H, m), 7.79 (1H, d, J = 2.2), 7.91-8.02 (3H, m), 9.02 (1H, d, J = 7.0), 9.37 (1H , br).

実施例223
3-(1-{3-[(5-クロロ-1-メチル-1H-インドール-2-イル)スルホニル]プロピオニル}-4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン塩酸塩
223a) 3-[(5-クロロ-1-メチル-1H-インドール-2-イル)チオ]プロピオン酸tert-ブチル
実施例211a)で得られた3-[(5-クロロ-1H-インドール-2-イル)チオ]プロピオン酸tert-ブチル(5.27g)のDMF(40mL)溶液へよう化メチル(5.26mL)を室温で加え、次いで水素化ナトリウム(60%油性： 0.81g)を0℃で加えた後、反応混合物を室温で16時間かき混ぜた。反応溶液へ氷水を加え、酢酸エチルで抽出した。抽出液を水と飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残留物をシリカゲルカラム(酢酸エチル/ヘキサン=1/4)により精製して、題記化合物(4.94g, 82%)を無色固体として得た。
NMR (200MHz, CDCl₃)δ：1.43 (9H, s), 2.51 (2H, t, J = 7.2), 2.96 (2H, t, J = 7.2), 3.79 (3H, s), 6.63 (1H, s), 7.06-7.24 (2H, m), 7.52 (1H, s).
223b) 3-[(5-クロロ-1-メチル-1H-インドール-2-イル)スルホニル]プロピオン酸tert-ブチル
実施例223a)で得られた3-[(5-クロロ-1-メチル-1H-インドール-2-イル)チオ]プロピオン酸tert-ブチル(4.90g) から実施例211b)と同様にして、題記化合物(1.87g, 38％)を白色固体として得た。
NMR (200MHz, CDCl₃)δ：1.26 (9H, s), 2.71 (2H, t, J = 7.2), 3.51 (2H, t, J = 7.2), 4.03 (3H, s), 7.21 (1H, s), 7.29-7.43 (2H, m), 7.67 (1H, s).
223c) 3-[(5-クロロ-1-メチル-1H-インドール-2-イル)スルホニル]プロピオン酸
実施例223b)で得られた3-[(5-クロロ-1-メチル-1H-インドール-2-イル)スルホニル]プロピオン酸tert-ブチル(1.87g)から実施例220c)と同様にして、題記化合物(1.24g, 79%)を淡茶色固体として得た。
NMR (200MHz, DMSO-d₆)δ：2.60 (2H, t, J = 7.0), 3.68 (2H, t, J = 7.0), 3.99 (3H, s), 7.23 (1H, s), 7.43 (1H, dd, J = 8.8, 2.2), 7.71 (1H, d, J = 8.8), 7.84 (1H, d, J = 2.2).
223d) 3-(1-{3-[(5-クロロ-1-メチル-1H-インドール-2-イル)スルホニル]プロピオニル}-4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン塩酸塩
実施例223c)で得られた3-[(5-クロロ-1-メチル-1H-インドール-2-イル)スルホニル]プロピオン酸と実施例209b)で得られた3-(4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン２塩酸塩から実施例207d)と同様にして、題記化合物(収率76%)を白色粉末として得た。
NMR (200MHz, DMSO-d₆)δ：1.27-1.37 (1H, m), 1.64-1.78 (1H, m), 1.78-2.07 (6H, m), 2.34-2.54 (1H, m), 2.78 (2H, t, J = 6.6), 2.87-3.12 (2H, m), 3.34-3.58 (2H, m), 3.61-3.94 (3H, m), 3.94-4.19 (3H, m), 4.00 (3H, s), 7.25 (1H, s), 7.36-7.43 (2H, m), 7.70 (1H, d, J = 8.8), 7.79 (1H, d, J = 2.2). Example 223
3- (1- {3-[(5-Chloro-1-methyl-1H-indol-2-yl) sulfonyl] propionyl} -4-piperidinyl) -5,6,7,8-tetrahydroimidazo [1,2 -a] pyridine hydrochloride
223a) tert-butyl 3-[(5-chloro-1-methyl-1H-indol-2-yl) thio] propionate 3-[(5-chloro-1H-indole-2) obtained in Example 211a) -Iyl) thio] Methyl iodide (5.26 mL) was added to a solution of tert-butyl propionate (5.27 g) in DMF (40 mL) at room temperature, followed by sodium hydride (60% oiliness: 0.81 g) at 0 ° C. After that, the reaction mixture was stirred at room temperature for 16 hours. Ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (ethyl acetate / hexane = 1/4) to obtain the title compound (4.94 g, 82%) as a colorless solid.
NMR (200MHz, CDCl ₃ ) δ: 1.43 (9H, s), 2.51 (2H, t, J = 7.2), 2.96 (2H, t, J = 7.2), 3.79 (3H, s), 6.63 (1H, s ), 7.06-7.24 (2H, m), 7.52 (1H, s).
223b) tert-butyl 3-[(5-chloro-1-methyl-1H-indol-2-yl) sulfonyl] propionate 3-[(5-chloro-1-methyl-1H obtained in Example 223a) The title compound (1.87 g, 38%) was obtained as a white solid in the same manner as in Example 211b) from tert-butyl (indol-2-yl) thio] propionate (4.90 g).
NMR (200MHz, CDCl ₃ ) δ: 1.26 (9H, s), 2.71 (2H, t, J = 7.2), 3.51 (2H, t, J = 7.2), 4.03 (3H, s), 7.21 (1H, s ), 7.29-7.43 (2H, m), 7.67 (1H, s).
223c) 3-[(5-Chloro-1-methyl-1H-indol-2-yl) sulfonyl] propionic acid 3-[(5-Chloro-1-methyl-1H-indole-) obtained in Example 223b) The title compound (1.24 g, 79%) was obtained as a light brown solid from tert-butyl 2-yl) sulfonyl] propionate (1.87 g) in the same manner as in Example 220c).
NMR (200MHz, DMSO-d ₆ ) δ: 2.60 (2H, t, J = 7.0), 3.68 (2H, t, J = 7.0), 3.99 (3H, s), 7.23 (1H, s), 7.43 (1H , dd, J = 8.8, 2.2), 7.71 (1H, d, J = 8.8), 7.84 (1H, d, J = 2.2).
223d) 3- (1- {3-[(5-Chloro-1-methyl-1H-indol-2-yl) sulfonyl] propionyl} -4-piperidinyl) -5,6,7,8-tetrahydroimidazo [1 , 2-a] pyridine hydrochloride 3-[(5-chloro-1-methyl-1H-indol-2-yl) sulfonyl] propionic acid obtained in Example 223c) and 3 obtained in Example 209b) -(4-Piperidinyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyridine dihydrochloride in the same manner as in Example 207d) to give the title compound (yield 76%) as a white powder Obtained.
NMR (200MHz, DMSO-d ₆ ) δ: 1.27-1.37 (1H, m), 1.64-1.78 (1H, m), 1.78-2.07 (6H, m), 2.34-2.54 (1H, m), 2.78 (2H , t, J = 6.6), 2.87-3.12 (2H, m), 3.34-3.58 (2H, m), 3.61-3.94 (3H, m), 3.94-4.19 (3H, m), 4.00 (3H, s) , 7.25 (1H, s), 7.36-7.43 (2H, m), 7.70 (1H, d, J = 8.8), 7.79 (1H, d, J = 2.2).

実施例224
2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロピオニル}-4-ピペリジニル)-1,2,3,4-テトラヒドロジピリド[1,2-a;4',3'-d]イミダゾール２塩酸塩
224a) 2-(3-オキソブチル)-1H-イソインドール-1,3(2H)-ジオン
フタルイミド(90.0g)、メチルビニルケトン(51mL)および40%トリトンBメタノール溶液(15.3mL)を酢酸エチル(400mL)に加え、1時間還流した。溶媒を減圧留去し、残留物をエタノールから再結晶して、題記化合物(114.4g, 86%)を無色結晶として得た。
NMR (200Mz, CDCl₃)δ：2.19 (3H, s), 2.88 (2H, t, J = 7.2), 3.96 (2H, t, J = 7.2), 7.70-7.74 (2H, m), 7.82-7.86 (2H, m).
224b) 2-(4-ブロモ-3-オキソブチル)-1H-イソインドール-1,3(2H)-ジオン
実施例224a)で得られた2-(3-オキソブチル)-1H-イソインドール-1,3(2H)-ジオン(54.31g)のメタノール(300mL)けん濁液へ臭素(40.0g)を0℃で滴下後、室温で16時間かき混ぜた。反応液へジクロロメタンを加え沈殿を溶解し、10N硫酸(50mL)を加え、室温で16時間かき混ぜた。反応液を減圧濃縮し、残留物を熱メタノール中で洗浄して、題記化合物(36.1g, 49%)を無色結晶として得た。
NMR (200Mz, CDCl₃)δ：3.12 (2H, t, J = 7.2), 3.92 (2H, s), 4.01 (2H, t, J = 7.2), 7.70-7.75 (2H, m), 7.83-7.87 (2H, m).
224c) 2-[2-(イミダゾ[1,2-a]ピリジン-2-イル)エチル]-1H-イソインドール-1,3(2H)-ジオン
実施例224b)で得られた2-(4-ブロモ-3-オキソブチル)-1H-イソインドール-1,3(2H)-ジオン(29.61g)、2-アミノピリジン(9.41g)および炭酸水素ナトリウム(8.40g)のDMF(100mL)混合液を100℃で1時間かき混ぜた。混合物の氷水を加え、析出した沈殿をろ取し、水洗して、題記化合物(21.85g, 75%)を褐色粉末として得た。
NMR (200Mz, CDCl₃)δ：3.21 (2H, t, J = 7.2), 4.12 (2H, t, J = 7.2), 6.69-6.76 (1H, m), 7.08-7.16 (1H, m), 7.45 (1H, s), 7.51 (1H, d, J = 8.8), 7.68-7.74 (2H, m), 7.79-7.86 (2H, m), 8.04 (1H, d, J = 7.2).
224d) 2-(イミダゾ[1,2-a]ピリジン-2-イル)エチルアミン２塩酸塩
実施例224c)で得られた2-[2-(イミダゾ[1,2-a]ピリジン-2-イル)エチル]-1H-イソインドール-1,3(2H)-ジオン(29.13g)の6N塩酸(500 mL)溶液を3時間還流した。反応液を室温まで冷却し、析出した結晶をろ取、エタノールで洗浄して、題記化合物(16.86g, 72%)を淡褐色結晶として得た。
NMR (200Mz, D₂O)δ：3.28-3.43 (2H, m), 3.43-3.58 (2H, m), 7.42 (1H, t, J = 6.6), 7.78-7.98 (2H, m), 8.03 (1H, s), 8.62 (1H, d, J = 6.6).
224e) 4-(1,2,3,4-テトラヒドロジピリド[1,2-a;4',3'-d]イミダゾール-2-イル)ピペリジン-1-カルボン酸tert-ブチル
実施例224d)で得られた2-(イミダゾ[1,2-a]ピリジン-2-イル)エチルアミン２塩酸塩(2.34g)とDBU(3.0mL)のエタノール(25 mL)溶液へ4-オキソピペリジン-1-カルボン酸-tert-ブチル(1.99g)を加え、2時間還流した。反応液を室温まで冷却し、トリアセトキシ水素化ホウ素ナトリウム(4.24g)を加え、室温で1時間かき混ぜた。不溶物をろ去し、ろ液を減圧濃縮した。残留物に氷冷下で8N水酸化ナトリウム(20mL)を加えクロロホルムで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥、溶媒を減圧留去した。得られた残留物の酢酸(50mL)溶液へ37%ホルムアルデヒド水溶液(15mL)を加え、100℃で20分間かき混ぜた。溶媒を減圧留去し、残留物に氷冷下で8N水酸化ナトリウム水溶液(20mL)を加え、クロロホルムで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、残留物をシリカゲルカラム (酢酸エチル/エタノール/トリエチルアミン=20/1/0.5→10/1/0.5)により精製し、題記化合物(2.14g, 60%)を無色粉末として得た。
NMR (200Mz, CDCl₃)δ：1.48 (9H, s), 1.52-1.73 (2H, m), 1.84-2.00 (2H, m), 2.64-2.88 (3H, m), 2.88-3.07 (4H, m), 3.88 (2H, s), 4.12-4.31 (2H, m), 6.78 (1H, dt, J = 7.0, 1.0), 7.12 (1H, dt, J = 8.0, 1.0), 7.54 (1H, d, J = 8.0), 7.73 (1H, d, J = 7.0).
224f) 2-(4-ピペリジニル)-1,2,3,4-テトラヒドロジピリド[1,2-a;4',3'-d]イミダゾール３塩酸塩
実施例224e)で得られた4-(1,2,3,4-テトラヒドロジピリド[1,2-a;4',3'-d]イミダゾール-2-イル)ピペリジン-1-カルボン酸tert-ブチル(1.78g)から実施例207c)と同様にして、題記化合物(1.66g, 91%)を白色結晶として得た。
NMR (200Mz, D₂O)δ：1.92-2.19 (2H, m), 2.38-2.55 (2H, m), 3.08-3.32 (4H, m), 3.48-3.78 (5H, m), 4.53 (2H, s), 7.50 (1H, t, J = 6.6), 7.85-8.03 (2H, m), 8.46 (1H, d, J = 6.8).
224g) 2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロピオニル}-4-ピペリジニル)-1,2,3,4-テトラヒドロジピリド[1,2-a;4',3'-d]イミダゾール２塩酸塩
実施例224f)で得られた2-(4-ピペリジニル)-1,2,3,4-テトラヒドロジピリド[1,2-a;4',3'-d]イミダゾール３塩酸塩と3-[(6-クロロ-2-ナフチル)スルホニル]プロピオン酸から実施例207d)と同様にして、題記化合物(75%)を白色粉末として得た。
NMR (200Mz, DMSO-d₆)δ：1.44-1.92 (2H, m), 2.11-2.33 (2H, m), 2.41-2.62 (1H, m), 2.79 (2H, t, J = 7.4), 2.93-3.12 (2H, m), 3.12-3.94 (5H, m), 3.94-4.12 (2H, m), 4.32-4.50 (1H, m), 4.75 (2H, br), 7.58 (1H, dt, J = 7.0, 1.8), 7.74 (1H, d, J = 8.8, 2.2), 7.19-8.03 (3H, m), 8.19-8.32 (3H, m), 8.66 (1H, s), 8.78 (1H, d, J = 6.8). Example 224
2- (1- {3-[(6-chloro-2-naphthyl) sulfonyl] propionyl} -4-piperidinyl) -1,2,3,4-tetrahydrodipyrido [1,2-a; 4 ′, 3'-d] imidazole dihydrochloride
224a) 2- (3-oxobutyl) -1H-isoindole-1,3 (2H) -dione phthalimide (90.0 g), methyl vinyl ketone (51 mL) and 40% Triton B methanol solution (15.3 mL) in ethyl acetate ( 400 mL) and refluxed for 1 hour. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to give the title compound (114.4 g, 86%) as colorless crystals.
NMR (200Mz, CDCl ₃ ) δ: 2.19 (3H, s), 2.88 (2H, t, J = 7.2), 3.96 (2H, t, J = 7.2), 7.70-7.74 (2H, m), 7.82-7.86 (2H, m).
224b) 2- (4-Bromo-3-oxobutyl) -1H-isoindole-1,3 (2H) -dione 2- (3-oxobutyl) -1H-isoindole-1, obtained in Example 224a) Bromine (40.0 g) was added dropwise to a suspension of 3 (2H) -dione (54.31 g) in methanol (300 mL) at 0 ° C., and the mixture was stirred at room temperature for 16 hr. Dichloromethane was added to the reaction solution to dissolve the precipitate, 10N sulfuric acid (50 mL) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was washed in hot methanol to give the title compound (36.1 g, 49%) as colorless crystals.
NMR (200Mz, CDCl ₃ ) δ: 3.12 (2H, t, J = 7.2), 3.92 (2H, s), 4.01 (2H, t, J = 7.2), 7.70-7.75 (2H, m), 7.83-7.87 (2H, m).
224c) 2- [2- (imidazo [1,2-a] pyridin-2-yl) ethyl] -1H-isoindole-1,3 (2H) -dione 2- (4 obtained in Example 224b) -Bromo-3-oxobutyl) -1H-isoindole-1,3 (2H) -dione (29.61 g), 2-aminopyridine (9.41 g) and sodium bicarbonate (8.40 g) in a DMF (100 mL) mixture Stir at 100 ° C. for 1 hour. Ice water of the mixture was added, and the deposited precipitate was collected by filtration and washed with water to give the title compound (21.85 g, 75%) as a brown powder.
NMR (200Mz, CDCl ₃ ) δ: 3.21 (2H, t, J = 7.2), 4.12 (2H, t, J = 7.2), 6.69-6.76 (1H, m), 7.08-7.16 (1H, m), 7.45 (1H, s), 7.51 (1H, d, J = 8.8), 7.68-7.74 (2H, m), 7.79-7.86 (2H, m), 8.04 (1H, d, J = 7.2).
224d) 2- (Imidazo [1,2-a] pyridin-2-yl) ethylamine dihydrochloride 2- [2- (imidazo [1,2-a] pyridin-2-yl obtained in Example 224c) ) Ethyl] -1H-isoindole-1,3 (2H) -dione (29.13 g) in 6N hydrochloric acid (500 mL) was refluxed for 3 hours. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration and washed with ethanol to give the title compound (16.86 g, 72%) as pale brown crystals.
NMR (200Mz, D ₂ O) δ: 3.28-3.43 (2H, m), 3.43-3.58 (2H, m), 7.42 (1H, t, J = 6.6), 7.78-7.98 (2H, m), 8.03 ( 1H, s), 8.62 (1H, d, J = 6.6).
224e) tert-butyl 4- (1,2,3,4-tetrahydrodipyrido [1,2-a; 4 ′, 3′-d] imidazol-2-yl) piperidine-1-carboxylate Example 224d 4-oxopiperidine-1 to a solution of 2- (imidazo [1,2-a] pyridin-2-yl) ethylamine dihydrochloride (2.34 g) and DBU (3.0 mL) in ethanol (25 mL) -Carboxylic acid-tert-butyl (1.99 g) was added, and the mixture was refluxed for 2 hours. The reaction mixture was cooled to room temperature, sodium triacetoxyborohydride (4.24 g) was added, and the mixture was stirred at room temperature for 1 hr. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. To the residue was added 8N sodium hydroxide (20 mL) under ice cooling, and the mixture was extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. A 37% aqueous formaldehyde solution (15 mL) was added to a solution of the obtained residue in acetic acid (50 mL), and the mixture was stirred at 100 ° C. for 20 min. The solvent was distilled off under reduced pressure, 8N aqueous sodium hydroxide solution (20 mL) was added to the residue under ice cooling, and the mixture was extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column (ethyl acetate / ethanol / triethylamine = 20/1 / 0.5 → 10/1 / 0.5) to give the title compound (2.14 g, 60%) as a colorless powder. It was.
NMR (200Mz, CDCl ₃ ) δ: 1.48 (9H, s), 1.52-1.73 (2H, m), 1.84-2.00 (2H, m), 2.64-2.88 (3H, m), 2.88-3.07 (4H, m ), 3.88 (2H, s), 4.12-4.31 (2H, m), 6.78 (1H, dt, J = 7.0, 1.0), 7.12 (1H, dt, J = 8.0, 1.0), 7.54 (1H, d, J = 8.0), 7.73 (1H, d, J = 7.0).
224f) 2- (4-Piperidinyl) -1,2,3,4-tetrahydrodipyrido [1,2-a; 4 ′, 3′-d] imidazole trihydrochloride 4 obtained in Example 224e) Performed from tert-butyl- (1,2,3,4-tetrahydrodipyrido [1,2-a; 4 ', 3'-d] imidazol-2-yl) piperidine-1-carboxylate In the same manner as in Example 207c), the title compound (1.66 g, 91%) was obtained as white crystals.
NMR (200Mz, D ₂ O) δ: 1.92-2.19 (2H, m), 2.38-2.55 (2H, m), 3.08-3.32 (4H, m), 3.48-3.78 (5H, m), 4.53 (2H, s), 7.50 (1H, t, J = 6.6), 7.85-8.03 (2H, m), 8.46 (1H, d, J = 6.8).
224g) 2- (1- {3-[(6-chloro-2-naphthyl) sulfonyl] propionyl} -4-piperidinyl) -1,2,3,4-tetrahydrodipyrido [1,2-a; 4 ', 3'-d] imidazole dihydrochloride 2- (4-piperidinyl) -1,2,3,4-tetrahydrodipyrido [1,2-a; 4', 3 obtained in Example 224f) The title compound (75%) was obtained as a white powder in the same manner as in Example 207d) from '-d] imidazole trihydrochloride and 3-[(6-chloro-2-naphthyl) sulfonyl] propionic acid.
NMR (200Mz, DMSO-d ₆ ) δ: 1.44-1.92 (2H, m), 2.11-2.33 (2H, m), 2.41-2.62 (1H, m), 2.79 (2H, t, J = 7.4), 2.93 -3.12 (2H, m), 3.12-3.94 (5H, m), 3.94-4.12 (2H, m), 4.32-4.50 (1H, m), 4.75 (2H, br), 7.58 (1H, dt, J = 7.0, 1.8), 7.74 (1H, d, J = 8.8, 2.2), 7.19-8.03 (3H, m), 8.19-8.32 (3H, m), 8.66 (1H, s), 8.78 (1H, d, J = 6.8).

実施例225
3-(1-{3-[(5-クロロ-1H-インドール-2-イル)スルホニル]プロピオニル}-4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,5-a]ピリジン塩酸塩
225a) N-(2-ピリジル)メチル-4-ピリジンカルボキサミド
イソニコチン酸クロライド塩酸塩(20.0g)のジクロロメタン(200mL)けん濁液へトリエチルアミン(94mL)を0℃で滴下し、次いで2-アミノメチルピリジン(11.6mL)を0℃で滴下した。反応混合物を室温で30分間かき混ぜた後、沈殿物をろ去し、ろ液を減圧濃縮した。残留物へ酢酸エチルを加え、6N塩酸(200mL)で抽出した。氷冷下で8N 水酸化ナトリウム水溶液を水層へ加えてpH11に調節し、クロロホルムで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去、残留物をシリカゲルカラム (クロロホルム/メタノール=10:1)により精製して、題記化合物(19.00g, 79%)を淡褐色固体として得た。
NMR (200Mz, CDCl₃)δ：4.75 (2H, d, J = 4.8), 7.21-7.25 (1H, m), 7.32 (1H, d, J = 8.2), 7.66-7.75 (3H, m), 8.12 (1H, br), 8.55 (1H, d, J = 5.2), 8.73 (2H, m).
225b) 3-(4-ピリジル)イミダゾ[1,5-a]ピリジン
実施例225a)で得られたN-(2-ピリジルメチル)-4-ピリジンカルボキサミド(19.00g)のトルエン(60mL)溶液へ0℃でオキシ塩化リン(24.9mL)を滴下し、3時間還流した。溶媒を減圧留去し、残留物を氷水中に注ぎ込み、2時間かき混ぜた。反応液へ氷冷下で8N 水酸化ナトリウム水溶液を加えてpH11に調節し、クロロホルムで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去、残留物をシリカゲルカラム(酢酸エチル/エタノール=10:1)により精製して、題記化合物(14.01g, 81%)を淡褐色固体として得た。
NMR (200Mz, CDCl₃)δ：6.65-6.72 (1H, m), 6.78-6.86 (1H, m), 7.50-7.56 (1H, m), 7.61 (1H, s), 7.74 (2H, dd, J = 4.8, 2.0), 8.36 (1H, dd, J = 7.4, 1.2), 8.72 (2H, dd, J = 4.8, 2.0).
225c) 3-(4-ピペリジル)-5,6,7,8-テトラヒドロイミダゾ[1,5-a]ピリジン２塩酸塩
実施例225b)で得られた3-(4-ピリジル)イミダゾ[1,5-a]ピリジン(5.13g)の酢酸(50mL)溶液へロジウムカーボン(500mg)を加え、60℃、100気圧で水素添加した。触媒をろ去し、ろ液へ濃塩酸(4.3mL)を加え、減圧濃縮した。残留物を2-プロパノールとジエチルエーテルで洗浄して、題記化合物(5.00g, 68%)を白色粉末として得た。
NMR (200Mz, D₂O)δ：1.78-1.97 (2H, m), 1.97-2.17 (4H, m), 2.23-2.38 (2H, m), 2.84 (2H, t, J = 6.2), 3.12-3.34 (2H, m), 3.43-3.57 (1H, m), 3.57-3.71 (2H, m), 4.16 (2H, t, J = 6.2), 7.11 (1H, s).
225d) 5-クロロ-2-({3-オキソ-3-[4-(5,6,7,8-テトラヒドロイミダゾ[1,5-a]ピリジン-3-イル)-1-ピペリジニル]プロピル}スルホニル)-1H-インドール-1-カルボン酸tert-ブチル
実施例225c)で得られた3-(4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾピリジン２塩酸塩(0.67g)と実施例211d)で得られた3-[(1-tert-ブトキシカルボニル-5-クロロ-1H-インドール-2-イル)スルホニル]プロピオン酸(0.78g)から実施例19と同様にして、題記化合物(0.87g, 76%)を褐色粉末として得た。
NMR (200Mz, CDCl₃)δ：1.55-2.06 (8H, m), 1.74 (9H, s), 2.67-2.98 (6H, m), 3.08-3.24 (1H, m), 3.85 (2H, t, J = 5.8), 3.90-4.19 (3H, m), 4.43-4.58 (1H, m), 6.65 (1H, s), 7.44 (1H, dd, J = 8.8, 2.2), 7.51 (1H, s), 7.64 (1H, d, J = 2.2), 8.02 (1H, d, J = 8.8).
225e) 3-(1-{3-[(5-クロロ-1H-インドール-2-イル)スルホニル]プロピオニル}-4-ピペリジニル)-5,6,7,8-テトラヒドロイミダゾ[1,5-a]ピリジン塩酸塩
実施例225d)で得られた5-クロロ-2-({3-オキソ-3-[4-(5,6,7,8-テトラヒドロイミダゾ[1,5-a]ピリジン-3-イル)-1-ピペリジニル]プロピル}スルホニル)-1H-インドール-1-カルボン酸tert-ブチル(0.40g)から実施例207c)と同様にして、題記化合物(0.28g, 78%)を白色結晶として得た。
NMR (200Mz, DMSO-d₆)δ：1.42-1.68 (2H, m), 1.68-2.03 (6H, m), 2.48-2.68 (1H, m), 2.71-2.87 (3H, m), 2.99-3.23 (1H, m), 3.27-3.51 (2H, m), 3.67 (2H, t, J = 6.8), 3.89-4.05 (1H, m), 4.14 (2H, t, J = 6.6), 4.31-4.48 (1H, m), 7.18 (1H, s), 7.31-7.37 (2H, m), 7.55 (1H, d, J = 8.8), 7.81 (1H, d, J = 2.2). Example 225
3- (1- {3-[(5-Chloro-1H-indol-2-yl) sulfonyl] propionyl} -4-piperidinyl) -5,6,7,8-tetrahydroimidazo [1,5-a] pyridine Hydrochloride
225a) N- (2-pyridyl) methyl-4-pyridinecarboxamide Triethylamine (94 mL) was added dropwise at 0 ° C to a suspension of isonicotinic acid chloride hydrochloride (20.0 g) in dichloromethane (200 mL), followed by 2-aminomethyl. Pyridine (11.6 mL) was added dropwise at 0 ° C. The reaction mixture was stirred at room temperature for 30 minutes, the precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was extracted with 6N hydrochloric acid (200 mL). Under ice cooling, 8N aqueous sodium hydroxide solution was added to the aqueous layer to adjust to pH 11, and the mixture was extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by a silica gel column (chloroform / methanol = 10: 1) to obtain the title compound (19.00 g, 79%) as a light brown solid.
NMR (200Mz, CDCl ₃ ) δ: 4.75 (2H, d, J = 4.8), 7.21-7.25 (1H, m), 7.32 (1H, d, J = 8.2), 7.66-7.75 (3H, m), 8.12 (1H, br), 8.55 (1H, d, J = 5.2), 8.73 (2H, m).
225b) 3- (4-pyridyl) imidazo [1,5-a] pyridine To a solution of N- (2-pyridylmethyl) -4-pyridinecarboxamide (19.00 g) obtained in Example 225a) in toluene (60 mL) Phosphorus oxychloride (24.9 mL) was added dropwise at 0 ° C. and refluxed for 3 hours. The solvent was distilled off under reduced pressure, and the residue was poured into ice water and stirred for 2 hours. The reaction solution was adjusted to pH 11 by adding 8N aqueous sodium hydroxide solution under ice cooling, and extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by a silica gel column (ethyl acetate / ethanol = 10: 1) to obtain the title compound (14.01 g, 81%) as a light brown solid.
NMR (200Mz, CDCl ₃ ) δ: 6.65-6.72 (1H, m), 6.78-6.86 (1H, m), 7.50-7.56 (1H, m), 7.61 (1H, s), 7.74 (2H, dd, J = 4.8, 2.0), 8.36 (1H, dd, J = 7.4, 1.2), 8.72 (2H, dd, J = 4.8, 2.0).
225c) 3- (4-Piperidyl) -5,6,7,8-tetrahydroimidazo [1,5-a] pyridine dihydrochloride 3- (4-Pyridyl) imidazo [1, obtained in Example 225b) Rhodium carbon (500 mg) was added to a solution of 5-a] pyridine (5.13 g) in acetic acid (50 mL), and hydrogenated at 60 ° C. and 100 atm. The catalyst was removed by filtration, concentrated hydrochloric acid (4.3 mL) was added to the filtrate, and the mixture was concentrated under reduced pressure. The residue was washed with 2-propanol and diethyl ether to give the title compound (5.00 g, 68%) as a white powder.
NMR (200Mz, D ₂ O) δ: 1.78-1.97 (2H, m), 1.97-2.17 (4H, m), 2.23-2.38 (2H, m), 2.84 (2H, t, J = 6.2), 3.12- 3.34 (2H, m), 3.43-3.57 (1H, m), 3.57-3.71 (2H, m), 4.16 (2H, t, J = 6.2), 7.11 (1H, s).
225d) 5-chloro-2-({3-oxo-3- [4- (5,6,7,8-tetrahydroimidazo [1,5-a] pyridin-3-yl) -1-piperidinyl] propyl} Sulfonyl) -1H-indole-1-carboxylate tert-butyl Performed with 3- (4-piperidinyl) -5,6,7,8-tetrahydroimidazopyridine dihydrochloride (0.67 g) obtained in Example 225c) The title compound (3-((1-tert-butoxycarbonyl-5-chloro-1H-indol-2-yl) sulfonyl) propionic acid (0.78 g) obtained in Example 211d) was prepared in the same manner as in Example 19. 0.87 g, 76%) was obtained as a brown powder.
NMR (200Mz, CDCl ₃ ) δ: 1.55-2.06 (8H, m), 1.74 (9H, s), 2.67-2.98 (6H, m), 3.08-3.24 (1H, m), 3.85 (2H, t, J = 5.8), 3.90-4.19 (3H, m), 4.43-4.58 (1H, m), 6.65 (1H, s), 7.44 (1H, dd, J = 8.8, 2.2), 7.51 (1H, s), 7.64 (1H, d, J = 2.2), 8.02 (1H, d, J = 8.8).
225e) 3- (1- {3-[(5-chloro-1H-indol-2-yl) sulfonyl] propionyl} -4-piperidinyl) -5,6,7,8-tetrahydroimidazo [1,5-a ] Pyridine hydrochloride 5-chloro-2-({3-oxo-3- [4- (5,6,7,8-tetrahydroimidazo [1,5-a] pyridine-3 obtained in Example 225d) -Yl) -1-piperidinyl] propyl} sulfonyl) -1H-indole-1-carboxylate from tert-butyl (0.40 g) in the same manner as in Example 207c) to give the title compound (0.28 g, 78%) as white crystals Got as.
NMR (200Mz, DMSO-d ₆ ) δ: 1.42-1.68 (2H, m), 1.68-2.03 (6H, m), 2.48-2.68 (1H, m), 2.71-2.87 (3H, m), 2.99-3.23 (1H, m), 3.27-3.51 (2H, m), 3.67 (2H, t, J = 6.8), 3.89-4.05 (1H, m), 4.14 (2H, t, J = 6.6), 4.31-4.48 ( 1H, m), 7.18 (1H, s), 7.31-7.37 (2H, m), 7.55 (1H, d, J = 8.8), 7.81 (1H, d, J = 2.2).

実施例226
2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-1,2,3,4,6,7,8,9-オクタヒドロジピリド[1,2-a;4',3'-d]イミダゾール２塩酸塩
226a) 4-(1,2,3,4,6,7,8,9-オクタヒドロジピリド[1,2-a;4',3'-d]イミダゾール-2-イル)ピペリジン-1-カルボン酸tert-ブチル
実施例224e)で得られた4-(1,2,3,4-テトラヒドロジピリド[1,2-a;4',3'-d]イミダゾール-2-イル)ピペリジン-1-カルボン酸tert-ブチル(2.19g)から実施例209a)と同様にして、題記化合物(2.21g, 定量的)を無色粉末として得た。
NMR (200Mz, CDCl₃)δ：1.44-1.65 (2H, m), 1.46 (9H, s), 1.79-2.04 (6H, m), 2.32-2.57 (1H, m), 2.59-2.78 (4H, m), 2.78-2.92 (4H, m), 3.58 (2H, s), 2.66-2.77 (2H, m), 4.09-4.28 (2H, m).
226) 2-(4-ピペリジニル)-1,2,3,4,6,7,8,9-オクタヒドロジピリド[1,2-a;4',3'-d]イミダゾール３塩酸塩
実施例226a)で得られた4-(1,2,3,4,6,7,8,9-オクタヒドロジピリド[1,2-a;4',3'-d]イミダゾール-2-イル)ピペリジン-1-カルボン酸tert-ブチル(1.80g)から実施例207c)と同様にして、題記化合物(1.59g, 86%)を白色結晶として得た。
NMR (200Mz, D₂O)δ：1.91-2.28 (6H, m), 2.42-2.59 (2H, m), 3.03 (2H, t, J = 6.4), 3.10-3.31 (4H, m), 3.60-3.89 (4H, m), 3.89-4.09 (3H, m), 4.58 (2H, s).
226c) 2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-1,2,3,4,6,7,8,9-オクタヒドロジピリド[1,2-a;4',3'-d]イミダゾール２塩酸塩
3-[(6-クロロ-2-ナフチル)スルホニル]プロピオン酸と実施例226b)で得られた2-(4-ピペリジニル)-1,2,3,4,6,7,8,9-オクタヒドロジピリド[1,2-a;4',3'-d]イミダゾール３塩酸塩から実施例207d)と同様にして、題記化合物(51%)を白色粉末として得た。
NMR (200Mz, DMSO-d₆)δ：1.43-1.70 (1H, m), 1.70-2.08 (5H, m), 2.08-2.29 (2H, m), 2.39-2.58 (2H, m), 2.78 (2H, t, J = 7.6), 2.91-3.27 (5H, m), 3.27-3.85 (4H, m), 3.85-4.18 (3H, m), 4.30-4.54 (3H, m), 7.74 (1H, dd, J = 8.4, 2.2), 8.01 (1H, dd, J = 8.4, 2.2), 8.19-8.32 (3H, m), 8.66 (1H, s). Example 226
2- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -1,2,3,4,6,7,8,9-octahydrodipyrido [ 1,2-a; 4 ', 3'-d] imidazole dihydrochloride
226a) 4- (1,2,3,4,6,7,8,9-octahydrodipyrido [1,2-a; 4 ', 3'-d] imidazol-2-yl) piperidine-1 Tert-butyl carboxylate 4- (1,2,3,4-tetrahydrodipyrido [1,2-a; 4 ′, 3′-d] imidazol-2-yl) obtained in Example 224e) The title compound (2.21 g, quantitative) was obtained as a colorless powder from piperidine-1-carboxylate tert-butyl (2.19 g) in the same manner as in Example 209a).
NMR (200Mz, CDCl ₃ ) δ: 1.44-1.65 (2H, m), 1.46 (9H, s), 1.79-2.04 (6H, m), 2.32-2.57 (1H, m), 2.59-2.78 (4H, m ), 2.78-2.92 (4H, m), 3.58 (2H, s), 2.66-2.77 (2H, m), 4.09-4.28 (2H, m).
226) 2- (4-Piperidinyl) -1,2,3,4,6,7,8,9-octahydrodipyrido [1,2-a; 4 ', 3'-d] imidazole trihydrochloride 4- (1,2,3,4,6,7,8,9-octahydrodipyrido [1,2-a; 4 ′, 3′-d] imidazole-2 obtained in Example 226a) The title compound (1.59 g, 86%) was obtained as white crystals in the same manner as in Example 207c) from tert-butyl (-yl) piperidine-1-carboxylate (1.80 g).
NMR (200Mz, D ₂ O) δ: 1.91-2.28 (6H, m), 2.42-2.59 (2H, m), 3.03 (2H, t, J = 6.4), 3.10-3.31 (4H, m), 3.60- 3.89 (4H, m), 3.89-4.09 (3H, m), 4.58 (2H, s).
226c) 2- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -1,2,3,4,6,7,8,9-octahydrodipyri [1,2-a; 4 ', 3'-d] imidazole dihydrochloride
3-[(6-Chloro-2-naphthyl) sulfonyl] propionic acid and 2- (4-piperidinyl) -1,2,3,4,6,7,8,9-octa obtained in Example 226b) The title compound (51%) was obtained as a white powder from hydrodipyrido [1,2-a; 4 ′, 3′-d] imidazole trihydrochloride in the same manner as in Example 207d).
NMR (200Mz, DMSO-d ₆ ) δ: 1.43-1.70 (1H, m), 1.70-2.08 (5H, m), 2.08-2.29 (2H, m), 2.39-2.58 (2H, m), 2.78 (2H , t, J = 7.6), 2.91-3.27 (5H, m), 3.27-3.85 (4H, m), 3.85-4.18 (3H, m), 4.30-4.54 (3H, m), 7.74 (1H, dd, J = 8.4, 2.2), 8.01 (1H, dd, J = 8.4, 2.2), 8.19-8.32 (3H, m), 8.66 (1H, s).

実施例227
2-(1-{3-[(5-クロロ-1H-インドール-2-イル)スルホニル]プロピオニル}-4-ピペリジニル)-1,2,3,4,6,7,8,9-オクタヒドロジピリド[1,2-a;4',3'-d]イミダゾール２塩酸塩
実施例211d)で得られた3-[(1-tert-ブトキシカルボニル-5-クロロ-1H-インドール-2-イル)スルホニル]プロピオン酸と実施例227b)で得られた2-(4-ピペリジニル)-1,2,3,4,6,7,8,9-オクタヒドロピリド[4',3':4,5]イミダゾ[1,2-a]ピリジン３塩酸塩から実施例207d)と同様にして、題記化合物(21%)を淡黄色粉末として得た。
NMR (200Mz, DMSO-d₆)δ：1.42-1.71 (1H, m), 1.71-2.09 (5H, m), 2.09-2.28 (2H, m), 2.39-2.59 (2H, m), 2.77 (2H, t, J = 7.6), 2.92-3.27 (5H, m), 3.26-3.85 (4H, m), 3.85-4.19 (3H, m), 4.31-4.55 (3H, m), 7.32-7.38 (2H, m), 7.54 (1H, d, J = 8.8), 7.72 (1H, br), 7.80 (1H, d, J = 1.8). Example 227
2- (1- {3-[(5-Chloro-1H-indol-2-yl) sulfonyl] propionyl} -4-piperidinyl) -1,2,3,4,6,7,8,9-octahydro Dipyrido [1,2-a; 4 ′, 3′-d] imidazole dihydrochloride 3-[(1-tert-butoxycarbonyl-5-chloro-1H-indole-2) obtained in Example 211d) -Yl) sulfonyl] propionic acid and 2- (4-piperidinyl) -1,2,3,4,6,7,8,9-octahydropyrido [4 ', 3' obtained in Example 227b) : 4,5] imidazo [1,2-a] pyridine trihydrochloride gave the title compound (21%) as a pale yellow powder in the same manner as in Example 207d).
NMR (200Mz, DMSO-d ₆ ) δ: 1.42-1.71 (1H, m), 1.71-2.09 (5H, m), 2.09-2.28 (2H, m), 2.39-2.59 (2H, m), 2.77 (2H , t, J = 7.6), 2.92-3.27 (5H, m), 3.26-3.85 (4H, m), 3.85-4.19 (3H, m), 4.31-4.55 (3H, m), 7.32-7.38 (2H, m), 7.54 (1H, d, J = 8.8), 7.72 (1H, br), 7.80 (1H, d, J = 1.8).

製剤例１
本発明における式（Ｉ）で表される化合物またはその塩を有効成分として含有するＦＸａ阻害剤（例、深部静脈血栓症治療剤、心原性脳梗塞治療剤など）は、例えば、次のような処方によって製造することができる。
なお、以下の処方において活性成分以外の成分（添加物）は、日本薬局方、日本薬局方外医薬品規格または医薬品添加物規格における収載品などを用いることができる。
１．カプセル剤
（１）実施例24で得られた化合物１２０ｍｇ
（２）ラクトース２１０ｍｇ
（３）微結晶セルロース２７ｍｇ
（４）ステアリン酸マグネシウム３ｍｇ
１カプセル３６０ｍｇ
（１）、（２）と（３）および（４）の１／２を混和した後、顆粒化する。これに残りの（４）を加えて全体をゼラチンカプセルに封入する。
２．カプセル剤
（１）実施例68で得られた化合物１２０ｍｇ
（２）ラクトース２１０ｍｇ
（３）微結晶セルロース２７ｍｇ
（４）ステアリン酸マグネシウム３ｍｇ
１カプセル３６０ｍｇ
（１）、（２）と（３）および（４）の１／２を混和した後、顆粒化する。これに残りの（４）を加えて全体をゼラチンカプセルに封入する。
３．錠剤
（１）実施例68で得られた化合物１２０ｍｇ
（２）ラクトース１７４ｍｇ
（３）コーンスターチ５４ｍｇ
（４）微結晶セルロース１０．５ｍｇ
（５）ステアリン酸マグネシウム１．５ｍｇ
１錠３６０ｍｇ
（１）、（２）、（３）、（４）の２／３および（５）の１／２を混和した後、顆粒化する。残りの（４）および（５）をこの顆粒に加えて錠剤に加圧成型する。
４．錠剤
（１）実施例72で得られた化合物１２０ｍｇ
（２）ラクトース１７４ｍｇ
（３）コーンスターチ５４ｍｇ
（４）微結晶セルロース１０．５ｍｇ
（５）ステアリン酸マグネシウム１．５ｍｇ
１錠３６０ｍｇ
（１）、（２）、（３）、（４）の２／３および（５）の１／２を混和した後、顆粒化する。残りの（４）および（５）をこの顆粒に加えて錠剤に加圧成型する。 Formulation Example 1
The FXa inhibitor (eg, therapeutic agent for deep vein thrombosis, therapeutic agent for cardiogenic cerebral infarction, etc.) containing the compound represented by the formula (I) or a salt thereof in the present invention as an active ingredient is, for example, as follows: Can be manufactured according to various formulations.
In addition, in the following prescription, components (additives) other than the active ingredient can be listed products in the Japanese Pharmacopoeia, the Japanese Pharmacopoeia Standards for Pharmaceuticals or the Standards for Pharmaceutical Additives, and the like.
1. Capsule (1) 120 mg of the compound obtained in Example 24
(2) Lactose 210mg
(3) Microcrystalline cellulose 27mg
(4) Magnesium stearate 3mg
1 capsule 360mg
After mixing (1), (2) and 1/2 of (3) and (4), granulate. The remaining (4) is added to this and the whole is enclosed in a gelatin capsule.
2. Capsule (1) 120 mg of the compound obtained in Example 68
(2) Lactose 210mg
(3) Microcrystalline cellulose 27mg
(4) Magnesium stearate 3mg
1 capsule 360mg
After mixing (1), (2) and 1/2 of (3) and (4), granulate. The remaining (4) is added to this and the whole is enclosed in a gelatin capsule.
3. Tablet (1) 120 mg of the compound obtained in Example 68
(2) Lactose 174mg
(3) Corn starch 54mg
(4) Microcrystalline cellulose 10.5mg
(5) Magnesium stearate 1.5mg
1 tablet 360mg
After mixing 2/3 of (1), (2), (3), (4) and 1/2 of (5), granulate. The remaining (4) and (5) are added to the granules and pressed into tablets.
4). Tablet (1) 120 mg of the compound obtained in Example 72
(2) Lactose 174mg
(3) Corn starch 54mg
(4) Microcrystalline cellulose 10.5mg
(5) Magnesium stearate 1.5mg
1 tablet 360mg
After mixing 2/3 of (1), (2), (3), (4) and 1/2 of (5), granulate. The remaining (4) and (5) are added to the granules and pressed into tablets.

製剤例２
日局注射用蒸留水５０ｍｌに実施例69で得られた化合物５０ｍｇを溶解した後、日局注射用蒸留水を加えて１００ｍｌとする。この溶液を滅菌条件下でろ過し、次にこの溶液１ｍｌずつを取り、滅菌条件下、注射用バイアルに充填し、凍結乾燥して密閉する。 Formulation Example 2
After dissolving 50 mg of the compound obtained in Example 69 in 50 ml of JP distilled water for injection, JP distilled water for injection is added to make 100 ml. The solution is filtered under sterile conditions, then 1 ml of this solution is taken, filled into injection vials under sterile conditions, lyophilized and sealed.

実験例１
（１）ヒト活性化血液凝固第Ｘ因子（ＦＸａ）阻害作用
実験方法：96穴マイクロプレートに０.１４５Ｍ食塩及び２ｍＭ塩化カルシウム含有０.０５Ｍトリス塩酸緩衝液（ｐＨ８.３）２２５μｌ、試料（試験化合物をジメチルスルフォキシドに溶解）５μｌ及びヒトＦＸａ（０.３ｕｎｉｔ／ｍｌ）１０μｌを加えて３７℃で約１０分間反応させた後、基質（３ｍＭ，Ｓ−２７６５）１０μｌを添加して３７℃で１０分間反応させた。次いで、５０％酢酸水２５μｌを加えて反応を停止させた後、分光光度計により４０５ｎｍの吸光度の変化を測定し、ＦＸａ作用を５０％阻害する濃度（ＩＣ_５０）を算出した。 Experimental example 1
(1) Human activated blood coagulation factor X (FXa) inhibitory effect Experimental method: 225 μl of 0.05M Tris-HCl buffer (pH 8.3) containing 0.145M sodium chloride and 2 mM calcium chloride in a 96-well microplate, sample (test) Compound (dissolved in dimethyl sulfoxide) 5 μl and human FXa (0.3 unit / ml) 10 μl were added and reacted at 37 ° C. for about 10 minutes, and then 10 μl of substrate (3 mM, S-2765) was added to 37 ° C. For 10 minutes. Subsequently, 25 μl of 50% aqueous acetic acid was added to stop the reaction, and the change in absorbance at 405 nm was measured with a spectrophotometer, and the concentration (IC ₅₀ ) that inhibits the FXa action by 50% was calculated.

（２）In vitro凝固時間測定法
（２−１）外因系凝固時間（PT）測定法：
PT試薬（DIAGNOSTICA STAGO）を用い、自動血液凝固時間測定装置（STA compact，DIAGNOSTICA STAGO）により測定した。ヒト正常血漿（新鮮ヒト血漿FFP，積水化学工業）97μｌに薬物3μlを添加し、37℃で4分間予備加温した。上記血漿50μlに対し、ウサギ脳由来組織トロンボプラスチン溶液を100μl添加した後、凝固までの時間を測定した。薬物はジメチルスルホキシド（DMSO）に溶解して使用した。凝固時間2倍延長濃度は、薬物の代わりにDMSOを添加したときの凝固時間をもとに算出した。
（２−２）内因系凝固時間（APTT）測定法：
STA-APTT-LT（DIAGNOSTICA STAGO）を用い、自動血液凝固時間測定装置により測定した。ヒト正常血漿97μlに薬物3μlを添加した。血漿50μlに対し活性部分トロンボプラスチン溶液を50μl添加し、37℃で4分間予備加温した。25 mmol/l のCaCl₂溶液50μlを添加して、凝固までの時間を測定した。薬物はDMSOに溶解して使用した。凝固時間2倍延長濃度は（2-1）と同様に算出した。
（２−３）トロンビン凝固時間（TT）測定法：
フィブリノーゲン試薬（DIAGNOSTICA STAGO）を用い、自動血液凝固時間測定装置により測定した。フィブリノーゲン試薬（トロンビン含有）を5mLの蒸留水にて溶解した後、0.5％ウシ血清アルブミン添加生理食塩水で20倍希釈して調整した。ヒト正常血漿（新鮮ヒト血漿FFP，積水化学工業）97μlに薬物3μlを添加し、37℃で3分間予備加温した。上記血漿50μlに対し、トロンビン溶液100μl添加し、凝固までの時間を測定した。薬物はDMSOに溶解して使用した。凝固時間2倍延長濃度は（2-1）と同様に算出した。 (2) In vitro clotting time measurement method (2-1) Extrinsic clotting time (PT) measurement method:
Using a PT reagent (DIAGNOSTICA STAGO), measurement was performed with an automatic blood coagulation time measurement device (STA compact, DIAGNOSTICA STAGO). 3 μl of drug was added to 97 μl of human normal plasma (fresh human plasma FFP, Sekisui Chemical Co., Ltd.), and pre-warmed at 37 ° C. for 4 minutes. After adding 100 μl of rabbit brain-derived tissue thromboplastin solution to 50 μl of the plasma, the time until coagulation was measured. The drug was dissolved in dimethyl sulfoxide (DMSO) and used. The clotting time double extension concentration was calculated based on the clotting time when DMSO was added instead of the drug.
(2-2) Endogenous clotting time (APTT) measurement method:
Using STA-APTT-LT (DIAGNOSTICA STAGO), measurement was performed with an automatic blood coagulation time measurement device. 3 μl of drug was added to 97 μl of human normal plasma. 50 μl of active partial thromboplastin solution was added to 50 μl of plasma, and pre-warmed at 37 ° C. for 4 minutes. 50 μl of a 25 mmol / l CaCl ₂ solution was added and the time to solidification was measured. The drug was dissolved in DMSO and used. The concentration at which the coagulation time was doubled was calculated in the same manner as (2-1).
(2-3) Thrombin clotting time (TT) measurement method:
Using a fibrinogen reagent (DIAGNOSTICA STAGO), it was measured by an automatic blood coagulation time measuring device. A fibrinogen reagent (containing thrombin) was dissolved in 5 mL of distilled water and then diluted 20-fold with 0.5% bovine serum albumin-added physiological saline. 3 μl of drug was added to 97 μl of normal human plasma (fresh human plasma FFP, Sekisui Chemical Co., Ltd.), and pre-warmed at 37 ° C. for 3 minutes. 100 μl of thrombin solution was added to 50 μl of the plasma, and the time until coagulation was measured. The drug was dissolved in DMSO and used. The concentration at which the coagulation time was doubled was calculated in the same manner as (2-1).

（３）Ex vivo 凝固時間測定法（マウス）
（３−１）静脈内投与：
雄性ICRマウス（25 - 35g，日本クレア）を使用した。ペントバルビタール（50 mg／kg，i.p.）麻酔下にて、尾静脈より薬物を5 ml/kgの容量で単回投与した。投与5分後に、腹部大動脈もしくは心臓より3.8％クエン酸ナトリウム（チトラール，山之内製薬）1/10容にて0.8 ml採血し、3000rpmで15分間遠心し血漿を得た。上記血漿50μlに対し、ウサギ脳由来組織トロンボプラスチン溶液を100μl添加した後、凝固までの時間を測定した。凝固時間はPT試薬（DIAGNOSTICA STAGO）を用い、自動血液凝固時間測定装置（STA compact）により測定した。薬物はジメチルアセトアミドと1/10 N塩酸と生理食塩液を混合した溶液に溶解して使用し、対照群には薬物の代わりにジメチルアセトアミドと1/10 N塩酸と生理食塩液を混合した溶液を投与した。薬物の活性は、対照群の凝固時間に対する薬物投与群の凝固時間の比（％）で示した。
（３−２）経口投与：
雄性ICRマウス（25 - 35g，日本クレア）を使用した。12時間以上絶食したマウスに薬物を5 ml/kgの容量にて強制経口投与した。投与1時間後にペントバルビタール（50mg／kg，i.p.）麻酔下にて腹部大動脈より採血した。薬物は0.5％メチルセルロースに懸濁して使用し、対照群には薬物の代わりに0.5％メチルセルロースを投与した。その他は（3-1）と同様に行った。 (3) Ex vivo clotting time measurement method (mouse)
(3-1) Intravenous administration:
Male ICR mice (25-35 g, CLEA Japan) were used. Under anesthesia with pentobarbital (50 mg / kg, ip), the drug was administered once in a volume of 5 ml / kg from the tail vein. Five minutes after administration, 0.8 ml of blood was collected from 1/10 volume of 3.8% sodium citrate (Citral, Yamanouchi Pharmaceutical) from the abdominal aorta or heart, and centrifuged at 3000 rpm for 15 minutes to obtain plasma. After adding 100 μl of rabbit brain-derived tissue thromboplastin solution to 50 μl of the plasma, the time until coagulation was measured. The clotting time was measured with an automatic blood clotting time measuring device (STA compact) using PT reagent (DIAGNOSTICA STAGO). The drug is used by dissolving it in a mixed solution of dimethylacetamide, 1/10 N hydrochloric acid and physiological saline. For the control group, a mixed solution of dimethylacetamide, 1/10 N hydrochloric acid and physiological saline is used instead of the drug. Administered. The activity of the drug was expressed as the ratio (%) of the clotting time of the drug administration group to the clotting time of the control group.
(3-2) Oral administration:
Male ICR mice (25-35 g, CLEA Japan) were used. Mice fasted for 12 hours or more were forcibly orally administered with a drug at a volume of 5 ml / kg. One hour after administration, blood was collected from the abdominal aorta under anesthesia with pentobarbital (50 mg / kg, ip). The drug was used suspended in 0.5% methylcellulose, and 0.5% methylcellulose was administered to the control group instead of the drug. Others were performed in the same manner as (3-1).

（４）In vivo抗血栓作用測定法
（４−１）ラット動静脈シャント法：
Umetsu らの方法（Thromb. Haemostas., 39, 74-73, (1978)）に準じた。雄性SD系ラット（200-350g,日本クレア）を用い、ペントバルビタール（50 mg／kg，i.p.）麻酔下にて、左頚静脈と右頚静脈との間に、絹糸を装着したポリエチレンチューブの体外循環路を作成した。血液凝固を防ぐため、予めチューブ内にヘパリン（50U/ml）を含む生理食塩水を満たした。血液を15分間循環させ、その間に絹糸に付着した血栓の湿重量を測定した。薬物の投与は経口あるいは静脈内投与にて行った。経口投与の場合、薬物は0.5％メチルセルロースに懸濁して絶食下で投与(2ml/kg)し、対照群には薬物の代わりに0.5％メチルセルロースを投与した。静脈内投与の場合は薬物は生理食塩水に溶解して尾静脈より1ml/kgの容量で投与し、対照群には薬物の代わりに生理食塩水を投与した。薬物の活性は対照群の血栓湿重量に対する薬物投与群の湿重量の比（％）で算出した。
（４−２）ラット腹部大静脈部分結紮モデル
雄性SD系ラット（200-400g，日本クレア）を使用した。ペントバルビタール（50mg／kg,i.p.）麻酔下にて腹部大静脈を丁寧に剥離した後、腹部大静脈の腎静脈分岐部およびその1cm下流の所に糸をかけ、間にある分枝をすべて結紮した。左大腿静脈よりバルーンカテーテル（Fogarty 2F, Baxter）を挿入し、2本の糸の間を200-300mlの空気で膨らませたバルーンで3回傷害した。バルーンカテーテルを抜き、腎静脈分岐部にかけた糸を26Gの針と一緒に結んだ後、針を取り除くことで部分結紮を作成した。30分後、もう1本の糸を結び、2本の糸の間にできた血栓を丁寧に摘出し、血栓の湿重量を風防付き分析天秤（BP110S，Satorius）により測定した。薬物の投与は経口あるいは静脈内投与にて（4-1）と同様に行った。薬物の活性は（4-1）と同様にして算出した。
（４−３）ラット深部静脈血栓症（DVT）モデル
雄性SD系ラット（200-350g,日本クレア）を用いた。ペントバルビタール（50 mg／kg，i.p.）麻酔下にて、左大腿静脈にポリエチレンチューブを挿入した。ポリエチレンチューブには、予めガイドワイヤーに接続した絹糸（長さ5cm）を挿入し、血液凝固を防ぐため、ヘパリン（50U/ml）を含む生理食塩水を満たした。ポリエチレンチューブを腹部大静脈に到達するまで挿入した後、ガイドワイヤーを用い絹糸を腹部大静脈に静置した。30分間静置後、尾静脈よりヘパリン（200U/kg）を静脈内投与した。上腕動脈切断により放血した後、腹部を開腹して絹糸を取り出し、付着した血栓の湿重量（絹糸の重量を含む）を測定した。薬物の投与は経口あるいは静脈内投与にて（4-1）と同様に行った。血栓のみの湿重量は、（絹糸に付着した血栓の湿重量）−（ヘパリン採血した静脈血に絹糸を浸して測定した湿重量）の計算式より求めた。薬物の活性は（4-1）と同様にして算出した。 (4) In vivo antithrombotic activity measurement method (4-1) Rat arteriovenous shunt method:
According to the method of Umetsu et al. (Thromb. Haemostas., 39, 74-73, (1978)). A male SD rat (200-350g, CLEA Japan) was used with an extracorporeal polyethylene tube with silk thread between the left jugular vein and right jugular vein under pentobarbital (50 mg / kg, ip) anesthesia. A circuit was created. In order to prevent blood coagulation, the tube was previously filled with physiological saline containing heparin (50 U / ml). The blood was circulated for 15 minutes, during which the wet weight of the thrombus attached to the silk thread was measured. The drug was administered orally or intravenously. In the case of oral administration, the drug was suspended in 0.5% methylcellulose and administered under fasting (2 ml / kg), and the control group was administered with 0.5% methylcellulose instead of the drug. In the case of intravenous administration, the drug was dissolved in physiological saline and administered at a volume of 1 ml / kg from the tail vein, and physiological saline was administered instead of the drug in the control group. The activity of the drug was calculated by the ratio (%) of the wet weight of the drug administration group to the wet blood clot weight of the control group.
(4-2) Rat Abdominal Vena Cava Partial Ligation Model Male SD rats (200-400 g, Nippon Claire) were used. After carefully removing the abdominal vena cava under anesthesia with pentobarbital (50 mg / kg, ip), threaded the branch of the renal vein of the abdominal vena cava and 1 cm downstream, and ligated all the branches in between. did. A balloon catheter (Fogarty 2F, Baxter) was inserted from the left femoral vein, and injured three times with a balloon inflated between two threads with 200-300 ml of air. After removing the balloon catheter and tying the thread on the renal vein bifurcation with a 26G needle, the needle was removed to create a partial ligation. After 30 minutes, another thread was tied, the thrombus formed between the two threads was carefully removed, and the wet weight of the thrombus was measured with an analytical balance with a windshield (BP110S, Satorius). The drug was administered orally or intravenously as in (4-1). Drug activity was calculated in the same manner as (4-1).
(4-3) Rat Deep Venous Thrombosis (DVT) Model Male SD rats (200-350 g, CLEA Japan) were used. Under anesthesia with pentobarbital (50 mg / kg, ip), a polyethylene tube was inserted into the left femoral vein. A silk thread (5 cm in length) previously connected to a guide wire was inserted into the polyethylene tube and filled with physiological saline containing heparin (50 U / ml) to prevent blood coagulation. After inserting the polyethylene tube until it reached the abdominal vena cava, the silk thread was allowed to stand in the abdominal vena cava using a guide wire. After standing for 30 minutes, heparin (200 U / kg) was intravenously administered from the tail vein. After exsanguination by cutting the brachial artery, the abdomen was opened, the silk thread was taken out, and the wet weight of the attached thrombus (including the weight of the silk thread) was measured. The drug was administered orally or intravenously as in (4-1). The wet weight of only the thrombus was determined from the formula of (wet weight of thrombus attached to silk thread) − (wet weight measured by immersing silk thread in venous blood collected from heparin). Drug activity was calculated in the same manner as (4-1).

実験結果
表１に実験例１（１）で求めたＩＣ_５０値を示す。これより、本発明の化合物は優れたＦＸａ阻害作用を示すことが明らかである。

Experimental Results Table 1 shows the IC ₅₀ values obtained in Experimental Example 1 (1). From this, it is clear that the compound of the present invention exhibits an excellent FXa inhibitory action.

本発明の化合物（Ｉ）またはその塩は、優れたＦＸａ阻害作用を有し、医薬としてより安全性が高く、また経口吸収しうる抗血液凝固剤として有用であり、血栓や梗塞に基づく各種疾病の予防・治療に有利に用いられる。

The compound (I) or a salt thereof of the present invention has an excellent FXa inhibitory action, is safer as a pharmaceutical, is useful as an anti-blood coagulant that can be absorbed orally, and has various diseases based on thrombus and infarction. It is advantageously used for the prevention and treatment of

Claims

式（Ｉａ）：

〔式中、Ｒはハロゲン原子で置換されていてもよいナフチルまたはハロゲン原子で置換されていてもよいインドリルを示し、Ｗは結合手を示し、Ｘは置換されていてもよいC _1-6 アルキレンを示し、Ｙは-CO-を示し、環Ａは置換されていてもよいピペリジン環を示し、Ｚ ^１は独立して結合手または置換されていてもよいC _1-6 アルキレンを示し、Ｚ ^２ａはＮまたはＣＨを示し、Ｚ ^３およびＺ ^４はそれぞれ独立してオキソ基で置換されていてもよいC _1-6 アルキレンを示し、環Ｂ’は置換されていてもよいイミダゾール環を示し、ａは０，１または２を示す。〕で表される化合物またはその塩。 Formula (Ia):

[In the formula, R represents naphthyl optionally substituted with a halogen atom or indolyl optionally substituted with a halogen atom, W represents a bond, and X represents an optionally substituted C _1-6 alkylene. Y represents —CO—, ring A represents an optionally substituted piperidine ring, Z ¹ independently represents a bond or optionally substituted C _1-6 alkylene, Z ^2a Represents N or CH, Z ³ and Z ⁴ each independently represent C _1-6 alkylene which may be substituted with an oxo group , ring B ′ represents an optionally substituted imidazole ring, a Represents 0, 1 or 2. Or a salt thereof.

Ｚ^２ａが窒素原子である請求項１記載の化合物。 The compound of claim 1 wherein Z ^2a is a nitrogen atom.

式（Ｉａ）が、式（Ｉｂ）：

〔式中、Ｒ^１４およびＲ^１５はそれぞれ独立して水素原子、それぞれ置換されていてもよい、アルキル、アルケニル、アルキニル、アリール、シクロアルキル、シクロアルケニルもしくはアラルキル基、置換されていてもよい水酸基、置換されていてもよいチオ−ル基、置換されていてもよいアルキルスルフィニル基、置換されていてもよいアルキルスルホニル基、それぞれ置換されていてもよい、スルホン酸由来のアシル基もしくはカルボン酸由来のアシル基、Ｃ_１−６アルコキシカルボニル、Ｃ_７−１２アリールオキシもしくはＣ_７−１０アラルキルオキシでエステル化されていてもよいカルボキシル基、置換されていてもよいカルバモイル基または置換されていてもよいアミノ基を示し、Ｒ^１４とＲ^１５とが互いに結合して置換されていてもよい環を形成していてもよく、他の記号は請求項１記載と同意義を示す。〕である請求項１記載の化合物。 Formula ( Ia ) is converted to Formula (Ib):

[Wherein, R ¹⁴ and R ¹⁵ each independently represent a hydrogen atom, an optionally substituted alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl or aralkyl group , an optionally substituted hydroxyl group, optionally substituted thio - group, substitution which may be alkylsulfinyl group, substitution which do may be an alkylsulfonyl group, which may be substituted respectively, acyl or carboxylic acid derived from sulfonic acid derived acyl group, C _1-6 alkoxycarbonyl, C _7-12 aryloxy or C _7-10 aralkyloxy esterified carboxyl group which may be, have also been carbamoyl group or a substituted optionally be substitution R ¹⁴ and R ¹⁵ are bonded to each other and substituted. The other symbols may have the same meaning as in claim 1 . The compound according to claim 1, wherein

式（Ｉａ）が、式（Ｉｃ）：

〔式中、Ｒ^１６およびＲ^１７はそれぞれ独立して水素原子、それぞれ置換されていてもよい、アルキル、アルケニル、アルキニル、アリール、シクロアルキル、シクロアルケニルもしくはアラルキル基、置換されていてもよい水酸基、置換されていてもよいチオ−ル基、置換されていてもよいアルキルスルフィニル基、置換されていてもよいアルキルスルホニル基、それぞれ置換されていてもよい、スルホン酸由来のアシル基もしくはカルボン酸由来のアシル基、Ｃ_１−６アルコキシカルボニル、Ｃ_７−１２アリールオキシもしくはＣ_７−１０アラルキルオキシでエステル化されていてもよいカルボキシル基、置換されていてもよいカルバモイル基または置換されていてもよいアミノ基を示し、Ｒ^１６とＲ^１７とが互いに結合して置換されていてもよい環を形成していてもよく、他の記号は請求項１記載と同意義を示す。〕である請求項１記載の化合物。 Formula ( Ia ) is converted to Formula (Ic):

Wherein, R ¹⁶ and R ¹⁷ are each independently a hydrogen atom, may be substituted respectively, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl or aralkyl group, a hydroxy group which may be substitution may thio be substitution - group, which may be substitution alkylsulfinyl group, substitution which may be an alkylsulfonyl group, which may be substituted respectively, or an acyl group derived from sulfonic acid acyl group derived from a carboxylic acid, C _1-6 alkoxycarbonyl, C _7-12 is aryloxy or C _7-10 aralkyloxy esterified carboxyl group which may be, or a substituted substitution which may be a carbamoyl group indicates an amino group optionally, replacement of attached and R ¹⁶ and R ¹⁷ are mutually The other symbols may have the same meaning as in claim 1 . The compound according to claim 1, wherein

式（Ｉａ）が、式（Ｉｄ）：

〔式中、Ｒ^１８およびＲ^１９はそれぞれ独立して水素原子、それぞれ置換されていてもよい、アルキル、アルケニル、アルキニル、アリール、シクロアルキル、シクロアルケニルもしくはアラルキル基、置換されていてもよい水酸基、置換されていてもよいチオ−ル基、置換されていてもよいアルキルスルフィニル基、置換されていてもよいアルキルスルホニル基、それぞれ置換されていてもよい、スルホン酸由来のアシル基もしくはカルボン酸由来のアシル基、Ｃ_１−６アルコキシカルボニル、Ｃ_７−１２アリールオキシもしくはＣ_７−１０アラルキルオキシでエステル化されていてもよいカルボキシル基、置換されていてもよいカルバモイル基または置換されていてもよいアミノ基を示し、他の記号は請求項１記載と同意義を示す。〕である請求項１記載の化合物。 Formula ( Ia ) is converted to Formula (Id):

Wherein, R ¹⁸ and R ¹⁹ each independently represent a hydrogen atom, may be substituted respectively, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl or aralkyl group, a hydroxy group which may be substitution may thio be substitution - group, which may be substitution alkylsulfinyl group, substitution which may be an alkylsulfonyl group, which may be substituted respectively, or an acyl group derived from sulfonic acid acyl group derived from a carboxylic acid, C _1-6 alkoxycarbonyl, C _7-12 is aryloxy or C _7-10 aralkyloxy esterified carboxyl group which may be, or a substituted substitution which may be a carbamoyl group And other symbols are as defined in claim 1 . The compound according to claim 1, wherein

ａが２である請求項１記載の化合物。 The compound according to claim 1, wherein a is 2.

7-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-3-メチル-6,7-ジヒドロイミダゾ[1,5-a]ピラジン-8(5H)-オン、7-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-1-メチル-6,7-ジヒドロイミダゾ[1,5-a]ピラジン-8(5H)-オン、2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン、2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-5,7-ジメチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン、2-(1-{3-[(7-クロロ-2H-クロメン-3-イル)スルホニル]プロパノイル}-4-ピペリジニル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン、2-[1-(3-{[(E)-2-(4-クロロフェニル)ビニル]スルホニル}プロパノイル)-4-ピペリジニル]-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン、2-(1-{3-[(5-クロロ-1H-インドール-2-イル)スルホニル]プロパノイル}-4-ピペリジニル)-5-メチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン、2-(1-{3-[(6-クロロ-2-ナフチル)スルホニル]プロパノイル}-4-ピペリジニル)-5-(ヒドロキシメチル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン、2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-5-(ヒドロキシメチル)-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オン、1-アセチルピペリジン-4-カルボン酸[2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル、3-(2-オキソ-1-ピロリジニル)プロピオン酸[2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル、(2-オキソ-1-ピロリジニル)酢酸 [2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル、4-(アセチルアミノ)ブタン酸 [2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-3-オキソ-2,3-ジヒドロ-1H-イミダゾ[1,5-c]イミダゾール-5-イル]メチル、および2-(1-{(2S)-3-[(6-クロロ-2-ナフチル)スルホニル]-2-ヒドロキシプロパノイル}-4-ピペリジニル)-5,7-ジメチル-1,2-ジヒドロ-3H-イミダゾ[1,5-c]イミダゾール-3-オンからなる群から選ばれた化合物またはその塩。 7- (1- {3-[(6-Chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -3-methyl-6,7-dihydroimidazo [1,5-a] pyrazine-8 (5H ) -One, 7- (1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -1-methyl-6,7-dihydroimidazo [1,5-a] pyrazine -8 (5H) -one, 2- (1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -5-methyl-1,2-dihydro-3H-imidazo [ 1,5-c] imidazol-3-one, 2- (1- {3-[(6-chloro-2-naphthyl) sulfonyl] propanoyl} -4-piperidinyl) -5,7-dimethyl-1,2- Dihydro-3H-imidazo [1,5-c] imidazol-3-one, 2- (1- {3-[(7-chloro-2H-chromen-3-yl) sulfonyl] propanoyl} -4-piperidinyl)- 5-Methyl-1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one, 2- [1- (3-{[(E) -2- (4-chlorophenyl) vinyl] sulfonyl } Propanoyl) -4-piperidinyl] -5-methi 1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one, 2- (1- {3-[(5-chloro-1H-indol-2-yl) sulfonyl] propanoyl} -4-piperidinyl) -5-methyl-1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one, 2- (1- {3-[(6-chloro-2-naphthyl) Sulfonyl] propanoyl} -4-piperidinyl) -5- (hydroxymethyl) -1,2-dihydro-3H-imidazo [1,5-c] imidazol-3-one, 2- (1-{(2S) -3 -[(6-Chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -5- (hydroxymethyl) -1,2-dihydro-3H-imidazo [1,5-c] imidazole -3-one, 1-acetylpiperidine-4-carboxylic acid [2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl ) -3-Oxo-2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl, 3- (2-oxo-1-pyrrolidinyl) propionic acid [2- (1- { (2S) -3-[(6- Chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -3-oxo-2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl, 2-oxo-1-pyrrolidinyl) acetic acid [2- (1-{(2S) -3-[(6-chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -3-oxo -2,3-Dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl, 4- (acetylamino) butanoic acid [2- (1-{(2S) -3-[(6- Chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -3-oxo-2,3-dihydro-1H-imidazo [1,5-c] imidazol-5-yl] methyl, and 2- (1-{(2S) -3-[(6-Chloro-2-naphthyl) sulfonyl] -2-hydroxypropanoyl} -4-piperidinyl) -5,7-dimethyl-1,2-dihydro-3H A compound selected from the group consisting of imidazo [1,5-c] imidazol-3-one or a salt thereof.

請求項１記載の化合物を含有することを特徴とする医薬。 A pharmaceutical comprising the compound according to claim 1.

抗血液凝固剤である請求項８記載の医薬。 The medicament according to claim 8 , which is an anticoagulant.

活性化血液凝固第Ｘ因子阻害剤である請求項８記載の医薬。 The medicament according to claim 8 , which is an activated blood coagulation factor X inhibitor.

心筋梗塞、脳梗塞、深部静脈血栓症、肺血栓塞栓症または閉塞性動脈硬化症の予防・治療剤である請求項８記載の医薬。 The medicament according to claim 8 , which is a prophylactic / therapeutic agent for myocardial infarction, cerebral infarction, deep vein thrombosis, pulmonary thromboembolism or obstructive arteriosclerosis.

エコノミークラス症候群、手術中・術後の血栓塞栓症または深部静脈血栓症の二次発症の予防・治療剤である請求項８記載の医薬。 The medicament according to claim 8 , which is a prophylactic / therapeutic agent for secondary onset of economy class syndrome, thromboembolism during or after surgery, or deep vein thrombosis.

血液凝固阻害のための医薬の製造のための請求項１記載の化合物の使用。 Use of a compound according to claim 1 for the manufacture of a medicament for inhibiting blood clotting.

活性化血液凝固第Ｘ因子阻害のための医薬の製造のための請求項１記載の化合物の使用。 Use of a compound according to claim 1 for the manufacture of a medicament for activated blood coagulation factor X inhibition.

心筋梗塞、脳梗塞、深部静脈血栓症、肺血栓塞栓症または閉塞性動脈硬化症の予防・治療のための医薬の製造のための請求項１記載の化合物の使用。 Use of the compound according to claim 1 for the manufacture of a medicament for the prevention / treatment of myocardial infarction, cerebral infarction, deep vein thrombosis, pulmonary thromboembolism or obstructive arteriosclerosis.